# pos

id: cord-252108-04xr5xdl
pos: .
token:
  -{2-[5-(4-methoxyphenyl)-3-naphthalen-2-yl-4,5-dihydropyrazol-1-yl]-2-oxoethylidene}-2,4-dioxothiazolidin-3-yl)-acetamide

lemma:
  -{2-[5-(4-methoxyphenyl)-3-naphthalen-2-yl-4,5-dihydropyrazol-1-yl]-2-oxoethylidene}-2,4-dioxothiazolidin-3-yl)-acetamide


id: cord-003539-tazd6dvm
pos: NNP
token:
  S)-1-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-1-oxopropan-2-aminium

lemma:
  S)-1-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-1-oxopropan-2-aminium


id: cord-003539-tazd6dvm
pos: NNP
token:
  S)-1-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-3-hydroxy-1-oxopropan-2-aminium

lemma:
  S)-1-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-3-hydroxy-1-oxopropan-2-aminium


id: cord-003539-tazd6dvm
pos: NNP
token:
  R)-1-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-3-methyl-1-oxobutan-2-aminium

lemma:
  R)-1-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-3-methyl-1-oxobutan-2-aminium


id: cord-003539-tazd6dvm
pos: CD
token:
  1-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-2-methyl-1-oxopropan-2aminium

lemma:
  1-(2-(4,5-dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-2-methyl-1-oxopropan-2aminium


id: cord-003539-tazd6dvm
pos: CD
token:
  3-((2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)carbonyl)oxetan-3-aminium

lemma:
  3-((2-(4,5-dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)carbonyl)oxetan-3-aminium


id: cord-003539-tazd6dvm
pos: NNP
token:
  R)-2-((2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)carbonyl)-pyrrolidinium

lemma:
  R)-2-((2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)carbonyl)-pyrrolidinium


id: cord-003539-tazd6dvm
pos: NN
token:
  S)-2-((2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)carbonyl)-pyrrolidinium

lemma:
  s)-2-((2-(4,5-dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)carbonyl)-pyrrolidinium


id: cord-003539-tazd6dvm
pos: NNP
token:
  R)-2-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-2-oxo-1-phenylethanaminium

lemma:
  R)-2-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-2-oxo-1-phenylethanaminium


id: cord-003539-tazd6dvm
pos: NNP
token:
  R)-2-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-1-(4-hydroxyphenyl)-2-oxoethanaminium

lemma:
  R)-2-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-1-(4-hydroxyphenyl)-2-oxoethanaminium


id: cord-003539-tazd6dvm
pos: NN
token:
  S)-2-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-1-(4-hydroxyphenyl)-2-oxoethanaminium

lemma:
  s)-2-(2-(4,5-dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-1-(4-hydroxyphenyl)-2-oxoethanaminium


id: cord-003539-tazd6dvm
pos: NNP
token:
  R)-2-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-1-(4-fluorophenyl)-2-oxoethanaminium

lemma:
  R)-2-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-1-(4-fluorophenyl)-2-oxoethanaminium


id: cord-003539-tazd6dvm
pos: NNP
token:
  S)-2-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-1-(4-fluorophenyl)-2oxoethanaminium

lemma:
  S)-2-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-1-(4-fluorophenyl)-2oxoethanaminium


id: cord-003539-tazd6dvm
pos: NNP
token:
  R)-1-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-3-(4-hydroxyphenyl)-1-oxopropan-2-aminium

lemma:
  R)-1-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-3-(4-hydroxyphenyl)-1-oxopropan-2-aminium


id: cord-003539-tazd6dvm
pos: NNP
token:
  S)-1-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-3-(4-hydroxyphenyl)-1-oxopropan-2-aminium

lemma:
  S)-1-(2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)-3-(4-hydroxyphenyl)-1-oxopropan-2-aminium


# ent

id: cord-000445-2x7dfl1q
type: PROTEIN
entity:
  N S benzyloxycarbonyl S 2 4dinitrophenylglutathione diester derivatives compounds 17 19 21 Figure 30


id: cord-003427-0dddrh4e
type: PROTEIN
entity:
  anti microbial 2 3 4 anti mycobacterial 5 6 anti convulsant 7 analgesic 8 anti inflammatory 9 anti platelet


id: cord-013387-q91052qw
type: DNA
entity:
  hCOX 2 receptor LMQC72 G 11 0 kcal mol LMQC36 G 10 6 kcal mol and LMQC50 G 10 2 kcal mol LMQC72 and LMQC36


id: cord-013387-q91052qw
type: ORG
entity:
  the Computer aided Drug Design An Overview Octanol Water Partition Coefficients of Simple Organic Compounds Predicting a Drug s Membrane Permeability A Computational Model Validated


id: cord-014863-jyti99xq
type: CELL_LINE
entity:
  human embryonic lung HEL fibroblasts African green monkey cells Vero human epithelial cervix carcinoma cells HeLa


id: cord-014863-jyti99xq
type: CELL_LINE
entity:
  feline herpes virus EC 50 17 8 54 3 mg mL All compounds were also not significantly inhibitory against a wide variety of RNA viruses including vesicular stomatitis virus VSV respiratory syncytial virus and Coxsackie virus in HeLa cell cultures


id: cord-012773-wtgk2d68
type: CL
entity:
  motor and nonmotor symptoms A timeline of PD from onset to death has been proposed 17 which not only promotes a comprehensive understanding of the overall disease process but is also a reminder that before a patient shows any PD related clinical symptoms the disease may have progressed severely and possibly irreversibly as a result of neuronal


id: cord-003539-tazd6dvm
type: PROTEIN
entity:
  anti tumour 5 6 7 anti inflammatory 8 9 antiviral 10 antibacterial 11 anti allergic 12 anti osteoporotic 13 anti diabetic 14 15 immunosuppressive 16 neuroprotective 17 and hepatoprotective 18 19


id: cord-003539-tazd6dvm
type: PROTEIN
entity:
  anti tumor anti osteoporotic 13 anti diabetic 14 15 immunosuppressive 16 neuroprotective 17 and hepatoprotective 18 19


id: cord-003539-tazd6dvm
type: GGP
entity:
  NMR S 1 2 4 5 Dihydroxy 7 methyl 9 10 dioxo 9 10 dihydroanthracen 2 yloxy ethoxy 3 hydroxy 1 oxopropan 2 aminium 2 2 2 trifluoroacetate


id: cord-003539-tazd6dvm
type: CHEMICAL
entity:
  give compound 7f Yellow solid 43 s 3H 1 83 1 76 m 2H 1 75 1 68 m 2H 1 56 1 46 m 2H 1 40 d J 7 1 Hz 3H


id: cord-252108-04xr5xdl
type: GGP
entity:
  arom 2 5 4 methoxyphenyl 3 naphthalen 2 yl 4 5 dihydropyrazol 1 yl 2 oxoethylidene 2 4 dioxothiazolidin 3 yl acetamide


id: cord-252108-04xr5xdl
type: ORG
entity:
  the Virology Branch Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases


id: cord-252108-04xr5xdl
type: CHEMICAL
entity:
  aryl 4 5 dihydropyrazol 1yl thiazolidine 2 4 dione derivatives 1a 2b 2c 137 9 133 9 133 3 133 2 130 1 129 3 128 9 128 7 128 6 128 2 127 6 127 2 127 1 123 6 A


id: cord-252108-04xr5xdl
type: CHEMICAL
entity:
  s 1H CH 7 56e7 60 m 2H arom 5 diaryl 4 5 dihydropyrazol 1 yl 2 oxoethylidene 2 4 dioxothiazolidin 3 yl N arylacetamides


id: cord-252108-04xr5xdl
type: CHEMICAL
entity:
  3 phenyl 4 5 dihydropyrazol 1 yl 2 oxoethylidene 2 4 dioxothiazolidin 3 yl N p tolylacetamide 5a 04 d 2H J ¼ 7 9 Hz arom 5 70 dd 1H CH 2 CH DMSO d 6 þ CCl 4 d 10 04 s 1H NH 8 02 s 4 d ioxoth iazolidin 3 yl N 4 chlorophenyl acetamide


id: cord-252108-04xr5xdl
type: CHEMICAL
entity:
  s 1H NH 7 98 s 1H COCH 7 83e7 86 m 2H arom 7 48e7 58 m 5H arom 7 34e7 42 m 3H arom 2 5 4 methoxyphenyl 3 naphthalen 2 yl 4 5 dihydropyrazol 1 yl 2 oxoethylidene 2 4 dioxothiazolidin 3 yl acetamide 5d


id: cord-252108-04xr5xdl
type: CHEMICAL
entity:
  4 3 aryl 4 oxo 2 thioxothiazolidin 5 ylimino 3 methyl 1 N N disubstituted aminomethyl pyrazolin 5 ones


id: cord-017041-0zxoq68m
type: PROTEIN
entity:
  N sup 1 2 furanidyl 5 fl uoro uracil Synthesis of tetrahydro 2 furyl derivatives of 5 substituted uracils Liepin sh E 1981 Nitrogen


id: cord-017041-0zxoq68m
type: CHEMICAL
entity:
  5 chloro N 2 1 S 1 5 fluoropyrimidin 2 yl ethyl N 4 5 methyl 1 H pyrazol 3 yl pyrimidine 2 4 diamine AZD1480


id: cord-017041-0zxoq68m
type: CHEMICAL
entity:
  manufacture 2R 3S 2 2 4 difl uorophenyl 3 5 fl uoropyrimidin 4 yl 1 1H 1 2 4 triazol 1 yl butan 2 ol Section VII Worldwide


id: cord-017041-0zxoq68m
type: CHEMICAL
entity:
  2 2 4 dichlorophenyl amino N tetrahydro 2 H pyran 4 yl methyl 4 trifl uoromethyl 5 pyrimidinecarboxamide


id: cord-021013-xvc791wx
type: CL
entity:
  stem and root barks in addition All these plant parts and organs have in common that they are important for the actual fitness or for the reproduction and thus the long term survival of the species Spiny species which invest in mechanical defense accumulate fewer alkaloids than soft bodied ones 15 examples are isoquinoline alkaloids


id: cord-021013-xvc791wx
type: WORK_OF_ART
entity:
  Apocynaceae Celestraceae Elaeocarpaceae Euphorbiaceae Fabaceae Orchidaceae Poaceae Ranunculaceae Rhizo


id: cord-021013-xvc791wx
type: ORG
entity:
  Okologische Biochemie Allelochemicals Role in Agriculture and Forestry Cell Culture and Somatic Cell Genetics of Plants F Constabel


id: cord-021013-xvc791wx
type: CHEMICAL
entity:
  quinolizidine alkaloids cryptopleurine haningtonine homohamngtonine haemanthamine isohamngtonine lycorine


id: cord-021013-xvc791wx
type: CHEMICAL
entity:
  glucosinolates nonproteinogenic amino acids cyanogenic glycosides acids aldehydes saponins triterpenes mono


id: cord-000536-0mn1gbll
type: GGP
entity:
  NADPH H 14 27 They are also co mentioned in many PubMed Abstracts such as 28 29 30 31 32 33 34 35 36 37 Another two interactive compounds dihydrouracil


id: cord-000536-0mn1gbll
type: GGP
entity:
  glycosyltransferases proteoglycans Glycosaminoglycan structures required for strong binding to midkine a heparinbinding growth factor Glycosulfatase


id: cord-021419-nypnib0h
type: PROTEIN
entity:
  AmB molecule C 16 3 H N sulfo derivative 87 and 3 H N mono and 3 H N N dialkyl derivatives 88a and 89 Scheme 22 52 Amide 83


id: cord-021419-nypnib0h
type: DNA
entity:
  C 6 atom 5 phenyldiazenyl olivomycin 112 5 4 sulfamidophenyldiazenyl olivomycin 113 5 4methoxyphenyldiazenyl olivomycin 114 5 3 4 dichlorophenyldiazenyl olivomycin 115 and 5 4 methylphenyldiazenyl olivomycin 116 see Scheme 31 72


id: cord-021419-nypnib0h
type: CHEMICAL
entity:
  olivomycin N tert butyl amide 122 and 2 H carboxymethoxime olivomycin N 1 3 dihydroxy 2 methylpropan 2 yl amide 123


id: cord-034363-6uscua0y
type: CHEMICAL
entity:
  indolyl propyl 4 methylbencensulfonate 1b 268 mg 0 72 mmol in CH 3 CN 50 mL 1 7 Fluoro 2 3 dihydro benzo b 1 4 1 4 oxazin 4 yl ethanamide


id: cord-034363-6uscua0y
type: CHEMICAL
entity:
  anhydrous K 2 CO 3 13 s 2H H 6 3 39 q 2H H 8 J 6 4 Hz 3 58 t 4H H 2 J 4 2 Hz 6 96 t 1H H 5 or H 6 J 7 2 Hz 7 06 t 1H H 6 or H 5 Piperazin 1 yl propyl 1H indole 9a


id: cord-033493-kslzdy8q
type: PROTEIN
entity:
  methylsulfanylazoloazines 5 amino 3 anilino N chlorophenyl 1H pyrazole 4 carboxamide ethanol solvate Novel synthesis of fluorinated cyanoketene N S


id: cord-033493-kslzdy8q
type: DNA
entity:
  pyrimidines 1 2 3 4 Tetrahydrobenzimidazo 2 1 b quinazoline 1 2 Dimethylpyrido 1 2 a benzimidazole 4 carbonitrile Antimetabolites A novel synthesis of nonclassical


id: cord-033493-kslzdy8q
type: CHEMICAL
entity:
  methylsulfanylazoloazines 5 amino 3 anilino N chlorophenyl 1H pyrazole 4 carboxamide ethanol solvate


id: cord-103271-l9n27ocf
type: PROTEIN
entity:
  Ecto nucleotide pyrophosphatase phosphodiesterase 1 Quinazolin 4 piperidin 4 methyl sulfamide PC 1 inhibitors Alleviating hERG


id: cord-024652-4i6kktl0
type: GGP
entity:
  cis 2 4 dimethylthiane S S dioxide cyclopentane butanoic acid 2 methyl methyl ester 1 butanol 3 methyl acetate


id: cord-024652-4i6kktl0
type: CL
entity:
  spp Trichoderma spp Phomopsis spp and Oxyporus latemarginatus are reported to produce VOCs that inhibit mycelial growth of phytopathogenic fungi


id: cord-024652-4i6kktl0
type: CL
entity:
  kelp an iodine rich substance needed for the normal functioning of thyroid gland Laminaria produces laminarin glucan polysaccharide


id: cord-024652-4i6kktl0
type: CHEMICAL
entity:
  dicotyledonous plants Apiaceae Asteraceae Convolvulaceae Chenopodiaceae Euphorbiaceae Linaceae Moraceae Piperaceae Rosaceae Rutaceae


id: cord-024652-4i6kktl0
type: CHEMICAL
entity:
  quinones phenols phenolic esters steroids terpenoids cytochalasins benzopyranone alkaloids isocoumarins


id: cord-024652-4i6kktl0
type: CHEMICAL
entity:
  S 5 methyl 1 heptanol ethyl acetate propanoic acid 2 methyl methyl ester cis 2 4 dimethylthiane S S dioxide cyclopentane butanoic acid 2 methyl methyl ester 1 butanol 3 methyl acetate


id: cord-024652-4i6kktl0
type: CHEMICAL
entity:
  methyl 1 butanol 1 methyl 1 3 cyclohexadiene 1 methyl 1 4 cyclohexadiene 4 heptanone isoamyl acetate 4 heptyn 2 ol 2 octenal octanal β


id: cord-024652-4i6kktl0
type: CHEMICAL
entity:
  alkylated phenols anthraquinones coumarins phenolic acid phenols phenylpropanoids quinines xanthones hydroxycinnamic acid p coumaric acid ferulic acid


id: cord-024652-4i6kktl0
type: CHEMICAL
entity:
  Asparagus racemosus Willd Insecticidal secondary metabolic products from the entomogenous fungus Fusarium larvarum 12 Heptadecenyl resorcinol


id: cord-024652-4i6kktl0
type: CHEMICAL
entity:
  dem Sachalin Staudenknoterich Reynoutria sachalinensis F Schmidt Nakai gegen Plizkrankheiten insbesondere Echte Mehltauplize Production of


id: cord-024652-4i6kktl0
type: CHEMICAL
entity:
  Cinnamomum camphora Muscodor kashayum sp nov a new volatile antimicrobial producing endophytic fungus Muscodor


id: cord-023284-i0ecxgus
type: PROTEIN
entity:
  ligand Abtstr 236 239 Quant Struct Act Relat 9 234 293 1990 binding unfolding kinetics conformational equilibria


id: cord-023284-i0ecxgus
type: PROTEIN
entity:
  type I 3 phenoxybenzyl 2 4 ethoxyphenyl 3 3 3 trifluoropropyl ether R Quant Struct Act Relat 9 234 293 1990 Abstr 308 271 isomer 11 a cyano 3 phenoxybenzyl 2 4 chlorophenyl 2 methylpropionate S isomer III


id: cord-023284-i0ecxgus
type: PROTEIN
entity:
  I 11 OH 0 Ho2C Quant Struct Act Relat 9 234 293 1990 Abstr 321 322 279 Biological material a Aspergillus ochraceus b Carbopeptidase A


id: cord-023284-i0ecxgus
type: DNA
entity:
  X ray structure d The combination of NMR and molecular modeling approaches however makes it possible to model virtually any molecule


id: cord-023284-i0ecxgus
type: GGP
entity:
  acetylcholine histamine cortisonelhydrocortisone indole 3 acetic acid phenoxyacetic acid herbicides c


id: cord-023284-i0ecxgus
type: GGP
entity:
  isosorbide l 1 5 monoacetate 1 2 monoacetate 1 5 mononitrate 1 2 mononitrate l diacetate 1 5 nitro 2 acetate 1 2 nitro 5 acetate l dinitrate Rn R I retention factors


id: cord-023284-i0ecxgus
type: CHEMICAL
entity:
  methyl 2 nitropheno1 2 4dichlorophenol 2 4 6 trichlorophenol 2 3 4 5 tetrachlorophenol 2 4 6 triiodophenol pentachlorophenol


id: cord-023284-i0ecxgus
type: CHEMICAL
entity:
  3 6a dihydroxy 8 9 methylenedioxy pterocarpan 6a 1 la dehydropisatin 3 hydroxy 8 9 methylenedioxy 6a 1 1 a dehydropterocarpan 3 hydroxy 9 methoxypterocarpan 3 hydroxy 9 zmethoxypterocarpan 3 zhydroxy 9 methoxypterocarpan vestitol sativan


id: cord-023284-i0ecxgus
type: CHEMICAL
entity:
  2 C1 3 C1 2 4 5 Cl 2 4 6 CI pentachlorophenol 4 CI 2 Me 4 C1 3 Me 4 C1 2 3 Me 4 C1 3 5 Me 4 CI 2 ally1 4 C1 2 Pr 5 Me 4Z1 2 3 C1 2 443 2 5 C1 2 6 Cl 3 4 C1 3 5 CI 2 3 6 C1 2 Cl 6 NO2 2 4 C1


id: cord-023284-i0ecxgus
type: CHEMICAL
entity:
  N substituted 3 methyl 4 nitropyrazole 5 carboxamides 11 6 N substituted 4 amino 3 methylpyrazole 5 carboxamides


id: cord-023284-i0ecxgus
type: CHEMICAL
entity:
  N substituted 3 methyl 4 diazopyrazole 5 carboxamides and N piperidiny 1 N 1 3 dimethyl 4 nitrosopyrazol 5 yl urea


id: cord-260014-q5sug7uu
type: ORG
entity:
  Borbás Anikó title Reprogramming of the Antibacterial Drug Vancomycin Results in Potent Antiviral Agents


id: cord-260014-q5sug7uu
type: CHEMICAL
entity:
  PyBOP reagent gave amide derivative 11 Scheme 4 Using the same conditions the reaction between compound 2 and maleimide


id: cord-260014-q5sug7uu
type: CHEMICAL
entity:
  2 4 13 4 decyloxy methyl 1H 1 2 3 triazol 1 yl 2 5 8 11 tetraoxatridecyl 1H 1 2 3 triazol 1 yl ethanamine 9 207


id: cord-273372-69rlh9or
type: ORG
entity:
  Vitro Activity Against Ebola Potential and Emerging Treatment Options for Ebola Virus Disease Protection


id: cord-283128-9mbi75de
type: ORG
entity:
  Vol II Academic Lipid Biochemistry An Introduction Oligonucleotide Synthesis a Practical Approach Methods for Dilution Antimicrobial Susceptibility Test


id: cord-020010-q58x6xb0
type: CELL_LINE
entity:
  Ulm Albert Einstein Allee 11 89081 Ulm Germany 2 IPF PharmaCeuticals GmbH Feodor Lynen Strasse 31 30625 Hannover Germany A


id: cord-020010-q58x6xb0
type: CELL_LINE
entity:
  British Columbia Vancouver BC Canada V6T 1Z3 2 GE Healthcare Bio Sciences Piscataway NJ 08855 USA 3 British Columbia Center for Disease Control Vancouver BC Canada V5Z 4R4


id: cord-020010-q58x6xb0
type: CELL_LINE
entity:
  British Columbia Vancouver BC Canada 2 AVI BioPharma Inc Corvallis OR USA Background Coxsackievirus B3 CVB3


id: cord-020010-q58x6xb0
type: DNA
entity:
  REP 9 Adriana Garozzo 1 Rossella Timpanaro 1 Aldo Stivala 1 Gianna Tempera 1 Christian C C Cutrì 2 Angelo Castro 1 1 Department


id: cord-020010-q58x6xb0
type: ORG
entity:
  Department of Biologic and Materials Sciences School of Dentistry 3 Interdepartmental Graduate Program


id: cord-020010-q58x6xb0
type: ORG
entity:
  Department of Life and Environmental Sciences Faculty of Engineering Chiba Institute of Technology Chiba


id: cord-020010-q58x6xb0
type: ORG
entity:
  University of Alabama School of Medicine Birmingham AL USA 2 Department of Medicine University of California San Diego


id: cord-020010-q58x6xb0
type: ORG
entity:
  Department of Pediatrics University of Alabama School of Medicine Birmingham AL USA 2 Southern Research Institute


id: cord-020010-q58x6xb0
type: ORG
entity:
  the Rocky Mountain Regional Centers of Excellence NIH Laboratory of Virology Department of Biological Chemistry School of Sciences


id: cord-020010-q58x6xb0
type: ORG
entity:
  the Virology Branch National Institute of Allergy and Infectious Diseases National Institutes of Health Slobodan Paessler 1 Laure Deflubé 1 Andrew Vaillant 2


id: cord-020010-q58x6xb0
type: LAW
entity:
  the REP 9 Adriana Garozzo 1 Rossella Timpanaro 1 Aldo Stivala 1 Gianna Tempera 1 Christian C C Cutrì 2 Angelo Castro 1 1 Department of Microbiological Sciences University of Catania Via Androne 8 95124


id: cord-020010-q58x6xb0
type: ORG
entity:
  Leuven Belgium 2 Department of Chemistry University of Nevada Reno USA 3 Service de Neurovirologie Fontenay aux


id: cord-020010-q58x6xb0
type: ORG
entity:
  Institute of Microbiology 2 Institute of Experimental Pathology and Parasitology 3 Institute of Botany


id: cord-020010-q58x6xb0
type: EVENT
entity:
  International Conference on Antiviral Research ISAR Conference Committee Future Conferences Acknowledgement


id: cord-020010-q58x6xb0
type: DISEASE
entity:
  influenza A H5N1 virus efficacy was compared to similar dosages of oseltamivir and oseltamivir carboxylate


id: cord-020010-q58x6xb0
type: CHEMICAL
entity:
  Magnani 4 E Garaci 5 A T Palamara 1 1 Department Public Health Sciences University Rome La Sapienza Rome Italy


id: cord-020010-q58x6xb0
type: CHEMICAL
entity:
  5 methylthio 3 4 3 phenyl 1 propoxy phenyl isoxazol 4 carbonitrile ON 7 and 5 methylthio 3 4 4 phenoxy 1 buthoxy phenyl isoxazol 4 carbonitrile


id: cord-264316-do0px1gq
type: GGP
entity:
  leucine aminopeptidase aminopeptidase N puromycin sensitive aminopeptidase and leukotriene A4 hydrolase aminopeptidase


id: cord-264316-do0px1gq
type: CHEMICAL
entity:
  N terminal Asp Arg bond whereas APN functions in subsequent inactivation of AngIII APA specific sulfonate


id: cord-264316-do0px1gq
type: CHEMICAL
entity:
  ovalicin 1S 2R 3S 4R 5S 7 hydroxy 8 methoxy 7 2 methyl 3 3 methylbut 2 enyl oxiran 2 yl 4 oxaspiro 2 5 octan 2 one


id: cord-290539-8ak2tths
type: PROTEIN
entity:
  MTS 3 4 5 dimethylthiazol 2 yl 5 3 carboxy methoxy phenyl 2 4 sulfophenyl 2H tetrazolium assay Cell cultures


id: cord-290539-8ak2tths
type: CHEMICAL
entity:
  iodides 1 or 2 and 5 formyl 2 furanylboronic acid 3 Basic hydrolysis of ester 5 provided the corresponding acid 6 Nucleophilic substitution between trithiocarbonate


id: cord-293867-c4wnr5xe
type: CHEMICAL
entity:
  N 2 nonsubstituted methyl 6 7 8 nonsubstituted alkyl aryl 3 oxo 1 thia 4 azaspiro 4 4 non 4 5 dec 4 yl acetamides 5a d 6a


id: cord-292380-ulsejzqt
type: ORG
entity:
  Aminophosphonic Acids of Potential Medical Importance Aminophosphonic Acids Phosphorus Analogues of Natural Amino Acids


id: cord-292380-ulsejzqt
type: WORK_OF_ART
entity:
  Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity Interpretation of Infrared Spectra a Practical Approach Synthesis


id: cord-292380-ulsejzqt
type: CHEMICAL
entity:
  diethyl chromonyl pyrazolyl 4 oxo 2 phenyl quinazolin 3 4H yl amino methyl phosphonates Phosphorus Sulfur


id: cord-283301-adjjkqt2
type: PROTEIN
entity:
  anti inflammatory active tetrahydrofuro 3 2 c pyridinone 2 carboxylate derivatives Dihydropyrimidones


id: cord-283301-adjjkqt2
type: CHEMICAL
entity:
  macrocyclic ketones ketones macrocyclic lactones macrocyclic oxalactones esters aldehydes alcohols ethers


id: cord-283301-adjjkqt2
type: CHEMICAL
entity:
  SAL D saccharic acid 1 4 lactone D SDL 2 5 di O acetyl D glucaro 1 4 6 3 dilactone D GL D glucurono g lactone


id: cord-296560-ehrww6uu
type: LAW
entity:
  Chapter 9 Molecular Similarity Advances in Methods Applications and Validations in Virtual Screening and QSAR


id: cord-300574-nclkfw4h
type: GGP
entity:
  vitamin E flavonoids phenolic acids minerals trace elements i e zinc iron calcium selenium germanium


id: cord-315193-z6v6s46n
type: CHEMICAL
entity:
  aryl Compound 4 the heteroaryl Compounds 6 7 or the long chain amide function Compounds 1 2 at Y position


id: cord-306934-29ljbl7g
type: PROTEIN
entity:
  Schistosoma mansonii 2 while 1 3 4 phenylazo 5 6 7 8 tetrahydronaphth 1 yl amino propylpiperidine 3 and 1 3 4 phenylazo 5 6 7 8 tetrahydro naphth 1


id: cord-306934-29ljbl7g
type: PROTEIN
entity:
  Coxsackie Virus type B2 CVB 2 Polio Virus type 1 Sabin strain Sb 1 Vesicular Stomatitis Virus VSV Vaccinia Virus VV Herpes Virus 1 HSV 1


id: cord-317628-1inxq7t5
type: GGP
entity:
  Alzheimer s disease 43 multiple sclerosis 44 and traumatic brain injury 45 and significant benefit has been achieved with monoclonal


id: cord-317628-1inxq7t5
type: WORK_OF_ART
entity:
  the Treatment of Cytokines in the Balance of Protection and Pathology During Mycobacterial Infections


id: cord-309052-3h0g7s9v
type: WORK_OF_ART
entity:
  Bakuchiol A Retinol Like Functional Compound Modulating Multiple Retinol and Non Retinol Targets New


id: cord-300872-blycbi4u
type: CHEMICAL
entity:
  umbelliferone 8hydroxyquinoline n 2 umbelliferone 8 hydroxyquinoline n 4 and umbelliferone 4hydroxyquinoline n


id: cord-326922-bajpr5a2
type: ORG
entity:
  Congress of Clinical Toxicology NACCT American College of Emergency Physicians ACEP Scientific Assembly Society for Academic Emergency Medicine


id: cord-326922-bajpr5a2
type: ORG
entity:
  Central Admixture Pharmacy Services Inc Summary Suspension Maryland State Board of Pharmacy Outbreak of Systemic Inflammatory Response Syndrome Linked


id: cord-318854-xaus3bma
type: PROTEIN
entity:
  heterogeneous nuclear ribonucleoprotein C C1 C2 heterogeneous nuclear ribonucleoprotein K non POU domain


id: cord-301349-m4nr3pqx
type: PROTEIN
entity:
  coreceptors 11 19 22 58 59 Comprehensive virtual screening experiments were carried out to investigate the multiple topographies of the


id: cord-301349-m4nr3pqx
type: GGP
entity:
  Pharm Sci DOI 10 1016 j ejps 2020 105537 sha 6c74a9edf1634063c325ede086197e2a26945742 doc_id 301349 cord_uid m4nr3pqx Chemokine receptors


id: cord-301349-m4nr3pqx
type: ORG
entity:
  a Traditional Chinese Medicine Library Antiviral Compounds Discovered by Virtual Screening of Small Molecule Libraries


id: cord-327946-mqakaisa
type: WORK_OF_ART
entity:
  Promising Novel Anti Influenza Agents Targeting the PA PB1 Protein Protein Interaction Structure Activity Relationships Exploration with the Aid of Molecular Modeling Structural


id: cord-328176-fck2ktxi
type: CELL_LINE
entity:
  human embryonic lung HEL fibroblast proliferation 5 3 μM 17 μM and 2 6 μM Compound IIc and IIl show antiviral activity against wild type herpes simplex virus HSV varicella zoster virus VZV and acyclovirresistant HSV


id: cord-328176-fck2ktxi
type: GGP
entity:
  herpes simplex virus 1 KOS herpes simplex virus 2 G herpes simplex virus 1 TK KOS ACV r varicella zoster virus


id: cord-328176-fck2ktxi
type: TAXON
entity:
  virus HIV type 1 III B and type 2 ROD coxsackie virus B4 respiratory syncytial virus parainfluenza 3 virus


id: cord-328176-fck2ktxi
type: DISEASE
entity:
  type 2 ROD coxsackie virus B4 respiratory syncytial virus parainfluenza 3 virus re Table 4 Compound IIl


id: cord-323093-u3ozc9ry
type: DISEASE
entity:
  Maithri M Battaile Kevin P Lovell Scott Perlman Stanley Groutas William C Chang Kyeong Ok title 3C like protease inhibitors block coronavirus replication


id: cord-323479-vlgv3nwq
type: ORG
entity:
  the Department of Chemical Biological Pharmaceutical and Environmental Sciences University of Messina Messina Italy


id: cord-323479-vlgv3nwq
type: CHEMICAL
entity:
  dioxindole glucosides dioxindole malonylglucoside Isatan C 6 hydroxyindole 3 carboxylic acid 6 O glucoside


id: cord-323479-vlgv3nwq
type: CHEMICAL
entity:
  p hydroxybenzoic o methoxybenzoic p methoxybenzoic dihydrocaffeic and 4 hydroxy 3 methoxyphenylpropanoic acid


id: cord-323479-vlgv3nwq
type: CHEMICAL
entity:
  acids alcohols aldehydes esters ethers furans hydrocarbons isothiocyanates thiocyanates ketones nitriles


id: cord-323479-vlgv3nwq
type: DISEASE
entity:
  influenza virus infected human bronchial epithelial cells Radix Isatidis polysaccharides inhibit Influenza A virus and Influenza A virus


id: cord-328834-yetnlb2j
type: CHEMICAL
entity:
  chromone conjugated derivatives of 2 4 thiazolidinedione 2 4 imidazolidinedione 2 thioxo imidazolidine 4 one


id: cord-328962-1c4vqaqr
type: GGP
entity:
  ACE2 Gln24 Thr27 Lys31 His34 Glu37 Asp38 Tyr41 Gln42 Leu45 Leu79 Met82 Tyr83 Asn90 Gln325 Glu329 Asn330 Lys353


id: cord-277802-f8pyn3rx
type: CELL_LINE
entity:
  HeLa cervical epithelioid carcinoma cell BT483 mammary gland adenocarcinoma cell SKHep hepatocellular carcinoma cell


id: cord-277802-f8pyn3rx
type: CELL_LINE
entity:
  MCF 7 human breast adenocarcinoma A549 human lung adenocarcinoma HT 29 human colon carcinoma and P388 murine leukemia


id: cord-277802-f8pyn3rx
type: CELL_LINE
entity:
  lung cancer NCI H460 tongue squamosa cell carcinoma TCA 8113 liver cancer BEL 7402 hepatocarcinoma HepG2 gastric carcinoma SGC 7901


id: cord-277802-f8pyn3rx
type: CELL_LINE
entity:
  A549 human lung adenocarcinoma SGC human gastric cancer K562 human myelogenous leukemia HCT116 human colorectal carcinoma and KB VCR human oral cancer cells


id: cord-277802-f8pyn3rx
type: PROTEIN
entity:
  Vuki cevi c Antibacterial 3 arylamino 1 ferrocenylpropan 1 ones synthesis spectral electrochemical and structural characterization Synthesis and characterization of some Mannich bases


id: cord-277802-f8pyn3rx
type: PROTEIN
entity:
  N 4 aryl 1 piperazinyl alkyl 1 phenyl 2 5 pyrrolidinedione and N 4 aryl 1 piperazinyl alkyl 3 3 methylphenyl 2 5


id: cord-277802-f8pyn3rx
type: PROTEIN
entity:
  5 0 methylthioadenosine nucleosidase and 5 0 methylthioadenosine phosphorylase Augustyns Narylmethyl substituted iminoribitol derivatives


id: cord-277802-f8pyn3rx
type: GGP
entity:
  NR 2 ¼ 4 morpholinyl 1 piperazinyl were 1 6 times more efficient than indomethacin at 10 mm without significant inhibition of COX 1


id: cord-277802-f8pyn3rx
type: GGP
entity:
  NR 2 ¼ 1 piperidinyl 4 methylpiperazin 1 yl 4 morpholinyl Fig 58 decreased the onset of phenobarbital induced sleep and prolonged the duration of hypnosis when administered in a dose equimolar


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  regioisomeric 2 3 4 7 tetrahydro 1 3 oxazino 6 5 b carbazoles 43 and 2 3 4 7tetrahydro 1 3 oxazino 5 6 a carbazoles 44 Use of allylamine 3 3 dimethylallylamine


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  alkyl phosphites R 3 ¼ CH 3 C 2 H 5 n C 3 H 7 i C 3 H 7 n C 4 H 9 fluorine substituted benzaldehydes


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  4 substituted thiosemicarbazones of 5 trifluoromethoxyisatin R ¼ c C 6 H 11 4 FC 6 H 4 4 ClC 6 H 4 4 BrC 6 H 4 Fig 32


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  pyrido 3 2 b indol 4 yl compounds 210 X ¼ NH 325 benzofuro 3 2 1 6 naphthyridin 5 yl compound 215 332


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  phenolic Mannich bases 258 R 1 ¼ 2 F 2 Cl 2 Br 3 F 3 Cl 3 Br of chalcone analogues Fig 48 having the same substitution pattern in ring A


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  ketonic Mannich bases 252 R 1 ¼ H CH 3 SO 2 CH 3 derived from 2 arylidenecyclohexanones and aromatic amines


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  4 4 fluorophenyl piperazin 1 yl IC 50 ¼ 245 nM and 4 2 methoxyphenyl piperazin 1 yl IC 50 ¼ 1 06 mM In


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  carbonyl function Phenolic Mannich bases 41 R ¼ R 1 ¼ OH R 2 ¼ aminomethyl of scutellarein Fig 7 were


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  pyridinyl R 2 ¼ CH 3 NR 2 ¼ 4 methylpiperazin 1 yl 300 R 1 ¼ 3 pyridinyl R 2 ¼ OCH 3 NR 2 ¼ 4 methylpiperazin 1 yl and 300 R 1 ¼ C 6 H 5 R 2 ¼ H NR 2 ¼ 4 morpholinyl


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  ketonic Mannich bases 305 NR 2 ¼ 1 piperidinyl 4 methylpiperazin 1 yl 4 morpholinyl Fig 58 decreased


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  primary aliphatic amines X ¼ NR R ¼ C 2 H 5 R 1 C 6 H 4 CH 2 CH 2 R 1 ¼ H 4 Cl 3 4 CH 3 O 2 or piperazine


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  phenolic Mannich bases 58 R 1 ¼ H CH 3 allyl prenyl NR 2 ¼ N CH 3 2 N C 2 H 5 2 1pyrrolidinyl 1 piperidinyl 4 morpholinyl of xanthone derivatives Fig 10


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  4 chlorophenyl moiety with 4 fluorophenyl 4 nitrophenyl 4 sulfonamidophenyl 4aminophenyl or pyridinyl


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  bis 3 aryl 3 oxo propyl methylamine hydrochlorides and 4 aryl 3 arylcarbonyl 1 methyl 4 piperidinol hydrochlorides


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  3 4 4 dimethylamino 6 4 methyl 2 oxo 2H chromen 7 yloxy 1 3 5 triazin 2 ylamino phenyl 2 phenyl 5 4 pyridin 2 yl piperazin 1 ylmethyl thiazolidin 4 one


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  4 dimethylamino 1 4 4a 5 5a 6 11 12a octahydro 3 6 10 12 12a pentahydroxynaphthacenecarboxamide Hydrophobic vancomycin


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  1 aryl 2 dimethylamino methyl 2 propen 1 one hydrochlorides Antifungal unsaturated cyclic Mannich ketones


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  ethyl 6 bromo 8 hydroxyimidazo 1 2 a pyridine 3 carboxylates Activity of Mannich bases of 7 hydroxycoumarin


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  bis 3 aryl 3 oxo propyl ethylamine hydrochlorides and 4 aryl 3 arylcarbonyl 1 ethyl 4 piperidinol hydrochlorides


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  ylidene 4 2 methyl phenyl 4 oxoquinazolin 3 4H yl benzohydrazide derivatives Synthesis pharmacological


id: cord-277802-f8pyn3rx
type: CHEMICAL
entity:
  3 3 substituted phenyl 4 piperidin 1 ylmethyl 4 morpholin 4 ylmethyl 4 5 dihydro isoxazol 5 yl 1H indoles


id: cord-338436-0z828org
type: GGP
entity:
  TMPRSS2 transmembrane serine protease 2 ACE2 angiotensin converting enzyme 2 IFN interferon DPP4 dipeptidyl peptidase 4 SV40 simian virus


id: cord-338436-0z828org
type: ORG
entity:
  a Notice of Special Interest National Institute of Allergy and Infectious Diseases NIAID Priorities for Biomedical Knowledgebases and Repositories


id: cord-338436-0z828org
type: EVENT
entity:
  The Global Phosphorylation Landscape of SARS CoV 2 Infection Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS CoV 2


id: cord-330465-16j5vm7h
type: PROTEIN
entity:
  aconitase PDB ID 1C96 cytochrome c PDB ID 1HRC carbamoyl phosphate synthetase 1 PDB ID 5DOU hypoxanthine guanine phosphoribosyltransferase PDB ID 6AR9 glutamate dehydrogenase PDB ID 1BVG


id: cord-330465-16j5vm7h
type: ORG
entity:
  Theoretical and Computational Biophysics Group University of Illinois at Urbana Champaign Illinois USA


id: cord-330465-16j5vm7h
type: CHEMICAL
entity:
  pyridine DMAP 1 5 mmol 0 19 g and 5 mmol of appropriate acid anhydride 2 2 dimethylsuccinic anhydride or 3 3 dimethylglutaric anhydride or 2 2 dimethylglutaric anhydride


id: cord-333675-vkk2frnf
type: CHEMICAL
entity:
  olefin cross metathesis reaction with bis POM allylphosphonate 1 using 5 mol of the NHC Ru CHR Nolan s catalyst Cl 2 PCy 3 IMes Ru CHPh 3 in


id: cord-333675-vkk2frnf
type: CHEMICAL
entity:
  petroleum ethereEtOAc 1 1 to give a mixture of Z minor E major N 4 N 4 bis Boc N 1 crotyl cytosine 6a 90 0 mg 85


id: cord-333675-vkk2frnf
type: CHEMICAL
entity:
  phosphinyl 2 0 butenyl 1 2 4 triazole 3 bis Boc carboxamide 20 44 3 mg 0 065 mmol in 1 mL of CH 3 CNeMeOH 1 1


id: cord-336759-cu1uprwm
type: GO
entity:
  vesicular stomatitis virus Coxsackie B4 virus respiratory syncytial virus parainfluenza 3 virus reovirus Sindbis virus


id: cord-336759-cu1uprwm
type: CHEBI
entity:
  ethyl acetate N 7 7 9 trimethyl 3 oxo 1 thia 4 The microdilution method was performed according to a standard protocol from the Clinical and Laboratory Standard Institute CLSI 27 28 The resazurin microtitre assay REMA has been developed as a colorimetric and standard method for drug


id: cord-336759-cu1uprwm
type: CHEMICAL
entity:
  5 chloro 3 phenyl N 2 7 8 9 substituted nonsubstituted 3 oxo 1 thia 4 azaspiro 4 4 nonan 4 5 decan 4 yl 1H indole 2 carboxamides 4a 4i 5a


id: cord-336759-cu1uprwm
type: CHEMICAL
entity:
  decan 4 yl 3 phenyl 1H indole 2 carboxamide 5h C 30 H 28 ClN 3 O 2 S Beige powder 3289 N H 2 CH 3 sp 1 58 2 00 8H m CH 2 sp 18 1H s NH ppm 13 C


id: cord-330994-6nu7utu1
type: PROTEIN
entity:
  coronaviruse genome spike glycoprotein S matrix glycoprotein M nucleocapsid protein N and small envelope protein E


id: cord-330994-6nu7utu1
type: CELL_LINE
entity:
  À256 44 27 55 kJ mol SASA equal to À28 58 4 32 kJ mol DE polar solvation equal to À283 58 44 53 kJ mol DE Electrostatic equal to À127 76 40 50 kJ mol and DE Van der Waal equal to À384 44 34 40 kJ mol inside 6LU7


id: cord-330994-6nu7utu1
type: GGP
entity:
  Alzheimer s disease 17 Due to the low toxicity and biological activity of all studied compounds especially caulerpin


id: cord-330994-6nu7utu1
type: ORG
entity:
  Statistical Potential for Assessment and Prediction of Protein Structures Homology Modeling and Virtual Screening to Discover Potent Inhibitors Targeting


id: cord-340832-412qre64
type: DNA
entity:
  N methyl derivative 42 2R 3R 4R 5R N methyl 2 acetamidomethyl 3 4 dihydroxy 5 hydroxymethyl pyrrolidine


id: cord-340832-412qre64
type: PROTEIN
entity:
  goat anti mouse fluorescein isothiocyanate FITC conjugated secondary antibody Jackson ImmunoResearch


id: cord-340331-51yq1rdo
type: GGP
entity:
  dihydrofolate reductase by 4 6 diamino 1 2 dihydro 2 2 dimethyl 1 4 substituted phenyl s triazines 1 m


id: cord-340331-51yq1rdo
type: WORK_OF_ART
entity:
  Repositioning of DHFR inhibitors Antimalarial Chemotherapy Mechanisms of Action Resistance and New Directions in Drug Discovery Inhibitors of pneumocystis carinii


id: cord-340331-51yq1rdo
type: CHEMICAL
entity:
  D 2 O superimposed signals 13 C NMR 50 MHz 5 ditrifluoromethylphenyl 1 2 dihydrotriazine hydrochloride


id: cord-340331-51yq1rdo
type: CHEMICAL
entity:
  D 2 O 8 26 s 1 arom H Chlorophenyl 2 2 cyclotetramethylene 4 6 diamino 1 2 dihydrotriazine hydrochloride


id: cord-340331-51yq1rdo
type: CHEMICAL
entity:
  D 2 O 6 61 br s 1H amino group MHz DMSOd 6 9 26 s 1H þ NH exchanges with D 2 O 8 05e7 40 m 4 arom H and 3H amino


id: cord-340331-51yq1rdo
type: CHEMICAL
entity:
  4 6 diamino 1 2 dihydro 2 2 dimethyl 1 4 substituted phenyl s triazines 1 m Trifluoromethylphenyl 4 5 diamino 1 2 dibydro 2 2 dimethyl 1 3 5 triazine


id: cord-345750-dk1exw9l
type: CHEMICAL
entity:
  4 methoxyphenyl 3a 3 4 di methoxyphenyl 3b 3 4 5 trimethoxyphenyl 3c 4 fluoro phenyl substituents 3f


id: cord-345750-dk1exw9l
type: CHEMICAL
entity:
  ethyl 1 4 aminofurazan 3 yl 5 R 1H 1 2 3 triazole 4 carboxylate 4a g 7 mmol The reaction mixture was refluxed for 1 h the undissolved residue


id: cord-352844-wggg3ynb
type: CELL_LINE
entity:
  HepG2 liver carcinoma HeLa cervical cancer A549 lung adenocarcinoma DU145 prostatic cancer SKOV3 ovarian carcinoma MCF 7 breast cancer and drug resistant MCF 7 DOX doxorubicin resistant MCF 7


id: cord-352844-wggg3ynb
type: CELL_LINE
entity:
  HepG2 liver carcinoma HeLa cervical cancer A549 lung adenocarcinoma DU145 prostatic cancer SKOV3 ovarian carcinoma MCF 7 breast cancer and drug resistant MCF 7 DOX doxorubicin resistant MCF 7 human cancer cell lines


id: cord-352844-wggg3ynb
type: GGP
entity:
  Alzheimer s disease Antioxidant and anticholinesterase potential of Ferulago cassia with farther bio guided isolation of active coumarin constituents A new and rapid colorimetric determination of acetylcholinesterase


id: cord-352844-wggg3ynb
type: WORK_OF_ART
entity:
  Thioxocoumarins Show an Alternative Carbonic Anhydrase Inhibition Mechanism Compared to Coumarins Inhibitory


id: cord-352844-wggg3ynb
type: CHEMICAL
entity:
  ABTS 2 2 azino bis 3ethylbenzothiazoline 6 sulfonic acid diammonium salt DPPH 2 2 diphenyl 1 picrylhydrazyl


id: cord-352844-wggg3ynb
type: CHEMICAL
entity:
  ABTS 2 2 azino bis 3 ethylbenzothiazoline 6 sulfonic acid diammonium salt DPPH 2 2 diphenyl 1 picrylhydrazyl


id: cord-352844-wggg3ynb
type: CHEMICAL
entity:
  N 2 3 5 disubstituted 4H 1 2 4 triazol 4 yl acetyl 6 7 8 substituted 2 oxo 2H chromen 3 carbohydrazides 158a e 159a e Figure 54 207


id: cord-352844-wggg3ynb
type: CHEMICAL
entity:
  N 2 3 5 disubstituted 4H 1 2 4 triazol 4 yl acetyl 6 7 8 substituted 2 oxo 2H chromen 3 carbohydrazide


# bib

id: cord-000445-2x7dfl1q
title: Neglected Disease – African Sleeping Sickness: Recent Synthetic and Modeling Advances
author: Paliwal, Sarvesh K.
date: 2011-05-10
txt: ./txt/cord-000445-2x7dfl1q.txt
cache: ./cache/cord-000445-2x7dfl1q.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163371/
doi: 10.3797/scipharm.1012-08
summary:
  brucei rhodesiense than the corresponding 2,5-substituted isomers (compounds 1-10, figure 4a), while among the 2, 5-substituted dications, the compounds possessing cationic substituents adjacent to nitrogen atoms in pyridine rings displayed superior activities against parasites compared to pentamidine as evident from compound 6 (figure 4b) which showed promising anti-trypanosomal activity (0.001µM) and lower cytotoxicity (4.90µM) than pentamidine and melarsoprol, but had poor in vivo activity giving only 1/4 cures in the STIB900 mouse model. Structure of two phenylbenzofuran dications with promising anti-trypanosomal activity Tidwell RR et al found that the in vitro anti-trypanosomal activities of bisbenzofuran derivatives against Trypanosoma brucei rhodesiense, and cytotoxicity against mammalian cells depended on the position and the type of cationic substituents as well as the length of the carbon linker between aromatic moieties. Thus promising in vitro, anti-trypanosomal activity, excellent potency in the acute mouse model of trypanosomiasis and the reduced cytotoxicity (1.9 µM) of compound 1 compared to pentamidine warrants further pre-clinical and clinical trials of this molecule.

abstract:
  Human African Trypanosomiasis (HAT) also called sleeping sickness is caused by subspecies of the parasitic hemoflagellate Trypanosoma brucei that mostly occurs in sub-Saharan Africa. The current chemotherapy of the human trypanosomiases relies on only six drugs, five of which have been developed more than 30 years ago, have undesirable toxic side effects and most of them show drug-resistance. Though development of new anti-trypanosomal drugs seems to be a priority area research in this area has lagged far behind. The given review mainly focus upon the recent synthetic and computer based approaches made by various research groups for the development of newer anti-trypanosomal analogues which may have improved efficacy and oral bioavailability than the present ones. The given paper also attempts to investigate the relationship between the various physiochemical parameters and anti-trypanosomal activity that may be helpful in development of potent anti-trypanosomal agents against sleeping sickness.


id: cord-000536-0mn1gbll
title: Predicting Biological Functions of Compounds Based on Chemical-Chemical Interactions
author: Hu, Le-Le
date: 2011-12-29
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248422/
doi: 10.1371/journal.pone.0029491
abstract:
  Given a compound, how can we effectively predict its biological function? It is a fundamentally important problem because the information thus obtained may benefit the understanding of many basic biological processes and provide useful clues for drug design. In this study, based on the information of chemical-chemical interactions, a novel method was developed that can be used to identify which of the following eleven metabolic pathway classes a query compound may be involved with: (1) Carbohydrate Metabolism, (2) Energy Metabolism, (3) Lipid Metabolism, (4) Nucleotide Metabolism, (5) Amino Acid Metabolism, (6) Metabolism of Other Amino Acids, (7) Glycan Biosynthesis and Metabolism, (8) Metabolism of Cofactors and Vitamins, (9) Metabolism of Terpenoids and Polyketides, (10) Biosynthesis of Other Secondary Metabolites, (11) Xenobiotics Biodegradation and Metabolism. It was observed that the overall success rate obtained by the method via the 5-fold cross-validation test on a benchmark dataset consisting of 3,137 compounds was 77.97%, which is much higher than 10.45%, the corresponding success rate obtained by the random guesses. Besides, to deal with the situation that some compounds may be involved with more than one metabolic pathway class, the method presented here is featured by the capacity able to provide a series of potential metabolic pathway classes ranked according to the descending order of their likelihood for each of the query compounds concerned. Furthermore, our method was also applied to predict 5,549 compounds whose metabolic pathway classes are unknown. Interestingly, the results thus obtained are quite consistent with the deductions from the reports by other investigators. It is anticipated that, with the continuous increase of the chemical-chemical interaction data, the current method will be further enhanced in its power and accuracy, so as to become a useful complementary vehicle in annotating uncharacterized compounds for their biological functions.


id: cord-002237-200ondzx
author: Dashtdar, Mehrab
date: 2016-09-17
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043089/
doi: 10.3831/kpi.2016.19.026
title:
  Phenol-Rich Compounds Sweet Gel: A Statistically More Effective Antibiotic than Cloxacillin Against Pseudomonas Aeruginosa

abstract:
  OBJECTIVES: The purpose of this study was to obtain a natural antibiotic from Phenol-rich compounds; for the dressing and the treatment of chronic wounds. METHODS: The Phenol-rich compound sweet gel was prepared by blending four natural herbal extracts, Acacia catechu (L.F.), Momia (Shilajit), Castanea sativa, and Ephedra sinica stapf, with combination of a sweet gel medium, including honey, maple saps, Phoenix dactylifera L. (date), pomegranate extract and Azadirachta indica gum as a stabilizer. The combinations were screened by using a well-diffusion assay with cloxacillin as a control. Pseudomonas spp. was tested with our novel antimicrobial compound. The zones of inhibition in agar culture were measured for each individual component and for the compound, and the results were compared with those of the control group which had been treated with cloxacillin. Data were expressed as means ± standard deviations. Quantitative analyses were performed using the paired t-test. RESULTS: The antibiotic effect of the Phenol-rich compound sweet gel was statistically shown to be more significant than that of cloxacillin against Pseudomonas aeruginosa (P < 0.05). CONCLUSION: Our novel approach to fighting the antibiotic resistance of Pseudomonas proved to be successful. The Phenol-rich compound sweet gel was found to be suitable for use as an alternative medicine and bioactive dressing material, for the treatment of patients with various types of wounds, including burns, venous leg ulcers, ulcers of various etiologies, leg ulcers on the feet of diabetic, unhealed graft sampling sites, abscesses, boils, surgical wounds, necrotic process, post-operative and neonatal wound infection, and should be considered as an alternative to the usual methods of cure.


id: cord-003341-z5w56zeq
title: In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4
author: Nguyen, Thi Thanh Hanh
date: 2013-12-13
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269914/
doi: 10.3390/molecules181215600
abstract:
  The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3(pro)) of dengue fever virus carries out all enzymatic activities needed for polyprotein processing and is considered to be amenable to antiviral inhibition by analogy. Virtual screening of 300,000 compounds using Autodock 3 on the GVSS platform was conducted to identify novel inhibitors against the NS2B-NS3(pro). Thirty-six compounds were selected for in vitro assay against NS2B-NS3(pro) expressed in Pichia pastoris. Seven novel compounds were identified as inhibitors with IC(50) values of 3.9 ± 0.6–86.7 ± 3.6 μM. Three strong NS2B-NS3(pro) inhibitors were further confirmed as competitive inhibitors with K(i) values of 4.0 ± 0.4, 4.9 ± 0.3, and 3.4 ± 0.1 μM, respectively. Hydrophobic and hydrogen bond interactions between amino acid residues in the NS3(pro) active site with inhibition compounds were also identified.


id: cord-003427-0dddrh4e
author: El-Faham, Ayman
date: 2015-08-13
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332339/
doi: 10.3390/molecules200814638
title:
  Synthesis, Characterization, and Anti-Cancer Activity of Some New N′-(2-Oxoindolin-3-ylidene)-2-propylpentane hydrazide-hydrazones Derivatives

abstract:
  Eight novel N′-(2-oxoindolin-3-ylidene)-2-propylpentane hydrazide-hydrazone derivatives 4a–h were synthesized and fully characterized by IR, NMR ((1)H-NMR and (13)C-NMR), elemental analysis, and X-ray crystallography. The cyto-toxicity and in vitro anti-cancer evaluation of the prepared compounds have been assessed against two different human tumour cell lines including human liver (HepG2) and leukaemia (Jurkat), as well as in normal cell lines derived from human embryonic kidney (HEK293) using MTT assay. The compounds 3e, 3f, 4a, 4c, and 4e revealed promising anti-cancer activities in tested human tumour cells lines (IC(50) values between 3 and 7 μM) as compared to the known anti-cancer drug 5-Fluorouracil (IC(50) 32–50 μM). Among the tested compounds, 4a showed specificity against leukaemia (Jurkat) cells, with an IC(50) value of 3.14 μM, but this compound was inactive in liver cancer and normal cell lines.


id: cord-003539-tazd6dvm
author: Yang, Kun
date: 2019-03-02
txt: ./txt/cord-003539-tazd6dvm.txt
cache: ./cache/cord-003539-tazd6dvm.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429262/
doi: 10.3390/molecules24050884
summary:
  According to the general procedure A, compound 2 was treated with 1-(Boc-amino)cyclopropanecarboxylic acid and then purified by reverse phase flash chromatography to give compound 3k: Yellow solid; yield, 28%; 1 H-NMR δ 11.96 (brs, 1H), 8 189.28, 180.10, 169.83, 164.69, 164.22, 161.39, 148.39, 134.15, 132.07, 123.98, 120.37, 112.73, 109.54, 107.67, 106.74, 66.57, 63.78 1-((2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)carbonyl)cyclobutan-aminium 2,2,2-trifluoroacetate (3l). According to the general procedure A, compound 2 was treated with 1-(Boc-amino)cyclobutanecarboxylic acid and then purified by reverse phase flash chromatography to give compound 3l: Yellow solid; yield, 28%; 1 H-NMR δ 11.95 (brs, 1H), 8 3-((2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)carbonyl)oxetan-3-aminium 2,2,2-trifluoroacetate (3m). According to the general procedure A, compound 2 was treated with 3-Boc-amino-3-oxetanecarboxylic acid and then purified by reverse phase flash chromatography to give compound 3m: Yellow solid; yield, 37%; 1 H-NMR δ 11.97 (brs, 2H), 8 1-((2-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)ethoxy)carbonyl)cyclopentan-aminium 2,2,2-trifluoroacetate (3n).

title:
  Design and Synthesis of Novel Anti-Proliferative Emodin Derivatives and Studies on their Cell Cycle Arrest, Apoptosis Pathway and Migration

abstract:
  Emodin is a cell arrest and apoptosis-inducing compound that is widely distributed in different plants (rhubarb, aloe), lichens and terrestrial fungi, and also isolated from marine-derived fungi and marine sponge-associated fungi. In this study, we designed and synthesized a novel series of emodin derivatives by binding emodin to an amino acid using linkers of varying lengths and composition, and evaluated their anti-proliferative activities using HepG2 cells (human hepatic carcinoma), MCF-7 cells (human breast cancer) and human normal liver L02 cells. Most of these derivatives showed moderate to potent anti-proliferative activities. Notably, compound 7a exhibited potent anti-proliferative activity against HepG2 cells with the half maximal inhibitory concentration (IC(50)) value of 4.95 µM, which was enhanced 8.8-fold compared to the parent compound emodin (IC(50) = 43.87 µM), and it also exhibited better selective anti-proliferative activity and specificity than emodin. Moreover, further experiments demonstrated that compound 7a displayed a significant efficacy of inducing apoptosis through mitochondrial pathway via release of cytochrome c from mitochondria and subsequent activation of caspase-9 and caspase-3, inducing cell arrest at G0/G1 phase, as well as suppression of cell migration of tumor cells. The preliminary results suggested that compound 7a could be a promising lead compound for the discovery of novel anti-tumor drugs and has the potential for further investigations as an anti-cancer drug.


id: cord-006139-9063uhox
title: Dual-functioning antimalarials that inhibit the chloroquine-resistance transporter
author: Egan, Timothy J
date: 2013-03-27
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099626/
doi: 10.2217/fmb.13.18
abstract:
  Malaria remains a major international health challenge. Resistance to a number of existing drugs and evidence of the emergence of artemisinin resistance has emphasized the need for new antimalarials. A new approach has been the preparation of dual-function compounds that include a chloroquine-like antimalarial group and a group that resembles a chloroquine chemosensitizer. This article reviews the recent discovery of such dual-function antimalarials that are proposed to target both hemozoin formation and the chloroquine resistance transporter, PfCRT. These are discussed in relation to the mechanism of action of 4-aminoquinolines, chloroquine resistance and resistance reversal.


id: cord-011251-rjyipcfv
author: Chernyshov, Vladimir V.
date: 2019-02-28
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223885/
doi: 10.1007/s11030-019-09932-9
title:
  Single-stage synthesis of heterocyclic alkaloid-like compounds from (+)-camphoric acid and their antiviral activity

abstract:
  ABSTRACT: An effective technique for one-stage synthesis of new polycyclic nitrogen-containing compounds has been developed. The procedure involves refluxing mixtures of camphoric acid with aliphatic or aromatic diamine without catalysts. In cases where the starting amine has a low boiling point (less than 200 °C), phenol is used as a solvent, as it is the most optimal one for obtaining products with good yields. It has been shown that the use of Lewis acids as catalysts reduces the yield of the reaction products. A set of compounds have been synthesized, which can be attributed to synthetic analogues of alkaloids. In vitro screening for activity influenza virus A was carried out for the obtained compounds. The synthesized quinazoline-like agent 14 has inhibitory activity against different strains of influenza viruses. GRAPHICAL ABSTRACT: [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11030-019-09932-9) contains supplementary material, which is available to authorized users.


id: cord-012773-wtgk2d68
title: Advances in the development of imaging probes and aggregation inhibitors for alpha-synuclein
author: Xu, Ming-ming
date: 2019-10-04
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470848/
doi: 10.1038/s41401-019-0304-y
abstract:
  Abnormal protein aggregation has been linked to many neurodegenerative diseases, including Parkinson’s disease (PD). The main pathological hallmark of PD is the formation of Lewy bodies (LBs) and Lewy neurites, both of which contain the presynaptic protein alpha-synuclein (α-syn). Under normal conditions, native α-syn exists in a soluble unfolded state but undergoes misfolding and aggregation into toxic aggregates under pathological conditions. Toxic α-syn species, especially oligomers, can cause oxidative stress, membrane penetration, synaptic and mitochondrial dysfunction, as well as other damage, leading to neuronal death and eventually neurodegeneration. Early diagnosis and treatments targeting PD pathogenesis are urgently needed. Given its critical role in PD, α-syn is an attractive target for the development of both diagnostic tools and effective therapeutics. This review summarizes the progress toward discovering imaging probes and aggregation inhibitors for α-syn. Relevant strategies and techniques in the discovery of α-syn-targeted drugs are also discussed.


id: cord-013387-q91052qw
title: Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach
author: Leão, Rozires P.
date: 2020-08-26
txt: ./txt/cord-013387-q91052qw.txt
cache: ./cache/cord-013387-q91052qw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559105/
doi: 10.3390/ph13090209
summary:
  In this initial stage, the pivot molecule rofecoxib was used as a research model for the virtual screening in six commercial molecule databases: Chembridge DIVERSetEXP, DIVERSet CORE Library (https://www.chembridge.com) [24] , Maybridge Collections (www.maybridge.com) [25, 26] , ZINC Drug Database, ZINC Natural Stock (http://zinc.docking.org) [27] , and Drug FDA BindingDB (http://www.bindingdb.org) [27] using the programs Rapid Overlay of Chemical Structures (ROCS) and electrostatic similarity (EON). The bioactivity scores of the LMQC72, LMQC36, and LMQC50 structures were calculated for different parameters, as receptor binding of the ligand to the G protein coupled (GPCR) and nuclear receptor ligand, modulating ion channel, kinase inhibition, protease inhibition, and inhibition of enzyme activity. The bioactivity scores of the LMQC72, LMQC36, and LMQC50 structures were calculated for different parameters, as receptor binding of the ligand to the G protein coupled (GPCR) and nuclear receptor ligand, modulating ion channel, kinase inhibition, protease inhibition, and inhibition of enzyme activity.

abstract:
  The cyclooxygenase-2 receptor is a therapeutic target for planning potential drugs with anti-inflammatory activity. The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was selected as a pivot molecule to perform virtual ligand-based screening from six commercial databases. We performed the search for similarly shaped Rapid Overlay of Chemical Structures (ROCS) and electrostatic (EON) compounds. After, we used pharmacokinetic and toxicological parameters to determine the best potential compounds, obtained through the softwares QikProp and Derek, respectively. Then, the compounds proceeded to the molecular anchorage study, which showed promising results of binding affinity with the hCOX-2 receptor: LMQC72 (∆G = −11.0 kcal/mol), LMQC36 (∆G = −10.6 kcal/mol), and LMQC50 (∆G = −10.2 kcal/mol). LMQC72 and LMQC36 showed higher binding affinity compared to rofecoxib (∆G = −10.4 kcal/mol). Finally, molecular dynamics (MD) simulations were used to evaluate the interaction of the compounds with the target hCOX-2 during 150 ns. In all MD simulation trajectories, the ligands remained interacting with the protein until the end of the simulation. The compounds were also complexing with hCOX-2 favorably. The compounds obtained the following affinity energy values: rofecoxib: ΔGbind = −45.31 kcal/mol; LMQC72: ΔGbind = −38.58 kcal/mol; LMQC36: ΔGbind = −36.10 kcal/mol; and LMQC50: ΔGbind = −39.40 kcal/mol. The selected LMQC72, LMQC50, and LMQC36 structures showed satisfactory pharmacokinetic results related to absorption and distribution. The toxicological predictions of these compounds did not display alerts for possible toxic groups and lower risk of cardiotoxicity compared to rofecoxib. Therefore, future in vitro and in vivo studies are needed to confirm the anti-inflammatory potential of the compounds selected here with bioinformatics approaches based on rofecoxib ligand.


id: cord-014863-jyti99xq
author: Karaküçük-İyidoğan, A.
date: 2019-05-15
txt: ./txt/cord-014863-jyti99xq.txt
cache: ./cache/cord-014863-jyti99xq.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089137/
doi: 10.1007/s11094-019-01968-3
summary:
  Encouraged by these results and aimed at developing effective anticancer agents, we designed two series of thiosemicarbazones by the pharmacophore hybridization method using two or more different pharmacophores in view of prospecting their cytostatic and antiviral activity (Fig. 1) . The synthesized compounds were also evaluated for their cytostatic activity against murine leukemia L1210, human CD 4 + T-lymphocyte CEM and cervix carcinoma HeLa cells (Table 4 ). The results showed that compounds Ia -Ig containing electron-withdrawing group, such as -CN located at the para position of the benzene ring, increased the cytostatic activity, according to the electron-donating group (-SCH 3 ) at the same position of the structure (like compounds Synthesis, Biological Evaluation and Ligand 147 IIa -IIg). It is established that Hb-acceptor (-CN; -SCH 3 ), hydrophobic groups (-N(CH 2 CH 2 Cl) 2 ), and 3D-conformations are responsible for the cytostatic activity of compounds such as Ig and IIg, according to ligand-based pharmacophore modeling.

title:
  Synthesis, Biological Evaluation and Ligand Based Pharmacophore Modeling of New Aromatic Thiosemicarbazones as Potential Anticancer Agents

abstract:
  Two series of new aromatic thiosemicarbazone derivatives were synthesized by condensation of N-(4-cyanophenyl)hydrazine carbothioamide (I) and N-(4-methylsulfanylphenyl)hydrazine carbothioamide (II) with appropriate aromatic aldehydes in order to investigate their antiviral and cytostatic potency. The chemical structures of all compounds were fully characterized by elemental analysis and spectroscopic techniques. The results of the bioassays indicated that compounds Id, Ie, If and IIf proved inhibitory against influenza virus A (EC(50) = 13 – 27 μg/mL for strain H1N1 and 9.3 – 18 μg/mL for strain H3N2). Compounds Ig and IIg were the most cytostatic compounds with inhibition of HeLa cell proliferation at an IC(50) = 0.3 μg/mL for Ig and 1.9 μg/mL for IIg. Especially, compound Ig showed the highest cytostatic activity with IC(50) of 0.30, 0.70 and 2.50 μg/mL against HeLa, CEM and L1210 cell lines, respectively. This inhibition range was within the same order of magnitude as that for cisplatin. Furthermore, molecular modeling was carried out to examine the cytostatic activity and determine the best pharmacophore model as a guide for the design and development of potential prodrugs in future studies.


id: cord-016425-8yd2bkf1
title: Novel Natural Products From Rainforest Endophytes
author: Strobel, Gary
date: 2005
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7120694/
doi: 10.1007/978-1-59259-976-9_15
abstract:
  Endophytic microorganisms are found in virtually every higher plant on earth. These organisms reside in the living tissues of the host plant and do so in a variety of relationships, ranging from symbiotic to pathogenic. Endophytes may contribute to their host plant by producing a plethora of substances that provide protection and survival value to the plant. Ultimately, these compounds, once isolated and characterized, may also have potential for use in modern medicine. Novel antibiotics, antimycotics, immunosuppressants, and anticancer compounds are only a few examples of what has been found after the isolation and culturing of individual endophytes followed by purification and characterization of some of their natural products. The potential of finding new drugs that may be effective candidates for treating newly developing diseases in humans is great.


id: cord-017041-0zxoq68m
title: Fluorine-Containing Diazines in Medicinal Chemistry and Agrochemistry
author: Volochnyuk, Dmitriy M.
date: 2014-06-13
txt: ./txt/cord-017041-0zxoq68m.txt
cache: ./cache/cord-017041-0zxoq68m.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7121506/
doi: 10.1007/978-3-319-04435-4_7
summary:
  Herein we give a comprehensive review on the biological activity and synthesis of fluorine containing, pyrimidine, pyrazine and pyridazine derivatives with relevance to medicinal and agrochemistry. Herein we give a comprehensive review on the biological activity and synthesis of fl uorine containing, pyrimidine, pyrazine and pyridazine derivatives with relevance to medicinal and agrochemistry. In an alternative approach, Fluorouracil was prepared by direct fl uorination of different pyrimidine derivatives, including uracil [ 15 ] , cytosine [ 16 ] , and orotic acid [ 17 ] . Early synthesis of Floxuridine commenced from Fluorouracil ( 1 ) which was transformed into its mercury salt 28 and then allowed to react with 2-deoxy-Dribofuranosyl chloride derivative 29 (Scheme 4 ) [ 18 ] . More precisely, Trifl uridine is transformed into α,α,α-trifl uorothymidine monophosphate ( 76 ) by thymidine kinase (Scheme 21 ); similarly to the Fluorouracil derivatives discussed in the previous sections, compound 76 is true inhibitor of thymidylate synthase.

abstract:
  The combination of a fluorine atom and a diazine ring, which both possess unique structural and chemical features, can generate new relevant building blocks for the discovery of efficient fluorinated biologically active agents. Herein we give a comprehensive review on the biological activity and synthesis of fluorine containing, pyrimidine, pyrazine and pyridazine derivatives with relevance to medicinal and agrochemistry.


id: cord-020010-q58x6xb0
title: 19th ICAR Abstracts:
author: nan
date: 2006-03-13
txt: ./txt/cord-020010-q58x6xb0.txt
cache: ./cache/cord-020010-q58x6xb0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133865/
doi: 10.1016/j.antiviral.2006.02.001
abstract: nan
summary:
  In the present study we reported the antiviral activity of neuraminidase inhibitor oseltamivir against lethal H5N1 influenza virus infection in ferrets, an appropriate animal model that closely resembles clinical signs of human influenza. Earl Kern 1 , Kathy Keith 2 , Robert Jordan 2 , Dennis Hruby 2 , Debra Quenelle 2 1 Department of Pediatrics, University of Alabama School of Medicine, Birmingham, AL, USA; 2 SIGA Technologies, Inc., Corvallis, OR, USA Although cidofovir (CDV) has been approved as an investigational new drug for emergency treatment of smallpox, its lack of oral activity and dose limiting toxicity dictates a need for continued development of better therapeutic agents for this potential bioterror disease. The in vitro antiviral activity of one of the most selective compounds, i.e. CHI-033, was assessed by (i) MTS-based cytopathic effect assays, (ii) virus yield reduction assays, (iii) real-time quantitative PCR (RT-QPCR) and (iv) by monitoring viral antigen expression.


id: cord-021013-xvc791wx
title: Chapter 1 Allelochemical Properties or the Raison D'être of Alkaloids
author: Wink, Michael
date: 2008-05-30
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148816/
doi: 10.1016/s0099-9598(08)60134-0
abstract:
  This chapter provides evidence that alkaloids are not waste products or functionless molecules as formerly assumed, but rather defense compounds employed by plants for survival against herbivores and against microorganisms and competing plants. These molecules were developed during evolution through natural selection in that they fit many important molecular targets, often receptors, of cells, which are seen in molecules that mimic endogenous neurotransmitters. The chapter discusses that microorganisms and herbivores rely on plants as a food source. Since both have survived, there must be mechanisms of adaptations toward the defensive chemistry of plants. Many herbivores have evolved strategies to avoid the extremely toxic plants and prefer the less toxic ones. Many herbivores have potent mechanisms to detoxify xenobiotics, which allow the exploitation of at least the less toxic plants. In insects, many specialists evolved that are adapted to the defense chemicals of their host plant, in that they accumulate these compounds and exploit them for their own defense. Alkaloids function as defense molecules against insect predators in the examples studied, and this is further support for the hypothesis that the same compound also serves for chemical defense in the host plant. It needs more experimental data to understand fully the intricate interconnections between plants, their alkaloids, and herbivores, microorganisms, and other plants.


id: cord-021419-nypnib0h
title: Main trends in the design of semi-synthetic antibiotics of a new generation
author: Olsufyeva, Evgenia N.
date: 2020-03-17
txt: ./txt/cord-021419-nypnib0h.txt
cache: ./cache/cord-021419-nypnib0h.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149660/
doi: 10.1070/rcr4892
summary:
  In this review, the following classes of compounds are considered as scaffolds for the synthesis of new antibiotics: polycyclic glycopeptides of the vancomycin ± teicoplanin group, classical macrolides, macrolides of the amphotericin B ± oligomycin group, anthracyclines, aureolic acid derivatives, heliomycin, synthetic benzoxaboroles and some other antibiotics. 42 Antibacterial activity of derivatives 52 ± 55 modified at the C(11)7OH group of the aglycone was evaluated compared to the starting antibiotics vancomycin (1) and azithromycin (30) on a panel of Gram-positive and Gramnegative bacterial strains (8 and 3 strains, respectively). In order to improve antifungal properties, cytotoxic and therapeutic characteristics and to study the mechanisms of action, series of new semi-synthetic derivatives based on AmB (63a) and bioengineered analogues S44HP (64a), BSG005 (65a), BSG022 (66a), BSG019 (67), BSG003 (68a) and BSG018 (69) were synthesized (in collaboration with the company BIOSERGEN, Norway) (Scheme 17).

abstract:
  This review summarizes main advances achieved by Russian researchers in the synthesis and characterization of semi-synthetic antibiotics of a new generation in the period from 2004 to 2019. The following classes of compounds are considered as the basis for modification: polycyclic antibacterial glycopeptides of the vancomycin group, classical macrolides, antifungal polyene macrolides, the antitumour antibiotic olivomycin A, antitumour anthracyclines and broad-spectrum antibiotics, in particular, oligomycin A, heliomycin and some other. Main trends in the design of modern anti-infective and antitumour agents over this period are considered in relation to original natural antibiotics, which have been independently discovered by Russian researchers. It is shown that a new type of hybrid structures can, in principle, be synthesized based on glycopeptides, macrolides and other antibiotics, including heterodimers containing a new benzoxaborole pharmacophore. The review addresses the influence of the length of the spacer between two antibiotic molecules on the biological activity of hybrid structures. A combination of genetic engineering techniques and methods of organic synthesis is shown to be useful for the design of new potent antifungal antibiotics based on polyenes of the amphotericin B group. Many new semi-synthetic analogues exhibit important biological properties, such as a broad spectrum of activity and low toxicity. Emphasis is given to certain aspects related to investigation of a broad range of biological activity and mechanisms of action of new derivatives. The bibliography includes 101 references.


id: cord-023284-i0ecxgus
title: Abstracts of publications related to QASR
author: nan
date: 2006-09-19
txt: ./txt/cord-023284-i0ecxgus.txt
cache: ./cache/cord-023284-i0ecxgus.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168536/
doi: 10.1002/qsar.19900090309
abstract: nan
summary:
  Results: Methods developed for the investigation for the relationships between structure and toxic effects of compounds are summarized: a) The extra-thermodynamic approach: the Hansch paradigm, physical chemical properties that influence biological activity and their parametrization, originality of the Hansch approach, receptors and pharmacophores: the natural content of the Hansch approach, predictive value of QSARs, a statistifa1 tool: multiple linear regression analysis, the problem of correlations among molecular descriptors, other mathematical utilizations of extrathermodynamic parameters; b) The substructural approach: when topological (substructural) descriptors are needed, how to use topological decriptors; c) QSAR in mutagenicity and carcinogenicity: general problems, specific versions of the substructural approach used for mutagenicity and carcinogenicity, applications to mutagenicity and carcinogenicity.


id: cord-023584-yaxawqhj
title: The Continuing Search for Antiviral Drugs
author: Bucknall, R.A.
date: 2008-04-10
txt: ./txt/cord-023584-yaxawqhj.txt
cache: ./cache/cord-023584-yaxawqhj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172480/
doi: 10.1016/s1054-3589(08)60460-3
summary:
  Of course, if wide-spectrum leads appear, the choice of test virus may be irrelevant, but the antiviral compounds (as distinct from interferon inducers) known at present are characterized by their relatively limited spectrum of activity, e.g., methisazone is active only against poxviruses (Bauer and Sadler, 1960) and possibly adenoviruses (Bauer and Apostolov, 1966) ; l-aminoadamantane is active only against influenza A1 and As and not against other myxo-or paramyxoviruses (Davies et al., 1964) ; guanidine and a-hydroxybenzyl benzimidazole are active only against picornaviruses and not against other small ribonucleic acid (RNA) viruses (Eggers and Tamm, 1961) . In summary, a tissue culture screen should be able to proccss large numbers of tcst compounds, using viruses as relevant as possible to the diseases for which a drug is required, and should employ normal rather than neoplastic cells.

abstract:
  This chapter discusses the continuing search for antiviral drugs. Many virus diseases, both of humans and animals, have been successfully controlled by vaccines. These successes have naturally led to improvements in the spectrum and duration of protection offered by vaccines until, at present it is difficult to see how antiviral drugs could compete with vaccines in the control of many virus diseases. One may cite smallpox, yellow fever, polio, and recently measles among human diseases, Newcastle disease, Marek's disease, and infectious bronchitis among poultry diseases—an area of veterinary disease control where vaccines have been particularly important. Research into the treatment of virus diseases by drugs is at present directed toward three general areas: (1) attempts to stimulate the defense mechanism of the host animal, (2) large screening programs to find drugs which directly block some virus-specific process, and (3) alleviation of the symptoms of the disease. The treatment of the symptoms, rather than the cause of a disease, has been the mainstay of medical practice from time immemorial, and this is still the case with most virus disease. The short incubation period of many virus diseases will inevitably restrict the therapeutic use of antiviral drugs and in cases where symptoms have already appeared.


id: cord-024652-4i6kktl0
title: Natural Products as Fungicide and Their Role in Crop Protection
author: Santra, Hiran Kanti
date: 2020-05-12
txt: ./txt/cord-024652-4i6kktl0.txt
cache: ./cache/cord-024652-4i6kktl0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212785/
doi: 10.1007/978-981-15-3024-1_9
summary:
  A large number of bioactive compounds ranging from direct plant (both cryptogams algae and moss and phanerogams)-derived natural extracts, essential oil of aromatic plants, and low-molecular-weight antimicrobial compounds known as phytoalexins to secondary metabolites that are both volatile and nonvolatile organic compounds of microbes (fungal and actinobacterial members) residing inside the host tissue, called endophyte, are widely used as agricultural bioweapons. Endophytic culture extracts are also known to be rich sources of phenolics; usually they are directly proportional to the antioxidative property of any fungal isolate, but in some particular cases, they are characterized with their antifungal potentials against phytopathogenic fungus. So it is a great opportunity to use the unique mixture of volatile organic compounds of the endophytic isolate to reduce the crop loss caused by the pathogenic infection on the commercially valuable plant of cherry tomato worldwide.

abstract:
  Seeking solutions from nature for solving one and all problems is the age-old practice for mankind, and natural products are proved to be the most effective one for keeping up the balance of development as well as the “healthy, wealthy, and well” condition of mother nature. Fungal pathogens are proved to be a common and popular contaminant of agroecosystem that approximately causes 70–80% of total microbial crop loss. To meet the proper global increasing need of food products as a result of population explosion, managing agricultural system in an eco-friendly and profitable manner is the prime target; thus the word “sustainable agriculture” plays it part, and this package is highly effective when coupled with nature-derived fungicidal products that can minimize the event of fungal infections in agrarian ecosystem. Present study enlists the most common and effective natural products that might be of plant or microbial origin, their mode of action, day-by-day development of phytopathogenic resistance against the prevailing fungicides, and also their role in maintenance of sustainability of agricultural practices with special emphasis on their acceptance over the synthetic or chemical one. A large number of bioactive compounds ranging from direct plant (both cryptogams algae and moss and phanerogams)-derived natural extracts, essential oil of aromatic plants, and low-molecular-weight antimicrobial compounds known as phytoalexins to secondary metabolites that are both volatile and nonvolatile organic compounds of microbes (fungal and actinobacterial members) residing inside the host tissue, called endophyte, are widely used as agricultural bioweapons. The rhizospheric partners of plant, mycorrhizae, are also a prime agent of this chemical warfare and protect their green partners from fungal invaders and emphasize the concept of “sustainable agriculture.”


id: cord-025119-201ac32t
title: Virtual screening of immunomodulatory medicinal compounds as promising anti-SARS-COV-2 inhibitors
author: Salman, Saad
date: 2020-05-21
txt: ./txt/cord-025119-201ac32t.txt
cache: ./cache/cord-025119-201ac32t.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243912/
doi: 10.2217/fvl-2020-0079
summary:
  Results: Out of more than 300 medicinal compounds, only six compounds: arzanol, ferulic acid, genistein, resveratrol, rosmanol and thymohydroquinone showed significant interaction with the SARS viral proteins by forming hydrogen bonds with the active site residues with low binding energy. Here, we analyzed different medicinal compounds using a virtual screening method to obtain promising inhibitors for these viral proteins that could be further utilized for SARS-COV-2 treatment. More than 300 medicinal compounds with immunomodulatory and antiviral activity were added to the Raccoon2 plugin of Autodock vina to perform virtual screening to obtain promising inhibitors for SARS-COV-2 proteins. This study aimed to obtain novel drug candidates that have the capability to interact with the active site of all of these viral proteins and should possess efficient pharmacokinetic profile with low toxicity to ensure safety during administration. • Docking interaction of immunomodulatory medicinal compounds library filtered six promising medicinal compounds against severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) viral proteins.

abstract:
  Aim: Severe acute respiratory syndrome coronavirus-2 (SARS-COV-2), a pernicious viral disease, causes acute respiratory distress responsible for mortality and morbidity worldwide. To screen different immunomodulatory medicinal compounds to unravel their interaction with SARS-COV-2 viral proteins. Materials & methods: A library of immunomodulatory medicinal compounds with antiviral capability were analyzed against SARS proteases, spike protein and nonstructural proteins (NSP-9, 15) using Autodock vina. Results: Out of more than 300 medicinal compounds, only six compounds: arzanol, ferulic acid, genistein, resveratrol, rosmanol and thymohydroquinone showed significant interaction with the SARS viral proteins by forming hydrogen bonds with the active site residues with low binding energy. Further ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis showed good pharmacokinetic properties and low acute toxicity of these compounds. Conclusion: The current study provides convincing evidence that these medicinal compounds exert antiviral activity against the SARS-COV-2 virus and could be further exploited for the treatment of this disease.


id: cord-033493-kslzdy8q
author: Hebishy, Ali M. S.
date: 2020-09-21
txt: ./txt/cord-033493-kslzdy8q.txt
cache: ./cache/cord-033493-kslzdy8q.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542596/
doi: 10.1021/acsomega.0c02675
summary:
  title: New Route to the Synthesis of Benzamide-Based 5-Aminopyrazoles and Their Fused Heterocycles Showing Remarkable Antiavian Influenza Virus Activity [Image: see text] This study describes a new route to the synthesis of novel benzamide-based 5-aminopyrazoles and their corresponding pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-c][1,2,4]triazine derivatives. 5-Aminopyrazole 4 was prepared by alkylation of the potassium 2-cyano-ethylene-1thiolate salt 2 with an alkyl halide at room temperature to offer N-(2,2-dicyano-1-(alkylthio)vinyl)benzamide 3 followed by a reaction with hydrazine hydrate by refluxing ethanol containing a catalytic amount of piperidine (Scheme 1). The antiviral activity was measured for the synthesized compounds with respect to the H5N1 influenza virus strain A/Egypt/M7217B/2013 using MTT 50 ) and plaque reduction assays 52 exploring the cytotoxicity and inhibition percentage values, respectively. Design, synthesis, docking, and antimicrobial evaluation of some novel pyrazolo[1,5-a] pyrimidines and their corresponding cycloalkane ring-fused derivatives as purine analogs

title:
  New Route to the Synthesis of Benzamide-Based 5-Aminopyrazoles and Their Fused Heterocycles Showing Remarkable Antiavian Influenza Virus Activity

abstract:
  [Image: see text] This study describes a new route to the synthesis of novel benzamide-based 5-aminopyrazoles and their corresponding pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-c][1,2,4]triazine derivatives. Benzamide-based 5-aminopyrazoles were prepared through a reaction of benzoyl isothiocyanate with malononitrile in KOH–EtOH followed by alkylation with alkyl halides and then a reaction with hydrazine. In an attempt to react benzoyl isothiocyanate with ethyl cyanoacetate in KOH–EtOH followed by alkylation with methyl iodide at room temperature and then a reaction with hydrazine has resulted in the formation of 3-ethoxy-5-phenyl-1H-1,2,4-triazole. The structures of the new compounds were characterized by mass spectroscopy, (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy, infrared spectroscopy (IR), and X-ray analysis. The new compounds were tested in vitro for their anti-influenza A virus (subtype H5N1) activity. Among the synthesized compounds, eight compounds 3b, 4, 10b, 10c, 12a, 19, 21a, and 21b were found to possess significant antiviral activities against bird flu influenza (H5N1) with viral reduction in the range of 85–65%.


id: cord-034363-6uscua0y
author: Cerda-Cavieres, Christopher
date: 2020-10-10
txt: ./txt/cord-034363-6uscua0y.txt
cache: ./cache/cord-034363-6uscua0y.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594025/
doi: 10.3390/molecules25204614
summary:
  title: Synthesis, Docking, 3-D-Qsar, and Biological Assays of Novel Indole Derivatives Targeting Serotonin Transporter, Dopamine D2 Receptor, and Mao-A Enzyme: In the Pursuit for Potential Multitarget Directed Ligands A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a–o) and (2-{4-[3-(1H-3-indolyl)-propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a–l) were synthesized and evaluated as novel multitarget ligands towards dopamine D(2) receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). Considering the pharmacological results, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds were carried out only in the human SERT (hSERT) and in selected cases at the D 2 receptor. Considering the pharmacological results, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds were carried out only in the human SERT (hSERT) and in selected cases at the D 2 receptor.

title:
  Synthesis, Docking, 3-D-Qsar, and Biological Assays of Novel Indole Derivatives Targeting Serotonin Transporter, Dopamine D2 Receptor, and Mao-A Enzyme: In the Pursuit for Potential Multitarget Directed Ligands

abstract:
  A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a–o) and (2-{4-[3-(1H-3-indolyl)-propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a–l) were synthesized and evaluated as novel multitarget ligands towards dopamine D(2) receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying Ki values from 5 to 10 nM. Compounds 7k, Ki = 5.63 ± 0.82 nM, and 13c, Ki = 6.85 ± 0.19 nM, showed the highest potencies. The affinities for D(2) ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D(2) receptor in the nanomolar range (7n: Ki = 307 ± 6 nM and 7m: Ki = 593 ± 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D(2) receptor (D(2)/SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure–activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q(2) = 0.625, 0.523 for CoMFA and CoMSIA and r(2)(ncv) = 0.967, 0.959 for CoMFA and CoMSIA, respectively).


id: cord-103271-l9n27ocf
author: Carozza, Jacqueline A
date: 2020-05-31
txt: ./txt/cord-103271-l9n27ocf.txt
cache: ./cache/cord-103271-l9n27ocf.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.05.30.125534
doi: 10.1101/2020.05.30.125534
summary:
  Cancer cells initiate an innate immune response by synthesizing and exporting the small molecule immunotransmitter cGAMP, which activates the anti-cancer Stimulator of Interferon Genes (STING) pathway in the host. Inspired by the molecular scaffold of a previous inhibitor, QS1, 26, 28 which lacks potency at physiological conditions, we build structure-activity relationships (SAR) around the three sections of the molecule -the zinc-binding head, the core, and the tail -and develop several inhibitors with nanomolar Ki values. Assays used to assess the potency of previously attempted ENPP1 inhibitors are inconsistent 26-34 ; however, developing an appropriate assay is key to determining the utility of the molecules in inhibiting cGAMP degradation under physiological conditions. Since our crystal structure suggests that the zinc-binding phosphonate head and quinazoline tail form the most important interactions with ENPP1, we next sought to explore the core region to achieve optimal geometry between these two functional groups ( Fig. 4a-b) .

title:
  Structure-aided development of small molecule inhibitors of ENPP1, the extracellular phosphodiesterase of the immunotransmitter cGAMP

abstract:
  Cancer cells initiate an innate immune response by synthesizing and exporting the small molecule immunotransmitter cGAMP, which activates the anti-cancer Stimulator of Interferon Genes (STING) pathway in the host. An extracellular enzyme, ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), hydrolyzes cGAMP and negatively regulates this anti-cancer immune response. Small molecule ENPP1 inhibitors are much needed as tools to study basic biology of extracellular cGAMP and as investigational cancer immunotherapy drugs. Here, we surveyed structure-activity relationships around a series of cell-impermeable and thus extracellular-targeting phosphonate inhibitors of ENPP1. Additionally, we solved the crystal structure of an exemplary phosphonate inhibitor to elucidate the interactions that drive potency. This study yielded several best-in-class compounds with Ki < 2 nM and excellent physicochemical and pharmacokinetic properties. Finally, we demonstrate that an ENPP1 inhibitor delays tumor growth in a breast cancer mouse model. Together, we have developed ENPP1 inhibitors that are excellent tool compounds and potential therapeutics.


id: cord-252108-04xr5xdl
title: Synthesis and biological activity evaluation of 5-pyrazoline substituted 4-thiazolidinones
author: Havrylyuk, Dmytro
date: 2013-06-06
url: https://www.ncbi.nlm.nih.gov/pubmed/23811085/
doi: 10.1016/j.ejmech.2013.05.044
abstract:
  A series of novel 5-pyrazoline substituted 4-thiazolidinones have been synthesized. Target compounds were evaluated for their anticancer activity in vitro within DTP NCI protocol. Among the tested compounds, the derivatives 4d and 4f were found to be the most active, which demonstrated certain sensitivity profile toward the leukemia subpanel cell lines with GI(50) value ranges of 2.12–4.58 μM (4d) and 1.64–3.20 μM (4f). The screening of antitrypanosomal and antiviral activities of 5-(3-naphthalen-2-yl-5-aryl-4,5-dihydropyrazol-1-yl)-thiazolidine-2,4-diones was carried out with the promising influence of the mentioned compounds on Trypanosoma brucei, but minimal effect on SARS coronavirus and influenza types A and B viruses.


id: cord-253276-mqcwk2ow
title: Synthesis, antimicrobial and cytotoxic activities of some novel thiazole clubbed 1,3,4-oxadiazoles
author: Desai, N. C.
date: 2013-09-30
txt: ./txt/cord-253276-mqcwk2ow.txt
cache: ./cache/cord-253276-mqcwk2ow.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0223523413003978
doi: 10.1016/j.ejmech.2013.06.029
summary:
  The structure activity relationship revealed that the presence of electron withdrawing groups at para position of phenyl ring remarkably enhanced the antibacterial activity of synthesized compounds. From the results of the antimicrobial activity of the synthesized compounds 5ael, the following structure activity relationships can be derived: the antibacterial activity was considerably affected by substitution pattern on the phenyl ring and the most active compounds contain electron withdrawing substituent at para and meta positions of the phenyl ring (p > m > o). Compounds 5c and 5i, substituted with inductively electron withdrawing fluoro and nitro groups, respectively at para position showed the highest antibacterial activity (F > NO 2 ). While, substituting the phenyl ring with fluoro and nitro group at ortho position resulted in noticeable decrease in the antibacterial activity of compounds 5a and 5g respectively. The contrasting nature of substitution pattern at para position of the phenyl ring of most active antibacterial and antifungal agents indicate that the structural requirements are different for binding of drug to bacterial or fungal targets, respectively [43] .

abstract:
  Abstract A series of thiazole clubbed 1,3,4-oxadiazole derivatives (5a–l) have been synthesized and characterized by IR, 1H NMR, 13C NMR and mass spectral analysis. Synthesized compounds were evaluated for their antimicrobial and cytotoxic activities. The results indicated that, compounds 5c and 5i exhibited the most potent antibacterial activity. Compound 5f was found to be the most potent antifungal agent. The structure activity relationship revealed that the presence of electron withdrawing groups at para position of phenyl ring remarkably enhanced the antibacterial activity of synthesized compounds. Further, the results of preliminary MTT cytotoxicity studies on HeLa cells suggested that potent antimicrobial activity of 5b, 5c, 5f, 5h and 5i is accompanied by low cytotoxicity.


id: cord-254036-0karwgz2
title: Bismuth: Environmental Pollution and Health Effects
author: Wang, Runming
date: 2019-09-12
url: https://www.sciencedirect.com/science/article/pii/B9780124095489118706
doi: 10.1016/b978-0-12-409548-9.11870-6
abstract:
  Although it has been used for centuries, bismuth remains one of the least understood elements in the periodic table. Metallic bismuth and bismuth compounds have been widely used in the manufacture of alloys, pigments, cosmetics, and pharmaceuticals. As a “green” heavy metal, the substitution of lead with bismuth in some industries may partially resolve the environmental problems related to heavy metal pollution. In health care, as bismuth has low toxicity to humans, bismuth-based drugs such as colloidal bismuth subcitrate (CBS), ranitidine bismuth citrate (RBC), bismuth subsalicylate (BSS), bismuth iodoform and radioactive bismuth ((212)Bi/(213)Bi) complexes have been developed and used in clinics to treat various diseases. In most cases, bismuth therapies exhibit high therapeutic efficacies and little side effects; nevertheless, there are still reported cases of bismuth toxicity caused by bismuth over-dosage.


id: cord-255862-84u3c33m
title: Antiviral escin derivatives from the seeds of Aesculus turbinata Blume (Japanese horse chestnut)
author: Kim, Ji Won
date: 2017-07-01
txt: ./txt/cord-255862-84u3c33m.txt
cache: ./cache/cord-255862-84u3c33m.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.bmcl.2017.05.022
doi: 10.1016/j.bmcl.2017.05.022
summary:
  In this research, we investigated whether escin derivatives 1–7 (including new compounds 2, 3, 5 and 6), without the angeloyl or tigloyl groups and with modified glycosidic linkages by hydrolysis, have PEDV inhibitory effects with less cytotoxicity. Interestingly, compounds 1-7 isolated from the fraction with the two-step hydrolysis were evaluated to have much lower cytotoxic effects than compounds 8-10 from the n-BuOH part at concentration of 20 lM (Fig. S22) . As compounds 8-10 showed strong cytotoxic effects on Vero cells at 20 lM, their PEDV inhibitory activities were evaluated at a concentration of 2 lM. 33 To measure the expression level of viral RNA encoding nucleocapsid and spike proteins, compounds 4 and 6 were treated in Vero cells at a concentration of 40 lM and total RNA was extracted for reverse transcription followed by polymerase chain reaction using the primers for PEDV (STable 1 ).

abstract:
  Abstract Porcine epidemic diarrhea virus (PEDV) causes severe diarrhea and high fatality of piglets, influencing the swine industry. Japanese horse chestnut (seed of Aesculus turbinata) contains many saponin mixtures, called escins, and has been used for a long time as a traditional medicinal plant. Structure-activity relationship (SAR) studies on escins have revealed that acylations at C-21 and C-22 with angeloyl or tigloyl groups were important for their cytotoxic effects. However, the strong cytotoxicity of escins makes them hard to utilize for other diseases and to develop as nutraceuticals. In this research, we investigated whether escin derivatives 1–7 (including new compounds 2, 3, 5 and 6), without the angeloyl or tigloyl groups and with modified glycosidic linkages by hydrolysis, have PEDV inhibitory effects with less cytotoxicity. Compounds 1–7 had no cytotoxicity at 20μM on VERO cells, while compounds 8–10 showed strong cytotoxicity at similar concentrations on PEDV. Our results suggest that escin derivatives showed strong inhibitory activities on PEDV replication with lowered cytotoxicity. These studies propose a method to utilize Japanese horse chestnut for treating PEDV and to increase the diversity of its bioactive compounds.


id: cord-259744-r9j5yzfc
title: Identification and characterisation of small molecule inhibitors of feline coronavirus replication
author: McDonagh, Phillip
date: 2014-12-05
txt: ./txt/cord-259744-r9j5yzfc.txt
cache: ./cache/cord-259744-r9j5yzfc.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0378113514005082
doi: 10.1016/j.vetmic.2014.10.030
summary:
  Plaque reduction and virus yield reduction assays were performed to confirm antiviral effects of candidate compounds identified during screening, and the possible antiviral mechanisms of action of these compounds were investigated using virucidal suspension assays and CPE inhibition and IFA-based time of addition assays. Plaque reduction and virus yield reduction assays were performed to confirm antiviral effects of candidate compounds identified during screening, and the possible antiviral mechanisms of action of these compounds were investigated using virucidal suspension assays and CPE inhibition and IFA-based time of addition assays. This study identifies three compounds (chloroquine, mefloquine, and hexamethylene amiloride) demonstrating a marked inhibitory effect on FCoV replication in vitro by significant reductions in virus induced CPE and viral titres at low micromolar concentrations when present during the early stages of viral replication. This study has identified three compounds demonstrating marked in vitro inhibition of FCoV in an immortalised cell line at low micromolar concentrations, including the first demonstration of antiviral effects of mefloquine against a coronavirus.

abstract:
  Feline infectious peritonitis (FIP), a feline coronavirus (FCoV) induced disease, is almost invariably fatal with median life expectancy measured in days. Current treatment options are, at best, palliative. The objectives of this study were to evaluate a panel of nineteen candidate compounds for antiviral activity against FCoV in vitro to determine viable candidates for therapy. A resazurin-based cytopathic effect inhibition assay, which detects viable cells through their reduction of the substrate resazurin to fluorescent resorufin, was developed for screening compounds for antiviral efficacy against FCoV. Plaque reduction and virus yield reduction assays were performed to confirm antiviral effects of candidate compounds identified during screening, and the possible antiviral mechanisms of action of these compounds were investigated using virucidal suspension assays and CPE inhibition and IFA-based time of addition assays. Three compounds, chloroquine, mefloquine, and hexamethylene amiloride demonstrated marked inhibition of virus induced CPE at low micromolar concentrations. Orthogonal assays confirmed inhibition of CPE was associated with significant reductions in viral replication. Selectivity indices calculated based on in vitro cytotoxicity screening and reductions in extracellular viral titre were 217, 24, and 20 for chloroquine, mefloquine, and hexamethylene amiloride respectively. Preliminary experiments performed to inform the antiviral mechanism of the compounds demonstrated all three acted at an early stage of viral replication. These results suggest that these direct acting antiviral compounds, or their derivatives, warrant further investigation for clinical use in cats with FIP.


id: cord-260014-q5sug7uu
author: Szűcs, Zsolt
date: 2020-06-29
txt: ./txt/cord-260014-q5sug7uu.txt
cache: ./cache/cord-260014-q5sug7uu.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32610683/
doi: 10.3390/ph13070139
summary:
  We prepared six vancomycin aglycone hexapeptide derivatives with the aim of obtaining compounds having anti-influenza virus but no antibacterial activity. On the other hand, this result is in line with our previous findings on ristocetin and teicoplanin aglycone derivatives, indicating that even minor structural differences in the peptide core can lead to significantly different anti-influenza virus activity [27] . On the other hand, this result is in line with our previous findings on ristocetin and teicoplanin aglycone derivatives, indicating that even minor structural differences in the peptide core can lead to significantly different anti-influenza virus activity [27] . Hence, we established, by virus yield assays, that compound 6 suppresses the replication of influenza virus and coronavirus, and for the other viruses, activity was indicated by the protection against viral CPE. Diazo transfer-click reaction route to new, lipophilic teicoplanin and ristocetin aglycon derivatives with high antibacterial and anti-influenza virus activity: An aggregation and receptor binding study

title:
  Reprogramming of the Antibacterial Drug Vancomycin Results in Potent Antiviral Agents Devoid of Antibacterial Activity

abstract:
  Influenza A and B viruses are a global threat to human health and increasing resistance to the existing antiviral drugs necessitates new concepts to expand the therapeutic options. Glycopeptide derivatives have emerged as a promising new class of antiviral agents. To avoid potential antibiotic resistance, these antiviral glycopeptides are preferably devoid of antibiotic activity. We prepared six vancomycin aglycone hexapeptide derivatives with the aim of obtaining compounds having anti-influenza virus but no antibacterial activity. Two of them exerted strong and selective inhibition of influenza A and B virus replication, while antibacterial activity was successfully eliminated by removing the critical N-terminal moiety. In addition, these two molecules offered protection against several other viruses, such as herpes simplex virus, yellow fever virus, Zika virus, and human coronavirus, classifying these glycopeptides as broad antiviral molecules with a favorable therapeutic index.


id: cord-261170-arnwk287
title: Chapter 18 Marine Metabolites Oceans of Opportunity
author: Gallimore, W.
date: 2017-12-31
txt: ./txt/cord-261170-arnwk287.txt
cache: ./cache/cord-261170-arnwk287.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/B9780128021040000184
doi: 10.1016/b978-0-12-802104-0.00018-4
summary:
  Typically without the benefit of folklore therapeutic knowledge, marine organisms are collected, extracted, and fractionated to afford compounds that undergo evaluation with in vivo and in vitro assays en route to clinical applications. To gain an understanding of the importance of marine natural products chemistry in drug development G To be able to map the process involved in drug development from marine natural products G To gain an appreciation of the range of biological activities associated with compounds isolated from micro-and macroorganisms G To identify the marine-derived drugs which are undergoing clinical evaluation Biological activities identified in extracts and metabolites of algal origin include anticancer, antiobesity, neuroprotective, and antioxidant activity and Scheme 18.2 shows chemical structures of representative bioactive compounds isolated from the macroalgae. Biologically active compounds from marine bacteria also include Streptomyces species from sediment and fish gut from which anticancer (e.g., halichomycin and δ-indomycinone) and antibacterial agents (e.g., phenazines) have been obtained [58À60].

abstract:
  Abstract The marine environment provides an array of compounds often with unique molecular architectures boasting an equally wide array of bioactivities including anticancer, antiinflammatory, and antimicrobial activity. Typically without the benefit of folklore therapeutic knowledge, marine organisms are collected, extracted, and fractionated to afford compounds that undergo evaluation with in vivo and in vitro assays en route to clinical applications. The pharmaceutical industry has benefited from research into marine metabolites with the development of marine-derived drugs including cytarabine, vidarabine, and ziconotide along with the more recently developed formulation Carragelose, an antiviral spray. Cosmetic applications incorporating marine extracts include Abyssine and RefirMAR. Research with macroinvertebrates, macroalgae, and microorganisms continue in the hope that drugs of the future will be culled from the oceans of the world. While obtaining a consistent and adequate supply of the bioactive compounds remains a challenge to be overcome, synthetic methods are being employed along with the application of biotechnological techniques to ensure that the drugs, when developed, will be in sufficient quantities for distribution to those who are in need.


id: cord-261366-mtcalbo5
author: da Rosa Guimarães, Tatiana
date: 2013-10-29
txt: ./txt/cord-261366-mtcalbo5.txt
cache: ./cache/cord-261366-mtcalbo5.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/24172213/
doi: 10.3390/md11114176
summary:
  The n-butanol fraction (BF) obtained from the crude extract of the marine sponge Petromica citrina, the halistanol-enriched fraction (TSH fraction), and the isolated compounds halistanol sulfate (1) and halistanol sulfate C (2), were evaluated for their inhibitory effects on the replication of the Herpes Simplex Virus type 1 (HSV-1, KOS strain) by the viral plaque number reduction assay. In a previous screening of the anti-infective potential of marine invertebrates and seaweeds [28] , we observed a promising activity for the n-butanol fraction (BF) obtained from the ethanolic crude extract of this sponge that led us to perform this study. As it is important to understand the targets and the mode of action of a potential useful new antiviral agent, a set of experiments was carried out to determine the stages at which the most active samples (TSH fraction and compounds 1 and 2) affect the viral replication cycle.

title:
  Anti HSV-1 Activity of Halistanol Sulfate and Halistanol Sulfate C Isolated from Brazilian Marine Sponge Petromica citrina (Demospongiae)

abstract:
  The n-butanol fraction (BF) obtained from the crude extract of the marine sponge Petromica citrina, the halistanol-enriched fraction (TSH fraction), and the isolated compounds halistanol sulfate (1) and halistanol sulfate C (2), were evaluated for their inhibitory effects on the replication of the Herpes Simplex Virus type 1 (HSV-1, KOS strain) by the viral plaque number reduction assay. The TSH fraction was the most effective against HSV-1 replication (SI = 15.33), whereas compounds 1 (SI = 2.46) and 2 (SI = 1.95) were less active. The most active fraction and these compounds were also assayed to determine the viral multiplication step(s) upon which they act as well as their potential synergistic effects. The anti-HSV-1 activity detected was mediated by the inhibition of virus attachment and by the penetration into Vero cells, the virucidal effect on virus particles, and by the impairment in levels of ICP27 and gD proteins of HSV-1. In summary, these results suggest that the anti-HSV-1 activity of TSH fraction detected is possibly related to the synergic effects of compounds 1 and 2.


id: cord-264316-do0px1gq
title: Metallo-aminopeptidase inhibitors
author: Mucha, Artur
date: 2010-05-10
txt: ./txt/cord-264316-do0px1gq.txt
cache: ./cache/cord-264316-do0px1gq.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0300908410001768
doi: 10.1016/j.biochi.2010.04.026
summary:
  This review focuses on the strict metallo-aminopeptidases because they constitute the largest and the most homogenous class of these enzymes and use one or two metal ions in their active sites to specifically release the N-terminal amino acid residues of polypeptides and proteins. Similar to other amino acid and peptide mimetics used as protease inhibitors, this is the effect of the incorporation of a covalent or non-covalent binding group (here involved in coordination of a catalytic metal ion(s) in the enzyme active site) into a substrate structure. Additionally, the P1 side chain of the aminophosphonic acid analogues (or more effectively, both P1 and P1 0 residues of the pseudopeptides phosphoryl moiety) gives further possibility of structural optimization of substituents interacting with the S1 and S1 0 binding pockets of the enzyme (Fig. 3) Fig. 4 ), appeared to be efficient inhibitors of LAP with a K i ¼ 0.15 [90] and 0.23 mM [87] for the R (L) enantiomers.

abstract:
  Aminopeptidases are enzymes that selectively hydrolyze an amino acid residue from the N-terminus of proteins and peptides. They are important for the proper functioning of prokaryotic and eukaryotic cells, but very often are central players in the devastating human diseases like cancer, malaria and diabetes. The largest aminopeptidase group include enzymes containing metal ion(s) in their active centers, which often determines the type of inhibitors that are the most suitable for them. Effective ligands mostly bind in a non-covalent mode by forming complexes with the metal ion(s). Here, we present several approaches for the design of inhibitors for metallo-aminopeptidases. The optimized structures should be considered as potential leads in the drug discovery process against endogenous and infectious diseases.


id: cord-270123-m8utyd1m
title: Andrographolide as a potential inhibitor of SARS-CoV-2 main protease: an in silico approach
author: Enmozhi, Sukanth Kumar
date: 2020-05-05
txt: ./txt/cord-270123-m8utyd1m.txt
cache: ./cache/cord-270123-m8utyd1m.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1080/07391102.2020.1760136
doi: 10.1080/07391102.2020.1760136
summary:
  This paper evaluates the compound Andrographolide from Andrographis paniculata as a potential inhibitor of the main protease of SARS-COV-2 (Mpro) through in silico studies such as molecular docking, target analysis, toxicity prediction and ADME prediction. And upon certain in vitro and some clinical data chloroquine phosphate and hydroxychloroquine sulphate was advised to be the treatment for COVID-19 and enough randomized trials on these compounds to be provided and allowed the administration of the above drugs to be used for emergency (https://www.fda.gov/emergency-use-authori-zation#covidtherapeutics). Though there are many targets are found for the treatment of COVID-19, the main protease (M pro ) of SARS-CoV-2 was chosen due to interest of treating infected patients, to stop the multiplication of virus within the cells, through which M pro was involved in the release of polypeptides which are functional extensive proteolysis and cleavage of the enzyme itself from the sites of genome, pp1a and ppa1ab .

abstract:
  SARS-CoV-2 virus which caused the global pandemic the Coronavirus Disease- 2019 (COVID-2019) has infected about 1,203,959 patients and brought forth death rate about 64,788 among 206 countries as mentioned by WHO in the month of April 2020. The clinical trials are underway for Remdesivir, an investigational anti-viral drug from Gilead Sciences. Antimalarial drugs such as Chloroquine and Hydroxychloroquine derivatives are being used in emergency cases; however, they are not suitable for patients with conditions like diabetes, hypertension and cardiac issues. The lack of availability of approved treatment for this disease calls forth the scientific community to find novel compounds with the ability to treat it. This paper evaluates the compound Andrographolide from Andrographis paniculata as a potential inhibitor of the main protease of SARS-COV-2 (Mpro) through in silico studies such as molecular docking, target analysis, toxicity prediction and ADME prediction. Andrographolide was docked successfully in the binding site of SARS-CoV-2 Mpro. Computational approaches also predicts this molecule to have good solubility, pharmacodynamics property and target accuracy. This molecule also obeys Lipinski’s rule, which makes it a promising compound to pursue further biochemical and cell based assays to explore its potential for use against COVID-19. Communicated by Ramaswamy H. Sarma


id: cord-273372-69rlh9or
title: Small molecules with antiviral activity against the Ebola virus
author: Litterman, Nadia
date: 2015-02-09
txt: ./txt/cord-273372-69rlh9or.txt
cache: ./cache/cord-273372-69rlh9or.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.12688/f1000research.6120.1
doi: 10.12688/f1000research.6120.1
summary:
  In addition we propose that a collaborative database for sharing such published and novel information on small molecules is needed for the research community studying the Ebola virus. We have found that indeed there is much prior knowledge regarding small molecules that have been shown to be active against the Ebola virus in vitro or in animal models 10-13 , including a number of FDA-approved drugs 14-16 . Medicinal chemistry analysis of small molecules active against the Ebola virus We have recently described an expert''s medicinal chemistry 26 analysis of the over 320 NIH probe compounds using public and commercial sources of chemical structures and the issues related to doing this type of analysis 27 . By organizing the data on small molecules tested against the Ebola virus similarly in a central database and using machine learning models based on public data may help identify additional compounds for testing.

abstract:
  The recent outbreak of the Ebola virus in West Africa has highlighted the clear shortage of broad-spectrum antiviral drugs for emerging viruses. There are numerous FDA approved drugs and other small molecules described in the literature that could be further evaluated for their potential as antiviral compounds. These molecules are in addition to the few new antivirals that have been tested in Ebola patients but were not originally developed against the Ebola virus, and may play an important role as we await an effective vaccine. The balance between using FDA approved drugs versus novel antivirals with minimal safety and no efficacy data in humans should be considered. We have evaluated 55 molecules from the perspective of an experienced medicinal chemist as well as using simple molecular properties and have highlighted 16 compounds that have desirable qualities as well as those that may be less desirable. In addition we propose that a collaborative database for sharing such published and novel information on small molecules is needed for the research community studying the Ebola virus.


id: cord-277802-f8pyn3rx
title: Mannich bases in medicinal chemistry and drug design
author: Roman, Gheorghe
date: 2015-01-07
txt: ./txt/cord-277802-f8pyn3rx.txt
cache: ./cache/cord-277802-f8pyn3rx.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/25462280/
doi: 10.1016/j.ejmech.2014.10.076
summary:
  Aminomethylated derivatives of hydroxycarbazoles have been also mentioned in a different study [60] , which described the synthesis of a small series of phenolic Mannich bases 47 (Fig. 8 ) obtained from 5-substituted 2-hydroxy-5H-benzo[b]carbazole-6,11-diones along with their in vitro anticancer evaluation at National Cancer Institute (NCI) using an in-house developed screening panel of approximately 60 cell lines derived from nine different types of cancer. Recently, Mannich bases 132 ( Fig. 24 ) obtained using Schiff bases derived from 5-fluoroisatin and 4-arylideneaminoanilines as substrates and ciprofloxacin as amine reagent were shown to be generally less potent antibacterials than reference drug ciprofloxacin, although some candidates had MIC values comparable to those of ciprofloxacin against the investigated bacteria [164] . Both types of Mannich bases 133l and 134l, featuring a 1,2,4-triazole moiety at position 5 of the triazolethione scaffold, showed good antibacterial activity, but compounds 134l were generally more potent than 133l, and two of candidates 134l actually had MIC values comparable to those of reference drug ciprofloxacin [177] .

abstract:
  The biological activity of Mannich bases, a structurally heterogeneous class of chemical compounds that are generated from various substrates through the introduction of an aminomethyl function by means of the Mannich reaction, is surveyed, with emphasis on the relationship between structure and biological activity. The review covers extensively the literature reports that have disclosed Mannich bases as anticancer and cytotoxic agents, or compounds with potential antibacterial and antifungal activity in the last decade. The most relevant studies on the activity of Mannich bases as antimycobacterial agents, antimalarials, or antiviral candidates have been included as well. The review contains also a thorough coverage of anticonvulsant, anti-inflammatory, analgesic and antioxidant activities of Mannich bases. In addition, several minor biological activities of Mannich bases, such as their ability to regulate blood pressure or inhibit platelet aggregation, their antiparasitic and anti-ulcer effects, as well as their use as agents for the treatment of mental disorders have been presented. The review gives in the end a brief overview of the potential of Mannich bases as inhibitors of various enzymes or ligands for several receptors.


id: cord-283128-9mbi75de
author: Singh, Ramendra K.
date: 2009-12-09
txt: ./txt/cord-283128-9mbi75de.txt
cache: ./cache/cord-283128-9mbi75de.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.ejmech.2009.12.002
doi: 10.1016/j.ejmech.2009.12.002
summary:
  The resulting product, dissolved in anhydrous pyridine, was added dropwise to the activated folate 5 in 1:1 molar proportion in the presence of DCC and DMAP to yield the compound 10 in 26% (Scheme 4). The molecules 2, 3, 4, 6 and 8 have shown remarkable antibacterial activities with MIC ranging between 0.09 and 0.67 mM (in vitro) against gram-positive cocci (Streptococcus virudans) as well as gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, Proteus mirabeilis) bacterial strains. The compound 7, dissolved in dry pyridine (5 ml), was added dropwise to the activated folate ester 5 (286 mg, 0.51 mmol) and stirred the reaction mixture for 15 min. Compound 9 (100 mg, 0.24 mmol), dissolved in dry pyridine (6 ml), was added dropwise to the activated ester 5 (157 mg, 0.28 mmol), stirred the reaction mixture for 20 min and TEA (0.5 ml), DCC (123 mg, 0.6 mmol) and DMAP (32 mg) were further added.

title:
  Synthesis, antibacterial and antiviral properties of curcumin bioconjugates bearing dipeptide, fatty acids and folic acid

abstract:
  Curcumin bioconjugates, viz. di-O-tryptophanylphenylalanine curcumin (2), di-O-decanoyl curcumin (3), di-O-pamitoyl curcumin (4), di-O-bis-(γ,γ)folyl curcumin (6), C(4)-ethyl-O-γ-folyl curcumin (8) and 4-O-ethyl-O-γ-folyl curcumin (10) have been synthesized and tested for their antibacterial and antiviral activities. The conjugates 2, 3, 4, 6 and 8 have shown very promising antibacterial activity with MIC ranging between 0.09 and 0.67 μM against Gram-positive cocci and Gram-negative bacilli. Further, the conjugates 2, 3, 6, 8 and 10 have been screened for their antiviral activities against HSV, VSV, FIPV, PIV-3, RSV and FHV and the molecules 2 and 3 have shown good results with EC(50) 0.011 μM and 0.029 μM against VSV and FIPV/FHV, respectively. However, the molecules did not show expected results against HIV-1 III(B) and ROD strains in MTT assay.


id: cord-283301-adjjkqt2
title: Therapeutic significance of β-glucuronidase activity and its inhibitors: A review
author: Awolade, Paul
date: 2020-02-01
txt: ./txt/cord-283301-adjjkqt2.txt
cache: ./cache/cord-283301-adjjkqt2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31835168/
doi: 10.1016/j.ejmech.2019.111921
summary:
  Based on the foregoing, we extrapolate that the development of potent, specific and non-cytotoxic inhibitors of bGLU is imperative to improving the clinical efficacy of therapeutic agents and effective disease management while bearing in mind the physiological significance of both human and bacterial orthologs of the glycosyl hydrolase. Considering the proven and encouraging potentials of enzyme inhibition and molecular target therapy in drug development, and in continuation of our exploits and expositions thereon [54e58], herein we present a comprehensive review of research undertakings in the present millennium (2000e2019) directed towards the development of potent inhibitors of bGLU that are either natural products or synthetic scaffolds. In a study which examined the protective effects of thymol (54, Fig. 9 ) on inflammation in isoproterenol-induced myocardial infarction using male albino Wistar rats [167] , the therapeutic benefit of inhibiting the release of bGLU, other lysosomal enzymes and pro-inflammatory cytokines was evident in the restoration of near-normal myocardial histology and function, compared to diseased controls.

abstract:
  The emergence of disease and dearth of effective pharmacological agents on most therapeutic fronts, constitutes a major threat to global public health and man’s existence. Consequently, this has created an exigency in the search for new drugs with improved clinical utility or means of potentiating available ones. To this end, accumulating empirical evidence supports molecular target therapy as a plausible egress and, β-glucuronidase (βGLU) – a lysosomal acid hydrolase responsible for the catalytic deconjugation of β-d-glucuronides has emerged as a viable molecular target for several therapeutic applications. The enzyme’s activity level in body fluids is also deemed a potential biomarker for the diagnosis of some pathological conditions. Moreover, due to its role in colon carcinogenesis and certain drug-induced dose-limiting toxicities, the development of potent inhibitors of βGLU in human intestinal microbiota has aroused increased attention over the years. Nevertheless, although our literature survey revealed both natural products and synthetic scaffolds as potential inhibitors of the enzyme, only few of these have found clinical utility, albeit with moderate to poor pharmacokinetic profile. Hence, in this review we present a compendium of exploits in the present millennium directed towards the inhibition of βGLU. The aim is to proffer a platform on which new scaffolds can be modelled for improved βGLU inhibitory potency and the development of new therapeutic agents in consequential.


id: cord-290539-8ak2tths
title: Novel broad spectrum virucidal molecules against enveloped viruses
author: Cagno, Valeria
date: 2018-12-07
txt: ./txt/cord-290539-8ak2tths.txt
cache: ./cache/cord-290539-8ak2tths.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1371/journal.pone.0208333
doi: 10.1371/journal.pone.0208333
summary:
  To further elucidate the mechanism of action we performed a virucidal assay in which 9d was incubated with the virus at 10 μM 5μM or 1μM concentration for different times (Fig 6A) or for 1h with serial dilutions of compound ( Fig 6B) ; subsequently, the mixture was titrated on cells and the viral titer was evaluated at dilutions at which the compound concentration was known not to be active in plaquing efficiency assays. The irreversibility of the mechanism was also tested with an assay in which the compound was incubated with the virus for 1h and subsequently the mixture has been diluted in drug free medium for additional 1, 2, 3 or 4 hours before the addition on cells (S2 Fig) .

abstract:
  Viral infections are an important cause of death worldwide. Unfortunately, there is still a lack of antiviral drugs or vaccines for a large number of viruses, and this represents a remarkable challenge particularly for emerging and re-emerging viruses. For this reason, the identification of broad spectrum antiviral compounds provides a valuable opportunity for developing efficient antiviral therapies. Here we report on a class of rhodanine and thiobarbituric derivatives displaying a broad spectrum antiviral activity against seven different enveloped viruses including an HSV-2 acyclovir resistant strain with favorable selectivity indexes. Due to their selective action on enveloped viruses and to their lipid oxidation ability, we hypothesize a mechanism on the viral envelope that affects the fluidity of the lipid bilayer, thus compromising the efficiency of virus-cell fusion and preventing viral entry.


id: cord-292380-ulsejzqt
author: Iwanejko, Jakub
date: 2020-05-22
txt: ./txt/cord-292380-ulsejzqt.txt
cache: ./cache/cord-292380-ulsejzqt.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32455965/
doi: 10.3390/ma13102393
summary:
  Bearing in mind the remarkable precedents of improving the efficacy of cytotoxicity against cancer cell lines by insertion of aminophosphonate moiety and the results of our previous research, we directed our examinations toward the evaluation of antiproliferative properties of the phosphonic derivatives of octahydroquinoxalin-2(1H)-one. Bearing in mind the remarkable precedents of improving the efficacy of cytotoxicity against cancer cell lines by insertion of aminophosphonate moiety and the results of our previous research, we directed our examinations toward the evaluation of antiproliferative properties of the phosphonic derivatives of octahydroquinoxalin-2(1H)-one. Afterwards, wells were washed five times with water and 50 µL of 0.4% solution of SRB (sulforhodamine B, Sigma-Aldrich Chemie GmbH, Steinheim, Germany) in 1% acetic acid (POCh, Gliwice, Poland) was added to each well and plates were again incubated at RT for 30 min. The unbound dye was removed by washing plates five times with 1% acetic acid, while stained cells were treated with 10 mM TRIS (Tris base, Sigma-Aldrich, Chemie GmbH, Steinheim, Germany).

title:
  Octahydroquinoxalin-2(1H)-One-Based Aminophosphonic Acids and Their Derivatives—Biological Activity towards Cancer Cells

abstract:
  In the search for new antitumor agents, aminophosphonic acids and their derivatives based on octahydroquinoxalin-2(1H)-one scaffold were obtained and their cytotoxic properties and a mechanism of action were evaluated. Phosphonic acid and phosphonate moieties increased the antiproliferative activity in comparison to phenolic Mannich bases previously reported. Most of the obtained compounds revealed a strong antiproliferative effect against leukemia cell line (MV-4-11) with simultaneous low cytotoxicity against normal cell line (mouse fibroblasts-BALB/3T3). The most active compound was diphenyl-[(1R,6R)-3-oxo-2,5-diazabicyclo[4.4.0]dec-4-yl]phosphonate. Preliminary evaluation of the mechanism of action showed the proapoptotic effect associated with caspase 3/7 induction.


id: cord-293867-c4wnr5xe
author: Gürsoy, Elif
date: 2019-12-06
txt: ./txt/cord-293867-c4wnr5xe.txt
cache: ./cache/cord-293867-c4wnr5xe.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0045206819309988
doi: 10.1016/j.bioorg.2019.103496
summary:
  Besides the wide biological activity spectrum of imidazo[2,1-b] thiazole derivatives, also the compounds bearing hydrazide, acyl-hydrazone and spirothiazolidinone moiety, have been reported in the literature with their various effects such as antibacterial [21] , antifungal [22] , antitubercular [23] , antiviral [24] , anticonvulsant [25] and antidepressant [26] . In this study, we further explored the scaffold containing the imidazo [2,1-b] thiazole ring as the aromatic moiety, that is linked by an amide to a spirothiazolidinone ring system as the aliphatic cyclic moiety and from this point forward, novel derivatives were synthesized (Table 1) , and broadly evaluated for their antiviral and antimycobacterial activity (Fig. 2) . General procedure for the synthesis of 6-(4-bromophenyl)-N 2 -(substituted/non-substituted cycloalkylidene)imidazo[2,1-b]thiazole-3-acetohydrazides (4a-d) 0,005 mol of 3 was boiled in a water bath under reflux with 30 mL of ethanol until a clear solution was obtained.

title:
  Design and synthesis of novel Imidazo[2,1-b]thiazole derivatives as potent antiviral and antimycobacterial agents

abstract:
  A series of novel acyl-hydrazone (4a-d) and spirothiazolidinone (5a-d, 6a-d) derivatives of imidazo[2,1-b]thiazole were synthesized and evaluated for their antiviral and antimycobacterial activity. The antituberculosis activity was evaluated by using the Microplate Alamar Blue Assay and the antiviral activity was evaluated against diverse viruses in mammalian cell cultures. According to the biological activity studies of the compounds, 5a-c displayed hope promising antitubercular activity, 6d was found as potent for Coxsackie B4 virus, 5d was found as effective against Feline corona and Feline herpes viruses. Consequently, the obtained results displayed that, 5a-d and 6d present a leading structure for future drug development due to its straightforward synthesis and relevant bioactivity.


id: cord-296560-ehrww6uu
author: Bender, Andreas
date: 2006-11-07
txt: ./txt/cord-296560-ehrww6uu.txt
cache: ./cache/cord-296560-ehrww6uu.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32362803/
doi: 10.1016/s1574-1400(06)02009-3
summary:
  This chapter discusses recent developments in some of the areas that exploit the molecular similarity principle, novel approaches to capture molecular properties by the use of novel descriptors, focuses on a crucial aspect of computational models—their validity, and discusses additional ways to examine data available, such as those from high-throughput screening (HTS) campaigns and to gain more knowledge from this data. The chapter also presents some of the recent applications of methods discussed focusing on the successes of virtual screening applications, database clustering and comparisons (such as drugand in-house-likeness), and the recent large-scale validations of docking and scoring programs. (Note that this has at the same time been shown empirically in virtual screening experiments [42, 43] .) Some of the methods, namely mutual information and genetic programing, have also been evaluated separately for their use in QSAR studies [44] with respect to a dataset which showed some (typical) problems present in the area, such as a very different sizes of ''active'' vs.

title:
  Chapter 9 Molecular Similarity: Advances in Methods, Applications and Validations in Virtual Screening and QSAR

abstract:
  This chapter discusses recent developments in some of the areas that exploit the molecular similarity principle, novel approaches to capture molecular properties by the use of novel descriptors, focuses on a crucial aspect of computational models—their validity, and discusses additional ways to examine data available, such as those from high-throughput screening (HTS) campaigns and to gain more knowledge from this data. The chapter also presents some of the recent applications of methods discussed focusing on the successes of virtual screening applications, database clustering and comparisons (such as drug- and in-house-likeness), and the recent large-scale validations of docking and scoring programs. While a great number of descriptors and modeling methods has been proposed until today, the recent trend toward proper model validation is very much appreciated. Although some of their limitations are surely because of underlying principles and limitations of fundamental concepts, others will certainly be eliminated in the future.


id: cord-296970-5yc6u5t3
title: iBioProVis: interactive visualization and analysis of compound bioactivity space
author: Donmez, Ataberk
date: 2020-08-15
txt: ./txt/cord-296970-5yc6u5t3.txt
cache: ./cache/cord-296970-5yc6u5t3.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32407491/
doi: 10.1093/bioinformatics/btaa496
summary:
  The sources of the set of compounds are not restricted; the compounds may be coming from a list of user-defined compounds indicated as canonical SMILES strings (e.g. the source of this list can be the output of a machine learning method, which predicts interacting compounds to the target of interest), drugs from DrugBank or target proteins'' active compounds that are extracted from a reliable compound-target bioactivity measurement dataset, which is a carefully processed and filtered subset of the ChEMBL (v25) database. We also provide a reliable compound-target bioactivity measurement dataset, which is a carefully processed and filtered subset of ChEMBL (v25) database, to be used with iBioProVis. iBioProVis is an interactive web-based visualization tool and it has advantages when compared with existing studies and tools.

abstract:
  SUMMARY: iBioProVis is an interactive tool for visual analysis of the compound bioactivity space in the context of target proteins, drugs and drug candidate compounds. iBioProVis tool takes target protein identifiers and, optionally, compound SMILES as input, and uses the state-of-the-art non-linear dimensionality reduction method t-Distributed Stochastic Neighbor Embedding (t-SNE) to plot the distribution of compounds embedded in a 2D map, based on the similarity of structural properties of compounds and in the context of compounds’ cognate targets. Similar compounds, which are embedded to proximate points on the 2D map, may bind the same or similar target proteins. Thus, iBioProVis can be used to easily observe the structural distribution of one or two target proteins’ known ligands on the 2D compound space, and to infer new binders to the same protein, or to infer new potential target(s) for a compound of interest, based on this distribution. Principal component analysis (PCA) projection of the input compounds is also provided, Hence the user can interactively observe the same compound or a group of selected compounds which is projected by both PCA and embedded by t-SNE. iBioProVis also provides detailed information about drugs and drug candidate compounds through cross-references to widely used and well-known databases, in the form of linked table views. Two use-case studies were demonstrated, one being on angiotensin-converting enzyme 2 (ACE2) protein which is Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein receptor. ACE2 binding compounds and seven antiviral drugs were closely embedded in which two of them have been under clinical trial for Coronavirus disease 19 (COVID-19). AVAILABILITY AND IMPLEMENTATION: iBioProVis and its carefully filtered dataset are available at https://ibpv.kansil.org/ for public use. CONTACT: vatalay@metu.edu.tr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


id: cord-300574-nclkfw4h
author: Donno, Dario
date: 2018-12-31
txt: ./txt/cord-300574-nclkfw4h.txt
cache: ./cache/cord-300574-nclkfw4h.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/B9780128114469000095
doi: 10.1016/b978-0-12-811446-9.00009-5
summary:
  Wild plant species are of interest to the food industry because of their ability to replace synthetic chemicals and nutraceuticals; however, the nutritional, economical, and sociocultural values of some neglected and underutilized natural resources have not yet been fully exploited. Some of these less well-known and underutilized fruits, which have the potential to provide novel sources of health-promoting agents, are presented in this chapter (i.e., Asimina triloba (L.) Dunal, Crataegus azarolus L., Lycium barbarum L., Morus nigra L., and Amelanchier canadensis (L.) Medicus). A diet containing high levels of fruits and vegetables has been associated with a lower risk of chronic diseases because, in addition to their high vitamin and mineral content, these foods also contain compounds with health-protective effects, in particular antioxidant and antiinflammatory compounds (Donno et al., 2013b) . Mulberries are sweet fruits and they play an important role in the food industry due to their high levels of bioactive compounds (mulberry fruits can vary in terms of their chemical composition and antioxidant properties).

title:
  Chapter 9 Nutraceuticals in Alternative and Underutilized Fruits as Functional Food Ingredients: Ancient Species for New Health Needs

abstract:
  Abstract A diet containing high levels of fruit has been associated with a lowered risk of chronic diseases as, in addition to their vitamin and mineral content, they also contain various compounds with health-protective effects, in particular antioxidant and antiinflammatory compounds. Wild plant species are of interest to the food industry because of their ability to replace synthetic chemicals and nutraceuticals; however, the nutritional, economical, and sociocultural values of some neglected and underutilized natural resources have not yet been fully exploited. Some of these less well-known and underutilized fruits, which have the potential to provide novel sources of health-promoting agents, are presented in this chapter (i.e., Asimina triloba (L.) Dunal, Crataegus azarolus L., Lycium barbarum L., Morus nigra L., and Amelanchier canadensis (L.) Medicus). Underutilized fruits could represent an opportunity for growers to gain access to these special markets where consumers place emphasis on high contents of nutrients that are capable of preventing degenerative diseases. The development of specific horticultural models for nutraceutical fruit production could be an interesting opportunity to obtain a highly standardized raw material for fresh or derived products.


id: cord-300872-blycbi4u
title: Recent Advances in the Synthesis and Biological Activity of 8-Hydroxyquinolines
author: Saadeh, Haythem A.
date: 2020-09-21
txt: ./txt/cord-300872-blycbi4u.txt
cache: ./cache/cord-300872-blycbi4u.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/molecules25184321
doi: 10.3390/molecules25184321
summary:
  Some of these strains have even become resistant to many antibiotics and chemotherapeutic agents; These prepared compounds were subjected to bioactivity screening against the highly pathogenic H5N1 avian influenza viruses, with the results expressed as percentages of growth inhibition, and to cytotoxicity evaluation against the A549 cell line. A synthetic procedure (Scheme 13) involved a condensation reaction between the amino group (NH2) in 49 and the carbonyl group in salicylic aldehyde (50), followed by intramolecular cyclization under a These prepared compounds were screened for potential anticancer activity against MCF-7, HCT 116, HepG-2, and A549 using the MMT assay. This compound was screened against MCF-7 and Hela cancer cell lines using MMT assay, giving IC50 values of 21.02 and 27.73 mM, respectively In addition, Shamsi and coworkers prepared 16 quinoline-based 1,3,4-oxadiazole-triazole derivatives (Scheme 14) based on the hybrid strategy of nitrogen-containing heterocyclic scaffolds [36] .

abstract:
  Compounds containing the 8-hydroxyquinoline (8-HQ) 1 nucleus exhibit a wide range of biological activities, including antimicrobial, anticancer, and antifungal effects. The chemistry and biology of this group have attracted the attention of chemists, medicinal chemists, and professionals in health sciences. A number of prescribed drugs incorporate this group, and numerous 8-HQ- based molecules can be used to develop potent lead compounds with good efficacy and low toxicity. This review focusses on the recent advances in the synthesis of 8-HQ derivatives with different pharmacological properties, including anticancer, antiviral, and antibacterial activities. For this purpose, recent relevant references were searched in different known databases and search engines, such as MEDLINE (PubMed), Google Scholar, Science Direct, Scopus, Cochrane, Scientific Information Database (SID), SciFinder, and Institute for Scientific Information (ISI) Web of Knowledge. This review article provides a literature overview of the various synthetic strategies and biological activities of 8-HQ derivatives and covers the recent related literature. Taken together, compounds containing the 8-HQ moiety have huge therapeutic value and can act as potential building blocks for various pharmacologically active scaffolds. In addition, several described compounds in this review could act leads for the development of drugs against numerous diseases including cancer.


id: cord-301349-m4nr3pqx
author: Mirza, Muhammad Usman
date: 2020-09-02
txt: ./txt/cord-301349-m4nr3pqx.txt
cache: ./cache/cord-301349-m4nr3pqx.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0928098720303250?v=s5
doi: 10.1016/j.ejps.2020.105537
summary:
  The aim of this study was to discover selective CCR5, CXCR4 and dual CCR5/CXCR4 antagonists based on both receptor-and ligand-based virtual screening methods together with molecular dynamics (MD) simulations and binding free energy calculations. The most promising compounds resulting from VS were evaluated for antiviral activity by a luciferase assay in TZM-bl cells infected with wild type HIV-1 strains NL4.3 (CXCR4-tropic strain, X4) and BaL (CCR5-tropic strain, R5). After a careful post-MD inspection, 43 compounds were selected based on the following criteria; (1) overall backbone stability of the protein/ligand complex, (2) electrostatic (ΔE ele ) and van der Waals (ΔE vdw ) interaction energy, (3) H-bonds occupancy, and (4) binding pocket residual contribution towards ligands. Compound 27, the most promising compound after receptor-based screening (IC 50 = 10.64 µM), showed a significant H-bond interaction profile with the residues lining the binding pocket of CCR5, as reported also for maraviroc [39, 80] .

title:
  Discovery of HIV entry inhibitors via a hybrid CXCR4 and CCR5 receptor pharmacophore‐based virtual screening approach

abstract:
  Chemokine receptors are key regulators of cell migration in terms of immunity and inflammation. Among these, CCR5 and CXCR4 play pivotal roles in cancer metastasis and HIV-1 transmission and infection. They act as essential co-receptors for HIV and furnish a route to the cell entry. In particular, inhibition of either CCR5 or CXCR4 leads very often the virus to shift to a more virulent dual-tropic strain. Therefore, dual receptor inhibition might improve the therapeutic strategies against HIV. In this study, we aimed to discover selective CCR5, CXCR4, and dual CCR5/CXCR4 antagonists using both receptor- and ligand-based computational methods. We employed this approach to fully incorporate the interaction attributes of the binding pocket together with molecular dynamics (MD) simulations and binding free energy calculations. The best hits were evaluated for their anti-HIV-1 activity against CXCR4- and CCR5-specific NL4.3 and BaL strains. Moreover, the Ca(2+) mobilization assay was used to evaluate their antagonistic activity. From the 27 tested compounds, three were identified as inhibitors: compounds 27 (CCR5), 6 (CXCR4) and 3 (dual) with IC(50) values ranging from 10.64 to 64.56 μM. The binding mode analysis suggests that the active compounds form a salt bridge with the glutamates and π-stacking interactions with the aromatic side chains binding site residues of the respective co-receptor. The presented hierarchical virtual screening approach provides essential aspects in identifying potential antagonists in terms of selectivity against a specific co-receptor. The compounds having multiple heterocyclic nitrogen atoms proved to be relatively more specific towards CXCR4 inhibition as compared to CCR5. The identified compounds serve as a starting point for further development of HIV entry inhibitors through synthesis and quantitative structure-activity relationship studies.


id: cord-306934-29ljbl7g
title: Antiviral and cytotoxic activities of aminoarylazo compounds and aryltriazene derivatives
author: Tonelli, Michele
date: 2009-07-01
txt: ./txt/cord-306934-29ljbl7g.txt
cache: ./cache/cord-306934-29ljbl7g.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/19482481/
doi: 10.1016/j.bmc.2009.05.020
summary:
  Finally, molecular modeling investigations indicated that compounds of structure A–C, active against BVDV, could work targeting the viral RNA-dependent RNA-polymerase (RdRp), having been observed a good agreement between the trends of the estimated IC50 and the experimental EC50 values. First of all, the binding site identified by our procedure is very close to the putative binding site proposed for two allosteric inhibitors of BVDV RdRp, VP32947 and BPIP, 23 Table 5 Cytotoxicity against MT-4, MDBK, BHK and Vero-76 cell lines and YFV, Reo-1, CVB-2, RSV, HSV-1 and Sb-1 inhibitory activity of triazene derivatives of structure F and G Tables 3 and 4. In view of these considerations, molecular modeling investigations were performed to study wether the active compounds of structures A-C could target the BVDV RNA-dependent RNA-polymerase (RdRp), which shares some structural similarity with HCV RdRp. Indeed a good agreement was observed between the trend exhibited by the IC 50 (calculated from the estimated free energies of binding) and the corresponding biological activities determined for these compounds in BVDV infected MDBK cell line.

abstract:
  Abstract Twelve aminoarylazocompounds (A–C) and 46 aryltriazene 7 derivatives (D–G) have been synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of 10 RNA and DNA viruses. Eight aminoazocompounds and 27 aryltriazene derivatives exhibited antiviral activity, sometimes of high level, against one or more viruses. A marked activity against BVDV and YFV was prevailing among the former compounds, while the latter type of compounds affected mainly CVB-2 and RSV. None of the active compounds inhibited the multiplication of HIV-1, VSV and VV. Arranged in order of decreasing potency and selectivity versus the host cell lines, the best compounds are the following; BVDV: 1 > 7 > 8 > 4; YFV: 7 > 5; CVB-2: 25 > 56 > 18; RSV: 14 > 20 > 55 > 38 > 18 > 19; HSV-1: 2. For these compounds the EC50 ranged from 1.6μM (1) to 12μM (18), and the S. I. from 19.4 (1) to 4.2 (2). Thus the aminoarylazo and aryltriazene substructures appear as interesting molecular component for developing antiviral agents against ss RNA viruses, particularly against RSV and BVDV, which are important human and veterinary pathogens. Finally, molecular modeling investigations indicated that compounds of structure A–C, active against BVDV, could work targeting the viral RNA-dependent RNA-polymerase (RdRp), having been observed a good agreement between the trends of the estimated IC50 and the experimental EC50 values.


id: cord-309052-3h0g7s9v
title: Psoralea corylifolia L: Ethnobotanical, biological, and chemical aspects: A review
author: Alam, Fiaz
date: 2017-12-15
txt: ./txt/cord-309052-3h0g7s9v.txt
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mime: text/plain
url: https://doi.org/10.1002/ptr.6006
doi: 10.1002/ptr.6006
summary:
  The Lymphangiogenesis inhibition (Jeong et al., 2013) Anti-Alzheimer (Chen et al., 2013) Carboxylesterase inhibitors 33 Isobavachin Flavonoid Seed/fruit Osteoblast (Li et al., 2014) 34 Isopsoralen Furanocoumarin Whole plant Antiprotozoal 35 Neobavaisoflavone Seeds Antibacterial (Khatune et al., 2004) 36 Psoralen Furanocoumarin Whole plant/root Leucoderma, psoriasis Anticancer (Hao et al., 2014) , antioxidant , anti-Alzheimer (Somani et al., 2015) , Collagengenesis 37 Psoralidin Coumarin Whole plant/seed Estrogen receptor modulator (Liu et al., 2014; Lim et al., 2011) Antioxidant (Wang, Yin, Zhang, Peng, & Kang, 2013b) , antibacterial (Khatune et al., 2004) Anti-diabetic (Behloul & Wu, 2013) , antiprotozoal Anticancer (Hao et al., 2014; Limper et al., 2013; Yang et al., 1996) , anti-depressent (Farahani et al., 2015) 38 Psoracorylifol D Flavonoid Seed Lymphangiogenesis inhibition (Jeong et al., 2013) Psoracoumestan Coumestans Seeds essential oil Anti-cancer (Limper et al., 2013) 39 Xanthoangelol Chalcone Seeds Anticancer (Limper et al., 2013) FIGURE 2 Structures of important compounds isolated from Psoralea corylifolia psoralester is a 10-membered lactone compound and the latter is an isomer of already known compound bayachromene (Tewari & Bhakuni, 2010) .

abstract:
  Psoralea corylifolia L. (Leguminosae) is a well‐known traditional medicinal plant used from ancient times for treatment of various ailments. It is widely distributed and an important part of therapeutics in Ayurveda and in Chinese medicines. The aim of this review is to present comprehensive and most up to date report on its ethnobotanical, ethnopharmacological, clinical, phytochemical, and side effects. Studies on the ethnobotanical, ethnopharmacological, clinical, phytochemical, and side effects of P. corylifolia were published until year 2017 and were searched using various scientific databases. The scientific literature searched revealed that these plant species has been extensively investigated in vivo and in vitro for various biological and phytochemical studies. It has cardiotonic, vasodilator, pigmentor, antitumor, antibacterial, cytotoxic, and anti‐helminthic properties and locally used for alopecia, inflammation, leukoderma, leprosy, psoriasis, and eczema. So far, about a hundred bioactive compounds have been isolated from seeds and fruits, and most important compounds identified belongs to coumarins, flavonoids, and meroterpenes groups. This review article summarized the most updated scientific literature on bioactive phytochemical and biological activities of P. corylifolia. This article will be a useful addition to providing information for future research, and more standard clinical trials are needed for the plant to be used as therapeutic agent.


id: cord-315193-z6v6s46n
title: Structural Insight Into the Viral 3C-Like Protease Inhibitors: Comparative SAR/QSAR Approaches
author: Adhikari, Nilanjan
date: 2017-07-14
txt: ./txt/cord-315193-z6v6s46n.txt
cache: ./cache/cord-315193-z6v6s46n.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/B9780128097120000113
doi: 10.1016/b978-0-12-809712-0.00011-3
summary:
  In the present report, quantitative structure-activity relationships (QSARs) techniques have been explored to understand the relation between the SARS-CoV 3CL pro and HRV 3C pro enzyme inhibitory activity with the physicochemical and structural properties of these inhibitors developed till now. (2008) reported some cinanserin analogs as SARS-CoV 3CL pro inhibitors (Table 11 .18), for which the QSAR model obtained was as shown by Eq. (2013b) reported a series of dipeptide-type SARS-CoV 3CL protease inhibitors (Table 11 .27) whose activity was shown to be controlled by the molar refractivity (CMR) and the polar volume (Pol Vol) of the compounds [Eq. QSAR models exhibited that the physicochemical parameters, such as dipole moment, PSA, polar volume, hydrophobicity, molar refractivity, SA, and molecular volume of the compounds play a crucial role in controlling both SARS-CoV 3CL pro and HRV 3C pro inhibitory activities.

abstract:
  Severe acute respiratory syndrome (SARS), caused by SARS-coronavirus (SARS-CoV), is a dreadful infection worldwide having economic and medical importance and a global threat for health. It was turned into an epidemic in South China followed by a chain of infections across three generations. A number of pathogeneses in human may occur due to the virus. This infection has not been taken into account before the SARS outbreak, and still it is a neglected one. Therefore, there is an urgent need to develop small molecule antivirals to combat the SARS-CoV. No vaccines are available till date though a number of SARS-CoV 3C-like and 3C protease inhibitors were reported. In this chapter, quantitative structure–activity relationship technique is used for development of anti-SARS and anti-HRV drugs and outcome discussed in details. This approach may be a useful strategy to design novel and potential anti-SARS drugs to combat these dreadful viral diseases.


id: cord-317628-1inxq7t5
author: Cuccarese, Michael F.
date: 2020-08-14
txt: ./txt/cord-317628-1inxq7t5.txt
cache: ./cache/cord-317628-1inxq7t5.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.08.02.233064
doi: 10.1101/2020.08.02.233064
summary:
  We deploy the platform to develop phenotypic models of active SARS-CoV-2 infection and of COVID-19-associated cytokine storm, surfacing compounds with demonstrated clinical benefit and identifying several new candidates for drug repurposing. We used these capabilities to rapidly develop high-throughput-ready disease models for both SARS-CoV-2 viral infection and the resulting cytokine storm, and immediately launched large-scale drug screens that recapitulated known effective and ineffective therapies and, more importantly, identified several new potential treatments for both SARS-CoV-2 infection and COVID-19-associated cytokine storm. To define the model, we evaluated the effect of SARS-CoV-2 infection in multiple cell types, of which three resulted in robust phenoprints as compared to either mock infected or inactivated virus control populations: Calu3 (a lung adenocarcinoma line), Vero (an immortalized interferondeficient African green monkey kidney line 55 ), and primary Human Renal Cortical Epithelium (HRCE) (Fig. 5C, Fig. S6D ).

title:
  Functional immune mapping with deep-learning enabled phenomics applied to immunomodulatory and COVID-19 drug discovery

abstract:
  Development of accurate disease models and discovery of immune-modulating drugs is challenged by the immune system’s highly interconnected and context-dependent nature. Here we apply deep-learning-driven analysis of cellular morphology to develop a scalable “phenomics” platform and demonstrate its ability to identify dose-dependent, high-dimensional relationships among and between immunomodulators, toxins, pathogens, genetic perturbations, and small and large molecules at scale. High-throughput screening on this platform demonstrates rapid identification and triage of hits for TGF-β- and TNF-α-driven phenotypes. We deploy the platform to develop phenotypic models of active SARS-CoV-2 infection and of COVID-19-associated cytokine storm, surfacing compounds with demonstrated clinical benefit and identifying several new candidates for drug repurposing. The presented library of images, deep learning features, and compound screening data from immune profiling and COVID-19 screens serves as a deep resource for immune biology and cellular-model drug discovery with immediate impact on the COVID-19 pandemic.


id: cord-318854-xaus3bma
title: Chapter 4 Bioactivity and Synthesis of Diarylheptanoids From Alpinia officinarum
author: Sun, Yi
date: 2016-12-31
txt: ./txt/cord-318854-xaus3bma.txt
cache: ./cache/cord-318854-xaus3bma.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/B9780444636010000041
doi: 10.1016/b978-0-444-63601-0.00004-1
summary:
  In this review, we discuss the antitumor-promoting, antiinflammatory, cytotoxic, antimicrobial, antiinfluenza, and antiherpes simplex-1 virus activities of diarylheptanoids isolated from galangal resulting from our own and other research groups'' investigation. Compound 6 showed the strongest activity among the four diarylheptanoids (IC 50 : 10 μM), and it also inhibited the mRNA expression of tyrosinase, tyrosinase-related protein (TRP)-1 and TRP-2, as well as protein levels of microphthalmia-associated transcription factor (MITF) [52] . Compounds 2, 6, 15, 16, 47, and 48 were tested for their inhibitory effects on NO production in the LPS-activated macrophage cell line RAW 264.7 [15] . Thus, the reports cited above suggest that diarylheptanoids possess inhibitory effects against inflammatory and tumor-promoting activities. Compound 4 was also active against influenza virus with an EC 50 value of <10 μg/mL [61] , which suggests that 4 is an effective diarylheptanoid against both RSV and influenza virus in vitro.

abstract:
  Abstract Many diarylheptanoids were isolated from the galangal (rhizome of Alpinia officinarum). We are reported the antitumor-promoting, antiinflammatory, cytotoxic, antiinfluenza virus, and antiherpes simplex-1 virus activities of diarylheptanoids. These components in our dietary and herbal supplements are considered to be relatively nontoxic to human. In addition, we synthesized the new compounds. In this review, we discuss the antitumor-promoting, antiinflammatory, cytotoxic, antimicrobial, antiinfluenza, and antiherpes simplex-1 virus activities of diarylheptanoids isolated from galangal resulting from our own and other research groups' investigation.


id: cord-320591-re99v1qt
author: Le, Thanh Ninh
date: 2020-07-27
txt: ./txt/cord-320591-re99v1qt.txt
cache: ./cache/cord-320591-re99v1qt.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32727144/
doi: 10.3390/plants9080946
summary:
  Particularly, these studies mostly focused on the antioxidant and anticancer activities of broccoli sprouts and microgreens owing to the functions of glucosinolates and phenolic compounds (Tables 4 and 5 ). Particularly, these studies mostly focused on the antioxidant and anticancer activities of broccoli sprouts and microgreens owing to the functions of glucosinolates and phenolic compounds (Tables 4 and 5 ). In summary, previous studies showed that broccoli sprout extracts rich in vitamins, carotenoids, and phenolic compounds showed very high antioxidant activity in both in vitro and in vivo tests (Table 4) . Moreover, the previous studies have focused on several biological activities of broccoli seedlings, such as antioxidant, anticancer, antimicrobial, and anti-inflammatory, as well as the potentially beneficial effects for patients with cancers, diabetes, and obesity.

title:
  Bioactive Compounds and Bioactivities of Brassica oleracea L. var. Italica Sprouts and Microgreens: An Updated Overview from a Nutraceutical Perspective

abstract:
  Sprouts and microgreens, the edible seedlings of vegetables and herbs, have received increasing attention in recent years and are considered as functional foods or superfoods owing to their valuable health-promoting properties. In particular, the seedlings of broccoli (Brassica oleracea L. var. Italica) have been highly prized for their substantial amount of bioactive constituents, including glucosinolates, phenolic compounds, vitamins, and essential minerals. These secondary metabolites are positively associated with potential health benefits. Numerous in vitro and in vivo studies demonstrated that broccoli seedlings possess various biological properties, including antioxidant, anticancer, anticancer, antimicrobial, anti-inflammatory, anti-obesity and antidiabetic activities. The present review summarizes the updated knowledge about bioactive compounds and bioactivities of these broccoli products and discusses the relevant mechanisms of action. This review will serve as a potential reference for food selections of consumers and applications in functional food and nutraceutical industries.


id: cord-323093-u3ozc9ry
author: Rathnayake, Athri D.
date: 2020-08-19
txt: ./txt/cord-323093-u3ozc9ry.txt
cache: ./cache/cord-323093-u3ozc9ry.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32747425/
doi: 10.1126/scitranslmed.abc5332
summary:
  After we observed that treatment with compound 6j resulted in the survival of MERS MA -CoV-infected hDPP4-KI mice, we conducted another study by delaying treatment initiation until 3 dpi. This nucleoside analog was originally developed as an antiviral drug against Ebola virus and has been shown to be effective against both MERS-CoV and SARS-CoV in cell culture assays and in animal models of coronavirus infection (23) (24) (25) (26) . Prophylactic treatment or early therapeutic treatment of infected mice with remdesivir reduced MERS-CoV-or SARS-CoV-mediated weight loss and decreased lung virus titers and lung injury scores compared to those of vehicle-treated animals (23, 26) . The goal of this study was to evaluate the efficacy of 3CLpro inhibitors against human coronaviruses, including SARS-CoV-2, in a FRET enzyme assay and cell culture assays, as well as in a mouse model of MERS-CoV infection.

title:
  3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV–infected mice

abstract:
  Pathogenic coronaviruses are a major threat to global public health, as exemplified by severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emerged SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). We describe herein the structure-guided optimization of a series of inhibitors of the coronavirus 3C-like protease (3CLpro), an enzyme essential for viral replication. The optimized compounds were effective against several human coronaviruses including MERS-CoV, SARS-CoV, and SARS-CoV-2 in an enzyme assay and in cell-based assays using Huh-7 and Vero E6 cell lines. Two selected compounds showed antiviral effects against SARS-CoV-2 in cultured primary human airway epithelial cells. In a mouse model of MERS-CoV infection, administration of a lead compound 1 day after virus infection increased survival from 0 to 100% and reduced lung viral titers and lung histopathology. These results suggest that this series of compounds has the potential to be developed further as antiviral drugs against human coronaviruses.


id: cord-323479-vlgv3nwq
author: Speranza, Jasmine
date: 2020-03-01
txt: ./txt/cord-323479-vlgv3nwq.txt
cache: ./cache/cord-323479-vlgv3nwq.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/plants9030298
doi: 10.3390/plants9030298
summary:
  tinctoria has been thoroughly investigated and the plant was proven to contain many valuable biologically active compounds, including several alkaloids, among which tryptanthrin, indirubin, indolinone, phenolic compounds, and polysaccharides as well as glucosinolates, carotenoids, volatile constituents, and fatty acids. In the lyophilized extracts'' analysis, beyond the characterization and quantification of 122 compounds previously described, the following indole derivatives were described for the first time: acetylindican, malonylindican, two Another important compound of this class is tryptanthrin, indolo-[2,1-b]-quinazoline alkaloid ( Figure 4 ), which is also responsible for some biological activities of I. In particular, the study concerned the evaluation of anti-microbial activity of fractions obtained from different parts of the plant (branches, flowers, leaves, and roots) by extraction with 14 different solvents, which was performed using a micro-titer plate method against seven bacterial and four fungal strains. Anti-inflammatory and antiallergic activity in vivo of lipophilic Isatis tinctoria extracts and tryptanthrin

title:
  Isatis tinctoria L. (Woad): A Review of Its Botany, Ethnobotanical Uses, Phytochemistry, Biological Activities, and Biotechnological Studies

abstract:
  Isatis tinctoria L. (Brassicaceae), which is commonly known as woad, is a species with an ancient and well-documented history as an indigo dye and medicinal plant. Currently, I. tinctoria is utilized more often as medicinal remedy and also as a cosmetic ingredient. In 2011, I. tinctoria root was accepted in the official European phytotherapy by introducing its monograph in the European Pharmacopoeia. The biological properties of raw material have been known from Traditional Chinese Medicine (TCM). Over recent decades, I. tinctoria has been investigated both from a phytochemical and a biological point of view. The modern in vitro and in vivo scientific studies proved anti-inflammatory, anti-tumour, antimicrobial, antiviral, analgesic, and antioxidant activities. The phytochemical composition of I. tinctoria has been thoroughly investigated and the plant was proven to contain many valuable biologically active compounds, including several alkaloids, among which tryptanthrin, indirubin, indolinone, phenolic compounds, and polysaccharides as well as glucosinolates, carotenoids, volatile constituents, and fatty acids. This article provides a general botanical and ethnobotanical overview that summarizes the up-to-date knowledge on the phytochemistry and biological properties of this valuable plant in order to support its therapeutic potential. Moreover, the biotechnological studies on I. tinctoria, which mainly focused on hairy root cultures for the enhanced production of flavonoids and alkaloids as well as on the establishment of shoot cultures and micropropagation protocols, were reviewed. They provide input for future research prospects.


id: cord-326922-bajpr5a2
author: Watson, C. James
date: 2020-11-02
txt: ./txt/cord-326922-bajpr5a2.txt
cache: ./cache/cord-326922-bajpr5a2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33140232/
doi: 10.1007/s13181-020-00814-3
summary:
  In the modern-day United States (US), medications are by-inlarge manufactured in commercial facilities, and this production is regulated and overseen by the US Food and Drug Administration (FDA). Furthermore, a new form of large-scale compounding has become commonplace, whereby pharmacies produce bulk volumes of medications which are not available commercially, and broadly distribute them to healthcare practices and individual patients. Patient harm caused by compounded medications has been the focus of media, medical, and legislative attention in recent years, especially following a multistate, multi-fatality outbreak of fungal meningitis caused by contaminated steroid injections compounded at a pharmacy in Framingham, MA [2, 3, 5, 6] . We categorized errors under the conceptual framework described by Sarah Sellers, PharmD, MPH, former board member for the FDA''s Advisory Committee on Pharmacy Compounding, in testimony to the US Senate Committee on Health, Education, Labor, and Pensions, namely, that "suprapotency," "subpotency," and "contamination" are the primary risks associated with pharmaceutical compounding [59] .

title:
  Pharmaceutical Compounding: a History, Regulatory Overview, and Systematic Review of Compounding Errors

abstract:
  INTRODUCTION: Medications are compounded when a formulation of a medication is needed but not commercially available. Regulatory oversight of compounding is piecemeal and compounding errors have resulted in patient harm. We review compounding in the United States (US), including a history of compounding, a critique of current regulatory oversight, and a systematic review of compounding errors recorded in the literature. METHODS: We gathered reports of compounding errors occurring in the US from 1990 to 2020 from PubMed, Embase, several relevant conference abstracts, and the US Food and Drug Administration “Drug Alerts and Statements” repository. We categorized reports into errors of “contamination,” suprapotency,” and “subpotency.” Errors were also subdivided by whether they resulted in morbidity and mortality. We reported demographic, medication, and outcome data where available. RESULTS: We screened 2155 reports and identified 63 errors. Twenty-one of 63 were errors of concentration, harming 36 patients. Twenty-seven of 63 were contamination errors, harming 1119 patients. Fifteen errors did not result in any identified harm. DISCUSSION: Compounding errors are attributed to contamination or concentration. Concentration errors predominantly result from compounding a prescription for a single patient, and disproportionately affect children. Contamination errors largely occur during bulk distribution of compounded medications for parenteral use, and affect more patients. The burden falls on the government, pharmacy industry, and medical providers to reduce the risk of patient harm caused by compounding errors. CONCLUSION: In the US, drug compounding is important in ensuring access to vital medications, but has the potential to cause patient harm without adequate safeguards.


id: cord-327946-mqakaisa
author: Massari, Serena
date: 2020-10-16
txt: ./txt/cord-327946-mqakaisa.txt
cache: ./cache/cord-327946-mqakaisa.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0223523420309168
doi: 10.1016/j.ejmech.2020.112944
summary:
  title: Synthesis and Characterization of 1,2,4-Triazolo[1,5-a]pyrimidine-2-carboxamide-based Compounds Targeting the PA-PB1 Interface of Influenza A Virus Polymerase In search for new anti-Flu drugs, our group has focused on viral RNA-dependent RNA polymerase (RdRP) developing disruptors of PA-PB1 subunits interface with the best compounds characterized by cycloheptathiophene-3-carboxamide and 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide scaffolds. In particular, a thorough exploration of the cycloheptathiophene-3-carboxamide moiety led to acquire important SAR insight and identify new active compounds showing both the ability to inhibit PA-PB1 interaction and viral replication in the micromolar range and at non-toxic concentrations. Finally, with the aim to gain information on how two different moieties, such as the cHTC and the 2-carbamoylphenyl, showed a favorable ability to disrupt PA-PB1 interaction, computational studies were performed to predict the binding mode of benzamide derivative 23 within the PA cavity with respect to hit compound 4.

title:
  Synthesis and Characterization of 1,2,4-Triazolo[1,5-a]pyrimidine-2-carboxamide-based Compounds Targeting the PA-PB1 Interface of Influenza A Virus Polymerase

abstract:
  Influenza viruses (Flu) are responsible for seasonal epidemics causing high rates of morbidity, which can dramatically increase during severe pandemic outbreaks. Antiviral drugs are an indispensable weapon to treat infected people and reduce the impact on human health, nevertheless anti-Flu armamentarium still remains inadequate. In search for new anti-Flu drugs, our group has focused on viral RNA-dependent RNA polymerase (RdRP) developing disruptors of PA-PB1 subunits interface with the best compounds characterized by cycloheptathiophene-3-carboxamide and 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide scaffolds. By merging these moieties, two very interesting hybrid compounds were recently identified, starting from which, in this paper, a series of analogues were designed and synthesized. In particular, a thorough exploration of the cycloheptathiophene-3-carboxamide moiety led to acquire important SAR insight and identify new active compounds showing both the ability to inhibit PA-PB1 interaction and viral replication in the micromolar range and at non-toxic concentrations. For few compounds, the ability to efficiently inhibit PA-PB1 subunits interaction did not translate into anti-Flu activity. Chemical/physical properties were investigated for a couple of compounds suggesting that the low solubility of compound 14, due to a strong crystal lattice, may have impaired its antiviral activity. Finally, computational studies performed on compound 23, in which the phenyl ring suitably replaced the cycloheptathiophene, suggested that, in addition to hydrophobic interactions, H-bonds enhanced its binding within the PA(C) cavity.


id: cord-328176-fck2ktxi
title: Methyl-2-arylidene hydrazinecarbodithioates: synthesis and biological activity
author: Mahapatra, Manojkumar
date: 2013-02-19
txt: ./txt/cord-328176-fck2ktxi.txt
cache: ./cache/cord-328176-fck2ktxi.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32214621/
doi: 10.2478/s11696-013-0346-4
summary:
  This study examined the cytostatic and antiviral activity of twelve methyl-2-arylidene hydrazinecarbodithioates reported by many researchers as intermediates for the synthesis of thiosemicarbazides and the preparation of their metal complexes. Compounds IIc, IIi, and IIl with tridentate ligand features were found to have the lowest IC(50) value (6.5 μM, ≈ 1 μM, and 0.8 μM, respectively) against HL60 human promyelocytic leukemia cells. Compound IIc and IIl show antiviral activity against wild-type herpes simplex virus (HSV), varicella zoster virus (VZV), and acyclovirresistant HSV; however, these activities were observed at concentrations at which the compounds also markedly inhibit HL60 and HEL cell proliferation. It is interesting to note that preferably compounds with tridentate ligand characteristics (IIl, IIi, and IIc) showed potent anti-proliferative activity against the HL60 cells (Table 3 ). The compounds investigated are known as intermediates in the synthesis of many thiosemicarbazones but their usefulness as medicinally active agents has not yet been studied.

abstract:
  Methyl-2-arylidene hydrazine-carbodithioate has not been of particular interest to researchers even though its metal complexes are extensively reported on due to their biological activity. This study examined the cytostatic and antiviral activity of twelve methyl-2-arylidene hydrazinecarbodithioates reported by many researchers as intermediates for the synthesis of thiosemicarbazides and the preparation of their metal complexes. Compounds IIc, IIi, and IIl with tridentate ligand features were found to have the lowest IC(50) value (6.5 μM, ≈ 1 μM, and 0.8 μM, respectively) against HL60 human promyelocytic leukemia cells. They were also most inhibitory to human embryonic lung (HEL) fibroblast proliferation (5.3 μM, 17 μM, and 2.6 μM). Compound IIc and IIl show antiviral activity against wild-type herpes simplex virus (HSV), varicella zoster virus (VZV), and acyclovirresistant HSV; however, these activities were observed at concentrations at which the compounds also markedly inhibit HL60 and HEL cell proliferation.


id: cord-328834-yetnlb2j
author: Mohsin, Noor ul Amin
date: 2020-06-15
txt: ./txt/cord-328834-yetnlb2j.txt
cache: ./cache/cord-328834-yetnlb2j.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32836513/
doi: 10.1007/s11094-020-02187-x
summary:
  Upon in vitro evaluation, compound 10 ( Fig. 3) showed prominent activity (87% growth inhibition) against colon cancer cell line (HCT-116) as compared to fluorouracil (67% inhibition). Derivatives bearing electron withdrawing groups at positions # 5, # 6 and # 7 of chromone scaffold showed better activity. Upon evaluation as anticancer agents by MTT assay, compounds 22 (IC 50 = 1.42 ± 0.13 mM) and 23 (IC 50 = 2.92 ± 0.94 mM) showed prominent in vitro activity versus breast cancer cell line (T47D) as compared to doxorubicin (IC 50 = 0.33 ± 0.05 mM). Incorporation of methyl and ethyl group in the heterocyclic ring showed comparable activity to unsubstituted derivatives [47] . Attachment of methyl group with chromone core also produced less active derivatives [51] . synthesized fluorine-containing chromone and tetrazole hybrid molecules by Ugi-azide reaction [63] These derivatives displayed moderate antimicrobial activity as is evident by compound 51 (MIC = 20 mg/mL) activity versus Pseudomonas aeruginosa (P.

title:
  Current Strategies in Development of New Chromone Derivatives with Diversified Pharmacological Activities: A Review

abstract:
  Chromone derivatives possess a spectrum of biological activities. Chromone has been recognized as a privileged structure for new drug invention and development. Substitution pattern of chromone scaffold determines different type of biological activities. The type, number and position of substituents connected to the chromone core play a vital role in determining pharmacological activities. In the present review, we have discussed new chromone derivatives as anticancer, anti-diabetic, antimicrobial, anti-inflammatory, antioxidant and as anti-Alzheimer agents. This review deals with the chromone derivatives prepared by combining chromone molecule with various natural and synthetic pharmacophores and pharmacological activities presented by them. The main aim is to highlight the diversified pharmacological activities exhibited by chromone hybrid molecules during the last eight to ten years.


id: cord-328962-1c4vqaqr
title: Potential inhibitors of the interaction between ACE2 and SARS-CoV-2 (RBD), to develop a drug
author: Benítez-Cardoza, Claudia Guadalupe
date: 2020-06-15
txt: ./txt/cord-328962-1c4vqaqr.txt
cache: ./cache/cord-328962-1c4vqaqr.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0024320520307207?v=s5
doi: 10.1016/j.lfs.2020.117970
summary:
  KEY FINDINGS: 20 best compounds directed to interact in ACE2 with a high probability to be safe in humans, validated by web servers of prediction of ADME and toxicity (ProTox-II and PreADMET), to difficult the interaction between ACE2 and region binding domain (RBD) of SARS-CoV-2. We use the amino acids reported in the crystallographic structure of the interaction between the S-protein-RBD of SARS-CoV-2 and ACE2 (Gln24, Asp30, His34, Tyr41, Gln42, Met82, Lys353 and Arg357 in ACE2) [10] [22] , therefore, using the crystallographic structure of ACE2 (PDB 1R42), we carried out a Docking directed to these mentioned residues using a library of compounds (EXPRESS-pick Collection from Chembridge Corp.) to select the best compounds, and that these can affect the interaction between ACE2 and SARS-CoV-2, making these results an important contribution to establishing the foundations that allow the development of a drug that optimizes the resolution of this pandemic.

abstract:
  AIMS: The COVID-19 disease caused by the SARS-CoV-2 has become a pandemic and there are no effective treatments that reduce the contagion. It is urgent to propose new treatment options, which are more effective in the interaction between viruses and cells. In this study was to develop a search for new pharmacological compounds against the angiotensin-converting enzyme 2 (ACE2), to inhibit the interaction with SARS-CoV-2. MATERIALS AND METHODS: Docking, virtual screening using almost 500,000 compounds directed to interact in the region between the residues (Gln24, Asp30, His34, Tyr41, Gln42, Met82, Lys353, and Arg357) in ACE2. The average of ΔG(binding), the standard deviation value and the theoretical toxicity from compounds were analyzed. KEY FINDINGS: 20 best compounds directed to interact in ACE2 with a high probability to be safe in humans, validated by web servers of prediction of ADME and toxicity (ProTox-II and PreADMET), to difficult the interaction between ACE2 and region binding domain (RBD) of SARS-CoV-2. SIGNIFICANCE: In this study, 20 compounds were determined by docking focused on the region of interaction between ACE2 and RBD of SARS-CoV-2 was carried out. The compounds are publicly available to validate the effect in in vitro tests.


id: cord-329078-gnnis7pl
author: Musella, Simona
date: 2016-11-29
txt: ./txt/cord-329078-gnnis7pl.txt
cache: ./cache/cord-329078-gnnis7pl.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0223523416307401
doi: 10.1016/j.ejmech.2016.09.014
summary:
  title: Identification of an indol-based derivative as potent and selective varicella zoster virus (VZV) inhibitor Tryptamine derivative 17a was found to have a selective inhibitory activity against human varicella zoster virus (VZV) replication in vitro, being inactive against a variety of other DNA and RNA viruses. Arbidol [34] and delavirdine [35] , are examples of marketed indole-containing antiviral drugs, whereas Panobinostat (LBH589) [36] , being a HDAC (histone deacetylase) inhibitor, is actively undergoing clinical evaluation against human immunodeficiency virus (HIV) type 1 (See Fig. 1 ). The antiviral activity was expressed as EC50, being the compound concentration required to reduce virus-plaque formation (VZV) by 50%. The mixture was stirred for 3 h at room temperature, then was washed with water (3 Â 50 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography using DCM/MeOH (9:1 v/v) as mobile phase. 4-Benzyloxy-gamma-sultone derivatives: discovery of a novel family of non-nucleoside inhibitors of human cytomegalovirus and varicella zoster virus

title:
  Identification of an indol-based derivative as potent and selective varicella zoster virus (VZV) inhibitor

abstract:
  We report the synthesis and antiviral activity of a new family of non-nucleoside antivirals, derived from the indole nucleus. Modifications of this template through Mannich and Friedel-Crafts reactions, coupled with nucleophilic displacement and reductive aminations led to 23 final derivatives, which were pharmacologically tested. Tryptamine derivative 17a was found to have a selective inhibitory activity against human varicella zoster virus (VZV) replication in vitro, being inactive against a variety of other DNA and RNA viruses. A structure-activity relationship (SAR) study showed that the presence of a biphenyl ethyl moiety and the acetylation at the amino group of tryptamine are a prerequisite for anti-VZV activity. The novel compound shows the same activity against thymidine kinase (TK)-competent (TK(+)) and TK-deficient (TK(−)) VZV strains, pointing to a novel mechanism of antiviral action.


id: cord-330465-16j5vm7h
author: Marciniec, Krzysztof
date: 2020-08-05
txt: ./txt/cord-330465-16j5vm7h.txt
cache: ./cache/cord-330465-16j5vm7h.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32764519/
doi: 10.3390/biom10081148
summary:
  The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3–5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid–spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3′,3′-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC(50) (half maximal inhibitory concentration) equal to 0.02 μM. In order to check the potential toxic properties of the compounds 3-5, docking study of phosphate betulin derivatives to cellular proteins was carried out. According to the results of docking (Table S1 ) obtained from AutoDock Vina, four potential SARS-CoV-2 inhibitors (BVM, betulinic acid, and compounds 4 and 6) were selected based on a lower negative dock energy value.

title:
  Phosphate Derivatives of 3-Carboxyacylbetulin: SynThesis, In Vitro Anti-HIV and Molecular Docking Study

abstract:
  Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3–5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid–spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3′,3′-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC(50) (half maximal inhibitory concentration) equal to 0.02 μM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat (BVM) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.


id: cord-330994-6nu7utu1
author: Abdelrheem, Doaa A.
date: 2020-10-01
txt: ./txt/cord-330994-6nu7utu1.txt
cache: ./cache/cord-330994-6nu7utu1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1080/10934529.2020.1826192
doi: 10.1080/10934529.2020.1826192
summary:
  title: The inhibitory effect of some natural bioactive compounds against SARS-CoV-2 main protease: insights from molecular docking analysis and molecular dynamic simulation This work aimed at evaluating the inhibitory effect of ten natural bioactive compounds (1–10) as potential inhibitors of SARS-CoV-2-3CL main protease (PDB ID: 6LU7) and SARS-CoV main proteases (PDB IDs: 2GTB and 3TNT) by molecular docking analysis. [6] So, we study the inhibitory effect of some bioactive compounds obtained from natural sources against SARS-CoV-2-3CLpro and SARS-CoV main proteases (PDB IDs: 2GTB and 3TNT). The crystal structures of SARS-CoV-2-3CLpro (PDB code: 6LU7) and main proteases of SARS-Coronavirus (Mpro) with (PDB IDs: 2GTB and 3TNT) were downloaded from the Protein Data Bank (www.pdb.org), and any heteroatoms and water molecules were removed before molecular docking studies. Based on our molecular docking analysis we found that among all studied compounds, caulerpin has the highest binding affinity against all studied receptors 6LU7, 3TNT, and 2GTB with compared to some proposed antiviral drug currently used in COVID-19 treatment.

title:
  The inhibitory effect of some natural bioactive compounds against SARS-CoV-2 main protease: insights from molecular docking analysis and molecular dynamic simulation

abstract:
  This work aimed at evaluating the inhibitory effect of ten natural bioactive compounds (1–10) as potential inhibitors of SARS-CoV-2-3CL main protease (PDB ID: 6LU7) and SARS-CoV main proteases (PDB IDs: 2GTB and 3TNT) by molecular docking analysis. The inhibitory effect of all studied compounds was studied with compared to some proposed antiviral drugs which currently used in COVID-19 treatment such as chloroquine, hydroxychloroquine, azithromycin, remdesivir, baloxvir, lopinavir, and favipiravir. Homology modeling and sequence alignment was computed to evaluate the similarity between the SARS-CoV-2-3CL main protease and other SARS-CoV receptors. ADMET properties of all studied compounds were computed and reported. Also, molecular dynamic (MD) simulation was performed on the compound which has the highest binding affinity inside 6LU7 obtained from molecular docking analysis to study it is stability inside receptor in explicit water solvent. Based on molecular docking analysis, we found that caulerpin has the highest binding affinity inside all studied receptors compared to other bioactive compounds and studied drugs. Our homology modeling and sequence alignment showed that SARS-CoV main protease (PDB ID: 3TNT) shares high similarity with 3CLpro (96.00%). Also, ADMET properties confirmed that caulerpin obeys Lipinski’s rule and passes ADMET property, which make it a promising compound to act as a new safe natural drug against SARS-CoV-2-3CL main protease. Finally, MD simulation confirmed that the complex formed between caulerpin and 3CLpro is stable in water explicit and had no major effect on the flexibility of the protein throughout the simulations and provided a suitable basis for our study. Also, binding free energy between caulerpin and 6LU7 confirmed the efficacy of the caulerpin molecule against SARS-CoV-2 main protease. So, this study suggested that caulerpin could be used as a potential candidate in COVID-19 treatment.


id: cord-333675-vkk2frnf
title: Synthesis and broad spectrum antiviral evaluation of bis(POM) prodrugs of novel acyclic nucleosides
author: Hamada, Manabu
date: 2013-07-04
txt: ./txt/cord-333675-vkk2frnf.txt
cache: ./cache/cord-333675-vkk2frnf.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0223523413004212
doi: 10.1016/j.ejmech.2013.06.053
summary:
  A series of seventeen hitherto unknown ANP analogs bearing the (E)-but-2-enyl aliphatic side chain and modified heterocyclic base such as cytosine and 5-fluorocytosine, 2-pyrazinecarboxamide, 1,2,4-triazole-3-carboxamide or 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as key synthetic step. N 1crotyl-1,2,4-triazole-3-bis-Boc-carboxamide 19 was then subjected to the olefin cross metathesis reaction, with bis(POM)-allylphosphonate in CH 2 Cl 2 to obtain the desired compound 20 in 16% yield. The title bis(POM) (E)-4-phosphono-but-2-en-1-yl acyclic nucleosides were subjected to an in vitro antiviral screening using a wide spectrum of viruses, in MDKC cell cultures for anti-influenza virus activity, in Vero cell cultures for an antiviral activity against Para-influenza3 shown) only compound 31 showed activity at an EC 50 of w10 mM (AD-169 strain) with no observed cytotoxicity at 100 mM ( Table 2) .

abstract:
  A series of seventeen hitherto unknown ANP analogs bearing the (E)-but-2-enyl aliphatic side chain and modified heterocyclic base such as cytosine and 5-fluorocytosine, 2-pyrazinecarboxamide, 1,2,4-triazole-3-carboxamide or 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as key synthetic step. All novel compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex virus type 1 and 2, varicella zoster virus, feline herpes virus, human cytomegalovirus, hepatitis C virus (HCV), HIV-1 and HIV-2. Among these molecules, only compound 31 showed activity against human cytomegalovirus in HEL cell cultures with at EC(50) of ∼10 μM. Compounds 8a, 13, 14, and 24 demonstrated pronounced anti-HCV activity without significant cytotoxicity at 100 μM.


id: cord-336759-cu1uprwm
title: Design, synthesis, antitubercular and antiviral properties of new spirocyclic indole derivatives
author: Cihan-Üstündağ, Gökçe
date: 2019-07-17
txt: ./txt/cord-336759-cu1uprwm.txt
cache: ./cache/cord-336759-cu1uprwm.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32214484/
doi: 10.1007/s00706-019-02457-9
summary:
  Compounds bearing a phenyl substituent at position 8 of the spiro ring, exhibited significant antitubercular activity against Mycobacterium tuberculosis H37Rv ATCC 27294 at concentrations of 3.9 and 7.8 µM. Based on these insights and our objective to optimize the antimicrobial activity of indolyl thiazolidinones and spirothiazolidinones, we here report the chemical synthesis, structural characterization and in vitro antitubercular, antiviral, antibacterial, and antifungal evaluation of new 5-chloro-3-phenyl-N(2,7,8,9substituted/nonsubstituted-3-oxo-1-thia-4-azaspiro [4.4] nonan/ [4.5] decan-4-yl)-1H-indole-2-carboxamides 4a-4i, 5a-5h (Fig. 1e ). As shown in Table 1 , compounds 4 h and 5h, bearing a phenyl substituent at position 8 of the spiro ring, exhibited the highest anti-TB activity at concentrations of 3.9 and 7.8 µM, respectively. The broad antibacterial and antifungal activity of compounds 4a-4i and 5a-5 h was further assessed using The experiment was performed twice and the same results were obtained a MIC, the actual minimum inhibitory concentration required to inhibit the growth of 100% of organisms 

abstract:
  ABSTRACT: A series of indole-based spirothiazolidinones have been designed, synthesized and evaluated, in vitro, for their antitubercular, antiviral, antibacterial, and antifungal activities. The structures of the new compounds were established by IR, (1)H NMR, (13)C NMR (proton decoupled, APT, and DEPT), electrospray ionization mass spectrometry, and microanalysis. Compounds bearing a phenyl substituent at position 8 of the spiro ring, exhibited significant antitubercular activity against Mycobacterium tuberculosis H37Rv ATCC 27294 at concentrations of 3.9 and 7.8 µM. Still, some of the tested compounds displayed activity on mycobacteria with MIC values of 16 and 31 µM. Four of the indole-spirothiazolidinone derivatives were found to be moderately active against Punta Toro virus, yellow fever virus or Sindbis virus in Vero cells. The antiviral EC(50) values were in the range of 1.9–12 µM and the selectivity index (ratio of cytotoxic to antivirally effective concentration) was above 10 in some cases. The most potent effect was seen with the compound that is methylated at positions 2 and 8 of the spirothiazolidinone system. GRAPHIC ABSTRACT: [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00706-019-02457-9) contains supplementary material, which is available to authorized users.


id: cord-338436-0z828org
author: Tzou, Philip L.
date: 2020-09-09
txt: ./txt/cord-338436-0z828org.txt
cache: ./cache/cord-338436-0z828org.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32916958/
doi: 10.3390/v12091006
summary:
  Results: As of August 2020, the Coronavirus Antiviral Research Database (CoV-RDB; covdb.stanford.edu) contained over 2800 cell culture, entry assay, and biochemical experiments, 259 animal model studies, and 73 clinical studies from over 400 published papers. Figure 4 displays EC 50 values for many of the directly acting antiviral compounds currently in clinical trials for the treatment of COVID-19 including six polymerase inhibitors (remdesivir, EIDD-2801, favipiravir, ribavirin, galidesivir, and sofosbuvir), three HIV-1 protease inhibitors (lopinavir, atazanavir, and darunavir), and three entry inhibitors (receptor binding monoclonal antibodies, soluble recombinant human ACE2, and umifenovir). Viruses 2020, 12, x FOR PEER REVIEW 11 of 22 Table 4 describes a set of the most promising compounds for the treatment of SARS-CoV-2 based on the following criteria: (i) act by a validated direct or indirect antiviral mechanism, (ii) display submicromolar activity in vitro and/or inhibitory activity in an animal model, and (iii) have a record of safety and favorable pharmacokinetics in human subjects.

title:
  Coronavirus Antiviral Research Database (CoV-RDB): An Online Database Designed to Facilitate Comparisons between Candidate Anti-Coronavirus Compounds

abstract:
  Background: To prioritize the development of antiviral compounds, it is necessary to compare their relative preclinical activity and clinical efficacy. Methods: We reviewed in vitro, animal model, and clinical studies of candidate anti-coronavirus compounds and placed extracted data in an online relational database. Results: As of August 2020, the Coronavirus Antiviral Research Database (CoV-RDB; covdb.stanford.edu) contained over 2800 cell culture, entry assay, and biochemical experiments, 259 animal model studies, and 73 clinical studies from over 400 published papers. SARS-CoV-2, SARS-CoV, and MERS-CoV account for 85% of the data. Approximately 75% of experiments involved compounds with known or likely mechanisms of action, including monoclonal antibodies and receptor binding inhibitors (21%), viral protease inhibitors (17%), miscellaneous host-acting inhibitors (10%), polymerase inhibitors (9%), interferons (7%), fusion inhibitors (5%), and host protease inhibitors (5%). Of 975 compounds with known or likely mechanism, 135 (14%) are licensed in the U.S. for other indications, 197 (20%) are licensed outside the U.S. or are in human trials, and 595 (61%) are pre-clinical investigational compounds. Conclusion: CoV-RDB facilitates comparisons between different candidate antiviral compounds, thereby helping scientists, clinical investigators, public health officials, and funding agencies prioritize the most promising compounds and repurposed drugs for further development.


id: cord-340331-51yq1rdo
author: Tonelli, Michele
date: 2017-07-28
txt: ./txt/cord-340331-51yq1rdo.txt
cache: ./cache/cord-340331-51yq1rdo.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.ejmech.2017.04.070
doi: 10.1016/j.ejmech.2017.04.070
summary:
  We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. The compounds, object of the present study, are characterized by the 1-aryl-4,6-diamino-1,2-dihydrotriazine scaffold, such as the cited cycloguanil, which was identified by us as prototype (1) of a new class of antiviral agents exploiting a host DHFR inhibition mechanism. Since host cell DHFR inhibition seemed the plausible explanation for the observed antiviral effect, we performed a combination experiment in which RSV-infected HeLa cells were exposed to compound 14 in combination with different concentrations of the natural DHFR substrate dihydrofolic acid ( reaction has a much higher impact on virus replication than on cell growth, which concurs with the promising antiviral selectivity of our host-directed DHFR inhibitors. The interesting dual activity of the 1-aryl-4,6-diamino-1,2dihydrotriazines against influenza and respiratory syncytial viruses, via inhibition of the cellular (human) DHFR enzyme, points to this host factor as a new therapeutic target for these two respiratory viruses.

title:
  Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

abstract:
  We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC(50) = 0.060 μM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC(50) ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC(50) = 5.8 μM, SI > 43).


id: cord-340832-412qre64
author: Liang, Pi‐Hui
date: 2006-01-05
txt: ./txt/cord-340832-412qre64.txt
cache: ./cache/cord-340832-412qre64.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/16397876/
doi: 10.1002/cbic.200500321
summary:
  In the screening for 166 www.chembiochem.org a-glucosidase (bakers'' yeast) inhibition, about two-thirds of reaction products were found to be more potent than 4 (see Supporting Information for overall library inhibitory activities). With the potent a-glucosidase inhibitors in hand, we tested their potential antiviral effect based on our previous assay system for JEV and DEN-2. [16] The weaker a-glucosidase inhibitors 39-41, derived from core 4 with eight to ten carbons (Scheme 3), were then evaluated, and we found that 39-41 at 10 or 50 mM did not inhibit either JEV or DEN-2 infection (data not shown) in the cell-based assay. The N-alkylated derivatives of compound 24 were also tested for antiviral activity, and 36-38, which contain lipophilic alkyl groups, were the most active, with an IC 50 of about 5-10 mM against JEV, DEN-2, and SARS-CoV infection. However, extending the alkyl chain at the ring nitrogen gave the most potent human b-hexosaminidase inhibitor known to date, that is, compound 54, with a K i value of 2.6 nM.

title:
  Novel Five‐Membered Iminocyclitol Derivatives as Selective and Potent Glycosidase Inhibitors: New Structures for Antivirals and Osteoarthritis

abstract:
  A novel 5‐membered iminocyclitol derivative was found to be a potent and selective inhibitor of the glycoprotein‐processing α‐glucosidase with a K(i) value of 53 nm. This compound was further derivatized to antiviral agents against Japanese encephalitis virus, dengue virus serotype 2 (DEN‐2), human SARS coronavirus, and human β‐hexosaminidase (K(i) =2.6 nm), a new target for the development of osteoarthritis therapeutics.


id: cord-344598-5drr3fyt
author: Khanna, Leena
date: 2020-03-19
txt: ./txt/cord-344598-5drr3fyt.txt
cache: ./cache/cord-344598-5drr3fyt.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32328514/
doi: 10.1002/slct.201904783
summary:
  Thus, in the present study, the biological importance of 22 compounds including six new spiro indole-coumarin hybrids as DNA quadruplex groove binders has been evaluated by performing molecular docking studies on DNA G-quadruplexes of the human genome. Finally, Density Functional Theory (DFT) calculations, NBO analysis, and MEP plots are drawn for hybrids to prove their chemical reactivity and stability. 1 H NMR spectrum showed the presence of methylene of thiazolidine as two doublets at δ 4.37 and δ 4.05 besides the usual aromatic protons of indole, indazole and coumarin moieties. Table 1 also shows all six newly synthesized spiro indolecoumarin hybrids 10 a-c and 12 a-c are having high binding energy as compared to intermediary Schiff bases, isatin, their non-hybrid counterparts and the reference compounds. Binding interaction of about 22 compounds including these hybrids with DNA G-quadruplex of the human genome, was screened using Molecular docking studies.

title:
  Spiro‐Indole‐Coumarin Hybrids: Synthesis, ADME, DFT, NBO Studies and In Silico Screening through Molecular Docking on DNA G‐Quadruplex

abstract:
  New series of hybrids were synthesized by combination of 4‐hydroxycoumarin with spiro[indol‐indazole‐thiazolidine]‐diones and spiro[indol‐pyrazole‐thiazolidine]‐diones, via hitherto unknown Schiff bases. The effects of substituents, such as ‐F, ‐Br and ‐CH(3), on the crucial characteristics pertaining to the hybrids were investigated through computational studies. In silico or virtual screening through molecular docking studies on the library of 22 compounds, including reference compounds, precursors, non‐hybrid and hybrid derivatives, was performed on DNA G‐quadruplex of the human genome. All six freshly synthesized hybrids showed high binding energy as compared to non‐hybrids as well as reference compounds. The presence of substituents at 5‐position of indole enhanced the binding tendency of the ligand. ADME studies indicated good oral bioavailability and absorption of these compounds. Density Functional Theory (DFT) calculations of hybrids were done at B3LYP/6‐311G++(d,p) level of computation. Their HOMO and LUMO energy plots reflected the presence of high charge transfer and chemical potential. Natural bond order (NBO) calculations predicted hyperconjugative interactions. The Molecular Electrostatic Potential (MEP) surface plots showed possible electrophilic and nucleophilic attacking sites of the hybrids. Compound 10 a (5‐fluoro‐spiro[indol‐indazole‐thiazolidine]‐dione‐coumarin hybrid), on the basis of global reactivity descriptors, was filtered to be chemically most reactive with the highest binding energy of −8.23 kcal/mol with DNA G‐quadruplex. The synthesized hybrid coumarin derivatives in correlation with theoretical docking studies validate that hybrid derivatives are more reactive compared to their non‐hybrid counterparts.


id: cord-345750-dk1exw9l
title: Synthesis and antineoplastic properties of (1H-1,2,3-triazol-1-yl)furazans
author: Kulikov, A. S.
date: 2014-01-07
txt: ./txt/cord-345750-dk1exw9l.txt
cache: ./cache/cord-345750-dk1exw9l.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s11172-013-0113-2
doi: 10.1007/s11172-013-0113-2
summary:
  All target compounds were evaluated for both antimitotic microtubule destabilizing effect in a phenotypic sea urchin embryo assay and cytotoxicity in a panel of 60 human cancer cell lines. Water soluble biologically active compounds contain ing both cycles, e.g., (1,2,3 triazol 1 yl)furazans 1, ex hibiting other mechanisms of action were synthesized. In addition, to extend the scope of triazolylfurazan derivatives with potential antineoplastic activity, we used the Clauson-Kaas pyrrole synthesis involving the reaction of primary amino group of the furazan ring with dimethoxytetra hydrofuran. Therefore, unpurified esters 4a-g were hydrolyzed to the corresponding acids 5a-g, which also without further purification were subsequently thermally decarboxylated to target 3 amino 4 [5 aryl(hetaryl) 1H 1,2,3 triazol 1 yl]furazans 6a-g in high yields. Subsequent Clauson-Kaas condensation of synthesized triazolylfurazans 6 with dimethoxytetrahydrofuran yielded a series of 4 [5 aryl (hetaryl) 1H 1,2,3 triazol 1 yl] (3 pyrrol 1 yl)furazans 7.

abstract:
  A method of 3-amino-4-[5-aryl(heteroaryl)-1H-1,2,3-triazol-1-yl)]furazan synthesis was optimized. Condensation of these compounds with 2,5-dimethoxytetrahydrofuran resulted in a series of previously unknown 4-[5-aryl(heteroaryl)-1H-1,2,3-triazol-1-yl)]-3-(pyrrol-1-yl)furazans. All target compounds were evaluated for both antimitotic microtubule destabilizing effect in a phenotypic sea urchin embryo assay and cytotoxicity in a panel of 60 human cancer cell lines. Pyrrolyl derivatives of triazolylfurazans were determined as antiproliferative compounds. The most potent microtubule targeting compounds 7a and 7e are of interest for further trials as antineoplastic agents.


id: cord-347547-makm0j09
title: Bioactivity Profile Similarities to Expand the Repertoire of COVID-19 Drugs
author: Duran-Frigola, Miquel
date: 2020-07-16
txt: ./txt/cord-347547-makm0j09.txt
cache: ./cache/cord-347547-makm0j09.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32672454/
doi: 10.1021/acs.jcim.0c00420
summary:
  By comparing the set of drugs reported to be potentially active against SARS-CoV-2 to a universe of 1 million bioactive molecules, we identify compounds that display analogous chemical and functional features to the current COVID-19 candidates. Searches can be filtered by level of evidence and mechanism of action, and results can be restricted to drug molecules or include the much broader space of bioactive compounds. Indeed, we conducted a limited review of the most relevant scientific literature and identified over 200 compounds that are potentially active against COVID-19 with different levels of experimental support, from purely computational predictions to preclinical and drugs already in clinical trials. We use the list of COVID-19 compounds extracted from the literature, with different levels of experimental evidence, as bait to search for compounds with similar bioactivity or chemical features among the 800,000 molecules contained in the CC.

abstract:
  [Image: see text] Until a vaccine becomes available, the current repertoire of drugs is our only therapeutic asset to fight the SARS-CoV-2 outbreak. Indeed, emergency clinical trials have been launched to assess the effectiveness of many marketed drugs, tackling the decrease of viral load through several mechanisms. Here, we present an online resource, based on small-molecule bioactivity signatures and natural language processing, to expand the portfolio of compounds with potential to treat COVID-19. By comparing the set of drugs reported to be potentially active against SARS-CoV-2 to a universe of 1 million bioactive molecules, we identify compounds that display analogous chemical and functional features to the current COVID-19 candidates. Searches can be filtered by level of evidence and mechanism of action, and results can be restricted to drug molecules or include the much broader space of bioactive compounds. Moreover, we allow users to contribute COVID-19 drug candidates, which are automatically incorporated to the pipeline once per day. The computational platform, as well as the source code, is available at https://sbnb.irbbarcelona.org/covid19.


id: cord-352844-wggg3ynb
author: Annunziata, Francesca
date: 2020-06-29
txt: ./txt/cord-352844-wggg3ynb.txt
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extension: .txt
mime: text/plain
url: https://doi.org/10.3390/ijms21134618
doi: 10.3390/ijms21134618
summary:
  Again, the coumarin derivative showed inhibitory activity on 15-LOX-1 in PC3 and DU145 cell lines, thus inducing apoptosis of the cancer cell, with the same mechanism of The results represent a good starting point for the design of novel derivatives, because most of the examined compounds exhibited selective toxicity on HeLa cells (IC 50 values between 136.4 ± 1.90 µM and 172.2 ± 1.80 µM after 24 h), whereas no negative effects on HDF normal cell''s growth was detected. Since tacrine is a well-known inhibitor of the catalytic site of AChE, whereas coumarins showed affinity for the peripheral anionic site (PAS) [161] , this new compounds may be potential dual-and therefore more powerful -inhibitors of ChEs. The in vitro AChE and BuChE inhibitory activity was evaluated using the Ellman''s method [159] ; among all the tested molecules, compound 105 resulted the best in AChE inhibition (IC 50 Thanks to their simple structural architecture and chemical stability, coumarins can be easily synthesized and modified in order to produce more active and selective compounds.

title:
  An Overview of Coumarin as a Versatile and Readily Accessible Scaffold with Broad-Ranging Biological Activities

abstract:
  Privileged structures have been widely used as an effective template for the research and discovery of high value chemicals. Coumarin is a simple scaffold widespread in Nature and it can be found in a considerable number of plants as well as in some fungi and bacteria. In the last years, these natural compounds have been gaining an increasing attention from the scientific community for their wide range of biological activities, mainly due to their ability to interact with diverse enzymes and receptors in living organisms. In addition, coumarin nucleus has proved to be easily synthetized and decorated, giving the possibility of designing new coumarin-based compounds and investigating their potential in the treatment of various diseases. The versatility of coumarin scaffold finds applications not only in medicinal chemistry but also in the agrochemical field as well as in the cosmetic and fragrances industry. This review is intended to be a critical overview on coumarins, comprehensive of natural sources, metabolites, biological evaluations and synthetic approaches.


