key: cord-0907252-i62uorya
authors: Zhao, Chuang; Rakesh, K.P.; Ravidar, L.; Fang, Wan-Yin; Qin, Hua-Li
title: Pharmaceutical and medicinal significance of sulfur (S(VI))-Containing motifs for drug discovery: A critical review
date: 2019-01-15
journal: Eur J Med Chem
DOI: 10.1016/j.ejmech.2018.11.017
sha: 3e5177ad97b163ddcd1fd2953f421eb913eddcb5
doc_id: 907252
cord_uid: i62uorya

Sulfur (S(VI)) based moieties, especially, the sulfonyl or sulfonamide based analogues have showed a variety of pharmacological properties, and its derivatives propose a high degree of structural diversity that has established useful for the finding of new therapeutic agents. The developments of new less toxic, low cost and highly active sulfonamides containing analogues are hot research topics in medicinal chemistry. Currently, more than 150 FDA approved Sulfur (S(VI))-based drugs are available in the market, and they are widely used to treat various types of diseases with therapeutic power. This comprehensive review highlights the recent developments of sulfonyl or sulfonamides based compounds in huge range of therapeutic applications such as antimicrobial, anti-inflammatory, antiviral, anticonvulsant, antitubercular, antidiabetic, antileishmanial, carbonic anhydrase, antimalarial, anticancer and other medicinal agents. We believe that, this review article is useful to inspire new ideas for structural design and developments of less toxic and powerful Sulfur (S(VI)) based drugs against the numerous death-causing diseases.

The sulfonamide or sulfonyl functional groups have been important motifs in medicinal chemistry since the early discovery of sulfonamide containing antibacterial drugs [1] . The applications of sulfonyl or sulfonamide functional groups in medicinal chemistry cannot be ignored, as it constitutes an important class of drugs used extensively as agricultural and pharmaceutical agents [2, 3] . The features of S VI -containing species of strong electron withdrawing nature, stability against hydrolysis, resistance to reduction at sulfur, and crisp preference for two-electron processes over radical processes, have already made this group applicable to many productive fields. Sulfonamides as synthetic antifolic agents have been widely used for the anticipation and treat of bacterial infections in biological systems and recently have evoked high favor in biology and medicine due to their wide array of biological activities such as antibacterial [4e6] , antifungal [7] , antiinflammatory [8e10], antioxidant [11, 12] [26, 27] , antitubercular [28, 29] , antidiabetic [30, 31] , HIV protease inhibitors [32, 33] , antiglaucoma [34e36], antiobesity [37, 38] , antiviral [39, 40] , antimalaria [41] , MMP inhibitors [42, 43] , non-peptidic vasopressin receptor antagonists [44] and translation initiation inhibitors [45] etc. Up to date, more than 150 FDA approved drugs bearing Sulfur (S VI ) motif are available in the market such as celecoxib, meloxicam, piroxicam, sulfasalazine, and so on [46] . The diverse pharmacological activity of S VI in organic molecules makes it a first choice for incorporation by the hybrid approach, which is present in most of the required medicines that are accessible in the market [47] .

Heterocyclic compounds play essential roles in life and biochemical processes [48] . Among them, a huge number of novel sulfonamide derivatives have been reported and tested for both in vivo and in vitro antitumor activities. Some of these highly potent analogues are tested in clinical trials. Hopefully, these may lead to new alternative anticancer drugs avoiding the side effects of the available pharmacological agents [49] . Sulfur (S VI )-containing drugs are still widely used for circumstances of spots and urinary tract infections, and are receiving more renewed interest for the treatment of infections caused by bacterial resistance of other antibiotics [50, 51] . The excellent biological profile, hydrolytic stability and crystalline nature of sulfonamides have grabbed significant attention from synthetic chemists [52, 53] . These sulfonamide analogues can be traced in a number of well established potential drugs belonging to various types of therapeutic agents. Some of the representative sulfonamides or sulfonyl functional group containing FDA approved drugs are listed in Table 1 .

In search of more new potent multi-targeted sulfonamide or sulfonyl drugs, many medicinal chemistry scholars focused on sulfonamide nucleus, which has importance in the area of medicinal chemistry, drug development as a core substituent of diverse biological agents [54] . In order to overcome the resistance and to reduce the adverse effects, continuous efforts are made to synthesize novel multi-targeted bioactive sulfonamide analogues. In this regard, combinations of certain sulfonamides and other drug molecules are being used to develop novel formulations with greater effectiveness as well as less toxicity [55] .

This present comprehensive review aims to recapitulate the recent biological applications made towards the discovery of novel sulfonyl or sulfonamides functional group containing analogues as potential therapeutic agents and the critical aspects of design and structure-activity relationship (SAR) studies were also briefly explained.

The problem of antibiotic resistance among pathogenic bacteria is as old as antibiotics itself [56] . The antibiotic resistance which was accelerated by the use and misuse of antimicrobial drugs has been a major global challenge for public health. Dramatic increase of human pathogenic bacteria was observed from the past decades due to their resistance to one or more antibiotics. A number of infections caused by resistant organisms fail at responding to the conventional treatment and in few cases, the last resort antibiotics have also lost their power [57] .

In search of some new antibiotics, the sulfonamide functional groups have been fundamental motifs in medicinal chemistry since the early discovery of sulphonamide containing antibacterial drugs [1] . To date, a number of sulfonyl or sulfonamide bearing aromatic heterocycles such as quinazolinones, oxazoles, benzimidazole, thiazole and pyridazine have been successfully developed and employed in clinics with the presence of sulfadiazine, sulfachlorpyridazine, sulfathiazole and sulfisoxazole exhibiting excellent antimicrobial activities [58] . Because of the weak effectiveness and even loss of resistance power of old antibiotics against new and upcoming bacterial pathogens, urgent alternatives were needed to develope novel, less toxic and highly effective antimicrobial agents with distinct structures to fight with emerging antibiotic-resistant bacterial infections. In the first part of this review article, we have focused on sulfonamide analogues as a core substituent of antibacterial agents for drug development. In this regard, the combinations of sulfonamides and other heterocyclic drug molecules are being used to develop novel antibiotic drugs [54] . Some of the sulfonyl or sulfonamides containing heterocycles as potential antimicrobial agents are summarized in Fig. 1 .

Zhou et al. designed and synthesized a novel series of benzimidazole-derived sulfonamide analogues and evaluated for in vitro antimicrobial activities against different microbial pathogens. Compound 107 (Fig. 2) showed excellent antibacterial activity against S. aureus with MIC values of 4 mg/mL. The replacement of 4fluorobenzyl group (107) by 2,4-dichlorobenzyl group, 108 (Fig. 2) showed good antibacterial activity against B. typhi with MIC values 4 mg/mL. Compound 108 showed eight folds higher activity (MIC ¼ 4 mg/mL) than standard Chloromycin against B. typhi [59] .

The above same research group further developed a class of new type of sulphonamide-containing azoles analogues as potential antimicrobial agents. Compound 109 (Fig. 2) showed excellent antibacterial activity against P. aeruginosa with MIC value of 16 mg/ mL [60] . Kamble et al. have reported pyrazole derived sulfonamide analogues as good antibacterial agents. Compound 110 (Fig. 2) showed potent antibacterial activity against tested bacterial strains S. aureus and S. typhimurium with MIC value of 10 mg/mL each.

Compound 111 (Fig. 2 ) showed excellent antibacterial activity against different bacterial pathogens namely B. subtillis and E. coli with MIC value of 10 mg/mL each. To elucidate the structure activity relationship (SAR) of compounds 110 and 111, the presence of electron withdrawing (Br and CF 3 ) groups (EWG) on the sulfonyl attached phenyl ring, increases the bacterial resistance against the tested S. aureus and S. typhimurium strains. But the same moiety with replacement of the -Br functional group, and the inserting of the Cl functional group, compound 111 was found to be highly active against another bacterial strains B. subtillis and E. coli. The lipophilicity as well as nature and position of the substituent present on benzene ring of sulfonamide end affected the antimicrobial activity [61] . In 2014, Nasr et al. developed a new type of (continued on next page) sulfonamide containing sulfisoxazole analogues and evaluated for antibacterial activity. Compound 112 (Fig. 2) showed promising antibacterial activities against most of the tested bacterial strains. Compound 113 (Fig. 2) showed excellent antibacterial activity against the S. epidermidis, P. vulgaris and K. pneumonia bacterial strains. The analysis of the SAR, revealed that the presence of sulfonamide group with heterocyclic moiety increases the lipophilic characters of the synthesized compounds [62] . The research group of Padmaja [63] synthesized heterocycles containing sulfonamides analogues and evaluated for in vitro antimicrobial activities against various microbial pathogens using agar disc diffusion method. Among all the synthesized analogues, isoxazole containing sulfone analog 114 (S. aureus -32 mm, B. subtilis -31 mm, K. pneumoniae-26 mm, P. vulgaris -28 mm in diameter) (Fig. 3 ) was found to exhibit the highest inhibitory activity against tested bacterial strains. The presence of EWG (Cl) on phenyl ring of the sulfonyl end and sulfone group infatuated stronger antimicrobial activities compared to the other EDGs. In the continuation of the potent antimicrobial drug developments of sulfone containing heterocyclic derivatives, Lavanya et al. [64] reported 1,4-phenylene) bis (arylsulfonylisoxazoles analogues to have potent antimicrobial properties. Compound 115 (Fig. 3 ) was found to have the highest antibacterial activity against B. subtilis with zone of inhibition of 38 mm at 100 mg/mL. The elucidating of the SAR indicated that the presence of EWG (Cl) on the phenyl ring of the sulfone end showed maximum antibacterial activity against B. subtilis strain. In another study, a 2-ureidothiophene-3carboxylic acid derivative was synthesized and screened as dual bacterial RNAP and HIV-1 RT inhibitors by Elgaher et al. [65] . Compound 116 (Fig. 3 ) displayed more potency against tested S. aureus with high cellular antiretroviral activity. This is probably due to the presence of non-bulky hydrophilic substituents at the ureido side chain for RT inhibition, the hydrophilic and hydrogen bond donor or acceptor substituents at the N-phenyl group are also to improve the inhibitory activity more than 2e3-fold compared with electron-withdrawing groups (EWGs). Novel N-sulfonaminoethyloxime derivatives of dehydroabietic acid were developed by Zhang et al. [68] and tested for antibacterial activity against various bacterial pathogens. Among those, compound 119 (Fig. 4) exhibited the superior activity against tested five multidrug-resistances of S. aureus with MIC values between 0.78 and 1.56 mg/mL. The meta-CF 3 phenyl derivative 119 showed the highest activity with MIC of 0.39e0.78 mg/mL against S. aureus Newman. To elucidate the SAR, they demonstrated that the introduce of an electron withdrawing trifluoromethyl group (-CF 3 ) at meta position on the phenyl ring is more beneficial for the increasing antibacterial activity and selectivity compared to other substituents such as chloro, bromo, fluoro, methyl or methoxy groups. Very interestingly, the ortho substituted CF 3 derivative exhibited no in vitro activity against any of the Gram-positive bacterial strains at 50 mg/mL. The tert-butyl and methoxy functional group containing analogues showed decreased antibacterial activity. In addition, the substitution position appeared to have slight influence on the antibacterial activity of electron withdrawing functional group substituted derivatives. Nimbarte and coworkers [69] developed novel sulfonamide linked piperidine and pyrazole analogues and evaluated for the inhibition of soluble epoxide hydrolysis. Compounds 120 and 121 (Fig. 4) showed the highest inhibitory activity against tested bacterial strains with IC 50 values of 0.220 mM and 0.224 mM, respectively. Zengin and coworkers found a new class of sulfanilamide as potent antimicrobial agents against tested bacterial and fungal strains. Compound 122 (Fig. 4 ) was found to have the highest antimicrobial activities against B. cereus (MIC value is 33 mm) and E. fecalis (MIC value is 33 mm). The SAR studies revealed that the lipophilicity of the analogues played a crucial role for producing antimicrobial activities. The dimethyl substituted compound 122 had high antimicrobial activity but low lipophilic character [70] . Series of sulfonamide containing benzothiazole hybrids were evaluated for in vitro antimicrobial properties against some microbial pathogens. Compounds 123 and 124 (Fig. 4) and were found to have higher antimicrobial activities compared to the reference Sulfamethoxazole-trimethoprim mixture. The SAR studies revealed that the presence of sulfonamides with an amino group (-NH 2 ) and nitro group (-NO 2 ) at the para position of the phenyl ring showed excellent antimicrobial properties. The replacement of the amino group with nitro group led to the decrease of the antibacterial activity [71] . In continuous study of sulphonamide containing benzothiazole analogues as powerful antimicrobial properties, a new class of sulphonamide containing benzothiazole hybrids were synthesized and screened for antimicrobial activity by Patel et al. presence of sulfonamide group at para position of the phenyl group has highly increases the antibacterial properties of all the tested bacterial pathogens. Furthermore, the presence of EWG (Cl) group on the phenyl ring also contributes to increasing the antibacterial activity [74] .

Diabetes is one of the most severe diseases rising in the world. According to the estimation data obtained in 2010, around 285 millions of people are suffering from diabetes all over the world and it may increase to 439 million by 2030 [75, 76] . Change in the blood glucose due to the insulin resistance is observed as the characteristic of being diabetic in 95% of the cases [77] which give raise to several more problems like high blood pressure, heart problem, kidney failure, stroke and blindness [78] . Therefore, it is highly demanded to develop additional electronic and steric requirements of arylsulfonamidothiazoles with antidiabetic effect [79] . Fig. 5 showed some representative sulfonyl of sulfonamides as potent anti-diabetic agents.

In 2014, Navarrete-V azquez and co-workers designed and developed naphthalene containing sulfonamides as potent antidiabetic agents against 11b-hydroxysteroid dehydrogenase type-1 (11b-HSD1). Among them, compounds 136, 137 and 138 (Fig. 6) showed promising anti-diabetic activity against 11b-hydroxysteroid dehydrogenase type-1 with % inhibition of 68, 67 and 55 at 10 mM respectively better than the standard drug BVT.14225 (55% inhibition). The SAR studies suggested that both piperidine and pyrrolidine core attached at the amide group were more active compounds to the tested all hybrids [80] . A novel class of thiazolidinedione based sulfonamide hybrids were evaluated for antidiabetic activity against the Peroxisome Proliferator Activated Receptor (PPARg) by Naim et al. [81] . Among these, compound 139 ( Fig. 6 ) was found to be excellent PPAR-g inhibitor of 61.2% with 1.9 folds increase in gene expression. In docking studies, compound 139 displayed good interaction with amino acids Tyr 473, Ser 289, Hie 449, Tyr 327, Arg 288, Met 329 and Leu 228 (Fig. 7) . This observation indicates that the presence of hydrophobic moiety in 139 is surrounded by hydrophobic amino acids. It is believed that such hydrophobic interactions enhances the ligand receptor complex as well as binding affinity of ligand towards PPARg.

Rathish et al. reported the synthesis and anti-diabetic activity of sulfonamide based pyridazinone derivatives. Compounds 140 and 141 (Fig. 8) showed excellent anti-diabetic agents with more than 50% reduction in the rise of blood glucose levels. The SAR may be summarized as the introduction of electron withdrawing Cl at para position of phenyl group caused slightly reduction in the activity. On the other hand, the presence of electron releasing functional groups such as methoxy or methyl functional group at phenyl ring slightly caused reduction in the activity. Moreover, the compounds containing less bulky side chains were found to be more favourable for increasing anti-diabetic activity [82] . The effect of in vivo antidiabetic activity in non-insulin dependent diabetes mellitus rat of sulfonamide end enhanced the anti-diabetic properties [84] . Recently, how to improve the drug resistance of potent antidiabetic drugs against PTP-1B, has emerged as a key role of insulin signalling target for type 2-diabetes. In 2018, Du and co-workers reported novel PTP-IB inhibitors of a series of ureodo-sulfonamides based analogues. Among these, compounds 146 and 147 (Fig. 8) showed superior PTP1B inhibitors with IC 50 values of 18.6 nM and 66.2 nM respectively. The SAR suggested that, compound 146 with 2-ethoxy group on B ring was identified to possess 10.9 fold more potent inhibitory activity against the PTP1B enzyme. Compound 147, with the presence of -CONH-(3,4-di-MeO-Ph) group on ring B displayed high potent activity [85] .

A series of piperazine-sulfonamide analogues were studied for in vitro a-amylase inhibition activity by Nawaz et al. [86] . Com- stronger cryptochrome modulator with EC 50 ¼ 0.144 mM. The SAR suggested that, the presence of sulfonamides functional group improved lipophilic efficiency of the potent analog [88] . Recently, Deka and co-workers have prepared a new series of thiazolidinediones hybrids and screened for potent peroxisome proliferatoractivated receptor g (PPARg). Among all the synthesized analogues, compounds 154 and 155 ( Fig. 9 ) showed maximum PPARg binding affinities (I max ) with 98% and 82% respectively. The SAR revealed that, the introduction of diverse aryl sulfonamides as the polar head group and 1-phenylpiperidine on the tail part highly influenced the PPARg activity. In addition, the presence of electron withdrawing Cl and eCF 3 groups on the phenyl ring of the sulfonamide linker also played a major role for the increases of activity. The presence of electron releasing (OH and eOCH 3 ) groups decreased the activity [89] . In 2017, Bruning and co-workers designed and synthesized a class of novel 2,4-dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy) phenyl)benzenesulfonamide analogues for potent PPARg-targeted antidiabetics agents. Compound 156 (Fig. 10) showed the most potent active PPARg inhibitor with EC 50 values is 2 nM. The SAR revealed that, the presence of EWGs (F and Br) on phenyl ring A increased the activity. The sulfonamide moiety and a bromine atom at the para position on the aromatic benzene ring A contributed the potent active PPARg inhibitor [90] . Gao and co-workers synthesized a novel series of sulfonamide-1,3,5-triazine-thiazoles derivatives and tested for in vitro inhibitory activity against several DPP enzymes, such as DPP-4, DPP-8 and DPP-9. Compound 157 ( Fig. 10 ) was found to be highly potent against DPP-4 enzyme with IC 50 value of 2.32 nM compared to standard drug alogliptin. The SAR suggested that, compounds containing EWGs had superior inhibitory activity compared to those with EDGs substituent. Furthermore, the presence of additional aromaticity did not influence the activity. Moreover, molecular docking results indicated that, ligand 157 was efficiently docked into the active site of the catalytic triad of Ser 630, Asp 708 and His 740 encompassing both S1 and S2 pocket with CDOCKER interaction energy of 57.80 [91] . At last, Iqbal and co-workers have developed arylsulfonylspiroimidazolidine-2,4-dione hybrids as potent hypoglycemic and ALR2 agents. Compound 158 ( Fig. 10 ) was found to have the most potent inhibitory activity against ALR2 with an IC 50 value of 0.89 mM. The in vivo hypoglycaemic activity of compound 158 exhibited 72.24% reduction in blood glucose, which was more potent than standard drug glibenclamide (60.92% reduction). The SAR suggested that, the presence of EWG (Cl) on the phenyl ring highly influenced the ALR2 activity. Replacing the halogen atom by methyl or methoxy group led to a reduced activity which was attributable to the lower lipophilicity of these substituents compared to the chlorine atom, and lesser interaction with the active site of aldose reductase. Activity was not really affected when the 2-naphthyl group replaced the para substituted phenyl ring; however, 2-anthraquinyl group was found to be detrimental to the activity. The large size of the 2anthraquinyl group might be responsible for this negative effect [92] .

Inflammation is a localised physical condition causing swellness, redness, heat with pain which is mediated by the release of proinflammatory mediators like bradykinin and cytosine increasing the prostaglandin synthesis rate [93, 94] . Nonsteroidal anti-inflammatory drugs (NSAIDs) existing in two isomeric forms, constitutive form (COX-1) and an inducible form (COX-2) inhibits cyclooxygenases (COX) and thereby inhibiting the biosynthesis of prostaglandins (PGs) [95, 96] . The role of COX-1 enzyme is maintaining the gastric integrity and kidney functioning whereas COX-2 is involved in inflammation and pain [97, 98] .

The sulfonamide moiety exists as one of the most ubiquitous pharmacophoric functional groups in medicinal chemistry. Sulfonamide group shows a diverse pharmacological activity in the organic molecules and hence it has become a priority while choosing functional group to incorporate in the optimizations by hybrid approach. It was reported earlier that a number of sulfonyl or sulphonamide functional group containing heterocyclic compounds were utilised to demonstrate potential anti-inflammatory activity [99e103]. Moreover, among the highly marketed COX-2 inhibitors that comprise the sulphonamide moiety, SC-558 (165) and celecoxib (166) (Fig. 11 ) are the major determinant for COX-2 selectivity and in vivo efficacy. Nimesulide (167) (Fig. 11) is an example of small molecule NSAID S sold in the market today that has the sulfonamide functionality [104, 105] . Some of them were potential anti-inflammatory analogues as showed in Fig. 11 .

A class of novel sulfonamides as potent anti-inflammatory agents were designed and synthesized bearing pyrazolyl derivatives by Bekhit et al. [106] . The para-chlorophenyl substituted compound 170 (Fig. 12 ) emerged as a potent anti-inflammatory agent with protection 77.4% exceeding that of indomethacin. Chowdhury and co-workers reported a family of pyrazole bearing sulfonamides analogues and evaluated for in vitro antiinflammatory activity. Compound 171 (Fig. 12 ) displayed attractive anti-inflammatory activity compared to the standard antiinflammatory drugs celecoxib and aspirin. SAR studies revealed that the presence of N-methyl-1,2,3,6-tetrahydropyridyl ring significantly increased the bioisosteric effects in the active analogues [107] . Next, the research group of El-Din et al. developed sulfonamides based hybrids with potent anti-inflammatory activity [108] . Compound 172 (Fig. 12 ) was found to be most significant candidate, no ulcerogenic effect and with minimal effects on renal function. Novel pyrazole based sulfonamides derivatives were prepared by Küçükgüzel and co-workers and screened for their in vitro anti-inflammatory activity. Among those, compound 173 ( Fig. 12) showed promising anti-inflammatory activity [109] . (IC 50 ¼ 0.22 mmoL/kg) (Fig. 12) showed excellent antiinflammatory activity (82% inhibition) and promising analgesic activity. The SAR suggested that, compounds containing 4chlorophenyl pharmacophore exhibited higher activity than other functional substituted analogues (except for benzenesulfonamide azomethine). The effect of the nature of substituent at the 3position of the pyrazole nucleus also played a major role in enhancing the anti-inflammatory activity [110] . Mohammed and Nissan reported novel pyrazole bearing sulphonamide-hydrazones derivatives as potent anti-inflammatory agents. Compound 175 (Fig. 13 ) was found to be a better antiinflammatory agent than the standard anti-inflammatory drug diclofenac and indomethacine. In addition, molecular docking study revealed that the compound 175 interacted with Tyr 385 and Ser 530 [111] . Hassan et al. synthesized a series of benzofuran bearing celecoxib-sulfonamides for the development of novel anti-inflammatory agents. Among those, compound 176 and 177 (Fig. 13 ) exposed the highest anti-inflammatory activities. Antiinflammatory data revealed that an essential role of compounds 176 and 177 bearing pyridine moiety enhanced the antiinflammatory efficiency in animal models [112] . Ahmed and coworkers synthesized a new class of curcumin-containing sulfonamides analogues to investigate the activity against antiinflammatory. Compound 178 (Fig. 13 ) was identified as a successful anti-inflammatory agent by 82% inhibition of induced edema which is comparable to standard drug indomethacin (84.4% inhibition) [113] . In 2014, Kumar et al. reported an eighteen pyrazolylpyrazolines bearing benzenesulfonamide as potent antiinflammatory agents. Among those, compounds 179 and 180 (Fig. 13) showed excellent anti-inflammatory effects [114] . Compounds containing sulfonamides based heterocycles have been highlighted for the search of new anti-inflammatory agents. 

Malaria is a parasitic infection which is spread worldwide mostly affecting and causing serious problems in the tropical and subtropical parts of Asia, Central and South America, Africa and also millions of people are affected in the parts of Middle East [117, 118] . A parasitic species called Plasmodium which is carried by the female of Anopheles mosquito is the cause of this disease which enters into bloodstream of humans by an infected mosquito. The treatment and management of this disease is unreasonably high not only because of medication but also due to low production [119] . The difficulty in controlling malaria lies at growing resistance of malaria parasite to most of the antimalarial drugs used [120] .

Hence there is a strong need to treat this drug-resistant disease by developing better performing drugs. A continued effort including exploration of potentially bioactive natural product derived compounds is required. Most of the biologically active antimalarial agents contains sulphonamide group [121e123]. The sulfonamide group present in a number of potential anti-malarial analogues were showed in Results from the study indicated that alkyl chain length was critical for antimalarial activity and also the presence of isopropyl groups on the phenyl ring of the sulfonamide end highly enhanced the antimalarial activity [126] . Recently, Oliveira and co-workers reported the potent sulfonamide containing chaclcone hybrids and evaluated for in vitro anti-malarial activity against P. falciparum.

Compound 200 (IC 50 ¼ 2.06 mM) (Fig. 16 ) was found to be the best antimalarial agent with good selectivity index [127] . Muthas and co-workers reported a class of new potent hydroxyethypiperazines bearing benzenesulfonyl hybrids as antimalarial agents. All the synthesized compounds were tested in vitro antimalarial activity against a W2 P. falciparum clone. Among those, compound 201 (IC 50 of 16.9 mM, Fig. 16 ) displayed superior antimalarial activity with IC 50 values of 4.80 mM against W2 P. falciparum clone [128] .

Recently, the combination of indoleamides with sulfonyl has been reported as the most active antimalarial agents against Pf3D7 and PfK1 strains. Among those, compounds 202, 203, 204 and 205 ( Fig. 17) respectively. SAR revealed that the presence of sulfonyl analogues containing bulky groups such as p-ter-butylphenyl (202 and 204) and 4-chloro-2,5-dimethyl phenyl groups (203 and 205) showed the most promising antiplasmodial activity with IC 50 values range between 1.60 and 2.19 mM [129] . Huang and co-workers reported sulphonamide bearing small analogues as potent dual inhibitors of FP-2 and DHFR. Compounds 206 and 207 (Fig. 17) bearing amide and sulphonamide moieties were found to be the most active FP-2 inhibitors. Compound 207 containing thiazole group on amide moiety was most active analogues against FP-2 (IC 50 ¼ 7.0 mM) and DHFR (IC 50 ¼ 6.3 mM). In addition, compound 207 showed reasonable in vivo antimalarial activities compared to standard drug chloroquine diphosphate salt. SAR suggested that the presence of amide, sulphonamide and thiazole groups played a crucial role for enhancing the antimalarial activity [130] . Caridha and co-workers reported potent thiophene and benzene sulfonamides as antimalarial agents. Among these, bromohydrosulfonylacetamides 208 (Fig. 17 ) was found to be promising growth inhibition of drug resistant P. falciparum W2 strain as well as low toxicity profiles against mammalian cell lines. Further exploration of 208 with variation in the thiophene and benzene ring substitutions may produce more potent PfCDK inhibitors [131] . Cunico and coworkers have developed hydroxyethylpiperazine analogues and evaluated in vitro anti-malarial agents against a W2 Plasmodium falciparum clone. Compound 209 was found to be the most potent anti-malarial agent with IC 50 value of 4.8 mM against W2 Plasmodium falciparum clone almost as active as standard lopinavir. The SAR revealed that the presence of amine group on the phenyl ring influenced the anti-malarial activity. In addition, the presence of piperazine moiety was also an essential for increases the activity. The sulfonamide functional groups were bridged between the two bioactive analogues [132] . (Ab) deposits, oxidative stress, dyshomeostasis of biometals, tauprotein aggregation are considered to be such pathophysiological factors [136e138] . Unfortunately the medicines for the cure of AD and its progression are not discovered yet. But certain medicines are approved and prescribed for the AD patients for the temporary relief [139, 140] . In this part of the review article, sulfonamide nucleus is focused as a core substituent of Alzheimers agents for the development of drug [141e144]. Some of the sulfonyl or sulfonamides containing heterocycles represented as potential Alzheimer's agents are summarized in Fig. 18 . Mutahir and co-workers performed novel biphenyl bissulfonamide derivatives as potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) agents. Among the tested compounds, compound 217 (Fig. 19 ) was found to be the most potent activity against AChE (IC 50 2.27 ± 0.01 mM), whereas 218 ( Fig. 19 ) exhibited the highest inhibition for BChE (IC 50 7.74 ± 0.07 mM). SAR studies revealed that both the 3,30dimethylbiphenyl functionality as well as benzyl moiety on nitrogens played a crucial role for the higher activity of compound 217. The higher activity of 218, bearing n-hexadecanyl moiety on nitrogens, is a similar trend as the case in AChE inhibition which could be attributed to the hydrophobic bulkiness of the n-hexadecanyl group. In addition, molecular docking studies were also performed for the analysis of the binding mode and hydrogen bonding interactions of compound 217 in both cholinesterases enzymes. Ligand binding within the active site of AChE was limited to hydrophobic interactions with Tyr334, Phe331, and Phe330 from anionic sub-site, Tyr70 from acyl pocket as well as Tyr121, Trp279, Asp276 and Phe228 from peripheral anionic site. Biphenyl fragment was engaged in more specific pep and CHep interactions with Tyr334. The arrangement of the most active compound 217 in the active gorge of AChE is shown in Fig. 20 . Ligand binding within the active site of AChE was limited to hydrophobic interactions with Trp84, Phe330, and Phe331 from anionic sub-site, Phe290 from acyl pocket as well as Tyr121, Trp279 and Tyr334 from peripheral anionic site (PAS). Biphenyl fragment was engaged in more specific pep and CH-p interactions with Trp279, Phe331 and Tyr334. Oxygen atoms in sulfonamide groups might create weak H-bonds with hydroxyl group of Tyr70 or unionized form of Asp72. The arrangement of the most active compound 217 in the active gorge of AChE is shown in Fig. 21 . And similar results were observed in case of docking to the active site of BChE. The binding of the tested compound 217 with AChE and BChE was mainly provided due to the presence of hydrophobic interactions. Summing up, it can be assumed that the binding of the tested compounds with AChE and BChE was mainly provided due to the presence of hydrophobic interactions. However, the obtained compounds are interesting starting point for their further development and synthesis of potent cholinesterase inhibitors. Structural modifications leading to increase of number of hydrogen bond donors and acceptors should augment the strength and specificity of binding to enzymes [145] . Yar et al. reported the novel potent pyridine 2,4,6tricarbohydrazide analogues as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) agents. Compound 219 (Fig. 19 ) exhibited the most potent activity against tested enzymes such as AChE (IC 50 50.2 mM) and BChE (IC 50 43.8 mM). Overall the compound 219 bearing phenyl group was found to be active against all these tested enzymes [146] . On the other hand, Ulus et al. described acridine-sulfonamide hybrids as potent acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. Compound 220 (Fig. 19 ) displayed superior activity against AChE with an IC 50 of 0.14 mM [147] . Later, the same research group (Ulus et al.) continued the development of new type of alzheimer's agents in which, sulfonamid bearing tacrine derivatives were synthesized and evaluated for in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. Compound 221 (Fig. 19 ) was found to have the highest inhibitory activity on AChE with IC 50 value of 0.009 mM. This value is 220-fold higher than that of galantamine (IC 50 ¼ 2.054 mM). Compound 222 (Fig. 19 ) displayed the strongest inhibition of BuChE with IC 50 value of 2.250 mM. To elucidate SAR, sulfonamide group present on the para position at the phenyl ring showed good acetylcholinesterase activity (AChE that the presence of electron releasing moiety was crucial for the higher activity of 223 and EWGs inactive against the AChE and BChE enzymes. At the next level of investigation, the authors also performed the molecular docking analysis of potent compound 223 for detailed exploration of its binding pattern within the active sites of AChE and BChE. In addition, docking technique is considered efficient in accurately predicting binding mode of small molecules. The most potent compound 223 was showed detailed exploration of its binding pattern (2D and 3D binding mode of interaction) within the active sites of AChE and BChE. Compound 223 had two hydrogenbond interactions with the peripheral anionic site residue Tyr279 upon binding to AChE (Fig. 22) . Additionally, the docked complex of BChE with 223 showed that the hydrophobic patch residue Tyr332 and the catalytic triad residue Gly116 were involved in intra molecular hydrogen bonding (Fig. 23) . The docking results showed that 223 were capable of establishing two hydrogen-bond interactions with the peripheral anionic site (PAS) residue Tyr121 upon binding to AChE (Fig. 24) . Additionally, the docked complex of BChE with 6j (BChE-6j) showed that the hydrophobic patch residue Tyr128 and the catalytic triad residue Ser198 were involved in intramolecular hydrogen bonding (Fig. 25) To elucidate the SAR, the presence of 3,4dihydroxy group in the B ring of the chalcone, produced more potent agent than the corresponding 4-hydroxy derivatives. Smaller electron donating groups (CH 3 , OH and NH 2 ) were more favoured than larger species such as OCH 3 and EWGs such as NO 2 [151] . Recently, Wieckowska et al. reported the sulfonamide based piperidine hybrids as potent 5-HT6 receptor antagonist with a cholinesterase inhibitor. Among these, compound 228 (Fig. 26 ) was found to be the most potent agent against the 5-HT6 receptor (K b ¼ 27 nM), AChE and BuChE (hAChE: IC 50 ¼ 12 nM, hBuChE: IC 50 ¼ 29 nM). In a further drug development program, a novel class of multi-functional ligands were evaluated, in which compound 229 (Fig. 26 ) the best derivative from the series, represented an excellent starting point for the development of an effective treatment for AD [152] .

Disseminated leishmaniasis has become an emerging infectious disease, mostly due to Leishmania braziliensis. L. braziliensis has caused both cutaneous and mucocutaneous leishmaniasis in several Latin American countries [153] . Presently this parasitic disease causes morbidity and mortality, mainly in the developing world [154] . Toxicity, high costs and development of drug resistance have become obstacles in the prevailing chemotherapic treatment [155] . Sodium stibogluconate (Pentostam ® ) and meglumine antimoniate (Glucantime ® ), the two pentavalent antimonial [Sb(V)] compounds, were first introduced in the 1940s and are being used for all forms of leishmaniasis through parenteral administration [156] . Therefore, drugs that are safe, inexpensive and easily available need to be developed immediately. Lead compounds are also now having taken important roles for the future treatment of this disease globally.

Sulfonamides, according to literature have shown versatile antileishmanial activity and have become a structural core in leishmanicidal therapy [157e160]. The sulfonamide group act as a chemical link that allows binding of other potential "active components" such as aromatic and heteroaromatic systems along with the demonstration of antiparasitic activity [161e163].

Marra et al. conducted a study aimed at the preparation and evaluation of potent novel 4-(1H-pyrazol-1-yl)benzenesulfonamide hybrids against the L. infantum and L. amazonensis strains. Compounds 230

(IC 50 ¼ 0.059 mM against L. infantum, IC 50 ¼ 0.070 mM against L. amazonensis) and 231 (IC 50 ¼ 0.065 mM against L. infantum, IC 50 ¼ 0.072 mM against L. amazonensis) (Fig. 27) showed most potent activity against the tested L. infantum and L. amazonensis strains. In this case, both compounds 230 and 231 pyrazole baring sulfonamide groups were active for treating infections caused by these two Leishmania strains [164] . Borges and co-workers reported a new class of pyrazolyl benzenesulfonamide hybrids as potent antileishmanially active candidates against Leishmania amazonensis. Among these, compound 232 (IC 50 value is 6.7 mM) (Fig. 27 ) was found to have the most potent activity against Leishmania amazonensis with IC 50 value higher than reference drug ketoconazole [165] . Gonz alez-Rosende et al. developed a new series of naphthalene-sulfonamide analogues as potent antileishmanial and trypanocidal inhibitors. Compound 233 (Fig. 27 ) displayed most potent inhibition on three Leishmania species entitled L. infantum (IC 50 ¼ 23.0 mM), L. amazonensis (IC 50 ¼ 42.9 mM) and T. cruzi (IC 50 ¼ 223.7 mM). In addition, compound 233 was found to be an excellent anti-T. cruzi candidate, and further clinical investigation could be useful in the development of new antichagasic drugs [166] . The group of Palop reported diselenide containing sulfonamide derivatives, which exhibited in vitro leishmanicidal activities against Leishmania infantum intracellular amastigotes and THP-1 cells. Compound 234 (Fig. 27) emerged as the most active compound (IC 50 ¼ 2.8 mM), showing higher activity and much less toxicity against THP-1 cells than reference drug edelfosine. SAR studies, no clear-cut relationship was found but, mutually these results suggested that the sulfonamide scaffold could be a valuable linker for the connection of parent diselenide and para-fluoro phenyl ring attaching both sulfonamide ends [167] . In addition, Rodrigues et al. designed and developed chalcone-sulfonamised analogues as potent antileishmanial agents. Compound 235 (Fig. 27 ) was found to be the best profile against L. braziliensis promastigotes with IC 50 value of 3.5 mM. Moreover, the presence of benzylamino group extensively contributed to this activity. These results revealed the sulfonamide based methoxychalcone hybrids as lead compounds for designing new candidates for leishmaniasis treatment [168] . 

Tuberculosis is a highly infectious chronic deadly disease caused by a bacteria called Mycobacterium tuberculosis (MTB). This disease is a threat to the human life affecting lungs primarily (pulmonary TB) apart from other vital organs. Drug-resistant TB (DR-TB), multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and totally drug resistant TB (TDR) are emerging now a day's which are completely resistant for the action of presently available standard drugs [169] . The infection of TB is so high that it has caused deaths of around 1.4 million and 10.4 million clinical cases all over globe as reported in 2015 [170, 171] . However the treatment of TB with the drugs such as Isoniazid (INH), Ethambutol (EMB0), Rifampicin (RIF) and Pyrazinamide (PZA) is observed to be highly effective for TB. Discovery of Rifampicin (RIF) have helped in obtaining handful of Anti-TB drug compounds to the humans. However, still a number of derivatives are to be explored to stop the activity of bacteria and further spreading of TB. Fig. 28 showed some of the sulfonyl or sulfonamides containing heterocycles as potential TB agents.

Shahul and co-workers reported aminoperidines with benzimidazole derivatives as potent anti-TB agents against Mtb and Mtb DNA gyrase. Compound 241 (Fig. 29) to be further exploited [175] . Several sulfonyl-hydrazones were also tested for in vitro anti-TB agents against Mycobacterium tuberculosis-PtpB. Among all the synthesized molecules, compounds 247 (IC 50 ¼ 18 mM), 248 (IC 50 ¼ 21 mM), 249 (IC 50 ¼ 39 mM) and 250 (IC 50 ¼ 41 mM) (Fig. 24) showed the most potent PtpB inhibitors.

The SAR suggested that the presence of EWGs (Cl, F and NO 2 ) on the phenyl ring of sulfonamide end enhanced the anti-TB properties [176] . As the continuous search of new type of potent anti-TB agents, Reddy and co-workers designed and developed new sulfonamide based indole hybrids as potent anti-TB agents. Compound (Fig. 29 ) was found to be the best inhibitor against MtbCM. The SAR showed that the indole containing an o-(RSO 2 NH) C 6 H 4 group at C-2 position and a sulfonamide moiety played a key role during its interaction with the active site of CM [179] . At last, novel 4-aryl/alkylsulfonylmethylcoumarins hybrids were synthesized and screened for in vitro anti-mycobacterial activity against MTBH 37 Rv. Among these, compound 254 (Fig. 29) showed excellent anti-TB activity with MIC value of 0.78 mg/mL, eight fold more potent than EMB (MIC: 1.56 mg/mL) and PZA (MIC: 6.25 mg/mL) [180] .

Viruses are infectious agents affecting the life forms. They are responsible for causing various dangerous diseases like human immunodeficiency virus (HIV), hepatitis B and C viruses (HBV and HCV, respectively), severe acute respiratory syndrome (SARS), corona viruses (Middle east respiratory Syndrome, MERS); influenza (seasonal, pandemic), viral haemorrhagic fevers (Ebola), dengue, and chikungunya etc. These diseases have caused adverse impact on human health leading to unexpected illnesses and deaths, troubling day-to-day normal life activities. Viruses are the major cause for the emergence of newer pandemics e.g. H1N1 influenza, Ebola, and Zika virus etc. threatening the public health [181, 182] .

On the same hand, more than 60 antiviral drugs of diverse chemical classes have been approved by the FDA, mainly for the management of HIV, the hepatitis B and C, herpes and influenza A and B viruses and still many molecules are in various stages of clinical trials. But there is still a pressing need for the development of new drugs acting through several mechanisms and combat the viral resistance as viruses are constantly evolving [183] . However it is always challenging for the medicinal chemists to develop newer drugs understanding unique biological features of viruses and treat the emerging viral disease in one or the other way without harming the host cells [184] . Fig. 30 showed some of the sulfonyl or sulfonamides potent anti-viral agents.

In recent years, various sulphonamide based isoxazolidines hybrids were synthesized and evaluated for in vitro HIV- (Fig. 31 ) was found to be the most potent activity against the single mutants Y181C and Y188L with EC 50 ¼ 0.428 and 0.675 mM, respectively, more potent than reference drug AZT. These results are expected to be helpful in the design of thiophenepyrimidine-based NNRTIs with more potent activity against HIV strains with RT mutations [188] . Zhang et al. explored pyridine-sulfonamides as potent Hepatitis C (HCV) NS4B inhibitor. Compound 267 (Fig. 31) has showed outstanding potency against the HCV 1b replicon, with an EC 50 ¼ 2 nM and a selectivity index of >5000 with respect to cellular GAPDH. The overall profile of compound 267 makes it a good aspirant for future drug development program [189] .

Several thiadiazole bearing sulfonamides analogues have also demonstrated promising antiviral activity against tobacco mosaic virus by the half leaf method explored by Yang et al. Compounds 268 (42%) and 269 (42%) (Fig. 32) showed promising TMV inhibition compared to the reference drug Ningnanmycin (54%). The SAR, structural modification in the sulfonamide moiety has a wide impact on anti-viral activity of the compounds [190] . Hu et al. developed and prepared a new class of chalcone-containing purines and benzenesulfonamide hybrids and tested for antiviral properties against TMV and CMV. Compound 270 (Fig. 32 ) was found to possess outstanding activity against TMV with the EC 50 value of 51.65 mg/mL, which was better than that of ribavirin (150.45 mg/mL). The SAR analysis showed that introducing EDGs at the 2-position of benzenesulfonamide aromatic rings and low steric hindrance group promoted antiviral properties. These findings indicated that chalcone derivatives were worthy of further research and development as templates for new antiviral agents [191] . Compound 271 (Fig. 32 ) was found to have potent (Ki ¼ 0.8 nM, IC 50 ¼ 1.5 mM) antiviral activity. Oral bioavailability of this compound ranged from 42% (rat) to 77% (dog) with t 1/2 ¼ 6 h [192, 193] . Saturation of the 5,6-double bond in the pyrone ring led to the identification of a compound 272 (Fig. 32) with excellent binding affinity for the HIV protease (Ki values in the 0.05 nM) and excellent antiviral activity in cell culture, with significantly less ED 50 value of 0.95 mM [194] . At last, the continuation of finding new class of potent coumarin-benzimidazole hybrids as potent anti-HCV activity by Hwu et al. Among these, compounds 273 (EC 50 ¼ 10.2 mM) and 274 (EC 50 ¼ 13 mM) (Fig. 32 ) displayed excellent antiviral activity against chikungunya virus (CHIKV). The SAR revealed that the extension of the doubly conjugated uracilecoumarins to triply conjugated uracilecoumarinearenes by use of the -SO 2 linker was fundamental to their anti-CHIKV activity. Bezouracil derivatives 273 (Fig. 32) had better selectivity indexes compared to uracil 274 (Fig. 32) or thymine [195] .

Carbonic anhydrases (CAs) are a class of metalloenzymes containing zinc as the metal. The roles of these metalloenzymes are the interconversion of carbon dioxide and water to bicarbonate and proton maintaining the acid-base balance in tissues and blood. This enzyme is a multidomain protein containing CA subdomain situated outside the cell. It also possesses high CO 2 hydrase catalytic activity which is inhibited by CA inhibitors belonging to sulphonamide, sulfamate and sulfamide classes of compounds [199] . Today around 15 different human CAs are known which are widely distributed in different tissues involving in different physiological process such as cell differentiation and proliferation, pH homeostasis, neurotransmission and pathologies like diuretics, epilepsy, glaucoma, obesity and cancer [196e198] .

Sulfonamide is considered to be a significant moiety due to its diverse pharmacological activities [200] and these have clinical use as carbonic anhydrase inhibitors (CAIs) primarily as diuretics and anti-glaucoma agents. Heterocyclic ring or the aromatic ring containing sulfonamide moieties as zinc binding group as tail approach afford CAIs possessing both high affinity and desired pharmacologic properties and have been already explored in literature [201, 202] .

Very recently, a family of sulfonamide based heterocycles hybrids were designed and biologically evaluated as potent carbonic anhydrase activity against hCA 11 and hCA 1V by Nocentini et al. Compound 275 (Fig. 33 ) was found to have superior activity with IC 50 values of hCA 11 is 0.4 nM and hCA 1V is 20.5 nM. The SAR revealed that the presence of key functional elements such as pyrazole, isoxazole and sulfonamide functional moiety was beneficial for the enhancing carbonic anhydrase activity [203] . Khalifah and co-workers designed and developed potent iminothiazolidinone-sulfonamide hybrids and evaluated for their inhibitory effect against four relevant human (h) isoforms of carbonic anydrases (CAs, EC 4.2.1.1) I, II, IV and IX by a stopped-flow CO 2 hydrase assay [204] . Compounds 276 and 277 (Fig. 33) showed the most potent active against hCAII with IC 50 values of KIs of 0.41 and 0.46 nM which may be due to the presence of EWGs (Cl and NO 2 ) for highly influencing the strongest inhibitors of hCAII [205] .

In 2008, a series benzenesulfonamide linked 1,3,5-triazine hybrids were synthesized in good yield and tested for in vitro carbonic (Fig. 33 ) was found to be incorporated with amino, hydrazino, ethylamino, dimethylamino or amino acyl moieties, and showed promising CA activity but incorporation of bulky groups viz., n-propyl, n-butyl, diethylaminoethyl, piperazinylethyl, pyridoxal amine or phenoxy showed least CA activities against hCA I, II and IX inhibitors [206] . Supuran et al. reported sulfonamides linked triazine moieties (279e283) (Fig. 33) and tested for carbonic anhydrase transmembrane isoforms IX, XII and XIV over cytosolic isoforms I and II. The longer spacer compound (n ¼ 2) has shown more effectiveness as an inhibitor than the intermediate spacer (n ¼ 1), which in turn was more effective than the shorter spacer derivative (n ¼ 0). The short amino alcohol derivative 279 (Fig. 33 ) has also shown more effective than the bulkier compound 281 [207] . Mert et al. reported the new class of 5-amino-1,3,4-thiadiazole-2-sulfonamide containing pyrazole hybrids and tested for in vitro inhibitory activity against the isoforms of human cytosolic carbonic anhydrase I and II.

Compounds 284 (Fig. 33 ) for hCA I (K i ¼ 0.119 mM) and the compound 285 (Fig. 33 ) for hCA II (K i ¼ 0.084 mM) showed the highest inhibitory activity compared to the rest of the analogues [208] .

Cannabinoid receptors 1 and 2 (CB 1 and CB 2 , respectively) were considered to be the members of the G protein-coupled receptor (GPCR) superfamily in the early of 1990's [209, 210] . Cannabinoid-1 receptor (CB1R) being most abundant neuroregulatory receptors present in the brain, peripheral organs such as adipose tissues, muscle and liver [211] regulates feeding and appetite [212] . Whereas cannabinoid-2 receptor (CB2R) is mostly expressed in the immune system regulating immunity and neurodegeneration [213] .

Compound 286 (Fig. 34) was the best example of sulfonamide group claimed potent cannabinoid receptor agonist. In addition to this finding of new sulfonamides containing cannabinoid receptor drugs, scientists from AstraZeneca have also reported a potent sulphonamide based drug 287 (Fig. 34 ) acts as both CB 1 /CB 2 dual agonists for the administration of pain [214] . Very recently, Watson and co-workers from Pfizer have reported sulfonylbenzimidazole hybrids (288 and 289) (Fig. 34 ) as selective CB 2 agonists and as potential analgesic agents devoid of the side effects associated with CB 1 agonists [215] . In 2012, Verbist and co-workers identified sulfonylbenzimidazole analogue 290 (Fig. 34 ) as potent CB 2 -receptor agonists. The compound 290 was found to have no analgesic effect which was demonstrated in pain models. Furthermore, to improve the metabolic stability and solubility, the same group optimized the compound 290 and led to the discovery of relatively polar and peripherally acting CB 2 agonists of compounds 291 and 292 (Fig. 34 ) [216] . Greig et al. designed and produced a new class of indole sulfonamides as potent cannabinoid receptor. Compounds 293 and 294 (Fig. 34 ) displayed outstanding potencies of 4 and 3 nM respectively, and showed good oral exposure and CNS penetration, making them highly versatile tools for investigating the therapeutic potential of allosteric modulation of the cannabinoid system [217] . The presence of sulfonamides functionalities has proved to be an extremely potent agonists at the hCB 2 receptor, compound 295 (EC 50 ¼ 5.1 nM) and 296 (EC 50 ¼ 7.0 nM) (Fig. 34) being the most potent hCB 2 receptor agents. These results inspired further development of in vitro profiling of sulfonamides on the hCB 1 receptor and on rat liver microsomes (RLM) [218] . Chang et al. developed pyrazole bearing sulfonamide hybrids and evaluated for potent cannabinoid-1 receptor antagonist. Compound 297 (Fig. 34 ) was found to be most potent cannabinoid-1 receptor antagonist with K i values of 0.3 nM (hCB1R), 21.0 nM (hCB2R) and EC 50 of 3 nM (CB1R). Compound 297 is currently under development for treating obesity and the related metabolic syndrome [219] .

Epilepsy is a family of neurological disorders caused due to disturbances in the nerve cell activity which is associated with progressively impaired cognition and function, brain damage and other neurological deficits. It has become a common neurological condition affecting 45e100 million people [220] . Fortunately there is availability of antiepileptic drugs [AED's] which allow epileptic patients to maintain a normal and undisturbed life by having satisfied control and total relief of seizers [221, 222] . Further improvement in the development of antiepileptic drugs is a requirement for the complete prevention of epilepsy and its progression.

Farag and co-workers developed a set of compounds (298e300) (Fig. 35 ) with pharmacophore hybrids and tested for picrotoxin (PIC)-induced convulsions (10 mg/kg, i.p.) in mice. Among them, compound 298 protected all animals better than the reference drug phenobarbital and did not show mortality. Other active compounds 299 and 300 also showed reasonable protections and they decreased the mortality rate up to fifty percent [223] . In continuation, the authors have further modified benzothiazole pharmacophore by introducing sulfonamide group and tested those molecules for their anticonvulsant activity using MES, sc-PTZ seizure tests in swiss albino mice [224] . Compounds 301 and 302 (Fig. 35 ) were found to be the most active in both seizure tests at variant doses and were neurotoxic at the higher doses of 300 mg/kg as similar to standard drug carbamazepine [225] .

Cancer is been universally known as a disease or a group of diseases causing death. It is found to exist all over the world [226, 227] . Cancer is meant to be a bunch of cells originated from a single cell due to its uncontrolled growth and rapid proliferation properties [228] . The problem with the drugs is that it is unable to differentiate between normal and cancerous cell type leading to several serious side effects [229] . Development of anticancer theraupetic agents has become a challenge for the medicinal chemists. But a continuous effort is being carried in this area of research to save millions of lives.

In 2017, Nitin and co-workers designed and developed a new class of benzothiazole derived methyl sulfonyl hybrids as potent anticancer agents. Among them, some of the compounds showed superior anticancer activity against human cervical HeLA cell lines. Compounds 303 and 304 (Fig. 36) were extensively inhibiting to the cell growth and GI 50 values were found to be 0.22 and 0.6 mM respectively. The SAR studies revealed that the presence of EWGs (NO 2 ) on the phenyl ring and two sulfonyl groups in the analogues increased the anticancer activity [230] . In addition, the search of novel class of potent sulfonamides bearing hybrids, Ibrahim and coworkers reported isatin-pyrazole benzenesulfonamide derivatives as potent CA inhibitors. Compounds 305 and 306 (Fig. 36) showed Fig. 28 . Some of the sulfonyl or sulfonamides containing heterocycles as potential TB agents. good carbonic anhydrases inhibition to the cell lines hCA IX (K i ¼ 15.7 and 7.4 nM, respectively) and hCA XII (K i ¼ 3.7 and 5.4 nM, respectively). The SAR studies suggested that the presence of EWGs (NO 2 ) on the phenyl ring to increased the activity and sulphonamide played a major role in the enhancing the CA activity [231] . In 2014, Tiangong and co-workers developed compound (307 and 308) (Fig. 36) , a new class of styrylsulfonyl-methylpyridines hybrids with the anticancer activity against A2780, MCF7 and HCT-116 cell lines by using MTT assay. Compound 307 was found to have the best antitumor activity in a xenograft HCT-116 colon cancer model with GI 50 value of 0.570 mmoL/L. Compound 308 displayed potent antitumor efficacy in the xenograft A2780 with GI 50 value of 0.007 mmoL/L. The SAR studies revealed that compounds containing 2,4,6-trimethoxy and two sulfoonamide group favourably increased the anticancer activity. The presence of EDGs was necessary for to increases the activity and also the presence of pyridine ring in the derivatives increased the oral bioavailability and solubility of the synthesized compounds [232] . R. Pingaew et al. [124] reported a new class of sulfonyl containing thiosemicarbazone and tetrahydroisoquinoline hybrids as potent anticancer agents. Some of the synthesized thiosemicarbazone analogues showed good cytotoxic potency against MOLT-3 cell lines with IC 50 value of 2.13 mg/mL. Compound 309 (Fig. 36 ) was found to have the best cytotoxic activity against HuCCA-1 and HepG2cells with IC 50 values of 31.00 mg/mL and 10.50 mg/mL respectively. The SAR displayed the presence of EDGs (OMe) and sulfonyl functionalities increased the cytotoxic activity [233] . At last, in 2014, Jun and co-workers designed and produced novel 1-sulfonyl indolines analogues in good yields and tested for their antiproliferative activity against various cancer cell lines. Among them, compounds 310 and 311 (Fig. 36 ) showed good cytotoxicity with IC 50 values in the range of 0.055e0.105 mM and 0.039e0.112 mM, respectively against four human cancer cell lines HCT116, PC3, HepG2 and SK-OV-3. The SAR demonstrated that the presence of EDGs (OMe) significantly increased the activity and the presence of oxazole moiety also influenced the antiproliferative activity [234] .

Romero and co-workers reported a new class of thiazolecontaining tryptamine hybrids as potent 5-HT6 receptor agonist. Compound 312 (Fig. 37 ) was found to have good Ki value of 2.2 nM against 5-HT6 receptor. Compound 312 displayed partial agonistic property in cAMP functional assay with pKi value 6.96 in HEK-293 F cell line. Further in vivo studies indicated that compound 312 effectively improved recognition memory by combined modulation of cholinergic as well as glutamatergic neurotransmission in rats [235] . Hayat et al. found that the benzothiazole-sulfonamide hybrids displayed powerful 5-HT6 receptor antagonists against HeLa cell line. Compounds 313 (IC 50 ¼ 14 mM) and 314 (IC 50 ¼ 3.9 mM) (Fig. 37 ) bearing 4-isopropylphenyl and 1-naphthylsulfonamide group at C-6 position of benzothiazole ring, respectively, showed promising inhibition of 5-HT6 receptor antagonists against HeLa cell line [236] . Prio et al. patented various N-phenyl-2,3dihydroimidazol [2,1-b]thiazole-5-sulfonamide derivatives as 5-HT6 receptor ligands. Numerous substitution on phenyl as well as imidazole ring provided suitable ligands and some of them displayed excellent affinity for 5-HT6 receptor. Particularly compounds 315, 316 and 317 (Fig. 37) showed good Ki value of 8.4, 16.9 and 5.4 nM, respectively [237] . At last, Liu et al. explored a number of sulphonamide based benzothiazole hybrids as 5-HT6 receptor agents. All the produced hybrids possessed nanomolar range affinity for 5-HT6 receptor. Among them, compound 318 (Fig. 37 ) was found to be the best potent 5-HT6 receptor with Ki value of 500 nM. In addition, in vitro and in vivo studies of this compound 318 (Fig. 37 ) may provide promising leads in future [238] .

Yang et al. designed and developed a class of potent quinolinebased ALDH1A1 inhibitors. The pharmacokinetics (PK) study demonstrated that compounds 319 and 320 (Fig. 38 ) had realistic drug exposure via po administration and would be suitable for in vivo proof of concept animal studies for a better understanding of the physiological and pathophysiological actions of this enzyme [239] . Very recently, Iqbal and co-workers found the sulfonamide bearing sultams analogues as potent alkaline phosphatase (bTNAP and bIAP) inhibitors. Among these, compound 321 (Fig. 38 ) containing a p-nitro substituent was found to be the best active inhibitor with IC 50 value of 0.11 ± 0.005 mM. This examination highlighted the significance of the presence of EWGs on the para position of phenyl ring for effective bTNAP inhibition. The presence of NO 2 on the para position of phenyl ring 321 was found to be very efficient and selective inhibitor of bTNAP over bIAP. Moreover, the homology built models were then used for the docking studies in order to rationalize the most probable binding interactions of inhibitors with the enzyme. Compound 321 was the most active bTNAP inhibitor, the sulfonamide group found to be oriented towards the Zn 2þ metal ions. Fig. 39 displayed the detailed binding site interactions of most active bTNAP inhibitor of compound 321.

Compound 321 was the only compound in which not the sulfonamide group, but the oxygen atom of the p-nitro group was in direct contact (2.1 Å) with the Zn 2þ ion of the active site, since 321 is the most active bTNAP inhibitor, this interaction might be responsible for exceptional inhibitory activity observed for this compound. The presence of a sulfonamide group, as a zinc binding function, is suggested to be the most prominent structural feature in the design of potent AP inhibitors [240] . Taha (Fig. 40) which only lacked the chloro at 5-position, was observed to be seven-fold decline in the activity. Another compounds 324 (Fig. 40 ) lacked chloro at position 4 was perceived to be nine times decline in the activity. The SAR revealed that the decrease of chloro substitution from tri-to di-substituted decreased the activity. It is worth displaying in that the synthesized hybrids of biologically active analogues such as oxadiazole ring, sulfone group, hydrazide moiety and aryl rings cordially played their role in exhibiting the activity.

Compound 322 was identified as a lead compound for bglucuronidase inhibitory activity and may be used for further research for finding a powerful inhibitor [241] . Very recently, Iqbal and coworkers developed a class of chalcone-sulfonamide hybrids as potent alkaline phosphatase inhibitors. Among them, compounds 325 and 326 (Fig. 40 ) showed maximum inhibition of human and rat e5ʹNT with IC 50 values of 0.26 and r5ʹNT with 0.33 mM, respectively. The SAR studies suggested that the presence of EDGs at meta position of phenyl ring displayed greater inhibition. Likewise, the presence of di-substituted bulky electron donating group i.e., methoxy group at 3/4 position showed greater inhibition of~161 fold higher than that of the standard compound sulfamic acid. The most potent inhibitor of 325 and 326 were analyzed in the active pocket of enzyme where its docking poses elaborate the presence of five strong hydrogen bonds with various amino acid residues. Compound 4e also showed strong electrostatic interactions. The two zinc ions within active pocket of h-e5ʹNT showed interaction with nitrogen of sulfonamide moiety by forming a metal acceptor phenomenon [242] . In 1997, the FDA approved compound Delavirdine (327) (Fig. 40 ) was found to be the second NNRTI agent authorized for treatment of HIV-1 [243] . Further, crystallographic analysis confirmed that methyl-sulfonamide group at indole ring was essential for enhancing the activity [244] . Moretto et al. identified a novel pyridothiophene inhibitor of PTP1B with a K i value of 0.370 mM [245] . The X-ray co-crystal structures of compounds 328 and 329 (Fig. 41) showed one of the sulphonamide oxygens hydrogen bonded to the backbone nitrogen of Gly259 and the other entered into interactions with Arg24 and Arg254 through bridging water molecules (Fig. 42) . These interactions could increase the inhibitor activity up to 25-fold more, but would not bring selectivity over TCPTP. In 2006, Klopfenstein and co-workers developed compound 329 as PTP1B inhibitors with 2-fold selectivity over TCPTP, in which the sulfamic acid moiety picked up hydrogen bonding interactions with Arg24, Arg254, and Gln262 (2F6Z, Fig. 43 ) [246] .

With the aim at further investigating the diverse chemical space, the introduction of imidazopyridine ring as a scaffold led to the discovery of two novel series of imidazopyridinylthioacetanilides hybrids. Among these, compounds 330 and 331 (EC 50 ¼ 0.75 mM and 0.21 mM, respectively) (Fig. 44) were identified as the most potent inhibitors in suppressing HIV-1 replication. These compounds 330 and 331 (Fig. 44) had higher anti-HIV-1 potency compared to reference drug dideoxycytidine [247] . Later, Kim et al. designed and developed sulfonamide containing hydroxylated chalcones 332 and 333 (Fig. 44) with potential inhibition of trans-sialidase enzyme which was demonstrated by IC 50 values 0.9 and 2.5 mM [248] . In continuous search of potential sulfonamide based chalcone hybrids as potent drugs against some diseases causing pathogens, in 2010, El-Ayache [249] reported polyphenol bearing two polyphenolic moieties separated by a bisarylsulfonamide 334 (Fig. 44) moiety was essential for the activity and the substitution at the benzylic methylene was detrimental to the inhibitory activity. Also, the presence of ortho substituent on the aromatic ring of the benzyl group especially trifluoromethyl group enhanced the Eg5 inhibitory activity [250] . Finally, Prachayasittikul and co-workers found triazoles derived sulfonamide analogues as potent aromatase inhibitory activity. Compound 337 (Fig. 44 ) bearing 6,7-dimethoxy substituents on the isoquinoline ring showed the most potent aromatase inhibitory activity (IC 50 ¼ 0.2 mM) without affecting normal cell. The SAR suggested that the lipophilic effect of dimethoxy groups enhanced the activity of compound 337. In addition, molecular docking studies were performed the most active compound 337 and mode of binding interaction of compound 337 was revealed that, the investigated triazoles could closely engage the active site of aromatase through the interactions of hydrophobic, pp stacking and H-bonding. Furthermore, hydrophobic interactions with Arg115 were observed 2D-ligand protein interaction (Fig. 45) . The compound 337 was arranged in such a way to appropriately form hydrogen bonding of the sulfonyl group with the amino group of Ala306 and Ala307 as well as hydrogen bonding of oxycoumarinyl moiety with Ser119. These hydrophobic and hydrogen bonding interactions were suggested to play pertinent roles contributing to the most potent activity of compound 337. Interestingly, isomeric coumarinyl and naphthalenyl triazoles play crucial roles in exerting more potent aromatase inhibitory activity than other tested compounds. This could be attributed to their binding interactions with the aromatase enzyme. The molecular requirements for the most potent triazole inhibitor 337 which contains 6,7-dimethoxy groups, 7-coumaryloxymethyl at position 4 of the triazole ring, and m-substitution of triazole and sulfonyl moieties on the phenyl ring. Such structural features were essential for engaging in hydrophobic, p-p stacking and H-bonding interactions with the aromatase enzyme, particularly, hydrogen bond forming with Arg115 and Ser119 [251] .

This review updates and summaries the importance of the sulfonyl or sulfonamide based scaffolds (S VI based moieties) in bioactive compounds. As described above, sulfonamide based hybrids have huge range of biological activities such as antimicrobial, anti-diabetic, anti-inflammatory, anti-malarial, anti-tubercular, antiviral, Alzheimer's activity, anti-convulsant, anti-cancer, antitubercular and other activities. Theoretically, sulfonyl or sulphonamide (S VI moieties) based drugs possess the immense potential therapeutic values on diversity of drug targets. The SAR based work will probably continue to play an important role to further optimize the full potential of sulfonamide hybrids. Many of these potential drugs are not yet in clinical trials, but emphasize the exigency in the need for their further derivatization to provide an opportunity for managing therapeutic values more efficiently and with greater efficacy in the future. In addition, these biological agents with promising activity and well-defined mechanisms of action can be considered valuable candidates as prototypes in the design and development of novel and more effective synthetic compounds based potent inhibitors.

Synopsis of some recent tactical application of bioisosteres in drug design

Recent developments in the synthesis of fused sultams

Synthesis of water-soluble, topically effective, intraocular pressure-lowering aromatic/heterocyclic sulfonamides containing cationic or anionic moieties: is the tail more important than the ring?

Inhibitors of the acetyltransferase domain of nacetylglucosamine-1-phosphate-uridylyltransferase/glucosamine-1-phosphate acetyltransferase (GlmU). Part 2: optimization of physical properties leading to antibacterial aryl sulfonamides

Synthesis and antimicrobial activity of novel benzoxazine sulfonamide derivatives

Synthesis, characterization, in vitro cytotoxicity and antimicrobial investigation and evaluation of physicochemical properties of novel 4-(2-methylacetamide)benzenesulfonamide derivatives

Biological activity, design, synthesis and structure activity relationship of some novel derivatives of curcumin containing sulphonamides

Synthesis of novel celecoxib analogues by bioisosteric replacement of sulfonamide as potent anti-inflammatory agents and cyclooxygenase inhibitors

Coumarin sulfonamides derivatives as potent and selective COX-2 inhibitors with efficacy in suppressing cancer proliferation and metastasis

Synthesis and biological evaluation of some new 2-pyrazolines bearing benzene sulfonamide moiety as potential anti-inflammatory and anti-cancer agents

Design, synthesis and pharmacological evaluation of (E)-3,4-dihydroxy styryl sulfonamides derivatives as multifunctional neuroprotective agents against oxidative and inflammatory injury

Synthesis, antioxidant, enzyme inhibition and DNA binding studies of novel N-benzylated derivatives of sulphonamide

Relations between structure and biological activity of sulphonamides

A general practice assessment of mefruside ('Baycaron') in the treatment of oedema and hypertension

2D-ligand protein interaction scheme of compound 337 (PDB code: 3EQM)

Antihypertensive efficacy of hydrochlorothiazide as evaluated by ambulatory blood pressure monitoring: a meta-analysis of randomized trials

Synthesis and anti-cancer activities of new sulphonamides 4-substituted-triazolyl nucleosides

Synthesis and SAR of sulfonyl-and phosphoryl amidine compounds as anti-resorptive agents

Novel 3,5-bis(arylidiene)-4-piperidone based monocarbonyl analogs of curcumin: anticancer activity evaluation and mode of action study

Biological evaluation of some new N-(2,6-dimethoxypyrimidinyl)thioureido benzenesulfonamide derivatives as potential antimicrobial and anticancer agents

-Substitutedphenyl)-3a,4-dihydro-3Hindeno[1,2-c]pyrazol-2-yl) benzenesulfonamides

Synthesis and carbonic anhydrase inhibitory activities of new thienyl-substituted pyrazoline benzenesulfonamides

Pyridazinone substituted benzenesulfonamides as potent carbonic anhydrase inhibitors

Novel sulphonamide derivatives for the treatment of cancer

A novel synthetic sulphonamide anticancer agent: in vitro and in vivo anti-pancreatic cancer activities and preclinical pharmacology

Sulfonamides as multifunctional agents for Alzheimer's disease

Divergent C-H functionalizations directed by sulfonamide pharmacophores: late-stage diversification as a tool for drug discovery

New cyrhetrenyl and ferrocenyl sulfonamides: synthesis, characterization, X-ray crystallography, theoretical study and anti-Mycobacterium tuberculosis activity

Carbonic anhydrase inhibitors, characterization and inhibition studies of the most active beta-carbonic anhydrase from Mycobacterium tuberculosis, Rv3588c

A 50-year history of new drugs in Japan-the development and progress of anti-diabetic drugs and the epidemiological aspects of diabetes mellitus

Efficacy of glimepiride in type 2 diabetic patients treated with glibenclamide

Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters

The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised noninferiority trial

Synthesis of novel acridine and bis acridine sulfonamides with effective inhibitory activity against the cytosolic carbonic anhydrase isoforms II and VII

Structural study of interaction between brinzolamide and dorzolamide inhibition of human carbonic anhydrases

Furazan and furoxan sulfonamides are strong a-carbonic anhydrase inhibitors and potential antiglaucoma agents

Antiobesity carbonic anhydrase inhibitors: a literature and patent review

Novel (4-piperidin-1-yl)-phenyl sulfonamides as potent and selective human b 3 agonists

Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl oxazolidinone-5-carboxamides as novel p2 ligands

Synthesis and antiviral evaluation of acyclic azanucleosides developed from sulfanilamide as a lead structure

Design and synthesis of new N-(5-Trifluoromethyl)-1H-1,2,4-triazol-3-yl benzenesulfonamides as possible antimalarial prototypes

Sulphonamides: deserving class as MMP inhibitors?

Role of sulfonamide group in matrix metalloproteinase inhibitors

An overview of SR121463, a selective non-peptide vasopressin V2 receptor antagonist

Novel arylsulfoanilide-oxindole hybrid as an anticancer agent that inhibits translation initiation

Sulfonamide as an essential functional group in drug design; metabolism, pharmacokinetics and toxicity of functional groups: impact of chemical building blocks on ADMET dennis A. Smith

Recent development of sulfonyl or sulfonamide hybrids as potential anticancer agents: a key review

Synthesis of isoxazole-containing sulfonamides with potent carbonic anhydrase II and VII inhibitory properties

Synthesis of some new 1,3,5-trisubstituted pyrazolines bearing benzene sulfonamide as anticancer and anti-inflammatory agents

Apricoxib, a novel inhibitor of COX-2, markedly improves standard therapy response in molecularly defined models of pancreatic cancer

Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir

Design and synthesis of cyclic sulfonamides and sulfamates as new calcium sensing receptor agonists

Synthesis of radiolabeled biphenylsulfonamide matrix metalloproteinase inhibitors as new potential PET cancer imaging agents

Molecular modeling, synthesis, antibacterial and cytotoxicity evaluation of sulfonamide derivatives of benzimidazole, indazole, benzothiazole and thiazole

Dofetilide, a new class III antiarrhythmic agent

Resistance to antibiotics: are we in the post-antibiotic era?

Targeting antibiotic resistance

Synthesis of novel sulfanilamide-derived 1,2,3-triazoles and their evaluation for antibacterial and antifungal activities

Design, synthesis and antimicrobial evaluation of novel benzimidazole-incorporated sulfonamide analogues

Synthesis of novel sulfonamide azoles via CeN cleavage of sulfonamides by azole ring and relational antimicrobial study

Synthesis, anti-inflammatory and antimicrobial evaluation of novel 1-acetyl-3,5-diaryl-4,5-dihydro (1H) pyrazole derivatives bearing urea, thiourea and sulfonamide moieties

Design, synthesis, antimicrobial evaluation and molecular docking studies of some new thiophene, pyrazole and pyridone derivatives bearing sulfisoxazole moiety

Synthesis, antimicrobial and antioxidant activities of substituted pyrazoles, isoxazoles, pyrimidine and thioxopyrimidine derivatives

Synthesis and antimicrobial activity of (1,4-phenylene) bis(arylsulfonylpyrazoles and isoxazoles)

Discovery and structure-based optimization of 2-Ureidothiophene-3-carboxylic acids as dual bacterial RNA polymerase and viral reverse transcriptase inhibitors

Structure activity relationships of new cyanothiophene inhibitors of the essential peptidoglycan biosynthesis enzyme MurF

Gobec, Design, synthesis and evaluation of second generation MurF inhibitors based on a cyanothiophene scaffold

The synthesis and antistaphylococcal activity of N-sulfonaminoethyloxime derivatives of dehydroabietic acid

Design, synthesis and biological evaluation of 4-(1-(4(sulphanilamide)phenyl)-3-(methyl)-1H-pyrazol-5-yl) dine urea and N-acyl derivatives as a soluble epoxide hydrolase inhibitors

Synthesis of sulfanilamide derivatives and investigation of in vitro inhibitory activities and antimicrobial and physical properties

Synthesis and biological evaluation of sulfonamide thiazole and benzothiazole derivatives as antimicrobial agents

Design, synthesis and characterization of novel molecules comprising benzothiazole and sulphonamide linked to substituted aryl group via azo link as potent antimicrobial agents

Synthesis and in vitro antimicrobial activity of some new 4-amino-N-(1,3-benzothiazol-2-yl) benzenesulphonamide derivatives

Synthesis and antibacterial activity of some heterocyclicderivatives of sulphanilamide

Global estimates of the prevalence of diabetes for

Global healthcare expenditure on diabetes for

Type 2 diabetes in the young: the evolving epidemic

Microvascular and macrovascular complications of diabetes

Synthesis of N-(5-chloro-6-(quinolin-3-yloxy) pyridin-3-yl)benzenesulfonamide derivatives as non-TZD peroxisome proliferator-activated receptor g(PPARg) agonist

Synthesis of 2-{2-[(a/b-naphthalen-1-ylsulfonyl)amino]-1,3-thiazol-4-yl} acetamides with 11b-hydroxysteroid dehydrogenase inhibition and in combo antidiabetic activities

Design, synthesis and molecular docking of thiazolidinedione based benzene sulphonamide derivatives containing pyrazole core as potential anti-diabetic agents

Synthesis and blood glucose lowering effect of novel pyridazinone substituted benzenesulfonylurea derivatives

Antidiabetic activity of N-(6-substituted-1,3-benzothiazol-2-yl)benzenesulfonamides

Synthesis, in vitro and computational studies of protein tyrosine phosphatase 1B inhibition of a small library of 2-arylsulfonylaminobenzothiazoles with antihyperglycemic activity

Discovery of novel high potent and cellular active ADC type PTP1B inhibitors with selectivity over TC-PTP via modification interacting with C site

Synthesis of piperazine sulfonamide analogs as diabetic-II inhibitors and their molecular docking study

Synthesis, biological evaluation and molecular docking studies of chromone hydrazone derivatives as a-glucosidase inhibitors

Carbazole-containing sulfonamides and sulfamides: discovery of cryptochrome modulators as antidiabetic agents

Design and synthesis of non-TZD peroxisome proliferatoractivated receptor g(PPARg) modulator

-(quinolin-3-yloxy)phenyl)benzenesulfonamide (INT131) analogs for PPARg-targeted antidiabetics

Sulfonamide-1,3,5-triazine-thiazoles: discovery of novel class of antidiabetic agent via inhibition of DPP-4

Synthesis, characterization, hypoglycemic and aldose reductase inhibition activity of arylsulfonylspiro

Microbiology Principles and Explorations

Cyclooxygenase inhibitory natural products: current status

Cyclooxygenase 2 inhibitors: discovery, selectivity and the future

Cyclooxygenase inhibitors-current status and future prospects

Prostaglandin endoperoxide H synthases-1 and -2

Prostaglandin synthase 2

A novel pyrimidine derivatives with aryl urea, thiourea and sulfonamide moieties: synthesis, anti-inflammatory and antimicrobial evaluation

Designing antiinflammatory drugs from parasitic worms: a synthetic small molecule analogue of the acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis

Design and synthesis of enantiomerically pure decahydroquinoxalines as potent and selective k-opioid receptor agonists with anti-inflammatory activity in vivo

Identification of a nonpeptidic and conformationally restricted bradykinin B1 receptor antagonist with anti-inflammatory activity

Design, synthesis, and pharmacological evaluation of pyridinic analogues of nimesulide as cyclooxygenase-2 selective inhibitors

Mechanism of action of novel anti-inflammatory drugs diflumidone and R-805

Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents

Synthesis of new 4-[2-(4-methyl(amino)sulfonylphenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-1,2,3,6-tetrahydropyridines: a search for novel nitric oxide donor antiinflammatory agents

Synthesis and characterization of celecoxib derivatives as possible anti-inflammatory, analgesic, antioxidant, anticancer and anti-HCV agents

Synthesis of novel 1,3,4-trisubstituted pyrazoles as anti-inflammatory and analgesic agents

Synthesis, molecular docking, and biological evaluation of some novel hydrazones and pyrazole derivatives as antiinflammatory agents

Celecoxib analogs bearing benzofuran moiety as cyclooxygenase-2 inhibitors: design, synthesis and evaluation as potential anti-inflammatory agents

Synthesis, characterization, biological activities and molecular modeling of Schiff bases of benzene sulfonamides bearing curcumin scaffold

Benzenesulfonamide bearing pyrazolylpyrazolines: synthesis and evaluation as anti-inflammatory, antimicrobial agents

Molecular hybrid design, synthesis and biological evaluation of nphenyl sulfonamide linked n-acyl hydrazone derivatives functioning as cox-2 inhibitors: new anti-inflammatory, anti-oxidant and anti-bacterial agents

New 1,2-diaryl-4-substituted-benzylidene-5-4H-imidazolone derivatives: design, synthesis and biological evaluation as potential anti-inflammatory and analgesic agents

World Health Organization

The global fight against HIV/AIDS, tuberculosis, and malaria: current status and future

The economic burden of illness for households in developing countries, a review of studies focusing on Malaria, Tuberculosis and HIV/ AIDS

Antimalarial drug resistance, artemisinin-based combination therapy, and the contribution of modeling to elucidating policy choices

New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins

Synthesis and antifungal properties of sulfanilamide derivatives of chitosan

Design, synthesis, molecular modeling, and biological evaluation of sulfanilamide-imines derivatives as potential anticanceragents

Novel 1,4-naphthoquinone-based sulfonamides: synthesis, QSAR, anticancer and antimalarial studies

Synthesis and antimalarial activity of sulfonamide chalcone derivatives

N-(7-Chloroquinolinyl-4-aminoalkyl)arylsulfonamides as antimalarial agents: rationale for the activity with reference to inhibition of hemozoin formation

Anti-malarial activity of 4-metoxychalcones: docking studies as falcipain/plasmepsin inhibitors, ADMET and lipophilic efficiency analysis to identify a putative oral lead candidate

Synthesis, biological evaluation, and modeling studies of inhibitors aimed at the malarial proteases plasmepsins I and II

Synthesis and antiplasmodial activity of novel indoleamide derivatives bearing sulfonamide and triazole pharmacophores

Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent

Synthesis, antimalarial evaluation and molecular modeling studies of hydroxyethylpiperazines, potential aspartyl protease inhibitors

Multi-targetable chalcone analogs to treat deadly Alzheimer's disease: current view and upcoming advice

Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in alzheimer's disease

Treatment of Alzheimer's disease: current status and new perspectives

Perspective on race and ethnicity in alzheimer's disease research, Alzheimer's Dementia

Synthesis and evaluation of multi-target-directed ligands against alzheimer's disease based on the fusion of donepezil and ebselen

The significance of the cholinergic system in the brain during aging and in Alzheimer's disease

Bioinorganic chemistry of Alzheimer's disease

Discovery of the 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative verubecestat (mk-8931)-ab-site amyloid precursor protein cleaving enzyme 1 inhibitor for the treatment of Alzheimer's disease

Discovery of sulphonamide-pyrazole g-secretase inhibitors

Synthesis and structure-activity relationship of a novel series of heterocyclic sulfonamide g-secretase inhibitors

Effect of novel N-aryl sulfonamide substituted 3-morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer's dementia models

Novel biphenyl bis-sulfonamides as acetyl and butyrylcholinesterase inhibitors: synthesis, biological evaluation and molecular modelling studies

Pyridine sulfonamide as a small key organic molecule for the potential treatment of type-II diabetes mellitus and Alzheimer's disease: In vitro studies against yeast a-glucosidase, acetylcholinesterase and butyrylcholinesterase

Synthesis of novel acridine-sulfonamide hybrid compounds as acetylcholinesterase inhibitor for the treatment of alzheimer's disease

Microwave assisted synthesis of novel hybrid tacrine-sulfonamide derivatives and investigation of their antioxidant and anticholinesterase activities

An efficient synthesis of bi-aryl pyrimidine heterocycles: potential new drug candidates to treat alzheimer's disease

N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: potential multifunctional anti-Alzheimer's agents

Inhibitory evaluation of sulfonamide chalcones on bsecretase and acylcholinesterase

Novel multitarget-directed ligands for Alzheimer's disease: combining cholinesterase inhibitors and 5-HT 6 receptor antagonists. Design, synthesis and biological evaluation

Differential effects of antigens from L. braziliensis isolates from disseminated and cutaneous leishmaniasis on in vitro cytokine production

Drug development for neglected diseases: a deficient market and a public-health policy failure

Combination therapy for visceral leishmaniasis

Chemotherapy of leishmaniasis: past, present and future

Selenocyanates and diselenides: a new class of potent antileishmanial agents

Novel 3-Nitro-1H-1,2,4-triazole-based amides and sulfonamides as potential anti-trypanosomal agents

Leishmania amazonensis growth inhibitors: biological and theoretical features of sulfonamide 4-methoxychalcone derivatives

QSAR and docking studies of novel antileishmanial diaryl sulfides and sulfonamides

Synthesis and antileishmanial activity of new imidazolidin-2-one derivatives

Synthesis and in vitro leishmanicidal activity of 2-(5-nitro-2-furyl) and 2-(5-nitro-2-thienyl)-5-substituted-1,3,4-thiadiazoles

4-(1H-Pyrazol-1-yl)benzenesulfonamide derivatives: identifying new active antileishmanial structures for use against a neglected disease

Synthesis and in vitro evaluation of new benzenesulfonamides as antileishmanial agents

Gonz alez-Rosende, In Vitro and in Vivo antileishmanial and trypanocidal studies of new N-Benzene and N-Naphthalene sulfonamide derivatives

Novel hybrid selenosulfonamides as potent antileishmanial agents

Synthesis, biological evaluation and SAR of sulphonamide 4-methoxychalcone derivatives with potential antileishmanial activity

Recent developments of coumarin-containing derivatives and their anti-tubercular activity

Quinoline: A promising antitubercular target

World Health Organization

Benzimidazoles: novel mycobacterial gyrase inhibitors from scaffold morphing

Design and synthesis of positional isomers of 5 and 6-bromo-1-[(phenyl) sulfonyl]-2-[(4nitrophenoxy)methyl]-1Hbenzimidazoles as possible antimicrobial and antitubercular agents

Design, synthesis and antimycobacterial activity of various 3-(4 (substitutedsulfonyl)piperazin-1-yl)benzo d isoxazole derivatives

High-throughput discovery of mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) inhibitors using click chemistry

Sulfonyl-hydrazones of cyclic imides derivatives as potent inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase B (PtpB)

A Pd-mediated new strategy to functionalized 2-aminochromenes: their in vitro evaluation as potential anti tuberculosis agents

Cu-mediated N-arylation of 1,2,3-triazin-4-ones: synthesis of fused triazinone derivatives as potential inhibitors of chorismate mutase

A new route to indolesvia in sit-udesilylationeSonogashira strategy: identification of novel small molecules as potential anti-tuberculosis agents

Synthesis and in vitro antitubercular activity of 4-aryl/alkylsulfonylmethylcoumarins as inhibitors of Mycobacterium tuberculosis

Emerging Infectious Diseases: MERS-COV, Avian Influenza Remind Us of the Ongoing Challenge

Emerging infectious diseases in 2012: 20 years after the institute of medicine report

HIV drug resistance: problems and perspectives

Plant derived antivirals: a potential source of drug development

Inhibition of HIV-1 replication by isoxazolidine and isoxazole sulfonamides

Structure based design, synthesis, and structureactivity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones

New pyrazolobenzothiazine derivatives as hepatitis C virus NS5B polymerase palm site I inhibitors

Discovery of thiophene[3,2-d] pyrimidine derivatives as potent HIV-1 NNRTIs targeting the tolerant region I of NNIBP

Structure-activity relationship (SAR) optimization of 6-(Indol-2-yl)pyridine-3-sulfonamides: identification of potent, selective, and orally bioavailable small molecules targeting hepatitis C (HCV) NS4B

Synthesis and antiviral activity of 5-(4-Chlorophenyl)-1,3,4-thiadiazole sulfonamides

Antiviral properties and interaction of novel chalcone derivatives containing a purine and benzenesulfonamide moiety

Structure-based design of sulfonamide-substituted non-peptidic HIV protease inhibitors

Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyranones

Cycloalkylpyranones and cycloalkyldihydropyrones as HIV protease inhibitors: exploring the impact of ring size on structure-activity relationships

Benzouracil-coumarin-arene conjugates as inhibiting agents for chikungunya virus

Synthesis and biological evaluation of cyclic imides incorporating benzenesulfonamide moieties as carbonic anhydrase I, II, IV and IX inhibitors

Benzimidazoles: a new class of carbonic anhydrase inhibitors

Discovery of 1, 10-biphenyl-4-sulfonamides as a new class of potent and selective carbonic anhydrase XIV inhibitors

Biochemical characterization of CA IX: one of the most active carbonic anhydrase isozymes

Carbonic anhydrase inhibitors and their therapeutic potential

Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: design, synthesis, inhibitory activity and 3D-QSAR analysis

Benzenesulfonamides incorporating bulky aromatic/heterocyclic tails with potent carbonic anhydrase inhibitory activity

Synthesis and biological evaluation of novel pyrazoline-based aromatic sulfamates with potent carbonic anhydrase isoforms II, IV and IX inhibitory efficacy

The carbon dioxide hydration activity of carbonic anhydrase

Synthesis, biological evaluation and computational studies of novel iminothiazolidinone benzenesulfonamides as potent carbonic anhydrase II and IX inhibitors

Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating 1,2,4-triazine moieties

The synthesis of novel pyrazole-3,4-dicarboxamides bearing 5-amino-1,3,4-thiadiazole-2-sulfonamide moiety with effective inhibitory activity against the isoforms of human cytosolic carbonic anhydrase I and II

Structure of a cannabinoid receptor and functional expression of the cloned cdna

Molecular characterization of a peripheral receptor for cannabinoids

International union of pharmacology XXVII. Classification of cannabinoid receptors

Endocannabinoid signaling in the brain

Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB 2 receptor-dependent mechanism

Targeting cannabinoid agonists for inflammatory and neuropathic pain

Optimisation of a novel series of selective CNS penetrant CB 2 agonists

Aerssens, 5-Sulfonyl-benzimidazoles as selective CB 2 agonists-Part 2

Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators

Rapid assessment of a novel series of selective CB 2 agonists using parallel synthesis protocols: a lipophilic efficiency (LipE) analysis

-(trifluoromethyl)phenyl)ethynyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide as a novel peripherally restricted cannabinoid-1receptor antagonist with significant weight-loss efficacy in diet-induced obese mice

New anticonvulsant agents

The epidemiology of epilepsy: the size of the problem

Novel approaches to epilepsy treatment

Synthesis and anticonvulsant activity of sulfonamide derivativeshydrophobic domain

Synthesis of benzothiazole semicarbazones as novel anticonvulsants-The role of hydrophobic domain

Synthesis of potent and selective inhibitors of Candida albicans N-myristoyltransferase based on the benzothiazole structure

Clinical implications of the p53 tumor-suppressor gene

Recent advances in the development of dual Topoisomerase I and II inhibitors as anticancer drugs

Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII

Discovery of (E)-3-((styrylsulfonyl)methyl)pyridine and (E)2-((Styrylsulfonyl)methyl)pyridine derivatives as anticancer agents: synthesis, structure-activity relationships, and biological activities

Synthesis and cytotoxicity of novel N-sulfonyl-1,2,3,4-tetrahydroisoquinoline thiosemicarbazone derivatives

Synthesis and structure-activity relationship of 4-azaheterocycle benzenesulfonamide derivatives as new microtubule-targeting agents

Efficacy of selective 5-HT6 receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways

Discovery of orally bioavailable, quinoline-based aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with potent cellular activity

Facile dimethyl amino group triggered cyclic sulfonamides synthesis and evaluation as alkaline phosphatase inhibitors

Synthesis and in silico studies of novel sulfonamides having oxadiazole ring: as b-glucuronidase inhibitors

Synthesis, characterization and biological evaluation of novel chalcone sulfonamide hybrids as potent intestinal alkaline phosphatase inhibitors

Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor

Bicyclic and tricyclic thiophenes as protein tyrosine phosphatase 1B inhibitors

,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP1B inhibitors

Arylazolyl(azinyl)thioacetanilides. Part 10: design, synthesis and biological evaluation of novel substituted imidazopyridinylthioacetanilides as potent HIV-1 inhibitors

Development of new and selective trypanosoma cruzi trans-sialidase inhibitors from sulphonamide chalcones and their derivatives

Novel bisarylsulfonamides and aryl sulfonimides as inactivators of plasminogen activator inhibitor-1 (PAI-1)

Substituted benzimidazoles: a novel chemotype for small molecule hKSP inhibitors

Synthesis and molecular docking of 1,2,3-triazole-based sulfonamides as aromatase inhibitors