key: cord-1004149-ipp0kahl
authors: Girgis, Adel S.; Panda, Siva S.; Srour, Aladdin M.; Abdelnaser, Anwar; Nasr, Soad; Moatasim, Yassmin; Kutkat, Omnia; El Taweel, Ahmed; Kandeil, Ahmed; Mostafa, Ahmed; Ali, Mohamed A.; Fawzy, Nehmedo G.; Bekheit, Mohamed S.; Shalaby, ElSayed M.; Gigli, Lara; Fayad, Walid; A. F. Soliman, Ahmed
title: 3-Alkenyl-2-oxindoles: Synthesis, antiproliferative and antiviral properties against SARS-CoV-2
date: 2021-06-30
journal: Bioorg Chem
DOI: 10.1016/j.bioorg.2021.105131
sha: 15f6f4267421b79bea449275a6e6c113032ce161
doc_id: 1004149
cord_uid: ipp0kahl

Sets of 3-alkenyl-2-oxindoles (6,10,13) were synthesized in a facile synthetic pathway through acid dehydration (EtOH/HCl) of the corresponding 3-hydroxy-2-oxoindolines (5,9,12). Single crystal (10a,c) and powder (12a,26f) X-ray studies supported the structures. Compounds 6c and 10b are the most effective agents synthesized (about 3.4, 3.3 folds, respectively) against PaCa2 (pancreatic) cancer cell line relative to the standard reference used (Sunitinib). Additionally, compound 10b reveals antiproliferative properties against MCF7 (breast) cancer cell with IC(50) close to that of Sunitinib. CAM testing reveals that compounds 6 and 10 demonstrated qualitative and quantitative decreases in blood vessel count and diameter with efficacy comparable to that of Sunitinib, supporting their anti-angiogenic properties. Kinase inhibitory properties support their multi-targeted inhibitory activities against VEGFR-2 and c-kit in similar behavior to that of Sunitinib. Cell cycle analysis studies utilizing MCF7 exhibit that compound 6b arrests the cell cycle at G1/S phase while, 10b reveals accumulation of the tested cell at S phase. Compounds 6a and 10b reveal potent antiviral properties against SARS-CoV-2 with high selectivity index relative to the standards (hydroxychloroquine, chloroquine). Safe profile of the potent synthesized agents, against normal cells (VERO-E6, RPE1), support the possible development of better hits based on the attained observations.

Many 3-alkenyl-2-oxindole analogs were naturally isolated revealing diverse biological properties [1] . Sunitinib (Sutent) which is a 3-alkenyl-2-oxindole derivative is an orally multi-target tyrosine kinase inhibitor approved by FDA (Food and Drug Administration on Jan. 26, 2006 and Nov. 16, 2017) for the treatment of gastrointestinal and advanced renal cancers. It has been also approved for the treatment of pancreatic cancer (May 20, 2011) [2, 3] . Semaxanib, another member of this family, is a VEGFR (vascular endothelial growth factor receptor) inhibitor discontinued in 2002 during phase III clinical trials for colorectal cancer [4] (Fig. 1) . Cancer is one of the most serious human health challenges universally. It is the second life deadly disease after cardiovascular disorders.

WHO (World Health Organization) reported 1/6 deaths globally is due to cancer in 2018 (9.6 million deaths) [5, 6] . Although many targeted drugs are developed and clinically approved, the associated side effects and limited efficacies diminished their applications and demanded the need for novel chemical entities with safer cures and higher potencies [7] .

Many of the investigated anticancer agents/drugs obey "one-molecule -one target -one disease" phenomenon. This allows the emerging of an agent selectively targeting a single biological entity to avoid the risk of off-target side effects. However, this hypothesis seems inadequate for multi-genic diseases (such as cancer, Alzheimer's or Parkinson's disease). This is why multi-targeted inhibitors were developed which can exhibit therapeutic potencies towards various mechanisms [8, 9] . It has been reported that cancer initiation and progression depend on several receptors or singling pathways. This is why multi-targeted agents can provide several advantages over mono-targeted therapies.

Several multi-target inhibitors (e.g. Sunitinib, Sorafenib, Altiratinib, Linifanib, and Regorafenib) were developed/approved, or investigated in clinical trials [10] (Fig. 1 ).

In our pursuit to develop novel antitumor agents [11] [12] [13] , the present study describes the synthesis of 3-alkenyl-2-oxindoles conjugated with sulfonamide function. Benzimidazolyl heterocycle is also considered for conjugation with the targeted compounds due to the diverse biological properties exhibited by its derivatives such as antitumor [24] [25] [26] [27] [28] [29] [30] [31] , anti-inflammatory [32] , antitubercular [33] [34] [35] , anti-HIV (human immunodeficiency virus) [36] [37] [38] , α-glucosidase inhibition [39] [40] [41] , cholinesterase inhibitor useful to combat the neuromuscular disorders [42] , pancreatic lipase inhibitor useful for fat absorption control [43] , α-amylase inhibitor useful for diabetes, obesity, and oral diseases [44] and Rho-kinase inhibitor useful for treatment of glaucoma [45] . Treanda (Bendamustine hydrochloride) is a benzimidazolyl derivative approved by FDA (2008) for chronic lymphocytic leukemia [46, 47] . carcinoma patients with antiviral drugs solely or in combination with anticancer drugs [66] , also prompted the current study targeting developing novel hits of dual functions (antiviral and antitumor) with much attention to their safety profile towards normal cells.

Reaction of 4-acetylphenyl alkanesulfonates 3a,b with isatins 4a,b in absolute ethanol containing quantitative amount of diethylamine at room temperature afforded the corresponding 4-[2-(3-hydroxy-2-oxoindolin-3-yl)acetyl]phenyl alkanesulfonates 5a-d in good yields (Scheme 1). Compounds 5a-d were isolated from the conducted reactions in adequate purity so, used directly in the next step without any further purification. IR spectrum of 5a (example of the agents prepared) reveals the ketonic and indolyl carbonyl bands at ν = 1701, 1675 cm -1 beside the hydroxyl, and indolyl NH as a broad-band at ν = 3291 cm -1 . The methylene protons are diastereotopic shown as two doublet signals at δ H = 3.61, 4.09 (J = 17.5 Hz). The 13 C-NMR spectrum of 5a exhibits the indolyl C-3 and C- On the other hand, the indexing of the investigated X-ray powder diffraction data of compounds 12a and 12f resulted in the triclinic P-1 and monoclinic P2 1 /n space group, respectively with one molecule per asymmetric unit in each (Fig. 4) . The torsion angles defined by C14-C13-C12-C9 show different values. It is nearly planar (176.5°) in compound 12a and out of plane the in compound 12f (72.79°). As a consequence, the benzimidazolyl and indolyl heterocycles form a dihedral angle of 79.63 ° and 49.02° in the 12a and 12f, respectively. Moreover, this fact leads to a different intramolecular bond between the benzimidazolyl and indolyl heterocycles as in compound 12a is ruled by the N7-O15 bond distance of 2.69Å. That is lost in the 12f and replaced by a slightly shorter N11-O1 bond distance of 2.52Å. In the 12f there is a strong intermolecular H-bond between the N(7)-H and the carbonyl group of the heterocycle with a bond length of 1.786Å (Supplementary Tables S5-S7, S9 ; Figs. S111, S112).

Standard MTT technique was considered for determining the antiproliferative properties of the synthesized compounds utilizing Sunitinib as a standard reference against pancreatic (PaCa-2), breast (MCF7), and colon (HCT116) cancer cell lines [67] . Table 1 reveals the cytotoxic properties of the targeted 3-alkenyl-2-oxindoles in IC 50 (μM, concentrations exhibiting 50% cell growth inhibition relative to the control experiment). It has been noticed that all the synthesized 3-alkenyl-2-oxindoles 6a-c and 10a-c show remarkable antiproliferative properties against pancreatic cancer (PaCa-2) cell line with potency higher than that of Sunitinib. Compounds 6c and 10b are the most effective agents synthesized (about 3.4, 3.3 folds, respectively) relative to Sunitinib. Compound 6b also reveals high potency against PaCa2, three time folds relative to Sunitinib. On the other hand compound 10b is the most potent agent synthesized against MCF7 (breast) cancer cell line exhibiting IC 50 close to that of the standard reference used (IC 50 = 4.15, 3.97 µM for 10b and Sunitinib, respectively). Compounds 6b and 6c also reveal similar behavior with efficacy close to that of Sunitinib (IC 50 = 4.25, 4.28 µM for 6b and 6c, respectively).

However, compound 6c is the only synthesized analog with cytotoxic properties against HCT116 (colon) cancer cell line close to the standard reference used (IC 50 = 5.33 and 5.03 μM corresponding to 6c and Sunitinib, respectively).

Based on the biological observations few SAR (structure-activity relationships) can be assigned. Attachment of the ethyl group to the sulfonate/sulfonamide fragment is critical in developing biological properties comparable with the methyl group as revealed in pairs 6a/6b and 10a/10b. It has also been noticed that in case of PaCa2 (pancreatic) and HCT116 CAMs treated with the proposed synthesized agents (the most promising antiproliferative agents synthesized) 6a-c and 10a-c, control (vehicles, DMSO, PBS "Phosphate-buffered saline", and ethanol) and positive control (Sunitinib) showed a significant difference in blood vessel number and diameter, either quantitatively (n = 4) or qualitatively (Fig. 5A ). In detail, CAMs treated with vehicle only showed the highest blood vessel diameters (14 mm). CAMs treated with Sunitinib showed reduction in blood vessel diameters in comparison to control (5 mm). Compounds 6a-c significantly reduced the blood vessel diameters to 3.2, 5.1, and 5.13 mm, respectively, compared to control.

Compounds 10a-c also reduced the blood vessel diameters to 3.5, 2.7, and 5 mm, respectively, compared to control (Fig. 5B , Table 2 ). In order to support these observations, H&E (haematoxylin and eosin) staining for CAMs was performed. In this regard, H&E staining confirmed the mentioned observations (revealing reductions in the number of blood vessels) for the CAMs treated with the positive control (Sunitinib) and the tested agents 6a-c, 10a-c.

The CAM assay is one of the most utilized techniques for determination of antiangiogenic effects [68] . This is attributed to the highly vascularized membrane and that the chorioallantoic membrane is mostly composed of type IV collagen, which resembles the human epithelium basement membrane [52] [53] [54] [55] [56] [57] . Our results show that the promising antiproliferative synthesized agents 6a-c and 10a-c possess anti-angiogenic properties as they can decrease the number and diameter of the blood vessels with potency comparable to that of Sunitinib, which is a well-known drug with anti-angiogenic properties [69] [70] [71] .

In conclusion, the synthesized agents 6 and 10 can be considered as potential anti-tumor agents with anti-angiogenic properties.

Angiogenesis is the formation of novel blood vessels/branches from the existing ones [72] . The new blood vessels are useful for nutrient and oxygen transportation to the endothelial cells that may stimulate and proliferate forming new sprouts. Regulated angiogenesis is an important process for embryonic development, reproduction, and wound healing due to cell growth and tissue re-generation [73] . On the other hand, dysregulated angiogenesis is observed in many diseases including solid cancers. This is why targeting dysregulated angiogenesis seems an important therapeutical approach for competing diverse cancer types and sometimes has been considered preferable to other chemotherapies to avoid the adverse effects on normal/healthy cells [74] . It has been reported that vascular endothelial growth factor receptors are three main categories (VEGFR-1, VEGFR-2, and VEGFR-3) responsible for tumor angiogenesis [75, 76] .

VEGFR-2 is the main receptor capable for anti-angiogenesis and controlling tumor proliferation [74] . and CAM testing (blood vessel diameter = 5.0 mm by both compound 10c and Sunitinib).

Additionally, the promising VEGFR-2 exhibited by compound 6a (IC 50 = 54.03 nM) also supports the revealed antiproliferative properties against MCF7 (IC 50 = 6.85 µM).

The c-Kit receptor is a member of class III tyrosine kinase receptor [77] .

Overexpression of c-kit initiates cell proliferation and tumor creation [78] . Suppressing the c-kit was reported as an efficient therapeutic strategy for controlling many cancer types [79] [80] [81] . It has been reported that, the VEGFR-2 inhibitors may block/inhibit other tyrosine kinase receptors (e.g. c-Kit, PDGFRs, FGFRs, and Flt-3); due to the structural similarities so, can be recognized as multi-targeted tyrosine kinase inhibitors with accessibility against different cancer types [82] . Additionally, the chemical structural resemblance of the antiproliferative agents synthesized and Sunitinib also prompted screening the inhibitory properties of 6a-c and 10a-c towards c-kit. Considering that Sunitinib is approved as multi-targeted inhibitor against various kinases including VEGFR, PDGFR, FLT-3 and c-kit [83] . 

Cell cycle analysis via quantitative DNA content is an important technique capable to identify the proliferation of culture cells and cell distribution in each phase of the cell cycle. Propidium iodide (PI) staining of DNA utilizing flow cytometry cell cycle analysis is an accessible technique for stoichiometric DNA cell content determination [84] .

Arresting cell cycle during the transition from G1 phase to S phase seems an important mode for many antiproliferative active agents [85] . Compounds 6b and 10b (the most effective antiproliferation agents synthesized against breast cancer cell line) were subjected for induced cell cycle study of MCF7 utilizing the assigned IC 50 value (Table 1) . This identifies the cell cycle distribution and phase arresting during the antiproliferation inhibitory process of the bio-active agents. From the results obtained ( Apoptosis induction [86] was also noticed by the bio-active agents synthesized 6b

and 10b against MCF7 cell utilizing IC 50 values discovered (Table 1) . From the results obtained (Table 5 , Fig. 8 ) it has been noticed that compound 6b is a higher apoptosis performing agent than 10b. This is due to the increased late stage of apoptosis observed by 6b than 10b (% late stage = 22.91, 17.15 by compounds 6b and 10b, respectively) .

Compound 6b also reveals higher necrosis induction than 10b (% necrosis = 9.29, 7.07 by compounds 6b and 10b, respectively).

Antiviral properties of the synthesized 3-alkenyl-2-oxindoles (6a-c, 10a-c) against SARS-CoV-2 were determined by the standard technique [87] [88] [89] and compared with that of hydroxychloroquine, chloroquine and Favipiravir, which are used as standard references. Compound 10c exhibits promising SI due to its high cytotoxicity value S117, S118) exhibits the molecular docking results for the promising antiproliferative agents synthesis (6a-c, 10a-c) and Sunitinib (reference standard used) in the PDB ID:

4AGD and 3G0E responsible for VEGFR-2 and c-kit inhibition, respectively. Fig. 117) reveals that, all the tested compounds aligned perfectly in the active site of the used protein in a similar manner/behavior to that of Sunitinib with different docking scores. All the tested compounds give hydrogen bonding interaction between the indolyl C=O and CYS919 of the protein active site. Additionally, compounds 6b and 10a-c reveal hydrogen bonding interaction of the indolyl NH with the GLU917 of the protein active site, which is also shown by Sunitinib (co-crystallized ligand in the protein active site. π-Interaction is only revealed by compound 6a. The minor docking score compatibility difference of the docked agents relative to the kinase inhibitory properties observed (Table 3) can be attributed to the effect of environmental conditions applied in the kinase investigation experimental technique, which are not considered in the computational studies.

All the tested compounds (6a-c, 10a-c) show two hydrogen-bonding interactions with CYS673 and GLU671 of the protein active site with alignment similar to that of Sunitinib and varied docking scores. Additionally, all the tested compounds (10b is an exception) support their alignment in the protein active site through π-σ interaction taking place between the indolyl heterocycle and VAL603. Again, the sigh compatibility differences observed due to docking scores and c-kit kinase inhibitory properties of the tested analogues can be attributed to the experimental conditions applied for the biochemical testing which are not considered in the computational work Table 7 ( Supplementary Fig. S118 ).

Generally, the docking studies especially, alignment and hydrogen bonding revealed by the docked agents in the protein active sites, support the multi-targeted kinase inhibitory properties of 6a-c and 10a-c in a comparable behavior to that known by Sunitinib.

In conclusion, 3-alkenyl-2-oxindoles with sulfonate or sulfonamide function seem promising results obtained can be adopted for developing higher effective hits.

Melting points were determined on a capillary point apparatus (Stuart SMP3) equipped with a digital thermometer. IR spectra (KBr) were recorded on a Shimadzu FT-IR 8400S spectrophotometer. Reactions were monitored using thin layer chromatography (TLC) on 0.2 mm silica gel F254 plates (Merck) utilizing various solvents for elution. The chemical structures of the synthesized compounds were characterized by nuclear magnetic resonance spectra ( 1 H-NMR, 13 C-NMR) and determined on a Bruker NMR spectrometer (500 MHz, 125 MHz for 1 H and 13 C, respectively). 13 C-NMR spectra are fully decoupled.

Chemical shifts were reported in parts per million (ppm) using the deuterated solvent peak or tetramethylsilane as an internal standard. (1) 

A mixture of equimolar amounts of the appropriate isatin 4a,b (5 mmol) and the corresponding acetophenone 3a,b in ethanol absolute (15 ml) containing quantitative amount of diethylamine was stirred at room temperature (20-25 °C) for the appropriate time. The separated solid 5a-d was collected washed with benzene (10 ml) and used in the next step without any more purification. 

It was obtained from the reaction of 3b and 4b as colorless solid, reaction time 24 h, with mp 171-173 °C and yield 86% (1.75 g). IR: ν max /cm -1 3244, 1701, 1690, 1620, 1597. 1 

Hydrochloric acid (25 ml, 25%) was added dropwise (10 min.) to a magnetically (7) 

A mixture of equimolar amounts of the appropriate isatin 4a-e (5 mmol) and the corresponding 2-acetylbenzimidazole 11a,b [95, 96] in ethanol absolute (15 ml) containing quantitative amount of diethylamine was stirred at room temperature (20-25 °C) for 3 h.

The reaction mixture was stored at room temperature overnight, the separated solid 12a-h was collected washed with benzene (10 ml) and used in the next step without any more purification.

(12a). It was obtained from the reaction of 4a and 11a as colorless solid with mp 139-141

Mentioned in details in the supplementary file.

There is no conflict to declare.

IR: ν max /cm -1 3568

1H upfield H of CH 2 CO), 3.84 (s, 3H

CH 2 CO)

It was obtained from the reaction of 4a and 11b as colorless solid with mp

H-NMR (DMSO-d 6 ) δ (ppm): 1.09 (t, J = 6.6 Hz, 3H, CH 3 ), 3.69 (d, J = 16.6 Hz, 1H upfield H of CH 2 CO), 4.38 (br d, 3H, NCH 2 CH 3 + downfield H of CH 2 CO), 6.29 (s, 1H, OH)

35 (s, 1H, NH). 13 C-NMR (DMSO-d 6 ) δ (ppm): 15.2 (CH 3 )

IR: ν max /cm -1 3348, 3298, 1717, 1686, 1670, 1624. 1 H-NMR (DMSO-d 6 ) δ (ppm): 3.82 (d, J = 17.7 Hz, 1H upfield H of CH 2 CO), 3.88 (s, 3H, NCH 3 ), 4.36 (d, J = 17.6 Hz, 1H, downfield H of CH 2 CO)

13 C-NMR (DMSO-d 6 ) δ (ppm): 32.0 (NCH 3 )

for C 18 H 14 ClN 3 O 3 (355.78): C, 60

It was obtained from the reaction of 4b and 11b as colorless solid with mp 169-171 °C and yield 75% (1.38 g)

6.41 (s, 1H, OH), 6.84 (d, J = 8.1 Hz, 1H, arom. H), 7.22 (d, J = 8.2 Hz, 1H, arom. H), 7.34-7.38 (m, 2H, arom. H), 7.43 (t, J = 7.3 Hz, 1H, arom. H), 7.67 (d, J = 8.1 Hz, 1H, arom. H), 7.86 (d, J = 8.1 Hz, 1H, arom. H), 10.50 (s, 1H, NH). 13 C-NMR (DMSO-d 6 ) δ

Hydroxy-5-methoxy-3-[2-(1-methyl-1H-benzo

IR: ν max /cm -1 3186, 1724, 1686, 1655, 1612. 1 H-NMR (DMSO-d 6 ) δ (ppm): 3.57 (s, 3H, OCH 3 ), 3.71 (d, J = 16

7.43 (t, J = 7.2 Hz, 1H, arom. H)

17 (s, 1H, NH). 13 C-NMR (DMSO-d 6 ) δ (ppm): 31

IR: ν max /cm -1 3422, 3167, 1709, 1682, 1639. 1 H-NMR (DMSO-d 6 ) δ (ppm): 1.11 (t, J = 6.3 Hz, 3H, CH 3 ), 3.54 (s, 3H

It was obtained from the reaction of 4d [97] and 11a as colorless solid with mp 147-149 °C and yield 75% (1.57 g). IR: ν max /cm -1 3321, 1701, 1686, 1616. 1 H-NMR (DMSO-d 6 ) δ (ppm): 1.36 (br s, 2H, piperidinyl H 2 C-4)

7.24 (t, J = 7.3 Hz, 1H, arom. H), 7.35 (br s, 2H, arom. H), 7.42 (t, J = 7.3 Hz, 1H, arom. H), 7.62 (d, J = 7.9 Hz, 1H, arom. H), 7.83 (d, J = 7.8 Hz, 1H, arom. H). 13 C-NMR (DMSO-d 6 ) δ (ppm): 23.8 (piperidinyl C-4)

IR: ν max /cm -1 3283, 1717, 1686, 1612. 1 H-NMR (DMSO-d 6 ) δ (ppm): 2.61 (br d, 4H, morpholinyl 2 NCH 2 ), 3.57 (br s, 4H, morpholinyl 2 OCH 2 ), 3.81 (d, J = 16.3 Hz, 1H upfield H of CH 2 CO), 3.83 (s, 3H

7.84 (d, J = 7.9 Hz, 1H, arom. H). 13 C-NMR (DMSO-d 6 ) δ (ppm

6 (morpholinyl NCH 2 ), 61.4 (NCH 2 N), 66.1 (morpholinyl OCH 2 )

min.) to a magnetically stirred solution of 12a-h (5 mmol) in absolute ethanol (12.5 ml) at room temperature (20-25 °C). The reaction mixture was kept stirring under the same conditions for 4 h and stored overnight at room temperature. The separated solid was collected

It was obtained from acidic dehydration of 12a, 12g or 12h as colorless microcrystals from N,N-dimethylformamide with mp 349-350 °C and yield 84

16 g from reaction of 12a, 12g and 12h, respectively)

66 (s, 1H, olefinic H), 8.83 (d, J = 8.5 Hz, 1H, arom. H), 11.50 (s, 1H, NH). 13 C-NMR

It was obtained from acidic dehydration of 12b as colorless microcrystals from nbutanol with mp 301-303 °C and yield 75% (1.19 g). IR: ν max /cm -1 3129, 1697, 1589. 1 H-NMR (CF 3 CO 2 D) δ (ppm): 1.75 (t, J = 7.2 Hz, 3H, NCH 2 CH 3 ), 4.99 (q, J = 7.2 Hz, 2H, NCH 2 ), 7.70-7.76 (m, 2H, arom. H), 7.84-7.85 (m, 2H, arom. H), 7.94 (t, J = 7.7 Hz, 1H, arom. H), 8.03 (t, J = 7.6 Hz, 1H, arom. H), 8.35 (d, J = 8.5 Hz, 1H, arom. H), 8.81 (s, 1H, olefinic H)

IR: ν max /cm -1 3117, 1694, 1585. 1 H-NMR (CF 3 CO 2 D) δ (ppm): 4.42 (s, 3H

It was obtained from acidic dehydration of 12d as colorless microcrystals from N,N-dimethylformamide with mp 325-327 °C and yield 93% (1.63 g). IR: ν max /cm -1 3129, 1694, 1585. 1 H-NMR

= 7.1 Hz, 2H, NCH 2 ), 7.69-7.75 (m, 2H, arom. H), 7.83-7.91 (m, 3H, arom. H)

50 (s, 1H, NH). 13 C-NMR (CF 3 CO 2 D) δ (ppm): 15

It was obtained from acidic dehydration of 12e as pale yellow microcrystals from N,N-dimethylformamide with mp 328-330 °C and yield 91% (1.52 g)

50 (s, 1H, NH). 13 C-NMR (CF 3 CO 2 D) δ (ppm): 35.1 (NCH 3 )

It was obtained from acidic dehydration of 12f as pale yellow microcrystals from N,N-dimethylformamide with mp 317-319 °C and yield 95% (1.65 g)

IR: ν max /cm -1 3121, 1694, 1620. 1 H-NMR

7.75 (t, J = 5.9 Hz

50 (s, 1H, NH). 13 C-NMR (CF 3 CO 2 D) δ (ppm): 15.6 (CH 3 )

Found: C, 68.96

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Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease

Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors

KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients

Cyanation of unactivated aryl chlorides and aryl mesylates catalyzed by palladium and hemilabile MOP-type ligands

Rational design, synthesis and QSAR study of vasorelaxant active 3-pyridinecarbonitriles incorporating 1H-benzimidazol-2-yl function

Design, synthesis and QSAR studies of dispiroindole derivatives as new antiproliferative agents

 The synthesized agents show potent properties against PaCa2 cell line

 CAM assay reveals the anti-angiogenic properties of the targeted agents

 The agents synthesized show multi-targeted inhibitory properties against VEGFR-2 and c-kit

Antiviral properties against SARS-CoV-2 and high SI were revealed by the synthesized agents

Graphical abstract Sets of 3-alkenyl-2-oxindoles were synthesized of potential antiproliferative (against PaCa-2 and MCF7cancer cell lines) and promising properties against SARS-CoV-2

This work was supported financially by National Research Centre, Egypt, project ID: 12060101.

X The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper