Design,synthesis, and anticancer evaluation of N6-hydrazone purine derivatives with potential antiplatelet aggregation activity

In our research on novel anticancer agents, a series of N⁶-hydrazone purine derivatives were designed and synthesized by analysis of a pharmacophore model for ATP-competitive inhibitors. The activities screening results showed that N⁶-hydrazone purine derivatives 21 and 26 not only showed potential antiproliferative activity against the A549 and MCF-7 cell lines comparable to Vandetanib as a positive control but also had moderate antiplatelet aggregation activity. In order to investigate the possible targets, a molecular docking study was carried out on the fourteen kinases associated with anticancer and antiplatelet aggregation activities. The results indicated that compounds 21 and 26 had the potential activity to target VEGFR-2, PI3Kα, EGFR, and HER2 kinases. The inhibition of the kinases assay showed that compound 26 could target VEGFR-2, PI3Kα, and EGFR (IC₅₀ = 0.822, 3.040 and 6.625 μM). All results indicated that compound 26 will be an encouraging framework as potential new multi-target anticancer agent with potential antiplatelet aggregation activity.     

New 1H‐Pyrazole‐4‐Carboxamides with Antiplatelet Activity

Nine title compounds were synthesized and investigated in the Born test for their antiplatelet activities against collagen, ADP, adrenaline, and platelet activating factor (PAF) as inducers of the aggregation. Using collagen three compounds with IC₅₀ values below 100 μM were found ( 3b , 3e , 3i ). Activities in nanomolar concentrations were observed against ADP ( 3b , IC₅₀ = 9.4 nM), adrenaline ( 3i , IC₅₀ = 5.8 nM), and platelet activating factor ( 3e , IC₅₀ = 0.45 nM).     

Design,synthesis, in silico and antiproliferative evaluation of novel pyrazole derivatives as VEGFR‐2 inhibitors

As the blockade of the VEGFR‐2 signaling pathway is a viable approach in cancer therapy, the present study focuses on a series of pyrazole based VEGFR‐2 inhibitors that were designed on the basis of the hybridization approach, supported by docking and in silico computational studies. The designed compounds were synthesized through facile synthetic methods and the structures were confirmed by ¹H NMR, ¹³C NMR, MS and elemental analysis. The compounds were screened for in vitro antiproliferative activity against the HT‐29 (human colon cancer) and MCF‐7 (human breast cancer) cell lines by MTT assay. The compounds were also studied for in vitro inhibitory activity against VEGFR‐2 kinase. Among all the tested compounds, compound 6h emerged as a potent agent in the antiproliferative study against HT‐29 and MCF‐7 cells, with IC₅₀ values of 2.36 and 6.59 μM, respectively. Moreover, the same compound exhibited the highest VEGFR‐2 inhibitory activity with an IC₅₀ value of 1.89 μM. In docking studies, the designed compounds showed similar and essential key interactions as those of known VEGFR‐2 inhibitors. The present study may lead to new molecules in the development of anticancer agents targeting VEGFR‐2.     

Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines,XXI: 4,4′-Alkylene-bis-sydnone Imines

Two methylene-, seven ethylene-, eleven propylene- and two 4,4′-butylene-bis-sydnone imines have been synthesized and tested for their antiplatelet (Born-test, collagen) and anticoagulant (Quick-test) activity in vitro. The most active compounds were found in the ethylene and propylene series. The most favourable substituents in 3-position of the sydnone were hexyl to octyl or phenylethyl to phenylbutyl groups. Six compounds exhibit an IC₅₀ ≤ 10 μmol/L against platelet aggregation. Three compounds showed an IC₇₅ ≤ 200 μmol/L concerning the fibrin formation (Quick Δt ≥ 7s).     

Synthesis,cytotoxicity, and molecular docking of substituted 3-(2-methylbenzofuran-3-yl)-5-(phenoxymethyl)-1,2,4-oxadiazoles

A series of new benzofuran/oxadiazole hybrids ( 8a – n ) was synthesized from 2H-chromene-3-carbonitriles ( 3a – c ) through the multistep synthetic methodology, and these hybrids are known to exhibit anticancer activities. All the compounds were evaluated for their in vitro cytotoxicity against the HCT116 and MIA PaCa2 cell lines. Compounds 6a (IC₅₀: 9.71 ± 1.9 μM), 6b (IC₅₀: 7.48 ± 0.6 μM), and 6c (IC₅₀: 3.27 ± 1.1 μM) displayed a significant cytotoxic activity, whereas compounds 8d and 8e exhibited good activity against both cell lines. The depletion of glycogen synthase kinase-3β (GSK3β) induces apoptosis through the inhibition of basal NF-κB activity in HCT116 colon cancer cells and MIA PaCa2 pancreatic cancer cells. Molecular docking of compounds 6a , 6b , 6c , 8d , and 8e with GSK3β demonstrated the best binding affinity, correlating with the biological activity assay. Furthermore, the structure–activity relationship of these novel compounds reveals promising features for their use in anticancer therapy.     

Design,synthesis, antileishmanial,and antifungal biological evaluation of novel 3,5-disubstituted isoxazole compounds based on 5-nitrofuran scaffolds

Nineteen 3,5-disubstituted-isoxazole analogs were synthesized based on nitrofuran scaffolds, by a [3 + 2] cycloaddition reaction between terminal acetylenes and 5-nitrofuran chloro-oxime. The compounds were obtained in moderate to very good yields (45–91%). The antileishmanial activity was assayed against the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. Alkylchlorinated compounds 14p–r were active on both the promastigote and amastigote forms, with emphasis on compound 14p , which showed strong activity against the amastigote form (IC₅₀ = 0.6 μM and selectivity index [SI] = 5.2). In the alkyl series, compound 14o stands out with an IC₅₀ = 8.5 μM and SI = 8.0 on the amastigote form. In the aromatic series, the most active compounds were those containing electron-donor groups, such as trimethoxy isoxazole 14g (IC₅₀ = 1.2 μM and SI = 20.2); compound 14h , with IC₅₀ = 7.0 μM and SI = 6.1; and compound 14j containing the 4-SCH₃ group, with IC₅₀ = 5.7 μM and SI = 10.2. In addition, the antifungal activity of 19 nitrofuran isoxazoles was evaluated against five strains of Candida (C. albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. glabrata). Eleven isoxazole derivatives were active against C. parapsilosis, and compound 14o was found to be the most active (minimal inhibitory concentration [MIC] = 3.4 μM) for this strain. Compound 14p was active against all the strains tested, with an MIC = 17.5 μM for C. glabrata, lower than that of the fluconazole used as the reference drug.     

Synthesis and docking studies of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamide analogues as potential alkaline phosphatase inhibitors

A series of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a–i were synthesized as alkaline phosphatase inhibitors. The intermediate 5-substituted 1,3,4-oxadiazole-2-thione 4 was synthesized starting with hippuric acid. Hippuric acid in the first step was converted into corresponding methyl ester 2 which upon reaction with hydrazine hydrate furnished the formation of hydrazide 3 . The hippuric acid hydrazide was then cyclized into 5-substituted 1,3,4-oxadiazole-2-thione 4 . The intermediate 4 was then reacted with alkyl or aryl halides 5a–5i to afford the title compounds N-(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a–i . The bioassay results showed that compounds 6a–i exhibited good to excellent alkaline phosphatase inhibitory activity. The most potent activity was exhibited by the compound 6i having IC₅₀ value 0.420 μM, whereas IC₅₀ value of standard (KH₂PO₄) was 2.80 μM. Molecular docking studies was performed against alkaline phosphatase enzyme (PDBID 1EW2) to check binding affinity of the synthesized compounds 6a–i against target protein. The docking results showed that three compounds 6c , 6e , and 6i have maximum binding interactions with binding energy values of −8 kcal/mol. The compound 6i displayed the interactions of oxadiazole ring nitrogen with amino acid His265 having a binding distance 2.13 Ǻ. It was concluded from our results that synthesized compounds, especially compound 6i may serve as lead structure to design more potent inhibitors of human alkaline phosphatase.     

Design and syntheses of diarylisoxazoles: Novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

A group of 4,5‐diphenylisoxazoles ( 11a–p ), 3,4‐diphenyl‐5‐trifluoromethylisoxazoles ( 15, 21 ), and 4,5‐diphenyl‐3‐methylsulfonamidoisoxazole ( 23 ) possessing a variety of substituents (H, F, MeS, MeSO, MeSO₂) at the para‐position of one of the phenyl rings were synthesized for evaluation as analgesic, and selective COX‐2 inhibitory antiinflammatory (AI), agents. Although the 4,5‐diphenylisoxazole group of compounds (11a–p) exhibited potent analgesic and AI activities, those compounds evaluated ( 11a, 11b, 11m ) were more selective inhibitors of COX‐1 than COX‐2, with the exception of 4‐(4‐methylsulphonylphenyl)‐5‐phenylisoxazole ( 11n ) that showed a modest COX‐2 selectivity index (SI) of 2.1. In contrast, 3‐(4‐methylsulphonylphenyl)‐4‐phenyl‐5‐trifluoromethylisoxazole ( 15 ), which retained good analgesic and AI activities, was a highly potent and selective COX‐2 inhibitor (COX‐1 IC₅₀ > 500 μM; COX‐2 IC₅₀ < 0.001 μM) with a COX‐2 SI of > 500,000, relative to the reference drug celecoxib (COX‐1 IC₅₀ = 22.9 μM; COX‐2 IC₅₀ = 0.0567 μM) with a COX‐2 SI of 404. The 3‐phenyl‐4‐(4‐methylsulphonylphenyl) regioisomer ( 21 ) was a less potent inhibitor (COX‐1 IC₅₀ = 252 μM; COX‐2 IC₅₀ = 0.2236 μM) with a COX‐2 SI of 1122, relative to the regioisomer ( 15 ). The related compound 4,5‐diphenyl‐3‐methylsulfonamidoisoxazole ( 23 ) exhibited similar (to 21 ) potency and COX‐2 selectivity (COX‐1 IC₅₀ > 200 μM; COX‐2 IC₅₀ = 0.226 μM) with an SI of 752. A molecular modeling (docking) study for the most potent, and selective, COX‐2 inhibitor (15) in the active site of the human COX‐2 enzyme showed the C‐5 CF₃ substituent is positioned 3.37 Å from the phenolic OH of Tyr³⁵⁵, and 6.91 Å from the Ser⁵³⁰ OH. The S‐atom of the MeSO₂ substituent is positioned deep (7.40 Å from the entrance) inside the COX‐2 secondary pocket (Val⁵²³). These studies indicate a C‐5 CF₃ ( 15, 21 ), or C‐3 NHSO₂Me ( 23 ), central isoxazole ring substituent is crucial to selective inhibition of COX‐2 for this class of compounds. Drug Dev. Res. 51:273–286, 2000. © 2001 Wiley‐Liss, Inc.     

Cytotoxic gelsedine-type indole alkaloids from Gelsemium elegans

The ethanol extract of the leaves and branches of Gelsemium elegans afforded three new gelsedine-type indole alkaloids, 11-methoxy-14,15-dihydroxyhumantenmine (1), 11-methoxy-14,15-dihydroxy-19-oxogelsenicine (2), and 11-methoxy-14-hydroxygelsedilam (3), along with one known alkaloid 11-methoxy-14-hydroxyhumantenmine (4). The structures of isolated compounds were established based on 1D and 2D (¹H-¹H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high-resolution mass spectrometry. The isolated alkaloids were tested in vitro for cytotoxic potential against four laryngeal tumor cell lines including Hep-2, LSC-1, TR-LCC-1, and FD-LSC-1. As a result, compounds 1 and 4 exhibited some cytotoxic activities against all tested tumor cell lines with IC₅₀ values of 10.9–12.1 μM and 9.2–10.8 μM, respectively.     

Fungal biofilm inhibition by piperazine‐sulphonamide linked Schiff bases: Design,synthesis, and biological evaluation

We report the synthesis of some new piperazine‐sulphonamide linked Schiff bases as fungal biofilm inhibitors with antibacterial and antifungal potential. The biofilm inhibition result of Candida albicans proposed that the compounds 6b (IC₅₀ = 32.1 μM) and 6j (IC₅₀ = 31.4 μM) showed higher inhibitory activity than the standard fluconazole (IC₅₀ = 40 μM). Compound 6d (MIC = 26.1 μg/mL) with a chloro group at the para position was found to be the most active antibacterial agent of the series against Bacillus subtilis when compared with the standard ciprofloxacin (MIC = 50 μg/mL). Compound 6j (MIC = 39.6 μg/mL) with an OH? group at the ortho position showed more potent antifungal activity as compared to that of the standard fluconazole (IC₅₀ = 50 μM) against C. albicans. Thus, the synthesized compounds 6a–k were found to be potent biofilm inhibitors as well as active antibacterial and antifungal agents. The molecular docking study of the synthesized compounds against the secreted aspartyl protease (SAP5) enzyme of C. albicans exhibited good binding properties. The in silico ADME properties of the synthesized compounds were also analyzed and showed their potential to be developed as potential oral drug candidates.

     

瓜蒌薤白白酒汤螺甾皂苷类活性成分研究

目的研究瓜蒌薤白白酒汤作用的物质基础。方法在药理活性指导下利用各种化学和色谱手段对复方进行追踪分离并鉴定其化学结构。结果从活性部位中分离得到7个活性螺甾类化合物。结论7个化合物均有抑制血小板聚集活性,其中化合物5和6的抑制活性最强。     

Synthesis,biological evaluation,and docking studies of some 5‐chloro‐2(3H)‐benzoxazolone Mannich bases derivatives as cholinesterase inhibitors

A series of N‐substituted‐5‐chloro‐2(3H)‐benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC₅₀ = 7.53 ± 0.17 μM), while compound 11 was found to be the most active compound against BuChE (IC₅₀ = 17.50 ± 0.29 μM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC₅₀ = 1.04 ± 0.04 mM) than Trolox (IC₅₀ = 1.50 ± 0.05 mM).

     

Antiplatelet aggregation activity of compounds isolated from Guttiferae species in human whole blood

Twenty compounds isolated from Calophyllum inophyllum L., C. inophylloides King, Garcinia opaca King, G. bancana Miq., and G. parvifolia Miq. (Guttiferae) were evaluated for their ability to inhibit platelet aggregation in human whole blood induced by arachidonic acid (AA), collagen, and adenosine diphosphate (ADP). The compounds inhibited platelet aggregation in a dose-dependent manner. Among the compounds tested, 2-(3-methylbut-2-enyl)-1,3,5-trihydroxyxanthone and 2-(3-methylbut-2-enyl)-1,3,5,6- tetrahydroxyxanthone showed strong inhibitory activity on platelet aggregation induced by AA with IC₅₀ values of 115.9 and 113.0?μM, respectively. Rubraxanthone showed inhibitory activity against aggregation caused by the three inducers, and was the most effective antiplatelet compound against collagen-induced platelet aggregation with an IC₅₀ value of 47.0?μM. Macluraxanthone, GB-1a, pyranoamentoflavone, and a neoflavonoid showed selective inhibitory activity on platelet aggregation induced by ADP.     

Steroid glycosides from the starfish Pentaceraster gracilis

Using combined chromatographic separations, two new steroid glycosides namely pentacerosides A (1) and B (2), and four known compounds were isolated from the methanol extract of the starfish Pentaceraster gracilis. Their structures were determined on the basis of spectroscopic data (¹H and ¹³C NMR, HSQC, HMBC, ¹H-¹H COSY, ROESY, and FT-ICR-MS) and by comparing obtained results to the literature values. Among the isolated compounds, only maculatoside (5) showed significant cytotoxic effect against Hep-G2 (IC₅₀ = 16.75 ± 0.69 μM) and SK-Mel2 (IC₅₀ = 19.44 ± 1.45 μM) cell lines and moderate effect on KB (IC₅₀ = 36.53 ± 0.78 μM), LNCaP (IC₅₀ = 39.75 ± 3.34 μM), and MCF7 (IC₅₀ = 47.34 ± 7.01 μM) cell lines.     

In Vitro Antiplatelet Activity of Flavonoids from Leuzea Carthamoides

Plants and their secondary metabolites, including flavonoids, exhibit a wide range of biological effects. Consequently, natural substances are receiving an increased attention in medicinal research. Owing to these facts, in vitro antiplatelet activity of ethanol summary extract and four flavonoids from Leuzea carthamoides was determined in human platelet-rich plasma. Arachidonic acid (AA), adenosine diphosphate (ADP), collagen (COL), and thrombin were used as agonists of platelet aggregation. The summary extract showed a significant inhibition of the aggregation induced by COL and ADP. Of the tested flavonoids, eriodictyol (1) and patuletin (2) influenced COL- and AA-induced aggregation. Their IC₅₀ values are presented. Flavonoid glycosides eriodictyol-7-β-glucopyranoside (3) and 6-hydroxykaempferol-7-O-(6″-O-acetyl-β-D[small cap]-glucopyranoside) (4) were found to be weak antiplatelet agents. These results confirmed the fact that glucosylation decreases the antiplatelet activity. Quantitative composition of tested flavonoids in L. carthamoides extract was also determined. Though two of the tested flavonoids inhibited platelet aggregation, further evaluation of L. carthamoides, in order to discover other antiplatelet active compounds and possible adverse health effects, is needed.     

Synthesis,antibacterial evaluation,and DNA gyrase inhibition profile of some new quinoline hybrids

Antibiotic‐resistant bacteria continue to play an important role in human health and disease. Inventive strategies are necessary to develop new therapeutic leads to challenge drug‐resistance problems. From this perception, new quinoline hybrids bearing bioactive pharmacophores were synthesized. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against nine bacterial pathogenic strains. The results revealed that most compounds exhibited good antibacterial activities. Seven compounds ( 2b , 3b , 4 , 6 , 8b , and 9c,d ) displayed enhanced activity against methicillin‐resistant Staphylococcus aureus compared to ampicillin. These compounds were subjected to an in vitro S. aureus DNA gyrase ATPase inhibition study, which revealed that compounds 8b , 9c , and 9d showed the highest inhibitory activity with IC₅₀ values of 1.89, 2.73, and 2.14 μM, respectively, comparable to novobiocin (IC₅₀, 1.636 μM). Compounds 2a–c , 3a , 7c , 9c,d , and 10a,b revealed half the potency of levofloxacin in inhibiting the growth of Pseudomonas aeruginosa. As an attempt to rationalize the observed antibacterial activity for the most active compounds 8b , 9c , and 9d , molecular docking in the ATP binding site of S. aureus gyrase B was performed using Glide. Such compounds could be considered as promising scaffolds for the development of new potent antibacterial agents.     

Cytotoxic C-Methylated Chalcones from Syzygium samarangense.

Abstract

The flavonoids 2′-hydroxy-4′,6′-dimethoxy-3′-methylchalcone (1), 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (2), 2′,4′-dihydroxy-6′-methoxy-3′-methylchalcone (3), 2′,4′-dihydroxy-6′-methoxy-3′-methyldihydrochalcone (4) and 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethyldihydrochalcone (5), isolated from Syzygium samarangense. (Blume) Merr. & L.M. Perry (Myrtaceae), were subjected to cytotoxicity testing using the dimethylthiazoldiphenyl tetrazolium (MTT) assay. The cell lines used were the Chinese hamster ovarian (CHO-AA8) and the human mammary adenocarcinoma, (MCF-7 and SKBR-3). Among the test compounds, 2 exhibited significant differential cytotoxicity against the MCF-7 cell line with an IC₅₀ of 0.0015 ± 0.0001 nM. It was also cytotoxic against the SKBR-3 cell line with an IC₅₀ of 0.0128 ± 0.0006 nM. Doxorubicin, the positive control, had an IC₅₀ of 2.60 ± 0.28 × 10^?4 nM against the MCF-7 cell line and an IC₅₀ of 2.76 ± 0.52 × 10^?5 nM against the SKBR-3 cell line. When tested in a mechanism-based yeast bioassay for detecting DNA-damaging agents using genetically engineered Saccharomyces cerevisiae. RS322Y (RAD52) mutant strain and (LF15/11) (RAD+) wild-type strain, 2 showed significant selective cytotoxicity against the RAD52 yeast mutant strain. It had an IC₁₂ of 0.1482 nM, as compared with the positive control, streptonigrin, which had an IC₁₂ of 0.0134 nM. Hence, 2 is a cytotoxic natural product with potential anticancer application.     

Synthesis,molecular docking studies,and biological evaluation of novel alkyl bis(4‐amino‐5‐cyanopyrimidine) derivatives

A series of bis(4‐amino‐5‐cyano‐pyrimidines) was synthesized and evaluated as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). To further explore the multifunctional properties of the new derivatives, their antioxidant and antibacterial activities were also tested. The results showed that most of these compounds could effectively inhibit AChE and BChE. Particularly, compound 7c exhibited the best AChE inhibitory activity (IC₅₀ = 5.72 ± 1.53 μM), whereas compound 7h was identified as the most potent BChE inhibitor (IC₅₀ = 12.19 ± 0.57 μM). Molecular modeling study revealed that compounds 7c, 7f , and 7b showed a higher inhibitory activity than that of galantamine against both AChE and BChE. Anticholinesterase activity of compounds 7h, 7b , and 7c was significant in vitro and in silico for both enzymes, since these compounds have hydrophobic rings (Br‐phenyl, dimethyl, and methoxyphenyl), which bind very well in both sites. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activities. Indeed, in the superoxide–dimethyl sulfoxide alkaline assay, compound 7j showed very high inhibition (IC₅₀ = 0.37 ± 0.28 μM). Also, compound 7l exhibited strong and good antibacterial activity against Staphylococcus epidermidis and Staphylococcus aureus, respectively. Taking into account the results of biological evaluation, further modifications will be designed to increase potency on different targets. In this study, the obtained results can be a new starting point for further development of multifunctional agents for the treatment of Alzheimer's disease.     

Synthesis,in silico and in vitro studies of hydrazide-hydrazone imine derivatives as potential cholinesterase inhibitors

A series of hydrazide-hydrazone imine derivative compounds (3a–k) were synthesized and their structures characterized using FTIR, ¹H, and ¹³C (NMR) spectroscopic methods. In addition, molecular structures of compounds 3a, 3d, and 3g were elucidated by X-ray diffraction technique. In vitro inhibition activities of hydrazide-hydrazone imine derivatives against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were investigated. Compound 3i (IC₅₀ = 2.01 μM) exhibited the best inhibitory activity against AChE, comparable to the control Galantamine (IC₅₀ = 2.60 μM). Against BChE, compound 3h (IC₅₀ = 2.83 μM) showed the best inhibitory property which is higher control Galantamine (IC₅₀ = 3.70 μM). The Ki values of compound 3i (Ki = 0.63 μM) and compound 3h (Ki = 0.94 μM) that have the strongest inhibitory potential were determined against AChE and BChE, respectively. According to the docking result, the most stable conformation of AChE and compound 3i showed that it has a binding affinity of −10.82 kcal/moL. The binding affinity of the most stable conformation formed by BChE and compound 3h is −8.60 kcal/moL. Finally, in silico results and pharmacokinetic parameters of ADME showed that these compounds have good oral bioavailability properties.     

Synthesis,anticancer activity,and molecular modeling of etodolac‐thioether derivatives as potent methionine aminopeptidase (type II) inhibitors

A series of (R,S)‐1‐{[5‐(substituted)sulfanyl‐4‐substituted‐4H‐1,2,4‐triazole‐3‐yl]methyl}‐1,8‐diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐b]indoles ( 5a–v ) were designed and synthesized using a five‐step synthetic protocol that involves substituted benzyl chlorides and (R,S)‐5‐[(1,8‐diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐b]indole‐1‐yl)methyl]‐4‐substituted‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones in the final step. The synthesized derivatives were evaluated for cytotoxicity and anticancer activity in vitro using the MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) colorimetric method against VERO, HEPG2 (human hepatocellular liver carcinoma), SKOV3 (ovarian carcinoma), MCF7 (human breast adenocarcinoma), PC3 and DU145 (prostate carcinoma) cells at 10^?5 M (10 μM) for 24 h. Compounds 5d and 5h showed the best biological potency against the SKOV3 cancer cell line (IC₅₀ = 7.22 and 5.10 μM, respectively) and did not display cytotoxicity toward VERO cells compared to etodolac. Compounds 5k , 5s , and 5v showed the most potent biological activity against the PC3 cancer cell line (IC₅₀ = 8.18, 3.10, and 4.00 μM, respectively) and did not display cytotoxicity. Moreover, these compounds were evaluated for caspase‐3, ‐9, and ‐8 protein expression and activation in the apoptosis pathway for 6, 12, and 24 h, which play a key role in the treatment of cancer. In this study, we also investigated the apoptotic mechanism and molecular modeling of compounds 5k and 5v on the methionine aminopeptidase (type II) enzyme active site in order to get insights into the binding mode and energy.