Selective inhibitory effects of HYIpro‐3‐1 on CYP1A2 in human liver microsomes

CYP1A2 is one of the main Cytochrome P450 enzymes in the human liver associated with the metabolism of several xenobiotics. CYP1A2 is especially involved in the metabolic activation of different procarcinogens. Therefore, the development of cancer may be inhibited by inhibiting CYP1A2 activity. Here, the inhibitory effect of HYIpro‐3‐1 and its derivatives on CYP1A2 activity in human liver microsomes (HLM) was studied through LC‐MS/MS using a cocktail assay. Among the four compounds, HYIpro‐3‐1 showed the most selective and strongest inhibitory effect on CYP1A2 at IC₅₀ values of 0.1 µM in HLMs and inhibition was confirmed using purified human CYP1A2. It was determined that inhibition is reversible because the inhibitory effect of HYIpro‐3‐1 is not dependent on preincubation time. HYIpro‐3‐1 showed a typical pattern of competitive inhibition for CYP1A2‐catalyzed phenacetin O‐deethylation, based on the Lineweaver‐Burk plot, with a Ki value of 0.05 μM in HLMs; the secondary plot also showed a linear pattern. In our study, HYIpro‐3‐1 was proposed as a novel inhibitor with the capacity to selectively inhibit CYP1A activity in HLMs.     

Virtual screening,SAR, and discovery of 5‐(indole‐3‐yl)‐2‐[(2‐nitrophenyl)amino] [1,3,4]‐oxadiazole as a novel Bcl‐2 inhibitor

A new series of oxadiazoles were designed to act as inhibitors of the anti‐apoptotic Bcl‐2 protein. Virtual screening led to the discovery of new hits that interact with Bcl‐2 at the BH3 binding pocket. Further study of the structure–activity relationship of the most active compound of the first series, compound 1 , led to the discovery of a novel oxadiazole analogue, compound 16j , that was a more potent small‐molecule inhibitor of Bcl‐2. 16j had good in vitro inhibitory activity with submicromolar IC₅₀ values in a metastatic human breast cancer cell line (MDA‐MB‐231) and a human cervical cancer cell line (HeLa). The antitumour effect of 16j is concomitant with its ability to bind to Bcl‐2 protein as shown by an enzyme‐linked immunosorbent assay (IC₅₀ = 4.27 μm ). Compound 16j has a great potential to develop into highly active anticancer agent.     

Acetylshikonin is a novel non‐selective cytochrome P450 inhibitor

Acetylshikonin is a biologically active compound with anti‐cancer and anti‐inflammatory activity, which is isolated from the roots of Lithospermum erythrorhizoma . An inhibitory effect of acetylshikonin against CYP2J2 activity was discovered recently. Based on this result, this study was expanded to evaluate the inhibitory effects of acetylshikonin against nine different cytochrome P450 (P450) isoforms in human liver microsomes (HLMs) using substrate cocktails incubation assay. Acetylshikonin showed a strong inhibitory effect against all P450s tested with IC₅₀ values of 1.4–4.0 μ m . Pre‐incubation of acetylshikonin with HLMs and NADPH did not alter the inhibition potency, indicating that acetylshikonin is not a mechanism‐based inhibitor. SKF‐525A, a widely used non‐specific P450 inhibitor, had no inhibitory activity against CYP1A2, 2A6, 2E1 and 2J2, while it showed an inhibitory effect against CYP2B6, CYP2C19 and 2D6 with IC₅₀ values of 2.5, 3.6 and 0.5 μ m , respectively. Our findings indicate that acetylshikonin may be a novel general P450 inhibitor, which could replace SKF‐525A.     

Synthesis and biological evaluation of novel N‐aryl‐ω‐(benzoazol‐2‐yl)‐sulfanylalkanamides as dual inhibitors of α‐glucosidase and protein tyrosine phosphatase 1B

α‐Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B (PTP1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity. Therefore, dual antagonists by targeting both α‐glucosidase and PTP1B may be potential candidates for type 2 diabetes therapy. In this work, three series of novel N‐aryl‐ω‐(benzoazol‐2‐yl)‐sulfanylalkanamides were synthesized and assayed for their α‐glucosidase and PTP1B inhibitory activities, respectively. Compound 3l , exhibiting the most effective α‐glucosidase inhibitory activity (IC₅₀ = 10.96 μm ( 3l ), IC₅₀ = 51.32 μm (Acarbose), IC₅₀ = 18.22 μm (Ursolic acid)) and potent PTP1B inhibitory activity (IC₅₀ = 13.46 μm ( 3l ), IC₅₀ = 14.50 μm (Ursolic acid)), was identified as a novel dual inhibitor of α‐glucosidase and PTP1B. Furthermore, 3l is a highly selective PTP1B inhibitor because no inhibition was showed by 3l at 100 μm against PTP‐MEG2, TCPTP, SHP2, or SHP1. Subsequent kinetic analysis revealed 3l inhibited α‐glucosidase in a reversible and mixed manner. Molecular docking study indicated that hydrogen bonds, van der Waals, charge interactions and Pi‐cation interactions all contributed to affinity between 3l and α‐glucosidase/PTP1B.     

Glaucarubulone glucoside from Castela macrophylla suppresses MCF‐7 breast cancer cell growth and attenuates benzo[a]pyrene‐mediated CYP1A gene induction

Quassinoids often exhibit antioxidant and antiproliferative activity. Emerging evidence suggests that these natural metabolites also display chemopreventive actions. In this study, we investigated the potential for the quassinoid glaucarubulone glucoside (Gg), isolated from the endemic Jamaican plant Castela macrophylla (Simaroubaceae), to display potent cytotoxicity and inhibit human cytochrome P450s (CYPs), particularly CYP1A enzymes, known to convert polyaromatic hydrocarbons into carcinogenic metabolites. Gg reduced the viability of MCF‐7 breast adenocarcinoma cells (IC₅₀ = 121 nm ) to a greater extent than standard of care anticancer agents 5‐fluorouracil, tamoxifen (IC₅₀ >10 μm ) and the tamoxifen metabolite 4‐hydroxytamoxifen (IC₅₀ = 2.6 μm ), yet was not cytotoxic to non‐tumorigenic MCF‐10A breast epithelial cells. Additionally, Gg induced MCF‐7 breast cancer cell death. Gg blocked increases in reactive oxygen species in MCF‐10A cells mediated by the polyaromatic hydrocarbon benzo[a ]pyrene (B[a ]P) metabolite B[a ]P 1,6‐quinone, yet downregulated the expression of genes that promote antioxidant activity in MCF‐7 cells. This implies that Gg exhibits antioxidant and cytoprotective actions in non‐tumorigenic breast epithelial cells and pro‐oxidant, cytotoxic actions in breast cancer cells. Furthermore, Gg inhibited the activities of human CYP1A according to non‐competitive kinetics and attenuated the ability of B[a ]P to induce CYP1A gene expression in MCF‐7 cells. These data indicate that Gg selectively suppresses MCF‐7 breast cancer cell growth without impacting non‐tumorigenic breast epithelial cells and blocks B[a ]P‐mediated CYP1A induction. Taken together, our data provide a rationale for further investigations of Gg and similar plant isolates as potential agents to treat and prevent breast cancer. Copyright © 2017 John Wiley & Sons, Ltd.     

The Synthesis and Evaluation of C7‐Substituted α‐Tetralone Derivatives as Inhibitors of Monoamine Oxidase

Based on a previous report that α‐tetralone (3,4‐dihydro‐2H‐naphthalen‐1‐one) is a promising scaffold for the design of highly potent inhibitors of the enzyme, monoamine oxidase, the present study investigates the monoamine oxidase inhibitory properties of a synthetic series of fifteen C7‐substituted α‐tetralone derivatives. Arylalkyloxy substitution on C7 of the α‐tetralone moiety yielded compounds with high inhibition potencies toward the human monoamine oxidase‐B isoform with all compounds possessing IC₅₀ values in the submicromolar range (0.00089–0.047 μm ). The C7‐substituted α‐tetralones also were highly potent monoamine oxidase‐A inhibitors with thirteen (of fifteen) compounds possessing IC₅₀ values in the submicromolar range (0.010–0.741 μm ). The α‐tetralones were, however, in each instance selective for monoamine oxidase‐B over the monoamine oxidase‐A isoform. Dialyses of enzyme–inhibitor mixtures show that, while a representative inhibitor acts as a reversible monoamine oxidase‐A inhibitor, inhibition of monoamine oxidase‐B is not readily reversed by dialysis. Using a molecular modeling approach, possible binding orientations and interactions of selected α‐tetralones with the active sites of the monoamine oxidases are also proposed. This study suggests that C7‐substituted α‐tetralones are promising monoamine oxidase inhibitors and may represent lead compounds for the development of therapies for Parkinson's disease and depression.     

Trimethyl‐4‐oxo‐4,5,6,7‐tetrahydroindazole‐1‐acetic Acid: A New Lead Compound with Selective COX‐2 Inhibitory Activity

A novel series of 3,6,6‐trimethyl‐4‐oxo‐4,5,6,7‐tetrahydroindazole‐1‐acetic acid derivatives was designed and synthesized by a new one‐step pathway. Structure elucidation of the synthesized compounds was confirmed by various spectral and elemental analyses. The prepared compounds were evaluated for their ability to inhibit cyclooxygenase‐2 (COX‐2) and cyclooxygenase‐1 (COX‐1) enzymes in vitro. Among the synthesized compounds, the 2‐(3,6,6‐trimethyl‐4‐oxo‐4,5,6,7‐tetrahydroindazol‐1‐yl)acetic acid 4 emerged as the most potent COX‐2 inhibitor (IC₅₀ value: 150 nM) with the highest selectivity index (COX‐1/COX‐2 inhibition ratio: 570.6). Docking studies of compound 4 in the active site of COX‐2 recognized its potential binding mode to the enzyme. Based on the preliminary results, compound 4 was considered as a lead compound for further optimization.     

Apoptotic and antiproliferative properties of 3β‐hydroxy‐Δ5‐steroidal congeners from a partially purified column fraction of Dendronephthya gigantea against HL‐60 and MCF‐7 cancer cells

Organisms belonging to the genus Dendronephthya are among a group of marine invertebrates that produce a variety of terpenoids with biofunctional properties. Many of these terpenoids have been proven effective as anticancer drugs. Here, we report the antiproliferative effect of 3β‐hydroxy‐Δ5‐steroidal congeners against the proliferation of HL‐60 human leukemia cells and MCF‐7 human breast cancer cells. The sterol‐rich fraction (DGEHF2‐1) inhibited the growth of HL‐60 and MCF‐7 cells with IC₅₀ values of 13.59 ± 1.40 and 29.41 ± 0.87 μg ml^–1 respectively. Treatment with DGEHF2‐1 caused a dose‐dependent increase in apoptotic body formation, DNA damage and the sub‐G₁ apoptotic cell population. Moreover, DGEHF2‐1 downregulated the expression of Bcl‐xL while upregulating Bax, caspase‐9, and PARP cleavage in both HL‐60 and MCF‐7 cells. The steroid fraction was found to act via the mitochondria‐mediated apoptosis pathway. Identification of the sterols was performed via gas chromatography–tandem mass spectrometry analysis. Studying the mechanism of the anticancer effect caused by these sterol derivatives could lead to the identification of other natural products with anticancer properties.     

Direct and metabolism‐dependent cytochrome P450 inhibition assays for evaluating drug–drug interactions

We developed methods for evaluating the ntial inhibition of human cytochrome P450 (CYP) enzymes, including CYP1A2, CYP2A6, CYP2B6, CYP2 C9, CYP2 C19, CYP2D6, CYP2E1 and CYP3A4, using pooled human liver microsomes (HLMs). The CYP inhibition assay used substrate cocktail sets [set A: phenacetin for CYP1A2, coumarin for CYP2A6, (S)‐(+)‐mephenytoin for CYP2C19, dextromethorphan for CYP2D6 and midazolam for CYP3A4; set B: bupropion for CYP2B6, tolbutamide for CYP2C9, chlorzoxazone for CYP2E1, and testosterone for CYP3A4] with quantitation by liquid chromatography–tandem mass spectrometry. A direct inhibition assay was performed with the substrate cocktails without β‐nicotinamide adenine dinucleotide phosphate (NADPH) pre‐incubation, and a metabolism‐dependent inhibition (MDI) assay was performed after 30 min of pre‐incubation with NADPH in HLMs. MDI was identified based on the half‐maximal inhibitory concentration (IC₅₀) shifts. The IC₅₀ values of the direct inhibitors determined using the probe substrate cocktails were in good agreement with previously reported values. Eight metabolism‐dependent inhibitors including furafylline, 8‐methoxypsoralen, tienilic acid, ticlopidine, fluoxetine, paroxetine, disulfiram and verapamil against CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, respectively, resulted in significant IC₅₀ shifts (≥2.5‐fold) after pre‐incubation. Thus, these CYP inhibition assays are considered to be useful tools for evaluating both direct inhibition and MDI at an early stage of the drug discovery and development process. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis and Anti‐neuroinflammatory Activity of Lactone Benzoyl Hydrazine and 2‐nitro‐1‐phenyl‐1H‐Indole Derivatives as p38α MAPK Inhibitors

Inhibition of p38 mitogen‐activated protein kinases (MAPKs) would allow significant modulation of the neuroinflammation condition associated with Alzheimer's disease (AD). Inspired from the pharmacophore of natural NF‐κB and p38α MAPK inhibitor 5,6‐dehydrokawain and p38α MAPK inhibitors 1a, 1‐pyrazolyl‐3‐(4‐((2‐anilinopyrimidin‐4‐yl)oxy)napththalen‐1‐yl)ureas, and 1b , a class of indole–pyrimidinyl compounds which were patented respectively, we designed, de novo synthesized, and evaluated two kinds of novel series of lactone benzoyl hydrazine derivatives and 2‐nitro‐1‐phenyl‐1H‐indole derivatives in an effort to develop pharmacologically tractable agents to alleviate the progression of AD. Fourteen of the seventeen synthesized compounds exhibit significant inhibitory effect on the nitric oxide (NO) production induced by lipopolysaccharide (LPS)‐induced microglia activation with IC₅₀ less than the control 5,6‐dehydrokawain. Notably, compound 27 , 6‐methoxy‐2‐nitro‐1‐(1H‐1, 2, 3‐triazol‐1‐yl)‐1H‐indole, with IC₅₀ values of 1.6  μ m can markedly inhibit p38 α MAPK and NO release in BV‐2 microglial cells. The molecular dynamic (MD) simulations demonstrate that compound 27 inhibits p38 α MAPK through binding to the Glu71 and Asp168 residues. Moreover, in vitro study shows that all compounds can easily cross the blood–brain barrier (BBB) and did not exhibit any acute cellular toxicity checked by MTT assay. These investigations provide promising chemical lead candidate as anti‐neuroinflammatory agents for AD.     

Screening of non‐steroidal anti‐inflammatory drugs for inhibitory effects on the activities of six UDP‐glucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC‐MS/MS

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are used widely to relieve pain and to decrease inflammation. Several clinical studies have reported that NSAIDs inhibit uridine 5′‐diphospho‐glucuronosyltransferase (UGT) enzymes. Therefore, the study evaluated the inhibitory potential of 15 NSAIDs on the activities of six UGT isoforms (i.e. UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes (HLMs). Among the 15 NSAIDs tested here, mefenamic acid and diclofenac inhibited all UGTs tested in this study. Piroxicam and niflumic acid inhibited UGT1A9 activity (IC₅₀ = 73.8 μm and 0.38 μm , respectively) and naproxen selectively inhibited UGT2B7 activity (IC₅₀ = 53.1 μm ), whereas it did not inhibit the other UGTs tested (IC₅₀ > 200 μm ). Diflunisal inhibited the UGT1A1 (IC₅₀ = 33.0 μm ) and UGT1A9 (IC₅₀ = 19.4 μm ). Acetaminophen, fenoprofen, ibuprofen, ketoprofen, meloxicam, phenylbutazone, salicylic acid and sulindac showed negligible inhibitory effects on the six UGTs (IC₅₀ > 100 μm ). These results suggest that some NSAIDs have the potential to inhibit UGTs in vitro. Copyright © 2014 John Wiley & Sons, Ltd.     

Design,syntheses, and evaluation of 2,3‐diphenylcycloprop‐2‐en‐1‐ones and oxime derivatives as potential cyclooxygenase‐2 (COX‐2) inhibitors with analgesic‐antiinflammatory activity

A group of 2,3‐diphenylcycloprop‐2‐enes having a variety of substituents at the para‐position of the C‐2 phenyl ring (H, F), and C‐3 phenyl ring (H, F, SMe, SOMe, SO₂Me), in conjunction with either a C‐1 carbonyl, oxime, oxime acetate, benzoyl hydrazone, or hydrogen substituent were synthesized for in vivo evaluation as analgesic and antiinflammatory (AI) agents, and as potential selective cyclooxygenase‐2 (COX‐2) inhibitors. This group of cycloprop‐2‐ene compounds exhibited significant analgesic activity, since 4% NaCl‐induced abdominal constriction was reduced by 43–90% at 30 min, and 41–100% at 60 min, after drug administration relative to the reference drugs aspirin and celecoxib (58% and 32% inhibition at 30 min after drug administration) for a 50 mg/kg intraperitoneal dose. AI activities, determined using the carrageenan‐induced rat paw edema assay, showed that this class of cycloprop‐2‐ene compounds exhibited AI activities in the inactive‐to‐modest activity range (0–26% inhibition) for a 50 mg/kg oral dose. The AI potency order for a group of 2,3‐diphenylcycloprop‐2‐enes with respect to the C‐1 substituent was oxime>hydrogen>carbonyl>benzoyl hydrazone. 2,3‐Diphenylcycloprop‐2‐en‐1‐one oxime ( 20 ) was the most active AI agent, inducing a 26% reduction in inflammation, relative to the reference drugs ibuprofen and celecoxib, which showed 52% and 58% reductions in inflammation, at 5 h after drug administration. In vitro COX‐1 and COX‐2 inhibition studies showed that 2,3‐diphenylcycloprop‐2‐en‐1‐one oxime ( 20 ) is a selective COX‐2 inhibitor (COX‐1 IC₅₀>100 μM; COX‐2 IC₅₀=2.94 μM; COX‐2 selectivity index>34). A molecular modeling study that docked the oxime ( 20 ) in the active site of the human COX‐2 isozyme showed that it binds in the vicinity of the mouth of the COX‐2 binding site with the O‐atom of the oxime (=N–OH) moiety separated from the NH₂ group of Arg¹²⁰ by about 3.65 Å. This orientation of the oxime compound ( 20 ) in the COX‐2 binding site could be due to a potentially strong ionic interaction between the =NOH oxime moiety and the guanidinium moiety of Arg¹²⁰. Drug Dev. Res. 57:6–17, 2002. © 2002 Wiley‐Liss, Inc.     

Synthesis of Novel 3‐aryl‐1‐oxa‐2,8‐diazaspiro[4.5]dec‐2‐ene Derivatives and Their Biological Evaluation Against Protein Tyrosine Phosphatase 1B

A series of novel 3‐aryl‐1‐oxa‐2,8‐diazaspiro[4.5]dec‐2‐ene derivatives were designed, synthesized, and evaluated as a new class of inhibitors against protein tyrosine phosphatase 1B. Among them, compound 6f displayed moderate inhibitory activity with IC₅₀ of 2.87 ± 0.24  μ m and can be used as a novel lead compound for the design of inhibitors of protein tyrosine phosphatase 1B.     

In vitro evaluation of potential drug interactions mediated by cytochrome P450 and transporters for luseogliflozin,an SGLT2 inhibitor

1.?We evaluated potential in vitro drug interactions of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, mediated by CYP inhibition, CYP induction and drug transporters using human liver microsomes, primary hepatocytes and recombinant cells-expressing efflux or uptake transporters, respectively.

2.?Human CYP inhibition studies indicated that luseogliflozin was a weak inhibitor for CYP2C19 with an IC₅₀ value of 58.3?μM, whereas it was not an inhibitor of the other eight major isoforms that were tested. The exposure of primary hepatocytes to luseogliflozin for 72?hrs weakly induced CYP3A4 at a concentration of 10?μM, whereas it did not induce CYP1A2 or CYP2B6 at concentrations of 0.1–10?μM.

3.?An in vitro transport study suggested that luseogliflozin is a substrate for human P-glycoprotein (P-gp), but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, organic anion transporter (OAT) 1 and OAT3, or organic cation transporter (OCT) 2. Luseogliflozin weakly inhibited OATP1B3 with an IC₅₀ value of 93.1?μM, but those for other transporters are greater than 100?μM.

4.?Based on the therapeutic plasma concentration of the drug, clinically relevant drug interactions are unlikely to occur between luseogliflozin and coadministered drugs mediated by CYPs and/or transporters.     

Design,synthesis, and biological evaluation of novel 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4H)‐imidazolone derivatives as cytotoxic agents and COX‐2/LOX inhibitors

A new series of 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4H)‐imidazolone derivatives 4a–l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, ¹H NMR, DEPT‐Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)‐1, COX‐2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX‐2 rather than COX‐1, and the IC₅₀ values (0.25–1.7 µM) were lower than that of indomethacin (IC₅₀ = 9.47 µM) and somewhat higher than that of celecoxib (IC₅₀ = 0.071 µM). The selectivity index for COX‐2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC₅₀ values of 0.02–74.03 µM, while the IC₅₀ of the reference zileuton was 0.83 µM. The most active compound 4c (4‐chlorobenzoxazole derivative) was found to have dual COX‐2/LOX activity. All the synthesized compounds were docked inside the active site of the COX‐2 and LOX enzymes. They linked to COX‐2 through the N atom of the azole scaffold, while C?O of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site.

     

Synthesis,biological evaluation and docking studies of trans‐stilbene methylthio derivatives as cytochromes P450 family 1 inhibitors

Cytochromes P450 family 1 (CYP1) are responsible for the metabolism of procarcinogens, for example polycyclic aromatic hydrocarbons and aromatic and heterocyclic amines. The inhibition of CYP1 activity is examined in terms of chemoprevention and cancer chemotherapy. We designed and synthesized a series of trans‐stilbene derivatives possessing a combination of methoxy and methylthio functional groups attached in different positions to the trans‐stilbene skeleton. We determined the effects of synthesized compounds on the activities of human recombinant CYP1A1, CYP1A2 and CYP1B1 and, to explain the variation of inhibitory potency of methoxystilbene derivatives and their methylthio analogues, we employed computational analysis. The compounds were docked to CYP1A1, CYP1A2 and CYP1B1 binding sites with the use of Accelrys Discovery Studio 4.0 by the CDOCKER procedure. For CYP1A2 and CYP1B1, values of scoring functions correlated well with inhibitory potency of stilbene derivatives. All compounds were relatively poor inhibitors of CYP1A2 that possess the most narrow and flat enzyme cavity among CYP1s. For the most active CYP1A1 inhibitor, 2‐methoxy‐4′‐methylthio‐trans‐stilbene, a high number of molecular interactions was observed, although the interaction energies were not distinctive.     

Synthesis,molecular docking and biological evaluation of 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives as novel potential tubulin assembling inhibitors

A series of new 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives were designed, synthesized and evaluated as potential inhibitors of tubulin polymerization and anthropic cancer cell lines. Among them, compound 33 displayed the most potent tubulin polymerization inhibitory activity in vitro (IC₅₀ = 1.41 μM) and strong antiproliferative activities against A549, Hela, HepG2 and MCF‐7 cell lines in vitro with GI₅₀ value of 1.6, 2.7, 2.9 and 4.3 μM, respectively, comparable with the positive control colchicine (GI₅₀ value of 4.1, 7.2, 9.5 and 14.5 μM, respectively) and CA‐4 (GI₅₀ value of 2.2, 4.3, 6.4 and 11.4 μM, respectively). Simultaneously, we evaluated that compound 33 could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Immunofluorescence microscopy also clearly indicated compound 33 a potent antimicrotubule agent. Docking simulation showed that compound 33 could bind tightly with the colchicine‐binding site and act as a tubulin inhibitor. Three‐dimensional‐QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent tubulin assembling inhibitory activity in the future.     

Novel pyridine‐2,4,6‐tricarbohydrazide thiourea compounds as small key organic molecules for the potential treatment of type‐2 diabetes mellitus: In vitro studies against yeast α‐ and β‐glucosidase and in silico molecular modeling

A range of novel pyridine‐2,4,6‐tricarbohydrazide thiourea compounds ( 4a–i ) were synthesized in good to excellent yields (63–92%). The enzyme inhibitory potentials of these compounds were investigated against α‐ and β‐glucosidases because these enzymes play a crucial role in treating type‐2 diabetes mellitus (T2DM). As compared to the reference compound acarbose (IC₅₀ 38.22 ± 0.12 μM), compounds 4i (IC₅₀ 25.49 ± 0.67 μM), 4f (IC₅₀ 28.91 ± 0.43 μM), 4h (IC₅₀ 30.66 ± 0.52 μM), and 4e (IC₅₀ 35.01 ± 0.45 μM) delivered better inhibition against α‐glucosidase and were quite inactive/completely inactive against β‐glucosidase. The structure–activity relationship of these compounds was developed and elaborated with the help of molecular docking studies.