Benzimidazolone-piperazine/triazole/thiadiazole/furan/thiophene conjugates: Synthesis, in vitro urease inhibition, and in silico molecular docking studies.

This study describes the synthesis, in vitro urease inhibition, and molecular docking studies of benzimidazolone derivatives incorporating the piperazine, triazole, thiadiazole, furan, thiophene, and thiosemicarbazide moieties. All newly synthesized compounds demonstrated varying degrees of urease inhibitory activity, with IC50 values ranging between 0.64 ± 0.099 and 0.11 ± 0.017 µM, when compared with the standard drug thiourea (IC50 value of 0.51 ± 0.028 µM). To confirm the experimental urease inhibition results and elucidate the mode of interaction of the synthesized compounds with the binding site of the urease enzyme, molecular docking studies were performed using the Schrödinger Suite package. Molecular docking studies showed that compounds with high in vitro urease inhibition interacted with key residues of the urease active site such as His221, Glu222, Asp223, His322, Arg338, and Ni2+ cations via hydrogen bonding, metal coordination, salt bridge, π-π stacking, and π-cation interactions.

Design and synthesis of benzimidazole derivatives as apoptosis-inducing agents by targeting Bcl-2 protein.

Bcl-2, an anti-apoptotic protein, is a well-known and appealing cancer therapy target. Novel series of benzimidazole derivatives were synthesized and tested for their activity as Bcl-2 inhibitors on T98G glioblastoma, PC3 prostate, MCF-7 breast, and H69AR lung cancer cells. MTT assay was used to evaluate the cytotoxic effect. PI Annexin V Apoptosis Detection Kit was used to detect apoptosis. Expression levels of the Bcl-2 protein were examined by the Western blot analysis and qRT-PCR. All synthesized benzimidazole derivatives exhibited a cytotoxic effect on cancer cells with IC50 values in the range of 25.2-88.2 µg/mL. Among all derivatives, compounds C1 and D1 demonstrated a higher cytotoxic effect on cancer cells with IC50 values < 50 µg/mL, while a lower cytotoxic effect against human embryonic kidney cells with IC50 values of > 100 µg/mL. C1 and D1 caused a significant increase in the percentage of apoptotic cells in all types of cancer cell cells and both Bcl-2 mRNA and protein levels were significantly reduced. These results suggest that the novel benzimidazole derivatives may be candidates for apoptosis-inducing agents in cancer treatment by targeting anti-Bcl-2 proteins in cancer cells.

Novel Coumarin Derivatives Containing a Triazole Moiety: A Study on Synthesis, Cytotoxicity, Membrane Dysfunction, Apoptosis, Cell Cycle, and Antiangiogenic Effects.

BACKGROUND: Coumarin is a functional compound with a pronounced wide range of biological activities and has recently been shown to have anticancer effects on various human cancer cells. Cisplatin is widely used in treating many cancers, but its effectiveness is limited due to acquired resistance and dose-related side effects. OBJECTIVE: This study aimed to reveal the chemosensitizing ability of novel synthesized coumarin-triazole hybrid compounds (3a-f) compared to the cisplatin in A549, MCF-7, and HeLa cancer cells. METHODS: Cytotoxicity was determined by MTT assay. Lactate dehydrogenase (LDH), antioxidant/oxidant status, and DNA fragmentation were determined spectrophotometrically using commercial kits. Muse™ Cell Analyzer was used to assess cell cycle progression. Pro/anti-apoptotic gene expressions were determined by Real-Time qPCR. The antiangiogenic activity was determined by VEGF expression and Hen's chorioallantoic membrane model. RESULTS: Compounds 3c, -d, -e, and -f potentiated the cisplatin-induced cytotoxicity by increasing LDH release and DNA fragmentation, inducing G2/M cell cycle arrest, overproducing oxidative stress, and decreasing cellular antioxidant levels. These compounds combined with cisplatin caused upregulation in the pro-apoptotic Bax, Bid, caspase-3, caspase-8, caspase-9, Fas, and p53 gene expressions while downregulating anti-apoptotic DFFA, NFkB1, and Bcl2 gene expressions. These combinations caused vascular loss and a reduction in VEGF expression. CONCLUSION: These results suggest that a combinational regimen of coumarin compounds with cisplatin could enhance the effect of cisplatin in A549 cells. Besides, these compounds exhibit relatively low toxicity in normal cells, thus decreasing the dose requirement of cisplatin in cancer treatments.

Synthesis, structural, spectral, antioxidant, bioactivity and molecular docking investigations of a novel triazole derivative.

The structural, spectroscopic and electronic properties of 4-(4-nitrophenyl)-5-(pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione have been analyzed by using single crystal X-ray diffraction (SCXRD), 1H and 13C NMR chemical shifts and FT-IR spectroscopic methods both theoretically and experimentally. The tautomeric (thiol and thione) energetic analysis results, structural optimization parameters (bond lengths and angles), vibrational wavenumbers, proton and carbon NMR chemical shifts, UV-Vis. parameters, the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) analyses and Molecular Electrostatic Potential (MEP) surface have been calculated by using DFT/B3LYP quantum chemical method with 6-311++G(2d,2p) basis set to compare with the experimental results. The computed geometry parameters, vibrational wavenumbers, and NMR chemical shifts have been in good agreement with the experimental results. It should be noted that the radical scavenging activities of the title compound have been evaluated by using different test methods i.e. 2,2-Diphenyl-1-picrylhydrazyl (DPPH), N,N-dimethyl-p-phenylenediamine (DMPD) and 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS). According to obtained results, the title compound displayed DPPH (SC50 19.42 ± 0.11 µg/mL), DMPD (SC50 21.13 ± 0.08 µg/mL) and ABTS (SC50 38.17 ± 0.25 µg/mL) scavenging activities. Also, these results have been compared with Butylated hydroxyanisole (BHA), Rutin (RUT) and Trolox (TRO) used as standard compounds. The physicochemical, pharmacokinetic, and toxicity features of the compound have been determined by using drug-likeness and in silico ADMET investigations. The interaction results with SARS-CoV-2 main protease (Mpro) of the title ligand compound have been analyzed via the help of molecular docking study. Communicated by Ramaswamy H. Sarma.

Synthesis and anticancer activities of some new coumarin derivatives including the triazole ring and their in silico molecular docking studies.

The synthesis, docking study, and investigation of the anticancer activities of some coumarin derivatives containing the triazole ring are reported in this study. The newly synthesized compounds were screened for their in vitro anticancer activity against the cell lines CRL5807 (human bronchioalveolar carcinoma), CRL5826 (human squamous cell carcinoma), MDA-MB231 (human breast cancer cells), HTB177 (human lung cancer), PC-3 (human prostate adenocarcinoma), PANC-1 (human pancreatic cancer cells), used as cancer cells, and CCD34Lu (normal human lung fibroblasts), used as a healthy cell line. Cytotoxicity effects of the samples were determined by the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay. In silico studies were also performed to explore the binding interactions of the molecules.

Synthesis, α-glucosidase inhibition and in silico studies of some 4-(5-fluoro-2-substituted-1H-benzimidazol-6-yl)morpholine derivatives.

In this study, a new series of 4-(5-fluoro-2-substituted-1H-benzimidazol-6-yl)morpholine derivatives has been synthesized and screened for their α-glucosidase inhibitory potential. All molecules showed a considerable α-glucosidase inhibitory potential with IC50 values ranging from 20.46 ± 0.21 to 0.18 ± 0.01 µg/mL when compared with the acarbose (IC50 = 8.16 ± 0.12 µg/mL) as the standard. Compound 4 k having methoxy group on phenyl ring had the highest inhibitory effect with IC50 = 0.18 ± 0.01 µg/mL value among the examined compounds. Electron-donating groups such as methyl and methoxy on the phenyl ring played an important role in the inhibition. Also, the Lineweaver-Burk plots analysis displayed that the inhibition type of 4k was the competitive mode like acarbose as standard. In silico studies were also performed to explore the binding interaction of the most active compound.

Synthesis and spectroscopic characterization of novel methoxy bridged benzimidazolyl-substituted phthalocyanines as potent inhibitors of urease.

In this study, novel peripherally 4-[(1H-benzimidazol-1-yl)methoxy] substituted Zn(II) (3) Cu(II) (4) and Co(II) (5) phthalocyanines were prepared and their structures were characterized spectroscopically. The light absorption behaviors of the synthesized compounds (3-5) were studied by UV-Vis spectroscopy at different concentrations in different solvents. The urease inhibition activities of the synthesized compounds were also investigated. Among the synthesized molecules, compound 4 showed the best inhibitory effect against jack bean urease with IC50 values of 0.0036 ±â€¯0.0010 µM.

Synthesis and kinetics studies of N'-(2-(3,5-disubstituted-4H-1,2,4-triazol-4-yl)acetyl)-6/7/8-substituted-2-oxo-2H-chromen-3-carbohydrazide derivatives as potent antidiabetic agents.

A novel series of N'-(2-(3,5-disubstituted-4H-1,2,4-triazol-4-yl)acetyl)-6/7/8-substituted-2-oxo-2H-chromen-3-carbohydrazides were synthesized and studied for their α-glucosidase inhibition activity. Most of the synthesized compounds exhibited potential α-glucosidase inhibition activity with IC50 values ranging from 0.96 ± 0.02 to 32.86 ± 0.73 µg/ml. Among them, compounds 3e and 4e, having a methoxy group on the coumarin ring, proved to be the most potent ones, showing an enzyme inhibition activity with IC50 = 0.96 ± 0.02 and 1.44 ± 0.06 µg/ml, respectively. The kinetic study through Lineweaver-Burk plots revealed that the inhibition mechanism of the most active compounds 3d, 3e, 4d, and 4e, on the α-glucosidase activity, was found to be in the competitive mode.

Design, molecular docking and synthesis of novel 5,6-dichloro-2-methyl-1H-benzimidazole derivatives as potential urease enzyme inhibitors.

A novel series of 5,6-dichloro-2-methyl-1H-benzimidazole derivatives was synthesized and then screened for their urease inhibitory activity. All compounds showed more potent inhibitory activity in the range of IC50 = 0.0294 ±â€¯0.0015-0.1494 ±â€¯0.0041 µM than thiourea (IC50 = 0.5117 ±â€¯0.0159 µM), as a reference inhibitor. Among all the tested compounds, the compound 15 (IC50 = 0.0294 ±â€¯0.0015 µM) having strong electron-withdrawing nitro group on the phenyl ring was recorded as the most potent inhibitor of urease. All compounds were docked at the active sites of the Jack bean urease enzyme to investigate the reason of the inhibitory activity and the possible binding interactions of enzyme-ligand complexes.

Synthesis, in vitro urease inhibition and molecular docking studies of some novel quinazolin-4(3H)-one derivatives containing triazole, thiadiazole and thiosemicarbazide functionalities.

A new series of quinazolinone derivatives containing triazole, thiadiazole, thiosemicarbazide functionalities was synthesized and then screened for their in vitro urease inhibition properties. Most of the compounds showed excellent activity with IC50 values ranging between 1.88 ±â€¯0.17 and 6.42 ±â€¯0.23 µg/mL, compared to that of thiourea (IC50 = 15.06 ±â€¯0.68) and acetohydroxamic acid (IC50 = 21.03 ±â€¯0.94), as reference inhibitors. Among the synthesized molecules, compounds 5c, 5e and 5a showed the best inhibitory effect against urease enzyme with IC50 values of 1.88 ±â€¯0.17 µg/mL, 1.90 ±â€¯0.10 and 1.96 ±â€¯0.07 µg/mL, respectively. Moreover in order to give better understanding of the inhibitory activity of synthesized compounds, molecular docking studies were applied at the target sites of jack bean urease enzyme (JBU). Their binding poses and energy calculations were analyzed using induced fit docking (IFD) and prime-MMGBSA tool. Binding poses of studied compounds were determined using induced fit docking (IFD) algorithms.

Synthesis of some novel quinazolin-4(3H)-one hybrid molecules as potent urease inhibitors.

A new series of quinazolinone hybrid molecules containing coumarin, furan, 1,2,4-triazole and 1,2,4-thiadiazole rings was designed, synthesized, and screened for their urease inhibition activities. All newly synthesized compounds showed outstanding urease inhibitory potentials with IC50 values ranging between 1.26 ± 0.07 and 7.35 ± 0.31 µg/mL. Among the series, coumarin derivatives (10a-d) exhibited the best inhibitory effect against urease in the range of IC50 = 1.26 ± 0.07 to 1.82 ± 0.10 µg/mL, when compared to standard urease inhibitors such as acetohydroxamic acid and thiourea (IC50 = 21.05 ± 0.96 and 15.08 ± 0.71 µg/mL, respectively). Molecular docking studies were also performed to analyze the binding mode of compound 10b, and supported the experimental results.

Synthesis and molecular docking study of some novel 2,3-disubstituted quinazolin-4(3H)-one derivatives as potent inhibitors of urease.

A new series of 2,3-disubstituted quinazolin-4(3H)-one compounds including oxadiazole and furan rings was synthesized. Their inhibitory activities on urease were assessed in vitro. All newly synthesized compounds exhibited potent urease inhibitory activity in the range of IC50 = 1.55 ±â€¯0.07-2.65 ±â€¯0.08 µg/mL, when compared with the standard urease inhibitors such as thiourea (IC50 = 15.08 ±â€¯0.71 µg/mL) and acetohydroxamic acid (IC50 = 21.05 ±â€¯0.96 µg/mL). 2,3-Disubstituted quinazolin-4(3H)-one derivatives containing furan ring (3a-e) were found to be the most active inhibitors when compared with the compounds 2a-e bearing oxadiazole ring. Compound 3a, bearing 4-chloro group on phenyl ring, was found as the most effective inhibitor of urease with the IC50 value of 1.55 ±â€¯0.11 µg/mL. The molecular docking studies of the newly synthesized compounds were performed to identify the probable binding modes in the active site of the Jack bean urease (JBU) enzymes.

Synthesis, molecular docking and biological evaluation of some benzimidazole derivatives as potent pancreatic lipase inhibitors.

In this study, a new series of benzimidazole and bisbenzimidazole derivatives were prepared via the reaction of iminoester hydrochlorides and o-phenylenediamines and then screened for their lipase inhibition properties. Among the synthesized molecules, compounds 7a, 8a and 8c showed the best inhibitory effect against lipase enzyme with IC50 values of 1.72 ±â€¯0.12 µM, 1.92 ±â€¯0.28 and 0.98 ±â€¯0.07 µM, respectively. Moreover, molecular modeling studies were performed in order to understand to the inhibitory activity of the molecules. Binding poses of the studied compounds were determined at the target sites using induced fit docking (IFD) algorithms.

Synthesis and molecular docking study of some 5,6-dichloro-2-cyclopropyl-1H-benzimidazole derivatives bearing triazole, oxadiazole, and imine functionalities as potent inhibitors of urease.

A new series of benzimidazole compounds including hydrazinecarbothioamide, 1,2,4-triazole, 1,3,4-oxadiazole and imine function were synthesized starting from 5,6-dichloro-2-cyclopropyl-1H-benzimidazole. All of the benzimidazole derivatives exhibited good urease inhibitor activity. Compound 6a proved to be the most potent showing an enzyme inhibitory activity with an IC50=0.06µM. Molecular docking studies were also conducted on enzyme extracted from Jack bean urease to identify the binding mode of the newly synthesized compounds.

Design, Synthesis, and Biological Evaluation of Coumarin-Triazole Hybrid Molecules as Potential Antitumor and Pancreatic Lipase Agents.

The design, synthesis, and investigation of antitumor and anti-lipase activities of some coumarin-triazole hybrid molecules are reported. The synthesis of these hybrid molecules was performed under microwave irradiation and conventional heating procedures. The newly synthesized hybrid molecules were investigated as inhibitors against four tumor cell lines (BT20 human breast carcinoma, SK-Mel 128 melanoma, DU-145 prostate carcinoma, and A549 lung carcinoma) and porcine pancreatic lipase (PPL). Most of these compounds showed notable antitumor activities against the tested tumor cell lines, and compounds 8i and 8l showed the best anti-lipase activity of 99.30 ± 0.56% and 99.85 ± 1.21%, respectively, at a concentration of 10 µM.

A New Fluorescent "Turn-Off" Coumarin-Based Chemosensor: Synthesis, Structure and Cu-Selective Fluorescent Sensing in Water Samples.

We report the synthesis and characterization two coumarin-based fluorescence probes, N'-{[7-(diethylamino)-2-oxo-2H-chromen-3-yl]carbonyl}pyridine-3-carbohydrazide (3) and N'-benzoyl-7-(diethylamino)-2-oxo-2H-chromene-3-carbohydrazide (4), proposed as a novel fluorescent chemosensor. The two probes designed showed an instant turn-off fluorescence response to Cu2+ over other metal ions in ethanol-water mixture based on intramolecular charge transfer (ICT). It was found that pyridine-analogue coumarin is highly selective and sensitive sensor for Cu2+. The 3 sensor coordinates Cu2+ in 1:1 stoichiometry with a binding constant, Ka = 5.22 M-1 and the detection limit was calculated 1.97 × 10-9 M.

Synthesis of some novel heterocylic compounds derived from 2-[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]acetohydrazide and investigation of their lipase and α-glucosidase inhibition.

In the present study, 2-[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]acetohydrazide (1) was used as starting compound for the synthesis of 2-{[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]acetyl}-4-thiosemicarbazides (2a-c) and 5-{[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]methyl}-1,3,4-oxadiazole-2-thione (5). The cyclization of compounds 2a-c in the presence of NaOH resulted in the formation of 5-{[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]methyl}-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones (3a-c). Aminomethylation of compounds 3a-c and 5 with formaldehyde and N-methyl/phenylpiperazine furnished Mannich bases (4a-f and 6a-b). The newly synthesized compounds were well-characterized by IR, (1)H NMR, (13)C NMR, elemental analysis and mass spectral studies. They were also screened for their lipase and α-glucosidase inhibition. Among the tested compound 2c (IC50 = 2.50 ± 0.50 µM) showed the best anti-lipase activity and compounds 2c (IC50 = 3.41 ± 0.16 µM) and 6a (IC50 = 4.36 ± 0.10 µM) showed the best anti-α-glucosidase activity.

Synthesis and antioxidant activities of some new triheterocyclic compounds containing benzimidazole, thiophene, and 1,2,4-triazole rings.

Various triheterocyclic compounds containing benzimidazole, thiophene, and 1,2,4-triazole rings (3-6) were synthesized and screened for their antioxidant activities. The structures of the synthesized compounds (2-6) were judged by (1)H NMR, (13)C NMR, elemental analysis, and LC-MS spectral data. Antioxidant activities of the synthesized compounds (2-6) were determined with CUPric Reducing Antioxidant Capacity (CUPRAC), ABTS (2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)/persulfate, and DPPH (1,1-diphenyl-2-picrylhydrazyl) assays. Most of the compounds showed a significant antioxidant activity and especially, compound 5c showed very good SC50 value for DPPH method and compound 5h exhibited very high scavenging activity to ABTS method.

Synthesis of some novel 1,2,4-triazol-3-one derivatives bearing the salicyl moiety and their anticonvulsant activities.

A series of new 1,2,4-triazole-3-one derivatives bearing the salicyl moiety were synthesized by using microwave irradiation, and their chemical structures were identified by IR, (1) H NMR, (13) C NMR, elemental analysis, and LC-MS. The anticonvulsant activities of the compounds 4a-c, 4e, and 5a-e were evaluated by the Anticonvulsant Screening Program of the National Institute of Health, USA. The compounds had moderate anticonvulsant activities in the maximum electroshock-induced seizure and minimal clonic seizure models in mice, without any neurotoxic effects.

Synthesis of some new 1,2,4-triazole derivatives starting from 3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol with anti-lipase and anti-urease activities.

In the present study, starting compound 4 was prepared by deamination of compound 2 in the presence of hypophosphorous acid and sodium nitrite. Treatment of compound 4 with ethyl bromoacetate produced ethyl[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]acetate (5), which was converted to the hydrazide derivative (6) by treatment with hydrazine hydrate. The reaction of compound 6 with aromatic aldehydes resulted in the formation of arylidene hydrazides (7). Treatment of 6 with CS2 in the presence of potassium hydroxide (KOH), followed by cyclization with hydrazine hydrate, afforded 4-amino-5-{[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazole-3-thione (9). The condensation of 9 with appropriate aldehydes gave Schiff bases (10), which were converted into Mannich bases (11) in the presence of formaldehyde. All the synthesized compounds were screened for their anti-lipase and anti-urease activities. Compounds 7b, 7d, 11b, 11c, and 11d showed moderate-to-good lipase inhibitory effects compared to orlistat. Compounds 7b and 7d exhibited better anti-lipase activity. Furthermore, among the compounds tested, 11a and 11d were found to show high inhibitory effect against urease with IC50 values of 12.39 ± 0.35 and 16.12 ± 1.06 µg/mL, respectively. Compound 11c showed moderate inhibitory activity. The Mannich base containing compound 11 may be a source of good leads for the synthesis of lipase and urease dual inhibitors.