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VEGFR2 has been proved to play a major role in the regulation of tumor angiogenesis. Twenty-one 4-alkoxyquinazoline-based derivatives have been designed and synthesized as vascular endothelial growth factor receptor 2 ( VEGFR2) inhibitors, and their biological activities were evaluated. Among these compounds, compound 3h exhibited the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, with the IC50 values of 2.89 n m (for VEGFR2) and 0.25 μ m (for MCF-7), which were comparable with the control compound. Docking simulation was performed to position compound 3h into the 4 ASE active site, and the result showed that compound 3h could bind well at the 4 ASE active site. [ABSTRACT FROM AUTHOR]

Two mononuclear copper(II) complexes, [Cu(C15H16NO2)2] ( 1) and [Cu(C6H9N2O4)2·3H2O] ( 2·3H2O), were synthesised and structurally characterised by single-crystal X-ray analysis. The copper(II) atom adopts a square-planar environment in complex 1, while the geometry in 2·3H2O could be described as the distorted square pyramidal. Complexes 1 and 2·3H2O were evaluated for their inhibitory activities against Helicobacter pylori ( H. pylori) urease in vitro. They both were found to have strong inhibitory activities against H. pylori urease comparable to that of acetohydroxamic acid (AHA). A docking simulation was performed to position 2 into the H. pylori urease active site to determine the probable binding conformation. [ABSTRACT FROM AUTHOR]

A Schiff-base copper(II) complex, bis(N-n-butylsalicylaldiminato)copper(II), was synthesized and its solid-state structure was determined by X-ray crystallography. Its inhibitory activity against Helicobacter pylori urease was evaluated in vitro and it showed strong inhibitory activity against urease (IC50 = 0.95 µM), compared with acetohydroxamic acid (IC50 = 42.47 µM) as a positive reference. A docking analysis using the AUTODOCK 4.0 program was performed to explain the potent inhibitory activity of the complex against urease. [ABSTRACT FROM AUTHOR]

Graphical abstract Compounds of novel cinnamic acyl sulfonamide derivatives as tubulin polymerization inhibitors were designed, synthesized and evaluated for the inhibitory activity against tubulin polymerization and cancer cell inhibitory activity. Docking simulation and 3D-QSAR of these compounds were also conducted. Highlights • 15 novel cinnamic acyl sulfonamide derivatives have been synthesized. • Their biological activities were as potential tubulin polymerization inhibitors. • Compound 5a showed the most inhibitory activity against tubulin and cancer cells. • Crystal structures of compounds 5b and 6c were determined. Abstract A new series of novel cinnamic acyl sulfonamide derivatives were designed and synthesized and evaluated their anti-tubulin polymerization activities and anticancer activities. One of these compounds, compound 5a with a benzdioxan group, was observed to be an excellent tubulin inhibitor (IC 50 = 0.88 µM) and display the best antiproliferative activity against MCF-7 with an IC 50 value of 0.17 μg/mL. Docking simulation was performed to insert compound 5a into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent anti-tubulin polymerization activity. [ABSTRACT FROM AUTHOR]

Four novel mononuclear complexes, [Cd( L ) 2 ·2H 2 O] ( 1 ), [Ni( L ) 2 ·2H 2 O] ( 2 ) [Cu( L ) 2 ·H 2 O] ( 3 ), and [Zn( L ) 2 ·2H 2 O] ( 4 ) (CCDC numbers: 1444630–1444633 for complexes 1 – 4 ) (HL = 4-(2,3-dichlorophenyl)piperazine-1-carboxylic acid) were synthesized, and have been characterized by IR spectroscopy, elemental analysis, and X-ray crystallography. Molecular docking study preliminarily revealed that complex 1 had potential telomerase inhibitory activity. In accordance with the result of calculation, in vitro tests of the inhibitory activities of complex 1 against telomerase showed complex 1 (IC 50 = 8.17 ± 0.91 μM) had better inhibitory activities, while complexes 2 , 3 and 4 showed no inhibitory activities. Antiproliferative activity in human cancer cell line HepG2 was further determined by MTT assays. The IC 50 value (6.5 ± 0.2 μM) for the complex 1 having good inhibitory activity against HepG2 was at the same micromolar concentrations with cis -platinum (2.2 ± 1.2 μM). While the IC 50 value for the metal-free ligand, complex 2 , 3 and 4 was more than 100 μM. These results indicated that telomerase was potentially an anticancer drug target and showed that complex 1 was a potent inhibitor of human telomerase as well as an antiproliferative compound. [ABSTRACT FROM AUTHOR]

Therapies based on urease inhibition are now seriously considered as the first line of treatment for infections caused by Helicobacter pylori . However, the present inhibitors are ineffective or unstable in highly acidic gastric juice. Here, we report a series of benzylanilines as effective inhibitors of H. pylori urease. Out of the obtained twenty-one compounds, N -(3,4-dihydroxybenzyl)-4-nitroaniline ( 4 ) was evaluated in detail and shows promising features for development as anti- H. pylori agent. Excellent potency against urease in both cell-free extract and intact cell was observed at low concentrations of 4 (IC 50 = 0.62 ± 0.04 and 1.92 ± 0.09 μM), which showed over 29- and 54-fold increase in potency with respect to the positive control AHA. The SAR analysis revealed that protection of 3,4-dihydroxy group of 4 as methoxy or changes of 4-NO 2 will result in a moderate to dramatic decrease in potency. [ABSTRACT FROM AUTHOR]

Many reports implied that the BRAF serine/threonine kinase was mutated in various types of human tumors, which were related with cell growth, survival and differentiation. To provide new therapeutic opportunities, a series of novel 4,5-dihydro-1 H -pyrazole derivatives ( 6a – 10d ) containing thiazole moiety as potential V600E mutant BRAF kinase (BRAF V600E ) inhibitors were designed and synthesized. All compounds were evaluated in vitro for anticancer activities against WM266.4 human melanoma cell line and breast cancer MCF-7 cell line. Compound 10d displayed the most potential antiproliferative activity with an IC 50 value of 0.12 μM against cell line WM266.4 and 0.16 μM against MCF-7 with positive control Sorafenib. Results of the inhibitory activity against BRAF V600E revealed that compound 10d was bearing the best bioactivity with IC 50 of 0.05 μM as well. On the basis of the result of flow cytometry, with the dose of compound 10d increasing, more and more cancer cell gradually encountered apoptosis or died, which indicated the compound 10d could induce remarkable apoptosis of MCF-7 and WM266.4 cells in a dose dependent manner. Furthermore, docking simulation of inhibitor analogues and 3D-QSAR modeling provided potential binding model and further knowledge of pharmacophore. [ABSTRACT FROM AUTHOR]

A series of novel 5-phenyl-1 H -pyrazole derivatives ( 5a – 5u ) containing niacinamide moiety were synthesized and evaluated for biological activity as potential BRAF V600E inhibitors. Among them, compound 5h exhibited the most potent inhibitory activity with an IC 50 value of 0.33 μM for BRAF V600E . Antiproliferative assay results indicated that compound 5h has better antiproliferative activity against WM266.4 and A375 in vitro with IC 50 value of 2.63 and 3.16 μM, respectively, being comparable with the positive control vemurafenib. Molecular docking of 5h into the BRAF V600E active site was performed to determine the probable binding mode. Furthermore, molecular docking and 3D QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives. [ABSTRACT FROM AUTHOR]

Abstract: A series of 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety (3a–3r) has been designed, synthesized and their biological activities were also evaluated as potential antiproliferation and focal adhesion kinase (FAK) inhibitors. Among all the compounds, 3p showed the most potent activity in vitro which inhibited the growth of A549 with IC50 value of 3.11μM and Hela with IC50 value of 2.54μM respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC50 =0.45μM). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model. [Copyright &y& Elsevier]

Abstract: The kinesin spindle protein (KSP) is involved in the formation of bipolar mitotic spindle during cell division and it becomes a new target to overcome the neurotoxicity of MTs inhibitors. A series of flavone and isoflavone derivatives (1a–7c) have been designed, synthesized and evaluated as potential KSP inhibitors. Among them, 2c displayed the most potent inhibitory activity in vitro, which inhibited the growth of MCF-7 and Hela cell lines with IC50 values of 4.8 and 4.3 μM, respectively, and also exhibited significant KSP inhibitory activity (IC50 = 0.023 μM). The new compounds can induce irregular monoastral spindles, the characteristic phenotype for KSP inhibiting agents. Docking simulation was further performed to determine the probable binding model. [Copyright &y& Elsevier]

Abstract: A series of novel aryl-2H-pyrazole derivatives bearing 1,4-benzodioxan or 1,3-benzodioxole moiety were designed as potential telomerase inhibitors to enhance the ability of aryl-2H-pyrazole derivatives to inhibit telomerase, a target of anticancer. The telomerase inhibition tests showed that compound 16A displayed the most potent inhibitory activity with IC50 value of 0.9μM for telomerase. The antiproliferative tests showed that compound 16A exhibited high activity against human gastric cancer cell SGC-7901 and human melanoma cell B16-F10 with IC50 values of 18.07 and 5.34μM, respectively. Docking simulation showed that compound 16A could bind well with the telomerase active site and act as telomerase inhibitor. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent telomerase inhibitory activity. [Copyright &y& Elsevier]

Abstract: Three series of novel heterocyclic azoles derivatives containing pyrazine (5a–5k, 8a–8k and 11a–11k) have been designed, synthesized, structurally determined, and their biological activities were evaluated as potential telomerase inhibitors. Among the oxadiazole derivatives, compound 5c showed the most potent biological activity against SW1116 cancer cell line (IC50 =2.46μM against SW1116 and IC50 =3.55μM for telomerase). Compound 8h performed the best in the thiadiazole derivatives (IC50 =0.78μM against HEPG2 and IC50 =1.24μM for telomerase), which was comparable to the positive control. While compound 11f showed the most potent biological activity (IC50 =4.12μM against SW1116 and IC50 =15.03μM for telomerase) among the triazole derivatives. Docking simulation by positioning compounds 5c, 8h and 11f into the telomerase structure active site was performed to explore the possible binding model. The results of apoptosis demonstrated that compound 8h possessed good antitumor activity against HEPG2 cancer cell line. Therefore, compound 8h with potent inhibitory activity in tumor growth inhibition may be a potential antitumor agent against HEPG2 cancer cell. Therefore, the introduction of oxadiazole, thiadiazole and triazole structures reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity. [Copyright &y& Elsevier]

Abstract: A series of 1,3,4-thiadiazol-2-amide derivatives (5a–5y) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and FAK inhibitors. Among all the compounds, 5h showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC50 values of 0.45 and 0.31μM, respectively. Compound 5h also exhibited significant FAK inhibitory activity (IC50 =5.32μM). Docking simulation was performed to position compound 5h into the FAK structure active site to determine the probable binding model. The results of antiproliferative and Western-blot assay demonstrated that compound 5h possessed good antiproliferative activity. Therefore, compound 5h with potent FAK inhibitory activity may be a potential anticancer agent. [Copyright &y& Elsevier]

Abstract: In present study, a series of new 1,3,4-oxadiazole derivatives containing 1,4-benzodioxan moiety (6a–6s) as potential telomerase inhibitors were synthesized. The bioassay tests demonstrated that compounds 6k, 6l, 6m, 6n and 6s exhibited broad-spectrum antitumor activity with IC50 concentration range from 7.21μM to 25.87μM against the four cancer cell lines, HEPG2, HELA, SW1116 and BGC823. Moreover, all the title compounds were assayed for telomerase inhibition using the TRAP-PCR-ELISA assay. The results showed compound 6k possessed the most potent telomerase activity (IC50 =1.27±0.05μM). Docking simulation was performed to position compound 6k into the active site of telomerase (3DU6) to determine the probable binding model. [Copyright &y& Elsevier]

Abstract: Thirty-five 3-aryl-4-arylaminofuran-2(5H)-one derivatives were designed, prepared and tested for their inhibitory activity against tyrosyl-tRNA synthetase. Out of these compounds, 3-(3-bromophenyl)-4-(3,5-dichlorophenylamino)furan-2(5H)-one (35) was the most active with IC50 of 0.09 ± 0.02 μM. The structure–activity relationship revealed that introduction of chlorine atoms at both meta positions of aniline moiety significantly increased the enzyme inhibitory activity. The results of antibacterial assay revealed that the tested compounds showed good activity against Gram-positive bacteria, with 35 being the most potent with MIC50 of 0.06 μg/mL against Staphylococcus aureus ATCC 25923. Molecular docking of 35 into S. aureus tyrosyl-tRNA synthetase active site was also performed. The inhibitor snugly fitting the active site may well explain its excellent inhibitory activity. [Copyright &y& Elsevier]

Abstract: Fourty-two thiazolyl-pyrazoline derivatives were synthesized to screen for their EGFR kinase inhibitory activity. Compound 4-(4-chlorophenyl)-2-(3-(3,4-dimethylphenyl)-5-p-tolyl-4,5-dihydro-1H-pyrazol-1-yl)thiazole (11) displayed the most potent EGFR TK inhibitory activity with IC50 of 0.06μM, which was comparable to the positive control. Molecular docking results indicated that compound 11 was nicely bound to the EGFR kinase. Compound 11 also showed significant antiproliferative activity against MCF-7 with IC50 of 0.07μM, which would be a potential anticancer agent. [Copyright &y& Elsevier]

Abstract: A series of novel 4-alkoxy-3-arylfuran-2(5H)-ones as tyrosyl-tRNA synthetase inhibitors were synthesized. Of these compounds, 3-(4-hydroxyphenyl)-4-(2-morpholinoethoxy)furan-2(5H)-one (27) was the most potent. The binding model and structure–activity relationship indicate that replacement of morpholine-ring in the side chain of 27 with a substituent containing more hydrophilic groups would be more suitable for further modification. Antibacterial assay revealed that the synthetic compounds are effective against growth of Gram-positive organisms, and 27 is the most potent agent against Staphylococcus aureus ATCC 25923 with MIC50 value of 0.23μg/mL. [Copyright &y& Elsevier]

Abstract: Twenty-three resveratrol derivatives possessing chalcone moiety were synthesized and characterized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Compound C19 exhibited the most potent activity in vitro, which inhibited the growth of HepG2, B16-F10, and A549 cell lines with IC50 values of 0.2, 0.1, and 1.4μg/mL, respectively. Compound C19 also exhibited significant tubulin polymerization inhibitory activity (IC50 =2.6μg/mL). Docking simulation was performed to position compound C19 into the tubulin–colchicine binding site to determine the probable binding mode. [Copyright &y& Elsevier]

Abstract: Thirty-one 3-aryl-4-alkylaminofuran-2(5H)-ones were designed, prepared and tested for their antibacterial activity. Some of them showed significant antibacterial activity against Gram-positive organisms, especially against Staphylococcus aureus ATCC 25923, but all were inactive against Gram-negative organisms. Out of these compounds, 3-(4-bromophenyl)-4-(2-(4-nitrophenyl)hydrazinyl)furan-2(5H)-one (4a11) showed the most potent antibacterial activity against S. aureus ATCC 25923 with MIC50 of 0.42μg/mL. The enzyme assay revealed that the possible antibacterial mechanism of the synthetic compounds might be due to their inhibitory activity against tyrosyl-tRNA synthetase. Molecular dockings of 4a11 into S. aureus tyrosyl-tRNA synthetase active site were also performed. This inhibitor snugly fitting the active site might well explain its excellent inhibitory activity. Meanwhile, this modeling disclosed that a more suitable optimization strategy might be to modify the benzene ring at 3-position of furanone with hydrophilic groups. [Copyright &y& Elsevier]

Abstract: A series of N-phenylnicotinamides (1–40) were designed and evaluated in vitro for their COX inhibitory activities. Most of the synthesized compounds were proved to be potent and selective inhibitors of COX-1. Compound 28 showed the most potent COX-1 inhibitory activity (COX-1 IC50 =0.68±0.07μM) and good selectivity (COX-2 IC50 >100μM). This compound may be useful as a lead compound for superior COX-1 inhibitors. On the basis of the biological results, structure–activity relationships for the COX-1-inhibitory activities of the synthesized N-phenylnicotinamides were discussed concisely. [Copyright &y& Elsevier]

Abstract: A series of N-(2-morpholinoethyl)nicotinamide (1–13) and N-(3-morpholinopropyl)nicotinamide derivatives (14–26) have been designed, synthesized and evaluated in vitro for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. Most of these synthesized compounds proved to be potent, and selective inhibitors of MAO-A rather than of MAO-B. 5-Chloro-6-hydroxy-N-(2-morpholinoethyl)nicotinamide (13) displayed the highest MAO-A inhibitory potency (IC50 =0.045μM) and a good selectivity. 2-Bromo-N-(2-morpholinoethyl)nicotinamide (3) was the most potent MAO-B inhibitor with the IC50 value of 0.32μM, but it was not selective. Molecular dockings of compound 13 were performed in order to give structural insights regarding the MAO-A selectivity. [Copyright &y& Elsevier]

Abstract: A series of amide-coupled benzoic nitrogen mustard derivatives as potential EGFR and HER-2 kinase inhibitors were synthesized and reported for the first time. Some of them exhibited significant EGFR and HER-2 inhibitory activity. Of all the studied compounds, compounds 5b and 5t exhibited the most potent inhibitory activity, which was comparable to the positive control erlotinib. Docking simulation was performed to position compounds 5b and 5t into the EGFR active site to determine the probable binding model. Antiproliferative assay results indicated that some of the benzoic nitrogen mustard derivatives possessed high antiproliferative activity against MCF-7. In particular, compounds 5b and 5t with potent inhibitory activity in tumor growth inhibition may function as potential antitumor agents. [Copyright &y& Elsevier]