Synthesis,biological evaluation,and molecular docking studies of novel 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety as FAK inhibitors with anticancer activity

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 3.11 μM and Hela with IC₅₀ value of 2.54 μM respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC₅₀ = 0.45 μM). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model.     

Synthesis, biological evaluation, and molecular docking studies of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan moiety as potential anticancer agents

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 IC(50) concentration range from 7.21 μM to 25.87 μM 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 (IC(50)=1.27 ± 0.05 μM). Docking simulation was performed to position compound 6k into the active site of telomerase (3DU6) to determine the probable binding model.     

Synthesis and antitumor activity of 1,3,4-oxadiazole possessing 1,4-benzodioxan moiety as a novel class of potent methionine aminopeptidase type II inhibitors

A series of 1,3,4-oxadiazole derivatives containing 1,4-benzodioxan moiety (7a–7q) have been designed, synthesized and evaluated for their antitumor activity. Most of the synthesized compounds were proved to have potent antitumor activity and low toxicity. Among them, compound 7a showed the most potent biological activity against Human Umbilical Vein Endothelial cells, which was comparable to the positive control. The results of apoptosis and flow cytometry (FCM) demonstrated that compound 7a induce cell apoptosis by the inhibition of MetAP2 pathway. Molecular docking was performed to position compound 7a into MetAP2 binding site in order to explore the potential target.     

Synthesis and biological evaluation of novel acylhydrazone derivatives as potential antitumor agents

We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4-yl)anthranilic acid hydrazide, and some analogues bearing a (2-trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4-(diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI₅₀ values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents.     

Synthesis, biological evaluation and molecular docking studies of 1,3,4-oxadiazole derivatives as potential immunosuppressive agents

A series of 1,3,4-oxadiazole derivatives derived from 4-methoxysalicylic acid or 4-methylsalicylic acid (6a-6z) have been first synthesized for their potential immunosuppressive activity. Among them, compound 6z displayed the most potent biological activity against lymph node cells (inhibition=38.76% for lymph node cells and IC(50)=0.31 μM for PI3Kγ). The preliminary mechanism of compound 6z inhibition effects was also detected by flow cytometry (FCM) and the compound exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Docking simulation was performed to position compound 6z into the PI3Kγ structure active site to determine the probable binding model.     

Synthesis, biological evaluation, and molecular docking studies of 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety as potential antitumor agents

A series of new 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety were synthesized. Antiproliferative assay results indicated that compounds 6o and 6u exhibited the most potent activity against gastric cancer cell SGC-7901, which was more potent than the positive control. Especially, compound 6o exhibited significant telomerase inhibitory activity (IC(50)=2.3±0.07μM), which was comparable to the positive control ethidium bromide. Docking simulation was performed to position compound 6o into the active site of telomerase (3DU6) to determine the probable binding model.     

Synthesis, biological evaluation, and molecular docking studies of cinnamic acyl 1,3,4-thiadiazole amide derivatives as novel antitubulin agents

A series of cinnamic acyl 1,3,4-thiadiazole amide derivatives (6a-10e) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Among all the compounds, 10e showed the most potent activity in vitro, which inhibited the growth of MCF-7 and A549 cell lines with IC(50) values of 0.28 and 0.52μg/mL, respectively. Compound 10e also exhibited significant tubulin polymerization inhibitory activity (IC(50)=1.16μg/mL). Docking simulation was performed to insert compound 10e into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. Based on the preliminary results, compound 10e with potent inhibitory activity in tumor growth may be a potential anticancer agent.     

Synthesis, molecular docking and biological evaluation of 1,3,4-oxadiazole derivatives as potential immunosuppressive agents

A series of novel 1,3,4-oxadiazole derivatives (5a-5s) have been designed, synthesized and evaluated for their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, compounds (5m-5r) showed the most potent biological activity against lymph node cells. The results of flow cytometry (FCM) and western blotting demonstrated that compound 5q induce cell apoptosis by the inhibition of PI3K/AKT pathway. Molecular docking was performed to position compound 5q into PI3Kγ binding site in order to explore the potential target.     

Synthesis,biological evaluation and molecular docking studies of amide-coupled benzoic nitrogen mustard derivatives as potential antitumor agents

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.     

Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents

A series of novel pazopanib derivatives, 7a–m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by ¹H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC₅₀ values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7m demonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.     

Synthesis,biological evaluation and molecular docking analysis of novel benzopyrimidinone derivatives as potential anti-tyrosinase agents

2-substitued-benzopyrimidinones 2 were synthesized in high to excellent yields in a single step via condensation of 2-aminobenzamide 1 with some aryl-aldehydes in the presence of iodine. Cyclocondensation reaction of hydrazides 3 which were obtained in two steps from benzopyrimidinones 2, with some electrophilic species such as 2,4-pentandione, 2,5-hexandione, 1-phenylbutan-1,3-dione and cyclic anyhdrides provided the new compounds 4a–c, 5a–c, 6a–c, 7a–c, 8a–c and 9a–c. The synthesized compounds were characterized by spectroscopic means. They were also evaluated for their anti-tyrosinase potential. The structure-activity relationship (SAR) was discussed on the basis of the molecular docking analysis.     

Synthesis,molecular docking and biological evaluation of coumarin derivatives containing piperazine skeleton as potential antibacterial agents

A series of 4-hydroxycoumarin derivatives were designed and synthesized in order to find some more potent antibacterial drugs. Their antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus were tested. These compounds showed good antibacterial activities against Gram-positive strains. Compound 4g represented the most potent antibacterial activity against Bacillus subtilis and S. aureus with MIC of 0.236, 0.355 μg/mL, respectively. What’s more, it showed the most potent activity against SaFabI with IC₅₀ of 0.57 μM. Molecular docking of 4g into S. aureus Enoyl-ACP-reductase active site were performed to determine the probable binding mode, while the QSAR model was built to check the previous work as well as to introduce new directions.     

Synthesis,molecular docking and biological evaluation of metronidazole derivatives containing piperazine skeleton as potential antibacterial agents

Metronidazole has a broad-spectrum antibacterial activity. Hereby a series of novel metronidazole derivatives were designed and synthesized based on nitroimidazole scaffold in order to find some more potent antibacterial drugs. For these compounds which were reported for the first time, their antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus were tested. These compounds showed good antibacterial activities against Gram-positive strains. Compound 4m represented the most potent antibacterial activity against S. aureus ATCC 25923 with MIC of 0.003 μg/mL and it showed the most potent activity against S. aureus TyrRS with IC₅₀ of 0.0024 μM. Molecular docking of 4m into S. aureus tyrosyl-tRNA synthetase active site were also performed to determine the probable binding mode.     

Synthesis, biological evaluation, and molecular docking studies of 1,3,4-thiadiazol-2-amide derivatives as novel anticancer agents

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 IC(50) values of 0.45 and 0.31 μM, respectively. Compound 5h also exhibited significant FAK inhibitory activity (IC(50)=5.32 μM). 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.     

Novel vanillin derivatives containing a 1,3,4-thiadiazole moiety as potential antibacterial agents

In this study, thirty-four novel vanillin derivatives containing a 1,3,4-thiadiazole structure were obtained and their antibacterial activities were evaluated. The results indicate that most of the title compounds displayed inhibitory effects on Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas oryzae pv. oryzicola (Xoc). Among them, compound 29 exhibited excellent antibacterial activities against Xoo and Xoc in vitro, with the EC₅₀ values of 3.14 and 8.83 μg/mL, respectively, much superior to thiodiazole copper (87.03 and 108.99 μg/mL) and bismerthiazol (67.64 and 79.26 μg/mL). Under greenhouse condition, the protective efficiency of compound 29 against rice bacterial leaf blight was 49.34%, and curative efficiency was 40.96%. In addition, compound 29 can reduce the exopolysaccharides production of Xoo, increase the permeability of cell membrane and damage cell membrane.     

Synthesis and molecular docking studies of novel 2-chloro-pyridine derivatives containing flavone moieties as potential antitumor agents

A series of novel 2-chloro-pyridine derivatives containing flavone, chrome or dihydropyrazole moieties as potential telomerase inhibitors were synthesized. The bioassay tests showed that compounds 6e and 6f exhibited some effect against gastric cancer cell SGC-7901 with IC₅₀ values of 22.28 ± 6.26 and 18.45 ± 2.79 μg/mL, respectively. All title compounds were assayed for telomerase inhibition by a modified TRAP assay, the results showed that compound 6e can strongly inhibit telomerase with IC₅₀ value of 0.8 ± 0.07 μM. Docking simulation was performed to position compound 6e into the active site of telomerase (3DU6) to determine the probable binding model.     

Synthesis and biological evaluation of baicalein derivatives as potent antitumor agents

Baicalein (5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one), a major flavonoid extracted from the root of Scutellaria baicalensis Georgi (Chinese name: Huangqin), showed potent anti-proliferative activity against a broad panel of human cancer cell lines both in vitro and in vivo. A novel series of baicalein derivatives were synthesized by introducing a group to C6-OH and a nitrogen-containing hydrophilic heterocyclic ring to C7-OH via a length of 3 or 4-carbon chain in this study. The in vitro antiproliferative activities of the 30 derivatives against HepG2, A549, BCG-823 cancer cell lines were evaluated. Among them, 10 compounds exhibit more potent cytotoxicity than baicalein against the three cancer cell lines. The most potent compound 9b possesses highest anti-proliferative potency against HepG2, A549, and BCG-823 with an IC₅₀ value of 2.0 μM, 0.8 μM and 3.2 μM, respectively. Preliminary mechanism studies with compound 9b using Annexin V/PI double-staining assay and DAPI staining assay indicated that 9b inhibits tumor cell proliferation potentially through inducing apoptosis.     

Synthesis,biological evaluation and molecular docking studies of aminochalcone derivatives as potential anticancer agents by targeting tubulin colchicine binding site

A series of aminochalcone derivatives have been synthesized, characterized by HRMS, ¹H NMR and ¹³C NMR and evaluated for their antiproliferative activity against HepG2 and HCT116 human cancer cell lines. The most of new synthesized compounds displayed moderate to potent antiproliferative activity against test cancer cell lines. Among the derivatives, compound 4 displayed potent inhibitory activity with IC₅₀ values ranged from 0.018 to 5.33 μM against all tested cancer cell lines including drug resistant HCT-8/T. Furthermore, this compound showed low cytotoxicity on normal human cell lines (LO2). The in vitro tubulin polymerization assay showed that compound 4 inhibited tubulin assembly in a concentration-dependent manner with IC₅₀ value of 7.1 μM, when compared to standard colchicine (IC₅₀ = 9.0 μM). Further biological evaluations revealed that compound 4 was able to arrest the cell cycle in G2/M phase. Molecular docking study demonstrated the interaction of compound 4 at the colchicine binding site of tubulin. All the results indicated that compound 4 is a promising inhibitor of tubulin polymerization for the treatment of cancer.     

Synthesis of matrinic amide derivatives containing 1,3,4-thiadiazole scaffold as insecticidal/acaricidal agents

In continuation of our program aimed at the development of natural product-based pesticidal agents, a series of matrinic amide derivatives containing 1,3,4-thiadiazole scaffold were prepared, and their insecticidal and acaricidal activities were evaluated against Mythimna separata and Tetranychus cinnabarinus. Some compounds exhibited potent insecticidal and acaricidal activities. It suggested that R¹ as a nitro group and R² as a fluorine atom, were important for the insecticidal activity; R¹ as the electron-donating groups and R² as the methyl group, were necessary for the acaricidal activity.     

Molecular docking studies,biological and toxicity evaluation of dihydroisoquinoline derivatives as potential anticancer agents

We report a study of a series of isoquinoline derivatives, including their synthesis, in vitro microsomal leucine aminopeptidase (LAP) inhibition and antiproliferative activity on cancer cell lines. Among fourteen tested compounds, one (compound 3b) was determined to have good activity against LAP and significant antiproliferative activity against HL-60 human promyelocytic leukemia, Burkitt’s lymphoma Raji, camptothecin resistant CEM/C2 leukemia cells with mutated catalytic site of topoisomerase I, its parental cell line CCRF/CEM and LoVo colon cancer. Its influence on the cell cycle was also observed. Moreover, we have confirmed that antiproliferative activity towards cancer cells is due to LAP inhibition. Docking simulation based on positioning compound 3b into the LAP active site was performed to explore the possible binding mode. The compound was able to form hydrogen bonds with Gly362 and coordinate zinc ions, which was previously suggested to be essential for inhibitory activity. Compound 3b was also characterized with a good selectivity index for cancer versus normal mammalian cells. Toxicological studies involving examination of skin sensitization, acute skin irritation/corrosion, acute dermal toxicity, acute oral toxicity and acute eye irritation/corrosion established that compound 3b is safe for use.