ABSTRACT
A series of novel 1,3,4-oxadiazole thioether derivatives (compounds 9-44) were designed and synthesized as potential inhibitors of thymidylate synthase (TS) and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 18 bearing a nitro substituent exhibited more potent in vitro anticancer activities with IC50 values of 0.7±0.2, 30.0±1.2, 18.3±1.4 µM, respectively, which was superior to the positive control. In the further study, it was identified as the most potent inhibitor against two kinds of TS protein (for human TS and Escherichia coli TS, IC50 values: 0.62 and 0.47 µM, respectively) in the TS inhibition assay in vitro and the most potent antibacterial agents with MIC (minimum inhibitory concentrations) of 1.56-3.13 µg/mL against the tested four bacterial strains. Molecular docking and 3D-QSAR study supported that compound 18 can be selected as dual antitumor/antibacterial candidate in the future study.
Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Thymidylate Synthase/antagonists & inhibitors , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Escherichia coli/enzymology , Humans , Kinetics , Microbial Sensitivity Tests , Models, Molecular , Quantitative Structure-Activity Relationship , Structure-Activity Relationship , Thermodynamics , Thymidylate Synthase/chemistryABSTRACT
Two series of novel naphthalin-containing pyrazoline derivatives C1-C14 and D1-D14 have been synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. Compound D14 displayed the most potent activity against EGFR and A549 cell line (IC(50)=0.05 µM and GI(50)=0.11 µM), being comparable with the positive control Erlotinib (IC(50)=0.03 µM and GI(50)=0.03 µM) and more potent than our previous compounds C0-A (IC(50)=5.31 µM and GI(50)=33.47 µM) and C0-B (IC(50)=0.09 µM and GI(50)=0.34 µM). Meanwhile, compound C14 displayed the most potent activity against HER-2 and MCF-7 cell line (IC(50)=0.88 µM and GI(50)=0.35 µM), being a little less potent than Erlotinib (IC(50)=0.16 µM and GI(50)=0.08 µM) but far more potent than C0-A (IC(50)=6.58 µM and GI(50)=27.62 µM) and C0-B (IC(50)=2.77 µM and GI(50)=3.79 µM). The docking simulation was performed to analyze the probable binding models and the QSAR models were built for reasonable design of EGFR/HER-2 inhibitors at present and in future. The structural modification of introducing naphthalin moiety reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity. Moreover, the replacement of thiourea skeleton by using benzene ring resulted in the slight diversity of the two series towards specific targets.
Subject(s)
Antineoplastic Agents/chemistry , Drug Design , Naphthalenes/chemistry , Pyrazoles/chemistry , Thiourea/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Binding Sites , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Erlotinib Hydrochloride , Humans , MCF-7 Cells , Molecular Conformation , Molecular Docking Simulation , Protein Structure, Tertiary , Pyrazoles/chemical synthesis , Pyrazoles/toxicity , Quantitative Structure-Activity Relationship , Quinazolines/chemistry , Quinazolines/toxicity , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/metabolismABSTRACT
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 IC(50) value of 0.9 µM 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 IC(50) values of 18.07 and 5.34 µM, 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.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Telomerase/antagonists & inhibitors , Binding Sites , Cell Growth Processes/drug effects , Enzyme Inhibitors/chemical synthesis , Humans , Models, Molecular , Pyrazoles/chemical synthesis , Quantitative Structure-Activity Relationship , Telomerase/chemistry , Telomerase/metabolismABSTRACT
Twenty new Schiff bases were synthesized by reacting 5-fluoro-salicylaldehyde and primary amine as potent inhibitors of FabH. These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas fluorescence, Bacillus subtilis and Staphylococcus aureus. Compounds with potent antibacterial activities were tested for their E. coli FabH inhibitory activity. (E)-4-fluoro-2-((4-hydroxyphenethylimino)methyl)phenol (10) showed the most potent antibacterial activity with MIC of 1.56-6.25 microg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC(50) of 2.7 microM. Docking simulation was performed to position compound 10 into the E. coli FabH active site to determine the probable binding conformation.