1. Synthesis and biological evaluation of some novel thiobenzimidazole derivatives as anti-renal cancer agents through inhibition of c-MET kinase.
- Author
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Ibrahim, Hany S., Albakri, Mohamed E., Mahmoud, Walaa R., Allam, Heba Abdelrasheed, Reda, Ahmed M., and Abdel-Aziz, Hatem A.
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BIOSYNTHESIS , *MITOGEN-activated protein kinases , *CELL populations , *CELL cycle , *CELL lines , *BENZIMIDAZOLES - Abstract
Graphical abstract Highlights • 2-Substituted thiobenzimidazoles were synthesized and screened against A498 cell line. • The best IC 50 value was for compound 4a with (IC 50 = 6.97 µM) compared to sunitinib. • Compound 4a affected G2/M phases basically and was proved as late apoptotic inducer. • Compound 4a revealed good inhibitory activity against c-Met kinase (IC 50 = 0.27 µM). • Docking of 4a at c-Met kinase active site demonstrated good binding interactions. • Compound 4a showed a suitable predicted ADME profile. Abstract Benzimidazole is an interesting scaffold constituting a main core in many anticancer agents against variable cell lines as Carbendazim (I) and Nocodazole (II). Accordingly, eighteen compounds of 2-((1H-benzoimidazol-2-yl)thio)-1-(aryl/heteroaryl)ethan-1-ones, in their sulfate salt and free forms, were designed and investigated as anticancer agents. In vitro preliminary screening of selected compounds by the National Cancer Institute (NCI) on a panel of 60 cell lines revealed renal cancer cell line (A498) as the most vulnerable cell line; accordingly, IC 50 values against A498 cell line were determined for compounds with the best results. The best inhibitory activity was for compound 4a with (IC 50 = 6.97 µM) compared to sunitinib as a reference drug (IC 50 = 6.99 µM). Compound 4a was further subjected to cell cycle analysis that indicated the decrease in cell population in the G2/M phase when compared to the untreated control cells. In addition, it showed significant increase in the late apoptosis in Annexin-V FTIC study compared to the control cells. An enzymatic inhibitory study on compound 4a against c-Met and MAP kinases revealed its better activity against c-Met kinase with (IC 50 = 0.27 µM) compared to sunitinib (IC 50 = 0.18 µM). Molecular docking study was conducted to reveal the interactions of compound 4a in the active site of c-Met kinase. Computational ADME study was performed to insure that compound 4a has proper pharmacokinetic and drug-likeness properties. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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