Synthesis and biological evaluation of some novel thiobenzimidazole derivatives as anti-renal cancer agents through inhibition of c-MET kinase.

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Ibrahim HS, Albakri ME, Mahmoud WR, Allam HA, Reda AM, Abdel-Aziz HA

Synthesis and biological evaluation of some novel thiobenzimidazole derivatives as anti-renal cancer agents through inhibition of c-MET kinase.

Bioorg Chem. 2019 Apr;85:337-348. doi: 10.1016/j.bioorg.2019.01.006. Epub 2019 Jan 8.

PubMed ID

30658233 [ View in PubMed

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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, IC50 values against A498 cell line were determined for compounds with the best results. The best inhibitory activity was for compound 4a with (IC50=6.97microM) compared to sunitinib as a reference drug (IC50=6.99microM). 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 (IC50=0.27microM) compared to sunitinib (IC50=0.18microM). 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.

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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Sunitinib	Hepatocyte growth factor receptor	Protein	Humans	Unknown	Inhibitor	Details