c-Met kinase is regarded as an emerging anti-cancer target for the novel drug discovery due to its central role in tumor cell biology. Dysregulated HGF/c-Met signaling is a driving factor for numerous malignancies and promotes tumor growth, invasion, dissemination and/or angiogenesis as well as resistance acquisition to some molecularly targeted therapies. In the present investigation, 3D QSAR studies were carried out to gain insight into the structural basis of the inhibitory properties of small molecules c Met kinase inhibitors. Based on the interpretation of obtained contour maps and binding mode analysis of reported Class I c-Met kinase inhibitors, key structural features have been identified for the designing of benzimidazole based c-Met kinase inhibitors. A series of sulfonyl linked benzimidazole derivatives were synthesized and characterized by 1H-NMR, 13C-NMR, and Mass (ESI-MS). The synthesized benzimidazole derivatives were screened for c-Met kinase enzyme inhibition assay and in vitro antiproliferative activity against human cancer cell line. The compound 9c was found as the most potent compound in cell based and enzyme based assays. Ligand based drug design studies and synthesis provided 1-substituted benzimidazole derivatives as c-Met kinase inhibitors and anti-cancer agents.

Design, synthesis and pharmacological evaluation of benzimidazole analogues as c-Met kinase inhibitors

ACS Spring Meeting 2021

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