Striking two targets with one scaffold via benzo[d]imidazole-isatin conjugates as potent dual VEGFR-2/c-MET antagonists.

Abstract

A series of benzo[d]imidazole-isatin hybrids (4a-d, 6a-d, and 8a-d) was developed and synthesized as prospective dual inhibitors of VEGFR-2 and c-MET to address tumor growth and resistance-related signaling pathways. The biological assessment demonstrated encouraging dual kinase inhibitory action, with compound 8b identified as the most balanced inhibitor, displaying IC50 values of 92 nM and 63 nM against VEGFR-2 and c-MET, respectively. In-vitro antiproliferative evaluation against MDA-MB-231 and A549 cancer cell lines revealed notable cytotoxicity for compound 8b, yielding IC50 values of 2.37 μM and 1.79 μM, respectively, exceeding the efficacy of the reference medication sunitinib. Additionally, 8b exhibited a favorable selectivity profile for normal MCF-10A cells. Mechanistic studies demonstrated that 8b caused substantial G2/M cell cycle arrest and facilitated apoptosis in MDA-MB-231 cells. Biomarker studies revealed a reduction in VEGF-A, MMP-9, and Bcl-2 levels, alongside an increase in Bax and Caspase-3, suggesting potential anti-angiogenic and pro-apoptotic characteristics in-vitro. Molecular docking analyses provided supporting models for the identified biological activities and exhibited advantageous binding interactions within both kinase active sites. These data collectively suggest that chemical 8b may serve as a promising candidate for further anticancer research.