Benzimidazole-Based VEGFR-2 Inhibitors Inspired by Sorafenib: Synthesis, Biological Evaluation, and Mechanistic Insights.

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a central role in tumor angiogenesis and remains a well-established therapeutic target in cancer treatment. In this study, twenty-six benzimidazole-based derivatives (3a-k, 5a-d, 8a-g, and 10a-d) were rationally designed to incorporate the essential structural and pharmacophoric features required for effective VEGFR-2 inhibition, followed by their synthesis and biological evaluation. In vitro kinase assays demonstrated that the synthesized derivatives inhibited VEGFR-2 with IC50 values ranging from 0.061 to 1.895 µM. Based on their enzymatic potency, the most active compounds (3f, 3h, 3j, 8d, and 8g) were further investigated for antiproliferative activity against HUVEC, MCF-7, and HepG2 cell lines. Among them, Compound 3f exhibited IC50 values of 13.34, 5.32, and 5.02 µM, respectively, showing activity comparable to sorafenib. Evaluation against normal MCF-10A and Vero cell lines indicated favorable biocompatibility and a reasonable selectivity profile. Mechanistic studies revealed that 3f induced G2/M-phase arrest, promoted apoptosis, and suppressed cell migration, accompanied by a reduction in VEGFR-2 protein expression levels. Molecular docking suggested that the synthesized derivatives adopt a binding mode consistent with Type II VEGFR-2 inhibitors, while in silico ADME and toxicity predictions supported an acceptable toxicity profile and drug-like characteristics.