New Benzimidazole Scaffolds Tagged With Isatin/Thiourea Motifs as Anti-Cancer Agents: Promising Approach for VEGFR-2 Inhibition.

Abstract

Inspired by the structural insights of the reported kinase inhibitor Sorafenib, two new series comprising 19 benzimidazole-based compounds incorporating isatin and thiourea motifs were rationally designed as a novel VEGFR-2-targeting anti-cancer chemotype. These compounds were synthesized and evaluated for their anti-cancer activity using the NCI single-dose antiproliferative assay against 60 cancer cell lines. The most potent and broad-spectrum compounds 8e, 9b, 9d, 9e, 9g, 9h, and 9i were further selected by NCI for the five-dose assay panel. These compounds were then assessed for anti-angiogenic activity against VEGFR-2, where compound 9i revealed promising activity (IC₅₀ = 58 nM) compared to Sorafenib (IC₅₀ = 72 nM), while the rest of the compounds gave an IC₅₀ range of 96-981 nM. The most active compound 9i showed considerable safety toward normal human WI-38 cells (IC₅₀ = 28.847 µM vs. Sorafenib IC₅₀ = 13.497 µM) and arrested cell growth in the G1/S phase with total apoptotic induction of 37.65%. Molecular docking studies revealed favorable binding modes of the designed compounds within the VEGFR-2 active site. Molecular dynamics (MD) simulation confirmed the high stability of VEGFR-2-9i complex. Physicochemical properties and bioavailability radar plot disclosed adequate drug-likeness properties. Collectively, a new benzimidazole-isatin/thiourea chemotype was introduced as a promising VEGFR-2-targeting anti-cancer scaffold, demonstrating enhanced potency and improved safety relative to Sorafenib, and providing a rational basis for further lead optimization.