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 (IC 50 = 58 nM) compared to Sorafenib (IC 50 = 72 nM), while the rest of the compounds gave an IC 50 range of 96–981 nM. The most active compound 9i showed considerable safety toward normal human WI‐38 cells (IC 50 = 28.847 µM vs. Sorafenib IC 50 = 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.