Structure-Guided Design of Benzothiazole and Benzimidazole-Based Urea Derivatives Curtailing Oncogenic Signaling via Concurrent Inhibition of VEGFR-2, EGFR, and c‑Met

Receptor Tyrosine Kinases (RTKs), including VEGFR-2, EGFR, and c-MET, have been recognized as promising oncogenic targets in tumor progression, invasion, and metastasis. Developing multitarget inhibitors that block these kinases simultaneously offers a powerful strategy to suppress angiogenesis and oncogenic signaling, while potentially minimizing adverse effects. A new series of benzothiazole- and benzimidazole-based urea derivatives was designed rationally through scaffold modification and linker optimization to enhance multikinase inhibition. Moreover, in vitro evaluation of the newly synthesized series revealed that compounds 6a-c, 7a, 12a, 17, and 18 exhibited multitarget inhibitory potential. Additionally, 11b, 12a, 17, and 18 showed the best antiproliferative potential against MCF7 and A549 cells, as indicated by the antiproliferative assay. While compounds 6b, 7a, 17, and 18 demonstrated negligible cytotoxicity against normal HEK-293 cells, with IC₅₀ values exceeding 100 μM (>100 μM). Furthermore, the antiangiogenic efficacy of 11b, 12a, 17, and 18 was validated through CAM assays, which markedly suppressed neovascularization. Molecular docking revealed efficient occupation of 6b, 7a, 12a, 17, and 18 with key binding pockets across VEGFR-2, EGFR, and c-Met. The 200 ns molecular dynamics (MD) simulations confirmed the stability of the 4ASD-6b complex with enhanced flexibility compared to sorafenib. Collectively, these findings establish benzothiazole, benzimidazole, and quinoline-based urea hybrids as promising leads with enhanced multikinase selectivity and reduced toxicity compared to existing inhibitors, offering strong therapeutic potential in angiogenesis-driven cancers.