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, <i>in vitro</i> evaluation of the newly synthesized series revealed that compounds <b>6a</b>-<b>c</b>, <b>7a</b>, <b>12a</b>, <b>17</b>, and <b>18</b> exhibited multitarget inhibitory potential. Additionally, <b>11b</b>, <b>12a</b>, <b>17</b>, and <b>18</b> showed the best antiproliferative potential against MCF7 and A549 cells, as indicated by the antiproliferative assay. While compounds <b>6b</b>, <b>7a</b>, <b>17</b>, and <b>18</b> demonstrated negligible cytotoxicity against normal HEK-293 cells, with IC₅₀ values exceeding 100 μM (>100 μM). Furthermore, the antiangiogenic efficacy of <b>11b</b>, <b>12a</b>, <b>17</b>, and <b>18</b> was validated through CAM assays, which markedly suppressed neovascularization. Molecular docking revealed efficient occupation of <b>6b</b>, <b>7a</b>, <b>12a</b>, <b>17,</b> and <b>18</b> with key binding pockets across VEGFR-2, EGFR, and c-Met. The 200 ns molecular dynamics (MD) simulations confirmed the stability of the <b>4ASD-6b</b> 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.