Thiadiazole‐Derived <scp>VEGFR</scp> ‐2 Inhibitors: From Design to Anticancer Evaluation

Abstract

ABSTRACT In this study, a series of novel thiadiazole derivatives ( 7a , 7b , 9a , 9b , and 9c ) were rationally designed as potential VEGFR‐2 inhibitors using a pharmacophore‐guided strategy. The compounds were synthesized and assessed for their antiangiogenic and anticancer effects. Among them, compound 9b showed the strongest VEGFR‐2 inhibition (IC 50 = 0.030 ± 0.001 μM), outperforming the reference drug Sorafenib. Cytotoxicity tests revealed that 9b was highly effective against MCF‐7 breast cancer cells (IC 50 = 8.06 ± 0.7 μM) while exhibiting minimal toxicity toward normal WI‐38 cells. Flow cytometry demonstrated that 9b induced significant G2/M cell cycle arrest and increased apoptosis, supported by molecular data showing upregulation of caspase‐3 and Bax and downregulation of Bcl‐2, indicating activation of the intrinsic apoptotic pathway. Extensive in silico studies—including molecular docking, 200 ns molecular dynamics simulations, interaction mapping, principal component analysis of trajectories, and free energy landscape analysis—confirmed that 9b binds stably and efficiently within the VEGFR‐2 active site. Overall, these results highlight compound 9b as a promising VEGFR‐2‐targeted antiangiogenic agent with potent enzymatic and cellular activity, favorable selectivity, and mechanistic validation through combined experimental and computational approaches.