Synthesis and Multiscale In Silico Assessment of Eugenol‐Derived Isoxazole‐Isoxazolines for VEGFR2 Inhibition

ABSTRACT This study explores the synthesis and evaluation of isoxazole‐isoxazoline derivatives of eugenol ( 1 ), a natural compound with notable bioactive properties. Employing a copper‐catalyzed cycloaddition, commonly referred to as a click reaction, these derivatives have been synthesized and subsequently assessed for their binding affinity to the vascular endothelial growth factor receptor 2 (VEGFR2) protein, which is crucial in angiogenesis and tumor growth through molecular docking. Among the synthesized derivatives, several displayed significant binding affinities to VEGFR2, surpassing that of the FDA‐approved drug sorafenib. Further molecular dynamics (MD) simulation studies of these compounds have been performed to evaluate the conformational stability of the ligand–protein complexes over 100 ns under explicit solvent conditions. This study highlights their potential as promising candidates for cancer therapy. This research underscores the therapeutic promise of eugenol‐based isoxazole‐isoxazoline derivatives in targeting VEGFR2 and contributes to the development of safer and more effective anticancer agents.