Design, Synthesis, Anticancer Properties, and Molecular Dynamics of New Quinazolinonethioacetohydrazide-1,2,3-Triazoles.

A novel series of quinazolinonethioacetohydrazide-1,2,3-triazole hybrids 13a-l was synthesized via a multi-step process starting from isatoic anhydride, followed by the condensation reaction with carbon disulfide (CS2), hydrazide formation, and the conduction of click chemistry reaction. Different spectroscopic techniques structurally characterized the synthesized compounds. The anticancer activity of the compounds was evaluated against MCF-7 (breast) and SW480 (colon) cancer cell lines, while HEK 293 (normal cells) was used as a noncancerous control. Compound 13c exhibited the most potent and selective cytotoxicity, particularly against SW480 (IC50 = 29.83 µM) and MCF-7 (IC50 = 17.32 µM) cancer cell lines, while demonstrating negligible toxicity toward normal HEK 293 cells. Cell cycle analysis indicated that 13c induced G2/M phase arrest and promoted apoptosis in MCF-7 cells, as confirmed by annexin V/PI staining. In silico docking studies revealed strong binding of 13c to the vascular endothelial growth factor (VEGF) receptor, with key hydrogen bonding and π-π interactions at critical active-site residues. In addition, 100 ns molecular dynamics simulations validated the stability of the VEGF-13c complex and the persistence of binding interactions, supporting its role as a strong and stable VEGFR inhibitor.