Design, Synthesis, Anticancer Properties, and Molecular Dynamics of New...

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.