Integrated in vitro and in silico evaluations of novel benzanilide derivatives as anticancer agents

This study aimed to design, synthesize, and evaluate novel benzanilide derivatives as potential anticancer agents targeting VEGFR-2-mediated tumor angiogenesis.

Eight benzanilide derivatives (7a-e, 9a-b, and 11) were synthesized and structurally confirmed using spectroscopic methods. The compounds were evaluated via molecular docking, in silico ADMET profiling, in vitro cytotoxicity against MCF-7, MDA-MB-231, HepG-2, and HCT-116 cancer cell lines, and selectivity assessment using WI-38 and WISH normal cell lines. VEGFR-2 enzyme inhibition was also determined for the most active compound.

Compound 11 exhibited the highest cytotoxic activity with IC₅₀ values of 6.08, 5.76, 7.94, and 4.64 µM against MCF-7, MDA-MB-231, HepG-2, and HCT-116, respectively, comparable to sorafenib. It showed potent VEGFR-2 inhibition (IC₅₀ = 0.414 µM) superior to sorafenib (0.809 µM). Mechanistic studies indicated activation of apoptosis via upregulation of Bax, Caspase-3, and Caspase-8 and downregulation of Bcl-2. ADMET results revealed favorable pharmacokinetic properties and acceptable safety profiles.

Compound 11 represents a promising VEGFR-2 inhibitor with potent anticancer activity and favorable drug-like properties, warranting further optimization and development.