Design, Synthesis, and Biological Evaluation of Quinolin-2-One-Indole Schiff Base Hybrids as Potential EGFR-Targeted Anticancer Agents Against Breast and Ovarian Cancer.

A series of new quinolin-2-one-indole Schiff base hybrids was designed, synthesized, and tested as potential anticancer agents targeting the epidermal growth factor receptor. The designed compounds were synthesized via a multistep synthetic route comprising phenylhydrazone formation, Fischer indole cyclization, Vilsmeier-Haack formylation, and subsequent Schiff base condensation. Structural elucidation was performed using IR, 1H NMR, 13C NMR, and mass spectral analysis. In silico studies demonstrated that the synthesized compounds exhibited strong binding affinities to both wild-type (PDB ID: 1M17) and mutant EGFR (PDB ID: 4ZAU), as evidenced by favorable docking scores, with PYd2 showing the strongest interaction. Molecular dynamics simulations over 100 ns further confirmed that the PYd2-EGFR complexes remained stable, maintaining consistent protein-ligand contacts and exhibiting stable RMSD and RMSF values throughout the simulation period. Predicted ADME-toxicity profiles demonstrated favorable drug-like properties, oral absorption, and acceptable toxicity profiles for most synthesized derivatives. In vitro anticancer evaluation against MDA-MB-231 and SK-OV-3 cell lines identified PYd2 as the most potent analog. ELISA-based studies demonstrated significant inhibition of EGFR expression and phosphorylation, while DAPI staining revealed characteristic apoptotic nuclear changes in treated cells. Overall, PYd2 showed favorable predicted EGFR binding and antiproliferative activity against both cancer cell lines.