A novel series of quinoline-quinazoline hybrid derivatives (7a–7n) was designed, synthesized, and evaluated for anticancer potential, EGFR inhibition, and mechanistic insights. The target compounds were efficiently prepared via a multistep synthetic route involving the condensation of quinoline-aldehyde intermediates with 2-amino benzohydrazide, and their structures were confirmed through FTIR, 1 H NMR, 13 C NMR, and mass spectrometry. In vitro cytotoxicity assessment against MCF7 breast cancer and Vero normal kidney epithelial cell lines revealed that compounds 7f, 7j, 7k, and 7g exhibited significant anticancer activity at low micromolar concentrations, with favorable selectivity indices highlighting preferential cytotoxicity toward cancer cells. Flow cytometric analysis using Annexin V-FITC/PI staining demonstrated that compound 7f induced substantial apoptosis, with total apoptotic rates (~73%) comparable to the reference EGFR inhibitor Lenvatinib (~76%). Cellular uptake studies using Rhodamine B and DAPI staining confirmed efficient internalization of 7f into MCF7 cells, predominantly in the cytoplasmic compartment. In vitro EGFR kinase assays revealed that 7f was the most potent inhibitor of the series (IC 50 : 2.461 μM), with structure–activity relationships indicating that electron-donating substituents and hydrogen bond-capable moieties enhance EGFR binding. Molecular docking studies elucidated key interactions of 7f within the ATP-binding pocket, notably hydrogen bonding with Cys773 and Pro770, along with hydrophobic and π–π stacking interactions stabilizing the ligand. Molecular dynamics simulations over 100 ns further confirmed the stability of the EGFR–7f complex, with low RMSD/RMSF fluctuations and persistent interactions of critical residues. Collectively, these findings suggest that quinoline-quinazoline hybrids, particularly 7f, represent promising leads for further development as selective EGFR-targeted anticancer agents. • Quinoline-quinazoline hybrids (7a–7n) were efficiently synthesized and structurally confirmed. • Compounds 7f, 7j, 7k, and 7g showed potent, selective cytotoxicity against MCF7 cells. • Compound 7f induced ~73% apoptosis, comparable to Lenvatinib (~76%). • 7f exhibited strong EGFR inhibition (IC 50 : 2.461 μM) with SAR favouring electron-donating groups. • Docking and 100 ns MD simulations confirmed stable binding via H-bonds, hydrophobic, and π–π interactions.
Kavalapure et al. (Sun,) studied this question.