Synthesis, biological evaluation, and theoretical studies of 2-amino-3-cyano-4-(L-phenylalaninyl)quinolines: anticancer potential and EGFR inhibition

Quinoline derivatives have garnered significant attention owing to their wide range of biological activities, particularly their anticancer potential. In this study, six novel 4-aminoquinoline derivatives incorporating a phenylalanine methyl ester moiety were synthesized and structurally characterized. The cytotoxic activities of the synthesized compounds were assessed against A549 and MCF-7 cancer cell lines, along with the noncancerous NIH3T3 fibroblast cell line. Compounds 4d and 4e displayed potent anticancer activity with low IC₅₀ values, while exhibiting negligible toxicity toward normal cells. Moreover, these compounds exhibited moderate inhibitory activity against EGFR. Molecular docking studies were conducted to elucidate the binding modes of compounds 4d and 4e at the EGFR active site. To better elucidate their electronic structures and reactivity profiles, density functional theory (DFT) calculations were carried out to determine frontier molecular orbital energies, global reactivity descriptors, dipole moments, and molecular electrostatic potential (MEP) maps. Theoretical data were correlated with the experimental biological activities, revealing consistent trends, particularly among the most active compounds. Furthermore, theoretical NMR chemical shift calculations were performed for the synthesized compounds.