Synthesis, biological evaluation and theoretical calculation of 2-amino-3-cyano-4-phenylalaninquinolines: anticancer potential and EGFR inhibition

Quinoline derivatives have attracted considerable attention due to their broad spectrum of biological activities, particularly their anticancer potential. In the present study, six novel 4-aminoquinoline derivatives bearing a phenylalanine methyl ester moiety were synthesized and structurally characterized. The cytotoxic activities of the compounds were evaluated against A549 and MCF7 cancer cell lines, as well as the healthy NIH3T3 cell line. Compounds 4d and 4e exhibited potent anticancer activity, with low IC₅₀ values, while showing no significant toxicity toward healthy cells. Additionally, these compounds demonstrated moderate inhibitory activity against the EGFR enzyme. Molecular docking studies were performed to reveal the binding modes of compounds 4d and 4e at the EGFR active site. To understand better their electronic structures and reactivity profiles, DFT calculations were performed to obtain frontier molecular orbital energies, global reactivity descriptors, dipole moments, and molecular electrostatic potential (MEP) maps. The theoretical data were correlated with the observed biological activities, revealing consistent trends particularly among the active compounds. Furthermore, theoretical NMR chemical shift calculations were also conducted for the synthesized molecules.