Synthesis, Anticancer Evaluation, Molecular Docking, and DFT Studies of Substituted Quinoline Derivatives

Abstract

Seven new quinoline derivatives with different functional groups at positions 2, 3, and 4 were synthesized and subsequently assessed for their biological activities. Four synthesized compounds exhibited significant cytotoxic effects against A549 and MCF7 cells. Compound 4f demonstrated IC₅₀ values comparable to that of the standard drug doxorubicin and showed a similar selectivity profile, exhibiting low toxicity toward healthy NIH3T3 cells. Furthermore, compound 4f displayed a strong EGFR inhibition profile with an IC₅₀ value of 0.015 ± 0.001 µM. Molecular docking studies revealed that 4f forms strong interactions with key amino acids on the active site of EGFR. Additionally, DFT analyses were conducted to calculate dipole moments, HOMO-LUMO energy gaps, and molecular electrostatic potential maps. Theoretical and experimental NMR chemical shift values showed a high correlation and confirmed the consistency of the computational results. These results indicate the potential of quinoline derivatives, especially of compound 4f, as promising candidates for the development of chemotherapeutic agents.