Rational design, synthesis, molecular docking, and preliminary cytotoxic evaluation of novel quinazolinone derivatives as potential EGFR inhibitors for lung cancer therapy

This study reports the synthesis and biological evaluation of novel quinazoline derivatives as potential inhibitors of epidermal growth factor receptor (EGFR) for lung cancer therapy. A series of quinazoline derivatives (۳a–۳f) were synthesized through a three-step process involving Schiff base formation, N-benzylidene amide formation, and subsequent cyclization. The structures of the synthesized compounds were confirmed using FT-IR and ¹H-NMR spectroscopy. In vitro cytotoxicity assays were conducted on the A۵۴۹ lung cancer cell line to evaluate the inhibitory activity of these compounds. Molecular docking studies were performed to investigate the binding interactions between the synthesized compounds and the EGFR active site.Cytotoxicity assays revealed that several quinazoline derivatives exhibited significant inhibitory activity. Notably, Compound IIIa demonstrated the highest potency, surpassing the IC₅₀ value of erlotinib. Molecular docking studies showed that Compounds IIIa–IIIe exhibited higher binding affinities for EGFR compared to erlotinib, correlating with the experimental IC₅₀ values. Key interactions, including hydrogen bonds with ASP۸۳۱ and hydrophobic contacts with Leu۷۱۸, Leu۷۶۴, and Met۷۶۹, were identified.The findings suggest that these synthesized quinazoline derivatives, particularly Compound IIIa, hold promise as potential EGFR inhibitors. The correlation between docking scores and experimental IC₅₀ values validates the predictive power of molecular docking in this context. Further studies are warranted to explore their biological mechanisms and systemic effects, aiming to translate these findings into clinical applications.

کلیدواژه ها:

Quinazoline derivatives ، EGFR Inhibitors ، Molecular docking ، Lung cancer ، Cytotoxic evaluation ، Drug design