Design, Synthesis, Antiproliferative Potency and In Silico Studies of Novel Alkynyl Quinazolines as Potential EGFR Inhibitors

The epidermal growth factor receptor (EGFR) is a highly attractive and promising target for novel anticancer agents, particularly for non-small-cell lung cancer (NSCLC), due to its crucial role in regulating cell survival and proliferation. Despite the development of first-generation reversible inhibitors like Gefitinib and Erlotinib, acquired resistance necessitated the discovery of highly potent irreversible inhibitors effective against drug-resistant mutants. Molecular docking calculations utilizing both EGFR conformations identified five top-ranked compounds (QN012, QN017, QN019, QN022, and QN023) proposed for synthesis and biological evaluation. These in silico studies predicted high inhibitory activity against the active and inactive state of EGFR. Herein, we report the design, synthesis and biological evaluation of novel 4-anilino quinazoline derivatives, bearing various alkynyl substituents at position 6, expected to bind to the hinge Met793 residue of EGFR. The effects of the derivatives on various cancer cell lines in terms of cytotoxic/cytostatic activity, interference with cell cycle phase distribution, and suppression of EGFR phosphorylation set the basis for the design of more potent derivatives.