Anticancer Activity of Fused Quinazoline-Quinazolinone: Synthesis, Biological Evaluations, and Computational Studies

This study presents the synthesis, biological evaluation, and computational analysis of a new quinazoline-quinazolinone fused ring derivative as a potential Epidermal Growth Factor Receptor (EGFR) inhibitor targeting non-small cell lung cancer (NSCLC). Compound 3a-e were synthesized through the cyclization of quinazolinone with respective aldehydes, yielding new quinazoline ring. Compound 3b recorded significant activity against H1975 cells (IC50: 15.9 ± 1.2 μM) and moderate activity against A549 cells (IC50: 32.9 ± 1.2 μM) in the MTT assay. It also demonstrated inhibition of EGFR and PI3K enzymes at 10 μM in the Western Blot assay. The compound induced apoptosis and cell cycle arrest at the G0/G1 phase in H1975 cells. Additionally, the Fish Embryo Toxicity assay showed non-toxicity at 400 μM on zebrafish embryos. In silico studies using molecular docking and molecular dynamics revealed that the binding of the compound to EGFR was stabilized by hydrophobic and hydrogen bonding interactions. These results suggest that the new quinazoline-quinazolinone derivative holds promise as an EGFR inhibitor and warrants further investigation.