Anticancer activity of fused quinazoline-quinazolinone: Synthesis, biological evaluations, and computational studies.

• A series of fused quinazoline-quinazolinone derivatives were synthesized through cyclization of amino-quinazolinone and aldehyde, achieving high yields. • Compound 3b demonstrated potent antiproliferative activity against H1975 non-small cell lung cancer (NSCLC) cells, with an IC 50 value of 15.9 ± 1.2 μM. • Compound 3b effectively inhibited EGFR and PI3K enzymes, induced apoptosis, and caused cell cycle arrest at the G0/G1 phase in H1975 cells. • In the Fish Embryo Toxicity (FET) assay, compound 3b showed no toxicity at concentrations up to 400 μM in zebrafish embryos. • Molecular dynamics simulations confirmed a stable and strong interaction between compound 3b and EGFR, supporting its potential as a targeted therapy. Although several methods for the synthesis of the fused quinazoline-quinazolinone derivatives have been reported, their biological activity has not been thoroughly investigated. The objectives of the present study were to synthesize a series of fused quinazoline-quinazolinone derivatives and evaluate them for their anticancer activity alongside their potential as EGFR inhibitors, through in vitro , in vivo and in silico studies. This study presents the synthesis, biological evaluation, and computational analysis of a series of quinazoline-quinazolinone fused ring derivatives as potential epidermal growth factor receptor (EGFR) inhibitor targeting non-small cell lung cancer (NSCLC). Compounds 3a-e were synthesized through the cyclization of quinazolinone with respective aldehydes, yielding new quinazoline ring. Compound 3b recorded significant activity against H1975 cells (IC 50 = 15.9 ± 1.2 μM) and moderate activity against A549 cells (IC 50 = 32.9 ± 1.2 μM) in the MTT assay, compared to gefitinib (IC 50 = 20.2 ± 1.1 μM and 34.0 ± 1.2 μM, respectively). It also inhibited 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 acute toxicity assay showed that the compound was non-toxic 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 quinazoline-quinazolinone derivative holds promise as an EGFR inhibitor and warrants further investigation. [ABSTRACT FROM AUTHOR]