Design, synthesis and <i>in vitro</i> biological evaluation of quinazolinone derivatives as EGFR inhibitors for antitumor treatment

Abstract

In this paper, a series of novel 3-methyl-quinazolinone derivatives was designed, synthesised and evaluated for antitumor activity <i>in vitro</i> on wild type epidermal growth factor receptor tyrosine kinase (EGFR^wt-TK) and three human cancer cell lines including A549, PC-3, and SMMC-7721. The results displayed that some of the compounds had good activities, especially 2-{4-[(3-Fluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (<b>5 g</b>), 2-{4-[(3,4-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (<b>5k</b>) and 2-{4-[(3,5-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (<b>5 l</b>) showed high antitumor activities against three cancer cell lines. Moreover, compound <b>5k</b> could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G2/M phase at tested concentrations. Also, compound <b>5k</b> could inhibit the EGFR^wt-TK with IC₅₀ value of 10 nM. Molecular docking data indicates that the compound <b>5k</b> may exert inhibitory activity by forming stable hydrogen bonds with the R817, T830 amino acid residues and cation-Π interaction with the K72 residue of EGFR^wt-TK.