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

• Main Authors: Yi Le, Yiyuan Gan, Yihong Fu, Jiamin Liu, Wen Li, Xue Zou, Zhixu Zhou, Zhenchao Wang, Guiping Ouyang, Longjia Yan
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2020-01-01
• Series: Journal of Enzyme Inhibition and Medicinal Chemistry
• Subjects: quinazolinone; egfr; tyrosine kinase inhibitor; antitumor; molecular docking
• Online Access: http://dx.doi.org/10.1080/14756366.2020.1715389

In this paper, a series of novel 3-methyl-quinazolinone derivatives was designed, synthesised and evaluated for antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-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 (5 g), 2-{4-[(3,4-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5k) and 2-{4-[(3,5-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 l) showed high antitumor activities against three cancer cell lines. Moreover, compound 5k 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 5k could inhibit the EGFRwt-TK with IC50 value of 10 nM. Molecular docking data indicates that the compound 5k 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 EGFRwt-TK.