Synthesis and preliminary structure-activity relationship study of 3-methylquinazolinone derivatives as EGFR inhibitors with enhanced antiproliferative activities against tumour cells

Abstract

In this paper, a set of 3-methylquniazolinone derivatives were designed, synthesised, and studied the preliminary structure-activity relationship for antiproliferative activities. All target compounds performed significantly inhibitory effects against wild type epidermal growth factor receptor tyrosine kinase (EGFR^wt-TK) and tumour cells (A431, A549, MCF-7, and NCI-H1975). In particular, compound <b>4d</b> 3-fluoro-<i>N</i>-(4-((3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)phenyl)benzamide showed higher antiproliferative activities against all tumour cells than Gefitinib (IC₅₀ of 3.48, 2.55, 0.87 and 6.42 μM, respectively). Furthermore, compound <b>4d</b> could induce apoptosis of MCF-7 cells and arrest in G2/M phase at the tested concentration. Molecular docking and ADMET studies showed that compound <b>4d</b> could closely form many hydrogen bonds with EGFR^wt-TK. Therefore, compound <b>4d</b> is potential to develop as novel anti-cancer drug.