Synthesis And Biological Activity Of Novel Quinazolinone Derivatives

Human epidermal growth factor receptor（EGFR）has received significant attention as an important drug target due to its fundamental role in signal transduction pathways in oncology.Recently,the synthesis of novel EGFR inhibitors has become a hotspot of pharmaceutical research,and the most attractive skeleton of representing EGFR inhibitors is quinazoline.Quinazolinone（quinazoline-4（3H）-one）,has broad biological activities,especially in antitumor activity.In this manuscript,we have designed and synthesized a series of compounds containing quinazolinone skeleton as EGFR inhibitors.Means of Computer-Aided Drug Design（CADD）was utilized,as well as all of the compounds were characterized by structural characterization.In addition,the antiproliferative activities and EGFR inhibitory activities of these synthetic compounds were systematically examined.The results were described briefly below.First,thioketone compound was first synthesized with phenyl isothiocyanate and anthranilic acid methyl ester as raw material by reaction of cyclization in ethanol.Then intermediate 4 was synthesized by reaction of nucleophilic substitution reaction and amidation reaction.Compound 4 as the intermediate was determined by single crystal X-ray structural analysis.Finally,19 novel quinazoline derivatives were synthesized by the amidation reaction with intermediate products as the starting materials and different substituted benzohydrazide.Subsequently,all of the compounds were characterized by ¹H NMR spectra.The biological activities of the synthesized compounds were tested,and the structure-activity relationships were discussed.The results exhibited that all of the compounds had potential anti-proliferation and EGFR inhibitory activities.In the comprehensive analysis of the tested compounds,the compound 9c showed the best anti-tumor cell proliferation activity(IC₅₀=3.95μM for MCF-7,IC₅₀=5.67μM for Hep G2,IC₅₀=6.03μM for SGC),and inhibitory acitivity on EGFR(IC₅₀=0.59μM),comparable to the positive control 5-FU(IC₅₀=33.73μM for MCF-7,IC₅₀=42.40μM for Hep G2,IC₅₀=49.14μM for SGC and IC₅₀=2.82μM for EGFR).The results of Compoutational docking studies also showed that compound 9c has interaction with EGFR key residues in the active site.And the hydrogen bonding,π-cation interactions between EGFR activity center and compound 9c provide a strong theoretical support for pymidine derivatives as EGFR inhibitors.