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

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 35; no. 1; pp. 555 - 564
• Main Authors: Le, Yi, Gan, Yiyuan, Fu, Yihong, Liu, Jiamin, Li, Wen, Zou, Xue, Zhou, Zhixu, Wang, Zhenchao, Ouyang, Guiping, Yan, Longjia
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.01.2020; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: A549 Cells; Amino acids; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor; Antitumor activity; Apoptosis; Apoptosis - drug effects; Biochemistry & Molecular Biology; Cell cycle; Cell Cycle - drug effects; Cell Proliferation - drug effects; Chemistry, Medicinal; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; EGFR; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Humans; Hydrogen bonding; Life Sciences & Biomedicine; Models, Molecular; molecular docking; Molecular Structure; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase receptors; Quinazolinone; Quinazolinones - chemical synthesis; Quinazolinones - chemistry; Quinazolinones - pharmacology; Rapid Communication; Science & Technology; Short Communication; Structure-Activity Relationship; Tumor cell lines; tyrosine kinase inhibitor; molecular docking; antitumor; KINASE; RESISTANCE; BEARING; Quinazolinone; tyrosine kinase inhibitor; DUAL INHIBITORS; EGFR
• ISSN: 1475-6366; 1475-6374; 1475-6374
• DOI: 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 (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 (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 EGFR wt -TK with IC 50 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 EGFR wt -TK.