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

Yan Zhang; Qin Wang; Luolan Li; Yi Le; Li Liu; Jing Yang; Yongliang Li; Guochen Bao; Longjia Yan

doi:10.1080/14756366.2021.1933466

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

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1205-1216. doi: 10.1080/14756366.2021.1933466.

Authors

Yan Zhang^{1

2

3}, Qin Wang^{1

2

3}, Luolan Li^{2

4}, Yi Le^{1

2

3}, Li Liu^{1

3}, Jing Yang¹, Yongliang Li⁵, Guochen Bao⁶, Longjia Yan^{1

2

3}

Affiliations

¹ School of Pharmaceutical Sciences, Guizhou University, Guiyang, China.
² State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China.
³ Guizhou Engineering Laboratory for Synthetic Drugs, Guiyang, China.
⁴ Shizhen College of Guizhou University of Traditional Chinese Medicine, Guiyang, China.
⁵ Faculty of Light Industry and Chemical Engineering, Guangdong University of Technology, Guangzhou, China.
⁶ Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, University of Technology Sydney, Sydney, Australia.

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 4d 3-fluoro-N-(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 4d 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 4d could closely form many hydrogen bonds with EGFR^wt-TK. Therefore, compound 4d is potential to develop as novel anti-cancer drug.

Keywords: EGFR; Quinazolinone; antiproliferative; kinase inhibitor; structure-activity relationship.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Line
Cell Proliferation / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinazolinones / chemical synthesis
Quinazolinones / chemistry
Quinazolinones / pharmacology*
Rats
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Quinazolinones
EGFR protein, human
ErbB Receptors

Grants and funding

This work was financially supported by GZU (Guizhou University) Found for Newly Enrolled Talent ([2019]15), GZU (Guizhou University) Found for Cultivation ([2019]65), and the State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University [Grant number FAMP202005K]; Guizhou Science and Technology Platform Talents [QKHRCPT [2019]5106].