Development of pyrimidone derivatives as nonpeptidic and noncovalent 3-chymotrypsin-like protease (3CLpro) inhibitors with anti-coronavirus activities

Fan Pan; Qifan Zhou; Ming Yan; Sidi Yang; Ruiyu Hu; Yongzhi Chen; Yuanmei Wen; Yang Chao; Cailing Xie; Weixin Ou; Yingjun Li; Hongmin Zhang; Deyin Guo; Xumu Zhang

doi:10.1016/j.bioorg.2024.107988

Development of pyrimidone derivatives as nonpeptidic and noncovalent 3-chymotrypsin-like protease (3CL^pro) inhibitors with anti-coronavirus activities

Bioorg Chem. 2024 Nov 22:154:107988. doi: 10.1016/j.bioorg.2024.107988. Online ahead of print.

Authors

Fan Pan¹, Qifan Zhou², Ming Yan³, Sidi Yang⁴, Ruiyu Hu¹, Yongzhi Chen¹, Yuanmei Wen¹, Yang Chao¹, Cailing Xie⁴, Weixin Ou⁴, Yingjun Li⁵, Hongmin Zhang⁶, Deyin Guo⁷, Xumu Zhang⁸

Affiliations

¹ Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518000, China.
² Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518000, China. Electronic address: zhouqf@sustech.edu.cn.
³ Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong 518000, China.
⁴ Guangzhou National Laboratory, Guangzhou, Guangdong Province 510005, China.
⁵ State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510180, China.
⁶ Institute of High Energy Physics, CAS, Beijing 100000, China; China Spallation Neutron Source, CAS, Dongguan, Guangdong 523000, China. Electronic address: zhanghongmin@ihep.ac.cn.
⁷ Guangzhou National Laboratory, Guangzhou, Guangdong Province 510005, China. Electronic address: guo_deyin@gzlab.ac.cn.
⁸ Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518000, China. Electronic address: zhangxm@sustech.edu.cn.

PMID: 39591689
DOI: 10.1016/j.bioorg.2024.107988

Abstract

3CL^Pro is crucial to the life cycle of SARS-CoV-2 and exhibits high sequence similarity with other coronaviruses, while being absent in human proteases. This makes it an ideal target for developing broad-spectrum antiviral drugs. Ensitrelvir (S-217622) is the only launched non-covalent, non-peptidomimetic 3CL^Pro inhibitor, offering certain advantages in terms of dosage and metabolism. Using S-217622 as the lead, we designed and synthesized 43 pyrimidone derivatives and conducted a systematic evaluation of their structure-activity relationships. Among them, A36 exhibited strong inhibitory activity against several β-coronaviruses and demonstrated low cytotoxicity. A36 also displayed moderate stability in mouse liver microsomes. Co-crystal structure analysis of 3CL^Pro in complex with A36 revealed the similar binding mode with S-217622. A36 shows strong potential as a promising lead for broad-spectrum anti-coronavirus therapy, warranting further investigation.

Keywords: 3CL(Pro); Anti-coronavirus; Pyrimidone derivatives; S-217622.