2. Academic Validation
  3. Discovery and evaluation of pyrimidine-2,4-dione derivatives as novel SARS-CoV-2 Mpro inhibitors with antiviral effect

Discovery and evaluation of pyrimidine-2,4-dione derivatives as novel SARS-CoV-2 Mpro inhibitors with antiviral effect

  • Bioorg Chem. 2025 Oct:165:109026. doi: 10.1016/j.bioorg.2025.109026.
Zixuan Rao 1,  Linyi Yu 1,  Zhenhao Tang 2,  Shun Liu 1,  Shunjing Wang 3,  Li Zhao 4,  Yihang Zhong 2,  Wei Peng 5,  Qingqing Zhang 6,  Wei Zhang 7,  Xupeng Huang 8,  Man Liu 9
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou 510005, China.
  • 2 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou 510005, China.
  • 3 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou 510005, China; School of Chemistry and Chemical Engineering, University of South China, Hengyang 421001, China.
  • 4 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou 510005, China; Guangzhou Medical University, Guangzhou 511436, China.
  • 5 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou 510005, China; School of Chemistry and Chemical Engineering, University of South China, Hengyang 421001, China; Guangzhou Medical University, Guangzhou 511436, China; Department of Infectious Diseases, The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital, Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 511436, China. Electronic address: [email protected].
  • 6 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou 510005, China. Electronic address: [email protected].
  • 7 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou 510005, China; Department of Infectious Diseases, The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital, Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 511436, China. Electronic address: [email protected].
  • 8 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou 510005, China. Electronic address: [email protected].
  • 9 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou 510005, China. Electronic address: [email protected].
PMID: 41043330 DOI: 10.1016/j.bioorg.2025.109026
Abstract

The COVID-19 pandemic has underscored the persistent threat of zoonotic coronavirus transmission to global health. In this study, we targeted the clinically validated SARS-CoV-2 main protease (Mpro) and implemented a scaffold-hopping strategy to design and synthesize 32 pyrimidine-2,4-dione derivatives, aiming to explore underutilized interactions within the S1, S1', and S2 subpockets. Structure-activity relationship (SAR) analysis identified compound 17 as a potent Mpro inhibitor (IC50 = 21.1 nM) with outstanding Antiviral activity against the SARS-CoV-2 JN.1 variant (EC50 < 2 nM). Furthermore, X-ray crystallography of the Mpro-compound 15 complex unveiled a previously unreported T-shaped π-π interaction between the P1'-phenyl ring and His41. These results demonstrate the effectiveness of structure-based optimization of the pyrimidine-2,4-dione scaffold for the development of novel coronavirus Mpro inhibitors.

Keywords

Antiviral activity; Pyrimidine-2,4-dione derivatives; SARS-CoV-2 main protease; X-ray crystallography; π-π interaction.

Figures
Products