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
  • 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.
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