tetano
Editor, Senior Moderator
Bioorg Chem
. 2025 Sep 24:165:109026.
doi: 10.1016/j.bioorg.2025.109026. Online ahead of print. Discovery and evaluation of pyrimidine-2,4-dione derivatives as novel SARS-CoV-2 M[SUP]pro[/SUP] inhibitors with antiviral effect
Zixuan Rao[SUP] 1 [/SUP], Linyi Yu[SUP] 1 [/SUP], Zhenhao Tang[SUP] 2 [/SUP], Shun Liu[SUP] 1 [/SUP], Shunjing Wang[SUP] 3 [/SUP], Li Zhao[SUP] 4 [/SUP], Yihang Zhong[SUP] 2 [/SUP], Wei Peng[SUP] 5 [/SUP], Qingqing Zhang[SUP] 6 [/SUP], Wei Zhang[SUP] 7 [/SUP], Xupeng Huang[SUP] 8 [/SUP], Man Liu[SUP] 9 [/SUP]
Affiliations
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 (M[SUP]pro[/SUP]) 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 M[SUP]pro[/SUP] inhibitor (IC[SUB]50[/SUB] = 21.1 nM) with outstanding antiviral activity against the SARS-CoV-2 JN.1 variant (EC[SUB]50[/SUB] < 2 nM). Furthermore, X-ray crystallography of the M[SUP]pro[/SUP]-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 M[SUP]pro[/SUP] inhibitors.
Keywords: Antiviral activity; Pyrimidine-2,4-dione derivatives; SARS-CoV-2 main protease; X-ray crystallography; π-π interaction.
. 2025 Sep 24:165:109026.
doi: 10.1016/j.bioorg.2025.109026. Online ahead of print. Discovery and evaluation of pyrimidine-2,4-dione derivatives as novel SARS-CoV-2 M[SUP]pro[/SUP] inhibitors with antiviral effect
Zixuan Rao[SUP] 1 [/SUP], Linyi Yu[SUP] 1 [/SUP], Zhenhao Tang[SUP] 2 [/SUP], Shun Liu[SUP] 1 [/SUP], Shunjing Wang[SUP] 3 [/SUP], Li Zhao[SUP] 4 [/SUP], Yihang Zhong[SUP] 2 [/SUP], Wei Peng[SUP] 5 [/SUP], Qingqing Zhang[SUP] 6 [/SUP], Wei Zhang[SUP] 7 [/SUP], Xupeng Huang[SUP] 8 [/SUP], Man Liu[SUP] 9 [/SUP]
Affiliations
- PMID: 41043330
- DOI: 10.1016/j.bioorg.2025.109026
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 (M[SUP]pro[/SUP]) 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 M[SUP]pro[/SUP] inhibitor (IC[SUB]50[/SUB] = 21.1 nM) with outstanding antiviral activity against the SARS-CoV-2 JN.1 variant (EC[SUB]50[/SUB] < 2 nM). Furthermore, X-ray crystallography of the M[SUP]pro[/SUP]-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 M[SUP]pro[/SUP] inhibitors.
Keywords: Antiviral activity; Pyrimidine-2,4-dione derivatives; SARS-CoV-2 main protease; X-ray crystallography; π-π interaction.