2. Academic Validation
  3. Modular synthesis of isoxazolopyrimidine derivatives with anti-SARS-CoV-2 activity

Modular synthesis of isoxazolopyrimidine derivatives with anti-SARS-CoV-2 activity

  • Bioorg Chem. 2025 Oct:165:108992. doi: 10.1016/j.bioorg.2025.108992.
Hui Chen 1,  Xin Wang 1,  Lianyou Zheng 1,  Lingling Shi 1,  Zhaoliang Chen 2,  Lei Zhang 2,  Yan Zhang 1,  Qiansong Gao 1,  Jie Wang 1,  Zhuoqi Zhang 1,  Zhendong Guo 3,  Jinbao Xiang 4
Affiliations

Affiliations

  • 1 The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, PR China.
  • 2 Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, State Key Laboratory of Pathogen and Biosecurity, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, 573 Tulip Street, Changchun, Jilin 130122, PR China.
  • 3 Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, State Key Laboratory of Pathogen and Biosecurity, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, 573 Tulip Street, Changchun, Jilin 130122, PR China. Electronic address: [email protected].
  • 4 The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, PR China. Electronic address: [email protected].
PMID: 40976188 DOI: 10.1016/j.bioorg.2025.108992
Abstract

A highly efficient synthetic route for the preparation of isoxazolopyrimidine derivatives has been developed, characterized by mild reaction conditions, operational simplicity and high yields. Building on this, we further functionalized the isoxazolopyrimidine scaffold to synthesize 7-morpholinoisoxazolo[4,5-d]pyrimidine derivatives. In vitro evaluations revealed that compounds 5a and 6g demonstrated significant anti-SARS-CoV-2 activity. Mechanistic studies indicated that the Antiviral effects of 5a and 6g were mediated through the inhibition of PI3Kδ kinase, highlighting their potential as targeted therapeutic agents. Moreover, in vivo experiments conducted in a golden hamster model demonstrated that compound 5a effectively suppressed SARS-CoV-2 replication in lung tissue, underscoring its therapeutic potential for combating COVID-19. These findings collectively suggest that isoxazolopyrimidine derivatives, particularly 5a, represent promising candidates for further development as anti-SARS-CoV-2 therapeutics.

Keywords

7-morpholinoisoxazolo[4,5-d]pyrimidine derivatives; Anti-SARS-CoV-2 activity; Isoxazolopyrimidine; PI3Kδ inhibitor.

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