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

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.