Gachuhi, SamuelKamunya, StephanieFienberg, StephenWambua, LynnSalomane, NicolaasMayoka, GodfreyTaylor, DaleCoertzen, DinaVan der Watt, Mariette ElizabethReader, JanetteBirkholtz, Lyn-MarieWittlin, SergioKrugmann, LiezlCoulson, Lauren B.Chibale, Kelly2025-07-092025-07-092025-06Gachuhi, S., Kamunya, S., Fienberg, S. et al. 2025, 'Medicinal chemistry progression of sapanisertib, the anticancer and dual Plasmodium phosphatidylinositol 4-kinase beta and cGMP-dependent protein kinase inhibitor, for malaria', Journal of Medicinal Chemistry, vol. 68, no. 11, pp. 10757-10770, doi : 10.1021/acs.jmedchem.4c02799.0022-2623 (print)1520-4804 (online)10.1021/acs.jmedchem.4c02799http://hdl.handle.net/2263/103246We recently demonstrated that the anticancer human mTOR inhibitor sapanisertib displays antimalarial activity in a malaria mouse model of infection and inhibits multiple Plasmodium kinases, including the high-value targets phosphatidylinositol 4-kinase type III beta (PI4Kβ) and cGMP-dependent protein kinase (PKG). Herein, we explore structure-activity relationships for sapanisertib analogues with benzyl and pyridyl substituents at the 7-position of the pyrazolopyrimidine core. New analogues with improved safety profiles were identified, including analogues with dual Plasmodium PI4Kβ and PKG inhibitory activity (exemplified by 19), as well as potent Plasmodium PI4Kβ inhibitors with minimal inhibitory activity against PKG (exemplified by 20). Compound 19 displayed potent antiplasmodium activity, high microsomal metabolic stability, and a good safety profile (hERG IC50 > 30; cytotoxicity selectivity index = 99). In vivo proof-of-concept, where a 4 × 50 mg kg-1 oral dose of 19 resulted in an 80% reduction in parasitemia in P. berghei-infected mice, further demonstrated the lead potential of this series. against respiratory-related infections with economic potential.en© 2025 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0 .MalariaSapanisertibPlasmodium kinasesPhosphatidy-linositol 4-kinase type III beta (PI4Kβ)GMP-dependent protein kinase (PKG)Article