Medicinal Chemistry Progression of Sapanisertib, the Anticancer and Dual <i>Plasmodium</i> Phosphatidylinositol 4‑Kinase Beta and cGMP-Dependent Protein Kinase Inhibitor, for Malaria

We recently demonstrated that the anticancer human mTOR inhibitor sapanisertib displays antimalarial activity in a malaria mouse model of infection and inhibits multiple <i>Plasmodium</i> 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 <i>Plasmodium</i> PI4Kβ and PKG inhibitory activity (exemplified by <b>19</b>), as well as potent <i>Plasmodium</i> PI4Kβ inhibitors with minimal inhibitory activity against PKG (exemplified by <b>20</b>). Compound <b>19</b> 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 <b>19</b> resulted in an 80% reduction in parasitemia in P. berghei-infected mice, further demonstrated the lead potential of this series.