2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of <i>Plasmodium falciparum</i> Phosphatidylinositol-4-kinase and Hemozoin Formation with <i>In Vivo</i> Efficacy.

ABSTRACT: Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of Plasmodium falciparum (Pf) phosphatidylinositol-4-kinase β (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained Plasmodium PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PfPI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against f

SUBMITTER: Dziwornu GA 

PROVIDER: S-EPMC11247499 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature