Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel <i>Plasmodium falciparum</i> Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria

A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure–activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite <i>Plasmodium falciparum</i>. In the humanized <i>P. falciparum</i> mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg^–1. In vitro mode-of-action studies revealed <i>Plasmodium falciparum</i> phosphatidylinositol-4-kinase as the target

Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel <i>Plasmodium falciparum</i> Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria

A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure–activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite <i>Plasmodium falciparum</i>. In the humanized <i>P. falciparum</i> mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg^–1. In vitro mode-of-action studies revealed <i>Plasmodium falciparum</i> phosphatidylinositol-4-kinase as the target

Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel <i>Plasmodium falciparum</i> Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria

A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure–activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite <i>Plasmodium falciparum</i>. In the humanized <i>P. falciparum</i> mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg^–1. In vitro mode-of-action studies revealed <i>Plasmodium falciparum</i> phosphatidylinositol-4-kinase as the target