Abstract
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 Plasmodium falciparum. In the humanized P. falciparum 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 Plasmodium falciparum phosphatidylinositol-4-kinase as the target.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Phosphatidylinositol 4-Kinase / antagonists & inhibitors*
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1-Phosphatidylinositol 4-Kinase / chemistry
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Animals
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Antimalarials / chemistry
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Antimalarials / pharmacokinetics
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Antimalarials / pharmacology
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Antimalarials / therapeutic use
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Disease Models, Animal
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Drug Design
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Humans
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Malaria / drug therapy*
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Mice
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Models, Molecular
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Naphthyridines / chemistry*
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Naphthyridines / pharmacokinetics
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Naphthyridines / pharmacology*
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Naphthyridines / therapeutic use
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Plasmodium falciparum / drug effects*
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Plasmodium falciparum / enzymology*
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Plasmodium falciparum / physiology
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Protein Conformation
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Structure-Activity Relationship
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Tissue Distribution
Substances
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Antimalarials
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Enzyme Inhibitors
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Naphthyridines
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1-Phosphatidylinositol 4-Kinase