ABSTRACT
Malaria is still one of the most prevalent parasitic infections in the world, with half of the world's population at risk for malaria. The effectiveness of current antimalarial therapies, even that of the most recent class of antimalarial drugs (artemisinin-combination therapies, ACTs), is under continuous threat by the spread of resistant Plasmodium strains. As a consequence, there is still an urgent requirement for new antimalarial drugs. We previously reported the identification of 4(1 H)-pyridones as a novel series with potent antimalarial activities. The low solubility was identified as an issue to address. In this paper, we describe the synthesis and biological evaluation of 4(1 H)-pyridones with potent antimalarial activities in vitro and in vivo and improved pharmacokinetic profiles. Their main structural novelties are the presence of polar moieties, such as hydroxyl groups, and the replacement of the lipophilic phenyl rings with pyridines on their lipophilic side chains.
Subject(s)
Antimalarials/pharmacology , Pyridones/pharmacology , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacokinetics , Female , Mice , Molecular Structure , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Plasmodium yoelii/drug effects , Pyridones/chemical synthesis , Pyridones/chemistry , Pyridones/pharmacokinetics , Structure-Activity RelationshipABSTRACT
The glyoxylate shunt plays an important role in fatty acid metabolism and has been shown to be critical to survival of several pathogens involved in chronic infections. For Mycobacterium tuberculosis (Mtb), a strain with a defective glyoxylate shunt was previously shown to be unable to establish infection in a mouse model. We report the development of phenyl-diketo acid (PDKA) inhibitors of malate synthase (GlcB), one of two glyoxylate shunt enzymes, using structure-based methods. PDKA inhibitors were active against Mtb grown on acetate, and overexpression of GlcB ameliorated this inhibition. Crystal structures of complexes of GlcB with PDKA inhibitors guided optimization of potency. A selected PDKA compound demonstrated efficacy in a mouse model of tuberculosis. The discovery of these PDKA derivatives provides chemical validation of GlcB as an attractive target for tuberculosis therapeutics.
Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/therapeutic use , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Malate Synthase/antagonists & inhibitors , Mycobacterium tuberculosis/enzymology , Tuberculosis/drug therapy , Animals , Antitubercular Agents/pharmacokinetics , Drug Design , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Malate Synthase/metabolism , Mice , Mice, Inbred C57BL , Models, Molecular , Mycobacterium tuberculosis/drug effectsABSTRACT
Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.