Abstract
Proteases that are expressed during the erythocytic stage of Plasmodium falciparum are newly explored drug targets for the treatment of malaria. We report here the discovery of potent inhibitors of PfA-M1, a metallo-aminopeptidase of the parasite. These compounds are based on a malonic hydroxamic template and present a very good selectivity toward neutral aminopeptidase (APN-CD13), a related protease in mammals. Structure-activity relationships in these series are described. Further optimization of the best inhibitor yielded a nanomolar, selective inhibitor of PfA-M1. This inhibitor displays good physicochemical and pharmacokinetic properties and a promising antimalarial activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopeptidases / antagonists & inhibitors*
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Aminopeptidases / chemistry
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Animals
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Antimalarials / chemical synthesis*
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Antimalarials / chemistry
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Antimalarials / pharmacology
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Cells, Cultured
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Erythrocytes / drug effects
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Erythrocytes / parasitology
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Humans
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Malonates / chemical synthesis*
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Malonates / chemistry
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Malonates / pharmacology
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Metalloproteases / antagonists & inhibitors*
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Metalloproteases / chemistry
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / enzymology*
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Quantitative Structure-Activity Relationship
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Solubility
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Zinc*
Substances
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2-benzyl-N-(4-fluorobenzyl)-N'-hydroxymalonamide
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Antimalarials
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Hydroxamic Acids
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Malonates
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N-(4-fluorobenzyl)-N'-hydroxy-2-(1-phenylmethylidene)malonamide
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Metalloproteases
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Aminopeptidases
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Zinc