Novel Selective Inhibitors of the Zinc Plasmodial Aminopeptidase Pfa-m1 As Potential Antimalarial Agents.
From: Inserm, U761, Biostructures and Drug Discovery, Lille F-59006 France.
Journal of medicinal chemistry
- Publish Date: Mar 2007
- ISSN: 0022-2623
- Volume: 50
- Issue: 6
- Pages: 1322-34
- Medium: Print
- Language: English
- Citation (JAMA): Flipo Marion, Beghyn Terence, Leroux Virginie, et al. Novel Selective Inhibitors of the Zinc Plasmodial Aminopeptidase Pfa-m1 As Potential Antimalarial Agents.. J. Med. Chem. Mar 2007;50:1322-34
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.
Mesh Headings (Keywords): Aminopeptidases, Animals, Antimalarials, Cells, Cultured, Erythrocytes, Humans, Hydroxamic Acids, Malonates, Metalloproteases, Plasmodium falciparum, Quantitative Structure-Activity Relationship, Solubility, Zinc
Check for Full Text / PubMed Unique Identifier (PMID): 17326615
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