Novel Selective Inhibitors of the Zinc Plasmodial Aminopeptidase PfA-M1 as Potential Antimalarial Agents
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- 作者：Marion Flipo ; Terence Beghyn ; Virginie Leroux ; Isabelle Florent ; Benoit P. Deprez ; Rebecca F. Deprez-Poulain
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：March 22, 2007
- 年：2007
- 卷：50
- 期：6
- 页码：1322 - 1334
- 全文大小：206K
- 年卷期：v.50,no.6(March 22, 2007)
- ISSN：1520-4804
文摘
Proteases that are expressed during the erythocytic stage of Plasmodium falciparum are newly exploreddrug targets for the treatment of malaria. We report here the discovery of potent inhibitors of PfA-M1, ametallo-aminopeptidase of the parasite. These compounds are based on a malonic hydroxamic template andpresent 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 yieldeda nanomolar, selective inhibitor of PfA-M1. This inhibitor displays good physicochemical and pharmacokineticproperties and a promising antimalarial activity.