Novel Selective Inhibitors of the Zinc Plasmodial Aminopeptidase PfA-M1 as Potential Antimalarial Agents

Marion Flipo (1) , Terence Beghyn (2) , Virginie Leroux (3) , Isabelle Florent (4) , Benoit Déprez (5) , Rebecca Deprez-Poulain (2)

1 M2SV - Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177
2 Biostructures et Decouverte de Medicament
3 URCA - Université de Reims Champagne-Ardenne
4 MCAM - Molécules de Communication et Adaptation des Micro-organismes
5 Chu (saint-Louis)/inserm

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.

Domaines: Biochimie [q-bio.BM]; Biologie moléculaire; Biologie cellulaire; Systématique, phylogénie et taxonomie; Protistologie; Microbiologie et Parasitologie; Biodiversité

Marion Flipo, Terence Beghyn, Virginie Leroux, Isabelle Florent, Benoit Déprez, et al.. Novel Selective Inhibitors of the Zinc Plasmodial Aminopeptidase PfA-M1 as Potential Antimalarial Agents. Journal of Medicinal Chemistry, 2007, 50 (6), pp.1322-1334. ⟨10.1021/jm061169b⟩. ⟨mnhn-02904302⟩