Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2012

Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors

Résumé

Malaria is a severe infectious disease that causes between 655 000 and 1.2 million deaths annually. To overcome the resistance to current drugs, new biological targets are needed for drug development. Aminopeptidase M1 (PfAM1), a zinc metalloprotease, has been proposed as a new drug target to fight malaria. Herein, we disclosed the structure–activity relationships of a selective family of hydroxamate PfAM1 inhibitors based on the malonic template. In particular, we performed a “fluoro-scanning” around hit 1 that enlightened the key positions of the halogen for activity. The docking of the best inhibitor 2 is consistent with in vitro results. The stability of 2 was evaluated in microsomes, in plasma, and toward glutathione. The in vivo distribution study performed with the nanomolar hydroxamate inhibitor 2 (BDM14471) revealed that it reaches its site of action. However, it fails to kill the parasite at concentrations relevant to the enzymatic inhibitory potency, suggesting that killing the parasite remains a challenge for potent and druglike catalytic-site binding PfAM1 inhibitors. In all, this study provides important insights for the design of inhibitors of PfAM1 and the validity of this target.
Fichier principal
Vignette du fichier
JMC_2012.pdf (844.1 Ko) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03051765 , version 1 (10-12-2020)

Identifiants

Citer

Rébecca F. Déprez-Poulain, Marion Flipo, Catherine Piveteau, Florence Leroux, Sandrine Dassonneville, et al.. Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors. Journal of Medicinal Chemistry, 2012, 55 (24), pp.10909-10917. ⟨10.1021/jm301506h⟩. ⟨hal-03051765⟩
43 Consultations
67 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More