Title
Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
Washington, D.C. ,
Subject
Biology
Pharmacology. Therapy
Human medicine
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Volume/pages
55(2012) :24 , p. 10909-10917
ISSN
0022-2623
ISI
000312681100007
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
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 structureactivity 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.
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