title: Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors.
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 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.
authors.affiliation: INSERM U761, Biostructures and Drug Discovery and Faculté de Pharmacie, Université Lille Nord de France, 3 rue du Pr Laguesse, Lille F-59000, France. rebecca.deprez@univ-lille2.fr
authors.forename: Rebecca
authors.initials: R
authors.lastname: Deprez-Poulain
authors.forename: Marion
authors.initials: M
authors.lastname: Flipo
authors.forename: Catherine
authors.initials: C
authors.lastname: Piveteau
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dassonneville
authors.forename: Isabelle
authors.initials: I
authors.lastname: Florent
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D008314:Malonates / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D051379:Mice; D062105:Molecular Docking Simulation; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D015032:Zinc
chemical_list: D000962:Antimalarials; D008314:Malonates; C578801:N-(4-fluorobenzyl)-N'-hydroxy-2-(1-phenylmeth-(Z)-ylidene)malonamide; D015800:Protozoan Proteins; D045726:Metalloproteases; D000626:Aminopeptidases; D015032:Zinc