Novel selective inhibitors of the zinc plasmodial aminopeptidase PfA-M1 as potential antimalarial agents.
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.
Flipo
Marion
M
Inserm, U761, Biostructures and Drug Discovery, Lille F-59006 France.
Beghyn
Terence
T
Leroux
Virginie
V
Florent
Isabelle
I
Deprez
Benoit P
BP
Deprez-Poulain
Rebecca F
RF
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008314:Malonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility; D015032:Zinc
C519105:2-benzyl-N-(4-fluorobenzyl)-N'-hydroxymalonamide; D000962:Antimalarials; D006877:Hydroxamic Acids; D008314:Malonates; C519106:N-(4-fluorobenzyl)-N'-hydroxy-2-(1-phenylmethylidene)malonamide; D045726:Metalloproteases; D000626:Aminopeptidases; D015032:Zinc