ABSTRACT
Amodiaquine (AQ) is an antimalarial which is effective against chloroquino-resistant strains of Plasmodium falciparum but whose clinical use is severely restricted because of associated hepatotoxicity and agranulocytosis. "One-pot" synthesis of formamidines likely to be transformed into AQ derivatives is reported. Compared with AQ, the new compounds were devoid of in vitro cytotoxicity upon human embryonic lung cells and mouse peritoneal macrophages. One showed a potent in vivo activity in mice infected with P berghei. Transformation of this compound by reductive amination led to a new type of AQ derivatives that displayed an in vitro activity similar to that of AQ but did not lead to toxic quinone-imines.
Subject(s)
Amidines/chemical synthesis , Antimalarials/chemical synthesis , Quinolines/chemical synthesis , Amidines/pharmacology , Amidines/therapeutic use , Amodiaquine/analogs & derivatives , Amodiaquine/pharmacology , Amodiaquine/therapeutic use , Animals , Antimalarials/pharmacology , Antimalarials/therapeutic use , Cell Line , Humans , Inhibitory Concentration 50 , Macrophages/drug effects , Malaria/drug therapy , Mice , Plasmodium berghei/drug effects , Quinolines/pharmacology , Quinolines/therapeutic useABSTRACT
A series of 10 1,4-bis(3-aminopropyl)piperazine compounds was found to display antiplasmodial activity with 50% growth inhibition between 30 and 250 nM, on three Plasmodium falciparum strains differently sensitive to chloroquine. By affinity chromatography using one of these compounds, a 52-kDa protein was isolated from P. falciparum, microsequenced and cloned. It corresponded to a single copy gene encoding a 453 amino acid protein displaying the typical features of protein disulfide isomerases, a thiol metabolizing enzyme belonging to the thiol: disulfide oxidoreductase superfamily, which was not previously described in malarial species.
