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Targeting of Hematin by the Antimalarial Pyronaridine

Division of Toxicology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital,¹ Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand,² Department of Immunology, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand³

Received 28 January 2006/ Returned for modification 7 March 2006/ Accepted 21 March 2006

Pyronaridine, 2-methoxy-7-chloro-10[3',5'-bis(pyrrolidinyl-1-methyl-)4'hydroxyphenyl]aminobenzyl-(b)-1,5-naphthyridine, a new Mannich base schizontocide originally developed in China and structurally related to the aminoacridine drug quinacrine, is currently undergoing clinical testing. We now show that pyronaridine targets hematin, as demonstrated by its ability to inhibit in vitro ß-hematin formation (at a concentration equal to that of chloroquine), to form a complex with hematin with a stoichiometry of 1:2, to enhance hematin-induced red blood cell lysis (but at 1/100 of the chloroquine concentration), and to inhibit glutathione-dependent degradation of hematin. Our observations that pyronaridine exerted this mechanism of action in situ, based on growth studies of Plasmodium falciparum K1 in culture showing antagonism of pyronaridine in combination with antimalarials (chloroquine, mefloquine, and quinine) that inhibit ß-hematin formation, were equivocal.

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