title: Targeting of hematin by the antimalarial pyronaridine.
abstract: 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 beta-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 beta-hematin formation, were equivocal.
authors.affiliation: Division of Toxicology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand.
authors.forename: Saranya
authors.initials: S
authors.lastname: Auparakkitanon
authors.forename: Soebsakul
authors.initials: S
authors.lastname: Chapoomram
authors.forename: Kannika
authors.initials: K
authors.lastname: Kuaha
authors.forename: Thamrong
authors.initials: T
authors.lastname: Chirachariyavej
authors.forename: Prapon
authors.initials: P
authors.lastname: Wilairat
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D004912:Erythrocytes / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006420:Hemeproteins / Q000037:antagonists & inhibitors; D006427:Hemin / Q000096:biosynthesis* / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009287:Naphthyridines / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D011485:Protein Binding
chemical_list: D000962:Antimalarials; D006420:Hemeproteins; D009287:Naphthyridines; C020753:hemozoin; D006427:Hemin; D002738:Chloroquine; D005978:Glutathione; C027871:pyronaridine