title: 2-tert-butyl-8-quinolinamines exhibit potent blood schizontocidal antimalarial activity via inhibition of heme crystallization.
abstract: We have recently reported that the attachment of a bulky metabolically stable tert-butyl group at the C-2 position of a quinoline ring in primaquine results in a tremendous improvement in the blood schizontocidal antimalarial activity of 8-quinolinamine. Because free heme released from hemoglobin catabolism in a malarial parasite is highly toxic, the parasite protects itself mainly by crystallization of heme into insoluble nontoxic hemozoin. We now demonstrate the ability of 2-tert-butylprimaquine to inhibit in vitro beta-hematin formation, to form a complex with heme with a stoichiometry of 1:1, and to enhance heme-induced hemolysis. The results described herein indicate that a major improvement in the blood-schizontocidal antimalarial activity of 2-tert-butylprimaquine might be due to a disturbance of heme catabolism pathway in the malarial parasite.
authors.affiliation: Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Kyoto, Japan.
authors.forename: Nguyen Tien
authors.initials: NT
authors.lastname: Huy
authors.forename: Keisuke
authors.initials: K
authors.lastname: Mizunuma
authors.forename: Kirandeep
authors.initials: K
authors.lastname: Kaur
authors.forename: Nguyen Thanh Thuy
authors.initials: NT
authors.lastname: Nhien
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Jain
authors.forename: Dinh Thanh
authors.initials: DT
authors.lastname: Uyen
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Harada
authors.forename: Rahul
authors.initials: R
authors.lastname: Jain
authors.forename: Kaeko
authors.initials: K
authors.lastname: Kamei
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects* / Q000469:parasitology* / Q000502:physiology; D006420:Hemeproteins / Q000378:metabolism; D006461:Hemolysis; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D011319:Primaquine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C482216:2-tert-butylprimaquine; D000962:Antimalarials; D006420:Hemeproteins; C020753:hemozoin; D011319:Primaquine