2-tert-butyl-8-quinolinamines exhibit potent blood schizontocidal antimalarial activity via inhibition of heme crystallization.
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.
Huy
Nguyen Tien
NT
Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Kyoto, Japan.
Mizunuma
Keisuke
K
Kaur
Kirandeep
K
Nhien
Nguyen Thanh Thuy
NT
Jain
Meenakshi
M
Uyen
Dinh Thanh
DT
Harada
Shigeharu
S
Jain
Rahul
R
Kamei
Kaeko
K
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
C482216:2-tert-butylprimaquine; D000962:Antimalarials; D006420:Hemeproteins; C020753:hemozoin; D011319:Primaquine