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: Nguyen Tien Huy, Keisuke Mizunuma, Kirandeep Kaur, Nguyen Thanh Thuy Nhien, Meenakshi Jain, Dinh Thanh Uyen, Shigeharu Harada, Rahul Jain, Kaeko Kamei
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 51 Issue 8 Pg. 2842-7 (Aug 2007) ISSN: 0066-4804 [Print] United States
• PMID: 17562796 (Publication Type: Journal Article)

Chemical References

• 2-tert-butylprimaquine
• Antimalarials
• Hemeproteins
• hemozoin
• Primaquine

Topics

• Animals
• Antimalarials (chemistry, pharmacology)
• Erythrocytes (drug effects, parasitology, physiology)
• Hemeproteins (metabolism)
• Hemolysis
• Humans
• Malaria, Falciparum (drug therapy, parasitology)
• Parasitic Sensitivity Tests
• Plasmodium falciparum (drug effects, metabolism)
• Primaquine (analogs & derivatives, chemistry, pharmacology)