2-tert-butyl-primaquine exhibit potent blood schizontocidal antimalarial activity via inhibition of heme crystallization
© Thanh Thuy et al; licensee BioMed Central Ltd. 2010
Published: 16 December 2010
Primaquine (PQ) is the only 8-quinolinamine available to treat the malarial parasites in the infections caused by Plasmodium vivax and P. ovale. PQ has broad range of antimalarial activities, including efficacy as a causal prophylactic, gametocytocide, and sporontocide. These encouraging pharmacological properties make PQ an ideal drug to emulate while designing new antimalarials with improved activities (). The placement of a metabolically stable tert-butyl group at the C-2 position of a quinoline ring in PQ (2-tert-Butyl-Primaquine - BPQ) results in a tremendous improvement in blood schizontocidal antimalarial activity ([1, 2]). 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 (). In this study, we investigate the mechanism of blood schizontocidal activity of BPQ.
IC50 values for inhibition of P. falciparum growth and heme crystallization
IC50 (μM) for inhibition of
P. falciparum D6 clone growth
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.
Our sincere thanks to all members in Structural Biotechnology Laboratory, Department of Applied Biology, Kyoto Institute of Technology who have contributed to and worked on this study.
- Jain M, Vangapandu S, Sachdeva S, Singh S, Singh PP, Jena GB, Tikoo K, Ramarao P, Kaul CL, Jain R: Discovery of a bulky 2-tert-butyl group containing primaquine analogue that exhibits potent blood-schizontocidal antimalarial activities and complete elimination of methemoglobin toxicity. J Med Chem. 2004, 47: 285-287. 10.1021/jm0304562.View ArticlePubMedGoogle Scholar
- Jain M, Vangapandu S, Sachdeva S, Jain R: Synthesis and blood-schizontocidal antimalarial activities of 2-substituted/2,5-disubstituted-8-quinolinamines and some of their amino acid conjugates. Bioorg Med Chem. 2004, 12: 1003-1010. 10.1016/j.bmc.2003.12.029.View ArticlePubMedGoogle Scholar
- Egan TJ, Combrinck JM, Egan J, Hearne GR, Marques HM, Ntenteni S, Sewell BT, Smith PJ, Taylor D, van Schalkwyk DA, Walden JC: Fate of haem iron in the malaria parasite Plasmodium falciparum. Biochem J. 2002, 365: 343-347. 10.1042/BJ20020793.PubMed CentralView ArticlePubMedGoogle Scholar
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