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2-tert-butyl-primaquine exhibit potent blood schizontocidal antimalarial activity via inhibition of heme crystallization
Malaria Journal volume 9, Article number: P69 (2010)
Background
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 ([1]). 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 ([3]). In this study, we investigate the mechanism of blood schizontocidal activity of BPQ.
Conclusion
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.
References
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.
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.
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.
Acknowledgements
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.
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Thanh Thuy, N.N., Tien, H.N., Jain, R. et al. 2-tert-butyl-primaquine exhibit potent blood schizontocidal antimalarial activity via inhibition of heme crystallization. Malar J 9 (Suppl 2), P69 (2010). https://doi.org/10.1186/1475-2875-9-S2-P69
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DOI: https://doi.org/10.1186/1475-2875-9-S2-P69