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Science 15 February 2002:
Vol. 295. no. 5558, pp. 1311 - 1314
DOI: 10.1126/science.1067236
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Reports

A Class of Potent Antimalarials and Their Specific Accumulation in Infected Erythrocytes

Kai Wengelnik,1 Valérie Vidal,2 Marie L. Ancelin,1 Anne-Marie Cathiard,1 Jean Louis Morgat,3 Clemens H. Kocken,4 Michèle Calas,2 Socrates Herrera,5 Alan W. Thomas,4 Henri J. Vial1*

During asexual development within erythrocytes, malaria parasites synthesize considerable amounts of membrane. This activity provides an attractive target for chemotherapy because it is absent from mature erythrocytes. We found that compounds that inhibit phosphatidylcholine biosynthesis de novo from choline were potent antimalarial drugs. The lead compound, G25, potently inhibited in vitro growth of the human malaria parasites Plasmodium falciparum and P. vivax and was 1000-fold less toxic to mammalian cell lines. A radioactive derivative specifically accumulated in infected erythrocytes to levels several hundredfold higher than in the surrounding medium, and very low dose G25 therapy completely cured monkeys infected with P. falciparum and P. cynomolgi.

1 CNRS UMR 5539, CP 107,
2 CNRS UMR 5810, CP 22, Université Montpellier II, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
3 CRBA CNRS UMR 5473, Université Montpellier I, Faculté de Pharmacie, 15 Av. Charles Flahault, 34060 Montpellier, France.
4 Department of Parasitology, Biomedical Primate Research Centre, Postbox 3306, 2280 GH Rijswijk, Netherlands.
5 Fundacion Centro de Primates, Universidad del Valle, Cali, Colombia.
*   To whom correspondence should be addressed. E-mail: vial{at}univ-montp2.fr

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Prodrugs of bisthiazolium salts are orally potent antimalarials.
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Heme Binding Contributes to Antimalarial Activity of Bis-Quaternary Ammoniums.
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Antimicrob. Agents Chemother. 47, 2590-2597
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In Vivo Antimalarial Activities of Mono- and Bis Quaternary Ammonium Salts Interfering with Plasmodium Phospholipid Metabolism.
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