Prodrugs of bisthiazolium salts are orally potent antimalarials

doi:10.1073/pnas.0404037101

Prodrugs of bisthiazolium salts are orally potent antimalarials

^*Unité Mixte de Recherche 5539, Centre National de la Recherche Scientifique/Université Montpellier II, Case 107, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France; ^‡Department of Parasitology, Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH, Rijswijk, The Netherlands; ^§Laboratoire de Pharmacocinétique Clinique, Faculté de Pharmacie, 34093 Montpellier, France; and ^¶Unité Mixte de Recherche 5810, Centre National de la Recherche Scientifique/Université Montpellier II, 34095 Montpellier Cedex 5, France

Edited by Anthony C. Cerami, The Kenneth S. Warren Institute, Kitchawan, NY (received for review June 7, 2004)

Abstract

We created neutral antimalarial prodrugs that deliver bisthiazolium compounds with antimalarial activity in the nanomolar range. These drugs primarily affect early intraerythrocytic stages through rapid, nonreversible cytotoxicity. The compounds are suitable for both parenteral and oral use and plasma promotes rapid conversion of the prodrug into the drug. We demonstrate that very low doses offer protection in a murine model of malaria. The drugs show great potential for curing high parasitemia with short-course treatments. Oral administration of the TE3 prodrug completely cures Plasmodium cynomolgi infection in rhesus monkeys. The drugs specifically accumulate inside infected erythrocytes, block phosphatidylcholine biosynthesis, and interact with hemozoin. To our knowledge, this class of compounds represents one of the most potent antimalarials tested to date. These unique properties signal a promising future for this class of antimalarial.

Footnotes

↵ † To whom correspondence should be addressed. E-mail: vial{at}univ-montp2.fr.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: G25, [1,16-hexadecamethylenebis(N-methylpyrrolidinium) dibromide]; LC/ESI-MS, liquid chromatography/electrospray ionization MS; PC, phosphatidylcholine; CQ, chloroquine.
Freely available online through the PNAS open access option.