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Identification of an antimalarial synthetic trioxolane drug development candidate


The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle1. Available evidence2,3,4 suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem5 and proteins (enzymes)6, one of which—the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)—may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs8. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes9. However, as a drug class, the artemisinins suffer from chemical10 (semi-synthetic availability, purity and cost), biopharmaceutical11 (poor bioavailability and limiting pharmacokinetics) and treatment8,11 (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.

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Figure 1: Trioxolane chemistry.
Figure 2: Effective dose and onset and recrudescence data.
Figure 3: Tissue concentrations of trioxolanes 6 (open bars) and 7 (hatched bars) after oral administration of approximately 35 mg kg-1 to rats.

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We thank R. G. Ridley and M. Tanner for inspiration; K. Griesbaum and A. Hudson for advice; C. Craft, S. Nwaka, S. Campbell, P. Hadvary and R. Imhof for their support; and J. M. Karle for performing X-ray crystallographic experiments. This work was supported by the World Health Organization and Medicines for Malaria Venture.

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Correspondence to Jonathan L. Vennerstrom.

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Supplementary information

Supplementary Data

This file contains a detailed Methods section with a complete description of the reaction of trioxolane 4 with ferrous acetate/TEMPO; Supplementary Table 1 (in vivo activity in P. berghei infected mice following a, single oral doses or b, three consecutive daily oral doses of trioxolanes 5–7 and the four comparator drugs), Table 2 (prophylactic activity following single 100 mg/kg oral doses of trioxolane 6 and 7 and the four comparator drugs) and Table 3 (in vitro cross-resistance (IC50, IC90) for trioxolanes 6 and 7, AS, and CQ with various strains of P. falciparum); and the legend to Supplementary Figure 1. (DOC 72 kb)

Supplementary Figure 1

This figure shows plasma concentration versus time profiles following oral administration of trioxolanes 6 and 7, AM, and AS to rats. (PDF 40 kb)

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Vennerstrom, J., Arbe-Barnes, S., Brun, R. et al. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 430, 900–904 (2004).

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