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Abstract

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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Acknowledgements

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.

Author information

Affiliations

  1. College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA

    • Jonathan L. Vennerstrom
    • , Yuxiang Dong
    • , Maniyan Padmanilayam
    •  & Yuanqing Tang
  2. Fulcrum Pharma Developments Ltd, Hemel Hempstead, Hertfordshire HP1 1JY, UK

    • Sarah Arbe-Barnes
  3. Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland

    • Reto Brun
    • , Jacques Chollet
    • , Josefina Santo Tomas
    • , Christian Scheurer
    • , Bernard Scorneaux
    •  & Sergio Wittlin
  4. Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia

    • Susan A. Charman
    • , Francis C. K. Chiu
    • , Kylie McIntosh
    •  & William N. Charman
  5. F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel, Switzerland

    • Arnulf Dorn
    • , Daniel Hunziker
    •  & Hugues Matile
  6. Basilea Pharmaceutica Ltd, Grenzacherstrasse 487, CH-4058 Basel, Switzerland

    • Heinrich Urwyler

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Competing interests

The authors declare that they have no competing financial interests.

Corresponding author

Correspondence to Jonathan L. Vennerstrom.

Supplementary information

Word documents

  1. 1.

    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.

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  1. 1.

    Supplementary Figure 1

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

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DOI

https://doi.org/10.1038/nature02779

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