Identification of an antimalarial synthetic trioxolane drug development candidate

Jonathan L. Vennerstrom (), Sarah Arbe-Barnes, Reto Brun, Susan A. Charman, Francis C. K. Chiu, Jacques Chollet, Yuxiang Dong, Arnulf Dorn, Daniel Hunziker, Hugues Matile, Kylie McIntosh, Maniyan Padmanilayam, Josefina Santo Tomas, Christian Scheurer, Bernard Scorneaux, Yuanqing Tang, Heinrich Urwyler, Sergio Wittlin and William N. Charman
Additional contact information
Jonathan L. Vennerstrom: College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center
Sarah Arbe-Barnes: Fulcrum Pharma Developments Ltd, Hemel Hempstead
Reto Brun: Swiss Tropical Institute
Susan A. Charman: Monash University
Francis C. K. Chiu: Monash University
Jacques Chollet: Swiss Tropical Institute
Yuxiang Dong: College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center
Arnulf Dorn: F. Hoffmann-La Roche Ltd
Daniel Hunziker: F. Hoffmann-La Roche Ltd
Hugues Matile: F. Hoffmann-La Roche Ltd
Kylie McIntosh: Monash University
Maniyan Padmanilayam: College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center
Josefina Santo Tomas: Swiss Tropical Institute
Christian Scheurer: Swiss Tropical Institute
Bernard Scorneaux: Swiss Tropical Institute
Yuanqing Tang: College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center
Heinrich Urwyler: Basilea Pharmaceutica Ltd
Sergio Wittlin: Swiss Tropical Institute
William N. Charman: Monash University

Nature, 2004, vol. 430, issue 7002, 900-904

Abstract: 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.

Date: 2004
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DOI: 10.1038/nature02779

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