1. College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA
2. Fulcrum Pharma Developments Ltd, Hemel Hempstead, Hertfordshire HP1 1JY, UK
3. Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland
4. Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
5. F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
6. Basilea Pharmaceutica Ltd, Grenzacherstrasse 487, CH-4058 Basel, Switzerland

Correspondence to: Jonathan L. Vennerstrom¹ Correspondence and requests for materials should be addressed to J.L.V. (Email: jvenners@unmc.edu).

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 evidence^{2, 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 treatment^{8, 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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