Evidence for a Common Non‐Heme Chelatable‐Iron‐Dependent Activation Mechanism for Semisynthetic and Synthetic Endoperoxide Antimalarial Drugs

• Published in: Angewandte Chemie International Edition Vol. 46; no. 33; pp. 6278 - 6283
• Main Authors: Stocks, Paul A., Bray, Patrick G., Barton, Victoria E., Al‐Helal, Mohammed, Jones, Michael, Araujo, Nuna C., Gibbons, Peter, Ward, Stephen A., Hughes, Ruth H., Biagini, Giancarlo A., Davies, Jill, Amewu, Richard, Mercer, Amy E., Ellis, Gemma, O'Neill, Paul M.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag 01.01.2007; Wiley
• Subjects: antimalarial agents; Antimalarials - chemistry; Antimalarials - pharmacology; chelates; Chemistry; Chemistry, Multidisciplinary; confocal imaging; fluorescence; Heme - chemistry; iron; Iron Chelating Agents - chemistry; Peroxides - chemistry; Peroxides - pharmacology; Physical Sciences; Science & Technology; antimalarial agents; DESIGN; ANALOGS; confocal imaging; TRIOXANES; DISPIRO-1,2,4,5-TETRAOXANES; MEDICINAL CHEMISTRY; 1,2,4-TRIOXANE; HEME; fluorescence; PLASMODIUM-FALCIPARUM; QINGHAOSU ARTEMISININ; chelates; iron; DERIVATIVES
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.200604697

The iron‐y of fate: Isobole analyses of fluorescently labeled antimalarial endoperoxides with chelators selective for non‐heme iron, and laser confocal microscopy studies within living malaria parasites have shown that the semisynthetic analogues of artemisinin and synthetic endoperoxides (see example) share a common mechanism of action involving chelatable‐iron‐mediated bioactivation (see images) and irreversible alkylation of parasite targets.