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Antimicrob. Agents Chemother. doi:10.1128/AAC.00609-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early Effects on Digestive Vacuole Morphology

Department of Biochemistry, and ARC Centre of Excellence for Coherent X-ray Science, La Trobe University, Melbourne, Victoria, 3086, Australia, Department of Chemistry, Adelaide University, South Australia, 5005, Australia

^* To whom correspondence should be addressed. Email: L.Tilley{at}latrobe.edu.au.

	Abstract

Artermisinin and derivatives are now the mainstay of antimalarial treatment however their mechanism of action is only poorly understood. We report the synthesis of a novel series of epoxy-endoperoxides that can be prepared in high yields from simple starting materials. Endoperoxides that are di-substituted with alkyl or benzyl side-chains show efficient inhibition of the growth of both chloroquine sensitive and resistant strains of P. falciparum. A trans-epoxide with respect to the peroxide linkage increases the activity compared to its cis-epoxy counterpart or the parent endoperoxide. The novel endoperoxides do not show a strong interaction with artemisinin. We have compared the mechanism of action of the novel endoperoxides with that of artemisinin. Electron microscopy reveals that the novel endoperoxides causes early accumulation of endocytic vesicles, while artemisinin causes disruption of the digestive vacuole membrane. At longer incubation times artemisinin causes extensive loss of organellar structures while the novel endoperoxides cause myelin body formation as well as an accumulation of endocytic vesicles. An early event following endoperoxide treatment is redistribution of the pH sensitive probe, LysoSensor^TM, from the digestive vacuole to punctuate structures. By contrast, neither artemisinin nor the novel endoperoxides cause alterations in endoplasmic reticulum morphology nor show antagonistic antimalarial activity with thapsigargin. Analysis of rhodamine 123 uptake by P. falciparum suggests that disruption of mitochondrial membrane potential occurs as a downstream effect rather than as an initiator of parasite killing. The data suggests that the digestive vacuole is an important initial site of endoperoxide antimalarial activity.