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Article
Investigating the Antimalarial Action of 1,2,4-Trioxolanes with Fluorescent Chemical Probes
Journal of Medicinal Chemistry
(2012)
Abstract
The 1,2,4-trioxolanes are a new class of synthetic peroxidic antimalarials currently in human clinical trials. The well known reactivity of the 1,2,4-trioxolane ring towards inorganic ferrous iron and ferrous iron heme is proposed to play a role in the antimalarial action of this class of compounds. We have designed structurally relevant fluorescent chemical probes to study the sub-cellular localization of 1,2,4-trioxolanes in cultured Plasmodium falciparum parasites. Microscopy experiments revealed that a probe fluorescently labeled on the adamantane ring accumulated specifically in digestive vacuole-associated neutral lipid bodies within the parasite while an isosteric, but non-peroxidic congener did not. Probes fluorescently labeled on the cyclohexane ring showed no distinct localization pattern. In their sub-cellular localization and peroxidative effects, 1,2,4-trioxolane probes behave much like artemisinin-based probes studied previously. Our results are consistent with a role for adamantane-derived carbon-centered radicals in the antimalarial action of 1,2,4-trioxolanes, as hypothesized previously on the basis of chemical reactivity studies.
Keywords
- Antimalarials,
- 1,
- 2,
- 4-Trioxolanes,
- Free radicals,
- Heme,
- Lipid Peroxidation
Disciplines
Publication Date
December 8, 2012
Publisher Statement
Originally published as Hartwig, C. L., Lauterwasser, E. M., Mahajan, S. S., Hoke, J. M., Cooper, R. A., & Renslo, A. R. (2011). Investigating the antimalarial action of 1, 2, 4-trioxolanes with fluorescent chemical probes. Journal of medicinal chemistry,54(23), 8207-8213.
Citation Information
Carmony L. Hartwig, Erica M. W. Lauterwasser, Sumit S. Mahajan, Jonathan M. Hoke, et al.. "Investigating the Antimalarial Action of 1,2,4-Trioxolanes with Fluorescent Chemical Probes" Journal of Medicinal Chemistry Vol. 54 Iss. 23 (2012) p. 8207 - 8213 ISSN: 0022-2623 Available at: http://works.bepress.com/roland_cooper/29/