Investigating the Antimalarial Action of 1,2,4-Trioxolanes with Fluorescent Chemical ProbesJournal of Medicinal Chemistry (2012)
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.
- Free radicals,
- Lipid Peroxidation
Publication DateDecember 8, 2012
Citation InformationCarmony 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/