Title

Investigating the Antimalarial Action of 1,2,4-Trioxolanes with Fluorescent Chemical Probes

Document Type

Article

Journal or Conference Title

Journal of Medicinal Chemistry

ISSN

0022-2623

Volume

54

Issue

23

First Page

8207

Last Page

8213

Publication Date

12-8-2012

Department

Natural Sciences and Mathematics

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.

Rights

Copyright © 2012 American Chemical Society. All rights reserved.

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.