Investigating the Antimalarial Action of 1,2,4-Trioxolanes with Fluorescent Chemical Probes
Journal of Medicinal Chemistry
Natural Sciences and Mathematics
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.
Hartwig, Carmony L.; Lauterwasser, Erica; Mahajan, Sumit; Hoke, Jonathan; Cooper, Roland; and Renslo, Adam, "Investigating the Antimalarial Action of 1,2,4-Trioxolanes with Fluorescent Chemical Probes" (2012). Collected Faculty and Staff Scholarship. 184.
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