Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs: Relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity

Xiaofang Wang, Darren John Creek, Charles E Schiaffo, Yuxiang Dong, Jacques Chollet, Christian Scheurer, Sergio Wittlin, Susan Ann Charman, Patrick H Dussault, James K Wood, Jonathan Vennerstrom

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Abstract

These data suggest that iron (II) reactivity for a set of homologous spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane peroxide heterocycles is a necessary, but insufficient, property of antimalarial peroxides. Heme alkylation efficiency appears to give a more accurate prediction of antimalarial activity than FeSO4-mediated reaction rates, suggesting that antimalarial activity is not merely dependent on peroxide bond cleavage, but also on the ability of reactive intermediates to alkylate heme or other proximal targets.
Original languageEnglish
Pages (from-to)4542 - 4545
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number16
DOIs
Publication statusPublished - 2009

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