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 J. Creek, Charles E. Schiaffo, Yuxiang Dong, Jacques Chollet, Christian Scheurer, Sergio Wittlin, Susan A. Charman, Patrick H. Dussault, James K. Wood, Jonathan L. Vennerstrom

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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 animalarial 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 (US)
Pages (from-to)4542-4545
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number16
DOIs
StatePublished - Aug 15 2009

Keywords

  • 1,2,4-Trioxane
  • 1,2,4-Trioxepane
  • 1,2,4-Trioxolane
  • Antimalarial
  • Artemisinin
  • Peroxide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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