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

Authors

• Xiaofang Wang, University of Nebraska Medical Center
• Darren J. Creek, Monash University, Parkville, Victoria, Australia
• Charles E. Schiaffo, University of Nebraska-Lincoln
• Yuxiang Dong, University of Nebraska Medical Center
• Jacques Chollet, Swiss Tropical Institute, Basel
• Christian Scheurer, Swiss Tropical Institute, Basel
• Segio Wittlin, Swiss Tropical Institute, Basel
• Susan A. Charman, Monash University, Parkville, Victoria, Australia
• Patrick Dussault, University of Nebraska-LincolnFollow
• James K. Wood, University of Nebraska at Omaha
• Jonathan L. Vennerstrom, University of Nebraska Medical CenterFollow

Document Type

Article

Date of this Version

8-2009

Comments

Published in Bioorganic & Medicinal Chemistry Letters 19:16 (August 15, 2009), pp. 4542–4545; doi: 10.1016/j.bmcl.2009.07.013 Copyright © 2009 Elsevier Ltd. Used by permission.

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.