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.