Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres

Xiaofang Wang, Yuxiang Dong, Sergio Wittlin, Susan A. Charman, Francis C.K. Chiu, Jacques Chollet, Kasiram Katneni, Janne Mannila, Julia Morizzi, Eileen Ryan, Christian Scheurer, Jessica Steuten, Josefina Santo Tomas, Christopher Snyder, Jonathan L. Vennerstrom

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51 Scopus citations

Abstract

To ascertain the structure-activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously observed for OZ439 versus OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides.

Original languageEnglish (US)
Pages (from-to)2547-2555
Number of pages9
JournalJournal of Medicinal Chemistry
Volume56
Issue number6
DOIs
StatePublished - Mar 28 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Wang, X., Dong, Y., Wittlin, S., Charman, S. A., Chiu, F. C. K., Chollet, J., Katneni, K., Mannila, J., Morizzi, J., Ryan, E., Scheurer, C., Steuten, J., Santo Tomas, J., Snyder, C., & Vennerstrom, J. L. (2013). Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Journal of Medicinal Chemistry, 56(6), 2547-2555. https://doi.org/10.1021/jm400004u