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 Ann Charman, Francis Chi Keung Chiu, Jacques Chollet, Kasiram Katneni, Janne Martti Mannila, Julia Morizzi, Eileen Ryan, Christian Scheurer, Jessica Anne Steuten, Josefina Santo Tomas, Christopher Snyder, Jonathan Vennerstrom

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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
Pages (from-to)2547 - 2555
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number6
Publication statusPublished - 2013

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