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

doi:10.1021/jm400004u

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

J Med Chem. 2013 Mar 28;56(6):2547-55. doi: 10.1021/jm400004u. Epub 2013 Mar 15.

Authors

Xiaofang Wang¹, 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

Affiliation

¹ College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska, USA.

PMID: 23489135
DOI: 10.1021/jm400004u

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Absorption
Adamantane / analogs & derivatives
Adamantane / chemistry
Adamantane / metabolism
Adamantane / pharmacokinetics
Adamantane / pharmacology
Animals
Antimalarials / chemistry
Antimalarials / metabolism*
Antimalarials / pharmacokinetics
Antimalarials / pharmacology*
Dioxolanes / chemistry*
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / metabolism
Heterocyclic Compounds / pharmacokinetics
Heterocyclic Compounds / pharmacology
Heterocyclic Compounds, 1-Ring / chemistry
Heterocyclic Compounds, 1-Ring / metabolism
Heterocyclic Compounds, 1-Ring / pharmacokinetics
Heterocyclic Compounds, 1-Ring / pharmacology
Male
Mice
Peroxides / chemistry
Peroxides / metabolism
Peroxides / pharmacokinetics
Peroxides / pharmacology
Plasmodium berghei / drug effects
Plasmodium falciparum / drug effects
Spiro Compounds / chemistry
Spiro Compounds / metabolism
Spiro Compounds / pharmacokinetics
Spiro Compounds / pharmacology
Structure-Activity Relationship
Tetraoxanes / chemistry*

Substances

1,2,4-trioxane
Antimalarials
Dioxolanes
Heterocyclic Compounds
Heterocyclic Compounds, 1-Ring
Peroxides
Spiro Compounds
Tetraoxanes
arterolane
Adamantane
artefenomel
formal glycol