TY - JOUR
T1 - 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
AU - Wang, Xiaofang
AU - Dong, Yuxiang
AU - Wittlin, Sergio
AU - Charman, Susan A.
AU - Chiu, Francis C.K.
AU - Chollet, Jacques
AU - Katneni, Kasiram
AU - Mannila, Janne
AU - Morizzi, Julia
AU - Ryan, Eileen
AU - Scheurer, Christian
AU - Steuten, Jessica
AU - Santo Tomas, Josefina
AU - Snyder, Christopher
AU - Vennerstrom, Jonathan L.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/3/28
Y1 - 2013/3/28
N2 - 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.
AB - 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.
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U2 - 10.1021/jm400004u
DO - 10.1021/jm400004u
M3 - Article
C2 - 23489135
AN - SCOPUS:84875737819
SN - 0022-2623
VL - 56
SP - 2547
EP - 2555
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 6
ER -