jm0c00069_si_001.pdf (1.48 MB)
Structure–Activity Relationship of Antischistosomal Ozonide Carboxylic Acids
journal contribution
posted on 2020-03-19, 17:43 authored by Jianbo Wu, Xiaofang Wang, Francis C. K. Chiu, Cécile Häberli, David M. Shackleford, Eileen Ryan, Sriraghavan Kamaraj, Vivek J. Bulbule, Alexander I. Wallick, Yuxiang Dong, Karen L. White, Paul H. Davis, Susan A. Charman, Jennifer Keiser, Jonathan L. VennerstromSemisynthetic artemisinins and other
bioactive peroxides are best
known for their powerful antimalarial activities, and they also show
substantial activity against schistosomesanother hemoglobin-degrading
pathogen. Building on this discovery, we now describe the initial
structure–activity relationship (SAR) of antischistosomal ozonide
carboxylic acids OZ418 (2) and OZ165 (3).
Irrespective of lipophilicity, these ozonide weak acids have relatively
low aqueous solubilities and high protein binding values. Ozonides
with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies.
It was possible to increase solubility, decrease protein binding,
and maintain the high antischistosomal activity in mice infected with
juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds.
In some cases, adding polar functional groups and heteroatoms to the
spiroadamantane substructure increased the solubility and metabolic
stability, but in all cases decreased the antischistosomal activity.