Open AccessStructure–Activity Relationship of Antischistosomal Ozonide Carboxylic Acids
Author(s) -
Jianbo Wu,
Xiaofang Wang,
Francis Chi Keung Chiu,
Cécile Häberli,
David M. Shackleford,
Eileen Ryan,
Sattu Kamaraj,
Vivek J. Bulbule,
Alexander Wallick,
Yuxiang Dong,
Karen L. White,
Paul H. Davis,
Susan A. Charman,
Jennifer Keiser,
Jonathan L. Vennerstrom
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00069
Subject(s) - chemistry , ozonide , solubility , lipophilicity , ozonolysis , stereochemistry , combinatorial chemistry , organic chemistry
Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another 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.