TY - JOUR
T1 - Structure-Activity Relationship of Antischistosomal Ozonide Carboxylic Acids
AU - Wu, Jianbo
AU - Wang, Xiaofang
AU - Chiu, Francis C.K.
AU - Häberli, Cécile
AU - Shackleford, David M.
AU - Ryan, Eileen
AU - Kamaraj, Sriraghavan
AU - Bulbule, Vivek J.
AU - Wallick, Alexander I.
AU - Dong, Yuxiang
AU - White, Karen L.
AU - Davis, Paul H.
AU - Charman, Susan A.
AU - Keiser, Jennifer
AU - Vennerstrom, Jonathan L.
N1 - Funding Information:
The authors acknowledge the U.S. National Institutes of Health (AI116723-01) and the European Research Council (ERC-2013-CoG 614739-A HERO) for financial support.
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/4/9
Y1 - 2020/4/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85083081270&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85083081270&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.0c00069
DO - 10.1021/acs.jmedchem.0c00069
M3 - Article
C2 - 32134263
AN - SCOPUS:85083081270
VL - 63
SP - 3723
EP - 3736
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 7
ER -