Structure-Activity Relationship of Antischistosomal Ozonide Carboxylic Acids

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. Vennerstrom

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3723-3736
Number of pages14
JournalJournal of Medicinal Chemistry
Volume63
Issue number7
DOIs
StatePublished - Apr 9 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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