Structure-activity relationship of an ozonide carboxylic acid (oz78) against fasciola hepatica

Qingjie Zhao, Mireille Vargas, Yuxiang Dong, Lin Zhou, Xiaofang Wang, Kamaraj Sriraghavan, Jennifer Keiser, Jonathan L. Vennerstrom

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Abstract

In this paper, we describe the SAR of ozonide carboxylic acid OZ78 (1) as the first part of our search for a trematocidal synthetic peroxide drug development candidate. We found that relatively small structural changes to 1 resulted most commonly in loss of activity against Fasciola hepatica in vivo. A spiroadamantane substructure and acidic functional group (or ester prodrug) were required for activity. Of 26 new compounds administered at single 100 mg/kg oral doses to F. hepatica infected rats, 8 had statistically significant worm burden reductions, 7 were partially curative, and 1 (acylsulfonamide 6) was completely curative and comparable to 1 in flukicidal efficacy. This study also showed that the activity of 1 is peroxide-bond-dependent, suggesting that its flukicidal efficacy depends upon hemoglobin digestion in F. hepatica.

Original languageEnglish (US)
Pages (from-to)4223-4233
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number10
DOIs
Publication statusPublished - May 27 2010

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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