SAR of a new antischistosomal urea carboxylic acid

Jianbo Wu, Chunkai Wang, Cécile Häberli, Karen L. White, David M. Shackleford, Gong Chen, Yuxiang Dong, Susan A. Charman, Jennifer Keiser, Jonathan L. Vennerstrom

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Urea carboxylic acids, products of aryl hydantoin hydrolysis, were recently identified as a new antischistosomal chemotype. We now describe a baseline structure–activity relationship (SAR) for this compound series. With one exception, analogs of lead urea carboxylic acid 2 were quite polar with Log D7.4 values ranging from −1.9 to 1.8, had high aqueous solubilities in the range of 25–100 µg/mL, and were metabolically stable. None of the compounds had measurable in vitro antischistosomal activity or cytotoxicity, but four of these had moderate worm burden reduction (WBR) values of 42–70% when they were administered as single 100 mg/kg oral doses to S. mansoni-infected mice. These data indicate that with the exception of the gem-dimethyl substructure and the distal nitrogen atom of the urea functional group, the rest of the structure of 2 is required for in vivo antischistosomal activity.

Original languageEnglish (US)
Pages (from-to)3648-3651
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number23-24
DOIs
StatePublished - Dec 15 2018

Keywords

  • Antischistosomal
  • SAR
  • Urea carboxylic acid

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Wu, J., Wang, C., Häberli, C., White, K. L., Shackleford, D. M., Chen, G., Dong, Y., Charman, S. A., Keiser, J., & Vennerstrom, J. L. (2018). SAR of a new antischistosomal urea carboxylic acid. Bioorganic and Medicinal Chemistry Letters, 28(23-24), 3648-3651. https://doi.org/10.1016/j.bmcl.2018.10.039