Progress in antischistosomal N,N′-diaryl urea SAR

Jianbo Wu, Chunkai Wang, Derek Leas, Mireille Vargas, Karen L. White, David M. Shackleford, Gong Chen, Austin G. Sanford, Ryan M. Hemsley, Paul H. Davis, Yuxiang Dong, Susan A. Charman, Jennifer Keiser, Jonathan L. Vennerstrom

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

N,N′-Diaryl ureas have recently emerged as a new antischistosomal chemotype. We now describe physicochemical profiling, in vitro ADME, plasma exposure, and ex vivo and in vivo activities against Schistosoma mansoni for twenty new N,N′-diaryl ureas designed primarily to increase aqueous solubility, but also to maximize structural diversity. Replacement of one of the 4-fluoro-3-trifluoromethylphenyl substructures of lead N,N′-diaryl urea 1 with azaheterocycles and benzoic acids, benzamides, or benzonitriles decreased lipophilicity, and in most cases, increased aqueous solubility. There was no clear relationship between lipophilicity and metabolic stability, although all compounds with 3-trifluoromethyl-4-pyridyl substructures were metabolically stable. N,N′-diaryl ureas containing 4-fluoro-3-trifluoromethylphenyl, 3-trifluoromethyl-4-pyridyl, 2,2-difluorobenzodioxole, or 4-benzonitrile substructures had high activity against ex vivo S. mansoni and relatively low cytotoxicity. N,N-diaryl ureas with 3-trifluoromethyl-4-pyridyl and 2,2-difluorobenzodioxole substructures had the highest exposures whereas those with 4-fluoro-3-trifluoromethylphenyl substructures had the best in vivo antischistosomal activities. There was no direct correlation between compound exposure and in vivo activity.

Original languageEnglish (US)
Pages (from-to)244-248
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number3
DOIs
StatePublished - Feb 1 2018

Keywords

  • Antischistosomal
  • N,N′-Diaryl urea
  • SAR

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., Leas, D., Vargas, M., White, K. L., Shackleford, D. M., Chen, G., Sanford, A. G., Hemsley, R. M., Davis, P. H., Dong, Y., Charman, S. A., Keiser, J., & Vennerstrom, J. L. (2018). Progress in antischistosomal N,N′-diaryl urea SAR. Bioorganic and Medicinal Chemistry Letters, 28(3), 244-248. https://doi.org/10.1016/j.bmcl.2017.12.064