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Progress in antischistosomal N,N'-diaryl urea SAR

Wu, Jianbo and Wang, Chunkai and Leas, Derek and Vargas, Mireille and White, Karen L. and Shackleford, David M. and Chen, Gong and Sanford, Austin G. and Hemsley, Ryan M. and Davis, Paul H. and Dong, Yuxiang and Charman, Susan A. and Keiser, Jennifer and Vennerstrom, Jonathan L.. (2018) Progress in antischistosomal N,N'-diaryl urea SAR. Bioorganic & medicinal chemistry letters : a Tetrahedron publication for the rapid dissemination of preliminary communications on all aspects of bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines, 28 (3). pp. 244-248.

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Official URL: https://edoc.unibas.ch/68240/

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Vargas, Mireille and Keiser, Jennifer
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0960-894X
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:29 Jan 2019 16:01
Deposited On:29 Jan 2019 16:01

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