Progress in antischistosomal N,N'-diaryl urea SAR

Bioorganic & Medicinal Chemistry Letters
Jianbo WuJ L Vennerstrom

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 cor...Continue Reading

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Citations

Sep 4, 2018·Chemical & Pharmaceutical Bulletin·Ryu YamasakiIwao Okamoto
Jan 23, 2021·RSC Medicinal Chemistry·Godwin Akpeko DziwornuKelly Chibale
May 11, 2021·ACS Infectious Diseases·Derek A LeasJonathan L Vennerstrom
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Jun 18, 2021·Frontiers in Immunology·José T Moreira-FilhoCarolina H Andrade

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