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SAR of a new antischistosomal urea carboxylic acid
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
4493023
Author(s)
Wu, Jianbo; Wang, Chunkai; Häberli, Cécile; White, Karen L.; Shackleford, David M.; Chen, Gong; Dong, Yuxiang; Charman, Susan A.; Keiser, Jennifer; Vennerstrom, Jonathan L.
SAR of a new antischistosomal urea carboxylic acid
Journal
Bioorganic & medicinal chemistry letters
Volume
28
Number
23-24
Pages / Article-Number
3648-3651
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 D; 7.4; 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.
