SAR of a new antischistosomal urea carboxylic acid

[摘要] 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 mu g/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.

[发布日期] 2018-12-15

[关键词] Urea carboxylic acid;Antischistosomal;SAR