Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities

Abstract

For the adult Schistosoma mansoni flatworm pathogen, we report further structure activity relationships (SAR) of 19 N-phenylbenzamide analogs. Our previous SAR studies, designed by selecting representative substituents from the Craig plot, identified 9 and 11 which possessed electron-withdrawing groups that benefited potency. This study sought to enhance the potency of this chemotype by incorporating other electron-withdrawing functionalities not studied previously and to overcome the potential pharmacokinetic liabilities associated with the high lipophilicity of frontrunner compounds. Compared to the most potent compound, 9 (EC50 = 80 nM), from our previous work, the most potent compounds in the current study (32 (EC50 = 1.17 µM), 34 (EC50 = 1.64 µM) and 38 (EC50 = 1.16 µM)) were less active although they retained single digit micromolar potency. Furthermore, compound 38 generated a CC50 value of > 20 µM in counter toxicity screens using HEK 293 cells, translating to a wide selectivity index of > 17.

Keywords

• N-phenylbenzamide analogs
• N-pyridazinylbenzamide analogs
• Schistosoma mansoni