We discovered medium-ring keto bislactams as a new antischistosomal chemotype. The ketone functional group and isoindolinone substructure were required for high antischistosomal activity. Aryl substitution with EWG functional groups decreased the chemical stability. These compounds were relatively polar with the measured LogD7.4 values ranging from <0 to 2.4, had kinetic aqueous solubilities between 40 and >320 μM, and had relatively low cytotoxicities with IC50s ranging from 52 to >390 μM. We identified two compounds with IC50 values < 5 μM against ex vivoSchistosoma mansoni (S. mansoni).