The IC50s of seven potent N,N′-arylurea compounds against juvenile and adult S. japonicum. Compounds 16 and 38 showed higher activities than the positive control MMV665852. Display omitted Although the antischistosomal activities of N,N′-arylurea analogs were reported, systematic structure–activity relationships have not been conducted. In this Letter, we reported the design, synthesis and evaluation of 45 N,N′-arylurea analogs. Among these prepared compounds, 13 compounds were urea linker modified and 32 were N,N′-arylurea derivatives. The activity evaluation revealed 12 analogs exhibited IC50 values lower than 22.6μM, and 7 of them had IC50 less than 10μM against the juvenile Schistosoma japonicum in vitro. Their worm killing potency was even higher against adult worm. Unfortunately, low to moderate worm burden reduction of 0–33.4% was recorded after administration of a single oral dose of 200mg/kg or 400mg/kg to mice harboring S. japonicum.