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Based on the 3\u2010chlorobenzothiophene\u20102\u2010hydroxamic acid <jats:bold>J1075<\/jats:bold>, a series of hydroxamic acids with different scaffolds were prepared as potential inhibitors of <jats:italic>Schistosoma mansoni<\/jats:italic> histone deacetylase\u20058 (<jats:italic>Sm<\/jats:italic>HDAC8). The crystal structures of <jats:italic>Sm<\/jats:italic>HDAC8 with four inhibitors provided insight into the binding mode and orientation of molecules in the binding pocket as well as the orientation of its flexible amino acid residues. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs. The most promising compounds were further investigated for their activity toward the major human HDAC isotypes. The most potent inhibitors were additionally screened for lethality against the schistosome larval stage using a fluorescence\u2010based assay. 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