Schistosomiasis is a chronic inflammatory disease caused by trematode flatworms of the genus Schistosoma. The disease remains a major neglected, poverty-related disease in many tropical areas. Praziquantel is currently the only drug administrated to treat schistosomiasis; as praziquantel-resistant worms have been found it is an urgent need to find new drugs to treat this disease. Thioredoxin glutathione reductase (TGR) from Schistosoma mansoni has been validated as an essential schistosome protein and a potential drug target. Indeed redox balance in schistosome parasites is maintained by TGR, which is the only protein in worms to reduce thioredoxin and glutathione and provide deglutathionylation (glutaredoxin) activity. Several furoxans (1,2,5-oxadiazole 2-oxides) have shown to be endowed with good activity against S. mansoni. The 4-phenyl-3-furoxancarbonitrile was the most active compound tested: it proved to be an irreversible inhibitor of TGR with a IC50 of 1.8 M.3 The proposed mechanism of action consists in the inhibition of TGR through nitrosylation of cysteine or selenocysteine residues of the protein. This reaction takes place as a consequence of the interaction of the compounds with the enzyme and the following NO release. In this study we investigate the activity of a series of R’’-sulfonyl substituted furoxan against S. mansoni TGR and cultured worms. Some related furazans (1,2,5-oxadiazoles) unable to release NO were also studied for a comparison. Among the synthesized furoxan derivatives, several 3-phenylsulfonyl substituted compounds proved to be more potent than I, showing submicromolar IC50. The present study highlights the 3-phenylsulfonylfuroxan moiety as a valuable structural motif that could be used, in addition to the 3-cyanofuroxan substructure, as scaffold for the development of new furoxan-based anti-schistosomal drugs.