From dithiocarbamates to branched dithiocarbazates: Compounds with potent antischistosomal activity

Schistosomiasis or bilharzia is caused by blood flukes of the genus Schistosoma and represents a considerable health and economic burden in tropical and subtropical regions. The treatment of this infectious disease relies on one single drug: praziquantel (PZQ). Therefore, new and potent antischistosomal compounds need to be developed. In our previous work, starting with the drug disulfiram, we developed dithiocarbamates with in vitro antischistosomal activities in the low micromolar range. Based on these results, we report in this study on the synthesis and biological testing of the structurally related dithiocarbazates against Schistosoma mansoni, one of the major species of schistosomes. In total, three series of dithiocarbazate derivatives were examined, and we found that the antischistosomal activity of N-unbranched dithiocarbazates increased by further N-substitution. Comparable tetra-substituted dithiocarbazates were rarely described in the literature, thus a synthesis route was established. Due to the elaborate synthesis, the branched dithiocarbazates (containing an N-aminopiperazine) were simplified, but the resulting branched dithiocarbamates (containing a 4-aminopiperidine) were considerably less active. Taken together, dithiocarbazate-containing compounds with an in vitro antischistosomal activity of 5 µM were obtained.