Disulfiram and dithiocarbamate analogues demonstrate promising antischistosomal effects

Abstract

Schistosomiasis is a neglected tropical disease with more than 200 million new infections per year. It is caused by parasites of the genus Schistosoma and can lead to death if left untreated. Currently, only two drugs are available to combat schistosomiasis: praziquantel and, to a limited extent, oxamniquine. However, the intensive use of these two drugs leads to an increased probability of the emergence of resistance. Thus, the search for new active substances and their targeted development are mandatory. In this study the substance class of "dithiocarbamates" and their potential as antischistosomal agents is highlighted. These compounds are derived from the basic structure of the human aldehyde dehydrogenase inhibitor disulfiram (tetraethylthiuram disulfide, DSF) and its metabolites. Our compounds revealed promising activity (in vitro) against adults of Schistosoma mansoni, such as the reduction of egg production, pairing stability, vitality, and motility. Moreover, tegument damage as well as gut dilatations or even the death of the parasite were observed. We performed detailed structure-activity relationship studies on both sides of the dithiocarbamate core leading to a library of approximately 300 derivatives (116 derivatives shown here). Starting with 100 μm we improved antischistosomal activity down to 25 μm by substitution of the single bonded sulfur atom for example with different benzyl moieties and integration of the two residues on the nitrogen atom into a cyclic structure like piperazine. Its derivatization at the 4-nitrogen with a sulfonyl group or an acyl group led to the most active derivatives of this study which were active at 10 μm. In light of this SAR study, we identified 17 derivatives that significantly reduced motility and induced several other phenotypes at 25 μm, and importantly five of them have antischistosomal activity also at 10 μm. These derivatives were found to be non-cytotoxic in two human cell lines at 100 μm. Therefore, dithiocarbamates seem to be interesting new candidates for further antischistosomal drug development.

Keywords: Aldehyde dehydrogenase; Disulfiram; Dithiocarbamates; Neglected tropical diseases; Schistosoma mansoni; Schistosomiasis; Structure-activity-relationships.