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Schistosomiasis is a neglected tropical disease caused by blood flukes of the genus Schistosoma. In silico screenings of compounds for the identification of novel anti-parasitic drug candidates have received considerable attention in recent years, including the screening of natural compounds. For the first time, we investigated molecules from insects, a rather neglected source in drug discovery, in an in silico screening approach to find novel antischistosomal compounds. Based on the Dictionary of Natural Products (DNP), we created a library of 1327 insect compounds suitable for molecular docking. A structure-based virtual screening against the crystal structure of a known druggable target in Schistosoma mansoni, the thioredoxin glutathione reductase (SmTGR), was performed. The top ten compounds predominantly originated from beetles and were predicted to interact particularly with amino acids in the doorstop pocket of SmTGR. For one compound from a jewel beetle, buprestin H, we tested and confirmed antischistosomal activity against adult and juvenile parasites in vitro. At concentrations with anti-parasitic activity, we could also exclude any unspecific cytotoxic activity against human HepG2 cells. This study highlights the potential of insect molecules for the identification of novel antischistosomal compounds. Our library of insect-derived molecules could serve not only as basis for future in silico screenings against additional target proteins of schistosomes, but also of other parasites.

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.