Project B5 - Dithiocarbamate and other compound classes as potential therapeutics for schistosomiasis and other parasitic diseases such as fasciolosis
- Project description
Starting from the anti-schistosomal effect of disulfiram (up to 25 µM; toxic beyond 25 µM)1, more than 300 dithiocarbamates from general Formula 1 were created in several consecutive cycles of design, synthesis, and testing against cultivated worms, and extensive structure-effect relationships were developed: i) dithiocarbamate structure is essential, and exchanging a heteroatom leads to a reduction/loss of effectiveness; ii) R1: remaining alkaryl with 0-3 methylene units and one (preferred – M) substituted aromatic compound; iii) R2, R3: preferred N-substituted piperazine; N4-sulfonyl group leads to an increase in anti-schistosomal effects and a reduction in toxicity. Currently the most active compound is Schl-32.3292. It is lethal for schistosomes at a 1 µM concentration (praziquantel 5 µM) (Fig. B5A) and leads to multiple injuries in the worm (loss of internal structures (B), tegument damages (C), bowel dilations (D)). At 200 µM, no toxicity was observed in two human cell lines2.
Scientific goals: Improving the activity and expanding the area of effectiveness to other parasites such as Fasciola, Echinococcus, etc.; increasing the substance similarity of the molecules; determining/improving ADTME parameters; obtaining a dithiocarbamate development candidate and a reserve development candidate, as well as a dithiocarbamate lead structure.
References B5: 1. Mäder et al. (2014) Annual meeting of the German Pharmaceutical Society, Frankfurt, 24. – 26.09.2014. 2. Schlitzer et al. (2016) Patent application EP16165936.2.