| Summary: | The metacestode stage of the fox tapeworm <i>Echinococcus multilocularis</i> causes the severe zoonotic disease alveolar echinococcosis. New treatment options are urgently needed. Disulfiram and dithiocarbamates were previously shown to exhibit activity against the trematode <i>Schistosoma mansoni.</i> As both parasites belong to the platyhelminths, here we investigated whether these compounds were also active against <i>E. multilocularis</i> metacestode vesicles in vitro. We used an in vitro drug-screening cascade for the identification of novel compounds against <i>E. multilocularis</i> metacestode vesicles with disulfiram and 51 dithiocarbamates. Five compounds showed activity against <i>E. multilocularis</i> metacestode vesicles after five days of drug incubation in a damage marker release assay. Structure–activity relationship analyses revealed that a <i>S</i>-2-hydroxy-5-nitro benzyl moiety was necessary for anti-echinococcal activity, as derivatives without this group had no effect on <i>E. multilocularis</i> metacestode vesicles. The five active compounds were further tested for potential cytotoxicity in mammalian cells. For two compounds with low toxicity (Schl-32.315 and Schl-33.652), IC<sub>50</sub> values in metacestode vesicles and IC<sub>50</sub> values in germinal layer cells were calculated. The compounds were not highly active on isolated GL cells with IC<sub>50</sub> values of 27.0 ± 4.2 µM for Schl-32.315 and 24.7 ± 11.5 µM for Schl-33.652, respectively. Against metacestode vesicles, Schl-32.315 was not very active either with an IC<sub>50</sub> value of 41.6 ± 3.2 µM, while Schl-33.652 showed a low IC<sub>50</sub> of 4.3 ± 1 µM and should be further investigated in the future for its activity against alveolar echinococcosis.
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