Synthese und biologische Testung von Biarylalkylcarbonsäure-Derivaten und Dithiocarbamat-Derivaten als potentielle anthelmintische Wirkstoffe gegen Schistosoma mansoni

Schistosomiasis is one of the most prevalent parasitic infections worldwide, affecting over 240 million people in the tropics and subtropics, while over 780 million people are at risk of infection. The disease is usually caused by one of three schistosome species mainly affecting human: S. japonicum, S. mansoni and S. haematobium. Since the 1980s, Praziquantel is the drug of choice for the treatment of schistosomiasis, because it is orally effective against all schistosome species with a one time treatment. However, the long-term utilization of one drug may result in drug-resistant parasites. Importantly, decreased susceptibility of S. mansoni and S. haematobium to Praziquantel has already been observed. Thus, there is an urgent need to develop novel antischistosomal compounds. Based on an initially tested series of compounds the substance class of biarylalkyl carboxylic acid derivatives was established as antischistosomal agents. In a first optimization series, the influence of the substitution pattern of the terminal phenyl ring was investigated. Introduction of a hydroxy substituent in position 3 of the terminal phenyl ring resulted in an increase of activity. New phenotypes were observed. In a second series, the influence of the chain length of the linker as well as the need of the carbonyl group in the linker was examined. Initial results indicated that the extension of the linker to a methylene unit resulted in a slight increase in activity. In the third optimization series, the carboxylic acid was functionalized. Improvement of activity was observed for the carboxamides. Combination of the most active residues resulted in a strong increase in activity and observation of new promising phenotypes. The efficacy against S. mansoni in vitro and the absence of toxicity make this class of compounds promising antischistosomal agents for future investigation. Based on the structure of disulfiram the substance class of dithiocarbamate derivatives was established as antischistosomal agents. First derivatives were synthesized with altered substituents of the sulfur of the dithiocarbamate. Especially the introduction of electron-poor, substituted benzyl residues at the sulfur of the dithiocarbamate resulted in a significant increase of activity. A total of 73 derivatives were synthesized. In this case, seven substituents have been found, and their introduction resulted in seven compounds with an activity up to a concentration of 10 µM. Three of the best seven derivatives showed also an activity at 5 µM. In vitro, these compounds are as effective as PZQ and revealing novel phenotypes. Following this, the influence of the substitution pattern at the nitrogen of the dithiocarbamate was investigated. Another 45 derivatives were synthesized. The introduction of (substituted) piperazine residues leading to an increase of activity. Imidazole-1-carbodithionates were also established as another promising class of compounds. A total of six imidazole derivatives are as effective as PZQ and revealed promising phenotypes. A total of 49 combinatorial derivatives were synthesized with the seven most effective substituents at the sulfur or the nitrogen of the dithiocarbamate. Six of these compounds were active at 5 µM, thus being as effective as PZQ again. Even at 1 µM, one of the derivatives exhibited clear antischistosomal activity. In a final optimization series the antischistosomal activity and the cytotoxic profile of the substance class of the dithiocarbamates were further improved. Especially the piperazinesulfonamide derivatives revealed a very good antischistosomal activity with promising phenotypes. Lethal effects occurred at low micromolar concentrations, which is a feature of this class of compounds. Two of the sulfonamide derivatives were also five times as effective as PZQ in vitro. All together, more than 300 dithiocarbamate derivatives were synthesized. By studies with adult schistosomes in an established in vitro model, 35 were selected which were effective against the worms at a concentration of 5 µM each or lower. Under the applied laboratory conditions, these compounds showed a significantly improved antischistosomal activity compared with PZQ. First structure activity relationships were also established. Multiple phenotypes were recorded. This suggested an effect of the compounds on one target molecule, which may be involved in different physiological processes, or different molecules organizing these processes. In either case this is very attractive with respect to applied aspects. Provided that different targets are hit by one single compound, or even a compound mix, this will significantly reduce the probability of resistance development because in that case more than one mutation has to occur at the same time under selection pressure. In addition, both classes of compounds may be modified extensively to provide other potential drug candidates for fighting schistosomiasis.