Synthese und in vitro-Testung von Biarylalkylcarbonsäure- und Ebselen-Derivaten gegen Schistosoma mansoni

Every year, 200 million people are infected and 200 000 die from Schistosomiasis, a parasitic disease caused by trematodes of the genus Schistosoma. This disease is mainly treated by praziquantel (PZQ) since the 1970s. In the past years, decreased sensitivity of the parasites towards PZQ was observed. Therefore, the concern of upcoming resistance is increasing and the need for new antischistosomal agents is urgent. The schistosomal aldose reductase (AR) was identified to be a potential target as it is believed that it plays a crucial role in the defence mechanism of the parasite towards its host. Inhibitors of the human AR were tested in vitro against Schistosoma mansoni couples and showed a good antischistosomal potency (Cooperation with the GREVELDING group). Starting point of this thesis was a biaryl alkyl carboxylic acid which was synthesised by PATRICK MÄDER in the SCHLITZER group. Aim of this thesis was to synthesize compounds based on the biaryl alkyl carboxylic acid and to test these in vitro against Schistosoma mansoni. Within the scope of this thesis, 170 compounds were synthesized and evaluated biologically with different modifications in order to establish structure activity relationships (SAR) for this substance class. The modifications included: • Derivatisation of the carboxyl group by synthesizing carboxylic amides • Derivatisation of the linker by reduction of the carbonyl group, by synthesizing pentadiene- and benzoic acid-derivatives and by synthesizing hydrazones • Replacement of the thiophene ring by an oxazole, thiazole and furan • Derivatisation of the hydroxyl group by synthesizing sulfonic acid- and carboxylic acid esters The SAR evaluation led to the conclusion that the carbonyl group is not essential for antischistosomal activity. The derivatisation of the hydroxyl group led to a compound with an activity up to 10 µM. Summing up, the biological activity of this compound class was improved from 100 µM to 10 µM. Furthermore, a second project was to gain knowledge in the synthesis of ebselen-derivatives and to elaborate whether this compound class has a promising biological activity against Schistosomes. In this project, seven different compounds with an exchanged aniline group were synthesized. The biological activity of these compounds ranged up to 5 µM, which is comparable to PZQ in the used in vitro assay. It was found that these compounds not only possess a very good antischistosomal activity but also promising neuroprotective properties (Cooperation with the CULMSEE group).