Entwicklung von Biarylalkylcarbonsäure- und Indol-Derivaten als potentielle anthelminthische Wirkstoffe gegen Schistosoma mansoni

Schistosomiasis is a parasitic disease that is responsible for more than 11,792 deaths and approximately 230 million infections in humans annually. The disease is caused by trematodes of the genus Schistosoma and has been classified by the WHO as a neglected tropical disease (NTD). It is endemic in 78 countries, including regions of Africa, the Middle East, and parts of South America. Treatment currently relies almost exclusively on praziquantel (PZQ). Vaccines are not yet available. As a result, the risk of the emergence of resistance to PZQ is on the rise. The development of new drugs is therefore urgently required. The group of Prof. Grevelding has identified schistosomal aldose reductase (SmAR) as a potential drug target in Schistosoma mansoni. On this basis, inhibitors of human aldose reductase with a biarylalkyl carboxylic acid moiety were tested in vitro against adult S. mansoni pairs. Antischistosomal activity was observed at a concentration of 100 μM. The initial compounds served as a starting point for further developing compounds containing a biarylalkyl carboxylic acid moiety. The work of P. Mäder and A. Peter Ventura in the group of Prof. Schlitzer has led to the identification of compounds with in vitro activity at 10 μM. The development of structurally related biarylalkyl carboxylic acid derivatives as possible anthelmintics is continued in the present work. The focus of the first part of the work was the synthesis of biarylalkyl carboxylic acid derivatives by means of modifications that had not been addressed in detail or at all in the previous work. A further development of the sulfonic acid ester derivatives that had led to the most active compound in the previous work was carried out. Investigating the structure-activity relationship of these compounds resulted in three aromatic sulfonic acid esters with similar activity at 10 μM. Modification of the carboxylic acid moiety to a basic amine resulted in a marked loss of activity. A series of further modifications to the biarylalkyl carboxylic acid moiety were not able to increase the antischistosomal activity any further. The second part of this work focused on targeting SmAR. In close collaboration with Prof. Grevelding’s group, the focus has been on the development of a novel SmAR inhibitor. In the absence of a crystal structure of the enzyme, a homology model should serve as the basis for the planned structure-based approach to potential SmAR inhibitor design. Therefore, the first step was the validation of the homology model. This revealed that the homology model did not provide a reliable basis for the design of a potential inhibitor. Instead, a ligand-based approach was pursued. This approach relied on 1H-indole-1-acetic acid, an inhibitor of human aldose reductase (hAR). A comprehensive study of the structure activity relationship of this basic indole motif involved (1) the introduction of various substitutions, (2) the expansion of the indole moiety through anellated aliphatic and aromatic cycles, (3) the replacement of the indole moiety, (4) the variation of the chain length of the acetic acid structure, and (5) the conversion of the carboxylic acid into amides. Repeated cycles of synthesis and testing of the resulting compounds on the SmAR and hAR provided important insights for the further development of the structures. The IC50 values of the best compounds were determined. An IC50 value in the low micromolar range was obtained for the most potent inhibitor (IC50 = 27.21 μM). In addition, the compounds were tested on adult S. mansoni couples. In spite of the good inhibitory properties of some inhibitors of SmAR, the compounds showed only poor antischistosomal activity. This may be an indication that SmAR is not a suitable target for the development of new antischistosomal agents.