Anti-schistosomal Biarylalkyl Carboxylic Acids Amides: Development and Target-Identification

血吸虫病是一种由血吸虫属寄生虫引起的“被忽视的热带传染病”，具有世界范围的重要性。由于没有可用的疫苗，而且只有一种常用药物（吡喹酮），抗击血吸虫病等被忽视的热带病已成为世卫组织和七国集团的优先事项。从曼氏血吸虫醛糖还原酶的鉴定开始，我们测试了一些从以前的研究中获得的人醛糖还原酶抑制剂对培养蠕虫的抑制作用，并鉴定了一个活性化合物。基于这一“命中”，我们进行了结构修饰，使我们获得了具有良好活性的双芳基羧酸酰胺，这导致了迄今未观察到的表型。下一步，我们打算进一步开发一类二芳基烷基羧酸酰胺，通过广泛的结构修饰和体外和体内测定评估来获得一个先导结构。该项目的第二个目标是通过全面的生化研究鉴定和表征这些化合物的进一步潜在靶蛋白。

Schistosomiasis represents one of the „neglegted tropical infectious diseases (NTDs)“ of worldwide importance and is caused by worm parasites of the genus Schistosoma. Because there is no vaccine available and only one commonly used drug (Praziquantel), fighting NTDs like schistosomiasis has been prioritized by the WHO and the G7-nations. Starting with the identification of aldose reductases in Schistosoma mansoni we tested some inhibitors of human aldose reductase available from previous studies against cultured worm pairs and identified one active compound. Based on this „hit“, we made structural modifications leading us to the biarylcarboxylic acid amides with promising activity, which led to phenotypes hitherto not observed. Next we intend to further develop the class of biarylalkyl carboxylic acid amides to obtain a lead structure by extensive structural modifications flanked by in vitro and in vivo-assays evaluation. The second aim of this project is the identification and characterisation of further potential target proteins of these compounds through comprehensive biochemical investigations.