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

血吸虫病是世界范围内重要的“传染性热带传染病（NTD）”之一，由血吸虫属的蠕虫寄生虫引起。由于没有可用的疫苗，只有一种常用药物（吡喹酮），世界卫生组织和七国集团国家优先考虑抗击血吸虫病等NTD。 从鉴定曼氏血吸虫中的醛糖还原酶开始，我们测试了以前研究中针对培养的蠕虫对的人醛糖还原酶的一些抑制剂，并鉴定了一种活性化合物。基于这一“命中”，我们进行了结构修饰，导致我们得到具有有希望的活性的联芳基羧酸酰胺，这导致迄今未观察到的表型。接下来，我们打算进一步开发这类联芳烷基羧酸酰胺，通过广泛的结构修饰获得先导结构，并进行体外和体内测定评价。该项目的第二个目的是通过全面的生物化学研究，进一步鉴定和表征这些化合物的潜在靶蛋白。

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.