Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marburg, Germany.
BFS, Institute of Parasitology, Justus Liebig University Giessen, Giessen, Germany.
Arch Pharm (Weinheim). 2021 Dec;354(12):e2100259. doi: 10.1002/ardp.202100259. Epub 2021 Sep 15.
Schistosomiasis is a neglected tropical disease caused by blood flukes of the genus Schistosoma and causes severe morbidity in infected patients. In 2018, 290.8 million people required treatment, and 200,000 deaths are reported per year. Treatment of this disease depends on a single drug, praziquantel (PZQ). However, in the past few years, reduced sensitivity of the parasites toward PZQ has been reported. Therefore, there is an urgent need for new drugs against this disease. In the past few years, we have focused on a new substance class called biaryl alkyl carboxylic acid derivatives, which showed promising antischistosomal activity in vitro. Structure-activity relationship (SAR) studies of the carboxylic acid moiety led to three promising carboxylic amides (morpholine, thiomorpholine, and methyl sulfonyl piperazine) with an antischistosomal activity down to 10 µM (morpholine derivative) and no cytotoxicity up to 100 µM. Here, we show our continued work on this substance class. We investigated, in extended SAR studies, whether modification of the linker and the thiophene ring could improve the antischistosomal activity. We found that the exchange of the alkyl linker by a pentadienyl or benzyl linker was tolerated and led to similar antischistosomal effects, whereas the exchange of the thiophene ring was not tolerated. Our data suggest that the thiophene ring is important for the antischistosomal activity of this compound class.
血吸虫病是一种由血吸虫属的血吸病虫引起的被忽视的热带病，会给感染患者带来严重的发病。2018 年，有 2.908 亿人需要治疗，每年报告有 20 万人死亡。这种疾病的治疗取决于一种药物，即吡喹酮（PZQ）。然而，在过去几年中，已经报道了寄生虫对 PZQ 的敏感性降低。因此，迫切需要针对这种疾病的新药。在过去的几年中，我们专注于一种新的物质类别，称为联芳基烷基羧酸衍生物，它在体外表现出有希望的抗血吸虫活性。羧酸部分的构效关系（SAR）研究导致了三种有前途的羧酸酰胺（吗啡啉、硫吗啉和甲基磺酰基哌嗪），其抗血吸虫活性低至 10μM（吗啡啉衍生物），且在 100μM 时无细胞毒性。在这里，我们展示了我们在这个物质类别上的持续工作。我们在扩展的 SAR 研究中调查了是否可以通过修饰连接子和噻吩环来提高抗血吸虫活性。我们发现，用戊二烯基或苄基连接子取代烷基连接子是可以耐受的，并且导致类似的抗血吸虫作用，而噻吩环的替换则不能耐受。我们的数据表明，噻吩环对于该化合物类别的抗血吸虫活性很重要。
