Synthesis and antischistosomal activity of linker‐ and thiophene‐modified biaryl alkyl carboxylic acid derivatives

• Published in: Archiv der Pharmazie (Weinheim) 2021-12, Vol.354 (12), p.e2100259-n/a
• Main Authors: Peter Ventura, Alejandra M., Haeberlein, Simone, Konopka, Leonie, Obermann, Wiebke, Grünweller, Arnold, Grevelding, Christoph G., Schlitzer, Martin
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; biaryl alkyl carboxylic acid derivatives; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Female; inhibitors; Male; Schistosoma - drug effects; schistosomiasis; Schistosomiasis - drug therapy; Schistosomicides - chemical synthesis; Schistosomicides - chemistry; Schistosomicides - pharmacology; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Tropical diseases
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202100259

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. Biaryl alkyl carboxylic acid derivatives show antischistosomal activity in vitro. Extended structure–activity relationship studies were used to investigate the effects of modifications of the linker and the thiophene ring on the activity. It was found that replacement of the alkyl linker by more rigid structures is tolerated whereas replacement of the thiophene in the biaryl moiety leads to complete loss of the antischistosomal activity.