Biarylalkyl Carboxylic Acid Derivatives as Novel Antischistosomal Agents

Abstract

Parasitic platyhelminths are responsible for serious infectious diseases, such as schistosomiasis, which affect humans as well as animals across vast regions of the world. The drug arsenal available for the treatment of these diseases is limited; for example, praziquantel is the only drug currently used to treat ≥240 million people each year infected with Schistosoma spp., and there is justified concern about the emergence of drug resistance. In this study, we screened biarylalkyl carboxylic acid derivatives for their antischistosomal activity against S. mansoni. These compounds showed significant influence on egg production, pairing stability, and vitality. Tegumental lesions or gut dilatation was also observed. Substitution of the terminal phenyl residue in the biaryl scaffold with a 3-hydroxy moiety and derivatization of the terminal carboxylic acid scaffold with carboxamides yielded compounds that displayed significant antischistosomal activity at concentrations as low as 10 μm with satisfying cytotoxicity values. The present study provides detailed insight into the structure-activity relationships of biarylalkyl carboxylic acid derivatives and thereby paves the way for a new drug-hit moiety for fighting schistosomiasis.

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

“…B) Chemical structures of isophthalic acid derivatives 27 and 28 . C) Chemical structures of the most potent BACADs . D) Chemical structures of AASs 33 – 35 with antischistosomal activity …”

“…Parameters, such as pairing stability, gut peristalsis, vitality, motility, and egg production, were investigated at different concentrations. PZQ ( 9 ), used as a positive control, caused tegumental damage and paralyzed the treated worms (at concentrations of 5 μ m and higher in vitro) . The antischistosomal activity of BACA derivatives was increased with an electron‐ and proton‐donating hydroxy substituent at the meta ‐position on the terminal phenyl ring ( 29 and 31 , Figure C).…”

“…However, derivatization of the carboxylic acid to N , N ‐diethyl carboxamides ( 30 and 32 , Figure C) led to improved activity. These observations suggested that schistosomal AR might not be the target of the tested BACA derivatives . The combination of the most‐active residues (found in SAR studies) on both sides of the molecule resulted in increased activity and the induction of new phenotypes such as tegumental damage, loss of internal structure, decreased egg production, and reduced pairing stability …”

“…In summary, the obtained data showed that BACA derivatives induced fatal effects on adult S. mansoni and are nontoxic to mammalian cell lines. Thus they are interesting candidates for further development . However, their antischistosomal activity remains to be confirmed in vivo.…”

Frontiers in Medicinal Chemistry 2017 in Bern, Switzerland

“…Norbert Furtmann (University of Bonn) briefly reported his research on the identification of interaction hot spots in structures of drug targets on the basis of 3D activity cliff formation . Patrick Mäder (ETH Zurich) spoke on his research on the synthesis and biological evaluation of two novel classes of anthelmintics against Schistosoma mansori . Finally Roman Sommer (University of Saarbrücken) presented his research on non‐natural carbohydrate‐based inhibitors of the Pseudomonas aeruginosa virulence factor lectin LecB …”