title: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mäder
authors.affiliation: BFS, Institute for Parasitology, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392, Gießen, Germany.
authors.forename: Ariane S
authors.initials: AS
authors.lastname: Blohm
authors.affiliation: BFS, Institute for Parasitology, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392, Gießen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quack
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lange-Grünweller
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
authors.forename: Arnold
authors.initials: A
authors.lastname: Grünweller
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
authors.forename: Roland K
authors.initials: RK
authors.lastname: Hartmann
authors.affiliation: BFS, Institute for Parasitology, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392, Gießen, Germany. christoph.grevelding@vetmed.uni-giessen.de.
authors.forename: Christoph G
authors.initials: CG
authors.lastname: Grevelding
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany. schlitzer@staff.uni-marburg.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlitzer
mesh_terms: D000818:Animals; D002087:Butyrates / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D010421:Pentanoic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D012550:Schistosoma mansoni / Q000187:drug effects; D012556:Schistosomicides / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C000622559:5-(5-(3-hydroxyphenyl)-2-thienyl)pentanoic acid; D002087:Butyrates; C000622560:N,N-diethyl-5-(5-(3-hydroxyphenyl)-2-thienyl)-5-oxopentanamide; D010421:Pentanoic Acids; D012556:Schistosomicides; D013876:Thiophenes
keywords: biaryls; carboxylic acids; inhibitors; parasites; structure-activity relationships