title: Derivatives of biarylalkyl carboxylic acid induce pleiotropic phenotypes in adult Schistosoma mansoni in vitro.
abstract: Schistosomes and other parasitic platyhelminths cause infectious diseases of worldwide significance for humans and animals. Despite their medical and economic importance, vaccines are not available and the number of drugs is alarmingly limited. For most platyhelminths including schistosomes, Praziquantel (PZQ) is the commonly used drug. With respect to its regular application in mass treatment programs, however, there is increasing concern about resistance development.Previous studies demonstrated that inhibitors used to treat non-parasitic human diseases may be useful to be tested for their effects on parasites. To this end, we focused on biarylalkyl carboxylic acids (BACAs) as basis, which had been shown before to be interesting candidates in the context of finding alternative approaches to treat diabetes mellitus. We tested 32 chemically modified derivatives of these substances (biarylalkyl carboxylic acid derivatives (BACADs)) for their effects on adult Schistosoma mansoni in vitro. Treatment with 18 BACADs resulted in egg production-associated phenotypes and reduced pairing stability. In addition, 12 of these derivatives affected vitality and/or caused severe tegument damage, gut dilatation, or other forms of tissue disintegration which led to the death of worms. In most cases (10/12), one derivative caused more than one phenotype at a time. In vitro experiments in the presence of serum albumin (SA) and alpha-acidic glycoprotein (AGP) indicated a varying influence of these blood components on the effects of two selected derivatives. The variety of observed phenotypes suggested that different targets were hit. The results demonstrated that BACADs are interesting substances with respect to their anti-schistosomal effects.
authors.affiliation: BFS, Institut for Parasitology, Justus-Liebig-University Gießen, Gießen, 35392, Germany.
authors.forename: Ariane S
authors.initials: AS
authors.lastname: Blohm
authors.affiliation: Institute for Pharmaceutic Chemistry, Philipps-University Marburg, Marburg, 35032, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mäder
authors.affiliation: BFS, Institut for Parasitology, Justus-Liebig-University Gießen, Gießen, 35392, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quack
authors.affiliation: BFS, Institut for Parasitology, Justus-Liebig-University Gießen, Gießen, 35392, Germany.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Lu
authors.affiliation: BFS, Institut for Parasitology, Justus-Liebig-University Gießen, Gießen, 35392, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Hahnel
authors.affiliation: Institute for Pharmaceutic Chemistry, Philipps-University Marburg, Marburg, 35032, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlitzer
authors.affiliation: BFS, Institut for Parasitology, Justus-Liebig-University Gießen, Gießen, 35392, Germany. christoph.grevelding@vetmed.uni-giessen.de.
authors.forename: Christoph G
authors.initials: CG
authors.lastname: Grevelding
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010641:Phenotype; D011223:Praziquantel / Q000494:pharmacology; D012550:Schistosoma mansoni / Q000187:drug effects*; D012555:Schistosomiasis mansoni / Q000188:drug therapy / Q000469:parasitology*
chemical_list: D002264:Carboxylic Acids; D011223:Praziquantel
keywords: Biarylalkyl carboxylic acid; Drug development; In vitro culture; Platyhelminths; Schistosoma mansoni; Serum component