title: Identification of antischistosomal leads by evaluating bridged 1,2,4,5-tetraoxanes, alphaperoxides, and tricyclic monoperoxides.
abstract: Although antischistosomal properties of peroxides were studied in recent years, systematic structure-activity relationships have not been conducted. We evaluated the antischistosomal potential of 64 peroxides belonging to bridged 1,2,4,5-tetraoxanes, alphaperoxides, and tricyclic monoperoxides. Thirty-nine compounds presented IC₅₀ values <15 μM on newly transformed schistosomula. Active drugs featured phenyl-, adamantane-, or alkyl residues at the methylene bridge. Lower susceptibility was documented on adult schistosomes, with most hit compounds being tricyclic monoperoxides (IC₅₀: 7.7-13.4 μM). A bridged 1,2,4,5-tetraoxane characterized by an adamantane residue showed the highest activity (IC₅₀: 0.3 μM) on adult Schistosoma mansoni . Studies with hemin and heme supplemented medium indicated that antischistosomal activation of peroxides is not necessarily triggered by iron porphyrins. Two compounds (tricyclic monoperoxide; bridged 1,2,4,5-tetraoxane) revealed high worm burden reductions in the chronic (WBR: 75.4-82.8%) but only moderate activity in the juvenile (WBR: 18.9-43.1%) S. mansoni mouse model. Our results might serve as starting point for the preparation and evaluation of related derivatives.
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland.
authors.forename: Katrin
authors.initials: K
authors.lastname: Ingram
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Yaremenko
authors.forename: Igor B
authors.initials: IB
authors.lastname: Krylov
authors.forename: Lorenz
authors.initials: L
authors.lastname: Hofer
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Terent'ev
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000494:pharmacology; D002908:Chronic Disease; D005260:Female; D006418:Heme / Q000378:metabolism; D006427:Hemin / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D051379:Mice; D010545:Peroxides / Q000737:chemistry* / Q000494:pharmacology; D012550:Schistosoma mansoni / Q000187:drug effects; D012555:Schistosomiasis mansoni / Q000188:drug therapy / Q000469:parasitology; D012556:Schistosomicides / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D045568:Tetraoxanes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D006575:Heterocyclic Compounds, 3-Ring; D010545:Peroxides; D012556:Schistosomicides; D045568:Tetraoxanes; D006418:Heme; D006427:Hemin