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Identification of antischistosomal leads by evaluating peroxides of beta-dicarbonyl compounds and their heteroanalogs : bridged 1,2,4,5-tetraoxanes and alphaperoxides, and beta,delta-triketones: tricyclic monoperoxides

Ingram, K. and Yaremenko, I. A. and Krylov, I. and Hofer, L. and Terent'ev, A. O. and Keiser, J.. (2012) Identification of antischistosomal leads by evaluating peroxides of beta-dicarbonyl compounds and their heteroanalogs : bridged 1,2,4,5-tetraoxanes and alphaperoxides, and beta,delta-triketones: tricyclic monoperoxides. Journal of medicinal chemistry, 55 (20). pp. 8700-8711.

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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 beta,delta-triketones. Thirty-nine compounds presented IC50 values > 15 microM 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 microM). A bridged 1,2,4,5-tetraoxane characterized by an adamantane residue showed the highest activity (IC50: 0.3 microM) 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
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Keiser, Jennifer
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Chemical Society
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:20 Oct 2017 11:54
Deposited On:19 Jul 2013 07:40

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