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Identification of antischistosomal leads by evaluating peroxides of β-dicarbonyl compounds and their heteroanalogs: bridged 1,2,4,5-tetraoxanes and alphaperoxides, and β,δ-triketones: tricyclic monoperoxides.
MedLine Citation:
PMID:  23013253     Owner:  NLM     Status:  Publisher    
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 β,δ-triketones. 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.
Katrin Ingram; Ivan Andreevich Yaremenko; Igor Krylov; Lorenz Hofer; Alexander Olegovich Terent'ev; Jennifer Keiser
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-27
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-9-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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