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

摘要

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