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.
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