Identification of Antischistosomal Leads by Evaluating Bridged 1,2,4,5-Tetraoxanes, Alphaperoxides, and Tricyclic Monoperoxides

Identification of Antischistosomal Leads by Evaluating Bridged 1,2,4,5-Tetraoxanes, Alphaperoxides, and Tricyclic Monoperoxides Full article

Journal

Journal of Medicinal Chemistry
ISSN: 0022-2623 , E-ISSN: 1520-4804

Output data

Year: 2012, Volume: 55, Number: 20, Pages: 8700-8711 Pages count : 12 DOI: 10.1021/jm3009184

Authors

Ingram Katrin ^1,2 , Yaremenko Ivan A. ³ , Krylov Igor B. ³ , Hofer Lorenz ^1,2 , Terent’ev Alexander O. ³ , Keiser Jennifer ^1,2

Affiliations

1	Department of Medical Parasitology#R#and Infection Biology, Swiss Tropical and Public Health Institute,#R#CH-4002 Basel, Switzerland
2	University of Basel, CH-4003#R#Basel, Switzerland
3	N. D.#R#Zelinsky Institute of Organic#R#Chemistry, Russian Academy of Sciences, 47 Leninsky Prospekt, 119991#R#Moscow, Russian Federation

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.

Ingram K. , Yaremenko I.A. , Krylov I.B. , Hofer L. , Terent’ev A.O. , Keiser J.
Identification of Antischistosomal Leads by Evaluating Bridged 1,2,4,5-Tetraoxanes, Alphaperoxides, and Tricyclic Monoperoxides
Journal of Medicinal Chemistry. 2012. V.55. N20. P.8700-8711. DOI: 10.1021/jm3009184 WOS Scopus OpenAlex

≡ Web of science:	WOS:000310120700011
≡ Scopus:	2-s2.0-84867769075
≡ OpenAlex:	W2082909041