Elucidation of the in vitro and in vivo activities of bridged 1,2,4-trioxolanes, bridged 1,2,4,5-tetraoxanes, tricyclic monoperoxides, silyl peroxides, and hydroxylamine derivatives against Schistosoma mansoni

Elucidation of the in vitro and in vivo activities of bridged 1,2,4-trioxolanes, bridged 1,2,4,5-tetraoxanes, tricyclic monoperoxides, silyl peroxides, and hydroxylamine derivatives against Schistosoma mansoni Научная публикация

Журнал

Bioorganic & Medicinal Chemistry
ISSN: 1464-3391 , E-ISSN: 0968-0896

Вых. Данные

Год: 2015, Том: 23, Номер: 16, Страницы: 5175-5181 Страниц : 7 DOI: 10.1016/j.bmc.2015.02.010

Авторы

Cowan Noemi ^1,2 , Yaremenko Ivan A. ³ , Krylov Igor B. ³ , Terent’ev Alexander O. ³ , Keiser Jennifer ^1,2

Организации

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

Praziquantel is currently the only drug available to treat schistosomiasis. Since drug resistance would be a major barrier for the increasing global attempts to eliminate schistosomiasis as a public health problem, efforts should go hand in hand with the discovery of novel treatment options. Synthetic peroxides might offer a good direction since their antischistosomal activity has been demonstrated in the laboratory. We studied 19 bridged 1,2,4,5-tetraoxanes, 2 tricyclic monoperoxides, 11 bridged 1,2,4-trioxolanes, 12 silyl peroxides, and 4 hydroxylamine derivatives against newly transformed schistosomula (NTS) and adult Schistosoma mansoni in vitro. Schistosomicidal compounds were tested for cytotoxicity followed by in vivo studies of the most promising compounds. Tricyclic monoperoxides, trioxolanes, and tetraoxanes revealed the highest in vitro activity against NTS (IC50s 0.4–20.2 μM) and adult schistosomes (IC50s 1.8–22.8 μM). Tetraoxanes showed higher cytotoxicity than antischistosomal activity. Selected trioxolane and tricyclic monoperoxides were tested in mice harboring an adult S. mansoni infection. The highest activity was observed for two trioxolanes, which showed moderate worm burden reductions (WBR) of 44.3% and 42.9% (p >0.05). Complexation of the compounds with β-cyclodextrin with the aim to improve solubility and gastrointestinal absorption did not increase in vivo antischistosomal efficacy. The high in vitro antischistosomal activity of trioxolanes and tricyclic monoperoxides is a promising basis for future investigations, with the focus on improving in vivo efficacy.

Cowan N. , Yaremenko I.A. , Krylov I.B. , Terent’ev A.O. , Keiser J.
Elucidation of the in vitro and in vivo activities of bridged 1,2,4-trioxolanes, bridged 1,2,4,5-tetraoxanes, tricyclic monoperoxides, silyl peroxides, and hydroxylamine derivatives against Schistosoma mansoni
Bioorganic & Medicinal Chemistry. 2015. V.23. N16. P.5175-5181. DOI: 10.1016/j.bmc.2015.02.010 WOS Scopus OpenAlex

≡ Web of science:	WOS:000359299100010
≡ Scopus:	2-s2.0-84938949244
≡ OpenAlex:	W2170279589