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Aryl hydantoin Ro 13-3978, a broad-spectrum antischistosomal

Keiser, Jennifer and Panic, Gordana and Vargas, Mireille and Wang, Chunkai and Dong, Yuxiang and Gautam, Nagsen and Vennerstrom, Jonathan L.. (2015) Aryl hydantoin Ro 13-3978, a broad-spectrum antischistosomal. The journal of antimicrobial chemotherapy, Vol. 70, H. 6. pp. 1788-1797.

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Official URL: http://edoc.unibas.ch/dok/A6391001

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Abstract

Praziquantel is the only drug available for the treatment of schistosomiasis and the state of the exhausted drug discovery pipeline is alarming. We restarted investigations on the abandoned antischistosomal Ro 13-3978, an aryl hydantoin discovered in the early 1980s by Hoffmann La-Roche.; Newly transformed schistosomula and adult Schistosoma mansoni were studied in the presence of Ro 13-3978 in vitro. The metabolic stability of Ro 13-3978 was determined in vitro using human and mouse liver S9 fractions. Dose-response relationship, stage specificity, hepatic shift and scanning electron microscopy studies were carried out in S. mansoni-infected mice. In addition, efficacy experiments were conducted in rodents infected with Echinostoma caproni and Fasciola hepatica as well as in S. mansoni-infected immunocompromised nude (Foxn1(nu)) mice.; Ro 13-3978 showed minor in vitro activity and no damage to the tegument was found. No cytotoxicity was detected for Ro 13-3978. Ro 13-3978 was metabolically stable. ED50 values of 138.9 and 14.6 mg/kg were calculated for the treatment of juvenile and adult S. mansoni infections, respectively, with a single oral dose of Ro 13-3978. SEM studies revealed severe damage to the worms 48 h post-treatment of infected mice. A single oral dose of Ro 13-3978 (100 mg/kg) administered to S. mansoni-infected (Foxn1(nu)) mice reduced the worm burden by 88%. Ro 13-3978 was not active against E. caproni and F. hepatica in vivo.; Ro 13-3978 has excellent antischistosomal properties in vivo. Structure-activity relationship studies with the aryl hydantoins have been launched in order to elucidate active pharmacophores, further investigate the mechanism of action and to identify a derivative with minimal antiandrogenic effects.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Keiser, Jennifer and Vargas, Mireille
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Academic Press
ISSN:0305-7453
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:03 Jul 2015 08:53
Deposited On:03 Jul 2015 08:53

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