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Ferrocenyl, ruthenocenyl, and benzyl oxamniquine derivatives with cross-species activity against Schistosoma mansoni and Schistosoma haematobium

Hess, Jeannine and Panic, Gordana and Patra, Malay and Mastrobuoni, Luciano and Spingler, Bernhard and Roy, Saonli and Keiser, Jennifer and Gasser, Gilles. (2017) Ferrocenyl, ruthenocenyl, and benzyl oxamniquine derivatives with cross-species activity against Schistosoma mansoni and Schistosoma haematobium. ACS infectious diseases, 3 (9). pp. 645-652.

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Official URL: http://edoc.unibas.ch/57837/

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Abstract

Schistosomiasis is a parasitic disease that affects more than 250 million people annually, mostly children in poor, tropical, rural areas. Only one treatment (praziquantel) is available, putting control efforts at risk should resistance occur. In pursuit of treatment alternatives, we derivatized an old antischistosomal agent, oxamniquine (OXA). Four organometallic derivatives of OXA were synthesized and tested against Schistosoma mansoni in vitro and in vivo. Of these, a ferrocenyl derivative, 1, killed larval and adult worms 24 h postexposure in vitro, in contrast to OXA, which lacks in vitro activity against adult worms. A dose of 200 mg/kg of 1 completely eliminated the worm burden in mice. Subsequently, a ruthenocenyl (5) and a benzyl derivative (6) of OXA were synthesized to probe the importance of the ferrocenyl group in 1. Compounds 1, 5, and 6 were lethal to both S. mansoni and S. haematobium adults in vitro. In vivo, at 100 mg/kg, all three compounds revealed S. mansoni worm burden reductions of 76 to 93%, commensurate with OXA. Our findings present three compounds with activity against S. mansoni in vitro, comparable activity in vivo, and high activity against S. haematobium in vitro. These compounds may possess a different binding mode or mode of action compared to OXA and present excellent starting points for further SAR studies.
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:Panic, Gordana and Keiser, Jennifer
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:ACS Publications
ISSN:2373-8227
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:21 Dec 2017 15:12
Deposited On:21 Dec 2017 15:12

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