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Ferrocenyl, Ruthenocenyl, and Benzyl Oxamniquine derivatives with cross-species activity against Schistosoma mansoni and Schistosoma haematobium


Hess, Jeannine; Panic, Gordana; Patra, Malay; Mastrobuoni, Luciano; Spingler, Bernhard; Roy, Saonli; Keiser, Jennifer; Gasser, Gilles (2017). Ferrocenyl, Ruthenocenyl, and Benzyl Oxamniquine derivatives with cross-species activity against Schistosoma mansoni and Schistosoma haematobium. ACS Infectious Diseases, 3(9):645-652.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Uncontrolled Keywords:anthelmintics, bioorganometallic chemistry, medicinal organometallic chemistry, oxamniquine, schistosomiasis
Language:English
Date:7 July 2017
Deposited On:05 Dec 2017 17:15
Last Modified:19 Aug 2018 11:41
Publisher:American Chemical Society (ACS)
ISSN:2373-8227
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acsinfecdis.7b00054
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P2_157545
  • : Project TitleCaged Metal Complexes as Tools in Inorganic Chemical Biology
  • : FunderSNSF
  • : Grant IDPP00P2_133568
  • : Project TitleCaged Metal Complexes as Tools in Inorganic Chemical Biology

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