1-aryl-4-nitro-1H-imidazoles, a new promising series for the treatment of human African trypanosomiasis

Bourdin Trunz B., and Jedrysiak, R. and Tweats, D. and Brun, R. and Kaiser, M. and Suwinski, J. and Torreele, E.. (2011) 1-aryl-4-nitro-1H-imidazoles, a new promising series for the treatment of human African trypanosomiasis. European journal of medicinal chemistry, 46 (5). pp. 1524-1535.

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Official URL: http://edoc.unibas.ch/dok/A6002080

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Nitroimidazoles are a well-known class of antibacterial and antiprotozoal drugs but in spite of the widespread clinical and veterinary use of these drugs, this family has been stigmatized in part due to associated genotoxicity problems. Here we report the synthesis, the anti-trypanosomal activity and a structure-activity relationship (SAR) study of a series of about fifty 1-aryl-4-nitro-1H-imidazoles, with an emphasis on selected in vivo active molecules. Compounds 4-nitro-1-{4-(trifluoromethoxy)phenyl}-1H-imidazole and 1-(3,4-dichlorophenyl)-4-nitro-1H-imidazole are curative in mouse models of both acute and chronic African trypanosomiasis when given orally at doses of 25-50 mg/kg for 4 days for the acute infection, and 50-100 mg/kg (bid) for 5 days in the chronic model. While both compounds are bacterial mutagens, activity is lost in strains lacking bacterial specific nitro-reductases. Mammalian nitro-reductases do not reduce nitroaromatic compounds with low redox potentials with same avidity as their bacterial counterparts and these compounds were shown to be devoid of genotoxicity in mammalian cells. Both compounds are promising leads for the treatment of human African trypanosomiasis (HAT or sleeping sickness), including the fatal stage 2 of the disease, for which new treatments are urgently needed
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto and Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:05 Dec 2017 10:03
Deposited On:11 Oct 2012 15:30

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