期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 46, 期 5, 页码 1524-1535出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.01.071
关键词
Nitroimidazole; Antiprotozoal activity; Sleeping sickness; Genotoxicity; Ames test; Micronucleus test
资金
- DNDi
- Foundation for the Polish Science [N204 065 31/1722]
- Ministry of Foreign and European Affairs of France
- Department for International Development (DFID) of the UK
- Swiss private foundation
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 nitroreductases 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. (C) 2011 Elsevier Masson SAS. All rights reserved.
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