title: 1-Aryl-4-nitro-1H-imidazoles, a new promising series for the treatment of human African trypanosomiasis.
abstract: 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.
authors.affiliation: Drugs for Neglected Diseases initiative, 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland. bbourdin@bluewin.ch
authors.forename: Bernadette Bourdin
authors.initials: BB
authors.lastname: Trunz
authors.forename: Rafał
authors.initials: R
authors.lastname: Jędrysiak
authors.forename: David
authors.initials: D
authors.lastname: Tweats
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Jerzy
authors.initials: J
authors.lastname: Suwiński
authors.forename: Els
authors.initials: E
authors.lastname: Torreele
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D000981:Antiprotozoal Agents; D009593:Nitroimidazoles