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

• Published in: European journal of medicinal chemistry Vol. 46; no. 5; pp. 1524 - 1535
• Main Authors: Trunz, Bernadette Bourdin, Jedrysiak, Rafal, Tweats, David, Brun, Reto, Kaiser, Marcel, Suwinski, Jerzy, Torreele, Els
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier 01.05.2011
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - therapeutic use; Biological and medical sciences; Cell Survival - drug effects; Chemistry, Medicinal; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Leukocytes, Mononuclear - drug effects; Life Sciences & Biomedicine; Medical sciences; Mice; Molecular Structure; Mutagenicity Tests; Nitroimidazoles - chemical synthesis; Nitroimidazoles - chemistry; Nitroimidazoles - therapeutic use; Oxidation-Reduction; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Trypanosomiasis, African - drug therapy; MEGAZOL; DRUG CANDIDATE; Micronucleus test; EFFICACY; Genotoxicity; RHODESIENSE; BRUCEI-BRUCEI; Nitroimidazole; Antiprotozoal activity; MUTAGENICITY; TRIAL; Sleeping sickness; Ames test; REDUCTION; BENZNIDAZOLE; Nitro compound; Imidazole derivatives; Protozoal disease; Toxicity; Nitrogen heterocycle; Antiprotozoal agent; Structure activity relation; Trypanosoma brucei; Trypanosomiasis; Kinetoplastida; Protozoa; Mutagenicity testing; Rodentia; Benzene derivatives; Oral administration; Parasitosis; African sickness; In vitro; Infection; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; DNA; Parasiticide
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.01.071

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.