Properties of substituted 2-trifluoromethylbenzimidazoles as uncouplers of oxidative phosphorylation.
1. The activity of 25 substituted 2-trifluoromethylbenzimidazoles in uncoupling oxidative phosphorylation by rat-liver mitochondria has been compared. 2. For halogen- or mixed-halogen- and alkyl-substituted analogues, uncoupling activity was proportional to the acidity of the imidazole -NH group. Tetrachloro-2-trifluoromethylbenzimidazole was the most active (50% uncoupling of oxidative phosphorylation at 7.9x10(-8)m, pK5.04). Nitro-substituted analogues were less active than predicted from pK considerations or from partition-coefficient measurements. 3. Introduction of an -NH(2) or -CO(2)H substitutent caused a loss of uncoupling activity, as did alkylation at position 1 of the imidazole ring. 4. Benzimidazoles active as uncouplers stimulated mitochondrial adenosine triphosphatase but not all stimulated the oxidation of succinate in the absence of a phosphate acceptor. 5. 4,5-Dichloro-2-trifluoromethylbenzimidazole inhibited the succinate-oxidase system at about the same concentration required for uncoupling (0.52mum for 50% inhibition of both activities) and the site of this inhibition appears to lie between succinate dehydrogenase and cytochrome b.
D000818:Animals; D002374:Catalase / Q000032:analysis; D002855:Chromatography, Thin Layer; D003576:Electron Transport Complex IV / Q000032:analysis; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008365:Manometry; D008928:Mitochondria / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010088:Oxidoreductases / Q000032:analysis; D051381:Rats; D013385:Succinate Dehydrogenase
D007093:Imidazoles; D010088:Oxidoreductases; D002374:Catalase; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV