Properties of substituted 2-trifluoromethylbenzimidazoles as uncouplers of oxidative phosphorylation

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Abstract
The activity of 25 sub-stituted 2-trifluoromethylbenzimidazoles in uncoupling oxidative phos-phorylation by rat-liver mitochondria has been compared. For halogen-or mixed-halogen- and alkyl-substituted analogues, uncoupling activity was proportional to the acidity of the imidazole -NH group. Tetra-chloro-2-trifluoromethylbenzimidazole was the most active (50% uncoupling of oxidative phosphorylation at 7.9 x 10-8 [image], pK 5.04). Nitro-substituted analogues were less active than predicted from pK considerations or from partition-coefficient measurements. Introduction of an -NH2 or CO2H substituent caused a loss of uncoupling activity, as did alkylation at position 1 of the imidazole ring. Benzimidazoles active as uncouplers stimulated mitochondrial adenosine triphosphatase but not all stimulated the oxidation of succinate in the absence of a phosphate acceptor. 4,5-Dichloro-2-trifluoromethylbenzimidazole inhibited the succinate-oxidase system at about the same concentration required for uncoupling (0.52 [mu][image] for 50% inhibition of both activities) and the site of this inhibition appears to lie between succinate dehydrogenase and cytochrome b.