Quantitative Structure-Activity Studies of Hydrazones, Uncouplers of Oxidative Phosphorylation

Abstract

α-Acyl-α-cyanocarbonyl-phenylhydrazones are effective uncouplers of oxidative phosphorylation. The pl₅₀-values of a series of 60 hydrazones with substituent variations in six positions of the molecule were determined in rat liver mitochondria. They ranged from 4.96 to 7.06. The biological data together with physico-chemical compound and substituent parameters were analysed by multiple regression techniques to establish the structure activity relationship. The integral parameters pK_a and log P (partition coefficient) gave correlations of only moderate significance. Good agreement of found and calculated pl₅₀-values was obtained by an equation with electronic (σ) and hydrophobic (π) substituent parameters in linear and quadratic terms. It is concluded that the contribution of a substituent to uncoupling activity depends on its position in the molecule. The activity is enhanced by hydrophobic shielding of the acidic NH-group. The relevancy of these results in relation to current theories on the mechanism of oxidative phosphorylation is discussed.