Abstract

The relationship between the physicochemical properties and uncoupling activity of flufenamic acid [N-(3'-trifluoromethylphenyl)anthranilic acid] and its structural analogues, which vary in position 3' of the phenyl ring, has been investigated. Some of these compounds are known to be potent anti-inflammatory agents. Their physicochemical properties were compared with their uncoupling activities, measured as their effects on State 4 respiration and on the ATP-P_i exchange reaction of rat liver mitochondria. The partition coefficients, determined in n-heptane—H₂O, n-hexane—H₂O, and chloroform—H₂O at pH 7, increased with introduction of hydrophobic groups such as -CF₃, -CH₃, and -C₆H₅ into N-phenylanthranilic acid, and decreased with introduction of hydrophilic groups such as -OH, -NH₂, and -SO₃H. Compounds with large partition coefficients had high uncoupling activity, and this correlation was highest in the chloroform—H₂O system. The formation of a dimer in the organic solvent phase was strongly suggested in chloroform, but not in n-hexane or n-heptane, with compounds possessing -H, -CF₃, -CH₃, or -NO₂ at position 3'. Higher uncoupling activity was correlated with larger pK_a values. Also, an important role of the hydrophobic nature of the acids with respect to uncoupling was confirmed for compounds that had similar ionization constants but different uncoupling activities.