THE EFFECT OF FLUORINE SUBSTITUTION ON THE PHYSICOCHEMICAL PROPERTIESAND THE ANALGESIC ACTIVITY OF PARACETAMOL

The physicochemical properties and analgesic action of six fluorinated analogues of 4-hydroxyacetanilide (paracetamol) have been investigate d. Fluorine substitution adjacent to the hydroxyl group increased lipo philicity and oxidation potential whilst substitution adjacent to the amide had little effect on lipophilicity but led to a greater increase in oxidation potential. Lack of coplanarity and conjugation of the am ide group and aromatic ring was also apparent with the analogues that had fluorine in the 2 and 6 positions. Introduction of fluorine into t he amide group of paracetamol increased the lipophilicity 4-fold and a lso increased the oxidation potential of paracetamol. ED50 values for analgesic activity in the phenylquinone-induced abdominal constriction test on male Swiss White mice showed that ring substitution by fluori ne reduced activity, especially at the 2,6-positions. Introduction of fluorine into the amide group enhanced activity significantly. Correla tion of the analgesic activity with the physicochemical properties ind icated that conjugation (and planarity) of the amide group with the ar omatic ring is essential for activity and that ease of oxidation may a lso be an important factor.