Effects of mono-, di- and tri-hydroxybenzoic acids on the nitrosation of propranolol: structure-activity relationship

Nitrosation of propranolol under standard conditions recommended by the Wor ld Health Organization (10 mM propranolol hydrochloridre, 40 mM sodium nitr ite, pH 3.5) was performed in the absence and in the presence of benzoic ac id and of twelve mono-, di- and tri-hydroxybenzoic acids, added to the nitr osation mixture in concentrations ranging from 2 to 40 mM. in order to exam ine their effect on the nitrosation reaction. The yield of N-nitrosopropran ol (NOP) was reduced by benzoic acid and, with potency decreasing in the fo llowing order, by 2,3,4-tri-hydroxybenzoic acid greater than or equal to 3, 4-tri-hydroxybenzoic acid > 2,5-di-hydroxybenzoic acid > 2,3-di-hydroxybenz oic acid > 3-hydroxybenzoic acid > 2-hydroxybenzoic acid > 3,4,5 -tri-hydro xybenzoic acid, 4-hydroxybenzoic acid; their inhibiting effect was concentr ation-dependent. In contrast, 2,4-di-hydroxybenzoic acid, 2,6-di-hydroxyben zoic acid and 2,3,6-tri-hydroxybenzoic acid caused an increase in the yield of NOP that was inversely related to their concentration. 3,5-Di-hydroxybe nzoic acid was substantially inactive. These findings indicate that, depend ing on the positions of carboxyl group and hydroxyl groups on the benzene r ing, mono-, di- and tri-hydroxybenzoic acids may inhibit or hasten nitrosat ion reactions. As compared with benzenediols and benzenetriols [Mutat. Res. 398 (1998) 75], hydroxybenzoic acids inhibit the nitrosation of propranolo l to a greater extent and have the advantage of being nonmutagenic and less toxic. (C) 2001 Elsevier Science B.V. All rights reserved.