Effects of charge and intramolecular structure on the lipophilicity of nitrophenols.

The lipophilicity of a series of phenolic compounds was studied in the 1,2-dichloroethane (1,2-DCE)/water system. Cyclic voltammetry at the ITIES was used to study the transfer characteristics of the charged species, and their partition coefficient was deduced from their formal transfer potential. For the neutral species, log P-DCE values were measured by a two-phase pi-I-metric method. The results are compared to those previously obtained in octanol/water and by linear solvation energy relationships (LSER) in the two solvent systems. It is shown that nitrophenols with intramolecular II-bonding deviate from the solvatochromic equation for the 1,2-DCE/water system, and discrepancies between both approaches are discussed on the basis of conformational and steric effects. When charged however, all the species have approximately the same partition coefficients because the effect of the intramolecular H-bond disappears and the differences in measured lipophilicity arise from the variation of the intramolecular charge delocalization due to resonance equilibria. Some biological implications of these properties are discusse

Ionic partition diagrams of ionisable drugs: pH-lipophilicity profiles, transfer mechanisms and charge effects on solvation.

The transfer of a series of weak acids, bases and ampholytes has been studied by cyclic voltammetry at the water \ 1,2-dichloroethane interface in order to determine their lipophilicity. Physicochemical parameters such as the standard Gibbs energy of transfer and the standard partition coefficients of the ionised forms I of these compounds (log P-I(0')) were measured as a function of aqueous pH, and the dissociation constants in the organic phase were deduced from these data. The results obtained are presented in the form of ionic partition diagrams which define the domains of predominance of all the species present in both phases. This representation affords both a precise description of the mechanisms governing the transfer from one phase to the other, and a reliable assessment of pH lipophilicity profiles. The various partition coefficients are compared to evaluate qualitatively the lipophilicity of each species, and the differences between the partition coefficients of the charged and the neutral form of a compound are interpreted in terms of their chemical structure, showing an increase in organic phase affinity for ions with intramolecular charge stabilisation. This study demonstrates also that both charged and neutral species can penetrate into the organic phase and shows the importance of the passive transfer of organic ions for drug disposition and pharmacokinetics. (C) 1999 Elsevier Science S.A. All rights reserve

Monoamine oxidase inhibitory properties of some benzazoles: Structure-; Activity relationships

Benzazoles containing two or three nitrogen atoms were screened for their inhibitory activity toward monoamine oxidases MAO-A and MAO-B. In order to clarify the mechanism of interaction of these compounds with the enzyme, their electronic structure was calculated at the ab initio level and the influence of lipophilicity on activity was investigated. The mode of binding of benzazoles to MAO-B appears different from that of previously investigated heterocycles