Structure-activity relationships in anti-inflammatory phenols, benzoates, and salicylates as obtained by quantum chemical methods

Abstract

Ab Initio, molecular orbital methods are being used to analyze and interpret structure-activity relationships in anti-inflammatory phenols, benzoates and salicylates. The results show a correlation between the potency of the active compounds as inhibitors of prostaglandin production in cell cultures and the orbital energy of the highest occupied molecular orbital with a correlation coefficient ofr ∼ 0.8.

The mode(s) of action and structural requirements of anti-inflammatory, non-narcotic analgesics continues to defy rationalization. Even the most plausible proposed molecular mechanism of their anti-inflammatory action, i.e., inhibition of prostaglandin biosynthesis [1], is still subject to controversy [2, 3]. Therefore other approaches may be fruitful for relating the NSAID's biological activity to molecular structure and properties.

One such approach is to relate the biological activity to structural indices obtained from molecular orbital theory. From the results of such quantum chemical calculations it is hoped that deeper insight can be obtained into the NSAID's mode(s) of action by evaluating their dependance on the electronic structure of the biologically active species. A complicating factor in the present studies is that the existence of a specific receptor has not yet been firmly established.

For the present work biological activity is defined as the potency of the given compound to inhibit the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced PGE₂ release from macrophages isolated from the peritoneum of young male NMRI mice. For methodological details see Ref. [4].

From about 80 compounds which have been assayed a sample of 30 molecules was selected for quantum chemical study. The sample comprises phenol, benzoic acid, and salicylic acid and their hydroxy, fluoro- and chloro congenrs. All calculations were carried out usingab initio molecular orbital methods with programs developed in this laboratory.

The σ and π orbital energies of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were analyzed for correlation with the potency of 18 (or 17) active molecules. As the correlation coefficients in Table 1 show, the π-HOMO orbital energies exhibit a significant correlation with the pIC₅₀'s, whereas the σ-HOMO and the LUMO orbital energies do not. The observed correlation shows that potency increases with increasing π-HOMO orbital energy, i.e., weaker binding of the π-HOMO electrons, which enhances the potential for interaction with specific or non-specific interaction sites.

Examination of the correlations reported in Table 1 suggests that the first and second row substituents correlate similarly with the π-HOMO orbital energy, but that the second row group is displaced from the first row group. Separate analysis of the two groups is also given in Table 1. These latter correlation coefficients are about 10% higher than for the whole sample. It is noteworthy that for the other orbital energies the single group correlation coefficients can also be quite high, but that the combined correlation is small to completely random.

Three models have been proposed for the cyclooxygenase receptor where the NSAID's carry out their purported inhibitory function [5–7]. Although these models differ considerably in their details, all three include a π-electron interaction (acceptor) region. The present results support the need for such a region and suggest that enhanced ability to donate π-electrons helps increase potency in inhibiting the release of PGE₂ in macrophages.

A detailed report of this work will be given elsewhere.