Quantitative Structure-Activity Relationship of Catechol Derivatives Inhibiting 5-Lipoxygenase

Abstract

Various catechol derivatives (β-substitued 3, 4-dihydroxystyrenes, 1-substituted 3, 4-dihydroxybenzenes, and 6-substituted 2, 3-dihydroxynaphthalenes) were synthesized and their inhibition of 5-lipoxygenease was assayed. Their structure-activity relationships were examined quantitatively with substituent and structural parameters and regression analysis. The variations in the inhibitory activity were explained in bilinear hydrophobic parameter (log P) terms, and steric (molecular thickness) and electronic (proton nuclear magnetic resonance (¹H-NMR) chemical shift of the proton adjacent to the catechol group) parameter terms. The hydrophobicity of the inhibitor molecule was important, and the optimum valur of log P was about 4.3-4.6, beyond which inhibition did not increase further. A lower electron density of the aromatic ring containing the catechol group and the greater thickness of the lipophilic side chains were unfavorable to the activity. The results added a physicochemical basis for the selection of candidate compounds for developmental studies.