Ortho effects in quantitative structure-activity relationships for acetylcholinesterase inhibition by aryl carbamates

Abstract

Ortho-substituted phenyl-N-butyl carbamates (1-9) are characterized as "pseudo-pseudo-substrate" inhibitors of acetylcholinesterase. Since the inhibitors protonate at pH 7.0 buffer solution, the virtual inhibition constants (Kils) of the protonated inhibitors are calculated from the equation, - logKi′ = - logKi - logKb. The logarithms of the inhibition constant (Ki), the carbamylation constant (kc), and the bimolecular inhibition constant (ki) for the enzyme inhibitions by carbamates 1-9 are multiply linearly correlated with the Hammett para-substituent constant (σp), the Taft-Kutter-Hansch ortho steric constant (Es), and the Swan-Lupton ortho polar constant (F). Values of ρ, δ, and f for the - logKi-, logkc-, and logki-correlations are - 0.6, - 0.16, 0.7; 0.11, 0.03, - 0.3; and - 0.5, - 0.12, 0.4, respectively. The Ki step further divides into two steps: 1) the pre-equilibrium protonation of the inhibitors, Kb step and 2) formation of a negatively charged enzyme-inhibitor Michaelis-Menten complex - virtual inhibition, Ki′ step. The Ki step has little ortho steric enhancement effect; moreover, the kc step is insensitive to the ortho steric effect. The f value of 0.7 for the Ki step indicates that ortho electron-withdrawing substituents of the inhibitors accelerate the inhibition reactions from the ortho polar effect; however, the f value of - 0.3 for the kc step implies that ortho electron-withdrawing substituents of the inhibitors lessen the inhibition reactions from the ortho polar effect. © 2004 Taylor & Francis Ltd.