Ortho Effects in Quantitative Structure-activity Relationships for Acetylcholinesterase Inhibition by Aryl Carbamates

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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 (Ki′s) 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 kcstep 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 kcstep implies that ortho electron-withdrawing substituents of the inhibitors lessen the inhibition reactions from the ortho polar effect.