Lin_2004_J.Enzyme.Inhib.Med.Chem_19_395

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 (K'is) of the protonated inhibitors are calculated from the equation, - logK'i = - logKi - logKb. The logarithms of the inhibition constant (Ki), the carbamylation constant (k(c)), and the bimolecular inhibition constant (k(i)) for the enzyme inhibitions by carbamates 1-9 are multiply linearly correlated with the Hammett para-substituent constant (sigma(p)), the Taft-Kutter-Hansch ortho steric constant (E(S)), and the Swan-Lupton ortho polar constant (F). Values of rho, delta, and f for the - logKi-, logk(c)-, and logk(i)-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, K'i step. The Ki step has little ortho steric enhancement effect; moreover, the k(c)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 k(c)step implies that ortho electron-withdrawing substituents of the inhibitors lessen the inhibition reactions from the ortho polar effect.