Structure‐Reactivity Relationships as Probes to Acetylcholinesterase Inhibition Mechanisms by Aryl Carbamates. II. Hammett‐Taft Cross‐Interaction Correlations

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AbstractSubstituted phenyl‐N‐butyl carbamates (1) and p‐nitrophenyl‐N‐substituted carbamates (2) are characterized as “pseudo‐pseudo‐substrate” inhibitors of acetylcholinesterase. Since the inhibitors protonate in pH 7.0 buffer solution, the virtual inhibition constants (Ki's) of the protonated inhibitors can be calculated from the equation, ‐logKi' = ‐logKi ‐ pKa + 14. The ‐logKi' and logkc values for acetylcholinesterase inhibitions by carbamates 1 correlate with the Hammett equation (log(k/k0) = ρσ); moreover, those by carbamates 2 correlate with the Taft equation (log(k/k0) = ρ* σ*). With modified Hammett‐Taft cross‐interaction variations, multiple linear regressions of the ‐logKi' and logkc values of carbamates 1 and 2 give good correlations, and the cross‐interaction constants (ρXR) are 0.5 and 0.0, respectively. The ρXR value of 0.5 indicates that the carbamate O‐C(O)‐N‐R geometries for the transition states that lead to enzyme‐carbamate tetrahedral intermediates are all pseudo‐trans conformations. Therefore, the carbamate moiety of the inhibitors stretches along the active site gorge of the enzyme but does not bind in the acyl binding site pocket of the enzyme. Overall, the carbamate O‐C(O)‐N‐R geometries for carbamates 1 and 2, protonated carbamates 1 and 2, and the tetrahedral intermediate are all retained in pseudo‐trans conformations. The ρXR value of 0.0 suggests that the transition states that lead to the carbamyl enzymes are breaking C‐O bonds and are excluding the leaving groups, substituted phenols.