- 作者: 林家立
- 作者服務機構: Department of Chemistry, National Chung-Hsing University, Taichung 402, Taiwan, R.O.C.
- 中文摘要: Substituted 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) = ρ σ); 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 rXR 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.
- 英文摘要: --
- 中文關鍵字: Acetylcholinesterase inhibition; LFER; QSAR; Cross-interaction; Carbamates; Enzyme mechanism.
- 英文關鍵字: --