Ortho effects and cross interaction correlations for the mechanisms of cholesterol esterase inhibition by aryl carbamates

Ortho ‐substituted phenyl‐ N ‐butyl carbamates ( 1 – 11 ) were synthesized to evaluate the inhibition mechanisms of porcine pancreatic cholesterol esterase. All carbamate inhibitors act as the active site‐directed pseudo substrate inhibitors of the enzymes. The logarithms of dissociation constant ( K i ), carbamylation constant ( k 2 ) and bimolecular inhibition constant ( k i ) multiply linearly correlate with the Hammett substituent constant (σ), the Taft–Kutter–Hansch ortho steric constant ( E S ), and the Swan–Lupton–Hansch ortho polar constant ( F ). For the –log  K i , log  k 2 and log  k i correlations, the reaction constant for ordinary polar effect (ρ), the intensity factor to ortho steric constant (δ) and the intensity factor to ortho polar constant ( f ) are 0.7, −0.07, and 0.5; 0.5, 0.04 and −0.5; and 1.1, −0.03 and 0.0, respectively. The cross interaction reaction constant ( ρXR ) for the –log  k i –, log  k 2 – and log  k i ‐‐σ–ασ*–ασσ* correlations are 3, −2, and 1, respectively. The K i step may be composed of the following two steps: (1) protonation of carbamates 1 – 11 and (2) the pseudo‐ trans to pseudo‐ cis conformation change of protonated carbamates 1 – 11 due to a large ρXR value of 3 and formation of the enzyme‐protonated carbamates 1 – 11 tetrahedral intermediate. The k 2 step involves departure of the leaving group, which is protonated by the active site histidine of the enzyme, from the tetrahedral intermediate to solution and formation of the carbamyl enzyme. Moreover, the distances between the carbamate and phenyl groups in all transition states of inhibition reactions are relatively short owing to large | ρXR | values. The K i step shows little ortho steric enhancement effect; moreover, the k 2 step shows little ortho steric inhibition effect. Copyright © 2004 John Wiley & Sons, Ltd.