QSARs for Peripheral Anionic Site of Butyrylcholinesterase with Inhibitions by 4-Acyloxy-biphenyl-4′-N-butylcarbamates

Abstract

4-Acyloxy-biphenyl-4'-N-butylcarbamates (1-8) are synthesized from 4,4'-biphenol by two-step reactions. Carbamates 1-7 are characterized as the pseudo-substrate inhibitors of butyrylcholinesterase. In other words, carbamates 1-7 bind to the enzyme and react with the enzyme to form the tetrahedral enzyme-inhibitor intermediates for the K, steps, and then the Michaelis complexs exclude various leaving groups to form a common N-butycarbamyl enzyme intermediate for the k c steps. Due to a linear character for the 4,4'-biphenyl moiety, the 4'-N-butylcarbamate moieties of carbamates 1-7 react with the Ser198 residue of the enzyme while the 4-acyloxy moieties of the inhibitors, on the other hand, should fit in the peripheral anionic site of the enzyme, which is located at the mouth of a deep active site gorge of the enzyme. With varied acyl substituents at the 4-position of the biphenyl ring, carbamates 1-7 are good candidates for probing QSARs for the peripheral anionic site of the enzyme. The fact that the pK,, log k c , and log k i values are correlated with neither Taft substituent constant (σ*) nor Taft steric constant (E s ) indicates that the 4-acyloxy moieties of the inhibitors are too far away from the reaction center. However, the pK i , log k c , and log k, values are linearly correlated with the Hansch hydrophobicity constant, π. The intensity constants (ψ) for these correlations are 0.26, 0.01, and 0.27, respectively. These results indicate that interactions between the 4-acyloxy groups of carbamates 1-7 and the peripheral anionic site of the enzyme are mainly hydrophobic ones. With a bulky triphenylacetoxy group, carbamate 8, on the other hand, is characterized as a mixed-type inhibitor of butyrylcholinesterase with the K i value of 2 μM. Thus, carbamate 8 does not react with the Ser198 of the enzyme. Therefore, the triphenylacetoxy moiety of carbamate 8 may bind to the peripheral anionic site of the enzyme, while the N-butylcarbamate moiety of the inhibitor, on the other hand, may interact with the anionic site of the enzyme, acting like a bivalent-ligand inhibitor.