Aryl N-methoxy- N-methylcarbamates: Potent competitive reversible inhibitors of cholinesterases

Abstract

A series of 27 substituted aryl N-methoxy- N-methylcarbamates were synthesized and their ability to reversibly inhibit house fly-head and bovine-erythrocyte acetylcholinesterase and horse-serum cholinesterase was determined. These compounds were all competitive, reversible inhibitors of bovine erythrocyte acetylcholinesterase but some of them showed mixed competitive inhibition against the house fly-head and horse-serum enzymes. Dissociation constants ( K i ) as small as 9.9 × 10 −9 M and as large as 1.4 × 10 −4 M were observed. A highly satisfactory correlation between log K i for the inhibition of fly-head acetylcholinesterase by the N-methoxy- N-methylcarbamates and −log I 50 for the inhibition of the same enzyme by the corresponding methylcarbamates was noted. Analysis of the anticholinesterase data by multiple regression showed -log K i to be related to Hansch's π constant and ring position terms. The results indicate that reversible binding of these compounds to acetylcholinesterase occurs by hydrophobic bonding.