Transition State Analog Inhibitors for Esterases.

The effect of electrophilic ketones on acetylcholinesterase activity has been investigated. For example, 1-phenoxy-2-propanone, 1-chloro-3-phenoxy-2-propane, and 1-fluoro-3-phenoxy-2-propanone are competitive acetylcholinesterase inhibitors with K sub I values of 30, 0.85 and 2.2 uM, respectively, compared to 2 mM for 4-phenyl-2-butanone. Substitutent and conformational effects on inhibition suggests that electrophilic ketones bind by formation of a tetrahedral adduct and are transition state analogs. A number of borinic and boronic acids have been found to inhibit acetylcholinesterase with K sub I values in the uM range. Aromatic trifluoromethanesulfonate triflate esters have been prepared and determined to be potent irreversible acetylcholinesterase inhibitors. Compounds of this type could be of use as anticholinesterases. Irradiation of 1-naphthoyltrimethylsilane in the presence of acetylcholinesterase leads to inactivation of the enzyme. Evidence has been developed that this inactivation is active-site-directed and that the acylsilane can be considered a photoaffinity label.