Inhibition of Human Acetyl- and Butyrylcholinesterase by Novel Carbamates of (−)- and (+)-Tetrahydrofurobenzofuran and Methanobenzodioxepine

A new enantiomeric synthesis utilizing classical resolution provided two novel series of optically active
inhibitors of cholinesterase:  (−)- and (+)-O-carbamoyl phenols of tetrahydrofurobenzofuran and methanobenzodioxepine. An additional two series of (−)- and (+)-O-carbamoyl phenols of pyrroloindole and
furoindole were obtained by known procedures, and their anticholinesterase actions were similarly quantified
against freshly prepared human acetyl- (AChE) and butyrylcholinesterase (BChE). Both enantiomeric forms
of each series demonstrated potent cholinesterase inhibitory activity (with IC50 values as low as 10 nM for
AChE and 3 nM for BChE), with the exception of the (+)-O-carbamoyl phenols of pyrroloindole, which
lacked activity (IC50 values >1 μM). Based on the biological data of these four series, a structure−activity
relationship (SAR) analysis was provided by molecular volume calculations. In addition, a probable transition-state model was established according to the known X-ray structure of a transition-state complex of Torpedo
californica AChE−m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone (TcAChE−TMTFA). This
model proved valuable in explaining the enantioselectivity and enzyme subtype selectivity of each series.
These carbamates are more potent than, or similarly potent to, anticholinesterases in current clinical use,
providing not only inhibitors of potential clinical relevance but also pharmacological tools to define drug−enzyme binding interactions within an enzyme crucial in the maintenance of cognition and numerous systemic
physiological functions in health, aging, and disease.