Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode

Butyrylcholinesterase
(BChE) is a promising target for the treatment
of later stage cognitive decline in Alzheimer’s disease. A
set of pseudo-irreversible BChE inhibitors with high selectivity over hAChE was synthesized based on carbamates attached to tetrahydroquinazoline
scaffolds with the 2-thiophenyl compound 2p as the most
potent inhibitor of eqBChE (KC = 14.3 nM) and also of hBChE (KC = 19.7 nM). The inhibitors transfer the carbamate moiety
onto the active site under release of the phenolic tetrahydroquinazoline
scaffolds that themselves act as neuroprotectants. By combination
of kinetic data with molecular docking studies, a plausible binding
model was probed describing how the tetrahydroquinazoline scaffold
guides the carbamate into a close position to the active site. The
model explains the influence of the carrier scaffold onto the affinity
of an inhibitor just before carbamate transfer. This strategy can
be used to utilize the binding mode of other carbamate-based inhibitors.