Homo- and hetero-bivalent edrophonium-like ammonium salts as highly potent, dual binding site AChE inhibitors

A number of mono- and bis-quaternary ammonium salts, containing edrophonium-like and coumarin moieties tethered by an appropriate linker, proved to be highly potent and selective dual binding site acetylcholinesterase inhibitors with good selectivity over butyrylcholinesterase. Homobivalent bis-quaternary inhibitors 11 and 12, differing by only one methylene unit in the linker, were the most potent and selective inhibitors exhibiting a sub-nanomolar affinity (IC50 = 0.49 and 0.17 nM, respectively) and a high butyryl-/acetylcholinesterase affinity ratio (SI = 1465 and 4165, respectively). The corresponding hetero-bivalent coumarinic inhibitors 13 and 14 were also endowed with excellent inhibitory potency but a lower AChE selectivity (IC50 = 2.1 and 1.0 nM, and SI = 505 and 708, respectively). Docking simulations enabled clear interpretation of the structure–affinity relationships and detection of key binding interactions at the primary and peripheral AChE binding sites.