Homo- and hetero-bivalent edrophonium-like ammonium salts as highly potent, dual binding site AChE i
July 3rd, 2008 | by admin |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 (IC(50)=0.49 and 0.17nM, 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 (IC(50)=2.1 and 1.0nM, 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.
Leonetti F, Catto M, Nicolotti O, Pisani L, Cappa A, Stefanachi A, Carotti A.
Dipartimento Farmaco-Chimico, Università di Bari, via Orabona 4, I-70125 Bari, Italy.