Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 16, Issue 15, Pages 7450-7456Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.06.022
Keywords
edrophonium-like ammonium salts; selective acetylcholinesterase inhibitors; butyrylcholinesterase inhibition; molecular docking
Funding
- MUR, Rome, Italy
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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. (C) 2008 Elsevier Ltd. All rights reserved.
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