Title : Homo- and hetero-bivalent edrophonium-like ammonium salts as highly potent, dual binding site AChE inhibitors - Leonetti_2008_Bioorg.Med.Chem_16_7450 |
Author(s) : Leonetti F , Catto M , Nicolotti O , Pisani L , Cappa A , Stefanachi A , Carotti A |
Ref : Bioorganic & Medicinal Chemistry , 16 :7450 , 2008 |
Abstract :
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 0.17 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 (IC(50)=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. |
PubMedSearch : Leonetti_2008_Bioorg.Med.Chem_16_7450 |
PubMedID: 18585045 |
Leonetti F, Catto M, Nicolotti O, Pisani L, Cappa A, Stefanachi A, Carotti A (2008)
Homo- and hetero-bivalent edrophonium-like ammonium salts as highly potent, dual binding site AChE inhibitors
Bioorganic & Medicinal Chemistry
16 :7450
Leonetti F, Catto M, Nicolotti O, Pisani L, Cappa A, Stefanachi A, Carotti A (2008)
Bioorganic & Medicinal Chemistry
16 :7450