title: Homo- and hetero-bivalent edrophonium-like ammonium salts as highly potent, dual binding site AChE inhibitors.
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.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Bari, via Orabona 4, I-70125 Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pisani
authors.forename: Anna
authors.initials: A
authors.lastname: Cappa
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanachi
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D015195:Drug Design; D004491:Edrophonium / Q000737:chemistry* / Q000494:pharmacology*; D006736:Horses; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D004491:Edrophonium; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase