title: Design, synthesis, and biological evaluation of coumarin derivatives tethered to an edrophonium-like fragment as highly potent and selective dual binding site acetylcholinesterase inhibitors.
abstract: A large series of substituted coumarins linked through an appropriate spacer to 3-hydroxy-N,N-dimethylanilino or 3-hydroxy-N,N,N-trialkylbenzaminium moieties were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The highest AChE inhibitory potency in the 3-hydroxy-N,N-dimethylanilino series was observed with a 6,7-dimethoxy-3-substituted coumarin derivative, which, along with an outstanding affinity (IC(50)=0.236 nM) exhibits excellent AChE/BChE selectivity (SI>300 000). Most of the synthesized 3-hydroxy-N,N,N-trialkylbenzaminium salts display an AChE affinity in the sub-nanomolar to picomolar range along with excellent AChE/BChE selectivities (SI values up to 138 333). The combined use of docking and molecular dynamics simulations permitted us to shed light on the observed structure-affinity and structure-selectivity relationships, to detect two possible alternative binding modes, and to assess the critical role of pi-pi stacking interactions in the AChE peripheral binding site.
authors.affiliation: Dipartimento Farmaco-chimico, Università degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pisani
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.forename: Ilenia
authors.initials: I
authors.lastname: Giangreco
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanachi
authors.forename: Saverio
authors.initials: S
authors.lastname: Cellamare
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004491:Edrophonium / Q000737:chemistry*; D006801:Humans; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D003374:Coumarins; D004491:Edrophonium; D000110:Acetylcholinesterase