title: Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase.
abstract: Acetylcholinesterase inhibitors (AChEIs) are currently the drugs of choice, although only symptomatic and palliative, for the treatment of Alzheimer's disease (AD). Donepezil is one of most used AChEIs in AD therapy, acting as a dual binding site, reversible inhibitor of AChE with high selectivity over butyrylcholinesterase (BChE). Through a combined target- and ligand-based approach, a series of coumarin alkylamines matching the structural determinants of donepezil were designed and prepared. 6,7-Dimethoxycoumarin derivatives carrying a protonatable benzylamino group, linked to position 3 by suitable linkers, exhibited fairly good AChE inhibitory activity and a high selectivity over BChE. The inhibitory potency was strongly influenced by the length and shape of the spacer and by the methoxy substituents on the coumarin scaffold. The inhibition mechanism, assessed for the most active compound 13 (IC(50) 7.6 nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Bari Aldo Moro, via E. Orabona 4, Bari 70125, Italy. marco.catto@uniba.it
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pisani
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: Paolo
authors.initials: P
authors.lastname: Pesce
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*; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000378:metabolism; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006736:Horses; D006801:Humans
chemical_list: D002800:Cholinesterase Inhibitors; D003374:Coumarins; C030123:coumarin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase