title: Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE.
abstract: A new series of donepezil-tacrine hybrid related derivatives have been synthesised as dual acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. These new hybrids combined a tacrine, 6-chlorotacrine or acridine unit as catalytic binding site and indanone (the heterocycle present in donepezil) or phthalimide moiety as peripheral binding site of the enzyme, connected through a different linker tether length. One of the synthesised compounds emerged as a potent and selective AChE inhibitor, which is able to displace propidium in a competition assay. These results seem to confirm the ability of this inhibitor to bind simultaneously to both sites of the enzyme and make it a promising lead for developing disease-modifying drugs for the future treatment of Alzheimer's disease. To gain insight into the molecular determinants that modulate the inhibitory activity of these compounds, a molecular modelling study was performed to explore their binding to the enzyme.
authors.affiliation: Neuropharma, S.A., Avda. de La Industria 52, 28760 Tres Cantos (Madrid), Spain.
authors.forename: D
authors.initials: D
authors.lastname: Alonso
authors.forename: I
authors.initials: I
authors.lastname: Dorronsoro
authors.forename: L
authors.initials: L
authors.lastname: Rubio
authors.forename: P
authors.initials: P
authors.lastname: Muñoz
authors.forename: E
authors.initials: E
authors.lastname: García-Palomero
authors.forename: M
authors.initials: M
authors.lastname: Del Monte
authors.forename: A
authors.initials: A
authors.lastname: Bidon-Chanal
authors.forename: M
authors.initials: M
authors.lastname: Orozco
authors.forename: F J
authors.initials: FJ
authors.lastname: Luque
authors.forename: A
authors.initials: A
authors.lastname: Castro
authors.forename: M
authors.initials: M
authors.lastname: Medina
authors.forename: A
authors.initials: A
authors.lastname: Martínez
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000077265:Donepezil; D006801:Humans; D007189:Indans / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry*
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D013619:Tacrine; D000077265:Donepezil; D000110:Acetylcholinesterase