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Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE

Posted June 8th, 2010 by pschmidtke
TitleDonepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE
Publication TypeJournal Article
Year of Publication2005
AuthorsAlonso, D, Dorronsoro I, Rubio L, Munoz P, Garcia-Palomero E, Monte DM, Bidon-Chanal A, Orozco M, Luque FJ, Castro A, Medina M, Martinez A
JournalBioorganic & medicinal chemistry
Volume13
Issue24
Pagination6588 - 6597
Date Published2005/12/15/
KeywordsAcetylcholinesterase/metabolism; Animals; Binding Sites; Cattle; Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology; Humans; Indans/chemistry; Inhibitory Concentration 50; Models, Molecular; Molecular Structure; Piperidines/chemistry; Structure-Activity Relationship; Tacrine/chemistry
AbstractA 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.