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  • Title: Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE.
    Author: Alonso D, Dorronsoro I, Rubio L, Muñoz P, García-Palomero E, Del Monte M, Bidon-Chanal A, Orozco M, Luque FJ, Castro A, Medina M, Martínez A.
    Journal: Bioorg Med Chem; 2005 Dec 15; 13(24):6588-97. PubMed ID: 16230018.
    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.
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