@article {178, title = {Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE}, journal = {Bioorganic \& medicinal chemistry}, volume = {13}, year = {2005}, month = {2005/12/15/}, pages = {6588 - 6597}, 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{\textquoteright}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.}, keywords = {Acetylcholinesterase/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}, author = {Alonso,D. and Dorronsoro,I. and Rubio,L. and Munoz,P. and Garcia-Palomero,E. and Monte,M. Del and A. Bidon-Chanal and M. Orozco and F. J. Luque and Castro,A. and Medina,M. and Martinez,A.} }