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

• Published in: Bioorganic & medicinal chemistry 2005-12, Vol.13 (24), p.6588-6597
• Main Authors: Alonso, D., Dorronsoro, I., Rubio, L., Muñoz, P., García-Palomero, E., Del Monte, M., Bidon-Chanal, A., Orozco, M., Luque, F.J., Castro, A., Medina, M., Martínez, A.
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Acetylcholinesterase inhibitors; Alzheimer’s disease; Animals; Binding Sites; Biological and medical sciences; Cattle; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Donepezil; Humans; Indans - chemistry; Inhibitory Concentration 50; Medical sciences; Models, Molecular; Molecular Structure; Neuropharmacology; Pharmacology. Drug treatments; Piperidines - chemistry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Structure-Activity Relationship; Tacrine; Tacrine - chemistry
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.09.029

A new series of donepezil–tacrine hybrid related derivatives have been synthesised as dual acetylcholinesterase inhibitors that are able to bind simultaneously to the peripheral and catalytic sites of the enzyme. The designed compounds may simultaneously alleviate cognitive deficits and behave as disease-modifying agents for the treatment of Alzheimer’s disease. 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.