Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation.
A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Barcelona, Spain. camps@ub.edu
Pelayo
P
Camps
Xavier
X
Formosa
Carles
C
Galdeano
Tània
T
Gómez
Diego
D
Muñoz-Torrero
Michele
M
Scarpellini
Elisabet
E
Viayna
Albert
A
Badia
M Victòria
MV
Clos
Antoni
A
Camins
Mercè
M
Pallàs
Manuela
M
Bartolini
Francesca
F
Mancini
Vincenza
V
Andrisano
Joan
J
Estelrich
Mònica
M
Lizondo
Axel
A
Bidon-Chanal
F Javier
FJ
Luque
D000110:Acetylcholinesterase / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D000077265:Donepezil; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D013619:Tacrine; D000077265:Donepezil; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase