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 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 antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.
P. Camps, X. Formosa, C. Galdeano, T. Gòmez, D. Munoz-Torrero, M. Scarpellini, et al. (2008). Novel Donepezil-Based Inhibitors of Acetyl- and Butyrylcholinesterase and Acetylcholinesterase-Induced Beta-Amyloid Aggregation. JOURNAL OF MEDICINAL CHEMISTRY, 51, 3588-3598 [10.1021/jm8001313].
Novel Donepezil-Based Inhibitors of Acetyl- and Butyrylcholinesterase and Acetylcholinesterase-Induced Beta-Amyloid Aggregation
BARTOLINI, MANUELA;MANCINI, FRANCESCA;ANDRISANO, VINCENZA;
2008
Abstract
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 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 antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
