1 research outputs found
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 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