Alzheimer's disease (AD) is a progressive brain disorder which occurs due to lower levels of acetylcholine
(ACh) neurotransmitters, and results in a gradual decline in memory and other cognitive processes. Acetycholinesterase
(AChE) and butyrylcholinesterase (BChE) are considered to be primary regulators of the ACh levels in the brain. Evidence
shows that AChE activity decreases in AD, while activity of BChE does not change or even elevate in advanced
AD, which suggests a key involvement of BChE in ACh hydrolysis during AD symptoms. Therefore, inhibiting the activity
of BChE may be an effective way to control AD associated disorders. In this regard, a series of quinoxaline derivatives
1-17 was synthesized and biologically evaluated against cholinesterases (AChE and BChE) and as well as against α-
chymotrypsin and urease. The compounds 1-17 were found to be selective inhibitors for BChE, as no activity was found
against other enzymes. Among the series, compounds 6 (IC50 = 7.7 ± 1.0 µM) and 7 (IC50 = 9.7 ± 0.9 µM) were found to
be the most active inhibitors against BChE. Their IC50 values are comparable to the standard, galantamine (IC50 = 6.6 ±
0.38 µM). Their considerable BChE inhibitory activity makes them selective candidates for the development of BChE inhibitors.
Structure-activity relationship (SAR) of this new class of selective BChE inhibitors has been discussed.
Keywords: Alzheimer's disease (AD), acetylcholine (ACh), quinoxaline, acetylcholinesterase (AChE), butyrylcholinesterase
(BChE), galantamine, urease, chymotrypsin.
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