Background:
Acetylcholine deficiency in the hippocampus and cortex, aggregation of
amyloid-beta, and beta-secretase overactivity have been introduced as the main reasons in the
formation of Alzheimer’s disease.
Objective:
A new series of cinnamic derived acids linked to 1-benzyl-1,2,3-triazole moiety were
designed, synthesized, and evaluated for their acetylcholinesterase (AChE) and
butyrylcholinesterase (BuChE) inhibitory activities.
Methods:
Colorimetric Ellman’s method was used for the determination of IC50% of AchE and
BuChE inhibitory activity. The kinetic studies, neuroprotective activity, BACE1 inhibitory activity,
evaluation of inhibitory potency on Aβ1-42 self-aggregation induced by AchE, and docking study
were performed for studying the mechanism of action.
Results:
Some of the synthesized compounds, compound 7b-4 ((E)-3-(3,4-dimethoxyphenyl)-N-((1-
(4-fluorobenzyl)-1H-1,2,3-triazole-4-yl) methyl) acrylamide) depicted the most potent
acetylcholinesterase inhibitory activities ( IC50 = 5.27 μM ) and compound 7a-1 (N- ( (1- benzyl-
1H- 1, 2, 3- triazole - 4-yl) methyl) cinnamamide) demonstrated the most potent
butyrylcholinesterase inhibitory activities (IC50 = 1.75 μM). Compound 7b-4 showed
neuroprotective and β-secretase (BACE1) inhibitory activitiy. In vivo studies of compound 7b-4 in
Scopolamine-induced dysfunction confirmed memory improvement.
Conculusion:
It should be noted that molecular modeling (compounds 7b-4 and 7a-1) and kinetic
studies (compounds 7a-1 and 7b-4) showed that these synthesis compounds interacted
simultaneously with both the catalytic site (CS) and peripheral anionic site (PAS) of AChE and
BuChE.
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