A novel series of cinnamic acid–tryptamine hybrids was designed, synthesized, and evaluated as cholinesterase inhibitors. Anticholinesterase assays showed that all of the synthesized compounds displayed a clearly selective inhibition of butyrylcholinesterase (BChE), but only a moderate inhibitory effect toward acetylcholinesterase (AChE) was detected. Among these cinnamic acid–tryptamine hybrids, compound 7d was found to be the most potent inhibitor of BChE with an IC50 value of 0.55 ± 0.04 μM. This compound showed a 14‐fold higher inhibitory potency than the standard drug donepezil (IC50 = 7.79 ± 0.81 μM) and inhibited BChE through a mixed‐type inhibition mode. Moreover, a docking study revealed that compound 7d binds to both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of BChE. Also, compound 7d was evaluated against β‐secretase, which exhibited low activity (inhibition percentage: 38%).
Background:
Acetylcholine deficiency in hippocampus and cortex, aggregation of amyloid beta, and beta-secretase over activity have been introduced as main reasons in formation of Alzheimer’s disease.
Objective:
A new series of cinnamic derived acids linked to 1-benzyl-1,2,3-triazole moiety have been designed, synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities.
Method:
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.
:
With regard to importance of quinazoline as privileged scaffold, here in we report the synthesis of twenty seven 2,4-disubstitute quinazoline derivatives in a new catalyst free condition. In current work, poly ethylene glycol (PEG1000) as an inexpensive, very simple commercially available, ecofriendly and low melting point solvent was used. Air bubbling, a green oxidant, for oxidation purpose was also used. This is the first report about using PEG1000 as solvent simultaneously with air bubbling as oxidant in quinazoline synthesis. All of the compounds 1-27 were synthesized in high yield with very simple work up and purification process without using column chromatography. All structures were confirmed using 1H NMR, 13C NMR, IR, MS and elemental analysis.
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