Discovery of New 1,3,4-Oxadiazoles with Dual Activity Targeting the Cholinergic Pathway as Effective Anti-Alzheimer Agents
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Finding an effective anti-Alzheimer agent is quite challenging due to its multifactorial nature. As such, multitarget directed ligands (MTDLs) could be a promising paradigm for finding potential therapeutically effective new small-molecule bioactive agents against Alzheimer's disease (AD). We herein present the design, synthesis, and biological evaluation of a new series of compounds based on a 5-pyrid-3-yl-1,3,4-oxadiazole scaffold. Our synthesized compounds displayed excellent in vitro enzyme inhibitory activity at nanomolar (nM) concentrations against two major AD disease-modifying targets, i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among our compounds, 5e was considered the best dual inhibitor of both AChE (IC50 = 50.87 nM) and BuChE (IC50 = 4.77 nM), where these values surpassed those of rivastagmine (the only FDA-approved dual AChE and BuChE inhibitor) in our study. Furthermore, in vivo and ex vivo testing of the hit compound 5e highlighted its significant AD-biotargeting effects including reducing the elevated levels of lipid peroxidation and glutathione (GSH), normalizing levels of 8-OHdG, and, most importantly, decreasing the levels of the well-known AD hallmark β-amyloid protein. Finally, the binding ability of 5e to each of our targets, AChE and BuChE, was confirmed through additional molecular docking and molecular dynamics (MD) simulations that reflected good interactions of 5e to the active site of both targets. Hence, we herein present a series of new 1,3,4-oxadiazoles that are promising leads for the development of dual-acting AChE and BuChE inhibitors for the management of AD.Keywords:
Butyrylcholinesterase
IC50
Docking (animal)
Antlion is used in traditional medicine by natives of the southern part of Nigeria particularly the Yorubas for memory enhancement. The progress made so far in the use of this organism as a memory booster lead to investigating the acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) (the key enzymes in the pathogenesis of Alzheimer's disease) inhibitory activities of methanolic and phosphate buffered saline (PBS) extracts. The activities of these enzymes were investigated using Ellman’s method. The kinetics of the inhibition patterns was also studied using eserine as the standard inhibitor. The concentration of the extract required for 50% inhibition (IC50) of the AChE was 49.00 ± 1.20 and 271.40 ± 0.10 µg/mL, for the PBS and methanolic extracts respectively, compared to Eserine with IC50 of 2.25 x 10-2 ± 0.15 x 10-2 µg/mL. Similarly, the IC50 for the BuChE was 66.30 ± 0.40 and 216.70 ± 1.10 µg/mL respectively, for the methanol and PBS extracts, compared to Eserine with IC50 of 1.10 ± 0.30 µg/mL. The pattern of inhibition of the BuChE in the presence of the extracts was non-competitive, while AChE exhibited non-competitive and competitive inhibitions for the methanolic and PBS extracts respectively. It is therefore evident that extracts of the antlion larvae contained cholinesterase inhibitors which might be binding to AChE and BuChE; with the PBS extract inhibitory activity towards AChE being more potent than the methanolic extract. Suggesting a beneficial effect in cognitive deficit and related dementia associated with Alzheimer’s disease.
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Cholinesterase
IC50
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Butyrylcholinesterase
Cholinesterase
Galantamine
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Butyrylcholinesterase
Chagas Disease
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Butyrylcholinesterase
IC50
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Objective To investigate the activities of two cholinesterases,plasma acetylcholinesterase(AChE)and butyrylcholinesterase(BuChE)of the patients with Alzheimer's disease(AD)and the normal aged and to explore the significance of their activities in pathogenesis of AD and the clinical diagnosis value.Methods The activities of plasma AChE and BuChE from 29 AD patients and 33 age-matched normal people were detected by Ellman's colorimetric methods.Results The level of plasma AChE activity(1.39±0.57)nmol·min-1·ml-1 in AD patients was significantly lower than that in normal controls(2.16±0.86)nmol·min-1·ml-1(P0.001);while there was no significant difference in plasma BuChE activity between AD patients and normal controls(P0.05);there were not any differences in the levels of both ChE activities between male and female or among different age groups(P0.05).Conclusions Plasma AChE activity in AD patients are significantly lower than that in normal aged,this decrease has no relation to gender and age.Plasma ChE activity could serve as an index of auxiliary diagnosis.
Butyrylcholinesterase
Cholinesterase
Pathogenesis
Plasma levels
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A series of C4-substituted tertiary nitrogen-bearing 2'-hydroxychalcones were designed and synthesised based on a previous mixed type acetylcholinesterase inhibitor. Majority of the 2'-hydroxychalcone analogues displayed a better inhibition against acetylcholinesterase (AChE) than butyrylcholinesterase (BuChE). Among them, compound 4c was identified as the most potent AChE inhibitor (IC50: 3.3 µM) and showed the highest selectivity for AChE over BuChE (ratio >30:1). Molecular docking studies suggested that compound 4c interacts with both the peripheral anionic site (PAS) and catalytic anionic site (CAS) regions of AChE. ADMET analysis confirmed the therapeutic potential of compound 4c based on its blood-brain barrier penetrating. Overall, the results suggest that this 2'-hydroxychalcone deserves further investigation into the therapeutic lead for Alzheimer's disease (AD).
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Acetylcholinesterase inhibitor
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Acetylcholinesterase (AChE) inhibitors are widely used as a drug for the symptomatic treatment of Alzheimer's disease (AD). BuChE appears to be a very important new therapeutic target. Especially as the activity of BuChE increases with the higher stage of the AD, while the activity of AChE decreases [1]. Herbal extracts seem to be a significant source of new potential AChE and butyrylcholinesterase (BuChE) inhibitors, like galantamine isolated from the bulbs of daffodils. Recent data have shown that Angelica sp. and coumarins are able to inhibit the activity of acetylcholinesterase, but their potency was not very strong. On the other hand, there is no much information about the effects of those groups of compounds on butyrylcholinesterase activity.
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