Flavonols and 4-thioflavonols as potential acetylcholinesterase and butyrylcholinesterase inhibitors: Synthesis, structure-activity relationship and molecular docking studies (original) (raw)
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World Journal of Advanced Research and Reviews, 2021
The main aim of this study is to identify inhibitory binding potent of the available commercially alkaloids, against the crystal structure of acetylcholinesterase (AChE) protein by in silico studies. The inhibitory data of the compounds should be compared with the internal ligand as well as standard AChE inhibitor Aricept (which is used for the treatment of all stages of Alzheimer's disease). AutoDock 4.0 is used for the docking study, conformational orientation site analysis, and, with the help of docking, we have calculated parameters like binding energy and inhibition constant. Docking's study showed that Glabridin, Isorosmanol, Quercetin, Honokiol, Eckol, Sargaquinoic acid, and Ginsedosides revealed strong binding affinity with the enzyme. Moreover, The ADMET profiling and physicochemical properties of the selected compounds are evaluated using the Molinspiration and Data warrior software. By showing a strong binding affinity value, positive bioactivity score, and good pharmacokinetic properties, the top compound was determined. After evaluation with all parameters, the compound Glabridin and Ginsedosides show the most potent inhibitory effect towards the acetylcholinesterase, so this compound could be used as a novel is required to treat Alzheimer's disease.
2021
The main aim of this study is to identify inhibitory binding potent of the available commercially alkaloids, against the crystal structure of acetylcholinesterase (AChE) protein by in silico studies. The inhibitory data of the compounds should be compared with the internal ligand as well as standard AChE inhibitor Aricept (which is used for the treatment of all stages of Alzheimer’s disease). AutoDock 4.0 is used for the docking study, conformational orientation site analysis, and, with the help of docking, we have calculated parameters like binding energy and inhibition constant. Docking's study showed that Glabridin, Isorosmanol, Quercetin, Honokiol, Eckol, Sargaquinoic acid, and Ginsedosides revealed strong binding affinity with the enzyme. Moreover, The ADMET profiling and physicochemical properties of the selected compounds are evaluated using the Molinspiration and Data warrior software. By showing a strong binding affinity value, positive bioactivity score, and good pharm...
Medicinal Chemistry Research, 2019
The binding interactions between acetylcholinesterase (AChE) and a series of antioxidant flavonoid analogs were studied by fluorescence spectroscopic assay. The present study incorporated different classes of naturally occurring and synthetic flavonoid compounds like flavones, isoflavones, and chalcones as well as a few standard antioxidants. The AChE inhibitory (AChEI) activity of these compounds was further analyzed using in silico techniques, namely pharmacophore mapping, quantitative structure-activity relationship (QSAR) analysis, and molecular docking studies. We have also compared the AChE inhibitory and radical scavenging antioxidant activities of these compounds. Both the AChE inhibitory and antioxidant activities of these compounds were found to be highly dependent on their structural patterns. However, it was observed that, in general, flavones are comparatively better AChE inhibitors as well as antioxidants compared to chalcones.
Prediction of Anti-Alzheimer's Activity of Flavonoids Targeting Acetylcholinesterase in silico
Phytochemical Analysis, 2017
Prediction of anti-Alzheimer's activity of flavonoids targeting acetylcholinesterase in silico http://researchonline.ljmu.ac.uk/id/eprint/5218/ Article LJMU has developed LJMU Research Online for users to access the research output of the University more effectively. and Talukdar, AD (2017) Prediction of anti-Alzheimer's activity of flavonoids targeting acetylcholinesterase in silico. Phytochemical Analysis, 28 (4). pp. 324-331.
European Journal of Medicinal Chemistry, 2011
On the pattern of the potent and selective butyrylcholinesterase (BChE) inhibitors ethopropazine and Astra1397, sets of quinolizidinyl derivatives of bi-and tricyclic (hetero)aromatic systems were studied as dual, or BChE-selective inhibitors. All compounds exhibited activity against both cholinesterases, but inhibition of BChE was generally stronger, with submicromolar IC 50 values for most of them (e.g. 15: IC 50 versus BChE ¼ 0.15 mM; SI ¼ 47). However, in a subset of quinolizidinyl derivatives of 6-hydroxycoumarin an inverted selectivity for acetylcholinesterase (AChE) was observed (e.g. 46: IC 50 versus AChE ¼ 0.35 mM; SI ¼ 0.06). Docking studies furnished a sound interpretation of the observed different enzyme activity. Several of the studied compounds have shown, in the past, additional pharmacological properties (as antagonism on presynaptic muscarinic autoreceptor; inhibition of enkephaline aminopeptidase and antipsychotic activity) of some relevance in Alzheimer's disease, and may, therefore, represent hits for the development of interesting single-entity multi-target drugs.
Chemico-Biological Interactions, 2009
Flavonoids are one of the largest classes of plant secondary metabolites and are known to possess a number of significant biological activities for human health. In this study, we examined in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of four flavonoid derivatives -quercetin, rutin, kaempferol 3-O--d-galactoside and macluraxanthone. The in vitro results showed that quercetin and macluraxanthone displayed a concentration-dependant inhibition of AChE and BChE. Macluraxanthone showed to be the most potent and specific inhibitor of both the enzymes having the IC 50 values of 8.47 and 29.8 M, respectively. The enzyme kinetic studies revealed that quercetin inhibited both the enzymes in competitive manner, whereas the mode of inhibition of macluraxanthone was noncompetitive against AChE and competitive against BChE. The inhibitory profiles of the compounds have been compared with standard AChE inhibitor galanthamine. To get insight of the intermolecular interactions, the molecular docking studies of these two compounds were performed at the active site 3D space of both the enzymes, using ICM-Dock TM module. Docking studies exhibited that macluraxanthone binds much more tightly with both the enzymes than quercetin. The calculated docking and binding energies also supported the in vitro inhibitory profiles (IC 50 values). Both the compounds showed several strong hydrogen bonds to several important amino acid residues of both the enzymes. A number of hydrophobic interactions could also explain the potency of the compounds to inhibit AChE and BChE.
Proposing novel natural compounds against Alzheimer’s disease targeting acetylcholinesterase
PLOS ONE
Alzheimer’s disease (AD) is a neurodegenerative disorder considered as a global public health threat influencing many people. Despite the concerning rise in the affected population, there is still a shortage of potent and safe therapeutic agents. The aim of this research is to discover novel natural source molecules with high therapeutic effects, stability and less toxicity for the treatment of AD, specifically targeting acetylcholinesterase (AChE). This research can be divided into two steps: in silico search for molecules by systematic simulations and in vitro experimental validations. We identified five leading compounds, namely Queuine, Etoperidone, Thiamine, Ademetionine and Tetrahydrofolic acid by screening natural molecule database, conducting molecular docking and druggability evaluations. Stability of the complexes were investigated by Molecular Dynamics simulations and free energy calculations were conducted by Molecular Mechanics Generalized Born Surface Area method. All ...
Journal of Biomolecular Structure and Dynamics, 2020
In this protocol, a series of 3-benzyloxyflavone derivatives have been designed, synthesized, characterized and investigated in vitro as cholinesterase inhibitors. The findings showed that all the synthesized target compounds (1-10) are potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes with varying IC 50 values. In comparison, they are more active against AChE than BChE. Remarkably, amongst the series, the compound 2 was identified as the most active inhibitor of both AChE (IC 50 ¼ 0.05 ± 0.01 lM) and BChE (IC 50 ¼ 0.09 ± 0.02 lM) relative to the standard Donepezil (IC 50 ¼ 0.09 ± 0.01 for AChE and 0.13 ± 0.04 lM for BChE). Moreover, the derivatives 5 (IC 50 ¼ 0.07 ± 0.02 lM) and 10 (0.08 ± 0.02 lM) exhibited the highest selective inhibition against AChE as compared to the standard. Preliminary structure-activity relationship was established and thus found that cholinesterase inhibitory activities of these compounds are highly dependent on the nature and position of various substituents on Ring-B of the 3-Benzyloxyflavone scaffolds. In order to find out the nature of binding interactions of the compounds and active sites of the enzymes, molecular docking studies were carried out. HIGHLIGHTS 1. 3-benzyloxyflavone analogues were designed, synthesized and characterized. 2. The target molecules (1-10) were evaluated for their inhibitory potential against AChE and BChE inhibitory activities. 3. Limited structure-activity relationship was developed based on the different substituent patterns on aryl part. 4. Molecular docking studies were conducted to correlate the in vitro results and to identify possible mode of interactions at the active pocket site of the enzyme.
Screening of various phenolic acids and flavonoid derivatives for their anticholinesterase potential
Zeitschrift Fur Naturforschung C Journal of Biosciences, 2007
Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disease characterized by progressive cognitive deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioural changes. The oldest, on which most currently available drug therapies are based, is known as the "cholinergic hypothesis" and suggests that AD begins as a deficiency in the production of the neurotransmitter acetylcholine. Therefore, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors have gained a great popularity for the treatment of AD. In this study, we screened in vitro inhibitory activities of a number of phenolic acids (chlorogenic, caffeic, gallic, and quinic acids) as well as of various flavonoid derivatives (genistein, biochanin A, naringin, apigenin, quercetin, luteolin-7-O-rutinoside, kaempferol-3-O-galactoside, diosmin, silibinin, and silymarin) against AChE and BChE at 1 mg/ml concentration using a microplate-reader assay based on the Ellman method. Among them, only quercetin showed a substantial inhibition (76.2%) against AChE, while genistein (65.7%), luteolin-7-O-rutinoside (54.9%), and silibinin (51.4%) exerted a moderate inhibition on BChE.
Molecules, 2020
Acetylcholinesterase (AChE) and β-secretase (BACE-1) have become attractive therapeutic targets for Alzheimer’s disease (AD). Flavones are flavonoid derivatives with various bioactive effects, including AChE and BACE-1 inhibition. In the present work, a series of 14 flavone derivatives was synthesized in relatively high yields (35–85%). Six of the synthetic flavones (B4, B5, B6, B8, D6 and D7) had completely new structures. The AChE and BACE-1 inhibitory activities were tested, giving pIC50 3.47–4.59 (AChE) and 4.15–5.80 (BACE-1). Three compounds (B3, D5 and D6) exhibited the highest biological effects on both AChE and BACE-1. A molecular docking investigation was conducted to explain the experimental results. These molecules could be employed for further studies to discover new structures with dual action on both AChE and BACE-1 that could serve as novel therapies for AD.