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Therapeutic potency of substituted chromones as Alzheimer’s drug: Elucidation of acetylcholinesterase inhibitory activity through spectroscopic and molecular modelling investigation
[Image: see text] Introduction: Documentation on the potency of chromones as acetylcholinesterase (AChE) antagonists has paved the way for the design and usage of new chromone analogues as inhibitors of AChE modelled on the hypothesis based on cholinergic pathway of Alzheimer’s disease (AD). Here, 2...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Tabriz University of Medical Sciences
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637216/ https://www.ncbi.nlm.nih.gov/pubmed/31334039 http://dx.doi.org/10.15171/bi.2019.11 |
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author | Baruah, Prayasee Rohman, Mostofa Ataur Yesylevskyy, Semen O. Mitra, Sivaprasad |
author_facet | Baruah, Prayasee Rohman, Mostofa Ataur Yesylevskyy, Semen O. Mitra, Sivaprasad |
author_sort | Baruah, Prayasee |
collection | PubMed |
description | [Image: see text] Introduction: Documentation on the potency of chromones as acetylcholinesterase (AChE) antagonists has paved the way for the design and usage of new chromone analogues as inhibitors of AChE modelled on the hypothesis based on cholinergic pathway of Alzheimer’s disease (AD). Here, 2 minimally substituted chromones, namely 3-cyanochromone (CyC) and 7-amino-3- methylchromone (AMC), were checked for their AChE inhibition efficacies and plasma protein modulation. Methods: Colorimetric enzymatic assay as well as fluorescence measurements were performed for obtaining the experimental results, which were further corroborated by molecular docking and simulation studies. Results: The investigated systems exhibited strong inhibition activities against AChE, with CyC (IC(50)= 85.12 ± 6.70 nM) acting as better inhibitor than AMC (IC(50) = 103.09 ± 11.90 nM) and both having IC50 values in the range of FDA approved cholinergic drug Donepezil (IC(50) = 74.13 ± 8.30 nM). Non-competitive inhibition was observed in both the cases with the inhibitors binding near the peripheral anionic site (PAS) of the enzyme. Having one planar nitrile group in CyC as compared to sp3 hybridised substituents in AMC facilitated stacking interactions in the former, accounting for its higher inhibitory efficacy. A significant decrease in the inhibition potency of CyC (~32%) was noted in comparison with AMC (~5%) when the experiments were performed in presence of human serum albumin (HSA) instead of pure aqueous buffer. Conclusion: This comparative study affirms the importance of meticulous substitution in the chromone scaffold to promote maximum inhibition potency, while considering their usage as AD drugs. |
format | Online Article Text |
id | pubmed-6637216 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Tabriz University of Medical Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-66372162019-07-22 Therapeutic potency of substituted chromones as Alzheimer’s drug: Elucidation of acetylcholinesterase inhibitory activity through spectroscopic and molecular modelling investigation Baruah, Prayasee Rohman, Mostofa Ataur Yesylevskyy, Semen O. Mitra, Sivaprasad Bioimpacts Original Research [Image: see text] Introduction: Documentation on the potency of chromones as acetylcholinesterase (AChE) antagonists has paved the way for the design and usage of new chromone analogues as inhibitors of AChE modelled on the hypothesis based on cholinergic pathway of Alzheimer’s disease (AD). Here, 2 minimally substituted chromones, namely 3-cyanochromone (CyC) and 7-amino-3- methylchromone (AMC), were checked for their AChE inhibition efficacies and plasma protein modulation. Methods: Colorimetric enzymatic assay as well as fluorescence measurements were performed for obtaining the experimental results, which were further corroborated by molecular docking and simulation studies. Results: The investigated systems exhibited strong inhibition activities against AChE, with CyC (IC(50)= 85.12 ± 6.70 nM) acting as better inhibitor than AMC (IC(50) = 103.09 ± 11.90 nM) and both having IC50 values in the range of FDA approved cholinergic drug Donepezil (IC(50) = 74.13 ± 8.30 nM). Non-competitive inhibition was observed in both the cases with the inhibitors binding near the peripheral anionic site (PAS) of the enzyme. Having one planar nitrile group in CyC as compared to sp3 hybridised substituents in AMC facilitated stacking interactions in the former, accounting for its higher inhibitory efficacy. A significant decrease in the inhibition potency of CyC (~32%) was noted in comparison with AMC (~5%) when the experiments were performed in presence of human serum albumin (HSA) instead of pure aqueous buffer. Conclusion: This comparative study affirms the importance of meticulous substitution in the chromone scaffold to promote maximum inhibition potency, while considering their usage as AD drugs. Tabriz University of Medical Sciences 2019 2019-03-08 /pmc/articles/PMC6637216/ /pubmed/31334039 http://dx.doi.org/10.15171/bi.2019.11 Text en © 2019 The Author(s) This work is published by BioImpacts as an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/). Non-commercial uses of the work are permitted, provided the original work is properly cited. |
spellingShingle | Original Research Baruah, Prayasee Rohman, Mostofa Ataur Yesylevskyy, Semen O. Mitra, Sivaprasad Therapeutic potency of substituted chromones as Alzheimer’s drug: Elucidation of acetylcholinesterase inhibitory activity through spectroscopic and molecular modelling investigation |
title | Therapeutic potency of substituted chromones as Alzheimer’s drug: Elucidation of acetylcholinesterase inhibitory activity through spectroscopic and molecular modelling investigation |
title_full | Therapeutic potency of substituted chromones as Alzheimer’s drug: Elucidation of acetylcholinesterase inhibitory activity through spectroscopic and molecular modelling investigation |
title_fullStr | Therapeutic potency of substituted chromones as Alzheimer’s drug: Elucidation of acetylcholinesterase inhibitory activity through spectroscopic and molecular modelling investigation |
title_full_unstemmed | Therapeutic potency of substituted chromones as Alzheimer’s drug: Elucidation of acetylcholinesterase inhibitory activity through spectroscopic and molecular modelling investigation |
title_short | Therapeutic potency of substituted chromones as Alzheimer’s drug: Elucidation of acetylcholinesterase inhibitory activity through spectroscopic and molecular modelling investigation |
title_sort | therapeutic potency of substituted chromones as alzheimer’s drug: elucidation of acetylcholinesterase inhibitory activity through spectroscopic and molecular modelling investigation |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637216/ https://www.ncbi.nlm.nih.gov/pubmed/31334039 http://dx.doi.org/10.15171/bi.2019.11 |
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