Bioimpacts. 2019;9(2):85-96.
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Original Research

Therapeutic potency of substituted chromones as Alzheimer’s drug: Elucidation of acetylcholinesterase inhibition activity through spectroscopic and molecular modelling investigation

Abstract

Introduction: Documentation on the potency of chromones as acetylcholinesterase (AChE) antagonists has paved the way for designing and usage of novel chromone derivatives as AChE inhibitors modelled on the cholinergic hypothesis of Alzheimer’s disease (AD). Here, two 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 was 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 (IC50= 85.12 ± 6.70 nM) acting as better inhibitor than AMC (IC50 = 103.09 ± 11.90 nM) and both having IC50 values in the range of FDA approved cholinergic drug Donepezil (IC50 = 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 AChE. Having a 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 experimental medium was switched from buffer to human serum albumin (HSA) matrix.

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.

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Submitted: 21 Aug 2018
Revised: 13 Nov 2018
Accepted: 17 Nov 2018
First published online: 08 Mar 2019
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