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

Abstract

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 (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 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.

Unveiling the binding details and esterase-like activity effect of methyl yellow on human serum albumin: spectroscopic and simulation study

“…Interestingly, when MY–Phz or MY–Ibf mixed, the values of v 0 and v max decrease, the values of K m are basically unchanged, which is a non-competitive inhibition mechanism. 64 When multiple inhibitors interact with HSA, the structure of HSA will be more flexible, which may interfere with the binding process of substrate and cause the change of inhibition mechanism. Therefore, the results can be concluded that the conformational and hydrophobic changes caused by the combination of MY and HSA will interfere with the specific environment of substrate catalytic degradation, thus affecting the expression of HSA esterase-like activity.…”

Elevated Fibrinogen Level Reduces Therapeutic Efficiency of AD Drugs: Biophysical Insights into the Interaction of FDA-Approved Cholinesterase Inhibitors with Human Fibrinogen

“…Mixed inhibition involves the binding of the inhibitor to both the native enzyme (E) and the enzyme–substrate (ES) complex following pathways A and B . Noncompetitive inhibition is a special kind of mixed inhibition observed for TAC and DON, where the inhibitor has equal affinity for both the pathways, resulting in similar magnitudes of α and α′. ,− In contrast, for ESE and HuPA, the values of α and α′ are different. Since the change in K m values (an increase of >95% in the case of both ESE and HuPA) are more significant than the change in V max values (a decrease of ∼25% for ESE and ∼15% for HuPA), the drugs have more affinity for the competitive pathway (path A ).…”

Computer Aided Drug Design Methodologies with Natural Products in the Drug Research Against Alzheimer’s Disease

“…The xanthones, in turn, are also oxygenated heterocyclic compounds that can be of natural origin (present in plants, fungi, ferns, lichens) or synthetic; however, its basic structure is dibenzo-γ-pyro or, as it is known, 9H-xanten-9-one, formed in plants by the combination of the chiquimate and acetate pathways [ 93 , 94 ]. In view of their respective molecular architectures and easy modification, coumarins, chromones and xanthones have been the target of several studies, presenting numerous pharmacological properties [ 89 , 90 , 93 , 95 ].…”

“…Baruah and Collaborators (2019) [ 95 ] motivated by the promising activity of chromones as AChE antagonists, analyzed through in silico and in vitro methods, 2 substituted chromones, one containing a methyl group and a primary amine in its chromone skeleton (7-amino-2-methylchro- mone) called of AMC, and the other containing a tertiary amine (3-cyanochromone), called CyC, as shown in Fig. ( 16 ).…”