Novel coumarin derivatives as potent acetylcholinesterase inhibitors: insight into efficacy, mode and site of inhibition

Abstract

The inhibitory efficacy of two substituted coumarin derivatives on the activity of neurodegenerative enzyme acetylcholinesterase (AChE) was assessed in aqueous buffer as well as in the presence of human serum albumin (HSA) and compared against standard cholinergic AD drug, Donepezil (DON). The experimental data revealed the inhibition to be of non-competitive type with both the systems showing substantial inhibitory activity on AChE. In fact, one of the tested compounds Chromenyl Coumarate (CC) was found to be better inhibitor (IC = 48.49 ± 5.6 nM) than the reference drug DON (IC = 74.13 ± 8.3 nM), unequivocally amplifying its importance. The structure of the compound was found to play a vital role in the inhibitory efficiency, validating previous Structure Activity Relationship (SAR) reviews for coumarin. The mechanism of inhibition remained impervious when the experimental medium was switched from aqueous buffer to HSA, albeit noticeable change in the inhibition potency of the compound 3, 3'- Methylene-bis (4-hydroxy coumarin) (MHC) (38%) and CC (35%). Both the coumarin derivatives were observed to bind to the peripheral anionic site (PAS) of AChE and also found to displace the fluorescence marker thioflavinT (ThT) from AChE binding pocket. All experimental observations were seconded by molecular docking and MD simulation results. The inferences drawn in this study form a foundation for further investigation on these compounds; magnifying the probability of their usage as AD drugs and re-emphasizes the significance of drug delivery media while considering the inhibition potencies of targeted drugs.

Effects of Coumarinyl Schiff Bases against Phytopathogenic Fungi, the Soil-Beneficial Bacteria and Entomopathogenic Nematodes: Deeper Insight into the Mechanism of Action

“…Additionally, van der Waals interactions were noted between compound 9 and residues ILE-275, ASP-276 and ILE-287. The involvement of the mentioned residues from the AS, AP, and PAS was confirmed to contribute stability to the complex between AChE and synthetic inhibitors such as coumarin-triazole-amino acid hybrids [ 55 ], tyrosol 1,2,3-triazole analogs [ 56 ], coumarin-3-carboxamide-N-morpholine hybrids [ 57 ], chromone derivatives [ 28 ], and chromenyl coumarate [ 58 ].…”

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

“…The estimated IC­ 50 values indicate that both the chromones showed inhibitory efficiency akin to the reference drug DON. However, experiments on 2 coumarin derivatives reported elsewhere 59 revealed that replacement of the coumarin moiety with chromones results in a loss of inhibitory efficiency. Similar observation has already been reported in several SAR reviews and it is well-known that coumarin derivatives normally show better inhibition potency toward AChE activity in comparison with their chromone counterparts.…”

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 ).…”