Synthesis of 2‐(2‐oxo‐2H‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions

Abstract

Sixteen novel coumarin-based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC 50 0.04 ± 0.01 µM), noncompetitively inhibited AChE with a higher potency than tacrine and galantamine.Compounds 5d, 5j, and 5 m showed a moderate antilipid peroxidation activity. The compounds showed cytotoxicity in the same range as the standard drugs in HEK-293 cells. Molecular docking demonstrated that 5a acted as a dual binding site inhibitor. The coumarin moiety occupied the peripheral anionic site and showed π-π interaction with Trp278. The tertiary amino group displayed significant cation-π interaction with Phe329.The aromatic group showed π-π interaction with Trp83 at the catalytic anionic site. The long chain of methylene lay along the gorge interacting with Phe330 via hydrophobic interaction. Molecular docking was applied to postulate the selectivity toward AChE of 5a in comparison with donepezil and tacrine. Structural insights into the selectivity of the coumarin derivatives toward huAChE were explored by molecular docking and 3D QSAR and molecular dynamics simulation for 20 ns. ADMET analysis suggested that the 2-(2oxo-2H-chromen-4-yl)acetamides showed a good pharmacokinetic profile and no hepatotoxicity. These coumarin derivatives showed high potential for further development as anti-Alzheimer agents. K E Y W O R D S 3D QSAR, acetylcholinesterase inhibitor, coumarin, lipid peroxidation, molecular docking 1 | INTRODUCTION Alzheimerʼs disease (AD) is the most common form of dementia. The symptoms start with difficulty in remembering new information and recent events, followed by apathy, depression, subsequent impaired judgment, confusion, and behavior change. Etiology of AD is complicated and still unclear. β-Amyloid aggregation and neurofibrillary tangles are major abnormalities found in the brain of patients with AD, which eventually lead to neuronal damage. This results in the decrease of acetylcholine (ACh), the neurotransmitter responsible for memory and learning. Acetylcholinesterase inhibitors (AChEIs), such as tacrine, donepezil, galantamine, and rivastigmine, Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Kara J, Suwanhom P, Wattanapiromsakul C, et al. Synthesis of 2-(2-oxo-2Hchromen-4-yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions.

Aminoalkoxy‐substituted coumarins: Synthesis and evaluation for reactivation of inhibited human acetylcholinesterase

“…The dual binding site design reported in this study started from the coumarin motif, which constitutes a privileged and versatile scaffold for bioactive compounds, [14][15][16][17] in particular for the assembly of inhibitors of AChE, where coumarins are known to bind to the peripheral site mainly by π-π interactions. [18][19][20][21][22][23][24][25][26][27] To discover further bases capable of efficient dephosphylation, we replaced the imidazole or pyridine functional groups of reported nonoxime reactivators with nonaromatic primary or secondary amines, which we attached through alkoxy-linkers of various lengths at position 6 and 7 of the coumarin ring system. The resulting primary amines 1-6 (Table 1) contained a linear, amino acid-like substructure, whereas the secondary amines in compounds 7-11 were mostly cyclic, that is, derived from piperidine or pyrrolidine.…”

Novel synthesis of 3-(Phenyl) (ethylamino) methyl)-4-hydroxy-2H-chromen-2-one derivatives using biogenic ZnO nanoparticles and their applications

“…Also, the number of H-bond acceptors ranges from 2-5 for synthesized compounds that are less than 10, and the number of H-bond donors for all synthesized compounds is 2 and thus, less than 5 as per the rule. According to the Lipinski (Pfizer's rule) of five for any chemical compound, as an oral drug would be biologically active if it does not violate more than one rule out of the proposed rules wherein, the first rule said, the octanol-water partition coefficient (milogP) must be ≤5; the second rule said, the molecular weight of the probable drug must be <500 Daltons; the third rule said, taking into consideration of the number of H-bond acceptors in the molecule under consideration must be ≤10 and the last rule said, the number of H-bond donors must be ≤5 [32,33]. Table 9 disclosed bioactivity results, showing that the parameters of all the synthesized compounds were within limits of Lipinski's rule of five with no violation of rules.…”

Design, Synthesis, Molecular Docking, and Cholinesterase Inhibitory Potential of Phthalimide‐Dithiocarbamate Hybrids as New Agents for Treatment of Alzheimer's Disease

“…Recent studies showed that activity of BuChE in the brain of AD patients with the progression of the AD increased while AChE activity in these patients declines. Therefore, inhibition of both types of ACh degrading enzymes may be beneficial in AD treatment …”

“…Therefore, inhibition of both types of ACh degrading enzymes may be beneficial in AD treatment. [7] The phthalimide is a bicyclic heterocyclic scaffold and its derivatives have diverse range of biologically activities such as anti-inflammatory, anticonvulsant, hypolipidemic, analgesic, and immunomodulatory activities. [8 -13] Recently, several derivatives of phthalimide with high inhibitory activity against AChE have been reported ( Figure 1A and B).…”