Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents

Shaik, Jeelan Basha; Palaka, Bhagath Kumar; Penumala, Mohan; Kotapati, Kasi Viswanath; Devineni, Subba Rao; Eadlapalli, Siddhartha; Darla, Mark Manidhar; Ampasala, Dinakara Rao; Vadde, Ramakrishna; Damu, Amooru G.

doi:10.1016/j.ejmech.2015.10.046

Cited by 67 publications

(34 citation statements)

References 45 publications

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“…Preliminarily, the preparation was preprocessed to assign bond orders to all bonds, add hygrogens to all atoms, creat disulfide bonds within 3.2 Å, cap termini to fill up ACE (N-acetyl) and NMA (N-methyl amide) and delete all unrelated waters [28]. Hydrogen bonding network and the orientation of Asn, Gln and His residues were optimized with H-bond assignment section [29]. A restraint minimization of the protein structure was performed with the root mean square deviation (RMSD) regulated to 0.5 and the force field set to Optimize Potentials for Liquid Simulations 2005 (OPLS_2005) [30, 31].…”

Section: Methodsmentioning

confidence: 99%

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

et al. 2017

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Peroxisome proliferators-activated receptors (PPARα, γ and δ) are potentially effective targets for Type 2 diabetes mellitus therapy. The severe effects of known glitazones and the successfully approved agents (saroglitazar and lobeglitazone) motivated us to study novelly potent PPARs drugs with improved safety profile. In this work, we received 15 carboxylic acids based on the combination principle to integrate the polar head of bezafibrate with the hydrophobic tail of pioglitazone. Another 12 tetrazoles based on the bioisosterism principle were obtained accordingly. Furthermore, in vitro PPARs transactivation assays on these 3- or 4-alkoxy substituted phenoxy derivatives afforded six compounds. Interactions and binding stability from the docking analysis and 20 ns molecular dynamic simulations confirmed the representative compounds to be suitable and plausible for PPARs pockets. The above-mentioned results demonstrated that the compounds may be used as reference for further optimization for enhanced PPARs activities and wide safety range.

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Section: Methodsmentioning

confidence: 99%

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

et al. 2017

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“…The coumarin ring has been of high interest as a scaffold for design of several potent AChEIs . In previous studies, coumarin moiety showed affinity to the PAS of AChE due to its aromatic character that facilitates the π‐π interaction with the amino acid residues in the region.…”

Section: Introductionmentioning

confidence: 99%

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

Kara

Suwanhom

Wattanapiromsakul

et al. 2019

Archiv der Pharmazie

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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.

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“…Alzheimer's disease (AD) is a dreadful neurodegenerative disorder affecting over 35 million people worldwide and is expected to reach 66 million by 2030 . It is characterized by the loss of brain functions, cognition, and memory through progressive degeneration of central nervous system (CNS) neurons . The etiology of AD is not yet fully understood, but common hallmarks, such as intracellular tau‐protein aggregation, extracellular beta‐amyloid plaques, the selective loss of cholinergic neurons, and increased oxidative stress are considered as key pathological features…”

Section: Introductionmentioning

confidence: 99%

“…Based on the pathological features of AD, different hypotheses have been developed. One of them is the cholinergic hypothesis defined by the decline of acetylcholine (ACh) in some parts of the brain such as hippocampus and cortex . In order to elevate ACh levels that are lowered by acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the CNS, inhibition of the cholinesterases is the main purpose.…”

Section: Introductionmentioning

confidence: 99%

Multifunctional cholinesterase inhibitors for Alzheimer's disease: Synthesis, biological evaluations, and docking studies of o/p‐propoxyphenylsubstituted‐1H‐benzimidazole derivatives

Sarıkaya

Çoban

Parlar

et al. 2018

Archiv der Pharmazie

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This study indicates the synthesis, cholinesterase (ChE) inhibitory activity, and molecular modeling studies of 48 compounds as o- and p-(3-substitutedethoxyphenyl)-1H-benzimidazole derivatives. According to the ChE inhibitor activity results, generally, para series are more active against acetylcholinesterase (AChE) whereas ortho series are more active against butyrylcholinesterase (BuChE). The most active compounds against AChE and BuChE are compounds A12 and B14 with IC values of 0.14 and 0.22 μM, respectively. Additionally, the most active 16 compounds against AChE/BuChE were chosen to investigate the neuroprotective effects, and the results indicated that most of the compounds have free radical scavenging properties and show their effects by reducing free radical production; moreover, some of the compounds significantly increased the viability of SH-SY5Y cells exposed to H O . Overall, compounds A12 and B14 with potential AChE and BuChE inhibitory activities, high neuroprotection against H O -induced toxicity, free radical scavenging properties, and metal chelating abilities may be considered as lead molecules for the development of multi-target-directed ligands against Alzheimer's disease.

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Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents

Cited by 67 publications

References 45 publications

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

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

Multifunctional cholinesterase inhibitors for Alzheimer's disease: Synthesis, biological evaluations, and docking studies of o/p‐propoxyphenylsubstituted‐1H‐benzimidazole derivatives

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