Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation

Panek, Dawid; Więckowska, Anna; Wichur, Tomasz; Bajda, Marek; Godyń, Justyna; Jończyk, Jakub; Mika, Kamil; Janočková, Jana; Soukup, Ondřej; Knez, Damijan; Korábečný, Jan; Gobec, Stanislav; Malawska, Barbara

doi:10.1016/j.ejmech.2016.09.078

Cited by 90 publications

(38 citation statements)

References 58 publications

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“…The compounds were minimized with Smart Minimizer method using CHARMm force field in DS. The molecular docking procedure was carried out by site-features directed docking (LibDock) for the screen of potent candidates, while the investigation of receptor–ligand interactions was conducted using Discovery Studio 2.5 (DS2.5) according to previously published studies (Panek et al, 2017). The binding site of the protein was defined for all the atoms within 9 Å.…”

Section: Methodsmentioning

confidence: 99%

Docking Studies and Biological Evaluation of a Potential β-Secretase Inhibitor of 3-Hydroxyhericenone F from Hericium erinaceus

Chen

Yong²,

Yang³

et al. 2017

Front. Pharmacol.

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Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting approximately more than 5% of the population worldwide over the age 65, annually. The incidence of AD is expected to be higher in the next 10 years. AD patients experience poor prognosis and as a consequence new drugs and therapeutic strategies are required in order to improve the clinical responses and outcomes of AD. The purpose of the present study was to screen a certain number of potential compounds from herbal sources and investigate their corresponding mode of action. In the present study, the learning and memory effects of ethanol:water (8:2) extracts from Hericium erinaceus were evaluated on a dementia rat model. The model was established by intraperitoneal injection of 100 mg/kg/d D-galactose in rats. The results indicated that the extracts can significantly ameliorate the learning and memory abilities. Specific active ingredients were screened in vivo assays and the results were combined with molecular docking studies. Potential receptor–ligand interactions on the BACE1-inhibitor namely, 3-Hydroxyhericenone F (3HF) were investigated. The isolation of a limited amount of 3HF from the fruit body of H. erinaceus by chemical separation was conducted, and the mode of action of this compound was verified in NaN3-induced PC12 cells. The cell-based assays demonstrated that 3HF can significantly down-regulate the expression of BACE1 (p < 0.01), while additional AD intracellular markers namely, p-Tau and Aβ1-42 were further down-regulated (p < 0.05). The data further indicate that 3HF can ameliorate certain mitochondrial dysfunction conditions by the reversal of the decreasing level of mitochondrial respiratory chain complexes, the calcium ion levels ([Ca2+]), the inhibiton in the production of ROS, the increase in the mitochondrial membrane potential and ATP levels, and the regulation of the expression levels of the genes encoding for the p21, COX I, COX II, PARP1, and NF-κB proteins. The observations suggest the use of H. erinaceus in traditional medicine for the treatment of various neurological diseases and render 3HF as a promising naturally occurring chemical constituent for the treatment of AD via the inhibition of the β-secretase enzyme.

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Section: Methodsmentioning

confidence: 99%

Docking Studies and Biological Evaluation of a Potential β-Secretase Inhibitor of 3-Hydroxyhericenone F from Hericium erinaceus

Chen

Yong²,

Yang³

et al. 2017

Front. Pharmacol.

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“…The rational combination of features from several molecules is a very useful strategy, as shown in the development of multifunctional antioxidants against AD [622], or phthalimide and saccharide derivatives that both target Aβ production and aggregation [618]. There are recent attempts to rationally combine most of the features defined above [623], which is attractive in terms of the chemical creativeness that it illustrates, but more importantly, it is perhaps a necessary approach to treating a complex multifactorial disease such as AD.…”

Section: Gain Of Toxic Functions: Redox Toxicity the Study Of Metal-mentioning

confidence: 99%

Alzheimer’s disease: How metal ions define β-amyloid function

Kepp

2017

Coordination Chemistry Reviews

133

139

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“…Although most reported coumarin derivatives were substituted with amino group‐containing moiety on position 3 or 7 of the coumarin ring system, potent AChEIs with phenyl piperazinyl moiety substituted on position 4 of the coumarin ring were also reported . Recently, isoindoline‐1,3‐dione and related derivatives of 1‐benzylpiperazine, which were developed by our group and others, showed relatively high acetylcholinesterase inhibitory activity and the benzyl‐piperazinyl moiety was suggested to be responsible for interaction with CAS . In this study, coumarin derivatives with N ‐substituted benzylpiperazinyl moiety replaced on position 4 of the coumarin ring were designed as shown in Figure .…”

Section: Introductionmentioning

confidence: 83%

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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Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation

Cited by 90 publications

References 58 publications

Docking Studies and Biological Evaluation of a Potential β-Secretase Inhibitor of 3-Hydroxyhericenone F from Hericium erinaceus

Docking Studies and Biological Evaluation of a Potential β-Secretase Inhibitor of 3-Hydroxyhericenone F from Hericium erinaceus

Alzheimer’s disease: How metal ions define β-amyloid function

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

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