Donepezil + chromone + melatonin hybrids as promising agents for Alzheimer’s disease therapy

Pachón-Angona, Irène; Refouvelet, Bernard; Andrýs, Rudolf; Martin, Hélène; Luzet, Vincent; Iriepa, Isabel; Moraleda, Ignacio; Diez‐Iriepa, Daniel; Oset-Gasque, María Jesús; Marco‐Contelles, José; Musílek, Kamil; Ismaïli, Lhassane

doi:10.1080/14756366.2018.1545766

Cited by 48 publications

(27 citation statements)

References 51 publications

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“…L-monoamine oxidases (MAOs) (EC 1.4.3.4) catalyse the oxidation of monoamines (76,77). Recently, a donepezil-chromone-melatonin hybrid has been developed as a multi-target agent with strong BChE and moderate hAChE inhibitory capacities, and with anti-MAO-A/B and antioxidant properties (78). Furthermore, tacrine-acridine hybrids have been developed as multi-target drugs for the treatment of AD (79).…”

Section: Hybrid Inhibitorsmentioning

confidence: 99%

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Cholinesterase inhibitors as Alzheimer's therapeutics (Review)

Sharma

2019

Mol Med Report

370

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Alzheimer's disease (AD) is one of the most common forms of dementia. AD is a chronic syndrome of the central nervous system that causes a decline in cognitive function and language ability. Cholinergic deficiency is associated with AD, and various cholinesterase inhibitors have been developed for the treatment of AD, including naturally-derived inhibitors, synthetic analogues and hybrids. Currently, the available drugs for AD are predominantly cholinesterase inhibitors. However, the efficacy of these drugs is limited as they may cause adverse side effects and are not able to completely arrest the progression of the disease. Since AD is multifactorial disease, dual and multi-target inhibitors have been developed. The clinical applications and the limitations of the inhibitors used to treat AD are discussed in the present review. Additionally, this review presents the current status and future directions for the development of novel drugs with reduced toxicity and preserved pharmacological activity.

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Section: Hybrid Inhibitorsmentioning

confidence: 99%

“…In addition, these compounds are able to limit the progression of AD. Recent reports investigated AChE inhibition (80,88,90), but only a few novel drugs have been tested in humans (18,60–62,78). Most of these inhibitors have been studied in animal models, or using in vitro and in silico models.…”

Section: Future Directionsmentioning

confidence: 99%

Cholinesterase inhibitors as Alzheimer's therapeutics (Review)

Sharma

2019

Mol Med Report

370

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“…Briefly, the reaction happens in a final volume of 3 mL of a 0.1 M phosphate-buffered solution at pH = 8.0, containing 5,5′-dithiobis-2-nitrobenzoic acid, EeAChE or eqBuChE, tested compound and bovine albumin serum phosphate-buffered (pH = 8) solution After this pre-incubation period, acetylthiocholine iodide or butyrylthiocholine iodide was added, allowing 15 min of additional incubation time. For IC 50 , inhibition curves were built by pre-incubating this blend at room temperature with nine concentrations of each compound for 10 min [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

Angona¹,

Martin²,

Daniel³

et al. 2020

IJMS

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We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca+2 channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl 2,6-dimethyl-4-(4-((5-aminoalkyl)oxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate 3a-p, have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL 3h [dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] as an attractive inhibitor of AChE (1.8 μM) and BuChE (2 μM), Ca+2 channel antagonist (47.72% at 10 μM), and antioxidant (2.54 TE) agent, showing significant neuroprotection 28.68% and 38.29% against H2O2, and O/R, respectively, at 0.3 μM, thus being considered a hit-compound for further investigation in our search for anti-Alzheimer’s disease agents.

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“…Some of the current treatments for AD are designed to increase the ability of biological systems to detoxify the reactive intermediates and repair the damage caused by them (18,19). Antioxidants offer a promising approach toward neuroprotection by Aβexposure (20,21). Of these groups, pelargonidin-3-o-galactoside (pg3g) shows protective activities in diabetic neuropathic hyperalgesia and Hemi-parkinsonism (22,23).…”

Section: Introductionmentioning

confidence: 99%

Pelargonidin exhibits restoring effects against amyloid β-induced deficits in the hippocampus of male rats

Asl

Bergen

Ashtari

et al. 2019

Med. J. Islam. Republ. Iran

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Background: Alzheimer's disease (AD) is characterized by amyloid-beta plaques, neuronal loss, and cognitive dysfunction. Oxidative stress plays a key role in the pathophysiology of AD, and it has been suggested that antioxidants may slow the progress of the disease. In this study, the possible protective effects of pelargonidin (a natural flavonoid) against amyloid β (Aβ)-induced behavioral deficits was investigated in rats. Methods: Adult Wistar male rats were treated with intrahippocampal injections of the Aβ (aa 25-35) and intraperitoneal injection of pelargonidin. Learning and spatial memory were tested using the Morris water maze (MWM) task. The antioxidant activity was evaluated using the ferric reducing/antioxidant power assay (FRAP assay). Data were analyzed using SPSS 20, and value of p≤0.05 was considered significant. Results: The results of this study showed that Aβ significantly increased escape latency and the distance traveled in the MWM, and pelargonidin attenuated these behavioral changes. Aβ induced a significant decrease in the total thiol content of hippocampus, and pelargonidin restored the hippocampal antioxidant capacity. Conclusion: The results of this study suggest that pelargonidin can improve Aβ-induced behavioral changes in rats.

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Donepezil + chromone + melatonin hybrids as promising agents for Alzheimer’s disease therapy

Cited by 48 publications

References 51 publications

Cholinesterase inhibitors as Alzheimer's therapeutics (Review)

Cholinesterase inhibitors as Alzheimer's therapeutics (Review)

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

Pelargonidin exhibits restoring effects against amyloid β-induced deficits in the hippocampus of male rats

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