scholarly journals Merged Tacrine-Based, Multitarget-Directed Acetylcholinesterase Inhibitors 2015–Present: Synthesis and Biological Activity

2020 ◽  
Vol 21 (17) ◽  
pp. 5965
Author(s):  
Todd J. Eckroat ◽  
Danielle L. Manross ◽  
Seth C. Cowan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Activity ◽  
Enzyme Inhibitor ◽  
Acetylcholinesterase Inhibitor ◽  
Acetylcholinesterase Inhibitors ◽  
New Drugs ◽  
Acetylcholinesterase Inhibition ◽  
Future Research ◽  
Starting Point

Acetylcholinesterase is an important biochemical enzyme in that it controls acetylcholine-mediated neuronal transmission in the central nervous system, contains a unique structure with two binding sites connected by a gorge region, and it has historically been the main pharmacological target for treatment of Alzheimer’s disease. Given the large projected increase in Alzheimer’s disease cases in the coming decades and its complex, multifactorial nature, new drugs that target multiple aspects of the disease at once are needed. Tacrine, the first acetylcholinesterase inhibitor used clinically but withdrawn due to hepatotoxicity concerns, remains an important starting point in research for the development of multitarget-directed acetylcholinesterase inhibitors. This review highlights tacrine-based, multitarget-directed acetylcholinesterase inhibitors published in the literature since 2015 with a specific focus on merged compounds (i.e., compounds where tacrine and a second pharmacophore show significant overlap in structure). The synthesis of these compounds from readily available starting materials is discussed, along with acetylcholinesterase inhibition data, relative to tacrine, and structure activity relationships. Where applicable, molecular modeling, to elucidate key enzyme-inhibitor interactions, and secondary biological activity is highlighted. Of the numerous compounds identified, there is a subset with promising preliminary screening results, which should inspire further development and future research in this field.

Identification of Human Acetylcholinesterase Inhibitors from the Constituents of EGb761 by Modeling Docking and Molecular Dynamics Simulations

2018 ◽  
Vol 21 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Lihu Zhang ◽  
Dongdong Li ◽  
Fuliang Cao ◽  
Wei Xiao ◽  
Linguo Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Serine Proteases ◽  
Colorimetric Method ◽  
Acetylcholinesterase Inhibitors ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Ache Inhibitors ◽  
Starting Point

Aim and Objective: EGb761, a standardized and well-defined product extract of Ginkgo biloba leaves, has beneficial role in the treatment of multiple diseases, particularly Alzheimer's disease (AD). Identification of natural acetylcholinesterase (AChE) inhibitors from EGb761 would provide a novel therapeutic approach against the Alzheimer's disease. Material and Method: A series of 21 kinds of promising EGb761 compounds were selected, and subsequently evaluated for their potential ability to bind AChE enzyme by molecular docking and a deep analysis of protein surface pocket features. Results: Docking results indicated that these compounds can bind tightly with the active site of human AChE, with favorable distinct interactions around several important residues Asp74, Leu289, Phe295, Ser293, Tyr341, Trp286 and Val294 in the active pocket. Most EGB761 compounds could form the hydrogen bond interactions with the negatively charged Asp74 and Phe295 residues. Among these compounds, diosmetin is the one with the best-predicted docking score while three key hydrogen bonds can be formed between small molecule and corresponding residues of the binding site. Besides, other three compounds luteolin, apigenin, and isorhamnetin have better predicted docking scores towards AChE than other serine proteases, i.e Elastase, Tryptase, Factor XA, exhibiting specificity for AChE inhibition. The RMSD and MM-GBSA results from molecular dymamic simulations indicated that the docking pose of diosmetin-AChE complex displayed highly stable, which can be used for validating the accuracy of molecular docking study. Subsequently, the AChE inhibitory activities of these compounds were evaluated by the Ellman's colorimetric method. Conclusion: The obtained results revealed that all the four compounds exhibited modest AChE inhibitory activity, among which Diosmetin manifested remarkable anti-AChE activity, comparable with the reference compound, Physostigmine. It can be deduced that these EGB761 compounds can be regarded as a promising starting point for developing AChE inhibitors against AD.

Xanthone: Potential Acetylcholinesterase Inhibitor for Alzheimer's Disease Treatment

2021 ◽  
Vol 21 ◽  
Author(s):  
Vincentsia Vienna Vanessa ◽  
Siau Hui Mah
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Acetylcholinesterase Inhibitor ◽  
Structure Activity Relationship ◽  
Acetylcholinesterase Inhibition ◽  
Activity Relationship ◽  
Structure Activity ◽  
Hydrophobic Moiety

: Alzheimer's disease is a neurodegenerative disorder that results in progressive and irreversible central nervous system impairment, which has become one of the severe issues recently. The most successful approach of Alzheimer’s treatment is the administration of cholinesterase inhibitors to prevent the hydrolysis of acetylcholine and subsequently improve the cholinergic postsynaptic transmission. This review highlights a class of heterocycle, namely xanthone and its remarkable acetylcholinesterase inhibitory activities. Naturally occurring xanthones, including oxygenated, prenylated, pyrano and glycosylated xanthones exhibited promising inhibition effects towards acetylcholinesterase. Interestingly, synthetic xanthone derivatives with complex substituents such as alkyl, pyrrolidine, piperidine and morpholine have shown greater acetylcholinesterase inhibition activities. Structure-activity relationship of xanthones revealed that the type and position of substituent(s) attached to the xanthone moiety influenced their acetylcholinesterase inhibition activities where hydrophobic moiety will lead to an improved activity by contributing the π-π interactions, as well as the hydroxy substituent(s) by forming hydrogen-bond interactions. Thus, further studies including quantitative structure-activity relationship, in vivo and clinical validation studies are crucial for the development of xanthones into novel anti-Alzheimer's disease drugs.

scholarly journals Essential Oil of Lippia origanoides H.B.K.: A Promising Compound Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease

2021 ◽  
Author(s):  
Aldenora Maria Ximenes Rodrigues ◽  
Brenda Nayranne Gomes dos Santos ◽  
Ranyelison Silva Machado ◽  
Rubens Renato de Sousa Carmo ◽  
Matheus Pedrosa de Oliveira ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Essential Oil ◽  
In Silico ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
New Drugs ◽  
Gas Chromatography Mass Spectrometry ◽  
Low Toxicity

Alzheimer's disease is characterized by a progressive decline of cognitive functions. The class of drugs used for the treatment are acetylcholinesterase inhibitors. Essential oils have contributed to folk medicine and discovery of new drugs for a long time. The purpose of the study was to investigate the in vitro and in silico the anti-acetylcholinesterase activity, as well as acute toxicity of the essential oil of Lippia origanoides. EOLO was obtained by hydrostelting and analyzed by gas chromatography-mass spectrometry. The inhibition assay of acetylcholinesterase enzyme activity was evaluated in vitro, as well as in silico by docking. The effects of EOLO on hematological, biochemical and behavioral parameters were analyzed in mices. We expose that EOLO shows good anti-acetylcholinesterase activity and low toxicity, possibly resulting from the action of the majority compounds thymol, carvacrol and p-cymene. The anti-acetylcholinesterase potential in vitro demonstrating a 70% inhibition. The docking results elucidated the participation of the major phenolics in AChE inhibition by interacting with the catalytic cavity of AchE. The acute oral toxicity test classified as low toxicity. These results contribute to expand the knowledge about essential oil of Lippia origanoides. Therefore, appears to be promising for herbal medicine production with anti-acetylcholinesterase and antioxidant activity.

Recent Advances in the Synthesis of Tacrine Derivatives as Multifunctional Agents for Alzheimer's Disease

2021 ◽  
Vol 25 ◽  
Author(s):  
Ikram Baba Ahmed ◽  
Zahira Kibou ◽  
Noureddine Choukchou-Braham
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Acetylcholinesterase Inhibitors ◽  
Ring Structure ◽  
New Drugs ◽  
Important Place ◽  
Structural Modifications ◽  
Current Trends ◽  
Tricyclic Compound ◽  
Multifunctional Agents

: Alzheimer's is a neurodegenerative pathology. The first therapeutic strategy for treating AD was mainly acetylcholinesterase inhibitors (AChEIs). One of them is Tacrine, a linear tricyclic compound that occupies an important place in treating this disease with its pharmacophore properties. In this regard, the development of tacrine-analogs more efficient and safe with new measures and investigations has drawn immense attention. Various structural modifications of Tacrine have been carried out on different parts. Mainly some change in the ring structure of Tacrine or by connecting the amino group with different hybrids based on natural or synthetic compounds and drugs already in existence. These tacrine congeners have considerable potential for developing new drugs for the treatment of Alzheimer's disease. Therefore, this review presents an overview of the essential structural modifications in tacrine rings based on the current trends reported in recent decades towards using natural products and synthetic analogs as a source of new anti-Alzheimer drugs.

Beyond Acetylcholinesterase Inhibitors: Novel Cholinergic Treatments for Alzheimer’s Disease

2017 ◽  
Vol 14 (4) ◽  
pp. 377-392 ◽  
Author(s):  
Asante R. Kamkwalala ◽  
Paul A. Newhouse
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Performance ◽  
Basal Forebrain ◽  
Cholinergic System ◽  
Acetylcholinesterase Inhibitor ◽  
Muscarinic Acetylcholine Receptors ◽  
Acetylcholinesterase Inhibition ◽  
Receptor System ◽  
Limited Effectiveness

The major components of the cholinergic receptor system of the human brain include projections from the basal forebrain nuclei, and utilize the two types of receptors that they synapse on, nicotinic and muscarinic acetylcholine receptors. With the widespread cortical and subcortical projections of the basal forebrain, activity of these two receptor systems provide modulation of neurotransmitter activity underlying normal cognitive processes, such as attention, episodic memory, and working memory. Alzheimer’s disease (AD) targets and damages cholinergic neurons in the basal forebrain, and as these projections are lost, cognitive performance progressively declines. Currently, the most widely prescribed treatment for AD is acetylcholinesterase inhibitor medications, which work by partially blocking the degradation of acetylcholine in the synapse and enabling more of the neurotransmitter to reach and activate cholinergic receptors. However since these medications have limited effectiveness, alternate treatments that focus on augmenting the activity of the receptors themselves, independent of acetylcholinesterase inhibition, are being explored. This review will discuss: 1) the role of the cholinergic system in modulating cognition, 2) novel cholinergic treatment strategies for AD-related cognitive decline, in particular treatments intended to increase cholinergic system activity by selectively targeting muscarinic and nicotinic acetylcholinergic receptors to improve cognitive performance, 3) risks, and additional considerations for cholinergic cognitive treatments for AD.

scholarly journals Neuroprotective Strategies Using Vegetal Compounds in the Treatment of Alzheimer’s Disease

2015 ◽  
Vol 45 ◽  
pp. 56-62
Author(s):  
Loredana Sandu ◽  
Alin Ciobica ◽  
Radu Lefter ◽  
Daniel Timofte ◽  
Emil Anton
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Research Effort ◽  
Treatment Options ◽  
Therapeutic Strategies ◽  
New Drugs ◽  
Simultaneous Application ◽  
Starting Point ◽  
Neuroprotective Strategies ◽  
Therapy Strategies

Lately, different therapy strategies for treating or slowing the progression of Alzheimer's disease are being analyzed. Moreover, the last two decades have seen a considerable research effort directed towards discovering the causes of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. In addition to the therapeutic strategies based on targeted drugs, the regimens will require the simultaneous application of neuroprotective drugs. Therefore, although there is currently no "cure" for Alzheimer's disease, a large number of potential therapeutic strategies emerged lately. In this small mini-review we will selectively describe some of the compounds derived from plants that could have a great potential in the treatment of various diseases, including Alzheimer's disease. In this way, there are many plant species that have been traditionally used for memory disorders. The differentiated results and powerful activity of these extracts are making these neuroprotective strategies to be somehow plausible for the treatment of Alzheimer's disease. In addition, these plants can be examined in order to isolate and identify their active ingredients and this can serve as a starting point to find safer and more effective agents for therapeutic use. On thing is certain: as the effective treatment options are limited, there is a demand for new drugs. Thus, plant extracts or vegetal compounds could represent an important part in this equation.

scholarly journals IN SILICO STUDY OF ACETYLCHOLINESTERASE INHIBITION IN ALZHEIMER'S DISEASE USING CHEMICAL CONSTITUENTS OF CANNABIS

2020 ◽  
Author(s):  
Roxanne Vasquez ◽  
Teobaldo Cuya
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Chemical Constituents ◽  
Acetylcholinesterase Inhibitor ◽  
Memory Loss ◽  
Acetylcholinesterase Inhibition ◽  
Chemical Derivatives ◽  
In Silico Study ◽  
Derivatives Of

In recent years, studies have shown that some chemical derivatives of the cannabis plant help in the prevention and treatment of neurological diseases. Alzheimer's disease (AD) is a progressive form of dementia, which there is no cure. Therefore, its pharmacological treatment is crucial as it can help reduce the symptoms such as memory loss. Due to the limited choices of drug treatments for AD, this research will be using 9 chemical derivatives of the Cannabis plant as potential drug alternative. There is reduced levels of acetylcholine (ACh) neurotransmitter with AD patients, due to its hydrolysis carried out by the enzyme acetylcholinesterase (AChE). Thus, the focus of this in silico study will be if these 9 substances have the capacity to act as a human enzyme acetylcholinesterase inhibitor (HssAChE). Results shows that at least one Cannabis compound “Cannabicyclol” have a comparable binding energy to the commercial drug Donepezil. Moreover, the results gives insights about the what are the relevant residues in the binding process and the potential therapeutic properties of the cannabis compounds relating to the AD treatment.

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

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