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BMC Chemistry Apr 2024In this article, we present the design and synthesis of amino-7,8-dihydro-4H-chromenone derivatives as possible inhibitors of acetylcholinesterase (AChE) and...
Amino-7,8-dihydro-4H-chromenone derivatives as potential inhibitors of acetylcholinesterase and butyrylcholinesterase for Alzheimer's disease management; in vitro and in silico study.
In this article, we present the design and synthesis of amino-7,8-dihydro-4H-chromenone derivatives as possible inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for the management of Alzheimer's disease (AD). The target compounds were evaluated against AChE and BChE in vitro, and 4k exhibited good potency against BChE (IC = 0.65 ± 0.13 µM) compared with donepezil used as a positive control. Kinetic studies revealed that compound 4k exhibited a competitive-type inhibition with a K value of 0.55 µM. Molecular docking and molecular dynamics simulations further supported the rationality of our design strategy, as 4k showed promising binding interactions with the active sites of BChE. Overall, our findings highlight the potential of amino-7,8-dihydro-4H-chromenone derivatives as promising candidates for developing novel therapeutics targeting cholinesterase in managing AD.
PubMed: 38600537
DOI: 10.1186/s13065-024-01170-x -
RSC Advances Apr 2024Alzheimer is an irreversible progressive neurodegenerative disease that causes failure of cerebral neurons and disability of the affected person to practice normal daily... (Review)
Review
Alzheimer is an irreversible progressive neurodegenerative disease that causes failure of cerebral neurons and disability of the affected person to practice normal daily life activities. There is no concrete evidence to identify the exact reason behind the disease, so several relevant hypotheses emerged, highlighting many possible therapeutic targets, such as acetylcholinesterase, cholinergic receptors, -methyl d-aspartate receptors, phosphodiesterase, amyloid β protein, protein phosphatase 2A, glycogen synthase kinase-3 beta, β-secretase, γ-secretase, α-secretase, serotonergic receptors, glutaminyl cyclase, tumor necrosis factor-α, γ-aminobutyric acid receptors, and mitochondria. All of these targets have been involved in the design of new potential drugs. An extensive number of these drugs have been studied in clinical trials. However, only galantamine, donepezil, and rivastigmine (ChEIs), memantine (NMDA antagonist), and aducanumab and lecanemab (selective anti-Aβ monoclonal antibodies) have been approved for AD treatment. Many drugs failed in the clinical trials to such an extent that questions have been posed about the significance of some of the aforementioned targets. On the contrary, the data of other drugs were promising and shed light on the significance of their targets for the development of new potent anti-alzheimer drugs.
PubMed: 38586442
DOI: 10.1039/d3ra08333k -
European Review For Medical and... Mar 2024Alzheimer's disease (AD) is identified by neuropathological symptoms, and there is now no effective treatment for the condition. A lack of the brain neurotransmitter...
OBJECTIVE
Alzheimer's disease (AD) is identified by neuropathological symptoms, and there is now no effective treatment for the condition. A lack of the brain neurotransmitter acetylcholine has been related to the etiology of Alzheimer's disease. Acetylcholinesterase is an enzyme that breaks down acetylcholine to an inactive form and causes the death of cholinergic neurons. Conventional treatments were used but had less effectiveness. Therefore, there is a crucial need to identify alternative compounds with potential anti-cholinesterase agents and minimal undesirable effects.
MATERIALS AND METHODS
Fluoroquinolones and benzimidazole-benzothiazole derivatives offer antimicrobial, anti-inflammatory, anti-oxidant, anti-diabetic, and anti-Alzheimer activities. To enhance the chemical portfolio of cholinesterase inhibitors, a variety of fluoroquinolones and benzimidazole-benzothiazole compounds were evaluated against acetylcholinesterase (AChE) butyrylcholinesterase (BChE) enzymes. For this purpose, molecular docking and adsorption, distribution, metabolism, excretion, and toxicology ADMET models were used for in-silico studies for both AChE and BChE enzymes to investigate possible binding mechanisms and drug-likeness of the compounds. The inhibitory effect of docked heterocyclic compounds was also verified in vitro against AChE and BChE enzymes. Fluoroquinolones (Z, Z3, Z4, Z6, Z8, Z12, Z15, and Z9) and benzimidazole-benzothiazole compounds (TBIS-16, TBAF-1 to 9) passed through the AChE inhibition assay and their IC50 values were calculated.
RESULTS
The compound 1-ethyl-6-fluoro-7-(4-(2-(4-nitrophenylamino)-2-oxoethyl)piperazin-1-yl) -4-oxo-1,4 di-hydroquinoline-3-carboxylic acid and 2-((1H-benzo[d]imidazol-2-yl)methyl)-N'-(3-bromobenzyl)-4-hydroxy-2H-thiochromene-3-carbohydrazide 1,1-dioxide (Z-9 and TBAF-6) showed the lowest IC50 values against AChE/BChE (0.37±0.02/2.93±0.03 µM and 0.638±0.001/1.31±0.01 µM, respectively) than the standard drug, donepezil (3.9±0.01/4.9±0.05 µM). During the in-vivo investigation, behavioral trials were performed to analyze the neuroprotective impact of Z-9 and TBAF-6 compounds on AD mouse models. The groups treated with Z-9 and TBAF-6 compounds had better cognitive behavior than the standard drug.
CONCLUSIONS
This study found that Z-9 (Fluoroquinolones) and TBAF-6 (benzimidazole-benzothiazole) compounds improve behavioral and biochemical parameters, thus treating neurodegenerative disorders effectively.
Topics: Mice; Animals; Cholinesterase Inhibitors; Acetylcholinesterase; Butyrylcholinesterase; Alzheimer Disease; Acetylcholine; Molecular Docking Simulation; Benzothiazoles; Benzimidazoles; Fluoroquinolones; Structure-Activity Relationship
PubMed: 38567612
DOI: 10.26355/eurrev_202403_35759 -
The Journal of International Medical... Mar 2024To systematically evaluate the efficacy and safety of butylphthalide combined with donepezil versus butylphthalide monotherapy for the treatment of vascular dementia. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To systematically evaluate the efficacy and safety of butylphthalide combined with donepezil versus butylphthalide monotherapy for the treatment of vascular dementia.
METHODS
Randomized controlled trials were searched in electronic databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database (VIP), Wan Fang, and China Biology Medicine from inception to 29 November 2022. Two reviewers independently screened the papers and extracted data from the included studies. The data were processed using RevMan5.4 statistical software.
RESULTS
Nine randomized controlled trials (n = 1024) were included in this meta-analysis. Regarding the primary outcomes, compared with butylphthalide monotherapy, combined butylphthalide and donepezil treatment exhibited significantly greater total clinical efficacy (relative risk = 1.24, 95% confidence interval [1.17, 1.31]) and did not increase the adverse event rate (relative risk = 1.39, 95% confidence interval [0.91, 2.14]). Regarding the secondary outcomes, the meta-analysis results for the Mini-Mental State Examination, abilities of daily living, and Montreal Cognitive Assessment scores and the interleukin-6, tumor necrosis factor-α, and superoxide dismutase blood levels all supported combined butylphthalide and donepezil treatment.
CONCLUSION
Butylphthalide combined with donepezil may be a better treatment strategy than donepezil alone for the treatment of vascular dementia in clinical practice.
Topics: Humans; Benzofurans; Dementia, Vascular; Donepezil; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 38546241
DOI: 10.1177/03000605231223081 -
Frontiers in Immunology 2024(AS) can improve sleep, enhance memory, and reduce fatigue and is considered as an effective drug for Alzheimer's disease (AD). The therapeutic effect and mechanism...
BACKGROUND
(AS) can improve sleep, enhance memory, and reduce fatigue and is considered as an effective drug for Alzheimer's disease (AD). The therapeutic effect and mechanism need to be further investigated.
METHODS
To confirm the AS play efficacy in alleviating memory impairment in mice, 5×FAD transgenic mice were subjected to an open-field experiment and a novelty recognition experiment. Network pharmacology technique was used to analyze the information of key compounds and potential key targets of AS for the treatment of AD, molecular docking technique was applied to predict the binding ability of targets and compounds, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were also performed on the targets to derive the possible metabolic processes and pathway mechanisms of AS in treating AD. Quantitative real-time PCR (qRT-PCR) and western blot technique were carried out to validate the candidate genes and pathways.
RESULTS
In the open-field experiment, compared with the wild-type (WT) group, the number of times the mice in the AD group crossed the central zone was significantly reduced (< 0.01). Compared with the AD group, the number of times the mice in the AS group crossed the central zone was significantly increased (< 0.001). In the new object recognition experiment, compared with the WT group, the percentage of times the AD group explored new objects was significantly reduced (< 0.05). Compared with the AD group, the AS group had an increase in the percentage of time spent exploring new things and the number of times it was explored (< 0.05). At the same time, the donepezil group had a significantly higher percentage of times exploring new things (< 0.01). By using network pharmacology technology, 395 common targets of AS and AD were retrieved. The Cytoscape software was used to construct the protein-protein interaction (PPI) network of common targets. Using the algorithm, nine key targets were retrieved: APP, NTRK1, ESR1, CFTR, CSNK2A1, EGFR, ESR2, GSK3B, and PAK1. The results of molecular docking indicate that 11 pairs of compounds and their corresponding targets have a significant binding ability, as the molecular binding energies were less than -7.0. In comparison to the AD group, the mRNA expression of the key target genes was significantly decreased in the AS treatment group (< 0.001). The KEGG analysis showed that the MAPK signaling pathway was significantly enriched, and Western blot confirmed that the TRAF6 protein decreased significantly (< 0.0001). Meanwhile, the levels of MAP3K7 and P38 phosphorylation increased, and there was also an increase in the expression of HSP27 proteins.
CONCLUSION
Our study indicates that the multi-component and multi-target properties of AS play an important role in the alleviation of anxiety and memory impairment caused by AD, and the mechanism is involved in the phosphorylation and activation of the MAPK signaling pathway. The results of this study could provide a novel perspective for the clinical treatment of AD.
Topics: Animals; Mice; Phosphorylation; Eleutherococcus; Alzheimer Disease; Molecular Docking Simulation; Signal Transduction; Cognitive Dysfunction
PubMed: 38545117
DOI: 10.3389/fimmu.2024.1383464 -
Sensors (Basel, Switzerland) Mar 2024Environmental screening is essential due to the increased occurrence of harmful substances in the environment. Open Meter Duo (OMD) is an open-source field...
Environmental screening is essential due to the increased occurrence of harmful substances in the environment. Open Meter Duo (OMD) is an open-source field photo/fluorimeter that uses an RGB diode that imitates a color according to the selected wavelength and uses a UV LED from the security kit diode as an excitation light source. The prepared PCB shield with a 3D-printed aperture was connected to Arduino UNO R4 WiFi. This system was used for the fluorescent detection of cholinesterase activity with the indoxyl acetate method. Carbofuran-a toxic pesticide-and donepezil-a drug used to treat Alzheimer's disease-were tested as model inhibitors of cholinesterase activity. The limit of detection of indoxyl acetate was 11.6 μmol/L, and the IC50 values of the inhibitors were evaluated. This system is optimized for wireless use in field analysis with added cloud support and power source. The time of analysis was 5 min for the fluorimetric assay and 20 min for the optional photometric assay. The time of field operation was approximately 4 h of continuous measurement. This system is ready to be used as a cheap and easy control platform for portable use in drug control and point-of-care testing.
Topics: Humans; Fluorometry; Donepezil; Alzheimer Disease; Cholinesterases; Cholinesterase Inhibitors
PubMed: 38544037
DOI: 10.3390/s24061774 -
Pharmaceuticals (Basel, Switzerland) Mar 2024Alzheimer's disease (AD) is the most common type of dementia and a significant concern to global public health due to the prevalence of aging populations. Donepezil is...
Alzheimer's disease (AD) is the most common type of dementia and a significant concern to global public health due to the prevalence of aging populations. Donepezil is one of only a few medications approved for use as an anti-AD agent but all have adverse side effects. Reducing the dosage of AD drugs with plant extracts (phytotherapy) while maintaining efficacy is one strategy to minimize adverse side effects. We previously reported the anti-AD properties of an edible fern, (Retz.) Sw. (DE), which inhibited key enzymes involved in AD pathogenesis including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase 1 (BACE-1). This study aimed to determine whether DE exhibited a synergistic effect with donepezil. The enzyme inhibitory assay showed that DE extract and its bioactive compounds, kaempferol, and quercetin, slightly impeded AChE inhibition with donepezil, while DE extract and quercetin showed synergistic or additive effects with donepezil against BChE and BACE-1, respectively. DE extract combined with donepezil also improved eye phenotypes in a model of AD by preventing ommatidia atrophia and bristle breakages. Furthermore, the DE extract exhibited no genotoxic activities, as determined by the Ames test. Our data revealed that DE extract showed promise when combined with donepezil during AD treatment by targeting BChE and BACE-1.
PubMed: 38543127
DOI: 10.3390/ph17030341 -
European Journal of Pharmacology May 2024Chronic treatment with acetylcholinesterase inhibitors may be a promising therapeutic strategy for treatment of cardiovascular diseases. The aim of our study was to...
Changes in cardiovascular autonomic control induced by chronic inhibition of acetylcholinesterase during pyridostigmine or donepezil treatment of spontaneously hypertensive rats.
Chronic treatment with acetylcholinesterase inhibitors may be a promising therapeutic strategy for treatment of cardiovascular diseases. The aim of our study was to analyze the changes in blood pressure (BP) and heart rate (HR) during 14 days of treatment with two different acetylcholinesterase inhibitors - pyridostigmine (PYR) having only peripheral effects or donepezil (DON) with both peripheral and central effects. In addition, we studied their effects on the cardiovascular response to restraint stress and on sympathovagal control of HR in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). SHR were characterized by elevated BP and increased low-frequency component of systolic BP variability (LF-SBPV), but their cardiac vagal tone and HR variability (HRV) were reduced compared with WKY. Chronic treatment with either acetylcholinesterase inhibitor decreased HR and increased HRV in both strains. PYR treatment slightly decreased BP and LF-SBPV in the dark phase of the day. Neither drug significantly altered BP response to stress, but PYR attenuated HR increase during restraint stress. Regarding sympathovagal balance, acute methylatropine administration caused a greater increase of HR in WKY than in SHR. Chronic PYR or DON treatment enhanced HRV and HR response to methylatropine (vagal tone) in WKY, whereas PYR but not DON treatment potentiated HRV and vagal tone in SHR. In conclusion, vagal tone was lower in SHR compared with WKY, but was enhanced by chronic PYR treatment in both strains. Thus, chronic peripheral, but not central, acetylcholinesterase inhibition has major effects on HR and its variability in both normotensive and hypertensive rats.
Topics: Rats; Animals; Rats, Inbred SHR; Pyridostigmine Bromide; Acetylcholinesterase; Cholinesterase Inhibitors; Donepezil; Rats, Inbred WKY; Hypertension; Blood Pressure; Heart Rate; Atropine Derivatives
PubMed: 38537804
DOI: 10.1016/j.ejphar.2024.176526 -
Journal of Functional Biomaterials Feb 2024Nanoporous membranes (NPMBs) have been the focus of interest of many scientists in the last decade. However, the fouling phenomenon that takes place during the...
Nanoporous membranes (NPMBs) have been the focus of interest of many scientists in the last decade. However, the fouling phenomenon that takes place during the implantation period blocks pores and causes failure in the local implant. In this study, alumina NPMBs were developed using electrochemical anodization through two steps. Furthermore, graphene oxide (GO), free and impregnated with ZIF-8 MOF, was synthesized and loaded in a mixture of PVDF/PVP polymer matrix at different ratios, and was applied to the produced NPMBs using spin-coater. The NPMBs were characterized before and after coating by SEM/EDX, TEM, FTIR, XRD, contact angle and AFM. The antifouling features of the NPMBs were analyzed against two different bacterial species. The prepared alumina NPMBs demonstrated homogeneous porous structures with pore sizes ranging from 36 to 39 nm. The coated layers were proven to possess microporous coatings on the surfaces of the NPMBs. The numbers of released ions (Al and Zn) from the coated NPMBs were below the allowed limits. Bovine serum albumin (BSA) uptake in artificial cerebrospinal fluid (ACSF) was impressively reduced with the presence of coating materials. In addition, the antifouling behavior of the coated NPMBs against the selected strains of bacteria was greatly enhanced compared with the pure alumina NPMBs. Finally, NPMBs' uncoated and polymer-coated membranes were tested for their ability to deliver donepezil HCl. The results reveal the downregulation of donepezil release, especially from NPMBs coated with PVDF/PVP 0.5GO. It is advised to use the current antifouling materials and techniques to overcome the limitations of the inorganic NPMBs implants.
PubMed: 38535243
DOI: 10.3390/jfb15030050 -
Journal of Medical Case Reports Mar 2024Trials of cholinergic and glutamatergic agents have improved cognition and memory for the geriatric schizophrenic population. Donepezil is an acetylcholinesterase... (Review)
Review
BACKGROUND
Trials of cholinergic and glutamatergic agents have improved cognition and memory for the geriatric schizophrenic population. Donepezil is an acetylcholinesterase inhibitor that improves cognition by preventing postsynaptic degradation of hippocampal acetylcholine in patients with mild-to-moderate dementia. Donepezil has been attributed to some adverse effects, especially gastrointestinal symptoms. However, cardiovascular adverse effects are not common as there remains a dearth of literature regarding donepezil-induced bradycardia.
CASE REPORT
Hence, we present the case of a 70-year-old Hispanic female with past psychiatry history of schizophrenia who developed bradycardia and syncope following the commencement of low-dose donepezil in the inpatient unit and subsequent resolution with cessation. She had no prior cardiovascular symptoms or diagnosis.
DISCUSSION
Considering there is no baseline cardiac monitoring requirement guideline for patients on Donepezil treatment, pre-assessment electrocardiogram is advised before the commencement of acetylcholinesterase inhibitors. Finally, routine monitoring of vital signs for at least the first 72 hours following the start of donepezil might be good proactive practice for all psychiatrists. Extending this practice to inpatient and outpatient service settings will be worthwhile.
Topics: Aged; Female; Humans; Bradycardia; Cholinesterase Inhibitors; Donepezil; Neurocognitive Disorders; Schizophrenia
PubMed: 38532522
DOI: 10.1186/s13256-024-04454-x