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(A) Lineweaver-Burk plot for the inhibition of eeAChE(A) and eqBChE (B) by compound 8i at different concentrations of substrate. (B) Lineweaver-Burk plot for the inhibition of eeAChE (C) and eqBChE (D) by compound 10s at different concentrations of substrate.
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A series of novel compounds 6a-h, 8i-1, 10s-v, and 16a-d were synthesized and evaluated, together with the known analogs 11a-f, for their inhibitory activities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The inhibitory activities of AChE and BChE were evaluated in vitro by Ellman method. The results show that some compound...
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Context 1
... each case, the kinetic types of enzyme inhibition were obtained by the modified Ellman's method and the Lineweaver-Burk secondary plots [35]. The Lineweaver-Burk plots showed both increasing slope (decreased Vmax) and increasing intercept (higher Km) for higher inhibitor concentrations, indicating a mixed-type inhibition, including competitive inhibition and non-competitive inhibition, which possibly was because compound 8i could bind to both CAS and PAS ( Figure 3A,B). According to the result of molecular docking study. ...
Citations
... Nghiên cứu cấu trúc của AChE đã chỉ ra rằng trung tâm hoạt động của enzym rộng khoảng 5 Å và sâu 20 Å tính từ bề mặt của enzym [5]. Cấu trúc enzym này đã tạo ra hai vị trí gắn cơ chất riêng biệt trên AChE, đó là vùng trung tâm hoạt động (CAS) nằm ở "đáy" kênh enzym và vùng ngoại vi hay vùng trung tâm dị lập thể (PAS) nằm ở "miệng" kênh enzym [6]. Các chất ức chế AChE được FDA phê duyệt đều có các liên kết với các amino acid tại vùng PAS và/hoặc CAS của AChE [7]. ...
Tetrazole derivatives are a prominent class of heterocycles that hold significant value in medicinal chemistry and drug design. Their importance stems from their bioisosteric resemblance to carboxylic acid and amide moieties and their favorable metabolic stability and other beneficial physicochemical properties. In light of this, novel derivatives bearing the (pyridine-2-yl)tetrazol scaffold were synthesized with the presence of acid, ester and amide moieties and evaluated for their inhibitory effects on the enzyme acetylcholinesterase (AChE). Through a three-step synthesis reaction initiated with 2-pyridine carbonitrile, compound IV was successfully obtained with II and III as the intermediates. All substances II - III - IV demonstrated inhibitory activity against the enzyme acetylcholinesterase. Notably, substance IV exhibited the highest percentage of inhibition, achieving 23,7 % at a concentration of 75 µM. Based on molecular docking simulations, compounds containing stronger nucleophilic substituents exhibit more robust AChE enzyme inhibitory activity due to a greater abundance of hydrogen bonds. This drug-likeness simulation and ADME prediction highlight the potential of tetrazole derivatives as a promising treatment for Alzheimer's disease.
... Several cholinesterase inhibitors (ChEIs) are employed in cognitive disorders and have delivered the primary drugs for the remedy of AD. [9,10] Various AChE inhibitors recommended as drugs for the treatment of AD include tacrine, donepezil, galantamine and rivastigmine. [11] These inhibitors have toxic effects and restrict the clinical interest, [12] and demand for more effective and non-toxic inhibitors in the market, although a substantial and vital challenge in recent years. ...
In the current work, new and diverse hydrazone derivatives were designed and synthesized through a facile and multistep synthetic approach. The chemical structures were elucidated by various spectroscopic techniques. In vitro bioactivity analysis demonstrated selective and potent inhibitory potential of hydrazone derivatives against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. (E)‐3‐chloro‐N′‐(1‐phenylethylidene) benzohydrazide remarkably emerged as a lead candidate exhibiting potent and selective inhibition of AChE with an IC50 value of 0.63±0.01 μM whereas (E)‐3‐chloro‐N′‐(1‐(thiophen‐2‐yl)ethylidene)benzohydrazide delivered the strong potency and selective inhibition towards monoamine oxidase A with an IC50 value of 0.89±0.04 μM. Moreover, (E)‐3‐chloro‐N′‐(1‐(4‐methylthiophen‐2‐yl)ethylidene)benzohydrazide (IC50=2.06±0.01 μM) and (E)‐3‐chloro‐N′‐(1‐(5‐chlorothiophen‐2‐yl)ethylidene)benzohydrazide (IC50=2.06±0.05 μM) were identified as lead inhibitors of monoamine oxidase B. Molecular docking studies of potent and selective inhibitors exhibited various important interactions with amino acid residues in the active pocket of both enzymes, thus strengthening our in vitro results. The kinetics analysis of the most potent compound against AChE revealed non‐competitive mode of inhibition, whereas against monoamine oxidase (A & B), the corresponding lead inhibitors exhibited mixed type of inhibition. Molecular dynamics simulations were also performed to investigate the energetically stable complex formation ability of potent compounds with the target protein. Finally, the results of in silico pharmacokinetic properties showed that the potent compounds have promising pharmacological effects that follow all the parameters of drug‐likeness and could serve as effective drug candidates for future investigations.
... Subsequently, the active conformation of Dolutegravir was further investigated in the active site of AChE (PDB: 4EY7) (Fig. 4). The visualizations demonstrated that the majority of the functional groups are located in the peripheral active site (PAS) of AChE, which is constructed mainly of Tyr34, Tyr72, Asp74, Tyr124, and Trp286 amino acids [63]. Tyr72, Tyr124 and Trp286 were involved in stabilizations with Dolutegravir. ...
An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel multitarget MAO-B/AChE agents in the treatment of Alzheimer’s disease (AD). GOLD 5.3 and Glide were employed in the virtual assessments and consensus superimpositions of the obtained poses were applied to increase the reliability of the docking protocols. Furthermore, the top ranked molecules were subjected to binding free energy calculations using MM/GBSA, Induced fit docking (IFD) simulations, and a literature review. Consequently, the top four multitarget drugs were examined for their in vitro MAO-B and AChE inhibition effects. The consensus molecular docking identified Dolutegravir, Rebamipide, Loracarbef and Diflunisal as potential multitarget drugs. The biological data demonstrated that most of the docking scores were in good correlation with the in vitro experiments, however the theoretical simulations in the active site of MAO-B identified two false-positives – Rebamipide and Diflunisal. Dolutegravir and Loracarbef were accessed as active MAO-B inhibitors, while Dolutegravir, Rebamapide and Diflunisal as potential AChE inhibitors. The antiretroviral agent Dolutegravir exhibited the most potent multitarget activity - 41% inhibition of MAO-B (1 μM) and 68% inhibition of AChE (10 μM). Visualizations of the intermolecular interactions of Dolutegravir in the active sites of MAO-B and AChE revealed the formation of several stable hydrogen bonds. Overall, Dolutegravir was identified as a potential anti-AD drug, however further in vivo evaluations should be considered.
... Cholinergic neuron loss in AD is compensated for by anti-AChE and anti-BuChE treatment. [53] In fact, AChE activity has been positively correlated with plaque deposition in AD, [54] and this has been shown to increase disease severity. In our study too, SCO administration resulted in enhancement in both AChE and BuChE activity in the hippocampal region, indicating AD pathogenicity. ...
Background: Disruptive cholinergic neurotransmission and abnormal cognitive functions were the characteristics of Alzheimer's disease leading to abnormal brain-liver inflammatory responses. Oxidative stress was prominent in Alzheimer's disease-related neurodegeneration leading to inflammatory communication through altered cytokines between the brain and peripheral organs, mainly the liver. Objectives: Current study would demonstrate the healthier effect of N-acetyl cysteine and rutin against AD in rats. Materials and Methods: Experimental Wistar rats have been grouped appropriately for the administration of scopolamine and treatment using a combination of N-acetyl cysteine and rutin for 10 weeks. Results: In our study, scopolamine (2 mg/kg b.w.i.p.) administered Alzheimer's disease model in Wistar rats showed abnormality in behavioural changes (Morris water maze test), pro-inflammatory cytokines, decreased activities of enzymatic antioxidants, decreased reduced glutathione content, elevated brain oxidative stress markers, increased amyloid-beta, elevated acetylcholinesterase, elevated butyrl cholinesterase, increased phosphorylated tau protein, increased GSK-3β, BDNF, altered expressions of β-secretase, NADPH oxidase 2, and Nrf2 genes in brain, and augmented oxidative stress in liver affecting brain-liver axis. Oxidative stress in the liver was evident through decreased activities of enzymatic antioxidants, decreased glutathione content, and elevated liver oxidative stress markers. Conclusion: Treatment with N-acetyl cysteine with rutin showed protective efficacy by modulating the pathways related to Nrf2, NOX-2, and BACE1 genes in combating these abnormalities in rats. Modulation in the gene expressions in the brain tissue showed direct evidence of the drug's neuroprotective efficacy for future therapeutic strategies in scopolamine-induced Alzheimer's disease.
... The Chinese Center for Disease Control and Prevention estimated that there are more than 9 million AD patients in China at present, and it is expected that 40 million could be affected by 2050. AD not only brings a heavy mental burden and economic pressure to the family members and friends of patients but also places a very large burden on the social economy [3]. At present, the typical events in AD pathogenesis are considered to be the formation of extracellular amyloid-β (Aβ) plaques, intracellular accumulation of abnormally phosphorylated tau, neuronal synaptic dysfunction, and neuronal loss [4][5][6][7]. ...
Alzheimer’s disease (AD) is a growing concern in modern society, and effective drugs for its treatment are lacking. Uncaria rhynchophylla (UR) and its main alkaloids have been studied to treat neurodegenerative diseases such as AD. This study aimed to uncover the key components and mechanism of the anti-AD effect of UR alkaloids through a network pharmacology approach. The analysis identified 10 alkaloids from UR based on HPLC that corresponded to 90 anti-AD targets. A potential alkaloid target-AD target network indicated that corynoxine, corynantheine, isorhynchophylline, dihydrocorynatheine, and isocorynoxeine are likely to become key components for AD treatment. KEGG pathway enrichment analysis revealed the Alzheimers disease (hsa05010) was the pathway most significantly enriched in alkaloids against AD. Further analysis revealed that 28 out of 90 targets were significantly correlated with Aβ and tau pathology. These targets were validated using a Gene Expression Omnibus (GEO) dataset. Molecular docking studies were carried out to verify the binding of corynoxine and corynantheine to core targets related to Aβ and tau pathology. In addition, the cholinergic synapse (hsa04725) and dopaminergic synapse (hsa04728) pathways were significantly enriched. Our findings indicate that UR alkaloids directly exert an AD treatment effect by acting on multiple pathological processes in AD.
... Moreover, it also showed lower cytotoxicity than that of Tacrine, indicating its safety as antiAD agents. [62] ...
Alzheimer‟s disease (AD) is a neurodegenerative disease in which there is a progressive loss in the structure and
function of neurons. In a neuron, myelin sheath is highly affected in this disease. AD mainly affects the older
people and is the fourth largest cause of death. In AD, because of overactivity of APP secretase, activation of βand γ-pathways initiate that causes the overproduction of toxic amyloid species i.e. Aβ oligomers and amyloid
plaques. The function of MAPs is to interact with tubulin and assemble them into microtubules to form a
microtubule network. Dementia a chronic loss of cognition usually affecting memory and Alzheimer causes 50% to
80% of dementia causes. Molecular mechanisms underlying the pathophysiology of AD are still not known.
Currently available drug therapies primarily consist of cholinesterase inhibitors and N-methyl-D-aspartate receptor
antagonist approved by the U.S. Food and Drug Administration (FDA) and some neuroprotective agents. Various
target specific drugs from natural, organic and inorganic origins are studied which with the help of animal models
can be evaluated to show a potential in the treatment of AD. All these available drugs show only symptomatic
relief but not treating the cause of this disease.
Native polysaccharide was obtained from Lonicera caerulea L. fruits (PLP). Two selenized polysaccharides (PSLP-1 and PSLP-2) were synthesized by the microwave-assisted HNO 3-Na 2 SeO 3 method, where the selenium (Se) contents were 228 ± 24 and 353 ± 36 μg/g, respectively. The molecular weights of PLP, PSLP-1, and PSLP-2 were 5.9 × 10 4 , 5.6 × 10 4 , and 5.1 × 10 4 kDa, respectively. PSLP-1 and PSLP-2 contained the same type of monosaccharides as PLP but with different molar ratios. The main chain structure of the native polysaccharide was not changed after selenization. PLP, PSLP-1, and PSLP-2 contained the same six types of glycosidic bonds. Bioactivity assays revealed that the two selenized polysaccharides possessed better antioxidant activities than PLP, but their bile acid-binding abilities and inhibitory activities on acetylcholinesterase (AChE) had weakened. In summary, PLP, PSLP-1, and PSLP-2 may be promising Se supplements in functional foods and inhibitors for the treatment of AChE.
Alzheimer’s disease (AD) is a neurodegenerative disorder that impairs neurocognitive function. Acetylcholinesterase (AChE) and β-site APP cleaving enzyme 1 (BACE1) are the two main proteins implicated in AD. Indeed, the major available commercial drugs (donepezil, rivastigmine, and galantamine) against Alzheimer’s are AChE inhibitors. However, none of these drugs are known to reverse or reduce the pathophysiological condition of the disease since there are multiple contributing factors to AD. Therefore, there is a need to develop a multitarget-directed ligand approach for its treatment. In the present study, plant bioactive compounds were screened for their AChE and BACE1 inhibition potential by conducting molecular docking studies. Considering their docking score and pharmacokinetic properties, limonin, peimisine, serratanine B, and withanolide A were selected as the lead compounds. Molecular dynamics simulations of these protein–ligand complexes confirmed the conformational and energetically stabilized enzyme–inhibitor complexes. The inhibition potential of the lead compounds was validated by in vitro enzyme assay. Withanolide A inhibited AChE (IC50 value of 107 μM) and showed mixed-type inhibition. At this concentration, it inhibited BACE1 activity by 57.10% and was stated as most effective. Both the compounds, as well as their crude extracts, were found to have no cytotoxic effect on the SH-SY5Y cell line.
