scholarly journals Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2540 ◽  
Author(s):  
Wenhao Wu ◽  
Xintong Liang ◽  
Guoquan Xie ◽  
Langdi Chen ◽  
Weixiong Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Docking Study ◽  
High Concentration ◽  
Molecular Docking Study ◽  
Catalytic Active Site ◽  
Aβ Aggregation ◽  
Ic50 Values ◽  
Targeted Inhibitors ◽  
Further Development

A series of novel ligustrazine derivatives 8a–r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer’s disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 × 106; for 8r, IC50 BuChE/IC50 AChE = 1.32 × 107). Of note, 8q and 8r also presented potent inhibitory activities against Aβ aggregation, with IC50 values of 17.36 µM and 49.14 µM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 μM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest.

scholarly journals Putative Molecular Mechanisms of Neuroprotective Cerebrosides and Their Docking Studies on Acetyl Cholinesterase Enzyme Inhibition for the Treatment of Alzheimer’s Disease

2021 ◽  
Author(s):  
SHAIK IBRAHIM KHALIVULLA ◽  
Kokkanti Mallikarjuna
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Enzyme Inhibition ◽  
Docking Study ◽  
Tau Proteins ◽  
World Health ◽  
Molecular Docking Study ◽  
Ache Inhibitors ◽  
Catalytic Active Site

Abstract The Dementia disease is characterised by neuropsychiatric disturbances due to lack of proper synaptic communication between neurons causing the cognitive behavioural problems. The Alzheimer’s disease (AD) in elderly population is one of the several forms of Dementia. Recent data by World Health Organisation indicates that nearly 10 million people are getting dementia every year, of which 60-70% accounts for AD. The etiology of AD involves the formation of amyloid-β plaques and neurofibrillary Tau tangles in the brain resulting in the death of neural cells. There is no permanent solution for AD treatment, except the FDA approved drugs like galantamine, donepezil, rivastigmine and memantine that are normally associated with side effects. At this juncture, cerebrosides, the natural secondary metabolites identified from different taxa with potential neuroprotective effects offer a promising scope for the treatment of AD. In this paper, cerebrosides reported from all taxa are pooled up along with their functions and listed. The review of literature revealed that Cerebrosides can increase the cognitive functions by regulating or interacting with the N-methyl-d-aspartate (NMDA) calcium ion (Ca2+) channels at post-synaptic receptor; nitric oxide (NO); Bcl2, Bax, amyloid precursor (APP) and Tau proteins; brain-derived neurotrophic factor (BDNF) and cAMP- response element-binding proteins (CREB).This indicates that the Cerebrosides could be potential therapeutic agents for the protection of neurons involved in neurodegenerative disease like Alzheimer’s disease. The current neuroprotective drugs are AChE inhibitors; hence, in the present investigation, in silico molecular docking study on cerebrosides for the inhibition of AChE was assessed to find out their capacity to interact with an active catalytic site of AChE. The results of present investigation revealed that all 22 cerebrosides selected for this work interacted with catalytic active site of AChE measured in terms of Gibbs free binding energy. Of all the cerebrosides assessed, compound 6 exhibited strong interaction, followed by 15. This is the first report of molecular docking study on cerebrosides for AChE enzyme inhibition for treatment of Alzheimer’s disease. Nevertheless, detailed in vitro and in vivo, biochemical and molecular investigations are needed to bring them to useful form.

Spirocyclohexadienones as an Uncommon Scaffold for Acetylcholinesterase Inhibitory Activity

2019 ◽  
Vol 15 (4) ◽  
pp. 373-382 ◽  
Author(s):  
Ralph C. Gomes ◽  
Renata P. Sakata ◽  
Wanda P. Almeida ◽  
Fernando Coelho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Population Aging ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
Docking Study ◽  
Biological Properties ◽  
Ache Inhibitor ◽  
Molecular Docking Study

Background: The most important cause of dementia affecting elderly people is the Alzheimer’s disease (AD). Patients affected by this progressive and neurodegenerative disease have severe memory and cognitive function impairments. Some medicines used for treating this disease in the early stages are based on inhibition of acetylcholinesterase. Population aging should contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the development of new therapeutic entities for the treatment of this disease. Methods: The objective of this work is to identify new substances that have spatial structural similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's disease, and to evaluate the capacity of inhibition of these new substances against the enzyme acetylcholinesterase. Results: Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones with different substitutions patterns in three steps and overall yield of up to 59%. These compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 µM. Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 µM), a mixedtype AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic (CAS) and the peripheral site (PAS). Conclusion: We described the first study aimed at investigating the biological properties of spirocyclohexadienones as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase inhibitors.

scholarly journals New Tetrahydroacridine Hybrids with Dichlorobenzoic Acid Moiety Demonstrating Multifunctional Potential for the Treatment of Alzheimer’s Disease

2020 ◽  
Vol 21 (11) ◽  
pp. 3765
Author(s):  
Kamila Czarnecka ◽  
Małgorzata Girek ◽  
Przemysław Wójtowicz ◽  
Paweł Kręcisz ◽  
Robert Skibiński ◽  
...  
Keyword(s):  
Active Compound ◽  
Inhibitory Activity ◽  
Docking Study ◽  
Free Radical Scavenger ◽  
Neuroprotective Activity ◽  
Radical Scavenger ◽  
Catalytic Active Site ◽  
Aβ Aggregation ◽  
Ic50 Values

A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, and evaluated for their ability to inhibit both cholinesterase enzymes. Compounds 3a, 3b, 3f, and 3g exhibited selective butyrylcholinesterase (EqBuChE) inhibition with IC50 values ranging from 24 to 607 nM. Among them, compound 3b was the most active (IC50 = 24 nM). Additionally, 3c (IC50 for EeAChE = 25 nM and IC50 for EqBuChE = 123 nM) displayed dual cholinesterase inhibitory activity and was the most active compound against acetylcholinesterase (AChE). Active compound 3c was also tested for the ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated using ACD Labs Percepta and Chemaxon. A Lineweaver–Burk plot and docking study showed that 3c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, 3c appears to possess neuroprotective activity and could be considered a free-radical scavenger. In addition, 3c did not cause DNA damage and was found to be less toxic than tacrine after oral administration; it also demonstrated little inhibitory activity towards hyaluronidase (HYAL), which may indicate that it possesses anti-inflammatory properties. The screening for new in vivo interactions between 3c and known receptors was realized by yeast three-hybrid technology (Y3H).

scholarly journals Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

BMC Chemistry ◽  
2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Hajar Karimi Askarani ◽  
Aida Iraji ◽  
Arezoo Rastegari ◽  
Syed Nasir Abbas Bukhari ◽  
Omidreza Firuzi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Activities ◽  
Neuroprotective Effects ◽  
Design And Synthesis ◽  
Catalytic Active Site ◽  
Aβ Aggregation ◽  
Multifunctional Agents ◽  
Potential Use

Abstract To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities included acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition as well as anti-Aβ aggregation, neuroprotective effects, and metal-chelating properties. The results indicated a highly selective BuChE inhibitory activity with an IC50 value of 21.71 μM for compound 10h as the most potent compound. Besides, compound 10h could inhibit self-induced Aβ1–42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition values, respectively. The Lineweaver–Burk plot and molecular modeling study showed that compound 10h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10h was able to chelate biometals. Thus, the designed scaffold could be considered as multifunctional agents in AD drug discovery developments.

Identification and molecular docking study of fish roe-derived peptides as potent BACE 1, AChE, and BChE inhibitors

2020 ◽  
Vol 11 (7) ◽  
pp. 6643-6651 ◽  
Author(s):  
Zhipeng Yu ◽  
Huizhuo Ji ◽  
Juntong Shen ◽  
Ruotong Kan ◽  
Wenzhu Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Beta Secretase ◽  
Fish Roe ◽  
Bace 1

Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and beta-secretase 1 (BACE 1) play vital roles in the development and progression of Alzheimer's disease (AD).

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.

scholarly journals Halogen-directed drug design for Alzheimer’s disease: a combined density functional and molecular docking study

SpringerPlus ◽  
2016 ◽  
Vol 5 (1) ◽  
Author(s):  
Adhip Rahman ◽  
Mohammad Tuhin Ali ◽  
Mohammad Mahfuz Ali Khan Shawan ◽  
Mohammed Golam Sarwar ◽  
Mohammad A. K. Khan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Drug Design ◽  
Density Functional ◽  
Docking Study ◽  
Molecular Docking Study
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