scholarly journals Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors

Molecules ◽  
2016 ◽  
Vol 21 (2) ◽  
pp. 193 ◽  
Author(s):  
Susimaire Mantoani ◽  
Talita Chierrito ◽  
Adriana Vilela ◽  
Carmen Cardoso ◽  
Ana Martínez ◽  
...  
Keyword(s):  
Binding Site ◽  
Neurodegenerative Disorder ◽  
Acetylcholinesterase Inhibitors ◽  
Synaptic Cleft ◽  
Biological Evaluation ◽  
Ache Inhibitor ◽  
Synthetic Approach ◽  
Chemical Library ◽  
Ache Inhibitors ◽  
Ic50 Values

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with the β-amyloid (Aβ) protein, acting as a chaperone and increasing the number and neurotoxicity of Aβ fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with Aβ, and the catalytic site, related with acetylcholine hydrolysis. In this work, we reported the synthesis and biological evaluation of a library of new tacrine-donepezil hybrids, as a potential dual binding site AChE inhibitor, containing a triazole-quinoline system. The synthesis of hybrids was performed in four steps using the click chemistry strategy. These compounds were evaluated as hAChE and hBChE inhibitors, and some derivatives showed IC50 values in the micro-molar range and were remarkably selective towards hAChE. Kinetic assays and molecular modeling studies confirm that these compounds block both catalytic and peripheral AChE sites. These results are quite interesting since the triazole-quinoline system is a new structural scaffold for AChE inhibitors. Furthermore, the synthetic approach is very efficient for the preparation of target compounds, allowing a further fruitful new chemical library optimization.

scholarly journals Synthesis, Biological Evaluation, and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4895
Author(s):  
Paptawan Suwanhom ◽  
Jirakrit Saetang ◽  
Pasarat Khongkow ◽  
Teerapat Nualnoi ◽  
Varomyalin Tipmanee ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
In Silico ◽  
Acetylcholinesterase Inhibitors ◽  
Biological Evaluation ◽  
Anionic Site ◽  
Human Neuroblastoma ◽  
Ache Inhibitors ◽  
In Silico Studies ◽  
Quinoxaline Derivatives ◽  
Ic50 Values

A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC50 values of 0.077 to 50.080 µM, along with promising predicted drug-likeness and blood–brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC50 values of 14.91 to 60.95 µM was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors.

scholarly journals Synthesis, Biological Evaluation and Docking Studies of Chalcone and Flavone Analogs as Antioxidants and Acetylcholinesterase Inhibitors

2019 ◽  
Vol 9 (3) ◽  
pp. 410 ◽  
Author(s):  
Laura Díaz-Rubio ◽  
Rufina Hernández-Martínez ◽  
Arturo Estolano-Cobián ◽  
Daniel Chávez-Velasco ◽  
Ricardo Salazar-Aranda ◽  
...  
Keyword(s):  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
Biological Evaluation ◽  
Chemotherapeutic Agents ◽  
Acetylcholinesterase Inhibition ◽  
Ache Inhibitors ◽  
Antioxidant Agents ◽  
Wide Range ◽  
Β Carotene

Several oxidative processes are related to a wide range of human chronic and degenerative diseases, like Alzheimer’s disease, which also has been related to cholinergic processes. Therefore, search for new or improved antioxidant molecules with acetylcholinesterase activity is essential to offer alternative chemotherapeutic agents to support current drug therapies. A series of chalcone (2a–2k) and flavone (3a–3k) analogs were synthesized, characterized, and evaluated as acetylcholinesterase (AChE) inhibitors, and antioxidant agents using 1,1-diphenyl-2-picrylhydrazyl (DPPH•), 2-2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS•), and β-carotene/linoleic acid bleaching assay. Compounds more active were 3j and 2k in DPPH with EC50 of 1 × 10−8 and 5.4 × 10−3 μg/mL, respectively; 2g and 3i in ABTS (1.14 × 10−2 and 1.9 × 10−3 μg/mL); 2e, 2f, 3f, 2j, and 3j exceeded the α-tocopherol control in the β-carotene assay (98–99% of antioxidant activity). At acetylcholinesterase inhibition assay, flavones were more active than chalcones; the best results were compounds 2d and 3d (IC50 21.5 and 26.8 µg/mL, respectively), suggesting that the presence of the nitro group enhances the inhibitory activity. The docking of these two structures were made to understand their interactions with the AChE receptor. Although further in vivo testing must be performed, our results represent an important step towards the identification of improved antioxidants and acetylcholinesterase inhibitors.

scholarly journals In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease

2018 ◽  
Vol 17 (1) ◽  
pp. 54-68 ◽  
Author(s):  
Kanzal Iman ◽  
Muhammad Usman Mirza ◽  
Nauman Mazhar ◽  
Michiel Vanmeert ◽  
Imran Irshad ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Neurodegenerative Disorder ◽  
In Silico Analysis ◽  
Acetylcholinesterase Inhibitors ◽  
Binding Energies ◽  
Therapeutic Interventions ◽  
Ache Inhibitors

Objective and Background: Inhibition of acetylcholinesterase (AChE) has gained much importance since the discovery of the involvement of peripheral anionic site as an allosteric regulator of AChE. Characterized by the formation of β-amyloid plaques, Alzheimer's disease (AD) is currently one of the leading causes of death across the world. Progression in this neurodegenerative disorder causes deficit in the cholinergic activity that leads towards cognitive decline. Therapeutic interventions in AD are largely focused upon AChE inhibitors designed essentially to prevent the loss of cholinergic function. The multifactorial AD pathology calls for Multitarget-directed ligands (MTDLs) to follow up on various components of the disease. Considering this approach, other related AD targets were also selected. Structure-based virtual screening was relied upon for the identification of lead compounds with anti-AD effect. Method: Several chemoinformatics approaches were used in this study, reporting four multi-target inhibitors: MCULE-7149246649-0-1, MCULE-6730554226-0-4, MCULE-1176268617-0-6 and MCULE-8592892575-0-1 with high binding energies that indicate better AChE inhibitory activity. Additional in-silico analysis hypothesized the abundant presence of aromatic interactions to be pivotal for interaction of selected compounds to the acetyl-cholinesterase. Additionally, we presented an alternative approach to determine protein-ligand stability by calculating the Gibbs-free energy change over time. Furthermore, this allows to rank potential hits for further in-vitro testing. Results and Conclusion: With no predicted indication of adverse effects on humans, this study unravels four active multi-target inhibitors against AChE with promising affinities and good ADMET profile for the potential use in AD treatment.

Tacrine-coumarin and Tacrine-7-chloroquinoline Hybrids with Thiourea Linkers: Cholinesterase Inhibition Properties, Kinetic Study, Molecular Docking and Permeability Assay for Blood-brain Barrier

2018 ◽  
Vol 15 (12) ◽  
pp. 1096-1105 ◽  
Author(s):  
Slavka Hamulakova ◽  
Ladislav Janovec ◽  
Ondrej Soukup ◽  
Daniel Jun ◽  
Jana Janockova ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Mixed Type ◽  
Acetylcholinesterase Inhibitors ◽  
Docking Studies ◽  
Brain Barrier ◽  
Ache Inhibitor ◽  
Cholinesterase Inhibition ◽  
Binding Modes ◽  
Blood Brain ◽  
Ic50 Values

Background: The design of new heterodimeric dual binding site acetylcholinesterase inhibitors constitutes the main goal-directed to the development of new anticholinesterase agents with the expanded pharmacological profile. Multi-target compounds are usually designed by combining in a hybrid molecule with two or more pharmacophoric moieties that are known to enable interaction with the selected molecular targets. Methods: All compounds were tested for their inhibitory activity on human AChE/BChE. The Ellman´s method was used to determine inhibition kinetics and IC50 values. In order to predict passive bloodbrain penetration of novel compounds, modification of the parallel artificial membrane permeation assay has been used. Docking studies were performed in order to predict the binding modes of new hybrids with hAChE/ hBChE respectively. Results: In this study, we described the design, synthesis, and evaluation of series tacrine-coumarin and tacrine-quinoline compounds which were found to show potential inhibition of ChEs and penetration of the blood-brain barrier. Conclusion: Tacrine-quinoline hybrids 7a exhibited the highest activity towards hBChE (IC50 = 0.97 µmol) and 7d towards hAChE (IC50 = 0.32 µmol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (Ki = 1.69 µmol) and 7a was a mixed-type BChE inhibitor (Ki = 1.09 µmol). Moreover, hybrid 5d and 7c could penetrate the CNS.

Anti-Acetylcholinesterase Derivatives: A Privileged Structural Framework in Drug Discovery to Treat Alzheimer’s Disease

2019 ◽  
Vol 15 (1) ◽  
pp. 8-21
Author(s):  
Monika Bhardwaj ◽  
Vaishali M. Patil ◽  
Rakhi Dhiman ◽  
Satya P. Gupta ◽  
Neeraj Masand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Acetylcholinesterase Inhibitors ◽  
Synaptic Cleft ◽  
Ache Inhibitors ◽  
Structural Framework ◽  
Natural Alkaloid ◽  
Synthetic Derivatives

Alzheimer’s disease (AD) is a complex neurological disorder characterised by decrease level of ACh and increased AChE expression. Inhibition of AChE is one of the common strategies to treat AD as it leads to increase Ach level quantitatively at the synaptic cleft. Acetylcholinesterase inhibitors (AChEIs) are used to treat various neurodegenerative disorders, and many are FDA approved for the management and cure of AD. AChEIs produce long term symptomatic effect, that contribute in other pathological mechanisms of the disease (e.g. formation of amyloid–β plaques) and have provided a rationale to the discovery of this class of inhibitors. Currently prescribed AChE inhibitors are Galantamine (natural alkaloid) and Rivastigmine (synthetic alkaloid compound) and have been considered beneficial for the treatment of mild to moderate AD. However, there is a need for the discovery of more effective compounds derived from natural sources as well as form synthetic sources as potential AChEIs. Findings and advances about natural and synthetic derivatives as potential sources of AChEIs will be collectively summarised in this review paper.

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