scholarly journals Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3341
Author(s):  
Georgi Stavrakov ◽  
Irena Philipova ◽  
Atanas Lukarski ◽  
Mariyana Atanasova ◽  
Dimitrina Zheleva ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Ache Activity ◽  
Combinatorial Library ◽  
Acetylcholinesterase Inhibitors ◽  
Aβ Oligomers ◽  
Ache Inhibitors ◽  
Adme Properties ◽  
Dual Site ◽  
Site Binding

Galantamine (GAL) and curcumin (CU) are alkaloids used to improve symptomatically neurodegenerative conditions like Alzheimer’s disease (AD). GAL acts mainly as an inhibitor of the enzyme acetylcholinesterase (AChE). CU binds to amyloid-beta (Aβ) oligomers and inhibits the formation of Aβ plaques. Here, we combine GAL core with CU fragments and design a combinatorial library of GAL-CU hybrids as dual-site binding AChE inhibitors. The designed hybrids are screened for optimal ADME properties and BBB permeability and docked on AChE. The 14 best performing compounds are synthesized and tested in vitro for neurotoxicity and anti-AChE activity. Five of them are less toxic than GAL and CU and show activities between 41 and 186 times higher than GAL.

(38) Computational approaches to the study of dual-site and peripheral site binding ache inhibitors

2005 ◽  
Vol 157-158 ◽  
pp. 414-415
Author(s):  
Maurizio Recanatini ◽  
Andrea Cavalli ◽  
Giovanni Bottegoni
Keyword(s):  
Computational Approaches ◽  
Ache Inhibitors ◽  
Peripheral Site ◽  
Dual Site ◽  
Site Binding

Structure—activity relationships for in vitro oxime reactivation of chlorpyrifos-inhibited acetylcholinesterase

2007 ◽  
Vol 61 (4) ◽  
Author(s):  
K. Kuča ◽  
V. Račáková ◽  
D. Jun
Keyword(s):  
Biological Activity ◽  
Active Site ◽  
Ache Activity ◽  
Chemical Structure ◽  
Organophosphorus Pesticides ◽  
Ache Inhibitors ◽  
Structure Activity ◽  
The Relationship ◽  
Representative Member

AbstractOrganophosphorus pesticides parathion, chlorpyrifos, and malathion inhibit the enzyme acetylcholinesterase (AChE; EC 3.1.1.7) via phosphorylation of its active site. AChE reactivators and anticholinergics are compounds used as antidotes in the case of intoxication by these AChE inhibitors. In this work, chlorpyrifos, a representative member of this pesticide family, was used to inhibit the AChE activity of rat brain. The effect of twenty-one structurally different AChE reactivators was tested in vitro and subsequently, the relationship between their chemical structure and biological activity was outlined.

In Vivo Studies on Novel Potent Acetylcholinesterase Inhibitors with Dual-site Binding for Treatment of Alzheimer’s Disease

2021 ◽  
Author(s):  
Rumiana Simeonova ◽  
Vessela Vitcheva ◽  
Ivanka Kostadinova ◽  
Iva Valkova ◽  
Irena Philipova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Acetylcholinesterase Inhibitors ◽  
In Vivo Studies ◽  
Dual Site ◽  
Site Binding

Novel Hybrid Acetylcholinesterase Inhibitors Induce Differentiation and Neuritogenesis in Neuronal Cells in vitro Through Activation of the AKT Pathway

2020 ◽  
Vol 78 (1) ◽  
pp. 353-370
Author(s):  
Natália Chermont dos Santos Moreira ◽  
Jéssica Ellen Barbosa de Freitas Lima ◽  
Talita Perez Cantuaria Chierrito ◽  
Ivone Carvalho ◽  
Elza Tiemi Sakamoto-Hojo
Keyword(s):  
Oxidative Stress ◽  
Amyloid Β ◽  
Acetylcholinesterase Inhibitors ◽  
Akt Pathway ◽  
Amyloid Β Peptide ◽  
Ache Inhibitors ◽  
Hybrid Molecules ◽  
Main Class ◽  
Ad Therapy

Background: Alzheimer’s disease (AD) is characterized by a progressive loss of episodic memory associated with amyloid-β peptide aggregation and the abnormal phosphorylation of the tau protein, leading to the loss of cholinergic function. Acetylcholinesterase (AChE) inhibitors are the main class of drugs used in AD therapy. Objective: The aim of the current study was to evaluate the potential of two tacrine-donepezil hybrid molecules (TA8Amino and TAHB3), which are AChE inhibitors, to induce neurodifferentiation and neuritogenesis in SH-SY5Y cells. Methods: The experiments were carried out to characterize neurodifferentiation, cellular changes related to responses to oxidative stress and pathways of cell survival in response to drug treatments. Results: The results indicated that the compounds did not present cytotoxic effects in SH-SY5Y or HepG2 cells. TA8Amino and TAHB3 induced neurodifferentiation and neuritogenesis in SH-SY5Y cells. These cells showed increased levels of intracellular and mitochondrial reactive oxygen species; the induction of oxidative stress was also demonstrated by an increase in SOD1 expression in TA8Amino and TAHB3-treated cells. Cells treated with the compounds showed an increase in PTEN(Ser380/Thr382/383) and AKT(Ser473) expression, suggesting the involvement of the AKT pathway. Conclusion: Our results demonstrated that TA8Amino and TAHB3 present advantages as potential drugs for AD therapy and that they are capable of inducing neurodifferentiation and neuritogenesis.

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.

scholarly journals Virtual Screening of Acetylcholinesterase Inhibitors Using the Lipinski’s Rule of Five and ZINC Databank

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Pablo Andrei Nogara ◽  
Rogério de Aquino Saraiva ◽  
Diones Caeran Bueno ◽  
Lílian Juliana Lissner ◽  
Cristiane Lenz Dalla Corte ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Ache Activity ◽  
Acetylcholinesterase Inhibitors ◽  
Behavioral Changes ◽  
Lipinski’S Rule ◽  
Memory Impairments ◽  
Compound C ◽  
Lipinski’S Rule Of Five

Alzheimer’s disease (AD) is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh) in the brain by using acetylcholinesterase inhibitors (AChEIs). In this study, we used the ZINC databank and the Lipinski’s rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1) aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE) activity. The molecules were obtained by screening and furtherin vitroassays were performed to analyze the most potent inhibitors through the IC50value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE) fromEquus ferus(EfBChE), with IC50ranging from 1.69 ± 0.46 to 5.64 ± 2.47 µM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor ofEfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms.

scholarly journals Design, synthesis and molecular modeling of isothiochromanone derivatives as acetylcholinesterase inhibitors

2019 ◽  
Vol 11 (20) ◽  
pp. 2687-2699
Author(s):  
Wen Shuai ◽  
Wenlong Li ◽  
Ying Yin ◽  
Limei Yang ◽  
Feijie Xu ◽  
...  
Keyword(s):  
Active Site ◽  
Ache Activity ◽  
Acetylcholinesterase Inhibitors ◽  
Docking Studies ◽  
Potential Candidate ◽  
Anionic Site ◽  
Design Synthesis ◽  
Ache Inhibitors ◽  
Catalytic Active Site ◽  
Mixed Type Inhibitor

Aim: A series of novel isothio- and isoselenochromanone derivatives bearing N-benzyl pyridinium moiety were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Results: Most of the target compounds exhibited potent anti-AChE activities with IC50 values in nanomolar ranges. Among them, compound 15a exhibited the most potent anti-AChE activity (IC50 = 2.7 nM), moderate antioxidant activity and low neurotoxicity. Moreover, the kinetic and docking studies revealed that compound 15a was a mixed-type inhibitor, which bounds to peripheral anionic site and catalytic active site of AChE. Conclusion: Those results suggested that compound 15a might be a potential candidate for AD treatment.

Dual-site binding of bivalent 4-aminopyridine- and 4-aminoquinoline-based AChE inhibitors: contribution of the hydrophobic alkylene tether to monomer and dimer affinities

1999 ◽  
Vol 7 (11) ◽  
pp. 2569-2575 ◽  
Author(s):  
Yi Fan Han ◽  
Crystal P.-L Li ◽  
Ella Chow ◽  
Hong Wang ◽  
Yuan-Ping Pang ◽  
...  
Keyword(s):  
Ache Inhibitors ◽  
Dual Site ◽  
Site Binding

scholarly journals Comparison of Two Schizophyllum commune Strains in Production of Acetylcholinesterase Inhibitors and Antioxidants from Submerged Cultivation

2021 ◽  
Vol 7 (2) ◽  
pp. 115
Author(s):  
Jovana Mišković ◽  
Maja Karaman ◽  
Milena Rašeta ◽  
Nenad Krsmanović ◽  
Sanja Berežni ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Ache Activity ◽  
Phenolic Content ◽  
Antioxidative Activity ◽  
Fermentation Broth ◽  
Schizophyllum Commune ◽  
Acetylcholinesterase Inhibitors ◽  
Submerged Cultivation ◽  
Total Phenolic ◽  
Ache Inhibitors

In recent years, fungi have been recognized as producers of acetylcholinesterase (AChE) inhibitors, agents important for the prevention of Alzheimer’s disease (AD). This study aimed to examine the AChE inhibitory, the antioxidative and antibacterial activity of two different Schizophyllum commune strains that originated from Serbia (SRB) and Italy (IT). Submerged cultivation of grown mycelia (M) and fermentation broth (F) of ethanol (EtOH) and polysaccharide (PSH) extracts lasted for 7, 14, 21 and 28 days. For AChE activity Ellman method was performed, while for antioxidative activity, sevendifferent assays were conducted: DPPH, ABTS, FRAP, SOA, OH, NO together with total phenolic content. Antimicrobial screen, LC–MS/MS technique and FTIR measurements were performed. Different isolates exhibited different AChE activity, with PSH being the strongest (SRB, M, 28 days IC90 79.73 ± 26.34 µg/mL), while in EtOH extracts, IT stood out (F, 14 days, IC50 0.8 ± 0.6 µg/mL). PSH extracts (7 days) exhibit significant antioxidative activity (AO), opposite to EtOH extracts where 14 and 21days periods stood out. Only tw extracts showed antibacterial activity. Following LC–MS/MS analysis p-hydroxybenzoic and gallic acids were the most abundant phenolics. PSH extracts demonstrated remarkable results, making this study debut and introducing S. commune as a valuable resource of AChE inhibitors.

Sign in / Sign up

Export Citation Format

Share Document