Alzheimer's disease (AD), the most common form of dementia in adults, is a progressive neurodegenerative disorder of the brain characterized by loss of memory and steady deterioration of cognition. ...Here, a series of symmetrical molecules containing biphenyl/bibenzyl scaffolds (
-
) were designed, synthesized, and evaluated for their ability to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A biological evaluation showed that most of these biphenyl derivatives were potent AChE and BuChE inhibitors. Among them, compound
displayed the greatest ability to inhibit BuChE (IC
= 0.74 µM) and was also a good AChE inhibitor (IC
= 1.18 µM). Compound
was not only a potent AChE inhibitor (IC
= 0.096 µM), but also a mild BuChE inhibitor (IC
=1.25 µM). Overall, these results suggested that compound
may be a promising agent in the treatment of AD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Alzheimer disease (AD) is the most common form of dementia characterized by the loss of cognitive abilities through the death of central neuronal cells. In this study, structure-based virtual screens ...of 2 central nervous system-targeted libraries followed by molecular mechanics/generalized born surface area rescoring were performed to discover novel, selective butyrylcholinesterase (BChE) inhibitors, which are one of the most effective therapeutic strategies for the treatments in late-stage AD. Satisfyingly, compound 5 was identified as a highly selective low micromolar inhibitor of BChE (BChE IC50 = 1.4 μM). The binding mode prediction and kinetic analysis were performed to obtain detailed information about compound 5. Besides, a preliminary structure–activity relationship investigation of compound 5 was carried out for further development of the series. The present results provided a valuable chemical template with a novel scaffold for the development of selective BChE inhibitors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer’s disease. Combination of both: a histamine H3 receptor ...antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands—chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range. The most potent in this group was 1-(7-(4-chlorophenoxy)heptyl)homopiperidine (18) inhibiting the both enzymes (EeAChE IC50=1.93μM and EqBuChE IC50=1.64μM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H3 receptor as well as with cholinesterases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Simultaneous modulation of several targets or pathological events with a key pathogenic role is
a promising strategy to tackle thus far difficult-to-cure or incurable multifactorial diseases ...
AA series of a,β-unsaturated carbonyl based piperidinone derivatives were synthesized and evaluated for their abilities to inhibit AChE and BuChE. All compounds exhibited AChE and BuChE inhibitory ...activity in different ratios. Among the series, compound 1d, (1-benzyl-3,5-bis(4-nitrobenzylidene)piperidine-4-one), was found to be the most potent derivative against AChE (IC50= 12.55 µM) and compound 1g, (1-benzyl-3,5-bis(4-chlorobenzylidene)piperidine-4-one) showed the best anti-BuChE activity (IC50= 17.28 µM). The derivatives exhibited selectivity on AChE enzyme with respect to BuChE. Only compound 1g, bearing chlorine substituents, demonstrated as a dual inhibitor of cholinesterases. Taken together, these results indicated that a,β-unsaturated carbonyl based piperidinone scaffold might be a promising drug candidate for further anti-AD drug development.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
The study presents the discovery of novel butyrylcholinesterase (BuChE) inhibitors among derivatives of azaphenothiazines by application of in silico and in vitro screening methods. From an ...in-house library of compounds, 143 heterocyclic molecules derived from the azaphenothiazine scaffold were chosen for virtual screening. Based on results of the docking procedure, 15 compounds were identified as exhibiting the best fit for the two screening complexes (ligand - AChE and ligand - BuChE). Five compounds displayed moderate AChE and good BuChE inhibitory activity at screening concentrations of 10 µM. The IC50 values for active BuChE inhibitors were in the 11.8-122.2 nM range. Three of the most active inhibitors are tetra- or pentacyclic derivatives of azaphenothiazines with the same N-methyl-2-piperidinethyl substituent.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Current pharmacotherapy for Alzheimer's disease involves compounds that are aimed at increasing the levels of acetylcholine in the brain by facilitating cholinergic neurotransmission through ...inhibition of cholinesterase. These drugs, known as acetylcholinesterase inhibitors, have been shown to improve cognition and global functions but have little impact on improving the eventual progression of the disease; however, there is evidence that other cholinesterases such as butyrylcholinesterase can play an important role in cholinergic function in the brain, and the long-suspected non-cholinergic actions of acetylcholinesterase, mainly the interference with the β-amyloid protein cascade, have recently driven a profound revolution in cholinesterase drug research. Several disease-modifying agents are under development that target these enzymes and have hope of becoming the next generation of effective drugs in the treatment of Alzheimer's disease.
The study presents novel biological properties of diether derivatives of homo‐ or substituted piperidine ligands of the histamine H3 receptor. The compounds were evaluated for their inhibitory ...potency against acetylcholinesterase (AChE) from the electric eel and butyrylcholinesterase (BuChE) from horse serum. The most interesting multifunctional compound 13 displayed high affinity for the cloned hH3R (Ki = 3.48 nM) and moderate inhibitory potency against both enzymes (IC50 AChE = 7.91 µM and BuChE = 4.97 µM). Molecular modeling studies revealed interactions with key amino acid residues in the homology model of histamine H3 receptor ligands, as well as the binding model for AChE and BuChE in the catalytic and peripheral active sites.
This study evaluates diether derivatives of homo‐ or substituted piperidine ligands of the histamine H3 receptor for inhibitory activity against acetylcholinesterase and butyrylcholinesterase.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To search for potent anti-Alzheimer’s disease (AD) agents with multifunctional effects, 12 NO-donating tacrine–flurbiprofen hybrid compounds (2a–l) were synthesized and biologically evaluated. It was ...found that all the new target compounds showed selective butyrylcholinesterase (BuChE) inhibitory activity in vitro comparable or higher than tacrine and the tacrine–flurbiprofen hybrid compounds 1a–c, and released moderate amount of NO in vitro. The kinetic study suggests that one of the most active and highest BuChE selective compounds 2d may not only compete with the substrate for the same catalytic active site (CAS) but also interact with a second binding site. Furthermore, 2d and 2l exhibited significant vascular relaxation effect, which is beneficial for the treatment of AD. All the results suggest that 2d and 2l might be promising lead compounds for further research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A virtual screening of the ZINC database was applied for the identification of novel cholinesterase inhibitors. The first step allowed to select compounds with favorable physicochemical properties. ...Then, the compounds were screened with the pharmacophore models built using crystal structures of donepezil, tacrine, decamethonium and bis-7-tacrine with acetylcholinesterase and well characterized interactions of bis-nor-meptazinol with butyrylcholinesterase. The selected compounds from the group of donepezil were docked to acetyl-cholinesterase giving 7 structures for further studies. These compounds were tested against cholinesterases and two of them, 1-4-(1H-indol-3-ylmethyl)piperazin-1-yl-2-phenoxyethanone 2 and 2-(1-benzylpiperidine-4- yl)amino-1-phenylethanol 4 displayed, respectively, 50.1% and 79.5% of inhibition against butyryl- cholinesterase at the concentration of 100 µM.
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