Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders with notable factor of dysfunction in cholinergic system. Low ACh level can be observed in the pathogenesis of AD. ...Several AChE inhibitors have already been used for clinical treatments. However, other than normal conditions, ACh is mostly hydrolyzed by BuChE in progressed AD. Account for an increased level of BuChE and decreased level of AChE in the late stage of AD, development of selective BuChE inhibitor is of vital importance. Up till now, compounds with various scaffolds have been discovered to selectively inhibit BuChE. Different effective anti-BuChE molecules are concluded in this review.
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•This review shows on recent progress in the discovery of selective BuChE inhibitor.•Highly selective compounds are selected as examples.•As far as we concern, previous reviews focusing on this topic are very limited.
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As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the ...combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT6 receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT6 receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT6 receptor (Kb = 27 nM), acetylcholinesterase and butyrylcholinesterase (IC50hAChE = 12 nM, IC50hBuChE = 29 nM). The compound also showed good in vitro blood-brain-barrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD.
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•Novel multi-target-directed ligands for Alzheimer's disease were developed.•The compounds combine cholinesterase inhibitory and 5-HT6 antagonist activities.•Compound 12 with balanced in vitro activity was selected for in-depth studies.•Central cholinergic activity of compound 12 was confirmed in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•A series of five isocyanide-derived UGI-4C reaction product compounds were synthesized and characterized and by 1H-RMN, 13C-RMN and HPLC.•Theoretical calculations were carried out; frontier orbitals ...and molecular reactivity, molecular electrostatic potential and pharmacokinetic predictions.•The molecular docking study revealed the interaction with residues Trp231, Phe396, Tyr332 y Trp430 and The120 for compound 7a.•Compound 7a proved to be the compound with the best activity in this series with an IC50 of 25.91 µM, more than 62.22 times selective for BChE than for AChE.•Molecular modeling indicated the interaction nature in the selectivity BChE.
Isocyanide-based multicomponent reactions turn out to be interesting synthetic strategies, with highly valued advantages such as atomic economy, selectivity, among others. Furthermore, Isocyanide-based multicomponent reactions have been shown to generate a wide range of products with significant biological activity. Recently, it has been described that the compounds of the Isocyanide-based multicomponent reactions product could be inhibitors of cholinesterase enzymes, acetylcholinesterase, and butyrylcholinesterase. cholinesterase enzymes have aroused great interest as pharmacological targets in the treatment of Alzheimer's disease, which is a disease that affects millions of people in the world, and its effects become disabling for those who suffer from it since it mainly has consequences on memory and cognitive ability. In this work, using Isocyanide-based multicomponent reactions, we report a series of five new compounds, their characterization, and their potential inhibitory biological activity on acetylcholinesterase and butyrylcholinesterase by spectrophotometric analysis. Our studies revealed that the compounds have moderate inhibitory activities against acetylcholinesterase and butyrylcholinesterase. Interestingly, compounds 7a and 7e showed a higher affinity for butyrylcholinesterase. Particularly compound 7a proved to be the compound with the best activity of this series with an IC50 of 25.91 µM for butyrylcholinesterase, more than 62.22 times selective for butyrylcholinesterase than for acetylcholinesterase. The study of molecular docking and molecular dynamics revealed that the hydrophobic character of these compounds favors the interaction with BChE. The favored interactions for compounds 7a and 7e are with the hydrophobic residues Trp82, Trp231, Val288, Phe329, Thr120. In addition, the molecular electrostatic potential and pharmacokinetic predictions also showed that compounds 7a and 7e have free energy values close to galantamine in the complex with butyrylcholinesterase, among others. These analyzes will allow us in the future to establish some structural modifications that would enable, on this basis, to obtain compounds with better activity against cholinesterase enzymes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inonotus obliquus, an edible and medicinal mushroom parasitic on birches, has been used in human diet and for traditional therapies in the high latitude regions of Europe and Asia for a long time. ...Our phytochemical study of this fungus led to the identification of fourteen triterpenoids including four undescribed ones, and two pairs of undescribed phenolic enantiomers. The undescribed compounds were elucidated by extensive spectroscopic analysis including 1D and 2D NMR and HRESIMS, quantum chemical NMR and ECD calculations, as well as single-crystal X-ray diffraction analysis. Bioassays revealed that eight compounds showed dual inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values ranging from 2.40 ± 0.05 to 28.72 ± 0.46 μM, while 3β-hydroxy-lanosra-8,24-dien-21-al and trametenolic acid only presented BuChE inhibitory activities with IC50 values of 22.21 ± 1.01 and 7.68 ± 0.13 μM, respectively. In the kinetic studies, the most active three compounds acted as non-competitive inhibitors for both cholinesterases. Furthermore, molecular docking simulations revealed that three compounds demonstrated dual-sites bounding to AChE/BuChE. These triterpenoids emerged as bivalent and dual inhibitors of AChE/BuChE and could be effective drug candidates to prevent and treat Alzheimer's disease in the future.
Phytochemical studies on Inonotus obliquus lead to identify bivalent and dual Inhibitors of acetylcholinesterase/butyrylcholinesterase. Display omitted
•Fouteen triterpenoids including four undescribed were identified from Inonotus obliquus.•Two pairs of undescribed phenolic enantiomers were identified from Inonotus obliquus.•Three triterpenoids acted as noncompetitive inhibitors for AChE and BuChE.•Three triterpenoids demonstrated dual-site bound to AChE/BuChE.•One triterpenoid presented inhibitory effect on NO production in RAW264.7 cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
6.
BChE inhibitors from marine organisms – A review Lins Alves, Luana Kamarowski; Cechinel Filho, Valdir; de Souza, Ricardo Lehtonen Rodrigues ...
Chemico-biological interactions,
11/2022, Volume:
367
Journal Article
Peer reviewed
Open access
Acetylcholine is a key neurotransmitter for brain and muscle function, that has its levels decreased in the brain of people with Alzheimer's Disease (AD). Cholinesterase inhibitors are medicines that ...decrease the breakdown of acetylcholine, through the inhibition of acetyl- and butyrylcholinesterase enzymes. Despite the fact that butyrylcholinesterase activity rises with the disease, while acetylcholinesterase activity declines, the cholinesterase inhibitors that are currently commercialized inhibit either acetylcholinesterase or both enzymes. The development of selective butyrylcholinesterase inhibitors is a promising strategy in the search for new drugs acting against AD. The marine environment is a rich source of molecules with therapeutic potential, which can provide compounds more easily than traditional methods, with reduced toxicity risks compared to synthetic molecules. This review comprises articles from 2003 to 2020, that assessed the butyrylcholinesterase inhibitory activities from marine organisms, considering their crude extracts and isolated compounds. Part of the articles reported a multi-target activity, inhibiting also other AD-related enzymes. Some of the marine compounds reported here have shown an excellent potential for butyrylcholinesterase inhibition compared to standard inhibitors. Further studies of some compounds reported here may lead to the development of a new treatment for AD.
•Selective BChE inhibitors may have a better outcome in Alzheimer's treatment.•The marine environment is a rich source of molecules with neuroprotective potentials.•Cholinesterases inhibitory activity may be found in marine substances.•Some marine substances have a multi-target activity against Alzheimer's disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The symptomatic and disease-modifying effects of butyrylcholinesterase (BuChE) inhibitors provide an encouraging premise for researching effective treatments for Alzheimer's disease. Here, we ...examined a series of compounds with a new chemical scaffold based on 3-(cyclohexylmethyl)amino-2-hydroxypropyl, and we identified a highly selective hBuChE inhibitor (29). Based on extensive in vitro and in vivo evaluations of the compound and its enantiomers, (R)-29 was identified as a promising candidate for further development. Compound (R)-29 is a potent hBuChE inhibitor (IC50 = 40 nM) with selectivity over AChE and relevant off-targets, including H1, M1, α1A and β1 receptors. The compound displays high metabolic stability on human liver microsomes (90% of the parent compound after 2 h of incubation), and its safety was confirmed through examining the cytotoxicity on the HepG2 cell line (LC50 = 2.85 μM) and hERG inhibition (less than 50% at 10 μM). While (rac)-29 lacked an effect in vivo and showed limited penetration to the CNS in pharmacokinetics studies, compound (R)-29 exhibited a procognitive effect at 15 mg/kg in the passive avoidance task in scopolamine-treated mice.
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•Series of novel potential anti-Alzheimer's agents were designed and synthesized.•Highly potent and selective inhibitors of hBuChE were discovered with 3-(cyclohexylmethyl)amino-2-hydroxypropyl chemotype.•Crystal structures of hBChE in complex with new selected inhibitors were solved.•In vitro ADME-tox, in vivo pharmacokinetic and pharmacodynamic studies were performed.
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•Design arylcarbamate-N-acylhydrazones derivatives were BuChE selective inhibitors.•The compounds were synthesized using low-cost and simple methodologies.•Compounds 10a-d are potent ...BuChE inhibitors, with IC50 values of 0.07–0.56 µM.•Best inhibitor 10c is non-competitive type of BuChE.•Docking studies confirmed important interactions of 10c with hBuChE active site.
A novel series of arylcarbamate-N-acylhydrazones derivatives have been designed and synthesized as potential anti-cholinesterase agents. In vitro studies revealed that these compounds demonstrated selective for butyrylcholinesterase (BuChE) with potent inhibitory activity. The compounds 10a-d, 12b and 12d were the most potent BuChE inhibitors with IC50 values of 0.07–2.07 µM, highlighting the compound 10c (IC50 = 0.07 µM) which showed inhibitory activity 50 times greater than the reference drug donepezil (IC50 = 3.54 µM). The activity data indicates that the position of the carbamate group in the aromatic ring has a greater influence on the inhibitory activity of the derivatives. The enzyme kinetics studies indicate that the compound 10c has a non-competitive inhibition against BuChE with Ki value of 0.097 mM. Molecular modeling studies corroborated the in vitro inhibitory mode of interaction and show that compound 10c is stabilized into hBuChE by strong hydrogen bond interaction with Tyr128, π-π stacking interaction with Trp82 and CH⋯O interactions with His438, Gly121 and Glu197. Based on these data, compound10cwas identified as low-cost promising candidate for a drug prototype for AD treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Dual binding site acetylcholinesterase (AChE) inhibitors and butyrylcholinesterase (BChE) inhibitors have recently emerged as two classes of new anti-Alzheimer agents to positively ...modify the disease’s course. In this work, a new series of 4-N-phenylaminoquinolines was synthesized and evaluated for their abilities to inhibit AChE and BChE. Compound 11b showed significant inhibitory activities on AChE and BChE with IC50 values of 0.86 and 2.65 μM, respectively, a lot better than that of reference drug galanthamine. Furthermore, docking study showed that compound 11b interacted simultaneously not only with active and peripheral sites of AChE, but also with all five regions of BChE active site. These findings suggest that these derivatives could be regarded as promising starting points for further drug discovery developments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This article aims to provide an updated description and comparison of the data currently available in the literature (from the last 15 years) on the studied natural inhibitors of cholinesterases ...(IChEs), namely, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These data also apply to the likely impact of the structures of the compounds on the therapeutic effects of available and potential cholinesterase inhibitors. IChEs are hitherto known compounds with various structures, activities and origins. Additionally, multiple different methods of analysis are used to determine the cholinesterase inhibitor potency. This summary indicates that natural sources are still suitable for the discovery of new compounds with prominent pharmacological activity. It also emphasizes that further studies are needed regarding the mechanisms of action or the structure-activity correlation to discuss the issue of cholinesterase inhibitors and their medical application.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
