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Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers.

ABSTRACT: The copper-catalysed azide-alkyne cycloaddition was applied to prepare three enantiomeric pairs of heterodimers containing a tacrine residue and a 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) or 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) moiety held together via linkers of variable lengths containing a 1,2,3-triazole ring and 3, 4, or 7 CH₂ groups. The heterodimers were tested as inhibitors of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE). The enantiomeric heterodimers with the longest linkers exhibited the highest inhibition potencies for AChE (IC₅₀ = 9.7 nM and 11 nM) and BuChE (IC₅₀ = 8.1 nM and 9.1 nM). AChE exhibited the highest enantioselectivity (ca. 4-fold). The enantiomeric pairs of the heterodimers were found to be inactive (GI₅₀ > 100 µM), or to have weak antiproliferative properties (GI₅₀ = 84-97 µM) against a panel of human cancer cells.

SUBMITTER: Vaaland IC

PROVIDER: S-EPMC9721440 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers.

Vaaland I Caroline IC López Óscar Ó Puerta Adrián A Fernandes Miguel X MX Padrón José M JM Fernández-Bolaños José G JG Sydnes Magne O MO Lindbäck Emil E

Journal of enzyme inhibition and medicinal chemistry 20231201 1

The copper-catalysed azide-alkyne cycloaddition was applied to prepare three enantiomeric pairs of heterodimers containing a tacrine residue and a 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) or 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) moiety held together <i>via</i> linkers of variable lengths containing a 1,2,3-triazole ring and 3, 4, or 7 CH<sub>2</sub> groups. The heterodimers were tested as inhibitors of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE). The enantiomeric heterodimer ...[more]

PMID: 36458374

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Project description:An important strategy for treating neurodegenerative disorders is to maintain the levels of acetylcholine in the synaptic cleft by blocking the cholinesterases. Searching for new effective compounds with inhibited acetylcholinesterase and butyrylcholinesterase activity is one of the most significant challenges of the modern scientific research. The aim of this study was the optimization of the condition for cholinesterase activity determination by high-performance liquid chromatography coupled with diode array detector (HPLC-DAD) in terms of concentrations of enzymatic reaction mixture components, temperature of incubation, and incubation time. In vitro investigation of acetylcholinesterase and butyrylcholinesterase activity inhibition by some isoquinoline alkaloids and extracts obtained from the aerial part and roots of Macleaya cordata collected in May, July, and September. Acetylcholinesterase and butyrylcholinesterase activity inhibition of the extracts obtained from the plant had not been tested previously. The application of the HPLC method allowed eliminating absorption of interfering components, for example, alkaloids such as sanguinarine and berberine. The HPLC method was successfully applied for the evaluation of the acetylcholinesterase inhibitory activity in samples such as plant extracts, especially those containing colored components adsorbing at the same wavelength as the adsorption wavelength of 5-thio-2-nitro-benzoic acid, which is the product of the reaction between thiocholine (product of the hydrolysis of acetyl/butyrylthiocholine reaction) with Ellman's reagent. Moreover, liquid chromatography coupled with a triple quadrupole mass spectrometer (LC-QqQ-ESI-MS/MS) analysis allowed evaluating the identification of relevant bioactive compounds in the obtained plant extracts. The investigated alkaloids, especially sanguinarine and chelerythrine, and all the Macleaya cordata extracts, especially the extract obtained from the aerial part collected in May, exhibited very high cholinesterase activity inhibition. HPLC-DAD was also applied for the kinetics study of the most active alkaloids sanguinarine and chelerythrine. Our investigations demonstrated that these plant extracts can be recommended for further in vivo experiments to confirm their cholinesterase inhibition activity.

Project description:BackgroundAcetylcholine deficiencies in hippocampus and cortex, aggregation of β-amyloid, and β-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer's disease.MethodsColorimetric Ellman's method was used for determination of IC50 value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and β-secretase inhibitory activities, evaluation of inhibitory potency on β-amyloid (Aβ) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action.Result and discussionA new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC50 = 11.51 μM) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC50 = 1.95 μM) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak β-secretase inhibitory activities. This compound also inhibited aggregation of β-amyloid (Aβ) in self-induced peptide aggregation test at concentration of 10 μM.ConclusionIt is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay. Graphical abstract A new series of cinnamic-derived acids-tryptamine hybrid derivatives were designed, synthesized and evaluated as butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors and neuroprotective agents. Compound 5b and 5q, as the more potent compounds, interacted with both the peripheral site and the choline binding site having mixed type inhibition. Results suggested that derivatives have a therapeutic potential for the treatment of AD.

Dataset Information

Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers.

Publications

Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers.

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