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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F18%3A50014989" target="_blank" >RIV/62690094:18470/18:50014989 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00179906:_____/18:10382435 RIV/60162694:G44__/18:43889627

Výsledek na webu

<a href="http://dx.doi.org/10.2174/1567205015666180711110750" target="_blank" >http://dx.doi.org/10.2174/1567205015666180711110750</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.2174/1567205015666180711110750" target="_blank" >10.2174/1567205015666180711110750</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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&apos;s method was used to determine inhibition kinetics and IC50 values. In order to predict passive blood-brain 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 tmol) and 7d towards hAChE (IC50 = 0.32 tmol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (K-i = 1.69 tmol) and 7a was a mixed-type BChE inhibitor (K-i = 1.09 mu mol). Moreover, hybrid 5d and 7c could penetrate the CNS.

Název v anglickém jazyce

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

Popis výsledku anglicky

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&apos;s method was used to determine inhibition kinetics and IC50 values. In order to predict passive blood-brain 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 tmol) and 7d towards hAChE (IC50 = 0.32 tmol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (K-i = 1.69 tmol) and 7a was a mixed-type BChE inhibitor (K-i = 1.09 mu mol). Moreover, hybrid 5d and 7c could penetrate the CNS.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30210 - Clinical neurology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Current Alzheimer research

ISSN

1567-2050

e-ISSN

—

Svazek periodika

15

Číslo periodika v rámci svazku

12

Stát vydavatele periodika

AE - Spojené arabské emiráty

Počet stran výsledku

10

Strana od-do

1096-1105

Kód UT WoS článku

000448421000002

EID výsledku v databázi Scopus

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