The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer's disase

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023752%3A_____%2F18%3A43919351" target="_blank" >RIV/00023752:_____/18:43919351 - isvavai.cz</a>

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S0223523418302265?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0223523418302265?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2018.02.083" target="_blank" >10.1016/j.ejmech.2018.02.083</a>

Result language

angličtina

Original language name

The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer's disase

Original language description

Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multitarget directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line. All the novel tacrine-BQCA hybrids were able to block the action of hAChE and hBChE in micromolar to nanomolar range. The hAChE kinetic profile of 5p was found to be mixed-type which is consistent with our docking experiments. Moreover, selected ligands were assessed for their potential hepatotoxicity on HepG2 cell line and presumable permeation through the blood-brain barrier by PAMPA assay. Expected agonistic profile towards M1 mAChRs delivered by BQCA moiety was not confirmed. From all the hybrids, 5o can be highlighted as non-selective cholinesterase inhibitor (hAChE IC50 ¼ 74.5 nM; hBChE IC50 ¼ 83.3 nM) with micromolar antagonistic activity towards M1 mAChR (IC50 ¼ 4.23 mM). A non-selective pattern of cholinesterase inhibition is likely to be valuable during the onset as well as later stages of AD.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/GA16-08554S" target="_blank" >GA16-08554S: Novel hybrid compounds in the cognitive decline caused by neurodegeneration</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2018

Confidentiality

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

Name of the periodical

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

—

Volume of the periodical

150

Issue of the periodical within the volume

April

Country of publishing house

FR - FRANCE

Number of pages

15

Pages from-to

292-306

UT code for WoS article

000430891400022

EID of the result in the Scopus database

2-s2.0-85043379628