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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F18%3A50014444" target="_blank" >RIV/62690094:18470/18:50014444 - isvavai.cz</a>

Alternative codes found

RIV/00179906:_____/18:10375579 RIV/60162694:G44__/18:43889520 RIV/00216208:11160/18:10375579

Result on the web

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

Original language description

Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target 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 = 74.5 nM; hBChE IC50 = 83.3 nM) with micromolar antagonistic activity towards M1 mAChR (IC50 = 4.23 mu M). 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

30107 - Medicinal chemistry

Project

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

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

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

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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

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