Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and gamma-aminobutyric acid transporters

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F21%3A10428582" target="_blank" >RIV/00179906:_____/21:10428582 - isvavai.cz</a>

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=eOVw7Bvtjx" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=eOVw7Bvtjx</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2021.113397" target="_blank" >10.1016/j.ejmech.2021.113397</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and gamma-aminobutyric acid transporters

Popis výsledku v původním jazyce

Looking for an effective anti-Alzheimer&apos;s agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: beta-secretase enzyme (BACE1) and amyloid beta (A beta) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and gamma-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 mu M; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 mu M; inhibition of A beta aggregation = 57.9% at 10 mu M; mGAT1 IC50 = 10.96 mu M; and mGAT2 IC50 = 19.05 mu M). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 mu M and IC50 = 2.95 mu M, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease. (c) 2021 Elsevier Masson SAS. All rights reserved.

Název v anglickém jazyce

Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and gamma-aminobutyric acid transporters

Popis výsledku anglicky

Looking for an effective anti-Alzheimer&apos;s agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: beta-secretase enzyme (BACE1) and amyloid beta (A beta) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and gamma-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 mu M; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 mu M; inhibition of A beta aggregation = 57.9% at 10 mu M; mGAT1 IC50 = 10.96 mu M; and mGAT2 IC50 = 19.05 mu M). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 mu M and IC50 = 2.95 mu M, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease. (c) 2021 Elsevier Masson SAS. All rights reserved.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GC20-29633J" target="_blank" >GC20-29633J: Multipotentní sloučeniny odvozené od Amiridinu jako potenciální léčiva Alzheimerovy choroby</a><br>

Návaznosti

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

Rok uplatnění

2021

Kód důvěrnosti údajů

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

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

—

Svazek periodika

218

Číslo periodika v rámci svazku

June

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

24

Strana od-do

113397

Kód UT WoS článku

000646195900021

EID výsledku v databázi Scopus

2-s2.0-85103794568