Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F21%3A10428686" target="_blank" >RIV/00179906:_____/21:10428686 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60162694:G44__/21:00556990

Výsledek na webu

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

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.1c00048" target="_blank" >10.1021/acs.jmedchem.1c00048</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease

Popis výsledku v původním jazyce

The multifactorial nature of Alzheimer&apos;s disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of &quot;multi-target-directed ligands&quot; (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 mu M), confirming the design rationale.

Název v anglickém jazyce

Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease

Popis výsledku anglicky

The multifactorial nature of Alzheimer&apos;s disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of &quot;multi-target-directed ligands&quot; (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 mu M), confirming the design rationale.

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/GA20-12047S" target="_blank" >GA20-12047S: Nové neuroprotektivní látky na bázi antagonismu NMDA receptorů a cholinergní stimulace</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

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

—

Svazek periodika

64

Číslo periodika v rámci svazku

8

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

19

Strana od-do

4972-4990

Kód UT WoS článku

000644437100037

EID výsledku v databázi Scopus

2-s2.0-85105093986