TacrineMINUS SIGN trolox hybrids: a novel class of centrally active, nonhepatotoxic multi-target-directed ligands exerting anticholinesterase and antioxidant activities with low in vivo toxicity

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023752%3A_____%2F15%3A43914847" target="_blank" >RIV/00023752:_____/15:43914847 - isvavai.cz</a>

Výsledek na webu

<a href="http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01325" target="_blank" >http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01325</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.5b01325" target="_blank" >10.1021/acs.jmedchem.5b01325</a>

Jazyk výsledku

angličtina

Název v původním jazyce

TacrineMINUS SIGN trolox hybrids: a novel class of centrally active, nonhepatotoxic multi-target-directed ligands exerting anticholinesterase and antioxidant activities with low in vivo toxicity

Popis výsledku v původním jazyce

Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory propertiestoward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrineMINUS SIGN trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across bloodMINUS SIGN brain barrier. All of these outstanding in vitro results in combinati

Název v anglickém jazyce

TacrineMINUS SIGN trolox hybrids: a novel class of centrally active, nonhepatotoxic multi-target-directed ligands exerting anticholinesterase and antioxidant activities with low in vivo toxicity

Popis výsledku anglicky

Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory propertiestoward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrineMINUS SIGN trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across bloodMINUS SIGN brain barrier. All of these outstanding in vitro results in combinati

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

FR - Farmakologie a lékárnická chemie

OECD FORD obor

—

Projekt

<a href="/cs/project/ED2.1.00%2F03.0078" target="_blank" >ED2.1.00/03.0078: Národní ústav duševního zdraví</a><br>

Návaznosti

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

Rok uplatnění

2015

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

58

Číslo periodika v rámci svazku

22

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

19

Strana od-do

8985-9003

Kód UT WoS článku

000366004600017

EID výsledku v databázi Scopus

2-s2.0-84948807652