Novel neuroprotective 5,6-dihydropyrido[2′,1':2,3]imidazo[4,5-c] quinoline derivatives acting through cholinesterase inhibition and CB2 signaling modulation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F24%3A00601083" target="_blank" >RIV/61389030:_____/24:00601083 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15110/24:73625290 RIV/61989592:15310/24:73625290 RIV/00216275:25310/24:39921852 RIV/00098892:_____/24:10158701

Výsledek na webu

<a href="https://doi.org/10.1016/j.ejmech.2024.116592" target="_blank" >https://doi.org/10.1016/j.ejmech.2024.116592</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2024.116592" target="_blank" >10.1016/j.ejmech.2024.116592</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Novel neuroprotective 5,6-dihydropyrido[2′,1':2,3]imidazo[4,5-c] quinoline derivatives acting through cholinesterase inhibition and CB2 signaling modulation

Popis výsledku v původním jazyce

A novel group of 5,6-dihydropyrido [2 ',1':2,3]imidazo [4,5-c]quinolines was prepared via a microwave assisted one-pot telescopic approach. The synthetic sequence involves the formation of an amine precursor of imidazo [1,2-a]pyridine via condensation and reduction under microwave irradiation. Subsequently, the Pictet-Spengler cyclisation reaction occurs with ketones (cyclic or acyclic) to obtain substituted 5,6-dihydropyrido [2 ',1':2,3] imidazo [4,5-c]quinolines in excellent yields. The compounds were tested as neuroprotective agents. Observed protection of neuron-like cells, SH-SY5Y differentiated with ATRA, in Parkinson's and Huntington's disease models inspired further mechanistic studies of protective activity against damage induced by 1-methyl-4-phenylpyridinium (MPP+), a compound causing Parkinson's disease. The novel compounds exhibit similar or higher potency than ebselen, an established drug with antioxidant activity, in the cells against MPP +induced total cellular superoxide production and cell death. However, they exhibit a significantly higher capacity to reduce mitochondrial superoxide and preserve mitochondrial membrane potential. We also observed marked differences between a selected derivative and ebselen in terms of normalizing MPP +induced phosphorylation of Akt and ERK1/2. The cytoprotective activity was abrogated when signaling through cannabinoid receptor CB2 was blocked. The compounds also inhibit both acetylcholine and butyrylcholine esterases. Overall the data show that novel 5,6-dihydropyrido [2 ',1':2,3]imidazo [4,5-c]quinoline have a broad cytoprotective activity which is mediated by several mechanisms including mitoprotection.

Název v anglickém jazyce

Novel neuroprotective 5,6-dihydropyrido[2′,1':2,3]imidazo[4,5-c] quinoline derivatives acting through cholinesterase inhibition and CB2 signaling modulation

Popis výsledku anglicky

A novel group of 5,6-dihydropyrido [2 ',1':2,3]imidazo [4,5-c]quinolines was prepared via a microwave assisted one-pot telescopic approach. The synthetic sequence involves the formation of an amine precursor of imidazo [1,2-a]pyridine via condensation and reduction under microwave irradiation. Subsequently, the Pictet-Spengler cyclisation reaction occurs with ketones (cyclic or acyclic) to obtain substituted 5,6-dihydropyrido [2 ',1':2,3] imidazo [4,5-c]quinolines in excellent yields. The compounds were tested as neuroprotective agents. Observed protection of neuron-like cells, SH-SY5Y differentiated with ATRA, in Parkinson's and Huntington's disease models inspired further mechanistic studies of protective activity against damage induced by 1-methyl-4-phenylpyridinium (MPP+), a compound causing Parkinson's disease. The novel compounds exhibit similar or higher potency than ebselen, an established drug with antioxidant activity, in the cells against MPP +induced total cellular superoxide production and cell death. However, they exhibit a significantly higher capacity to reduce mitochondrial superoxide and preserve mitochondrial membrane potential. We also observed marked differences between a selected derivative and ebselen in terms of normalizing MPP +induced phosphorylation of Akt and ERK1/2. The cytoprotective activity was abrogated when signaling through cannabinoid receptor CB2 was blocked. The compounds also inhibit both acetylcholine and butyrylcholine esterases. Overall the data show that novel 5,6-dihydropyrido [2 ',1':2,3]imidazo [4,5-c]quinoline have a broad cytoprotective activity which is mediated by several mechanisms including mitoprotection.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

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

1768-3254

Svazek periodika

276

Číslo periodika v rámci svazku

OCT 5

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

15

Strana od-do

116592

Kód UT WoS článku

001271874400001

EID výsledku v databázi Scopus

2-s2.0-85198538522