Novel neuroprotective 5,6-dihydropyrido[2',1':2,3]imidazo[4,5-c]quinoline derivatives acting through cholinesterase inhibition and CB2 signaling modulation
Language English Country France Media print-electronic
Document type Journal Article
PubMed
39013357
DOI
10.1016/j.ejmech.2024.116592
PII: S0223-5234(24)00472-0
Knihovny.cz E-resources
- Keywords
- Choline esterase, Microwave-assisted synthesis, Mitochondria, Neurodegeneration, One-pot synthesis, Parkinson's disease, Telescopic approach,
- MeSH
- Quinolines * pharmacology chemistry chemical synthesis MeSH
- Cholinesterase Inhibitors * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Neuroprotective Agents * pharmacology chemistry chemical synthesis MeSH
- Receptor, Cannabinoid, CB2 * metabolism antagonists & inhibitors MeSH
- Signal Transduction * drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Quinolines * MeSH
- Cholinesterase Inhibitors * MeSH
- Neuroprotective Agents * MeSH
- Receptor, Cannabinoid, CB2 * MeSH
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.
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