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

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

  • Eur J Med Chem. 2024 Oct 5:276:116592. doi: 10.1016/j.ejmech.2024.116592.
Sushovan Jena 1,  Gabriel Gonzalez 2,  Dominik Vítek 3,  Marie Kvasnicová 4,  Šárka Štěpánková 5,  Miroslav Strnad 6,  Jiří Voller 7,  Kaushik Chanda 8
Affiliations

Affiliations

  • 1 Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
  • 2 Department of Experimental Biology, Palacky University Olomouc, Faculty of Science, Šlechtitelů 27, 78371, Olomouc, Czech Republic; Department of Neurology, University Hospital in Olomouc, I. P. Pavlova 6, 77520, Olomouc, Czech Republic.
  • 3 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77515, Olomouc, Czech Republic.
  • 4 Department of Experimental Biology, Palacky University Olomouc, Faculty of Science, Šlechtitelů 27, 78371, Olomouc, Czech Republic; Laboratory of Growth Regulators, Faculty of Science, Palacký University Olomouc, and Institute of Experimental Botany of the Czech Academy of Sciences, Šlechtitelů 27, CZ-78371, Olomouc, Czech Republic.
  • 5 Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 53210, Pardubice, Czech Republic.
  • 6 Laboratory of Growth Regulators, Faculty of Science, Palacký University Olomouc, and Institute of Experimental Botany of the Czech Academy of Sciences, Šlechtitelů 27, CZ-78371, Olomouc, Czech Republic.
  • 7 Department of Experimental Biology, Palacky University Olomouc, Faculty of Science, Šlechtitelů 27, 78371, Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77515, Olomouc, Czech Republic. Electronic address: jiri.voller@upol.cz.
  • 8 Department of Chemistry, Rabindranath Tagore University, Hojai, Assam, 782435, India. Electronic address: chandakaushik1@gmail.com.
PMID: 39013357 DOI: 10.1016/j.ejmech.2024.116592
Abstract

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.

Keywords

Choline esterase; Microwave-assisted synthesis; Mitochondria; Neurodegeneration; One-pot synthesis; Parkinson's disease; Telescopic approach.

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