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.

Department of Biological and Biochemical Sciences Faculty of Chemical Technology University of Pardubice Studentská 573 53210 Pardubice Czech Republic

Department of Chemistry Rabindranath Tagore University Hojai Assam 782435 India

Department of Chemistry School of Advanced Sciences Vellore Institute of Technology Vellore Tamil Nadu 632014 India

Department of Experimental Biology Palacky University Olomouc Faculty of Science Šlechtitelů 27 78371 Olomouc Czech Republic

Department of Neurology University Hospital in Olomouc 1 P Pavlova 6 77520 Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Hněvotínská 5 77515 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

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