Evaluation of the anti-AChE and protective effect of New Imidazole Derivatives: In Silico Analysis and Experimental study on oxidative stress and Oligodendrocyte Death

Abstract

Abstract Purpose : Neurodegenerative diseases, including Alzheimer disease, are associated with oxidative stress and disruption of cholinergic neurotransmission. Thus the search for molecules capable of modulating ROS production and acetylcholine function is crucial. The aim of this study was to evaluate the inhibitory potential of nine imidazole derivatives against AChE in vitro. In silico Molecular Docking and ADMET studies were conducted on the most potent compounds 3a, 3e, 3g, and 3h to predict their drug-likeness, pharmacokinetics, and toxicity properties. In Addition, we evaluated the potential protective effects of the compound 3a (2-metyl-3H-imidazo[2,1-c][1,2,4]triazol-3-yl)(4-phenyl)methanone), on murine oligodendrocytes (158N) cultured in the absence or presence of 7β-OHC (20 μg/mL, 24 h). Methods: The cell viability was measured at 570 nm wavelength. We analyzed Catalase (CAT) and glutathione peroxidase (GPx) activity using photometric techniques. Results: Among the tested compounds, compounds 3a, 3e, 3g, and 3h exhibited significant inhibition effects on acetylcholinesterase (AChE) in comparison to the positive control donopezil. Molecular docking studies indicated that the compound 3a, with a favorable affinity, occupied the active site of AChE. Furthermore, the results demonstrated that a concentration of 31,5μg/mL of compound 3a could attenuate the toxic effect induced by 7β-OHC on 158N cells, and GPx and CAT activities were restored to normal. Conclusion : These data demonstrate the anticholinesterase and protective activities of (2-metyl-3H-imidazo[2,1-c][1,2,4]triazol-3-yl)(4-phenyl)methanone) against the toxicity induced by 7β-OHC in 158N cells.