Discovery of New Antioxidant Molecules Enhancing the Nrf2-Mediated Pathway: Docking Studies and Biological Evaluation

Oxidative stress has been reported to be implicated in the pathogenesis of many neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Enhancing antioxidant response, through the activation of the transcription factor Nrf2, may represent a potential strategy, based on in vitro models. To identify scaffolds potentially able to modulate the Nrf2-Keap1 interaction, docking experiments were carried out using a library of commercially available and in-house synthesized molecules. Compounds 1-4 were selected, and their direct and indirect antioxidant activity was evaluated in an acute oxidative stress model induced by Fenton's reaction in the human neuroblastoma SH-SY5Y cell line. Results showed that these compounds exerted the most pronounced protective effect under the tested conditions at the following concentrations: 10 μM for 1, 25 μM for 2, 10 μM for 3, and 5 μM for 4. Moreover, these molecules notably decreased intracellular ROS production and lipid peroxidation by-products and increased the GSH/GSSG ratio. Furthermore, these molecules promoted the protein expression of antioxidant enzymes downstream of the Nrf2 transcriptional pathway. Interestingly, compound 3 resulted in being the most active among the four.