Neurodegenerative diseases impose a considerable medical and public health burden on populations throughout the world. Oxidative stress, an imbalance in prooxidant/antioxidant homeostasis that leads to the generation of reactive oxygen species (ROS), has been implicated in the progression of a number of neurodegenerative diseases. The manipulation of ROS levels may represent a promising treatment option to slow down neurodegeneration, although adequate potency of treatments has not yet been achieved. Using a hybrid pharmacology approach, free radical nitroxide antioxidants were hybridised with a class of natural antioxidants, flavonoids, to form a potential multitargeted antioxidant. Modification of the Baker-Venkataraman reaction achieved the flavonoid-nitroxide hybrids (6-9) in modest yields. Antioxidant evaluation of the hybrids by cyclic voltammetry showed both redox functionalities were still active, with little influence on oxidation potential. Assessment of the peroxyl radical scavenging ability through an ORAC assay showed reduced antioxidant activity of the hybrids compared to their individual components. It was hypothesized that the presence of the phenol in the hybrids creates a more acidic medium which does not favour regeneration of the nitroxide from the corresponding oxammonium ion, disturbing the typical catalytic cycle of peroxyl radical scavenging by nitroxides. This work highlights the potential intricacies involved with drug hybridization as a strategy for new therapeutic development.

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