Nowadays, most
stroke patients are treated exclusively with recombinant
tissue plasminogen activator, a
drug with serious side effects and limited therapeutic window. For this reason, and because of the known effects of oxidative stress on
stroke, a more tolerable and efficient
therapy for
stroke is being sought that focuses on the control and scavenging of highly toxic
reactive oxygen species by appropriate small molecules, such as
nitrones with
antioxidant properties. In this context, herein we report here the synthesis,
antioxidant, and neuroprotective properties of twelve novel polyfunctionalized α-phenyl-tert-butyl(benzyl)
nitrones. The
antioxidant capacity of these
nitrones was investigated by various assays, including the inhibition of lipid peroxidation induced by
AAPH,
hydroxyl radical scavenging assay,
ABTS+-decoloration assay, DPPH scavenging assay, and inhibition of soybean
lipoxygenase. The inhibitory effect on monoamine
oxidases and
cholinesterases and inhibition of β-
amyloid aggregation were also investigated. As a result, (Z)-N-benzyl-1-(2-(3-(piperidin-1-yl)propoxy)phenyl)methanimine
oxide (5) was found to be one of the most potent
antioxidants, with high ABTS+ scavenging activity (19%), and potent
lipoxygenase inhibitory capacity (IC50 = 10 µM), selectively inhibiting
butyrylcholinesterase (IC50 = 3.46 ± 0.27 µM), and exhibited neuroprotective profile against the neurotoxicant
okadaic acid in a neuronal damage model. Overall, these results pave the way for the further in-depth analysis of the neuroprotection of nitrone 5 in in vitro and in vivo models of
stroke and possibly other
neurodegenerative diseases in which oxidative stress is identified as a critical player.