Polyfunctionalized α-Phenyl-tert-butyl(benzyl)nitrones: Multifunctional Antioxidants for Stroke Treatment

Abstract

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.

Electronic Medical Record Data Analysis and Prediction of Stroke Disease Using Explainable Artificial Intelligence (XAI)

“…It can be caused by the burden on the mind of someone married to be more than the unmarried. This burden of thought can cause feelings of stress and trigger a stroke [36]. The link between stress and stroke is significantly correlated and undeniable [37].…”

“…First, stress can cause the heart to work harder, raise blood pressure, and increase blood sugar and fat levels. If left continuously, these things are very likely to increase the risk of forming clots in the heart or brain, causing strokes [36]. In other words, chronic stress can trigger problems with the blockage or rupture of blood vessels in the brain (stroke).…”

N-Hydroxy-N-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases

“…Compound 4 at concentrations of 3.125–50 µM was incubated for 1.5 h with 2,2-diphenyl-1-picrylhydrazyl radical (DPPH, 70 µM) in MeOH, and absorbance was measured (λ = 517 nm) using a Synergy™ H4 reader (BioTek Instruments, Inc., Winooski, VT, USA) [ 41 ]. The experiment was performed in three technical replicates, and the blank sample (compound 4 without DPPH) was subtracted.…”

α-Phenyl-N-tert-Butylnitrone and Analogous α-Aryl-N-alkylnitrones as Neuroprotective Antioxidant Agents for Stroke

“…In looking for new potent PBN analogues with improved spin-trapping power and strong neuroprotection, in the last ten years I have designed, synthesized, and evaluated a number of simple, easily available PBN-derived nitrones whose neuroprotective and antioxidant profile will be highlighted in this section [87][88][89][90][91][92][93][94][95][96].…”

“…In one of the most recent contributions from our group in the search for new and neuroprotective PBN-nitrones [95], we recently described the design and synthesis of the polyfunctionalized PBN-derived para-, meta-, and ortho-substituted nitrones 54-65 (Figure 13), bearing piperidinepropoxy-and N-propargyl-piperazinepropoxy, reputed pharmacophore groups, to allow the inhibition of cholinesterase and monoamino oxidase enzymes by these nitrones. The final target is to identify neuroprotective multivalent PBNnitrones for the combined therapy of AD and stroke.…”