5-Aryl-2-(3,5-dialkyl-4-hydroxyphenyl)-4,4-dimethyl-4H-imidazole 3-Oxides and Their Redox Species: How Antioxidant Activity of 1-Hydroxy-2,5-dihydro-1H-imidazoles Correlates with the Stability of Hybrid Phenoxyl-Nitroxides.

Svetlana A Amitina,Dmitrii G Mazhukin,Alyona V Lomanovich,Alexander F Markov,Natalya A Dmitrieva,Elena V Zaytseva,Ilya A Artamonov,Yury A Ten,Natalya V Kandalintseva

doi:10.3390/molecules25143118

Abstract

Cyclic nitrones of the imidazole series, containing a sterically hindered phenol group, are promising objects for studying antioxidant activity; on the other hand, they can form persistent hybrid phenoxyl–nitroxyl radicals (HPNs) upon oxidation. Here, a series of 5-aryl-4,4-dimethyl-4H-imidazole 3-oxides was obtained by condensation of aromatic 2-hydroxylaminoketones with 4-formyl-2,6-dialkylphenols followed by oxidation of the initially formed N-hydroxy derivatives. It was shown that the antioxidant activity of both 1-hydroxy-2,5-dihydroimidazoles and 4H-imidazole 3-oxides increases with a decrease in steric volume of the alkyl substituent in the phenol group, while the stability of the corresponding HPNs generated from 4H-imidazole 3-oxides reveals the opposite tendency.

Highlights

4-Formyl-2,6-dialkylphenols 23a–e required for the further condensation with 2-hydroxylamino ketones were obtained with high yields via the Duff reaction of α,α0 -dialkyl–substituted phenols 24a–e ketones were obtained with high yields via the Duff reaction of α,α′-dialkyl–substituted phenols 24a
A large set of cyclic hydroxylamines of the 2,5-dihydroimidazole series was obtained via condensation of para-formyl–substituted 2,6-dialkylphenols with different aromatic
It was shown that the antioxidant activity of the investigated imidazole derivatives strongly depends on i) the number of active centers in a molecule able to react with reactive oxygen species (ROS); ii) the structure and effective volume of alkyl substituents in the phenolic moiety, making 1-hydroxy-2-(3,5-dialkyl-4-hydroxyphenyl)-2,5-dihydroimidazole derivatives more active than the widely known BHT

Summary

Introduction

Nitrones are unique free-radical scavengers acting as spin traps of very cytotoxic reactive oxygen species (ROS) accumulating in tissues at high concentrations under oxidative stress. One of the first nitrones to be used as a neuroprotector reducing ischemic hippocampal damage in animals was N-tert-butyl-α-phenylnitrone (PBN) 1a [7]. A series of 1a derivatives has been synthesized and applied as (i) hydrophilic spin traps for different types of organic radicals 1b for OH , CO2 - ) [8] and (ii) spin traps for the hydroxymethyl radical and promising agents for Molecules 2020, 25, 3118; doi:10.3390/molecules25143118 www.mdpi.com/journal/molecules. Molecules 2020, 25, x damage in animals was N-tert-butyl-α-phenylnitrone (PBN) 1a [7].

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Results

Conclusion