Design and Antioxidant Properties of Bifunctional 2H-Imidazole-Derived Phenolic Compounds—A New Family of Effective Inhibitors for Oxidative Stress-Associated Destructive Processes

Abstract

The synthesis of inhibitors for oxidative stress-associated destructive processes based on 2H-imidazole-derived phenolic compounds affording the bifunctional 2H-imidazole-derived phenolic compounds in good-to-excellent yields was reported. In particular, a series of bifunctional organic molecules of the 5-aryl-2H-imidazole family of various architectures bearing both electron-donating and electron-withdrawing substituents in the aryl fragment along with the different arrangements of the hydroxy groups in the polyphenol moiety, namely derivatives of phloroglucinol, pyrogallol, hydroxyquinol, including previously unknown water-soluble molecules, were studied. The structural and antioxidant properties of these bifunctional 5-aryl-2H-imidazoles were comprehensively studied. The redox transformations of the synthesized compounds were carried out. The integrated approach based on single and mixed mechanisms of antioxidant action, namely the AOC, ARC, Folin, and DPPH assays, were applied to estimate antioxidant activities. The relationship “structure-antioxidant properties” was established for each of the antioxidant action mechanisms. The conjugation effect was shown to result in a decrease in the mobility of the hydrogen atom, thus complicating the process of electron transfer in nearly all cases. On the contrary, the conjugation in imidazolyl substituted phloroglucinols was found to enhance their activity through the hydrogen transfer mechanism. Imidazole-derived polyphenolic compounds bearing the most electron-withdrawing functionality, namely the nitro group, were established to possess the higher values for both antioxidant and antiradical capacities. It was demonstrated that in the case of phloroglucinol derivatives, the conjugation effect resulted in a significant increase in the antiradical capacity (ARC) for a whole family of the considered 2H-imidazole-derived phenolic compounds in comparison with the corresponding unsubstituted phenols. Particularly, conjugation of the polyphenolic subunit with 2,2-dimethyl-5-(4-nitrophenyl)-2H-imidazol-4-yl fragment was shown to increase ARC from 2.26 to 5.16 (104 mol-eq/L). This means that the considered family of compounds is capable of exhibiting an antioxidant activity via transferring a hydrogen atom, exceeding the activity of known natural polyphenolic compounds.

Methoxy‐activated indole‐7‐carbohydrazides; synthesis, antioxidant, and anticancer properties

“…The results suggest that introduction of nitro substituent remarkably improved antioxidant activity when 14c and 14d were compared (Table 1). This result is in accordance with a previous study reporting enhanced antioxidant capacity for imidazole derivatives with nitro groups (Gerasimova et al, 2021) [35].…”

The Novel Potentiometric Approach to Antioxidant Capacity Assay Based on the Reaction with Stable Radical 2,2′-diphenyl-1-picrylhydrazyl

“…Previously, we have described and successfully applied a potentiometric approach have been study antioxidant properties using the Ox-Red components of the system on an example of the K 3 [Fe(CN) 6 ]/K 4 [Fe(CN) 6 ], for a wide range of objects [ 19 , 21 , 22 , 23 ]. However, the use of this approach for other models of oxidizing agents is difficult due to the inaccessibility of the Red component of the system, and consequently, the complexity of using two components of the system simultaneously.…”

“…For the successful implementation of this concept, the requirements for the models of oxidizing agent, used in the methods for studying AO properties, were formulated. Approaches to the potentiometric study of antioxidants, based on the reactions of electron and hydrogen atom transfer, have been successfully developed by our group for a long time [ 18 , 19 , 20 , 21 , 22 , 23 ]. Previously, we have shown that reactions with radical systems can be studied by the potentiometric method [ 20 , 21 , 22 , 23 ].…”

“…Approaches to the potentiometric study of antioxidants, based on the reactions of electron and hydrogen atom transfer, have been successfully developed by our group for a long time [ 18 , 19 , 20 , 21 , 22 , 23 ]. Previously, we have shown that reactions with radical systems can be studied by the potentiometric method [ 20 , 21 , 22 , 23 ]. At the same time, this approach has a number of advantages associated with the absence of expensive equipment and activators of the analytical signal, for example, luminophore.…”

“…For the first time, we proposed the hypothesis of a regular change in the potential during the reactions of peroxyl radical’s generation and inhibition ones. This regularity formed the basis for the approach using the radical generating system based on AAPH (2,2′-azobis(2-amidinopropane) dihydrochloride) [ 20 , 21 , 22 , 23 ]. The proposed new approach is based on the dependence of the potential change of radical systems in the process of reaction with an antioxidant by the hydrogen atom transfer mechanism, in an aqueous medium, coupled with the electron transfer process.…”