Synthesis and evaluation of antioxidant activity of some novel hydroxypyridinone derivatives: a DFT approach for explanation of their radical scavenging activity

Abstract

Background and purpose: Reactive oxygen species (ROSs) are continuously produced as byproducts of cell metabolism. Free radicals are an unstable form of ROSs with the tendency to react readily with biomolecules such as amino acids, lipids and DNA. These reactions lead to oxidative damages to the cell. Oxidative stress occurs when the concentration of the ROSs exceeds the capacity of antioxidative protection systems of the body. 5-Hydroxypyridin-4-one derivatives can chelate Fe 2+ and Fe 3+ due to their α-hydroxyketone moiety. Also, tautomerism in hydroxypyridinone ring leads to enough level of aromaticity resulting in a catechol-like behavior that provides them with good chelating and radical scavenging properties. Experimental approach: Different compounds were synthesized with 5-hydroxypyridine-4-one moiety as the core. The antioxidant properties of molecules were evaluated experimentally by DPPH scavenging method and theoretically using DFT/B3LYP with a 6-31++G (d,p) basis set. Electronic properties were investigated using frontier molecular orbital theory calculations. Furthermore, global descriptive parameters were obtained to find the chemical reactivity of molecules. The natural bond orbital analysis was performed to investigate charge distribution and hydrogen bonding. Findings/Results: Structures of the synthesized compounds were confirmed using IR, 1 H-NMR, and 13 C-NMR spectral analyses. Among all the synthesized compounds, Va and Vb showed the best antioxidant effect experimentally and computationally. Conclusion and implications: Results of this study were valuable in terms of synthesis, in silico , and in vitro antioxidant evaluations and can be useful for future investigations about the design of novel 5-hydroxypyridin- 4-one derivatives possessing iron-chelating and radical scavenging abilities.

Design, Synthesis, Molecular Docking, and Molecular Dynamics Simulation Studies of Novel 3‐Hydroxypyridine‐4‐one Derivatives as Potential Acetylcholinesterase Inhibitors

“…Furthermore, they exhibited good antioxidant ability, as reported in our previous manuscript. [19] Docking pose analysis of these compounds into the active site of AChE demonstrated that they behave like donepezil. Indeed, 5-hydroxypyridine-4-one moiety behaves similar to the ketone group of indanone moiety of donepezil to interact with active site gorge of AChE.…”

“…Furthermore, when this scaffold is added to AChE inhibitor while bearing hydroxy moiety at C-5 position of pyridin-4-one ring, it confers good antioxidant and metal chelation abilities in designing compounds. [19] In another fascinating aspect, hydroxypyridin-4-one scaffold which contains benzyloxy moiety at C-5 position of pyridin-4-one ring can play a role similar to the benzylpiperidine scaffold for interaction with the active site gorge amino acids.…”

A Comparative DFT Study on the Antioxidant Activity of Some Novel 3‐Hydroxypyridine‐4‐One Derivatives

“…Chemicals with iron chelating ability can potentially suppress oxidative stress to alleviate the destroying effects of the free radicals [21] . A prospective strategy for delivering new antioxidants may be a chemical compound with dual functionality – iron chelation to prevent Fenton and Haber‐Weiss reactions and the ability to scavenge radicals [22–25] …”

“…Two strategies are usually used to investigate mechanisms of antioxidant activity. The first strategy uses vertical energies, which are based on the difference of total electronic and thermal enthalpies [23] . The second consists of the frontier orbital calculations, which computes the difference between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies of the neutral molecules, and is known as the orbital vertical method [50] …”

“…The first strategy uses vertical energies, which are based on the difference of total electronic and thermal enthalpies. [23] The second consists of the frontier orbital calculations, which computes the difference between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies of the neutral molecules, and is known as the orbital vertical method. [50] In this article we report a comparative theoretical study, using DFT calculations, of the antioxidant properties of some 3-hydroxypyridine-4-one derivatives.…”