Theoretical insights into the antiradical activity and copper-catalysed oxidative damage of mexidol in the physiological environment.

Nguyen Thi Hoa,Mai Van Bay,Quan V Vo,Adam Mechler

doi:10.1098/rsos.211239

Nguyen Thi Hoa, Mai Van Bay + Show 2 more

Open Access

https://doi.org/10.1098/rsos.211239

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Abstract

Mexidol (MD, 2-ethyl-6-methyl-3-hydroxypyridine) is a registered therapeutic agent for the treatment of anxiety disorders. The chemical structure suggests that MD may also act as an antioxidant. In this study, the hydroperoxyl radical scavenging activity of MD was studied to establish baseline antioxidant activity, followed by an investigation of the effect of MD on the copper-catalysed oxidative damage in biological systems, using computational methods. It was found that MD exhibits moderate radical scavenging activity against HOO• in water and pentyl ethanoate solvents following the single electron transfer and formal hydrogen transfer mechanisms, respectively. MD can chelate Cu(II), forming complexes that are much harder to reduce than free Cu(II): MD chelation completely quenches the Cu(II) reduction by ascorbic acid and suppresses the rate of reduction reaction by that are the main reductants of Cu(II) in biological environments. Therefore, MD exerts its anti-HO• activity primarily as an OIL-1 inhibitor.

Highlights

Mexidol (MD, emoxypine, 2-ethyl-6-methyl-3-hydroxypyridine) is a drug used primarily for the treatment of anxiety
The radical scavenging activity of MD was first evaluated in the gas phase following the liturature [16,40], according to the three main reaction pathways: formal hydrogen transfer (FHT), single electron transfer followed by proton transfer (SETPT) and sequential proton loss electron transfer (SPLET) [41,42]
The probabilities of the three feasible antioxidant mechanisms (FHT, SETPT and SPLET) were first evaluated by computing the main thermodynamic parameters associated with these mechanisms: bond dissociation enthalpy (BDE), ionization energy (IE) and proton affinity (PA), respectively

Summary

Introduction

Mexidol (MD, emoxypine, 2-ethyl-6-methyl-3-hydroxypyridine) is a drug used primarily for the treatment of anxiety. The rate constant of MD reaction with peroxyl radical in methyl oleate was measured as k = 2.8 × 104 M−1 s−1 [4], while that for 1,4-dioxane solvent was k = 2.1 ± 0.3 × 104 M−1 s−1 [3]. Organic solutions such as methyl oleate and 1,4-. The radical scavenging activity of organic compounds in physiological environments was successfully evaluated by quantum chemistry calculations [20,21,22,23]. Cu(II) chelation ability was assessed and the ability of MD to act as an OIL-1 inhibitor of the copper-catalysed oxidative damage in biological systems was investigated

Computational details

Gas phase evaluation

OIL-1 inhibition of copper-catalysed oxidative damage in biological systems

Conclusion