The radical scavenging activity of 4-mercaptoimidazole: theoretical insights into the mechanism, kinetics and solvent effects

Abstract

4-Mercaptoimidazole (4MC) is related to natural ovothiols known to be potent radical scavengers. In spite of early reports of its good antioxidant activity, 4MC has attracted little attention thus far. In particular, details of the mechanism and kinetics of its antiradical activity against common free radicals such as HO˙ and HOO˙ have not been explored as of yet. In this study, DFT simulations were used to examine the potential of 4MC as a radical scavenger. Calculations suggested that 4MC is likely an effective HO˙ scavenger in both nonpolar and aqueous environments (k_overall values of 1.10 × 10¹⁰ and 9.58 × 10⁹ M⁻¹ s⁻¹, respectively). The computed kinetic data of the HO˙ antiradical activity are close to the experimental rate constant in water yielding a k_calculated/k_experimental ratio of 0.2–0.5. The formal hydrogen transfer (FHT) and radical adduct formation (RAF) reactions dominated the hydroxyl radical scavenging activity in the studied media; however, the HOO˙ antiradical activity in water followed the single electron transfer (SET) pathway. The hydrogen transfer of the N–H bond takes place by the proton-coupled electron transfer (PCET) mechanism, whereas that of the S–H bond is defined by the hydrogen atom transfer (HAT) pathway. Furthermore, 4MC showed excellent antiradical activity against CH₃O˙, CCl₃O˙, HOO˙, CH₃OO˙, CCl₃OO˙, NO₂, O₂˙⁻, SO₄˙⁻, DPPH and ABTS˙⁺in silico, with a k_SET of ≈ 10⁹ M⁻¹ s⁻¹. In water, at physiological pH, the HOO˙ antiradical activity of 4MC is higher than that of typical antioxidants including ascorbic acid, trolox and trans-resveratrol. It was noted that the radical product of the initial reaction can consecutively react strongly with the O₂˙⁻ radical with a rate constant of 5.62 × 10⁹ M⁻¹ s⁻¹. Thus, a regeneration cycle involving the scavenging of O₂˙⁻ and HOO˙ radicals may enhance the bioactivity of 4MC.