Antioxidant Activities of Monosubstituted Indolinonic Hydroxylamines: A Thermodynamic and Kinetic Study

Indolinonic hydroxylamine (IH) is known as a potential artificial antioxidant in apolar environments. Here, a library of 108 monosubstituted derivatives was screened in silico to identify a lead compound for increased antioxidant activity, following a strategy of shortlisting based on thermochemical and kinetic properties. It was found that the presence of substituents at the 2, 4, and 7 positions increased, while substituents in other positions decreased the BDE(O-H) values, in good correlation to the electron-donating ability of substituents. Among the studied compounds, the N and 5 amine-substituted derivatives have the lowest BDE(O-H) values (62.4-64.0 kcal mol^-1). The presence of the strong electron-withdrawing substituents can decrease the proton affinities of the derivatives, whereas the decrease of ionization energies correlates to the electron-donating ability of the substituents. It was also found that the formal hydrogen transfer (FHT) mechanism is the favored pathway for the HOO^· radical scavenging. Kinetic calculations showed that the rate constant of the reaction between N-NHMe-IH compound and HOO^· radical following the FHT mechanism (k = 3.00 × 10⁷ M^-1 s^-1) is about 8223 and 5253 times higher than those of Trolox and ascorbic acid, respectively, in the pentyl ethanoate solvent. Thus, N-NHMe-IH is expected to be the most powerful antioxidant reported to date in lipid environments.