Antioxidant mechanism of Edaravone and its amine analogs: Combined kinetic and DFT study

The antioxidant activity of edaravone (1) and its amine analogs namely 5-amino-1-phenyl-1H-pyrazol-3-ol (2), 3-amino-1-phenyl-1H-pyrazol-5-ol (3), and their synthetic precursor 2-cyano-N'-phenylacetohydrazide (4), was investigated in initiated peroxidation systems. Rate constants for their reactions with peroxyl radicals of tetrahydrofuran (THF) at 309 K were measured as (4.4 ± 0.5) × 10⁴, (2.7 ± 0.5) × 10⁴, (1.9 ± 0.3) × 10³, and (2.4 ± 0.3) × 10⁴ L mol^-1 s^-1 for compounds 1-4, respectively. The stoichiometric inhibition coefficient varied from 1 to ∼2. Quantum chemical calculations (SMD-M06-2X/MG3S) revealed that compound 1 and 2 exists as two tautomers, while compound 3 predominantly exists as a single tautomer. The inhibition mechanism is consistent with hydrogen atom transfer (HAT) by peroxyl radicals, supported by the observation of a pronounced kinetic isotope effect and by SMD-M05/6-311 + G(2df,2p) modeling. These findings suggest compounds 2 and 4 as promising candidates for further antioxidant drug development.