Synthesis and evaluation of the antioxidant activity of 3-pyrroline-2-ones: experimental and theoretical insights

Abstract

The heterocyclic γ-lactam ring 2-pyrrolidinone has four carbon atoms and one nitrogen atom. Among the group of derivatives of 2-pyrrolidinones, 1,5-dihydro-2H-pyrrol-2-ones, also known as 3-pyrroline-2-ones, play a significant structural role in a variety of bioactive natural compounds. In this study, three-component reactions were used to successfully synthesize six polysubstituted 3-hydroxy-3-pyrroline-2-one derivatives. The antioxidant activity of the compounds was tested by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, identifying 4-ethoxycarbonyl-3-hydroxy-5-(4-methylphenyl)-1-phenyl-3-pyrroline-2-one (4b) as the most promising radical scavenger. Quantum chemistry calculations of the thermodynamics and kinetics of the radical scavenging activity also suggest that 4b is an effective HO˙ radical scavenger, with k _overall values of 2.05 × 10⁹ and 1.54 × 10¹⁰ M^-1 s^-1 in pentyl ethanoate and water, respectively. On the other hand, 4b could not scavenge hydroperoxyl radicals in either media. The ability of 4b to scavenge hydroxyl radicals in polar and non-polar environments is comparable to that of conventional antioxidants such as melatonin, gallic acid, indole-3-carbinol, ramalin, or Trolox. Thus 4b may be classed as a promising HO˙ radical scavenger in the physiological environment.

Fig. 1. Natural products containing 3-pyrroline-2-one subunit.

Scheme 1. Mechanism for the synthesis of polysubstituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones.

Fig. 2. Optimized geometries of the main transition states between 4b and HO˙/HOO˙ radicals according to FHT and RAF processes.

Fig. 3. The deprotonation of 4b at pH = 7.40.