Synthesis, Antioxidant and Anti-inflammatoy Effects of Antioxidant Acid Amides with GABA and N-Acyl-pyrrolidin-2-ones

Background: Given the important role of GABA in the central nervous system, the nootropic-neuroprotective activity of aniracetam, a cyclised derivative of GABA, the participation of inflammation and oxidative stress in degenerative disorders, some novel compounds combining the above characteristics are studied. Objectives: A series of amides of GABA with the antioxidant acids lipoic acid, 3,5-di-tert-butyl-4- hydroxybenzoic acid, 3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid and trolox, their ethyl or methyl esters and their cyclised N-acyl-pyrrolidin-2-ones have been prepared as antioxidants, possible nootropics aniracetam related structures. Results: The most potent antioxidant was (R)-1-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl) pyrrolidin-2-one (11), which was found to inhibit the ferrous/ascorbate induced lipid peroxidation of microsomal membrane lipids, with IC50 13 μM. The majority of the tested compounds inhibited cyclooxygenases (18-72%); 1-(3,5-di-tert-butyl-4-hydroxybenzoyl)pyrrolidin-2-one (6), (E)-methyl 4-(3- (3,5-di-tert-butyl-4-hydroxyphenyl)acrylamido)butanoate (8) and (R)-ethyl 4-(6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamido)butanoate (10), which are potent inhibitors of soybean lipoxygenase, having IC50 value 47-48 μM. They reduced carrageenan-induced rat paw oedema by 41-62%. Conclusion: Since inflammation and oxidative stress are common characteristics of degenerative disorders, agents combining anti-inflammatory, antioxidant and cytoprotective properties could be proven useful for their treatment.