Title:Synthesis, Antioxidant and Anti-inflammatoy Effects of Antioxidant Acid Amides with GABA and N-Acyl-pyrrolidin-2-ones
Volume: 11
Issue: 2
Author(s): Karyophyllis C. Tsiakitzis, Georgios Papagiouvannis, Panagiotis Theodosis-Nobelos, Paraskevi Tziona, Panos N. Kourounakis and Eleni A. Rekka*
Affiliation:
- Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki,Greece
Keywords:
GABA amides, N-acyl-pyrrolidin-2-ones, antioxidants, cycloxygenase inhibition, antiinflammatory
activity, cytoprotective.
Abstract: 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.