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

Author(s): Karyophyllis C. Tsiakitzis, Georgios Papagiouvannis, Panagiotis Theodosis-Nobelos, Paraskevi Tziona, Panos N. Kourounakis, Eleni A. Rekka*.

Journal Name: Current Chemical Biology

Volume 11 , Issue 2 , 2017

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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.

Keywords: GABA amides, N-acyl-pyrrolidin-2-ones, antioxidants, cycloxygenase inhibition, antiinflammatory activity, cytoprotective.

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Article Details

VOLUME: 11
ISSUE: 2
Year: 2017
Page: [127 - 139]
Pages: 13
DOI: 10.2174/2212796811666170509123209
Price: $58

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