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

[ Vol. 11 , Issue. 2 ]

Author(s):

Karyophyllis C. Tsiakitzis, Georgios Papagiouvannis, Panagiotis Theodosis-Nobelos, Paraskevi Tziona, Panos N. Kourounakis and Eleni A. Rekka*   Pages 127 - 139 ( 13 )

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.

Affiliation:

Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki, Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki, Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki, Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki, Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki, Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki

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