Gabapentin Antioxidant Derivatives with Anti-Inflammatory and Neuroprotective Potency

Aims: The aim of this work is to investigate the antioxidant and anti-inflammatory potency of novel gabapentin derivatives, which could be proven useful as neuroprotective agents. Background: Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders worldwide. Due to its multi-factorial character, no effective treatment has been obtained yet. In this direction, the multi-targeting compounds approach could be useful for the development of novel, more effective drugs against AD. Oxidative stress and inflammation are highly involved in the progression of neurodegeneration, while gabapentin has been investigated for the treatment of behavioral symptoms in AD. Objective: In this work, derivatives of cinnamic acid, Trolox, and 3,5-di-tertbutyl-4-hydroxybenzoic acid amidated with gabapentin methyl ester were designed and studied. Compounds with these structural characteristics are expected to act in various biochemical pathways, affecting neurodegenerative processes. Methods: The designed compounds were synthesized with classical amidation methods, purified by flash column chromatography, and identified spectrometrically (1H-NMR and 13C-NMR). Their purity was determined by CHN elemental analysis. They were tested in vitro for their antioxidant and antiinflammatory properties and for their inhibitory effect on acetylcholinesterase. Their in vivo antiinflammatory activity was also tested. Results: Molecules that incorporated antioxidant moiety possessed inhibitory activity against rat microsomal membrane lipid peroxidation and oxidative protein glycation, as well as radical scavenging activity. Moreover, most of them presented moderate inhibition towards lipoxygenase (up to 51% at 100μΜ) and acetylcholinesterase (AchE) (IC50 up to 274μΜ) activities. Finally, all synthesized compounds presented in vivo anti-inflammatory activity, decreasing carrageenan-induced rat paw edema up to 53%, and some of them could inhibit cyclooxygenase significantly. Conclusion: These results indicate that the designed compounds could be proven useful as multitargeting molecules against AD since they affect various biochemical pathways associated with neurodegeneration. Thus, more effective drugs can be obtained, and the possible adverse effects of drug combinations can be limited.