Synthesis of New Ferulic/Lipoic/Comenic Acid-Melatonin Hybrids as Antioxidants and Nrf2 Activators via Ugi Reaction

Abstract

Aim: Oxidative stress has been implicated in the pathogenesis of many neurodegenerative diseases, and particularly in Alzheimer’s disease. Results: This work describes the Ugi multicomponent synthesis, antioxidant power and Nrf2 pathway induction in antioxidant response element cells of (E)-N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-N-(2-(5-(benzyloxy)-1H-indol-3-yl)ethyl)-3-(4-hydroxy-3-methoxyphenyl)acryl amides 8a–d, N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-N-(2-(5-(benzyloxy)-1H-indol-3-yl)ethyl)-5-(1,2-dithiolan-3-yl)pentanamides 8e–h and N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-N-(2-(5-(benzyloxy)-1H-indol-3-yl)ethyl)-5-hydroxy-4-oxo-4H-pyran-2-carboxamides 8i,j. Conclusion: We have identified compounds 8e and 8g, showing a potent antioxidant capacity, a remarkable neuroprotective effect against the cell death induced by H₂O₂ in SH-SY5Y cells, and a performing activation of the Nrf2 signaling pathway, as very interesting new antioxidant agents for pathologies that curse with oxidative stress.

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Keywords: :

• antioxidants
• ARE cells
• Nrf2 pathway
• ORAC
• Ugi multicomponent reaction

Acknowledgements

J Marco-Contelles and L Ismaili acknowledge the MuTaLig (CA15135) Cost Action.

Financial & competing interests disclosure

This work was supported by the Regional Council of Franche-Comté (2016YC-04540 and 04560). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.