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Synthesis of new ferulic/lipoic/comenic acid-melatonin hybrids as antioxidants and Nrf2 activators via Ugi reaction

    Irene Pachón-Angona

    Laboratoire Neurosciences intégratives et cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France

    ,
    Helène Martin

    PEPITE EA4267, Laboratoire de Toxicologie Cellulaire, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France

    ,
    Stecy Chhor

    Laboratoire Neurosciences intégratives et cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France

    PEPITE EA4267, Laboratoire de Toxicologie Cellulaire, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France

    ,
    María-Jesús Oset-Gasque

    Department of Biochemistry & Molecular Biology, School of Pharmacy, Complutense University, 28040, Madrid, Spain

    ,
    Bernard Refouvelet

    Laboratoire Neurosciences intégratives et cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France

    ,
    José Marco-Contelles

    Laboratory of Medicinal Chemistry (IQOG, CSIC), C/Juan de la Cierva, 3 – 28006, Madrid, Spain

    &
    Lhassane Ismaili

    *Author for correspondence: Tel.: +33 38 166 5543;

    E-mail Address: lhassane.ismaili@univ-fcomte.fr

    Laboratoire Neurosciences intégratives et cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France

    Published Online:https://doi.org/10.4155/fmc-2019-0191

    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.

    Graphical abstract

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