MAO Inhibitory Activity of 2-Arylbenzofurans versus 3-Arylcoumarins: Synthesis, in vitro Study, and Docking Calculations

Authors

  • Dr. Giulio Ferino,

    1. Department of Chemical and Geological Sciences, University of Cagiari, S.S. 554, 09042 Monserrato Cagliari (Italy)
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  • Prof. Enzo Cadoni,

    1. Department of Chemical and Geological Sciences, University of Cagiari, S.S. 554, 09042 Monserrato Cagliari (Italy)
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  • Dr. Maria João Matos,

    Corresponding author
    1. Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain)
    • Maria João Matos, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain)

      Giovanna Delogu, Department of Life Sciences and Environment, Section of Pharmaceutical Sciences, University of Cagliari, 09124 Cagliari (Italy)

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  • Dr. Elias Quezada,

    1. Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain)
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  • Prof. Eugenio Uriarte,

    1. Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain)
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  • Prof. Lourdes Santana,

    1. Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain)
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  • Dr. Santiago Vilar,

    1. Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032 (USA)
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  • Dr. Nicholas P. Tatonetti,

    1. Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032 (USA)
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  • Matilde Yáñez,

    1. Department of Pharmacology, CIMUS, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain)
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  • Dolores Viña,

    1. Department of Pharmacology, CIMUS, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain)
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  • Dr. Carmen Picciau,

    1. Department of Life Sciences and Environment, Section of Pharmaceutical Sciences, University of Cagliari, 09124 Cagliari (Italy)
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  • Dr. Silvia Serra,

    1. Department of Life Sciences and Environment, Section of Pharmaceutical Sciences, University of Cagliari, 09124 Cagliari (Italy)
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  • Prof. Giovanna Delogu

    Corresponding author
    1. Department of Life Sciences and Environment, Section of Pharmaceutical Sciences, University of Cagliari, 09124 Cagliari (Italy)
    • Maria João Matos, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain)

      Giovanna Delogu, Department of Life Sciences and Environment, Section of Pharmaceutical Sciences, University of Cagliari, 09124 Cagliari (Italy)

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Abstract

Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3-arylcoumarin derivatives were previously described as interesting selective MAO-B inhibitors. Preserving the trans-stilbene structure, a series of 2-arylbenzofuran and corresponding 3-arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO-A and MAO-B. In general, both types of derivatives were found to be selective MAO-B inhibitors, with IC50 values in the nano- to micromolar range. 5-Nitro-2-(4-methoxyphenyl)benzofuran (8) is the most active compound of the benzofuran series, presenting MAO-B selectivity and reversible inhibition (IC50=140 nM). 3-(4′-Methoxyphenyl)-6-nitrocoumarin (15), with the same substitution pattern as that of compound 8, was found to be the most active MAO-B inhibitor of the coumarin series (IC50=3 nM). However, 3-phenylcoumarin 14 showed activity in the same range (IC50=6 nM), is reversible, and also severalfold more selective than compound 15. Docking experiments for the most active compounds into the MAO-B and MAO-A binding pockets highlighted different interactions between the derivative classes (2-arylbenzofurans and 3-arylcoumarins), and provided new information about the enzyme–inhibitor interaction and the potential therapeutic application of these scaffolds.

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