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Virtual Drug Design

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Front. Chem. | doi: 10.3389/fchem.2018.00041

Structure-Activity Relationship Analysis of 3-phenylcoumarin-Based Monoamine Oxidase B Inhibitors

 Sanna Rauhamäki1,  Pekka A. Postila1, Sanna Niinivehmas1,  Sami Kortet1, 2, Emmi Schildt1, 2, Mira Pasanen1,  Elangovan Manivannan1, 3,  Mira Ahinko1,  Pasi Koskimies4, Niina Nyberg5, Pasi Huuskonen5, Elina Multamäki1,  Markku Pasanen5,  Risto O. Juvonen5,  Hannu Raunio5, Juhani Huuskonen2* and  Olli T. Pentikäinen1, 6*
  • 1Department of Biological and Environmental Science, University of Jyväskylä, Finland
  • 2Department of Chemistry, University of Jyväskylä, Finland
  • 3School of Pharmacy, Devi Ahilya Vishwavidyalaya, India
  • 4Forendo Pharma Ltd, Finland
  • 5School of Pharmacy, University of Eastern Finland, Kuopio, Finland
  • 6Institute of Biomedicine, University of Turku, Finland

Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson’s disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry. The derivatives inhibited the MAO-B at 100 nM - 1 µM. The IC50 value of the most potent derivative 1 was 56 nM. A docking-based structure-activity relationship analysis summarizes the atom-level determinants of the MAO-B inhibition by the derivatives. Finally, the cross-reactivity of the derivatives was tested against monoamine oxidase A and a specific subset of enzymes linked to estradiol metabolism, known to have coumarin-based inhibitors. Overall, the results indicate that the 3-phenylcoumarins, especially derivative 1, present unique pharmacological features worth considering in future drug development.

Keywords: 3-phenylcoumarin, monoamine oxidase B (MAO-B), Structure-activity relationship (SAR), Virtual Drug Design, Parkinson’s disease

Received: 10 Jan 2018; Accepted: 14 Feb 2018.

Edited by:

Daniela Schuster, Paracelsus Private Medical University of Salzburg, Austria

Reviewed by:

Justin W. Hicks, Lawson Health Research Institute, Canada
Julian Fuchs, University of Innsbruck, Austria
Outi M. Salo-Ahen, Åbo Akademi University, Finland  

Copyright: © 2018 Rauhamäki, Postila, Niinivehmas, Kortet, Schildt, Pasanen, Manivannan, Ahinko, Koskimies, Nyberg, Huuskonen, Multamäki, Pasanen, Juvonen, Raunio, Huuskonen and Pentikäinen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Juhani Huuskonen, University of Jyväskylä, Department of Chemistry, Jyväskylä, Finland, juhani.s-p.huuskonen@jyu.fi
Prof. Olli T. Pentikäinen, University of Jyväskylä, Department of Biological and Environmental Science, Jyväskylä, Finland, olli.pentikainen@utu.fi