A1 Refereed original research article in a scientific journal
Structure-Activity Relationship Analysis of 3-Phenylcoumarin-Based Monoamine Oxidase B Inhibitors
Authors: Sanna Rauhamäki, Pekka A. Postila, Sanna Niinivehmas, Sami Kortet, Emmi Schildt, Mira Pasanen, Elangovan Manivannan, Mira Ahinko, Pasi Koskimies, Niina Nyberg, Pasi Huuskonen, Elina Multamäki, Markku Pasanen, Risto O. Juvonen, Hannu Raunio, Juhani Huuskonen, Olli T. Pentikäinen
Publisher: FRONTIERS MEDIA SA
Publication year: 2018
Journal: Frontiers in Chemistry
Journal name in source: FRONTIERS IN CHEMISTRY
Journal acronym: FRONT CHEM
Article number: ARTN 41
Volume: 6
Number of pages: 18
ISSN: 2296-2646
eISSN: 2296-2646
DOI: https://doi.org/10.3389/fchem.2018.00041
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/30711695
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 mu M. 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.
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