A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Structure-Activity Relationship Analysis of 3-Phenylcoumarin-Based Monoamine Oxidase B Inhibitors
Tekijät: 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
Kustantaja: FRONTIERS MEDIA SA
Julkaisuvuosi: 2018
Journal: Frontiers in Chemistry
Tietokannassa oleva lehden nimi: FRONTIERS IN CHEMISTRY
Lehden akronyymi: FRONT CHEM
Artikkelin numero: ARTN 41
Vuosikerta: 6
Sivujen määrä: 18
ISSN: 2296-2646
eISSN: 2296-2646
DOI: https://doi.org/10.3389/fchem.2018.00041
Rinnakkaistallenteen osoite: 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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
