AUTHOR=Rauhamäki Sanna , Postila Pekka A. , Niinivehmas Sanna , Kortet Sami , Schildt Emmi , Pasanen Mira , Manivannan Elangovan , Ahinko Mira , Koskimies Pasi , Nyberg Niina , Huuskonen Pasi , Multamäki Elina , Pasanen Markku , Juvonen Risto O. , Raunio Hannu , Huuskonen Juhani , Pentikäinen Olli T. 

TITLE=Structure-Activity Relationship Analysis of 3-Phenylcoumarin-Based Monoamine Oxidase B Inhibitors

JOURNAL=Frontiers in Chemistry

VOLUME=6

YEAR=2018

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2018.00041

DOI=10.3389/fchem.2018.00041

ISSN=2296-2646

ABSTRACT=<p>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 <italic>de novo</italic> and synthesized using microwave chemistry. The derivatives inhibited the MAO-B at 100 nM−1 μM. The IC<sub>50</sub> value of the most potent derivative <bold>1</bold> 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 <bold>1</bold>, present unique pharmacological features worth considering in future drug development.</p>