Title |
Structure-Activity Relationship Analysis of 3-Phenylcoumarin-Based Monoamine Oxidase B Inhibitors
|
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Published in |
Frontiers in Chemistry, March 2018
|
DOI | 10.3389/fchem.2018.00041 |
Pubmed ID | |
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 |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Switzerland | 1 | 50% |
Unknown | 1 | 50% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 50% |
Scientists | 1 | 50% |
Mendeley readers
Geographical breakdown
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Unknown | 52 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 8 | 15% |
Student > Ph. D. Student | 6 | 12% |
Student > Bachelor | 5 | 10% |
Student > Doctoral Student | 3 | 6% |
Other | 3 | 6% |
Other | 9 | 17% |
Unknown | 18 | 35% |
Readers by discipline | Count | As % |
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Chemistry | 14 | 27% |
Pharmacology, Toxicology and Pharmaceutical Science | 8 | 15% |
Biochemistry, Genetics and Molecular Biology | 4 | 8% |
Agricultural and Biological Sciences | 4 | 8% |
Computer Science | 2 | 4% |
Other | 2 | 4% |
Unknown | 18 | 35% |