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8‐Substituted 3‐Arylcoumarins as Potent and Selective MAO‐B Inhibitors: Synthesis, Pharmacological Evaluation, and Docking Studies
Author(s) -
Viña Dolores,
Matos Maria J.,
Ferino Giulio,
Cadoni Enzo,
Laguna Reyes,
Borges Fernanda,
Uriarte Eugenio,
Santana Lourdes
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100538
Subject(s) - selegiline , docking (animal) , selectivity , chemistry , stereochemistry , pharmacology , monoamine oxidase b , enzyme , active site , combinatorial chemistry , biochemistry , monoamine oxidase , medicine , parkinson's disease , nursing , disease , catalysis
Abstract Neurodegenerative disorders are becoming more prevalent given the increase in the aging population. This has inspired active research in the development of new drugs that could mark an important advance in the treatment of complex diseases such as Alzheimer′s and Parkinson′s. With the aim of finding new MAO‐B‐selective inhibitors, we report the synthesis, in vitro evaluation, and docking simulation of a new series of 3‐arylcoumarins variously substituted at the 8‐position. Most of the studied compounds show high affinity and selectivity for the hMAO‐B isoform, with IC 50 values in the low micro‐ to nanomolar range. Some of them have greater hMAO‐B inhibitory activity and selectivity than the reference compound, selegiline. Compounds 7 and 8 are the most active of this series, with compound 8 being fivefold more potent against MAO‐B and severalfold more selective than selegiline. Docking experiments were carried out with hMAO‐B crystal structures, providing new information about the enzyme–inhibitor interaction and the potential therapeutic application of the new 8‐substituted 3‐arylcoumarins.