Monoamine Oxidase (MAO) Inhibitory Activity: 3‐Phenylcoumarins versus 4‐Hydroxy‐3‐phenylcoumarins |
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Authors: | Dr Giovanna L Delogu Dr Silvia Serra Dr Elias Quezada Prof Eugenio Uriarte Dr Santiago Vilar Dr Nicholas P Tatonetti Dr Dolores Viña |
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Affiliation: | 1. Department of Life Sciences & Environment, Section of Pharmaceutical Sciences, University of Cagliari, Palazzo delle Scienze, Via Ospedale, 72, 09124 Cagliari (Italy);2. Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain);3. Department of Biomedical Informatics, Columbia University Medical Center of New York, 622 W. 168th St., Vanderbilt Clinic 5th Floor, 10032 New York, NY (USA);4. Department of Pharmacology, Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), University of Santiago de Compostela, Avda. Barcelona s/n, Campus Vida, 15782 Santiago de Compostela (Spain) |
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Abstract: | Monoamine oxidase (MAO) is a useful target in the treatment of neurodegenerative diseases and depressive disorders. Both isoforms, MAO‐A and MAO‐B, are known to play critical roles in disease progression, and as such, the identification of novel, potent and selective inhibitors is an important research goal. Here, two series of 3‐phenylcoumarin derivatives were synthesized and evaluated against MAO‐A and MAO‐B. Most of the compounds tested acted preferentially on MAO‐B, with IC50 values in the micromolar to nanomolar range. Only 6‐chloro‐4‐hydroxy‐3‐(2’‐hydroxyphenyl)coumarin exhibited activity against the MAO‐A isoform, while still retaining good selectivity for MAO‐B. 6‐Chloro‐3‐phenylcoumarins unsubstituted at the 4 position were found to be more active as MAO‐B inhibitors than the corresponding 4‐hydroxylated coumarins. For 4‐unsubstituted coumarins, meta and para positions on the 3‐phenyl ring seem to be the most favorable for substitution. Molecular docking simulations were used to explain the observed hMAO‐B structure–activity relationships for this type of compound. 6‐Chloro‐3‐(3’‐methoxyphenyl)coumarin was the most active compound identified (IC50=0.001 μM ) and is several times more potent and selective than the reference compound, R‐(?)‐deprenyl hydrochloride. This compound represents a novel tool for the further investigation of the therapeutic potential of MAO‐B inhibitors. |
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Keywords: | 3‐arylcoumarins molecular docking monoamine oxidases inhibitors |
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