Monoamine Oxidase (MAO) Inhibitory Activity: 3-Phenylcoumarins versus 4-Hydroxy-3-phenylcoumarins

被引:24
作者
Delogu, Giovanna L. [1 ]
Serra, Silvia [1 ]
Quezada, Elias [2 ]
Uriarte, Eugenio [2 ]
Vilar, Santiago [2 ,3 ]
Tatonetti, Nicholas P. [3 ]
Vina, Dolores [4 ]
机构
[1] Univ Cagliari, Dept Life Sci & Environm, Sect Pharmaceut Sci, I-09124 Cagliari, Italy
[2] Univ Santiago de Compostela, Fac Pharm, Dept Organ Chem, Santiago De Compostela 15782, Spain
[3] Columbia Univ, Med Ctr New York, Dept Biomed Informat, New York, NY 10032 USA
[4] Univ Santiago de Compostela, Dept Pharmacol, Ctr Res Mol Med & Chron Dis CIMUS, Santiago De Compostela 15782, Spain
关键词
3-arylcoumarins; molecular docking; monoamine oxidases; inhibitors; COUMARIN DERIVATIVES; IN-VITRO; POTENT; 3-ARYLCOUMARINS; SERIES; PHARMACOLOGY; INSIGHTS;
D O I
10.1002/cmdc.201402010
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 mu m) 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.
引用
收藏
页码:1672 / 1676
页数:5
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