title: Inhibition of monoamine oxidase by indole-5,6-dicarbonitrile derivatives.
abstract: Recent studies have found that phthalonitrile derivatives are remarkably potent inhibitors of human monoamine oxidase (MAO) A and B. In an attempt to further determine the structure-activity relationships (SARs) for MAO inhibition by this class of compounds and to discover novel potent MAO inhibitors, the present study investigated the MAO inhibition properties of a series consisting of indole-5,6-dicarbonitrile derivatives. The results document that 3-chloro-1H-indole-5,6-dicarbonitrile derivatives exhibited potent inhibition of the MAOs. For example, 3-chloro-2-(4-methylphenyl)-1H-indole-5,6-dicarbonitrile inhibited MAO-A and MAO-B with IC50 values of 0.014μM and 0.017μM, respectively. It was further shown that this compound acts as a reversible and competitive inhibitor of both MAO isoforms. An analysis of the SARs for MAO inhibition by 3-chloro-1H-indole-5,6-dicarbonitriles showed that methylation of the indole nitrogen eliminates MAO-B inhibition activity, and replacement of the 2-phenyl ring with the thienyl results in a 9-fold reduction of MAO-B inhibition activity. A series of 3-bromo-1-hydroxy-1H-indole-5,6-dicarbonitriles are, in turn, comparatively weaker MAO inhibitors. It may be concluded that indole-5,6-dicarbonitrile derivatives are suitable leads for the design MAO inhibitors for the treatment of disorders such as Parkinson's disease and depression.
authors.affiliation: Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation.
authors.forename: Zhanna V
authors.initials: ZV
authors.lastname: Chirkova
authors.affiliation: Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation.
authors.forename: Mariya V
authors.initials: MV
authors.lastname: Kabanova
authors.affiliation: Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation.
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Filimonov
authors.affiliation: Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation.
authors.forename: Igor G
authors.initials: IG
authors.lastname: Abramov
authors.affiliation: Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa.
authors.forename: Anél
authors.initials: A
authors.lastname: Petzer
authors.affiliation: Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa. Electronic address: jacques.petzer@nwu.ac.za.
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Firgang
authors.affiliation: A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov St., 119991 Moscow, Russian Federation.
authors.forename: Kyrill Yu
authors.initials: KY
authors.lastname: Suponitsky
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000737:chemistry; D007700:Kinetics; D008968:Molecular Conformation; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D009570:Nitriles / Q000737:chemistry; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; D009570:Nitriles; D020033:Protein Isoforms; C030374:indole; D008995:Monoamine Oxidase
keywords: Indole‐5,6‐dicarbonitrile; Inhibition; MAO; Monoamine oxidase; Phthalonitrile; Reversible