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Bioorg Med Chem Lett. 2015 Mar 15;25(6):1206-11. doi: 10.1016/j.bmcl.2015.01.061. Epub 2015 Feb 4.

Inhibition of monoamine oxidase by indole-5,6-dicarbonitrile derivatives.

Author information

1
Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation.
2
Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa.
3
Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa. Electronic address: jacques.petzer@nwu.ac.za.
4
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
5
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov St., 119991 Moscow, Russian Federation.

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.

KEYWORDS:

Indole‐5,6‐dicarbonitrile; Inhibition; MAO; Monoamine oxidase; Phthalonitrile; Reversible

PMID:
25701250
DOI:
10.1016/j.bmcl.2015.01.061
[Indexed for MEDLINE]

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