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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Chirkova ZV,Kabanova MV,Filimonov SI,Abramov IG,Petzer A,Petzer JP,Firgang SI,Suponitsky KY

doi

10.1016/j.bmcl.2015.01.061

subject

Has Abstract

pub_date

2015-03-15 00:00:00

pages

1206-11

issue

6

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(15)00082-7

journal_volume

25

pub_type

杂志文章

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