An evaluation of synthetic indole derivatives as inhibitors of monoamine oxidase

Article abstract of DOI:10.1016/j.bmcl.2016.03.060

In a recent study we have shown that several indole-5,6-dicarbonitrile derivatives are potent inhibitors of human monoamine oxidase (MAO) A and B. To expand on these results and to further determine structure-activity relationships (SARs) for MAO inhibiti

Full text of DOI:10.1016/j.bmcl.2016.03.060

Accepted Manuscript
An evaluation of synthetic indole derivatives as inhibitors of monoamine oxi-
dase
Zhanna V. Chirkova, Mariya V. Kabanova, Sergey I. Filimonov, Igor G.
Abramov, Anél Petzer, Jacobus P. Petzer, Kyrill Yu. Suponitsky
PII:
S0960-894X(16)30280-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.03.060
BMCL 23703
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 January 2016
14 March 2016
15 March 2016
Please cite this article as: Chirkova, Z.V., Kabanova, M.V., Filimonov, S.I., Abramov, I.G., Petzer, A., Petzer, J.P.,
Suponitsky, K.Y., An evaluation of synthetic indole derivatives as inhibitors of monoamine oxidase, Bioorganic &
Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.03.060
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An evaluation of synthetic indole derivatives as inhibitors of monoamine
oxidase
a
a
Zhanna V. Chirkova , Mariya V. Kabanova , Sergey I. Filimonov a, Igor G. Abramov a, Anél Petzer
b, Jacobus P. Petzer b, Kyrill Yu. Suponitsky c
a
Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation
b
Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University,
Potchefstroom 2520, South Africa
c
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov St.,
119991 Moscow, Russian Federation
Abstract: In a recent study we have shown that several indole‐5,6‐dicarbonitrile derivatives are
potent inhibitors of human monoamine oxidase (MAO) A and B. To expand on these results and to
further determine structure-activity relationships (SARs) for MAO inhibition by this chemical class,
the present study investigates the MAO inhibition properties of additional indole‐5,6‐dicarbonitriles
and related indole-5,6-dicarboxylic acid and pyrrolo[3,4‐f]indole‐5,7‐dione derivatives. Among the
active compounds two pyrrolo[3,4‐f]indole‐5,7‐dione derivatives inhibited MAO-A (4g) and MAO-B
(4d) with IC50 values of 0.250 and 0.581 µM, respectively. In general indole‐5,6‐dicarbonitriles,
however, exhibit higher MAO inhibition potencies while indole-5,6-dicarboxylic acids are weak
MAO inhibitors. Active MAO inhibitors such as 4g and 4d may be used as leads for the development
of drugs for the treatment of disease states such as Parkinson’s disease and depression. MAO
inhibitors are also under investigation as potential agents for the treatment of prostate cancer, certain
types of cardiomyopathies and Alzheimer’s disease.
Keywords: monoamine oxidase; MAO; inhibition; selective; indole; dicarbonitrile.
1

The monoamine oxidase (MAO) enzymes consist of two isoforms, MAO-A and MAO-B, which are
expressed in most human tissues including the brain, liver and heart. These enzymes play key roles in
the metabolism of neurotransmitter amines and are therefore important drug targets for disease states
arising from deficient levels of particular neurotransmitters.1,2 Reduced central serotonin levels are
linked to depressive illness and since serotonin is a specific substrate of MAO-A, inhibitors of this
isoform are used in the clinic as antidepressants.3.4 In Parkinson’s disease, central dopamine is
depleted and inhibitors of the MAO-B isoform is thus used to inhibit dopamine metabolism, a strategy
often combined with therapy with L-Dopa, the metabolic precursor of dopamine.5 MAO inhibitors
may also decrease oxidative stress by reducing the tissue levels of hydrogen peroxide formed as by-
product in the MAO catalytic cycle. In this respect, MAO-A is an important source of hydrogen
peroxide in the heart and MAO-A inhibitors may find future use in certain types of
cardiomyopathies.6,7 Hydrogen peroxide production by MAO in the brain has been implicated in the
neurodegenerative process of Parkinson’s disease, thus providing a rationale for MAO inhibitors as
potential neuroprotectants.8 Recently, MAO inhibitors have also been investigated as potential therapy
for Alzheimer’s disease, acting via various molecular mechanisms.9 Interestingly, laboratory evidence
suggests that MAO-A inhibitors may represent potential therapy for advanced prostate cancer.10
Fig. 1. The structure of indole‐5,6‐dicarbonitrile derivatives 1a and 1b.
Based on the therapeutic significance of MAO inhibitors the discovery of new classes of chemical
compounds that exhibit MAO inhibition properties are pursued by several research groups. We have
recently shown that several indole‐5,6‐dicarbonitrile derivatives are potent inhibitors of the human
MAOs.11 For example derivative 1a was shown to inhibit MAO-A and MAO-B with IC50 values of
2

0.014 and 0.017 µM, respectively (Fig. 1). This compound also is a reversible and competitive
inhibitor of both MAOs. Based on the potent activities of 1a and other derivatives in this class, the
present study investigates the MAO inhibition properties of additional indole‐5,6‐dicarbonitrile
derivatives (2) and related indole-5,6-dicarboxylic acid (3) and pyrrolo[3,4‐f]indole‐5,7‐dione
derivatives (4). In addition, several related compounds (5) and intermediates (6) in the synthetic
pathway of these compounds were also evaluated in an attempt to discover new chemical classes that
may be used as leads for MAO inhibitor design. The derivatives examined in this study are given in
tables 1–4. The importance of indole derivatives are illustrated by the fact that they are found in many
natural compounds12 and pharmaceuticals.13 Indole derivatives influence the neurotransmitter
serotonin14,15 and are potent PPAR-c binding agents with potential application for the treatment of
osteoporosis.16 Indoles also are reported to be potent anti-inflammatory17 and antimicrobial agents,18
and may possess neuroprotective properties by modulating oxidative stress.19
Table 1. The human MAO inhibition potencies of indole‐5,6‐dicarbonitrile derivatives 2.
IC50 (µM)a
SIb
1.5
R1
R2
R3
MAO-A
MAO-B
OH
H
6.92 ± 0.955
10.3 ± 1.83
2a
2b
2c
2d
2e
2f
OH
H
1.14 ± 0.097
1.84 ± 0.121
11.1 ± 0.865
0.522 ± 0.067
0.405 ± 0.049
0.821 ± 0.035
1.79 ± 0.473
>100
0.72
0.97
>9
OH
H
OH
H
OCH3
OCH3
CHO
CHO
>100
>192
185
74.8 ± 12.0
3

OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OAc
CHO
CH2OH
CH2OH
CH2OH
Br
0.147 ± 0.033
4.99 ± 0.468
5.12 ± 0.525
1.13 ± 0.248
>100
>100
>680
>20
>20
>88
–
2g
2h
2i
>100
>100
>100
2j
>100
2k
2l
Br
>100
7.46 ± 2.08
1.94 ± 0.401
<0.075
0.93
H
2.08 ± 0.269
2m
a
All values are expressed as the mean ± standard deviation (SD) of triplicate determinations.
The selectivity index is the selectivity for the MAO-A isoform and is given as the ratio of
IC50(MAO-B)/IC50(MAO-A).
b
Table 2. The human MAO inhibition potencies of indole-5,6-dicarboxylic acid derivatives 3.
IC50 (µM)a
SIb
2.4
R1
R2
R3
MAO-A
MAO-B
OH
H
23.3 ± 4.14
56.2 ± 3.06
3a
3b
3c
3d
3e
OH
H
>100
>100
>100
>100
>100
–
OH
H
>100
OH
H
>100
–
OCH3
CH3
19.0 ± 5.63
>5. 3
See table 1 for footnotes.
4

Table 3. The human MAO inhibition potencies of pyrrolo[3,4‐f]indole‐5,7‐dione derivatives 4.
IC50 (µM)a
R1
R2
R3
R4
MAO-A
>100
MAO-B
SIb
OH
H
H
83.1 ± 4.62
<0.83
4a
4b
4c
4d
4e
4f
OH
H
H
H
H
H
Cl
H
1.16 ± 0.121
6.35 ± 0.317
1.75 ± 0.106
6.70 ± 0.606
1.24 ± 0.030
0.250 ± 0.099
8.09 ± 0.240
>100
7
OH
H
16
OCH3
OCH3
OCH3
H
H
0.581 ± 0.066
3.75 ± 0.532
>100
0.33
0.56
>81
>400
H
CH3
H
>100
4g
See table 1 for footnotes.
Table 4. The human MAO inhibition potencies 5 and 6.
IC50 (µM)a
SIb
1.3
R2
R4
MAO-A
MAO-B
H
5.38 ± 0.357
6.79 ± 1.07
5a
5b
H
2.11 ± 0.492
0.923 ± 0.122
0.44
5

H
0.661 ± 0.024
6.12 ± 0.042
5.51 ± 1.39
>100
1.21 ± 0.080
>100
1.8
>16
>18
–
5c
5d
5e
5f
H
CH2Ph
>100
CH2Ph
>100
–
–
–
–
>100
>100
–
6a
6b
6c
>100
>100
–
>100
>100
–
>100
>100
–
6d
See table 1 for footnotes.
4-Nitro-5-(2-oxo-2-arylethyl)benzene-1,2-dicarbonitriles 7a–d are convenient building-blocks for the
synthesis of substituted indoles.20 These dicarbonitriles with multiple reactive centres can be used in
reactions such as intramolecular cyclisation followed by the introduction of various substituents on a
number of positions. Using these compounds as starting materials it is possible to develop general
methods for the synthesis of new indoles with various functional groups. The preparation of 2-aryl-1-
hydroxy-1H-indole-5,6-dicarbonitriles
2a–d,20
2-aryl-3-formyl-1-methoxy-1H-indole-5,6-
dicarbonitriles 2e–g21 and 2-aryl-3-bromo-1-methoxy-1H-indole-5,6-dicarbonitriles 2k–l11 have been
reported previously (Scheme 1). The formyl groups of compounds 2e–g were found to be relatively
inert in chemical reactions, and practically unreactive towards hydrazine. It was therefore not possible
to carry out simple chemical transformations with the formyl groups of 2e–g, or hydrazides that may
have been prepared from these. However, substituted 3-(hydroxymethyl)-1-methoxy-1H-indole-5,6-
dicarbonitriles 2h–j were prepared by reduction of formylindoles 2e–g with NaBH4 in alcohol to give
the desired products with yields of 37–57%. The structures of these compounds were confirmed by IR
6

and NMR spectroscopy, as well as by mass spectrometry and in certain instances X-ray diffraction
(2i) (Fig. 2).
Scheme 1. Synthetic route to derivatives 2a–m.
Fig. 2. The X-ray structures of 2i (left) and 5a (right) with the atoms represented by thermal
displacements ellipsoids with 50% probability.
Substituted indoles containing the imide moiety (4) and indole-5,6-dicarboxylic acids (3) have not
been studied extensively and convenient methods for their syntheses are not available. Previously
described synthetic pathways for the syntheses of these compounds are complex multi-step processes
7

using metal-catalysis (Heck reaction).22–24 Since substituted indole-5,6-dicarbonitriles 2a–d are highly
resistant to acid and alkaline hydrolysis, imide derivatives 5a–d were synthesised by firstly
hydrolysing 4-nitro-5-(2-oxo-2-arylethyl)benzene-1,2-dicarbonitriles 7a–d (Scheme 2). Alkaline
hydrolysis of 7a–d is not suitable since these compounds readily undergoes nitro-nitrite
rearrangement to yield 1,2-benzoxazoles.20 For this purpose, acid hydrolysis proved to be more
successful. To carry out acid hydrolysis polyphosphoric acid (PPA) was employed. Hydrolysis of 7a–
d in PPA at 80–110 °C for 2–4 h gave the 5-(2-aryl-2-oxoethyl)-6-nitro-1H-isoindol-1,3(2H)-diones
5a–d as the major products in yields of 40–87%. The structures of the synthesised compounds 5a–d
were confirmed by IR and NMR spectroscopy.
Scheme 2. Synthetic route to derivatives 4a–g and 5a–d.
Reduction of the nitro groups of 5a–b and 5d were carried out using SnCl2 in HCl.25 This resulted in
cyclisation to give 1-hydroxy-2-arylpyrrolo[3,4-f]indole-5,7(1H,6H)-diones 4a–c in yields of 50–
85%. Formation of N-hydroxyindole moiety was confirmed after methylation of 4b–c with methyl
iodide in DMF with potassium carbonate serving as a deprotonation agent. Methylation proceeded
firstly at the OH-group followed by reaction at the NH-group. The mono-O-methyl products 4d–e
could thus selectively be obtained and only after employing threefold excess of methyl iodide and
increasing the reaction time was the fully methylated product 4f obtained. Proof for the formation of
8

the mono-O-methyl products were a characteristic downfield signal of the OCH3-group (3.89–4.11
1
ppm) and the signal of the NH-proton at 11.12–11.13 ppm on the H NMR spectrum, as well as a
13
carbon signal of the OCH3-group (65.31 ppm) on the C NMR spectrum. The structures of all the
newly synthesised compounds (5a–d, 4a–c, 4d–e, 4f) were confirmed by IR and NMR spectroscopy
as well as by mass spectrometry and X-ray diffraction analysis (compound 5a).
For the synthesis of 2-aryl-1-hydroxy-1H-indole-5,6-dicarboxylic acids 3a–d, the nitrile groups of
compounds 7a–d were hydrolysed under acidic conditions (to yield 6a–d) followed by reduction and
subsequent cyclisation to yield 3a–d (Scheme 3). Thus, 4-nitro-5-(2-oxo-2-arylethyl)benzene-1,2-
dicarboxylic acids 6a–d were prepared in yields of 82–91% by heating the 4-nitro-5-(2-oxo-2-
arylethyl)benzene-1,2-dicarbonitriles 7a–d in 85% sulphuric acid at 80–110 °C for 20–36 h. The
dicarboxylic acids 6a–d were transformed into the corresponding indoles 3a–d by reduction with
SnCl2. The yields of the target indoles were 71–83%. The structures of the dicarboxylic acids 6a–d
and 3a–d were confirmed by IR and NMR spectroscopy, mass spectrometry and chemically by
complete methylation of the carboxylic acid and hydroxyl groups of 3c with methyl iodide to give 3e.
The mass spectra of 3a–d did not show an intense molecular ion peak, but rather a prominent
fragment ion of [M+-H2O]. On the 1H NMR spectra the signals of the carboxylic acid protons were not
13
observed due to exchange with the deuterated solvent. On the C NMR spectra the pair of carbon
signals of the carboxylic acid groups (in the region of 168–169 ppm) were, however, observed
although the chemical shifts are similar to that of imides.26
9

Scheme 3. Synthetic route to derivatives 3a–e, 5e–f and 6a–d.
The synthesis of 2-substituted 5-(2-oxoethyl)-6-nitro-1H-isoindol-1,3(2H)-diones 5e–f was carried out
in two steps starting from dicarboxylic acids 6c–d. Firstly anhydrides 8a–b were obtained by heating
compounds 6c–d in acetic anhydride for to 2 h at 120–140 °C. The anhydrides 8a–b were converted
to the imides 5e–f by heating with benzylamine in glacial acetic acid at 100–120 °C for 2–3 h. Yields
of 62–64% were obtained. The structures of compounds 8a–b and 5e–f were confirmed by NMR
spectroscopy. It should be noted that we were unable to obtain mass spectra for these compounds with
electron impact ionisation. To determine the mass of the molecular ions of 5e–f, the softer
electrospray ionisation (LCMS) was employed.
The MAO inhibition potencies of the test compounds were measured using the recombinant human
MAO-A and MAO-B enzymes and kynuramine as substrate for both enzymes. Kynyramine is
oxidised by the MAOs to yield 4-hydroxyquinoline, a fluorescent metabolite which was quantified by
fluorescence spectrophotometry.27 After measuring the rates of kynuramine oxidation in the absence
and presence of the test inhibitor (0.003–100 µM), sigmoidal dose-response curves were constructed
in triplicate from which IC50 values were estimated. An example of such a sigmoidal dose-response
curve is given in Fig. 3. Since the IC50 values of previously reported indole‐5,6‐dicarbonitrile
10

derivatives were recorded under identical conditions as this study, direct comparison of the inhibition
data is possible.11
100
75
50
25
0
-3
-2
-1
0
1
2
3
Log[I], M
Fig. 3. Sigmoidal dose-response curves for the inhibition of MAO-A (circles) and MAO-B (triangles)
by 4b.
The results of the MAO inhibition studies are provided in tables 1–4. With the exception of 2l, the
indole‐5,6‐dicarbonitrile derivatives 2 are specific inhibitors of MAO-A with 7 of 13 homologues
displaying MAO-B inhibition potencies >100 µM. Compounds 2b, 2c and 2m may be viewed as
nonspecific MAO-A/B inhibitors. The most potent MAO inhibitors among the
indole‐5,6‐dicarbonitriles are 2e–g with IC50 values for the inhibition of MAO-A in the
submicromolar range. In fact 2g (IC50 = 0.147 µM) is the most potent MAO inhibitor of the present
study and also the most selective with an IC50 >100 µM for the inhibition of MAO-B. To place this
inhibition potency in perspective, the clinically used inhibitor, toloxatone, inhibits MAO-A with an
IC50 value of 3.92 µM under identical conditions.28 The reference MAO-B inhibitors, lazabemide and
safinamide, in turn display IC50 values of 0.091 µM and 0.048 µM under identical experimental
conditions to this study.28 It is noteworthy the 2e–g are the formyl-substituted derivatives, which
suggests that among the indole‐5,6‐dicarbonitriles examined here, the 3-formyl-1-methoxy
substitution pattern is most suitable for MAO-A inhibition. It should be noted that reaction between
11

the formyl groups and kynuramine may occur leading to low IC50 values for MAO-A. This, however,
seems unlikely since weak MAO-B inhibition was recorded for these compounds although the MAO-
A and MAO-B inhibition studies were conducted under the same conditions. 3-Chloro-1H-indole-5,6-
dicarbonitriles (e.g. 1a) previously reported are significantly more potent MAO-A (IC50 = 0.004–
0.121 µM) and MAO-B (IC50 = 0.017–1.27 µM) inhibitors.11 Interestingly, similar to the formyl
substituted compounds the C3 hydroxymethyl substituted derivatives 2h–j all are weak MAO-B
inhibitors (IC50 >100 µM).
As shown in table 2 indole-5,6-dicarboxylic acid derivatives 3 including ester 3e are weak MAO
inhibitors. Since 3a–d are weaker MAO inhibitors than their dicarbonitrile homologues 2a–d, it may
be concluded that for indoles, dicarbonitrile substitution yields higher potency MAO inhibitors than
dicarboxylic acid substitution. Among the pyrrolo[3,4‐f]indole‐5,7‐dione derivatives (table 3)
compounds 4d and 4g are noteworthy MAO inhibitors. These compounds inhibit MAO-A (4g) and
MAO-B (4d) with IC50 values of 0.250 and 0.581 µM, respectively. Compound 4d is thus the most
potent MAO-B inhibitor of the present study while 4g is the second most potent MAO-A inhibitor.
The finding that these imides are relatively good MAO inhibitors are to be expected since related
phthalimides have previously been reported to inhibit the MAOs, with selectivity for the MAO-B
isoform.29 Thus imide derivatives 5 also exhibit MAO inhibition with 5c (IC50 = 0.661 µM) being the
most noteworthy inhibitor (table 4). As with 3a–d, dicarboxylic acids 6 also proved to be weak MAO
inhibitors, and in fact did not inhibit the MAOs at 100 µM.
In conclusion, nitrile containing compounds, particularly dicarbonitriles have recently emerged as
privileged structures for the design of MAO inhibitors.30,31 A recent study have shown that
indole‐5,6‐dicarbonitrile derivatives, such as 1a, are potent inhibitors of both human MAOs.11 In the
present manuscript we have expanded on the structure-activity relationships (SARs) of MAO
inhibition by indole‐5,6‐dicarbonitriles. The importance of the nitrile group was demonstrated by the
observation that dicarboxylic acid homologues possess weak MAO inhibition properties and in most
instances exhibit IC50 >100 µM. Even esterification does not lead to improved inhibition. It is clear
12

that, with the appropriate substitution indole‐5,6‐dicarbonitriles can be obtained with good potency
MAO inhibition and isoform selectivity. This is exemplified by 2g (SI >680), a compound displaying
potent MAO-A inhibition and weak MAO-B inhibition. Since other homologues (e.g. 2e, 2f) also
possess good MAO-A inhibition potencies and isoform selectivities (SI = 185 and >192) it may be
concluded that the 3-formyl-1-methoxy substitution pattern of indole‐5,6‐dicarbonitriles is a viable
strategy for the design of MAO-A selective inhibitors. Although previously reported 3-chloro-1H-
indole-5,6-dicarbonitriles (e.g. 1a) are significantly more potent MAO-A and MAO-B inhibitors they
display little isoform selectivity (SI = 1.2–10.8).11 It should, however, be noted that in the reported
study, methylated indole-5,6-dicarbonitriles (e.g. 1b) also represent a class of compounds with potent
and selective MAO-A inhibition properties.11 These compounds inhibit MAO-A with IC50 values of
0.035–19.4 µM and MAO-B with IC50 values > 100 µM. Another interesting finding is that imides
such as 4d, 4g and 5c also display good potency MAO inhibition. This is in accordance with literature
reports that numerous members of the phthalimide class of compounds are high potency MAO-B
selective inhibitors. Good potency and isoform selective MAO inhibitors such as 2g and 4g may thus
represent leads for the design of drugs for the treatment of a variety of disease states such as
depression, prostate cancer and certain cardiomyopathies.
Acknowledgements
This work is based on the research supported in part by the Medical Research Council and National
Research Foundation of South Africa (Grant specific unique reference numbers (UID) 85642 and
96180). The Grantholders acknowledge that opinions, findings and conclusions or recommendations
expressed in any publication generated by the NRF supported research are that of the authors, and that
the NRF accepts no liability whatsoever in this regard.
13

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Graphical abstract:
Indole derivatives and related compounds were evaluated as inhibitors of the human
monoamine oxidases
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