Sulfanylphthalonitrile analogues as selective and potent inhibitors of monoamine oxidase B

Article abstract of DOI:10.1016/j.bmcl.2012.10.070

It has recently been reported that nitrile containing compounds frequently act as potent monoamine oxidase B (MAO-B) inhibitors. Modelling studies suggest that this high potency inhibition may rely, at least in part, on polar interactions between nitrile functional groups and polar moieties within the MAO-B substrate cavity. In an attempt to identify potent and selective inhibitors of MAO-B and to contribute to the known structure-activity relationships of MAO inhibition by nitrile containing compounds, the present study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and sulfanylbenzonitriles. The results document that the evaluated compounds are potent and selective MAO-B inhibitors with most homologues possessing IC₅₀ values in the nanomolar range. In general, the sulfanylphthalonitriles exhibited higher binding affinities for MAO-B than the corresponding sulfanylbenzonitrile homologues. Among the compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold) for MAO-B over MAO-A, and potent MAO-B inhibition (IC₅₀ = 0.025 μM). Based on these observations, this structure may serve as a lead for the development of therapies for neurodegenerative disorders such as Parkinson's disease.

Full text of DOI:10.1016/j.bmcl.2012.10.070

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7367–7370
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Sulfanylphthalonitrile analogues as selective and potent inhibitors
of monoamine oxidase B
Mietha M. Van der Walt a, Gisella Terre’Blanche a, Anna C. U. Lourens a, Anél Petzer b, Jacobus P. Petzer a,
⇑
a Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
b Unit for Drug Research and Development, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
It has recently been reported that nitrile containing compounds frequently act as potent monoamine oxi-
dase B (MAO-B) inhibitors. Modelling studies suggest that this high potency inhibition may rely, at least
in part, on polar interactions between nitrile functional groups and polar moieties within the MAO-B sub-
strate cavity. In an attempt to identify potent and selective inhibitors of MAO-B and to contribute to the
known structure–activity relationships of MAO inhibition by nitrile containing compounds, the present
study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and
sulfanylbenzonitriles. The results document that the evaluated compounds are potent and selective
MAO-B inhibitors with most homologues possessing IC50 values in the nanomolar range. In general,
the sulfanylphthalonitriles exhibited higher binding affinities for MAO-B than the corresponding sul-
fanylbenzonitrile homologues. Among the compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalo-
nitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold)
Received 27 August 2012
Revised 10 October 2012
Accepted 15 October 2012
Available online 22 October 2012
Keywords:
Phthalonitrile
Benzonitrile
Monoamine oxidase
MAO
Inhibition
Parkinson’s disease
for MAO-B over MAO-A, and potent MAO-B inhibition (IC50 = 0.025 lM). Based on these observations, this
structure may serve as a lead for the development of therapies for neurodegenerative disorders such as
Parkinson’s disease.
Ó 2012 Elsevier Ltd. All rights reserved.
The enzyme monoamine oxidase B (MAO-B) is considered to be
a major dopamine metabolizing enzyme in the human brain and,
as such, a target for the treatment of Parkinson’s disease.1–3 Inhib-
itors of MAO-B are thought to reduce the metabolic degradation of
central dopamine and as a result increase dopaminergic neuro-
transmission.4,5 MAO-B inhibitors are frequently combined with
levodopa in the therapy of Parkinson’s disease since this may en-
hance the dopamine levels derived from levodopa and allow for a
reduction of the effective levodopa dose.6 In the initial stages of
the disease, MAO-B inhibitors may also delay the emergence of dis-
abilities that require the initiation of levodopa therapy. The inhibi-
tion of MAO-B has also been associated with a neuroprotective
effect. This effect may, at least in part, depend on blocking the for-
mation of H2O2 and aldehyde species, metabolic by-products of
substrate metabolism by MAO-B.7 These metabolites may be
harmful if not rapidly cleared from the central nervous system.
Considering that central MAO-B activity increases with age,8–10
inhibition of the MAO-B-catalyzed formation of toxic by-products
in the aged parkinsonian brain is of particular relevance. Interest-
ingly, dopamine is also oxidized by the MAO-A isoform in the hu-
man brain, and MAO-A inhibitors have been shown to enhance
central dopamine levels in primates.4,5 MAO-A inhibitors may,
however, lead to serious adverse effects when combined with cer-
tain drugs and food. Most notably, when MAO-A inhibitors are
used with indirectly acting sympathomimetic amines such as tyra-
mine, which is present is certain foods, a potentially fatal hyper-
tensive response may occur.7,11 MAO-A inhibitors should also be
used with caution in combination with levodopa since this may eli-
cit a hypertensive crisis.12 For these reasons, inhibitors that are
selective for the MAO-B isoform are more desirable as antiparkin-
sonian agents.
Based on these considerations, the present study aims to dis-
cover novel compounds that bind selectively and with high binding
affinities to MAO-B. Among the various types of structures that
have been reported to inhibit the MAO enzymes are nitrile contain-
ing compounds. Both phthalonitriles and benzonitriles have been
found to act as potent and selective MAO-B inhibitors.13,14 For
example, 4-benzyloxyphthalonitrile (1) and 4-benzyloxybenzonit-
rile (2) inhibit human MAO-B reversibly with IC50 values of 0.0079
and 0.785 l
M, respectively (Fig. 1).13 These homologues display
227- and 41-fold selectivities, respectively, for the MAO-B isoform.
Based on its good selectivity and high potency, compound 1 may
be viewed as a particularly promising inhibitor. The high binding
affinities of nitrile containing compounds to MAO-B may be ex-
plained by the highly polar nature of this functional group. Model-
ling studies predict that the nitrile group interacts with the polar
regions in the substrate cavity of the MAO-B enzyme.13 This seems
⇑
Corresponding author. Tel.: +27 18 2992206; fax: +27 18 2994243.
E-mail address: jacques.petzer@nwu.ac.za (J.P. Petzer).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.070

7368
M. M. Van der Walt et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7367–7370
O
CN
CN
S
S
CN
CN
1
6a
7a
O
CN
2
CN
Figure 1. The structures of 4-benzyloxyphthalonitrile (1) and 4-benzyloxybenzo-
nitrile (2).
Figure 3. The general structures of 4–(benzylsulfanyl)phthalonitrile (6a) and 4–
(benzylsulfanyl)benzonitrile (7a).
to be a prerequisite for potent inhibition since elimination of the
nitrile results in a loss of MAO-B inhibitory activity. Literature also
documents that phthalonitriles are in general more potent MAO-B
inhibitors than benzonitriles, which suggests that the productive
interactions between nitrile groups and the MAO-B enzyme are
additive. The active site cavity of MAO-B is, however, bipartite
and besides the substrate cavity where the phthalonitrile and ben-
zonitrile moieties are predicted to bind, the active site also pos-
sesses an entrance cavity.15 The benzyloxy side chains of
compounds 1 and 2 are predicted to bind within the entrance cav-
ity of MAO-B, where they are most likely stabilized via Van der
Waals interactions. The interactions between the benzyloxy side
chain and the entrance cavity are thought to also contribute signif-
icantly to the binding affinities of these inhibitors, since modifica-
tion (e.g. replacement with a phenoxy) leads to a two orders of
magnitude loss in MAO-B inhibition activity. In addition, several
other potent MAO-B inhibitors possess the benzyloxy side chain.
These include safinamide (3) and 8-benzyloxycaffeine (4) (Fig. 2).
Crystallographic as well as modelling studies have shown that
the benzyloxy side chains of these inhibitors bind within the
MAO-B entrance cavity.16,17 Of note is a recent report that the ben-
zylsulfanyl side chain exhibit similar properties to that of the ben-
zyloxy moiety, since a series of 8-(benzylsulfanyl)caffeines (5)
possesses similar MAO-B inhibition potencies to those of the 8-
benzyloxycaffeines (4).18 In addition, modelling suggests that the
binding modes of the benzylsulfanyl and benzyloxy side chains
within the entrance cavity of MAO-B are highly comparable. Based
on these observations, the present study examines the possibility
that benzylsulfanyl substitution on the phthalonitrile and benzoni-
trile moieties, to yield compounds 6a and 7a, would also lead to
highly potent and selective MAO-B inhibition (Fig. 3). To explore
the structure–activity relationships (SARs) of MAO inhibition by
these compounds, the effects that substitution (Cl, Br, F and
OCH3) on the benzylsulfanyl ring have on MAO inhibition were
considered. Halogen substitution on the benzylsulfanyl ring of 5
has been shown to be beneficial for MAO-B inhibition.18 In addi-
tion, substitution on the phthalonitrile and benzonitrile moieties
with phenylsulfanyl, (2-phenylethyl)sulfanyl, cyclohexylsulfanyl,
cyclopentylsulfanyl and (3-methylbutyl)sulfanyl substituents were
also considered.
The target sulfanylphthalonitriles (6a–l) and sulfanylbenzonitr-
iles (7a–j) were synthesized according to the procedures described
in literature.13,19 The sulfanylphthalonitriles were synthesized in
fair to good yields (16–83%) by reacting an appropriate thiol with
4-nitrophthalonitrile in the presence of K2CO3 in dimethyl sulfox-
ide (DMSO) (Scheme 1). The crude products were purified by
recrystallization from an appropriate solvent as indicated in the
Supplementary data. The sulfanylbenzonitriles were synthesized
in an analogous manner by reacting 4-nitrobenzonitrile with an
appropriate thiol (2–72%). The structures of the target nitrile deriv-
atives were verified by 1H NMR, 13C NMR and mass spectrometry,
while their purities were estimated by HPLC analysis as cited in the
Supplementary data.
The MAO inhibitory activities of the sulfanylphthalonitriles and
sulfanylbenzonitriles were evaluated by employing recombinant
human MAO-A and -B as enzyme sources.20 Kynuramine, a mixed
MAO-A/B substrate, served as enzyme substrate for these inhibi-
tion studies. Kynuramine undergoes MAO-catalyzed oxidation to
yield the fluorescent metabolite, 4–hydroxyquinoline, which may
be conveniently measured by fluorescence spectrophotometry
without interference from the substrate and inhibitors evaluated
in this study.21 The inhibitory potencies of the nitriles are ex-
pressed as the corresponding IC50 values, and their selectivities
for the MAO-B isoform are expressed as the selectivity index (SI)
value [IC50(MAO–A)]/[(IC50(MAO–B)].
The results document that the sulfanylphthalonitriles (6) are
potent MAO-B inhibitors with all homologues, except 6f, possess-
ing IC50 values in the submicromolar range (Table 1). In accordance
to expectation, benzylsulfanyl substitution on the phthalonitrile
H
CH3
O
NH2
N
F
H
O
moiety, to yield 6a (IC50 = 0.167
lM), resulted in potent MAO-B
3
inhibition. Substitution (Cl, Br, F and OCH3) on the benzylsulfanyl
O
N
CN
CN
CN
CN
N
N
a
O
S
R
R
SH
SH
+
+
R
R
N
O
O
N
O
O2N
S
S
4
6a−l
7a−j
CN
CN
N
a
O2N
N
N
5
Figure 2. The structures of safinamide (3), 8-benzyloxycaffeine (4) and 8-(ben-
zylsulfanyl)caffeine (5).
Scheme 1. Synthetic pathway to sulfanylphthalonitriles (6a–l) and sulfanylbenzo-
nitriles (7a–j). Reagents and conditions: (a) K2CO3, DMSO, argon.

M. M. Van der Walt et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7367–7370
7369
Table 1
Table 2
The IC50 values for the inhibition of recombinant human MAO-A and –B by
The IC50 values for the inhibition of recombinant human MAO-A and –B by
sulfanylphthalonitriles 6a–l
sulfanylbenzonitriles 7a–j
2
R
4
CN
CN
R
4
1
1
CN
R
IC50
(
l
M)a
R
IC50
MAO-B
(l
M)a
MAO-A
MAO-B
SIb
SIc,d
MAO-A
SIb
SIc,d
6a –S–(CH2)-C6H5
6b –S–(CH2)-(4-Cl-C6H4)
6c –S–(CH2)-(4-Br-C6H4)
6d –S–(CH2)-(4-F-C6H4)
6e –S–(CH2)-(4-OCH3-C6H4)
6f –S–C6H5
6g –S–(4-Cl-C6H4)
6h –S–(4-Br-C6H4)
6i –S–(CH2)2-C6H5
6j –S–C6H11
9.02 0.896 0.167 0.016 54
0.623 0.053 0.014 0.004 45
218 23.9 0.025 0.003 8720 5334
2.10 0.218 0.034 0.006 62 38
129 78.1 0.067 0.021 1925 1178
3.58 0.592 2.13 0.067 1.7
11.1 1.17 0.114 0.002 97
19.0 8.27 0.079 0.017 240 147.1
7.19 1.35 0.124 0.009 58
5.96 0.382 0.223 0.039 27
2.78 0.936 0.887 0.072 3.1
1.45 0.203 0.242 0.035 6.0
33
27
7a
7b
7c
7d
7e
7f
7g
7h
7i
–S–(CH2)-C6H5
42.4 3.10
20.3 6.62
129 18.5
54.7 22.8
5.59 0.744
36.9 1.02
18.2 2.17
8.52 0.869
54.3 11.9
9.87 3.03
1.58 0.327
0.531 0.114
0.484 0.052
0.449 0.128
0.861 0.165
11.2 0.584
4.28 2.09
0.637 0.162
1.81 0.130
4.77 0.383
27
38
16
23
163
75
4.0
2.0
2.6
8.2
18
– S–(CH2)-(4-Cl-C6H4)
– S–(CH2)-(4-Br-C6H4)
– S–(CH2)-(4-F-C6H4)
–S–(CH2)-(4-OCH3-C6H4)
–S–C6H5
267
122
6.5
3.3
4.3
13
1.0
59.6
–S–(4-Cl-C6H4)
– S–(4-Br-C6H4)
–S–(CH2)2-C6H5
–S–C6H11
35.5
16.3
1.9
30
2.1
7j
1.3
6k –S–C5H9
6l –S–(CH2)2-CH(CH3)2
a
All values are expressed as the mean SD of triplicate determinations.
The selectivity index is the selectivity for the MAO-B isoform and is given as the
3.7
b
a
All values are expressed as the mean SD of triplicate determinations.
The selectivity index is the selectivity for the MAO-B isoform and is given as the
ratio of [IC50(MAO-A)]/[IC50(MAO-B)].
b
c
The selectivity index is the selectivity for the MAO-B isoform and is given as the
ratio of [IC50 (MAO-A)]/[IC50(MAO-B)].
ratio of Ki(MAO-A)/Ki(MAO-B).
c
d
The selectivity index is the selectivity for the MAO-B isoform and is given as the
The Ki values were calculated from the experimental IC50 values according to
ratio of Ki (MAO-A)/Ki(MAO-B).
The Ki values were calculated from the experimental IC50 values according to
the equation by Cheng and Prusoff: Ki = IC50/(1 + [S]/Km). For human MAO-A,
the equation by Cheng and Prusoff: Ki = IC50/(1 + [S]/Km). For human MAO-A,
d
[S] = 45
l
M and Km (kynuramine) = 16.1
lM, while for human MAO-B, [S] = 30 lM
and Km (kynuramine) = 22.7
l
M.17,23
[S] = 45
and Km (kynuramine) = 22.7
l
M and Km (kynuramine) = 16.1
lM, while for human MAO-B, [S] = 30 lM
l
M.17,23
are more favourable for MAO-B inhibition compared to
sulfanylbenzonitriles.
The results given in Tables 1 and 2 show that the sulfanylpht-
halonitriles and sulfanylbenzonitriles also are inhibitors of MAO-
A. In all instances, these compounds are, however, selective for
MAO-B with SI values ranging from 1.7–8720. Only one compound,
ring further enhanced MAO-B inhibition potency with compounds
6b–e exhibiting IC50 values of 0.014–0.067 M. In fact, 6b proved
to be the most potent MAO-B inhibitor of the present series. In con-
trast to the effect of the benzylsulfanyl moiety, phenylsulfanyl sub-
stitution on the phthalonitrile moiety, to yield 6f (IC50 = 2.13 lM),
l
resulted in only moderate MAO-B inhibition. Interestingly, halogen
substitution on the phenyl ring of 6f improved MAO-B inhibition
6b (IC50 = 0.623
range for the inhibition of MAO-A. Based on IC50 values of 0.623–
218 M, it may therefore be concluded that sulfanylphthalonitriles
lM), exhibited an IC50 value in the submicromolar
with 6g–h exhibiting IC50 values of 0.079–0.114
lM. Substitution
l
on the phthalonitrile moiety with (2-phenylethyl)sulfanyl, cyclo-
hexylsulfanyl, cyclopentylsulfanyl and (3-methylbutyl)sulfanyl
side chains also resulted in potent MAO-B inhibition. These homo-
and sulfanylbenzonitriles are in general weak to moderate inhibi-
tors of MAO-A. It is noteworthy that two compounds, 6c and 6e,
exhibited SI values in excess of 1000. These compounds, particu-
larly 6c (SI = 8720), may therefore be considered as highly selective
for MAO-B. Compounds 6c and 6e are also highly potent MAO-B
inhibitors. As mentioned, selective and potent MAO-B inhibitors
represent good candidates for antiparkinsonian therapy.
It has been reported that phthalonitriles act as reversible MAO-
B inhibitors.13 To verify that the sulfanylphthalonitrile class of
compounds also interacts reversibly with MAO-B, the reversibility
of MAO-B inhibition by 6c was examined. For this purpose 6c, at
concentrations of 10 Â IC50 and 100 Â IC50, was preincubated with
MAO-B for 30 min and the extent of enzyme recovery after dilution
of the enzyme–inhibitor complex was measured.22 The results
show that, after dilution of the enzyme-inhibitor complexes to
concentrations of 6c equal to 0.1 Â IC50 and 1 Â IC50, the MAO-B
catalytic activities are recovered to levels of approximately 76%
and 48%, respectively, of the control value (Fig. 4). This recovery
of MAO-B activity is consistent with a reversible interaction be-
tween 6c and MAO-B. For comparison, MAO-B was treated in a
similar manner with the irreversible inhibitor, (R)-deprenyl, at a
concentration of 10 Â IC50. After 100-fold dilution, MAO-B activity
was, however, not recovered (0.8% of control).
logues (6i–l) displayed IC50 values of 0.124–0.887
worthy that the (2-phenylethyl)sulfanyl substituted homologue
6i (IC50 = 0.124 M) is slightly more potent than the benzylsulfanyl
lM. It is note-
l
substituted phthalonitrile 6a. This suggests that extension of the
benzylsulfanyl side chain result in slightly improved MAO-B inhi-
bition. Reduction of the length of the benzylsulfanyl side chain of
6a to yield 6f, however, markedly lowers MAO-B inhibition
potency.
The MAO inhibitory properties of the sulfanylbenzonitriles are
given in Table 2. The results show that, although several com-
pounds exhibit IC50 values in the submicromolar range, the sul-
fanylbenzonitriles exhibited lower binding affinities for MAO-B
than the corresponding sulfanylphthalonitrile homologues. The
MAO-B inhibitor potencies of the sulfanylbenzonitriles ranged
from 0.449–11.2 lM with the most potent inhibitor being com-
pound 7d. As observed for the sulfanylphthalonitriles, substitution
(Cl, Br, F and OCH3) on the benzylsulfanyl ring enhanced MAO-B
inhibition potency compared to the unsubstituted homologue 7a
(IC50 = 1.58
e, possessed IC50 values of 0.449–0.861
stitution on the phenyl ring of 7f (IC50 = 11.2
inhibition with 7g–h exhibiting IC50 values of 0.637–4.28
l
M). These substituted homologues, compounds 7b–
M. Similarly, halogen sub-
M) improved MAO-B
M.
l
l
In conclusion, the present study shows that the sulfanylpht-
halonitrile and to a lesser extent the sulfanylbenzonitrile classes
of compounds are in general highly potent inhibitors of MAO-B.
A particularly promising compound among those examined is the
para bromo substituted derivative of 4-(benzylsulfanyl)phthalonit-
rile, compound 6c. This compound displays potent MAO-B
l
Among the sulfanylbenzonitriles, phenylsulfanyl substitution (to
yield 7f) resulted in the weakest MAO-B inhibition. This result is
similar to that obtained with the sulfanylphthalonitriles. Based
on these results it may be concluded that sulfanylphthalonitriles

7370
M. M. Van der Walt et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7367–7370
more potent than 6c (Fig. 5).13 Compound 6c is, however, a consid-
100
75
50
25
0
erably (66-fold) more selective MAO-B inhibitor than 8 (SI = 134).
From this analysis it may be concluded that among the phthalonit-
rile and benzonitrile derivatives examined to date, 6c is the most
appropriate candidate for Parkinson’s disease therapy.13,14
Acknowledgments
We are grateful to André Joubert and Johan Jordaan of the SA-
SOL Centre for Chemistry, North-West University for recording
the NMR and MS spectra, respectively. Financial support for this
work was provided by the North-West University, the National Re-
search Foundation and the Medical Research Council, South Africa.
C50
=
C50
Supplementary data
x I
1 x I
1
.
0
]
=
I
[
]
(R)-Deprenyl
I
[
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.10.070.
Figure 4. The reversibility of the interaction between MAO-B by 6c. Compound 6c
at concentrations of 10 Â IC50 and 100 Â IC50 was preincubated with MAO-B for
30 min. The resulting reactions were diluted 100-fold to yield inhibitor concentra-
tions of 0.1 Â IC50 and 1 Â IC50, respectively. The control reactions were conducted
in the absence of inhibitor. For comparison, reactions containing (R)-deprenyl, at
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fold) for MAO-B over MAO-A. For comparison, (R)-deprenyl exhib-
lM) and a high degree of selectivity (8720-
its an IC50 value for the inhibition of MAO-B of 0.079 lM under
identical experimental conditions.22 Compared to (R)-deprenyl,
compound 6c is a threefold more potent MAO-B inhibitor. The
MAO-A inhibitor, clorgyline, exhibits an IC50 value for the inhibi-
tion of MAO-A of 0.0026 lM under identical experimental
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conditions.22 The most potent MAO-A inhibitor of the present ser-
ies, compound 6b (IC50 = 0.623) is therefore 240-fold less potent as
a MAO-A inhibitor than clorgyline. Compared to the lead com-
pounds of this study, the 4-benzyloxyphthalonitrile (1) class of
compounds, the sulfanylphthalonitriles are, however, less potent
MAO-B inhibitors. For example, the para bromo substituted homo-
logue of 4-benzyloxyphthalonitrile, compound 8, inhibits human
23. Cheng, Y. C.; Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 3099.
MAO-B with an IC50 value of 0.0048 lM, approximately fivefold