Inhibition of monoamine oxidase by benzoxathiolone analogues

Article abstract of DOI:10.1016/j.bmcl.2016.01.034

Inhibitors of the monoamine oxidase (MAO) enzymes are considered useful therapeutic agents, and are used in the clinic for the treatment of depressive illness and Parkinson's disease. In addition, MAO inhibitors are also under investigation for the treatm

Full text of DOI:10.1016/j.bmcl.2016.01.034

Bioorganic & Medicinal Chemistry Letters 26 (2016) 1200–1204
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Inhibition of monoamine oxidase by benzoxathiolone analogues
Samantha Mostert a,b, Anél Petzer b, Jacobus P. Petzer a,b,
⇑
a Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
b Centre of Excellence for Pharmaceutical Sciences, 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:
Inhibitors of the monoamine oxidase (MAO) enzymes are considered useful therapeutic agents, and are
used in the clinic for the treatment of depressive illness and Parkinson’s disease. In addition, MAO inhi-
bitors are also under investigation for the treatment of certain cardiovascular pathologies and as possible
aids to smoking cessation. In an attempt to discover novel classes of compounds that inhibit the MAOs,
the current study examines the human MAO inhibitory properties of a small series of 2H-1,3-ben-
zoxathiol-2-one analogues. The results show that the benzoxathiolones are potent MAO-B inhibitors with
Received 17 November 2015
Revised 12 January 2016
Accepted 14 January 2016
Available online 16 January 2016
Keywords:
Monoamine oxidase
MAO
Inhibition
Reversible
IC50 values ranging from 0.003 to 0.051
isoform, two compounds display good MAO-A inhibition with IC50 values of 0.189 and 0.424
l
M. Although the benzoxathiolones are selective for the MAO-B
M. Dialysis
l
studies show that a selected compound inhibits the MAOs reversibly. It may thus be concluded that the
benzoxathiolone class is suitable for the design and development of MAO-B inhibitors, and that in some
instances good MAO-A inhibition may also be achieved.
Benzoxathiolone
Ó 2016 Elsevier Ltd. All rights reserved.
The monoamine oxidase (MAO) enzymes are responsible for the
oxidation of a variety of amine substrates.1,2 MAO consists of two
isoforms, MAO-A and MAO-B, which share overall similar struc-
tures and possess covalently attached flavin adenine dinucleotide
(FAD) cofactors.3 Substrate oxidation occurs by two half reactions,
the reductive half reaction where the FAD cofactor is reduced when
accepting two electrons from the substrate amine, and an oxidative
half reaction where the reduced FAD is reoxidised by molecular
oxygen to yield hydrogen peroxide as by-product.4–6 In most
instances, the product of amine oxidation, the corresponding
imine, is hydrolysed to yield an aldehyde. Since the MAOs metabo-
lise neurotransmitter amines, they have become targets for the
treatment of neuropsychiatric and neurodegenerative disorders.3
Drugs that inhibit MAO-A are established antidepressants, and
are thought to act by elevating central serotonin levels.7,8
Examples of clinically used agents are phenelzine (1), isocarbox-
azid (2), tranylcypromine (3) and iproniazid (4) (Fig. 1). Phenelzine
and iproniazid (now discontinued) are non-selective MAO inhibi-
tors. Drugs that inhibit the MAO-B isoform, in turn, are used in
the treatment of Parkinson’s disease, often in combination with
(R)-deprenyl (5) and rasagiline (6). MAO-B inhibitors are also
thought to protect against neurodegeneration in Parkinson’s
disease. In this respect, central inhibition of MAO-B reduces the
formation of hydrogen peroxide and aldehydes, species which
may cause neuronal injury if not adequately cleared from the
brain.1 This risk may be particularly important in the aged brain
where MAO-B activity is significantly increased.12
The MAOs have also attracted attention as targets for the devel-
opment of therapy for Alzheimer’s disease. Laboratory evidence
suggests that MAO inhibitors improve cognitive deficits and
reverse amyloid b peptide (Ab) pathology.13 In cardiovascular
pathophysiology, MAO inhibitors may reduce the formation of
hydrogen peroxide and thus improve cardiac function in patients
with congestive heart failure.14 MAO-A appears to be the relevant
isoform here since cardiac MAO-A activity and hydrogen peroxide
generated by MAO-A show an age-dependent increase in the
hearts of rats. MAO-A could be a major source of hydrogen perox-
ide in the ageing heart, and thus a contributor to cardiac cellular
degeneration.15 Another potential application of MAO inhibitors,
particularly MAO-B inhibitors, is the possible treatment of smoking
cessation. This is based on reports that MAO-B activity is reduced
in smokers, and by increasing synaptic monoamines, MAO-B inhi-
bitors may mimic the effects of smoking, at least in part.16 Interest-
ingly, MAO-A levels are reported to be elevated in certain types of
cancer tissue such as prostate cancer, and MAO-A inhibition may,
in synergism with survivin suppressants, inhibit cancer cell
growth, migration and invasion.17,18
L
-Dopa.9 Since MAO-B metabolise dopamine in the brain, inhibitors
are thought to enhance dopamine levels, particularly following
therapy with L
-Dopa.10,11 Examples of clinically used agents are
⇑
Corresponding author. Tel.: +27 18 2992206; fax: +27 18 2994243.
E-mail address: jacques.petzer@nwu.ac.za (J.P. Petzer).
http://dx.doi.org/10.1016/j.bmcl.2016.01.034
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

S. Mostert et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1200–1204
1201
Table 1
O
N
H
N
H
N
The IC50 values for the inhibition of recombinant human MAO-A and MAO-B by
2H-1,3-benzoxathiol-2-one analogues, 7a–e
NH2
N
H
O
S
1
2
Phenelzine ( )
Isocarboxazid ( )
O
R
O
O
O
H
N
R
IC50
(
l
M)a
MAO-B
SIb
NH2
N
H
N
MAO-A
5.14 0.928
0.424 0.092
0.189 0.012
2.55 0.258
21.3 0.826
9.77 0.480
Tranylcypromine (3)
Iproniazid (4)
7a
7b
7c
7d
7e
11
C6H5CH2–
0.051 0.011
0.004 0.0003
0.003 0.001
0.005 0.001
0.033 0.006
9.57 1.07
101
106
63
510
645
1
3-ClC6H4CH2–
4-ClC6H4CH2–
4-CH3C6H4CH2–
C6H5(CH2)3–
H–
N
N
H
(R)-Deprenyl (5)
a
All values are expressed as the mean standard deviation (SD) of triplicate
6
Rasagiline ( )
determinations.
b
The selectivity index is the selectivity for the MAO-B isoform and is given as the
Figure 1. The structures of known MAO inhibitors.
ratio of IC50(MAO-A)/IC50(MAO-B).
Based on the current therapeutic value and future potential of
MAO inhibitors, the discovery of new classes of compounds that
inhibit the MAOs are justified. In the present study we have inves-
tigated a small series of 2H-1,3-benzoxathiol-2-one analogues (7)
as potential human MAO inhibitors (Fig. 2). These compounds
are structurally related to a number of heterocycles that have been
found in previous studies to be MAO inhibitors. For example, both
5-benzyloxyisatin (8) and 5-benzyloxyphthalimide (9) are potent
and selective (over the MAO-A isoform) inhibitors of human
MAO-B.19,20 A recent study has reported that 3-coumaranone
derivatives, such as compound 10, also are potent MAO-B
inhibitors.21 The benzyloxy side chains of these heterocycles
appear to be required for MAO inhibition since the removal thereof
results is significant reduction or abolishment of MAO inhibition.
The first benzoxathiolone analogue of the present study, 7a, has
thus been substituted on the C6 position with the benzyloxy moi-
ety (Table 1). Since substitution on the benzyloxy ring frequently
enhances MAO inhibition we have included the chlorine and
methyl substituted homologues, 7b–d. The effect of side chain
elongation was investigated with phenylpropoxy substitution
(7e). Although the series is limited, the objective was to determine
if the benzoxathiolone class of compounds may possess MAO inhi-
bition activity. This study will also investigate the reversibility of
MAO inhibition by selected benzoxathiolones. For MAO-A inhibi-
tion, reversibility is an important consideration since irreversible
acting MAO-A inhibitors are associated with a potentially fatal
increase in blood pressure when taken with certain foods and
can only be used in the clinic if dietary restrictions are followed.22
Reversible MAO-A inhibitors, on the other hand, appear to be safe
in this regard.23,24
The benzoxathiolone analogues were synthesized in poor to fair
yields (4–53%) by reacting commercially available 6-hydroxy-1,3-
benzoxathiol-2-one (11) with an appropriate substituted arylalkyl
bromide in acetone (Scheme 1). Potassium carbonate served as
base. The reactions were carried out at 60 °C for 5–24 h and mon-
itored with thin-layer chromatography (TLC). After completion,
ethyl acetate was added to the reaction and the resulting mixture
was washed with water and brine. The crude obtained after evap-
oration of the organic phase was purified by recrystallization. The
structures and purities of the target compounds were verified by
1H NMR, 13C NMR, mass spectrometry and HPLC analysis as cited
in the Supplementary data.
The MAO inhibitory properties of the benzoxathiolone
analogues 7a–e were evaluated using the recombinant human
MAO-A and MAO-B enzymes. Inhibition potencies are expressed
as the IC50 values, which were determined from sigmoidal plots
of residual enzyme activity versus the logarithm of inhibitor con-
centration. Residual enzyme activity, in turn, was measured by
using kynuramine as substrate for both MAO isoforms. Kynu-
ramine is oxidised by the MAOs to yield 4-hydroxyquinoline,
which was quantified by fluorescence spectrophotometry.25,26
Figure 3 provides examples of sigmoidal plots obtained for the
inhibition of the MAOs by compound 7c.
The inhibition potencies of the benzoxathiolone analogues are
given in Table 1. From the results it is evident that these com-
pounds are selective for MAO-B over the MAO-A isoform. In this
respect selectivity index (SI) values range from 63 to 645. All com-
pounds may be viewed as potent MAO-B inhibitors with IC50 val-
H
N
S
O
O
R
O
O
O
O
7
8
ues <0.051
lazabemide (12; IC50 = 0.091
benzoxathiolones examined here, while the reversible MAO-B inhi-
l
M. For comparison, the known MAO-B inhibitor,
MAO-A: IC50 = 4.62 µM
MAO-B: IC50 = 0.103 µM
l
M), is a weaker inhibitor than the
bitor safinamide (13; IC50 = 0.048 lM) is approximately equipotent
O
O
to 7a (Fig. 4).27 It should be noted that the IC50 values of the
N H
reference inhibitors have been measured and reported in previous
O
O
O
O
9
10
S
S
MAO-A: IC50 = 4.17 µM
MAO-B: IC50 = 0.043 µM
MAO-A: IC50 = 26.7 µM
MAO-B: IC50 = 0.062 µM
a
O
+
O
R
Br
R
O
O
HO
O
11
7a−e
Figure 2. The structures of the 2H-1,3-benzoxathiol-2-one analogues (7) that will
be investigated in this study as well as those of the lead compounds, 5-
benzyloxyisatin (8), 5-benzyloxyphthalimide (9) and 3-coumaranone derivative
10.19–21
Scheme 1. Synthetic route to the 2H-1,3-benzoxathiol-2-one analogues, 7a–e.
Reagents and conditions: (a) acetone, K2CO3, 60 °C, 5–24 h.

1202
S. Mostert et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1200–1204
H
N
O
100
75
50
25
0
N H
O
O
O
O
16
15
Br
MAO-A: IC50 = 0.233 µM
MAO-B: IC50 = 0.009 µM
MAO-A: IC50 = 0.22 µM
MAO-B: IC50 = 0.0069 µM
MAO-B
-3
MAO-A
Figure 5. The structures of isatin (15) and phthalimide (16) analogues, both
reported MAO inhibitors.19,20
were combined with the irreversible inhibitors, pargyline (MAO-A)
and (R)-deprenyl (MAO-B), and dialysed. For reversible inhibitors,
enzyme activity is expected to recover to 100% of the negative con-
trol value following dialysis. For irreversible inhibition, enzyme
activity is not recovered by dialysis. The results are given in
Figure 6, and show that, upon inhibition by 7c, both MAO-A and
MAO-B activities are recovered by dialysis to 93% and 78%, respec-
tively. The MAO activities in undialysed mixtures of the MAOs and
7c, in contrast are 73% and 39%, respectively. This result show that
7c is a reversible inhibitor of both MAO isoforms. As expected, after
dialysis of mixtures of the MAOs and the irreversible inhibitors,
pargyline and (R)-deprenyl, enzyme activity is not recovered with
MAO-A and MAO-B at 0.9% and 4.8%, respectively, of the negative
control.
-4
-2
-1
0
1
2
3
Log[I], µM
Figure 3. The sigmoidal plots for the inhibition of MAO-A (filled circles) and MAO-B
(open circles) by 7c.
studies employing identical experimental conditions to the current
study. Although weaker as MAO-A inhibitors, two compounds dis-
play good MAO-A inhibition. These are 7b and 7c with IC50 values
of 0.424
ically used reversible MAO-A inhibitor, toloxatone (14), inhibits
MAO-A with an IC50 value of 3.92
M.27 These compounds as well
as 7d (IC50 = 2.55 M) are thus more potent MAO-A inhibitors than
toloxatone. This study also finds that 6-hydroxy-1,3-benzoxathiol-
2-one (11) is a weak MAO-B inhibitor with an IC50 of 9.57 M. This
lM and 0.189 lM, respectively. For comparison, the clin-
l
l
To investigate the mode (e.g., competitive) of MAO-A and MAO-
B inhibition by 7c, Lineweaver–Burk plots were constructed. For
each MAO isoform a set consisting of six Lineweaver–Burk plots
was constructed by measuring the enzyme activities in the pres-
l
shows that the C6 substituent is indeed a requirement for potent
MAO-B inhibition by the benzoxathiolone analogues, and is in
agreement with similar findings with other heterocycles, such as
isatins (e.g., 8) and phthalimides (e.g., 9), for which an appropriate
side chain also is a requirement for MAO-B inhibition.19,20 Based on
the inhibition potencies it may thus be concluded that, similar to
the isatins and phthalimides reported previously, benzoxathi-
olones represent a class of highly potent MAO-B inhibitors. When
comparing 7a with the corresponding isatin and phthalimide
homologues, it is evident that 7a is a more potent MAO-B inhibitor
than 5-benzyloxyisatin (8; IC50 = 0.103
5-benzyloxyphthalimide (9; IC50 = 0.043
show that with the appropriate substitution good MAO-A inhibi-
tion may be obtained with the benzoxathiolones. Good MAO-A
inhibitors also exist among the reported isatins and phthalimides
ence of the following inhibitor concentrations: 0
l
M, ¼ Â IC50
,
½ Â IC50, ¾ Â IC50, 1 Â IC50 and 1¼ Â IC50. For each plot, eight dif-
ferent substrate (kynuramine) concentrations were used, ranging
from 15 to 250 lM. The results are given in Figure 7 and show that,
for both MAO-A and MAO-B inhibition, the lines are linear and
intersect on the y-axis. This is in agreement with a competitive
mode of inhibition of both MAO-A and MAO-B by 7c. By plotting
the slopes of the Lineweaver–Burk plots versus the inhibitor con-
centration, Ki values of 0.36 lM and 0.0035 lM for the inhibition
l
l
M) and equipotent to
of MAO-A and MAO-B, respectively, are estimated. The Ki values
can also be determined by global (shared) fitting of the inhibition
data directly to the Michaelis–Menten equation. This yielded sim-
ilar results with Ki values of 0.56 0.07
M (R2 = 0.98)
0.0039 0.0005 M for the inhibition of MAO-A
and MAO-B, respectively.
M).19,20 The results also
lM
(R2 = 0.99) and
l
l
as exemplified by 15 (IC50 = 0.233 lM) and 16 (IC50 = 0.22 lM)
(Fig. 5).19,20
Since benzoxathiolone analogues show good promise as MAO
inhibitors, selected properties were measured for the series as part
of a preliminary investigation of the suitability of these compounds
as drugs. For this purpose, the lipophilicity (logP) and aqueous sol-
ubility of the compounds were experimentally determined and are
listed in Table 2. Log P was determined with the shake-flask
method and represents the partitioning of the test compounds
between n-octanol and water. The logP value, in general, provides
an estimation of how readily a compound may diffuse passively
across the lipid bilayer, an important process for absorption from
the gastrointestinal tract and permeation across the blood–brain
barrier. It is generally accepted that, for a compound to display
good oral bioavailability and blood–brain barrier permeation, the
logP value should be in a range of 0–3.28 The logP values of the
benzoxathiolone analogues are 3.80–5.61, indicating that a high
degree of lipophilicity may be a concern, particularly from a solu-
As mentioned, reversibility of MAO inhibition is an important
consideration in inhibitor design. This study thus investigates the
reversibility of MAO-A and MAO-B inhibition by a selected ben-
zoxathiolone analogue, compound 7c. To examine the reversibility
of inhibition, the MAO enzymes and test inhibitor (at a concentra-
tion of 4 Â IC50) were combined for 15 min and subsequently dial-
ysed for 24 h. As negative control, similar dialysis of the MAOs in
absence of inhibitor was carried out. As positive controls, the MAOs
O
O
O
N
NH2
N
H
N
OH
Cl
12
Lazabemide (
)
Toloxatone (14)
bility point of view. Indeed, the aqueous solubilities are <0.081 lM
NH2
N
H
and may be considered to be in the very weak solubility range. To
improve the properties of the benzoxathiolone analogues, this
study recommends that in future studies polar, and possibly ionis-
able groups should by incorporated in the C6 side chain to reduce
lipophilicity and improve solubility. This would yield compounds
F
O
O
13
Safinamide(
)
Figure 4. The structures of reference MAO inhibitors.

S. Mostert et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1200–1204
1203
MAO-A
MAO-B
100
100
75
50
25
0
75
50
25
0
NI
7c
dialysed
parg
7c
NI
7c
depr
7c
undialysed
dialysed
undialysed
Figure 6. Dialysis reverses MAO-A and MAO-B inhibition by 7c. The MAO enzymes and 7c (at a concentration of 4 Â IC50) were combined for 15 min, dialysed for 24 h and the
residual enzyme activity was measured (7c dialysed). Similar incubation and dialysis of the MAOs in the absence (NI dialysed) and presence of the irreversible inhibitors,
pargyline (parg dialysed) and (R)-deprenyl (depr dialysed) were also carried out. The residual MAO activity of undialysed mixtures of the MAOs with 7c was also recorded (7c
undialysed).
MAO-A
100
1200
800
MAO-B
100
1200
800
400
400
75
50
25
0
75
50
25
0
−0.4
−0.2
0.0
[I], µ
0.2
−0.003
0.000
[I], µ
0.003
M
M
−0.02
0.00
0.02
1/[S]
0.04
0.06
−0.02
0.00
0.02
1/[S]
0.04
0.06
Figure 7. Lineweaver–Burk plots for the inhibition of human MAO-A and MAO-B by 7c. The insets are plots of the slopes of the Lineweaver–Burk plots versus inhibitor
concentration.
Table 2
properties may be particularly relevant where depression is a
comorbidity of Parkinson’s disease.
The logP values and aqueous solubilities of 2H-1,3-benzoxathiol-2-one analogues,
7a–e
LogP
Solubility (lM)
Acknowledgements
7a
7b
7c
7d
7e
3.80 0.03
4.72 0.12
5.61 0.24
4.54 0.25
4.70 0.17
0.064 0.066
0.081 0.015
0.072 0.013
0.051 0.005
0.013 0.006
The NMR and MS spectra were recorded by André Joubert and
Johan Jordaan of the SASOL Centre for Chemistry, North-West
University. 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, 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.
All values are expressed as the mean SD of triplicate determinations.
with improved properties. The effect of polar groups on MAO inhi-
bition, however, remains to be determined.
In conclusion, the present study shows that a small series of 2H-
1,3-benzoxathiol-2-one analogues are potent human MAO-B inhi-
bitors, and may thus act as leads for the future design for therapies
for disorders such as Parkinson’s disease. The physicochemical
properties of these compounds, however, are a concern and the
high degree of lipophilicity and low aqueous solubilities require
optimisation. Two of the 2H-1,3-benzoxathiol-2-one analogues
also are relatively potent human MAO-A inhibitors, and may thus
be suitable as leads for drugs aimed at the treatment of depression,
certain cardiovascular pathologies and certain types of cancer. In
this regard, the observation that a selected analogue is a reversible
MAO-A inhibitor is of significance. Reversible MAO-A inhibitors are
not likely to cause tyramine-induced changes in blood pressure
and have better safety profiles than irreversible MAO-A
inhibitors.23,24 Compounds with dual MAO-A/B inhibition
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.01.
034.
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