Selected furanochalcones as inhibitors of monoamine oxidase

Article abstract of DOI:10.1016/j.bmcl.2013.06.050

The validity of the chalcone scaffold for the design of inhibitors of monoamine oxidase has previously been illustrated. In a systematic attempt to investigate the effect of heterocyclic substitution on the monoamine oxidase inhibitory properties of this

Full text of DOI:10.1016/j.bmcl.2013.06.050

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4985–4989
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Selected furanochalcones as inhibitors of monoamine oxidase
Sarel J. Robinson a, Jacobus P. Petzer a, Anél Petzer b, Jacobus J. Bergh a, Anna C. U. Lourens a,
⇑
a Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
b Centre of Excellence for Pharmaceutical Sciences, 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:
The validity of the chalcone scaffold for the design of inhibitors of monoamine oxidase has previously
been illustrated. In a systematic attempt to investigate the effect of heterocyclic substitution on the
monoamine oxidase inhibitory properties of this versatile scaffold, a series of furanochalcones were syn-
thesized. The results demonstrate that these furan substituted phenylpropenones exhibited moderate to
good inhibitory activities towards MAO-B, but showed weak or no inhibition of the MAO-A enzyme. The
most active compound, 2E-3-(5-chlorofuran-2-yl)-1-(3-chlorophenyl)prop-2-en-1-one, exhibited an IC50
Received 6 March 2013
Revised 12 June 2013
Accepted 17 June 2013
Available online 28 June 2013
Keywords:
Chalcone
Monoamine oxidase
MAO-B
Reversible inhibition
Competitive
value of 0.174 lM for the inhibition of MAO-B and 28.6 lM for the inhibition of MAO-A. Interestingly,
contrary to data previously reported for chalcones, these furan substituted derivatives acted as reversible
inhibitors, while kinetic analysis revealed a competitive mode of binding.
Ó 2013 Elsevier Ltd. All rights reserved.
Monoaminergic signalling plays an essential role in the modula-
tion of mood and emotion and also in the control of motor and cog-
nitive functions. Correct functioning of synaptic neurotransmission
is ensured by the effective degradation of monoamine neurotrans-
mitters, such as dopamine, noradrenaline and serotonin.1 This deg-
radation includes the oxidative deamination of monoamines to
yield the corresponding imine product and hydrogen peroxide
and is catalyzed by the monoamine oxidases (MAOs).2–4 Mono-
amine oxidase inhibitors have thus found application in the treat-
ment of depression, and also in neurodegenerative conditions such
as Alzheimer’s and Parkinson’s disease.5 MAOs are flavin adenine
dinucleotide (FAD)-containing enzymes which are located on the
outer membranes of mitochondria throughout the brain.6 Two sub-
types, namely MAO-A and MAO-B, have been identified based on
substrate selectivity and inhibitor sensitivity.7,8 It is noteworthy
that MAO-B is the isoform that is predominant in the human
brain.9 MAO-B inhibitors are clinically used in the treatment of
Parkinson’s disease and since the activity of both endogenously
and exogenously derived dopamine can be prolonged by adminis-
tering MAO-B selective inhibitors, they can either be used as
adjunctive therapy in Parkinson’s disease patients treated with
levodopa or as monotherapy in early Parkinson’s disease.10
tions of these molecules, are thought to possess neuroprotective
properties. This possible neuroprotective role for MAO inhibitors
has been extensively reviewed.11–14 As the concentration of
MAO-B is reported to increase in the human brain with age, inhibi-
tion of this enzyme is especially relevant in the treatment of age-
related neurodegenerative diseases, such as Parkinson’s disease.15
Chalcones (1,3-diphenyl-2-propen-1-ones) (1, Fig. 1) are open
chain flavonoids that are ubiquitous in edible plants and have a
broad range of reported biological activities,16,17 which include
anti-inflammatory and neuroprotective effects.18,19 These versatile
compounds and their heterocyclic (e.g., furan) counterparts are
synthetically easily accessible and are often used as intermediates
in the syntheses of inhibitors of MAO.20–26 The MAO inhibitory
activities of chalcones themselves have however, only been deter-
mined in a few instances for naturally occurring chalcones (e.g., 2,
Fig. 2) using rat,27–29 bovine30 and hamster31 monoamine oxidases,
while some synthetic derivatives, such as 3 (Fig. 2), were screened
against human MAO (hMAO).32 Generally, chalcones show a higher
degree of inhibition of MAO-B than of MAO-A,28,32 as illustrated by
the inhibitory activities observed for chalcone 3, where an IC50 of
0.0044
lM was determined for the inhibition of MAO-B and no
The by-products of MAO-mediated reactions include several
chemical species with neurotoxic potential, such as hydrogen per-
oxide (which is a source of oxidative stress), ammonia and alde-
hydes. Since these species may contribute to neuronal
degeneration, MAO inhibitors, by reducing the central concentra-
O
'
2
A
B
'
4
4
1
⇑
Corresponding author. Tel.: +27 18 2992266; fax: +27 18 2994243.
E-mail address: Arina.Lourens@nwu.ac.za (A.C.U. Lourens).
Figure 1. The structure of 1,3-diphenyl-prop-2-one (chalcone).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.06.050

4986
S. J. Robinson et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4985–4989
OH
O
heteroaromatic substitution on the monoamine oxidase inhibitory
OH
O
potencies of 3-phenylpropenones has not been previously exam-
ined. In order to further investigate the monoamine oxidase inhib-
itory properties of this useful scaffold, and as part of a systematic
investigation of the effect of heteroaromatic substitution, a series
of furan substituted chalcones (5a–r), which incorporated mainly
electron withdrawing substituents in either the A- or B-rings, were
synthesized and screened as monoamine oxidase inhibitors.
The furan moiety was selected as starting point, since this ring
quite often appears in other scaffolds associated with MAO inhib-
itory activity,21,22,25 although literature regarding variation in the
substitution of this ring and its role in the inhibition of MAO are
limited. The furan moiety in brofaromine for example, is one of
HO
OH
CH3O
Cl
3
2
Figure 2. Examples of natural (2) and synthetic chalcones (3) for which MAO-
inhibitory activities have been determined.27,30,32
O
O
O
i
Ar1
Ar
Ar1
Ar
H
5a - 5r
the two regions in this molecule associated with high
p electron
density which contributes to its interaction with the flavin nucleus
Scheme 1. Synthetic route to furanochalcones 5a–r. Reagents and conditions: (i)
NaOH, EtOH, rt, 3 h; Ar = substituted phenyl or furan; Ar1 = substituted phenyl or
furan.
of the co-factor.34
Furanochalcones were obtained by a Claisen–Schmidt conden-
sation between commercially available ketones and aldehydes un-
der basic conditions (Scheme 1).35 In each instance, the structures
of the target compounds were verified by 1H NMR and 13C NMR
spectroscopy and mass spectrometry, as cited in the Supplemen-
tary material.
inhibition of MAO-A was observed at 50
exceptions. For example, isoliquiritigenin (2) inhibits MAO-A
(13.9 M) more potently than MAO-B (47.2
M).29
l
M.32 However, there are
l
l
Kinetic analyses of the inhibition of MAO by chalcones have
only been carried out in a few instances and the results indicate
that chalcones are substrate-competitive inhibitors of rat
MAO.27,28 The issue regarding the reversibility of binding of chal-
cones to MAO has also not been thoroughly explored. In one study,
chalcones have been shown to bind irreversibly to hMAO-B,32 by a
binding mode similar to those of rasagiline and (R)-deprenyl, two
clinically used MAO-B inhibitors.10 Since adverse effects, such as
psychotoxic and cardiovascular effects, are associated with the
irreversible inhibition of particularly MAO-A, obtaining selective
MAO-B inhibitors, and preferably reversible inhibitors, are of
value.33
To investigate the MAO inhibitory properties of the synthesized
chalcones, recombinant hMAO-A and hMAO-B, expressed in micro-
somes from insect cells, were used. A fluorometric method, mea-
suring the MAO-catalyzed formation of 4-hydroxyquinoline (kex
310 nm; kem 400 nm) from the MAO-A/B mixed substrate, kynur-
amine, was used to measure the enzyme activities.36,37 The inhib-
itory potencies (IC50 values) of the chalcones were determined
from sigmoidal dose–response curves, which were constructed
by measuring the MAO catalytic activities in the presence of vari-
ous concentrations of the test inhibitors. The IC50 values for the
inhibition of MAO-A and MAO-B by compounds 5a–r (Fig. 3) are gi-
ven inTable 1.
The focus of previous studies were mainly on the MAO inhibi-
tory activities of chalcones substituted with electron donating sub-
stituents (e.g., OH groups) on the A-ring,27,32 while the effect of
The results show that the synthesized furanochalcones are
moderate to good inhibitors of MAO-B, but exhibited weak or no
inhibition of MAO-A. These results are thus in agreement with pre-
O
O
O
Cl
R
5b
5c
R = Cl
R = OCH3
5a
O
O
O
O
R2
R1
R1
R
R
R1 = H R2 = CH3
R1 = H R2 = Cl
R1 = H
R1 = Cl
R1 = H
R1 = Br
R1 = H
R1 = F
R1 = F
5d
5e
5f
5g
5h
5i
5j
5k
5l
R = Cl
R = H
R = Br
R = H
R = F
R = H
R = Br
R = CF3
R = H
5n
5o
5p
5q
5r
R = Cl
R = Cl
R = Cl
R = H
R = H
R1 = H
R1 = F
R1 = F
R2 = Br
R2 = H
R2 = Br
R1 = H
R1 = CF3
R1 = H
5m
R = OCH3
Figure 3. The structures of the target furanochalcone derivatives 5a–r.

S. J. Robinson et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4985–4989
4987
Table 1
The IC50 values for the inhibition of recombinant hMAO-A and hMAO-B by furanochalcone derivatives 5a–r
O
R1
R2
R1
R2
IC50
(l
M)a
SIb
MAO-A
MAO-B
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
3-Cl-phenyl
3-Cl-phenyl
3-OMe-phenyl
3-Cl-phenyl
4-Cl-phenyl
3-Br-phenyl
4-Br-phenyl
3-F-phenyl
Phenyl
2-Furyl
2-Furyl
No inhibitionc
21.1 3.42
19.2 4.21
18.0 5.46
40.9 46.6
15.0 0.342
85.7 8.13
24.0 0.588
18.6 6.17
1.95 0.025
83.7 10.3
31.8 33.0
No inhibitionc
59.5 7.01
28.6 5.03
30.2 3.63
41.8 3.11
61.6 5.35
0.529 0.034
2.10 0.142
3.20 0.366
0.490 0.064
0.616 0.047
0.449 0.048
0.707 0.122
0.619 0.060
0.924 0.197
0.200 0.049
0.288 0.057
0.275 0.038
2.79 0.835
0.344 0.062
0.174 0.033
0.206 0.091
7.67 0.688
0.543 0.047
—
10
6
53
66
33
121
39
20
5-Me-2-furanyl
5-Me-2-furanyl
5-Me-2-furanyl
5-Me-2-furanyl
5-Me-2-furanyl
5-Me-2-furanyl
5-Me-2-furanyl
5-Me-2-furanyl
5-Me-2-furanyl
5-Me-2-furanyl
3-Cl-phenyl
3-Cl-phenyl
3-Cl-phenyl
4-F-phenyl
4-F-phenyl
3-Br-4-F-phenyl
3-CF3-phenyl
4-CF3-phenyl
3-OMe-phenyl
5-Me-2-furanyl
5-Cl-2-furanyl
5-Br-2-furanyl
2-Furyl
10
290
116
—
173
164
147
5
5-Br-2-furanyl
4-F-phenyl
113
a
b
c
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).
No significant inhibition observed at a maximal tested concentration of 100 M.
l
vious studies which reported that chalcones are, in general, MAO-B
selective inhibitors.28,32 The selectivity of the chalcones for MAO-B
is exemplified by compound 5k, which is 290-fold more potent as
an inhibitor of MAO-B than of MAO-A, and compounds 5a and 5m,
which exhibited no inhibition of MAO-A at the highest concentra-
withdrawing group in the meta position of the phenyl ring gener-
ally appears to yield more potent MAO-B inhibitors than substitu-
tion in the para position (e.g., 5d vs 5e; 5f vs 5g and 5h vs 5i).
However, the two trifluoromethyl substituted derivatives, 5k and
5l, exhibited very similar MAO-B inhibitory activities
tion tested (100
l
M). Of the 18 furanochalcones evaluated in this
(IC50 = 0.288
electron withdrawing substituents in both the meta and para posi-
tions (5j, IC50 = 0.200 M) resulted in improved MAO-B inhibitory
activity compared to the monosubstituted homologues, 5i
(IC50 = 0.924 M) and 5f (IC50 = 0.449 M), but caused a decrease
in MAO-A/B selectivity.
Interestingly, when the positions of the furan and phenyl rings
were interchanged, for example, 5n (IC50 = 0.344 M) versus 5d
(IC50 = 0.490 M), comparable MAO-B inhibitory activities were
obtained, although 5n, with the phenyl group in the A-ring posi-
tion, yielded slightly more potent MAO-B inhibition. Substitution
on the furan ring with an electron withdrawing group (chlorine
and bromine), further led to improved MAO-B inhibitory activity,
lM and 0.275 lM, respectively). Incorporating two
study, fourteen compounds exhibited promising MAO-B inhibitory
activities, with IC50 values in the submicromolar range. Compound
5o proved to be the most potent MAO-B inhibitor with an IC50 va-
l
lue of 0.174
lM.
l
l
Some structure–activity relationships could be derived for the
MAO-B inhibitory activities of this series of furanochalcones. For
example, to compare the effects of furan, phenyl and methylfuran
substitution on MAO-B inhibition potency, the activities of com-
pounds 5a, 5b and 5d, as well as 5c and 5m were compared. For
compounds 5a and 5d, similar MAO-B inhibitory potencies were
obtained (although 5a exhibited higher selectivity for MAO-B).
These are the phenyl (5a) and methylfuran (5d) substituted deriv-
atives. The furan substituted derivative (5b) was approximately
four-fold weaker as an inhibitor of MAO-B than 5a and 5d. A sim-
ilar trend was also observed for the methoxy derivatives 5c
l
l
for example, compounds 5o (IC50 = 0.174
lM) and 5p
(IC50 = 0.206 M) versus 5n (IC50 = 0.344 M). Considering these
l
l
results, both steric and electronic effects appear to affect the
(IC50 = 3.20 lM) and 5m (IC50 = 2.79 lM), as furan substitution
MAO-B inhibitory properties of these compounds.
(5c) also yielded a compound with lower MAO-B inhibitory activity
(although the effect was not as pronounced). The notion that the
unsubstituted furyl moiety is less suitable for potent MAO-B inhi-
bition is further supported by the observation that the two weakest
MAO-B inhibitors (5q and 5c), among the chalcones examined,
possess the unsubstituted furyl moiety. This suggests that substi-
tution of the furan ring is required to obtain reasonable MAO-B
inhibitory activity.
The results further show that the combination of a furan or
methylfuran moiety (as the A-ring) with a phenyl moiety (as the
B-ring) substituted with electron withdrawing groups such as
chlorine, bromine, fluorine and trifluoromethyl groups (e.g., 5b,
5d–l) results in better MAO-B inhibitory activity than obtained
with substituting the phenyl ring with the electron donating meth-
oxy (OCH3) group (e.g., 5c and 5m). Substitution of the electron
Kinetic analyses for the inhibition of MAO-B, using kynuramine
as substrate, were carried out for the most potent inhibitor, 5o, as
well as for a less potent compound, 5d. The purpose with these
experiments was to determine the mode of MAO-B inhibition
exhibited by the furanochalcones. A set of Lineweaver–Burke plots
were constructed for each of the test furanochalcones, by measur-
ing the MAO-B catalytic activities at four different substrate
(kynuramine) concentrations, in the absence and presence of three
different concentrations of the test inhibitor. These results are
shown in Figure 4 and indicate that these compounds exhibit com-
petitive inhibition against kynuramine, as the double reciprocal
plots are linear and each set has a common y-intercept. From the
replots of the slopes of the Lineweaver–Burk plots versus inhibitor
concentration, Ki values of 0.294 and 0.144
5d and 5o, respectively.
lM were estimated for

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S. J. Robinson et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4985–4989
1800
Compound 5o
Compound 5d
1200
800
1200
100
75
50
25
0
100
600
400
75
-0.2
-0.1
0.0
[I], uM
0.1
0.2
-0.2
0.0
0.2
[I], uM
0.4
50
25
0
-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 4. Lineweaver–Burk plots of the oxidation of kynuramine by recombinant human MAO-B. The plots were constructed in the absence and presence of various
concentrations of compounds 5d and 5o. The concentrations of 5d employed were: 0.123, 0.245, and 0.49 M. The concentrations of 5o employed were: 0.044, 0.087, and
0.174 M. The rates (V) are expressed as nmol product formed/min/mg protein. The insets are replots of the slopes of the Lineweaver–Burk plots versus inhibitor
concentration.
l
l
Compound 5o
Compound 5d
100
75
50
25
0
100
75
50
25
0
l
r
y
C50
I
C50
o
t
i
n
I
e
r
b
i
x
x
h
p
e
n
1
1
D
0.
=
-
o I
)
]
I
[
N
=
R
]
(
I
[
Figure 5. Reversibility of inhibition of recombinant hMAO-B by compounds 5d and 5o. The enzyme was preincubated with inhibitor at 10 Â IC50 and 100 Â IC50 for 30 min
and then diluted to 0.1 Â IC50 and 1 Â IC50, respectively. As control, MAO-B was also preincubated with (R)-deprenyl at 10Â IC50 and subsequently diluted to 0.1 Â IC50. The
residual enzyme activities were subsequently measured.
To establish whether the binding of the furanochalcones to
MAO-B is reversible or irreversible, two representative compounds,
5d and 5o, were investigated. For this purpose, the recovery of
enzymatic activity after dilution of the enzyme–inhibitor com-
plexes was examined.38 MAO-B was pre-incubated with com-
pounds 5o and 5d at concentrations of 0, 10 and 100 Â IC50 for
30 min and then diluted 100-fold, to yield concentrations of 0,
0.1 and 1 Â IC50. For reversible inhibition, enzymatic activity is ex-
MAO-B catalytic activities are recovered to levels of 52% and 36%,
respectively, for the studies with 5d and 5o. This behavior is con-
sistent with a reversible interaction of these compounds with
MAO-B. After similar incubation of MAO-B with the irreversible
inhibitor (R)-deprenyl at 10 Â IC50, and dilution of the enzyme–
inhibitor complex to 0.1 Â IC50, the MAO-B activities were not
recovered (approximately 2–4% of control). Interestingly, the
reversibility found for the compounds studied here, is contrary to
results obtained previously for the inhibition of hMAO-B by chal-
cones32 and further investigation in this regard is required.
pected to recover to approximately 90% after dilution to 0.1 Â IC50
,
and 50% after dilution to 1 Â IC50. For an irreversible inhibitor, such
as (R)-deprenyl, enzyme activity is expected not to recover after
dilution of the enzyme–inhibitor complex. The results of these
studies are given in Figure 5 and show that, after the dilution of
5d and 5o to 0.1 Â IC50 the MAO-B catalytic activities are recovered
to levels of 82% and 79%, respectively, of the control value (re-
corded in absence of inhibitor). After dilution to 1 Â IC50, the
The above results indicate that furanochalcones, which consist
of a phenyl ring substituted with electron withdrawing substitu-
ents, and a substituted furan ring are potent and selective MAO-
B inhibitors. The substitution patterns investigated in this study
[most potent inhibitor, 5o (IC50 value = 0.174
lM)] are however
not as effective in generating potent MAO-B inhibitors as those

S. J. Robinson et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4985–4989
4989
investigated by Chimenti et al.32 where an IC50value of 0.0044
lM
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Any opinion, findings and conclusions or recommendations ex-
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online
version,
at
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j.bmcl.2013.06.050.
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