Selected chromone derivatives as inhibitors of monoamine oxidase

Article abstract of DOI:10.1016/j.bmcl.2012.07.025

A previous study has shown that a series of C6-benzyloxy substituted chromones exhibit high binding affinities for human monoamine oxidase (MAO) B. In an attempt to discover additional chromones with potent and selective MAO-B inhibitory potencies and to

Full text of DOI:10.1016/j.bmcl.2012.07.025

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5480–5484
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Selected chromone derivatives as inhibitors of monoamine oxidase
Lesetja J. Legoabe a, Anél Petzer a, Jacobus P. Petzer b,
⇑
a Unit for Drug Research and Development, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
b Pharmaceutical Chemistry, 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:
A previous study has shown that a series of C6-benzyloxy substituted chromones exhibit high binding
affinities for human monoamine oxidase (MAO) B. In an attempt to discover additional chromones with
potent and selective MAO-B inhibitory potencies and to further examine the structure–activity relation-
ships of MAO-B inhibition by chromones, the series was expanded with homologues containing polar
functional groups on C3 of the chromone ring. The results demonstrate that 6-[(3-bromobenzyl)oxy]
chromones containing acidic and aldehydic functional groups on C3 act as potent reversible MAO-B
inhibitors with IC50 values of 2.8 and 3.7 nM, respectively. Interestingly, a 2-hydroxy-2,3-dihydro-1-
benzopyran-4-one derivative as well as open-ring 2-acetylphenol analogues of the chromones also were
potent MAO-B inhibitors with IC50 values ranging from 4 to 11 nM. Chromone derivatives containing the
benzyloxy substituent on C5 of the chromone ring, however, exhibit MAO-B inhibition potencies that are
several orders of magnitude weaker. High potency inhibitors of MAO-B may find application in the
therapy of neurodegenerative disorders such as Parkinson’s disease.
Received 15 June 2012
Revised 5 July 2012
Accepted 6 July 2012
Available online 14 July 2012
Keywords:
Chromone
Benzopyran-4-one
Monoamine oxidase
MAO-B
Reversible inhibition
Structure–activity relationships
Ó 2012 Elsevier Ltd. All rights reserved.
The monoamine oxidase B (MAO-B) catalyzed
a
-carbon oxida-
values in the low nanomolar range (2–76 nM). This suggests that
C6-substituted chromone derivatives are good candidates for the
design of MAO-B inhibitors since structural modifications that
may lead to better drug properties are less likely to be associated
with a loss of activity. Interestingly, although selective for MAO-B,
C6-substituted chromones also inhibit MAO-A reversibly with
many derivatives exhibiting IC50 values in the nanomolar range.
Also of interest, is a recent study which reports that carboxylic acid
tion of dopamine is one of the major catabolic pathways of this neu-
rotramsmitter in the brain.1 Inhibitors of MAO-B lead to enhanced
dopaminergic neurotransmission and are therefore considered use-
ful in the early therapy of Parkinson’s disease (PD).2 MAO-B inhib-
itors also enhance the levels of dopamine derived from levodopa,
the metabolic precursor of dopamine, and are therefore frequently
combined with levodopa in PD therapy.3,4 Since the oxidative
metabolism of dopamine yields potentially neurotoxic metabolites,
which may contribute to neurodegenerative processes, MAO-B
inhibitors may also provide a neuroprotective effect in PD.5,6
Considering that MAO-B activity in the human brain increases with
age, inhibition of this enzyme is especially relevant in PD therapy.7
Based on the therapeutic value of MAO-B inhibitors, considerable
effort has been devoted to the design of novel inhibitors and the
elucidation of the structure–activity relationships (SAR) for
MAO-B inhibition. Consequently, a variety of oxygen and nitrogen
containing heterocycles have been found privileged for MAO-B
inhibition.8 Among these chromone (benzopyran-4-one) (1) has
emerged as a useful scaffold for the design of potent and reversible
substitution on C3 of the
derivative 2, results in high potency MAO-B inhibition (IC50
0.048
M).11 This remarkable finding suggests that the addition of
simple polar functional groups to the -pyrone moiety of chromone
c-pyrone moiety, to yield chromone
=
l
c
may be an effective strategy to enhance the MAO-B inhibition
potencies of this class of compounds. An added advantage of car-
boxylic acid substitution is the elimination of the MAO-A inhibition
component which is frequently encountered when designing MAO-
B inhibitors.11 While MAO-A also metabolizes dopamine in the hu-
man brain, MAO-A inhibition is in general not a desired property of
drugs used in PD therapy. Inhibitors of MAO-A potentiates the sym-
pathomimetic effects of dietary amines such as tyramine, which
may lead to serious adverse effects. In addition, the combination
of MAO-A inhibitors and levodopa in PD therapy should be avoided
since this may lead to a hypertensive response.13
Based on this analysis, the present study investigates the possi-
bility of combining the favourable MAO inhibitory properties of the
C6 and C3 substituents, respectively, in an attempt to design high
potency MAO-B inhibitors with an acceptable selectivity profile.
For this purpose, the MAO inhibitory properties of a series of
MAO-B inhibitors (Fig. 1).9–12 Substitution on C6 of the benzo-
c-
pyrone moiety has been shown to yield structures with potent
MAO-B inhibition activities.12 In fact, a relatively large degree of tol-
erance exists for different C6 substituents and substitution pat-
terns, and a variety of C6-substituted chromones exhibit IC50
⇑
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.2012.07.025

L. J. Legoabe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5480–5484
5481
O
O
O
O
O
O
O
O
O
O
O
OH
R
OH
1
2
7a
6a: R = H
Br
O
6b: R = Br
O
O
O
O
Br
3
Br
O
OH
7b
Figure 1. The structures of chromone (1), chromone-3-carboxylic acid (2) and 6-
[(3-bromobenzyl)oxy]-4H-chromen-4-one (3).
Figure 3. The structures of the C5-substituted chromones 6a–b, and 2-hydroxy-
2,3-dihydro-1-benzopyran-4-one derivatives 7a–b.
chromone derivatives containing substituents on C6 of the benzo-
To synthesize the test compounds several synthetic protocols
were employed. The 2-acetylphenol analogues 5a–f were synthe-
sized in low to good yields (12–91%) by reacting the appropriate
dihydroxyacetophenone (8) with 3- or 4-bromobenzyl bromide
(9a–b) in the presence of K2CO3 (Scheme 1). Treatment of the
2-acetylphenol analogue 5c with phosphoryl chloride (POCl3) and
N,N-dimethylformamide (DMF) yielded the formyl derivative 4b
(95%). Compound 4b was subsequently converted to the corre-
sponding carboxylic acid 4a with sodium chlorite (NaClO2) and sul-
famic acid (NH2SO3H) (51%). After converting 4a to the acyl
chloride with oxalyl chloride and subsequent treatment with
methanol, the ester derivative 4c was obtained (73%).15 The 2-hy-
droxy-2,3-dihydro-1-benzopyran-4-one derivatives, compounds
7a–b, were synthesized from the 2-acetylphenol analogues 5c
and 5b, respectively, by reaction with ethyl formate in the pres-
ence of sodium methoxide as base (72–78%) (Scheme 2). The
C5-substituted chromones, compounds 6a–b, were synthesized
by treating 7b and 7c with concentrated HCl in acetone (36–
84%).16 In each instance, 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.
To examine the MAO inhibitory properties of the chromone de-
rived structures, recombinant human MAO-A and -B were em-
ployed.17 The enzyme activity measurements were based on
fluorometrically measuring the MAO-catalyzed formation of
4-hydroxyquinoline from the MAO-A/B mixed substrate, kynur-
amine.18 The IC50 values for the inhibition of MAO-A and -B by
compounds 4a–c are given in Table 1. The results show that both
the carboxylic acid and formyl derivatives, structures 4a and 4b,
are highly potent MAO-B inhibitors with IC50 values of 0.0028
c-pyrone ring as well as polar substituents on C3 of the c-pyrone
moiety were examined. Such compounds may potentially possess
high affinity for MAO-B, a property imparted by the C6 substituent,
as well as improved selectivity for MAO-B, a property imparted by
the polar C3 substituent. The 3-bromobenzyloxy substituent was
selected as C6 substituent in this study since this moiety has been
shown to be particularly favourable for MAO-B inhibition by
C6-substituted chromone derivatives, with 6-[(3-bromoben-
zyl)oxy]-4H-chromen-4-one (3) exhibiting an IC50 value of
0.002 l
M.12 As polar C3 substituents, the carboxylic acid, formyl
and methyl ester functional groups were selected. The structures
of these derivatives, compounds 4a–c, are illustrated in Figure 2.
In addition, several other chromone derived structures were inves-
tigated with the aim of further examining the SAR of MAO inhibi-
tion. These include compounds 5a–f, which are open-ring 2-
acetylphenol analogues of the chromone 3. The objective with
these open-ring analogues is to examine the importance of an in-
tact c-pyrone moiety for MAO-B inhibition. This study also reports,
for the first time, the MAO inhibitory properties of C5-substituted
chromones, compounds 6a–b, and 2-hydroxy-2,3-dihydro-1-benz-
opyran-4-one derivatives, compounds 7a–b (Fig. 3). These deriva-
tives will provide insight into the importance of the position of
the substituent on C6 versus C5 for MAO-B inhibition, and the ef-
fect of saturation of the
c-pyrone moiety on the MAO inhibition
properties of chromones. Unpublished observations have shown
that, although not as potent as C6-substituted chromones, C7-
substituted chromones also exhibit potent MAO-B inhibitory
activities.14
and 0.0037
lM, respectively. The potencies of these compounds
are therefore similar to that of 3 (IC50 = 0.002
l
M), the structure
O
O
R
O
from which they were derived.12 It may therefore be concluded
that the additions of the carboxylic acid and formyl groups to 3
lead to neither an enhancement nor a loss of MAO-B inhibition po-
tency. In contrast, 4a and 4b were found to be comparatively weak
O
R
OH
5a: R = −O−CH2−(3-Br-C6H5)
5b: R = −O−CH2−(4-Br−C6H5)
4a: R = CO2H
MAO-A inhibitors with IC50 values of 1.04 and 2.20 lM, respec-
Br
4b: R = CHO
tively. These inhibitors are therefore 371- and 595-fold, respec-
tively, more selective for the MAO-B isoform. The selectivity
profiles of these compounds are better than that of compound 3,
which is reported to be 193-fold more selective for MAO-B [IC50
4c: R = CO2CH3
O
O
l
M].12 Although not as potent as 4a–b, the ester
R
(MAO-A) = 0.386
derivative 4c also proved to be a potent MAO-B inhibitor with an
IC50 value of 0.0774 M. Compound 4c, however, exhibited a lower
R
OH
l
OH
degree of selectivity with a selectivity index (SI) of 83. These re-
sults indicate that substitution with the carboxylic acid and formyl
groups on C3 of the chromone moiety results in an improved selec-
tivity profile without a significant loss of MAO-B inhibition po-
tency. The importance of the C3 and C6 substituents for MAO-B
5c: R = −O−CH2−(3-Br-C6H5)
5d: R = −O−CH2−(4-Br−C6H5)
5e: R = −O−CH2−(3-Br-C6H5)
5f: R = −O−CH2−(4-Br−C6H5)
Figure 2. The structures of the target chromone derivatives 4a–c and 2-acetylphe-
nol analogues 5a–f.

5482
L. J. Legoabe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5480–5484
O
O
Br
R
i
O
Br
HO
+
OH
OH
5a-f
9a: R = 3-Br
9b: R = 4-Br
8
ii
O
O
O
O
O
O
O
O
O
O
O
iv, v
O
OH
H
iii
O
4c
4a
4b
Br
Br
Br
Scheme 1. Synthetic route to 2-acetylphenol analogues 5a–f and chromone derivatives 4a–c. Reagents and conditions: (i) K2CO3, acetone, reflux; (ii) POCl3, DMF, À15 °C; (iii)
NaClO2, NH2SO3H, CH2Cl2, 0 °C; (iv) oxalyl chloride, rt; (v) CH3OH, rt.
O
O
O
O
O
O
O
O
R
R
R
ii
i
OH
OH
5g: R = H
5b: R = Br
7c: R = H
7b: R = Br
6a: R = H
6b: R = Br
O
O
O
O
i
OH
O
OH
5c
7a
Br
Br
Scheme 2. Synthetic route to C5-substituted chromones 6a–b, and 2-hydroxy-2,3-dihydro-1-benzopyran-4-one derivatives 7a–b. Reagents and conditions: (i) Ethyl formate,
CH3ONa, rt; (ii) HCl (32%).
Table 1
Table 2
The IC50 values for the inhibition of recombinant human MAO-A and -B by chromone
derivatives 4a–c, chromone (1) and chromone-3-carbaldehyde (10)
The IC50 values for the inhibition of recombinant human MAO-A and -B by 2-
acetylphenol analogues 5a–f
O
O
O
R
O
R2
R1
R
O
OH
R
OH
OH
5a, b
5c, d
5e, f
R1
H
R2
H
IC50
(lM)
SIb
a
5a, c, e: R = −O−CH2−(3-Br-C6H5)
5b, d, f: R = −O−CH2−(4-Br−C6H5)
MAO-A
MAO-B
54.9 1.14
1
39.9 3.46
1
SIb
a
4a –CO2H
4b –CHO
3-BrC6H4-CH2-O– 1.04 0.003 0.0028 0.00002 371
3-BrC6H4-CH2-O– 2.20 0.202 0.0037 0.0012
–CO2CH3 3-BrC6H4-CH2-O– 6.46 1.07 0.0774 0.006
IC50
(l
M)
595
83
1
MAO-A
MAO-B
4c
5a
5b
5c
5d
5e
5f
103 5.76
143 25.9
19.7 3.34
2.90 0.232
15.8 1.66
6.26 0.829
5.96 2.11
17
53
34
17
3950
569
10 –CHO
H
28.9 4.42
23.5 1.32
2.69 0.465
0.576 0.065
0.172 0.006
0.004 0.0016
0.011 0.0014
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
b
ratio of IC50 (MAO-A)/IC50 (MAO-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
b
inhibition was examined by inclusion of structures 1 and 10 (from
Sigma–Aldrich). The results show that chromone (1) is a weak
ratio of IC50 (MAO-A)/IC50 (MAO-B).
MAO-B inhibitor (IC50 = 54.9 lM), which confirms the notion that
either a bromobenzyloxy side chain at C6 or a carboxylic acid
group at C3 are requirements for potent inhibition. The finding that
chromone-3-carbaldehyde 10 is also a weak MAO-B inhibitor
5e and 5f were found to be highly potent MAO-B inhibitors with
IC50 values of 0.004 and 0.011 lM, respectively. These structures
(IC50 = 23.5
for inhibitory activity.
The results of the MAO inhibition studies with the 2-acetylphe-
nol analogues 5a–f are given in Table 2. Among these homologues,
l
M) further supports the importance of C6 substitution
are substituted with the benzyloxy side chain on C5 of the phenol
ring. Altering the position of the benzyloxy side chain resulted in
weaker MAO-B inhibition. For example, substitution on C4 of the
phenol ring to yield 5c (IC50 = 0.576 lM) and 5d (IC50 = 0.172 lM)

L. J. Legoabe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5480–5484
5483
Table 3
Since 6a–b are also weak MAO-A inhibitors, it may be concluded
that substitution on C5 of the chromone ring is not an effective
strategy to enhance the MAO inhibitory properties of chromones.
This point of view is supported by the finding that substitution
on C5 of the 2-hydroxy-2,3-dihydro-1-benzopyran-4-one moiety
to yield 7b also results in weak MAO-B inhibition. In contrast sub-
stitution on C6 with a benzyloxy moiety yields compound 7a,
The IC50 values for the inhibition of recombinant human MAO-A and -B by C5-
substituted chromones 6a–b, and 2-hydroxy-2,3-dihydro-1-benzopyran-4-one deriv-
atives 7a–b
O
O
O
O
Br
R
which is
a potent MAO-B inhibitor with an IC50 value of
O
OH
0.0057 M. Compound 7a also is a selective MAO-B inhibitor with
l
O
7a, b
a SI of 269. This study therefore concludes that the 2-hydroxy-2,3-
dihydro-1-benzopyran-4-one moiety represents a new scaffold for
the design of MAO-B inhibitors, with substitution on C6 yielding
highly potent and selective inhibitors.
6a: R = H; 6b: R = Br
a
IC50
(
l
M)
SIb
MAO-A
MAO-B
Interestingly, it has been reported that chromone 3-carboxam-
ide derivatives behave as quasi-reversible MAO-B inhibitors.9 In
the current study, the reversibility of MAO-B inhibition by three
highly potent MAO-B inhibitors, structures 4a, 5e and 7a, were also
examined. For this purpose, the recovery of the enzymatic activity
after dilution of the enzyme-inhibitor complex was evaluated.
MAO-B was preincubated with compounds 4a, 5e and 7a at a con-
6a
6b
7a
7b
143 5.09
52.9 3.89
1.53 0.029
60.6 2.89
8.03 2.31
4.34 0.120
0.0057 0.00021
44.8 8.98
18
12
269
1.4
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
centration of 10 Â IC50 for 30 min and then diluted to 0.1 Â IC50
.
The results are given in Figure 4 and show that, for all three com-
pounds, after dilution to concentrations equal to 0.1 Â IC50, the
MAO-B catalytic activities are recovered to levels of approximately
68% of the control value. This behaviour is consistent with a revers-
ible interaction of these compounds with MAO-B, since after
similar treatment of MAO-B with the irreversible inhibitor
(R)-deprenyl, the MAO-B activities were not recovered (3.4–5% of
control). Interestingly, after dilution, the enzyme activities are
not recovered to 90% as may be expected. This result suggests that
the binding of 4a, 5e and 7a may possess a quasi-reversible or
tight-binding component. Further investigation is necessary to
clarify this point.
In conclusion, this study finds that the addition of polar func-
tional groups, particularly the carboxylic acid and formyl groups,
to C3 of the chromone moiety is an effective strategy to enhance
the MAO-B selectivities of derivatives already possessing MAO
inhibitory properties. This occurs without a significant loss of
MAO-B inhibition potency. The study also discovers that the 2-
acetylphenol ring represents a promising scaffold for the design
of MAO-B inhibitors, since substitution on the C5 position yields
highly potent and selective MAO-B inhibitors. Furthermore, the
MAO-B inhibition potencies of the most active inhibitors of the
present study compares favourably to those of recently reported
series of 3-carbonyl coumarin19 and 3-carboxamido coumarin20
was associated by at least a 15-fold reduction of MAO-B inhibition
potency. Substitution on C3 of the phenol ring to give 5a
(IC50 = 5.96 lM) and 5b (IC50 = 2.69 lM) yielded even weaker
MAO-B inhibitors. The results also document that the 2-acetylphe-
nol analogues are weak MAO-A inhibitors with IC50 values ranging
from 2.90 to 143 lM. As evident from the SI values, these homo-
logues are all selective for the MAO-B isoform. Remarkably, 5e
exhibited an SI value of 3950, the highest degree of selectivity
among the compounds examined here. These results demonstrate
that substitution on C5 of the 2-acetylphenol ring yields structures
with exceptionally potent MAO-B inhibition activities. The 2-acet-
ylphenol ring therefore represents a new promising scaffold for the
design of potent and selective MAO-B inhibitors. It may be con-
cluded that an intact
c-pyrone moiety is not a prerequisite for
MAO-B inhibition as long as the substituent is in the C5 position
of the ring-opened 2-acetylphenol moiety.
The importance of the position of the benzyloxy substituent for
MAO-B inhibition is further demonstrated by the finding that C5-
substituted chromone analogues 6a–b are weak MAO-B inhibitors
with IC50 values of 8.03 and 4.34 lM, respectively (Table 3). These
inhibitors are at least 1300-fold weaker as MAO-B inhibitors than
the corresponding C6-substituted chromones, compound 3 and
6-[(4-bromobenzyl)oxy]-4H-chromen-4-one (IC50 = 0.0033
l
M).12
100
75
50
25
0
100
75
50
25
0
100
4a
5e
7a
75
50
25
0
l
l
l
y
r
y
C50
y
C50
C50
o
t
n
e
n
n
e
r
i
I
I
e
I
b
r
i
r
x
x
x
p
h
p
p
e
e
n
I
e
1
.
1
.
1
.
D
D
D
-
-
0
0
-
o
)
)
)
= 0
N
=
]
I
[
R
R
(
R
(
]
(
] =
I
I
[
[
Figure 4. Reversibility of inhibition of MAO-B by compounds 4a, 5e and 7a. The enzyme was preincubated with the test inhibitors and (R)-deprenyl, at 10 Â IC50 for 30 min
and then diluted to 0.1 Â IC50. The residual enzyme activities were subsequently measured.

5484
L. J. Legoabe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5480–5484
4. Finberg, J. P.; Wang, J.; Bankiewich, K.; Harvey-White, J.; Kopin, I. J.; Goldstein,
D. S. J. Neural Transm. Suppl. 1998, 52, 279.
5. Menazza, S.; Blaauw, B.; Tiepolo, T.; Toniolo, L.; Braghetta, P.; Spolaore, B.;
Reggiani, C.; Di Lisa, F.; Bonaldo, P.; Canton, M. Hum. Mol. Genet. 2010, 19,
4207.
6. Trouche, E.; Mias, C.; Seguelas, M. H.; Ordener, C.; Cussac, D.; Parini, A. Stem
Cells Dev. 2010, 19, 1571.
7. Fowler, J. S.; Volkow, N. D.; Wang, G. J.; Logan, J.; Pappas, N.; Shea, C.;
MacGregor, R. Neurobiol. Aging. 1997, 18, 431.
8. Gnerre, C.; Catto, M.; Leonetti, F.; Weber, P.; Carrupt, P.-A.; Altomare, C.;
Carotti, A.; Testa, B. J. Med. Chem. 2000, 43, 4747.
9. Gaspar, A.; Silva, T.; Yáñez, M.; Viña, D.; Orallo, F.; Ortuso, F.; Uriarte, E.; Alcaro,
S.; Borges, F. J. Med. Chem. 2011, 54, 5165.
derivatives. For example, the most potent MAO-B inhibitor among
the 3-carbonyl coumarins exhibited an IC50 value of 0.14
M19
while the most potent inhibitor among the 3-carboxamido couma-
rins displayed an IC50 value of 0.0014
M.20 These inhibitors thus
have potential as novel therapeutic agents in Parkinson’s disease
and further investigation is necessary to determine if they possess
the necessary properties to merit further development.
l
l
Acknowledgments
10. Gaspar, A.; Reis, J.; Fonseca, A.; Milhazes, N.; Viña, D.; Uriarte, E.; Borges, F.
Bioorg. Med. Chem. Lett. 2011, 21, 707.
11. Alcaro, S.; Gaspar, A.; Ortuso, F.; Milhazes, N.; Orallo, F.; Uriarte, E.; Yáñez, M.;
Borges, F. Bioorg. Med. Chem. Lett. 2010, 20, 2709.
12. Legoabe, L. J.; Petzer, A.; Petzer, J. P. Eur. J. Med. Chem. 2012, 49,
343.
13. Zesiewicz, T. A.; Hauser, R. A. In Parkinson’s disease: diagnosis and clinical
management; Factor, S. A., Weiner, W. J., Eds.; Demos Medical Publishing: New
York, 2002; pp 365–378.
We are grateful to André Joubert of the SASOL Centre for Chem-
istry, North-West University, and the Mass Spectrometry Service,
University of the Witwatersrand for recording the NMR and MS
spectra, respectively. Financial support for this work was provided
by the North-West University, the National Research Foundation
and the Medical Research Council, South Africa.
14. Legoabe, L. J.; Petzer, A.; Petzer, J. P., in preparation.
15. Ishizuka, N.; Matsumura, K.; Sakai, K.; Fujimoto, M.; Mihara, S.; Yamamori, T. J.
Med. Chem. 2002, 45, 2041.
Supplementary data
16. Schonberg, A.; Sina, A. J. Am. Chem. Soc. 1950, 72, 3396.
17. Novaroli, L.; Reist, M.; Favre, E.; Carotti, A.; Catto, M.; Carrupt, P. A. Bioorg. Med.
Chem. 2005, 13, 6212.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.07.025.
18. Strydom, B.; Malan, S. F.; Castagnoli, N.; Bergh, J. J.; Petzer, J. P. Bioorg. Med.
Chem. 2010, 18, 1018.
19. Secci, D.; Carradori, S.; Bolasco, A.; Chimenti, P.; Yáñez, M.; Ortuso, F.; Alcaro, S.
Eur. J. Med. Chem. 2011, 46, 4846.
20. Chimenti, F.; Secci, D.; Bolasco, A.; Chimenti, P.; Bizzarri, B.; Granese, A.;
Carradori, S.; Yáñez, M.; Orallo, F.; Ortuso, F.; Alcaro, S. J. Med. Chem. 1935,
2009, 52.
References and notes
1. Youdim, M. B. H.; Bakhle, Y. S. Br. J. Pharmacol. 2006, 147, S287.
2. Youdim, M. B. H.; Edmondson, D.; Tipton, K. F. Nat. Rev. Neurosci. 2006, 7, 295.
3. Di Monte, D. A.; DeLanney, L. E.; Irwin, I.; Royland, J. E.; Chan, P.; Jakowec, M.
W.; Langston, J. W. Brain Res. 1996, 738, 53.