Synthesis and evaluation of aplysinopsin analogs as inhibitors of human monoamine oxidase A and B

Article abstract of DOI:10.1016/j.bmcl.2012.06.058

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms. Previous studies have shown aplysinopsin analogs to possess a variety of biological activities, including modulation of neurotransmissions. A series of fifty aplysinopsin analogs was synthesized and assayed for monoamine oxidase A and B inhibitory activity. Three compounds displayed significant MAO inhibitory activity and selectivity. The compound (E)-5-[(6-bromo-1H-indol-3-yl)methylene]-2-imino-1,3- dimethylimidazolidin-4-one (3x) possessed an IC₅₀ of 5.6 nM at MAO-A and had a selectivity index of 80.24. An SAR study revealed that multiple N-methylations, one of which should be at position N-2′, and bromination at C-5 or C-6 are important factors for MAO-A potency and selectivity.

Full text of DOI:10.1016/j.bmcl.2012.06.058

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4926–4929
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of aplysinopsin analogs as inhibitors of human
monoamine oxidase A and B
Kevin Lewellyn a, Dobroslawa Bialonska a,b, Narayan D. Chaurasiya c, Babu L. Tekwani c,d
,
Jordan K. Zjawiony a,
⇑
a Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA
b Institute of Environmental Sciences, Jagiellonian University, 30-387 Krakow, Poland
c National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA
d Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS 38677, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine
organisms. Previous studies have shown aplysinopsin analogs to possess a variety of biological activities,
including modulation of neurotransmissions. A series of fifty aplysinopsin analogs was synthesized and
assayed for monoamine oxidase A and B inhibitory activity. Three compounds displayed significant
MAO inhibitory activity and selectivity. The compound (E)-5-[(6-bromo-1H-indol-3-yl)methylene]-2-
imino-1,3-dimethylimidazolidin-4-one (3x) possessed an IC50 of 5.6 nM at MAO-A and had a selectivity
index of 80.24. An SAR study revealed that multiple N-methylations, one of which should be at position
N-20, and bromination at C-5 or C-6 are important factors for MAO-A potency and selectivity.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 8 May 2012
Revised 13 June 2012
Accepted 18 June 2012
Available online 23 June 2012
Keywords:
Monoamine oxidase inhibitors
Aplysinopsin analogs
Neurotransmitters
Natural product
Indole alkaloids
Depression effects nearly 1 in 10 adults in the US according to a
study by the CDC.1 The WHO estimates that by 2020 depression
will be the second most disabling condition in the world.2 Based
on these statistics it is obvious that there is a need for new drug
candidates in the treatment of depression.3 Monoamine oxidase
inhibitors (MAOIs) initially were first line medications in the treat-
ment of depressive illness, however, due to serious side effects, the
interest in these drugs diminished.4 When the two isoforms, MAO-
A and MAO-B, were discovered, interest was renewed in their po-
tential therapeutic use and several new generations of selective
MAO inhibitors have been developed.5 Today, much more is known
about the use of selective MAO inhibitors to treat various mental
disorders such as depression, anxiety, Parkinson’s, and Alzheimer’s
disease.6 Due to this increased understanding of neurological dis-
ease states, there is an increased interest in development of potent
and selective MAOIs.
Aplysinopsins (Fig. 1) are tryptophan-derived natural products
isolated from a variety of marine organisms and found to have var-
ious biological activities.7 Natural analogs differ in the bromination
pattern of the indole ring as well as in the number and position of
N-methylations of the imidazolidinone ring. Aplysinopsins have
received considerable attention as promising neuromodulators
with significant affinity to serotonin receptors8 and the potential
to inhibit MAO activity.9 Since these two mechanisms account
for antidepressant action, aplysinopsins represent potentially use-
ful candidates in antidepressant drug development.
Structurally, aplysinopsins are made up of two distinct moie-
ties: an indole and an imidazolidinone ring. The indole scaffold is
known to contribute to MAO inhibitory activities, and many ana-
logs have been prepared using it.10 Furthermore, a recent study
has shown that imidazolines possess potent and selective activity
at both MAO isoforms.11 Based on this information, we sought to
design a series of aplysinopsin analogs with potent and selective
MAOI activity. In the current work, the synthesis and structure–
activity relationship (SAR) study of this series of aplysinopsin ana-
logs are described.
A series of aplysinopsin analogs, 3a–ii, were synthesized utiliz-
ing the condensation of indole-3-carboxyaldehydes and the appro-
priate imidazolidinones.12a,b (Scheme 1) The indole aldehydes 1a–
e were commercially available and the imidazolidinones 2a–h
have been obtained according to the published procedures.13–15
Our attempts to obtain the imidazolidinone 2c following the
published procedure14 and the condensation of glyoxal with
N-methylguanidine16 failed (Scheme 2). Eventually, the analogs
with methylamine substitution, 7a–e, were synthesized by
condensation of corresponding indole-3-carboxyaldehydes 1a–e
with thiohydantoin (4), methylation of intermediate thiones 5a–
e, followed by substitution of thioethers 6a–e with methylamine
(Scheme 3).12c–e
⇑
Corresponding author.
E-mail address: jordan@olemiss.edu (J.K. Zjawiony).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.06.058

K. Lewellyn et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4926–4929
4927
R2
2'
CHO
O
H
N
1
b
4
a
c
R
1
R1
6
8
N
R
S
NH
S
N
N
H
N
H
3
HN
R3
O
O
4'
N
H
5'
N
2
R4
1a-e
4
5a-e
N
H
O
O
1
1
R
R
Figure 1. General structure of aplysinopsin analogs.
N
NH
HN
HN
CH
3
CH
3
S
N
H
6a-e
N
N
H
7a-e
R2
N
R2
N
CHO
R1
Compound
R1
N
Δ
R1
N
R3
5a, 6a, 7a
-
N
H
R3
N
-H2O
N
5b, 6b, 7b 4-Br
O
R4
N
H
O
R4
5c, 6c, 7c
5d, 6d, 7d 6-Br
5e, 6e, 7e
7-Br
5-Br
1a-e
2a-h
3a-ii
Scheme 3. The synthesis of C-30 N-methylamine aplysinopsin analogs (7a–e).
Reagents and conditions: (a) ETA, EtOH, reflux, 1 h; (b) CH3I, NaOH, MeOH, rt, 18 h;
(c) CH3NH2, EtOH, sealed vessel, 70 °C, 24h
Compd
1a
R1
Compd
2a
R2
H
R3
H
R4
-
H
H
1b
4-Br
5-Br
6-Br
7-Br
2b
Me
H
H
1c
2c
Me
H
H
The 50 new aplysinopsin analogs (3a–ii, 5a–e, 6a–e, 7a–e) were
evaluated for their MAO-A and MAO-B inhibitory activity.21,22 (Ta-
ble 1) In addition, clorgyline and deprenyl were evaluated as refer-
ence compounds. The results, expressed as IC50 and SI (selectivity
index given by the MAO B IC50/MAO A IC50 ratio) values are sum-
marized in Table 1. In general we found that most aplysinopsin
analogs showed greater inhibitory activity at MAO-A compared
1d
2d
H
Me
H
1e
2e
Me Me
2f
Me
H
H
Me
2g
Me Me
2h
Me Me Me
to MAO-B, with IC50 values ranging from 0.0056 to 26.12
MAO-A and 0.207 to 100 M for MAO-B. In particular, compound
3x displayed excellent MAO-A inhibitory activity, with an IC50 va-
lue of 0.0056 M and an SI of 80.24. It possesses a lower MAO-A
IC50 than reference compound clorgyline (0.0067 M).
lM for
Compd
R1
-
4-Br
5-Br
6-Br
7-Br
-
R2
H
R3
R4
Compd
R1
R2
R3
R4
H
H
H
Me
Me
Me
Me
Me
l
3a
3b
3c
3d
3e
3f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3r
5-Br Me Me
6-Br Me Me
7-Br Me Me
H
H
H
3s
l
H
3t
l
H
H
3u
-
Me
H
H
H
H
H
To understand the SAR of the 50 aplysinopsin analogs, we pre-
pared eight groups of analogs, based on the substitution pattern of
their imidazolidinone moiety. In each of those eight groups there
are five analogs, one non-brominated and four analogs brominated
at positions 4, 5, 6, and 7 of the indole ring. In general, we found
that analogs which did not have N-methyl groups on the imidazo-
lidinone moiety displayed less inhibitory activity at both MAO-A
and MAO-B, indicating that N-methylation of the imidazolidinone
moiety is important for MAO inhibitory activity. Furthermore,
mono-N-methylated compounds (3f–o, 7a–e) did not possess sig-
nificant activity at MAO-A or MAO-B. As we advanced to di-N-
methylated analogs (3p–dd), we saw an overall increase in MAO
inhibitory activity. The aforementioned 3x as well as 3s and 3u,
all displayed potent inhibition of MAO A with IC50 values of
H
H
3v
4-Br Me
5-Br Me
6-Br Me
7-Br Me
Me
H
3w
3x
3g
3h
3i
4-Br Me
5-Br Me
6-Br Me
7-Br Me
H
H
3y
H
3z
-
H
H
H
H
H
Me Me
Me Me
Me Me
Me Me
Me Me
3j
H
3aa
3bb
3cc
3dd
3ee
3ff
3gg
3hh
3ii
4-Br
5-Br
6-Br
7-Br
-
3k
3l
-
H
H
H
H
H
Me
Me
Me
Me
Me
H
4-Br
5-Br
6-Br
7-Br
-
3m
3n
3o
3p
3q
Me Me Me
4-Br Me Me Me
5-Br Me Me Me
6-Br Me Me Me
7-Br Me Me Me
Me Me
4-Br Me Me
H
0.0056, 0.029, and 0.035 lM, respectively. Compounds 3u and 3x
are identical in their N-methylation pattern on the imidazolidi-
none, with positions N-20 and N-40 methylated, but differ in their
indole bromination pattern. All three (3s, 3u, 3x) are di-N-methyl-
ated, with one of the N-methylations occurring at N-20, which ap-
pears to play a large role in activity, as similar di-N-methylated
compounds 3z–dd, which are un-substituted at N-20, are signifi-
cantly less active. All three of the aforementioned compounds also
possess a high SI, especially 3u, which has an SI of 290.34.
Scheme 1. Synthetic route to aplysinopsin analogs (3a–ii).
H
N
H
N
N
NH
2
N
NH
CH
X
N
CH
N
H
3
N
3
O
O
O
The series of five tri-N-methylated analogs (3ee–ii) yielded the
two lowest MAO-B IC50 values in compounds 3gg and 3hh (0.370
and 0.207 lM, respectively). These compounds lacked selectivity
CH
3
2d
2c
though, as they were both quite active at MAO-A as well.
X
O
H
H
Concerning the bromination pattern, we found that bromina-
tion at C-5 and C-6 resulted in the lowering of IC50 values across
all eight groups of analogs. This is not surprising considering that
most naturally occurring halogenated aplysinopsin analogs are
+
N-methylguanidine
O
Scheme 2. Synthetic scheme to obtain imidazolidinone 2c.

4928
K. Lewellyn et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4926–4929
Table 1
a
Aplysinopsin analogs tested for inhibition (IC50
)
of human MAO-A and MAO-B activities in vitro
Compound
MAO-A IC50
(
l
M)
MAO-B IC50
(
lM)
SIb
Compound
MAO-A IC50
(
lM)
MAO-B IC50
(
lM)
SIb
4.9
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
12.750 0.250
2.467 0.208
5.867 0.551
3.683 0.448
5.517 0.511
12.167 0.764
26.167 1.756
8.000 0.781
6.075 0.175
6.107 0.257
1.967 0.153
1.517 0.126
0.327 0.025
0.165 0.039
1.197 0.090
3.075 0.075
2.583 0.362
0.263 0.025
0.029 0.001
1.900 0.050
0.035 0.001
2.067 0.208
0.236 0.307
33.000 2.000
28.333 0.577
11.333 0.289
25.333 1.041
27.800 0.721
43.167 3.055
>100
2.59
11.49
1.93
6.88
5.04
3.55
—
3.06
5.87
3aa
3bb
3cc
3dd
3ee
3ff
3gg
3hh
3ii
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
5.475 0.125
3.250 0.563
1.123 0.587
1.080 0.364
0.098 0.024
0.623 0.153
0.085 0.006
0.018 0.001
0.153 0.008
14.333 0.577
0.267 0.029
1.233 0.252
1.533 0.153
0.543 0.038
2.783 0.202
0.677 0.050
7.133 0.321
0.533 0.035
0.627 0.843
13.333 1.422
1.800 0.173
1.200 0.265
4.433 0.231
3.900 0.794
0.0067 0.002
26.833 1.041
16.767 0.751
25.733 1.537
4.260 0.177
9.017 0.076
5.217 0.257
0.370 0.017
0.207 0.015
2.817 0.076
24.333 4.041
0.450 0.095
2.567 0.176
2.567 0.208
1.237 1.614
59.333 4.041
3.733 0.321
8.750 0.250
1.417 0.202
2.433 0.115
6.000 0.819
7.033 1.419
2.000 0.781
20.700 2.858
26.000 1.000
5.16
22.91
3.94
92.32
8.37
4.38
11.19
18.37
1.69
1.68
2.08
1.67
2.27
21.31
5.51
1.22
2.65
3.88
0.45
3.9
24.500 1.803
35.667 1.607
34.333 0.577
34.333 1.893
37.000 1.000
4.300 0.200
3.800 0.100
14.267 0.681
33.833 2.363
26.333 0.577
11.633 0.777
2.667 0.153
12.833 0.666
10.017 0.076
51.167 1.607
2.700 0.050
0.447 0.035
3.117 0.126
30.467 0.896
5.62
17.46
24.4
13.16
23.03
11.92
11
10.19
44.18
91.95
6.75
290.34
24.76
11.44
80.24
60.52
5.24
3s
3t
3u
3v
3w
3x
3y
3z
7c
7d
7e
Clorgyline
Deprenyl
1.66
4.66
6.66
0.0056 0.0002
0.052 0.001
5.817 0.535
0.045 0.01
a
The values are IC50s computed from dose response curves and are mean S.D. of at least triplicate observations.
The relative selectivity for MAO-A is defined by the ratio of IC50 (MAO-B)/IC50 (MAO-A) for each compound.
b
brominated at these positions,17 and this is in agreement with a re-
cent SAR study of indole analogs which revealed that substitution
at C-5 lead to increased potency and selectivity for MAO-B.18 Bro-
mination at C-6 appears to be especially crucial for MAO-A inhibi-
tion, as halogenation at that position resulted in the lowest IC50
values for each group of compounds.
Acknowledgments
The authors are thankful to Dr. Lalit M. Tripathi for initial eval-
uation of the compounds for MAO inhibition. The NCNPR biological
screening activities are partly supported by the USDA-ARS cooper-
ative scientific agreement No. 58-6408-2-0009.
Another area of interest was the relationship between the
geometry of the C8–C10 double bond and MAO inhibitory activity.
During synthesis of the analogs, the E or Z configuration is deter-
mined by the presence, or lack thereof, of a substituent at the N-
20 position.19 If N-20 is substituted with a methyl or larger group,
then the condensation will result in a double bond with predomi-
nantly E configuration. If N-20 is non-methylated, bearing either a
hydrogen atom or a lone pair, then the major product will be Z con-
figured at the C8–C10 double bond. This stereochemical outcome is
confirmed using 1H, 13C heteronuclear coupling constants between
H-8 and C-50.20 The E isomer possesses a larger H-8, C-50 heteronu-
clear coupling constant compared to the Z isomer. It appears that E
configuration is important for MAO-A selectivity and potency. The
aforementioned three most active groups (3p–t, 3u–y, and 3ee–ii)
are all E configured due to their N-20 methylations. Compounds
3z–dd, which are also di-methylated, but Z configured, are signifi-
cantly less active, insinuating that E configuration is an important
SAR factor.
The authors would like to thank Frontier Scientific, Inc.
(www.frontiersci.com, Logan, UT) for graciously donating 4-bro-
moindole-3-carboxyaldehyde
carboxaldehyde.
and
7-bromoindole-3-
This study was supported by the Research Institute of Pharma-
ceutical Sciences Grant No. 100111603G.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.
2012.06.058.
References and notes
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In summary, we designed and synthesized a new series of
aplysinopsin analogs. Biological evaluation of the MAO-A and
MAO-B inhibitory activities of these compounds revealed some po-
tent and selective MAO inhibitors. The most active compound 3x,
which is brominated at position C-6 and methylated at positions
N-20 and N-40, showed strong inhibitory activity at MAO-A (IC50
of 0.0056 lM) and had an SI of 80.24. We found several factors
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(b)General procedure for synthesis of 3a–ii: Equimolar amounts of the
appropriate indole aldehydes 1a–e and imidazolidinones 2a–h were mixed
important in selectivity and potency. First is multiple N-methyla-
tions of the imidazolidinone moiety, one of which should be the
methylation of N-20 in addition to either N-30 or N-40. Secondly,
bromination at position C-5 or C-6 is important for MAO-A potency
and selectivity. These results suggest that the aplysinopsin scaffold
may be useful in designing selective MAO inhibitors.

K. Lewellyn et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4926–4929
4929
under nitrogen and heated over an open flame until the reaction mixture began
effervescing. Several minutes after the mixture stopped effervescing it was
cooled to room temperature. The crude mixture was then extracted with
MeOH and insoluble materials filtered off. The solution was then concentrated
and loaded on to silica gel for purification using hexane/EtOAc 1:1 as eluent.
(c) Porwal, S.; Chauhan, S. S.; Chauhan, P. M. S.; Shakya, N.; Verma, A.; Gupta, S.
J. Med. Chem. 2009, 52, 5793.
General procedure for synthesis of 5a–e: equimolar amounts of the
appropriate indole aldehydes 1a–e and thiohydantoin 4 were dissolved in
abs. EtOH and 1 mL of ETA was added. The mixture was heated at reflux for 1 h.
After cooling the precipitate was filtered off and dried to yield compounds 5a–
e, which were used without further purification.
(d) Gadwood, R. C.; Kamdar, B. V.; Dubray, L. A.; Wolfe, M. L.; Smith, M. P.;
Watt, W.; Mizsak, S. A.; Groppi, V. E. J. Med. Chem. 1993, 36, 1480.
General procedure for synthesis of 6a–e: equimolar amounts of appropriate
intermediates 5a–e, NaOH, and MeI were suspended in MeOH and stirred at
room temperature for 18 h. The precipitant was then filtered and dried to yield
compounds 6a–e, which were used without further purification.
(e) General Procedure for synthesis of 7a–e: compounds 6a–e were dissolved
in abs. EtOH and 2ꢀ molar equivalents of NH2CH3 was added. The mixture was
heated to 70 °C in a sealed vessel for 24 h. After cooling the crude mixture was
purified on silica gel using hexane/EtOAc 1:1 as eluent.
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21. Materials—Recombinant human MAO-A and
B were obtained from BD
Biosciences (Bedford, MA, USA). Kynuramine bromide, 4-hydroxyquinoline,
clorgyline and R (ꢁ) deprenyl were purchased from Sigma (St. Louis, MO, USA).
22. Methods—An in vitro assay was designed to measure the effect of aplysinopsin
analogs on MAO-A and
B
activity. Aplysinopsin analogs (10ꢁ9–10ꢁ2 M),
clorgyline and deprenyl (10ꢁ12–10ꢁ5 M) were tested for inhibition of human
MAO-A and B activity. MAO-activity was assessed by a modification of the
fluorometric method of Krajl23 and was adopted for 96 well plate’s format. The
200
(5
l
l reaction mixtures containing recombinant human MAO-A or MAO-B
l
g/ml) and the test compounds in potassium phosphate buffer (100 mM; pH
7.4) were pre-incubated at 37 °C for 15 min. The reactions with positive control
wells with standard MAO inhibitors and controls without inhibitors were also
set up simultaneously. The reaction was initiated by addition of kynuramine
(250
further at 37 °C for 20 min. After incubation the reaction was stopped by
the addition of 75 l of 2 N NaOH. The deaminated product of kynuramine,
lM) in potassium phosphate buffer (100 mM; pH 7.4) and incubated
l
which spontaneously cyclizes to 4-hydroxyquinoline, was determined
fluorometrically at 320 nm excitation and 460 nm emission wavelengths in a
plate reader (SpectraMax M5, Molecular Devices, Sunnyvale, CA, USA). Wells
receiving no test compounds were used as controls to calculate the inhibition
percentage. The IC-50 values were computed from the dose response inhibition
curves prepared by GraphPad.
NOTE: Complete spectral data for all compounds can be found in the
Supplementary data online.
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