Design and synthesis of new series of coumarin-aminopyran derivatives possessing potential anti-depressant-like activity

Article abstract of DOI:10.1016/j.bmcl.2014.11.036

A new series of coumarin based aminopyran derivatives were designed, synthesized and evaluated for their preclinical antidepressant effect on Swiss albino mice. Among the series, compounds 21, 25, 26, 27, 32 and 33 exhibited significant activity profile i

Full text of DOI:10.1016/j.bmcl.2014.11.036

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of new series of coumarin–aminopyran
derivatives possessing potential anti-depressant-like activity q
a
b
a
b
Koneni V. Sashidhara a, , Ram K. Modukuri , Seema Singh , K. Bhaskara Rao , G. Aruna Teja ,
⇑
Sampa Gupta a, Shubha Shukla b
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
b Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of coumarin based aminopyran derivatives were designed, synthesized and evaluated for
their preclinical antidepressant effect on Swiss albino mice. Among the series, compounds 21, 25, 26,
27, 32 and 33 exhibited significant activity profile in forced swimming test (FST). Compound 27 was most
efficacious, which at a very low dose of 0.5 mg/kg reduced the time of immobility by 86.5% as compared
to the standard drug fluoxetine (FXT) which reduced the immobility time by 69.8% at the dose of 20 mg/
kg, ip. In addition, all active compounds were screened in dose dependent manner (at doses of 0.25, 0.5,
1 mg/kg ip) in FST and tail suspension test (TST). Interestingly, all active compounds did not caused any
significant alteration of locomotor activity in mice as compared to control, indicating that the hybrids did
not produce any motor impairment effects. The results indicate that coumarin–aminopyran derivatives
may have potential therapeutic value for the management of mental depression.
Received 13 June 2014
Revised 21 October 2014
Accepted 13 November 2014
Available online xxxx
Keywords:
Coumarin
Aminopyran
Depression
Forced swimming test
Tail suspension test
Locomotor activity
Ó 2014 Elsevier Ltd. All rights reserved.
Major depression disorder (MDD) is described as a depressive
state of mind, which is associated with faulty mood, loss of inter-
est, disruption in sleep patterns, fatigue and sometimes suicidal
tendencies. It is a chronic and life-threatening mental illness,
which remains hidden and untreated at most of the times.1 World
Health Organisation (WHO) had estimated that ‘at least 350 mil-
lion people live with depression and it is the leading cause of dis-
ability worldwide’.2 Epidemiological studies have indicated that
about 2/3 of people who commit suicide are depressed at the time
of their death.3 Exact cause of depression is not clearly known, but
it is believed that imbalance of neurotransmitters in brain, genetic
vulnerability, stressful life events and medical problems are the
main factors leading to depression.4 Currently available antide-
pressant treatments are selective serotonin reuptake inhibitors
(SSRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antide-
pressants (TCAs), serotonin-norepinephrine reuptake inhibitors
(SNRI) and some nonmedication therapeutic options.5
relapse and experience serious side effects after treatment with
current therapies.7 In Feb 2007, the USFDA displayed ‘black box’
label on currently available antidepressants indicating that their
use may increase the risk of suicidal thinking behaviour in few
cases of children, adolescents and adults.8 Hence, there is an urgent
need to develop new class of prototypes that are more effective,
tolerable and safe in depressed individuals against this deadly
disorder.
Coumarins are prominent class of benzopyrones, which belong
to natural as well as synthetic origin that exhibit diverse biological
activities.9 Many reports suggest that coumarins and their syn-
thetic analogues possess antidepressant properties.10 Coumarin
containing natural product scopoletin, isolated from the Polygala
sabulosa was found to have significant in vivo antidepressant activ-
ity.11 In addition, xanthotoxin and praeruptorin-A belongs to the
new generation of MAOIs exhibiting potent antidepressant proper-
ties.12 Our research group has been involved for past several years
in the development of 3-phenylcoumarin based scaffolds as poten-
tial antidepressant agents, which significantly decreased the
immobility time compared to the standard drug fluoxetine (FXT),
(Fig. 1).13 The promising hit compound may serve as a valuable
template to design further analogue to improve activity and
efficacy.14
Even though wide range of conventional therapies is available,
nearly 15% of depressed people are still refractory to the current
existing therapies.6 In addition, most of the people suffer from
q
Part 32 in the series, ‘Advances in drug design and discovery’.
⇑
Corresponding author. Tel.: +91 9919317940; fax: +91 522 2771942.
During recent years aminopyran containing compounds have
E-mail
addresses:
sashidhar123@gmail.com,
kv_sashidhara@cdri.res.in
shown prominent antidepressant activity.15 Dutta et al. have
(K.V. Sashidhara).
http://dx.doi.org/10.1016/j.bmcl.2014.11.036
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sashidhara, K. V.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.11.036

2
K.V. Sashidhara et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
O
OCH3
OCH3
OAc O
O
Praeruptorin-A12
OHC
H3CO
HO
O
O
O
OCH3
O
O
O
O
O
O
CH3
3-Phenylcoumarin derivative13
Our previous approach
R2
Scopoletin11
Xanthotoxin12
R3
R4
OH
H
O
OH
H
H
N
N
N
O
R1
O
O
O
R
O
CN
NH2
OCH3
R5
R5
NH
O
D-16116 R = OH
D-16816
D-14215
coumarin based
amino pyrans
D-185
= NH2
Figure 1. Designing of coumarin–aminopyran hybrids based on coumarin and aminopyran scaffolds showing antidepressant activity.
Scheme 1. Synthesis of 3-aryl coumarin based aminopyran derivatives. Reagents and conditions: (i) HMTA, TFA, 120 °C, 4 h. (ii) aq H2SO4, 100 °C, 2 h. (iii) appropriate
phenylaceticacid, cyanuric chloride, NMM, DMF, 110 °C, 30–90 min, (vi) malononitrile, different 1,3-cyclohexadiones, DMAP, EtOH, reflux, 0.5 h.
synthesized a series of substituted aminopyran derivatives, as new
generation of triple reuptake inhibitors (TRI) and observed signifi-
cant antidepressant effects.16 In the search of drug like molecules,
molecular hybridisation technique is an emerging strategy in
which two active pharmacophores are fused in a single frame
work.17 The resultant hybrid molecule may modulate the potency
and efficacy, compared to that of parent subunits. Thus inspired
from the molecular hybridisation approach,18–20 we have ratio-
nally designed and synthesized some new 3-phenylcoumarin-
aminopyran hybrids for a possible antidepressant activity.
The synthesis of intermediate and final compounds is described
in the scheme 1. The Duff reaction on ortho-substituted phenols
Please cite this article in press as: Sashidhara, K. V.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.11.036

K.V. Sashidhara et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
FST
250
200
150
100
50
***
***
***
***
***
***
***
21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 FXT
0
C
Figure 2. Effect of coumarin–aminopyran derivatives on the immobility duration of mice in the forced swimming test (FST). All values are expressed as mean SEM (n = 8
each). Mice were intraperitoneally administrated 1% DMSO, compounds (0.5 mg/kg) and fluoxetine FXT (20 mg/kg), respectively, ***P <0.001, when compared with the control.
Table 1
Tabular representation of percentage change in immobility duration in forced
swimming test (FST) after administration of different compounds and standard drug
FXT to mice
(1–4) in the presence of hexamethylene-tetraamine (HMTA) and
TFA at 120 °C afforded aromatic dicarbaldehydes (5–8).21 These
dicarbaldehyde intermediates were then allowed to react with dif-
Compound
Mean SEM
% Decrease of immobility
ferent substituted phenyl acetic acids in the presence of cyanuric
chloride and N-methylmorpholine (NMM) in DMF for 1 h, resulting
in a good yield of respective 3-aryl coumarin aldehydes (9–20).22
Finally, the multi component reaction23 with malononitrile and
different 1,3-cyclohexadiones gave the desired coumarin–amino-
pyran hybrids (21–40).24 The structures of the compounds were
substantiated by 1H NMR, 13C NMR, and mass spectrometry (for
further details see the Supporting information).
All the coumarin–aminopyran compounds were screened at a
dose of 0.5 mg/kg ip in adult male Swiss albino mice in FST.25
Among the 20 compounds screened, 6 compounds were found to
be active in forced swimming model (Fig. 2). Compounds 21, 26,
32 and 33 significantly reduced immobility time by 64.8%, 57.1%,
57.3% and 56.0%, respectively, when compared to control group.
Much better activity was shown by compound 25 which reduced
immobility time by 69.7% that was comparable to the standard
drug FXT (69.8%). However, highest activity was exhibited by com-
pound 27 which reduced immobility time by 86.5% suggesting it to
be the most potent among the series (Table 1).
Control
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
182.00 9.74
63.95 25.87
163.00 15.41
172.50 15.47
170.40 14.26
55.07 18.53
77.95 29.17
24.40 4.817
124.00 14.55
128.80 23.05
118.20 25.54
133.10 29.00
77.60 26.82
79.93 18.17
130.70 33.74
126.20 31.87
132.50 8.744
212.30 15.94
141.10 22.31
172.30 20.36
127.20 16.37
—
64.86***
10.44
5.22
6.37
69.74***
57.17***
86.59***
31.87
29.23
35.05
26.87
57.36***
56.08***
28.18
30.65
27.20
ꢀ16.64
22.47
5.33
30.10
Fluoxetine (FXT)
54.92 12.11
69.82***
Further, effective compounds were studied at lower and higher
doses in FST. Figure 3 reveals that compound 26, 27 and 32 at
⁄⁄⁄P <0.001, when compared with the control.
a
b
c
21
25
26
250
250
200
150
250
200
150
100
50
200
150
100
50
*
***
***
100
50
0
***
***
***
***
0
0
l
L
g
g
g
g
g
g
k
k
/
kg
/
kg
/
/k
5 mg
ro
kg
g/
/k
/k
OL
TR
/k
/
g
RO
nt
Co
m
NT
m
0mg
1.
0mg
1.
0mg
.
5 mg
5 mg
.
0
5 mg
0.
O
25
0.
2
25
0.
1
0.
.
C
CON
0
d
e
f
250
33
27
32
250
200
150
100
50
250
200
150
100
50
200
150
100
50
*
**
***
***
***
***
***
***
0
0
0
g
ol
kg
g/
kg
/
r
/k
5 mg
t
n
Co
l
ro
nt
Co
l
ro
nt
Co
g
g
g
g
g
k
k
0mg
1.
/
/k
/
/k
/kg
mg
5 m
2
.
g
g/k
g
0
0.
m
m
0m
1.
0
5 mg
0.
5 mg
25
25
0.
1.
0.
0.
Figure 3. Graded dose response of effective compounds (a) 21, (b) 25, (c) 26, (d) 27, (e) 32 and (f) 33 in FST. The figure shows significant and dose dependent reduction in
immobility time. Results are expressed as mean SEM, *P <0.05, **P <0.01 and ***P <0.001 when compared with the control group.
Please cite this article in press as: Sashidhara, K. V.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.11.036

4
K.V. Sashidhara et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
showed activity at 0.5 mg/kg, therefore, we selected this dose as
300
200
100
0
the effective dose for further screening in tail suspension test
(TST), which is another model for testing antidepressant drugs.26
Thus, compounds 21, 25, 26, 27, 32 and 33 were further evaluated
in a second test, TST, which also quantifies immobility period. As
represented in Figure 4, mice treated with all active compounds
showed significant reduction of immobility duration in TST when
compared with control mice. However, noteworthy activity was
exhibited by compound 27, which at a very low dose of 0.5 mg/
kg ip, produced comparable reduction in immobility time as shown
by standard drugs FXT and imipramine (IMI). This confirms that
our prototypes exhibited antidepressant type activity.
Next, in order to determine if active compounds exhibit any
effect on locomotor activity, open field test was performed at the
effective dose of 0.5 mg/kg ip. All active compounds were evalu-
ated for both horizontal activity (Fig. 5a) and total distance trav-
elled (Fig. 5b), which are important parameters to check
behavioural response of the mice.27 During this experiment, mice
were treated with compounds at 30 min time point and further
examined up to 120 min. However no statistically significant dif-
ference was observed between control mice and compounds trea-
ted mice in this experiment. Thus, it indicates that the compounds
did not induce any anxiety and hyper-activity like effects after
administration to the mice. Thereafter, to examine the effect of
active compounds on neuromuscular coordination, rotarod test28
*** ***
***
***
***
***
***
***
l
T
FX
21
25
26
27
32
33
ro
IMI
nt
Co
Figure 4. Effect of compounds on immobility duration of mice in TST at a dose of
0.5 mg/kg ip imipramine (IMI), fluoxetine (FXT) were the standard drugs used in
this study at a dose of 30 mg/kg and 20 mg/kg, respectively. Results are expressed
as mean SEM (n = 8 each). ***P <0.001 as compared to that of control.
0.25 mg/kg, ip significantly attenuated immobility time by 49%,
41% and 35%, respectively, in FST. However, the other active com-
pounds 21, 25 and 33 at lower dose, were unable to reduce immo-
bility time. Interestingly all effective compounds, when
administered at higher doses of 0.5 and 1.0 mg/kg, ip showed
significant reduction of immobility duration. As all the compounds
400
a
Control
21
300
compounds treatment
25
26
27
32
33
200
100
0
n
0mi
n
n
n
n
n
i
min
15
min
30
mi
45
min
60
mi
75
0m
5mi
10
0mi
12
9
b
250
200
150
100
50
compounds treatment
Control
21
25
26
27
32
33
0
n
0mi
n
n
min
15
min
30
min
45
min
60
min
75
min
5mi
10
0mi
12
90
Time points (mins)
Figure 5. Effect of compounds on locomotor activity (a) horizontal activity and (b) total distance travelled. Compounds were administered at 30 min time point and counts
were recorded for total 120 min in digiscan animal activity monitor. All the values are represented as mean SEM (n = 8 each).
Please cite this article in press as: Sashidhara, K. V.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.11.036

K.V. Sashidhara et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
5
3. Al-Habeeb, A. A.; Sherra, K. S.; Al-Sharqi, A. M.; Qureshi, N. A. East Mediterr.
Health J. 2013, 19, 248.
4. DeWeerdt, S. Nature 2013, 497, S14.
5. Chancellor, D. Nat. Rev. Drug Discov. 2011, 10, 809.
6. Anderson, H. D.; Pace, W. D.; Libby, A. M.; West, D. R.; Valuck, R. J. Clin. Ther.
2012, 34, 113.
7. (a) Check, E. Nature 2004, 431, 122; (b) Licinio, J.; Wong, M. L. Nat. Rev. Drug
Discov. 2005, 4, 165.
8. Friedman, R. A.; Leon, A. C. N. Engl. J. Med. 2007, 356, 2343.
9. Peng, X. M.; Damu, G. L.; Zhou, C. Curr. Pharm. Des. 2013, 19, 3884.
10. Patil, P. O.; Bari, S. B.; Firke, S. D.; Deshmukh, P. K.; Donda, S. T.; Patil, D. A.
Bioorg. Med. Chem. 2013, 21, 2434.
11. Capra, J. C.; Cunha, M. P.; Machado, D. G.; Zomkowski, A. D.; Mendes, B. G.;
Santos, A. R.; Pizzolatti, M. G.; Rodrigues, A. L. Eur. J. Pharmacol. 2010, 643, 232.
12. Huong, D. T.; Huong, L.; Choi, H. C.; Rho, T. C.; Lee, H. S.; Lee, M. K.; Kim, Y. H.
Arch. Pharm. Res. 1999, 22, 324.
13. (a) Sashidhara, K. V.; Kumar, A.; Chatterjee, M.; Rao, K. B.; Singh, S.; Verma, A. K.;
Palit, G. Bioorg. Med. Chem. Lett. 2011, 21, 1937; (b) Sashidhara, K. V.; Rao, K. B.;
Singh, S.; Modukuri, R. K.; Aruna Teja, G.; Chandasana, H.; Shukla, S.; Bhatta, R. S.
Bioorg. Med. Chem. Lett. 2014, 20, 4876.
was carried out at the highest dose of 1.0 mg/kg, ip. In this test, the
control mice and active compounds treated mice stayed for 120 s
on the rotating rod (Supporting information Table S3). Both the
above behavioural findings confirmed that active compounds do
not have any motor impairment effects.
In terms of structure activity relationship, it is interesting to
note that the activity profile differs depending upon the number
of methoxy substituents attached to that of 3-phenyl ring and alkyl
group attached to the C8 position. In common, compounds con-
taining mono and di methoxy substituted groups (25, 27, 21 and
26) potentially reduced the percentage of immobility time than
compounds containing tri methoxy substituted groups (23, 24,
28, 29, 33, 34, and 39). But, the presence of bulky aliphatic groups
like sec-butyl, tert-butyl group on C8 position, tends to decrease
the percentage of immobility duration (30, 35, 34, 36, 38 and
39). However, a different trend was observed in the case of com-
pounds 32, 31, 22 and 30.
14. Keseru, G. M.; Makara, G. M. Drug Discov. Today 2006, 11, 741.
15. Dutta, A. K.; Gopishetty, B.; Gogoi, S.; Ali, S.; Zhen, J.; Reith, M. Eur. J. Pharmacol.
2011, 671, 39.
In conclusion, our drug design and discovery program led us to
develop a new series of coumarin–aminopyran derivatives as
potential antidepressant agents. The preclinical antidepressant
FST test has provided evidence that compound 27 reduced the
immobility time by 86.5% at very low dose of 0.5 mg/kg ip, which
is more potent than the standard drug FXT (20 mg/kg, ip). The
activity of compound 27 was also proved in TST. Additionally, all
active compounds including compound 27 did not exhibit any
neurotoxicity as confirmed by rotarod test. Our ongoing studies
are directed towards the detailed mechanistic and pharmacoki-
netic studies on compound 27 so as to advance this molecule into
a therapeutic option.
16. (a) Dutta, A. K.; Ghosh, B.; Biswas, S.; Reith, M. E. Eur. J. Pharmacol. 2008, 589,
73; (b) Gopishetty, B.; Hazeldine, S.; Santra, S.; Johnson, M.; Modi, G.; Ali, S.;
Zhen, J.; Reith, M.; Dutta, A. J. Med. Chem. 2011, 54, 2924.
17. Viegas-Junior, C.; Danuello, A.; Bolzani, V. D. S.; Barreiro, E. J.; Fraga, C. A. M.
Curr. Med. Chem. 2007, 14, 1829.
18. Sashidhara, K. V.; Kumar, M.; Khedgikar, V.; Kushwaha, P.; Modukuri, R. K.;
Kumar, A.; Gautam, J.; Singh, D.; Sridhar, B.; Trivedi, R. J. Med. Chem. 2013, 56,
109.
19. Sashidhara, K. V.; Kumar, M.; Sonkar, R.; Singh, B. S.; Khanna, A. K.; Bhatia, G. J.
Med. Chem. 2012, 55, 2769.
20. Sashidhara, K. V.; Kumar, M.; Modukuri, R. K.; Srivastava, R. K.; Soni, A.;
Srivastava, K.; Singh, S. V.; Saxena, J. K.; Gauniyal, H. M.; Puri, S. K. Bioorg. Med.
Chem. 2012, 20, 2971.
21. Sashidhara, K. V.; Kumar, M.; Modukuri, R. K.; Srivastava, A.; Puri, A. Bioorg.
Med. Chem. Lett. 2011, 21, 6709.
22. (a) Sashidhara, K. V.; Palnati, G. R.; Avula, S. R.; Kumar, A. Synlett 2012, 23, 611;
(b) Sashidhara, K. V.; Modukuri, R. K.; Jadiya, P.; Rao, K. B.; Sharma, T.; Haque,
R.; Singh, D. K.; Banerjee, D.; Siddiqi, M. I.; Nazir, A. ACS Med. Chem. Lett. 2014,
5, 1099.
Acknowledgments
The authors are grateful to the Director, CDRI, Lucknow, India
for constant encouragement in drug development program, S. P.
Singh for technical support, SAIF for NMR, IR, and mass spectral
data. This work is supported in part by CSIR Network Grants THUN-
DER (BSC0102) and miND (BSC0115) to Shubha Shukla. Authors
also acknowledge the Council of Scientific & Industrial Research
(CSIR) for providing research fellowship to R.K.M., K.B.R. and S.S.
The CSIR-CDRI communication number of this article is 8864.
23. Khan, A. T.; Lal, M.; Ali, S.; Khan, M. M. Tetrahedron Lett. 2011, 52, 5327.
24. General synthetic procedure for preparation of compounds (21–40): A mixture of
3-phenylcoumarin intermediates (1 equiv), malononitrile (1 equiv) and DMAP
(0.2 equiv) in 4 mL of ethanol was allow to stirred at room temperature for 20–
30 min. Then different 1,3-cyclohexadione (1 equiv) was added into the
reaction mixture and stirring continued under reflux conditions till the
completion of reaction (monitored by TLC). The reaction mixture was
concentrated to dryness under reduced pressure. The crude product was
purified on a silica gel column (100–200 mesh) using ethylacetate/hexane
(50:50, v/v) as eluent to afford compounds 21-40 in good yields.
( )2-Amino-80-tert-butyl-20,5-dioxo-30-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-
20H,4H-4,60-bichromene-3-carbonitrile (39).
Supplementary data
Light yellow solid, yield: 60%; mp: 230–231 °C; IR (KBr): 3412, 3012, 2970, 2182,
1669, 1582, 1029 cmꢀ1 1H NMR (DMSO-d6, 300 MHz) d: 8.30 (s, 1H), 7.41 (s, 1H),
;
7.40 (s, 1H), 7.11 (s, 2H), 7.04 (s, 2H), 4.32 (s, 1H), 3.84 (s, 6H), 3.72 (s, 3H), 2.64 (br s,
2H), 2.31 (br s, 2H), 1.98 (br s, 2H), 1.48 (s, 9H); 13C NMR (DMSO-d6, 75 MHz)
d:195.9, 164.7, 159.2, 158.5, 152.5, 150.1, 141.1, 140.4,137.9, 135.9, 129.9, 128.2,
125.5, 124.7, 119.8, 113.4, 106.1, 60.0, 57.8, 56.0, 36.3, 35.1, 34.3, 29.5, 26.5, 19.8;
ESI-MS (m/z): 557 (M+H)+.
Supplementary data (details for synthesis and characterization
of all compounds together with protocols for biological materials
and methods) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.bmcl.2014.11.036.
25. Petit-Demouliere, B.; Chenu, F.; Bourin, M. Psychopharmacology (Berl.) 2005,
177, 245.
26. Steru, L.; Chermat, R.; Thierry, B.; Simon, P. Psychopharmacology (Berl.) 1985,
85, 367.
27. Ishola, I. O.; Chatterjee, M.; Tota, S.; Tadigopulla, N.; Adeyemi, O. O.; Palit, G.;
Shukla, R. Pharmacol. Biochem. Behav. 2012, 103, 322.
28. Chatterjee, M.; Verma, P.; Maurya, R.; Palit, G. Pharm. Biol. 2011, 49, 477.
References and notes
1. Hampton, T. JAMA 2012, 308, 4442.
2. World Health Organisation. Available at: http://www.who.int/entity/
mental_health/management/depression/flyer_depression_2012.pdf (accessed
July 23, 2013).
Please cite this article in press as: Sashidhara, K. V.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.11.036