Synthesis and evaluation of new 3-phenylcoumarin derivatives as potential antidepressant agents

Article abstract of DOI:10.1016/j.bmcl.2014.08.037

A series of amine substituted 3-phenyl coumarin derivatives were designed and synthesized as potential antidepressant agents. In preliminary screening, all compounds were evaluated in forced swimming test (FST), a model to screen antidepressant activity i

Full text of DOI:10.1016/j.bmcl.2014.08.037

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of new 3-phenylcoumarin derivatives
q
as potential antidepressant agents
a,
⇑
a
b
a
b
Koneni V. Sashidhara , K. Bhaskara Rao , Seema Singh , Ram K. Modukuri , G. Aruna Teja ,
c
b
c
Hardik Chandasana , Shubha Shukla , Rabi S. Bhatta
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
Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of amine substituted 3-phenyl coumarin derivatives were designed and synthesized as potential
antidepressant agents. In preliminary screening, all compounds were evaluated in forced swimming test
Received 1 August 2014
Accepted 19 August 2014
Available online xxxx
(FST), a model to screen antidepressant activity in rodents. Among the series, compounds 5c and 6a
potentially decreased the immobility time by 73.4% and 79.7% at a low dose of 0.5 mg/kg as compared
to standard drug fluoxetine (FXT) which reduced the immobility time by 74% at a dose of 20 mg/kg, ip.
Additionally, these active compounds also exhibited significant efficacy in tail suspension test (TST)
Keywords:
Forced swim test
Tail suspension test
Depression
(another model to screen antidepressant compounds). Interestingly, rotarod and locomotor activity tests
confirmed that these two compounds do not have any motor impairment effect and neurotoxicity in
mice. Our studies demonstrate that the new 3-phenylcoumarin derivatives may serve as a promising
antidepressant lead and hence pave the way for further investigation around this chemical space.
Ó 2014 Elsevier Ltd. All rights reserved.
Coumarin
Depression, is a widespread and burdensome psychiatric disor-
der. It affects approximately 350 million people globally. The
motif in numerous natural products. Many coumarins and their
derivatives are known to possess a broad range of biological activ-
1
6
–11
World Health Organization has indicated that by year 2020,
depression will be the second leading cause of disability through-
ities depending on their substitution pattern.
The activity
reported for coumarins include anticancer, antioxidant, anti-
2
12–15
out the world. Pathophysiology of depression is commonly
inflammatory, antimicrobial, and antiviral.
In particular, sev-
associated with decrease in the synaptic concentration of mono-
aminergic neurotransmitters. All the available antidepressants
increase the synaptic concentration of these neurotransmitters.
The commercially available of antidepressants such as tricyclic
antidepressants (TCA), monoamine oxidase inhibitors (MAOI),
selective serotonin reuptake inhibitors (SSRI) and serotonin nor-
adrenaline reuptake inhibitors (SNRI) require several weeks for
onset of action, and are associated with numerous side effects such
as, emesis and sexual dysfunction.3 Moreover approximately 30%
of patients do not respond to the currently available antidepres-
sants and the remaining 70% do not experience remission.
Hence, discovery and development of new antidepressants with
greater efficacy is still desirable.
Coumarins (chromen-2-ones or benzopyran-2-ones) are inter-
esting heterocyclic molecules, which are present as a structural
eral coumarin derivatives have been reported for their significant
antidepressant activities (Fig. 1).
1
6,17
Several reports have appeared in the literature that 4-methyl
and 3,4-dimethyl-7-oxycoumarins incorporated with oxadiazoles,
thiadiazoles, triazoles and thiazolidinones preferentially inhibit
1
7
MAO activity. Psoralen, a major furocoumarin isolated from
Psoralea corylifolia, displayed antidepressant activity in the FST in
mice, a model of ‘learned helplessness’ that is used in the antide-
18
pressant screening. Psoralen has been reported to decrease the
immobility time of the animal in FST. In previous work, our
research group had reported the design, synthesis and pharmaco-
logical evaluation of 3-phenylcoumarin derivatives as potential
4
,5
1
9
antidepressant agents. The good results encouraged us to explore
the chemical diversity around this pharmacophore. In addition,
since the structures of well known antidepressants like nefazo-
done, aripiprazole bear a piperazine ring in their molecular
makeup, and also the drugs like fluoxetine, duloxetine, amitifadine
have secondary amine in their structures, it was of interest to syn-
thesize a series of new amine substituted 3-phenylcoumarin deriv-
atives. These derivatives had a number of substituents that could
q
Part 34 in the series ‘Advances in drug design and discovery’.
⇑
Corresponding author. Tel.: +91 9919317940; fax: +91 522 2771942.
E-mail addresses: sashidhar123@gmail.com, kv_sashidhara@cdri.res.in
K.V. Sashidhara).
(
http://dx.doi.org/10.1016/j.bmcl.2014.08.037
960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
0
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2
K.V. Sashidhara et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
R1
O
R
O
Cl
O
S
H
N
Cl
X
R
O
N
O
O
O
O
O
O
O
R1
7-oxycoumarin derivative 17
Coumarin-3-acyl chloride derivative 16
O
O
O
O
O
O
O
O
O
O
EtO S
O
O
3
N
H
CHO
Our previous lead
compound 6a
Our prototype
Psoralen 18
19
Esuprone
Figure 1. Chemical structures of some biologically important coumarins and our prototype.
influence lipophilic or electronic characteristics (H-bonding prop-
erties). Figure 1 shows the chemical structures of some coumarin
containing potent antidepressant molecules and our designed
prototype.
Synthetic procedure for the preparation of substituted 3-phen-
ylcoumarins is presented in Scheme 1. The 2-alkyl phenols (1a,b) were
subjectedto the Duff formylation in thepresence of hexamethylenetet-
ramine (HMTA) and trifluoroacetic acid (TFA) at 120 °C to furnish the
dicarbaldehyde intermediates (2a,b).20 These intermediates were then
reacted with different substituted phenyl acetic acids in the presence of
cyanuric chloride and N-methylmorpholine to give 3-arylcoumarins
21
4
(3a–d). Reduction of 3-arylcoumarins with NaBH in methanol gave
primary alcohol derivatives (4a–d). Nucleophilic substitution of these
2
2
alcohols with PBr
3
gave alkyl bromides (5a–d), which on reaction
23
with amines produced N-substituted products (6a–g). All the new
synthesized compounds were characterized by using H NMR,
1
13
C
NMR, 2D NMR, Mass spectrometry and IR spectroscopy (see Support-
ing information).
Screening of compounds for antidepressant activity in FST model:
To see the antidepressant activity of 3-phenylcoumarins, FST was
Scheme 1. Synthesis of 3-phenylcoumarin derivatives. Reagents and conditions: (i) HMTA, TFA, 120 °C, 4 h; (ii) aq H
2 4
SO , 100 °C, 2 h; (iii) phenylacetic acid derivatives,
cyanuric chloride, N-methylmorpholine, DMF, reflux, 1 h; (iv) NaBH , rt, 5 min; (v) PBr , benzene, reflux, 30 min; (vi) different amines, EtOH, reflux, 1 h.
4
3
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K.V. Sashidhara et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
2
2
1
1
50
00
50
00
***
***
***
***
***
5
0
***
0
Figure 2. Effect of 3-phenylcoumarin derivatives on the immobility duration of mice in the FST. Results are expressed as mean ± SEM (n = 8 each). Mice were
⁄
⁄⁄
intraperitoneally administrated 1% DMSO, 3-phenylcoumarin derivatives (0.5 mg/kg) and FXT (20 mg/kg), respectively. p < 0.001 when compared with the control.
5
c
6a
2
2
1
1
50
00
50
00
250
200
150
100
50
***
***
***
5
0
***
0
0
Figure 3. Graded dose response of effective compounds 5c and 6a shows significant reduction in immobility time of mice. Data are represented as mean ± SEM (n = 8).
⁄⁄⁄
p < 0.001 versus control.
performed.24 Compounds were administered intraperitoneally (ip)
at a dose of 0.5 mg/kg into Swiss mice. After 30 min, mice were
subjected to FST and immobility time was recorded by using
ANY-maze software. Results in Figure 2 indicate that compounds
TST
3
00
200
4
d, 5b, 5c, 5d and 6a significantly reduced the immobility time
(
p < 0.001) of mice, when compared with vehicle treated group.
*
**
***
***
This figure further suggest that compounds 4d, 5b and 5d reduced
the immobility time by 58%, 61% and 55%, respectively, while 5c
and 6a reduced it by 73% and 80%, respectively. The standard drug
FXT, however was able to reduce the immobility time by 74% only,
at a dose of 20 mg/kg body weight (Fig. 2).
1
00
0
Control
5c
6a
FXT (20mg/kg)
Evaluation of effect of active compounds on immobility time in
dose dependant manner in FST model: Further effective compounds
Figure 4. Effect of compounds 5c and 6a (0.5 mg/kg, ip) and FXT (20 mg/kg, ip) on
immobility duration in TST. Results are expressed as mean ± SEM (n = 8).
(
>60% activity) were studied at graded doses (0.25, 0.5 and 1.0 mg/
⁄
⁄⁄
p < 0.001 when compared with the control.
kg, ip) in the FST model. Compounds 5c and 6a reduced immobility
time by 16% and 17%, respectively at a dose of 0.25 mg/kg, ip. Inter-
estingly, compound 5c at the higher doses of 0.5 and 1.0 mg/kg sig-
nificantly reduced the immobility duration by 73% and 71%,
respectively. Similarly, compound 6a reduced the immobility time
by 80% and 75% at 0.5 and 1.0 mg/kg doses, respectively (Fig. 3).
However, since the difference in percentage between the two doses
53% (p < 0.001), respectively, which is comparable to 54% reduction
in immobility time shown by standard drug FXT (Fig. 4).
Effect of active compounds on locomotor activity: In order to
examine the effect of 3-phenylcoumarins on central nervous sys-
tem stimulating/depressing effect, we performed open field loco-
(
0.5 and 1 mg/kg) of both compounds was not statistically signifi-
cant, we selected the lower dose of both compounds for further
screening on TST model of depression.
motor activity test. Locomotor activity is a standard test
2
6
performed during drug discovery phase. Effect of compounds
5c and 6a were examined on horizontal activity counts (HC) and
total distance travelled (TD) at the dose of 0.5 mg/kg ip. For this,
mice were placed into digiscan test chambers and after 30 min,
active compounds were administered. The activity of mice was
Effect of active compounds on immobility in tail suspension test
(
TST): In order to confirm the activity of compounds 5c and 6a at
25
the effective dose of 0.5 mg/kg, TST was performed. Compounds
c and 6a significantly reduced the immobility time by 49% and
5
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K.V. Sashidhara et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
2
2
1
1
50
00
50
00
4
00
00
00
00
Control
5c
6a
Control
5c
compounds
treatment
compounds
treatment
3
6a
2
1
5
0
0
0
Time points (mins)
Time points (mins)
Figure 5. Effect of compounds on locomotor activity (a) horizontal activity (HC) and (b) Total distance travelled (TD). Compounds were administered at 30 min time point
and counts were recorded for total 120 min in digiscan animal activity monitor. Values are expressed as mean ± SEM (n = 8).
Figure 6. SAR of synthesized hybrid.
monitored up to 120 min. Mice treated with compounds did not
Intravenous
show any statistical significant difference from the vehicle-treated
control groups in both the parameters (HC and TD). This confirms
that the active compounds at their effective dose did not altered
locomotor activity in mice as shown in Figure 5. Further, com-
pounds were tested on rotarod27 to rule out any effect on neuro-
muscular coordination and no fall was observed in any animal dur-
ing the entire 120 s duration of the trial (Supporting information
Table S1).
1000
00
Oral
1
10
1
Structure–activity relationships (SARs) were inferred from
in vivo activity on Swiss albino mice. The initial examination of
SAR revealed that the presence of methyl group at position 8 of
the phenyl ring and the presence of 3-phenylcoumarin scaffold is
crucial for activity. Substituents such as bromomethyl, (p-tolylami-
no)methyl at position 6 are favoured (5b, 5c and 6a) as these consid-
0.1
0
5
10
Time(h)
15
20
25
Figure 7. Pharmacokinetic profile of Compound 6a after ip and iv administration.
erably enhanced the antidepressant activity.
representation of the SAR is depicted in Figure 6.
A
pictorial
Intraperitoneal and intravenous pharmacokinetics of compound 6a
in mice: The pharmacokinetic studies were conducted in the
pharmacological activity model (Swiss albino mice). Compound
6a shows rapid absorption after ip dose helps in the rapid onset
of action. This pharmacokinetic study underscores the utility of
6a as potential antidepressant lead. Positive control FXT bioavail-
2
8
6
a shows ꢀ73% bioavailability at 10 mg i.p dose. The pharmacoki-
netic estimates such as max were 105.00 ± 9.89 and
56.00 ± 46.66 ng/mL while AUC0–1 were 315.78 ± 31.48 and
329.00 ± 440.17 h ng/mL for intravenous and ip, respectively
ability was 60–90% as reported in the literature.
C
In conclusion, among all the compounds prepared, compounds
5b, 5c and 6a displayed significant antidepressant-like activity in
the FST model. Interestingly compounds 5c and 6a exhibited
higher potency in reducing immobility time by 73% and 80% at a
dose of 0.5 mg/kg, which is comparable to the standard drug FXT.
2
2
(
(
Fig. 7 and Table 1). Longer half-life after ip administration
7.57 ± 1.27 h) favors the once a day dosing interval. Compound
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K.V. Sashidhara et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
5
Table 1
14. Ostrov, D. A.; Hernandez Prada, J. A.; Corsino, P. E.; Finton, K. A.; Le, N.; Rowe, T.
Pharmacokinetic parameters of compound 6a
C. Antimicrob. Agents Chemother. 2007, 51, 3688.
1
1
1
1
5. Neyts, J.; DeClercq, E.; Singha, R.; Chang, Y. H.; Das, A. R.; Chakraborty, S. K.;
Hong, S. C.; Tsay, S. C.; Hsu, M. H.; Hwu, J. R. J. Med. Chem. 2009, 52, 1486.
6. Patil, P. O.; Bari, S. B.; Firke, S. D.; Deshmukh, P. K.; Donda, S. T.; Patil, D. A.
Bioorg. Med. Chem. 2013, 21, 2434.
7. Abdelhafez, O. M.; Amin, K. M.; Ali, H. I.; Abdalla, M. M.; Batran, R. Z. J. Med.
Chem. 2012, 55, 10424.
Parameters
max (ng/mL)
max (h)
AUC0–1(h ng/mL)
(L/kg)
Cl (L/h/kg)
1/2 (h)
F (%)
Intravenous (1 mg/kg)
105.00 ± 9.89
Intraperitoneal (10 mg/kg)
C
T
256.00 ± 46.66
2.00 ± 0.00
2329.00 ± 440.17
30.45 ± 1.64
2.83 ± 0.62
315.78 ± 31.48
18.01 ± 3.84
4.04 ± 1.57
V
d
8. Xu, Q.; Pan, Y.; Yi, L. T.; Li, Y. C.; Mo, S. F.; Jiang, F. X.; Qiao, C. F.; Xu, H. X.; Lu, X.
B.; Kong, L. D.; Kung, H. F. Biol. Pharm. Bull. 2008, 31, 1109.
t
3.21 ± 0.58
7.57 ± 1.27
73.42 ± 6.62
19. Sashidhara, K. V.; Kumar, A.; Chatterjee, M.; Rao, K. B.; Singh, S.; Verma, A. K.;
Palit, G. Bioorg. Med. Chem. Lett. 2011, 21, 1937.
2
0. Sashidhara, K. V.; Modukuri, R. K.; Sonkar, R.; Rao, K. B.; Bhatia, G. Eur. J. Med.
Chem. 2013, 68, 38.
T
max, time at which maximum concentration achieved in plasma; Cmax, maximum
concentration achieved in plasma; AUC0–1, area under the curve from 0 to 1 h; V
d
,
21. Sashidhara, K. V.; Palnati, G. R.; Avula, S. R.; Kumar, A. Synlett 2012, 611.
volume of distribution; Cl, clearance;
bioavailability.
t
1/2
,
terminal half-life; F, absolute
22. Nicolaou, K. C.; Lister, T.; Denton, R. M.; Gelin, C. F. Tetrahedron 2008, 64, 4736.
23. Preparation of 3-(4-methoxyphenyl)-8-methyl-6-((p-tolylamino) methyl)-2H-
chromen-2-one (6a): In 50 mL round-bottomed flask, compound 5a (0.200 g,
1
mmol) was dissolved with 20 mL of ethanol, then added 4-methylaniline
(
0.059 g, 1 mmol) successively. The mixed solution was stirred at 75 °C for
about 1 h by TLC detected. After the completion of the reaction, the solvent was
removed by evaporation and the residue was chromatographed with CHCl3–
MeOH (95:5, v/v) to afford the desired compound 6a as white solid, yield: 72%;
However, 6a was more effective than FXT in this antidepressant
model. Further, the potency of compound 5c and 6a was also con-
firmed by TST model. In addition, active compounds did not exhibit
any motor impairment effect as confirmed by rotarod and digiscan
animal activity monitor. Taken together, among the 3-phenyl-
coumarin derivatives, we identified compound 6a as a potential
antidepressant lead candidate.
ꢁ
1
1
mp 121–122 °C; IR (KBr): 3019, 1407, 1071, 757 cm
00 MHz) d: 7.70 (s, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.35 (s, 2H), 7.26 (s, 1H), 7.00–
6.95 (m, 4H), 6.56 (d, J = 8.3 Hz, 2H), 4.34 (s, 2H), 3.85 (s, 3H), 2.48 (s, 3H), 2.23
(s, 3H); 13C NMR (CDCl
, 75 MHz): 167.9, 161.1, 160.2, 150.9, 145.7, 139.0,
35.7, 132.5, 131.5, 131.0, 129.9, 128.9, 127.6, 127.3, 127.2, 126.2, 123.8, 119.6,
;
3
H NMR (CDCl ,
3
3
1
1
+
14.0, 113.1, 55.4, 20.5, 15.6; ESI-MS: (m/z): 386 (M+H) .
2
4. Forced swimming test (FST): Swiss mice were divided into three groups and each
group was treated with vehicle, 3-phenylcoumarins (0.5 mg/kg, ip) and
standard drug FXT (20 mg/kg, ip). After 30 min of administration, mice were
Acknowledgments
subjected to FST,
a behavioural despair model of depression. FST was
performed according to the procedure described by Porsolt et al. ( Porsolt, R.
D.; Le Pichon, M.; Jalfre, M. Nature 1977, 266, 730. ). Briefly, mice were forced to
individually swim in water maintained at 25 °C in a transparent glass cylinder
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 Project Grant,
THUNDER (BSC0102) to Shubha Shukla. K.B.R., R.K.M., S.S. and A.T.
are thankful to CSIR, New Delhi, India for financial support. This is
CSIR-CDRI communication number 8770.
(
20 cm height, 10 cm diameter) having a height of 10 cm. After 5 min, the
animals were removed from water, wiped and returned back to their home
cages. They were again placed in the cylinder 24 h later and the total duration
of immobility during swimming was recorded by a digital camera during the
last 5 min of a 6 min recording session by using ANY-maze software. Initial
1
min was however considered as an acclimatization period..
25. Tail suspension test (TST): TST was conducted as previously described by Steru
et al. ( Steru, L.; Chermat, R.; Thierry, B.; Simon, P. Psychopharmacology 1985,
8
5, 367. ). Briefly, Swiss mice were individually suspended 60 cm above the
Supplementary data
surface of a table by their tail with an adhesive tape placed approximately one
cm away from the tip of tail. Mice were suspended for 6 min after 1 min
acclimatization period and the immobility duration was recorded for the last
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.08.
5
min of the session by using ANY maze software. Mice were considered
immobile only when they were hanging passively or remained completely
motionless..
0
37.
2
6. Open-field locomotor activity test (Spontaneous motor activity): The open-field
test to evaluate spontaneous locomotor activity (SLA) is routinely done during
drug screening process to rule out any adverse effect of test compound on
locomotion. SLA include different types of movements such as distance
travelled, rearing, and grooming. Open field activity was performed by using
Digiscan Infrared Photocell system, Omnitech Electronics, Columbus, Ohio
consisting of 42 cm ꢂ 42 cm ꢂ 30 cm plexiglas arenas, fitted with infrared
beam containing metallic grid ( Sanberg, P. R.; Zoloty, S. A.; Willis, R.; Ticarich,
C. D.; Rhoads, K.; Nagy, R. P.; Mitchell, S. G.; Laforest, A. R.; Jenks, J. A.;
Harkabus, L. J.; Gurson, D. B.; Finnefrock, J. A.; Bednarik, E. J. Pharmacol.
Biochem. Behav. 1987, 27, 569. ). Activity of the animals was observed by
interruption of infrared beams. During experiments, initially the control and
treated animals (Swiss mice) were habituated in the experimental cage for
30 min. Following this, drugs were administered at appropriate doses and
activity of animals was monitored for 2 min at regular intervals of 30 min for
total 2 h duration. Gross locomotor activity of animals is represented in terms
of horizontal activity. All cages were connected with a counting module, which
counts the number of interruptions..
27. Rotarod test: Rotarod test is commonly used for evaluation of neuromuscular
coordination in rodents upon administration of any test compound and the
protocol was used as described by Dunham et al. and studied in the Rotamex 4/
8 apparatus (M/s Columbus Instruments, USA) ( Dunham, N. W.; Miya, T. S. J.
Am. Pharm. Assoc. Am. Pharm. Assoc. (Baltim) 1957, 46, 208. ). Basically, the
rotarod consists of a rotating rod which is coated with polypropylene foam to
provide friction and to prevent animals from slipping off the rod. The distance
between the rod and floor is kept 15 cm to avoid intentional jumping of mice.
The rod is driven by a motor and the rotational speed was maintained at 8 rpm
in our study. Swiss mice were trained for two days on the rotarod for duration
of 2 min per trial, with 3 trials per day. On the third day, mice were given trials
before and after administration of test compounds..
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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.2014.08.037