Synthesis and studies on antidepressant activity of 2′,4′, 6′-trihydroxychalcone derivatives

Article abstract of DOI:10.1007/s00044-011-9640-2

In this study, we synthesized a series of 2′,4′,6′- trihydroxychalcone derivatives and evaluated their antidepressant activities. The results of the nine compounds showed significantly reduced times during the forced swimming test at a dose of 10 mg/kg, indicative of antidepressant activity. Among the compounds, 2-bromo-2′,4′,6′- trihydroxychalcone (3h) was found to be the most potent, and it was observed that compound 3h at dose of 10, 20, and 40 mg/kg significantly reduced the duration of immobility times in the FST and TST in mice 30 min after treatment. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9640-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1290–1296
DOI 10.1007/s00044-011-9640-2
ORIGINAL RESEARCH
Synthesis and studies on antidepressant activity
of 20,40,60-trihydroxychalcone derivatives
•
Xin Sui Ying-Chun Quan Yue Chang
•
•
•
Rui-Peng Zhang Yin-Feng Xu Li-Ping Guan
•
Received: 24 November 2010 / Accepted: 31 March 2011 / Published online: 19 April 2011
Ó Springer Science+Business Media, LLC 2011
Abstract In this study, we synthesized a series of 20,40,60-
trihydroxychalcone derivatives and evaluated their antide-
pressant activities. The results of the nine compounds
showed significantly reduced times during the forced
swimming test at a dose of 10 mg/kg, indicative of anti-
depressant activity. Among the compounds, 2-bromo-
20,40,60-trihydroxychalcone (3h) was found to be the most
potent, and it was observed that compound 3h at dose of
10, 20, and 40 mg/kg significantly reduced the duration of
immobility times in the FST and TST in mice 30 min after
treatment.
Introduction
Depression is one of the major mental disorders. Symptoms
of depression include lowered mood and reduced interest
and pleasure. According to latest available data from the
World Health Organization (WHO), depression is expected
to become the second leading cause of disease-related
disability by the year 2020 (Murray and Lopez, 1996;
Rybnikova et al., 2007). It is a serious disorder with an
estimate of lifetime prevalence as high as 20% and a
significant number of patients (30%) do not respond to
current medical treatment (Charney et al., 2002; Cryan
et al., 2002). Most of these drugs, however, have unde-
sirable side effects. Thus, there is an unmet need for new
antidepressants.
Keywords 20,40,60-Trihydroxychalcone derivatives ꢀ
Synthesis ꢀ Antidepressant activity
Chalcones are a group of flavonoids that exhibit a wide
variety of pharmacological effects, including antibacterial,
antifungal, antiviral, and analgesic properties (Bekhit et al.,
2001; Lopez et al., 2001; Viana et al., 2003; Wu et al.,
2003) et al. In recent years, it is reported that flavonoids
possess antidepressant activity (Butterweck et al., 2000;
Nakazawa et al., 2003). Wang et al. (2007) also reported
that ten natural flavonoid compounds exhibited antide-
pressant activity. Apigenin (5,7,40-trihydroxyflavonoid)
(Fig. 1), one type of bioflavonoid widely found in citrus
fruit, was reported to possess antidepressant effect (Yi
et al., 2008). Analyzing the structure of apigenin, if C-ring
of apigenin is opened, the chalcone compound I (4,20,40,60-
tetrahydroxychalcone) was obtained and its antidepressant
activity was examined. The pharmacological results
showed that the compound I reduced significantly the
duration of immobility times at 10 mg/kg dose level when
compared to the control (P \ 0.05), indicative of antide-
pressant activity. In order to obtain compounds with better
antidepressant activity, in this article, we designed and
X. Sui ꢀ Y.-F. Xu ꢀ L.-P. Guan (&)
Food and Pharmacy College, Zhejiang Ocean University,
Zhoushan City, Zhejiang Province 316004,
People’s Republic of China
e-mail: glp730@yahoo.com.cn
X. Sui
e-mail: suixin_iam@163.com
Y.-F. Xu
e-mail: YFxu@zjou.edu.cn
X. Sui ꢀ Y.-C. Quan ꢀ Y. Chang ꢀ R.-P. Zhang
College of Pharmacy, Yanbian University, Yanji, Jilin 133000,
People’s Republic of China
e-mail: ycquan@yahoo.com.cn
Y. Chang
e-mail: chyba207@yahoo.com.cn
R.-P. Zhang
e-mail: rui-pengazhang@126.com
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Med Chem Res (2012) 21:1290–1296
1291
MP 70–72°C; yield = 71%; 1H-NMR (CDCl3,
300 MHz): d 3.49 (s, 3H, OCH3), 3.54 (s, 3H, OCH3), 5.20
(s, 2H, CH2), 5.30 (s, 2H, CH2), 6.25–7.37 (m, 6H, Ar–H).
7.73 (d, 1H, J = 15.6 Hz, Ha), 7.91 (d, 1H, J = 15.6 Hz,
Hb), 13.76 (s, H, –OH); IR (KBr) cm-1: 3312 (OH), 1636
(C=O); MS m/z 363 (M ? 1).
OH
B
OH
4
B
6'
4'
HO
O
C
HO
OH
O
A
A
2'
OH
O
OH
Apigenin
I
R
HO
OH
O
General procedure for the preparation of compounds
(3a–q)
OH
3a-q
In a round-bottomed flask, to a stirred solution of chalcones
2a–q (0.25 mmol) in methanol was added dropwise 3 M
HCl, the mixture was refluxed for 30 min. The solvents
were removed under reduced pressure and diluted with
water, and extracted with ethyl acetate. The organic layer
was washed with water and brine, dried over anhydrous
Na2SO4. After concentration under reduced pressure, the
resultant was recrystallized from ethanol. The yield,
melting point, and spectral data of part compounds are
given below.
Fig. 1 Apigenin: 5,7,40-trihydroxyflavonoid; I: 4,20,40,60-tetrahydr-
oxychalcone; 3a–q: 20,40,60-trihydroxychalcone derivatives
synthesized a series of 20,40,60-trihydroxychalcone deriva-
tives with ring C opened using compound I as the lead
compound. The antidepressant activities of the synthesized
compounds were also determined by using Porsolt’s
behavioral despair (Forced Swimming Test: FST) (Porsolt
et al., 1977) and Steru’s behavioral despair (Tail Suspen-
sion Test: TST) (Steru et al., 1985).The synthesized com-
1
20,40,6-Trihydroxychalcone (3a)
pounds were characterized by IR, H-NMR, and MS.
MP 124–126°C; yield = 81%; 1H-NMR (DMSO-d6,
300 MHz): d 5.86–7.46 (m, 7H, Ar–H), 7.69 (d, 1H,
J = 15.9 Hz, Ha), 8.13 (d, 1H, J = 15.7 Hz, Hb), 10.48 (s,
H, –OH), 12.48 (s, H, –OH); IR (KBr) cm-1: 3328(OH),
1646 (C=O); MS m/z 257 (M ? 1).
Experimental
Melting points were determined in open capillary tubes and
were uncorrected. IR spectra were recorded (in KBr) on a
1
FT-IR1730 (Bruker, Switzerland), H-NMR spectra were
2-Fluoro-20,40,60-trihydroxychalcone (3b)
measured on an AV-300 (Bruker, Switzerland), and all
chemical shifts were given in ppm relative to tetrameth-
ylsilane. Mass spectra were measured on an HP1100LC
(Agilent Technologies, USA). The major chemicals were
purchased from Alderich Chemical Corporation. All other
chemicals were of the analytical grade.
MP 172–174°C; yield = 62%; 1H-NMR (DMSO-d6,
300 MHz): d 5.87–7.79 (m, 6H, Ar–H), 7.73 (d, 1H,
J = 15.9 Hz, Ha), 8.24 (d, 1H, J = 15.9 Hz, Hb), 10.54 (s,
H, –OH), 12.47 (s, H, –OH); IR (KBr) cm-1: 3334 (OH),
1646 (C=O); MS m/z 275 (M ? 1).
Synthesis of 20-hydroxy-3-fluoro-40,60-
3-Fluoro-20,40,60-trihydroxychalcone (3c)
bis(methoxymethoxy)chalcone (2c)
MP 178–180°C; yield = 66%; 1H-NMR (DMSO-d6,
300 MHz): d 5.86–7.53 (m, 6H, Ar–H), 7.66 (d, 1H,
J = 15.7 Hz, Ha), 8.12 (d, 1H, J = 15.7 Hz, Hb), 10.52 (s,
H, –OH), 12.44 (s, H, –OH); IR (KBr) cm-1: 3328 (OH),
1642 (C=O); MS m/z 275 (M ? 1).
To a stirred solution of KOH (2.0 g, 45.6 mmol) in
water (2 ml) cooled to 0°C in an ice bath was added
dropwise a solution of 2-hydroxy-4,6-bis (methoxyme-
thoxy) acetophenone (1.0 mmol), and 3-fluorobenzalde-
hyde (2.0 mmol) in ethanol under nitrogen (Nishida and
Kawabata, 2006). The reaction mixture was kept at room
for 24 h. The mixture was poured into ice-water, adjusted
to pH 2–3 with 1 M HCl, and then extracted with ethyl
acetate. The organic layer was washed with water and
saturated brine, dried over anhydrous MgSO4. After
removing solvents, products were purified by silica gel
column chromatography (petroleum ether:ethyl ace-
tate = 6:1). The yellow solid was obtained.
4-Fluoro-20,40,60-trihydroxychalcone (3d)
MP 168–170°C; yield = 70%; 1H-NMR (DMSO-d6,
300 MHz): d 5.85–7.53 (m, 6H, Ar–H), 7.68 (d, 1H,
J = 16.2 Hz, Ha), 8.12 (d, 1H, J = 16.2 Hz, Hb), 10.48 (s,
H, –OH), 12.47 (s, H, –OH); IR (KBr) cm-1: 3330 (OH),
1644 (C=O); MS m/z 275 (M ? 1).
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Med Chem Res (2012) 21:1290–1296
H, –OH), 12.41 (s, H, –OH); IR (KBr) cm-1: 3328 (OH),
2-Chloro-20,40,60-trihydroxychalcone (3e)
1649 (C=O); MS m/z 325 (M ? 1).
MP 160–162°C; yield = 63%; 1H-NMR (DMSO-d6,
300 MHz): d 5.88–7.84 (m, 6H, Ar–H), 7.94 (d, 1H,
J = 15.6 Hz, Ha), 8.16 (d, 1H, J = 15.6 Hz, Hb), 10.57 (s,
H, –OH), 12.45 (s, H, –OH); IR (KBr) cm-1: 3322 (OH),
1644 (C=O); MS m/z 291 (M ? 1).
4-Methyl-20,40,60-trihydroxychalcone (3l)
MP 117–119°C; yield = 60%; 1H-NMR (DMSO-d6,
300 MHz): d 2.35 (s, 3H, CH3), 5.90–7.44 (m, 6H, Ar–H),
7.67 (d, 1H, J = 15.7 Hz, Ha), 8.09 (d, 1H, J = 15.7 Hz,
Hb), 10.46 (s, H, –OH), 12.50 (s, H, –OH); IR (KBr) cm-1
:
3-Chloro-20,40,60-trihydroxychalcone (3f)
3330 (OH), 1646 (C=O); MS m/z 271 (M ? 1).
MP 178–180°C; yield = 72%; 1H-NMR (DMSO-d6,
300 MHz): d 5.92–7.74 (m, 6H, Ar–H), 7.63 (d, 1H,
J = 15.7 Hz, Ha), 8.13 (d, 1H, J = 15.7 Hz, Hb), 10.53 (s,
H, –OH), 12.45 (s, H, –OH); IR (KBr) cm-1: 3327 (OH),
1647 (C=O); MS m/z 291 (M ? 1).
3,4-Dimethyl-20,40,60-trihydroxychalcone (3m)
MP 156–158°C; yield = 68%; 1H-NMR (DMSO-d6,
300 MHz): d 2.23 (s, 6H, (CH3)2), 5.85–7.44 (m, 5H, Ar–
H), 7.64 (d, 1H, J = 15.7 Hz, Ha), 8.09 (d, 1H,
J = 15.7 Hz, Hb), 10.44 (s, H, –OH), 12.50 (s, H, –OH);
IR (KBr) cm-1: 3329 (OH), 1645 (C=O); MS m/z 285
(M ? 1).
4-Chloro-20,40,60-trihydroxychalcone (3g)
MP 175–177°C; yield = 78%; 1H-NMR (DMSO-d6,
300 MHz): d 5.86–7.71 (m, 6H, Ar–H), 7.67 (d, 1H,
J = 15.1 Hz, Ha), 8.11 (d, 1H, J = 15.7 Hz, Hb), 10.51 (s,
H, –OH), 12.46 (s, H, –OH); IR (KBr) cm-1: 3328 (OH),
1649 (C=O); MS m/z 291 (M ? 1).
4-Methoxyl-20,40,60-trihydroxychalcone (3n)
MP 107–109°C; yield = 68%; 1H-NMR (DMSO-d6,
300 MHz):d 3.82 (s, 3H, OCH3), 5.85–7.65 (m, 6H, Ar–H),
7.69 (d, 1H, J = 15.8 Hz, Ha), 8.03 (d, 1H, J = 15.6 Hz,
2-Bromo-20,40,60-trihydroxychalcone (3h)
Hb), 10.42 (s, H, –OH), 12.52 (s, H, –OH); IR (KBr) cm-1
:
MP 186–188°C; yield = 53%; 1H-NMR (DMSO-d6,
300 MHz): d 5.87–7.82 (m, 6H, Ar–H), 7.90 (d, 1H,
J = 15.5 Hz, Ha), 8.10 (d, 1H, J = 15.5 Hz, Hb), 10.55 (s,
H, –OH), 12.43 (s, H, –OH); IR (KBr) cm-1: 3328 (OH),
1640 (C=O); MS m/z 334 (M ? 1).
3327 (OH), 1646 (C=O); MS m/z 287 (M ? 1).
3,4-Dimethoxy-20,40,60-trihydroxychalcone (3o)
MP 112–114°C; yield = 68%; 1H-NMR (DMSO-d6,
300 MHz): d 3.77, 3.82 (each s, 3H, OCH3-3,4), 5.90–7.65
(m, 5H, Ar–H), 7.64 (d, 1H, J = 15.7 Hz, Ha), 8.09 (d, 1H,
J = 15.7 Hz, Hb), 10.41 (s, H, –OH), 12.53 (s, H, –OH);
IR (KBr) cm-1: 3327 (OH), 1646 (C=O); MS m/z 317
(M ? 1).
3-Bromo-20,40,60-trihydroxychalcone (3i)
MP 182–184°C; yield = 65%; 1H-NMR (DMSO-d6,
300 MHz): d 5.86–7.88 (m, 6H, Ar–H), 7.63 (d, 1H,
J = 15.7 Hz, Ha), 8.12 (d, 1H, J = 15.7 Hz, Hb), 10.52 (s,
H, –OH), 12.45 (s, H, –OH); IR (KBr) cm-1: 3335 (OH),
1651 (C=O); MS m/z 334 (M ? 1).
3,4,20,40,60-Pentahydroxychalcone (3p)
MP 202–204°C; yield = 68%; 1H-NMR (DMSO-d6,
300 MHz): d 5.89–7.41 (m, 5H, Ar–H), 7.65 (d, 1H,
J = 15.6 Hz, Ha), 8.06 (d, 1H, J = 15.7 Hz, Hb), 9.67 (s,
H, –OH), 10.37 (s, H, –OH), 12.12 (s, H, –OH), 12.51
(s, H, –OH); IR (KBr) cm-1: 3328 (OH), 1647 (C=O); MS
m/z 289 (M ? 1).
4-Bromo-20,40,60-trihydroxychalcone (3j)
MP 192–194°C; yield = 69%; 1H-NMR (DMSO-d6,
300 MHz): d 5.86–7.65 (m, 6H, Ar–H), 7.65 (d, 1H,
J = 15.7 Hz, Ha), 8.12 (d, 1H, J = 15.7 Hz, Hb), 10.51 (s,
H, –OH), 12.46 (s, H, –OH); IR (KBr) cm-1: 3322 (OH),
1647 (C=O); MS m/z 334 (M ? 1).
3-Methoxy-4,20,40,60-tetrahydroxychalcone (3q)
2,4-Dichloro-20,40,60-trihydroxychalcone (3k)
MP 188–190°C; yield = 68%; 1H-NMR (DMSO-d6,
300 MHz): d 3.83 (s, 3H, OCH3), 5.89–7.27 (m, 5H, Ar–
H), 7.65 (d, 1H, J = 15.5 Hz, Ha), 7.99 (d, 1H,
J = 15.7 Hz, Hb), 10.38 (s, H, –OH), 10.78 (s, H, –OH);
MP 179–181°C; yield = 71%; 1H-NMR (DMSO-d6,
300 MHz): d 5.88–7.76 (m, 5H, Ar–H), 7.86 (d, 1H,
J = 15.7 Hz, Ha), 8.14 (d, 1H, J = 15.6 Hz, Hb), 10.57 (s,
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Med Chem Res (2012) 21:1290–1296
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12.16 (s, H, –OH), 12.54 (s, H, –OH); IR (KBr) cm-1
:
Statistical analysis
3329 (OH), 1645 (C=O); MS m/z 303 (M ? 1).
Results are expressed as mean SEM; n represents the
number of animals. Data obtained from pharmacological
experiments were analyzed with one-way analysis of var-
iance (ANOVA) followed by Dunnet’s post hoc test, using
Pharmacologic Calculation System Version 4.1. (Micro-
computer Specialists). A P-value of less than 0.05 was
considered statistically significant.
Pharmacology
Forced swimming test (FST)
The synthesized compounds were screened for their anti-
depressant activity using Porsolt’s behavioral despair
(forced swimming) test (Porsolt et al., 1977). Local breed,
male Kunming mice (20–24 g) were used in the forced
swimming test under standard conditions with free access
to food and water. They were housed in groups of six. On
the test day, mice were dropped one at a time into a
plexiglass cylinder (height 25 cm, diameter 10 cm3) con-
taining 10 cm of water at 23–25°C. On this day, mice
were assigned into different groups (n = 10 for each
group). The synthesized compounds (10 mg/kg) and Flu-
oxetine as a reference antidepressant drug (10 mg/kg)
were suspended in a 0.5% aqueous solution of methyl-
cellulose injected intraperitoneally (ip) in a standard vol-
ume of 0.05 ml/20 g body weight, 30 min prior to the test.
Control animal received 0.5% aqueous solution of meth-
ylcellulose. Then, the mice were dropped individually into
the plexiglass cylinder and left in the water for 6 min.
After the first 2 min of the initial vigorous struggling, the
animals were immobile. A mouse was judged immobile if
it floated in the water in an upright position and made only
slight movements in order to prevent sinking. The duration
of immobility was recorded during the last 4 min of the
6 min test.
Results and discussion
The target compounds 3a–q was synthesized according to
Scheme 1. Compound 1 (1-(2-hydroxy-4,6-bismethox-
ymethoxy-phenyl)-ethanone was prepared as reported
previously (Raiendra Prasad et al., 2005). Intermediates
2a–q was prepared by Claisen–Schmidt condensation of 1
with appropriate aromatic aldehydes or hydroxyaro-
matic aldehydes, protected as chloromethyl methyl ether
(Raiendra Prasad et al., 2005; Zhao et al., 2005; Nishida
et al., 2007). Then intermediates 2a–q were treated with
3 M HCl in methanol to yield the hydroxychalcones
3a–q in good yield.
First, the forced swimming test is a behavioral test used
to predict the efficacy of antidepressant treatments (Porsolt
et al., 1977). It is used effectively in predicting the activity
of a wide variety of antidepressants such as MAO inhibi-
tors and atypical antidepressants (Porsolt, 1981). It has
good predictive value for antidepressant potency in humans
(Willner and Mitchell, 2002). The obtained data on the
antidepressant activity of the compounds and reference
drug are given in Table 1. In our study, all of the com-
pounds except 3a, 3c, 3d, 3e, 3j, 3l, 3m, 3n, and 3o sig-
nificantly reduced the duration of immobility time at
10 mg/kg compared to control (P \ 0.05, P \ 0.01, or
P \ 0.001, Table 1). Among the compounds, 3h (2-bromo-
20,40,60-trihydroxychalcone) was the most antidepressant
activity and significantly reduced the duration of immo-
bility times at 10 mg/kg dose level when compared to the
control (P \ 0.001).
Analyzing the antidepressant activities of synthesized
compounds 3a–q, the following SAR was gained. From
compounds 3b–j, as halogen substituted on B ring of
chalcone compounds, alternating variations of activity
were observed. The atom Br gave more contribution to the
antidepressant activity than atoms F and Cl, the rank of
activity order of halogen substituted derivatives was
Br [ Cl [ F. Among the compounds, 3h (2-bromo-
20,40,60-trihydroxychalcone) showed the most antidepres-
sant activity, which reduced immobility time by 50.04% at
10 mg/kg compared with the same dose of Fluoxetine
(58.68%), and compared with the leading compound
Tail suspension test (TST)
The tail suspension test was based on the method of Steru
et al. (1985). Briefly, each mouse was individually sus-
pended by its tail using a clamp (2 cm from the end) for
6 min in a box (25 9 25 9 30 cm) with the head 5 cm
from the bottom. Testing was carried out in a darkened
room with minimal background noise. On this day, mice
were assigned into different groups (n = 10 for each
group). The synthesized compounds (10 mg/kg) and Flu-
oxetine as a reference antidepressant drug (10 mg/kg)
were suspended in a 0.5% aqueous solution of methyl-
cellulose injected intraperitoneally (ip) in a standard vol-
ume of 0.05 ml/20 g body weight, 30 min prior to the test.
Control animal received 0.5% aqueous solution of meth-
ylcellulose. After the first 2 min of the initial vigorous
struggling, the animals were immobile. The duration of
immobility was recorded during the last 4 min of the
6 min test.
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Med Chem Res (2012) 21:1290–1296
HO
OH
O
Scheme 1 The synthesis route
of target compounds
3a–q. Reagents and
conditions:(i) ClCH2OCH3,
K2CO3, acetone; (ii) aromatic
aldehyde, KOH, EtOH;
(iii) 3 M HCl, MeOH
O
O
O
O
O
O
O
OH
O
i
ii
R
CH3
CH3
OH
OH
O
O
2a-q
1
HO
OH
iii
R
OH
O
3a-q
R:
3a = H
3b = 2-F
3g = 4-Cl
3c = 3-F
3d = 4-F
3i = 3-Br
3e = 2-Cl
3f = 3-Cl
3k = 2,4-Cl2
3h = 2-Br
3j = 4-Br
3l = 4-CH3
3m = 3,4-(CH3)2
3n = 4-OCH3
3o = 3,4-(OCH3)2
3p = 3,4-(OH)2 3q = 3-OCH3-4-OH
Table 1 Antidepressant activities of the compounds
Compounds
R
Dose (mg/kg)
Antidepressant activities
Duration of immobility (s)
(mean SEM)
Change from
control (%)
I
–
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
–
99.3 15.1*
121.6 17.4
92.3 12.9**
115.0 14.0
132.8 15.8
112.9 11.6
100.6 13.0**
101.3 14.4*
69.4 9.1***
101.9 12.0**
112.1 15.1
100.8 14.5*
114.8 12.8
120.4 13.5
123.5 14.7
114.3 15.2
98.5 11.0**
107.1 11.6**
57.4 8.9***
138.9 25.3
-28.51
-14.23
-33.55
-17.21
-4.39
3a
H
3b
2-F
3c
3-F
3d
4-F
3e
2-Cl
-18.72
-27.57
-27.07
-50.04
-26.64
-19.29
-27.43
-17.35
-13.31
-11.09
-17.57
-29.09
-22.89
-58.68
–
3f
3-Cl
3g
4-Cl
3h
2-Br
3i
3-Br
3j
4-Br
3k
2,4-Cl2
4-CH3
3,4-(CH3)2
4-OCH3
3,4-(OCH3)2
3,4-(OH)2
3-OCH3-4-OH
3l
3m
3n
3o
3p
3q
Fluoxetine
Control
Values represent the mean SEM (n = 10)
* Significantly compared to control (Dunnet’s test: * P \ 0.05, ** P \ 0.01, *** P \ 0.001)
I exhibited enhanced antidepressant activity. In addition,
the position of halogen substituted on the phenyl ring
greatly influenced the antidepressant activity, compared
with the derivatives with different F-substituted positions
on phenyl ring, their rank of activity order was 2-F [
3-F [ 4-F. The rank of activity order of the Cl-substituted
derivatives was 3-Cl [ 2,4-Cl2 [ 4-Cl [ 2-Cl. The rank of
activity order of the Br-substituted derivatives was
2-Br [ 3-Br [ 4-Br.
Next, the influence of the electron-donor group with
antidepressant activity was compared (Table 1). Their
contribution order was 3,4-(OH)2 [ 4-OH (I) [ 3-OCH3-
4-OH [ 3,4-(OCH3)2 [ 4-CH3 [ H [ 3,4-(CH3)2 [ 4-
OCH3. Comparing with the compound 3a, compounds 3p,
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Med Chem Res (2012) 21:1290–1296
1295
potency and the potency of antidepressant in both models.
The compound 3h produced significant antidepressant-like
activity in both the FST and TST in mice, which indicates
that compound 3h has some antidepressant effects.
Conclusion
In conclusion, a series 20,40,60-trihydroxychalcone deriva-
tives were synthesized and their antidepressant activities
was evaluated. The results showed that compound 3h
(2-bromo-20,40,60-trihydroxy-chalcone) was the most prom-
ising compound and significantly reduced the duration of
immobility times at 10 mg/kg dose level when compared to
the control (P \ 0.001) in the FST and the TST. Further
studies should be initiated to reveal the mechanism of the
antidepressant-like effect of the compound 3h.
Fig. 2 Immobility time of compound 3h in mouse FST. Data
expressed as mean SEM (n = 10). Statistical analysis of data
was carried out by one-way analysis of variance followed by the
t-test. ***P \ 0.001 versus control
Acknowledgments This is provided by Zhejiang Ocean University
R&D start funding.
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