Synthesis and antidepressant-like action of N-(2-hydroxyethyl) cinnamamide derivatives in mice

Article abstract of DOI:10.1007/s00044-010-9470-7

This study described the chemical synthesis and pharmacological evaluation of a series of N-(2-hydroxyethyl) cinnamamide derivatives. The structures of them were characterized by IR, ¹H-NMR, MS and elemental analysis. Their antidepressant activities were evaluated by the forced swimming test (FST) and tail suspension test (TST). Pharmacological results of these compounds showed that some of them, given orally, significantly reduced the immobility time in the FST and TST, indicating the antidepressant-like action. Among them, compounds N-(2-hydroxyethyl)cinnamamide (1g), (E)-3-(4-hydroxy-3- methoxyphenyl)-N-(2-hydroxyethyl)acrylamide (1i) and (E)-N-(2-hydroxyethyl)-3- (3-hydroxyphenyl)acrylamide (1n), active in the two models, were considered as the most promising compounds in this study. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9470-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1273–1279
DOI 10.1007/s00044-010-9470-7
ORIGINAL RESEARCH
Synthesis and antidepressant-like action of N-(2-hydroxyethyl)
cinnamamide derivatives in mice
•
•
•
Xian-Qing Deng Di Wu Cheng-Xi Wei
Zhe-Shan Quan
Received: 3 June 2010 / Accepted: 7 October 2010 / Published online: 21 October 2010
Ó Springer Science+Business Media, LLC 2010
Abstract This study described the chemical synthesis and
pharmacological evaluation of a series of N-(2-hydroxy-
ethyl) cinnamamide derivatives. The structures of them
were characterized by IR, 1H-NMR, MS and elemental
analysis. Their antidepressant activities were evaluated by
the forced swimming test (FST) and tail suspension test
(TST). Pharmacological results of these compounds showed
that some of them, given orally, significantly reduced
the immobility time in the FST and TST, indicating
the antidepressant-like action. Among them, compounds
N-(2-hydroxyethyl)cinnamamide (1g), (E)-3-(4-hydroxy-3-
methoxyphenyl)-N-(2-hydroxyethyl)acrylamide (1i) and
(E)-N-(2-hydroxyethyl)-3-(3-hydroxyphenyl)acrylamide (1n),
active in the two models, were considered as the most
promising compounds in this study.
tricyclic antidepressants and monoamine oxidase inhibitors
(MAOIs) to treat depression and more recent advances in
antidepressant treatment, including the discovery of selec-
tive serotonin reuptake inhibitors (SSRIs) and specific
serotonin–noradrenaline reuptake inhibitors (SNRIs), the
therapeutic result is not satisfactory with one third remission
rate and the subjects always suffer from the side effects of
those clinical antidepressants such as anxiety, sleep distur-
bance, weight gain and sexual dysfunction (Thase, 2003;
Thase et al., 2007; Hirschfeld 1999). Therefore, the dis-
covery of new antidepressant drugs with less side-effects
and better efficacy is still necessary.
The cinnamamide derivatives exhibit a variety of bio-
logical activities, such as central nervous depression, sed-
ative-hypnosis, anticonvulsant, muscle relaxation, local
anesthesia, inhibit fungal, and antidepressant activities
(Bruce Moffett, 1964; Van Heyningen et al., 1966; Bal-
samo et al., 1981, 1975). N-(3-hydroxypropyl) cinnama-
mide was found possessing antidepressant activity in the
forced swimming test (FST) in our previous work (Guan
et al., 2010). In our further search for new compounds with
antidepressant activity, N-(2-hydroxyethyl) cinnamamide
(Fig. 1, compound I) was synthesized and tested its anti-
depressant activity in the FST, in which N-(2-hydroxy-
ethyl) cinnamamide showed a positive antidepressant
activity at the dose of 40 mg/kg. In order to obtain com-
pounds with better antidepressant activity, we synthesized
N-(2-hydroxyethyl) cinnamamide derivatives via modify-
ing the aromatic ring by introducing some substituents to it.
Considering that multitude of antidepressant agents are
natural produces, methoxyl and hydroxyl substituted
compounds are the major in this study. The synthesized
Keywords N-(2-hydroxyethyl) cinnamamide ꢀ
Antidepressant ꢀ Forced swimming test ꢀ
Tail suspension test
Introduction
Depression is one of the most prevalent psychopathologies.
It is ranked by the World Health Organization as the fourth
greatest cause of global illness burden in the year 2000, and
investigations indicate that it will become the second
leading cause of disease worldwide by 2020 (Meyer, 2004;
Lopez and Murray 1998). Despite the introduction of
X.-Q. Deng ꢀ D. Wu ꢀ C.-X. Wei ꢀ Z.-S. Quan (&)
College of Pharmacy, Yanbian University, No. 977,
Park road, Yanji 133002, Jilin, China
1
compounds were characterized by IR, H-NMR, MS and
elemental analysis. Their antidepressant activities were
evaluated by the FST and tail suspension test (TST), two
e-mail: zsquan@ybu.edu.cn
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Med Chem Res (2011) 20:1273–1279
Fig. 1 Structure of N-(2-
hydroxyethyl) cinnamamide and
its derivatives
O
O
OH
OH
N
H
N
R
H
1a-1o
Pharmacological evaluations
well-established animal models that have been extensively
used as screening models for new antidepressant agents
(Porsolt et al., 1977; Steru et al., 1985).
Compounds prepared were screened for their antidepres-
sant activities in mice using the FST and tail suspension
test (TST). The FST was designed by porsolt as a primary
screening test for antidepressants, and it remains one of the
best models for this purpose for several reasons. It is a low
cost, fast, and reliable model to test potential antidepressant
treatments with a strong predictive validity. The immo-
bility time observed in the test reflected a state of lowered
mood or hopelessness in animal; thus, this animal model is
the most widely used tool for preclinical screening of
putative antidepressant agents (Cryan et al., 2002; Cryan
et al., 2005; Bourin et al., 2005; Petit-Demouliere et al.,
2005). The TST is also considered as a mature model for
predicting antidepressant activity (Steru et al., 1985).
The results of FST revealed that some of the compounds
prepared displayed good antidepressant activity. Acute
treatment with the compounds 1g, 1h, 1i, and 1n promoted
a significant decrease in the immobility time in the FST at
40 mg/kg, as depicted in Fig. 2 (control = 183.3 12.67;
1g = 101.2 17.77; 1h = 105.5 9.06; 1i = 55.00
11.12; 1n = 102.8 28.27; Fluoxetine = 93.50 22.61).
Results and discussion
Synthesis
Target compounds were prepared according to Scheme 1.
Compounds 1a–1l were obtained in high yield through a
one-step reaction using substituted cinnamic acid, methyl
chloroformate, triethylamine, and ethanolamine as the
reaction materials. Compounds 1m–1o were obtained by
demethylation of compounds 1a–1c, respectively. All the
compounds were identified by spectral data. In general, IR
spectra showed the C=O peak at 1620–1662, the NH
stretching vibrations at 3215–3286 cm-1, and the OH
stretching vibrations at 3332–3408 cm-1. In the nuclear
magnetic resonance spectra (1H-NMR) the signals of the
respective protons of the synthesized compounds were
verified on the basis of their chemical shifts, multiplicities
and coupling constants.
Scheme 1 Synthesis of
compounds 1a–1o
O
O
OH
r.t.
N
OH
R
H
+
ClCOOCH3 + H2NCH2CH2OH
R
3-4h
1a-1l
O
O
OH
OH
BBr3
N
N
HO
H3CO
H
H
r.t., 4h
1m-1o
1a-1c
R:
1a: o -OCH3
1e: 3,4-(OCH3) 2
1f: 3,4,5-(OCH3) 3
1g: -H
1i: 4-OH, 3-OCH3
1j: -C6H4(p-F)
1m: o -OH
1n: m -OH
1o: p -OH
1b: m -OCH3
1c: p -OCH3
1k: -C6H4(p-Cl )
1l: -C6H4(p-Br)
1d: 2,4-(OCH3) 2
1h: -N(CH3) 2
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1275
250
200
150
100
50
150
*
*
*
**
*
**
100
**
** **
**
**
***
***
***
50
0
***
0
Fig. 2 Effects of the acute treatment with compounds 1a–1o, 40 mg/
kg, p.o.) and the standard antidepressant fluoxetine (FLU, 40 mg/kg,
p.o.) on the immobility time in the forced swimming test. Each
column represents mean SEM. * P \ 0.05, ** P \ 0.01, *** P \
0.001 as compared to control (all comparisons were made by
ANOVA followed by Dunnett’s test)
Fig. 3 Effects of the acute treatment with compounds 1a–1o, 40 mg/
kg, p.o.) and the standard antidepressant fluoxetine (FLU, 40 mg/kg,
p.o.) on the immobility time in tail suspension test. Each column
represents mean SEM. * P \ 0.05, ** P \ 0.01, *** P \ 0.001 as
compared to control (all comparisons were made by ANOVA
followed by Dunnett’s test)
The immobility time of mice treated with the other
compounds 1a, 1b, 1c, 1d, 1e, 1f, 1j, 1k, 1l, 1m, and 1o did
not statistically differ from control values as shown in
Fig. 2 (control = 183.3 12.67; 1a = 159.1 20.33; 1b =
141.0 11.77; 1c = 167.5 8.95; 1d = 143.5 15.76;
1e = 157.8 10.06; 1f = 165.5 24.21; 1j = 130.8
18.65; 1k = 168.0 16.47; 1l = 119.7 24.07; 1m =
146.7 16.49; 1o = 133.3 22.37).
activity increase by enhancing the affinity between com-
pounds and receptors. While compounds substituted by
methoxyl or halogen groups such as 1a–1f, 1j–1l were all
inactive. This might also be the reason of their weak
affinity with receptor in vivo. Of the four compounds
contained hydroxyl group, 1i and 1n were active, and
1m, 1o also obviously decrease the immobility time
(1m = 146.7 16.49; 1o = 133.3 22.37 versus con-
trol = 183.3 12.67) though did not statistically differ
from control, indicating that the hydroxyl group in the
aromatic ring make a contribution to the antidepressant
activity in this series. Comparing the derivatives with dif-
ferent OH-substitution positions on the benzol ring, their
activity order was m-OH [ p-OH [ o-OH.
The results in the TST confirmed previous speculation
that molecules contained methoxyl and hydroxyl group
might be more active. Compounds 1a–1e, substituted by
methoxyl group were all active. Compounds 1m–1o,
substituted by hydroxyl group were all active except 1o. It
is cleared that the compounds 1j, 1k, and 1l were inactive
in the two models, which indicated that halogen groups in
aromatic ring reduced the antidepressant activity in cinn-
amamide derivatives. Compounds 1g, 1i, and 1n, both
active in the two models, were considered as the most
promising compounds in this series.
The results of TST revealed that most of the compounds
prepared displayed antidepressant activity. Acute treatment
with the compounds 1a–1e, 1g, 1i, and 1m–1n promoted a
significant decrease in the immobility time in the TST at
40 mg/kg, as depicted in Fig. 3 (control = 105.7 10.03;
1a = 38.67 13.24; 1b = 43.33 8.76; 1c = 31.33
8.31; 1d = 39.67 13.89; 1e = 39.33 14.48; 1g =
25.00 6.89; 1i = 45.00 11.74; 1m = 44.83 5.15;
1n = 54.00 20.15; Fluoxetine = 14.17 4.70). The
immobility time of mice treated with the other compounds
1f, 1h, 1j, 1k, 1l, and 1o did not statistically differ from
control values as shown in Fig. 3 (control = 105.7
10.03; 1f = 76.33 16.30; 1h = 64.67 9.29; 1j =
75.00 14.01; 1k = 76.67 16.78; 1l = 57.00 10.51;
1o = 71.00 11.74).
The pharmacology results showed some relationship
between structure and antidepressant activity. In the FST,
four compounds prepared displayed antidepressant activity.
Besides the lead compound 1g, compounds 1h, 1i, and 1n
were also active. The substitutes of compounds 1h, 1i, and
1n, contained dimethyl amine group and hydroxyl group,
respectively, are the possible devoter to their antidepressant
activity. The dimethyl amine group and hydroxyl group
might form hydroxyl bonds with receptors, which lead to
In conclusion, a series of N-(2-hydroxyethyl) cinnama-
mide derivatives were synthesized and their antidepressant
activities were investigated using the FST and TST. Most
compounds contained methoxyl and hydroxyl group are
active in FST or TST. Compounds 1g, 1i, and 1n, active in
the two models, were consider as the most promising
compounds in this study.
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Experimental
Chemistry
(m/z): 222 (M ? 1). Anal. Calcd. for C12H15N1O3: C,
65.14; H, 6.83; N, 6.33. Found: C, 65.27; H, 6.91; N, 6.21.
(E)-N-(2-hydroxyethyl)-3-(3-methoxyphenyl)acrylamide
(1b)
Melting points were determined in open capillary tubes and
were uncorrected. IR spectra were recorded (in KBr) on a
IRPrestige-21. 1H-NMR spectra were measured on an
1
Yield: 66.1%; mp 76–78°C. H-NMR (CDCl3, 300 MHz):
¨
AV-300(Bruker, Fallanden, Switzerland), and all chemical
d 2.16 (s, 1H, –OH), 3.54 (t, 2H, J = 5.4 Hz, –CH2),
3.72–3.84 (m, 5H, –CH2, OCH3), 6.44 (d, 1H,
J = 15.6 Hz, CH=C), 6.62 (s, 1H, –NHCO), 6.88 (d, 1H,
J = 8.3 Hz, Ar–H), 6.99 (s, 1H, Ar–H), 7.06 (d, 1H,
J = 7.5 Hz, Ar–H), 7.24 (t, 1H, J = 8.0 Hz, Ar–H), 7.58
(d, 1H, J = 15.6 Hz, CH=C). IR (KBr) cm-1: 3389 (OH),
3266 (NH), 1649 (C=O). MS (m/z): 222 (M ? 1). Anal.
Calcd. for C12H15N1O3: C, 65.14; H, 6.83; N, 6.33. Found:
C, 65.25; H, 6.87; N, 6.09.
shifts were given in ppm relative to tetramethysilane. Mass
spectra were measured on an HP1100LC (Agilent Tech-
nologies, Santa Clara, CA, USA). Elemental analyses were
performed on a 204Q CHN (Perkin Elmer, Fremont, CA,
USA). The chemicals were purchased from Aldrich
Chemical Corporation (Shanghai, China).
General procedures for the synthesis of the compounds
1a–1l
(E)-N-(2-hydroxyethyl)-3-(4-methoxyphenyl)acrylamide
(1c)
In a three-necked round-bottomed flask containing substi-
tuted cinnamic acid 2 g (0.05 mol), 50 ml dichloromethane
and triethylamine (0.1 mol), methyl cholroformate
(0.1 mol) was added dropwise slowly under an ice bath
with stirring, the mixture was stirred 2 h at room temper-
ature. Then ethanolanmine (0.05 mol) was added dropwise
slowly under an ice bath with stirring, the mixture was
stirred 3–4 h at room temperature. The solvents were
removed under reduced pressure. The residue was poured
into 100 ml ice water and stirred for 10 min. The solid
obtained after filtration was recrystallized in water to afford
a white solid.
Yield: 54.9%; mp 110–112°C. 1H-NMR (CDCl3,
300 MHz): d 2.23 (s, 1H, –OH), 3.55 (q, 2H, J = 5.3 Hz,
–CH2), 3.79 (t, 2H, J = 4.8 Hz, –CH2), 3.92 (s, 3H,
–OCH3), 6.29 (s, 1H, –NHCO), 6.38 (d, 1H, J = 15.8 Hz,
CH=C), 7.18 (d, 1H, J = 8.6 Hz, Ar–H), 7.50 (d, 1H,
J = 8.6 Hz, Ar–H), 7.61(d, 1H, J = 15.8 Hz, CH=C). IR
(KBr) cm-1: 3408 (OH), 3224 (NH), 1651 (C=O). MS (m/z):
222 (M ? 1). Anal. Calcd. for C12H15N1O3: C, 65.14; H,
6.83; N, 6.33. Found: C, 65.22; H, 6.93; N, 6.27.
(E)-3-(2,4-dimethoxyphenyl)-N-(2-
hydroxyethyl)acrylamide (1d)
General procedures for the synthesis of the compounds
1m–1o
Yield: 71.6%; mp 114–116°C. 1H-NMR (CDCl3,
300 MHz): d 2.57 (s, 1H, –OH), 3.55 (t, 2H, J = 4.9 Hz,
CH2), 3.70–3.87 (m, 8H, –CH2, –OCH3, –OCH3), 6.33 (s,
1H, –NHCO), 6.41–6.54 (m, 3H, Ar–H), 7.37 (d, 1H,
J = 15.7 Hz, CH=C), 7.80 (d, 1H, J = 15.7 Hz, CH=C).
IR (KBr) cm-1: 3374 (OH), 3265 (NH), 1629 (C=O). MS
(m/z): 252 (M ? 1). Anal. Calcd. for C13H17N1O4: C,
62.14; H, 6.82; N, 5.57. Found: C, 65.26; H, 6.95; N, 5.53.
Compound 1a (1.10 g, 5 mmol) was dissolved in dichlo-
romethane (50 ml). BBr3 (25 mmol) was added dropwise
to the solution under an ice bath then the mixture was
stirred at room temperature. After 4 h, the mixture was
added slowly 20 ml ice cold water and allowed to stir for
half an hour. The resulting precipitate was filtrated and
recrystallized (in water) to afford compound 1m.
Compounds 1n, 1o were obtained similarly from 1b, 1c
(E)-N-(2-hydroxyethyl)-3-(2-methoxyphenyl)acrylamide 1a
(E)-3-(3,4-dimethoxyphenyl)-N-(2-
hydroxyethyl)acrylamide (1e)
Yield: 57.8%; mp 116–118°C. 1H-NMR (CDCl3,
300 MHz): d 2.61 (s, 1H, –OH), 3.57 (q, 2H, J = 4.5 Hz,
–CH2), 3.80 (t, 2H, J = 4.9 Hz, –CH2), 3.89 (s, 6H,
–OCH3, –OCH3), 6.30 (s, 1H, –NHCO), 6.33 (d, 1H,
J = 15.5 Hz, CH=C), 6.84 (d, 1H, J = 8.3 Hz, Ar–H),
7.02 (s, 1H, Ar–H), 7.08 (d, 1H, J = 8.3 Hz, Ar–H), 7.58
(d, 1H, J = 15.5 Hz, CH=C). IR (KBr) cm-1: 3398 (OH),
3284 (NH), 1624 (C=O). MS (m/z): 252 (M ? 1). Anal.
1
Yield: 65.7%; mp 80–82°C. H-NMR (CDCl3, 300 MHz):
d 2.10 (s, 1H, –OH), 3.32 (q, 2H, J = 4.3 Hz, –CH2), 3.77
(t, 2H, J = 4.7 Hz, –CH2), 3.81 (s, 3H, OCH3), 6.56 (d,
1H, J = 15.8 Hz, CH=C), 6.71 (s, 1H, –NHCO), 6.82–6.90
(m, 2H, Ar–H), 7.26 (t, 1H, J = 7.2 Hz, Ar–H), 7.41 (d,
1H, J = 6.8 Hz, Ar–H), 7.88 (d, 1H, J = 15.8 Hz, CH=C).
IR (KBr) cm-1: 3364 (OH), 3286 (NH), 1626 (C=O). MS
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Med Chem Res (2011) 20:1273–1279
1277
Calcd. for C13H17N1O4: C, 62.14; H, 6.82; N, 5.57. Found:
C, 65.24; H, 6.90; N, 5.51.
Anal. Calcd. for C12H15N1O4: C, 60.75; H, 6.37; N, 5.90.
Found: C, 60.91; H, 6.44; N, 5.76.
(E)-3-(4-fluorophenyl)-N-(2-hydroxyethyl)acrylamide (1j)
(E)-N-(2-hydroxyethyl)-3-(3,4,
5-trimethoxyphenyl)acrylamide (1f)
1
Yield: 56.1%; mp 90–92°C. H-NMR (CDCl3, 300 MHz):
d 2.19 (s, 1H, –OH), 3.56 (q, 2H, J = 5.3 Hz, –CH2), 3.80
(t, 2H, J = 4.7 Hz, –CH2), 6.25 (s, 1H, –NHCO), 6.35 (d,
1H, J = 15.6 Hz, CH=C), 6.77 (d, 2H, J = 8.2 Hz, Ar–H),
7.30 (d, 1H, J = 15.7 Hz, CH=C), 7.37 (d, 2H,
J = 8.2 Hz, Ar–H). IR (KBr) cm-1: 3332 (OH), 3220
(NH), 1640 (C=O). MS (m/z): 210 (M ? 1). Anal. Calcd.
for C11H13N1O3: C, 63.15; H, 5.78; N, 6.69. Found: C,
63.34; H, 5.85; N, 6.78.
Yield: 46.3%; mp 120–122°C. 1H-NMR (CDCl3,
300 MHz): d 2.55 (s, 1H, -OH), 3.57 (q, 2H, J = 4.8 Hz,
–CH2), 3.80 (t, 2H, J = 4.7 Hz, –CH2), 3.84 (s, 9H,
–OCH3, –OCH3, –OCH3), 6.33 (s, 1H, –NHCO), 6.35 (d,
1H, J = 15.5 Hz, CH=C), 6.71 (s, 2H, Ar–H), 7.54 (d, 1H,
J = 15.5 Hz, CH=C). IR (KBr) cm-1: 3405 (OH), 3266
(NH), 1620 (C=O). MS (m/z): 282 (M ? 1). Anal. Calcd.
for C14H19N1O5: C, 59.78; H, 6.81; N, 4.98. Found: C,
59.93; H, 6.80; N, 5.06.
(E)-3-(4-chlorophenyl)-N-(2-hydroxyethyl)acrylamide (1k)
N-(2-hydroxyethyl)cinnamamide (1g)
Yield: 63.6%; mp 130–132°C. 1H-NMR (CDCl3,
300 MHz): d 2.28 (s, 1H, –OH), 3.58 (q, 2H, J = 5.3 Hz,
–CH2), 3.82 (t, 2H, J = 4.8 Hz, –CH2), 6.22 (d, 1H,
J = 15.7 Hz, CH=C), 6.30 (s, 1H, –NHCO), 6.89 (d, 2H,
J = 8.2 Hz, Ar–H), 7.36 (d, 1H, J = 15.7 Hz, CH=C),
7.42 (d, 2H, J = 8.2 Hz, Ar–H). IR (KBr) cm-1: 3339
(OH), 3218 (NH), 1644 (C=O). MS (m/z): 226 (M ? 1).
Anal. Calcd. for C11H13N1O3: C, 58.54; H, 5.36; N, 6.21.
Found: C, 58.71; H, 5.44; N, 6.08.
Yield: 52.7%; mp 100–102°C. 1H-NMR (CDCl3,
300 MHz): d 2.61(s, 1H, –OH), 3.56 (q, 2H, J = 5.0 Hz,
–CH2), 3.80 (t, 2H, J = 4.8 Hz, –CH2), 6.42 (s, 1H,
–NHCO), 6.44 (d, 1H, J = 15.7 Hz, CH=C), 7.36–7.47 (m,
5H, Ar–H), 7.69(d, 1H, J = 15.7 Hz, CH=C). IR (KBr)
cm-1: 3389 (OH), 3215 (NH), 1661 (C=O). MS (m/z): 192
(M ? 1). Anal. Calcd. for C11H13NO2: C, 69.09; H, 6.85;
N, 7.32. Found: C, 69.20; H, 6.92; N, 7.39.
(E)-3-(4-bromophenyl)-N-(2-hydroxyethyl)acrylamide (1l)
(E)-3-(4-(dimethylamino)phenyl)-N-
(2-hydroxyethyl)acrylamide (1h)
Yield: 59.3%; mp 142–144°C. 1H-NMR (CDCl3,
300 MHz): d 1.61 (s, 1H, –OH), 3.57 (s, 1H, –CH2), 3.82
(t, 2H, J = 4.7 Hz, –CH2), 6.13 (s, 1H, –NHCO), 6.44 (d,
1H, J = 16.0 Hz, CH=C), 7.39 (d, 2H, J = 8.3 Hz, Ar–H),
7.53 (d, 2H, J = 8.3 Hz, Ar–H), 7.63 (d, 1H, J = 16.0 Hz,
CH=C). IR (KBr) cm-1: 3342 (OH), 3266 (NH), 1638
(C=O). MS (m/z): 271 (M ? 1). Anal. Calcd. for
C11H12N1O3Br: C, 48.91; H, 4.48; N, 5.19. Found: C,
49.09; H, 4.40; N, 5.04.
Yield: 43.8%; mp 110–112°C. 1H-NMR (CDCl3,
300 MHz): d 2.77 (s, 1H, –OH), 3.01 (s, 6H, –(NH3)2),
3.56 (q, 2H, J = 5.3 Hz, –CH2), 3.79 (t, 2H, J = 4.7 Hz,
–CH2), 5.98 (s, 1H, –NHCO), 6.21 (d, 1H, J = 15.4 Hz,
CH=C), 6.68 (d, 2H, J = 8.4 Hz, Ar–H), 7.40 (d, 2H,
J = 8.4 Hz, Ar–H), 7.58 (d, 1H, J = 15.4 Hz, CH=C). IR
(KBr) cm-1: 3356 (OH), 3228 (NH), 1647 (C=O). MS (m/z):
235 (M ? 1). Anal. Calcd. for C13H18N2O2: C, 66.64; H,
7.74; N, 11.96. Found: C, 66.77; H, 7.79; N, 11.85.
(E)-N-(2-hydroxyethyl)-3-(2-hydroxyphenyl)acrylamide
(1m)
(E)-3-(4-hydroxy-3-methoxyphenyl)-N-
(2-hydroxyethyl)acrylamide (1i)
Yield: 49.7%; mp 152–154°C. 1H-NMR (DMSO-d6,
300 MHz): d 3.23 (q, 2H, J = 5.7 Hz, –CH2), 3.41 (t, 2H,
J = 5.7 Hz, –CH2), 4.83 (s, 1H, –OH), 6.65 (d, 1H,
J = 15.9 Hz, CH=C), 6.80 (t, 1H, J = 7.4 Hz, Ar–H), 6.86
(d, 1H, J = 8.1 Hz, Ar–H), 7.16 (t, 1H, J = 6.8 Hz, Ar–
H), 7.41 (d, 1H, J = 7.2 Hz, Ar–H), 7.62 (d, 1H,
J = 15.9 Hz, CH=C), 8.09 (s, 1H, –NHCO), 10.1 (s, 1H,
Ar–OH). IR (KBr) cm-1: 3345 (OH), 3229 (NH), 1648
(C=O). MS (m/z): 208 (M ? 1). Anal. Calcd. for
Yield: 69.6%; mp 114–116°C. 1H-NMR (DMSO-d6,
300 MHz): d 3.23 (q, 2H, J = 5.8 Hz, –CH2), 3.44 (t, 2H,
J = 4.5 Hz, –CH2), 3.79 (s, 3H, –CH3), 4.71 (s, 1H, –OH),
6.49 (d, 1H, J = 15.7 Hz, CH=C), 6.78 (d, 1H,
J = 8.1 Hz, Ar–H), 6.94 (d, 1H, J = 8.1 Hz, Ar–H), 7.10
(s, 1H, Ar–H), 7.31 (d, 1H, J = 15.7 Hz, CH=C), 7.94 (s,
1H, –NHCO), 9.37 (s, 1H, Ar–OH). IR (KBr) cm-1: 3376
(OH), 3222 (NH), 1632 (C=O). MS (m/z): 238 (M ? 1).
123

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Med Chem Res (2011) 20:1273–1279
Tail suspension test (TST)
C11H13N1O3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.92;
H, 6.41; N, 6.58.
On testing day, totally 102 male KunMing (20–22 g) mice
were randomly chosen and divided into 17 groups (n = 6
for each group): control group, groups of various of com-
pounds (1a–1o), and positive control group (Fluoxetine),
used in the tail suspension test (Steru et al., 1985). The
synthesized compounds and the standard drug Fluoxetine
were given as an intraperitoneal injection to mice. Control
animals received 3% aqueous solution of Tween 80. Thirty
minutes later, the total duration of immobility induced by
tail suspension was measured according to the method
described previously. Mice were both acoustically and
visually isolated and suspended 50 cm above the floor by
adhesive tape placed approximately 1 cm from the tip of
the tail. Immobility time was recorded during a 6 min
period. The total duration of immobility was recorded
during the last 4 min of the 6 min test.
(E)-N-(2-hydroxyethyl)-3-(3-hydroxyphenyl)acrylamide
(1n)
Yield: 45.5%; mp 70–72°C. 1H-NMR (DMSO-d6,
300 MHz): d 3.32 (q, 2H, J = 5.4 Hz, –CH2), 3.55 (t, 2H,
J = 5.7 Hz, –CH2), 4.69 (s, 1H, –OH), 6.60 (d, 1H,
J = 15.6 Hz, CH=C), 6.77 (d, 1H, J = 7.7 Hz, Ar–H),
6.92 (s, 1H, Ar–H), 7.08 (d, 1H, J = 10.6 Hz, Ar–H), 7.16
(t, 1H, J = 8.0 Hz, Ar–H), 7.35 (d, 1H, J = 15.6 Hz,
CH=C), 8.10 (s, 1H, –NHCO), 9.38 (s, 1H, Ar–OH). IR
(KBr) cm-1: 3379 (OH), 3242 (NH), 1662 (C=O). MS (m/
z): 208 (M ? 1). Anal. Calcd. for C11H13N1O3: C, 63.76;
H, 6.32; N, 6.76. Found: C, 63.97; H, 6.43; N, 6.57.
(E)-N-(2-hydroxyethyl)-3-(4-hydroxyphenyl)acrylamide
(1o)
Statistical analysis
Yield: 53.1%; mp 138*140°C. 1H-NMR (DMSO-d6,
300 MHz): d 2.51 (s, 1H, –OH), 3.22 (t, 2H, J = 5.7 Hz,
–CH2), 3.42 (q, 2H, J = 5.9 Hz, –CH2), 6.43 (d, 1H,
J = 15.7 Hz, CH=C), 6.78 (d, 2H, J = 8.2 Hz, Ar–H),
7.30 (d, 1H, J = 15.7 Hz, CH=C), 7.38 (d, 2H,
J = 8.2 Hz, Ar–H), 8.00 (s, 1H, –NHCO) 8.97 (s, 1H,
Ar–OH). IR (KBr) cm-1: 3379 (OH), 3219 (NH), 1632
(C=O). MS (m/z): 208 (M ? 1). Anal. Calcd. for
C11H13N1O3: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.92; H, 6.39; N, 6.67.
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 statistical significance.
Acknowledgment This work was supported by the National Natural
Science Foundation of China (No. 30860340).
Pharmacology
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