Synthesis and study of the antidepressant activity of novel 4,5-dihydro-7-Alkoxy(phenoxy)-tetrazolo[1,5-A]quinoline derivatives

Article abstract of DOI:10.1007/s00044-011-9922-8

In this study, a novel series of 4,5-dihydro-7-Alkoxy(phenoxy)-tetrazolo[1, 5-A]quinoline derivatives was synthesized as potential antidepressant agents. Their antidepressant activities were evaluated by the forced swimming test and tail suspension test m

Full text of DOI:10.1007/s00044-011-9922-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3692–3698
DOI 10.1007/s00044-011-9922-8
ORIGINAL RESEARCH
Synthesis and study of the antidepressant activity of novel
4,5-dihydro-7-alkoxy(phenoxy)-tetrazolo[1,5-a]quinoline
derivatives
•
Xian-Yu Sun Xian-Jing He Chun-Yuan Pan
•
•
•
Yan-Peng Liu Yun-Peng Zou
Received: 12 August 2011 / Accepted: 17 November 2011 / Published online: 1 December 2011
Ó Springer Science+Business Media, LLC 2011
Abstract In this study, a novel series of 4,5-dihydro-7-
alkoxy(phenoxy)-tetrazolo[1,5-a]quinoline derivatives was
synthesized as potential antidepressant agents. Their anti-
depressant activities were evaluated by the forced swimming
test and tail suspension test models. The pharmacological
results showed that 7-(4-fluorobenzyloxy)-4,5-dihydrotet-
razolo[1,5-a]quinoline 7j was found possessing strong
activity in the both tests, especially in the FTS model, which
was considered as the most promising compounds in this
study.
with the currently available antidepressants showed full
remission, with a large number showing residual and
relapsing symptoms and generally poor outcomes in a high
number of cases (Rush and Star, 2007; Trivedi and Daly,
2008). Therefore, the discovery of new antidepressant drugs
with lesser side effects and better efficacy is essential.
In the process of finding effective compounds with out-
standing antidepressant activity, a series of 4,5-dihydro-7-
alkoxy(phenoxy)-tetrazolo[1,5-a]quinoline derivatives was
designed and synthesized. Quinoline derivatives were
reported to display variable pharmacological activity, such
as antimicrobial (Kaur et al., 2010), anticonvulsant (Guan
et al., 2008; Schove et al., 1994), antimalarial (N’Da et al.,
2010), anti-inflammatory (El-Gazzar et al., 2009), etc. In an
attempt to discover novel antidepressant compounds with
better activity, we introduced a tetrazole ring at the first and
second positions of the quinoline ring and designed a novel
series of tetrazolo[1,5-a]quinoline derivatives. Their anti-
depressant activities were evaluated by the force swimming
test (FTS) and tail suspension test (TST), two well-estab-
lished animal models that have been extensively used as
screening models for new antidepressant agents (Porsolt
et al., 1977; Steru et al., 1985). 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 as it is low cost, fast, and reliable (Deng et al., 2010).
Keywords Tetrazole Á Quinoline Á
Forced swimming test Á Tail suspension test
Introduction
Depression is a common mental disorder; however, the
current definition, and thus, the diagnosis essentially rely on
the presence of a depressed mood. Counter to this, depression
represents a multidimensional condition, which involves,
among other factors, psychomotor symptoms, sleep distur-
bances, somatic pain symptoms, anxiety, diurnal variation,
and seasonal patterns (Gaspar-Barba et al., 2009). In par-
ticular, depression is a common condition in older people,
affecting around 10–15% of those living in the community
(McDougall et al., 2007; Beekman et al., 1999). In primary
care, depression is largely treated with antidepressant drugs,
which are also the most commonly prescribed drug groups in
primary care. However, less than 50% of all patients treated
Results and discussion
Synthesis
X.-Y. Sun (&) Á X.-J. He Á C.-Y. Pan Á Y.-P. Liu Á Y.-P. Zou
College of Animal Science and Technique, Heilongjiang Bayi
Agriculture University, Daqing 163319, Heilongjiang, China
e-mail: sxianyu@163.com
Target compounds 7a–7s were synthesised according to
Scheme 1. Compounds 2–4 were prepared using previously
reported methods (Sun et al., 2008). The starting material
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Med Chem Res (2012) 21:3692–3698
3693
6-hydroxy-3,4-dihydro-1H-quinolin-2-one was reacted
with benzyl chloride prepared in ethanol in the presence of
sodium hydroxide; this reaction yielded 6-alkoxy-3,4-di-
hydroquinolin-2(1H)-one [compound 2]. 6-Benzyloxy-3,4-
dihydroquinolin-2(1H)-thione [compound 3] was prepared
by the reaction between compound 2 and phosphorous
pentasulphide in a mixture of acetonitrile and triethyl-
amine. The starting material had no benzyl protection, and
therefore, directly reacted with phosphorous pentasulphide
to generate a poor yield of sulphide product. Compound 3
was reacted further with hydrazine hydrate in tetrahydro-
furan to produce 6-benzyloxy-3,4-dihydro-2-hydrazine-
1H-quinoline [compound 4], which was maintained at
\0°C until use in the next step.
synthesised compounds and the standard drug fluoxetine
were dissolved in a 3% aqueous solution of Tween 80 and
administered via the per-oral (p.o.) route to the mice at a
dose of 40 mg/kg. We chose 40 mg/kg because we found
that fluoxetine reduced the duration of immobility in a
dose-dependent manner, and because it has a moderate
antidepressant activity at this concentration (Villard et al.,
2011).
As depicted in Fig. 1, most of the compounds showed
remarkable antidepressant activity. Acute treatment with the
compounds 5, 7c–7e, and 7h–7q promoted a significant
decrease in the immobility time in the FST. Using a dose of
40 mg/kg, we found that the immobility time measured by the
FST ranged from 65.17 11.69 s to 163.50 8.07 s, com-
pared with the control value of 177.67 10.88 s. The
immobility time of the mice treated with the other compounds
(7a, 7b, 7f, 7g, 7r, and 7s) did not statistically differ from the
control value (control, 177.67 10.88 s; 7a, 179.83
11.74 s; 7b, 181.50 15.50 s; 7f, 170.50 10.89 s;
7g, 172.83 12.35 s; 7r, 178.00 8.67 s; and 7s,
176.00 10.79 s).
Compound 5 was prepared via the diazotisation of com-
pound 4 with sodium nitrite in 30% H2SO4 at a temperature
´
below 2°C (Hernandez et al., 2007). In this process, different
concentrations of hydrochloric acid were employed as the
solvent, but all of them generated poor product yields. Com-
pound5 washydrogenatedunderH2 atmosphere usingPd/Cas
a catalyst to give 7-hydroxyl-4,5-dihydrotetrazolo[1,5-
a]quinoline [compound 6]. Finally, the scaffold reacted with
variable amounts of alkyl halide prepared in dimethylform-
amide (DMF) to afford the compound 4,5-dihydro-7-alk-
oxy(phenoxy)-tetrazolo[1,5-a]quinoline (7a–7r). In the
process of preparing compounds 7a–7g, alkyl bromides were
used in the reaction, while different substituted benzyl chlo-
rides were used for preparing compounds 7h–7r.
All the compounds synthesised were characterised by 1H
NMR, mass spectrometry (MS), and elemental analysis
techniques. We report in the experimental section, the
details (synthetic procedure and characterisation) about
the final step of production of all compounds evaluated in
the FST and TST.
The results of pharmacological analysis and the structural
features of the compounds tested enabled generalisation of
the structure activity relationships (SARs). Subsequently,
two sets of substituents containing aliphatic and aromatic
derivatives were chosen and prepared. Among the aliphatic
derivatives 7a–7g, the results of pharmacological analysis
revealed that the length of the alkyl chain had a direct impact
on the antidepressant activity of the 4,5-dihydro-7-alkoxy-
tetrazolo[1,5-a]quinoline derivatives. As alkyl chain length
increased, the immobility time decreased, with compound 7e
(with the n-hexyl substituted group) being the most active
compound. On the other hand, compounds 7a, 7b, 7f, and 7g
showing substitution of the ethoxy, propoxy, heptyloxy, and
octyloxy groups, respectively, were all inactive. The pentoxy
and hexyloxy derivatives, namely, 7d and 7e, exhibited
outstanding antidepressant activity with FST immobility
times of 135.67 12.13 and 133.50 10.45 s, respec-
tively. To penetrate the blood–brain barrier, a molecule must
Pharmacological evaluations
Compounds prepared were screened for their antidepres-
sant activities in mice by using the FST and TST. All the
O
HO
O
Bn
Bn
a
c
b
N
H
S
N
O
N
H
O
H
1
2
3
O
O
RO
HO
Bn
Bn
d
e
f
N
N
N
N
N
N
N
N
N
N
N
N
H
NH2
N
N
4
5
6
7a-7s
Scheme 1 Synthesis of compounds 7a–7s. a BnCl, NaOH/C2H5OH, refluxing. b P2S5/CH3CN, TEA, refluxing. c N2H4ÁH2O/THF, 60°C.
d NaNO2/30% H2SO4, \2°C. e Pd/C, EtOH, 60°C. f RX, NaOH/DMF
123

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Med Chem Res (2012) 21:3692–3698
Fig. 1 Effects of the acute
treatment with the compounds
(5, 7a–7s, 40 mg/kg p.o) and the
antidepressant fluoxetine (FLU,
40 mg/kg p.o.) on the
immobility time in the FST.
Each column represents the
mean standard error.
*P \ 0.05, **P \ 0.01, and
***P \ 0.001 as compared to
the control (all comparisons
were analysed with Student’s
t test)
250
200
150
100
50
*
**
**
** ***
**
***
***
***
**
***
***
***
***
***
0
escape the polar environment of plasma water and plasma
proteins, and enter the non-polar environment. These results
demonstrate that compounds 7d and 7e possess better lipid-
water partition coefficients compared with the other aliphatic
derivatives.
the p-CH3 derivative 7q showed weak antidepressant
activity, while the p-OCH3 derivative 7r and the p-NH2
derivative 7s were both inactive.
As shown in Fig. 2, most of the compounds tested
exhibited antidepressant activity in the TST. Acute treat-
ment with the compounds 5, 7c–7f, and 7h–7q at a dose
of 40 mg/kg significantly decreased the immobility time
in the TST, with the immobility time ranging from
20.00 5.14 to 100.83 18.41 s, compared with the
control value of 110.67 11.52 s. The immobility time of
the mice treated with the other compounds 7a, 7b, 7g, 7r,
and 7s did not statistically differ from the control value
(control, 110.67 11.52 s; 7a, 108.17 17.80 s; 7b, 93.00
17.31 s; 7g, 107.50 13.90 s; 7r, 98.50 8.24 s; and 7s,
93.33 10.39 s).
Analysis of the activities of these aromatic derivatives
demonstrated that the benzyl derivative, i.e. compound 5,
exhibited activity similar to that of the antidepressant drug
fluoxetine (immobility times: fluoxetine, 93.17 8.33;
compound 5, 95.17 11.51 s). As shown in Fig. 1, com-
pared with derivative 5, halogen derivatives 7h–7m pos-
sess stronger or similar activity. In addition, the smaller
halogens F and Cl exhibited slightly better overall protec-
tion compared with the larger halogen Br derivatives. The
position of the halogen atom on the phenyl ring greatly
influenced the antidepressant activity; the activity order
was p [ 0 [ m. The p-F derivative 7j exhibited the
strongest antidepressant activity of all the derivatives, with
an immobility time of 65.17 11.69 s; the activity was
slightly faster than that of the positive drug fluoxetine.
Nonetheless, of the three electric-donor derivatives 7q–7s,
It is obvious that the SAR derived from the TST is
similar to that obtained from the former test; however, no
derivative exhibited activity stronger than that of fluoxe-
tine. In the aliphatic set, derivatives 7c–7f exhibited anti-
depressant potency, whereas derivatives 7c–7e did not
demonstrate a significant difference (compared with 7c; 7d,
Fig. 2 Effects of the acute
treatment with the compounds
(5, 7a–7s, 40 mg/kg p.o.) and
the antidepressant fluoxetine
(FLU, 40 mg/kg p.o.) on the
immobility time in the TST.
Each column represents the
mean standard error.
*P \ 0.05, **P \ 0.01, and
***P \ 0.001 as compared to
the control (all comparisons
were analyzed with Student’s
t test)
140
120
100
80
*
**
**
**
**
**
***
***
***
***
60
***
***
***
40
***
***
**
20
0
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Med Chem Res (2012) 21:3692–3698
3695
P = 0.362; 7e, P = 0.086). In the set of aromatic deriva-
tives, the p-Cl derivative 7m exhibited the strongest
activity with an immobility time of 20.00 5.14 s, which
was slightly higher than that of fluoxetine (P = 0.013).
The compounds 7r and 7s were inactive in both tests,
which indicates that electron-donor groups in the aromatic
ring reduce the antidepressant activity of the 4,5-dihydro-7-
benzyloxy-tetrazolo[1,5-a]quinoline derivatives.
nitrogen. After cooling, the light yellow precipitate was
collected through filtration and dried in a vacuum to pro-
duce the crude products 3.
6-Benzyloxy-3,4-dihydro-2-hydrazine-1H-quinoline (4)
A solution of compounds 3 (25 mmol) in THF (60 ml) was
added dropwise to a solution of hydrazine hydrate
(100 mmol) in THF (40 ml) at room temperature, then the
mixture was stirred and heated at 60°C for 1 h. After the
reaction, half of the solvent was evaporated under reduced
pressure, and then poured the solution to petroleum ether;
the yellow precipitate was filtered and kept at 0°C for the
next step.
In conclusion, we prepared and characterised 20 novel
compounds, which were evaluated for their antidepressant
activity by using the FST and TST. We determined the p-F
derivative 7j was highly active in both tests, particularly in
the FST. Furthermore, our finding that tetrazole is a valu-
able moiety for the design of active antidepressant thera-
pies requires further research. In addition, it will be
beneficial to identify structural modifications to the quin-
oline ring or phenoxy side chain to improve these
compounds.
7-Benzyloxy-4,5-dihydrotetrazolo[1,5-a]quinoline (5)
To a solution of compound 4 (10 mmol) in H2SO4 (30%,
50 ml) was added a solution of NaNO2 (12 mmol) in H2O
(15 ml) under ice-bath, and made the reaction temperature
below 2°C. The reaction mixture was stirred for 1 h at
room temperature, and then extracted with CH2Cl2
(3 9 50 ml). The organic layers were collected and dried
with anhydrous MgSO4. After the solvent was removed
under reduced pressure, the solid residue was purified by
silica gel chromatography with ethyl acetate: petroleum
ether (1:2) to give a light yellow solid with yield of
33.10%.
M.p. 177–179°C. 1H NMR (CDCl3, 300 MHz), d
3.09–3.36 (m, 4H, H-4, H-5), 5.12 (s, 2H, –OCH2–),
6.98–7.04 (m, 2H, H-6, H-8), 7.36–7.44 (m, 5H, Ar–H),
7.91–7.93 (m, 1H, H-9). MS m/z 279 (M ? 1). Anal.
Calcd. for C16H14N4O: C, 69.05; H, 5.07; N, 20.13. Found:
C 69.11, H 4.97, N 20.02.
Experimental
Chemistry
Melting points were determined in open capillary tubes and
1
were uncorrected. H NMR spectra were measured on an
AV-300 (Bruker, Fallanden, Switzerland), and all chemical
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).
6-Benzyloxy-3,4-dihydroquinolin-2(1H)-one (2)
7-Hydroxyl-4,5-dihydrotetrazolo[1,5-a]quinolin (6)
Benzyl chloride (0.11 mol) was added to a solution of the
starting compound 6-hydroxy-3,4-dihydro-1H-quinolin-2-
one 1 (0.1 mol) and sodium hydroxide (0.11 mol) in eth-
anol (100 ml), the reaction mixture was stirred for 3 h
under refluxing. The reaction mixture was cooled and then
poured into ice water. The white precipitate was collected
through filtration and dried in a vacuum to produce the
crude products 2 with a yield of 81%.
The solution of compound 5 (3.60 mmol) and Pd/C (10%,
55% H2O, 0.5 g) in ethanol (30 ml) was hydrogenated
under H2 atmosphere (45 psi) at 60°C for 2 h. The mixture
was filtered and the solvent was evaporated in the vacuum
to give a light yellow solid.
General procedure for the synthesis of 4,5-dihydro-7-
alkoxy(phenoxy)-tetrazolo[1,5-a]quinoline (7a–7r)
6-Benzyloxy-3,4-dihydroquinoline-2(1H)-thione (3)
Appropriate alkyl halide (2.2 mmol) was added to a solu-
tion of the compound 6 (2.0 mmol) and NaOH (2.0 mmol)
in DMF (40 ml), the mixture was heated to 80°C with
stirring. The reaction end was monitored by the TLC; then
the solvent was removed in a vacuum and the crude
product was purified by silica gel chromatography with
ethyl acetate: petroleum ether (1:2) to give a light yellow
To a stirring mixture of acetonitrile (90 ml) and triethyl-
amine (30 ml) in a three-necked round-bottomed flask in
an ice-bath, P2S5 (40 mmol) divided into multiple portions,
was added one portion at a time after the previous portion
had completely dissolved. Then, compounds 2 (40 mmol)
was added and the solution was refluxed for 3 h under
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Med Chem Res (2012) 21:3692–3698
4,5-Dihydro-7-heptyloxy-tetrazolo[1,5-a]quinoline (7f)
solid with a moderate yield. The yield, melting point and
spectral data of each compound is given below.
M.p. 104–106°C, yield = 85.5. 1H NMR (CDCl3,
300 MHz) d 0.86–1.84 (m, 13H, –(CH2)5CH3), 2.97–3.20
(m, 2H, H-4, H-5), 3.99 (t, 2H, J = 6.5Hz, –OCH2–),
6.86–3.94 (m, 2H, H-6, H-8), 7.84–7.87 (m, 1H, H-9). MS
m/z 287 (M ? 1). Anal. Calcd. for C16H22N4O: C, 67.11;
H, 7.74; N, 19.56. Found: C 67.17, H 7.68, N 19.49.
4,5-Dihydro-7-ethoxy-tetrazolo[1,5-a]quinoline (7a)
M.p. 175–177°C, yield = 89.3%. 1H NMR (CDCl3,
300 MHz) d 1.45 (t, 3H, J = 7.0 Hz, –CH3), 3.02–3.27 (m,
4H, H-4, H-5), 4.05–4.10 (q, 2H, J = 7.0 Hz, –OCH2–),
6.82–6.88 (m, 2H, H-6, H-8), 7.87–7.89 (m, 1H, H-9). MS
m/z 217 (M ? 1). Anal. Calcd. for C11H12N4O: C, 61.10;
H, 5.59; N, 25.91. Found: C 61.18, H 5.52, N 25.84.
4,5-Dihydro-7-octyloxy-tetrazolo[1,5-a]quinoline (7g)
M.p. 73–75°C, yield = 89.7%. 1H NMR (CDCl3,
300 MHz) d 0.86–1.79 (m, 15H, –(CH2)6CH3), 2.97–3.20
(m, 2H, H-5, H-6), 3.94 (t, 2H, J = 6.5 Hz, –OCH2–),
6.87–3.94 (m, 2H, H-6, H-8), 7.87–7.90 (m, 1H, H-9). MS
m/z 301 (M ? 1). Anal. Calcd. for C17H24N4O: C, 67.97;
H, 8.05; N, 18.65. Found: C 68.06, H 7.99, N 18.60.
4,5-Dihydro-7-propoxy-tetrazolo[1,5-a]quinoline (7b)
M.p. 133–135°C, yield = 87.4%. 1H NMR (CDCl3,
300 MHz) d 1.05 (t, 3H, J = 7.0 Hz, –CH3), 1.76-1.85 (m,
2H, –CH2–), 3.02–3.21 (m, 4H, H-4, H-5), 3.97 (t, 2H,
J = 6.5 Hz, –OCH2–), 6.85–6.91 (m, 2H, H-6, H-8),
7.85–7.87 (m, 1H, H-9). MS m/z 231 (M ? 1). Anal.
Calcd. for C12H14N4O: C 62.59; H, 6.13; N, 24.33. Found:
C 62.65, H 6.03, N 24.29.
7-(2-Fluorobenzyloxy)-4,5-dihydrotetrazolo[1,5-a]
quinoline (7h)
M.p. 187–189°C, yield = 87.5%. 1H NMR (CDCl3,
300 MHz) d 3.02–3.24 (m, 4H, H-4, H-5), 5.17 (s, 2H,
–OCH2–), 6.95–7.01 (m, 2H, H-6, H-8), 7.33–7.44 (m, 4H,
Ar–H), 7.89–7.91 (m, 1H, H-9). MS m/z 297 (M ? 1).
Anal. Calcd. for C16H13FN4O: C, 64.86; H, 4.42; N, 18.91.
Found: C 64.91, H 4.38, N 18.86.
4,5-Dihydro-7-butoxy-tetrazolo[1,5-a]quinoline (7c)
M.p. 110–112°C, yield = 91.8%. 1H NMR (CDCl3,
300 MHz) d 0.96 (t, 3H, J = 7.4 Hz, –CH3), 1.42–1.81 (m,
4H, –CH2–CH2–), 3.01–3.24 (m, 4H, H-4, H-5), 4.03 (t,
2H, J = 9.5 Hz, –OCH2–), 6.83–6.88 (m, 2H, H-6, H-8),
7.78–7.81 (m, 1H, H-9). MS m/z 245 (M ? 1). Anal.
Calcd. for C13H16N4O: 63.91; H, 6.60; N, 22.93. Found: C
63.98, H 6.52, N 22.88.
7-(3-Fluorobenzyloxy)-4,5-dihydrotetrazolo[1,5-a]
quinoline (7i)
M.p. 131–133°C, yield = 85.2%. 1H NMR (CDCl3,
300 MHz) d 3.01–3.23 (m, 4H, H-4, H-5), 5.11 (s, 2H,
–OCH2–), 6.97–7.01 (m, 2H, H-6, H-8), 7.37–7.47 (m, 4H,
Ar–H), 7.91–7.93 (m, 1H, H-9). MS m/z 297 (M ? 1).
Anal. Calcd. for C16H13FN4O: C, 64.86; H, 4.42; N, 18.91.
Found: C 64.92, H 4.38, N 18.87.
4,5-Dihydro-7-pentoxy-tetrazolo[1,5-a]quinoline (7d)
M.p. 125–127°C, yield = 84.5%. 1H NMR (CDCl3,
300 MHz) d 0.93 (t, 3H, J = 7.1 Hz, –CH3), 1.32–1.80 (m,
6H, –(CH2)3–), 2.97–3.18 (m, 4H, H-4, H-5), 4.00 (t, 2H,
J = 6.5 Hz, –OCH2–), 6.85–6.92 (m, 2H, H-6, H-8),
7.80–7.82 (m, 1H, H-9). MS m/z 259 (M ? 1). Anal.
Calcd. for C14H18N4O: C, 65.09; H, 7.02; N, 21.69. Found:
C 65.15, H 6.97, N 21.64.
7-(4-Fluorobenzyloxy)-4,5-dihydrotetrazolo[1,5-a]
quinoline (7j)
M.p. 136–138°C, yield = 81.9%. 1H NMR (CDCl3,
300 MHz), d 3.01–3.23 (m, 4H, H-4, H-5), 5.06 (s, 2H,
–OCH2–), 6.89–6.95 (m, 2H, H-6, H-8), 7.42–7.52 (m, 4H,
Ar–H), 7.93–7.95 (m, 1H, H-9). MS m/z 297 (M ? 1).
Anal. Calcd. for C16H13FN4O: C, 64.86; H, 4.42; N, 18.91.
Found: C 64.93, H 4.39, N 18.87.
4,5-Dihydro-7-hexyloxy-tetrazolo[1,5-a]quinoline (7e)
M.p. 108–110°C, yield = 83.2%. 1H NMR (CDCl3,
300 MHz) d 0.90 (t, 3H, J = 7.0 Hz, –CH3), 1.33–1.81 (m,
8H, –(CH2)4–), 2.98–3.22 (m, 2H, H-4, H-5), 3.95 (t, 2H,
J = 6.5 Hz, –OCH2–), 6.83–6.90 (m, 2H, H-6, H-8),
7.81–7.84 (m, 1H, H-9). MS m/z 273 (M ? 1). Anal.
Calcd. for C15H20N4O: C, 66.15; H, 7.40; N, 20.57. Found:
C 66.19, H 7.35, N 20.51.
7-(2-Chlorobenzyloxy)-4,5-dihydrotetrazolo[1,5-a]
quinoline (7k)
M.p. 195–197°C, yield = 86.8%. 1H NMR (CDCl3,
300 MHz) d 3.03–3.25 (m, 4H, H-4, H-5), 5.20 (s, 2H,
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–OCH2–), 6.78–6.84 (m, 2H, H-6, H-8), 7.38–7.49 (m, 4H,
Ar–H), 7.90–7.92 (m, 1H, H-9). MS m/z 313 (M ? 1), 315
(M?3). Anal. Calcd. for C16H13ClN4O: C, 61.44; H, 4.19;
N, 17.91. Found: C 61.50, H 4.14, N 17.86.
C17H16N4O: C, 69.85; H, 5.52; N, 19.17. Found: C 69.93,
H 5.45, N 139.13.
7-(4-Methoxybenzyloxy)-4,5-dihydrotetrazolo[1,5-a]
quinoline (7q)
7-(3-Chlorobenzyloxy)-4,5-dihydrotetrazolo[1,5-a]
quinoline (7l)
M.p. 163–165°C, yield = 87.6%. 1H NMR (CDCl3,
300 MHz) d 3.02–3.25 (m, 4H, H-4, H-5), 3.87 (s, 3H,
–OCH3), 5.08 (s, 2H, –OCH2–), 6.94–7.01 (m, 2H, H-6,
H-8), 7.44–7.55 (m, 4H, Ar–H), 7.79–7.81 (m, 1H, H-9).
MS m/z 309 (M ? 1). Anal. Calcd. for C17H16N4O2: C,
66.22; H, 5.23; N, 18.17. Found: C 66.30, H 5.18, N 18.14.
M.p. 124–126°C, yield = 82.0%. 1H NMR (CDCl3,
300 MHz) d 3.01–3.24 (m, 4H, H-4, H-5), 5.08 (s, 2H,
–OCH2–), 6.82–6.88 (m, 2H, H-6, H-8), 7.41–7.50 (m, 4H,
Ar–H), 7.95–7.97 (m, 1H, H-9). MS m/z 313 (M ? 1), 315
(M ? 3). Anal. Calcd. for C16H13ClN4O: C, 61.44; H,
4.19; N, 17.91. Found: C 61.50, H 4.14, N 17.87.
7-(4-Aminobenzyloxy)-4,5-dihydrotetrazolo[1,5-a]
quinoline (7r)
7-(4-Chlorobenzyloxy)-4,5-dihydrotetrazolo[1,5-a]
quinoline (7m)
M.p. 197–199°C, yield = 78.4%. 1H NMR (CDCl3,
300 MHz) d 3.04–3.27 (m, 4H, H-4, H-5), 4.26 (s, 2H,
–NH2), 5.17 (s, 2H, –OCH2–), 6.87–6.96 (m, 2H, H-6,
H-8), 7.34–7.57 (m, 4H, Ar–H), 7.82–7.84 (m, 1H, H-9).
MS m/z 294 (M ? 1). Anal. Calcd. for C16H15N5O: C,
65.52; H, 5.15; N, 23.88. Found: C 65.59, H 5.10, N 23.82.
M.p. 189–191°C, yield = 85.6%. 1H NMR (CDCl3,
300 MHz) d 3.01–3.25 (m, 4H, H-4, H-5), 5.07 (s, 2H,
–OCH2–), 6.92–6.97 (m, 2H, H-6, H-8), 7.43–7.52 (m, 4H,
Ar–H), 7.88–7.90 (m, 1H, H-9). MS m/z 313 (M ? 1), 315
(M ? 3). Anal. Calcd. for C16H13ClN4O: C, 61.44; H,
4.19; N, 17.91. Found: C 61.51, H 4.14, N 17.89.
Pharmacology
7-(2-Brominebenzyloxy)-4,5-dihydrotetrazolo[1,5-a]
quinoline (7n)
Forced swimming test (FST) (Porsolt et al., 1977)
In the FST, 132 male KunMing mice (20–22 g) were
randomly chosen and divided into 22 groups (six in each
group): control group, experimental groups (compounds 5,
7a–7s), and positive control group (fluoxetine), on the day
of testing. All the synthesised compounds and the standard
drug fluoxetine were dissolved in a 3% aqueous solution of
Tween 80 and administered p.o. to the mice at a dose of
40 mg/kg. Control animals received only the 3% aqueous
solution of Tween 80 p.o. Thirty minutes later, the mice
were dropped, one at a time, into a plexiglas cylinder
(height, 25 cm; diameter, 10 cm; filled with water to a
height of 10 cm; temperature, 24–26°C) and left for 6 min.
After the first 2 min of 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 to prevent sinking. The total duration of
immobility was recorded during the last 4 min of the 6-min
test.
M.p. 168–170°C, yield = 89.7%. 1H NMR (CDCl3,
300 MHz) d 3.02–3.24 (m, 4H, H-4, H-5), 5.17 (s, 2H,
–OCH2–), 6.95–7.01 (m, 2H, H-6, H-8), 7.48–7.57 (m, 4H,
Ar–H), 7.79–7.81 (m, 1H, H-9). MS m/z 357 (M ? 1), 359
(M ? 3). Anal. Calcd. for C16H13BrN4O: C, 53.80; H,
3.67; N, 15.68. Found: C 53.86, H 3.62, N 15.62.
7-(3-Brominebenzyloxy)-4,5-dihydrotetrazolo[1,5-a]
quinoline (7o)
M.p. 205–207°C, yield = 81.1%. 1H NMR (CDCl3,
300 MHz) d 3.01–3.24 (m, 4H, H-4, H-5), 5.05 (s, 2H,
–OCH2–), 6.88–6.90 (m, 2H, H-6, H-8), 7.43–7.51 (m, 4H,
Ar–H), 7.82–7.84 (m, 1H, H-9). MS m/z 357 (M ? 1), 359
(M ? 3). Anal. Calcd. for C16H13BrN4O: C, 53.80; H,
3.67; N, 15.68. Found: C 53.87, H 3.63, N 15.61.
7-(4-Methylbenzyloxy)-4,5-dihydrotetrazolo[1,5-a]
quinoline (7p)
Tail suspension test (TST) (Steru et al., 1985)
M.p. 143–145°C, yield = 79.4. 1H NMR (CDCl3,
300 MHz) d 2.38 (s, 3H, –CH3), 2.89–3.23 (m, 4H, H-4,
H-5), 3.85 (s, 3H, –CH3), 5.30 (s, 2H, –OCH2–), 6.92–6.98
(m, 2H, H-6, H-8), 7.38–7.52 (m, 4H, Ar–H), 7.89–7.91
(m, 1H, H-9). MS m/z 293 (M ? 1). Anal. Calcd. for
On the day of testing, 132 male KunMing mice (20–22 g)
were randomly chosen and divided into 22 groups (six in
each group): control group, experimental groups (com-
pounds 5, 7a–7s), and positive control group (Fluoxetine).
All the synthesised compounds and the standard drug
123

3698
Med Chem Res (2012) 21:3692–3698
symptomatology is influenced by chronotypes. J Affect Disord
119:100–106
Guan LP, Jin QH, Wang SF, Li FN, Quan ZS (2008) Synthesis and
anticonvulsant activity of 5-phenyl-[1,2,4]-triazolo[4,3-a]quino-
lines. Arch Pharm (Weinheim) 341:774–779
fluoxetine were dissolved in a 3% aqueous solution of
Tween 80 and administered p.o. to the mice at the dose of
40 mg/kg. Control animals received only the 3% aqueous
solution of Tween 80 p.o. Thirty minutes later, the total
duration of immobility induced by tail suspension was
measured, according to a previously described method.
Mice were both acoustically and visually isolated and
suspended 50 cm above the floor by using an 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.
´
Hernandez AS, Cheng PT, Musial CM, Swartz SG, George RJ,
Grover G, Slusarchyk D, Seethala RK (2007) Discovery,
synthesis, and structure-activity studies of tetrazole based growth
hormone secretagogues. Bioorg Med Chem Lett 17:5928–5933
Kaur K, Jain M, Khan SI, Jacob MR, Tekwani BL, Singh S, Singh PP,
Jain R (2010) Synthesis, antiprotozoal, antimicrobial, b-hematin
inhibition, cytotoxicity and methemoglobin (MetHb) formation
activities of bis(8-aminoquinolines). Bioorg Med Chem 19:
197–210
McDougall FA, Matthews FE, Kvaal K, Dewey ME, Brayne C (2007)
Prevalence and symptomatology of depression in older people
living in institutions in England and Wales. Age Ageing 36:
562–568
N’Da DD, Breytenbach JC, Smith PJ, Lategan C (2010) Synthesis,
cytotoxicity and antimalarial activity of ferrocenyl amides of
4-aminoquinolines. Arzneimittelforschung 60:627–635
Porsolt RD, Bertin A, Jalfre M (1977) Behavioural despair in mice: a
primary screening test for antidepressants. Arch Int Pharmaco-
dyn Ther 229:327–336
Statistical analysis
Results are expressed as mean SEM; n represents the
number of animals. Data obtained from pharmacological
experiments were analyzed with Student’s t test. P value of
less than 0.05 was considered statistical significance.
Rush AJ, Star D (2007) What have we learned? Am J Psychiatry
164:201–204
Schove LT, Perez JJ, Maguire PA, Loew GH (1994) Comparison of a
new class of pyrrole containing benzodiazepine ligands to the
pyrazoloquinolinones CGS 9896, 9895, and 8216. Med Chem
Res 4:307–314
Acknowledgments This study was supported by the Doctor
Research Start Foundation of Heilongjiang Bayi Agriculture Uni-
versity and the Project of Animal Good farming Innovation Team
(SCX2011-10) of Heilongjiang Higher Education Committee.
Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension
test: a new method for screening antidepressants in mice.
Psychopharmacology 85:367–370
Sun XY, Zhang L, Wei CX, Piao HR, Quan ZS (2008) Design,
synthesis of 8-alkoxy-5,6-dihydro-[1,2,4]triazino[4,3-a]quinolin-
1-ones with anticonvulsant activity. Eur J Med Chem 44:
1265–1270
Trivedi MH, Daly EJ (2008) Treatment strategies to improve and
sustain remission in major depressive disorder. Dialog Clin
Neurosci 10:377–384
Villard V, Meunier J, Chevallier N, Maurice T (2011) Pharmacolog-
ical Interaction With the Sigma 1 (r1)-receptor in the acute
behavioral effects of antidepressants. J Pharmacol Sci 115:
279–292
References
Beekman AT, Copeland JR, Prince MJ (1999) Review of community
prevalence of depression in later life. Br J Psychiatry 174:307–311
Deng XQ, Wu D, Wei CX, Quan ZS (2010) Synthesis and
antidepressant-like action of N-(2-hydroxyethyl) cinnamamide
derivatives in mice. Med Chem Res. doi:10.1007/s00044-
010-9470-7
El-Gazzar AB, Youssef MM, Youssef AM, Abu-Hashem AA, Badria
FA (2009) Design and synthesis of azolopyrimidoquinolines,
pyrimidoquinazolines as anti-oxidant, anti-inflammatory and
analgesic activities. Eur J Med Chem 44:609–624
Gaspar-Barba E, Calati R, Cruz-Fuentes CS, Ontiveros-Uribe MP,
Natale V, De Ronchi D, Serretti
A (2009) Depressive
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