Design, synthesis and evaluation of the antidepressant and anticonvulsant activities of triazole-containing quinolinones

Article abstract of DOI:10.1016/j.ejmech.2013.12.014

A series of 1-substituted-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydroquinolin- 2(1H)-ones were designed, synthesized, and screened for their antidepressant and anticonvulsant activities. Interestingly, compounds 5i, 5j, 5m, and 5n led to significant reductions in the immobility time in the forced swimming test at a dose of 50 mg/kg, and exhibited higher levels of efficacy than the reference standard fluoxetine. In addition, compound 5i exhibited greater efficacy than fluoxetine in the tail suspension test. The results of an open field test further confirmed that compound 5i provided a good antidepressant effect. In the maximal electroshock seizure screen, compounds 5c and 5d showed moderate levels of anticonvulsant activity and protected 100% of the animals at a dose of 100 mg/kg. None of the synthesized compounds showed any neurotoxicity in the rotarod test at a dose of 100 mg/kg.

Full text of DOI:10.1016/j.ejmech.2013.12.014

European Journal of Medicinal Chemistry 73 (2014) 217e224
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and evaluation of the antidepressant and
anticonvulsant activities of triazole-containing quinolinones
,
a,
Xian-Qing Deng b, Ming-Xia Song b, Yan Zheng a , Zhe-Shan Quan
**
*
a College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
b Medical College, Jinggangshan University, Ji’an, Jiangxi 343009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1-substituted-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydroquinolin-2(1H)-ones were designed, syn-
thesized, and screened for their antidepressant and anticonvulsant activities. Interestingly, compounds
5i, 5j, 5m, and 5n led to significant reductions in the immobility time in the forced swimming test at a
dose of 50 mg/kg, and exhibited higher levels of efficacy than the reference standard fluoxetine. In
addition, compound 5i exhibited greater efficacy than fluoxetine in the tail suspension test. The results of
an open field test further confirmed that compound 5i provided a good antidepressant effect. In the
maximal electroshock seizure screen, compounds 5c and 5d showed moderate levels of anticonvulsant
activity and protected 100% of the animals at a dose of 100 mg/kg. None of the synthesized compounds
showed any neurotoxicity in the rotarod test at a dose of 100 mg/kg.
Received 12 July 2013
Received in revised form
11 December 2013
Accepted 12 December 2013
Available online 25 December 2013
Keywords:
Antidepressant
Anticonvulsant
Quinolinone
Ó 2013 Published by Elsevier Masson SAS.
Triazole
Forced swimming test
Maximal electroshock seizure
1. Introduction
depressive symptoms of the patients had been reduced by 89%, the
frequency of their seizures had increased by 79%. These results
Depression and epilepsy are two of the most commonly
encountered neurological disorders [1,2], and several reports have
recently appeared in the literature concerning the connection be-
tween these two disorders [3e6]. It is now effectively well recog-
nized that depression is common among people suffering with
epilepsy, and in a community-based study of people with epilepsy,
the rate of depression was found to be 37% [7]. In patients typically
referred to epilepsy centers (representing a group of people with
seizures that are particularly refractory to medication), the rate of
depression was found to be 50 percent (Fig.1) [7]. A large number of
patients with epilepsy require some form of antidepressant medi-
cation, and this has recently led many experts in the field to
question whether the prescribing of antidepressants to this special
group could exacerbate the occurrence of seizures. Ojemann et al.
[8] performed a retrospective study of the use of the tricyclic an-
tidepressant doxepin in epilepsy patients, and found that whilst the
therefore suggested the existence of a negative relationship be-
tween these two effects. In contrast, favale et al. [9] used fluoxetine
(20 mg/day) to treat 17 epilepsy patients with symptoms of
depression, and reported the complete remission of seizures in six
patients. Furthermore, the other patients also experienced a 30%
reduction in the frequency of their seizures. The two antidepres-
sants described in these cases clearly have different effects (i.e.,
positive and negative) on patients with epilepsy. Research on an-
tidepressants for the treatment of depressive symptoms in patients
with epilepsy is currently an area of considerable activity, and the
search for novel and increasingly effective drugs with anticonvul-
sant and antidepressant activities (the same type as fluoxetine)
represent an important and challenging area of medicinal
chemistry.
There is a growing body of evidence in the literature that
suggests that quinolinone derivatives possess a broad range of
biologically interesting properties, including anticonvulsant [10e
12], anti-cancer [13,14], antifungal and anti-inflammatory [15],
antibacterial [16,17], and antidepressant activities [18e20]. Earlier
studies by Oshiro et al. [21] have demonstrated that 3,4-dihydro-
2(1H)-quinolinones (Fig. 2, I) have promising antidepressant ac-
tivities [21]. Several studies in this area have recently confirmed
* Corresponding author. Tel./fax: þ86 433 2436020.
** Corresponding author. Tel./fax: þ86 433 2436004.
E-mail addresses: yzheng@ybu.edu.cn (Y. Zheng), zsquan@ybu.edu.cn
(Z.-S. Quan).
0223-5234/$ e see front matter Ó 2013 Published by Elsevier Masson SAS.
http://dx.doi.org/10.1016/j.ejmech.2013.12.014

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X.-Q. Deng et al. / European Journal of Medicinal Chemistry 73 (2014) 217e224
2. Chemistry
All of the target compounds were synthesized according to the
route depicted in Scheme 1. Compound 3 was synthesized via the
sequential nitration and catalytic hydrogenation of the commer-
cially available 3,4-dihydro-2(1H)-quinolinone according to
methods previously described in the literature [42]. Compound 3
was then treated with dimethoxy-N,N-dimethylmethanamine
(DMF-DMA) and formylhydrazine in acetonitrile to provide com-
pound 4 [43]. The subsequent alkylation of compound 4 with a
variety of different alkylating agents gave the target compounds
(5aes). The chemical structures of these compounds were charac-
terized by IR, 1H and 13C NMR, and mass spectroscopy. The physical
and analytical data are listed in Section 6.
Fig. 1. Epilepsy and depression: estimates of their occurrence.
3. Pharmacology
the antidepressant properties of aripiprazole, which is a 3,4-
dihydro-2(1H)-quinolinone-containing compound (Fig. 2) that
was initially marketed as an antipsychotic agent [22e27]. Triazole
is the core structural motif in a variety of different compounds
in medicinal chemistry and has been reported to exhibit a
broad range of biological properties, including antimicrobial
[28,29], enzyme inhibition [30,31], antinociceptive [32], anti-
inflammatory [33], antidepressant [34,35], and anticonvulsant
activities [36,37]. Our previous work towards the synthesis and
evaluation of a series of triazole-containing compounds showed
that the addition of a triazole ring to other heterocycles effectively
strengthened their anticonvulsant activities (Fig. 2, II and III) [38e
41]. Based on these results, we recently embarked on a program to
combine the antidepressant and anticonvulsant activities of 3,4-
dihydro-2(1H)-quinolinone and triazole through the preparation
of a hybrid molecule composed on the two individual units
(Fig. 2). Herein, we describe our most recent work towards the
design, synthesis, and evaluated of 19 new triazole-containing
quinolinones (5ae5s) for their antidepressant and anticonvul-
sant activities.
All of the compounds synthesized in the current study were
screened for their antidepressant activities using Porsolt’s behav-
ioral despair (forced swimming) test [44]. The anticonvulsant ac-
tivities and neurotoxicities of the compounds were also evaluated.
We followed the protocols issued for the phase I tests by the Epi-
lepsy Branch of the Antiepileptic Drug Development (ADD) pro-
gram at the National Institutes of Health [45,46] with two
exceptions. We used a different strain of mice and seizures were
elicited in mice with ear stimulation. Compound 5i was also eval-
uated using the tail suspension test (TST) [47,48] and the open field
test [49] to further confirm its antidepressant activity.
All of the compounds tested in the pharmacology experiments
were dissolved in dimethylsulfoxide and administrated intraperi-
toneally (i.p.) to KunMing mice (22 ꢀ 2 g). The mice were housed
collectively in polycarbonate cages in groups of ten, where they
were maintained on a 12 h light/dark cycle in a temperature
controlled (25 ꢀ 2 ꢁC) laboratory with free access to food and water.
Each animal was used only once. All efforts were made to minimize
both the suffering of the animals and the number of animals used in
the experiments.
4. Results and discussion
4.1. Antidepressant activities
The antidepressant activities of the compounds were investi-
gated in mice using the forced swimming test (FST). The FST was
designed by Porsolt et al. [44] as a primary screening test for an-
tidepressants and remains one of the best models of depression
because it provides a low-cost, fast and reliable platform for testing
potential antidepressants with a strong predictive validity. This
animal model is therefore still one of the most widely used tools for
the preclinical screening of putative antidepressant agents [50e
53]. In the FST, the mice are forced to swim under inescapable
conditions, and consequently adopt an immobility behavior
Fig. 2. Design of compounds 5ae5s.
Scheme 1. The synthesis route of compounds 5ae5s.

X.-Q. Deng et al. / European Journal of Medicinal Chemistry 73 (2014) 217e224
219
Fig. 4. Effect of treatment of mice with 5i (at dose of 50 mg/kg) and fluoxetine (FXT,
50 mg/kg) given intraperitoneally (i.p.) on the immobility time in the tail suspension
test. Results are represented as mean ꢀ SEM with n ¼ 8 in each group. Values are
significant at *p < 0.05, **p < 0.01, ***p < 0.001 as compared to control (all compar-
isons were made by ANOVA followed by Dunnett’s test).
used as the reference drug, and also caused a significant reduction
in the immobility time with P < 0.01. For a more detailed and
comprehensive understanding of the antidepressant activities of
the test compounds and fluoxetine, their values for the percentage
decrease in the immobility duration (% DID) were calculated using
the following formula:
Fig. 3. Effects of treatment of mice with 5ae5s (50 mg/kg) and fluoxetine (FXT, 50 mg/
kg) given intraperitoneally (i.p.) on the immobility time in the forced swim test (FST).
Results are represented as mean ꢀ SEM with n ¼ 8 in each group. Values are significant
at *p < 0.05, **p < 0.01, ***p < 0.001 as compared to control (all comparisons were
made by ANOVA followed by Dunnett’s test).
following an initial period of agitation/flurry. In this established
behavioral model, the ability of a compound to reduce the duration
of the immobility behavior is taken as a measure of its antide-
pressant activity. The antidepressant activities of compounds 5aes
and the reference drug fluoxetine at a dose of 50 mg/kg (i.p.) are
shown in Fig. 3. The results of the FST revealed that some of the
compounds (including 5b, 5h, 5i, 5j, 5k, 5m and 5n) displayed
potent antidepressant activities. Compounds 5i, 5j, 5m, and 5n in
particular led to significant reductions in the duration of the
immobility time compared with the control group with P < 0.001.
Fluoxetine, which is a selective serotonin reuptake inhibitor, was
%DID ¼ ½ðA ꢂ BÞ=Aꢃ *100
where A is the duration of immobility (s) in the control group and B
is the duration of immobility (s) in the test group.
As shown in Table 1, the majority of the synthesized compounds
reduced the duration of immobility and gave high % DID values,
although statistical significance values were not obtained for these
results. Compounds 5i, 5j, 5m, and 5n exhibited higher % DID
values (in the range of 59.1e72.7) than that of fluoxetine (%
DID ¼ 49.5), and appeared to be provide higher levels of antide-
pressant activity compared with fluoxetine.
Compound 5i that was found most potent in the FST, and was
further evaluated in a TST to effectively confirm its antidepressant
activity. The TST is a behavioral despair test that is commonly used
to predict the activities of antidepressant agents. In the current
study, compound 5i showed a good activity profile at a dose of
50 mg/kg compared with the standard drug fluoxetine. The results
of this test are shown in Fig. 4.
Having confirmed the antidepressant activity of compound 5i,
we proceeded to conduct a dose-dependent study of this com-
pound as doses of 10, 25, and 50 mg/kg using the FST. As shown in
Fig. 5, compound 5i produced an antidepressant effect in a dose-
Table 1
Antidepressant activities of the compounds 5ae5s in FST.
Compounds
R
Antidepressant activitiesa
Duration of immobility (s)b
% DIDc
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
eC3H7
eC4H9
eC5H11
eC6H13
eC7H15
eC8H17
eC10H21
eCH2C6H5
eCH2C6H4(o-F)
eCH2C6H4(m-F)
eCH2C6H4(p-F)
eCH2C6H4(o-Cl)
eCH2C6H4(m-Cl)
eCH2C6H4(p-Cl)
eCH2C6H3(2,4-2Cl)
eCH2C6H3(2,6-2Cl)
eCH2C6H4(m-CF3)
eCH2C6H4(p-CH3)
eCH2C6H4(p-OCH3)
123.6 ꢀ 21.13
70.0 ꢀ 8.65*
129.8 ꢀ 9.56
98.5 ꢀ 14.19
77.9 ꢀ 18.26
83.3 ꢀ 12.69
101.0 ꢀ 10.92
68.1 ꢀ 15.85*
35.6 ꢀ 11.05***
43.0 ꢀ 12.16***
71.1 ꢀ 9.90*
77.8 ꢀ 9.02
5.3
46.4
0.5
24.5
40.3
35.8
22.6
47.8
72.7
67.0
45.5
40.4
59.1
72.3
18.9
15.7
37.2
39.6
6.8
53.4 ꢀ 8.31***
36.1 ꢀ 12.93***
105.8 ꢀ 13.93
111.0 ꢀ 16.04
93.3 ꢀ 12.74
78.8 ꢀ 10.61
121.6 ꢀ 8.81
65.9 ꢀ 11.77**
130.5 ꢀ 10.34
5q
5r
5s
Fluoxetine
Control
49.5
e
*p < 0.05 as compared to control, **p < 0.01 as compared to control, ***p < 0.001 as
compared to control (all comparisons were made by ANOVA followed by Dunnett’s
test).
Fig. 5. Effect of treatment of mice with 5i given intraperitoneally (i.p.) at graded doses
on the immobility time in the forced swim test (FST). Results are represented as
mean ꢀ SEM with n ¼ 8 in each group. Values are significant at *p < 0.05, **p < 0.01,
***p < 0.001 as compared to control (all comparisons were made by ANOVA followed
by Dunnett’s test).
a
Compounds prepared were administered intraperitoneally at 50 mg/kg,
Fluoxetine was administered at 50 mg/kg.
b
Represent the mean ꢀ SEM. (n ¼ 8).
c
%DID: percentage decrease in immobility duration.

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X.-Q. Deng et al. / European Journal of Medicinal Chemistry 73 (2014) 217e224
Table 2
dependent manner. Compound 5i led to a significant reduction in
the immobility time in the FST when it was administered at doses
of 50 and 25 mg/kg, whereas no significant changes were observed
following the administration of a dose of 10 mg/kg.
Preliminary anticonvulsant activity and neurotoxocity of compounds 5ae5s
administered intraperitoneally (i.p.) to mice.
To determine whether the observed changes in the immobility
were associated with changes in the motor activity, compound 5i
was also evaluated for its effect on the locomotor activities of mice
using the open-field test, which is a classical animal test used to
evaluate the autonomic effects of drugs and the general activities of
animals [49]. The results revealed that compound 5i did not have a
significant impact on motor activities (i.e., crossing, rearing, or
grooming) in mice (Fig. 6). The results of this study suggested that
the antidepressant activity of 5i observed in the FST did not result
from any CNS stimulant properties.
Compds.
R
MESa
0.5 h
Neurotoxicity
4 h
0.5 h
4 h
5a
5b
5c
5d
5e
5f
5g
eC3H7
n-C4H9
n-C5H11
n-C6H13
n-C7H15
n-C8H17
n-C10H21
e
e
e
300
300
300
300
300
300
e
e
e
e
4.2. Anticonvulsant activity
100
100
300
300
e
e
300
300
300
e
300
e
The anticonvulsant activities of the synthesized compounds
were also evaluated using the maximal electroshock seizure (MES)
test. Compounds 5aes were administrated intraperitoneally to the
mice using doses of 30, 100 and 300 mg/kg, and the observations
were taken at time intervals of 0.5 and 4 h. The results are shown in
Table 2.
Compounds 5c and 5d were found to be the most potent com-
pounds and provided 100% protection at a dose of 100 mg/kg
following 0.5 h. Compound 5d was also active following 4 h, albeit
at the higher dose of 300 mg/kg. Compounds 5e, 5f, 5o, and 5q
were also found to be active at a dose of 300 mg/kg in the MES
screen. Furthermore, compounds 5f, 5o and 5q also continued to
provide protection from seizures following 4 h, indicating that they
all have a long duration of anticonvulsant activity. Compound 5i
and compounds 5lem gave protection against the seizures
following 4 h.
300
e
e
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
Valproate
Phenytoin
eCH2C6H5
e
e
e
e
eCH2C6H4(o-F)
eCH2C6H4(m-F)
eCH2C6H4(p-F)
eCH2C6H4(o-Cl)
eCH2C6H4(m-Cl)
eCH2C6H4(p-Cl)
eCH2C6H3(2,4-2Cl)
eCH2C6H3(2,6-2Cl)
eCH2C6H4(m-CF3)
eCH2C6H4(p-CH3)
eCH2C6H4(p-OCH3)
e
e
300
e
e
e
e
e
e
e
300
300
300
e
e
e
e
e
e
e
e
e
e
e
e
300
e
300
e
e
e
e
e
300
e
300
e
e
e
e
e
e
e
e
e
300
30
e
e
e
e
100
100
100
a
30,100, and 300 mg/kg of doses were administered (i.p.). The figures in the table
indicate the minimal dose whereby bioactivity was demonstrated in half or more of
the mice. The animals were examined at 0.5 h and 4.0 h after injection. A dash in-
dicates an absence of activity or toxicity at maximum dose administered (300 mg/
kg).
4.3. Neurotoxicity
The neurotoxicities of the compounds synthesized in the cur-
rent study were determined using the minimal motor impairment-
rotorod screen. As shown in Table 2, compounds 5ges did not show
any neurotoxic effects at the maximum dose administered
(300 mg/kg) following 0.5 and 4 h. The rest of the compounds (5ae
e) did display neurotoxic activities at a dose of 300 mg/kg following
0.5 and 4 h. Pleasingly, however, none of the compounds exhibited
neurotoxic activity at the dose (50 mg/kg) used in the FST or TST.
In the current study, a series of triazole-containing quinolinones
have been designed, synthesized and tested for their antidepres-
sant and anticonvulsant activities. Consideration of the biological
activities of the synthesized compounds revealed the following
structureeactivity relationships (SARs). Compounds 5ae5g con-
tained different alkyl groups attached to the core quinolinone
fragment, ranging from a propyl group to a decyl group. Although
the length of the alkyl chain on these derivatives did not have a
discernible impact on their antidepressant activities, the chain
length did appear to have an impact on their anticonvulsant ac-
tivities. Compounds 5c and 5d (bearing an n-pentyl and a hexyl
chain, respectively) showed the greatest anticonvulsant activities,
indicating that these compounds possessed the optimum level of
lipophilicity for the congeners to act on the central nervous system.
Compound 5h was substituted with a benzyl group at the 1-
position of the quinolinone core and the subsequent addition of F,
Cl, CF3, CH3 and OCH3 groups to different positions of the phenyl
ring of the benzyl group of 5h provided compounds 5ie5s. Pleas-
ingly, the introduction of an F atom (5i and 5j) or a Cl atom (5m and
5n) to the phenyl ring led to an increase in the antidepressant ac-
tivity compared with 5h. In contrast, the introduction of two Cl
atoms to give compounds 5o and 5p resulted in no antidepressant
activity in the FST.
Fig. 6. Effects of treatment of mice with 5i (50 mg/kg) on the behavioral parameters
(locomotion, rearing and grooming) evaluated in the open-field test. Locomotion:
number of line crossings; rearing: number of times seen standing on hind legs;
grooming: number of modifications. Each column represents means ꢀ SEM. *P < 0.05
as compared to control (all comparisons were made by ANOVA followed by bonfer-
roni’s test).
The antidepressant activity of the target compounds was
desirable, while their anticonvulsant activities kept a certain dis-
tance from being satisfactory. Compared with compounds II or III
prepared formerly, the anticonvulsant activities of 5ae5s decreased

X.-Q. Deng et al. / European Journal of Medicinal Chemistry 73 (2014) 217e224
221
significantly. The biggest structural difference among them was the
piperidone ring. Therefore, further modifications will be focused on
the piperidone part with the aim of increasing the anticonvulsant
activity.
300 MHz)
d
: 0.98 (t, 3H, J ¼ 7.5 Hz, eCH3), 1.64e1.72 (m, 2H, eCH2e
), 2.70 (t, 2H, J ¼ 7.3 Hz, H-3), 2.98 (t, 2H, J ¼ 7.3 Hz, H-4), 3.93 (t, 2H,
J ¼ 7.6 Hz, NCH2e), 7.11 (d,1H, J ¼ 8.6, H-8), 7.21 (d,1H, J ¼ 2.5 Hz, H-
5), 7.28 (dd,1H, J1 ¼ 2.5 Hz, J2 ¼ 8.6 Hz, H-7), 8.44 (s, 2H, Triazole-H).
13C NMR (CDCl3, 75 MHz)
d: 169.6, 141.6, 140.4, 128.8, 128.3, 122.2,
5. Conclusion
121.5, 116.1, 43.8, 31.3, 25.5, 20.3, 11.2. IR (KBr) cmꢂ1: 1651 (C]O),
1527 (C]N). MS-EI m/z 257 (M þ Hþ). ESI-HRMS calcd for
In conclusion, a series of novel triazole-containing quinolinones
has been designed and synthesized and their antidepressant and
anticonvulsant activities have been evaluated. In general, the new
compounds displayed higher levels of antidepressant efficacy than
fluoxetine in the FST and TST, and showed some degree of anti-
convulsant activity. Although these compounds could potentially
be used as adjuncts of other antidepressants to treat depression in
patients with epilepsy, further studies should be conducted to
reveal the mechanism of their antidepressant-like effects.
C
14H17N4Oþ ([M þ H]þ): 257.1397; found: 257.1395.
6.1.2.2. 1-Butyl-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydroquinolin-
2(1H)-one (5b). Yield: 74%, mp: 154e155 ꢁC; 1H NMR (CDCl3,
300 MHz)
d
: 0.97 (t, 3H, J ¼ 7.5 Hz, eCH3), 1.37e1.68 (m, 4H, e
(CH2)2e), 2.70 (t, 2H, J ¼ 6.0 Hz, H-3), 2.98 (t, 2H, J ¼ 6.0 Hz, H-4),
3.97 (t, 2H, J ¼ 7.5 Hz, NeCH2e), 7.11e7.28 (m, 3H, Ph-H), 8.44 (s, 2H,
Triazole-H). 13C NMR (CDCl3, 75 MHz)
d: 169.5, 141.6, 140.4, 128.8,
128.3, 122.2, 121.5, 116.1, 42.0, 31.3, 29.1, 25.5, 20.1, 13.8. IR (KBr)
cmꢂ1: 1651 (C]O), 1526 (C]N). MS-EI m/z 271 (M þ Hþ). ESI-
HRMS calcd for C15H18N4Oþ ([M þ H]þ): 271.1553; found: 271.1550.
6. Experimental protocols
6.1. Chemistry
6.1.2.3. 1-Pentyl-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydroquinolin-
2(1H)-one (5c). Yield: 63%, mp: 139e140 ꢁC; 1H NMR (CDCl3,
Melting points were determined in open capillary-tubes and
were uncorrected. Infrared spectra were recorded (in KBr) using a
FTIR1730 spectrometer (PerkineElmer, Waltham, MA, USA). 1H
NMR and 13C NMR spectra were recorded using an AV-300 spec-
trometer (Bruker, Switzerland), and all chemical shifts were given
in parts per million relative to tetramethylsilane. Mass spectra were
measured using an HP1100LC spectrometer (Agilent Technologies,
Santa Clara, USA). High resolution mass spectra were measured on
an MALDI-TOF/TOF mass spectrometer (Bruker Daltonik, Germany).
The chemicals were purchased from Aldrich Chemical Corporation
(St Louis, USA).
300 MHz)
d
: 0.92 (t, 3H, J ¼ 6.4 Hz, eCH3), 1.37e1.66 (m, 6H, e
(CH2)3e), 2.71 (t, 2H, J ¼ 7.3 Hz, H-3), 2.99 (t, 2H, J ¼ 7.3 Hz, H-4),
3.97 (t, 2H, J ¼ 7.5 Hz, NCH2e), 7.10e7.29 (m, 3H, Ph-H), 8.45 (s, 2H,
Triazole-H). 13C NMR (CDCl3, 75 MHz)
d: 169.5, 141.6, 140.4, 128.8,
128.3, 122.2, 121.5, 116.1, 42.3, 31.3, 29.0, 26.7, 25.5, 22.4, 14.0. IR
(KBr) cmꢂ1: 1652 (C]O),1525 (C]N). MS-EI m/z 285 (M þ Hþ). ESI-
HRMS calcd for C16H21N4Oþ ([M þ H]þ): 285.1710; found: 285.1711.
6.1.2.4. 1-Hexyl-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydroquinolin-
2(1H)-one (5d). Yield: 57%, mp: 111e113 ꢁC; 1H NMR (CDCl3,
300 MHz)
d
: 0.90 (t, 3H, J ¼ 6.5 Hz, eCH3), 1.16e1.65 (m, 8H, e
(CH2)4e), 2.70 (t, 2H, J ¼ 7.3 Hz, H-3), 2.99 (t, 2H, J ¼ 7.3 Hz, H-4),
6.1.1. Synthesis of 6-(4H-1,2,4-triazol-4-yl)-3,4-dihydroquinolin-
2(1H)-one (4)
3.96 (t, 2H, J ¼ 7.5 Hz, NCH2e), 7.10e7.28 (m, 3H, Ph-H), 8.45 (s, 2H,
Triazole-H). 13C NMR (CDCl3, 75 MHz)
d: 169.5, 141.6, 140.3, 128.7,
Dimethoxy-N, N-dimethylmethanamine (DMF-DMA) 6.0
g
128.3, 122.2, 121.5, 116.1, 42.3, 31.4, 31.3, 27.0, 26.5, 25.5, 22.5, 14.0.
IR (KBr) cmꢂ1: 1659 (C]O), 1528 (C]N) .MS-EI m/z 299 (M þ Hþ).
ESI-HRMS calcd for C17H23N4Oþ ([M þ H]þ): 299.1866; found:
299.1860.
(50 mmol) was added to a solution of formylhydrazine 3.0 g
(50 mmol) in acetonitrile (50 ml) in a 100-ml round-bottomed flask
equipped with a reflux condenser. The reaction mixture was
warmed to 60 ꢁC for 1 h and then 6-amino-3,4-dihydroquinolin-
2(1H)-one 4.1 g (25 mmol) was added accompanied with acetic acid
(5 ml). The reaction temperature was raised to 120 ꢁC for 12 h. After
being cooled and concentrated, the precipitate was filtrated, and
recrystallized in ethanol to produce the pure compound 4. Yield
6.1.2.5. 1-Heptyl-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydroquinolin-
2(1H)-one (5e). Yield: 62%, mp: 134e135 ꢁC; 1H NMR (CDCl3,
300 MHz)
d
: 0.87 (t, 3 H, J ¼ 6.5 Hz, eCH3), 1.28e1.64 (m, 10H, e
(CH2)5e), 2.70 (t, 2H, J ¼ 7.3 Hz, H-3), 2.98 (t, 2H, J ¼ 7.3 Hz, H-4),
3.95 (t, 2H, J ¼ 7.7 Hz, NCH2e), 7.10e7.20 (m, 3H, Ph-H), 8.44 (s, 2H,
67%; m.p. 294e296 ꢁC; 1H NMR (CDCl3, 300 MHz),
d 2.49 (t, 2H,
J ¼ 7.4 Hz, H-3), 2.94 (t, 2H, J ¼ 7.4 Hz, H-4), 6.97 (d,1H, J ¼ 8.4 Hz, H-
8), 7.44 (dd, 1H, J1 ¼ 2.3 Hz, J2 ¼ 8.4 Hz, H-7), 7.54 (d, 1H, J ¼ 2.3 Hz,
H-5), 9.00 (s, 2H, Triazole-H), 10.29 (s, 1H, CONH). MS m/z 215.2
(M þ Hþ).
Triazole-H). 13C NMR (CDCl3, 75 MHz)
d: 169.5, 141.6, 140.4, 128.8,
128.3, 122.2, 121.5, 116.1, 42.3, 31.7, 31.3, 29.0, 27.0, 26.8, 25.5, 22.6,
14.1. IR (KBr) cmꢂ1: 1667 (C]O), 1529 (C]N). MS-EI m/z 313
(M þ Hþ). ESI-HRMS calcd for C18H25N4Oþ ([M þ H]þ): 313.2023;
found: 313.2016.
6.1.2. Synthesis of 1-substituted-6-(4H-1,2,4-triazol-4-yl)-3,4-
dihydroquinolin-2(1H)-ones (5ae5s)
6.1.2.6. 1-Octyl-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydroquinolin-2(1H)-
Sodium methylate (5 mmol, 0.27 g) and 6-(4H-1,2,4-triazol-4-
yl)-3,4-dihydroquinolin-2(1H)-one (4) (5 mmol, 1.1 g) were dis-
solved in acetonitrile (50 mL) and refluxed for 1 h. Then the
appropriate alkyl bromide or benzyl chloride (6 mmol) was added
to the mixture. The reaction mixture was heated at reflux tem-
perature for 2e4 h. After removing half of the solvent, 100 mL of
water was poured into the flask and the precipitate formed was
filtered, which was recrystallized in ethanol (or mix of ether and
dichloromethane) to produce a white solid. The yield, melting point
and spectral data of each compound were given below.
one (5f). Yield: 62%, mp: 126e127 ꢁC; 1H NMR (CDCl3, 300 MHz)
d:
0.87 (t, 3 H, J ¼ 6.4 Hz, eCH3), 1.27e1.64 (m, 12H, e(CH2)6e), 2.70 (t,
2H, J ¼ 7.3 Hz, H-3), 2.98 (t, 2H, J ¼ 7.3 Hz, H-4), 3.95 (t, 2H,
J ¼ 7.7 Hz, NCH2e), 7.11 (d,1H, J ¼ 8.6, H-8), 7.23 (d,1H, J ¼ 2.5 Hz, H-
5), 7.29 (dd,1H, J1 ¼ 2.5 Hz, J2 ¼ 8.6 Hz, H-7), 8.45 (s, 2H, Triazole-H).
13C NMR (CDCl3, 75 MHz)
d: 169.4, 141.6, 140.4, 128.8, 128.3, 122.2,
121.5, 116.1, 42.3, 31.7, 31.4, 29.3, 29.2, 26.9, 22.6, 22.5, 14.1. IR (KBr)
cmꢂ1: 1669 (C]O), 1528 (C]N). MS-EI m/z 327 (M þ Hþ). ESI-
HRMS calcd for C19H27N4Oþ ([M þ H]þ): 327.2179; found: 327.2182.
6.1.2.7. 1-Decyl-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydroquinolin-
6.1.2.1. 1-Propyl-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydroquinolin-
2(1H)-one (5g). Yield: 84%, mp: 130e132 ꢁC; 1H NMR (CDCl3,
2(1H)-one (5a). Yield: 69%, mp: 169e170 ꢁC; 1H NMR (CDCl3,
300 MHz)
d: 0.87 (t, 3H, J ¼ 6.5 Hz, eCH3), 1.25e1.64 (m, 16H, e

222
X.-Q. Deng et al. / European Journal of Medicinal Chemistry 73 (2014) 217e224
(CH2)8e), 2.70 (t, 2H, J ¼ 7.3 Hz, H-3), 2.98 (t, 2H, J ¼ 7.3 Hz, H-4),
3.95 (t, 2H, J ¼ 7.7 Hz, NeCH2e), 7.11 (d, 1H, J ¼ 8.6, H-8), 7.22 (d, 1H,
J ¼ 2.5 Hz, H-5), 7.29 (dd, 1H, J1 ¼ 2.5 Hz, J2 ¼ 8.6 Hz, H-7), 8.45 (s,
J ¼ 7.2 Hz, H-4), 5.20 (s, 2H, NCH2), 6.94e7.31 (m, 7H, Ph-H), 8.41 (s,
2H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
: 169.9, 141.5, 140.2,
138.4, 134.9, 130.3, 128.8, 128.5, 127.8, 126.5, 124.6, 122.2, 121.6,
116.7, 45.7, 31.2, 25.5. IR (KBr) cmꢂ1: 1671 (C]O), 1528 (C]N). MS-
EI m/z 339 (M þ Hþ). ESI-HRMS calcd for C18H16ClN4Oþ ([M þ H]þ):
339.1007; found: 339.1014.
d
2H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
d: 169.5, 141.6, 140.4,
128.7, 128.3, 122.2, 121.5, 116.1, 42.3, 31.8, 31.3, 29.5, 29.5, 29.3, 29.3,
27.0, 26.8, 25.5, 22.6, 14.1. IR (KBr) cmꢂ1: 1671 (C]O), 1529 (C]N).
MS-EI m/z 355 (M
þ
Hþ). ESI-HRMS calcd for C21H31N4Oþ
([M þ H]þ): 355.2492; found: 355.2496.
6.1.2.14. 1-(4-Chlorobenzyl)-6-(4H-1,2,4-triazol-4-yl)-3,4-
dihydroquinolin-2(1H)-one (5n). Yield: 63%, mp: 222e224 ꢁC; 1H
6.1.2.8. 1-Benzyl-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydroquinolin-
NMR (CDCl3, 300 MHz)
J ¼ 7.2 Hz, H-4), 5.19 (s, 2 H, NCH2), 7.14e7.31 (m, 7H, Ph-H), 8.40 (s,
2 H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
: 169.9, 141.5, 140.2,
134.7, 133.3, 129.1, 128.7, 128.6, 127.8, 122.2, 121.5, 116.7, 45.5, 31.2,
25.4. IR (KBr) cmꢂ1: 1674 (C]O), 1526 (C]N). MS-EI m/z 339
(M þ Hþ). ESI-HRMS calcd for C18H16ClN4Oþ ([M þ H]þ): 339.1007;
found: 339.1012.
d
: 2.85 (t, 2H, J ¼ 7.2 Hz, H-3), 3.10 (t, 2H,
2(1H)-one (5h). Yield: 57%, mp: 224e226 ꢁC; 1H NMR (CDCl3,
300 MHz)
d
: 2.86 (t, 2H, J ¼ 7.2 Hz, H-3), 3.08 (t, 2H, J ¼ 7.2 Hz, H-4),
d
5.22 (s, 2H, NCH2), 6.99 (d, 1H, J ¼ 8.7, H-8), 7.13 (dd, 1H, J1 ¼ 2.5 Hz,
J2 ¼ 8.7 Hz, H-7), 6.98e7.36 (m, 6H, Ph-H, H-5), 8.40 (s, 2H, Triazole-
H). 13C NMR (CDCl3, 75 MHz)
d: 170.0, 141.6, 140.4, 136.1, 129.0,
128.5, 127.4, 126.3, 122.0, 121.5, 116.9, 113.9, 46.1, 31.3, 25.5. IR (KBr)
cmꢂ1: 1669 (C]O), 1525 (C]N). MS-EI m/z 305 (M þ Hþ). ESI-
HRMS calcd for C18H17N4Oþ ([M þ H]þ): 305.1397; found: 305.1393.
6.1.2.15. 1-(2,4-Dichlorobenzyl)-6-(4H-1,2,4-triazol-4-yl)-3,4-
dihydroquinolin-2(1H)-one (5o). Yield: 64%, mp: 204e205 ꢁC; 1H
6.1.2.9. 1-(2-Fluorobenzyl)-6-(4H-1,2,4-triazol-4-yl)-3,4-
NMR (CDCl3, 300 MHz)
J ¼ 7.3 Hz, H-4), 5.25 (s, 2H, NCH2), 6.79e7.46 (m, 6H, Ph-H), 8.41 (s,
2H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
: 169.9, 141.2, 140.0,
133.8,133.4,131.8, 129.7, 128.9,128.5,127.8, 127.6,122.2,121.7, 116.5,
43.7, 31.2, 25.4. IR (KBr) cmꢂ1: 1676 (C]O), 1528 (C]N). MS-EI m/z
373 (M þ Hþ). ESI-HRMS calcd for C18H15Cl2N4Oþ ([M þ H]þ):
373.0617; found: 373.0621.
d
: 2.88 (t, 2H, J ¼ 7.3 Hz, H-3), 3.12 (t, 2H,
dihydroquinolin-2(1H)-one (5i). Yield: 63%, mp: 202e203 ꢁC; 1H
NMR (CDCl3, 300 MHz)
d
: 2.86 (t, 2H, J ¼ 7.2 Hz, H-3), 3.09 (t, 2H,
d
J ¼ 7.3 Hz, H-4), 5.28 (s, 2H, NCH2), 6.98e7.28 (m, 7H, Ph-H), 8.40 (s,
2 H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
d: 170.0, 160.4 (d, Jce
1
¼ 244 Hz), 141.5, 140.1, 129. 1 (d, 3Jcef ¼ 8.0 Hz), 128.7, 128.6, 127.9
f
(d, 3Jcef ¼ 3.6 Hz), 124.6, 123.1 (d, 2Jcef ¼ 13.8 Hz), 122.1, 121.5, 116.5,
115.7 (d, 2Jcef ¼ 21.1 Hz), 39.8, 31.3, 25.4. IR (KBr) cmꢂ1: 1668 (C]O),
1530 (C]N). MS-EI m/z 323 (M þ Hþ). ESI-HRMS calcd for
6.1.2.16. 1-(2,6-Dichlorobenzyl)-6-(4H-1,2,4-triazol-4-yl)-3,4-
C
18H16FN4Oþ ([M þ H]þ): 323.1303; found: 323.1304.
dihydroquinolin-2(1H)-one (5p). Yield: 65%, mp: 251e252 ꢁC; 1H
NMR (CDCl3, 300 MHz)
J ¼ 7.3 Hz, H-4), 5.55 (s, 2H, NCH2), 7.11e7.29 (m, 6H, Ph-H), 8.39 (s,
2H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
: 170.1, 141.4, 139.3,
d
: 2.78 (t, 2H, J ¼ 7.3 Hz, H-3), 3.01 (t, 2H,
6.1.2.10. 1-(3-Fluorobenzyl)-6-(4H-1,2,4-triazol-4-yl)-3,4-
dihydroquinolin-2(1H)-one (5j). Yield: 58%, mp: 179e180 ꢁC; 1H
d
NMR (CDCl3, 300 MHz)
d
: 2.87 (t, 2H, J ¼ 7.2 Hz, H-3), 3.09 (t, 2H,
135.9, 131.1, 130.1, 129.4, 129.2, 128.6, 121.9, 121.0, 117.3, 41.2, 31.9,
25.1. IR (KBr) cmꢂ1: 1677 (C]O), 1529 (C]N). MS-EI m/z 373
(M þ Hþ). ESI-HRMS calcd for C18H15Cl2N4Oþ ([M þ H]þ): 373.0617;
found: 373.0614.
J ¼ 7.2 Hz, H-4), 5.22 (s, 2H, NCH2), 6.94e7.30 (m, 7H, Ph-H), 8.41 (s,
2 H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
d
: 169.9, 163.2 (d, 1Jce
3
3
¼ 244 Hz), 141.5, 140.3, 138.9 (d, Jcef ¼ 6.9 Hz), 130.6 (d, Jce
f
f
f
2
¼ 8.0 Hz), 128.7, 128.5, 122.2, 122.0, 121.6, 116.7, 114.5 (d, Jce
¼ 20.9 Hz), 113.4 (d, 2Jcef ¼ 22.1 Hz), 45.7, 31.2, 25.5. IR (KBr) cmꢂ1
:
6.1.2.17. 1-(3-(Trifluoromethyl)benzyl)-6-(4H-1,2,4-triazol-4-yl)-3,4-
dihydroquinolin-2(1H)-one (5q). Yield: 58%, mp: 195e196 ꢁC; 1H
1666 (C]O), 1530 (C]N). MS-EI m/z 323 (M þ Hþ). ESI-HRMS calcd
for C18H16FN4Oþ ([M þ H]þ): 323.1303; found: 323.1303.
NMR (CDCl3, 300 MHz)
d
: 2.88 (t, 2H, J ¼ 7.2 Hz, H-3), 3.11 (t, 2H,
J ¼ 7.2 Hz, H-4), 5.28 (s, 2 H, NCH2), 6.92e7.56 (m, 7H, Ph-H), 8.41 (s,
6.1.2.11. 1-(4-Fluorobenzyl)-6-(4H-1,2,4-triazol-4-yl)-3,4-
2H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
d: 169.9, 141.4, 140.2,
dihydroquinolin-2(1H)-one (5k). Yield: 61%, mp: 227e228 ꢁC; 1H
137.4, 131.3 (q, Jcef ¼ 30.3 Hz) 129.7, 129.5, 128.8, 128.6, 124.4 (q,
2
3
1
NMR (CDCl3, 300 MHz)
d: 2.86 (t, 2H, J ¼ 7.5 Hz, H-3), 3.08 (t, 2H,
3Jcef ¼ 3.8 Hz), 123.2 (q, Jcef ¼ 3.9 Hz), 123.9 (q, Jcef ¼ 271 Hz),
122.3, 121.6, 116.6, 45.9, 31.2, 25.5. IR (KBr) cmꢂ1: 1681 (C]O), 1530
(C]N). MS-EI m/z 373 (M þ Hþ). ESI-HRMS calcd for C19H16F3N4Oþ
([M þ H]þ): 373.1271; found: 373.1276.
J ¼ 7.5 Hz, H-4), 5.20 (s, 2H, NCH2), 7.01e7.28 (m, 7H, Ph-H), 8.40 (s,
2H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
d
:
13C NMR (CDCl3,
1
75 MHz)
d
: 169.9, 162.2 (d, Jcef ¼ 234.9 Hz), 141.5, 140.3, 131.9,
128.7, 128.6, 128.1 (d, 3Jcef ¼ 5.9 Hz), 122.1, 121.5, 116.7, 115.9 (d, 2Jce
¼ 21.5 Hz), 45.5, 31.3, 25.5. IR (KBr) cmꢂ1: 1668 (C]O), 1532 (C]
6.1.2.18. 1-(4-Methylbenzyl)-6-(4H-1,2,4-triazol-4-yl)-3,4-
f
N). MS-EI m/z 323 (M þ Hþ). ESI-HRMS calcd for C18H16FN4Oþ
dihydroquinolin-2(1H)-one (5r). Yield: 54%, mp: 234e236 ꢁC; 1H
([M þ H]þ): 323.1303; found: 323.1301.
NMR (CDCl3, 300 MHz)
H-3), 3.08 (t, 2H, J ¼ 7.2 Hz, H-4), 5.19 (s, 2H, NCH2), 7.00e7.27 (m,
7H, Ph-H), 8.39 (s, 2H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
d:
d: 2.33 (s, 3H, Ph-CH3), 2.86 (t, 2H, J ¼ 7.2 Hz,
6.1.2.12. 1-(2-Chlorobenzyl)-6-(4H-1,2,4-triazol-4-yl)-3,4-
dihydroquinolin-2(1H)-one (5l). Yield: 60%, mp: 192e194 ꢁC; 1H
169.9, 141.5, 140.5, 137.1, 133.1, 129.6, 128.5, 126.3, 122.0, 121.5, 116.9,
NMR (CDCl3, 300 MHz)
J ¼ 7.2 Hz, H-4), 5.19 (s, 2H, NCH2), 7.14e7.31 (m, 7H, Ph-H), 8.42 (s,
2H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
: 169.9, 141.5, 140.2,
133.0,132.7, 129.9, 128.8, 128.7, 128.4, 127.2, 126.7, 122.1, 121.6, 116.7,
44.1, 31.3, 25.4. IR (KBr) cmꢂ1: 1670 (C]O), 1526 (C]N). MS-EI m/z
339 (M þ Hþ). ESI-HRMS calcd for C18H16ClN4Oþ ([M þ H]þ):
339.1007; found: 339.1006.
d
: 2.89 (t, 2 H, J ¼ 7.2 Hz, H-3), 3.12 (t, 2H,
109.5, 45.9, 31.3, 25.5, 21.1. IR (KBr) cmꢂ1: 1669 (C]O), 1527 (C]N).
MS-EI m/z 319 (M
þ
Hþ). ESI-HRMS calcd for C19H19N4Oþ
d
([M þ H]þ): 319.1553; found: 319.1556.
6.1.2.19. 1-(4-Methoxybenzyl)-6-(4H-1,2,4-triazol-4-yl)-3,4-
dihydroquinolin-2(1H)-one (5s). Yield: 57%, mp: 200e201 ꢁC; 1H
NMR (CDCl3, 300 MHz)
J ¼ 7.3 Hz, H-4), 3.78 (s, 3H, eOCH3), 5.17 (s, 2H, NCH2), 6.84e7.28
(m, 7H, Ph-H), 8.40 (s, 2H, Triazole-H). 13C NMR (CDCl3, 75 MHz)
d:
d: 2.85 (t, 2H, J ¼ 7.3 Hz, H-3), 3.06 (t, 2H,
6.1.2.13. 1-(3-Chlorobenzyl)-6-(4H-1,2,4-triazol-4-yl)-3,4-
dihydroquinolin-2(1H)-one (5m). Yield: 79%, mp: 218e220 ꢁC; 1H
169.9, 158.9, 141.5, 140.5, 128.6, 128.5, 128.2, 127.7, 122.0, 121.4,
NMR (CDCl3, 300 MHz)
d
: 2.87 (t, 2H, J ¼ 7.2 Hz, H-3), 3.10 (t, 2H,
116.9, 114.3, 55.3, 45.5, 31.3, 25.5. IR (KBr) cmꢂ1: 1670 (C]O), 1526

X.-Q. Deng et al. / European Journal of Medicinal Chemistry 73 (2014) 217e224
223
(C]N). MS-EI m/z 335 (M þ Hþ ESI-HRMS calcd for C19H19N4O2þ
using one-way analysis of variance followed by the Dunnet’s test
using software GraphPad Prism 5. Differences were considered
significant if the probability of error was less than 5% (P < 0.05).
).
([M þ H]þ): 335.1503; found: 335.1506.
6.2. Pharmacology
Acknowledgment
6.2.1. Forced swimming test (FST)
Male Kun-Ming mice were used in the FST. On the test day, mice
were assigned to different groups (n ¼ 8 for each group). The
synthesized compounds and the standard drug fluoxetine were
administered as intraperitoneal injections. After 30 min, the mice
were dropped one at a time into a Plexiglas cylinder (height 25 cm,
diameter 10 cm, containing water to a height of 18 cm at 23e25 ꢁC).
A mouse was judged immobile if it floated in the water in an up-
right position and made only slight movements to prevent sinking.
The total duration of immobility was recorded in the last 4 min of a
total period of 6 min. A decrease in the duration of immobility may
indicate antidepressant-like effect.
This work was supported by the National Natural Science
Foundation of China (No. 81160382) and National Science and
Technology Major Project of China (No. 2011ZX09102-003-03).
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6.2.2. Tail suspension test (TST)
Male mice were individually suspended by the tail above the
floor and affixed with adhesive tape placed approximately 1e2 cm
from the tip of the tail. The total duration of immobility was
recorded in the last 6 min of a total period of 7 min. Mice were
determined to be immobile when they were completely motionless
and hung passively.
6.2.3. Open-field test
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of the animal [20]. The investigated compound 5i was administered
(i.p.) 30 min before the experiment. The study was carried out on
mice according to Archer’s method [27], with slight modifications.
Each mouse was placed individually in the center of the open field
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