Study on synthesis and biological effects of a series of 3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives

Article abstract of DOI:10.1007/s00044-018-2261-2

In this paper, we have reported the synthesis and biological evaluation of nineteen (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives as novel candidate antidepressant and anticonvulsant agents. Compounds 2h, 2k, 2r, and 2s exhibited better potent antidepressant activity and displayed the antidepressant effects in a dose-dependent manner from 10 to 30 mg/kg in the FST and TST. And, we found that the best antidepressant effect of compounds 2r and 2s are likely mediated by an increase in central nervous system 5-HT and NE. In addition, compounds 2r and 2s also exhibited the anticonvulsant activity against MES-induced seizures. Thus, compounds 2r and 2s may be a useful antidepressant adjunct therapy for treating depression in patients with epilepsy. In addition, compounds 2r and 2s showed the anti-inflammatory activity and the excellent analgesic activity. Several scholars have postulated the anti-inflammatory and analgesic effects of antidepressant drugs, suggesting that they may be possess a similar mechanism of action.

Full text of DOI:10.1007/s00044-018-2261-2

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-018-2261-2
ORIGINAL RESEARCH
Study on synthesis and biological effects of a series of 3,4-
dihydroisoquinoline-2(1H)-carboxamide derivatives
Zhi-Yang Fu1 Qing-Hao Jin2 Ya-Nan Xia1 Hai-Ying Jiang3 Li-Ping Guan1
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Received: 4 July 2018 / Accepted: 12 November 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
In this paper, we have reported the synthesis and biological evaluation of nineteen (S)-N-substituted-1-phenyl-3,4-
dihydroisoquinoline-2(1H)-carboxamide derivatives as novel candidate antidepressant and anticonvulsant agents.
Compounds 2h, 2k, 2r, and 2s exhibited better potent antidepressant activity and displayed the antidepressant effects in
a dose-dependent manner from 10 to 30 mg/kg in the FST and TST. And, we found that the best antidepressant effect of
compounds 2r and 2s are likely mediated by an increase in central nervous system 5-HT and NE. In addition, compounds 2r
and 2s also exhibited the anticonvulsant activity against MES-induced seizures. Thus, compounds 2r and 2s may be a useful
antidepressant adjunct therapy for treating depression in patients with epilepsy. In addition, compounds 2r and 2s showed
the anti-inflammatory activity and the excellent analgesic activity. Several scholars have postulated the anti-inflammatory
and analgesic effects of antidepressant drugs, suggesting that they may be possess a similar mechanism of action.
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Keywords Isoquinoline-2(1H)-carboxamide Synthesis Antidepressant Anticonvulsant Neurotransmitter
Introduction
Quinolinone compounds are generally used in medicine
and in the literature due to their broad biological effects,
including anti-cancer (Brajša et al. 2016; Fang et al. 2015;
Franci et al. 2015), antibacterial (Naeem et al. 2016; Gai-
dukevich et al. 2016), anticonvulsant (Deng et al. 2014; Jin
et al. 2017; Sun et al. 2009), anti-inflammatory, and anti-
fungal (D’Angelo et al. 2016; Liu et al. 2016) and anti-
depressant effects (Kumar et al. 2011; Obaid et al. 2013;
Sun et al. 2012). In addition, Oshiro et al. (2000) reported
3,4-dihydro-2-(1H)-quinolinones derivatives (I) possessed
the antidepressant activity. Bauman et al. (2008) described
the antidepressant properties of aripiprazole with 3,4-dihy-
dro-2(1H)-quinolinone-containing compound, which was
initially marketed as an antipsychotic agent. Deng et al.
(2014) have recently confirmed that 19 new triazole-
containing 3,4-dihydroquinolinones (II) exhibited the anti-
depressant and anticonvulsant in this area (Fig. 1).
Depression and epilepsy are the commonly encountered
neurological disorders (McNamara 2011; Meyer 2004).
Depression is a common comorbidity associated with epi-
lepsy and an important factor that affects quality of life in
the individuals and contributing considerably to the global
burden of the disease. The search for a novel and increas-
ingly effective drugs with antidepressant and anticonvulsant
effects represents an important and challenging in the area
of the medicinal chemistry.
* Hai-Ying Jiang
jiangyang7689@aliyun.com
Our research group has been studying with the chemical
structure and biological properties of the antidepressant and
anticonvulsant effect of heterocyclic. We found drug solife-
nacin including isoquinoline showed antidepressant activity at
a dose of 100 mg/kg. In addition, the antidepressant drug
moclobemide possess formamide (–CONH–) (Fig. 2), so,
research attempt to find the new antidepressant and antic-
onvulsant compounds with improved safety profile and ther-
apeutic potency, in this work, the electronic isostere principle
* Li-Ping Guan
glp730@163.com
1
Food and Pharmacy College, Zhejiang Ocean University, 316022
ZhouShan, Zhejiang, China
2
Donghai Science and Technology College, Zhejiang Ocean
University, 316000 Zhoushan, Zhejiang, China
3
College of Medicine, Jiaxing University, 314001
Jiaxing, Zhejiang, China

Medicinal Chemistry Research
Fig. 1 Chemical structures of
quinolinone derivatives possess
antidepressant effects
The synthesis of (S)-ethyl-1-phenyl-3,4-
dihydroisoquinoline-2(1H)-carboxylate (1)
A mixture of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline
(1 mmol, 0.6 g) and K2CO3 (0.52 mmol, 0.4 g) in 30 mL
toluene and water (3:2, v/v) was stirred at room temperature
for 5 min, then was slowly added ethyl chlorocarbonate
(0.52 mmol, 2.8 mL) at ice-water. The reaction mixture was
stirred at room temperature for 20 min. The organic layer
was successively washed with 30 mL water, 1 mol/mL 5 mL
HCl, 10 mL water, and 15 mL saturated solution of NaCl,
dried with MgSO4 and concentrated to give the oil products.
The crude products were washed with hexane to furnish the
pure compound.
Fig. 2 Chemical structures of solifenacin and antidepressant drug
moclobemide and the designed derivatives 2a–2s
The synthesis of (S)-substitued-1-phenyl-3,4-
dihydroisoquinoline-2(1H)-carboxamide (2a–2s)
was developed by introducing –NH– to replace –O– for
solifenacin, which obtained isoquinoline, meanwhile, a series
of (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-
carboxamide derivatives was designed, synthesized and
evaluated their antidepressant and anticonvulsant activities.
To a flask containing toluene (30 mL) and compound 1
(1 mmol, 0.75 g) was heated at 110 °C under reflux for 2 h.
Then, substituted aniline (5 mmol) and NaH (1.6 mmol,
0.1 g) was added, the reaction mixture was heated at
110–120 °C. The reaction was monitored by TLC until the
reaction was over. Then the products was added sodium
chloride and extracted with acetic ether (30 mL × 2), acetic
ether layer was washed with 5 mL 20 % HCl, then adjusted
pH 10 with 2 mol/L NaOH, the crude product was purified
using 95 % EtOH. The yield, melting point and spectral data
of each compound are given as below.
Methods and materials
Chemistry
A positive control, fluoxetine-HCl and valproate (purity >
99%), was purchased from Sigma-Aldrich (Saint Louis,
MO, USA). Melting points were determined using a digital-
display melting point instrument (WRS-1B; Shanghai YiCe
Apparatus & Equipment, Shanghai, China). Infrared (IR)
spectra were recorded (using KBr disks) on a Fourier
transform-infrared (FT-IR)1730 system (Bruker, Billerica,
MA, USA). Nuclear magnetic resonance (1H-NMR and
13C-NMR) spectra were measured on an AV-300 system
(Bruker) and all chemical shifts are given in ppm relative to
tetramethylsilane. High resolution mass spectra were mea-
sured on an MALDI-TOF/TOF mass spectrometer (Bruker,
Germany). Most chemicals were purchased from Sigma-
Aldrich and were of analytical grade.
(S)-N,1-diphenyl-3,4-dihydroisoquinoline-2(1H)-
carboxamide (2a)
Yield 64.7%, m.p. 132–133 °C; 1H-NMR (CDCl3, 300
MHz): δ 2.93–2.95 (2H, t, –CH2), 3.70–3.75 (2H, t, –CH2),
6.44 (1H, s, –CH), 6.54 (1H, s, –NH), 6.96–7.00 (4H, m, –
C6H4), 7.01–7.27 (5H, m, –C6H5), 7.29–7.35 (5H, m, –
C6H5). 13C-NMR (CDCl3, 75 MHz): δ 28.50, 40.43, 58.04,
120.02, 123.10, 126.52, 127.27, 127.50, 128.21, 128.44,
128.66, 128.84, 134.90, 136.21, 139.03, 142.54, 155.08; IR
(KBr) cm−1: 3281, 1719, 1610, 1249; ESI-HRMS calcd for
C22H20N2O+([M+H]+): 328.4070; found: 328.4062.

Medicinal Chemistry Research
(S)-1-phenyl-N-o-tolyl-3,4-dihydroisoquinoline-2(1H)-
(S)-N-(m-methoxyphenyl)-1-phenyl-3,4-
carboxamide (2b)
dihydroisoquinoline-2(1H)-carboxamide (2f)
Yield 59.5%, m.p. 149–152 °C; 1H-NMR (CDCl3, 300
MHz): δ 2.02 (3H, s, –CH3), 2.91–3.03 (2H, t, –CH2), 3.81–
3.85 (2H, t, –CH2), 6.40 (1H, s, –CH), 6.47 (1H, s, –NH),
7.00–7.15 (4H, m, –C6H4), 7.01–7.43 (4H, m, –C6H4),
7.13–7.37 (5H, m, –C6H5); 13C-NMR (CDCl3, 75 MHz): δ
17.52, 28.68, 40.86, 58.67, 122.70, 123.84, 126.58, 126.73,
127.34, 127.69, 128.06, 128.37, 128.46, 128.80, 130.23,
135.04, 136.34, 137.10, 142.68, 155.44; IR (KBr) cm–1:
3287, 1721, 1611, 1247; ESI-HRMS calcd for C23H22N2O
+([M+H]+): 342.4336; found: 342.4330.
Yield 63.5%, m.p. 117–119 °C; 1H-NMR (CDCl3, 300
MHz): δ 2.83–3.12 (2H, t, –CH2), 3.74 (3H, s, –OCH3),
4.10–4.17 (2H, t, –CH2), 6.46 (1H, s, –CH), 6.80 (1H, s, –
NH), 6.90–7.29 (4H, m, –C6H4), 7.20–7.35 (4H, m, –C6H4),
7.22–7.35 (5H, m, –C6H5); 13C-NMR (CDCl3, 75 MHz): δ
29.70, 40.42, 55.51, 57.92, 114.12, 122.33, 126.52, 127.27,
127.42, 127.57, 128.25, 128.46, 128.62, 134.90, 136.34,
142.65, 155.46; IR (KBr) cm–1: 3287, 1721, 1621, 1248;
ESI-HRMS calcd for C23H22N2O2+([M+H]+): 358.4330;
found: 358.4321.
(S)-1-phenyl-N-m-tolyl-3,4-dihydroisoquinoline-2(1H)-
carboxamide (2c)
(S)-N-(p-methoxyphenyl)-1-phenyl-3,4-dihydroisoquinoline-
2(1H)-carboxamide (2g)
Yield 70%, m.p. 116–117 °C; 1H-NMR (CDCl3, 300 MHz):
δ 2.30 (3H, s, –CH3), 2.92–2.98 (2H, t, –CH2), 3.80–3.84
(2H, t, –CH2), 6.47 (1H, s, –CH), 6.48 (1H, s, –NH), 6.86–
7.12 (4H, m, –C6H4), 7.05–7.30 (4H, m, –C6H4), 7.10–7.33
(5H, m, –C6H5); 13C-NMR (CDCl3, 75 MHz): δ 21.51,
28.52, 40.46, 58.01, 117.03, 120.71, 123.92, 126.50,
127.27, 127.50, 128.23, 128.45, 128.67, 134.90, 136.28,
138.79, 138.91, 142.53, 155.10; IR (KBr) cm–1: 3284,
1721, 1610, 1251; ESI-HRMS calcd for C23H22N2O+([M
+H]+): 342.4336; found: 342.4342.
Yield 77%, m.p. 148–150 °C; 1H-NMR (CDCl3, 300 MHz):
δ 2.85–3.07 (2H, t, –CH2), 3.74 (3H, s, –OCH3), 4.10–4.17
(2H, t, –CH2), 6.46 (1H, s, –CH), 6.83 (1H, s, –NH), 6.88–
7.24 (4H, m, –C6H4), 7.20–7.34 (4H, m, –C6H4), 7.20–7.31
(5H, m, –C6H5); 13C-NMR (CDCl3, 75 MHz): δ 29.70,
40.42, 55.51, 57.94, 114.12, 122.35, 126.46, 127.24,
127.46, 127.55, 128.22, 128.45, 128.62, 134.90, 136.33,
142.61, 155.87; IR (KBr) cm–1: 3239, 1719, 1617, 1248;
ESI-HRMS calcd for C23H22N2O2+([M+H]+): 358.4330;
found: 358.4342.
(S)-1-phenyl-N-p-tolyl-3,4-dihydroisoquinoline-2(1H)-
carboxamide (2d)
(S)-N-(o-fluorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2
(1H)-carboxamide (2h)
1
Yield 53%, m.p. 128–130 °C; 1H-NMR (CDCl3, 300 MHz):
δ 2.32 (3H, s, –CH3), 2.90–2.97 (2H, t, –CH2), 3.72–3.73
(2H, t, –CH2), 6.46 (1H, s, –CH), 6.52 (1H, s, –NH), 7.10–
7.24 (4H, m, –C6H4), 7.21–7.33 (4H, m, –C6H4), 7.25–7.34
(5H, m, –C6H5); 13C-NMR (CDCl3, 75 MHz): δ 21.73,
28.51, 40.40, 57.96, 120.30, 126.43, 127.29, 127.48,
127.55, 128.26, 128.65, 129.38, 142.55, 155.28; IR (KBr)
cm–1: 3227, 1718, 1621, 1249; ESI-HRMS calcd for
C23H22N2O+([M+H]+): 342.4336; found: 342.4326.
Yield: 63%, m.p. 107–108 °C; H-NMR (CDCl3, 300 MHz):
δ
2.92–3.03 (2H, t, –CH2–), 3.74–3.82 (2H, t,
–CH2–), 6.46 (1H, s, –CH), 6.93 (1H, s, –NH), 7.12–7.26 (4H,
m, –C6H4), 7.22–7.35 (5H, m, –C6H5), 7.25–7.33 (4H, m, –
C6H4); 13C-NMR (CDCl3, 75 MHz): δ 28.43, 40.44, 58.10,
114.37, 126.56, 127.48, 127.55, 128.23, 128.48, 128.70,
134.82, 136.12, 142.25, 154.42; IR (KBr) cm–1: 3285, 1721,
1620, 1250; ESI-HRMS calcd for C22H19FN2O+([M+H]+):
346.3975; found: 346.3961.
(S)-N-(o-methoxyphenyl)-1-phenyl-3,4-dihydroisoquinoline-
2(1H)-carboxamide (2e)
(S)-N-(m-fluorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2
(1H)-carboxamide (2i)
1
Yield 68%, m.p. 78–80 °C; H-NMR (CDCl3, 300 MHz): δ
Yield 65.7%, m.p. 149–150 °C; 1H-NMR (CDCl3, 300
MHz): δ 2.82–2.89 (2H, t, –CH2–), 3.73–3.84 (2H, t,
–CH2–), 6.45 (1H, s, –CH), 6.70 (1H, s, –NH), 6.71–6.98
(4H, m, –C6H4), 6.78–7.32 (5H, m, –C6H5), 7.19–7.33 (4H,
m, –C6H4); 13C-NMR (CDCl3, 75 MHz): δ 28.47, 40.50,
58.12, 109.54, 109.79, 114.93, 126.59, 127.36, 127.45,
127.66, 128.20, 128.46, 128.73, 134.70, 136.08, 142.30,
154.61; IR (KBr) cm−1: 3228, 1720, 1621, 1248; ESI-
2.80–2.97 (2H, t, –CH2), 3.71 (3H, s, –OCH3), 3.47–4.09
(2H, t, –CH2), 6.47 (1H, s, –CH), 6.82 (1H, s, –NH), 6.91–
7.24 (4H, m, –C6H4), 7.21–7.34 (4H, m, –C6H4), 7.21–7.35
(5H, m, –C6H5); 13C-NMR (CDCl3, 75 MHz): δ 28.45, 40.41,
55.52, 57.86, 114.06, 122.33, 126.51, 127.27, 127.45, 127.54,
128.25, 128.47, 128.62, 134.80, 136.32, 142.64, 155.53; IR
(KBr) cm−1: 3235, 1719, 1612, 1246; ESI-HRMS calcd for
+
C23H22N2O2 ([M+H]+): 358.4330; found: 358.4340.

Medicinal Chemistry Research
HRMS calcd for C22H19FN2O+([M+H]+): 346.3975;
found: 346.3967.
128.78, 134.14, 134.87, 136.07, 137.58, 142.32, 154.82; IR
(KBr) cm−1: 3256, 1720, 1620, 1248; ESI-HRMS calcd for
C14H10N2O+([M+H]+): C22H19ClN2O+([M+H]+): 362.8521;
found: 362.8531.
(S)-N-(p-fluorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2
(1H)-carboxamide (2j)
(S)-N-(2,6-dichlorophenyl)-1-phenyl-3,4-
dihydroisoquinoline-2(1H)-carboxamide (2n)
Yield 78.3%, m.p. 115–116 °C; 1H-NMR (CDCl3, 300 MHz):
δ 2.89–2.98 (2H, t, –CH2–), 3.70–3.81 (2H, t, –CH2–), 6.45
(1H, s, –CH), 6.65 (1H, s, –NH), 6.90–7.76 (4H, m, –C6H4),
6.93–7.32 (5H, m, –C6H5), 7.21–7.35 (4H, m, –C6H4); 13C-
NMR (CDCl3, 75 MHz): δ 28.51, 40.43, 58.12, 115.45,
115.62, 127.43, 127.53, 128.25, 128.66, 128.87, 134.83,
136.26, 142.46, 155.28; IR (KBr) cm–1: 3283, 1721, 1619,
1249; ESI-HRMS calcd for C22H19FN2O+([M+H]+):
346.3975; found: 346.3980.
Yield 77.5%, m.p. 185–187 °C; 1H-NMR (CDCl3, 300
MHz): δ 3.11–3.18 (2H, t, –CH2–), 3.73–3.80 (2H, t, –
CH2–), 6.54 (1H, s, –CH), 6.65 (1H, s, –NH), 6.87–7.18
(4H, m, –C6H4), 7.00–7.31 (5H, m, –C6H5), 7.21–7.33 (3H,
m, –C6H3); 13C-NMR (CDCl3, 75 MHz): δ 29.70, 39.08,
68.49, 118.43, 121.45, 125.59, 125.84, 127.57, 127.69,
127.93, 128.22, 128.35, 128.49, 128.61, 128.79, 130.03,
132.85, 135.55, 137.46, 145.22, 153.57; IR (KBr) cm−1
:
(S)-N-(o-chlorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2
(1H)-carboxamide (2k)
3285, 1718, 1615, 1252; ESI-HRMS calcd for
C22H18Cl2N2O+([M+H]+): 397.2971; found: 397.2960.
Yield 69.6%, m.p. 123–124 °C; 1H-NMR (CDCl3, 300
MHz): δ 2.93–3.01 (2H, t, –CH2–), 3.83–3.85 (2H, t, –
CH2–), 6.48 (1H, s, –CH), 6.68 (1H, s, –NH), 6.90–7.11
(4H, m, –C6H4), 6.87–7.32 (5H, m, –C6H5), 7.21–7.81 (4H,
m, –C6H4); 13C-NMR (CDCl3, 75 MHz): δ 28.33, 40.69,
58.13, 115.20, 121.15, 122.36, 123.15, 126.66, 127.42,
127.50, 127.59, 127.67, 128.20, 128.45, 128.69, 128.73,
134.87, 135.80, 136.19, 142.12, 154.38. IR (KBr) cm–1:
3281, 1722, 1619, 1252; ESI-HRMS calcd for
C22H19ClN2O+([M+H]+): 362.8521; found: 362.8530.
(S)-N-(o-bromophenyl)-1-phenyl-3,4-dihydroisoquinoline-2
(1H)-carboxamide (2o)
1
Yield 74.5%, m.p. 118.4–119.4 °C; H-NMR (CDCl3, 300
MHz): δ 2.93–3.02 (2H, t, –CH2–), 3.70–3.72 (2H, t,
–CH2–), 6.44 (1H, s, –CH), 6.65 (1H, s, –NH), 6.91–7.19
(4H, m, –C6H4), 7.21–7.34 (5H, m, –C6H5), 7.23–7.41 (4H,
m, –C6H4); 13C-NMR (CDCl3, 75 MHz): δ 28.43, 40.42,
58.04, 115.22, 115.50, 127.31, 127.50, 128.22, 128.46,
128.64, 134.86, 136.18, 142.41, 155.24; IR (KBr) cm–1:
3286, 1721, 1621, 1247; ESI-HRMS calcd for
C22H19BrN2O+([M+H]+): 407.3031; found: 407.3020.
(S)-N-(m-chlorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2
(1H)-carboxamide (2l)
(S)-N-(m-bromophenyl)-1-phenyl-3,4-dihydroisoquinoline-2
(1H)-carboxamide (2p)
Yield 66%, m.p. 172–173 °C; 1H-NMR (CDCl3, 300 MHz): δ
2.91–2.97 (2H, t, –CH2–), 3.71–3.73 (2H, t, –CH2–), 6.46
(1H, s, –CH), 6.59 (1H, s, –NH), 6.93–7.14 (4H, m, –C6H4),
6.96–7.33 (5H, m, –C6H5), 7.17–7.50 (4H, m, –C6H4); 13C-
NMR (CDCl3, 75 MHz): δ 28.44, 40.51, 58.15, 117.84,
119.97, 123.12, 126.63, 127.38, 127.47, 127.63, 128.20,
128.47, 128.73, 129.78, 134.49, 134.76, 136.05, 140.30,
142.26, 154.59; IR (KBr) cm−1: 3286, 1720, 1619, 1248;
ESI-HRMS calcd for C22H19ClN2O+([M+H]+): 362.8521;
found: 362.8534.
Yield 77.5%, m.p. 181–183 °C; 1H-NMR (CDCl3, 300
MHz): δ 2.93–3.04 (2H, t, –CH2–), 3.71–3.76 (2H, t,
–CH2–), 6.46 (1H, s, –CH), 6.65 (1H, s, –NH), 7.09–7.19
(4H, m, –C6H4), 7.11–7.34 (5H, m, –C6H5), 7.21–7.54 (4H,
m, –C6H4); 13C-NMR (CDCl3, 75 MHz): δ 28.40, 40.54,
58.12, 118.41, 122.47, 122.80, 125.96, 126.63, 127.40,
127.46, 127.64, 128.21, 128.49, 128.72, 130.04, 134.71,
136.04, 140.40, 142.22, 154.62. IR (KBr) cm−1: 3278,
1721, 1619, 1251; ESI-HRMS calcd for C22H19BrN2O+([M
+H]+): 407.3031; found: 407.3044.
(S)-N-(p-chlorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2
(1H)-carboxamide (2m)
(S)-N-(p-bromophenyl)-1-phenyl-3,4-dihydroisoquinoline-2
(1H)-carboxamide (2q)
1
Yield 81%, m.p. 183–184C; H-NMR (CDCl3, 300 MHz): δ
2.91–2.93 (2H, t, –CH2–), 3.71–3.78 (2H, t, –CH2–), 6.45
(1H, s, –CH), 6.66 (1H, s, –NH), 7.11–7.21 (4H, m, –C6H4),
7.15–7.32 (5H, m, –C6H5), 7.21–7.33 (4H, m, –C6H4); 13C-
NMR (CDCl3, 75 MHz): δ 28.43, 40.44, 58.07, 114.68,
120.18, 121.29, 126.37, 127.37, 127.44, 128.17, 128.73,
Yield 61.6%, m.p. 120–121 °C; 1H-NMR (CDCl3, 300
MHz): δ 2.91–2.93 (2H, t, –CH2–), 3.71–3.85 (2H, t,
–CH2–), 6.45 (1H, s, –CH), 6.58 (1H, s, –NH), 7.10–7.25
(4H, m, –C6H4), 7.20–7.32 (5H, m, –C6H5), 7.20–7.38 (4H,

Medicinal Chemistry Research
m, –C6H4); 13C-NMR (CDCl3, 75 MHz): δ 28.41, 40.49,
58.10, 115.66, 121.89, 126.56, 127.36, 127.47, 127.63,
128.20, 128.49, 128.71, 131.74, 134.78, 136.08, 138.21,
142.27, 154.81; IR (KBr) cm–1: 3249, 1722, 1617, 1248;
ESI-HRMS calcd for C22H19BrN2O+([M+H]+): 407.3031;
found: 407.3043.
by the mouse floating in the water without struggling and
making only those movements necessary to keep its head
above the water (Porsolt et al. 1997).
The tail suspension test (TST)
Male ICR mice were individually suspended by tail with
clamp (2 cm from the tip of the end) in a box (25 × 25 × 30
cm) with the head 5 cm to the bottom. Testing was carried
out in a darkened room with minimal background noise. All
animals were suspended for total 6 min, and the duration of
immobility was observed and measured during the final 4-
min interval of the test. Mice were considered to be
immobile only when they hung passively and completely
motionless (Steru et al. 1985).
(S)-N,N,1-triphenyl-3,4-dihydroisoquinoline-2(1H)-
carboxamide (2r)
Yield 84%, m.p. 189–190 °C; 1H-NMR (CDCl3, 300 MHz):
δ 2.88–2.94 (2H, t, –CH2–), 3.82–4.06 (2H, t, –CH2–), 6.40
(1H, s, –CH), 6.92–7.05 (4H, m, –C6H4), 7.02–7.26 (5H, m,
–C6H5), 7.30–7.41 (5H, m, –C6H5), 7.34–7.40 (5H, m,
–C6H5); 13C-NMR (CDCl3, 75 MHz): δ 29.70, 43.64, 72.18,
116.21, 119.33, 119.95, 122.68, 125.81, 126.95, 127.52,
127.93, 128.54, 128.61, 129.19, 129.72, 136.66, 138.63,
143.05, 143.46, 155.90; IR (KBr) cm−1: 1721, 1617, 1249;
ESI-HRMS calcd for C28H24N2O+([M+H]+): 404.5030;
found: 404.5039.
The sample preparation
The doses of 20 mg/kg 2r, 2s and fluoxetine were employed
for testing the effect on monoamine neurotransmitter con-
centrations in the rat brain. Mice were randomly divided
into five groups (10 mice per group were used). Normal
vehicle, stress vehicle, 2r, 2s and fluoxetine were given
orally daily for 7 days. On the last day, the drugs were given
1 h prior to the test. At the end of the experiment, the mice
were immediately sacrificed by cervical dislocation, the
brain tissue was quickly removed, and rapidly frozen and
stored at −80 °C until they were processed for biochemical
estimations.
(S)-N-benzyl-1-phenyl-3,4-dihydroisoquinoline-2(1H)-
carboxamide (2s)
Yield 73%, m.p. 116–118 °C; 1H-NMR (CDCl3, 300 MHz):
δ 2.86–2.98 (2H, t, –CH2–), 3.73–3.87 (2H, t, –CH2–), 4.48
(2H, s, –CH2), 6.45 (1H, s, –CH), 6.67 (1H, s, –NH), 6.90–
7.10 (4H, m, –C6H4), 6.95–7.31 (5H, m, –C6H5), 7.25–7.40
(5H, m, –C6H5); 13C-NMR (CDCl3, 75 MHz): δ 28.32,
40.15, 45.11, 57.80, 126.41, 127.19, 127.25, 127.52,
127.67, 128.31, 128.46, 128.49, 128.62, 135.06, 136.54,
139.49, 142.82, 157.48; IR (KBr) cm−1: 3280, 1718, 1619,
1247; ESI-HRMS calcd for C23H22N2O +([M+H]+):
342.4336; found: 342.4342.
HPLC condition and test
The brain tissues were sonicated in 0.1 M NaH2PO4
aqueous solution including 0.85 mM OSA, 0.5 mM
Na2·EDTA (ethylenediamine tetraacetic acid disodium)
and centrifuged at 13,000×g for 15 min at 4 °C. Then 5-
HT, NE, and 5-HIAA were assayed by HPLC-ECD.
Equipment: Shimadzu LC-10ATVP HPLC system, Shi-
madzu L-ECD-6A electrochemical detector, N2000
HPLC workstation software, Hypersil ODS C18 Column
4.6 × 150 mm 5 μM. The mobile phase consisted of 0.1 M
NaH2PO4 aqueous solution including 0.85 mM OSA, 0.5
mM Na2·EDTA and 11% methanol adjusted to pH 3.4
with phosphate acid and filtered through 0.45 μM pore
size filter. External standard curves were used to quantify
the amounts of 5-HT, NE and 5-HIAA in each sample
calculated by area under curve. The volume of injection
was 20 μL. The detection limit of the assay was 20 pg/g
sample. The filtrate sample was used for quantification of
5-HT, NE and 5-HIAA by HPLC coupled with electro-
chemical detection in brain region.
Pharmacology
The forced swimming test
Male ICR mice (20 2 g) were used in the forced swim-
ming test (FST) 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 plex-
iglass cylinder (height 25 cm, diameter 10 cm) containing
10 cm of water at 22 3 °C. Mice were assigned into dif-
ferent groups (n = 8 for each group). Then, the mice were
dropped individually into the pelxiglass cylinder and left in
the water for 6 min. After the first 2 min of the initial vig-
orous struggling, the animals were immobile. The duration
of immobility was recorded during the last 4 min of the 6-
min test. Immobility period was regarded as the time spent

Medicinal Chemistry Research
1
Anticonvulsant effects in the maximal electroshock seizure
(MES) test
group, respectively. H-NMR showed disappearance of the
–NH group as singlet signals at 6.46–6.71 ppm and the –CH
group as singlet signals at 6.38–6.58 ppm. 13C-NMR spec-
tra displayed the appearance of the new peak at 153.38–
157.49 ppm for the O=C group.
Half male and female ICR mice (20 2 g) was used the
maximal electroshock seizure test. Seizures were elicited
with a 60 Hz alternating current of 50 mA intensity in mice.
The current was applied via corneal electrodes for 0.2 s.
Protection against the spread of the maximal electroshock
seizure-induced seizures was defined as the abolition of the
hind leg and tonic maximal extension component of the
seizure. At 30 min after the administration of compounds,
the effects were evaluated in the maximal electroshock
seizure test (Porter et al. 1984).
Biological evaluation
The antidepressant effects of the synthesized compounds
were evaluated applying the FST and TST in mice in vivo.
Both the FST and TST, which is the behavioral test, used
to predict the efficacy of antidepressant treatments (Zhen
et al. 2016). In the two models, mice are restricted and
cannot escape, inducing a characteristic behavior of
immobility. It also has a good predictive value for the
antidepressant potency in humans (Xu et al. 2015).
Neurotoxicity screening
The neurotoxicity of the compounds was measured in mice
by the rotarod test. The mice were trained to stay on an
accelerating rotarod of diameter 3.2 cm that rotates at 10
circles per minutes. Trained animals were given an intra-
peritoneal injection of the tested compounds. Neurotoxicity
was indicated by the inability of the animal to maintain
equilibrium on the rod for at least 1 min in each of the trials
(Guan et al. 2013).
The obtained data on the antidepressant activity of the
synthesized compounds was comparable to fluoxetine as
reference drugs (Table 1). Except compounds 2i, 2n, and
2q, other compounds showed the antidepressant activity at a
dose of 50 mg/kg administered intraperitoneally with per-
centage decrease in immobility duration values range of
39.1–87.7% (Duration of immobility(s): 11.0 7.1–54.6
10.2). Among the synthesized compounds 2h and 2k, both
with electron-withdrawing substituent o-fluoro and o-chloro
for the phenly ring, and compounds 2r (N,N-diphenyl) and
2s (N-benzyl) with electron-donor groups, showed the best
antidepressant activity in the FST (DID: 82.4, 81.3, 85.5,
and 87.7%, respectively), which was greater than that or
nearly equivalent to that of fluoxetine (79.1%).
Next, compounds 2h, 2k, 2r, and 2s exhibited the most
potent antidepressant activity and were further evaluated
antidepressant effects after treatment with three low doses
(10, 20, and 30 mg/kg) (Table 2). It should be noted that
compounds 2h, 2k, 2r, and 2s displayed to reduce the
duration of immobility in the FST in mice, and also
exhibited the antidepressant effects in a dose-dependent
manner from 10 to 30 mg/kg. Compound 2s showed anti-
depressant activity with DID value 74.2% which was better
than that of fluoxetine (70.4%) at a dose of 20 mg/kg.
In addition, compounds 2h, 2k, 2r, and 2s were further
evaluated antidepressant effects after treatment with three
low doses (10, 20, and 30 mg/kg) in the TST (Table 3).
Compounds 2h, 2k, 2r, and 2s also showed to reduce the
duration of immobility in the TST in mice and displayed the
antidepressant effects in a dose-dependent manner from 10
to 30 mg/kg. Compound 2s showed the antidepressant
activity with DID value 39.1% which was nearly equivalent
to that of fluoxetine (39.5%) with a dose of 20 mg/kg.
Structure–activity relationship (SAR) studies for the
antidepressant activity of derivatives 2a–2s mentioned
above in the FST (Table 1) displayed that: (1) all com-
pounds except compounds 2i, 2n, and 2q reduce the
Statistical analysis
Results are expressed as mean SEM. n represents the
number of animals. Data obtained from pharmacological
experiments were analyzed with the Turkey’s comparison
tests, using GRAPHPAD PRISM program (GraphPad
Software, Inc., San Diego, CA, USA). A p-value of < 0.05
was considered statistically significant.
Results and discussion
Chemistry
The synthetic routes of the target derivatives are illustrated
in Scheme 1. Compound 1 was synthesized to underwent a
nucleophile substitution reaction with commercial com-
pound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline at room
temperature in a good yield (95%). (S)-N-substituted-1-
phenyl-3,4-dihydro-isoquinoline-2(1H)-carboxamide deri-
vatives (2a–2s) were obtained by stirring compound 1 with
the appropriate substituted aniline in methylbenzene con-
taining sodium hydride at 110–120 °C in 53–84% yield.
The structures of compounds 2a–2s were confirmed by
spectral data and high resolution mass spectra. The IR
spectra of the synthesized target derivatives 2a–2s showed
absorption bands at 3221–3287, 1718–1722, 1610–1621 cm
−1
corresponding to (NH), C=O stretching and (C=N)

Medicinal Chemistry Research
Scheme 1 Synthesis routes of
target compounds 2a–2s
duration of immobility not only with electron-donating
substituent, but also with electron-withdrawing substituent
groups. (2) For six electron-donor groups on the phenyl ring
with the introduction of –CH3 and –OCH3, it was obvious to
afford the excellent antidepressant activity at the meta-
positions of the phenyl ring as compounds 2c and 2f. In
addition, the position of the substituted greatly influenced
antidepressant effects, the obtained data clearly revealed
that the six compounds with –CH3 and –OCH3 substituent
are active in the order of: 2c > 2d > 2b and 2f > 2g > 2e,
respectively. (3) For nine with electron-withdrawing sub-
stituent with the introduction of F atoms (2h, 2i, and 2j), Cl
atoms (2k, 2l, and 2m), or Br atoms (2o, 2p, and 2q), which
also exhibited the excellent antidepressant activity at the
orth-positions of the phenyl ring as compounds 2h, 2k, and
2o. The position of the halogen atom substituted greatly
influenced the antidepressant effects. Compared with com-
pounds with different F-substituted positions on the phenyl
ring, the order of activity was o-F > p-F > m-F, and the order
of activity observed for Cl-substituted positions was o-Cl >
m-Cl > p-Cl. The order of activity for with different Br-
substituted positions was o-Br > m-Br > p-Br. But com-
pound 2n with 2,6-dichlolo substituent did not show the
antidepressant activity. (4) Compounds 2r and 2s with N,N-
diphenyl and N-benzyl substituent marked reduced the
duration of immobility and displayed the excellent anti-
depressant activity in mice, by 85.5 and 87.7%, respec-
tively. For this reason, it was difficult to determine a
structure–activity relationship for the different substituent
group attached to phenyl ring. (5) It is worth mentioning
that the presence of no substituent on the phenyl ring
compound 2a showed the antidepressant effect (63.4%),
which was similar to the lead compound solifenacin
(64.8%).
A dysregulation of the central nervous system including
the neurotransmitters 5-HT and NE has been suggested to
play a role in the pathogenesis of depression and the
mainstream of research has principally focused on 5-HT and
NE systems in depression. In the central nervous system, a
metabolic disorder of monoamine neurotransmitters is
believed to be the main biochemical cause of depression,
and depression can thus be alleviated by increasing the
levels of monoamine neurotransmitters in the central ner-
vous system (Hao et al. 2013; Dhanda and Sandhir 2015).
The levels of monoamine neurotransmitters and their
metabolites detected in mice brain are summarized in
Table 4. In the present study, compounds 2r and 2s sig-
nificantly increased 5-HT and NE levels at the highest doses
during the FST in mice brain, similar to the positive control
drug fluoxetine. In addition, compounds 2r and 2s sig-
nificantly increased 5-HIAA levels, indicating a reduced 5-
HT metabolism. These findings indicate that the anti-
depressant effect of EECS is likely mediated through an
increase 5-HT and NE in central nervous system.
The anticonvulsant activities of the synthesized com-
pounds were also investigated by maximal electroshock and
results from these experiments are shown in Table 5. Sei-
zure assays and neurotoxicity were determined by rotarod
toxicity test. Eight compounds 2a, 2b, 2e, 2h, 2n, 2p, 2r,
and 2s exhibited better anticonvulsant activity against MES
at a dose of 100 mg/kg. Eight compounds 2c, 2f, 2j–2m, 2o,
and 2q showed the anticonvulsant effect against MES at a
dose of 300 mg/kg. Three compounds 2d, 2g, and 2i did not
display the anticonvulsant activity against MES at a dose of
300 mg/kg. But the lead compound solifenacin and refer-
ence drug valproate exhibited the excellent anticonvulsant
activity against MES at a dose of 100 mg/kg. The rotarod
toxicity test results displayed that all compounds did not

Medicinal Chemistry Research
Table 1 Evaluation of antidepressant activity of compounds 2a–2s in
the FST
Table 2 Evaluation of antidepressant activity of compounds 2h, 2k,
2r, and 2s in the FST
Compounds
Antidepressant activitya
Duration of immobility(s)
Compounds Dose (mg/kg) Antidepressant activitya
Duration of immobility (s) DID (%)b
DID (%)b
Solifenacin
31.5 7.8**
32.8 9.5**
43.4 9.5*
24.6 12.1**
34.6 7.4*
50.2 7.2*
24.4 10.0**
42.8 6.8*
15.8 9.4***
82.3 9.5
35.2 8.4**
16.8 11.4***
19.4 11.8***
24.6 9.4***
63.2 10.6
28.2 11.9***
54.6 10.2*
83.1 7.9
64.8
63.4
51.6
72.5
61.4
44.0
72.8
52.2
82.4
8.1
2h
2k
2r
2s
10
20
30
10
20
30
10
20
30
10
20
30
20
–
70.2 7.5*
66.8 9.5*
52.4 10.5**
69.7 7.1*
54.8 9.5**
42.4 10.5**
64.0 5.7*
51.0 9.0**
41.4 11.0**
40.0 6.9**
25.4 7.1***
15.4 3.1***
29.2 8.5***
98.6 9.7
28.8
32.3
46.9
29.3
44.4
57.0
35.1
48.3
58.0
59.4
74.2
84.4
70.4
–
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
60.7
81.3
78.3
72.5
29.5
68.5
39.1
7.3
2k
2l
Fluoxetine
Control
2m
2n
Values are the mean S.E.M. (n = 8)
2o
*Significantly different compared with control (*p < 0.05, **p < 0.01,
***p < 0.001)
aCompounds and fluoxetine were administered intraperitoneally
2p
2q
b% DID: percentage decrease in immobility duration
2r
13.0 8.4***
11.0 7.1***
18.7 9.1***
89.6 16.1
85.5
87.7
79.1
–
2s
Table 3 Evaluation of antidepressant activity of compounds 2h, 2k,
2r, and 2s in the TST
Fluoxetine
Control
Compounds Dose (mg/kg) Antidepressant activitya
Duration of immobility(s) DID (%)b
Values are the mean S.E.M. (n = 8)
*Significantly different compared with control (*p < 0.05, **p < 0.01,
***p < 0.001)
2h
2k
2r
2s
10
20
30
10
20
30
10
20
30
10
20
30
20
–
124.1 11.5*
110.4 12.4*
72.5 10.5***
124.3 5.5*
120.2 7.8*
88.5 6.5***
107.7 8.5*
99.3 13.1**
86.7 7.8***
89.7 7.3**
91.2 8.0**
85.0 9.4***
90.4 9.6**
149.5 13.8
17.0
26.2
51.5
16.9
19.6
40.8
28.0
33.6
42.0
40.0
39.0
43.1
39.5
–
aCompounds and fluoxetine were administered intraperitoneally at 50
mg/kg
b% DID: percentage decrease in immobility duration. %DID =
[(Y−X)/Y] × 100, where Y is the duration of immobility (s) in the
control group and X is the duration of immobility (s) in the test group.
show the neurotoxic effects for doses up to and including
300 mg/kg.
Depression and epilepsy are common neurological dis-
orders (Schröder et al. 2014). Patients with epilepsy are at
high risk of developing depressive symptoms, Antic-
onvulsant drugs may improve depressive symptoms though
clinical research. Treatment of depression may indepen-
dently improve outcome for epilepsy and for quality of life
(Drinovac et al. 2015). The present study demonstrated that
compounds 2r and 2s induced significant antidepressant
effects in the FST and TST. And, we found that the anti-
depressant effect of compounds 2r and 2s are likely medi-
ated by an increase in central nervous system 5-HT and NE.
In addition, compounds 2r and 2s also exhibited the
anticonvulsant activity against MES-induced seizures.
Thus, compounds 2r and 2s may be a useful antidepressant
Fluoxetine
Control
Values are the mean S.E.M. (n = 8)
*Significantly different compared with control (*p < 0.05, **p < 0.01,
***p < 0.001)
aCompounds and Fluoxetine were administered intraperitoneally
b% DID: percentage decrease in immobility duration

Medicinal Chemistry Research
Table 4 Effect of FST exposure and 2r, 2s on brain monoamine
neurotransmitter levels
in people suffering from chronic pain. It has been suggested
that pain and depression possess similar neurochemical
mechanisms (Boufidou and Nikolaou 2016). Anti-
depressants have been used as analgesic agents for neuro-
pathic and non-neuropathic pain because they display
intrinsic anti-nociceptive effects (Ismail et al. 2017).
Monoamine uptake is inhibited, which leads to increases in
levels of noradrenaline and serotonin, which reinforce pain-
inhibitory pathways (Uddin et al. 2018). In our previous
studies (Guan et al. 2017), we found that compounds 2r and
2s displayed to be able to decrease the ear edema in mice,
by 86.3 and 77.4%, respectively showed the anti-
inflammatory activity. Compounds 2r and 2s also exhib-
ited the excellent analgesic activity (inhibition rate: 73.3 and
96.3%, respectively). Several scholars have postulated the
anti-inflammatory and analgesic effects of antidepressant
drugs, suggesting that they may be possess a similar
mechanism of action.
Groups
5-HT
5-HIAA
NE
Normal vehicle 326.3 30.6
237.1 29.2
157.8 19.5
313.0 26.5
205.4 24.7
346.6 30.4
Stress vehicle
202.6 31.0
a,d
2r
378.3 31.7a,e 243.8 21.4a
2s
398.2 32.7c,d 250.1 28.2a,e 337.1 30.0a,e
391.6 33.1c,e 248.5 30.3a,e 325.4 28.3b,e
fluoxetine
The doses of 2r, 2s, and fluoxetine were 20 mg/kg. Neurotransmitter
levels are expressed as ng/g per brain region wet weight. Data are
expressed as mean S.E.M. (n = 10). Statistical analyses of data were
conducted using one-way analysis of variance followed by Turkey’s
test
aP < 0.05
bP < 0.01
cP < 0.001 vs. stress vehicle
dP < 0.05
eP < 0.01 vs. normal vehicle
Table 5 Anticonvulsant effects and neurotoxocity of compounds 2a–
2s
Conclusion
Compounds
Dosage (mg/kg)
MESa
0.5 h
Neurotoxocityb
In summary, we have reported the synthesis and biological
evaluation of nineteen (S)-N-substituted-1-phenyl-3,4-
dihydroisoquinoline-2(1H)-carboxamide derivatives as
novel candidate antidepressant and anticonvulsant agents.
Compounds 2h, 2k, 2r, and 2s exhibited the most potent
antidepressant activity, which was greater than that or
nearly equivalent to that of fluoxetine in the FST, and dis-
played the antidepressant effects in a dose-dependent
manner from 10 mg/kg to 30 mg/kg in the FST and TST.
And, we found that the antidepressant effect of compounds
2r and 2s are likely mediated by an increase in central
nervous system 5-HT and NE. In addition, compounds 2r
and 2s also exhibited the anticonvulsant activity against
MES-induced seizures. Thus, compounds 2r and 2s may be
a useful antidepressant adjunct therapy for treating depres-
sion in patients with epilepsy. In addition, compounds 2r
and 2s showed the anti-inflammatory activity and the
excellent analgesic activity. Several scholars have postu-
lated the anti-inflammatory and analgesic effects of anti-
depressant drugs, suggesting that they may be possess a
similar mechanism of action.
4 h
0.5 h
4 h
Solifenacin
100
100
100
300
300
100
300
300
100
300
300
300
300
300
100
300
100
300
100
100
100
3/3
2/3
1/3
1/3
0/3
1/3
1/3
0/3
1/3
0/3
1/3
1/3
1/3
1/3
1/3
2/3
1/3
1/3
1/3
1/3
3/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3c
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
Valproate
aMaximal electroshock seizure test (number of animals protected/
number of animals tested)
bToxicity: rotarod test (number of animals exhibiting toxicity/number
of animals tested). The animals were examined at 0.5 h and 4.0 h after
injection
Acknowledgements This research was funded by the National Natural
Science Foundation of China (No. 81560149) and 13th Five-Year Key
Projects of Jilin Provincial Education Department of China (No.
JJKH2016261H).
cCompounds are metabolized/excreted at 4 h
Compliance with ethical standards
adjunct therapy for treating depression in patients with
epilepsy.
In addition, inflammation is characterized by pain,
swelling, redness and heat, whereas depression is common
Conflict of interest The authors declare that they have no conflict of
interest.

Medicinal Chemistry Research
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