Synthesis and biological effects of naphthalene-chalcone derivatives

Article abstract of DOI:10.1007/s00044-020-02525-4

In this paper, 21 naphthalene-chalcone derivatives were synthesized and their biological effects were evaluated. The results showed that compounds 2a–2u displayed clear antidepressant activity at 30 mg/kg in the forced swimming test. Compounds 2h, 2o, 2t,

Full text of DOI:10.1007/s00044-020-02525-4

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-020-02525-4
ORIGINAL RESEARCH
Synthesis and biological effects of naphthalene-chalcone derivatives
Qing-Hao Jin1 Hong-Hai Chen2 Wen-Bo Chen2 Zhi-Yang Fu3 Li-Ping Guan3 Hai-Ying Jiang4
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Received: 26 May 2019 / Accepted: 17 February 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
In this paper, 21 naphthalene-chalcone derivatives were synthesized and their biological effects were evaluated. The results
showed that compounds 2a–2u displayed clear antidepressant activity at 30 mg/kg in the forced swimming test. Compounds
2h, 2o, 2t, and 2u exhibited a good antidepressant effect in the forced swimming test and tail suspension test at 30 mg/kg.
Compounds 2h, 2o, 2t, and 2u but had no effect on locomotor activity in the open-field test in mice. In addition, the most
antidepressant activity of compound 2o is likely mediated by increased serotonin and norepinephrine levels in central
nervous system. Compounds 2a–2u also showed the analgesic and anti-inflammatory effects at 30 mg/kg.
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Keywords Chalcone Forced swimming test Tail suspension test Anti-inflammatory Analgesic
Introduction
antidepressant activity using the forced swimming test and tail
suspension test. Among these synthesized compounds,
chalcone-1203 (Fig. 1) (Guan et al. 2014), after replacement
of the phenyl ring with a naphthalene ring on the chalcone B
ring, was employed in two classic tests of animal despair, the
forced swimming test and tail suspension test, to evaluate
antidepressant activity. The immobility duration was dimin-
ished significantly for chalcone-1203 at 1, 5, and 10 mg/kg,
suggesting significant antidepressant activity at low doses.
To obtain new compounds with better antidepressant
effects and as part of our ongoing research on structure-
based design, the naphthalene ring of chalcone-1203 was
fixed, and there was no substituent on the phenyl ring.
Then, 3-naphthyl-1-phenyl-2-propylene-1-ketone (I) was
synthesized and its antidepressant effect evaluated. Com-
pound I was found to reduce the duration of immobility and
showed weaker antidepressant activity. Hence, determina-
tion of the structure-activity relationship for the substituent
group attached to the phenyl ring could be important.
Therefore, introduction of a different group on the phenyl
ring was used to prepare a series of novel derivatives of
naphthalene-chalcone derivatives (2a–2u; Scheme 1) and
screening for their antidepressant effects. Antidepressants
have been used as analgesic agents for neuropathic and non-
neuropathic pain. To explore further the possible mechan-
ism of action, we also evaluated the anti-inflammatory and
analgesic effects of compounds 2a–2u using the xylene-
induced ear-edema test and acetic acid-induced abdominal
writhing in mice.
Several flavonoids extracted from plants have been reported
to possess antidepressant effects in animal studies (Karim
et al. 2017; Carradori et al. 2016; Guan and Liu 2016). One
of the subclasses of flavonoids are phenolic α,β-unsaturated
ketones called “chalcones,” which contain a 1,3-diphenyl-2-
en-1-one core. They are intermediates and end products in
flavonoid biosynthesis, participate in plant–insect interac-
tions, and contribute to the medicinal value of herbs.
Previously, our research team designed and synthesized
derivatives of the chalcones 2′,4′,6′- trihydroxychalcone, 2,4-
dihydroxychalcone, 2′-hydroxy-4′-isoprenyloxychalcone, and
2′-hydroxy-4′,6′- diisoprenyloxychalcone (Sui et al. 2012;
Guan et al. 2013a, b; Xie et al. 2014) and evaluated their
* Hai-Ying Jiang
jiangyang7689@aliyun.com
1
Donghai Science and Technology College, Zhejiang Ocean
University, Zhoushan 316000 Zhejiang, PR China
2
Hailisheng Pharmaceutical Co Ltd, Zhoushan 316000 Zhejiang,
PR China
3
Food and Pharmacy College, Zhejiang Ocean University,
Zhoushan 316022 Zhejiang, PR China
4
College of Medicine, Jiaxing University, Zhejiang 314001 Jiaxing,
PR China

Medicinal Chemistry Research
Fig. 1 Structure of chalcone-
1203, compound I and 2a–2u
Scheme 1 Synthesis routes of
target compounds 2a–2u
Materials and method
at room temperature for 6–12 h. The mixture was poured
into ice–water, adjusted to pH 2–3 with 1 M HCl, and
extracted with ether. The ether layer was washed with
ice–water and saturated brine, and dried over anhydrous
Na2SO4. After solvent removal, products were purified by
silica-gel column chromatography (petroleum ether:ethyl
acetate = 20:1). A yellow solid or oil was obtained. The
yield, melting point, and spectral data of compounds were
elucidated.
Materials
Fluoxetine-HCl (purity >99%), was purchased from Sigma-
Aldrich (Saint Louis, MO, USA). All compounds were
synthesized by our research team. 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 mag-
netic 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. Mass
spectra were measured on a HP1100LC/MS system (Agi-
lent Technologies, Santa Clara, CA, USA). Most chemicals
were purchased from Sigma-Aldrich and were of
analytical grade.
1-(2-fluorophenyl)-3-(naphthalen-1-yl)-2-propen-1-one
(2a) Yellow solid; Yield: 67.5%, mp: 82–83 °C. H-NMR
1
(CDCl3, 300 MHz): δ = 7.32–7.62 (m, 7H, −ArH), 7.54
(d, 1H, J = 15 Hz, =CH), 7.23–7.79 (m, 4H, −C6H4), 8.66
(d, 1H, J = 15 Hz, =CH). 13C-NMR (CDCl3, 75 MHz): δ =
2
2
115.24 (d, J c-f = 21.50 Hz), 119.78 (d, J c-f = 21.74 Hz),
123.25, 123.78 (d, 3J c-f = 12.75 Hz), 124.00, 125.22
(d, 3J c-f = 12.55 Hz), 125.64, 126.40, 127.10, 128.84,
129.31, 130.41, 131.13, 132.10, 133.76, 140.21, 142.41,
1
145.23, 154.30, 162.95 (d, J c-f = 245.75 Hz), 188.78(C,
Chemistry
C=O). IR (KBr) νmax 1698, 1622, 1231 cm−1. MS m/z 277
(MH+).
Synthesis of naphthalene-chalcone derivatives 2a–2u
1-(3-fluorophenyl)-3-(naphthalen-1-yl)-2-propen-1-one
1
To a stirred solution of KOH (2.0 g, 46 mmol) in water
(5 mL) cooled to 0 °C in an ice bath was added dropwise a
solution of substituted acetophenone (1.0 mmol) and
1-naphthalene formaldehyde (2.0 mmol) in ethanol under
nitrogen (Guan et al. 2013a; Zhang et al. 2010; Zhao et al.
2005) (Scheme 1). The reaction mixture was maintained
(2b) Yellow solid; Yield: 36.7%, mp: 92–93 °C. H-NMR
(CDCl3, 300 MHz): δ = 7.33–7.65(m, 7H, −ArH), 7.55
(d, 1H, J = 15 Hz, =CH), 7.35–7.81 (m, 4H, −C6H4), 8.73
(d, 1H, J = 15 Hz, =CH). 13C-NMR (CDCl3, 75 MHz): δ =
115.39 (d, J c-f = 22.50 Hz), 119.93 (d, J c-f = 21.75 Hz),
123.34 (d, J c-f = 12.75 Hz), 124.00, 124.26, 125.56 (d,
2
2
3

Medicinal Chemistry Research
3J c-f = 12.75 Hz), 125.97, 126.44, 127.12, 128.74, 129.56,
1H-NMR (CDCl3, 300 MHz): δ = 7.29–7.65(m, 7H,
−ArH), 7.56 (d, 1H, J = 15 Hz, =CH), 7.20–8.01 (m, 4H,
−C6H4), 8.70 (d, 1H, J = 15 Hz, =CH). 13C-NMR
(CDCl3, 75 MHz): δ = 123.31, 125.54, 125.50, 126.42,
127.06, 127.21, 128.46, 128.90, 129.71, 130.45, 131.19,
131.44, 131.68, 131.70, 133.83, 139.52, 142.89, 143.65,
154.76, 167.18, 193.21(C, C=O). IR (KBr) νmax: 1695,
1621, 1229 cm−1. MS m/z 327(MH+), 329(MH+ +2).
130.31, 131.78, 132.43, 133.56, 140.35, 142.47, 145.33,
1
156.3, 162.95 (d, J c-f = 246.75 Hz), 188.88(C, C=O). IR
(KBr) νmax 1696, 1623, 1230 cm−1. MS m/z 277 (MH+).
1-(4-fluorophenyl)-3-(naphthalen-1-yl)-2-propen-1-one
1
(2c) Yellow solid; Yield: 40.7%, mp: 84–85 °C. H-NMR
(CDCl3, 300 MHz): δ = 7.18–7.74(m, 7H, −ArH), 7.68 (d,
1H, J = 15 Hz, =CH), 7.07–8.18 (m, 4H, −C6H4), 8.58 (d,
1H, J = 15 Hz, =CH). 13C-NMR (CDCl3, 75 MHz): δ =
116.02, 118.32, 120.44 (d, 2J c-f = 21.65 Hz), 124.53,
125.92 (d, 3J c-f = 12.70 Hz), 126.51, 126.94, 127.14,
1-(2-bromophenyl)-3-(naphthalen-1-yl)-2-propen-1-one
(2h) Yellow solid; Yield: 61.98%, mp: 71–72 °C.
1H-NMR (CDCl3, 300 MHz): δ = 7.40–7.73(m, 7H, -ArH),
7.54 (d, 1H, J = 15 Hz, =CH), 7.21–8.12 (m, 4H, -C6H4),
8.36 (d, 1H, J = 15 Hz, = CH). 13C-NMR (CDCl3,
75 MHz): δ = 119.60, 123.18, 125.50, 125.53, 126.36,
127.11, 127.51, 128.45, 128.86, 129.38, 131.22, 131.57,
131.72, 133.54, 141.27, 143.33, 194.53(C, C = O). IR
(KBr) νmax 1698, 1620, 1230 cm−1. MS m/z 337(MH+), 339
(MH+ +2).
128.81, 129.30, 130.11, 131.08, 132.72, 134.41, 135.25,
1
135.81, 143.80, 140.30, 144.63, 155.3, 158.60 (d, J
=
c-f
244.56 Hz), 191.31(C, C=O). IR (KBr) νmax 1696, 1620,
1231 cm−1. MS m/z 277 (MH+).
1-(2-chlorophenyl)-3-(naphthalen-1-yl)-2-propen-1-one
1
(2d) Yellow solid; Yield: 75.4%, mp: 69–70 °C. H-NMR
(CDCl3, 300 MHz): δ = 7.30–7.60(m, 7H, −ArH), 7.54 (d,
1H, J = 15 Hz, =CH), 7.25–7.96 (m, 4H, −C6H4), 8.40 (d,
1H, J = 15 Hz, =CH). 13C-NMR (CDCl3, 75 MHz): δ =
123.21, 125.49, 125.52, 126.36, 127.01, 127.10, 128.60,
128.87, 129.58, 130.41, 131.20, 131.43, 131.62, 131.74,
133.73, 139.22, 142.96, 143.56, 154.56, 167.08, 193.63(C,
C=O). IR (KBr) νmax 1697, 1623, 1230 cm−1. MS m/z 293
(MH+), 295 (MH+ +2).
1-(3-bromophenyl)-3-(naphthalen-1-yl)-2-propen-1-one
(2i) Yellow solid; Yield: 67.9%, mp: 116.5–117 °C.
1H-NMR (CDCl3, 300 MHz): δ = 7.40–7.61(m, 7H,
−ArH), 7.98 (d, 1H, J = 15 Hz, =CH), 7.43–8.03 (m, 4H,
−C6H4), 8.72 (d, 1H, J = 15 Hz, =CH). 13C-NMR (CDCl3,
75 MHz): δ = 123.06, 123.41, 123.98, 125.25, 125.46,
126.40, 127.09, 127.13, 128.84, 130.28, 131.17, 131.62,
131.78, 132.05, 133.76, 135.73, 139.98, 142.59, 188.78(C,
C=O). IR (KBr) νmax 1696, 1623, 1230 cm−1. MS m/z 337
(MH+), 339 (MH+ +2).
1-(3-chlorophenyl)-3-(naphthalen-1-yl)-2-propen-1-one
(2e) Yellow solid; Yield: 55%, mp: 104–105 °C. 1H-NMR
(CDCl3, 300 MHz): δ = 7.52–7.63(m, 7H, −ArH), 7.59 (d,
1H, J = 15 Hz, =CH), 7.49–8.29 (m, 4H, −C6H4), 8.73 (d,
1H, J = 15 Hz, =CH). 13C-NMR (CDCl3, 75 MHz): δ =
123.41, 123.90, 125.25, 125.47, 126.41, 126.65, 127.13,
128.69, 128.85, 130.04, 131.17, 131.78, 132.05, 132.83,
133.76, 135.01, 139.76, 142.55, 188.87(C, C=O). IR (KBr)
νmax 1698, 1623, 1230 cm−1. MS m/z 293 (MH+), 295
(MH+ +2).
1-(4-bromophenyl)-3-(naphthalen-1-yl)-2-propen-1-one
(2j) Yellow solid; Yield: 64.9%, mp: 110–111 °C.
1H-NMR (CDCl3, 300 MHz): δ = 7.54–7.66(m, 7H,
−ArH), 7.75 (d, 1H, J = 15 Hz, =CH), 7.72–8.20 (m, 4H,
−C6H4), 8.58 (d, 1H, J = 15 Hz, = CH). 13C-NMR (CDCl3,
75 MHz): δ = 123.12, 123.45, 123.78, 125.24, 125.49,
126.47, 127.12, 127.23, 128.67, 130.30, 131.21, 131.72,
131.80, 132.09, 133.55, 135.82, 139.45, 142.61, 188.90(C,
C=O). IR (KBr) νmax 1699, 1612, 1221 cm−1. MS m/z 337
(MH+), 339 (MH+ +2).
1-(4-chlorophenyl)-3-(naphthalen-1-yl)-2-propen-1-one
1
(2f) Yellow solid; Yield: 37.9%, mp: 81–82 °C. H-NMR
(CDCl3, 300 MHz): δ = 7.29–7.65(m, 7H, −ArH), 7.56
(d, 1H, J = 15 Hz, =CH), 7.20–8.01 (m, 4H, −C6H4), 8.70
(d, 1H, J = 15 Hz, =CH). 13C-NMR (CDCl3, 75 MHz): δ =
123.31, 125.54, 125.50, 126.42, 127.06, 127.21, 128.46,
128.90, 129.71, 130.45, 131.19, 131.44, 131.68, 131.70,
133.83, 139.52, 142.89, 143.65, 154.76, 167.18, 193.21(C,
C=O). IR (KBr) νmax 1697, 1621, 1230 cm−1. MS m/z 293
(MH+), 295 (MH+ +2).
1-(4-trifluoromethylphenyl)-3-(naphthalen-1-yl)-2-propen-
1-one (2k) Yellow solid; Yield: 57.7%, mp: 85–86 °C.
1H -NMR (CDCl3, 300 MHz): δ = 7.54–7.66 (m, 7H,
−ArH), 7.75 (d, 1H, J = 15 Hz, =CH), 7.72–8.20 (m, 4H,
−C6H4), 8.58 (d, 1H, J = 15 Hz, =CH). 13C-NMR (CDCl3,
75 MHz): δ = 123.12, 123.45, 123.78, 125.24, 125.49,
126.47, 127.12, 127.23, 128.67, 130.30, 131.21, 131.72,
131.80, 132.09, 133.55, 135.82, 139.45, 142.61, 188.90(C,
C=O). IR (KBr) νmax 1698, 1622, 1229 cm−1. MS m/z 327
(MH+).
1-(2,4-dichlorophenyl)-3-(naphthalen-1-yl)-2-propen-1-
one (2g) Yellow solid; Yield: 65.9%, mp: 113.5–114 °C.

Medicinal Chemistry Research
1-(4-nitrophenyl)-3-(naphthalen-1-yl)-2-propen-1-one (2l)
Yellow solid; Yield: 39.5%, mp: 146–147 °C. 1H-NMR
(CDCl3, 300 MHz): δ = 7.34–7.67(m, 7H, −ArH), 7.56 (d,
1H, J = 15 Hz, =CH), 7.32–8.41 (m, 4H, −C6H4), 8.28 (d,
1H, J = 15 Hz, =CH). 13C-NMR (CDCl3, 75 MHz): δ =
115.10, 122.35, 123.23, 124.74, 125.37, 126.27, 127.10,
127.33, 128.57, 130.25, 131.11, 131.62, 131.87, 132.10,
133.35, 135.62, 138.89, 142.73, 188.93(C, C=O). IR (KBr)
νmax 1699, 1632, 1222 cm−1. MS m/z 304(MH+).
1-(4-hydroxyphenyl)-3-(naphthalen-1-yl)-2-propen-1-one
(2q) Yellow solid; Yield: 58.6%, mp: 218–219 °C.
1H-NMR (CDCl3, 300 MHz): δ = 7.50–7.85 (m, 7H, −ArH),
7.70 (d, 1H, J = 15 Hz, =CH), 6.88–8.20 (m, 4H, −C6H4),
8.58 (d, 1H, J = 15 Hz, =CH), 10.04 (s, 1H, −OH). 13C-
NMR (CDCl3, 75 MHz): δ = 115.73, 123.32, 124.77,
125.74, 126.38, 127.09, 128.89, 130.58, 131.19, 139.58,
162.60, 188.56 (C, C=O). IR (KBr) νmax 3345, 1698, 1624,
1220 cm−1. MS m/z 275 (MH+).
1-(4-methylphenyl)-3-(naphthalen-1-yl)-2-propen-1-one
(2m) Yellow solid; Yield: 95.4%, mp: 85.7–87 °C. H-
1-(4-ethylphenyl)-3-(naphthalen-1-yl)-2-propen-1-one
(2r) Yellow solid; Yield: 49%, mp: 66-67 °C. H-NMR
1
1
NMR (CDCl3, 300 MHz): δ = 2.14 (s, 3H, −CH3),
7.35–7.63(m, 7H, −ArH), 7.55 (d, 1H, J = 15 Hz, =CH),
7.33–8.25 (m, 4H, −C6H4), 8.55 (d, 1H, J = 15 Hz, =CH).
13C-NMR (CDCl3, 75 MHz): δ = 23.5 (C,−CH3), 116.11,
122.34, 123.34, 123.67, 124.23, 125.29, 125.51, 126.58,
127.13, 127.26, 129.17, 130.29, 131.13, 131.58, 131.90,
132.19, 132.98, 135.62, 139.51, 142.70, 188.98 (C, C=O).
IR (KBr) νmax 1697, 1622, 1224 cm−1. MS m/z 273 (MH+).
(CDCl3, 300 MHz): δ = 2.41 (t, 3H, −CH3), 3.36 (s, 2H,
−CH2), 7.35–7.63(m, 7H, −ArH), 7.55 (d, 1H, J = 15 Hz,
= CH), 7.33–8.3(m, 4H, −C6H4), 8.55 (d, 1H, J = 15 Hz,
=CH). 13C-NMR (CDCl3, 75 MHz): δ = 19.8 (C, −CH2),
25.7 (C,−CH2), 118.12, 123.21, 123.66, 123.66, 125.26,
125.50, 126.49, 127.19, 127.33, 128.77, 130.29, 131.22,
131.68, 131.78, 132.10, 133.45, 135.92, 139.33, 142.71,
189.57 (C, C=O). IR (KBr) νmax 1697, 1622, 1223 cm−1
MS m/z 287 (MH+).
.
1-(4-methoxylphenyl)-3-(naphthalen-1-yl)-2-propen-1-one
1
(2n) Yellow solid; Yield: 46%, mp: 96–97 °C. H-NMR
1-(3-methoxyl-4-hydroxyphenyl)-3-(naphthalen-1-yl)-2-pro-
pen-1-one (2s) Yellow oil; Yield: 47.6%. 1H-NMR
(CDCl3, 300 MHz): δ = 3.92(s, 3H, −OCH3), 7.44–7.65
(m, 7H, −ArH), 7.56 (d, 1H, J = 15 Hz, =CH), 6.88–8.23
(m, 4H, −C6H3), 8.60 (d, 1H, J = 15 Hz, =CH), 10.09
(s, 1H, -OH). 13C-NMR (CDCl3, 75 MHz): δ = 55.95 (C,
−OCH3), 110.15, 110.97, 114.32, 114.45, 117.21, 123.49,
123.75, 124.97, 125.46, 126.24, 126.87, 128.71, 130.53,
140.57, 147.20, 147.56, 151.15, 151.30, 188.34 (C, C=O).
IR (KBr) νmax 3350, 1698, 1632, 1221 cm−1. MS m/z 305
(MH+).
(CDCl3, 300 MHz): δ = 3.28(s, 3H, −OCH3), 7.38–7.68(m,
7H, −ArH), 7.76 (d, 1H, J = 15 Hz, =CH), 7.50–8.19 (m,
4H, −C6H4), 8.57 (d, 1H, J = 15 Hz, =CH). 13C-NMR
(CDCl3, 75 MHz): δ = 55.65 (C, −OCH3), 98.50, 105.80,
121.81, 123.43, 125.07, 125.68, 126.26, 126.87, 128.79,
129.90, 130.28, 131.63, 132.59, 132.79, 133.69, 138.19,
106.60, 164.48, 189.84 (C, C=O). IR (KBr) νmax 1696,
1622, 1222 cm−1. MS m/z 289 (MH+).
1-(4-dimethylaminephenyl)-3-(naphthalen-1-yl)-2-propen-
1-one (2o) Yellow solid; Yield: 39.2%, mp: 133–134 °C.
1H -NMR (CDCl3, 300 MHz): δ = 3.11(s, 3H, −NCH3),
3.16(s, 3H, −NCH3), 7.55–7.72 (m, 7H, −ArH), 7.55 (d,
1H, J = 15 Hz, =CH), 7.55–8.31 (m, 4H, −C6H4), 8.66 (d,
1H, J = 15 Hz, =CH). 13C-NMR (CDCl3, 75 MHz): δ =
40.09 (C, −NCH3), 40.14 (C, −NCH3), 110.88, 123.81,
124.83, 125.08, 125.48, 125.91, 126.19, 126.76, 128.66,
130.16, 130.96, 139.53, 153.47, 189.43 (C, C=O). IR
(KBr) νmax 1698, 1632, 1221 cm−1. MS m/z 302(MH+).
1-(3,4-dimethylphenyl)-3-(naphthalen-1-yl)-2-propen-1-one
1
(2t) Yellow solid; Yield: 54.6%, mp: 92.7–93.5 °C. H-
NMR (CDCl3, 300 MHz): δ = 2.36 (s, 3H, −CH3), 2.45
(s, 3H, −CH3), 7.47–7.69 (m, 7H, −ArH), 7.56 (d, 1H, J =
15 Hz, =CH), 7.16–8.15 (m, 4H, -C6H3), 8.35 (d, 1H, J =
15 Hz, =CH). 13C-NMR (CDCl3, 75 MHz): δ = 22.81 (C,
−CH3), 23.10 (C, −CH3), 117.12, 123.55, 123.88, 125.20,
125.56, 126.57, 127.11, 127.33, 128.77, 130.33, 131.24,
131.82, 131.85, 132.19, 133.75, 135.77, 139.65, 142.63,
1-(4-aminophenyl)-3-(naphthalen-1-yl)-2-propen-1-one
(2p) Yellow solid; Yield: 41.4%, mp: 199–202 °C.
1H-NMR (CDCl3, 300 MHz): δ = 7.49–7.73(m, 7H,
−ArH), 7.64 (d, 1H, J = 15 Hz, =CH), 7.51–8.20 (m, 4H,
−C6H4), 8.47 (d, 1H, J = 15 Hz, =CH), 9.30, (s, 1H,
−NH), 10.34 (s, 1H, −NH). 13C-NMR (CDCl3, 75 MHz): δ
= 113.48, 123.40, 125.00, 125.70, 126.29, 126.92, 128.80,
130.26, 131.21, 131.63, 132.63, 133.68, 138.73, 153.50,
187.46 (C, C=O). IR (KBr) νmax 3420, 1697, 1622,
1221 cm−1. MS m/z 274 (MH+).
188.94 (C, C=O). IR (KBr) ν
1697, 1619, 1220 cm−1
.
max
MS m/z 287 (MH+).
1-(3,4-dimethoxylphenyl)-3-(naphthalen-1-yl)-2-propen-1-
1
one (2u) Yellow solid; Yield: 41.5%, mp: 77–78 °C. H-
NMR (CDCl3, 300 MHz): δ = 3.87 (s, 3H, −OCH3), 3.90
(s, 3H, −OCH3), 7.34–7.65 (m, 7H, −ArH), 7.56 (d, 1H,
J = 15 Hz, =CH), 7.32–8.23 (m, 4H, −C6H3), 8.57 (d, 1H,
J = 15 Hz, =CH). 13C-NMR (CDCl3, 75 MHz): δ = 55.65
(C, −OCH3), 55.90 (C, −OCH3), 115.78, 117.61, 121.81,

Medicinal Chemistry Research
123.43, 125.07, 125.68, 126.26, 126.87, 128.79, 129.90,
130.28, 131.63, 132.59, 132.79, 133.69, 138.19, 151.36,
155.62, 189.84 (C,C=O). IR (KBr) νmax 1698, 1622,
1221 cm−1. MS m/z 319 (MH+).
the open-field apparatus, and his locomotor activity asses-
sed. The open-field apparatus was a nontransparent plastic
container (80 × 60 × 30 cm), with the underside divided into
48 units of size 10 × 10 cm, without walls. Mice were
placed gently in the center of the platform and allowed to
explore their surroundings. Hand-operated counters were
used to score locomotion (ambulation, numbers of line
crossed with four paws) and rearing frequencies (number of
times the mouse stood on his hind legs) for 5 min. The
researchers, who did not know which groups had been
treated, scored the behaviors in the open field. Experiments
were carried out in a dark room and the apparatus was
illuminated by a 60-W bulb giving a yellowish light, posi-
tioned 1 m above the center of the apparatus.
Animals
All animal-handling procedures were conducted in accor-
dance with regulatory guidelines set by the Chinese govern-
ment. ICR mice (20 2g) were provided by the Laboratory of
Animal Research, College of Pharmacy, Zhejiang Academy
of Medical Sciences (Zhejiang, China). Animals were allowed
to acclimatize for 1 week before experimentation. Before and
during experiments, mice were housed under controlled
environmental conditions of temperature (23 2 °C) and a 12-
h light–dark cycle and maintained (unless stated otherwise) on
standard food pellets and tap water ad libitum.
The sample preparation
The doses of 30 mg/kg compound 2o and fluoxetine were
employed for testing the effect on monoamine neuro-
transmitter concentrations in the rat brain. Mice were ran-
domly divided into five groups (eight mice per group were
used). Fluoxetine, compound 2o, normal vehicle and stress
vehicle were given orally daily for 7 days. On the last day,
the drugs and compound 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.
The forced swimming test
All compounds were dissolved in polyethylene glycol-400.
Fluoxetine was dissolved in isotonic (0.9%) saline solution.
The vehicle solvent served as a negative control, and
fluoxetine as a positive control. All compounds and fluox-
etine were administered intraperitoneal 30 min before the
forced swimming test. Male ICR mice were housed in
groups of eight. On the test day, mice were dropped, one at
a time, into a Plexiglass™ cylinder (height, 25 cm; dia-
meter, 10 cm) containing 10 cm of water at 22 3 °C and
left in the water for 6 min. After the first 2 min of vigorous
struggling, the animals were immobile. The duration of
immobility was recorded during the last 4 min of the 6-min
test. The immobility duration was regarded to be the time
spent by the mouse floating in water without struggling and
making only those movements necessary to keep his head
above the water (Porsolt et al. 1997; Guan et al. 2013b).
HPLC condition and test
The brain tissues were sonicated in 0.1M NaH2PO4 aqueous
solution including 0.85 mM OSA, 0.5 mM Na2·EDTA and
centrifuged at 13,000 × g for 15 min at 4 °C. Then serotonin
and norepinephrine were assayed by HPLC-ECD. Equipment:
Shimadzu LC-10ATVP HPLC system, Shimadzu
L-ECD-6A electrochemical detector, N2000 HPLC work-
station software, Hypersil ODS C18 Column 4.6 × 150 mm
5 μM. The mobile phase consisted of 0.1M 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 serotonin and
norepinephrine 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 serotonin and norepinephrine by HPLC
coupled with electrochemical detection in brain region.
The tail suspension test
Each mouse was suspended by his tail with a clamp (2 cm
from the tail tip) in a box (25 × 25 × 30 cm) with his head
5 cm from the bottom of the box. Testing was carried out in a
darkened room with minimal background noise. Mice were
suspended for 6 min, and the duration of immobility measured
during the final 4 min of the tail suspension test. Mice were
considered to be immobile only if they hung passively and
completely motionless (Steru et al. 1985; Zhen et al. 2016).
The open-field test
Anti-inflammatory effect
The open-field test was carried out in mice according to the
method of Archer with slight modifications (Archer 1973;
Elliott et al. 1986). Each mouse was placed in the center of
There were ICR eight mice per group. Edema was
induced by xylene administered by topical application

Medicinal Chemistry Research
(0.05 mL per ear) (Rajahamsa et al. 2013; Gouvea et al.
2016; Abdel-Aziz et al. 2016). Each group of mice was
injected intraperitoneally with compounds 2a–2u and
indomethacin, both at 30 mg/kg. Edema was expressed as
an increase in ear thickness due to inflammation. Ear
thickness was measured before and after inflammation
induction. A 6-mm section of ear was obtained and
weighed using an analytical balance. The ear swelling
induced by xylene was evaluated as the increase in ear
weight of the treated group over that of the untreated
group, and was called the Edema Index. Percentage anti-
inflammatory activity was calculated according to the
formula:
Results and discussion
The structure of target compounds was confirmed by FT-IR,
1H-NMR, 13C-NMR, and mass spectroscopy. Molecular ion
peaks were observed in accordance with the molecular
weight of the respective compound. The IR spectrum of
compounds 2q and 2s exhibited characteristic absorption
bands at 1695–1699 cm−1 for −C=O stretching and at 3345
and 3350 cm−1 for −OH stretching, respectively. In the 1H-
NMR spectra of compounds 2a–2u, −CH=CH protons of
the propylene group were observed at 7.55–7.98 and
8.35–8.73 ppm. In the 13C-NMR spectra of compounds
2a–2u, −C=O signals were seen at 187.61–194.53 ppm.
The forced swimming test and tail suspension test are
validated stress models of depression. These tests induce
despair in animals and have good reliability and predictive
validity in mice (De Oliveira et al. 2011). In two models,
mice are restricted and cannot escape, which induces the
characteristic behavior of immobility. The immobility dis-
played in both of these models has been hypothesized to
reflect behavioral despair which, in turn, may reflect
depressive disorders in humans. These two models are
usually employed to screen/evaluate antidepressant activity
(Borsini et al. 1986). In the forced swimming test or tail
suspension test, the total duration of immobility is reduced
by most antidepressants if administered acutely or sub-
chronically to animals.
The forced swimming test is the most widely used model
to screen new antidepressant drugs. A wide variety of
antidepressants and compounds with potential anti-
depressant effects have been shown to reduce the duration
of immobility in the forced swimming test (Ma et al. 2016;
Jin et al. 2017). In the forced swimming test, the anti-
depressant effect of target compounds 2a–2u and fluoxetine
is shown in Table 1. All compounds produced a marked
reduction in the duration of immobility at 30 mg/kg, indi-
cating important antidepressant effects. Among them,
compounds 2h, 2o, 2t and 2u led to a significant reduction
in the duration of immobility compared with the control
group (p < 0.001) and exhibited an antidepressant effect
better than or similar to the positive control fluoxetine (p <
0.001). For more detailed understanding of the anti-
depressant effects of these target compounds, the percent
decrease in immobility duration (% DID) was calculated
using the formula:
Percent anti-inflammatory activity ¼ ½ðWc À WtÞ=WcŠ  100
where Wc and Wt represent the mean ear weight of control
and treated mice, respectively.
Analgesic effect in vivo
The analgesic activity of compounds and drugs was studied
by observing the writhing response (i.e., contraction of
abdominal muscles and stretching of hind limbs) of mice
through intraperitoneal administration of acetic acid (Koster
et al. 1959). Test mice were selected randomly and divided
into groups (n = 8). Compounds 2a–2u and indomethacin
were dissolved in PEG-400 and administered (30 mg/kg,
intraperitoneal) to each group of mice 40 min before
administration of 0.7% acetic acid (0.1 mL/10 g, intraper-
itoneal). This 40-min interval was employed to ensure
absorption of administered samples. Five minutes after
administration of acetic acid, each animal was isolated in an
individual observation chamber, and the cumulative number
of writhing responses for 10 min recorded. The percent
inhibition of writhing in comparison with the control group
was taken as an index of analgesia, and was calculated
using the formula:
Inhibition ð%Þ ¼ ðXc À Yt=YcÞ Â 100
where Xc is the mean number of writhing reflexes in the
control group, and Yt is the mean number of writhing
reflexes in the test group. Then, the reaction time was
retested 60 min after injection, and the percent change in the
reaction was calculated.
Statistical analyses
% DID ¼ ½ðX À YÞ=XŠ  100
Statistical analyses were carried out using Prism v2.0
(GraphPad, San Diego, CA, USA). Results are the mean
SEM. The Student’s t test was used to compare differ-
ences between the two groups. P < 0.05 was considered
significant.
where X is the duration of immobility (s) in the control
group and Y is the duration of immobility (s) in the test
group (Table 1). Compounds 2h, 2o, 2t, and 2u reduced the
duration of immobility and gave high values of % DID.
Among them, the % DID of compounds 2h (76.7%), 2o

Medicinal Chemistry Research
Table 1 Evaluation of the antidepressant effects of compounds 2a–2u
in the FST
fluoxetine (63.4%) at 30 mg/kg in the tail suspension test,
suggesting considerable antidepressant activity.
Antidepressant effectsa
The structure–activity relationship studies for the anti-
depressant activity of compounds 2a–2u shown in Table 1
elicited five main findings. First, all compounds displayed a
significant decrease in immobility duration and exhibited
good antidepressant activity with electron-withdrawing and
electron-donating substituents on the phenyl ring. Second, for
nine compounds with an electron-donor substituent such as a
−CH3, −OCH3, −N(CH3)2, −NH2, −OH, −CH2CH3,
−OCH3−OH3, −(CH3)2, or −(OCH3)2 group, the anti-
depressant activity was in the order 4−N(CH3)2 > 3.4
−(OCH3)2 > 3,4−(CH3)2 > 4−NH2 > 4−CH3 > 3−OCH3−4
−OH > 4−CH2CH3 > 4−OH > 4−OCH3, respectively. Com-
pound 2o with a -N(CH3)2 substituent reduced the immobility
duration in the FST significantly, and displayed the greatest
antidepressant effect on the phenyl ring. Third, nine com-
pounds with an electron-withdrawing substituent such as an F
atom (2a, 2b, and 2c), Cl atom (2d, 2e, and 2f), or Br atom
(2g, 2h, and 2i) exhibited an excellent antidepressant effect.
The position of the halogen substitution greatly influenced the
antidepressant effect. For derivatives with varying halogen-
substitution patterns on the phenyl ring, the orders of activity
were p-F > m-F > o-F, m-Cl > o-Cl > p-Cl, o-Br > m-Br > p-
Br. Fourth, compounds 2k and 2l with a trifluoromethyl
(−CF3) or nitro group (−NO2) substituent showed an anti-
depressant effect and decreased the immobility duration in
mice by 54.5 and 63.0%, respectively. Also, compound 2j
with a 2,4-dichlolo substituent exhibited antidepressant
activity of 51.4%. Finally, absence of a substituent on the
phenyl ring of lead compound I led to weaker antidepressant
activity than that for other compounds. Hence, determination
of the structure–activity relationship for the substituent group
attached to the phenyl ring may be important.
In the forced swimming test or tail suspension test, some
compounds or drugs that change motor activity may give
false-positive/false-negative effects. In particular, psycho-
motor stimulants and drugs can enhance motor activity,
which decreases the immobility duration by stimulating the
locomotor effect (Elliott et al. 1986). We evaluated the
effect of compounds 2h, 2o, 2t, and 2u on spontaneous
locomotor activity in the open-field test. Compounds 2h,
2o, 2t, and 2u did not change motor activity (crossing,
rearing, or grooming) significantly in mice (Table 3). These
results suggested that the antidepressant effects induced by
compounds 2h, 2o, 2t, and 2u were not caused by central
nervous system-stimulating effects.
Compounds
R
Duration of immobility(s) DID (%)
I
–
99.3 15.1*
88.4 5.2**
68.4 3.9**
59.0 6.9***
79.6 9.0**
74.0 6.3**
82.8 7.5**
76.4 5.8**
36.6 7.6***
57.3 8.1***
78.2 5.7**
71.6 4.5**
58.2 4.2***
70.2 7.3**
95.8 4.4*
36.8
43.8
56.5
62.5
49.4
52.9
47.3
51.4
76.7
63.5
50.3
54.5
63.0
55.3
39.1
82.8
63.7
41.5
45.4
46.6
69.1
74.2
73.4
–
2a
2-F
2b
3-F
2c
4-F
2d
2-Cl
2e
3-Cl
2f
4-Cl
2g
2,4-Cl2
2-Br
2h
2i
3-Br
2j
4-Br
2k
4-CF3
4-NO2
4-CH3
4-OCH3
4-N(CH3)2
4-NH2
4-OH
2l
2m
2n
2o
27.0 5.0***
57.0 9.4***
92.0 4.8*
2p
2q
2r
4-CH2CH3
3-OCH3-4-OH
3,4-(CH3)2
3.4-(OCH3)2
85.8 7.7**
84.0 3.9**
48.6 6.8***
40.6 4.9***
41.8 8.3***
157.2 4.2
2s
2t
2u
Fluoxetine
Control
Values are the mean SEM (n = 8)
% DID percentage decrease in immobility duration
*Significantly different compared with control (p < 0.05; **p < 0.01;
***p < 0.001)
aCompounds and fluoxetine were administered intraperitoneally at
30 mg/kg
(82.8%), 2t (69.1%), and 2u (74.2%) was higher than or
similar to that of fluoxetine (73.4%) at 30 mg/kg in the
forced swimming test. Compound 2o led to the greatest
reduction in the immobility duration compared with the
control group (p < 0.001).
Compounds 2h, 2o, 2t, and 2u had the most potent
antidepressant activity in the forced swimming test, and
were evaluated further to confirm their antidepressant
activity in the tail suspension test (Table 2). In the latter, the
decrease in immobility duration of compounds 2h, 2o, 2t,
and 2u was similar to that in the forced swimming test.
Compounds 2h, 2o, 2t, and 2u displayed a significant
decrease in immobility duration at 30 mg/kg that was
similar to or greater than that of the positive control
fluoxetine. The % DID of compounds 2h (67.6%), 2o
(52.3%), 2t (47.1%), and 2u (58.8%) was similar to that of
Serotonin and norepinephrine have been suggested to
play a role in the pathogenesis of depression. In the central
nervous system, a metabolic disorder of monoamine neu-
rotransmitters 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

Medicinal Chemistry Research
Table 2 Evaluation of the antidepressant effects of compounds 2h, 2o,
2t and 2u in the TST
Table 4 Effect of FST exposure and 2o on brain monoamine
neurotransmitter levels
Compounds Antidepressant effectsa
Groups
Serotonin
Norepinephrine
Duration of immobility(s) Change from control (%)b
Normal vehicle
Stress vehicle
2o
254.7 29.2
287.1 30.2
124.1 26.1
268.2 31.2***,****
283.4 30.0***,*****
115.6 20.4
299.4 29.1*,*****
302.6 30.4**,*****
2h
37.2 5.5***
54.5 5.2**
60.4 9.8*
67.6
52.3
47.1
58.8
63.4
–
2o
Fluoxetine
2t
2u
47.1 3.5**
41.8 8.3***
114.2 4.8
The doses of 2o and fluoxetine were 20 mg/kg. Neurotransmitter levels
are expressed as ng/g per brain region wet weight. Data are expressed
as mean SEM (n = 10). Statistical analyses of data were conducted
using one-way analysis of variance followed by Turkey’s test
Fluoxetine
Control
Values are the mean SEM (n = 8)
*p < 0.05; **p < 0.01; ***p < 0.001 vs. stress vehicle; **** p < 0.05;
*****p < 0.01 vs. normal vehicle
*Significantly different compared with control (p < 0.05; **p < 0.01;
***p < 0.001)
aCompounds and fluoxetine were administered intraperitoneally at
30 mg/kg
b% DID percentage decrease in immobility duration
Table 5 Anti-inflammatory activities of the designed compounds
2a–2u
Anti-inflammatory activitya
Table 3 Compounds 2h, 2o, 2t, and 2u on exploratory activity in the
open-field test
Compounds
R
Ear edema
Inhibition rate (%)
2a
2-F
1.40 0.53**
0.85 0.06*** 84.7
2.12 1.12*
1.31 0.93**
2.05 1.12*
2.33 1.06*
75.1
Compounds
Crossing
Rearing
Grooming
2b
3-F
2h
87.5 6.7
86.9 7.2
88.7 8.8
87.0 7.5
88.6 5.8
9.7 5.0
9.9 9.8
9.0 5.1
9.4 6.2
9.8 3.9
10.5 6.1
10.2 6.9
9.8 4.7
9.6 5.3
10.1 3.9
2c
4-F
62.3
76.7
63.5
58.5
2o
2d
2-Cl
2t
2e
3-Cl
2u
2f
4-Cl
Control
2g
2,4-Cl2
2-Br
0.95 0.18*** 83.1
2.22 1.11*
1.24 0.38**
1.59 1.47**
60.5
77.9
71.1
Crossing: number of line crossings; rearing: number of times observed
standing on hind legs; grooming: number of modifications. Values
represent the mean SEM (n = 8)
2h
2i
3-Br
2j
4-Br
2k
4-CF3
4-NO2
4-CH3
4-OCH3
4-N(CH3)2
4-NH2
4-OH
4-CH2CH3
0.72 0.32*** 87.2
2.82 1.06*
50.0
0.51 0.29*** 90.9
central nervous 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, compound 2o significantly
increased serotonin and norepinephrine levels at the highest
doses during the forced swimming test in mice brain,
similar to the positive control drug fluoxetine. These find-
ings indicate that the antidepressant effect of compound 2o
is likely mediated by increased serotonin and nor-
epinephrine levels in central nervous system.
We evaluated the anti-inflammatory and analgesic
activities of compounds 2a–2u using the xylene-induced
ear-edema test and acetic acid-induced abdominal writhing
in mice (Gouvea et al. 2016; Abdel-Sayed et al. 2016). All
compounds showed a significant reduction in writhing at
30 mg/kg. The percent inhibition of writhing increased from
52.99 to 99.73% and displayed analgesic activity. Com-
2l
2m
2n
2.17 1.20*
1.23 0.22**
1.53 0.52**
1.29 0.46**
61.4
78.1
72.8
77.0
2o
2p
2q
2r
0.63 0.37*** 88.8
67.4
0.82 0.33*** 85.4
2s
3-OCH3-4-OH 1.83 0.84*
2t
3,4-(CH3)2
2u
3.4-(OCH3)2
2.26 1.11*
1.33 .013**
5.62 2.5
59.8
76.9
–
Indomethacin
Control
–
–
*p < 0.05; ** p < 0.01; *** p < 0.001 compared with control group
a% at 60 min of anti-inflammatory activity
suffering from chronic pain. It has been suggested that pain
and depression possess similar neurochemical mechanisms
(Boufidou and Nikolaou 2016). Antidepressants have been
used as analgesic agents for neuropathic and non-
neuropathic pain because they display intrinsic anti-
nociceptive effects (Ismail et al. 2017). Monoamine uptake
pounds 2a–2u also displayed
a
significant anti-
inflammatory effect (p < 0.05, p < 0.01, p < 0.001) at
30 mg/kg body compared with the control group (Table 5
and Fig. 2). Inflammation is characterized by pain, swelling,
redness and heat, whereas depression is common in people

Medicinal Chemistry Research
Fig. 2 Analgesic effect of the
designed compounds 2a–2u
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
is inhibited, which leads to increases in levels of nora-
drenaline and serotonin, which reinforce pain-inhibitory
pathways (Uddin et al. 2018). Several scholars have pos-
tulated that the antidepressant drugs displayed the anti-
inflammatory and analgesic effects (Ismail et al. 2016),
suggesting that they may possess a similar mechanism of
action.
References
Archer J (1973) Tests for emotionality in rats and mice: a review.
Anim Behav 21:205–235
Abdel-Aziz AAM, Abou-Zeid LA, El-Tahir KEH, Ayyad RR, El-Sayed
MAA, El-Azab AS (2016) Synthesis, anti-inflammatory, analgesic,
COX-1/2 inhibitory activities and molecular docking studies of
substituted 2-mercapto-4(3H)-quinazolinones. Eur J Med Chem
121:410–421
Conclusion
Abdel-Sayed MA, Bayomi SM, El-Sherbeny MA, Abdel-Aziz NI,
ElTahir KEH, Shehatou GSG, Abdel-Aziz AAM (2016) Synthesis,
anti-inflammatory, analgesic, COX-1/2 inhibition activities and
molecular docking study of pyrazoline derivatives. Bioorg & Med
Chem 24:2032–2042
In this paper, 21 naphthalene-chalcone derivatives were
assessed the antidepressant, anti-inflammatory and analge-
sic effects. Compounds 2a–2u showed clear antidepressant
activity at 30 mg/kg in the FST. Compounds 2h, 2o, 2t, and
2u exhibited a good antidepressant effect. And, we found
that the antidepressant effect of compound 2o is likely
mediated by increased serotonin and norepinephrine levels
in central nervous system. Compounds 2a–2u also showed
analgesic and anti-inflammatory effects. Several scholars
have postulated the anti-inflammatory and analgesic effects
of antidepressant drugs, suggesting that they may be pos-
sess a similar mechanism of action.
Borsini F, Voltera G, Meli AA (1986) Dose the behavioral ‘despair’
test measure ‘despair’. Physiol Behav 38:385–389
Boufidou F, Nikolaou C (2016) Αnti-inflammatory medication as
adjunctive antidepressive treatment. Psychiatriki 27(2):106–117
Carradori S, Gidaro MC, Petzer A, Costa G, Guglielmi P, Chimenti P,
Alcaro S, Petzer JP (2016) Inhibition of human monoamine
oxidase: biological and molecular modeling studies on selected
natural flavonoids. J Agric Food Chem 64(47):9004–9011
De Oliveira KN, Costa P, Santin JR, Mazzambani L, Bürger C, Mora
C, Nunes RJ, de Souza MM (2011) Synthesis and antidepressant-
like activity evaluation of sulphonamides and sulphonyl-
hydrazones. Bioorg Med Chem 19:4295–4306
Dhanda S, Sandhir R (2015) Role of dopaminergic and serotonergic
neurotransmitters in behavioral alterations observed in rodent
model of hepatic encephalopathy. Behav Brain Res 286:222–235
Elliott PJ, Chan J, Parker YM (1986) Behavioral effects of neurotensin
in the open field: structure-activity studies. Brain Res
381:259–265
Acknowledgements This research was funded by the National Natural
Science Foundation of China (No. 81760207 and 81560149) and
Zhejiang Province Public Technology Application Project of China
(No. LGJ20H090001) and Research project of laboratory work in
Colleges and universities of Zhejiang Province (No. YB201946). We
thank Arshad Makhdum, PhD, from Liwen Bianji, Edanz Group China
(www.liwenbianji.cn/ac), for editing the English text of a draft of this
manuscript.
Gouvea DP, Vasconcellos FA, Berwaldt GDA, Seixas Neto ACP,
Fischer G, Sakata RP, Almeida WP, Cunico W (2016) 2-Aryl-3-(2-
morpholinoethyl)thiazolidin-4-ones: synthesis, anti-inflammatory
in vivo, cytotoxicity in vitro and molecular docking studies. Eur J
Med Chem 118:259–265
Compliance with ethical standards
Guan LP, Liu BY (2016) Antidepressant-like effects and mechanisms
of flavonoids and related analogues. Eur J Med Chem 121:47–57
Conflict of interest The authors declare that they have no conflict of
interest.

Medicinal Chemistry Research
Guan LP, Zhao DH, Chang Y, Sun Y, Ding XL, Jiang JF (2013a) Design,
synthesis and antidepressant activity evaluation 2'-hydroxy-4',6'-dii-
soprenyloxychalcone derivatives Med Chem Res 22:5218–5226
Guan LP, Zhao DH, Chang Y, Wen ZS, Tang LM, Huang FF (2013b)
Synthesis of 2,4-dihydroxychalcone derivatives as potential
antidepressant effect. Drug Res 63:46–51
Guan LP, Tang LM, Pan CY, Zhao SL, Wang SH (2014) Evaluation
of potential antidepressant-like activity of chalcone-1203 in var-
ious murine experimental depressant models. Neurochem Res
39:313–320
Hao CW, Lai WS, Ho CT, Sheen LY (2013) Antidepressant-like effect
of lemon essential oil is through a modulation in the levels of
norepinephrine, dopamine, and serotonin in mice: use of the tail
suspension test. J Funct Foods 5(1):370–379
Ismail H, Dilshad E, Waheed MT, Sajid M, Kayani WK, Mirza B
(2016) Transformation of Lactuca sativa L with rol C gene results
in increased antioxidant potential and enhanced analgesic, anti-
inflammatory and antidepressant activities in vivo. 3 Biotech 6
(2):215
Ismail H, Dilshad E, Waheed MT, Mirza B (2017) Transformation of
Lettuce with rol ABC genes: extracts show enhanced antioxidant,
analgesic, anti-inflammatory, antidepressant, and anticoagulant
activities in rats. Appl Biochem Biotechnol 181(3):1179–1198
Jin HG, Zhou M, Jin QH, Liu BY, Guan LP (2017) Antidepressant-
like effects of saringosterol, a sterol from Sargassum fusiforme by
performing in vivo behavioral tests. Med Chem Res 26:909–915
Karim N, Khan I, Ahmad N, Umar MN, Gavande N (2017) Anti-
depressant, anticonvulsant and antinociceptive effects of 3'-
methoxy-6-methylflavone and 3'-hydroxy-6-methylflavone may
involve GABAergic mechanisms. Pharm Rep. 69(5):1014–1020
Koster R, Anderson M, De Beer E (1959) Acetic acid-induced
analgesic screening. Fed Proc 18:412–418
3-phenyliminoindolin-2-one derivatives. Chem Biol Drug Des
87:342–351
Porsolt RD, Bertin A, Jalfre M (1997) Behavioural despair in mice: a
primary screening test for antidepressants. Arch Int Pharmacodyn
229:327–336
Rajahamsa AKL, Deepak KS, Rao TKVK, Kumar AVRP, Reddy
GRS, Potbhare MS (2013) Multi-model confirmatory evaluation
of anti-inflammatory, analgesic and antioxidant activities of
Puranjiva roxburghii wall. Int J Biomed Adv Res 12:921–932
Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension
test: a new method for screening antidepressants in mice. Psy-
chopharmacol 85:367–370
Sui X, Quan YC, Chang Y, Zhang RP, Xu YF, Guan LP (2012)
Synthesis and studies on antidepressant activity of 2',4',6'-trihy-
droxychalcone derivatives. Med Chem Res 21:1290–1296
Uddin MMN, Kabir MSH, Hasan M, Al Mahmud Z, Alam Bhuiya
NMM, Ahmed F, Hasan MR, Hosen MT, Alam MS (2018)
Assenssment of the antioxidant, thrombolytic, analgesic, anti-
inflammatory, antidepressant and anxiolytic activities of leaf
extracts and fractions of Tetracera sarmentosa (L.) Vahl. J Basic
Clin Physiol Pharm 29(1):81–93
Xie C, Peng Z, Zhao SL, Pan CY, Guan LP, Sun XY (2014) Synthesis
of 2´-hydroxy-4´-isoprenyloxychalcone derivatives with potential
antidepressant-like activity. Med Chem 10:789–799
Zhang XW, Zhao DH, Quan YC, Sun LP, Yin XM, Guan LP (2010)
Synthesis and evaluation of antiinflammatory activity of sub-
stituted chalcone derivatives. Med Chem Res 19:403–412
Zhao LM, Jin HS, Sun LP, Piao HR, Quan ZS (2005) Synthesis and
evaluation of antiplatellet activity of trihydroxychalcone deriva-
tives. Bioorg Med Chem Lett 15:5027–5029
Zhen XH, Quan YC, Peng Z, Han Y, Zheng ZJ, Guan LP (2016)
Design, synthesis, and potential antidepressant-like activity of 7-
prenyloxy-2,3-dihydroflavanone derivatives. Chem Biol Drug
Des 87:858–866
Ma JY, Quan YC, Jin HG, Zhen XH, Zhang XW, Guan LP (2016)
Practical synthesis, antidepressant, and anticonvulsant activity of