Design, Synthesis, and Potential Antidepressant-like Activity of 7-prenyloxy-2,3-dihydroflavanone Derivatives

Article abstract of DOI:10.1111/cbdd.12717

A series of 7-prenyloxy-2, 3-dihydroflavanone derivatives were synthesized and screened for their antidepressant-like activity. Among them, it was observed that compounds 5j and 5k were found to be the most antidepressant-like activity. In addition, it was found that compounds 5j and 5k significantly increased the concentrations of the main neurotransmitters 5-HT and NE in the hippocampus, hypothalamus, and cortex. Compounds 5j and 5k also significantly increased the contents of 5-HIAA in the hippocampus and cortex, shut down 5-HT metabolism compared with mice treated with stress vehicle. These results suggested that compounds 5j and 5k displayed potent antidepressant-like properties that were mediated via neurochemical systems.

Full text of DOI:10.1111/cbdd.12717

Chem Biol Drug Des 2016; 87: 858–866
Research Article
Design, Synthesis, and Potential Antidepressant-like
Activity of 7-prenyloxy-2,3-dihydroflavanone
Derivatives
Xing-Hua Zhen1,2, Ying-Chun Quan3,
the second leading cause of disease-related disability by
2020 (1,2). Although there are many effective antidepres-
sants available today, the current remission of therapy is
Zhou Peng1,2, Yan Han4, Zhou-Jun Zheng4,*
and Li-Ping Guan1,2,
*
often inadequate with unsatisfactory results in about one-
third of all subjects treated (3,4). Therefore, the discovery
of new antidepressant drugs with fewer side-effects and
better efficacy is necessary.
1Food and Pharmacy College, Zhejiang Ocean University,
Zhoushan, Zhejiang 316022, China
2Zhejiang Provincial Engineering Technology Research
Center of Marine Biomedical Products, Zhoushan,
Zhejiang 316022, China
It reports that gamma-amino butyric acid and brain-
derived neurotrophic factor are associated with depressive
disorders, but a metabolic disorder of monoamine neuro-
transmitters in the CNS is believed to be the main bio-
chemical cause of depression. The monoamine hypothesis
supposed that depression was a result of the depletion of
NE, 5-HT, and DA in addition to activation of monoamine
oxidase in the CNS. Depression can be alleviated by
increasing the levels of monoamine neurotransmitters in
the CNS. NE, 5-HT, and DA play important roles in medi-
ating behavioral effects of antidepressant drugs (5,6).
3College of Medicine, Yanbian University, Park Street 977,
Yanji, Jilin 133002, China
4Zhejiang Ocean University Donghai Science and
Technology College, Zhoushan, Zhejiang 316000, China
*Corresponding authors: Zhou-Jun Zheng,
zhengzj_good@126.com; Li-Ping Guan,
glp730@zjou.edu.cn
A series of 7-prenyloxy-2, 3-dihydroflavanone deriva-
tives were synthesized and screened for their antide-
pressant-like activity. Among them, it was observed
that compounds 5j and 5k were found to be the most
antidepressant-like activity. In addition, it was found
that compounds 5j and 5k significantly increased the
concentrations of the main neurotransmitters 5-HT and
NE in the hippocampus, hypothalamus, and cortex.
Compounds 5j and 5k also significantly increased the
contents of 5-HIAA in the hippocampus and cortex,
shut down 5-HT metabolism compared with mice trea-
ted with stress vehicle. These results suggested that
compounds 5j and 5k displayed potent antidepres-
sant-like properties that were mediated via neuro-
chemical systems.
In recent years, it has been reported that flavonoids pos-
sess antidepressant-like activities (7–12). Grosso et al. (13)
reported that flavonoids displayed the antioxidant activities
thus preventing oxidative stress, which is believe to be
one of the causes of disorders affecting the central ner-
vous system. Moreover, the benefits of flavonoids have
been found in the diet in the treatment of depression,
Alzheimer’s disease, Parkinson’s disease, and epilepsy.
Pathak et al. (14) also reported that the natural polyphe-
nols modulate monoaminergic neurotransmission in the
brain and thus possess antidepressant-like activity in ani-
mal models of depression, such as amentoflavone and
rutin. Flavanones are a group of flavonoids, a previous
study from our laboratory found that 20-hydroxy- 40-preny-
loxychalcone derivatives(I) and 5,7-dihydroxyflavanone
derivatives(II) demonstrated the antidepressant effect in the
FST and TST in mice (15,16) (Figure 1). The prenyl frag-
ment is featured widely in many drugs and natural products
(17,18). The underlying hypothesis was that introduction of
a substituted prenyl group would increase the lipophilic
property of compounds and increase their permeability
across the blood–brain barrier, which would probably
enhance their antidepressant-like activity. So, in this study,
we introduce the prenyl group to the 7 position on com-
pounds II, and a series of 7-prenyloxy-2,3-dihydroflavanone
Key words: 7-Prenyloxy-2,3-dihydroflavanon, antidepressant
activity, FST, neurotransmitters, TST
Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT,
serotonin; CNS, central nervous system; DA, dopamine; FLU,
fluoxetine; FST, forced swimming test; NE, noradrenaline;
TST, tail suspension test.
Received 28 July 2015, revised 14 October 2015 and
accepted for publication 24 November 2015
Depression is one of the most prevalent psychopatholo-
gies. Symptoms of depression include lowered mood and
reduced pleasure and interest. It is expected to become
858
ª 2015 John Wiley & Sons A/S. doi: 10.1111/cbdd.12717

7-prenyloxy-2,3-dihydroflavanone Derivatives
7-prenyloxy-2,3-dihydroflavanone (5a)
2,3-Dihydroflavanone
Yield: 66.7%. 1H NMR(CDCl3, 300 MHz) d: 1.69(s, 3H, -CH3),
1.74(s, 3H, -CH3), 2.73(d, 2H, CH2), 2.97(t, 1H, -CH), 4.51
(d, 2H, -CH2), 5.46(t, 1H, =CH), 6.48-6.56(m, 3H, -C6H3),
7.34-7.94(m, 5H, -C6H5). 13C NMR(CDCl3, 75 MHz) d:
18.37, 25.86, 44.11, 65.30, 79.67, 101.76, 110.65, 114.69,
119.12, 126.48, 128.38, 128.68, 128.78, 138.42, 139.10,
163.39, 165.34, 189.95. IR (KBr) cmꢀ1: 2928, 2913, 1676,
1446, 1261, 960. ESI-HRMS calcd for C20H20O3+([M + H]+):
309.1412; found: 309.1426.
Prenyl
R2
HO
O
O
R1
OH
O
OH
O
II
I
R
B
O
O
A
20-Fluoro-7-prenyloxy-2,3-dihydroflavanone (5b)
Yield: 66.9%. 1H NMR (CDCl3, 300 MHz) d: 1.68(s,
3H, -CH3), 1.73(s, 3H, -CH3), 2.86(d, 2H, -CH2), 3.01(t,
1H, -CH), 4.51(d, 2H, -CH2), 5.39(t, 1H, =CH), 6.48–6.58
(m, 3H, -C6H3), 7.07–7.91(m, 4H, -C6H4). 13C NMR
(CDCl3, 75 MHz) d: 18.36, 25.85, 42.99, 65.33, 74.09,
101.73, 110.85, 114.57, 115.63, 115.91, 119.06, 124.79,
128.00, 128.47, 130.48, 130.59, 138.48, 163.31, 165.36,
189.56. IR (KBr) cmꢀ1: 2927, 2915, 1675, 1444, 1260,
961. ESI-HRMS calcd for C20H19FO3+([M + H]+):327.1318;
found: 327.1322.
O
5a-5n
Figure 1: Design of compounds 5a–5n.
derivatives were obtained and investigated to determ-
ine their antidepressant-like activities. In addition, the
probable mechanism of antidepressant-like activity was
explored by analyzing monoamine neurotransmitters in the
mice brain.
30-Fluoro-7-prenyloxy-2,3-dihydroflavanone (5c)
Yield: 65.7%. 1H NMR(CDCl3, 300 MHz) d: 1.68(s,
3H, -CH3), 1.73(s, 3H, -CH3), 2.75(d, 2H, -CH2), 2.92(t,
1H, -CH), 4.50(d, 2H, -CH2), 5.39(t, 1H, =CH), 6.47–6.56
(m, 3H, -C6H3), 6.99–7.80(m, 4H, -C6H4). 13C NMR
(CDCl3, 75 MHz)d: 18.34, 25.85, 44.10, 65.31, 101.72,
110.80, 113.13, 113.42, 114.63, 115.25, 115.54, 118.93,
122.02, 128.41, 130.62, 138.60, 141.77, 163.12, 165.41,
189.61. IR (KBr) cmꢀ1: 2930, 2917, 1677, 1445, 1265,
960. ESI-HRMS calcd for C20H19FO3+([M + H]+): 327.1318;
found: 327.1324.
Methods and Materials
Chemistry
Melting points were determined in open capillary tubes
and were uncorrected. IR spectra were recorded (in KBr)
on a FT-IR1730 (Bruker, Karlsruhe, Germany), 1H-NMR
and 13C-NMR spectra were measured on an AV-300 (Bru-
ker, Rheinstetten, Germany), and all chemical shifts were
given in ppm relative to tetramethysilane. High-resolution
mass spectra were measured on an MALDI-TOF/TOF
mass spectrometer (Bruker Daltonik, Bremen, Germany).
The major chemicals were purchased from Aldrich Chemi-
cal Corporation (Shanghai, China). All other chemicals
were of the analytical grade.
40-Fluoro-7-prenyloxy-2,3-dihydroflavanone (5d)
Yield: 76.5%. 1H NMR(CDCl3, 300 MHz)d: 1.69(s, 3H, -CH3),
1.74(s, 3H, -CH3), 2.75(d, 2H, -CH2), 3.00(t, 1H, -CH),
4.53(d, 2H, -CH2), 5.40(t, 1H, =CH), 6.50–6.54(m,
3H, -C6H3), 7.09–7.71(m, 4H, -C6H4). 13CNMR(CDCl3,
75 MHz)d: 18.40, 25.87, 44.03, 101.82, 110.74, 114.68,
115.47, 115.76, 119.25, 129.37, 128.77, 135.32, 138.34,
For synthesis of compound 1, compounds 2a–2n, 3a–3n,
and 4a–4n, see in references [Xie et al. (15); Guan et al.
(19; Guan et al. (20)].
149.99, 163.32, 164.10, 165.33, 189.85. IR (KBr) cmꢀ1
:
Synthesis of 7-prenyloxy-2,3-dihydroflavanone
derivatives (5a–5n)
2925, 2920, 1674, 1446, 1263, 962. ESI-HRMS calcd for
C20H19FO3+([M +H]+):327.1318; found: 327.1314.
A stirred solution of 4a–4n (0.35 mmol) and sodium acet-
ate in 30 mL methanol, anhydrous K2CO3 (1.40 mmol)
was added to the above solution, the mixture was stirred
at 50 °C for 1 h, and then, prenyl bromide (0.50 mmol
and 4 mL anhydrous acetone) was added slowly to the
above mixture. The mixture was refluxed for 5–8 h, after
the completion of the reaction (monitored by TLC). Filtered
K2CO3 was washed with acetone. After concentration
under reduced pressure, the resultant was recrystallized
from ethanol. The yield, melting point, and spectral data of
each compound are given as below.
20-Chloro-7-prenyloxy-2,3-dihydroflavanone (5e)
Yield: 65.0%. 1H NMR(CDCl3, 300 MHz)d: 1.69(s,
3H, -CH3), 1.74(s, 3H, -CH3), 2.78(d, 2H, -CH2), 2.81(t,
1H, -CH), 4.53(d, 2H, -CH2), 5.40(t, 1H, =CH), 6.51–6.60
(m, 3H, -C6H3), 7.30–7.99(m, 4H, -C6H4). 13C NMR
(CDCl3, 75 MHz) d: 18.39, 25.87, 42.87, 65.37, 76.64,
98.04, 101.82, 110.93, 114.58, 119.14, 127.74, 128.48,
129.75, 130.03, 131.55, 136.63, 138.44, 163.33, 165.38,
Chem Biol Drug Des 2016; 87: 858–866
859

Zhen et al.
189.45. IR (KBr) cmꢀ1: 2930, 2917, 1673, 1446, 1261,
960. ESI-HRMS calcd for
1023; found: 343.1029.
1H, -CH), 4.49(d, 2H, -CH2), 5.41(t, 1H, =CH), 6.43–6.55
(m, 3H, -C6H3), 7.33–7.75(m, 4H, -C6H4). 13C NMR
(CDCl3, 75 MHz) d: 18.33, 25.85, 44.03, 65.30, 78.93,
101.70, 110.77, 114.60, 118.90, 122.28, 128.20, 128.42,
131.79, 138.23, 138.63, 159.76, 163.16, 165.40, 189.66.
IR (KBr) cmꢀ1: 2928, 2913, 1676, 1444, 1261, 960. ESI-
HRMS calcd for C20H19BrO3+([M + H]+): 386.0518; found:
387.0522.
C
20H19ClO3+([M + H]+):343.
30-Chloro-7-prenyloxy-2,3-dihydroflavanone (5f)
Yield: 75.0%. 1H NMR(CDCl3, 300 MHz): d 1.75(s, 3H, -CH3),
1.80(s, 3H, -CH3), 2.84(d, 2H, -CH2), 2.93(t, 1H, -CH), 4.56
(d, 2H, -CH2), 5.47(t, 1H, =CH), 6.51–6.63(m, 3H, -C6H3),
7.37–7.82(m, 4H, -C6H4). 13C NMR(CDCl3, 75 MHz) d:
23.02, 30.56, 48.92, 70.03, 83.65, 106.35, 115.64, 119.30,
123.40, 129.10, 131.01, 133.25, 134.95, 139.23, 143.69,
20,40-Dichloro-7-prenyloxy-2,3-dihydroflavanone
(5k)
145.74, 165.01, 167.84, 170.23, 194.47. IR (KBr) cmꢀ1
:
Yield: 66.7%. 1H NMR(CDCl3, 300 MHz) d: 1.67(s, 3H, -
CH3), 1.72(s, 3H, -CH3), 2.77(d, 2H, -CH2), 2.79(t, 1H, -
CH), 4.49(d, 2H, -CH2), 5.38(t, 1H, =CH), 6.44-6.57(m,
3H, -C6H3), 7.31–7.74(m, 3H, -C6H3). 13C NMR(CDCl3,
75 MHz) d: 18.30, 25.82, 42.85, 65.32, 76.23, 101.69,
110.99, 114.50, 118.76, 127.86, 128.60, 129.34, 132.21,
134.57, 135.49, 138.79, 160.95, 163.14, 165.45, 189.34.
IR (KBr) cmꢀ1: 2927, 2915, 1675, 1446, 1259, 962. ESI-
HRMS calcd for C20H18Cl2O3+([M + H]+): 377.0633; found:
377.0637.
2929, 2919, 1676, 1445, 1263, 962. ESI-HRMS calcd for
C20H19ClO3+([M + H]+): 343.1023; found: 343.1025.
40-Chloro-7-prenyloxy-2,3-dihydroflavanone (5g)
Yield: 75.3%. 1H NMR (CDCl3, 300 MHz) d: 1.69(s, 3H, -CH3),
1.73(s, 3H, -CH3), 2.76(d, 2H, -CH2), 2.92(t, 1H, -CH), 4.51
(d, 2H, -CH2), 5.45(t, 1H, =CH), 6.45–6.56(m, 3H, -C6H3),
7.33–7.83(m, 4H, -C6H4). 13C NMR(CDCl3, 75 MHz) d:
18.35, 25.85, 44.06, 65.31, 78.10, 101.74, 110.22, 110.76,
114.63, 118.97, 123.10, 127.98, 128.41, 128.84, 133.98,
137.81, 138.57, 163.20, 165.40, 189.69. IR (KBr) cmꢀ1
:
20,60-Dichloro-7-prenyloxy-2,3-dihydroflavanone
(5l)
2930, 2915, 1675, 1443, 1269, 960. ESI-HRMS calcd for
C20H19ClO3+([M + H]+):343.1023; found: 343.1028.
Yield: 76.3%. 1H NMR(CDCl3, 300 MHz) d: 1.69(s,
3H, -CH3), 1.74(s, 3H, -CH3), 2.54(d, 2H, -CH2), 3.59(t,
1H, -CH), 4.55(d, 2H, -CH2), 5.40(t, 1H, =CH), 6.60–6.63
(m, 3H, -C6H3), 7.36–7.74(m, 3H, -C6H3). 13C NMR
(CDCl3, 75 MHz) d: 18.26, 26.07, 43.50, 65.19, 76.65,
103.81, 110.93, 113.72, 114.31, 115.32, 119.33, 128.60,
130.11, 131.21, 132.19, 134.89, 138.38, 163.09, 165.44,
188.95. IR (KBr) cmꢀ1: 2928, 2916, 1674, 1444, 1265,
960. ESI-HRMS calcd for C20H18Cl2O3+([M + H]+): 377.
0633; found: 377.0630.
20-Bromo-7-prenyloxy-2,3-dihydroflavanone (5h)
Yield: 73.2%. 1H NMR(CDCl3, 300 MHz) d: 1.57(s,
3H, -CH3), 1.63(s, 3H, -CH3), 2.73(d, 2H, -CH2), 2.97(t,
1H, -CH), 4.39(d, 2H, -CH2), 5.30(t, 1H, =CH), 6.35–7.08
(m, 3H, -C6H3), 7.11–7.69(m, 4H, -C6H4). 13C NMR
(CDCl3, 75 MHz) d: 18.14, 25.70, 43.05, 65.17, 77.81,
101.50, 110.80, 114.48, 118.52, 121.29, 127.43, 127.98,
128.52, 129.85, 132.82, 138.16, 138.91, 163.25, 165.36,
189.77. IR (KBr) cmꢀ1: 2928, 2919, 1676, 1444, 1263,
961. ESI-HRMS calcd for C20H19BrO3+([M + H]+): 386.
0518; found: 387.0511.
40-Methyl-7-prenyloxy-2,3-dihydroflavanone (5m)
Yield: 82.6%. 1H NMR(CDCl3, 300 MHz) d: 1.67(s, 3H, -CH3),
1.73(s, 3H, -CH3), 2.30(s, 3H, -CH3), 2.72(d, 2H, -CH2),
2.89(t, 1H, -CH), 4.47(d, 2H, -CH2), 5.40(t, 1H, =CH),
6.41–6.45(m, 3H, -C6H3), 7.14-7.72(m, 4H, -C6H4). 13C
NMR(CDCl3, 75M Hz) d: 18.29, 20.92, 21.22, 25.82,
44.10, 45.15, 65.23, 79.67, 101.64, 110.58, 114.63,
118.86, 126.30, 128.41, 129.39, 135.91, 138.38, 138.67,
163.45, 165.37, 190.27. IR (KBr) cmꢀ1: 2930, 2917,
30-Bromo-7-prenyloxy-2,3-dihydroflavanone (5i)
Yield: 85.7%, mp: 1H NMR(CDCl3, 300 MHz) d: 1.76(s,
3H, -CH3), 1.83(s, 3H, -CH3), 2.87(d, 2H, -CH2), 2.99(t,
1H, -CH), 4.57(d, 2H, -CH2), 5.48(t, 1H, =CH), 6.52–6.67
(m, 3H, -C6H3), 7.28–7.89(m, 4H, -C6H4). 13C NMR
(CDCl3, 75 MHz) d: 18.27, 25.84, 44.34, 65.32, 79.05,
101.55, 111.05, 114.62, 118.61, 122.93, 124.65, 128.76,
129.26, 130.41, 131.77, 129.24, 141.16, 163.15, 165.61,
189.95. IR (KBr) cmꢀ1: 2927, 2912, 1675, 1445, 1255,
961. ESI-HRMS calcd for C20H19BrO3+([M + H]+):
386.0518; found: 387.0521.
+
1677, 1445, 1263, 961. ESI-HRMS calcd for C21H22O3
([M + H]+): 323.1569; found: 323.1572.
40-Methoxy-7-prenyloxy-2,3-dihydroflavanone (5n)
Yield: 74.0%. 1H NMR(CDCl3, 300 MHz) d: 1.69(s,
3H, -CH3), 1.74(s, 3H, -CH3), 2.70(d, 2H, -CH2), 3.04(t,
1H, -CH), 4.52(d, 2H, -CH2), 5.43(t, 1H, =CH), 6.49–6.92
(m, 3H, -C6H3), 7.38–7.70(m, 4H, -C6H4). 13C NMR
(CDCl3, 75 MHz) d: 18.40, 25.86, 40.93, 55.39, 65.33,
99.97, 101.82, 110.58, 114.11, 114.70, 115.89, 119.31,
40-Bromo-7-prenyloxy-2,3-dihydroflavanone (5j)
Yield: 77.1%. 1H NMR(CDCl3, 300 MHz) d: 1.67(s,
3H, -CH3), 1.73(s, 3H, -CH3), 2.75(d, 2H, -CH2), 2.90(t,
860
Chem Biol Drug Des 2016; 87: 858–866

7-prenyloxy-2,3-dihydroflavanone Derivatives
127.15, 128.21, 128.34, 131.14, 138.28, 159.80, 163.50,
165.40, 190.21. IR (KBr) cmꢀ1: 2929, 2915, 1671, 1446,
1265, 960. ESI-HRMS calcd for C21H22O4+([M + H]+):339.
1518; found: 339.1522.
were suspended for total 6 min, and the duration of immo-
bility was observed and measured during the final 4-min
interval of the test. All test sessions were recorded by a
video camera positioned directly above the box. Two com-
petent observers blind to treatment scored the videotapes.
Mice were considered to be immobile only when they
hung passively and completely motionless. The animals
were used only once in this test. All TSTs were performed
between 11:00 a.m. and 17:00 p.m.
Pharmacology
The target compounds synthesized in this study were
screened for their antidepressant-like activities using Por-
solt’s behavioral despair (forced swimming test) (21). Com-
pounds 5j and 5k were also evaluated using the tail
suspension test (22,23) and the open-field test (24,25) to
further confirm its antidepressant activity. The tested com-
pounds in the pharmacology experiments were dissolved in
DMSO, and administrated intraperitoneally (i.p.) to Balb/e
mice (20 ꢁ 2 g). The mice were housed collectively in poly-
carbonate cages in groups of ten, where they were main-
tained 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. All procedures used in
this study were in accordance with the guide for the Care
and Use of Laboratory Animals as adapted by the NIH, and
the laboratory got ethical approval from National Science
and Technology Commission of China.
The open-field test
Open-field tests were used to evaluate the exploratory activ-
ity of the animal (26). The investigated compounds were
administered 60 min before the experiment. The study was
carried out on mice according to Archer’s method (24), with
slight modifications. Each mouse was placed individually in
the center of the open-field apparatus, and the locomotor
activity was assessed. The open-field apparatus was a non-
transparent plastic container (80 9 60 9 30 cm), with the
underside divided into 48 units of size 10 9 10 cm, without
walls. The animals were gently placed in the center of the
platform and were allowed to explore their surroundings.
Hand-operated counters were used to score locomotion
(ambulation, numbers of crossing lines with all four paws)
and rearing frequencies (number of times an animal stood
on its hind legs) for 3 min. The researchers, who did not
know which groups had been treated, scored the behaviors
in the open field. The experiments were performed in a dark
room, and the apparatus was illuminated by a 60-W bulb
giving a yellowish light, positioned 1 m above the center of
the apparatus.
The forced swimming test (FST)
Local breed, male Balb/e mice (20 ꢁ 2 g) were used in the
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 plexiglass cylinder
(height 25 cm, diameter 10 cm) containing 10 cm of water
at 22 ꢁ 3 °C. On this day, mice were assigned into different
groups (n = 10 for each group). Then, the mice were
dropped individually into the plexiglass cylinder and left in
the water for 6 min. After the first 2 min of the initial vigorous
struggling, the animals were immobile. The duration of
immobility was recorded during the last 4 min of the 6 min
test. All test swim sessions were recorded by a video camera
positioned directly above the cylinder. Two competent
observers, who were unaware of the treatment each mouse
had received, scored the videotapes. Immobility period was
regarded as the time spent by the mouse floating in the
water without struggling and making only those movements
necessary to keep its head above the water. Following
swimming sessions, they were then towel dried and returned
to their housing condition. The animals were used only once
in this test. All FSTs were performed between 11:00 a.m.
and 17:00 p.m.
The sample preparation
The doses of 10 mg/kg compounds 5j, 5k, and FLU were
employed for testing the effect of these on monoamine
neurotransmitter concentrations in the mouse brain. A
vehicle control group (vehicle was DMSO) without any
stress was added as a control group for normal condition
comparison. The vehicle group in animal test was marked
as vehicle + stress group. When the activity tests were
completed, mice were killed by decapitation, the brains
were rapidly removed and the hippocampus, hypothala-
mus and cortex were dissected on an ice-cold plate, and
stored at ꢀ80 °C until assay. All brain regions were
weighted and homogenized by ultrasonication in ice-cold
0.02 M perchloric acid. An internal standard (DHBA) at a
concentration of 1.0 lm was also included. The homoge-
nates were centrifuged at 11 000 9 g for 15 min at 4 °C,
and the supernatant was separated and filtered through a
membrane filter pore size 0.45 lm.
The tail suspension test (TST)
Mice were individually suspended by tail with clamp (2 cm
from the tip of the end) in a box (25 9 25 9 30 cm) with
the head 5 cm to the bottom. Testing was carried out in a
darkened room with minimal background noise. All animals
HPLC condition and test
Following decapitation, the brains were rapidly removed,
dissected on an ice-chilled glass plate, and subsequently,
prefrontal hypothalamus, hippocampus, and cortex were
Chem Biol Drug Des 2016; 87: 858–866
861

Zhen et al.
isolated. The tissues were weighed, sonicated in 0.1 M
NaH2PO4 aqueous solution including 0.85 mM OSA,
0.5 mM EDTAꢂNa2 and centrifuged (13 000 9 g for 30 min).
Then, 5-HT, 5-HIAA, NE, DA, and DHBA were assayed by
HPLC-ECD. The HPLC system consisted of a microbore
reverse-phase column (Shimadzu LC-10ATVP HPLC sys-
tem, Tokyo, Japan, Shimadzu L-ECD-6A electrochemical
detector, N2000 HPLC workstation software, Hypersil ODS
C18 Column 4.6 9 150 mm 5 lm, Thermo, Waltham, MA,
USA). The mobile phase consisted of 0.1M NaH2PO4 aque-
ous solution including 0.85 mM OSA, 0.5 mM EDTAꢂNa2 and
11% methanol adjusted to pH 3.4 with phosphate acid and
filtered through 0.45 lm pore size filter. External standard
curves were used to quantify the amounts of 5-HT, 5-HIAA,
NE and DA in each sample calculated by area under curve
(AUC). The volume of injection was 20 lL. The detection
limit of the assay was 20 pg/g sample. The filtrate sam-
ple was used for quantification of NE (y = 0.03731 9
+0.003125, r = 0.9992), 5-HT (y = 0.04382 9 +0.002763,
r = 0.9983), DA (y = 0.07152 9 +0.00563, r = 0.9985),
and 5-HIAA (y = 0.05482 9 +0.003442, r = 0.9989) by
HPLC coupled with electro-chemical detection in all brain
regions.
intermediates 2a–2n were synthesized by the Claisen–Sch-
midt condensation of compound 1 protected as methoxy-
methyl ether with substituted aromatic aldehydes (15,27).
Then, the intermediates 2a–2n were treated with 3M HCl in
methanol to yield the hydroxychalcones 3a–3n (22). The lat-
ter compounds subsequently underwent a substitution
reaction with prenyl bromide in acetone under reflux to give
compounds 4a–4n. The derivatives 5a–5n were obtained
with NaOAc in ethanol in good yield. The chemical struc-
tures of target compounds were characterized by IR, 1H
NMR, 13C NMR, and high-resolution mass spectroscopy.
The IR spectra of the compounds afforded C=O stretching
(1761–1767/cm) and C-O-C stretching (1441–1446/cm). In
the 1H-NMR spectra of the compounds, =CH protons of
prenyloxy group were observed at 5.30–5.48 ppm, and
13C-NMR spectra of the compounds C=O were seen at
188.95–194.47 ppm.
Effects on immobility periods in FST and TST
through i.p. injection
Both the FST and TST are the accepted stress models of
depression. Immobility has been shown to reflect a state
of ‘behavioral despair and variants’ or ‘failure to adapt to
stress’ (28). Immobility displayed in both of these behav-
ioral despair models has been hypothesized to reflect
behavioral despair which in turn may reflect depressive
disorders in human (29). There was a significant correlation
between clinical potency and the potency of antidepres-
sants in both models. Thus, two models are usually used
to screen or evaluate antidepressant activity (30). In the
present study, a series of 7-prenyloxy-2, 3-dihydroflava-
none derivatives have been designed, synthesized, and
evaluated for their antidepressant-like activities. The dose-
course effects of compounds 5a–5n in the FST test after
the i.p. injection. The pharmacological experiments
showed that the percentage of duration of immobility was
the maximum value at the dose of 10 mg/kg. Moreover,
the percentage of duration of immobility was steady from
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 multiple
comparison tests, using GRAPHPAD PRISM program (Graph-
Pad Software, Inc., San Diego, CA, USA). A p-value of
< 0.05 was considered statistically significant.
Results and Discussion
Chemistry
Target compounds were prepared as outlined in Scheme 1.
Compound 1 was prepared as reported previously (21). The
HO
O
O
O
O
i
R
iii
CH3
ii
CH3
OH
O
O
OH
O
OH
O
1
2a-2n
O
O
HO
O
O
O
O
R
V
iV
R
R
O
O
3a-3n
4a-4n
5a-5n
R:
5a = H
5b = 2-F
5g = 4-Cl
5c = 3-F
5d = 4-F
5i = 3-Br
5e = 2-Cl
5j = 4-Br
5f = 3-Cl
5h = 2-Br
5k = 2,4-Cl2
5l = 2,6-Cl2 5m = 4-CH3
5n = 4-OCH3
Reagents and conditions:
(i) ClCH2OCH3, K2CO3; (ii) aromatic aldehyde, KOH; (iii) NaOAc; (iV) 3 M HCl; (V) prenyl bromide,
anhydrous K2CO3
Scheme 1: Synthesis routes of target
compounds 5a–5n.
862
Chem Biol Drug Des 2016; 87: 858–866

7-prenyloxy-2,3-dihydroflavanone Derivatives
Table 1: Evaluation of the antidepressant-like activity of
compounds 5a–5n in the FST
120
100
80
60
40
20
0
Antidepressant activitya
Compounds
R
Duration of immobility
DID (%)b
*
*
*
*
5a
5b
H
2-F
3-F
4-F
75.40 ꢁ 10.50
54.20 ꢁ 8.30
43.60 ꢁ 9.00*
46.40 ꢁ 10.40*
37.20 ꢁ 4.30**
54.80 ꢁ 6.80
48.00 ꢁ 6.90*
46.00 ꢁ 8.60*
59.00 ꢁ 11.80
21.80 ꢁ 6.00***
24.00 ꢁ 9.70***
84.00 ꢁ 9.03
57.00 ꢁ 9.80
80.20 ꢁ 9.50
22.80 ꢁ 9.96***
90.00 ꢁ 18.01
16.22
39.78
51.56
48.44
58.67
39.11
46.67
48.89
34.44
75.78
73.33
6.67
**
***
5c
5d
***
5e
2-Cl
3-Cl
4-Cl
2-Br
3-Br
4-Br
2,4-Cl2
2,6-Cl2
4-CH3
4-OCH3
—
5f
5g
l
o
5i 5j
5l
5m
5f
5a
5c
5e
5b
5d
5g 5h
5k
5n
ntr FLU
5h
5i
Co
5j
5k
Figure 2: Effect of 5a–5n and FLU on immobility time in the
forced swimming test in mice. Data are expressed as the
mean ꢁ SEM (n = 10). Compounds and FLU were administered
intraperitoneally at 10 mg/kg. Symbol (*, ***, or ***) indicates
statistically significance in comparison with vehicle at p < 0.05,
p < 0.01, p < 0.001.
5l
5m
36.67
10.89
74.67
—
5n
Fluoxetine
Control
—
Values are the mean ꢁ SEM (n = 10).
Significantly different compared with control (*p < 0.05,
**p < 0.01, ***p < 0.001).
an oral dose of 10–40 mg/kg. The dose of 10 mg/kg was
chosen to evaluate the antidepressant-like activity in the
FST. Compounds 5a–5n and the reference drug fluoxetine
on immobility time at a dose of 10 mg/kg are shown in
Figure 2. The immobility times were significantly reduced
after treatment with seven compounds (5c–5e, 5g, 5h, 5j,
and 5k) in the FST, indicating to possess antidepressant-
like effects. Compounds 5j and 5k in particular led to sig-
nificant reductions in the duration of the immobility time
compared with the control group with p < 0.001, and this
result is similar to that following administration of the posi-
tive control fluoxetine. For a more detailed and compre-
hensive understanding of the antidepressant-like effects of
the tested compounds 5a–5n and fluoxetine, their values
for the percentage decrease in the immobility duration (%
aCompounds and fluoxetine were administered intraperitoneally at
10 mg/kg.
b%DID: percentage decrease in immobility duration.
F atom (5c and 5d), a Cl atom (5g, 5h and 5k), or Br
atom (5h and 5j) led to decrease significantly the immobil-
ity times compared with 5a. And it was found that the
position of the halogen atom substituted on the B ring of
flavanone greatly influenced the antidepressant-like activity.
Compared with compounds with different Br-substituted
positions on the phenyl ring, the order of activity was
4-Br > 2-Br > 3-Br, the order of activity was observed
for F-substituted positions with 3-F > 4-F > 2-F, and
2-Cl > 4-Cl > 3-Cl for F-substituted positions. The order
of activity for with different Cl-substituted positions on the
phenyl ring was 2, 4-Cl2 > 2-Cl > 4-Cl > 3-Cl > 6-Cl2.
Among, the introduction of a 4-Br atom and two Cl atoms
to give compounds 5j and 5k showed the most antide-
pressant-like effect, similar to the positive control drug flu-
oxetine. In contrast, two electron-donor groups with the
introduction of -CH3 and –OCH3 to give compounds 5m
and 5n resulted in no antidepressant-like activity in the FST.
DID) were calculated using the following formula:
%
DID = [(Y-X)/Y] 9 100, where Y is the duration of immobil-
ity (s) in the control group and X is the duration of immobil-
ity (s) in the test group.
As shown in Table 1, seven compounds examined
reduced the duration of immobility and gave high % DID
values. Among them, the % DID for compounds 5j and 5k
was similar to that for fluoxetine in the FST, and exhibited
higher % DID values of 75.78% and 73.33%, respectively,
similar to fluoxetine (74.67%), and appeared to provide
higher levels of antidepressant-like effects.
Compounds 5j and 5k were exhibited the most potent
antidepressant-like activity in the FST and were further
evaluated in the TST to effectively confirm its antidepres-
sant-like activity. Next, the antidepressant-like effect of 5j,
and 5k in the TST test after the i.p. injection was shown in
Figure 3. The pharmacological experiments showed that
the percentage of duration of immobility was the maximum
value at the dose of 10 mg/kg. Moreover, the percentage
of duration of immobility was steady from an oral dose of
10–30 mg/kg. The dose of 10 mg/kg was chosen to evalu-
ate the antidepressant-like activity in the TST. Compounds
Consideration of the biological activities of the synthesized
compounds revealed the following structure activity rela-
tionships (SARs). In general, the activity of an organic
compound may be changed after the introduction of a
halogen atom. For compounds 5b–5l, the electron-with-
drawing groups with F, Cl, and Br groups, were substi-
tuted on the B ring of flavanone fragment, which variations
in activity were observed. Pleasingly, the introduction of an
Chem Biol Drug Des 2016; 87: 858–866
863

Zhen et al.
10
15
90
80
70
60
50
40
30
20
10
0
20
30
40
Open field test
40
30
20
Crossing
Rearing
Grooming
5
1
5j
5k
10
0
mg/kg
Figure 3: The dose course of 5j and 5k in the TST test (the
number of animals at each point was 10).
Control
5j
5k
Figure 5: Exploratory activity (counts) in the open-field test. The
behavioral parameters were recorded for 3 min. Locomotion:
number of line crossings; rearing: number of times seen standing
on hind legs; grooming: number of modifications; 5j and 5k was
administered 60 min before the test. 5j and 5k were administered
intraperitoneally at 10 mg/kg. The values represent the mean ꢁ
SEM (n = 10).
125
100
75
5j and 5k produced a marked reduction in immobility time
at a dose of 10 mg/kg, and the clinically effective antide-
pressant fluoxetine significantly reduced immobility time at
the same dose points. The results are shown in Figure 4.
The immobility displayed in both rodent behavioral test of
behavioral despair has been hypothesized to reflect
depressive disorders in humans. These findings suggested
that compounds 5j and 5k displayed the antidepressant-
like effects.
***
***
***
50
25
0
Control
FLU
5j
5k
Figure 4: Effect of 5j, 5k on immobility time in the TST in mice.
Data are expressed as the mean ꢁ SEM (n = 12). 5j, 5k, and
FLU were administered intraperitoneally at 10 mg/kg. Symbol (***)
indicates statistically significant in comparison with vehicle at
p < 0.001.
Effects of the acute treatment in the open-field test
As some compounds that alter motor activity may give
false-positive/negative effects in the FST, in particular
Table 2: Effects of FST exposure and 5j, 5k treatment on monoamine neurotransmitter concentrations in mouse brain
Region
Group
5-HT
5-HIAA
NE
DA
Hippocampus
Stress vehicle
5j
5k
302.5 ꢁ 18.7y
495.2 ꢁ 15.6b,y
476.8 ꢁ 18.7b,z
507.8 ꢁ 13.4a,y
701.2 ꢁ 65.9b
356.8 ꢁ 10.8z
602.2 ꢁ 60.6a
571.4 ꢁ 58.3b
617.6 ꢁ 60.2.6a
703.2 ꢁ 99.8c
203.9 ꢁ 20.3x
544.7 ꢁ 35.7a,z
516.1 ꢁ 28.7a
549.0 ꢁ 38.7a
696.4 ꢁ 60.8a
327.7 ꢁ 49.3y
876.8 ꢁ 25.4a,z
946.8 ꢁ 38.7a
396.8 ꢁ 55.4a,x
1001.6 ꢁ 67.4a
1787.5 ꢁ 68.3
3843.6 ꢁ 121a,y
3676.3 ꢁ 78.9a,z
3808.6 ꢁ 41.6a,y
1845.4 ꢁ 167
264.6 ꢁ 18.1y
289.4 ꢁ 28.2z
276.5 ꢁ 31.7z
220.6 ꢁ 19.4y
393.4 ꢁ 13.8b
93.4 ꢁ 9.3z
32.7 ꢁ 8.4
143.9 ꢁ 10.4b
156.8 ꢁ 11.7a
129.7 ꢁ 10.2a
181.6 ꢁ 9.6c
137.5 ꢁ 10.5z
389.6 ꢁ 35.4a,y
275.7 ꢁ 28.8a
437.3 ꢁ 37.0a,y
473.7 ꢁ 70.7c
179.5 ꢁ 11.8z
217.7 ꢁ 9.7a
200.8 ꢁ 8.7b
228.7 ꢁ 6.4a
199.0 ꢁ 21.8c
29.6 ꢁ 5.6z
28.8 ꢁ 8.1z
Fluoxetine
Vehicle control
Stress vehicle
5j
30.3 ꢁ 5.3z
52.3 ꢁ 7.7
Hypothalamus
Cortex
149.3 ꢁ 10.3
145.9 ꢁ 14.3
136.9 ꢁ 13.6
148.6 ꢁ 9.9
5k
Fluoxetine
Vehicle control
Stress vehicle
5j
176.3 ꢁ 33.8
2068.0 ꢁ 77.9z
2463.4 ꢁ 93.8y
2376.7 ꢁ 58.7z
2553.7 ꢁ 86.5z
3429 ꢁ 160c
5k
Fluoxetine
Vehicle control
The dose of 5j, 5k, and fluoxetine was 10 mg/kg. Neurotransmitter concentrations were expressed as ng/g per brain region wet weight.
Data expressed as mean ꢁ SEM (n = 10). Statistical analysis of data was carried out by one-way analysis of variance followed by Turkey’s
x
y
z
test. ap < 0.001, bp < 0.01, cp < 0.05 versus Stress vehicle, p < 0.001, p < 0.01, p < 0.05 versus vehicle control.
864
Chem Biol Drug Des 2016; 87: 858–866

7-prenyloxy-2,3-dihydroflavanone Derivatives
psychomotor stimulants and drugs enhancing motor activ-
ity, which decrease immobility time by stimulating locomotor
activity (25), an additional measurement was carried out with
the specific aim of observing motor activity. To determine
whether the observed reductions in immobility were associ-
ated with alterations in motor activity, in this study, the
effects of compounds 5j and 5k on spontaneous locomotor
activity were evaluated in the open-field test, a classical ani-
mal test used to evaluate the autonomic effects of drugs
and general activity of animals. This study demonstrated
that compounds 5j and 5k did not significantly change the
motor activity (crossing, rearing, or grooming) in mice (Fig-
ure 5), indicating that the immobility reductions were not
caused by possible CNS-stimulating effects in the FST and
TST. The results suggest that compounds 5j and 5k pos-
sess the antidepressant-like effect in mice.
compounds 5j and 5k significantly decreased the immobil-
ity times and showed the most antidepressant-like activi-
ties in the FST and TST. And it suggested that the
mechanisms of action of compounds 5j and 5k are likely
related to the increase in 5-HT and NE in the CNS,
although other neurochemical systems may also be
involved. These results suggest that compounds 5j and
5k are a potential candidate for the treatment of depres-
sion.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (No. 30960458), the Natural Science
Foundation of Zhejiang Province of China (No.
LY14C190001; LY14H090001), and the National Spark
Plan Project of China (No. 2013GA700255).
Effects on monoamine neurotransmitter
concentrations in the mouse brain
Monoamine neurotransmitters are believed to be involved
in mental depression and play important roles in mediating
behavioral effects of antidepressant drugs. The monoa-
mine hypothesis supposed that depression was a result of
the depletion of NE, 5-HT, and DA in addition to activation
of monoamine oxidase in the CNS (31). Depression can
be alleviated by increasing the levels of monoamine neuro-
transmitters in the CNS (32,33). The effects of compounds
5j and 5k and fluoxetine after on whole brain monoamine
neurotransmitter levels in stressed and normal mice were
summarized in Table 2. We found that compounds 5j and
5k significantly increased 5-HT and NE levels in mouse
hippocampus, hypothalamus, and cortex, similar to the
positive control fluoxetine in the FST. However, no signifi-
cant change in brain DA level was observed in all mea-
sured brain regions. Compared with the stress vehicle
group, compounds 5j and 5k administration are signifi-
cantly changes in 5-HIAA levels in some brain parts, espe-
cially in hypothalamus, compounds 5j and 5k exhibited to
increase 5-HIAA contents in all measured brain regions.
As the ratio of neurotransmitter compared to its metabo-
lites can be used as an index of neurotransmitter metabo-
lism (34), the reduction in metabolites/neurotransmitters
suggests a shut down in the metabolism of neurotransmit-
ters (35). Therefore, 5-HIAA was increased in the present
study, it is likely that the metabolism of 5-HT was shut
down. No significant changes in DA content were
observed following the FST. Synthesis of DA occurs in the
striatum and remains relatively stable in the brain regions
investigated in this study (36). So, the probable mecha-
nism of action of compounds 5j and 5k is thought to be
related to the increase in 5-HT and NE in the CNS.
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