Screening of chalcone analogs with anti-depressant, anti-inflammatory, analgesic, and COX-2-inhibiting effects

Article abstract of DOI:10.1016/j.bmcl.2020.127173

A group of 2-methyl-4-phenylquinoline-chalcone analogs (2a–2x) was synthesized and investigated for anti-depressant, anti-inflammatory, and analgesic effects as cyclooxygenase-2 inhibitors. Pharmacological experiments identified 24 analogs that exhibited anti-depressant, anti-inflammatory, and analgesic activities. In particular, compounds 2c, 2k, and 2w markedly shortened immobility times and exhibited the most anti-depressant activity. In addition, the mechanisms of action of the analogs 2c, 2k, and 2w were likely related to increased serotonin levels in the central nervous system. Compounds 2c, 2k, and 2w displayed reasonable cyclooxygenase-2 inhibitory effects (IC₅₀ values from 0.21 to 0.29 μmol/L) similar to celecoxib (IC₅₀: 0.19 μmol/L) in vitro. A molecular docking study of compound 2k also was conducted.

Full text of DOI:10.1016/j.bmcl.2020.127173

Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Screening of chalcone analogs with anti-depressant, anti-inflammatory,
analgesic, and COX-2-inhibiting effects
⁎
⁎
Zhe-Hao Huanga,1, Li-Quan Yinb,1, Li-Ping Guanc, Zhao-Hui Lia, , Cheng Tand,
a Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
b Rehabilitation Medicine Department, China-Japan Union Hospital of Jilin University, Changchun 130033, China
c Food and Pharmacy College, Zhejiang Ocean University, Zhoushan 316022, China
d Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
A group of 2-methyl-4-phenylquinoline-chalcone analogs (2a–2x) was synthesized and investigated for anti-
depressant, anti-inflammatory, and analgesic effects as cyclooxygenase-2 inhibitors. Pharmacological experi-
ments identified 24 analogs that exhibited anti-depressant, anti-inflammatory, and analgesic activities. In par-
ticular, compounds 2c, 2k, and 2w markedly shortened immobility times and exhibited the most anti-depressant
activity. In addition, the mechanisms of action of the analogs 2c, 2k, and 2w were likely related to increased
serotonin levels in the central nervous system. Compounds 2c, 2k, and 2w displayed reasonable cyclooxygenase-
2 inhibitory effects (IC50 values from 0.21 to 0.29 µmol/L) similar to celecoxib (IC50: 0.19 µmol/L) in vitro. A
molecular docking study of compound 2k also was conducted.
Quinoline-chalcone
Anti-depressant
Anti-inflammatory
Analgesic
Neurotransmitters
COX-2-inhibitory
Depressive diseases are life-threatening conditions that can greatly
affect the health of a population. The World Health Organization has
determined that depressive disorders may become the second biggest
cause of disability after cardio-cerebrovascular disorders in the future.1
Inflammation generally presents as heat, swelling, pain, and redness;
however, depressive patients are usually chronic pain patients, and
depression and pain may display similar neurochemical mechanisms.2
Although the exact mechanism is unknown, a link between depression
and pain has been suggested.
distributed in vegetables, tea, fruits, and spices, and are present in a
variety of plant species.5,6 The chalcone structure contains a ring-
opened flavone, in which there are two aromatic nuclei joined through
a three carbon α,β-unsaturated carbonyl group. Chalcone analogs have
demonstrated anti-depressant, anti-inflammatory, and analgesic activ-
ities.7–11 Quinoline alkaloids belong to a class of hetero cycles. Qui-
noline compounds have aroused interest in drug development research
because of their anti-depressant, anti-inflammatory, and analgesic ef-
fects.12–14 Quinoline hybrids incorporating chalcone pharmacophores
have also attracted interest in drug development because of their wide
range of biological effects, includinganti-tumor,15 anti-plasmodial,16
anti-ulcer,17 anti-malarial,18 anti-inflammatory, analgesic, and im-
munomodulatory effects.19 In addition, Zaib et al.20 have reported that
quinoline hybrids incorporating chalcones could inhibit monoamine
oxidase activity (Fig. 1).
In addition, anti-depressive drugs have been used as analgesics for
several pain-associated disorders, such as non-neuropathic and neuro-
pathic pain. These drugs can inhibit the uptake of monoamines, by
increasing serotonin and noradrenaline levels in the synaptic cleft.3
Most classic non-steroidal anti-inflammatory drugs are non-selective
inhibitors of both cyclooxygenase-1(COX-1)and cyclooxygenase-2
(COX-2). The non-selective nature of these drugs can bring about many
side effects, for example renaldys function, gastrointestinal side effect
and bleeding. Identifying useful classic non-steroidal anti-inflammatory
drugs that only suppress COX-2 is desirable to relieve inflammation
without affecting physical functions. Thus, new anti-depressant, anti-
inflammatory, and analgesic agents with high therapeutic efficacy and
fewer side effects are needed.4
Furthermore, structure–activity relationship studies have revealed
the various chemical structures of anti-depressant and anti-in-
flammatory agents, including COX-2 inhibitors. Generally, these com-
pounds have two aromatic groups linked by a central α,β-unsaturated
ketone structure (Fig. 1).21
Considering these findings, we continued our previous work to de-
velop new anti-depressant, anti-inflammatory, and analgesic agents
with high therapeutic value and minimal side effects. In the present
Chalcones are an important natural product, which are widely
⁎ Corresponding authors.
E-mail addresses: ruosong@163.com (Z.-H. Li), tancheng@jlu.edu.cn (C. Tan).
1 These authors have made the same contribution to this work.
https://doi.org/10.1016/j.bmcl.2020.127173
Received 18 January 2020; Received in revised form 1 April 2020; Accepted 5 April 2020
0960-894X/©2020PublishedbyElsevierLtd.
Pleasecitethisarticleas:Zhe-HaoHuang,etal.,Bioorganic&MedicinalChemistryLetters,https://doi.org/10.1016/j.bmcl.2020.127173

Z.-H. Huang, et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Table 1
Evaluation of the anti-depressant effects of compounds 2a–2x.
Compounds
R
Duration of immobility (s)
a
2a
2-F
49.3
38.3
25.8
51.5
136.3
48.5
29.3
31.5
52.0
60.3
13.8
75.8
32.8
79.3
86.3
57.5
63.0
109.3
48.5
83.5
52.3
47.5
22.8
46.8
88.1
172.3
4.2***
3.7***
2.3***
8.9***
6.6*
2b
3-F
2c
4-F
Fig. 1. The structures of chalcone derivatives reported to be monoamine oxi-
2d
2,4-F2
2-Cl
dase and selective cyclooxygenase-2 inhibitors.
2e
2f
3-Cl
9.6***
7.2***
6.8***
5.4***
7.1**
9.4***
2.3**
4.4***
5.6**
9.3**
4.7**
6.0**
6.4*
2g
4-Cl
2h
2,4-Cl2
2,6-Cl2
2-Br
2i
2j
2k
3-Br
2l
4-Br
2m
2n
3-OH
4-OH
2o
2-CH3
3-CH3
4-CH3
2-OCH3
3-OCH3
4-OCH3
3-OH-4-OCH3
4-N(CH3)2
4-CH(CH3)2
4-NO2
3 mg/kg
–
2p
2q
2r
2s
7.6***
6.9**
6.7***
2t
2u
***
2v
10
2w
2x
2.9***
6.86***
9.9**
Fig. 2. Design of the new compounds 2a–2x.
fluoxetine
control
9.67
study, we synthesized novel quinoline hybrids incorporating chalcone
derivatives (2a–2x, Fig. 2) and investigated their in vivo anti-de-
pressant, anti-inflammatory, and analgesic effects, and COX-1/COX-2
enzyme inhibition. In addition, molecular docking simulations were
used to study the probable binding mode of the most promising com-
pound in the COX-2 active site.
a
Significant differences versus control values. * P < 0.05, ** P < 0.01, ***
P < 0.001.
Biology
The forced swimming test (FST), a validated and rapid animal test,
is widely used to screen for anti-depressant activity. In this model, a
mouse is subjected to a short-term and inevitable pressure to imitate the
condition of despair, and this has been shown to have a good prediction
effect.23 The observed immobility is thought to be a behavioral re-
sponse to despair that may be related to human depression. The mo-
tionless state adopted is associated with depressive behavior in mice;
therefore, drugs that reduce the frequency or duration of the motionless
state are expected to have anti-depressant effects.24 The target com-
pounds 2a–2x were administered by intraperitoneal injection to mice at
30 mg/kg and fluoxetine (3 mg/kg), as a reference anti-depressant
drug, and the mice were subjected to the FST. The anti-depressant ef-
fects of compounds 2a–2x and fluoxetine, as indicated by the motion-
less time, are shown in Table 1. All compounds and fluoxetine markedly
reduced the motionless times of the animals. In particular, compounds
2c, 2g, 2k, and 2w exhibited strong anti-depressant effects, sig-
nificantly reducing the motionless times compared withthat of the
control group (P < 0.001).
Synthesis
As illustrated in Scheme 1, the reaction routes of the analogs 2a–2x
started from commercially available 2-aminobenzophenone and acet-
ylacetone by
a 2-step reaction. 1-(2-Methyl-4-phenylquinolin-3-yl)
ethanone (1) was obtained through a nucleophilic addition–elimination
reaction. After that, a Claisen-Schmidt condensation reaction of com-
pound 1 with substituted aromatic aldehydes in an EtOH solution of
sodium hydroxide gave the 2-methyl-4-phenylquinoline derivatives
incorporating chalcone moieties2a–2x. The structure of analogs 2a–2x
was determined from the infrared, proton nuclear magnetic resonance,
and carbon nuclear magnetic resonance spectra, as well as from high
resolution mass spectrometry. In the infrared spectra, the stretching
band of the –C]O group was observed from 1640 to 1647 cm−1. In the
proton nuclear magnetic resonance spectra, the –CH3 group on the
quinoline ring was observed as a singlet signal at 2.44–2.72 ppm. In the
carbon nuclear magnetic resonance spectra, the peaks at
194.60–206.31 and 23.87–29.70 ppm were assigned to the carbons of
the –C]O and –CH3 groups, respectively. The High Performance Liquid
Chromatography (HPLC) data of the target compounds indicated a
purity of > 98% and there were no impurity peaks found within 5 min
before or after the retention time of the main peak.22
To further investigate the anti-depressant activities of compounds
2a–2x and fluoxetine, we calculated the percentage reduction in mo-
tionless time through the following equation:
% decrease in immobility time = [(W V )/W] × 100,
In which W is the motionless time for the control groups and V is the
motionless time for the experimental groups. All compounds strongly
reduced the duration of immobility. Among them, compounds 2b, 2c,
2g, 2h, 2k, 2m, and 2w more strongly reduced the duration of im-
mobility than the other compounds (Fig. 3). The percent decreases in
the duration of immobility for compounds 2b (77.8%), 2g (83.0%), 2h
(81%), and 2m (80.0%) at a concentration of 30 mg/kg were more than
that of fluoxetine (3 mg/kg, 48.9%). However, compounds 2c, 2k, and
2w more strongly decreased the duration of immobility compared with
fluoxetine (85.0%, 92.0%, and 86.8%, respectively), indicating that
these three analogs might possess better anti-depressant activity than
Scheme 1. The synthetic route of new derivatives 2a–2x.
fluoxetine (duration of motionlessness (s): 2c
=
25.8
2.3;
2

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Table 2
Anti-inflammatory effects of compounds 2a–2x.
a
Anti-inflammatory effects
Ear edema SEM (mg)
Compounds
R
Inhibition rate (%)
2a
2-F
1.85
3.03
1.15
3.37
2.64
4.57
1.43
1.84
5.25
4.43
2.67
2.55
3.42
2.09
2.86
3.24
3.81
3.73
2.50
3.28
3.39
2.98
2.28
5.62
4.81
9.84
0.92***
81.2
69.2
88.3
65.8
73.2
53.6
85.5
81.3
46.7
55.0
72.9
74.1
65.2
78.8
70.9
67.1
61.3
62.1
74.6
66.7
65.5
69.7
76.8
42.9
51.1
–
2b
3-F
0.71**
2c
4-F
0.68***
1.12**
0.42**
1.10*
2d
2,4-F2
2-Cl
2e
2f
3-Cl
2g
4-Cl
0.43***
0.94***
0.96*
2h
2,4-Cl2
2,6-Cl2
2-Br
2i
2j
1.21*
2k
3-Br
0.68**
0.67***
0.41**
0.43***
0.59**
1.42**
0.58**
0.95**
0.47***
1.01**
1.11**
1.14**
0.79***
1.13*
2l
4-Br
Fig. 3. Percent decrease in the duration of immobility for compounds 2a–2x.
2m
3-OH
(Notes: flu: fluoxetine).
2n
4-OH
2o
2-CH3
3-CH3
4-CH3
2-OCH3
3-OCH3
4-OCH3
3-OH-4-OCH3
4-N(CH3)2
4-CH(CH3)2
4-NO2
3 mg/kg
–
2p
2k = 13.8
9.4; 2w = 22.8
2.9; fluoxetine = 88.1
9.9).
2q
Structure–activity relationship studies of derivatives 2a–2x (Table 1
and Fig. 3) revealed that substitution with either electron donor groups
or electron acceptor groups on the benzene ring gave compounds that
were able reduce the immobility time of the animals and elicit anti-
depressant effects. Second, regarding the introduction of an electron
donor group substituent [–OH, –CH3, –OCH3, 3-OH-4-OCH3, –N(CH3)2,
and –CH(CH3)2], the data clearly indicated that the 11 compounds were
2r
2s
2t
2u
2v
2w
2x
indomethacin
control
0.96*
1.73
active in the order: 4-CH(CH3)2
>
3-OH
>
4-N(CH3)2
4-OH
>
>
3-
4-
a
OCH3 3-OH-4-OCH3 3-CH3
>
>
>
4-CH3 >
Percent anti-inflammatory activity versus control at 60 min. * P < 0.05,
** P < 0.01, *** P < 0.001 compared with the control group.
OCH3 > 2-CH3 > 2-OCH3. Compounds 2m, 2p, and 2s had sub-
stitution at the 3-position of the benzene ring, and exhibited excellent
anti-depressant activities. Comparing 2m and 2n, which featured –OH
substitutions in different places on the benzene ring, the order of ac-
potent anti-inflammatory activities (Table 2). The trend in activity was
4-F > 2-F > 3-F > 2,4-F2 for F-substituted positions; the sequence of
effect was 4-Cl > 2,4-Cl2 > 2-Cl > 3-Cl > 2,6-Cl2 for Cl-substituted
positions; the order of activity was4-Br > 3-Br > 2-Br for Br-sub-
stituted positions. We found that compounds that contained a halogen
atom at the 4-positionon the phenyl ring (2c, 2g, and 2l) showed good
anti-inflammatory effects. Compound 2x (with a strong electron with-
drawing –NO2 group) exhibited a potent anti-inflammatory effect.
Compounds 2m–2w with electron donating substituents also displayed
anti-inflammatory activity compared with the control group (p < 0.01
or p < 0.001), the order of activity was 4-OH > 4-CH(CH3)2 > 3-
tivity was 3-OH
> 4-OH, and the order of activity for the
-CH3substituted analogs 2o, 2p, and 2q was 3-CH3 > 4-CH3 > 2-CH3.
The order of activity for the –OCH3 substituted compounds 2r, 2s, and
2t was 3-OCH3
> 4-OCH3 > 2-OCH3. Third, concerning the 12
compounds with the electron withdrawing substitutions, F (2a, 2b, 2c,
and 2d), Cl (2e, 2f, 2g, 2h, and 2i), and Br (2j, 2k, and 2l), the location
of the halogen atom on the benzene ring affected the anti-depressant
activity. Comparing 2a, 2b, 2c, and 2d, which featured F substitutions
at different positions, the order of activity was 4-F
> 3-F > 2-
F > 2,4-F2. The order of activity for the Cl-substituted compounds 2e,
2f, 2g, 2h, and 2i was 4-Cl > 2,4-Cl2 > 3-Cl > 2,6-Cl2 > 2-Cl. The
order of activity for the Br-substituted derivatives 2j, 2k, and 2l was 3-
OCH3
> 2-CH3 > 4-N(CH3)2 > 3-CH3 > 4-OCH3 > 3-OH-4-
OCH3 > 3-OH > 2-OCH3 > 4-CH3.Compounds 2n and 2w exhibited
the highest anti-inflammatory activity with 78.8% and 76.8% reduction
in ear edema, respectively. The anti-inflammatory effects of 2n and 2w
were greater than that of indomethacin (51.1%).
Br
> 2-Br > 4-Br. Finally, compound 2x (featuring an electron
withdrawing –NO2 group) also exhibited anti-depressant activity as
indicated by a 72.8% decrease in the immobility time.
The analgesic effects of compounds 2a–2x and the reference drug
indomethacin were assessed by the acetic acid-induced abdominal
writhing test. All compounds, when administered intraperitoneally at
3 mg/kg, displayed potential analgesic effects with inhibition rates
from 62.3% to 76.4% (Fig. 4). Among them, compounds 2c, 2i, 2m, and
2q displayed the best analgesic effects with inhibition rates of 76.30,
75.26, 76.41, and 76.32%, respectively, which were similar to that of
indomethacin (78.3%). We found that variation in the substituents on
the phenyl group affected activity. An electron donating group was
better for activity than an electron withdrawing group, and regarding
the introduction of the 11donor groups, the sequence of activity was
2q > 2m > 2w > 2v > 2t > 2p > 2n > 2s > 2r > 2u > 2o.
Different locations of the halogen atom on the phenyl ring also affected
the analgesic activity. The trend in activity was 4-F > 2-F > 3-
F > 2,4-F2 for F-substituted positions; 2,6-Cl2 > 2,4-Cl2 > 2-Cl >
3-Cl > 4-Cl for Cl-substituted positions; and 4-Br > 2-Br > 3-Br for
Cl-substituted positions. Researchers have described the anti-in-
flammatory and analgesic activities of anti-depressant drugs,27,28 and
from our results it can be suggested the compounds in our study have a
Anti-depressants can be regarded as anti-inflammatory and an-
algesic compounds for mental disorders and non-neurological injuries
because they possess inherent anti-nociceptive effects.25,26 To explore
possible mechanisms of action, we also evaluated the anti-inflammatory
and analgesic effects of derivatives 2a–2x and indomethacin (as a re-
ference drug) using the dimethylbenzene-induced ear edema mouse
model, the results of which are displayed in Table 2.The anti-in-
flammatory effects of compounds 2a–2x (30 mg/kg) corresponded to
that of indomethacin (3 mg/kg). All compounds displayed anti-in-
flammatory effects when intraperitoneally injected before administra-
tion of the inflammatory compound dimethylbenzene, with ear in-
flammation values ranging from 1.15
0.68 to 5.62
1.13 mg, and
inhibition rates of inflammation from 42.9% to 88.3%. Seven com-
pounds, namely 2c, 2g 2h, 2l, 2n, 2s, and 2w, exhibited anti-in-
flammatory activities with inhibition rates of 88.3%, 85.5%, 81.3%,
74.1%, 78.8%, 74.6%, and 76.8%, respectively, which were more ac-
tive than indomethacin (51.1%).
Furthermore, derivatives 2a–2l with F, Cl, and Br groups displayed
3

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Table 4
COX-1/COX-2 inhibition by compounds 2c, 2k, and 2w.
a
b
Compds
COX-1, IC50(μM)
COX-2, IC50(μM)
COX-2, SI
2c
10.21
9.14
8.95
9.34
0.10
0.29
0.19
0.32
0.10
0.09
0.13
0.18
0.07
35.21
48.11
27.97
93.40
2k
0.15
2w
0.11
0.05
Celecoxib
a
IC
is the concentration required to inhibit COX-1 or COX-2 activity by
50
50%. The results are presented as the mean and SD of three measurements, and
the deviation was < 10% of the mean value.
b
SI: selectivity index (COX-1 IC50/COX-2 IC50).
onlyweakCOX-1 inhibitory activity (IC50 = 8.95–10.21 µM) and a
moderate COX-2 inhibitory effect (IC50 values from 0.19 to 0.32 µM;
COX-2 selectivity index [SI] = 27.97–48.11). Compound 2k displayed
the best value (IC50 = 0.19 µM) close to the value for celecoxib
(IC50 = 0.10 µM).
Fig. 4. Analgesic effects of compounds 2a-2x. (Notes: idm: indomethacin).
similar mechanism of action to these drugs.
Serotonin, norepinephrine, and dopamine have been shown to
produce a marked effect in patients with depression. In the central
nervous system, monoamine neurotransmitters are considered to be
fundamental neurochemical transmitters and dysregulation of mono-
amine neurotransmitter metabolism can lead to depression, thus de-
pressive illness can be relieved by raising the concentrations of mono-
amine neurochemical transmitters in the central nervous system.29 To
further investigate possible mechanisms of action, the compounds 2c,
2k, and 2w with good anti-depressant, anti-inflammatory, and an-
algesic effects were tested for effects on the monoamine levels in the
mouse brain in the forced swimming test (Table 3). We found that
compounds 2c, 2k, and 2w markedly increased serotonin levels, but did
not change dopamine or norepinephrine levels, in a similar manner to
fluoxetine. Treatments for depression contain compounds that can en-
hance the levels of serotonin or norepinephrine.30 Increasing the levels
of serotonin or norepinephrine also can reduce the reuptake of mono-
amine neurotransmitters, which acts to raise the levels of serotonin,
thereby reinforcing pathways for pain relief. Thus, the anti-depressant
activity of analogs 2c, 2k, and 2w may be reflected in the concentra-
tions of serotonin in the central nervous system. These findings revealed
that the serotonergic system, rather than the noradrenergic system,
plays an important role in the anti-depressant activities of analogs 2c,
2k, and 2w.
The selective suppression of COX-2 over COX-1 is considered a
useful approach for treating inflammation, and this strategy is re-
sponsible for the analgesic activities of anti-depressants with reduced
gastrointestinal side effects. Hence, a number of selective COX-2 in-
hibitors have been developed and approved for marketing.31,32 It is
desirable to develop new selective COX-2 inhibitors by pharmaceutical
chemistry. The ability of target compounds to inhibit ovine COX-1 and
COX-2 enzymes was determined via measuring their peroxidase activity
using a colorimetric enzyme immune assay (EIA) kit. The inhibitory
effects of analogs 2c, 2k, 2w, and celecoxib were expressed as IC50
values. The selectivity index (SI) values for COX-2 were calculated as
[IC50 (COX-1)/IC50 (COX-2)] (Table 4). The experimental data obtained
from the colorimetric assays demonstrated that the compounds had
Table 3
Effects of compounds 2c, 2k, and 2w on monoamine levels.
Groups
Serotonin
Norepinephrine
Dopamine
Normal vehicle
256.2
102.4
249.4
268.5
257.9
270.3
25.7
18.4c
19.6
199.5
187.3
190.1
179.9
204.4
201.1
20.4
25.7
21.0
19.7
22.6
21.1
255.4
228.0
209.7
211.7
217.1
208.2
19.7
20.4
19.5
17.2
21.7
19.0
Stress vehicle
a,c
20.9a,c
2c
2k
a,c
2w
21.0
Fluoxetine
22.1a,c
c
Fig. 5. (A) 2D interaction of the proposed binding mode; (B) 3D interaction of
compound 2k (pink line represents 2k) inside the COX-1 active site.
Values are given as the mean
SEM (n = 8).a P < 0.01 vs. stress vehicle;
P < 0.05 vs. normal vehicle.
4

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(3 mg/kg) and showed the greatest antidepressant effects in the forced
swimming test. In addition, we identified that the antidepressant effects
of analogs 2c, 2k, and 2w may be mediated through increases in ser-
otonin levels in the central nervous system. These compounds had
moderate inhibitory effects on COX-2, similar to celecoxib. In addition,
molecular modeling studies also indicated the most probable binding
site interactions of compound 2k in the active site. Therefore, further
studies to investigate the possible mechanisms of action of compound
2k are warranted.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgments
This research was financially supplied through the Science and
Technology Development Program of Jilin Provincial of China (No.
20190201148JC, 20190101006Jh). We thank Victoria Muir, PhD, from
Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing
the English text of a draft of this manuscript.
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Fig. 6. (A) 2D interaction of the proposed binding mode; (B) 3D interaction of
compound 2k (pink line represents 2k) inside the COX-2 active site.
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Next, to predict the possible binding interactions of compound 2k in
theCOX-1/COX-2 enzyme active site and to predict its mechanism of
action as an anti-inflammatory and analgesic agent, a molecular
docking study was conducted using Auto-Dock Vina.30 The compound
2k was found to dock into the active site of COX-1 with an interaction
energy of –13.496 kcal/mol. Compound 2k was found to form two
hydrogen bonds with Arg-120 and Tyr-355 amino acid residues inside
COX-1 active site with a distance range of 3.89 Ao. The compound 2k
also could dock successfully into the COX-2 active site and the binding
energy of interaction obtained (–16.517 kcal/mol) and form two hy-
drogen bonds with Arg-120 and Tyr-355 amino acid residues inside
COX-2 active site with a distance range of 2.65 Ao. The greater inter-
action energy for compound 2k with the COX-2 enzyme complex in-
dicated tighter binding of compound 2k into the COX-2 active site,
compared with COX-1, and this binding might be attributed to the two
hydrogen bonding interactions with Arg-120 and Tyr-355. Two-di-
mensional and three-dimensional showed perfect docking scores and
effectively bind interaction with amino acid residues inside COX-2 ac-
tive site, which are shown in Figs. 5 and 6. The results of this study were
in line with those of Labib et al.21
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22. Synthesis of 1-(2-methyl-4-phenylquinolin-3-yl)ethanone (1). A dded 2-amino-
benzophenone (3.0 mmol) refluxed with citric acid (1.5 mmol) in dioxane to the
flask, then slowly added to acetylacetone (3.0 mmol) and refluxed for 12 h. The
reaction was identified by TLC. After completion of the reaction, sodium hydroxide
solution was added to the reaction mixture. The precipitate separated by filtration
and washed with 0.2 mol/mL HCl water. The crude product was purified by silica gel
column. Synthesis of 2-methyl-4phenylquinolin-chalcone derivatives 2a-2x A mix-
ture of 1-(2-methyl-4-phenylquinolin-3-yl)ethanone (1.5 mmol) and different alde-
hydes (1.5 mmol) in ethanolic solution of NaOH was stirred at room temperature for
24 h. The reaction was identified by TLC. After completion of reaction, the reaction
mixture was dumped into water and extracted with ether. The extract was repeatedly
washed with water, dried over anhydrous sodium sulfate and concentration to give
target compounds 2a-2x, which was crystallized from ethanol (Scheme 1). (E)-3-(2-
fluorophenyl)-1-(2-methyl-4-phenylquinolin-3-yl)prop-2-en-1-one (2a). Yield: 72.1
%; yellow solid. mp 120.1-123.0 °C. IR (KBr) cm-1: 2930, 1644, 1564. 1H NMR
(CDCl3, DMSO-d6, 300 MHz): 2.44 (s, 3H, quinolin-CH3), 7.33 (d, 1H, J = 15.1 Hz,
-CO-CH=CH), 7.04-7.62 (m, 4H, ph-H), 7.15-7.51 (m, 5H, ph-H), 7.59-8.08 (m, 4H,
ph-H), 7.72 (d, 1H, J = 15.1 Hz, -CH=CH). 13C NMR (CDCl3, DMSO-d6, 75 MHz):
28.75 (CH3), 120.78 (CH), 121.07 (CH), 131.04 (CH), 131.51 (CH), 133.25 (CH),
133.52 (CH), 133.69 (CH), 134.84 (CH), 135.02 (CH), 139.89 (C), 149.94 (C), 152.
41 (C), 159.27 (C), 201.85 (C). HRMS (m/z): [M+H]+ calcd. for C25H18FNO: 367.
41; found: 367.38. Purity: 98.6 % by HPLC.
Twenty-four 2-methyl-4-phenylquinoline-chalcone analogs were
prepared, and their anti-depressant, analgesic, and anti-inflammatory
effects were evaluated. Pharmacological experiments revealed that 24
analogs showed clear anti-depressant, anti-inflammatory activities at a
dose of 30 mg/kg, and analgesic (3 mg/kg) effects. Among them,
analogs 2c, 2k, and 2w more strongly decreased the duration of im-
mobility (85.0%, 92.0%, and 86.8%, respectively) than fluoxetine
23. Borsini F, Voltera G, Meli A. Physiol Behav. 1986;38:385.
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