Chalcone derivatives bearing chromen or benzo[f]chromen moieties: Design, synthesis, and evaluations of anti-inflammatory, analgesic, selective COX-2 inhibitory activities

Article abstract of DOI:10.1016/j.bmcl.2019.05.051

Thirty-eight chalcone derivatives bearing a chromen or benzo[f]chromen moiety were synthesized and evaluated for their anti-inflammatory and analgesic activities. Using an ear edema model, anti-inflammatory activities were observed for compounds 3a-3s (ear inflammation: 1.75–3.71 mg) and 4a-4s (ear inflammation: 1.71–4.94 mg). All compounds also displayed analgesic effects with inhibition values of 66.7–100% (3a-3s) and 96.2–100% (4a-4s). The 12 compounds that displayed excellent anti-inflammatory and analgesic effects were tested for their inhibitory activity against ovine COX-1 and COX-2. Six compounds bearing a chromen moiety were weak inhibitors of the COX-1 isozyme but showed moderate COX-2 isozyme inhibitory effects (IC₅₀s from 0.37 μM to 0.83 μM) and COX-2 selectivity indexes (SI: 22.49–9.34). Those bearing a benzo[f]chromen moiety were more selective toward COX-2 than those bearing a chromen moiety with IC₅₀s from 0.25 μM to 0.43 μM and COX-2 selectivity indexes from SI: 31.08 to 20.67.

Full text of DOI:10.1016/j.bmcl.2019.05.051

Accepted Manuscript
Chalcone derivatives bearing chromen or benzo[f]chromen moieties: design,
synthesis, and evaluations of anti-inflammatory, analgesic, selective COX-2 in-
hibitory activities
Zhi-Yang Fu, Qing-Hao Jin, Yu-Le Qu, Li-Ping Guan
PII:
S0960-894X(19)30357-9
https://doi.org/10.1016/j.bmcl.2019.05.051
BMCL 26471
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
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16 May 2019
27 May 2019
Please cite this article as: Fu, Z-Y., Jin, Q-H., Qu, Y-L., Guan, L-P., Chalcone derivatives bearing chromen or
benzo[f]chromen moieties: design, synthesis, and evaluations of anti-inflammatory, analgesic, selective COX-2
inhibitory activities, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.
2
019.05.051
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Bioorganic & Medicinal Chemistry Letters
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Chalcone derivatives bearing chromen or benzo[f]chromen moieties: design,
synthesis, and evaluations of anti-inflammatory, analgesic, selective COX-2
inhibitory activities
a
b*
a
a*
Zhi-Yang Fu , Qing-Hao Jin , Yu-Le Qu , Li-Ping Guan
a
Food and Pharmacy College, Zhejiang Ocean University, Zhejiang, Zhoushan 316022, P. R.China
Donghai Science and Technology College, Zhejiang Ocean University, Zhejiang, Zhoushan 316000, P. R.China.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Thirty-eight chalcone derivatives bearing a chromen or benzo[f]chromen moiety were synthesized and
evaluated for their anti-inflammatory and analgesic activities. Using an ear edema model, anti-
inflammatory activities were observed for compounds 3a-3s (ear inflammation: 1.75-3.71 mg) and 4a-
4
s (ear inflammation: 1.71-4.94 mg). All compounds also displayed analgesic effects with inhibition
values of 66.7–100 % (3a-3s) and 96.2–100 % (4a-4s). The 12 compounds that displayed excellent
anti-inflammatory and analgesic effects were tested for their inhibitory activity against ovine COX-1
and COX-2. Six compounds bearing a chromen moiety were weak inhibitors of the COX-1 isozyme
but showed moderate COX-2 isozyme inhibitory effects (IC50s from 0.37 μM to 0.83 μM) and COX-2
selectivity indexes (SI: 22.49 to 9.34). Those bearing a benzo[f]chromen moiety were more selective
toward COX-2 than those bearing a chromen moiety with IC50s from 0.25 μM to 0.43 μM and COX-2
selectivity indexes from SI: 31.08 to 20.67.
Keywords:
chalcone derivatives
chromen or benzo[f]chromen
Anti-inflammatory
Analgesic
COX-1/COX-2
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely
used therapeutics to treat inflammation and pain from various
pathological disorders. NSAIDs work by inhibiting
cyclooxygenase (COX) enzymes, which catalyze prostaglandin
biosynthesis through arachidonic acid. COX-1 and COX-2 are
two known COX isoforms. However, the use of NSAIDs may
result in severe side effects including pepticulcers, renal
dysfunction and bleeding. Interestingly selective inhibition of
COX-2 over COX-1 is believed to reduce gastric ulceration side
effects and identification of clinically useful NSAIDs via
selective inhibition of COX-2 is an ongoing goal in medicinal
and organic chemistry. 7 Hence, the development of efficient,
new selective COX-2 inhibitory compounds is essential.
CH3
O
N3
N
NO2
O
O
O
COX-2: IC50: 0.3 μM
COX-2: IC50: 0.12 μM
O
O
Chalcones are flavonoids that possess a phenolic ,β-
unsaturated ketone structure containing a 1,3-diphenyl-2-en-1-
N
Cl
N
N
Cl
F
one core and show anti-inflammatory and analgesic effects.8-11
A
previous study determined that the presence of an ,β-
COX-2: IC 50 = 46.6 μM
COX-2: IC 50 =36.3 μM
unsaturated ketone structure in a chalcone derivative is critical
1
2
for its effects. Additionally, structure activity relationship
studies showed that reported COX-2 inhibitors generally contain
two aryl ring substituents on a core scaffold.13 One of the core
systems contains an α,β-unsaturated ketone and this hydrophobic
structural feature (-C=C-C=O) may be responsible for the
observed pharmacological effects because of its ability to help
facilitate compound transport across various biological
Figure 1. Chemical structures of reported anti-inflammatory chalcone
derivatives as selective COX-2 inhibitors.
chalcone derivatives, we synthesized 19 3-(2H-chromen-3-yl)-1-
phenylprop-2-en-1-one derivatives (3a-3s) and 19 3-(3H-benzo
[f]chromen-2-yl)-1-phenylprop-2-en-1-one derivatives (4a-4s)
(Figure 2), and evaluated their anti-inflammatory and analgesic
activities in vivo. The COX-1 and COX-2 inhibition effects of
selected compounds were also determined in vitro.
1
4
membranes. Previous studies have shown that the chalcone
moiety may contribute to the anti-inflammatory effect by
modulation of pro-inflammatory gene expression as exemplified
by the comparable activities observed for selective COX-2
inhibitory compounds and common drugs as shown Figure 1.15-17
As part of our continuous search for potential anti-
inflammatory, analgesic and selective COX-2 inhibitory
compounds with the chemical and biological properties of
O
O
R
O
4a-4s
O
R
3a-3s
———
 Corresponding author. Tel.: +86-580-2555280; fax: +86-580-8186396;
E-mail: qhjin2012@163.com(Q.-H. Jin); glp730@163.com (L.-P. Guan).
Figure 2. The structures of designed chalcone derivatives 3a-3s and 4a-4s.

shown in Table 1 illustrated that the 38 compounds that reduced
the ear inflammation and showed anti-inflammatory activities not
only contained electron-withdrawing substituents but also
Table 1. Anti-inflammatory effect of compounds 3a-3s and 4a-4s in vivo
Anti-inflammatory activity
The synthetic routes of the target compounds are illustrated
in Scheme 1. The treatment of 2-hydroxybenzaldehyde or 2-
hydroxy-1-naphthaldehyde with acrolein, a Michael acceptor, in
refluxing dioxane in the presence of potassium carbonate
afforded 2H-chromene-3-carbaldehyde 1 (yield: 96%) or 3H-
benzo[f]chromene-2-carbaldehyde 2 (yield: 92 %), respectively.
The Claisen–Schmidt condensation of 2H-chromene-3-
carbaldehyde 1 or 3H-benzo[f]chromene-2-carbaldehyde 2 with
the appropriate acetophenone in an ethanolic solution of NaOH
yielded nineteen 3-(2H-chromen-3-yl)-1-phenylprop-2-en-1-ones
Compd Edema mean Inhibition
Edema mean
±SD (mg)
Inhibition
rate %
±SD (mg)
2.54±1.17**
3.40±1.55*
2.46±0.22**
3.41±1.34*
rate %a
64.4
52.4
65.6
52.3
51.0
56.1
53.3
56.6
51.7
66.0
75.5
50.8
53.1
66.2
57.3
52.6
68.1
48.1
67.6
64.3
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
4f
2.88±1.12**
3.22±0.87*
4.60±1.96*
3.66±1.33*
2.70±1.50**
73.3
70.1
57.3
66.1
75.0
67.1
84.1
79.8
67.9
57.5
83.6
76.3
74.6
79.3
67.2
67.1
83.1
54.2
55.1
82.2
(3a-3s) and nineteen 3-(3H-benzo[f]chromen-2-yl)-1-phenylprop-
3.50±0.70
*
2
-en-1-ones (4a-4s) in yields of 76–93 % and 67–85 % at room
3.14±0.72*
3.34±1.24*
3.10±1.30*
3.45±1.22*
2.43±0.75**
3.55±0.61*
1.71±0.89***
2.18±1.35**
3.46±0.56*
4.58±1.54*
1.77±0.67***
2.56±0.78**
2.74±1.37**
2.23±1.74**
3.54±1.24*
3.55±1.17*
1.82±0.85***
4.94±0.87*
4.84±1.17*
1.92±0.9***
10.78±1.70
3
f
temperature, respectively.
3
g
4g
4h
4i
The structures of products 3a–3s and 4a–4s were confirmed
by IR, NMR and mass spectrometry. The IR spectra of the
synthesized target derivatives showed absorption bands at 1695–
3
h
3
i
3
j
4j
-1
-1
1
-
(
701 cm for the -C=O stretching vibration and 3340 cm for the
NH stretching vibration. Chalcones were always obtained as the
E)-isomer as determined from the H-NMR spectra. The H-
3
k
1.75±0.07***
3.52±1.74**
3.35±0.35*
2.42±0.97**
3.05±1.02*
3.39±0.52*
2.28±1.20**
3.71±0.89*
2.32±0.92**
2.55±1.3**
7.15±1.42
4k
4l
2
3
l
1
1
3
m
4m
4n
4o
4p
4q
4r
4s
NMR coupling constants of the  and β-vinylic protons in the
chalcone derivatives had large J a,β values of 15.0 Hz suggesting a
3
n
3
o
1
trans-configuration. The H-NMR data confirmed the presence of
3
p
2 2
an –NH group as a singlet signal at 10.3 ppm and the –OCH
1
3
3q
group as singlet signals from 5.03–5.15 ppm. The C-NMR
spectra showed the appearance of a new peak from 186.08–
3
r
97.59 ppm for the O=C group.18-20
3s
Idm
1
Idm
O
O
control
—
—
CHO
control
H
R
O
Idm: Indomethacin.
OH
O
acrolein, 1,4-dioxane
CO
appropriate acetophenone
3a-3s
1
a
%
at 1 h of anti-inflammatory activity.
O
CHO
K2
3
O
NaOH
*
p<0.05,** p<0.01,*** p<0.001 compared with the PEG-400 (control) group
OH
H
O
R
O
4
a-4s
2
electron-donating substituents on the chromen or benzo[f]
chromen moiety. Of nine compounds with electron-withdrawing
with halogen atom substituent groups, the introduction of F (3a,
R:
3
3
3
a,4a=2-F
e,4e=4-Cl
i,4i=3-Br
3b,4b=3-F
3f,4f=4-Cl
3j,4j=4-Br
3c,4c=4-F
3g,4g=2,4-Cl
3d,4d=2-Cl
3h,4h=2-Br
3l,4l=4-NO
2
2
3
b and 3c), Cl (3d, 3e and 3f ), or Br (3h, 3i and 3j), resulted in
3k,4k=4-CF
3o,4o=4-N(CH
3 2
3s,4s=3,4-(OCH )
3
the best anti-inflammatory activity when substituted at the p-
position of the phenyl ring as demonstrated for compounds 3c, 3f
and 3j, with the best compound being 3j with ear inflammation
values 66%. Within 4a-4c and 4h-4j, excellent anti-inflammatory
effects were observed when an electron-donating group was
substituted at the o-position of the phenyl ring as shown for
compounds 4a and 4h. Compound 4e showed the best activity of
4d-4f with substitution at the m-position of the phenyl ring. Thus,
the substitution position of the halogen atom greatly influenced
the anti-inflammatory activities. The order of activity for 3a-3f
and 3h-3j compounds containing substitutions on the phenyl ring
was p-F > o-F > m-F, p-Cl > o-Cl > m-Cl, and p-Br > o-Br > m-
Br. The order of activity for 4a-4c and 4h-4j compounds
containing the benzo[f]chromen moiety with substitutions on the
phenyl ring was o-F > m-F > p-F and the order of activity for Br-
substituted positions was o-Br > m-Br > p-Br. However, for 4d-
4f compounds containing the benzo[f]chromen moiety where the
phenyl was substituted with a Cl, the order of activity was m-Cl >
p-Cl > o-Cl. Compound 4g with a 2,4-dichlolo substituent
showed the best anti-inflammatory activity (84.1 %). Compounds
3
3
m,4m=4-CH
q,4q=4-CH
3
3n,4n=4-OCH
3r,4r=3,4-(CH
3
3
)
2
3p,4p=4-NH
2
2
CH
3
3
)
2
Scheme 1. The synthesis routes of target compounds 3a–3s .and 4a-4s
Thirty-eight of the chalcone derivatives and the reference
drug indomethacin were examined for their anti-inflammatory
activities using an in vivo xylene-induced ear edema model. 21,22
The percentage inhibition of the inflammation for the chalcone
compounds was tested after 1 h of treatment with xylene. The
anti-inflammatory effects of chalcone derivatives 3a-3s and 4a-4s
30 mg/kg) were comparable to indomethacin (30 mg/kg) (Table
). Compounds 3a-3s showed anti-inflammatory activity at a
dose of 30 mg/kg administered intraperitoneally before the
inflammatory agent xylene with ear inflammation values of 1.75
0.07 mg to 3.71 ± 0.89 mg and inhibition of inflammation of
(
1
±
4
9.4–75.5 %. Eight compounds, 3a, 3c, 3g, 3j, 3k, 3n, 3q and 3s,
displayed good anti-inflammatory activity with inhibition values
greater than 60 %, which was nearly equivalent to that of
indomethacin (64.3 %). Chalcone derivatives 4a-4s also
exhibited anti-inflammatory activity at a dose of 30 mg/kg
administered intraperitoneally before the inflammatory agent
xylene with ear inflammation values of 1.71 ± 0.89 mg to 4.94 ±
3 2
3k, 3l, 4k and 4l with a trifluoromethyl (-CF ) or nitro (-NO )
group on the phenyl or naphthalene ring decreased the ear edema
in mice by 75.5 %, 50.8 %, 83.6 %, and 76.3 %, respectively,
with the best compound being 4k with an ear edema value of
1.75 mg. For compounds containing the electron-donating groups
0
.87 mg and inhibition of inflammation of 54.2–84.1 %. Ten
compounds, 4a, 4b, 4e, 4g, 4h, 4k-4n, and 4q, showed anti-
inflammatory activities with inhibition of inflammation of more
than 70 %, which was nearly equivalent to that of indomethacin
of -CH
(OCH
3
, -OCH
3 3 2 2 2 3 3 2
, - N(CH ) , -NH , -CH CH , -(CH ) , and -
(
82.2 %).
The structure activity relationship studies for the anti-
inflammatory effects of chalcone derivatives 3a-3s and 4a-4s
3
)
2
on the phenyl ring, the anti-inflammatory activities were
in the order of 3q > 3s > 3n > 3o > 3m > 3p > 3r. Compounds

containing the benzo[f]chromen moiety had activities in the order
of 4q> 4n > 4m > 4o > 4p> 4s > 4r.
selective inhibition of both COX-1 and COX-2.26,27 The bleeding,
gastrointestinal irritation and ulceration side effects of the
classical NSAIDs are attributed to their selectivity for COX-1
versus COX-2. Therefore, the development of novel selective
The analgesic activities of the target derivatives 3a-3s and
4
a-4s were evaluated using a hot plate technique at 60 min after
intraperitoneal injection in mice at 58 °C and compared with
COX-2 inhibitors through medicinal chemistry approaches is
indomethacin as the reference.23-25 All compounds (3a-3s and 4a-
essential.
28,29
. 12 compounds that displayed excellent anti-
4
s) displayed potent analgesic effects not only with electron-
inflammatory and analgesic effects were tested for their
inhibitory activity against ovine COX-1 and COX-2 (Table 2).
The results indicated that six compounds containing a chromen
moiety were weak inhibitors of the COX-1 isozyme but showed
moderate COX-2 isozyme inhibitory effects (IC50 from 0.37 μM
to 0.83 μM) and COX-2 selectivity indexes (SI: 22.49 to 9.34).
Furthermore, six compounds containing the benzo[f]chromen
moiety were weak inhibitors of the COX-1 isozyme but showed
moderate COX-2 isozyme inhibitory effects (IC50: from 0.25 μM
to 0.43 μM) and COX-2 selectivity indexes (SI: 31.08 to 20.67).
The active compounds containing the benzo[f]chromen moiety
were more sensitive to structural modifications in terms of their
selectivity for COX-2 than those containing the chromen moiety.
Additionally, the activity of compound 4l (IC50=0.25 μM,
SI=31.08) was more similar to inhibitors of the COX-2 isozyme
than the reference drug celecoxib (IC50 =0.22 μM, SI=27.86).
donating substituents but also with electron-withdrawing
substituents on the phenyl ring at a dose of 30 mg/kg
administered intraperitoneally with inhibition values of 66.7–100
%
(3a-3s) and 96.2–100 % (4a-4s) (Figure 3). For compounds
containing the electron-donor groups of -CH , -OCH , - N(CH
NH , -CH CH , -(CH , and - (OCH on the phenyl ring, the
3
3
3 2
) ,
-
2
2
3
3
)
2
3 2
)
order of the analgesic effects was 3p > 3r > 3n, 3q > 3m, 3o > 3s.
For compounds containing the benzo[f] chromen moiety, the
activity order was 4n, 4o, 4p, 4r > 4s > 4q > 4m. For nine
compounds with electron-withdrawing with halogen atom
substituent groups, the introduction of F (3a, 3b and 3c), Cl (3d,
3
e and 3f ), or Br (3h, 3i and 3j), excellent analgesic activities
were observed for those substituted at the p-position of the
phenyl ring as shown for compounds 3c, 3f and 3j. Thus, the
position of the halogen atom substitution greatly influenced the
analgesic effects. In this assay, the order of activity for
compounds containing substitutions on the phenyl ring was p-F >
m-F > o-F and p-Br > m-Br > o-Br. The order of activity
observed for compounds containing a Cl-substituent was p-Cl >
o-Cl > m-Cl. For compounds 4a-4f and 4h-4j, those that
displayed the best analgesic activities contained substituents at
the o-position of the phenyl ring as shown by compounds 4a, 4d
and 4h. For derivatives bearing a benzo[f]chromen moiety, with
substitutions on the phenyl ring, the order of activity was o-F >
p-F > m-F, o-Cl > p-Cl > m-Cl, and o-Br > p-Br > m-Br.
Compound 4g with a 2,4-dichlolo substituent showed the best
anti-inflammatory activity with inhibition values of 100 %.
Table 2. COX-1/COX-2 enzyme inhibition assay in vitro
Compound
COX-1, IC50(μM) a
COX-2, IC50(μM) COX-2, SI b
3c
3j
8.32±0.19
7.21±0.25
0.37±0.22
0.42±0.30
22.49
17.17
3k
3n
7.75±0.26
9.20±0.30
6.22±0.28
7.08±0.24
6.41±0.27
7.92±0.13
8.63±0.17
7.77±0.31
0.83±0.10
0.46±0.18
0.39±0.16
0.46±0.13
0.31±0.06
0.29±0.11
0.33±0.07
0.25±0.21
9.34
20.0
3
q
15.95
15.39
20.68
27.31
26.15
31.08
3
s
4
a
4
g
4
4
k
4
l
Compounds 3k, 3l, 4k and 4l with a trifluoromethyl (-CF
nitro (-NO ) group substituted on the phenyl or naphthalene ring
decreased the ear edema in mice by 100 %, 85.1%, 100 %, and
00 %, respectively.
3
) or
n
9.04±0.19
8.89±0.24
6.13±0.08
0.38±0.05
0.43±0.12
0.22±0.09
23.79
2
4q
2
2
0.67
7.86
Celecoxib
1
a
IC 50 value is the compound concentration required to produce 50%
inhibition of COX-1 or COX-2 for means of three determinations and
deviation from the mean is <10% of the mean value.
Analgesic activity
b
SI: selectivity index (COX-1 IC50/COX-2 IC50 ).
1
1
20
00
The results indicated that the molecular hybridization of the
chalcone pharmacophore of the COX-2 inhibitors was a useful
building block to produce effective hybrid scaffolds with
improved analgesic and anti-inflammatory activity potential.
In conclusion, a series of chalcone derivatives bearing a
chromen or benzo[f]chromen moiety were synthesized and
evaluated for their anti-inflammatory and analgesic effects in
vivo. The results indicated that all compounds exhibited good
anti-inflammatory and analgesic effects. Among them, 12
compounds that exhibited the best anti-inflammatory and
analgesic activities were tested for their inhibitory activity
against ovine COX-1 and COX-2. All target compounds were
more selective toward COX-2 compared with COX-1. The
activity of compound 4l was more similar in magnitude to
inhibitors of the COX-2 isozyme than the reference drug
celecoxib. Hence, the compounds reported herein are promising
starting points for the development of an inhibitor of COX-2.
8
6
4
2
0
0
0
0
0
3a
3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q 3r 3s Idm
compounds
101
Analgesic activity
100
9
9
9
8
9
7
9
6
9
5
94
Idm 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s
compounds
This work was supported by Zhejiang Province Public
Technology Application Project (No. 2017C33131). We thank
Renee Mosi, PhD, from Liwen Bianji, Edanz Group China
Notes: Idm: Indomethacin
Figure 3. Analgesic effect of the designed compounds 3a-3s and 4a-4s
(
www.liwenbianji.cn/ac), for editing the English test of a draft of
this manuscript.
Traditional NSAIDs such as aspirin, indomethacin and
ibuprofen provide their anti-inflammatory activity through non-

=
CH). 13C-NMR (CDCl
, 75 MHz): 65.13, 115.89, 120.78,
3
1
1
21.94, 123.88, 128.51, 129.89, 131.33, 133.22, 142.77,
50.06, 154.83, 188.09. IR (KBr) cm : 1698 (C=O), 1622
1
. Quach, N.D.; Arnold, R.D.; Cummings, B.S. Biochem.
Pharmacol. 2014, 90, 338.
－１
(C-O). MS m/z 331.22 (M + 1). 4g: Yield: 68.4 %, mp: 98.3-
2
. Lokeshwari, D.M.; Achutha, D.K.; Srinivasan, B.;
Shivalingegowda, N.; Krishnappagowda, L.N.; Kariyappa
A.K. Bioorg. Med. Chem. Lett. 2017, 27, 3806.
1
1
6
C
7
00.8 °C. H-NMR (CDCl
.49 (d, 1H, J=15 Hz, =CH), 7.07-7.10 (d, 1H, J=9 Hz, -
), 7.38 (s, 1H, =CH), 7.33-7.51 (m, 3H, -C ), 7.36-
.77 (m, 4H, -C ), 7.53 (d, 1H, J=15 Hz, =CH). 7.96-7.99
d, 1H, J=9 Hz, -C
3 2
, 300 MHz): δ 5.11 (s, 2H, -CH ),
6
H
2
6 3
H
3
4
5
. Hassan, G.S.; Abou-Seri, S.M.; Kamel, G.; Ali, M.M. Eur. J.
Med. Chem. 2014, 78, 482.
6 4
H
1
3
(
6
H
2
). C-NMR (CDCl
3
, 75 MHz): 64.86,
. Ugwu, D.I.; Okoro, U.C.; Ukoha, P.O.; Gupta, A.; Okafor,
S.N. J. Enzyme. Inhib. Med. Chem. 2018, 33, 405.
. Abdel-Sayed, M.A.; Bayomi, S.M.; El-Sherbeny, M.A.;
Abdel-Aziz, N.I.; ElTahir, K-E. H.; Shehatou, G.S.G.; Abdel-
Aziz. A.A.-M. Bioorg. Med. Chem. 2016, 24, 2032.
. Makhdoumi, P.; Zarghi, A.; Daraei, B.; Karimi, G. J.
Pharmacopuncture 2017, 20, 207.
. Gouvea, D.P.; Vasconcellos, F.A.; Berwaldt, Gabriele dos A.;
Seixas Neto, A.C. P.; Fischer, G.; Sakata, R.P.; Almeida,
W.P.; Cunico, W. Eur. J. Med. Chem. 2016, 118, 259.
. Raj, R.; Saini, A.; Gut, J.; Rosenthal, P.J.; Kumar, V. Eur. J.
Med. Chem. 2015, 95, 230.
1
1
1
14.98, 117.36, 121.22, 124.23, 124.38, 126.99, 127.39,
27.57, 128.77, 129.35, 129.64, 130.08, 130.13, 130.37,
32.05, 132.11, 136.64, 137.42, 143.82, 153.94, 192.04. IR
－
１
(KBr) cm : 1685 (C=O), 1618 (C-O). MS m/z 381.29 (M +
1
).
6
7
2
2
1. Ohlsson, L. Acta Pharmacol. Toxicol. 1953, 9, 322.
2. Cordeiro, K.W.; Felipe, J.L.; Malange, K.F.; do Prado, P.R.;
de Oliveira Figueiredo, P.; Garcez, F.R.; de Cássia Freitas, K.;
Garcez, W.S.; Toffoli-Kadri, M.C. J. Ethnopharmacol. 183
2
016, 183, 128.
8
9
2
2
2
2
2
2
3. Leighton, G.; Johnson, M.; Meecham, K.; Hill, R.; Hughes, J.
Br. J. Pharmacol. 1987, 92, 915.
4. Shaaban, O.G.; Rizk, O.H.; Bayad, A.E.; El-Ashmawy, I.M.
Open Med. Chem. J. 2013, 7, 49.
5. Guan, L.P.; Xia, Y.N.; Jin, Q.H.; Liu, B.Y.; Wang, S.H.
Bioorg. Med. Chem. Lett. 2017, 27, 3378.
6. Shi, L.; Aixi, H.; X. Jiangpina, Yiping, J. Chin. J. Chem.
. Sashidhara, K.V.; Kumar, M.; Modukuri, R.K.; Sonkar, R.;
Bhatia, G.; Khanna, A.K.; Rai, S.; Shukla, R. Bioorg. Med.
Chem. Lett. 2011, 21, 4480.
1
1
0. Chen, W.B.; Ge, X.T.; Xu, F.L.; Zhang, Y.L.; Liu, Z.G.; Pan,
J.L.; Song, J.; Dai, Y.R.; Zhou, J.M.; Feng, J.P.; Liang, G.
Bioorg. Med. Chem. Lett. 2015, 25, 2998.
1. Wei, Z.Y.; Chi, K.Q.; Yu, Z.K.; Liu, H.Y.; Sun, L.P.; Zheng,
C.J.; Pia, H.R. Bioorg. Med. Chem. Lett. 2016, 26, 5920.
2. Guan, L.P.; Liu, B.Y. Eur J Med Chem. 2016, 121, 47.
3. Ahmed, H.E.A.; Abdel-Salam, H.A.; Shaker, M.A. Bioorg.
Chem. 2016, 66, 1.
2
012, 30, 1339.
7. Dou, J.; Shi, L.; Hu, A.; Dong, M.; Xu, J.; Liu, A.; Jiang, Y.
Arch. Pharm. Chem. Life Sci. 2014, 347, 89.
8. Eleftheriou, P.; Geronikaki, A.; Hadjipavlou-Litina, D.;
Vicini, P.; Filz, O.; Filimonov, D.; Poroikov, V.; Chaudhaery,
S.S.; Roy, K.K.; Saxena, A.K. Eur. J. Med. Chem. 2012, 47,
1
1
1
1
1
1
4. Badrey, M.G.; Abdel-Aziz, H.M.; Gomha, S.M.; Abdalla,
M.M.; Mayhoub, A.S. Molecules 2015, 20, 15287
5. Labib, M.B.; Sharkawi, S.M.Z.; El-Daly, M. Bioorg. Chem.
1
11.
2
9. El-Sayed, M.; Abdel-Aziz, N.I.; Abdel-Aziz, A.A.-M.; El-
Azab, A.S.; ElTahir, K. Bioorg. Med. Chem. 2012, 20, 3306.
2
018, 80, 70.
6. Zarghi, A.; Zebardast, T.; Hakiminon, F.; Shirazi, F.H.; Rao,
P.N.P.; Knaus, E.E. Bioorg. Med. Chem. 2006, 14, 7044.
7. Bano, S.; Javed, K.; Ahmad, S.; Rathish, I.G.; Singh, S.;
Chaitanya, M.; Arunasree, K.M.; Alam, M.S. Eur. J. Med.
Chem. 2013, 65, 51.
1
1
2
8. Foroumadi, A.; Emami, S.; Sorkhi, M.; Nakhjiri, M.;
Nazarian, Z.; Heydari, S.; Ardestani, S.K.; Poorrajab, F.;
Shafiee, A. Chem. Biol. Drug Des. 2010, 75, 590.
9. Nazarian, Z.; Emami, S.; Heydari, S.; Ardestani, S.K.;
Nakhjiri, M.; Poorrajab, F.; Shafiee, A.; Foroumadi, A. Eur. J.
Med. Chem. 2010, 45, 1424.
0. The synthesis of 3-(2H-chromen-3-yl)-1-(2,4-dichloro)phenyl
-prop-2-en-1-one 3g and nineteen 3-(3H-benzo[f]chromen-2-
yl)-1-(2,4-dichloro)phenylprop-2-en-1-one 4g: To a solution
of 2H-chromene-3-carbaldehyde 1 or 3H-benzo[f]chromene-
2
-carbaldehyde 2 (1 mmol) and 2,4-dichloroacetophenone (1
mmol) in absolute ethanol (20 mL), NaOH solution (3.5 M,
mL) was added and stirred overnight at room temperature.
8
The reaction mixture was diluted with water and the
precipitate was filtered and crystallized from ethanol to give
o
the target compounds. 3g: Yield: 76.5 %, m.p. 92.1-92.9 C.
1
H-NMR (CDCl
m, 3H, -C ), 7.12 (d, 1H, J=15 Hz, =CH), 6.89 (s, 1H,
CH), 7.17-8.34 (m, 4H, -C ), 7.53 (d, 1H, J=15 Hz,
3 2
, 300 MHz): δ 5.14 (s, 2H, -CH ), 6.81-7.03
(
=
6 3
H
6 4
H
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Chalcone derivatives bearing chromen or benzo[f]
chromen moieties: design, synthesis, and evaluations
of anti-inflammatory, analgesic, selective COX-2
inhibitory activities
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a
b*
a
a*
Zhi-Yang Fu , Qing-Hao Jin , Yu-Le Qu , Li-Ping Guan
O
O
CHO
H
R
OH
O
O
acrolein, 1,4-dioxane
CO
appropriate acetophenone
NaOH
3a-3s
1
O
CHO
K2
3
O
OH
H
O
R
O
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