Synthesis of some chalcones and pyrazolines carrying morpholinophenyl moiety as potential anti-inflammatory agents

Article abstract of DOI:10.1002/ardp.201000245

Chalcones of 2a-f and their corresponding products, pyrazolines 3a-f, were synthesized and evaluated for their anti-inflammatory activity against carrageenan edema in albino rats at a dose of 10 mg/kg. All the compounds of this series showed promising anti-inflammatory activity. The most active compounds of this series, 2a, 2b, and 2d, were found to be most potent. They showed higher percentage of inhibition of edema than the standard drug indomethacin.

Full text of DOI:10.1002/ardp.201000245

242
Arch. Pharm. Chem. Life Sci. 2011, 11, 242–247
Full Paper
Synthesis of Some Chalcones and Pyrazolines Carrying
Morpholinophenyl Moiety as Potential Anti-Inflammatory
Agents
Omneya M. Khalil
Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Chalcones of 2a–f and their corresponding products, pyrazolines 3a–f, were synthesized and
evaluated for their anti-inflammatory activity against carrageenan edema in albino rats at a dose
of 10 mg/kg. All the compounds of this series showed promising anti-inflammatory activity. The most
active compounds of this series, 2a, 2b, and 2d, were found to be most potent. They showed higher
percentage of inhibition of edema than the standard drug indomethacin.
Keywords: Anti-inflammatory activity / Chalcones / Pyrazolines
Received: August 25, 2010; Revised: October 3, 2010; Accepted: October 8, 2010
DOI 10.1002/ardp.201000245
Introduction
pyrazoline structure which is known to possess a broad
spectrum of biological activities such as antiamoebic [13,
14], antimicrobial [15], monoamine oxidase inhibitors [16],
antimycobacterial [17, 18], antidepressant [19, 20], anticon-
vulsant [21], and anti-inflammatory [22, 23] activities.
It is pertinent to mention that 4-phenylmorpholine deriva-
tives have been reported to show anti-inflammatory [24, 25]
and antimicrobial [26, 27] activities.
Most currently used non steroidal anti-inflammatory drugs
(NSAIDs) have limitations in their therapeutic use since they
cause gastrointestinal and renal side effects that are insepa-
rable from their pharmacological activities. Therefore, devel-
opment of novel compounds having anti-inflammatory
activity with an improved safety profile is a great deal of
interest to many researchers.
Therefore, both the chalcones and the pyrazolines possess
worthy and imperative bioactivities which render them use-
ful substances in drug research. In this study, based on the
above findings, our aim was to synthesize a new series of
chalcones and pyrazoline derivatives carrying a morpholino-
phenyl moiety and to investigate their possible anti-inflam-
matory activities.
Chalcones are a,b-unsaturated ketones and they are wide-
spread in the plant kingdom. It is well known that the majority
of natural or synthetic chalcones are highly biologically active
with great pharmaceutical and medicinal applications. For a
structurally simple group of compounds, chalcones have been
shown to display a diverse array of biological activities among
with antimalarial [1, 2], antimicrobial [3–5], anticancer [6, 7],
antioxidant [8], antiallergic [9], antihyperglycemic [10], and Results and discussion
anti-inflammatory [11, 12] activities.
Moreover, chalcones are useful synthons in the synthesis of
a large number of bioactive molecules such as pyrazolines
that are well known nitrogen containing heterocyclic com-
pounds. Considerable interest has been focused on the
Chemistry
The synthesis of the target compounds was accomplished
according to the reaction sequence illustrated in Scheme 1.
Chalcones 2a–f were synthesized by a base catalyzed
Claisen-Schmidt condensation reaction [28, 29] of 1-(4-mor-
pholinophenyl)ethanone with appropriate aldehydes. The
reaction between the newly synthesized chalcones 2a–f with
hydrazine hydrate in ethanol [30] led to a synthesis of novel
pyrazoline derivatives 3a–f. All synthesized compounds were
Correspondence: Omneya M. Khalil, Organic Chemistry Department,
Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
E-mail: omneyafawzy@yahoo.com
Fax: þ202-23635140
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Arch. Pharm. Chem. Life Sci. 2011, 11, 242–247
Chalcones and Pyrazolines as Potential Anti-Inflammatory Agents
243
R
R
NH2NH2
RCHO
O
N
O
N
O
N
NH
N
NaOH
O
O
2a-f
1
3a-f
2a, 3a R = 2-thienyl
2b, 3b R = 4-Br-C6H4
2c, 3c R = 2-(OCH3)-C6H4
2d, 3d R = 3,4-(OCH3)2-C6H3
2e, 3e R = 3,5-(OCH3)2-C6H3
2f, 3f R = 3,4,5-(OCH3)3-C6H2
Scheme 1. Synthesis of chalcones 2a–f and pyrazolines 3a–f.
characterized by their physical and spectral data (IR, 1H-NMR)
and confirmed the structures of the novel compounds. The IR
other aromatic and aliphatic protons were observed at the
expected regions.
spectra of the chalcones showed the characteristic band for
conjugated C O at 1639–1654 cmꢀ1. In the H-NMR spectra
1
–
–
Anti-inflammatory activity
of 2a–f, a pair of the trans-olefinic proton doublets appeared
at d ¼ 7.58–7.68 and d ¼ 7.79–7.89 ppm, respectively, with a
J value of 14.8–15.6 Hz. IR data of 3a–f were very informative.
The IR spectra of all the pyrazoline products showed disap-
All the newly synthesized compounds were screened for their
anti-inflammatory activities against carrageenan-induced
rat’s paw edema at 10 mg/kg. The anti-inflammatory proper-
ties were compared with that of indomethacin (in a dose
of 10 mg/kg) which was used as a reference standard.
Chalcones 2a–f, the first stage compounds, have elicited
significant anti-inflammatory activity of varying degree
(32.13–65.70%).
–
pearance of C O band of chalcones. A strong band appeared
–
at 1589–1608 cmꢀ1 assigned to C N because of ring closure.
–
–
Compounds 3a–f showed an additional sharp band in the
region 3325–3395 cmꢀ1 due to the NH stretch. Their 1H-NMR
spectra revealed, in each case, the signals of CH2 protons of
the pyrazoline ring in the region 2.77–3.33 and 3.40–
3.76 ppm. The CH proton appeared as a multiplet at 4.75–
5.40 ppm, while for compounds 3b and 3c it appeared as one
double doublet at 4.76 and 5.40 ppm, respectively. All the
Cyclization of these chalcones into their corresponding
pyrazolines 3a–f showed moderate anti-inflammatory
activity (13.00–57.76%). In general, they exhibited less degree
of inhibition of edema compared to their parent compounds
except for compound 3c (Table 1, Figs. 1 to 3).
Table 1. Anti-inflammatory activity of the test compounds assessed in comparison to indomethacin as reference.
Compound
Mean swelling volume (mL)
% Inhibition of edema
Potencyc
Control
Indomethacin
0.55 ꢁ 0.05
0.23 ꢁ 0.03
0.21a ꢁ 0.05
0.19a ꢁ 0.03
0.36 ꢁ 0.07
0.22a ꢁ 0.03
0.38 ꢁ 0.05
0.28a ꢁ 0.05
0.25a ꢁ 0.06
0.41 ꢁ 0.08
0.23a ꢁ 0.06
0.40 ꢁ 0.03
0.45a,b ꢁ 0.07
0.48a,b ꢁ 0.05
0.00
58.84
62.09
65.70
34.66
60.65
32.13
48.74
55.23
25.63
57.76
27.44
19.13
13.00
–
100.00
105.52
111.66
58.90
103.07
54.60
82.82
93.87
43.56
98.16
46.63
32.52
22.09
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
a
Statistically significant from the control at p < 0.05
Statistically significant from the indomethacin at p < 0.05
Potency was expressed as % edema inhibition of the tested compounds relative to % edema inhibition of indomethacin (reference
b
c
standard)
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244
O. M. Khalil
Arch. Pharm. Chem. Life Sci. 2011, 11, 242–247
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Test compounds
Figure 1. Mean edema volume (mL) of the test compounds.
70
60
50
40
30
20
10
0
Test compounds
Figure 2. % Inhibition of edema for the test compounds.
The presence of 4-bromine (2b), or 3,4-dimethoxy groups (2d),
in the aromatic ring of 3-position of the chalcone nucleus
gave rise to an increased anti-inflammatory activity (65.70 or
60.65%, respectively).
preferable for obtaining an effective pharmacological agent
as exhibited in pairs 2a or 3a (65.70 or 55.23%, respectively).
On the other hand, compounds 3b, 3d, 3e, and 3f in the
pyrazoline series, when phenyl ring was substituted with 4-
bromo, 3,4-dimethoxy, 3,5-dimethoxy or 3,4,5-trimethoxy
groups, showed lower degree of anti-inflammatory activity
(25.63, 27.44, 19.13, 13.00%, respectively).
It is also obvious that adopting a thienyl function (a bio-
isostere of the phenyl group) at the 2-position of the chalcone
or the 5-position of the pyrazoline heterocycle seems
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Arch. Pharm. Chem. Life Sci. 2011, 11, 242–247
Chalcones and Pyrazolines as Potential Anti-Inflammatory Agents
245
120
100
80
60
40
20
0
Test compounds
Figure 3. Anti-inflammatory activity potency of the test compounds relative to indomethacin which was used as a reference standard.
Conclusion
General procedure for the synthesis of chalcones (2a–f)
A mixture of 1-(4-morpholinophenyl)ethanone (0.05 mol), appro-
priate aromatic aldehyde (0.05 mol) and 10% aqueous sodium
hydroxide (10 mL) in ethanol (30 mL) was stirred at room
temperature for about 3 h. The resulting solid was filtered off,
rinsed with water, dried, and crystallized from ethanol.
The investigation of anti-inflammatory screening data
revealed that the entire investigated compounds exhibit
considerable anti-inflammatory properties with the percent-
age inhibition of edema formation ranging from 13.0 to
65.7%, while the reference drug indomethacin showed
58.84% inhibition. All chalcone derivatives, except 2c, were
found to be more potent than their cyclized pyrazolines.
Three chalcones 2a, 2b and 2d showed remarkable activities
with potency of 105.52, 111.66 and 103.07%, respectively,
while two pyrazoline derivatives 3a and 3c exhibited com-
parable activity to indomethacin, although not equal
(potency 93.87 and 98.16%, respectively).
1-(4-Morpholinophenyl)-3-(2-thienyl)-2-propen-1-one (2a)
Mp: 232–2338C; yield: 83%; IR (cmꢀ1): n 3082 (arom-H), 2962, 2843
1
(aliph-H), 1643 (C O); H-NMR (DMSO-d ): d 3.35 (t, 4H, N(CH ) ),
–
–
6
2 2
3.74 (t, 4H, O(CH2)2), 7.07 (d, 2H, Ar-H, J ¼ 8.6 Hz), 7.23 (dd, 1H,
–
thienyl H4, J ¼ 3.4, 4.6 Hz), 7.60 (d, 1H, CH, J ¼ 14.8 Hz), 7.69
–
(d, 1H, thienyl H3, J ¼ 3.0 Hz), 7.80 (d, 1H, thienyl H5,
–
J ¼ 5.2 Hz), 7.88 (d, 1H, CH, J ¼ 15.4 Hz), 8.05 (d, 2H, Ar-H,
–
J ¼ 8.8 Hz). Anal. calcd. for C17H17NO2S (299.38): C, 68.20, H,
5.72, N, 4.67. Found: C, 68.34, H, 5.81, N, 4.60.
Hence, it is concluded that there is ample scope for
further study in developing these as good lead
compounds.
3-(4-Bromophenyl)-1-(4-morpholinophenyl)-2-propen-1-
one (2b)
Mp: 203–2048C; yield: 90%; IR (cmꢀ1): n 3082 (arom-H), 2965,
2862, 2835 (aliph-H), 1654 (C O); 1H-NMR (DMSO-d6): d 3.31 (t,
–
–
Experimental
4H, N(CH2)2), 3.77 (t, 4H, O (CH2)2), 7.01 (d, 2H, Ar-H, J ¼ 8.2 Hz),
7.40 (d, 2H, Ar-H, J ¼ 7.4 Hz), 7.54 (d, 2H, Ar-H, J ¼ 7.8 Hz), 7.68
–
–
–
Melting points were obtained on a Griffin apparatus and are
uncorrected. Microanalyses were carried out at the
Microanalytical Center, Faculty of Science, Cairo University. IR
spectra were recorded on a Shimadzu 435 spectrometer, using
KBr discs. 1H-NMR spectra were performed on a Joel NMR Varian
Gemini 200 MHz Spectrometer and Varian Mercury VX-300 MHz
NMR Spectrometer using TMS as the internal standard.
(d, 1H, CH, J ¼ 15.4 Hz), 7.86 (d, 1H, CH, J ¼ 15.4 Hz), 8.12 (d,
–
2H, Ar-H, J ¼ 8.2 Hz). Anal. calcd. for C19H18BrNO2 (372.25): C,
61.30, H, 4.87, N, 3.76. Found: C, 61.18, H, 4.75, N, 3.83.
3-(2-Methoxyphenyl)-1-(4-morpholinophenyl)-2-propen-1-
one (2c)
Mp; 133–1348C; yield: 81%; IR (cmꢀ1): n 3051 (arom-H), 2962,
Reagents used in synthesis were obtained commercially from
Sigma-Aldrich1 and Merck1
2889, 2839 (aliph-H), 1647 (C O); 1H-NMR (DMSO-d6): d 3.35 (m,
–
–
.
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246
O. M. Khalil
Arch. Pharm. Chem. Life Sci. 2011, 11, 242–247
4H, N(CH2)2), 3.77 (m, 4H, O(CH2)2), 3.92 (s, 3H, OCH3), 6.98–7.22
–
pyrazoline H4, J ¼ 16.2, 5.7 Hz), 3.14 (t, 4H, N(CH2)2), 3.40 (dd,
1H, pyrazoline H4, J ¼ 16.2, 10.5 Hz), 3.73 (t, 4H, O(CH2)2), 4.76
(dd, 1H, pyrazoline H5, J ¼ 10.5, 5.4 Hz), 6.93 (d, 2H, Ar-H,
J ¼ 8.4 Hz), 7.33 (d, 2H, Ar-H, J ¼ 8.1 Hz), 7.48 (d, 2H, Ar-H,
J ¼ 8.7 Hz), 7.52 (d, 2H, Ar-H, J ¼ 8.7 Hz). Anal. calcd.
for C19H20BrN3O (386.28): C, 59.07, H, 5.21, N, 10.87. Found: C,
59.20, H, 5.00, N, 10.98.
(m, 4H, Ar-H), 7.46 (distorted d, 1H, CH), 7.86–8.10 (m, 5H, Ar-H
–
–
and CH). Anal. calcd. for C20H21NO3 (323.38): C, 74.28, H, 6.54, N,
–
4.33. Found: C, 74.41, H, 6.61, N, 4.32.
3-(3,4-Dimethoxyphenyl)-1-(4-morpholinophenyl)-2-
propen-1-one (2d)
Mp: 168–1698C; yield 54%; IR (cmꢀ1): n 3005 (arom-H), 2966, 2893,
2835 (aliph-H), 1639 (C O); 1H-NMR (DMSO-d6): d 3.31 (t, 4H,
N(CH2)2), 3.74 (t, 4H, O(CH2)2), 3.81 (s, 3H, OCH3), 3.86 (s, 3H,
–
–
5-(2-Methoxyphenyl)-4,5-dihydro-3-(4-morpholinophenyl)-
1H-pyrazole (3c)
OCH3), 7.00 (d, 1H, Ar-H, J ¼ 8.4 Hz), 7.02 (d, 2H, Ar-H, J ¼ 9.0 Hz),
Mp: 107–1088C; yield 33%; IR (cmꢀ1): n 3340 (NH), 2958, 2835
–
7.34 (d, 1H, Ar-H, J ¼ 8.7 Hz), 7.50 (s, 1H, Ar-H), 7.61 (d, 1H, CH,
1
(aliph-H), 1597 (C N); H-NMR (DMSO-d ): d 3.20 (dd, 1H, pyrazo-
–
–
–
6
–
J ¼ 15.6 Hz), 7.79 (d, 1H, CH, J ¼ 15.3 Hz), 8.06 (d, 2H, Ar-H,
–
line H4, J ¼ 17.7, 4.8 Hz), 3.31 (t, 4H, N(CH2)2), 3.76 (dd, 1H,
pyrazoline H4, J ¼ 17.7, 11.7 Hz), 3.87 (t, 4H, O(CH2)2), 3.94 (s,
3H, OCH3), 5.15 (s, 1H, NH, D2O exchangeable), 5.40 (dd, 1H,
pyrazoline H5, J ¼ 11.7, 4.8 Hz), 7.04 (m, 1H, Ar-H), 7.10 (d,
2H, Ar-H, J ¼ 9.0 Hz), 7.49 (m, 2H, Ar-H), 7.81 (d, 2H, Ar-H,
J ¼ 9.0 Hz), 7.87 (m, 1H, Ar-H). Anal. calcd. for C20H23N3O2
(337.41): C, 71.19, H, 6.87, N, 12.45. Found: C, 71.31, H, 6.91,
N, 12.60.
J ¼ 9.0 Hz). Anal. calcd. for C21H23NO4 (353.41): C, 71.36, H, 6.55,
N, 3.96. Found: C, 71.22, H, 6.41, N, 4.12.
3-(3,5-Dimethoxyphenyl)-1-(4-morpholinophenyl)-2-
propen-1-one (2e)
Mp: 180–1818C; yield: 85%; IR (cmꢀ1): n 3005 (arom-H), 2978,
2943, 2862 (aliph-H), 1651 (C O); 1H-NMR (DMSO-d6): d 3.34 (t,
4H, N(CH2)2), 3.73 (t, 4H, O(CH2)2), 3.79 (s, 3H, OCH3), 3.80 (s, 3H,
–
–
OCH3), 6.55 (s, 1H, Ar-H), 7.02 (d, 2H, Ar-H, J ¼ 8.7 Hz), 7.03 (s, 2H,
5-(3,4-Dimethoxyphenyl)-4,5-dihydro-3-(4-
morpholinophenyl)-1H-pyrazole (3d)
–
–
–
Ar-H), 7.58 (d, 1H, CH, J ¼ 15.6 Hz), 7.89 (d, 1H, CH,
–
J ¼ 15.6 Hz), 8.07 (d, 2H, Ar-H, J ¼ 9.0 Hz). Anal. calcd.
for C21H23NO4 (353.41): C, 71.36, H, 6.55, N, 3.96. Found: C,
71.30, H, 6.48, N, 3.88.
Mp: 125–1268C; yield 40%; IR (cmꢀ1): n 3394 (NH), 2931, 2831,
2849 (aliph-H), 1600 (C N); 1H-NMR (DMSO-d6): d 3.16 (dd, 1H,
–
–
pyrazoline H4, J ¼ 17.1, 6.0 Hz), 3.30 (t, 4H, N(CH2)2), 3.74 (m, 4H,
O(CH2)2), 3.76 (dd, 1H, pyrazoline H4, J ¼ 17.4, 11.1 Hz), 3.83 (s,
3H, OCH3), 3.85 (s, 3H, OCH3), 5.05 (m, 1H, pyrazoline H5), 6.87 (d,
2H, Ar-H, J ¼ 9.0 Hz), 7.06–7.52 (m, 3H, Ar-H), 8.04 (d, 2H, Ar-H,
J ¼ 9.0 Hz). Anal. calcd. for C21H25N3O3 (367.44): C, 68.64, H, 6.85,
N, 11.43. Found: C, 68.50, H, 6.73, N, 11.52.
3-(3,4,5-Trimethoxyphenyl)-1-(4-morpholinophenyl)-2-
propen-1-one (2f)
Mp: 156–1578C; yield 73%; IR (cmꢀ1): n 3070, 3005 (arom-H), 2962,
1
2920, 2897, 2839 (aliph-H), 1654 (C O); H-NMR (DMSO-d ): d 3.31
–
–
(t, 2H, N(CH2)2), 3.72 (t, 2H, O(CH2)2), 3.83 (s, 3H, OCH3), 3.86 (s, 6H,
6
2 ꢂ OCH3), 7.02 (d, 2H, Ar-H, J ¼ 9.0 Hz), 7.192 (s, 2H, Ar-H), 7.61
5-(3,5-Dimethoxyphenyl)-4,5-dihydro-3-(4-
morpholinophenyl)-1H-pyrazole (3e)
–
–
–
(d, 1H, CH, J ¼ 15.3 Hz), 7.85 (d, 1H, CH, J ¼ 15.6 Hz), 8.07 (d,
–
2H, Ar-H, J ¼ 9.3 Hz). Anal. calcd. for C22H25NO5 (383.43): C,
68.91, H, 6.57, N, 3.65. Found: C, 69.12, H, 6.55, N, 3.60.
Mp: 105–1068C; yield 42%; IR (cmꢀ1): n 3325 (NH), 2947, 2843
1
(aliph-H), 1608 (C N); H-NMR (DMSO-d ): d 3.33 (m, 5H, N(CH )
–
–
and pyrazoline H4), 3.72 (t, 4H, O(CH2)2), 3.76 (d, 1H, pyrazoline
6
2 2
General Procedure for the synthesis of 5-aryl-3-(4-
morpholinophenyl)-4,5-dihydro-1H-pyrazoles (3a–f)
A solution of the appropriate chalcone (0.03 mol) 2a–f and
hydrazine monohydrate (0.06 mol) in ethanol (30 mL) was
refluxed for 3 h. The reaction mixture was cooled and kept at
08C overnight. The resulting solid was crystallized from ethanol.
H4, J ¼ 16.2, 11.1 Hz), 3.80 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.68
(s, 1H, NH, D2O exchangeable), 5.23 (m, 1H, pyrazoline H5), 6.55
(s, 1H, Ar-H), 6.99 (d, 2H, Ar-H, J ¼ 9.0 Hz), 7.23 (s, 2H, Ar-H), 8.07
(d, 2H, Ar-H, J ¼ 9.0 Hz). Anal. calcd. for C21H25N3O3 (367.44): C,
68.64, H, 6.85, N, 11.43. Found: C, 68.53, H, 6.70, N, 11.24.
5-(3,4,5-Trimethoxyphenyl)-4,5-dihydro-3-(4-morpholino-
phenyl)-1H-pyrazole (3f)
3-(4-Morpholinophenyl)-4,5-dihydro-5-(2-thienyl)-1H-
pyrazole (3a)
Mp: 109–1108C; yield 38%; IR (cmꢀ1): n 3395 (NH), 2931, 2831
Mp: 91–928C; yield: 44% IR (cmꢀ1): n 3390 (NH), 2958, 2854 (aliph-
1
(aliph-H), 1589 (C N); H-NMR (DMSO-d ): d 3.15 (dd, 1H, pyrazo-
–
–
1
H), 1597 (C N); H-NMR (DMSO-d ): d 2.88 (dd, 1H, pyrazoline H4,
6
–
–
6
line H4, J ¼ 16.8, 4.8 Hz), 3.29 (t, 4H, N(CH2)2), 3.65 (dd, 1H,
pyrazoline H4, J ¼ 16.2, 11.1 Hz), 3.72 (t, 4H, O(CH2)2), 3.82 (s,
3H, OCH3), 3.84 (s, 6H, 2 ꢂ OCH3), 4.75 (m, 1H, pyrazoline H5),
6.49 (s, 2H, Ar-H), 6.96 (d, 2H, Ar-H, J ¼ 8.4 Hz), 7.68 (d, 2H, Ar-H,
J ¼ 8.4 Hz). Anal. calcd. for C22H27N3O4 (397.46): C, 66.48, H, 6.84,
N, 10.57. Found: C, 66.53, H, 7.01, N, 10.71.
J ¼ 15.9, 4.8 Hz), 3.11 (t, 4H, N(CH2)4), 3.62 (dd, 1H, pyrazoline
H4, J ¼ 16.0, 11.0 Hz), 3.72 (t, 4H, O(CH2)2), 5.33 (m, 1H, pyrazo-
line H5), 5.55 (s, 1H, NH, D2O exchangeable), 6.93–7.15 (m, 3H, Ar-
H, thienyl H4), 7.39 (d, 1H, thienyl H5, J ¼ 4.5 Hz), 7.61 (d, 1H,
thienyl H3, J ¼ 2.7 Hz), 7.93 (d, 2H, Ar-H, J ¼ 9.0 Hz). Anal. calcd.
for C17H19N3OS (313.41): C, 65.14, H, 6.11, N, 13.40. Found: C,
65.23, H, 5.98, N, 13.32.
Anti-inflammatory activity screening
5-(4-Bromophenyl)- 4,5-dihydro-3-(4-morpholinophenyl)-
1H-pyrazole (3b)
Adult male albino rats (180–200 g) were used. All animals were
kept under uniform and controlled conditions of temperature
and light/dark (12/12 h) cycles, fed with standard rodent diet and
water ad libitum. Animals were allowed to adapt to the laboratory
Mp: 147–1498C; yield 46%; IR (cmꢀ1): n 3336 (NH), 2958, 2835
(aliph-H), 1604 (C N); 1H-NMR (DMSO-d6): d 2.77 (dd, 1H,
–
–
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Arch. Pharm. Chem. Life Sci. 2011, 11, 242–247
Chalcones and Pyrazolines as Potential Anti-Inflammatory Agents
247
environment for one week prior to experiments. The experimen-
tal tests on animals have been performed in accordance with the
Institutional Ethical Committee approval. The anti-inflamma-
tory effect of the newly synthesized compounds was evaluated
in correspondence to the carrageenan-induced paw edema
method [31]. Fourteen groups of animals each consisting of five
rats weighing 180–200 g were selected. The first group was
injected with 0.05 mL of 1% carrageenan in the subplantar tissue
of the right hind paw and served as untreated control.
The positive control group was given 10 mg/kg indomethacin
one hour before carrageenan injection.
[8] R. N. Gacche, N. A. Dhole, S. G. Kamble, B. P. Bandgar,
J. Enzym. Inhib. Med. Chem. 2008, 23, 28–31.
[9] T. Hirano, J. Arimitsu, S. Higa, T. Naka, A. Ogata, Y. Shima, M.
Fujimoto, T. Yamadori, T. Ohkawara, Y. Kuwabara, M.
Kawai, I. Kawase, T. Tanaka, Int. Arch. Allergy Immunol.
2006, 140, 150–156.
[10] M. Satyanarayana, P. Tiwari, B. K. Tripathi, A. K. Srivastava,
R. Pratap, Bioorg. Med. Chem. 2004, 12, 883–889.
[11] F. Jin, X. Y. Jin, Y. L. Jin, D. W. Sohn, S.-A. Kim, D. H. Sohn, Y. C.
Kim, H. S. Kim, Arch. Pharm. Res. 2007, 30, 1359–136.
[12] X.-W. Zhang, D.-H. Zhao, Y.-C. Quan, L.-P. Sun, X.-M. Yin, L.-P.
Guan, Med. Chem. Res. 2010, 19, 403–412.
The test compounds were suspended in 0.5% carboxymethyl-
cellulose (CMC) and given to the rats at a dose of 10 mg/kg one
hour prior to carrageenan injection. The paw volume of each rat
was measured before 1 h and after 3 h of carrageenan treatment
with the help of a Plethysmometer. Quantitative variables from
normal distribution were expressed as means ꢁ SE (standard
error). The significant difference between groups was tested by
using one-way ANOVA and the chosen level of significance was
p < 0.05.
[13] M. Abid, A. Azam, Bioorg. Med. Chem. Lett. 2006, 16, 2812–
2816.
[14] M. Abid, A. R. Bhat, F. Athar, A. Azam, Eur. J. Med. Chem. 2009,
44, 417–425.
[15] B. F. Abdel-Wahab, H. A. Abdel-Aziz, E. M. Ahmed, Eur. J. Med.
Chem. 2009, 44, 2632–2635.
[16] A. Sahoo, S. Yabanoglu, B. N. Sinha, G. Ucar, A. Basu, V.
Jayaprakash, Bioorg. Med. Chem. Lett. 2010, 20, 132–136.
The anti-inflammatory activity was expressed as percentage
inhibition of edema volume in treated animals in comparison
with the control group (Table 1, Figs. 1 to 3):
[17] M. Shaharyar, A. A. Siddiqui, M. A. Ali, D. Sriram, P.
Yogeeswari, Bioorg. Med. Chem. Lett. 2006, 16, 3947–
3949.
% Inhibition of edema ¼ VcꢀVt=Vc ꢂ 100 (1)
where, Vc and Vt are the volumes of edema for the control and
drug-treated animal groups, respectively.
[18] M. A. Ali, M. Shaharyar, A. A. Siddiqui, Eur. J. Med. Chem. 2007,
42, 268–275.
[19] Y. R. Prasad, A. L. Rao, L. Prasoona, K. Murali, P. R. Kumar,
Bioorg. Med. Chem. Lett. 2005, 15, 5030–5034.
Potency of the tested compounds was calculated relative to
indomethacin (reference standard) treated group according to
the following equation:
[20] S. Gok, M. M. Demet, A. Ozdemir, G. Turan-Zitouni, Med.
Chem. Res. 2010, 19, 94–101.
Potency ¼ ð% edema inhibition of tested compound
treated groupÞ=ð% edema inhibition of
indomethacin treated groupÞ:
[21] Z. Ozdemir, H. B. Kandilci, B. Gumusel, U. Calıs, A. A. Bilgin,
Eur. J. Med. Chem. 2007, 42, 373–379.
[22] I. G. Rathish, K. Javed, S. Ahmad, S. Bano, M. S. Alam, K. K.
Pillai, S. Singh, V. Bagchi, Bioorg. Med. Chem. Lett. 2009, 19,
255–258.
The author is thankful to Associate professor Dr. Hala Fahmi, Department
of Pharmacology, Faculty of Pharmacy, Cairo University for her valuable
support and laboratory facilities for pharmacological studies.
¨
[23] N. Go¨khan-Kelekc¸i, S. Yabanog˘lu, E. Ku¨peli, U. Salgın, O.
¨
Ozgen, G. Uc¸ar, E. Yes¸ilada, E. Kendi, A. Yes¸ilada, A. A. Bilgin,
Bioorg. Med. Chem. 2007, 15, 5775–5786.
[24] M. Verma, V. R. Gujrati, M. Sharma, A. K. Saxena, T. N.
Bhalla, J. N. Sinha, K. P. Bhargava, K. Shanker, Pharmacol.
Res. Commun. 1984, 16, 9–20.
The author has declared no conflict of interest.
[25] R. S. Joshi, P. G. Mandhane, S. D. Diwakar, S. K. Dabhade,
C. H. Gill, Bioorg. Med. Chem. Lett. 2010, 20, 3721–3725.
References
[1] S. K. Awasthi, N. Mishra, B. Kumar, M. Sharma, A.
Bhattacharya, L. C. Mishra, V. K. Bhasin, Med. Chem. Res.
2009, 18, 407–420.
[26] P. Panneerselvam, R. R. Nair, G. Vijayalakshmi, E. H.
Subramanian, S. K. Sridhar, Eur. J. Med. Chem. 2005, 40,
225–229.
[2] V. Tomar, G. Bhattacharjee, Kamaluddin, S. Rajakumar,
K. Srivastava, S. K. Puri, Eur. J. Med. Chem. 2010, 45, 745–751.
[27] P. Panneerselvam, M. Gnanarupa Priya, N. R. Kumar, G.
Saravanan, Indian J. Pharm. Sci. 2009, 71, 428–432.
[3] Z. Nowakowska, B. K˛edzia, G. Schroeder, Eur. J. Med. Chem.
2008, 43, 707–713.
[28] T. P. Robinson, R. B. Hubbard, T. J. Ehlers, J. L. Arbiser, D. J.
Goldsmith, J. P. Bowen, Bioorg. Med. Chem. 2005, 13, 4007–
4013.
[4] M. A. Alvarez, N. B. Debattista, N. B. Pappano, Folia Microbiol.
2008, 53, 23–28.
[29] S. H. Jung, S. Y. Park, Y. Kim-Pak, H. K. Lee, K. S. Park, K. H.
Shin, K. Ohuchi, H.-K. Shin, S. R. Keum, S. S. Lim, Chem.
Pharm. Bull. 2006, 54, 368–371.
[5] M. Gopalakrishnan, J. Thanusu, V. Kanagarajan,
R. Govindaraju, Med. Chem. Res. 2009, 18, 341–350.
[30] U. Bauer, B. J. Egner, I. Nilsson, M. Berghult, Tetrahedron Lett.
2000, 41, 2713–2717.
[6] M. Goniotaki, S. Hatziantoniou, K. Dimas, M. Wagner,
C. Demetzos, J. Pharm. Pharmacol. 2004, 56, 1217–1224.
[31] C. A. Winter, E. A. Fisley, G. W. Nuss, Proc. Soc. Exp. Biol. Med.
1962, 111, 544–547.
[7] A. Modzelewska, C. Pettit, G. Achanta, N. E. Davidson, P.
Huang, S. R. Khan, Bioorg. Med. Chem. 2006, 14, 3491–3495.
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