Synthesis and anti-inflammatory activity of 1-acetyl/propanoyl-5- aryl-3-(4-morpholinophenyl)-4,5-dihydro-1H-pyrazole derivatives

Article abstract of DOI:10.1007/s00044-011-9862-3

A series of novel pyrazoline derivatives containing 4-morpholinophenyl moiety were synthesized to investigate their potential anti-inflammatory activity. The chemical structures of the compounds were elucidated by spectral data and element analyses. The test compounds in the series exhibited different levels of anti-inflammatory activities when compared with reference drug indomethacin. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9862-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-011-9862-3
ORIGINAL RESEARCH
Synthesis and anti-inflammatory activity of 1-acetyl/propanoyl-5-
aryl-3-(4-morpholinophenyl)-4,5-dihydro-1H-pyrazole derivatives
Omneya M. Khalil
Received: 31 July 2011 / Accepted: 31 October 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of novel pyrazoline derivatives con-
taining 4-morpholinophenyl moiety were synthesized to
investigate their potential anti-inflammatory activity. The
chemical structures of the compounds were elucidated by
spectral data and element analyses. The test compounds in
the series exhibited different levels of anti-inflammatory
activities when compared with reference drug indo-
methacin.
antioxidant (Jeong et al., 2004), anticancer (Shaharyar
et al., 2010; Congiu et al., 2010; Liu et al., 2010) and anti-
inflammatory (Bansal et al., 2001; Shoman et al., 2009;
Barsoum and Girgis, 2009; Chandra et al., 2010) activities.
In addition, 4-phenylmorpholine derivatives have been
reported to show quite interesting anti-inflammatory
(Verma et al., 1984; Joshi et al., 2010) and antimicrobial
(Panneerselvam et al., 2005, 2009) activities.
In our previous study, 5-aryl-3-(4-morpholinophenyl)-4,
5-dihydro-1H-pyrazoles A (Fig. 1) were synthesized and
reported to have significant anti-inflammatory activity
(Khalil, 2011). As part of our continuous efforts in this
area, and in order to better understand the role of N-1
substituent for anti-inflammatory activity, a series of some
new 1-acetyl/propanoyl-5-aryl-3-(4-morpholinophenyl)-4,
5-dihydro-1H-pyrazole derivatives have been synthesized
with no changes in position-5 of the pyrazoline ring com-
pared to the previous unsubstituted N-1 series; A (Fig. 1).
Keywords Synthesis ꢀ Pyrazolines ꢀ
Anti-inflammatory activity
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs), alleviate
pain by counteracting the cyclooxygenase (COX) enzyme.
On its own, COX enzyme synthesizes prostaglandins,
creating inflammation. Over all, the NSAIDs prevent the
prostaglandins ever from being synthesized, reducing or
eliminating the pain. Therefore, studies for discovering and
developing new anti-inflammatory drugs with greater
effectiveness are still preferable. 2-Pyrazolines have been
gaining prominence because their derivatives have been
found to possess wide spectrum of biological activities,
such as antimalarial (Acharya et al., 2010), antimicrobial
(Padmavathi et al., 2008; Abdel-Wahab et al., 2009;
Dawane et al., 2010), antidepressant (Can et al., 2009;
Results and discussion
Chemistry
The synthesis of hitherto unreported title compounds was
prepared as outlined in Scheme 1.
The key intermediates, chalcones, 1a–f were previously
prepared (Khalil, 2011). Reactions of 1a–f with hydrazine
hydrate in hot acetic acid or propionic acid afforded the
corresponding pyrazolines 2a–f and 3a–f in yields
(56–86%).
¨
Kaplancikli et al., 2010), anticonvulsant (Ozdemir et al.,
2007), antihypertensive (Turan-Zitouni et al. 1984),
In the IR spectra of compounds 2a–f and 3a–f, the
carbonyl absorption bands were observed in the region of
1700–1739 cm-1. The C=N stretching was observed
around 1600–1608 cm-1 because of the ring closure.
O. M. Khalil (&)
Organic Chemistry Department, Faculty of Pharmacy,
Cairo University, Cairo 11562, Egypt
e-mail: omneyafawzy@yahoo.com
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Med Chem Res
Fig. 1 General formula of
derivatives A, 2 and 3
R
R
O
N
O
N
N
O
N
NH
N
R'
2, 3
A
R = 2-thienyl, 4-Br-C6H4, 2-(OCH3)-C6H4, 3, 4-(OCH3)2-C6H3,
3, 5-(OCH3)2-C6H3, 3, 4, 5-(OCH3)3-C6H2
2, R' =CH3
3, R' =CH2CH3
Scheme 1 Synthesis of
compounds 2a–f and 3a–f
R
R
NH2NH2
O
N
O
N
N
O
O
N
CH3COOH
2a-f
1a-f
NH2NH2
CH3CH2COOH
R
2a, 3a R = 2-thienyl
2b, 3b R = 4-Br-C6H4
O
N
N
2c, 3c R = 2-(OCH3)-C6H4
2d, 3d R = 3,4-(OCH3)2-C6H3
N
O
2e, 3e R = 3,5-(OCH3)2-C6H3
2f, 3f R = 3,4,5-(OCH3)3-C6H2
3a-f
1H NMR spectra of 2a–f and 3a–f revealed the signals
of CH2 protons of the pyrazoline ring as a double doublet
in the regions of 2.32–3.27 and 3.62–3.80 ppm, while CH
proton appeared at 5.40–5.78 ppm.
from 1.08 to 31.05% at the dose of 10 mg/kg given in
Table 1. Indomethacin, which is one of the most potent
anti-inflammatory agents, was used as the reference drug in
a dose of 10 mg/kg. The anti-inflammatory activity of
compounds 2a–f having 1-N-acetyl group and 3a–f with
1-N-propanoyl substituent were 3.61–31.05%, and 1.08–
31.05% respectively.
In addition, 1H NMR spectra of 2a–f indicated the
presence of an N-acetyl group as a singlet signal between
d = 2.21 and 2.30 ppm. On the other hand, a triplet
(around 1.06 ppm) and a quartet (approximately 2.7 ppm)
signals belonging to an N-propanoyl unit were assigned in
the 1H NMR spectra of 3a–f. 13C-NMR chemical shift
values of the carbon atoms at 39.5 (C-4), 54.1–54.7 (C-5),
and about 152.0 or 152.9 ppm (C-3) corroborate the
Among the compounds 2a–f, compound 2c, in which
phenyl ring was substituted with a methoxy group at
position-2 exhibited 31.05% protection against carra-
geenan-induced edema. A similar behavior could be
observed in the case of compound 3d, bearing a 3,4-
dimethoxyphenyl moiety in position-5 of the pyrazoline.
The rest of the pyrazoline derivatives showed weak anti-
inflammatory activity.
1
2-pyrazoline character deduced from the H- NMR data.
The presence of an N-acetyl group was also confirmed by
the 13C- chemical shifts of these two carbon atoms detected
at about 21 (CH3) and 166.3–174.4 (C=O) ppm. In addi-
tion, N-propanoyl groups have also been observed at
8.5–9.2 (CH3) and at about 26 (CH2) ppm.
Conclusion
Anti-inflammatory activity
A series of acetyl/propanoyl pyrazolines carrying a mor-
pholinophenyl moiety have been synthesized in good yield
and screened for their anti-inflammatory activity. The
results indicated that compounds 2c and 3d showed con-
siderable anti-inflammatory action, reaching about 52.76%
All the newly synthesized pyrazoline derivatives were
screened for their anti-inflammatory activities. All the
compounds have shown anti-inflammatory activity ranging
123

Med Chem Res
60
50
40
30
20
10
0
Table 1 Anti-inflammatory activity of the test compounds assessed
in comparison to indomethacin as reference
Compound
Mean swelling
volume (ml)
% Inhibition
of edema
Potencyb
Control
0.55 0.05
0.23 0.03
0.52 0.08
0.49 0.10
0.38 0.09
0.52 0.10
0.48 0.06
0.53 0.10
0.55 0.13
0.45 0.14
0.52 0.06
0.38 0.06
0.47 0.09
0.55a 0.10
0.00
–
Indomethacin
58.84
6.86
100.00
11.66
19.02
52.76
9.82
2a
2b
2c
2d
2e
2f
11.19
31.05
5.78
13.36
3.61
22.70
6.13
Test compounds
3a
3b
3c
3d
3e
3f
1.08
1.84
18.41
6.14
31.29
10.43
52.76
26.99
1.84
Fig. 2 % Inhibition of edema for the test compounds
31.05
15.88
1.08
crushed ice. The precipitate was separated by filtration,
washed with water, and crystallized from ethanol.
a
Statistically significant from the indomethacin at P \ 0.05
Potency was expressed as % edema inhibition of the tested com-
b
1-Acetyl-3-(4-morpholinophenyl)-5-(2-thienyl)-4,
pounds relative to % edema inhibition of indomethacin ‘‘reference
standard’’
5-dihydro-1H-pyrazole (2a)
Mp: 149–150°C; yield: 62%; IR (cm-1): t 3082 (arom–H),
2962, 2893, 2835 (aliph–H), 3.27 (dd, 1H, 1710 (C=O),
1
1600 (C=N); HNMR (DMSO-d6): d 2.24 (s, 3H, CH3),
of the action of indomethacin (Table 1, Fig. 2). On the
basis of this research, we could show that the anti-inflam-
matory activity is correlated with N-1 substituent; in fact,
the elongation of the N-1 chain decreased the anti-inflam-
matory activity, regardless of the nature of other substitu-
ents. Therefore, they deserve further attention to develop
new leads.
3.27 (dd, 1H, pyrazoline H4, J = 16.8, 3.3 Hz), 3.18 (t, 4H,
N(CH2)2, J = 3.9 Hz), 3.72 (t, 4H, O(CH2)2, J = 4.5 Hz),
3.76 (dd, 1H, pyrazoline H4, J = 16.2, 11.4 Hz), 5.78 (dd,
1H, pyrazoline H5, J = 11.4, 3.3 Hz), 6.93 (dd, 1H, thie-
nyl–H, J = 3.6, 5.1 Hz), 6.99 (d, 2H, Ar–H, J = 8.4 Hz),
7.36 (d, 1H, thienyl–H, J = 3.9 Hz), 7.64 (d, 1H, thienyl–
H, J = 5.7 Hz), 7.99 (d, 2H, Ar–H, J = 8.7 Hz). 13CNMR
(DMSO-d6): q 21.6, 39.5, 46.7, 54.5, 65.8, 114.1, 120.9,
124.7, 126.5, 127.7, 130.2, 145.0, 152.2, 154.3, 166.9.
Anal. Calcd. for C19H21N3O2S (355.45): C, 64.20, H, 5.95,
N, 11.82. Found: C, 64.24, H, 6.05, N, 12.15.
Experimental
Melting points were obtained on a Griffin apparatus and are
uncorrected. Microanalyses were carried out at the micro-
analytical center, Faculty of Science, Cairo University. IR
spectra were recorded on a Shimadzu 435 spectrometer,
1-Acetyl-5-(4-bromophenyl)-3-(4-morpholinophenyl)-
1
using KBr disks. H-NMR and 13CNMRspectra were per-
4, 5-dihydro-1H-pyrazole (2b)
formed on a Varian Mercury VX-300 MHz NMR Spec-
trometer using TMS as the internal standard. Mass spectra
were recorded using Shimadzu Gas Chromatograph Mass
spectrometer-QP 1000 EX (Shimadzu, Kyoto, Japan).
Compounds 1a–f were synthesized and reported (Khalil,
2011) according to known procedures.
Mp: 108–109°C; yield: 70%; IR (cm-1): t 3039 (arom–H),
2893, 2839(aliph–H), 1701 (C=O), 1608 (C=N); HNMR
1
(DMSO-d6): d 2.26(s, 3H, CH3), 3.07 (dd, 1H, pyrazoline
H4, J = 17.7, 3.3 Hz), 3.18 (t, 4H, N(CH2)2, J = 4.5 Hz),
3.72 (t, 4H, O(CH2)2, J = 4.2 Hz), 4.12 (m, 1H, pyrazoline
H4), 5.46 (dd, 1H, pyrazoline H5, J = 11.4, 3.3 Hz), 6.97
(d, 2H, Ar–H, J = 8.1 Hz), 7.22 (d, 2H, Ar–H,
J = 8.1 Hz), 7.43 (d, 2H, Ar–H, J = 8.4 Hz), 7.78 (d, 2H,
Ar–H, J = 8.4 Hz). Anal. Calcd. for C21H22BrN3O2
(428.31): C, 58.88, H, 5.17, N, 9.81. Found: C, 59.00, H,
5.22, N, 9.95. MS (%, rel int) m/z 428.00 (M?, 26.04).
General procedure for the synthesis of 2a–f and 3a–f
A solution of the appropriate chalcone (0.03 mol) 1a–f,
hydrazine hydrate (0.06 mol) in 15 ml of acetic/propionic
acid was heated under reflux for 6 h, then poured onto
123

Med Chem Res
1-Acetyl-5-(2-methoxyphenyl)-3-(4-
1-Acetyl-5-(3,4,5-trimethoxyphenyl)-3-(4-
morpholinophenyl)-4, 5-dihydro-1H-pyrazole (2c)
morpholinophenyl)-4, 5-dihydro-1H-pyrazole (2f)
Mp: 107–108°C; yield: 58%; IR (cm-1): t 3001, 3055
(arom–H), 2976, 2927, 2855 (aliph–H), 1739 (C=O), 1604
(C=N); 1HNMR (DMSO-d6): d 2.30(s, 3H, CH3), 2.90 (dd,
1H, pyrazoline H4, J = 17.1, 4.2 Hz), 3.18 (t, 4H,
N(CH2)2, J = 4.5 Hz), 3.72 (t, 4H, O(CH2)2, J = 4.2 Hz),
3.80(dd, 1H, pyrazoline H4, J = 17.7, 10.5 Hz)), 3.90 (s,
3H, OCH3), 5.62 (dd, 1H, pyrazoline H5, J = 11.1,
4.2 Hz), 6.90 (m, 1H, Ar–H), 7.02 (d, 2H, Ar–H,
J = 8.1 Hz), 7.21(m, 2H, Ar–H), 7.60 (d, 2H, Ar–H,
J = 8.1 Hz), 7.80 (m, 1H, Ar–H). Anal. Calcd. for
C22H25N3O3 (379.45): C, 69.63, H, 6.64, N, 11.07. Found:
C, 69.49, H, 6.40, N, 11.0. MS (%, rel int) m/z 380.00
(M ? 1?, 100.00).
Mp: 148–149°C; yield: 73%; IR (cm-1): t 3005 (arom–H),
2931, 2855 (aliph–H), 1737 (C=O), 1604 (C=N); HNMR
1
(DMSO-d6): d 2.29 (s, 3H, CH3), 3.08 (dd, 1H, pyrazoline
H4, J = 17.7, 4.2 Hz), 3.18 (t, 4H, N(CH2)2, J = 3.9 Hz),
3.62 (dd, 1H, pyrazoline H4, J = 17.7, 11.7 Hz), 3.71 (t,
4H, O(CH2)2, J = 3.6 Hz), 3.79 (s, 3H, OCH3), 3.85 (s,
6H, 2 9 OCH3), 5.41 (dd, 1H, pyrazoline H5, J = 11.7,
4.5 Hz), 6.43 (s, 2H, Ar–H), 6.97 (d, 2H, Ar–H,
J = 8.7 Hz), 7.62 (d, 2H, Ar–H, J = 8.4 Hz). Anal. Calcd.
for C24H29N3O5 (439.50): C, 65.58, H, 6.65, N, 9.56.
Found: C, 65.79, H, 6.38, N, 9.35.
3-(4-Morpholinophenyl)-1-propanoyl-5-(2-thienyl)-4,
5-dihydro-1H-pyrazole (3a)
Mp: 122–123°C; yield: 64% IR (cm-1): t 3078, 3047
(arom–H), 2962, 2916, 2854 (aliph–H), 1732 (C=O), 1604
(C=N); 1HNMR (DMSO-d6): d 1.05 (t, 3H, CH3,
J = 7.5 Hz), 2.64 (q, 2H, CH2, J = 7.5 Hz), 3.18 (t, 4H,
N(CH2)4, J = 3.9 Hz), 3.22 (dd, 1H, pyrazoline H4,
J = 17.4, 3.9 Hz), 3.73 (t, 4H, O(CH2)2, J = 3.6 Hz), 4.14
(m, 1H, pyrazoline H4), 5.78 (dd, 1H, pyrazoline H5,
J = 11.4, 3.9 Hz), 6.93 (dd, 1H, thienyl–H, J = 3.6,
4.8 Hz), 6.98 (d, 1H, thienyl–H, J = 3.9 Hz), 7.36 (d, 1H,
thienyl– H, J = 4.5 Hz), 7.64 (d, 2H, Ar–H, J = 8.4 Hz),
7.98 (d, 2H, Ar–H, J = 8.4 Hz). 13CNMR (DMSO-d6): q
8.5, 26.8, 39.5, 47.3, 54.1, 65.7, 96.0, 113.0, 114.1, 117.3,
120.7, 122.4, 124.5, 127.7, 129.5, 130.2, 133.2, 152.8,
156.4, 159.8, 166.3, 174.4. Anal. Calcd. for C20H23N3O2S
(369.48): C, 65.01, H, 6.27, N, 11.37. Found: C, 64.85, H,
5.97, N, 11.02. MS (%, rel int) m/z 369.00 (M?, 0.68),
370.00 (M ? 1?, 0.43).
1-Acetyl-5-(3,4-dimethoxyphenyl)-3-(4-
morpholinophenyl)-4, 5-dihydro-1H-pyrazole (2d)
Mp: 88–89°C; yield: 59%; IR (cm-1): t 3001 (arom–H),
2954, 2931, 2835 (aliph–H), 1735 (C=O), 1604 (C=N);
1HNMR (DMSO-d6): d 2.21 (s, 3H, CH3), 2.39 (dd, 1H,
pyrazoline H4, J = 17.7, 3.9 Hz), 3.18 (t, 4H, N(CH2)2,
J = 4.5 Hz), 3.54 (dd, 1H, pyrazoline H4, J = 17.7,
11.7 Hz), 3.78 (t, 4H, O(CH2)2, J = 3.9 Hz), 3.82 (s, 3H,
OCH3), 3.84 (s, 3H, OCH3), 5.40 (m, 1H, pyrazoline H5),
6.80 (m, 1H, Ar–H), 7.32 (d, 2H, Ar–H, J = 9.6 Hz), 7.48
(m, 1H, Ar–H), 7.60 (d, 2H, Ar–H, J = 9.6 Hz), 7.70 (m,
1H, Ar–H). Anal. Calcd. for C23H27N3O4 (409.47): C,
67.46, H, 6.64, N, 10.26. Found: C, 67.50, H, 6.40, N,
10.42. MS (%, rel int) m/z 409.00 (M?, 28.70), 410.00
(M ? 1?, 17.54).
1-Acetyl-5-(3,5-dimethoxyphenyl)-3-(4-
5-(4-Bromophenyl)-3-(4-morpholinophenyl)-1-
morpholinophenyl)-4, 5-dihydro-1H-pyrazole (2e)
propanoyl-4, 5-dihydro-1H-pyrazole (3b)
Mp: 101–102°C; yield: 65%; IR (cm-1): t 3035, 3008
(arom–H), 2966, 2939, 2893, 2835 (aliph–H), 1700 (C=O),
Mp: 177–178°C; yield: 86%; IR (cm-1): t 3074 (arom–H),
2958, 2893, 2854 (aliph–H), 1732 (C=O), 1604 (C=N);
1HNMR (DMSO-d6): d 1.05 (t, 3H, CH3, J = 7.2 Hz), 2.65
(q, 2H, CH2, J = 7.2 Hz), 3.05 (dd, 1H, pyrazoline H4,
J = 17.7, 4.5 Hz), 3.19 (t, 4H, N(CH2)2, J = 4.5 Hz), 3.73
(t, 4H, O(CH2)2, J = 4.5 Hz), 3.79 (dd, 1H, pyrazoline H4,
J = 17.7, 11.7 Hz), 5.47 (dd, 1H, pyrazoline H5, J = 11.7,
4.5 Hz), 6.97 (d, 2H, Ar–H, J = 8.7 Hz), 7.12 (d, 2H, Ar–
H, J = 8.7 Hz), 7.50 (d, 2H, Ar–H, J = 8.4 Hz), 7.61 (d,
2H, Ar–H, J = 8.7 Hz). 13CNMR (DMSO-d6): q 8.9, 26.8,
39.4, 47.4, 58.6, 65.8, 114.1, 127.7, 131.4, 142.0, 168.0.
Anal. Calcd. for C22H24BrN3O2 (442.34): C, 59.73, H,
5.46, N, 9.49. Found: C, 59.79, H, 5.59, N, 9.60. MS (%,
rel int) m/z 443.00 (M?, 1.04).
1
1608 (C=N); HNMR (DMSO-d6): d 2.28 (s, 3H, CH3),
3.04 (dd, 1H, pyrazoline H4, J = 18, 4.2 Hz), 3.18 (t, 4H,
N(CH2)2, J = 3.9 Hz), 3.73 (t, 4H, O(CH2)2, J = 4.5 Hz),
3.78 (dd, 1H, pyrazoline H4, J = 17.4, 11.1 Hz), 3.79 (s,
6H, 2 9 OCH3), 5.42 (dd, 1H, pyrazoline H5, J = 11.1,
4.2 Hz), 6.29 (s, 2H, Ar–H), 6.37 (s, 1H, Ar–H), 6.97 (d,
2H, Ar–H, J = 8.7 Hz), 7.61 (d, 2H, Ar–H, J = 8.7 Hz).
13CNMR (DMSO-d6): q 21.5, 39.5, 47.3, 55.0, 59.0, 65.7,
98.3, 103.2, 114.0, 121.0, 127.6, 144.8, 152.0, 154.0,
160.6, 166.8. Anal. Calcd. for C23H27N3O4 (409.47): C,
67.46, H, 6.64, N, 10.26. Found: C, 67.49, H, 6.45, N,
10.50.
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Med Chem Res
1HNMR (DMSO-d6): d 1.08 (t, 3H, CH3, J = 7.2 Hz), 2.63
(m, 2H, CH2), 3.18 (t, 4H, N(CH2)2, J = 4.8 Hz), 3.20 (dd,
1H, pyrazoline H4, J = 17.7, 4.2 Hz), 3.67 (dd, 1H, pyr-
azoline H4, J = 18, 11.2 Hz), 3.71 (t, 4H, O(CH2)2,
J = 4.5 Hz), 3.77 (s, 3H, OCH3), 3.85 (s, 6H, 2 9 OCH3),
5.40 (m, 1H, pyrazoline H5), 6.42 (s, 2H, Ar–H), 6.96 (d,
2H, Ar–H, J = 8.4 Hz), 7.61 (d, 2H, Ar–H, J = 8.1 Hz).
13CNMR (DMSO-d6): q 9.2, 26.9, 39.5, 47.4, 55.8, 59.2,
59.8, 65.8, 102.3, 114.1, 120.5, 127.7, 138.3, 152.1, 152.9,
154.1, 170.0. Anal. Calcd. for C25H31N3O5 (453.53): C,
66.20, H, 6.88, N, 9.26. Found: C, 66.39, H, 6.90, N, 9.18.
MS (%, rel int) m/z 453.00 (M?, 9.51).
5-(2-Methoxyphenyl)-3-(4-morpholinophenyl)-1-
propanoyl-4, 5-dihydro-1H-pyrazole (3c)
Mp: 79–80°C;yield:63%;IR(cm-1):t3062, 3043(arom–H),
2962, 2935, 2893 (aliph–H), 1710 (C=O), 1604 (C=N);
1HNMR (DMSO-d6): d 1.07 (t, 3H, CH3, J = 7.2 Hz), 2.70
(q, 2H, CH2, J = 7.2 Hz), 2.85 (dd, 1H, pyrazoline H4,
J = 17.4, 4.5 Hz), 3.17 (t, 4H, N(CH2)2, J = 3.9 Hz), 3.72 (t,
4H, O(CH2)2, J = 3.9 Hz), 3.80 (m, 1H, pyrazoline H4), 3.87
(s, 3H, OCH3), 5.62 (dd, 1H, pyrazoline H5, J = 11.1,
4.5 Hz), 6.91(m, 1H, Ar–H), 7.08(d, 2H, Ar–H, J = 8.1 Hz),
7.21(m, 2H, Ar–H), 7.59 (d, 2H, Ar–H, J = 8.1 Hz), 7.83 (m,
1H, Ar–H). 13CNMR (DMSO-d6): q 9.1, 26.8, 39.5, 47.4,
54.7, 55.5, 65.8, 110.5, 111.5, 113.0, 114.1, 120.4, 121.3,
122.0, 124.9, 127.4, 128.4, 129.6, 130.3, 131.7, 136.8, 152.1,
154.4,155.0,170.2.Anal. Calcd.forC23H27N3O3 (393.47):C,
70.20, H, 6.91, N, 10.67. Found: C, 70.15, H, 6.90, N, 10.95.
Anti-Inflammatory activity screening
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 environment for 1 week
before to experiments. The experimental tests on animals
have been performed in accordance with the Institutional
Ethical Committee approval. The anti-inflammatory effect
of the newly synthesized compounds was evaluated in
correspondence with the carrageenan-induced paw edema
method (Winter et al., 1962). 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.
5-(3,4-Dimethoxyphenyl)-3-(4-morpholinophenyl)-1-
propanoyl-4, 5-dihydro-1H-pyrazole (3d)
Mp: 68–69°C;yield:56%;IR(cm-1):t3051(arom–H), 2962,
2935, 2835 (aliph–H), 1735 (C=O), 1600 (C=N); HNMR
1
(DMSO-d6): d 1.06 (m, 3H, CH3), 2.32 (m, 1H, pyrazoline
H4), 2.69 (q, 2H, CH2, J = 7.5 Hz), 3.18 (t, 4H, N(CH2)2,
J = 5.1 Hz), 3.74(m, 4H, O(CH2)2, J = 4.5 Hz), 3.80(s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 4.10 (m, 1H, pyrazoline H4), 5.40
(m, 1H, pyrazoline H5), 6.80 (m, 1H, Ar–H), 7.35 (m, 2H, Ar–
H), 7.49 (m, 1H, Ar–H), 7.61 (d, 2H, Ar–H, J = 9.3 Hz), 7.68
(m, 1H, Ar–H). Anal. Calcd. for C24H29N3O4 (423.50): C,
68.06, H, 6.90, N, 9.92. Found: C, 67.80, H, 6.71, N, 10.02.
MS (%, rel int) m/z 423.00 (M?, 1.04).
The positive control group was given 10 mg/kg i.p.
indomethacin 1 h before carrageenan injection.
The test compounds were suspended in 0.5% carboxy-
methylcellulose (CMC) and given to the rats at a dose of
10 mg/kg i.p. 1 h before carrageenan injection. The paw
volume of each rat was measured before 1 h and after 3 h
of carrageenan treatment using Plethysmometer. Quanti-
tative variables from normal distribution were expressed
as means SE ‘‘standard error’’. The significant differ-
ence between groups was tested by means of one-way
ANOVA, and the chosen level of significance was
P \ 0.05.
5-(3,5-Dimethoxyphenyl)-3-(4-morpholinophenyl)-1-
propanoyl-4, 5-dihydro-1H-pyrazole (3e)
Mp: 133–134°C; yield: 62%; IR (cm-1): t 3005 (arom–H),
2954, 2924, 2850 (aliph–H), 1710 (C=O), 1608 (C=N);
1HNMR (DMSO-d6): d 1.06 (t, 3H, CH3, J = 7.5 Hz), 2.69
(q, 2H, CH2, J = 7.5 Hz), 2.96 (m, 1H, pyrazoline H4), 3.18
(m, 4H, N(CH2)2, J = 4.2 Hz), 3.71 (t, 4H, O(CH2)2,
J = 3.6 Hz), 3.79 (s, 6H, 2 9 OCH3), 4.12 (m, 1H, pyraz-
oline H4), 5.42 (m, 1H, pyrazoline H5), 6.26 (s, 1H, Ar–H),
6.36 (s, 2H, Ar–H), 6.97 (d, 2H, Ar–H, J = 8.1 Hz), 7.60 (d,
2H, Ar–H, J = 8.1 Hz). Anal. Calcd. for C24H29N3O4
(423.50): C, 68.06, H, 6.90, N, 9.92. Found: C, 67.80, H,
6.63, N, 10.15. MS (%, rel int) m/z 423.00 (M?, 2.06).
The anti-inflammatory activity was expressed as per-
centage inhibition of edema volume in treated animals in
comparison with the control group (Table 1; Fig. 2):
% Inhibition of edema ¼ Vc ꢁ Vt=Vc ꢂ 100
where, Vc and Vt are the volumes of edema for the control
and drug-treated animal groups, respectively.
3-(4-Morpholinophenyl)-1-propanoyl-5-(3,4,5-
trimethoxy-phenyl)-4, 5-dihydro-1H-pyrazole (3f)
Potency of the tested compounds was calculated relative
to indomethacin ‘‘reference standard’’-treated group
according to the following equation:
Mp: 143–144°C; yield: 78%; IR (cm-1): t 3050 (arom–H),
2962, 2939, 2839 (aliph–H), 1701 (C=O), 1604 (C=N);
123

Med Chem Res
(LDL) oxidation inhibitor. Bioorg Med Chem Lett 14:2719–
2723
Potency
¼ ð% edema inhibition of tested compound treated groupÞ=
ð% edema inhibition of indomethacin treated groupÞ:
Joshi RS, Mandhane PG, Diwakar SD, Dabhade SK, Gill CH (2010)
Synthesis, analgesic and anti-inflammatory activities of some
novel pyrazolines derivatives. Bioorg Med Chem Lett 20:3721–
3725
Acknowledgment The author is thankful to Dr. Hala Fahmi,
Associate professor Department of Toxicology and Pharmacology,
Faculty of Pharmacy, Cairo University for her valuable support and
laboratory facilities for pharmacological studies.
¨
¨
Kaplancikli ZA, Ozdemir A, Turan-Zitouni G, Altintop MD, Can OD
(2010) New pyrazoline derivatives and their antidepressant
activity. Eur J Med Chem 45:4383–4387
Khalil OM (2011) Synthesis of some chalcones and pyrazolines
carrying morpholinophenyl moiety as potential anti-inflamma-
tory agents. Arch Pharm 11:242–247
Liu X-H, Liu H-F, Chen J, Yang Y, Song B-A, Bai L-S, Liu J-X, Zhu
H-L, Qi X-B (2010) Synthesis and molecular docking study of
novel coumarin derivatives containing 4,5-dihydropyrazole
moiety as potential antitumor agents. Bioorg Med Chem Lett 20:
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