Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4- phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives

Article abstract of DOI:10.1016/j.bmcl.2011.05.105

A new series of 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5- carboxamide derivatives were synthesized and investigated their anti-inflammatory activities using carrageenan-induced rat paw edema model in vivo. All the synthesized compounds were found to be potent anti-inflammatory agents.

Full text of DOI:10.1016/j.bmcl.2011.05.105

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4138–4140
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and anti-inflammatory activity of some novel
3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide
derivatives
Lingaiah Nagarapu a, , Jhansi Mateti a, Hanmant K. Gaikwad a, Rajashaker Bantu a, M. Sheeba Rani a,
⇑
N. J. Prameela Subhashini b
a Organic Chemistry Division-II, Indian Institute of Chemical Technology (CSIR), Tarnaka, Hyderabad 500607, India
b Department of Pharmacy, University College of Technology, Osmania University, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives
were synthesized and investigated their anti-inflammatory activities using carrageenan-induced rat
paw edema model in vivo. All the synthesized compounds were found to be potent anti-inflammatory
agents.
Received 6 April 2011
Revised 24 May 2011
Accepted 26 May 2011
Available online 6 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Nonsterodial anti-inflammatory drugs
Pyrazole carboxamide derivative
Ibuprofen
Celecoxib
Inflammation and different types of arthritis are inflammatory
disordersthatdealablow tohumanity. Nonsterodialanti-inflamma-
tory drugs (NSAIDs) are one kind of therapeutics, widely used in the
world because of their high efficacy in reducing pain and inhibiting
inflammation.1,2 NSAIDs drugs such as ibuprofen, Celecoxib, Cetri-
zine, Diclofenac (Fig. 1) can inhibit the enzyme cyclooxygenase
(COX-1 and COX-2)3,4, which catalyze the biotransformation of
arachidonic acid to prostaglandins (PGs) and to Thromboxane
A2.5–9 These are the mediators of pain, inflammation, fever, stimu-
lates platelet aggregation and leading to the formation of blood
clots.10–12 Hence, the development and discovery of new reagents
that can inhibit the COX-1 and COX-2 activity will be of importance
for the controlling inflammation.13–15
devoted to arylpyrazole derivatives such as Celecoxib, a well-
known COX-2 inhibitor.21–25
In our research programme for synthesis of novel and, alterna-
tive NSAID with similar or greater efficacy and to minimize the risk
of unwanted side effects,26,27 we have conducted exploratory
research.28 A new series of 3-phenyl-N-[3-(4-phenylpiperazin-
1yl)propyl]-1H-pyrazole-5-carboxamide derivatives were synthe-
sized and evaluated their anti-inflammatory activity to inhibit
carrageenan-induced paw edema in rats.
O
O
S
Many pharmaceuticals are synthetic compounds, and a large
number of them are heterocycles. Common examples are the
widely used arylpyrazoles in medicinal and pesticide chemistry.16
Many pyrazole derivatives are known to exhibit a wide range of
biological activities such as anti-hyperglycemic, analgesic, anti-
inflammatory, anti-pyretic, anti-bacterial, hypoglycemic, seda-
tive–hypnotic activity,17,18 and anticoagulant activity.19 Recently,
some arylpyrazoles were reported to have non-nucleoside HIV-1
reverse transcriptase inhibitory activity.20 They may prove to be
clinically useful compounds and extensive studies have been
H2N
OH
N
N
CF3
O
Celecoxib
Ibuprofen
Cl
OH
Cl
OH
N
O
N
O
O
Cl
Cetrizine
Diclofenac
⇑
Corresponding author. Tel.: +91 40 27191509; fax: +91 40 27193382.
E-mail address: lnagarapuiict@yahoo.com (L. Nagarapu).
Figure 1. Structure of the nonsterodial anti-inflammatory drugs.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.105

L. Nagarapu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4138–4140
4139
Table 2
O
O
N
The percentage anti-inflammatory activity of the target compounds against the
carrageenan-induced paw edema in rats
i
ii
NH
+ Br
Br
N
Br
Compound
% Activity
1 h
O
O
2
3
1
O
N
2 h
3 h
4 h
N
iii
Control
10a
10b
10c
10d
10e
10f
10g
Ibuprofen
–
–
–
–
N
N
H2N
47.3
55.2
52.6
60.5
60.5
53.9
67.0
42.1
55.5
69.4
62.5
55.5
65.2
75.6
75.0
55.5
61.9
75.0
65.2
67.3
70.6
76.0
78.0
72.8
58.8
70.0
64.4
63.3
70.0
72.2
75.5
63.3
O
4
5
Scheme 1. Reagents and conditions: (i) K2CO3, DMF, rt, 3 h, 85%; (ii) N-phenyl-
piprazine, K2CO3, DMF, rt, 24 h, 95%; (iii) NH2NH2, methanol, rt, 24 h, 72%.
H
O
O
O
N
COOEt
N
OEt
ii
CH3
i
R
R
of phthalimide (1) with 1,3-dibromoporpane (2) to give 2-(3-bro-
mopropyl)isoindoline-1,3-dione (3) which on reaction with N-phe-
nylpiperzine, potassium carbonate in dimethylformamide followed
by subsequent deprotection of phthalimide by hydrazine hydrate
(Scheme 1). Compounds, ethyl 3-aryl-1H-pyrazole-5-carboxylic
acids (9a–g), were readily prepared by the reaction of various ace-
tophenones (6a–g) with diethyl oxalate in sodium methoxide solu-
tion to give ethyl 2,4-dioxo-4-arylbutanoate (7a–g), which on
reaction with hydrazine hydrate in the presence of acetic acid at
room temperature, followed by subsequent hydrolysis of ester lith-
ium hydroxide in THF (Scheme 2). All the compounds have been
characterized by micro-analytical and spectral data.28,29
O
R
7a-g
8a-g
6a-g
iii
Where, R =
a = H
b = 4-OCH3
e = 3-CH3
f = 4-NO2
H
N
COOH
N
c = 3-OCH3 g = 3-NO2
d = 4-CH3
R
9a-g
Scheme 2. Reagents and conditions: (i) diethyl oxalate, NaOMe, diethyl ether, rt,
15 h, 73–82%; (ii) NH2NH2, AcOH, rt, 12 h, 81–91%; (iii) LiOH, THF, rt, 12 h, 84–97%.
Anti-inflammatory activity was evaluated using in vivo rat car-
rageenan-induced foot paw edema model reported previously.30
A
O
H
either sex of rats (130–180 g) were fasted with free access to water
at least 16 h. The rats were divided in to two groups (Control, test
compounds and Standard) of six animals each. Edema was pro-
duced by injecting 0.1 mL suspension of 1% carrageenan in the hind
paw. One group was kept as control and the animals in other group
were treated with the test drug in 1% CMC solution, given orally 1 h
before the carrageenan injection. Paw volume of foot was mea-
sured by mercury displacement with plethysmometer (UGO BASIL)
before and 1, 2, 3, 4 h after carrageenan treatment. The mean
increase in paw volume in each group was measured and the per-
centage was calculated by the following equation: anti-inflamma-
N
N
N
H
N
i
N
9a-g
+
5
R
10a-g
Where, R =
a = H
e = 3-CH3
f = 4-NO2
g = 3-NO2
b = 4-OCH3
c = 3-OCH3
d = 4-CH3
Scheme 3. Reagents and conditions: (i) EDCÁHCl, HOBt, DIPEA, CH2Cl2, rt, 12 h, 69–
81%.
tory activity (%) = (1 À D/C) Â 100, where
D represents the
difference in paw volume before and after compound was admin-
istrated to the rats, and C stands for the difference of volume in the
control groups.
Synthesis of target compounds 3-phenyl-N-(3-(4-phenylpipera-
zin-1yl)propyl)-1H-pyrazole-5-carboxamide derivatives (10a–g)
was achieved by the reaction of 3-aryl-1H-pyrazole-5-carboxylic
acids (9a–g) with 3-(4-phenylpiperzin-1-yl)propan-1-amine (5)
in presence of peptide coupling reagents EDCÁHCl and HOBt in
good to excellent yields (Scheme 3). Compound, 3-(4-phenylpiper-
zin-1-yl)propan-1-amine (5) was readily prepared by the reaction
All the target compounds (10a–g) showed potent anti-inflam-
matory activity (Tables 1 and 2). Four derivatives 10a, 10e, 10f,
10g were found to be more potent at 3 h (75%, 70%, 76%, and
78%, respectively). These test compounds were treated at a dose
of 100 mg/kg (P < 0.01 and P < 0.0001) to determine the potential-
Table 1
Anti-inflammatory activity of the target compounds against the carrageenan-induced paw edema in rats
Compound
Dose (mg/kg)
Increase in paw volumea (mL)
1 h
2 h
3 h
4 h
Control
Standard
10a
10b
10c
10d
10e
10f
10g
1% CMC
100
100
100
100
100
100
100
100
0.38 0.045
0.22 0.011
0.72 0.021
0.92 0.056
0.90 0.018
0.32 0.010⁄⁄⁄
0.25 0.018⁄⁄⁄
0.33 0.010⁄⁄⁄
0.20 0.018⁄⁄⁄
0.32 0.011
0.35 0.044
0.37 0.033
0.17 0.011
0.22 0.011⁄⁄⁄
0.27 0.033⁄⁄⁄
0.32 0.033⁄⁄
0.25 0.022⁄⁄⁄
0.17 0.022
0.23 0.040⁄⁄⁄
0.32 0.010⁄⁄⁄
0.30 0.067⁄⁄⁄
0.27 0.033
0.27 0.011⁄⁄⁄
0.32 0.010⁄⁄⁄
0.33 0.010⁄⁄⁄
0.27 0.078⁄⁄⁄
0.25 0.055⁄⁄⁄
0.22 0.044⁄⁄⁄
0.18 0.011⁄⁄⁄
0.15 0.033⁄⁄
0.15 0.022⁄⁄
0.17 0.044⁄⁄⁄
0.12 0.033⁄⁄⁄
0.22 0.067⁄⁄
0.20 0.044⁄⁄
0.18 0.055⁄⁄⁄
Standard: ibuprofen, each value is the mean SEM for six rats, ⁄⁄P < 0.01; ⁄⁄⁄P < 0.0001 compared with control.
a
Increase in paw volume was calculated as (the volume after carrageen in injection) À (the volume before injection). Data analyzed by one-way ANOVA followed by
Student’s t-test.

4140
L. Nagarapu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4138–4140
F.; Seibel, S. B.; Silvia, A. M.; George, D. M.; Lund, L. A.; St. Denis, S.; Hickman,
A.; Michelle, L.; Haven, M. L.; Lynch, M. P. Bioorg. Med. Chem. Lett. 2006, 16, 288.
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28. Nagarapu, L.; Gaikwad, H. K.; Sarikonda, K.; Mateti, J.; Rajashaker, B.; Mahduri,
K. M.; Kalvendi, S. V. Eur. J. Med. Chem. 2010, 46, 4720.
ity along with the reference drug ibuprofen. The study of all the
derivatives showed anti-inflammatory activity greater than ibu-
profen. All the target compounds (10a–g) potentially reduced the
carrageenan-induced inflammation in rats. The SAR study of the
compounds revealed that the substitution of methoxy- and nitro-
group on aryl ring had developed the active compounds.
In summary, a new series of pyrazole carboxamides (10a–g)
were synthesized and has been identified as anti-inflammatory
agents. Biological evaluation revealed that the all the target com-
pounds displayed potent anti-inflammatory activity. Therefore,
our finding may aid in the strong future potential of new and safe
anti-inflammatory agents for the further investigation.
29. Spectral data: Compound 10a: mp 133–135 °C, 79.8% yield; IR (vmax cmÀ1, KBr):
3232, 2936, 2874, 1643, 1560, 1244, 1152, 761, 690, 1H NMR (500 MHz, DMSO-
d6): d 1.77–1.86(m, 2H, CH2), 2.57–2.69(m, 4H, 2Â CH2), 3.19–3.31(m, 6H, 3Â
CH2), 3.46(d, J = 5.52 Hz, 2H, CH2), 6.76(t, J = 7.36 Hz, 1H, Ar-H), 6.87(d,
J = 8.28 Hz, 2H, Ar-H), 6.95(s, 1H, Ar-H), 7.18(t, J = 7.54 Hz, 2H, Ar-H), 7.24–
7.43(m, 3H, Ar-H), 7.69(d, J = 8.28 Hz, 2H, Ar-H), 7.94(s, 1H, NH), 13.29(br, 1H,
NH); 13C NMR (75 MHz, DMSO-d6): 24.97, 37.17, 47.49, 52.16, 55.80, 95.49,
101.91, 115.38, 119.01, 124.90, 127.46, 128.21, 128.46, 150.15, 161.02; HRMS
(ESI+) Calcd for C23H27N5O [M+H]+: 390.2293. Found: 390.2302. Compound
10b: mp 207–209 °C, 76.5% yield; IR (vmax cmÀ1, KBr): 3286, 3225, 2960, 2870,
1642, 1599, 1564, 1510, 1259, 1022, 819, 756, 1H NMR (500 MHz, DMSO-d6): d
1.71–1.81(m, 2H, CH2), 2.39–2.50(m, 2H, CH2), 3.13–3.24(m, 4H, 2Â CH2),
3.32–3.44(m, 6H, 3Â CH2); 3.83(s, 3H, OCH3), 6.76–6.84(m, 1H, Ar-H), 6.92–
7.01(m, 3H, Ar-H); 7.05(d, J = 7.34 Hz, 2H, Ar-H), 7.24(t, J = 7.34 Hz, 2H, Ar-H),
7.74(d, J = 7.34 Hz, 1H, Ar-H), 8.26(s, 1H, NH), 13.47(br, 1H, NH); HRMS (ESI+)
Calcd for C24H29N5O2 [M+H]+: 420.2399. Found: 420.2408. Compound 10c: mp
174–176 °C, 72.1% yield; IR (vmax cmÀ1, KBr): 3293, 3225, 2931, 2829, 1645,
1562, 1497, 1453, 1235, 1041, 754, 688, 1H NMR (300 MHz, DMSO-d6): d 1.73–
1.86(m, 2H, CH2), 2.45–2.55(m, 2H, CH2), 2.55–2.66(m, 4H, 2Â CH2), 3.17–
3.28(m, 4H, 2Â CH2), 3.38–3.49(m, Hz, 2H, CH2), 3.82(s, 3H, OCH3), 6.75(t,
J = 7.17 Hz, 1H, Ar-H), 6.82(s, 1H, Ar-H), 6.86(d, J = 8.30 Hz, 2H, Ar-H), 6.96(s,
1H, Ar-H), 7.17(t, J = 7.83 Hz, 2H, Ar-H), 7.22–7.34(m, 3H, Ar-H), 8.01(s, 1H,
NH), 13.36(br, 1H, NH); 13C NMR (75 MHz, DMSO-d6): 26.21, 38.07, 48.61,
53.14, 56.78, 96.11, 102.69, 110.80, 113.95, 116.81, 117.93, 119.23, 129.08,
129.95, 151.19, 159.97; HRMS (ESI+) Calcd for C24H29N5O2 [M+H]+: 420.2399.
Acknowledgments
Authors thank the Director and Head, Organic Chemistry Divi-
sion-II, IICT for their support. Hanmant K. Gaikwad thanks UGC,
New Delhi for research fellowship.
References and notes
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Found: 420.2395. Compound 10d: mp 191–193 °C, 71.7% yield; IR (vmax cmÀ1
,
KBr): 3290, 3211, 2925, 1643, 1563, 1504, 1383, 1245, 1155, 817, 756, 690, 1
H
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NMR (300 MHz, DMSO-d6): d 1.74–1.86(m, 2H, CH2), 2.36(s, 3H, CH3), 2.58–
2.69(s, 6H, 3Â CH2), 3.17–3.31(m, 4H, 2Â CH2), 3.36–3.49(m, 2H, CH2), 6.75(t,
J = 7.35 Hz, 1H, Ar-H), 6.83–6.94(m, 3H, Ar-H), 7.11–7.24(m, 3H, Ar-H), 7.58(d,
J = 7.93 Hz, 2H, Ar-H), 7.90(d, J = 6.98 Hz, 1H, Ar-H), 7.99(s, 1H, NH), 13.22(s,
1H, NH); HRMS (ESI+) Calcd for C24H29N5O [M+H]+: 404.2450. Found:
404.2469. Compound 10e: mp 116–118 °C, 74% yield; IR (vmax cmÀ1, KBr):
3298, 3236, 2927, 2872, 1643, 1556, 1497, 1384, 1243, 1150, 1002, 757, 689,
1H NMR (300 MHz, DMSO-d6): d 1.71–1.85(m, 2H, CH2), 2.38(s, 3H, CH3), 2.47–
2.54(m, 2H, CH2), 3.2(s, 4H, CH2), 2.55–2.65(m, 4H, 2Â CH2), 3.30–3.38(m, 4H,
2Â CH2), 3.36–3.46(m, 2H, CH2), 6.75(t, J = 7.17 Hz, 1H, Ar-H), 6.87(d,
J = 7.93 Hz, 2H, Ar-H), 6.95(s, 1H, Ar-H), 7.10(d, J = 7.36 Hz, 1H, Ar-H), 7.17(t,
J = 7.83 Hz, 2H, Ar-H), 7.25(t, J = 7.45 Hz, 1H, Ar-H), 7.49(d, J = 7.93 Hz, 1H, Ar-
H), 7.54(s, 1H, Ar-H), 8.07(s, 1H, NH), 13.35(s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6): 20.95, 25.59, 37.42, 47.94, 52.51, 56.06, 95.51, 101.89, 115.21,
118.65, 122.13, 125.61, 128.25, 128.49, 137.59, 150.56, 160.76; HRMS (ESI+)
Calcd for C24H29N5O [M+H]+: 404.2450. Found: 404.2442. Compound 10f: mp
201–203 °C, 73.7% yield; IR (vmax cmÀ1, KBr): 3190, 2945, 2825, 1647, 1600,
1513, 1342, 1236, 1114, 854, 754, 690, 1H NMR (300 MHz, DMSO-d6): d 1.74–
1.88(m, 2H, CH2), 2.47–2.68(m, 6H, 3Â CH2), 3.15–3.30(m, 4H, 2Â CH2), 3.36–
3.51(s, 2H, CH2), 6.77(t, J = 7.17 Hz, 1H, Ar-H), 6.87(d, J = 8.12 Hz, 2H, Ar-H),
7.14–7.25(m, 3H, Ar-H), 7.89–8.02(m, 2H, Ar-H), 8.11–8.27(m, 2H, Ar-H),
8.41(s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): 25.35, 37.60, 48.01, 52.50,
56.15, 95.42, 115.09, 118.63, 123.49, 125.38, 128.38, 146.23, 150.48; HRMS
(ESI+) Calcd for C23H26N6O3 [M+H]+: 435.2144. Found: 453.2139. Compound
10g: mp 174–176 °C, 70.7% yield; IR (vmax cmÀ1, KBr): 3239, 3143, 2941, 2820,
1649, 1532, 1347, 1235, 1146, 743, 693, 1H NMR (300 MHz, DMSO-d6): d 1.74–
1.87(m, 2H, CH2), 2.57–2.68(m, 6H, 3Â CH2), 3.11–3.29(m, 4H, 2Â CH2), 3.35–
3.48(m, 2H, CH2), 6.75(t, J = 7.26 Hz, 1H, Ar-H), 6.87(d, J = 7.93 Hz, 2H, Ar-H),
7.18(t, J = 7.83 Hz, 2H, Ar-H), 7.54–7.55(m, 2H, Ar-H), 8.00(s, 1H, Ar-H), 8.14(d,
J = 7.74 Hz, 2H, Ar-H), 8.64(s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): 25.59,
37.39, 48.03, 52.49, 55.90, 95.44, 115.14, 118.61, 119.25, 121.63, 128.40,
129.55, 130.83, 148.02, 150.55; HRMS (ESI+) Calcd for C23H26N6O3 [M+H]+:
435.2144. Found: 453.2134.
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