Synthesis, anti-inflammatory, analgesic and antipyretic activity of novel 1,3,5-trisubstituted pyrazole derivatives

Article abstract of DOI:10.14233/ajchem.2019.21781

A novel series of 1,3,5-trisubstituted pyrazole derivatives were synthesized by the cycloaddition reaction between the electron rich N-substituted aryl hydrazones and nitro-olefins. Different N-substituted aryl hydrazones (1a-j) on reacting with 4-methyl-

Full text of DOI:10.14233/ajchem.2019.21781

Asian Journal of Chemistry; Vol. 31, No. 6 (2019), 1225-1229
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.21781
Synthesis, Anti-inflammatory, Analgesic and Antipyretic Activity of
Novel 1,3,5-Trisubstituted Pyrazole Derivatives
*
THATAVARTHI PADMINI and BIGALA RAJ KAMAL
Department of Chemistry, Mewar University, Chittorgarh-312901, India
*Corresponding author: E-mail: thatap@yahoo.com
Received: 29 October 2018; Accepted: 24 December 2018;
Published online: 29 April 2019;
AJC-19359
A novel series of 1,3,5-trisubstituted pyrazole derivatives were synthesized by the cycloaddition reaction between the electron rich
N-substituted aryl hydrazones and nitro-olefins. Different N-substituted aryl hydrazones (1a-j) on reacting with 4-methyl-β-nitrostyrene
(2) in ethylene glycol or trifluoroethanol-trifluoro acetic acid mixture (for acid stable hydrazones) at 120 ºC, yielded various 1,3,5-
trisubstituted pyrazoles (3a-j). The final products were characterized by spectral analysis using Mass, NMR and IR spectroscopy. All the
products were assessed for their anti-inflammatory, analgesic and antipyretic activities on Swiss albino rats. All the compounds (3a-j)
exhibited noteworthy defence against inflammation, nociception and hyperthermia. Compounds (3e and 3h) disclosed better anti-
inflammatory, analgesic and antipyretic activities while compound 3c had highest anti-inflammatory activity compared to the standard
nimesulide.
Keywords: Cycloaddition, Nitro olefins, Hydrazones, Anti-inflammatory, Analgesic, Antipyretic.
antidepressant [21-23], anticonvulsant [24,25], antidiabetic
[26,27], antiangio-genetic [28], antitubercular [29] and
anticancer [30-33] activities.
INTRODUCTION
Inflammation, pain and fever are the common problems
over the sphere. In spite of the fact that numerous drugs are
accessible in the market, there is dependably a chase for the
new agents for the management of these problems [1]. NSAID
are the essential selection of medications for inflammation,
pain and are subsuming unwanted responses like gastric distur-
bances. Extensive research is climbing up to culminate these
side effects [2].
Poly substituted pyrazole based drugs are acquiring signi-
ficance in medicinal and natural products research by virtue
of its multifarious properties and broad spectrum of applica-
tions for various ailments [3]. Particularly 1,3,5-trisubstituted
pyrazoles build a crucial place in pharmaceutical industry as
they constitute the fundamental structure for many commercial
drugs such as celecoxib, sildenafil and rimonabant.
Since the inception of foremost synthetic method of pyra-
zole i.e. Paal-Knorr synthesis by condensation of 1,3-diketones
with hydrazine which yield 1,3,5-trisubstituted pyrazoles, it
is the subject of interest for researchers to synthesize the 1,3,5-
trisubstituted pyrazoles. Due to the convenience and versatility,
Paal-Knorr synthesis had been the principal synthetic method
for pyrazole synthesis. There are many accustomed approaches
for the synthesis of various pyrazole derivatives. A bunch of
literature in connection to the modification of Paal-Knorr
synthesis with better yields, reported by researchers, by suppla-
nting one of the starting material 1,3-diketone with acetylenic
and olefinic ketone moieties. Distinctive reagents have been
developed for synthesizing diverse pyrazole cross breeds. To
swamp the harsh reaction conditions and to have regioselecti-
vity, a basic and beneficial strategy was utilized for the synthesis
of 1,3,5-trisubstituted pyrazoles [34].
The plenteous literature affirms the ubiquitous nature of
aza-heterocyclic compounds especially the pyrazole deriva-
tives. They are documented to possess anti-inflammatory [4-
7], antibacterial, antifungal [8-11], antiviral [12,13],
antimalarial [14,15], analgesic [16-18], antipyretic [19,20],
In this regard, an endeavor was made to integrate a novel
series of 1,3,5-trisubstituted pyrazoles by cycloaddition of N-
arylhydrazones and nitro olefins to screen for anti-inflammatory
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1226 Padmini et al.
Asian J. Chem.
(by carrageenan induced rodent paw edema model), analgesic
(acetic acid induced writhing model and hot plate method)
and antipyretic (yeast induced pyrexia model) in Swiss albino
rats.
General procedure for the synthesis of pyrazole derivatives
Method 1: Each, exactly weighed 1 mmol of 4-methyl-
β-nitrostyrene (163 mg) and previously prepared different N-
substituted hydrazones were dissolved in 10 mL of ethylene
glycol. The reaction was carried at reflux conditions (120 °C)
in an open environment for 16 h.After cooling to room tempe-
rature, workup has been done by portioning the reaction
mixture in ethyl acetate and brine solution. Ethyl acetate layer
was collected, dried and crude purified over column chromato-
graphy eluting with n-hexane and ethyl acetate (Scheme-I).
Method 2: 4-Methyl-β-nitrostyrene (1 mmol, 163 mg)
and acid stable previously prepared hydrazones (1 mmol) were
dissolved in 10 mL of trifluoroethanol. To this mixture 0.77 mL
of trifluoroacetic acid (TFA) was added drop wise with conti-
nuous stirring at room temperature for 48 h. After cooling to
room temperature, workup has been done by portioning the
reaction mixture in ethyl acetate and brine solution. Ethyl
acetate layer was collected, dried and crude product was purified
over column chromatography eluting with n-hexane and ethyl
acetate [35] (Scheme-I).
EXPERIMENTAL
All the solvents and reagents were procured from Sigma-
Aldrich and purified wherever necessary. Melting points were
uncorrected and determined in open capillary Electro thermal
REMI CT-30 capillary melting point apparatus. NMR spectra
were recorded on Bruker 300 MHz using CDCl3. IR was recor-
ded on Shimadzu-8400 spectrometer using KBr as medium.
EI mass spectra were recorded on JEOL SX 102/DA-6000
mass spectrometer in positive mode.
AdultWistar rats (180-200 g) were employed for the experi-
ments. They were catered from Jeeva Life Sciences, Hyderabad.
After stochastically dividing into different groups, the rats were
adopted to the conditions for a period of 10 days before initia-
tion of the experiment. Animals were accommodated in poly-
propylene cages and maintained under standard environmental
conditions such as temperature (26 2 °C) and relative humidity
(45-55 %) for 12 h dark/light cycle. The rats were fed with
rodent pellet diet (Golden Mohur Lipton India Ltd.) and water
ad libitum. The study protocol was approved by the institutional
animal ethics committee (IAEC) before the commencement
of experiment (1292/ac/09/CPCSEA).
Spectral data
3-(4-Chlorophenyl)-1-(4-methoxy-phenyl)-5-p-tolyl-
1H-pyrazole (3a): Pale yellow solid, yield: 60 %, m.p. 165
°C, 1H NMR (400 MHz, CDCl3), δ = 7.35 (dt, J = 8.5, 2.0 Hz,
2H), 7.84 (dt, J = 8.5, 2.0Hz, 2H), 6.86 (dt, J = 9.0, 2.2 Hz,
R1
N
NO2
N
R1
N
R2
120 °C, 16-20 h
R2
N
H
+
(1a-j)
Ethylene glycol
or
Trifluoroethanol - TFA
(2)
N-aryl hydrazone
(3a-j)
R2
4-Methyl nitrostyrene
R2
R1
R1
CH3
H3CO
O2N
O2N
1a
1b
Cl
1f
Cl
H3CO
1g
1h
F
Cl
Cl
1c
F
N
1d
NC
1i
1j
HO
1e
Cl
H3CO2S
H3COOC
Scheme-I: Synthesis for 1,3,5-trisubstituted pyrazoles

Vol. 31, No. 6 (2019)
Synthesis and Biological Activity of Novel 1,3,5-Trisubstituted Pyrazole Derivatives 1227
2H), 7.25 (dt, J = 9.0, 2.2 Hz, 2H), 7.16-7.1 (m, 4H), 6.74 (s,
1H), 2.35 (s, 3H), 3.82 (s, 3H); 13C NMR (125.7 MHz, CDCl3):
55.5, 21.2, 158.9, 150.4, 144.6, 138.2, 133.5, 133.4, 131.8,
129.1, 128.7, 128.5, 127.5, 127.0, 126.7, 114.1, 104.2; ESI-
MS (m/z): [M+H]+ for C23H20N2OClis 375.1.
125.3, 114.0, 104.6, ESI-MS (m/z): [M+H]+ for C23H21N2Ois
341.2.
Dimethyl-[4-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)-
phenyl]amine (3h): Yield: 55 %, m.p. 184 °C, 1H NMR (400
MHz, CDCl3), δ = 7.80 (dt, J = 9.0, 2.0 Hz, 2H), 7.15 (dt, J =
8.2, 1.7 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 6.77 (dt, J = 9.0,
2.0 Hz, 2H), 6.70 (s, 1H),, 2.32 (s, 3H), 7.40-7.20 (m, 5H),
2.96 (s, 6H); 13C NMR (125.7 MHz, CDCl3): 40.5, 21.2, 152.3,
150.4, 144.1, 140.4, 138.0, 129.1, 128.8, 128.6, 128.0, 127.0,
126.7, 125.3, 121.5, 112.4, 104.3; ESI-MS (m/z): [M+H]+ for.
C24H24N3 is 354.2.
3-(4-Chlorophenyl)-1-(4-nitro-phenyl)-5-p-tolyl-1H-
pyrazole (3b):Yield: 15 %, m.p. 217 °C,1H NMR (400 MHz,
CDCl3), δ = 8.20 (dt, J = 9.0, 2.0 Hz, 2H), 7.82 (dt, J = 8.4,
2.0 Hz, 2H), 7.55 (dt, J = 9.0, 2.0 Hz, 2H), 7.41 (dt, J = 8.6,
2.0 Hz, 2H), 6.80 (s, 1H), 2.42 (s, 3H), 7.22-7.18 (m, 4H). 13C
NMR (125.7 MHz, CDCl3): 21.3152.1, 145.9, 144.9, 139.4,
134.4, 131.0, 129.7, 129.0, 128.7, 127.2, 127.0, 124.5, 124.4,
106.8; HRMS-ESI (m/z): [M+H]+ for C22H17N3O2Cl is 390.1.
3-(4-Chlorophenyl)-1-(2,4-difluoro-phenyl)-5-p-tolyl-
3-(1-Phenyl-5-p-tolyl-1H-pyrazol-3-yl)phenol (3i):
1
Yield: 80 %, m.p. 212 °C, H NMR (400 MHz, CDCl3), δ =
7.40-7.34 (m, 2H), 7.05 (br. s, 1H), 6.74 (dd, J = 8.0, 2.3 Hz,
1
1H-pyrazole (3c): Yield: 75 %, m.p. 167 °C, H NMR (400
1H), 6.70 (s, 1H), 2.32 (s, 3H), 7.12-7.06 (m, 4H), 7.34-7.17
13
MHz, CDCl3), δ = 7.36 (dt J = 8.5, 2.0 Hz, 2H), 7.80 (dt, J =
8.5, 2.0 Hz, 2H), 7.17-7.10 (m, 4H), 7.55-7.45 (m, 1H), 7.00-
6.90 (m, 1H), 6.90-6.84 (m, 1H), 2.34 (s, 3H), 6.76 (s, 1H);
21.2. 13C NMR (125.7 MHz, CDCl3): 162.5 (dd, JC-F = 255.9,
12.6 Hz), 162.5 (dd, JCF 151.7, 146.7, 138.6, 133.9, 131.4,
130.1 (d, JC-F = 9.8 Hz), 129.3, 128.8, 127.7, 127.1, 126.8,
124.9 (dd, JC-F = 12.3, 3.9 Hz), 111.9 (dd, JC-F = 22.4, 3.8 Hz),
105.1 (dd, JC-F = 26.3, 23.6 Hz), 103.9, 251.6, 11.1 Hz), Hz),
111.9 (dd, JC-F = 22.4, 3.8 Hz), 105.1 (dd, JC-F = 26.3, 23.6
Hz), 103.9, 21.2; ESI-MS (m/z): [M+H]+ for C22H16N2F2Cl,
381.
(m, 6H); C NMR (125.7 MHz, CDCl3): 21.2.156.3, 151.8,
144.6, 139.9, 138.3, 134.1, 129.8, 129.1, 128.9, 128.5, 127.5,
127.4, 125.4, 118.1, 115.4, 112.9,105.1, ESI-MS (m/z):
[M+H]+ for C22H19N2 O is 327.1.
4-(1-Phenyl-5-p-tolyl-1H-pyrazol-3-yl)benzoic acid
1
methyl ester (3j): Yield: 30 %, m.p. 152 °C, H NMR (400
MHz, CDCl3), δ = 7.99 (dt, J = 8.4, 1.8 Hz, 2H), 8.10 (dt, J =
8.4, 1.8 Hz, 2H), 6.84 (s, 1H), 3.93 (s, 3H), 2.35 (s, 3H), 7.26-
7.10 (m, 4H), 7.48-7.28 (m, 5H); 13C NMR (125.7 MHz,
CDCl3): 52.0, 21.2, 166.9, 150.7, 144.7, 140.0, 138.4, 137.5,
129.9, 129.2, 129.2, 128.9, 128.5, 127.5, 127.3, 125.5, 125.2,
105.3, ESI-MS (m/z): [M+H]+ for C24H21N2O2 is 369.
Anti-inflammatory activity (carrageenan-induced rat
paw oedema test): All the synthesized pyrazoles (3a-j) were
administered in two doses of 50 mg/kg body weight based
upon their acute toxicity studies using standard protocols [36].
Nimesulide at a dose of 50 mg/kg body weight was served as
reference standard. The compounds were suspended in 0.5 %
carboxymethyl cellulose (CMC) and administered orally to
the Wister rats. The control animals received 0.5 % carboxy-
methyl cellulose.After 30 min drug administration, 0.1 mL of
1 % carrageenan in normal saline solution was injected into
the sub plantar region of one of the hind paws. The paw oedema
volume was recorded using a plethysmometer (UGO Basile,
Italy) at different time intervals.
Analgesic activity (acetic acid-induced writhing model):
This experiment was carried out by standard procedures using
Wistar rats of either sex [37]. Three groups of six animals each
served as control, test and standard. The control group was
administered with the normal saline solution, the test group
supplied with 50 mg/kg body weight of the compounds. The
standard group was administered with nimesulide at a dose
of 50 mg/kg prepared in water. Food was restricted during
experiments. Writhings were induced 30 min after the last dose
by intraperitoneal injection of 10 mL/kg of 0.6 % acetic acid
in distilled water. The number of writhings that is a number of
abdominal contractions, trunk twist responses and extension
of hind limbs was recorded immediately for a period of 10
min.
4-[3-(4-Chlorophenyl)-5-p-tolyl-pyrazol-1-yl]-
1
benzonitrile (3d): Yield: 50 %, m.p. 186 °C, H NMR (400
MHz, CDCl3), δ = 7.80 (dt, J = 8.5, 2.0 Hz, 2H), 7.40 (dt, J =
8.5, 2.0 Hz, 2H), 7.60 (dt, J = 8.7, 2.0 Hz, 2H), 7.46 (dt, J =
8.7, 2.0 Hz, 2H), 2.40 (s, 3H), 7.22-7.13 (m, 4H), 6.76 (s,
1H); 13C NMR (125.7 MHz, CDCl3): 21.3, 151.9, 145.1, 143.4,
139.2, 134.2, 132.8, 131.0,129.6, 128.9, 128.7, 127.1, 127.0,
124.8, 118.3, 110.5, 106.5; ESI-MS (m/z): [M+H]+ for
C14H16N2Clis 247.1.
3-(4-Chlorophenyl)-1-(4-methanesulfonyl-phenyl)-5-p-
tolyl-1H-pyrazole (3e): Yield: 60 %, m.p. 210 °C, 1H NMR
(400 MHz, CDCl3), δ = 7.55 (dt, J = 8.5, 1.8 Hz, 2H), 7.90
(dt, J = 8.5, 1.8 Hz, 2H), 7.42 (dt, J = 8.5, 1.8 Hz, 2H), 7.85
(dt, J = 8.5, 1.8 Hz, 2H), 6.77 (s, 1H), 3.04 (s, 3H), 2.40 (s,
3H), 7.20-7.15 (m, 4H); 13C NMR (125.7 MHz, CDCl3): 44.5,
21.3.151.9, 145.1, 144.2, 139.2, 138.5, 134.2, 131.0, 129.6,
128.9, 128.6, 128.3, 127.1, 126.9, 124.9, 106.4; ESI-MS (m/z):
[M+H]+ for C23H20N2O2SCl, 423.1
1-Methyl-3-(4-nitrophenyl)-5-p-tolyl-1H-pyrazole (3f):
1
Yield: 52 %, m.p. 158 °C, H NMR (400 MHz, CDCl3), δ =
7.67 (dt, J = 9.0, 2.0 Hz, 2H), 8.10 (dt, J = 9.0, 2.0 Hz, 2H),
7.16-7.10 (m, 4H), 7.44 (s, 1H); 13C NMR (125.7 MHz,
CDCl3): 39.2, 21.1.146.8, 146.1, 140.3, 137.0, 130.8, 129.5,
129.4, 128.6, 128.4, 123.5, 122.0, MS (m/z): [M+H]+ for
C17H16N3O2 is 294.1.
3-(4-Methoxyphenyl)-1-phenyl-5-p-tolyl-1H-pyrazole
(3g): Yield: 75 %, m.p. 162 °C, 1H NMR (400 MHz, CDCl3),
δ = 7.42-7.26 (m, 4H), 7.84 (dt, J = 8.8, 2.0 Hz, 2H), 7.16 (dt,
J = 8.2, 1.8 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.96 (dt, J =
8.8, 2.0 Hz, 2H), 6.72 (s, 1H), 3.85 (s, 3H), 2.35 (s, 3H), 13C
NMR (125.7 MHz, CDCl3): 55.2, 21.2159.6, 151.7, 144.4,
140.3, 138.2, 129.1, 128.8, 128.6, 127.8, 127.2, 127.1, 126.0,
Antipyretic activity (yeast-induced pyrexia model): The
antipyretic activity of the test compounds was screened by
yeast-induced pyrexia model in rats [38]. The rectal tempera-
ture of each rat was recorded at predetermined time intervals.

1228 Padmini et al.
Asian J. Chem.
Fever was induced by injecting 15 % Brewer’s yeast (Saccharo-
myces cerevisiae) suspension. The animals were acclimatized
for some time. A thermistor probe was inserted 3-4 cm deep
into the rectum after fastening the tail to record the basal rectal
temperature. The animals were then given a subcutaneous
injection of 10 mL/kg of 15 %w/v Brewer’s yeast suspended
in 0.5 % w/v carboxymethyl cellulose solution and the animals
were returned to their housing cages.After 19 h, yeast injection,
the rats were again restrained in individual cages to record their
rectal temperature before and at 1 h intervals up to 3 h after the
administration of prescribed dose of test compounds, vehicle
and paracetamol (50 mg/kg).
and compound 3h had rapid onset of action (17.5 % in 1 h)
than the other pyrazoles. However, the maximum inhibition
of oedema was produced by compounds 3c, 3b and 3d as com-
pared to standard nimesulide (44.8 % after 3 h).
Analgesic activity: Similarly, all the prepared pyrazole
derivatives had shown significant inhibition of acetic acid
induced writhings in rats at a dose of 50 mg/kg (Table-1) when
compared with the standard drug nimesulide (50 mg/kg). How-
ever, the maximum inhibition of writhings was produced by
compounds 3h (52.9 % of inhibition), 3e (52.6 % of inhibition)
and 3i (48.7 % of inhibition) as compared to standard nime-
sulide (57.9 % of inhibition).
Antipyretic activity: Similar to the anti-inflammatory
activity results, all the derivatives of pyrazoles had shown signi-
ficant antipyretic activity in yeast induced rat pyrexia test at a
dose of 50 mg/kg (Table-2) when compared with the standard
drug nimesulide (50 mg/kg). Among all the synthesized pyra-
zoles, Compound 3h had the highest antipyretic activity (36.03
0.14 after 3 h) and rapid onset of action (37.39 0.27 in 1 h)
than the other synthesized compounds. However, the maximum
inhibition of temperature was produced by compounds 3h, 3i,
3c and 3e as compared to standard nimesulide (35.45 0.21
after 3 h).
RESULTS AND DISCUSSION
All the synthesized 1,3,5-trisubstituted pyrazoles were
evaluated for anti-inflammatory, analgesic and antipyretic
activities in rats.
Anti-inflammatory activity: The experimental results
were compared with the standard drug nimesulide (50 mg/kg)
states that the 1,3,5-trisubstituted pyrazoles had shown subs-
tantial antiinflammatory activity in carrageenan-induced rat
paw oedema test at a dose of 50 mg/kg (Table-1). Compound
3c had the highest anti-inflammatory activity (41 % after 3 h)
TABLE-1
MICROBIAL ACTIVITY OF 1,3,5-TRISUBSTITUTED PYRAZOLES IN CARRAGEENAN-INDUCED RAT PAW OEDEMA TEST
Anti-inflammatory activity Analgesic activity
Mean paw volume at different
time intervals (mL)
Percentage inhibition of
edema volume
Compd.
Dose (mg/kg)
Writhing
response
Percentage
inhibition
1 h
3 h
1 h
3 h
Control
Nimesulide
50
50
50
50
50
50
50
50
50
50
50
50
5.87 0.052
4.82 0.027
5.12 0.047**
5.02 0.064**
4.90 0.051**
5.04 0.018
4.98 0.048**
5.06 0.013**
5.09 0.045
4.84 0.041**
5.13 0.090**
5.10 0.032**
6.85 0.012
3.78 0.024
5.26 0.044
4.12 0.056**
4.04 0.061**
4.19 0.043**
3.97 0.067
4.32 0.049**
4.57 0.023**
4.46 0.018**
4.85 0.031**
4.61 0.092
0.0
0.0
37.12 0.54
15.63 0.71
24.31 0.65**
21.04 1.47
17.25 0.83**
21.44 0.32**
17.59 0.97**
24.36 1.55
19.73 1.65**
17.50 1.38**
19.03 1.91
23.50 1.56**
0.0
17.9
12.8
14.5
16.5
14.1
15.2
13.8
13.3
17.5
12.6
10.6
44.8
23.2
39.9
41.0
38.8
20.3
36.9
33.3
34.8
29.2
32.7
57.9
34.5
44.5
43.3
42.2
52.6
34.4
46.8
52.9
48.7
36.7
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
N = 6, Values are Mean SEM; **P < 0.01 (significant), values are compared with control group.
TABLE-2
ANTIPYRETIC ACTIVITY OF SYNTHESIZED 1,3,5-TRISUBSTITUTED PYRAZOLES IN YEAST INDUCED RAT PYREXIA TEST
Yeast induced pyrexia (temperature in °C)
Compd.
Dose (mg/kg)
0 h
1/2 h
1 h
3 h
Control
Nimesulide
50
50
50
50
50
50
50
50
50
50
50
50
37.65 0.24
37.47 0.19
37.54 0.30
37.58 0.38**
37.37 0.34
37.58 1.37**
37.46 0.22*
37.44 0.35
37.72 0.27**
37.88 0.35*
37.74 0.27**
37.54 0.11
37.48 0.22
36.88 0.06
37.38 1.01
37.47 0.57**
36.85 0.68**
37.38 0.15*
36.87 0.21**
37.14 0.46
37.45 0.36**
37.39 0.27**
37.08 0.12**
37.34 0.16**
37.24 0.25
36.67 0.02
37.25 0.10**
36.21 0.12**
36.64 0.22
37.16 0.17**
36.58 0.25
36.81 0.15**
37.22 0.13*
36.32 0.15
36.55 0.18**
37.15 0.07**
36.56 0.15
35.45 0.21
36.52 0.06*
36.14 0.07**
36.10 0.18**
36.69 0.06
36.24 0.16**
36.68 0.12**
36.98 0.05*
36.03 0.14**
36.12 0.18**
36.61 0.02*
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
N = 6, Values are Mean SEM; **P < 0.01 (significant); *P < 0.05 (significant) values are compared with control group.

Vol. 31, No. 6 (2019)
Synthesis and Biological Activity of Novel 1,3,5-Trisubstituted Pyrazole Derivatives 1229
Charman, I. Angulo-Barturen, S. Ferrer, M. Belén Jiménez-Díaz, M.S.
Martínez, F.J. Gamo, V.M. Avery, A. Ruecker, M. Delves, K. Kirk, M.
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In conclusion, the synthesis of various 1,3,5-trisubstituted
pyrazoles (3a-j) have been achieved by the cycloaddition of
nitro olefins with N-mono substituted hydrazones with good
yields.All the synthesized pyrazoles (3a-j) have been evaluated
for their anti-inflammatory, analgesic and antipyretic activities.
Results revealed that all the compounds had shown significant
anti-inflammatory, analgesic and antipyretic activities. Comp-
ound 3h had shown comparatively better anti-inflammatory,
analgesic and antipyretic activities and compound 3c had
highest anti-inflammatory property compared to the standard
nimesulide. There is a need to continue the research further in
structural and molecular aspects to figure out the exact mecha-
nism to develop them as potential leads for inflammation, pain
and fever.
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