Synthesis and anti-inflammatory activity of some new 4,5-dihydro-1,5- diaryl-1H-pyrazole-3-substituted-heteroazole derivatives

Article abstract of DOI:10.1016/j.bmcl.2011.08.061

A series of 4,5-dihydro-1,5-diaryl-1H-pyrazole-3-substituted-heteroazoles were designed and synthesized in order to obtain new compounds with potential anti-inflammatory activity. The title compounds were screened for in vivo anti-inflammatory activity by

Full text of DOI:10.1016/j.bmcl.2011.08.061

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6527–6532
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and anti-inflammatory activity of some new 4,5-dihydro-1,5-diaryl-
1H-pyrazole-3-substituted-heteroazole derivatives
Deepak V. Dekhane a, Shivaji S. Pawar a, Sunil Gupta a, Murlidhar S. Shingare b, C.R. Patil c,
Shivaji N. Thore a,
⇑
a Department of Chemistry, Vinyakrao Patil Mahavidyala Vaijapur, Aurangabad, M.S. 423701, India
b Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, M.S. 431004, India
c R.C. Patel College of Pharmacy, Shirpur, M.S. 425405, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 June 2011
Revised 10 August 2011
Accepted 12 August 2011
Available online 10 September 2011
A series of 4,5-dihydro-1,5-diaryl-1H-pyrazole-3-substituted-heteroazoles were designed and synthe-
sized in order to obtain new compounds with potential anti-inflammatory activity. The title compounds
were screened for in vivo anti-inflammatory activity by using Carrageenan induced rat paw edema
method. Diclofenac sodium was used as a standard drug for comparison. Out of the 30 compounds tested,
compound 19a, 19b, 25a, 25b exhibited significant anti-inflammatory activity. Selected compounds were
also screened for in vitro COX-2 inhibition assay and analgesic activity in the acetic acid induced writhing
model.
Keywords:
Anti-inflammatory
Analgesic
Ó 2011 Elsevier Ltd. All rights reserved.
NSAIDs
Pyrazoline
Cyclooxygenases (COXs) are key enzymes in the synthesis of
prostaglandin H2 which is a precursor for the biosynthesis of pros-
taglandins, thromboxanes, and prostacyclins.1 COX enzymes exist
in two isoforms: cyclooxygenase-1 (COX-1) and cyclooxygenase-
2 (COX-2).2 The COX-1 enzyme is constitutively expressed and is
critical for protection of gastric mucosa, platelet aggregation, and
renal blood flow whereas the COX-2 enzyme is inducible and ex-
pressed during inflammation, pain, and oncogenesis.3 The associa-
tion of COX-2 with induced inflammation has led to the hypothesis
that selective inhibition of COX-2 over COX-1 might provide good
anti-inflammatory agents with reduced side effects than classical
NSAIDs. Therefore, selective COX-2 inhibitors (coxibs) with better
safety profile have been marketed as a new generation NSAIDs.4,5
But careful prospective examination of coxibs has revealed unex-
pected cardiovascular adverse effect.6 Therefore, development of
novel compounds having anti-inflammatory and analgesic activi-
ties with an improved safety profile is still a necessity. In addition,
inflammation is known not only as a symptom of great deal of
common diseases but also as an early phase of some life-threaten-
ing diseases such as cancer, heart vascular diseases and Alzhei-
mer’s dementia. Thus the discovery of novel anti-inflammatory
agents has been attracting a lot of interests.
revealed that numerous pyrazole derivatives have found their clin-
ical application as NSAIDs. Antipyrine, 2,3-dimethyl-1-phenyl-3-
pyrazolin-5-one, was the first pyrazolone derivative used in the
management of pain and inflammation. Several analogues of pyr-
azolidin-3,5-diones, pyrazolin-3-ones and pyrazolin-5-ones are
also available as NSAIDs; examples are felcobuzone, mefobutazone,
morazone, famprofazone, and ramifenazone.7 Besides these, many
pyrazole derivatives are also reported in literature as having potent
anti-inflammatory activity8–11 (Fig. 1).
Recently Javed et al. reported synthesis and anti-inflammatory
activity of 1,3,5-trisubstituted pyrazoline bearing benzene sulfon-
amide moiety.12 These compounds exhibited excellent in vitro
and in vivo anti-inflammatory profile.
Based on the report of Javed et al., we have considered the
1,5-diaryl pyrazoline moiety as our parent nucleus. The present
work describes the synthesis of 4,5-dihydro-1,5-diaryl-1H-pyra-
zole-3-substituted-heteroazole derivatives with the aim to dis-
cover novel and potent anti-inflammatory agents. Here, we have
synthesized 1,5-diaryl-pyrazoline-3-carbohydrazide, carbonitrile
and carboxamidine compounds. These compounds were then
converted to acid or amide heterocycles such as 1,3,4-oxadiazole,
1,3,4-thiadiazole, 1,2,4-oxadiazole, tetrazole bearing acidic, basic
or neutral functionality. Keeping the 1,5-diaryl pyrazoline moiety
constant, we have studied the effect of different azoles on the
anti-inflammatory effect in the series.
Pyrazoles and its derivatives are an important nitrogenous five-
membered heterocyclic component of the drugs. Literature survey
The 4-(4-chlorophenyl)-2-oxo-but-3-enoic acid ethyl ester 1
was prepared by esterification of potassium salt of 4-(4-chloro-
⇑
Corresponding author. Tel.: +91 2436 222086; fax: +91 2436 224581.
E-mail address: snthore@rediffmail.com (S.N. Thore).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.061

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D. V. Dekhane et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6527–6532
O
O
O
NH2
NH2
S
S
S
O
O
O
F
N
N
O
N
F
O
O
F
Valdecoxib
Rofecoxib
Celecoxib
O
NH2
S
O
NH2
O
S
F
Cl
N
N
O
F
N
N
HN
N
F
N
NH
-
N
+
O
Cl
Na
O
Br
Cl
Diclofenac sodium
SC-558
25b
Figure 1. Structure of marketed NSAIDs and synthesized compound.
O
O
O
NH2
N
H
O
A
N
N
B
O
N
R
N
R
Cl
Cl
O
Cl
1
3a,b
2a,b
C
O
N
OH
N
N
NH2
NH2
N
D
N
R
N
R
E
Cl
Cl
N
N
R
Cl
5a,b
6a,b
4a,b
Where for a. R= H, b. R = SO 2NH2
Scheme 1. Reagents and conditions: (A) p-R-phenyl hydrazine, ethanol, acetic acid, reflux; (B) hydrazine hydrate, ethanol, reflux; (C) 30% aq ammonia, THF, 50–55 °C; (D)
DMF, oxallyl chloride, 0 °C; (E) hydroxyl amine HCl, Na2CO3, methanol, 25–30 °C.
phenyl)-2-oxobut-3-enoic acid13 in ethanol using thionyl chloride
(Scheme 1). Ester on reaction with different substituted phenyl
hydrazine hydrochlorides in ethanol and acetic acid furnished
ethyl 5-(4-chloro-phenyl)-4,5-dihydro-1-phenyl-1H-pyrazole-3-
carboxylate 2a and 5-(4-chloro-phenyl)-1-(4-sulfamoyl-phenyl)-
4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester 2b. These
esters were further converted to respective hydrazides 3a,b using
hydrazine hydrate in ethanol at reflux. The esters 2a,b were also
used to prepare amide derivatives 4a,b using ammonium
hydroxide in tetrahydrofuran. The nitrile cores 5a,b were prepared
by dehydrating corresponding amides using N,N0-dimethylform-
amide and oxalyl chloride as dehydrating agent. Nitriles were
further reacted with hydroxylamine hydrochloride in presence of
Na2CO3 to furnish amidoxime cores 6a,b.
The carbohydrazides 3a,b were converted to different amide
hetrocycles (Scheme 2). The 2-hydroxy-1,3,4-oxadiazoles 7a,b were
prepared by reaction of carbonyldiimidazole with 3a,b in tetrahy-
drofuran using triethylamine as base. The 2-thiol-1,3,4-oxadiazoles

D. V. Dekhane et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6527–6532
6529
N
N
OH
N
SH
N
N
O
O
N
N
N
R
Cl
Cl
R
7a,b
8 a,b
F
G
H
3a,b
I
N
N
S
N
N
NH2
N
S
O
N
N
R
N
Cl
Cl
R
9 a,b
10 a,b
Where For a. R=H, b. R = SO2NH2
Scheme 2. Reagents and conditions: (F) CDI, Et3N, THF, 25–30 °C; (G) CS2, KOH, methanol, 60–65 °C; (H) CNBr, NaHCO3, dioxane–water, 25–30 °C; (I) (1) CS2, KOH, MeI,
methanol, 25–30 °C; (2) p-toluene sulphonic acid, toluene, reflux.
O
O
OH
SH
N
N
N
N
N
N
K
J
6a,b
N
R
N
Cl
Cl
R
12a,b
11a,b
For a R = H, For b R = SO2NH2
Scheme 3. Reagents and condition: (J) (1) ethylchloroformate, pyridine; (2) xylene, reflux; (K) (1) Ac2O, Et3N, 0–5 °C; (2) NaH, CS2, 0–5 °C.
8a,b were obtained by reaction of 3a,b with carbon disulfide under
basic condition. The 2-amino-l,3,4-oxadiazoles 9a,b resulted from
the reaction of cyanogen bromide and NaHCO3 with 3a,b. The
2-thiomethyl-1,3,4-thiadiazoles 10a,b were synthesized by reaction
of hydrazide with KOH and carbon disulfide followed by methyla-
tion using methyl iodide. These compounds were further cyclised
in refluxing toluene using p-toluene sulphonic acid.
12a,b were obtained by acylation of 6a and further cyclization with
carbon disulfide in basic condition.
The 2-alkyl-1,3,4-oxadiazoles were synthesized by general
procedure (Scheme 4), wherein hydrazides 3a–b on reaction with
various acid chlorides or anhydrides in presence of triethylamine
as base yielded an open chain diamide intermediate, which
in situ on reaction with p-toluene sulphonyl chloride and triethyl-
amine underwent cyclization to give 2-alkyl-1,3,4-oxadiazoles
13a–16a. The esters 15a, 16a were converted into respective acids
17a and 18a by hydrolysis using lithium hydroxide monohydrate
in tetrahydrofuran, water mixture of solvent.
The 1,2,4-oxadiazoles were synthesized using another key
intermediate
phenyl-4,5-dihydro-1H-pyrazole-3-carboxamidine
5-(4-chloro-phenyl)-N-hydroxy-1-substituted-
6a,b. The
carboxamidines 6a,b were converted to different hetrocycles
(Scheme 3). 5-Hydroxy-1,2,4-oxadiazoles 11a,b were prepared by
reaction of ethyl chloroformate with 6a,b in pyridine and further
their cyclization in refluxing xylene. The 2-thiol-1,2,4-oxadiazoles
The 5-alkyl-1,2,4-oxadiazoles were synthesized by general
procedure (Scheme 5). The carboxamidine 6a on reaction with
various acid chlorides or anhydrides in pyridine at reflux gives

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D. V. Dekhane et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6527–6532
R1
N
O
NH2
NH
N
N
O
L
N
N
N
Cl
Cl
5a
13 a-16a
for 15a, 16a
M
R1
N
N
N
O
N
Cl
17a-18a
R1 = CH3 (13a), CF3 (14a), COOEt (15a), CH2COOEt (16a), COOH (17a), CH2COOH (18a)
Scheme 4. Reagent and conditions: (L) (1) R1COCl, Et3N, p-toluene sulfonyl chloride, 0–25 °C; (M) LiOH, THF, water, 25–30 °C.
O
OH
R1
N
N
N
N
N
NH2
N
N
Cl
N
Cl
19a-22a
6a
O for 21a & 22a
O
R1
N
N
N
N
Cl
23a-24a
Where R1 = CH3 (19a), CF3 (20a), COOEt (21a), CH2COOEt (22a), COOH (23a), CH2COOH (24a)
Scheme 5. Reagent and conditions: (N) R1COCl/(R1CO)2O, pyridine, heat 100 °C; (O) LiOH–H2O, THF, water, 25–30 °C.
cyclised 5-alkyl-1,2,4-oxadiazoles 19a–22a. The esters were con-
verted to respective acids 23a and 24a by treatment with LiOH
in tetrahydrofuran, water solvent mixture.
The 5-(4-chloro-phenyl)-N-hydroxy-1-substituted-phenyl-4,5-
dihydro-1H-pyrazole-3-carbonitriles 5a,b were converted to
tetrazole derivatives 25a,b by reaction of azidotrimethylsilane in
toluene using dibutyltin oxide as catalyst (Scheme 6). These were
further methylated to give 26a,b.
The experimental data of rat paw edema have revealed very
interesting result.14 It is observed form the data that, the various
synthesized analogs of 1,5-diaryl pyrazoline moiety like
1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole and tetrazole

D. V. Dekhane et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6527–6532
6531
N
N
N
N
N
N
N
NH
N
N
N
N
P
N
R
Q
Cl
N
R
N
R
Cl
Cl
25 a,b
5a,b
For a R=H and For b R=SO2NH2
26 a,b
Scheme 6. Reagents and conditions: (P) (1) TMSN3, DBTO, toluene, reflux; (Q) MeI, CsCO3, DMF, 25–30 °C.
have shown variety in activity from proinflammatory effect to
equipotent activity as compared to standard diclofenac sodium.
The results are given in Table 1
proinflammatory behavior, while the positioning of trifluoro-
methyl group present in 1,3,4-oxadiazole 14a may be considered
responsible for this effect. The most potent compound in the
1,3,4-heterodiazole series was 8a which has shown 32.74% inhibi-
tion against inflammation. Surprisingly, we have not noticed any
influence of introduction of sulfonamide group on 1-phenyl ring.
Among the different compounds in 1,3,4-heterodiazole series like
7b, 8b, 9b, 10b which are comprising of sulfonamide group, only
the compound 8b showed 36.76% protection.
The 1,2,4-oxadiazoles on the other hand showed much increase
in anti-inflammatory activity as compared to 1,3,4-heterodiazoles.
The compounds 11a, 11b, 12a, 12b were found to be less active as
compared to the standard diclofenac sodium. They have shown
32–48% protection against inflammation, wherein 12b which was
equipotent to that of standard. We have noticed very different
observation in case of alkyl substituent on 1,2,4-oxadiazoles like
19a, 20a, 21a, 22a, 23a, 24a having methyl, trifluoromethyl, ethyl
ester, acetic acid ethyl ester, carboxylic acid and acetic acid carbox-
ylic acid, respectively. Out of these compounds, 19a and 20a were
equipotent to the standard, showing 49.24% and 49.45% protection
against inflammation, respectively. Totally reverse trend was ob-
served as compared to proinflammatory behavior of 1,3,4-oxadiaz-
ole derivatives like 13a and 14a. The acids 23a and 24a have
confirmed that the free carboxylic acid substituent on heterodiaz-
oles was responsible for proinflammatory behavior of the
compounds.
In the 1,3,4-heterodiazoles series, compounds 7a, 8a, 9a, 10a
having hydroxyl, thiol, amino and thiomethyl substituent’s,
respectively, showed very low% protection against inflammation.
The 1,3,4-oxadiazoles 13a, 14a, 15a, 16a, 17a, 18a having alkyl
substituent’s like methyl, trifluoromethyl, ethyl ester, acetic acid
ethyl ester, carboxylic acid and acetic acid carboxylic acid showed
proinflammatory behavior. It was assumed that the free carboxylic
acid group present in 17a and 18a may be responsible for the
Table 1
Results of anti-inflammatory effect of pyrazoline derivatives against carrageenan
induced rat paw edema model in rats
Compound Test
% Rise in inflammation % Protection at
entry
compounds
at 4 ha
4th h
Control
STD
5a
5b
7a
7b
8a
8b
9a
Control
Diclofenac sodium
R = H
R = SO2NH2
R = H
R = SO2NH2
R = H, R’ = SH
R = SO2NH2
R = H
R = SO2NH2
R = H
R = SO2NH2
R = H
R = SO2NH2
R = H
84.22 6.23
41.32 6.15
51.01 2.35
42.38 1.12
63.78 3.25
54.42 4.11
56.64 1.08
53.23 4.23
80.42 2.62
68.74 2.36
74.24 1.25
62.36 4.42
56.69 3.65
45.32 2.59
50.10 1.65
43.10 3.25
70.36 7.25
123.74 7.25
80.43 3.96
99.05 2.68
0
50.93 7.18
39.43 6.02
49.67 1.23
24.26 4.10
35.38 5.56
32.74 1.85
36.76 3.12
4.50 4.14
18.38 2.32
11.84 3.07
26.12 2.98
32.68 1.97
46.18 3.11
40.51 5.23
48.82 3.36
16.45 8.06
ꢀ46.9 4.28
4.50 4.25
9b
Tetrazoles 25a, 25b, 26a, 26b were equipotent to the standard
diclofenac sodium, while the substitution of sulfonamide group
on para 1-phenyl ring of tetrazole analogue showed increase in
anti-inflammatory activity than that of their parent unsubstituted
compounds. The 25b was the most potent derivative among all the
compounds showing 54.58% protection at 4th hour. Nitriles
substituted compound 15a and 15b also showed good activity.
The compound 15b was found to possess 49.67% protection.
The four selected compounds were tested for their analgesic
activity by acetic acid induced writhing method.15 The compounds
19a, 20a, 25b and 26b showed mild analgesic activity. Out of four
tested compounds, 25b showed 36.08% decrease in writhings and
all other compound were ineffective in reducing the number of
writhings. The results are summarized in Table 2.
10a
10b
11a
11b
12a
12b
13a
14a
15a
16a
R = SO2NH2
R = H, Rl = CH3
R = H, Rl = CF3
R = H, Rl = COOEt
R = H,
ꢀ17.6 9.69
Rl = CH2COOEt
R = H, Rl = COOH
R = H, Rl = CH2COOH
R = H, Rl = CH3
R = H, Rl = CF3
R = H, R1 = COOEt
R = H,
17a
18a
19a
20a
21a
22a
100.47 6.39
77.93 2.18
42.75 6.04
42.57 4.71
67.08 2.35
58.16 3.75
ꢀ19.3 3.25
7.46 2.67
49.24 1.23
49.45 7.07
20.35 2.68
30.94 2.65
The % inhibition of COX-2 in human whole blood16 for the com-
pounds 19a, 20a, 25b, 26b ranged from 4% to 11% at 10 lM concen-
Rl = CH2COOEt
R = H, Rl = COOH
R = H, Rl = CH2COOH
R = H
R = SO2NH2
R = H
23a
24a
25a
25b
26a
26b
72.09 1.69
78.25 3.56
52.38 1.58
38.25 4.68
55.32 5.23
43.30 2.98
14.40 4.05
7.08 5.65
37.80 3.23
54.58 3.26
34.31 6.35
48.58 4.16
tration. The selected compounds showed insignificant COX-2
inhibition activity, these compounds might be acting by some dif-
ferent mechanism of action in vivo. The results are summarized in
Table 2
The four selected compounds were further evaluated for their
ulcerogenic potential in rats.17 Gross observation of the isolated
rat stomachs showed a normal stomach texture for all of the tested
R = SO2NH2
a
The results are expressed as means SEM (n = 6) following a 100 mg/kg oral
dose of the test compound.

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D. V. Dekhane et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6527–6532
Table 2
compounds 19a, 20a, 25b deserve further attention in order to de-
velop new leads in this series.
Results of analgesic effect of selected pyrazoline derivatives against acetic acid
induced writhing method and % inhibition of COX-2 at 10
l
M
Entry
Test
compound
No. of
writhings
% Inhibition
% Inhibition of
COX-2a
Supplementary data
19a
20a
25b
26b
Control
STD
R = H, Rl = CH3
R = H, Rl = CF3
R = SO2NH2
R = SO2NH2
Control
22.2 1.35
24.5 2.34
18.6 1.65
22.2 2.65
29.1 1.21
6.8 0.51
23.71 1.45
15.80 1.98
30.08 1.28
23.71 2.35
—
4
6
7
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.08.061.
11
0
References and notes
Diclofenac
76.63 0.88
99b
a
Data are indicated as percentage of inhibition at 10
Diclofenac was assayed at 20 lM for COX-2.
l
M mean of two tests.
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