Synthesis, anti-inflammatory and antimicrobial evaluation of novel 1-acetyl-3,5-diaryl-4,5-dihydro (1H) pyrazole derivatives bearing urea, thiourea and sulfonamide moieties

Article abstract of DOI:10.1016/j.bmcl.2012.08.118

A series of novel 1-acetyl-3-(3,4-dimethoxypheny)-5-(4-(3-(arylureido/ arylthioureido/arylsulfonamido) phenyl)-4,5-dihydropyrazole derivatives of biological interest have been prepared by sequential cyclization of 1-(4-nitrophenyl)-3-(3,4-dimethoxyphenyl)-pro-2-ene-1 with hydrazine hydrate, reduction followed by reaction of resulting amine with different arylisocyanates or arylisothiocyanates or arylsulfonyl chlorides. All the synthesized compounds (1-32) have been screened for their pro-inflammatory cytokines (TNF-α and IL-6) and antimicrobial activity (antibacterial and antifungal). Biological evaluation study showed, the compounds 4, 5, 9, 11, 14 and 16 found to have promising anti-inflammatory activity (up to 61-85% TNF-α and 76-93% IL-6 inhibitory activity) at concentration of 10 μM with reference to standard dexamethasone (76% TNF-α and 86% IL-6 inhibitory activity at 1 μM). Compounds 24, 26, 27, 28 and 29 exhibited promising antimicrobial activity at MIC values ranging from 70 to 10 μg/mL against all the selected pathogenic bacteria and fungi.

Full text of DOI:10.1016/j.bmcl.2012.08.118

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6611–6615
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, anti-inflammatory and antimicrobial evaluation of novel
1-acetyl-3,5-diaryl-4,5-dihydro (1H) pyrazole derivatives bearing urea,
thiourea and sulfonamide moieties
Ashish P. Keche a, Girish D. Hatnapure a, Rajesh H. Tale c, , Atish H. Rodge c, Vandana M. Kamble a,b,
⇑
⇑
a Department of Chemistry, Maharashtra Udaygiri Mahavidayla, Udgir, India
b Department of Chemistry, The Institute of Science Bombay, India
c Dendrimer and Bio-organic Chemistry Laboratory, School of Chemical Science, S.R.T.M. University, Nanded, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2012
Revised 31 July 2012
Accepted 30 August 2012
Available online 8 September 2012
A series of novel 1-acetyl-3-(3,4-dimethoxypheny)-5-(4-(3-(arylureido/arylthioureido/arylsulfonamido)
phenyl)-4,5-dihydropyrazole derivatives of biological interest have been prepared by sequential cycliza-
tion of 1-(4-nitrophenyl)-3-(3,4-dimethoxyphenyl)-pro-2-ene-1 with hydrazine hydrate, reduction
followed by reaction of resulting amine with different arylisocyanates or arylisothiocyanates or arylsulfo-
nyl chlorides. All the synthesized compounds (1–32) have been screened for their pro-inflammatory
cytokines (TNF-
study showed, the compounds 4, 5, 9, 11, 14 and 16 found to have promising anti-inflammatory activity
(up to 61–85% TNF- and 76–93% IL-6 inhibitory activity) at concentration of 10 M with reference to
standard dexamethasone (76% TNF- and 86% IL-6 inhibitory activity at 1 M). Compounds 24, 26, 27,
28 and 29 exhibited promising antimicrobial activity at MIC values ranging from 70 to 10 lg/mL against
all the selected pathogenic bacteria and fungi.
a and IL-6) and antimicrobial activity (antibacterial and antifungal). Biological evaluation
Keywords:
1-Acetyl-3,5-diaryl-4,5-dihydro (1H)
pyrazole
Urea
Thiourea and sulfonamide derivatives
Anti-inflammatory
Anti-bacterial
a
l
a
l
Ó 2012 Elsevier Ltd. All rights reserved.
Anti-fungal
The treatment of bacterial infections remains a challenging
therapeutic disaster because of emerging infectious diseases and
the increasing number of multidrug-resistant microbial pathogens.
Despite of many antibiotics and chemotherapeutics available, the
emergence of old and new antibiotic-resistant bacterial strains in
the last decades lead to a substantial need for new classes of
anti-microbial agents.
anticancer.16–18 In addition, pyrazole derivatives enclose urea,
thiourea and sulfonamide moieties have been reported as potent
anticancer agents,19,20 antiplatelet agents,21 inhibitors of p38
MAP kinase22 and also inhibit a growth of gram-positive bacteria.23
Moreover, the potential of 1-acetyl-3,5-diaryl-4,5-dihydro (1H)
pyrazole derivatives bearing urea, thiourea and sulfonamide moie-
ties as their anti-inflammatory activity against the pro-inflamma-
Several pyrazole derivatives possess important pharmacological
activities therefore they are useful materials in drug research. The
changes in their structure offered a high degree of diversity which
is useful for the development of new therapeutic agents. Among
the existing various pyrazole type derivatives ‘1-acetyl-3,5-dia-
ryl-4,5-dihydro (1H) pyrazole’ have been identified as one of the
most promising scaffold in medicinal chemistry, which have been
previously reported to exhibit a variety of biological activities such
as inhibitors of monoamine oxidases, swine kidney oxidase and
bovine serum amine oxidases,1,2 antibacterial activity,3–5 analge-
sic/anti-inflammatory/ulcerogenic/antipyretic,6–8 anti-helicobac-
tor pylori,9 antiviral,10 antimicrobial/antitubercular,11–13 kinesin
spindle protein (KSP) inhibitors,14 xanthine oxidase inhibitors,15
tory cytokines (TNF-a and IL-6) hitherto remained untested.
Non-steroidal anti-inflammatory drugs (NSAIDs) are therapeu-
tically important in the treatment of rheumatoid arthritis and in
various types of inflammatory conditions, but their therapeutic
utility has been limited due to their frequently observed gastroin-
testinal side effects. Thus, there is an urgent need of new target
which required the design and development of novel anti-inflam-
matory agents as an alternative to NSAIDs. Tumor necrosis factor
alpha (TNF-a) and interleukin-6 (IL-6) are the two important
multifunctional pro-inflammatory cytokines involved in the path-
ogenesis of autoimmune, inflammatory, cardiovascular, neurode-
generative and cancer diseases through a series of cytokine
signaling pathways.24,25 IL-6 contributes to the initiation and
extension of the inflammatory process and considered as a central
mediator in a range of inflammatory diseases but it has not re-
ceived the desired attention in drug discovery.26 TNF-
a and IL-6
⇑
Corresponding authors. Tel.: +91 22 22829293; fax: +91 22 22047962.
E-mail addresses: m.vandana248@gmail. com (V.M. Kamble), rkht_2008@
are thus pharmaceutically important molecular targets for the
treatment of the above-mentioned diseases.
rediffmail.com (R.H. Tale).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.08.118

6612
A. P. Keche et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6611–6615
Motivated by the afore-mentioned literature and in persistence
4,5-dihydropyrazole derivatives is illustrated in Scheme 1. The
reaction of 1 with hydrazine hydrate in acetic acid at 120 °C for
12 h afforded 1-acetyl-3-(3,4-dimetoxypheny)-5-(4-nitropheny)-
pyrazole 2 in 65% yield. The desired amino analog 3 to be used in
subsequent nucleophlic addition reaction was achieved by reduc-
tion of 2 using SnCl2ÁH2O in ethyl acetate at room temperature in
70% yield. Next the 1-acetyl-3,5-diaryl-4,5-dihydro (1H) pyrazole
derivatives bearing urea (4–13), thiourea (14–23) and sulfonamide
(24–32) moieties have been synthesized in good to high yields by
reacting 3 with appropriate arylisocyanate, arylisothiocyanate and
sulfonyl chloride respectively at room temperature under mild
conditions. The purity of compounds checked by TLC and HPLC.
of our earlier work on different heterocyclic derivatives bearing
urea, thiourea and sulfonamide moieties,27–30 we envision our
approach towards the design and synthesis of novel structurally
diverse series of 1-acetyl-3,5-diaryl-4,5-dihydro (1H) pyrazole
derivatives bearing urea, thiourea and sulfonamide moieties for
their anti-inflammatory and antimicrobial activity. Therefore, a
single molecule containing more than one pharmacophore each
with different mode of action could be beneficial for the treatment
of inflammation and microbial diseases.
Our synthetic strategy for novel 1-acetyl-3-(3,4-dimethoxyphe-
ny)-5-(4-(3-(arylureido/arylthioureido/arylsulfonamido) phenyl))-
O
O
O
N
N
a
O
O
NO2
O
NO2
1
2
b
O
N
N
O
O
NH2
3
e
c
O
O
O
O
N
N
N
N
d
O
O
O
S
O
R
N
H
N
H
N
H
R
O
R = 24) 2-CH3, 5F 25) 4-Br
R = 4) 2-F 5) 2-F, 3-Cl 6) 2-CH3, 5-F
26) 2-Br, 4-CF3 27) 2-Cl, 4-CF3
28) 4-CF3 29) 4-OCF3
30) 4-CH3 31) 3, 4-OCH3
32) 2-CN
7) 3,4-CH3 8) 2-Cl, 4-CF3 9) 2-OCF3
10) 4-OCF3 11) 2-CF3 12) 4-CF3
13) 4-CH(CH3)2
O
O
N
N
O
S
R
N
H
N
H
R = 14) 2-F 15) 4-F 16) 4-Cl
17) 4-CH3 18) 2-OCH3 19) 3-OCH3
20) 4-OCH3 21) 2-CF3 22) 3-CF3
23) 4-CN
Reagents and Conditions :- a) NH2NH2.H2O, CH3COOH, 120 °C, 12h, b) SnCl2.H2O/EtOAc, r.t. 12h,
c) Isocyanate/THF, r.t. 1-2h, d) Isothiocyanate/THF, r.t. 1-2h,
e) Sulf onyl chlorides/DCM, Et3N, r.t. 1-2h.
Scheme 1. Synthesis of 1-acetyl-3-(3,4-dimethoxypheny)-5-(4-(3-(arylureido/arylthioureido/arylsulfonamido) phenyl)-4,5-dihydropyrazole derivatives.

A. P. Keche et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6611–6615
6613
Spectral data 1H NMR, 13C NMR, IR HRMS and MS of the newly syn-
thesized compounds 1–32 were in full agreement with their pro-
posed structures.
diaryl-4,5-dihydro (1H) pyrazole scaffold is of immense impor-
tance in order to have potent anti-inflammatory agent.
It can be seen that anti-inflammatory activity can be attributed
to the presence of urea or thiourea functionality in pyrazole scaf-
fold as the most potent compounds 4, 5, 9, 11, 14, 16 and 21 are
the pyrazole derivatives bearing either urea or thiourea moiety
and similarly as our previously reported work27 here also none of
the members from the corresponding sulfonamide series
(compounds 24–32) was found to be a potent anti-inflammatory
agent. It is to be noted that the nature of the substituent present
on benzene ring of urea or thiourea terminus found to have strong
influence to the activity and which can be confirmed by the fact
that the presence of lipophilic H-bond acceptor type functionalities
like F, CF3 or OCF3 at ortho position and Cl at para position leading
to the moderately potent anti-inflammatory compounds 4, 5, 9, 11,
14 and 16. Also the position of the substituent on the urea or thio-
urea terminal ring has dramatic effect on the said activity. Accord-
ingly the compound 9 with OCF3 and 11 with CF3 at ortho position
The synthesized compounds 1–32 have been evaluated for in-
vitro anti-inflammatory activity against the pro-inflammatory
cytokines (TNF-
a and IL-6) by TNF-a
and IL-6 inhibition assay31
and antimicrobial activity against various gram-positive, gram-
negative bacteria and fungal strains by using an agar well diffusion
method with little modifications.32
SAR of 1-acetyl-3,5-diaryl-4,5-dihydro (1H) pyrazole deriva-
tives for their anti-inflammatory, antibacterial and antifungal
activity have been presented in Tables 1–3. Some interesting trend
was observed since the lipophilicity as well as nature and position
of the substituent presents on benzene ring of urea, thiourea and
sulfonamide terminus affecting the biological activity of the syn-
thesized analogues.
As from Table 1, compound 4 and 14 exhibited the good TNF-
a
(85% and 78%) and IL-6 (93% and 84%) inhibitory activity as com-
pared to the standard dexamethasone but at higher concentration
on benzene ring of urea terminus exhibited 58–61% TNF-a and 75–
(10
agents while compounds 5, 9, 11, 16 and 21 exhibited moderate
inhibitory activity (68–40% TNF- and 80–65% IL-6) and other
compounds exhibited low or no activity at the same level of con-
centration (10 M). It is to be noted that all these active com-
l
M) and found to be moderately potent anti-inflammatory
80% IL-6 inhibitory activity and proved to be a moderately potent
anti-inflammatory agent, while the presence of same substituent
at para position on benzene ring of urea terminus leading to com-
pound 10 and 12 found to have very low TNF-a/IL-6 inhibitory
activity. Similarly in thiourea series the compound 14 with F at
a
l
pounds viz 4, 5, 9, 11, 14 and 16 are either urea or thiourea
derivatives, unfortunately only compound 27 from sulfonamide
derivatives having Cl at ortho and CF3 at para position on the ben-
zene ring of sulfonamide terminus was found to be moderately
ortho position on benzene ring of thiourea terminus exhibited
78% TNF-
a and 84% IL-6 inhibitory activity and proved to be a
moderately potent anti-inflammatory agent, while the presence
of same substituent at para position on benzene ring of thiourea
effective against TNF-a (38%) or IL-6 (55%) and rest are almost very
low to no active. This finding implicates that the presence of spe-
cial chemical space viz urea or thiourea in the novel 1-acetyl-3,5-
Table 2
Antibacterial activity of novel 1-acetyl-3-(3,4-dimethoxypheny)-5-(4-(3-(arylureido/
arylthioureido/arylsulfonamido) phenyl)-4,5-dihydropyrazole derivatives. (MICa val-
ues lg/mL)
Table 1
Compounds
Gram-positive
Gram-negative
Anti-inflammatory activity of novel 1-acetyl-3-(3,4-dimethoxypheny)-5-(4-(3-(ary-
lureido/arylthioureido/arylsulfonamido) phenyl)-4,5-dihydropyrazole derivatives
Staphylococcus
aureus
Bacillus
subtilis
Escherichia
coli
Salmonella
typhimurium
Compounds
% Inhibition at 10 lM
1
2
3
4
5
6
7
8
—
90
—
60
90
—
90
50
—
80
90
—
80
65
90
45
90
90
—
45
40
25
60
15
30
55
80
—
90
90
—
80
90
—
TNF-
a
IL-6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
0
0
0
85
61
28
18
3
58
8
61
3
11
78
3
68
0
0
11
3
40
0
0
0
0
0
38
0
0
0
0
93
76
31
30
8
75
11
80
21
16
84
10
76
3
—
—
—
35
55
30
75
25
30
80
80
—
—
—
55
45
—
60
40
20
90
25
40
80
—
90
—
—
90
65
—
80
60
45
90
40
55
90
—
—
—
—
90
35
—
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
—
90
70
20
95
—
30
20
30
10
10
35
15
75
90
90
15
0
26
10
65
8
21
0
0
8
55
0
30
0
—
—
—
60
55
30
10
15
70
20
90
—
35
20
65
15
10
55
45
90
90
65
15
45
40
30
10
15
25
65
90
90
90
20
8
0
0
80
Ciprofloxacin 20
0
32
10
76
31
84
No activity was observed up to 200
l
g/mL.
Dexamethasone (1 lM)
a
Values are the average of three reading.

6614
A. P. Keche et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6611–6615
Table 3
Surprisingly compound 12 bearing CF3 at para position on benzene
ring of urea terminus found to be comparable active against Esch-
erichia coli while moderately active against other tested strains.
Concerning the antifungal activity data represented in Table 3,
compounds 26, 27 and 28 from sulfonamide series exhibited com-
parable or higher activities while compounds 10, 12, 13 and 25
showed moderate or comparable antibacterial activities than
miconazole according to the strain tested. Other compounds (23,
24 and 29) exhibited lower activities and rest are inactive. Com-
pound 26 is 1.5-fold more potent against Aspergillus niger and
Fusarium solani and twofold more potent against Aspergillus flavus
while comparable against Candida albicans while compound 27 is
1.5- to 1.3-fold more potent against Aspergillus flavus and Fusarium
solani respectively while comparable against Aspergillus niger.
Compound 28 bearing CF3 at para position on benzene ring of sul-
fonamide terminus is 1.5- to 2-fold more potent against Fusarium
solani and Aspergillus flavus respectively. Surprisingly compound
12 bearing CF3 at para position on benzene ring of urea terminus
found to be 1.3-fold more potent against Candida albicans and
Aspergillus flavus while comparable against Fusarium solani.
From the above activity data we bring to a close that, the com-
pounds 26 and 27 are the most potent antimicrobial agents. The
high potency or comparable activity of compounds 25, 26, 27, 28
and 29 may be attributed to the presence of lipophilic H-bond
acceptor type group’s like Br, Cl, CF3, and OCF3 at ortho or para po-
sition on benzene ring of sulfonamide functionality. This is further
supported by the fact that the presence of group’s like Cl, CF3, OCF3
or OCH3 at ortho or para position on benzene ring of urea and thio-
urea terminus leading to compounds 8, 10, 12, 13 and 20 showed
moderate to comparable antimicrobial activity. No activity was ob-
Antifungal activity of novel 1-acetyl-3-(3,4-dimethoxypheny)-5-(4-(3-(arylureido/
arylthioureido/arylsulfonamido) phenyl)-4,5-dihydropyrazole derivatives. (MICa val-
ues lg/mL)
Compounds Candida
Aspergillus
niger
Fusarium
solani
Aspergillus
flavus
albicans
1
2
3
4
5
6
7
8
90
90
—
80
90
—
90
55
40
25
80
15
20
80
—
—
90
—
80
—
—
—
—
—
90
—
—
90
—
80
—
—
90
20
30
20
80
15
20
90
—
—
—
90
20
60
20
75
15
20
90
90
90
—
35
75
35
90
25
40
—
—
—
—
—
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Miconazole
90
—
90
80
90
—
90
—
—
95
90
—
75
0
90
—
95
—
—
—
—
—
—
55
30
25
20
40
35
45
70
—
20
60
15
10
15
20
25
90
—
20
20
15
10
10
10
35
65
90
80
15
35
20
40
10
15
10
20
90
—
served in rest of the compounds up to concentration of 200 lg/mL.
It is clear from results (Tables 2 and 3) that the antibacterial
activity SAR of 1-acetyl-3,5-diaryl-4,5-dihydro (1H) pyrazole deriv-
atives strongly correlates with their antifungal activity SAR. To our
surprise, none of the most active anti-inflammatory agents 4, 5, 9,
11, 14 and 16 was found to be active antibacterial or antifungal
agent screened but importantly which indicates the low toxicity
associate with them and should be considered as ideal anti-inflam-
matory agents.
In conclusion, we have synthesized and evaluated the anti-
inflammatory and antimicrobial activity for structurally diverse
1-acetyl-3-(3,4-dimethoxypheny)-5-(4-(3-(arylureido/arylthioure-
ido/arylsulfonamido) phenyl)-4, 5-dihydropyrazole derivatives.
The compounds 4, 5, 9, 11, 14 and 16 having functionalities like
F, CF3 or OCF3 at ortho position and Cl at para position on the ben-
zene ring of urea or thiourea terminus found to be favorable for the
anti-inflammatory activity while compounds 24, 26, 27, 28 and 29
having functionalities like F, Cl, Br, CF3, and OCF3 at ortho or para
position on benzene ring of sulfonamide terminus found to be
effective antimicrobial agents. The lipophilicity as well as nature
and position of the substituent present on benzene ring of urea,
thiourea and sulfonamide terminus affecting the biological activity
of the synthesized analogues.
65
20
40
15
70
20
No activity was observed up to 200
lg/ml.
a
Values are the average of three reading.
terminus leading to compound 15 found to have very low TNF-a/
IL-6 inhibitory activity. Until now, though we have not a concrete
evidence in hand in support of the actual role of urea or thiourea
moieties on this activity, we can at least speculate that the H-bond
donor ability of the urea or thiourea (not present in sulfonamide
framework) along with the lipophilicity and electronic effect of
ortho or para substituent might be responsible for their anti-
inflammatory activity.
The antimicrobial activity data is represented in Tables 2 and 3.
As shown in our results, some analogues of this series were found
to have even more potency than the standard drugs while some of
them have comparable potency.
As can be seen the antibacterial activity data represented in Ta-
ble 2, the compounds 26 and 27 from sulfonamide series exhibited
higher antibacterial activities against each strain tested while com-
pounds 10, 12, 24 and 29 showed moderate or comparable antibac-
terial activities than ciprofloxacin according to the strain tested.
Other compounds (13, 23 and 25) exhibited lower activities and
rest are inactive. Compound 26 bearing Br at ortho and CF3 at para
position on benzene ring of sulfonamide terminus is twofold more
potent against Staphylococcus aureus and Salmonella typhimurium
while 1.5-fold more potent against Escherichia coli and comparable
against Bacillus subtilis while compound 27 bearing Cl at ortho and
CF3 at para position on benzene ring of sulfonamide terminus is
1.5-fold more potent against Bacillus subtilis and Escherichia coli
while 1.3-fold more potent against Staphylococcus aureus and
Salmonella typhimurium. Compounds 29 bearing OCF3 at para
position on benzene ring of sulfonamide terminus showed compa-
rable activities against Staphylococcus aureus and Escherichia Coli.
Acknowledgment
We are grateful to the Department of Chemistry, Maharashtra
Udaygiri Mahavidayla, Udgir for all type support to succeed our
research.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
08.118.

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