Synthesis and evaluation of antibacterial and antifungal activities of new (Z)-3-bromo-4-(1,3-diaryl-1H-pyrazol-4-yl)but-3-en-2-ones and 4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1,3-diaryl-1H-pyrazoles

Article abstract of DOI:10.1007/s00044-013-0480-0

Bromination of 4-(1, 3-diaryl-1H-pyrazol-4-yl) but-3-en-2-ones, triggered by a combination of potassium bromide and cerium(IV) ammonium nitrate in a biphasic system consisting of water and dichloromethane furnishes the corresponding monobromo compounds 2 directly, instead of the expected dibromo compounds. The α-bromo compounds 2 were utilized as efficient precursors for the synthesis of several bipyrazolyl derivatives, 4-(3-methyl-1-phenyl-1H- pyrazol-5-yl)-1, 3-diaryl-1H-pyrazoles (3). All the α-bromoenones 2 and bipyrazoles 3 are new compounds and their identity was established by m.p., spectral and analytical data. The new products 2 and 3 were tested for their in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis (Gram positive), Escherichia coli, and Pseudomonas aeruginosa (Gram negative) and antifungal activity against Aspergilus flavus and Aspergillus niger. The antimicrobial activity of the tested compounds is compared with the commercially available antibiotic, ciprofloxacin and antifungal agent, fluconazole.

Full text of DOI:10.1007/s00044-013-0480-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:4715–4726
DOI 10.1007/s00044-013-0480-0
ORIGINAL RESEARCH
Synthesis and evaluation of antibacterial and antifungal activities
of new (Z)-3-bromo-4-(1,3-diaryl-1H-pyrazol-4-yl)but-3-en-2-ones
and 4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1,3-diaryl-1H-
pyrazoles
•
Rashmi Pundeer Sushma Vijay Kiran
•
•
•
Chetan Sharma K. R. Aneja Om Prakash
•
Received: 16 August 2012 / Accepted: 9 January 2013 / Published online: 22 January 2013
Ó Springer Science+Business Media New York 2013
Abstract Bromination of 4-(1, 3-diaryl-1H-pyrazol-4-yl)
but-3-en-2-ones, triggered by a combination of potassium
bromide and cerium(IV) ammonium nitrate in a biphasic
system consisting of water and dichloromethane furnishes
the corresponding monobromo compounds 2 directly,
instead of the expected dibromo compounds. The a-bromo
compounds 2 were utilized as efficient precursors for the
synthesis of several bipyrazolyl derivatives, 4-(3-methyl-1-
phenyl-1H-pyrazol-5-yl)-1, 3-diaryl-1H-pyrazoles (3). All
the a-bromoenones 2 and bipyrazoles 3 are new com-
pounds and their identity was established by m.p., spectral
and analytical data. The new products 2 and 3 were tested
for their in vitro antibacterial activity against Staphylo-
coccus aureus, Bacillus subtilis (Gram positive), Esche-
richia coli, and Pseudomonas aeruginosa (Gram negative)
and antifungal activity against Aspergilus flavus and
Aspergillus niger. The antimicrobial activity of the tested
compounds is compared with the commercially available
antibiotic, ciprofloxacin and antifungal agent, fluconazole.
Introduction
Carbon-heteroatom (C-X) bond forming reactions are of
rattling importance in the domain of organic synthesis. The
function of most of the organic compounds is derived from
the presence of heteroatoms. For example, almost all nat-
ural products contain ether, ester or ketone C–O bonds;
pharmaceuticals and conductive polymers often contain
amine C–N bonds; and the heterocycles having C–N, C–O,
and C–S bonds in the ring structure are found in all
applications of chemistry (Hartwig, 2008). Recently, cer-
ium(IV) ammonium nitrate [Ce(NH4)4(NO3)6] has been
employed for affecting a wide range of chemical trans-
formations (Chen et al., 2011; Kesselring et al., 2008; Nair
and Deepthi, 2007; Chu et al., 2007; Dhakshinamoorthy,
2005; Nair et al., 2004; Nair et al., 2003; Nair et al., 1997a,
1997b) specifically C–C and C-X bond forming reactions
(Hwu and King, 2001; Nair et al., 1997a, 1997b; Ho,
1973). Cerium(IV) ammonium nitrate is proved to be a
selective, mild, and easy-to-handle mediator for the facile
formation of C-X bonds by the addition of soft anions to
alkenes. Since an early report by Trahanovsky and Robbins
on the cerium(IV) ammonium nitrate mediated addition of
azides to alkenes in 1971, a large number of C-X bond
forming reactions have been accomplished by employing
the catalytic amounts of cerium(IV) ammonium nitrate. It
has efficiently been applied for thiocsyanations, selenocy-
anations, and azidations of various olefins (Nair and
George, 2000; Nair et al., 1999; Nair and Nair, 1998;
Trahanovsky and Robbins, 1971). Similar strategy has been
applied for the C–Br bond formation (bromination) of
alkenes without the direct use of bromine (Nair et al.,
2001). Bromination of a,b-unsaturated carbonyl com-
pounds is quite interesting as different brominated products
can be obtained depending upon the reagents and the
Keywords Bromination ꢀ Cerium(IV) ammonium nitrate ꢀ
Bipyrazoles ꢀ Antibacterial activity ꢀ Antifungal activity
R. Pundeer (&) ꢀ Sushma ꢀ V. Kiran
Department of Chemistry, Kurukshetra University, Kurukshetra
136119, India
e-mail: dr.rashmipundeer@gmail.com
C. Sharma ꢀ K. R. Aneja
Department of Microbiology, Kurukshetra University,
Kurukshetra 136119, India
O. Prakash
Institute of Pharmaceutical Sciences, Kurukshetra University,
Kurukshetra 136119, India
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Med Chem Res (2013) 22:4715–4726
reaction conditions (Dieter et al., 1996; Nardo et al., 1995;
Guaciaro et al., 1978; Awang and Wolfe, 1969; Cromwell
and Benson 1955; Nishimura 1953; Southwick et al.,
1950). The a-bromo derivatives of a,b-unsaturated ketones
exhibit high reactivity toward the nucleophilic reagents and
are advantageous as valuable synthons for the preparation
of various biologically active heterocycles and analogs of
natural compounds (Ngatimin et al., 2009; Hayashi et al.,
2005; Bovonsombat et al., 2007; Rho et al., 2002; Smith
et al., 1982).
pyrazol-4-yl) but-3-ene-2-one. The 1H NMR spectrum of 2a
exhibited two characteristic singlets at d 9.14 and 8.1 for
b-proton and pyrazolyl proton, respectively. In the mass
spectrum, high abundant molecular ion peaks at 367.1
[M] and 369.1 [M ? 2] in 1:1 ratio confirmed the presence
of one bromine in the product 2a.
To access the generality of this reaction, different b-(1,
3-diarylpyrazolyl)-a,b-unsaturated ketones (1b–j) were
subjected to similar conditions and in all the cases, corre-
sponding monobromo compounds 2b–j were obtained in
high yields (87–95 %).
The development of novel antimicrobial agents is a
critical worldwide healthcare need because of the high
incidence of bacterial infections and the emergence of
antimicrobial resistance among bacteria (Courvalin and
Cuot, 2001; Page et al., 2009). Structural modification of
antimicrobial drugs to which resistance has developed has
proven to be an effective means of extending the lifespan
of antimicrobial agents (Jeu et al., 2003). 1-Arylpyrazole
motif is known to exhibit an array of bioactive properties
(Chang et al., 2013; Lee et al., 2003; Sakya and Rast, 2003;
Diaz et al., 2012). For example, 4-Amino-N-(1-phenyl-1H-
pyrazol-5-yl) benzenesulfonamide (sulfaphenazole) is a
potent antibacterial drug (Ha-Duong et al., 2001).
Recently, the significance of 1,3-diarylpyrazole derivatives
as antibacterial and antifungal agents have been elaborated
in some reports from our research group (Pundeer et al.,
2009; Prakash et al., 2008; Prakash et al., 2009a; Prakash
et al., 2009b; Prakash et al., 2010). Considering all the
above facts it was considered worthwhile, in the present
study, to synthesize some new bromo derivatives of the
b-pyrazolyl-a,b-unsaturated ketones, 4-(1,3-diaryl-4-pyr-
azolyl)but-3-en-2-ones (1) which seem to be valuable
precursors for the synthesis of several new pyrazolyl het-
erocycles of potential medicinal importance.
It is noteworthy to mention here that cerium(IV)
ammonium nitrate mediated bromination of a,b-unsatu-
rated ketones, which in general, results in the addition of
bromine to the double bond to give a,b-dibromo ketones
(Nair et al., 2001). The corresponding a-bromoenones can
then be obtained by the subsequent dehydrobromination of
the dibromo derivatives (Khurana and Sehgal, 1996;
Dauben and Warshawsky, 1988; Kowalski et al., 1982;
Guaciaro et al., 1978; Dunn et al., 1968). Fortunately, in
the present study, a-bromoenones were obtained directly
without the intermediacy of the corresponding dibromo
compounds. The reason for the one-step formation of the
monobromo products 2, inexplicably, may be the influence
of the basic nature of the pyrazole moiety to effect the
addition–elimination reaction.
It is pertinent that the two-phase, H2O–CH2Cl2 solvent
system was necessary for the reaction to occur. The reac-
tion success in two phases might be attributed to the fact
that the bromine radicals generated by cerium(IV) ammo-
nium nitrate were predominantly distributed in the organic
phase along with the pyrazolyl butenone, thus facilitating
the bromination, whereas the oxidant remained in the
aqueous phase; its limited contact with the substrate min-
imized the possibility of unwanted side reactions (Nair
et al., 2001).
Results and discussion
The new polyfunctional bromo products 2 were specu-
lated to play an important role in the synthetic organic and
medicinal chemistry. They can undergo different transfor-
mations with various nucleophiles and can produce a
plethora of new pyrazolyl heterocyclic derivatives of
potential pharmacological interest. Restricting ourselves to
the study of pyrazole core, an effort was made in the
present study to utilize the bromo compounds as the facile
precursors for the synthesis of some new bipyrazoles of
biological importance. In this regard, the (Z)-3-bromo-4-
(1,3-diaryl-1H-pyrazol-4-yl)but-3-en-2-ones (2) were made
to react with phenylhydrazine. Initially, taking the com-
pound 2a with PhNHNH2, the reaction was allowed to
proceed in AcOH (Scheme 2). A single product appeared
in TLC after 10 h of refluxing. The reaction mixture was
poured in ice-cold water. The solid thus separated out was
filtered, washed with water, dried and crystallized from
Chemistry
The compound, 4-(1,3-diphenyl-1H-pyrazol-4-yl)but-3-
ene-2-one (1a) was used as a model to perform the initial
studies. The enone 1a was made to react with a combination
of potassium bromide and cerium(IV) ammonium nitrate in
the solvent, H2O–CH2Cl2 while stirring at ambient tem-
perature (Scheme 1). A facile reaction occurred in 7 h and
thin layer chromatography indicated the formation of single
product. After completion of the reaction, the mixture was
washed with brine solution, extracted with dichlorometh-
ane, and dried over sodium sulfate. A monobromo product,
(Z)-3-bromo-4-(1,3-diphenyl-1H-pyrazol-4-yl) but-3-ene-
2-one (2a) was obtained, unexpectedly, instead of the
dibromo compound, 3,4-dibromo-4-(1,3-diphenyl-1H-
123

Med Chem Res (2013) 22:4715–4726
4717
Scheme 1 Cerium(IV)
ammonium nitrate mediated
bromination of 4-(1,3-diaryl-
1H-pyrazol-4-yl)but-3-ene-2-
ones(2a-j)
Ar
Ar
N N
Ar
N N
N N
Ar'
Ar'
Ar'
(i)
H
H
Br
Br
H
Br
C
H3C
O
C
C
H3C
O
H3C
O
1
2
(i) Cerium (IV) ammonium nitrate/potassium bromide
H2O-CH2Cl2
Ar
Ar’
C6H5
C6H5
2a
2b
2c
2d
2e
2f
C6H5
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
C6H5
C6H5
C6H5
C6H5
4-NO2C6H4
4-OCH3C6H4
C6H5
C6H5
2g
2h
2i
4-NO2 C6H4
4-NO2 C6H4
4-NO2 C6H4
4-FC6H4
4-OCH3C6H4
2j
ethanol. The pure product 3a was fully characterized with
the help of proper data. The loss of peak at 1690 cm-1 in
the IR spectrum and at d 191.89 in the 13C NMR spectrum
due to C=O gave a useful indication for the formation of
expected product, 4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-
1,3-diphenyl-1H-pyrazole (3a). In the NMR spectrum, two
singlets appeared at d 6.27 and 7.84 due to two pyrazolyl
protons along with the accurate number of aromatic pro-
tons. Also, the mass spectrum showed moleculer ion peak
at 377 (M ? 1) as a base peak confirming the presence of
the bipyrazole 3a. The reaction of a-halo-a,b-unsaturated
ketone with hydrazine is a well-known reaction and the
plausible mechanism is as shown in Scheme 2. Some new
bipyrazoles were prepared accordingly in good yields
(75–85 %) by adopting the similar procedure and were
utilized for biological screening.
and analytical (C, H, N) data. The starting pyrazolyl enones
1 needed for the present study were prepared from the
reaction of 4-formylpyrazoles with acetone (Bratenko
et al., 2008). The formylpyrazoles were, in turn, prepared
by the Villsmeir-Haack reaction of the corresponding
hydrazones (Kira et al., 1969, Scheme 3).
Biological results
All the twenty new products, the bromo compounds 2 and
the bipyrazoles 3 were tested for their in vitro antibacterial
activity against the Gram-positive bacteria, Staphylococcus
aureus (MTCC 96) and Bacillus subtilis (MTCC 121);
Gram-negative bacteria, Escherichia coli (MTCC 1652)
and Pseudomonas aeruginosa (MTCC 741); and the yeasts
Aspergillus niger and Aspergillus flavus. Standard antibi-
otic ciprofloxacin was used for the comparison of the
The identity of the new compounds 2 and 3 were
1
established by m.p., spectral (IR, NMR, and 13C, mass)
123

4718
Med Chem Res (2013) 22:4715–4726
Ar
Ar
N N
N N
Ar'
PhNHNH2
Ar'
CH C C CH3
Br
Ph
N
N
,reflux
AcOH
O
CH3
3
2
Plausible Mechanism
Ar
Ar
N N
Ar
N N
Ar'
H
N N
Ar'
PhNHNH2
-H2O
Ar'
Ph
H
N
N
H C
C
C CH3
N
Br
CH C C CH3
Br
CH3
Br
O
NH Ph
2
-HBr
Ar
N N
Ar'
Ph
N
N
CH3
3
Ar
Ar’
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3a
3b
3c
3d
3e
3f
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
4-NO2C6H4
4-OCH3C6H4
C6H5
3g
3h
3i
4-NO2 C6H4
4-NO2 C6H4
4-NO2 C6H4
4-FC6H4
4-OCH3C6H4
3j
Scheme 2 Synthesis of 4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1,3-diaryl-1H-pyrazoles(3a-j)
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Med Chem Res (2013) 22:4715–4726
4719
Ar
O
N N
ArNHNH2
EtOH
POCl3
DMF
NNHAr
CH3
Ar'
Ar'
CH3
Ar'
CHO
Mechanism
NNHAr
CH2
H
N
NNHAr
CH2CH=NMe2
O
NNHAr
ArNHNH2
EtOH
DMF-POCl3
Me2N=CHCl
Ar'
Ar'
H
Ar'
CH3
Ar'
CH2
Ar
N NHAr
Ar
Ar
N N
N N
N N
hydrolysis
NMe2
NMe2
Ar'
CH=NMe2
Ar'
Ar'
H
CH
Ar'
CHO
CH=NMe2
NMe2
Scheme 3 Villsmeir-Haack reaction in the synthesis of 1,3-diaryl-4-formylpyrazoles
antibacterial activity and fluconazole was used for the
comparison of the antifungal activity of the new com-
pounds. Positive controls produced significantly sized
inhibition zones against the tested bacteria and fungi;
however, negative control produced no observable inhibi-
tory effect against any of the test organism as shown in
Table 1.
none of the tested compound was found to be effective
against the Gram-negative bacteria.
Antifungal activity
A careful analysis of the percentage mycelial growth
inhibition revealed that all the newly synthesized com-
pounds inhibited the growth of both the fungal strains
(Table 3; Fig. 2). Compound 2d displayed maximum
inhibition against the fungi, A. flavus (58.8) and A. niger
(55.5). The title compound 2e also exhibited good inhibi-
tion against the fungi, A. flavus (55.5) and A. niger (53.3).
On comparing with Fluconazole, it was found that all the
tested compounds showed more than 55 % antifungal
activity.
Antibacterial activity
All the tested compounds displayed good inhibitory
activity against both the Gram-positive bacteria. The
compounds 2 showed zone of inhibition ranging between
14.6 and 21.6 mm and the bipyrazoles 3 showed the zone
from 13.6 to 20.6 mm for S. aureus and B. subtilis. On the
basis of zone of inhibition produced, compounds 2d and 3d
were found to be most effective with maximum values of
inhibition, i.e., 21.3 and 19.3 mm, respectively, against
S. aureus. Compounds 2e and 3d showed maximum anti-
bacterial activity against B. subtilis, with values 21.6 and
20.6 mm, respectively, for the inhibited zone.
Conclusion
Efficient bromination of 4-(1,3-diaryl-1H-pyrazol-4-yl)but-
3-ene-2-one (1a–j) is achieved using a combination of
cerium(IV) ammonium nitrate and potassium bromide in
two-phase solvent system of H2O:CH2Cl2 and several new
monobromo derivatives i.e., (Z)-3-bromo-4-(1,3-diaryl-1H-
pyrazol-4-yl)but-3-en-2-ones (2a–j) are obtained directly in
good yields (87–95 %). The new a-bromoenones 2 are
found to be valuable precursors for the synthesis of some
new bipyrazole compounds, 4-(3-methyl-1-phenyl-1H-
pyrazol-5-yl)-1,3-diaryl-1H-pyrazoles (3a–j). All the new
Minimum inhibitory concentration (MIC) of the com-
pounds 2 and 3 was determined which showed activity in
primary screening and was found to be 32-256 lg/ml.
Compounds 2d and 2e had the lowest MIC (32 lg/ml)
against S. aureus while 2e and 3d showed the lowest MIC
(32 lg/ml) against B. subtilis. Overall, among all the tested
compounds, 2e was found to be the best antibacterial
compound with MIC 32 lg/ml (Table 2; Fig. 1). However,
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Med Chem Res (2013) 22:4715–4726
Table 1 In vitro antibacterial activity of compounds (2a–j) and
(3a–j) through agar well diffusion method
Table 2 Minimum inhibitory concentration (MIC) (lg/ml) of com-
pounds by macrodilution method
Compounds
Diameter of growth of inhibition zone (mm)a
Compounds
S. aureus
B. subtilis
S. aureus B. subtilis E. coli P. aeruginosa
2a
128
64
128
128
128
64
2b
2a
2b
2c
2d
2e
2f
15.3
18.3
14.6
21.3
20.6
16.0
15.6
19.3
16.6
15.6
16.3
14.6
14.3
19.3
15.0
17.6
15.3
13.6
13.6
15.3
16.6
17.0
16.3
19.3
21.6
17.6
16.3
17.3
17.3
16.0
15.6
16.3
16.3
20.6
16.3
18.6
14.0
14.3
15.6
14.0
24.0
–
–
2c
256
32
–
–
2d
–
–
2e
32
32
–
–
2f
128
128
64
128
128
128
128
128
128
128
128
32
–
–
2g
–
–
2h
2g
2h
2i
–
–
2i
128
128
128
256
256
64
–
–
2j
–
–
3a
2j
–
–
3b
3a
3b
3c
3d
3e
3f
–
–
3c
–
–
3d
–
–
3e
128
64
128
64
–
–
3f
–
–
3g
128
256
256
256
5
256
256
128
128
5
–
–
3h
3g
3h
3i
–
–
3i
–
–
3j
–
–
Ciprofloxacin
3j
–
–
Ciprofloxacin 26.0
25.0
25.3
– Represents no activity
a
Values, including diameter of the well (8 mm), are means of three
replicates
compounds, 2 and 3, possess variable activity against the
bacterial strains, S. aureus and B. subtilis. The compound 2e
is found to be best showing the least MIC value (32 lg/ml).
All the products of the present study are found to be active
(more than 55 %) against the fungal strains A. flavus and
A. niger, and compound 2d displays best antifungal activity
against both the fungal strains.
Further experiments dealing with exploring the synthetic
utility of the new a-bromo-b-pyrazolyl-a,b-unsaturated
ketones 2 with different N, S, and O nucleophiles are
underway. Attempts are also going on to synthesize new
dibromo and tribromo derivatives of b-pyrazolyl-a,b-
unsaturated ketones 1 to evaluate their synthetic and
pharmacological potentiality.
Fig. 1 Comparison of the MIC of title compounds with Ciprofloxacin
(up to MIC 256 lg/ml)
shifts were expressed in ppm units downfield from an
internal TMS standard. Mass spectra were recorded at
2500 eV (ESI-source) using a Water’s Q-TOF microin-
strument. All chemicals were purchased from commercial
suppliers and were used without further purification.
Various 4-formylpyrazoles and 4-(1,3-diaryl-1H-pyra-
zol-4-yl)but-3-en-2-ones (1a–j) needed for the present
study were prepared according to the literature procedure
(Kira et al., 1969; Bratenko et al., 2008).
Experimental
Melting points were taken in open capillaries and are
uncorrected. IR spectra were recorded on Perkin-Elmer
1800 FT-IR spectrophotometer. The 1H NMR spectra were
recorded on Bruker 300 MHz instrument. The chemical
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Med Chem Res (2013) 22:4715–4726
4721
added followed by aqueous solution of cerium(IV)
ammonium nitrate (2.3 mmol). The reaction mixture was
stirred for about 7 h at room temperature. After completion
of the reaction as indicated by TLC, the reaction mixture
was washed with NaCl solution, extracted with dichloro-
methane, and dried over sodium sulfate. The solid so
obtained was recrystallized with ethanol to give 2a. The
other monobromo derivatives (2b–j) were prepared fol-
lowing the similar procedure.
Table 3 Antifungal activity of the prepared compounds through
poisoned food method
Compound No.
Mycelial growth inhibition (%)
A. flavus
A. niger
2a
48.8
52.2
45.5
58.8
55.5
52.2
44.4
53.3
50
51.1
51.1
50
2b
2c
2d
55.5
53.3
48.8
45.5
51.1
48.8
45.5
44.4
44.4
48.8
55.5
43.3
51.1
41.1
43.3
44.4
46.6
81.1
2e
2f
Characterization data of (Z)-3-bromo-4-(1,3-diaryl-1H-
2g
pyrazol-4-yl)but-3-en-2-one (2)
2h
2i
(Z)-3-Bromo-4-(1,3-diphenyl-1H-pyrazol-4-yl)but-3-en-2-
2j
50
one (2a)
3a
46.6
45.5
51.1
52.2
44.4
53.3
44.4
45.5
47.7
44.4
77.7
cm-1):
3b
Mp 155–156 °C; Yield 93 %; IR (mmax
,
1690 cm-1(C=O); H NMR d (CDCl3, 300 MHz): 2.53 (s,
3H, COCH3), 8.11 (s, 1H, pyrazole), 9.14 (s, 1H,
CH=CBr), 7.33–7.86 (m, 10H, aromatic); 13C NMR
(CDCl3, 75 MHz): 26.44, 115.81, 119.70, 122.85, 127.55,
128.68, 128.90, 129.01, 129.07, 129.62, 131.85, 132.22,
139.44, 155.57, 191.89; MS: m/z 367.1 (M), 369.1
[M ? 2]; Elemental analysis for C19H15BrN2O: % Calcd.
(Found) C, 62.14 (62.07); H, 4.12 (4.10); N, 7.63 (7.57).
1
3c
3d
3e
3f
3g
3h
3i
3j
Fluconazole
(Z)-3-Bromo-4-(1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)but-3-
en-2-one (2b)
Mp 158–159 °C; Yield 95 %; IR (mmax
,
cm-1):
1670 cm-1(C=O); H NMR d (CDCl3, 300 MHz): 2.46 (s,
3H, CH3), 2.53 (s, 3H, COCH3), 8.11 (s, 1H, pyrazole),
9.12 (s, 1H, CH=CBr), 7.30–7.86 (m, 9H, aromatic); 13C
NMR d (CDCl3, 75 MHz): 21.36, 26.41, 115.76, 119.69,
122.23, 127.47, 128.63, 128.94, 129.45, 129.60, 132.49,
139.00, 139.47, 155.65, 191.86; MS: m/z 381 [M], 383
[M ? 2]; Elemental analysis for C20H17BrN2O: % Calcd.
(Found) C, 63.00 (62.93); H, 4.49 (4.40); N, 7.35 (7.30).
1
(Z)-3-Bromo-4-(3-(4-chlorophenyl) 1-phenyl-1H-pyrazol-
4-yl)but-3-en-2-one (2c)
Fig. 2 In vitro antifungal assay of tested compounds as compared to
commercial antifungal Fluconazole
Mp 168–170 °C; Yield 94 %; IR (mmax
,
cm-1):
1690 cm-1(C=O); H NMR d (CDCl3, 300 MHz): 2.54 (s,
3H, COCH3), 8.08 (s, 1H, pyrazole), 9.11 (s, 1H,
CH=CBr), 7.40–7.84 (m, 9H, aromatic); 13C NMR d
(CDCl3, 75 MHz): 26.39, 115.80, 119.68, 122.80, 127.59,
128.72, 128.90, 129.0, 129.09, 129.71, 131.80, 132.20,
139.49, 155.63, 191.90; MS: m/z 401.02 [M], 403.02
[M ? 2], 405.02 [M ? 4]; Elemental analysis for
C19H14BrClN2O: % Calcd. (Found) C, 56.81 (56.75); H,
3.51 (3.47); N, 6.97 (6.90).
1
Synthesis of (Z)-3-bromo-4-(1,3-diaryl-1H-pyrazol-4-
yl)but-3-en-2-one (2)
Bromination with cerium(IV) ammonium nitrate, potassium
bromide, H2O:CH2Cl2
General procedure To the dichloromethane (10 ml) solu-
tion of 1a (1 mmol), potassium bromide (2.2 mmol) was
123

4722
Med Chem Res (2013) 22:4715–4726
(Z)-3-Bromo-4-(3-(4-bromophenyl)-1-phenyl-1H-pyrazol-
[M ? 2]. Elemental analysis for C20H17BrN2O2: % Calcd.
4-yl)but-3-en-2-one (2d)
(Found) C, 60.47 (60.42); H, 4.31 (4.26); N, 7.05 (6.99).
Mp 158–160 °C; Yield 89 %; IR (mmax
,
cm-1):
(Z)-3-Bromo-4-(1-(4-nitrophenyl)-3-phenyl-1H-pyrazol-4-
1666 cm-1(C=O); H NMR d (CDCl3, 300 MHz): 2.54 (s,
3H, COCH3), 8.05 (s, 1H, pyrazole), 9.11 (s, 1H,
CH=CBr), 7.34–7.83 (m, 9H, aromatic); 13C NMR d
(CDCl3, 75 MHz): 26.36, 115.82, 119.64, 122.85, 127.62,
128.79, 128.81, 129.01, 129.02, 129.65, 131.72, 132.15,
139.55, 155.69, 191.92; Elemental analysis for
C19H14Br2N2O: % Calcd. (Found) C, 51.15 (51.10); H,
3.16 (3.11); N, 6.28 (6.22).
1
yl)but-3-en-2-one (2h)
Mp 202–204 °C; Yield 87 %; IR (mmax
,
cm-1):
1690 cm-1(C=O); H NMR d (CDCl3, 300 MHz): 2.55 (s,
3H, COCH3), 9.22 (s, 1H, CH=CBr), 7.47–8.43 (m, 10H,
aromatic); 13C NMR d (CDCl3, 75 MHz): 29.61, 96.60,
113.88, 114.39, 118.18, 119.39, 123.40, 125.49, 128.88,
129.30, 130.29, 143.60, 145.61, 151.50, 160.30; Elemental
analysis for C19H14BrN3O3: % Calcd. (Found) C, 55.36
(55.30); H, 3.42 (3.37); N, 10.19 (10.13).
1
(Z)-3-Bromo-4-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-
4-yl)but-3-en-2-one (2e)
(Z)-3-Bromo-4-(3-(4-fluorophenyl)-1-(4-nitrophenyl)-1H-
Mp 180–182 °C; Yield 91 %; IR (mmax
,
cm-1):
pyrazol-4-yl)but-3-en-2-one (2i)
1674 cm-1(C=O); H NMR d (CDCl3, 300 MHz): 2.54 (s,
3H, COCH3), 8.05 (s, 1H, pyrazole), 9.11 (s, 1H,
CH=CBr), 7.21–7.84 (m, 9H, aromatic); 13C NMR d
(CDCl3, 75 MHz): 26.57, 115.75, 115.84, 116.13, 119.69,
122.32, 127.63, 127.96, 128.66, 129.64, 130.79, 130.90,
131.56, 139.37, 154.61, 161.68, 164.97, 191.95; Elemental
analysis for C19H14BrFN2O: % Calcd. (Found) C, 59.24
(59.19); H, 3.66 (3.62); N, 7.27 (7.24).
1
Mp 199–201 °C; Yield 88 %; IR (mmax
,
cm-1):
1682 cm-1(C=O); H NMR d (CDCl3, 300 MHz): 2.56 (s,
3H, COCH3), 9.20 (s, 1H, CH=CBr), 7.62–8.43 (m, 9H,
aromatic); 13C NMR d (CDCl3, 75 MHz): 29.65, 96.66,
113.90, 114.36, 118.12, 119.41, 123.49, 125.52, 128.80,
129.25, 130.33, 143.67, 145.60, 151.55, 160.32; Elemental
analysis for C19H13BrFN3O3; % Calcd. (Found) C, 53.04
(52.99); H, 3.05 (2.99); N, 9.77 (9.73).
1
(Z)-3-Bromo-4-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-
(Z)-3-Bromo-4-(3-(4-methoxyphenyl)-1-(4-nitrophenyl)-
yl)but-3-en-2-one (2f)
1H-pyrazol-4-yl)but-3-en-2-one (2j)
Mp 210–212 °C; Yield 88 %; IR (mmax
,
cm-1):
Mp 215–217 °C; Yield 88 %; IR (mmax
,
cm-1):
1
1
1674 cm-1(C=O); H NMR d (CDCl3, 300 MHz): 2.57 (s,
3H, COCH3), 9.12 (s, 1H, CH=CBr), 7.44–8.24 (m, 10H,
aromatic); 13C NMR d (CDCl3, 75 MHz): 26.49, 115.72,
115.84, 116.09, 119.60, 122.22, 127.59, 127.90, 128.49,
129.68, 130.67, 130.85, 131.59, 139.42, 154.67, 161.79,
164.89, 191.97; Elemental analysis for C19H14BrN3O3: %
Calcd. (Found) C, 55.36 (55.32); H, 3.42 (3.38); N, 10.19
(10.13).
1680 cm-1(C=O); H NMR d (CDCl3, 300 MHz): 2.56 (s,
3H, COCH3), 3.90 (s, 3H, OCH3), 9.20 (s, 1H, CH=CBr),
7.62–8.43 (m, 9H, aromatic); 13C NMR d (CDCl3,
75 MHz): 29.69, 55.35, 96.58, 113.96, 114.35, 118.09,
119.43, 123.45, 125.48, 128.84, 129.20, 130.27, 143.61,
145.58, 151.52, 160.33; Elemental analysis for
C20H16BrN3O4; % Calcd. (Found) C, 54.31 (54.28); H,
3.65 (3.59); N, 9.50 (9.46).
Synthesis of 4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-
1,3-diaryl-1H-pyrazole
(Z)-3-Bromo-4-(3-(4-methoxyphenyl)-1-phenyl-1H-
pyrazol-4-yl)but-3-en-2-one (2g)
General procedure An equimolar solution of 2a and
phenylhydrazine in AcOH was refluxed for about 10–12 h.
The reaction completion was monitored by TLC. The
reaction mixture was poured in ice-cold water. The solid
thus separated out was filtered, washed with water, and
dried. The product was recrystallized from ethanol. The
brown-colored crystals of 3a were obtained. All other
pyrazolyl compounds 3b–j were prepared similarly.
Mp 189–190 °C; Yield 94 %; IR (mmax
,
cm-1):
1682 cm-1(C=O); H NMR d (CDCl3, 300 MHz): 2.53 (s,
3H, COCH3), 3.90 (s, 3H, OCH3), 8.09 (s, 1H, pyrazole), 9.11
(s, 1H, CH=CBr), 7.05–7.85 (m, 9H, aromatic); 13C NMR d
(CDCl3, 75 MHz): 26.45, 55.40, 114.38, 115.68, 119.66,
122.10, 124.26, 127.45, 128.59, 129.59, 130.33, 132.43,
139.46, 155.43, 160.33, 191.90; MS: m/z 397.1 [M], 399.1
1
123

Med Chem Res (2013) 22:4715–4726
4723
4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1,3-diphenyl-1H-
3-(4-Fluorophenyl)-4-(3-methyl-1-phenyl-1H-pyrazol-5-
pyrazole (3a)
yl)-1-phenyl-1H-pyrazole (3e)
1
Mp 164 °C; Yield 79 %; H NMR d (CDCl3, 300 MHz,):
Mp 160–162 °C; Yield 82 %; 1H NMR d (CDCl3,
300 MHz,): 2.41 (s, 3H, CH3), 6.28 (s, 1H, pyrazole), 7.88
(s, 1H, pyrazole), 6.90–7.73 (m, 14H, aromatic); 13C NMR
d (CDCl3, 75 MHz,): 13.67, 109.09, 110.89, 118.81,
122.22, 126.09, 126.91, 127.95, 128.50, 128.82, 129.50,
130.28, 131.45, 134.69, 139.58, 139.69, 149.63, 150.21;
Elemental analysis for C25H19FN4; % Calcd. (Found) C,
76.12 (76.10); H, 4.86 (4.82); N, 14.20 (14.17).
2.41 (s, 3H, CH3), 6.27 (s, 1H, pyrazole), 7.84 (s, 1H,
pyrazole), 7.16–7.73 (m, 15H, aromatic); 13C NMR d
(CDCl3, 75 MHz,): 13.68, 108.88, 111.75, 118.94, 124.46,
126.76, 126.81, 127.44, 127.76, 128.02, 128.26, 128.55,1
29.48, 132.36, 135.01, 139.62, 139.82, 149.47; Mass: 377
[M ? 1]; Elemental analysis for C25H20N4; % Calcd.
(Found) C, 79.76 (79.72); H, 5.35 (5.31); N, 14.88 (14.86).
4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-phenyl-3-p-tolyl-
1H-pyrazole (3b)
4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-3-(4-nitrophenyl)-
1-phenyl-1H-pyrazole (3f)
Mp 170–172 °C; Yield 85 %; 1H NMR d (CDCl3,
300 MHz,): 2.40 (s, 3H, CH3), 6.25 (s, 1H, pyrazole), 7.78
(s, 1H, pyrazole), 7.07–7.71 (m, 14H, aromatic); 13C NMR
d (CDCl3, 75 MHz,): 13.67, 21.26, 30.89, 108.94, 111.57,
118.91, 124.49, 126.65, 126.84, 127.33, 127.73, 128.55,
128.45, 128.98, 129.45, 129.49, 135.17, 137.85, 139.66,
139.87, 149.43, 151.40; Mass: 391.3 [M ? 1]; Elemental
analysis for C26H22N4; % Calcd. (Found) C, 79.97 (79.92);
H, 5.68 (5.63); N, 14.35 (14.33).
Mp 166–168 °C; Yield 76 %; 1H NMR d (CDCl3,
300 MHz,): 2.41 (s, 3H, CH3), 6.27 (s, 1H, pyrazole), 7.84
(s, 1H, pyrazole), 7.16–7.73 (m, 14H, aromatic); 13C NMR
d (CDCl3, 75 MHz,): 13.67, 109.11, 112.57, 119.11,
123.51, 124.18, 126.98, 127.40, 127.87, 128.35, 128.65,
129.66, 134.00, 138.77, 139.30, 139.51, 147.21, 148.77,
149.84; Elemental analysis for C25H19N5O2; % Calcd.
(Found) C, 71.25 (71.23); H, 4.54 (4.51); N, 16.62 (16.58).
3-(4-Chlorophenyl)-4-(3-methyl-1-phenyl-1H-pyrazol-5-
3-(4-Methoxyphenyl)-4-(3-methyl-1-phenyl-1H-pyrazol-5-
yl)-1-phenyl-1H-pyrazole (3c)
yl)-1-phenyl-1H-pyrazole (3g)
Mp 176–178 °C; Yield 83 %; 1H NMR d (CDCl3,
300 MHz,): 2.41 (s, 3H, CH3), 6.28 (s, 1H, pyrazole), 7.87
(s, 1H, pyrazole), 7.16–7.72 (m,14H, aromatic); 13C NMR
d (CDCl3, 75 MHz,): 13.67, 108.89, 111.81, 118.95,
122.20, 124.32, 126.91, 126.95, 127.90, 128.55, 128.93,
129.50, 131.28, 131.40, 134.59, 139.49, 139.66, 149.62,
150.14; Elemental analysis for C25H19ClN4; % Calcd.
(Found) C, 73.08 (73.05); H, 4.66 (4.63); N, 13.64 (13.66).
Mp 188–190 °C; Yield 84 %; 1H NMR d (CDCl3,
300 MHz,): 2.41 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 6.26 (s,
1H, pyrazole), 7.80 (s, 1H, pyrazole), 6.79–7.70 (m, 14H,
aromatic); 13C NMR d (CDCl3, 75 MHz,): 13.61, 109.09,
112.54, 119.07, 123.58, 124.25, 126.91, 127.33, 127.88,
128.31, 128.67, 129.76, 134.08, 138.70, 139.31, 139.47,
147.18, 148.76, 149.81; Mass: 407 [M ? 1]; Elemental
analysis for C26H22N4O; % Calcd. (Found) C, 76.83
(76.81); H, 5.46 (5.42); N, 13.78 (13.76).
3-(4-Bromophenyl)-4-(3-methyl-1-phenyl-1H-pyrazol-5-
yl)-1-phenyl-1H-pyrazole (3d)
4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-(4-nitrophenyl)-
3-phenyl-1H-pyrazole (3h)
1
Mp 174 °C; Yield 80 %; H NMR d (CDCl3, 300 MHz,):
Mp 208–210 °C; Yield 78 %; 1H NMR d 2.41 (s, 3H,
CH3), 6.28 (s, 1H, pyrazole), 7.80 (s, 1H, pyrazole),
7.16–7.79 (m, 14H, aromatic); 13C NMR d (CDCl3,
75 MHz,): 13.67, 109.11, 112.54, 119.12, 123.53, 124.17,
126.99, 127.42, 127.85, 128.33, 128.67, 129.66, 134.00,
138.79, 139.30, 139.51, 147.25, 148.75, 149.84; Elemental
analysis for C25H19N5O2; % Calcd. (Found) C, 71.25
(71.22); H, 4.54 (4.50); N, 16.62 (16.59).
2.41 (s, 3H, CH3), 6.27 (s, 1H, pyrazole), 7.87 (s, 1H,
pyrazole), 7.16–7.78 (m,14H, aromatic); 13C NMR d
(CDCl3, 75 MHz,): 13.67, 108.91, 111.80, 118.98, 122.23,
124.38, 126.93, 126.95, 127.92, 128.59, 128.97, 129.54,
131.31, 131.40, 134.61, 139.49, 139.68, 149.60, 150.16;
Mass: 455.2 [M], 457.2 [M ? 2], 214, 216; Elemental
analysis for C25H19BrN4; % Calcd. (Found) C, 65.94
(65.90); H, 4.21 (4.18); N, 12.30 (12.28).
123

4724
Med Chem Res (2013) 22:4715–4726
3-(4-Fluorophenyl)-4-(3-methyl-1-phenyl-1H-pyrazol-5-
bacterium and kept for 15 min for adsorption. Using sterile
cork borer of 8 mm diameter, wells were bored into the
seeded agar plates and these were loaded with a 100 ll
volume with concentration of 2.0 mg/ml of each compound
reconstituted in the dimethylsulfoxide (DMSO). All the
plates were incubated at 37 °C for 24 h. Antibacterial
activity of each synthetic compound was evaluated by
measuring the zone of growth inhibition against the test
organisms with zone reader (Hi Antibiotic zone scale).
DMSO was used as a negative control whereas ciproflox-
acin was used as a positive control. This procedure was
performed in three replicate plates for each organism
(Ahmed and Beg, 2001; Andrews, 2001).
yl)-1-(4-nitrophenyl)-1H-pyrazole (3i)
Mp 232–234 °C; Yield 77 %; 1H NMR d (CDCl3,
300 MHz,): 2.42 (s, 3H, CH3), 6.31 (s, 1H, pyrazole), 8.0
(s, 1H, pyrazole), 6.92–8.43 (m,13H, aromatic); 13C NMR
d (CDCl3, 75 MHz,): 13.68, 108.80, 111.71, 118.97,
124.40, 126.75, 126.81, 127.40, 127.78, 128.02, 128.25,
128.55, 129.50, 132.36, 135.07, 139.64, 139.82, 149.50;
Elemental analysis for C25H18FN5O2; % Calcd. (Found) C,
68.33 (68.31); H, 4.13 (4.10); N, 15.94 (15.91).
3-(4-Methoxyphenyl)-4-(3-methyl-1-phenyl-1H-pyrazol-5-
yl)-1-(4-nitrophenyl)-1H-pyrazole (3j)
Determination of MIC of chemically synthesized
compounds
Mp 228–230 °C; Yield 76 %; 1H NMR d (CDCl3,
300 MHz,): 2.41 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 6.30 (s,
1H, pyrazole), 7.94 (s, 1H, pyrazole), 6.91–8.40 (m, 13H,
aromatic); 13C NMR d (CDCl3, 75 MHz,): 13.65, 109.09,
112.57, 119.11, 123.53, 124.17, 126.95, 127.40, 127.88,
128.34, 128.60, 129.66, 134.01, 138.72, 139.31, 139.49,
147.20, 148.77, 149.81; Elemental analysis for
C26H21N5O3; % Calcd. (Found) C, 69.17 (69.14); H, 4.69
(4.65); N, 15.51 (15.49).
MIC is the lowest concentration of an antimicrobial com-
pound that will inhibit the visible growth of a microor-
ganism after overnight incubation.
MIC of the various compounds against bacterial strains
was tested through a macrodilution tube method as rec-
ommended by NCCLS. In this method, various test con-
centrations of chemically synthesized compounds were
made from 256 to 0.5 lg/ml in sterile tubes No. 1–10.
100 ll sterile Mueller–Hinton Broth (MHB) was poured in
each sterile tube followed by addition of 200 ll test com-
pound in tube 1. Two-fold serial dilutions were carried out
and to each tube, 100 ll of standard inoculum
(1.5 9 108 cfu/ml) was added. Ciprofloxacin was used as
control. Turbidity was observed after incubating the inoc-
ulated tubes at 37 °C for 24 h.
Biological assay
Test microorganisms
Total six microbial strains were selected on the basis of
their clinical importance in causing diseases in humans.
Two Gram-positive bacteria (S. aureus MTCC 96 and
B. subtilis MTCC 121); two Gram-negative bacteria
(E. coli MTCC 1652 and P. aeruginosa MTCC 741); and
two fungi, A. niger and A. flavus, the ear pathogens isolated
from the patients of Kurukshetra (Aneja et al., 2010), were
used in the present study for evaluation of antimicrobial
activity of the chemical compounds. All the cultures were
procured from Microbial Type Culture Collection
(MTCC), IMTECH, Chandigarh. The bacteria were sub-
cultured on Nutrient agar whereas fungi on Sabouraud,
dextrose agar.
In vitro antifungal activity
The antifungal activity of the synthesized chemical com-
pounds was evaluated by poison food technique. The molds
were grown on Sabouraud dextrose agar (SDA) at 25 °C for
7 days and used as inocula. 15 ml of molten SDA (45 °C)
was poisoned by the addition of 100 ll volume of each
compound having concentration of 4.0 mg/ml, reconsti-
tuted in the DMSO, poured into a sterile Petri plate, and
allowed to solidify at room temperature. The solidified
poisoned agar plates were inoculated at the center with
fungal plugs (8 mm diameter), obtained from the actively
growing colony and incubated at 25 °C for 7 days. DMSO
was used as the negative control whereas fluconazole was
used as the positive control. The experiments were per-
formed in triplicates. Diameter of the fungal colonies was
measured and expressed as percent mycelial inhibition
determined by applying the formula given by Al-Burtamani
et al., 2005.
Antibacterial activity
The antibacterial activity of chemical compounds was
evaluated by the agar well diffusion method. All the cul-
tures were adjusted to 0.5 McFarland standard, which is
visually comparable to a microbial suspension of approx-
imately 1.5 9 108 cfu/ml. 20 ml of Mueller–Hinton agar
medium was poured into each Petri plate and the agar
plates were swabbed with 100 ll inocula of each test
123

Med Chem Res (2013) 22:4715–4726
4725
Dunn GL, DePasquo VJ, Hoover JRE (1968) Synthesis of pentacy-
clo[4.3.0.02, 5.02.8.04, 7]nonane (homocubane) and some of its
derivatives. J Org Chem 33:1454–1459
Guaciaro MA, Wovkulich PM, Smith AB (1978) An efficient
synthesis of a-substituted-a,b-ketones employing a versatile
latent a-ketovinyl anion equivalent. Tetrahedron Lett 47:4661–
4664
Inhibition of myelial growth % ¼ ðdc ꢁ dtÞ=dc ꢂ 100
dc is average diameter of fungal colony in negative control
plates; dt is average diameter of fungal colony in experi-
mental plates.
Acknowledgments We are thankful to Council of Scientific and
Industrial Research (CSIR), New Delhi, India, for the award of senior
research fellowship to Sushma to carry out this work.
Ha-Duong NT, Dijols S, Marques-Soares C, Minoletti C, Dansette
PM, Mansuy D (2001) Synthesis of sulfaphenazole derivatives
and their use as inhibitors and tools for comparing the active
sites of human liver cytochromes P450 of the 2C subfamily.
J Med Chem 44:3622–3631
Hartwig JF (2008) Carbon–heteroatom bond formation catalysed by
organometallic Complexes. Nature 18:455
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