Synthesis of 1,3,5-trisubstituted pyrazoline nucleus containing compounds and screening for antimicrobial activity

Article abstract of DOI:10.1007/s00044-011-9871-2

In this study, a novel series of heterocyclic compounds containing pyrazoline nucleus has been synthesized. The compounds were synthesized in two steps. Chalcone was synthesized in the first step by Claisen-Schmidt reaction, using 1-Acetylnaphthalene and

Full text of DOI:10.1007/s00044-011-9871-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3376–3381
DOI 10.1007/s00044-011-9871-2
ORIGINAL RESEARCH
Synthesis of 1,3,5-trisubstituted pyrazoline nucleus containing
compounds and screening for antimicrobial activity
•
Manish Agrawal Pankaj Kumar Sonar
•
Shailendra K. Saraf
Received: 9 August 2011 / Accepted: 1 November 2011 / Published online: 17 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract In this study, a novel series of heterocyclic
compounds containing pyrazoline nucleus has been syn-
thesized. The compounds were synthesized in two steps.
Chalcone was synthesized in the first step by Claisen-
Schmidt reaction, using 1-acetylnaphthalene and p-nitro
benzaldehyde as reactants. In the second step, the chalcone
was cyclized in an acidic medium with some hydra-
zine derivatives to form pyrazolines. All the compounds
were characterized by physical, chromatographic, spectro-
scopic, and elemental analysis and evaluated in vitro for
antimicrobial activity against nine microorganisms by cup-
plate method. The minimum inhibitory concentration of all
the compounds was determined by tube dilution method.
All the compounds exhibited higher antibacterial activity
as compared to the antifungal activity. Compound 5g
(3-Naphthalen-1-yl-1-(2-nitro-phenyl)-5-(4-nitro-phenyl)-
4,5-dihydro-1H-pyrazole) exhibited maximum antibacte-
rial and antifungal activity and may be designated as the
most potent member of the series, with 2-nitrophenyl group
at N-1 position of the 2-pyrazoline ring.
unique position due to dominant applications. Pyrazolines
have played a crucial role in the development of theory in
heterocyclic chemistry and are also used extensively as
agents in organic synthesis. A classical synthesis of these
compounds involves the base-catalyzed aldol condensa-
tion reaction of aromatic ketones and aldehydes to give a,
b-unsaturated ketones (chalcones), which undergo a sub-
sequent cyclization reaction with hydrazines affording
2-pyrazolines. In this reaction, hydrazones are formed as
intermediates which can be subsequently cyclized to
2-pyrazolines in the presence of a suitable cyclizing
reagent like acetic acid (Azarifar and Ghasemnejad,
2003). Electron-rich nitrogen heterocyclics play an
important role in diverse biological activities. Pyrazoline
nucleus is a privileged pharmacophore for various phar-
macological activities, such as antimicrobial (Ozdemir
et al., 2007a; Azarifar and Shaebanzadeh, 2002; Ashok
and Holla, 2006; Kumar et al., 2005; Abunada et al.,
2008; Abdel-Wahab et al., 2009; Rai et al., 2009; Prakash
et al., 2009), analgesic and anti-inflammatory (Sahu et al.,
2008; Venkataraman et al., 2010; Girisha et al., 2010;
Bashir et al., 2011), antinociceptive (Kaplancikli et al.,
2009), antidepressant and anticonvulsant (Ozdemir et al.,
2007b; Palaska et al., 2001) and anti-amoebic (Bhat
et al., 2009). Recently, 5-(substituted) aryl-3-(3-coumari-
nyl)-1-phenyl-2-pyrazolines have been utilized as versatile
templates for synthesizing compounds that act as potential
anti-inflammatory and analgesic agents (Khode et al.,
2009). Some pyrazoline derivatives have shown antican-
cer activity against leukemia, melanoma, lung, colon,
CNS, ovarian, renal, prostate, and breast cancer cell lines
(Havrylyuk et al., 2009; Rostom et al., 2011; Havrylyuk
et al., 2011). Thus, pyrazoline moiety has attracted con-
siderable interest in the development of biologically
active compounds.
Keywords Pyrazoline Á Chalcone Á
Antimicrobial activity Á Claisen-Schmidt reaction
Introduction
Heterocyclic compounds are well known for their wide
range of biological applications and pyrazolines occupy a
M. Agrawal Á P. K. Sonar Á S. K. Saraf (&)
Faculty of Pharmacy, Northern India Engineering College,
Sec-II, Dr. Akhilesh Das Nagar, Faizabad Road,
Lucknow 227105, Uttar Pradesh, India
e-mail: dirpharmniec@gmail.com
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Med Chem Res (2012) 21:3376–3381
Materials and methods
Chemistry
3377
time period as given in the Scheme 2. The progress of the
reaction was monitored by TLC. The reaction mixture was
cooled and poured into ice water. Crude product was fil-
tered, washed with cold water and recrystallized with
chloroform.
All the chemicals used in this study were procured as LR
grade reagents from S. D. Fine Chem. Ltd., Mumbai and
Sigma–Aldrich Chemie, Germany. The melting points were
determined by open capillary method and are uncorrected.
Purity of the compounds was checked by TLC on precoated
silica gel G plates using chloroform: methanol, ethyl acetate:
n-hexane and diethyl ether: n-hexane as solvent systems. The
IR spectra were recorded on Shimadzu FTIR-8400S and
Perkin Elmer Spectrum RX1 FTIR spectrophotometers.
Mass spectra were recorded on JEOL-Accu TOF JMS-
T100LC spectrometer and Micromass Quattro II triple
quadrupole mass spectrometer. NMR spectra were recorded
on Bruker DRX-300 spectrometer and elemental analysis
was performed on Elemental Vario EL III analyzer from
Central Drug Research Institute, Lucknow, India.
3-Naphthalen-1-yl-5-(4-nitro-phenyl)-4,5-dihydro-1H-
pyrazole (5a)
A red solid, yield 47.35%, melting range 104–108°C; IR
(KBr) 1660.60, 1514.02, 1344.29, and 1108.99 cm-1
;
1HNMR (CDCI3, d, ppm): 7.26–8.25 (m, 11H), 7.0 (s, H),
4.02 (s, H) 2.54 (s, 2H); ms: m/z 360.09 (100). Anal. Calcd.
for C19H15N3O2: C, 71.91; H, 4.76; N, 13.24. Found: C,
70.92; H, 4.82; N, 12.18.
3-Naphthalen-1-yl-5-(4-nitro-phenyl)-1-phenyl-4,5-
dihydro-1H-pyrazole (5b)
A yellow solid, yield 48.34%, melting range 132–136°C;
1-Naphthalen-1-yl-3-(4-nitro-phenyl)-propenone (3)
IR (KBr) 1647.10, 1107.06, 1508.23, and 1340.43 cm-1
;
1HNMR (CDCI3, d, ppm): 6.5–8.4 (m, 16H), 4.4 (s, H),
1.25 (d, 2H); ms: m/z 393.10 (100). Anal. Calcd. for
C25H19N3O2: C, 76.32; H, 4.87; N, 10.68. Found: C, 75.46;
H, 4.50; N, 10.63.
A solution of sodium hydroxide (0.5 g, 0.012 mol), water
(5 ml), and ethanol (3 ml) was poured over 1-acetylnaphtha-
lene (1.519 ml, 0.01 mol) in a 50 ml round bottom flask and
the reaction mixture was stirred by a magnetic stirrer at room
temperature. Then, 4-nitro benzaldehyde (1.51 g, 0.01 mol)
was added to the above mixture and a thick paste was formed
after 6 h. The progress of the reaction was monitored by TLC.
The reaction mixture was kept in a refrigerator overnight. The
product was filtered and washed with cold water, followed by
cold ethanol and recrystallized fromchloroform (Furnisset al.,
2007) as pale yellow solid (Scheme 1), yield 73.06%, melting
range 114–118°C; IR (KBr) 1658.67, 1589.23, 1514.02, and
1340.43 cm-1; ms: m/z 304.10 (100).
3-Naphthalen-1-yl-1,5-bis-(4-nitro-phenyl)-4,5-dihydro-
1H-pyrazole (5c)
A dark brown solid, yield 13.74%, melting range
174–178°C; IR (KBr) 1593.09, 1517.87, 1342.36 and
1099.35 cm-1
;
1HNMR (CDCI3, d, ppm): 7.40–8.45
(m, 16H), 2.06 (s, 2H), 2.74 (s, H); ms: m/z 438 (20). Anal.
Calcd. for C25H18N4O4: C, 68.49; H, 4.14; N, 12.78.
Found: C, 71.62; H, 3.95; N, 12.23.
General procedure for the synthesis of pyrazoline
derivatives (5a–e)
3-Naphthalen-1-yl-5-(4-nitro-phenyl)-4,5-dihydro-
pyrazole-1-carbothioic acid amide (5d)
An equimolar mixture of (3) and hydrazine derivatives in
4–6 ml of glacial acetic acid was refluxed for the respective
A yellow solid, yield 57.84%, melting range 157–161°C;
IR (KBr) 1660.90, 1517.90, 1343.40, and 1105.40 cm-1
;
O
Claisen-Schmidt
reaction
C
CH CH
NO2
H
C
O
NO2
1.NaOH
2.C2H5OH
COCH3
1-acetylnaphthalene
(1)
4-nitro benzaldehyde
(2)
1-Naphthalen-1-yl-3-(4-nitro-phenyl)
-propenone
(3)
Scheme 1 Synthesis of chalcone (3)
123

3378
Med Chem Res (2012) 21:3376–3381
R
O
N
N
H
C
CH CH
NO2
AcOH
RNHNH2
H
H
Reflux in oil bath
NO2
(4a-g)
1-Naphthalen-1-yl-3-(4-nitro-phenyl)
-propenone
(5a-g)
(3)
Compounds
R
Refluxing time
Solvent system for TLC
Chloroform:MeOH (99:1)
Chloroform:MeOH (99:1)
n-Hexane:Ethyl acetate (60:40)
Chloroform:MeOH (99:1)
n-Hexane:Diethyl ether (60:40)
Chloroform:MeOH (99:1)
Chloroform:MeOH (99:1)
5a-
5b-
5c-
5d-
5e-
5f-
-H
34-hrs
8-hrs
-C6H5
-C6H4(p)NO2
46-hrs
28-hrs
-CSNH2
-C6H3(o, p)(NO2)2
-CONH2
12-hrs
5-6-hrs
5g-
-C6H4(o)NO2
8-hrs
Scheme 2 Synthesis of pyrazoline derivatives (5a–g)
1HNMR (CDCI3, d, ppm): 7.35–8.45 (m, 12H), 4.01 (s, H),
2.2 (s, 2H), 1.35 (s, H); ms: m/z 377 (20). Anal. Calcd. for
C20H16N4O2S: C, 63.81; H, 4.28; N, 14.88. Found: C,
64.69; H, 3.93; N, 13.77.
(50). Anal. Calcd. for C20H16N4O3: C, 66.66; H, 4.48; N,
15.55. Found: C, 65.85; H, 4.10; N, 15.12.
3-Naphthalen-1-yl-1-(2-nitro-phenyl)-5-(4-nitro-phenyl)-
4,5-dihydro-1H-pyrazole (5g)
1-(2,4-Dinitro-phenyl)-3-naphthalen-1-yl-5-(4-nitro-
phenyl)-4,5-dihydro-1H-pyrazole (5e)
A mixture of the (3) (0.606 g, 0.002 mol) and 2-nitro-
phenyl hydrazine (0.306 g, 0.002 mol) in 4–6 ml of glacial
acetic acid was refluxed for 8 h. The progress of the
reaction was monitored by TLC using solvent system
methanol: chloroform (1:99). The reaction mixture was
cooled and poured into ice water. Crude product was fil-
tered, washed with cold water and recrystallized with
chloroform as red solid, yield 36.57%, melting range
183–187°C; IR (KBr) 3021.7, 2363.7, 1659.2, 1605.1,
1516.1, 1342.1, 1220.2, 1138.7, and 1105.5 cm-1; 1HNMR
(CDCI3, d, ppm): 6.81–8.40 (m, 15H), 2.75 (s, H), 1.65 (s,
2H); ms: m/z 439 (60). Anal. Calcd. for C25H18N4O4: C,
68.49; H, 4.14; N, 12.78. Found: C, 70.89; H, 3.68; N,
11.34.
A yellow solid, yield 60.31%, melting range 204–208°C;
IR (KBr) 1665.80, 1519.90, 1343.20, and 1106.30 cm-1
;
1HNMR (CDCI3, d, ppm): 7.40–8.45 (m, 14H), 1.65 (s,
2H), 2.80 (s, H); ms: m/z 484 (10). Anal. Calcd. for
C25H17N5O6: C, 62.11; H, 3.54; N, 14.49. Found: C, 60.04;
H, 2.75; N, 11.76.
3-Naphthalen-1-yl-5-(4-nitro-phenyl)-4,5-dihydro-
pyrazole-1-carboxylic acid amide (5f)
Semicarbazide hydrochloride (0.111 g, 0.001 mol) was
added to the suspension of 3 (0.303 g, 0.001 mol) and
sodium hydroxide (0.01 g, 0.0025 mol) in ethanol (5 ml).
The mixture was refluxed for 5–6 h. The progress of the
reaction was monitored by TLC using the solvent system
methanol: chloroform (1:99). The reaction mixture was
cooled and poured on to crushed ice. Crude product was
filtered, washed with cold water, and recrystallized with
ethanol as black solid, yield 44.24%, melting range
173–176°C; IR (KBr) 3021.9, 2359.3, 1522, 1426, 1216,
and 1027.2 cm-1; 1HNMR (CDCI3, d, ppm): 7.04–8.70 (m,
12H), 5.45 (s, 2H), 4.94 (s, H), 1.30 (s, H); ms: m/z 360
Microbiological activities
Test microorganisms
Nine microorganisms Bacillus subtilis (MTCC 441),
Staphylococcus aureus (MTCC 1430), Pseudomonas
aeruginosa (MTCC 424), B. pumilus (MTCC 1456), P.
fluorescens (MTCC 2421), Aspergillus niger (MTCC
2546), Penicillium chrysogenum (MTCC 161), Escherichia
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Med Chem Res (2012) 21:3376–3381
3379
Table 1 Mean diameter of zone of inhibition (mm) of synthesized compounds (5a–g), standard and control against various microorganisms
S. no.
Compounds
Concentration
(lg/ml)
Gram ?ve strains
Gram -ve strains
Fungal strains
BS
SA
BP
ML
PA
EC
PF
AN
PC
1
5a
100
250
500
750
1000
1250
100
250
500
750
1000
1250
100
250
500
750
1000
1250
100
250
500
750
1000
1250
100
250
500
750
1000
1250
100
250
500
750
1000
1250
100
250
500
750
1000
1250
10
10
12
13
15
16
19
12
14
15
17
19
21
11
12
13
15
17
19
9
9
10
11
13
14
16
–
8
9
9
10
11
12
13
15
–
9
10
11
12
13
15
9
–
10
11
13
15
18
9
–
9
8
9
8
9
10
14
17
22
–
11
14
15
17
8
10
14
16
18
10
12
13
18
21
23
12
13
14
16
20
25
10
11
17
22
24
26
–
10
14
15
17
10
12
13
15
16
18
9
2
3
4
5
6
7
5b
5c
5d
5e
5f
10
11
12
15
18
–
9
8
10
12
14
17
20
9
10
11
13
15
18
10
11
12
13
15
17
8
9
10
14
16
18
–
9
10
13
16
19
9
11
13
17
–
9
8
9
10
11
13
16
19
10
11
12
16
19
22
10
11
12
13
14
17
9
10
11
14
18
21
8
10
12
14
15
17
10
11
16
19
21
23
–
10
11
12
13
–
10
15
18
20
10
11
16
18
19
21
10
11
18
20
22
24
–
11
12
13
15
–
11
12
16
19
22
11
12
13
14
15
16
10
12
13
14
15
16
12
13
14
15
16
17
25
–
9
9
9
10
18
22
23
24
–
10
11
12
14
–
11
14
16
19
8
11
14
16
18
9
8
9
10
11
12
14
17
9
–
–
–
9
10
11
12
14
–
18
21
22
25
8
16
20
21
23
10
11
13
15
17
19
10
11
12
19
23
25
–
18
22
24
26
8
10
12
14
–
9
8
–
10
11
12
13
15
13
14
15
16
17
18
24
–
10
11
12
13
15
9
9
9
10
11
12
14
–
9
–
10
11
12
14
10
11
13
18
21
24
27
–
10
11
12
13
13
14
15
20
24
26
–
10
11
12
10
11
12
18
23
25
27
–
9
10
11
–
5g
9
8
10
11
13
17
20
27
–
10
12
13
15
28
–
9
13
15
17
32
–
8
Norfloxacin
9
Fluconazole
10
24
–
25
–
10
Control (DMSO)
–
–
–
–
–
–
–
–
BS Bacillus subtilis, SA Staphylococcus aureus, BP Bacillus pumilus, ML Micrococcus luteus, PA Pseudomonas aeruginosa, EC Escherichia
coli, PF Pseudomonas fluorescens, AN Aspergillus niger, PC Penicillium chrysogenum
123

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Med Chem Res (2012) 21:3376–3381
each tube was recorded by using a UV–visible spectro-
photometer (Pandey et al., 2011). The observed MICs (lg/
ml) are presented in Table 2.
Table 2 Minimum inhibitory concentration of synthesized com-
pounds (5a–g)
Strains
MIC (lg/ml)
5a
5b
5c
5d
5e
5f
5g
50
Bacillus subtilis
30
50
50
30
50
50
Results and discussion
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus pumilus
50 150 200 150 150 200 150
In this study, chalcone (3) was synthesized by stirring 4-nitro
benzaldehyde with 1-acetyl naphthalene in the presence of
ethanolic sodium hydroxide solution. Synthesis of interme-
diate-chalcone was confirmed on the basis of its IR and mass
spectra. The IR spectra of chalcone displayed peak at
1658.67 cm-1 indicating the presence of a conjugated car-
bonyl group (C=O). Mass spectra showed the [M ? 1] peak.
The chalcone was then reacted with hydrazines (4a–g) to give
2-pyrazoline derivatives (5a–g) (Scheme 2). This reaction
probably takesplace through modification of an appropriate a,
b-unsaturated carbonyl group, which cyclizes to give pyraz-
oline compounds in the presence of a suitable cyclizing agent
(glacial acetic acid) under prolonged refluxing condition.
All the synthesized compounds were characterized by
physical, spectral, and elemental analysis. The IR spectra
in pyrazoline derivatives exhibited C=N stretching vibra-
tions in the range of 1522–1665.8 cm-1. [M]? or [M ? 1]
peaks were observed for the various compounds synthe-
30
50
30
50
30
30
50
50
50
30
50
50
30
30
30
30
30
30
30 150
30 200
Pseudomonas fluorescens 150
30
30
30
50
30 150
30 150
50
50
50
30
Aspergillus niger
50
50
Penicillium chrysogenum
Escherichia coli
30
50
200
50 150
Micrococcus luteus
30 200 150 150 150 400 150
coli (MTCC 1573), and Micrococcus luteus (MTCC 1538)
were procured from the Institute of Microbial Technology,
Chandigarh, India.
Screening for antimicrobial activity
Nutrient broth suspension of test microorganism (10 ml) was
added to 100 ml of sterile molten nutrient agar growth media
(cooled to 45°C), mixed well and poured into sterile Petri
plates. The agar was allowed to solidify and was then pun-
ched to make six wells/cups using a 6 mm sterile cork borer
(separate borer for each organism) to insure proper distri-
bution of wells in periphery and one in center. Agar plugs
were removed and 50 ll solution of test samples (each
compound in six concentrations) was poured into corre-
sponding marked well by micropipettes. Triplicate plates of
each organism were prepared. The plates were left at room
temperature for 2 h to allow diffusion of samples and incu-
bated face upward at corresponding temperature of each
organism for 48 h. (Gautam et al., 2010). The diameters of
zone of inhibition were measured to the nearest millimeters
(the cup size also included) and are presented in the Table 1.
1
sized. In all the H-NMR spectra, a multiplet indicating
various naphthyl and aromatic protons appears at the d
values of &6.5–8.5 ppm. The synthesized pyrazoline
derivatives were evaluated for antimicrobial activity
against bacterial and fungal strains by cup-plate method.
The microorganisms selected for antibacterial activity were
B. subtilis, S. aureus, P. aeruginosa, B. pumilus, P. fluo-
rescens, E. coli, M. luteus. A. niger, and P. chrysogenum
were selected for antifungal activity. The MIC was deter-
mined by tube dilution method for the said microorgan-
isms. Four compounds (5b, 5d, 5e, and 5g) exhibited good
antimicrobial activity. MIC of these compounds was found
to be 30 lg/ml against most of the strains. Compounds (5d)
and (5g) exhibited potent activity against two Gram-
positive bacterial strains (B. pumilus, B. subtilis), three
Gram-negative bacterial strains (E. coli, P. aeruginosa,
P. fluorescens) and two fungal strains (A. niger, P. chrys-
ogenum). All the compounds were active against one
Gram-positive strain (B. subtilis) and one Gram-negative
(P. aeruginosa) at all concentrations. Compounds (5b–f)
and (5g) were active against one Gram-negative strain (E.
coli). Thus, it can be concluded that all the compounds
exhibited higher antibacterial activity as compared to the
antifungal activity. Also, it is evident that compounds (5e)
and (5g) exhibited maximum antibacterial activity and
compound (5g) exhibited maximum antifungal activity.
Compound (5g) (3-naphthalen-1-yl-1-(2-nitro-phenyl)-
5-(4-nitro-phenyl)-4,5-dihydro-1H-pyrazole) may thus be
Determination of minimum inhibitory concentrations
(MICs)
A series of glass tubes containing different concentrations
of the synthesized compounds (in dimethyl sulphoxide)
with nutrient broth was inoculated with the required
amount of the inoculum to obtain a suspension of micro-
organism, which contains 105 colony forming units per
milliliter. Norfloxacin and Fluconazole were used as stan-
dard drugs for antibacterial and antifungal activities,
respectively. One tube was prepared with the addition of
the solvent (DMSO) and one blank tube was prepared
without the addition of microorganism. The tubes were
incubated at 37°C for 24–48 h. The turbidity produced in
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Med Chem Res (2012) 21:3376–3381
3381
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designated as the potent member of the series. The
2-nitrophenyl group at N-1 position of the 2-pyrazoline
ring offers not only the potent compound in the series but
also wide spectrum of activity.
Conclusion
In this study, a series of 1,3,5-trisubstituted compounds
containing a pyrazoline nucleus were synthesized. The
compounds were characterized using spectral techniques.
The antimicrobial activities of the compounds were
determined using the cup-plate method and tube dilution
method. Most of the compounds exhibited potent antimi-
crobial activity, which was also found to be concentration
dependent. The compounds exhibited higher antibacterial
activity as compared to the antifungal activity. The com-
pounds 5d, 5e, and 5g exhibited potent broad spectrum
antimicrobial activity. The compound 5g was the most
promising in the series as it was not only active against the
bacteria but also the fungi. It may also be deduced that
the presence of a 2-nitrophenyl group at N-1 position of the
2-pyrazoline ring offers a potent agent which is, very
interestingly, capable of inhibiting bacteria as well as
fungi. From the biological point of view, all the compounds
in the series offer novel leads to a new generation of
antimicrobial agents. Thus, it can be concluded that 1,3,5-
trisubstituted pyrazoline derivatives are capable of exhib-
iting potent antimicrobial activity.
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