Synthesis and antimicrobial evaluation of some pyrazole derivatives

Article abstract of DOI:10.3390/molecules17054962

Reaction of a series of (E)-3-phenyl-4-(p-substituted phenyl)-3-buten-2- ones with p-sulfamylphenyl hydrazine in glacial acetic acid gave the corresponding hydrazones, subsequent treatment of which with 30% HCl afforded pyrazole-1-sulphonamides. On the ot

Full text of DOI:10.3390/molecules17054962

Molecules 2012, 17, 4962-4971; doi:10.3390/molecules17054962
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Antimicrobial Evaluation of
Some Pyrazole Derivatives
Essam Mohamed Sharshira 1,* and Nagwa Mohamed Mahrous Hamada 2,*
1
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria 21321, Egypt
2
Department of Chemistry, Faculty of Education, Alexandria University, Alexandria 21526, Egypt
* Authors to whom correspondence should be addressed; E-Mails: dressamsharshira@yahoo.com
(E.M.S.); nagwahamada2002@yahoo.com (N.M.M.H.).
Received: 20 February 2012; in revised form: 23 March 2012 / Accepted: 18 April 2012 /
Published: 30 April 2012
Abstract: Reaction of a series of (E)-3-phenyl-4-(p-substituted phenyl)-3-buten-2-ones
with p-sulfamylphenyl hydrazine in glacial acetic acid gave the corresponding hydrazones,
subsequent treatment of which with 30% HCl afforded pyrazole-1-sulphonamides. On
the other hand, refluxing of chalcones with either thiosemicarbazide or isonicotinic
acid hydrazide in ethanol containing a few drops of acetic acid gave pyrazoline-1-
thiocarboxamides and isonicotinoyl pyrazolines, respectively. The structures of the
synthesized compounds were determined on the basis of their elemental analyses and
spectroscopic data. The antimicrobial activity of the newly isolated heterocyclic
compounds was evaluated against Gram-positive, Gram-negative bacteria and fungi. Most
of the compounds showed a moderate degree of potent antimicrobial activity.
Keywords: isonicotinic acid hydrazide; sulphonamide; pyrazoles; antimicrobial activities
1. Introduction
Pyrazoles and their variously substituted derivatives are important biological agents and a
significant amount of research activity has been directed towards this class. In particular, they are used
as antitumor [1], antibacterial and antifungal, antiviral, antiparasitic, anti-tubercular and insecticidal
agents [2–10]. Some of these compounds have also anti-inflammatory, anti-diabetic, anesthetic and
analgesic properties [11–14]. Moreover, chalcones have played a crucial part in the development of
theory of heterocyclic compounds, and also they used extensively in organic synthesis [15–19].

Molecules 2012, 17
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A classical synthesis of these compounds involves the base-catalyzed aldol condensation reaction of
ketones and aldehydes to give α,β-unsaturated ketones (chalcones), which undergo a subsequent
cyclization reaction with hydrazines affording pyrazoles [11,20–22]. In recent years, a significant
portion of research in heterocyclic chemistry has been devoted to pyrazoles containing different aryl
groups, as evident from the literature [23–30].
2. Results and Discussion
A convenient route for the synthesis of α,β-unsaturated ketones 1a–e is achieved by base catalyzed
condensation of benzyl methyl ketone with the appropriate p-substituted benzaldehyde in the presence
of piperidine [31] (Scheme 1).
Scheme 1. Synthesis of compounds 1a–e, 2a–e, 3a–e, 4a–e, 5a–e.
The (E)-Configuration for 1a–e comes from 1H-NMR measurements where the vinyl proton of the
(E)-isomer appears at relatively higher field than the (Z)-one [32]. The hydrazone derivatives 2a–e
were obtained in good yields by heating 1a–e with p-sulphamylphenyl hydrazine in ethanol containing
few drops of glacial acetic acid. The IR of 2a–e showed the characteristic bands for C=N at
1,626–1,633, and primary and secondary amine bands at 3,379–3,391 and 3,289–3,310 cm−1,
1
respectively. The H-NMR spectra showed the presence of a singlet equivalent to one proton in the
range δ = 8.21–8.73 ppm characteristic for a hydrazone NH proton, while the primary amine NH2
protons appeared at δ = 9.23–9.40 ppm, a multiplet at δ = 7.31–7.82 ppm characteristic for the

Molecules 2012, 17
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aromatic protons, a singlet at δ = 6.89–6.97 ppm for N=C–C=CH and a singlet equivalent to three
protons at δ = 2.19–2.37 ppm characteristic for N=C-CH3 protons. Treatment of 2a–e with 30% HCl
produced the pyrazole derivatives 3a–e in good yields.
The IR of 3a–e showed the characteristic bands for C=N at 1,632–1,656, C=C at 1,500–1,520
1
whereas NH2 band appeared at 3,378–3,393 cm−1. The H-NMR spectra for 3a–e revealed the
following signals: A singlet equivalent to two exchangeable protons at δ = 9.33–10.37 ppm
characteristic for NH2 protons, a multiplet at δ = 7.13–8.29 ppm characteristic for the aromatic protons.
The methyl protons at C3 of the pyrazole ring appeared as a singlet at δ 2.22–2.28 ppm. In the case of
3b, another singlet appeared at δ = 3.34 ppm characteristic for OCH3 group at the p-position to phenyl
group. Finally, condensation of 1a–e with either thiosemicarbazide or isonicotinic acid hydrazide in
ethanol containing few drops of acetic acid gave pyrazolines 4a–e or 5a–e, respectively. The
pyrazoline structures were fully confirmed by spectral and elemental analyses methods (Tables 1 and 2).
The IR spectra of 4a–e lacked the carbonyl band but showed a thiocarbonyl band at 1,232–1,248 and
primary and secondary amine absorption bands at 3,387–3,394 and 3,282–3,316 cm−1 respectively. On
the other hand the IR of 5a–e showed an amide carbonyl band at 1,628–1,634 cm−1 and a primary
1
amine absorption band only. The H-NMR of either 4a–e or 5a–e revealed the presence of
an exchangeable hydrogen of one proton intensity for a NH proton at δ = 8.26–8.48 ppm or
8.31–8.51 ppm, respectively. In the case of 4a–e, another exchangeable hydrogens of two protons
intensity was also appeared at δ = 10.71–10.93 ppm characteristic for thiocarboxamide protons
(S=C–NH2). The pyrazole-C5-H for 4a–e and 5a–e appeared as a singlet at δ = 5.39–5.46 ppm and
5.37–5.47 ppm, respectively.
Table 1. Physical and analytical data of compounds 2a–e, 3a–e, 4a–e, and 5a–e.
Yield M.P.
(%) (°C)
Calculated %
H
Found %
H
Molecular
Formula
Compound
R
C
N
C
N
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
H
67
147 C22H21N3SO2
160 C23H23N3SO3
103 C22H20N3SO2Cl 61.97
110 C22H20N3SO2Br 56.17
135 C22H20N4SO4
187 C22H19N3SO2
193 C23H21N3SO3
172 C22H18N3SO2Cl 62.26
177 C22H18N3SO2Br 56.41
67.52
65.56
5.37
5.46
4.69
4.26
4.59
4.88
5.01
4.25
3.85
4.15
5.76
5.85
4.85
4.28
4.71
5.57
5.66
4.79
4.29
4.66
10.74
9.98
9.86
67.50
65.60
61.94
56.20
60.50
67.84
65.90
62.30
56.45
60.80
69.10
66.50
61.86
54.50
59.99
77.45
74.35
70.25
62.82
68.44
5.40
5.44
4.66
4.30
4.63
4.92
5.05
4.21
3.90
4.15
5.76
5.85
4.88
4.29
4.66
5.59
5.69
4.74
4.25
4.60
10.70
9.95
9.90
OCH3 90
Cl
Br
NO2
H
OCH3 91
Cl
Br
NO2
H
OCH3 83
Cl
Br
NO2
H
OCH3 69
Cl
Br
NO2
87
93
79
69
8.94
8.97
60.55
67.87
65.87
12.84
10.80
10.02
9.91
12.80
10.84
10.06
9.94
76
78
69
81
8.97
8.95
197 C22H18N4SO4
149 C17H17N3S
60.83
69.15
66.46
61.82
54.55
60.00
77.42
74.39
70.21
62.86
68.39
12.90
14.24
12.92
12.73
11.23
16.47
12.32
11.32
11.17
10.00
14.51
12.94
14.20
12.95
12.69
11.20
16.43
12.36
11.30
11.24
10.05
14.55
156 C18H19N3SO
172 C17H16N3SCl
146 C17H16N3SBr
166 C17H16N4SO2
159 C22H19N3O
166 C23H21N3O2
142 C22H18N3OCl
168 C22H18N3OBr
171 C22H18N4O3
87
79
93
81
89
86
97

Molecules 2012, 17
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Table 2. IR and 1H-NMR spectral data of compounds 2a–e, 3a–e, 4a–e, and 5a–e.
IR cm−1 (KBr)
1H-NMR (δ / ppm) a
Compound
Vinyl
HC=CH
1603
1609
1612
1604
1619
1515
1510
1500
1515
1520
1527
1522
1531
1527
1526
1517
1530
1522
1519
1524
NH and/or
NH2
N=C-C=CH pyrazoline-
CH3 and/or
Ar- OCH3 (s)
2.33
C=N
C=O
C=S
Ar-H’S (m)
NH and/or NH2
(s)
C5-H (s)
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
1632
-
-
-
-
-
-
-
-
-
-
-
3391, 3291
3389, 3309
3382, 3289
3383, 3302
3379,3310
3386
7.33–7.82
7.31–7.81
6.91
-
-
8.21 and 9.23
8.46 and 9.29
8.54 and 9.31
8.61 and 9.39
8.73 and 9.40
9.33
1629
-
6.93
2.22 and 3.26
2.22
1626
-
7.36–7.61
6.97
-
1633
-
7.41–7.71
6.89
-
2.19
1627
-
7.26–7.76
6.95
-
2.37
1632
-
7.24–8.29
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2.25
1641
-
3384
7.35–7.94
-
2.28 and 3.34
2.22
9.76
1644
-
3378
7.29–7.86
-
9.92
1654
-
3391
7.13–7.64
-
2.25
9.71
1656
-
3393
7.29–8.10
-
2.28
10.37
-
-
-
-
-
-
-
-
-
-
-
-
1246 3394, 3287
1245 3390, 3293
1248 3390, 3282
1247 3393, 3311
1232 3387, 3316
7.26–7.82
5.39
5.42
5.44
5.46
5.39
5.40
5.37
5.46
5.47
5.42
2.25
10.73 and 8.26
10.77 and 8.37
10.79 and 8.42
10.93 and 8.43
10.71 and 8.48
8.31
7.27–7.77
2.32 and 3.39
2.27
-
7.29–8.01
-
7.23–7.61
2.29
-
7.27–7.99
2.32
1630
1628
1631
1633
1634
-
-
-
-
-
3291
3293
3287
3289
3311
6.81–7.09 and 7.32–7.48
6.79–7.12 and 7.29–7.49
6.83–7.08 and 7.27–7.51
6.82–7.11 and 7.27–7.52
6.84–7.10 and 7.26–7.71
2.32
2.25 and 3.31
2.27
8.36
8.45
2.22
8.47
2.39
8.51
a Solution in DMSO-d6.

Molecules 2012, 17
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2.1. Antimicrobial Activity
All of our compounds, i.e., hydrazones 2a–e, pyrazoles 3a–e, pyrazolines 4a–e and 5a–e were
tested for antimicrobial activity against four test organisms: Staphylococcus aureus ATCC6538P,
Escherichia coli ATCC873, Pseudomonas aeruginosa ATCC9027 and Candida albicans ATCC2091
using rifampicin (5 g/disc) and ampicillin (10 g/disc) as standard drugs (Table 3).
Table 3. Antimicrobial activities of all the synthesized compounds.
Zone of inhibition (mm)
Minimum inhibition concentration (MIC) g/mL
Compound
S. aureus
C. albicans
S. aureus
C. albicans
2a
-
20
15
20
20
15
22
25
26
20
17
15
15
20
18
15
15
15
24
15
17
-
-
-
250
-
2b
-
2c
17
14
12
19
18
22
18
17
-
100
120
-
50
500
-
2d
2e
3a
63
125
50
63
-
31
31
50
125
-
3b
3c
3d
3e
4a
-
-
4b
-
-
-
4c
21
15
-
100
63
-
50
63
-
4d
4e
5a
5b
-
-
-
-
-
-
5c
21
-
50
-
50
-
5d
5e
17
32
30
-
-
-
Rifampicin
Ampicillin
DMSO
-
-
-
-
-
14
-
-
(-) Indicates no activity.
The agar well-diffusion method [33] was used for studying the potential activities of these
compounds. All compounds only showed potent activity against Staphylococcus aureus and
Candida albicans in the following ranking: 3a–e > 5a–e > 4a–e ≥ 2a–e. Minimum inhibitory
concentration (MIC) values for the individual compounds that showed inhibition zones > 10 were
determined by means of the agar well-diffusion method in DMSO. The results of antimicrobial
activities of our synthesized compounds against S. aureus and C. albicans are shown in Table 3 as
zone of inhibition (in mm) and minimum inhibitory concentration, MIC (mg/mL). The trend of activity
was observed as follows: X > H > OMe > NO2 where X = Cl, Br. Minimum bactericidal
concentrations (MBC) were determined for all chloro derivatives such as 1c, 2c, 3c, 4c and 5c which
exhibit good activities. These results are listed in Table 4.

Molecules 2012, 17
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Table 4. Determination of minimum bactericidal concentration (MBC) µg/mL of chloro-derivatives.
Concentrations µg/mL 1000 500 250 125 63
31 1000 500 250 125 63 31
Microorganism Growth
S. aureus
C. albicans
2c
3c
4c
5c
-
-
-
-
-
-
-
-
-
-
+
+
+
+
+
+
+
+
+
+
+
+
-
-
-
-
-
-
-
-
-
-
-
+
+
-
+
+
+
+
+
+
+
+
-
+
-
+
3. Experimental
3.1. General
Melting points were taken in open capillary tubes using an Electrothermal apparatus 9100
(Rochford, UK) and are uncorrected. Microanalyses were performed at Faculty of Science, Cairo
University, Cairo, Egypt, using an Elementary Vario el III C, H, N, S analyzer (Hanau, Germany). IR
spectra were recorded using potassium bromide disks on a Perkin Elmer Spectrum RXI/FT-IR System
1
(Faculty of Pharmacy, Alexandria University, Alexandria, Egypt). H-NMR spectra were determined
on a Varian EM-390 MHz spectrophotometer, using TMS as internal standard.
3.2. General Procedure for Preparation of 3-Phenyl-4-(p-substituted phenyl)-3-buten-1-ones 1a–e
Compounds 1a–d were obtained in a good yield according to a published method [31]. The physical
properties and all the spectral data were as reported in the literature
3.3. General Procedure for Preparation of 3-Phenyl-4-(p-substituted phenyl)-3-buten-1-
(p-sulphamyl-phenyl)hydrazones 2a–e
A solution of the chalcone 1a–e (10 mmol) in ethanol (30 mL) was refluxed with the appropriate
amount of p-sulphamylphenylhydrazine (10 mmol) in glacial acetic acid (2 mL) for six hours, then the
reaction mixture was poured into crushed ice and kept overnight at room temperature. The separated
crude solid was filtered off, washed successively with water, dried and recrystallized from ethanol
(95%) to give 2a–e as needles. Physical and analytical data for the prepared compounds are shown in
Table 1. IR and 1H-NMR data are listed in Table 2.
3.4. General Procedure for Preparation of 3-Methyl-4-phenyl-5-(p-substituted phenyl)-1-
(p-sulphamyl-phenyl)pyrazoles 3a–e
A mixture of the appropriate hydrazones 2a–e (10 mmol) and 30% HCl (15 mL) was heated under
reflux for three hours and left to cool. After the reaction mixture reached room temperature, it was
poured into crushed ice and the oily product deposited was decanted from water and extracted with
ether. The ether layer was washed two times by water, dried over anhydrous sodium sulphate and
evaporated. The precipitate obtained was recrystallized from ethanol (95%) to afford the corresponding
pyrazoles 3a–e as needles. Physical and analytical data for 3a–e are as shown in Table 1. IR and
1H-NMR data are shown in Table 2.

Molecules 2012, 17
4968
3.5. General Procedure for Preparation of 4,5-Dihydro-3-methyl-4-phenyl-5-(p-substituted phenyl)-
pyrazole-1-thiocarboxamides 4a–e
A mixture of the appropriate chalcone 1a–e (10 mmol) in ethanol (30 mL) was refluxed with the
appropriate amount of thiosemicarbazide (12 mmol) in glacial acetic acid (2 mL) for 17 hours, then the
reaction mixture was poured into crushed ice and was kept overnight at room temperature. The
separated crude solid was filtered off, washed successively with water, dried and recrystallized
from ethanol/chloroform to give 4a–e as needles. The results and characterization data are listed in
Tables 1 and 2.
3.6. General Procedure for Preparation of 4,5-Dihydro-3-methyl-4-phenyl-5-(p-substituted phenyl)-1-
isonicotinoylpyrazoles 5a–e
A mixture of the appropriate chalcone 1a–e (10 mmol) in ethanol (30 mL) was refluxed with
the appropriate amount of isonicotinic acid hydrazide (10 mmol) in glacial acetic acid (2 mL) for
five hours. The reaction mixture was treated as mentioned for the preparation of 4a–e to give
the corresponding pyrazole 5a–e. Physical and spectroscopic data of 5a–e are listed in Table 1 and
Table 2, respectively.
3.7. Determination of Antimicrobial Activity
All compounds were tested against four different microorganisms: Staphylococcus aurous,
Escherichia coli, Pseudomonas aeruginosa and Candida albicans. The agar well-diffusion method was
applied for the determination of inhibition zone and minimum inhibitory concentration (MIC). Briefly,
broth culture (0.75 mL) containing ca. 106 colon-forming units (CFU) per mL of the test strain was
added to nutrient agar medium (75 mL) at 45 °C, mixed well, and then poured into a 15 cm sterile
metallic Petri plate. The medium was allowed to solidify and 8 mm wells were dug with a sterile
metallic borer, then a DMSO solution of the test sample (1 mL) at 1 mg/mL was added to the
respective wells. DMSO served as negative control, and the standard antimicrobial drugs rifampicin
(5 g/disc) and ampicillin (10 g/disc) were used as positive controls. Triplicate plates for each
microorganism strain were prepared and were incubated aerobically at 37 °C for 24 h. The activity was
determined by measuring the diameter of zone showing complete inhibition (mm), thereby, the zones
were precisely measured with the aid of a Venier caliper (precision 0.1 mm). The growth inhibition
was calculated with reference to the positive control. For the individual compounds that showed
inhibition zones >10 mm, MIC values were determined by means of the agar well-diffusion method
for concentrations of 1.0, 0.50, 0.25, 0.125, 0.063 and 0.031 mg/mL in DMSO. The tests were
performed in triplicate, and the results were averaged. Minimum bactericidal concentrations (MBC)
were determined for all chloro derivatives which exhibit good activities (1c, 2c, 4c and 5c) for
concentrations of 1.0, 0.50, 0.25, 0.125, 0.063 and 0.031 mg/mL in DMSO. The results are listed in
Tables 3 and 4.

Molecules 2012, 17
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4. Conclusions
This work demonstrates a rapid, efficient method for synthesis of some pyrazole derivatives.
Compounds having pharmacophores such as chloro- and bromo-substituents with lipophilic properties
showed the greatest antimicrobial activity.
Acknowledgements
The authors wish to thank the management of microbiology lab, Faculty of Pharmacy, Alexandria
University, for their support to carry out the antimicrobial activity.
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Sample Availability: Samples of all the compounds are available from the authors.
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