Synthesis and in vitro antimicrobial activity of some pyrazolyl-1- carboxamide derivatives

Article abstract of DOI:10.3390/molecules16097736

A series of 3,5-disubstituted pyrazole-1-carboxamides were obtained by treatment of chalcones with semicarbazide hydrochloride in dioxane containing sodium acetate/acetic acid as a buffer solution. N-acetyl derivatives of pyrazole-1-carboxamides were isol

Full text of DOI:10.3390/molecules16097736

Molecules 2011, 16, 7736-7745; doi:10.3390/molecules16097736
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and in Vitro Antimicrobial Activity of Some
Pyrazolyl-1-carboxamide Derivatives
Essam Mohamed Sharshira 1,* and Nagwa Mohamed Mahrous Hamada 2
1
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria 426, Egypt
2
Department of Chemistry, Faculty of Education, Alexandria University, Alexandria 21526, Egypt;
E-Mail: nagwahamada2002@yahoo.com
* Author to whom correspondence should be addressed; E-Mail: dressamsharshira@yahoo.com.
Received: 13 August 2011; in revised form: 25 August 2011 / Accepted: 31 August 2011 /
Published: 9 September 2011
Abstract: A series of 3,5-disubstituted pyrazole-1-carboxamides were obtained by
treatment of chalcones with semicarbazide hydrochloride in dioxane containing sodium
acetate/acetic acid as a buffer solution. N-acetyl derivatives of pyrazole-1-carboxamides
were isolated in good yields either by treatment of the carboxamide derivatives with acetic
anhydride or refluxing chalcones with semicarbazide in ethanol containing few drops of
acetic acid to give the corresponding hydrazones. Subsequent treatment of hydrazones
with acetic anhydride gave the desired N-acetyl pyrazole-1-carboxamides derivatives.
When chalcones were refluxed with dioxane containing few drops of acetic acid,
4,5-dihydropyrazole-1-carboxamides were isolated, which were subsequently oxidized
using 5% sodium hypochlorite in dioxane to afford pyrazole-1-carboxamides. The
structures of isolated compounds were confirmed by elemental analyses and spectral
methods. The isolated compounds were tested for their antimicrobial activities.
Keywords: chalcones; hydrazones; pyrazoles; pyrazolines
1. Introduction
Pyrazoles are an important class of five-membered heterocyclic compounds and were found
to have potential antimicrobial [1-3], anti-inflammatory [4], antipyretic [5], antidepressant [6,7],
tranquillizing [8], anticancer [9,10], antiviral [11], antihypertensive [12], antiarrhythmic [13],

Molecules 2011, 16
7737
antitubercular [14], psychoanaleptic [15], anticonvulsant [16] and antidiabetic [17] activities. In view
of this and our continued interest in the synthesis of pyrazoles [1,2,18,19], it was thought of interest to
synthesize some new pyrazole derivatives starting from chalcone and semicarbazide [16,20].
2. Results and Discussion
The synthetic routes to our prepared compounds are shown in Scheme 1. The starting chalcones 1a-f
were prepared in good yields by conventional Claisen-Schmidt condensation by reacting appropriately
substituted benzaldehydes and cyclopropylmethyl ketone in the presence of a base [1,21].
Scheme 1. Synthesis of 2a-f, 3a-f, 4a-f and 5a-f.
X
H
C
C
H
O
1a, X = H;
1b, X = OCH3;
1c, X = CH3; 1d, X = Cl;
1e, X = Br;
1f, X = NO2
O
C
O
C
NH2
NHNH2 .HCl
NH2
NHNH2 .HCl
EtOH / AcOH / reflux
AcOH / dioxane / reflux
O
NH2
C NHNH2.HCl
dioxane / RT
AcOH / NaOAc
H
N
O
C
N
NH2
C
O
O
C
CH CH
X
N
N
C
NH2
NH2
N
N
2a-f
HB
HA HX
Ac2O / reflux
X
X
3a-f
5a-f
O
H
N
N
C
N
Ac
Ac2O / reflux
NaOCl / dioxane / Δ
X
4a-f
The method is attractive since it specifically generates the (E)-isomers of the products [22]. In this
paper we show that reaction of chalcones 1a-f with semicarbazide under different reaction conditions
can affect the type of the product obtained and reaction pathways. For example, refluxing of chalcones
1a-f with semicarbazide hydrochloride in ethanol containing acetic acid gave the corresponding
1
semicarbazones 2a-f. The structures of the isolated compounds were determined by IR and H-NMR
spectra. The IR of the new semicarbazones revealed characteristic bands for vinyl CH=CH at
1,597–1,608, C=N at 1,627–1,663, C=O at 1,660–1,671, primary and secondary amines at 3,390–3,411
and 3,222–3,240 cm−1. The 1H-NMR spectra showed the presence of two broad exchangeable singlets
at δ = 9.37–10.31 ppm, δ = 10.42–10.82 ppm characteristic for the NH2 and NH protons, respectively.

Molecules 2011, 16
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A multiplet at δ = 7.12–7.89 ppm characteristic for the aromatic protons and the olefinic =C–CH=CH,
a doublet at δ = 6.77–6.93 ppm for the olefinic =C–CH=CH proton. The cyclopropyl ring protons
appeared as two multiplets in the range δ = 1.63–2.67 ppm (CH) and δ = 0.69–1.41 ppm (2 CH2),
respectively. When chalcones 1a-f were stirred at room temperature with semicarbazide hydrochloride
in dioxane containing acetic acid/sodium acetate buffer solution, pyrazole-1-carboxamides 3a-f were
obtained in good yields. The IR of 3a-f revealed the characteristic bands for Ar–C=C at 1,587–1,617,
1
C=N at 1,629–1,657 and amide carbonyl bands at 1,652–1,670 cm−1, while the H-NMR spectra
showed a singlet at δ = 6.73–6.83 for the pyrazole-C4-H. The N-acetyl derivatives 4a-f were obtained
by two different methods. In the first method, pyrazoles 3a-f were heated under reflux with acetic
anhydride, while in the second one, semicarbazones 2a-f were cyclized to N-acetylpyrazoles 4a-f
1
using acetic anhydride. The H-NMR of 4a-f exhibited a singlet of one proton intensity at
δ = 6.75–6.87 ppm and another singlet of 3 protons intensity at δ = 2.11–2.18 ppm characteristic for
pyrazole-C4–H and N–acetyl protons, respectively.
These results and the previous data reported in hydrazones derived from chalcones [1,2,23-27]
showed that the substituent (G) attached to the hydrazono NH function (C=N–NH–G) plays a crucial
role in changing reaction pathways and reaction products. For example, when G = aroyl group,
cyclization occurs in the presence of acetic anhydride to give 1,3,4-oxadiazoles [1,23-26]. On the other
hand, when G = carboxamide or aryl group, cyclization with acetic anhydride gave exclusive
formation of pyrazole derivatives [2,27,28]. Finally, treatment of chalcones 1a-f with semicarbazide
hydrochloride in dioxane containing few drops of acetic acid gave pyrazolines 5a-f in good yields.
The IR of 5 showed the presence of bands characteristic for an amide function at 1,657–1,679
(C=O) and 3,387–3,403 cm−1 (NH2). The pyrazoline ring CH2 protons resonated as a pair of doublets
of doublets at δ = 3.07–3.17 ppm and δ = 3.71–3.86 ppm. The CH protons (HX) appeared as s doublet
of doublets at δ = 5.37–5.45 ppm due to vicinal coupling with the two magnetically non-equivalent
protons of the methylene group at position 4 of the pyrazoline ring (JAB = 16 Hz, JAX = 3.6 Hz,
JBX = 12 Hz). Finally, the structure of pyrazoles 3a-f were confirmed by preparation through an
alternative route via oxidation of pyrazoline 5a-f using NaOCl/dioxane. The structures were verified
by m.p. and mixed melting point experiments. The structures of all isolated compounds were
confirmed by spectral and elemental analyses methods (Tables 1 and 2).
2.1. Antimicrobial Activity
The in vitro antimicrobial activities of the newly synthesized compounds 3-5 were assayed against
four test organisms (Staphylococcus aureus ATCC6538P, Escherichia coli ATCC8739, Pseudomonas
aeruginosa ATCC9027 and Candida albicans ATCC2091) following the agar well-diffusion
method [29] and using rifampicin (5 μg/disc) and ampicillin (10 μg/disc) as standard drugs. The tested
compounds showed no significant effect against Pseudomonas aeruginosa, whereas they showed
potent activity against Staphylococcus aureus, Escherichia coli and Candida albicans.

Molecules 2011, 16
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Table 1. Physical and Analytical Data of Compounds 2a-f, 3a-f, 4a-f, and 5a-f.
Calculated %
Found %
H
Compound
X
Yield (%) M.P.°C
Molecular Formula
C
H
N
C
N
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
H
OCH3
CH3
Cl
Br
NO2
H
OCH3
CH3
Cl
Br
NO2
H
76
82
80
71
89
93
77
66
67
81
88
91
69
62
73
82
71
79
161
171
174
163
179
182
193
183
176
169
170
199
188
172
181
169
176
197
C13H15N3O
C14H17N3O2
C14H17N3O
C13H14N3ClO
C13H14N3BrO
C13H14N4O3
C13H13N3O
68.12
64.86
69.14
59.09
50.65
56.93
68.72
65.37
69.71
59.54
50.98
57.35
66.91
64.21
67.84
59.21
51.72
57.32
6.55
6.56
7.00
5.30
4.55
5.11
5.73
8.84
6.22
4.58
3.92
4.41
5.58
5.69
6.01
4.61
4.02
4.46
18.34
16.22
17.28
15.91
13.64
20.44
18.50
16.34
17.43
16.03
13.73
20.59
15.61
14.05
14.84
13.82
12.07
17.83
68.06
64.85
69.09
59.11
50.69
56.95
68.77
65.39
69.75
59.60
50.94
57.32
66.88
64.19
67.91
59.17
51.73
57.32
6.49
6.48
6,97
5.31
4.52
5.13
5.69
5.76
6.19
4.58
3.89
4.43
5.56
5.66
6.03
4.62
4.07
4.46
18.31
16.19
17.31
15.88
13.51
20.47
18.49
16.38
17.44
16.04
13.80
20.51
15.66
14.08
14.89
13.78
12.03
17.80
C14H15N3O2
C14H15N3O
C13H12N3ClO
C13H12N3BrO
C13H12N4O3
C15H15N3O2
C16H17N3O3
C16H17N3O2
C15H14N3ClO2
C15H14N3BrO2
C15H14N4O4
OCH3
CH3
Cl
Br
NO2
5a
5b
2c
5d
H
OCH3
CH3
Cl
71
62
69
77
152
149
143
161
C13H15N3O
C14H17N3O2
C14H17N3O
C13H14N3ClO
68.12
64.86
69.14
59.09
6.55
6.56
7.00
5.30
18.34
16.22
17.28
15.91
68.16
64.89
69.17
59.11
6.49
6.51
6.97
5.27
18.36
16.21
17.29
15.88
5e
5f
Br
NO2
60
77
158
169
C13H14N3BrO
C13H14N4O3
50.65
56.93
4.55
5.11
13.64
20.44
50.59
56.97
4.57
5.17
13.67
20.39

Molecules 2011, 16
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Table 2. IR and 1H-NMR Spectral Data of Compounds 2a-f, 3a-f, 4a-f, and 5a-f.
1H-NMR (δ / ppm) a
IR cm−1 (KBr)
VinylHC
=CH
orAr–
C=C
1603
1607
1597
1604
1608
1598
1597
1593
1587
1591
1617
1614
1607
1602
1601
1598
1603
1611
–
Cyclopropyl ring H’S
Ar–CH3,
Ar-H’S and
C=N C=O NHand/orNH2 =C-CH=CH
(m)
Pyrazoline–HA Pyrazoline–HB Pyrazoline–HX
NH and/or
Comp.
=C-CH=CH Pyrazole
Ar–OCH3,
dd,JAX = 3.6Hz, dd,JAB = 16Hz, dd,JAX = 3.6Hz, NH2 (s), D2O
dd, JAB = 16Hz dd,JBX = 12Hz dd,JBX=12Hz exchangeable
(d), J=12 Hz C4–H (s)
CH3CO–
2(CH2) (m)
CH(m)
(S)
–
2a
2b
2c
2d
2e
2f
1631 1664 3234 and 3402
1633 1661 3235 and 3390
1627 1669 3240 and 3401
1645 1668 3227 and 3400
1650 1660 3222 and 3409
1663 1671 3228 and 3411
7.31–7.76
7.29–7.86
6.77
–
–
–
–
–
–
–
–
10.11, 10.63 1.89–2.54 0.73–1.36
10.31, 10.57 1.83–2.36 0.72–1.38
9.37, 10.42 1.84–2.42 0.69–1.41
9.87, 10.73 1.79–2.41 0.75–1.36
9.91, 10.61 1.71–2.45 0.78–1.26
9.77, 10.82 1.63–2.67 0.77–1.31
6.81
3.66
2.22
–
7.26–7.74
6.79
–
–
–
–
7.19–7.89
6.84
6.87
6.93
–
–
–
–
–
7.17–7.77
–
–
–
–
–
7.12–7.81
–
–
–
–
–
3a
3b
3c
3d
3e
3f
1634 1652
1629 1660
1633 1665
1644 1659
1650 1655
1657 1670
1634 1659
1636 1660
1622 1663
1639 1662
1651 1663
1657 1676
1635 1657
1638 1659
1627 1661
1634 1667
1660 1668
1667 1679
3387
3381
3401
3397
3395
3402
3230
3261
3233
3241
3237
3227
3398
3387
3403
3396
3391
3398
7.24–7.86 b
7.26–8.02 b
7.21–7.98 b
7.13–7.79 b
7.11–7.75 b
7.31–7.64 b
7.25–7.83 b
7.23–7.91 b
7.23–7.89 b
7.17–7.83 b
7.16–7.73 b
7.33–7.60 b
7.21–7.79 b
7.26–7.89 b
7.22–7.87 b
7.19–7.74 b
7.15–7.77 b
7.36–6.69
6.83
6.74
6.82
6.81
6.73
6.79
6.84
6.75
6.81
6.86
6.77
6.87
–
–
–
–
10.54
10.61
10.33
10.39
10.31
10.70
9.39
1.76–2.53 0.74–1.34
1.81–2.33 0.71–1.36
1.87–2.39 0.67–1.39
1.66–2.43 0.69–1.32
1.72–2.49 0.66–1.33
1.70–2.62 0.71–1.29
1.77–2.54 0.72–1.31
–
–
–
–
–
3.71
2.29
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
4a
4b
4c
4d
4e
4f
–
–
–
–
2.11
–
–
–
–
9.29
1.79–2.55 0.73–1.37 2.13,3.69
1.82–2.41 0.70–1.36 2.13,2.21
–
–
–
–
9.30
–
–
–
–
9.27
1.69–2.43 0.72–1.32
1.71–2.53 0.69–2.39
1.73–2.59 0.73–2.58
1.74–2.51 0.71–1.32
1.76–2.53 0.76–1.36
1.80–2.41 0.69–1.40
1.72–2.47 0.76–1.45
1.70–2.55 0.69–2.43
1.75–2.61 0.78–2.60
2.14
2.17
2.18
–
–
–
–
–
9.23
–
–
–
–
9.37
5a
5b
5c
5d
5e
5f
–
3.09
3.11
3.07
3.13
3.14
3.17
3.79
3.71
3.72
3.81
3.77
3.86
5.42
5.45
5.39
5.44
5.37
5.40
10.63
10.65
10.57
10.49
10.44
10.56
–
–
–
3.67
2.24
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
a Solution in DMSO-d6; b The chemical shift only indicates Ar–H’s.

Molecules 2011, 16
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The maximum activity (+++; MIC = 25 μg/mL) was indicated for compounds 3d, 3e, 4f, and 5f.
These results suggest that electron-withdrawing groups (X = Cl, Br and NO2) in the pyrazolyl
compounds 3 play a crucial role in enhancing the activity. For Staphylococcus aureus, compounds 3a,
3b, 3c and 3e showed moderate activity (++; MIC = 50 μg /mL), while compounds 4a, 4b, 5a and 5b
showed only slight activity (+; MIC = 75 μg/mL). Compounds 3b, 3c, 4d, 4e, 5d and 5e exhibited
moderate activity against Escherichia coli whereas, compounds 3a, 3e and 4b showed a slight activity
against this organism. Moreover, compounds 3b, 3c, 3e, 4a, 4d, 4e, 5b, 5d and 5e showed moderate
activity against Candida albicans, whereas compounds 3a, 4b, 4c, 5a and 5c showed slight activity. In
summary, all of the tested compounds showed antifungal activities, and compounds 3d, 3f, 4f and 5f
were found to be the most active against all the tested microorganisms. The results are summarized in
Table 3.
Table 3. Antimicrobial activities of newly synthesized compounds 3–5.
Sta
Escherichia
Candida
albicans
+
Compound
X
staphylococcus
coli
+
3a
3b
3c
3d
3e
3f
H
OCH3
CH3
Cl
++
++
++
+++
++
+++
+
++
++
+++
+
++
+ +
+++
++
Br
NO2
H
+++
−
+++
++
4a
4b
4c
4d
4e
4f
OCH3
CH3
Cl
+
+
+
−
−
+
++
++
+++
+
++
++
+++
−
++
Br
++
NO2
H
+++
+
5a
5b
5c
5d
5e
5f
OCH3
CH3
Cl
+
−
++
+
−
+
++
++
+++
++
++
+++
++
Br
++
NO2
+++
+++ for high activity (MIC = 25 μg/mL); ++ for moderate activity (MIC = 50 μg/mL);
+ for slight activity (MIC = 75 μg/mL) and − for inactive.
3. Experimental
3.1. General
Melting points were taken in open capillary tubes using an Electrothermal apparatus 9100 (UK) and
are uncorrected. Microanalyses were performed at the Faculty of Science, Cairo University, Cairo,
Egypt, using an Elementary Vario el III C, H, N, S Analyzer (Germany). IR spectra were recorded
using potassium bromide disks on a Perkin-Elmer 1650 spectrophotometer (Faculty of Science,
Alexandria University, Alexandria, Egypt). 1H-NMR spectra were determined on a Varian

Molecules 2011, 16
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EM-390 MHz spectrophotometer, using TMS as internal standard. The biological activities were
evaluated at the lab of microbiology, Faculty of pharmacy, Alexandria University, Alexandria, Egypt.
3.2. General Procedure for Preparation of E-1-Cyclopropyl-3-(p-substituted-phenyl)-2-propenones 1a-f
To a cold solution of sodium hydroxide (3 g) in aqueous ethanol (50 mL, 60%), cyclopropylmethyl
ketone (10 mmol) was added dropwise (30 min), while rapidly stirring, then the desired p-substituted
benzaldehyde (10 mmol) was added dropwise (30 min). After five hours, the mixture was left overnight
in refrigerator. The separated solid was filtered, washed with water and dried, then recrystallized from
ethanol as colorless needles. The physical properties and all the spectral data were as reported in the
literature [1,21].
3.3. General Procedure for Preparation of 1-Cyclopropyl-3-(p-substituted-phenyl)-2-propene-1-
semicarbazones 2a-f
A solution of chalcones 1a-f (10 mmol) in ethanol (10 mL) was refluxed with the appropriate
semicarbazide hydrochloride (10 mmol) in glacial acetic acid (2 mL) for about five hours, then the
reaction mixture was poured onto crushed ice and was kept overnight at room temperature, the
separated solid was filtered off, washed successively with water and dried, then recrystallized from
methanol. Melting points, IR and NMR data: see Tables 1 and 2.
3.4. General Procedure for Preparation of 3-Cyclopropyl-5-(p-substituted-phenyl)-pyrazole-1-carbox-
amides 3a-f
Method A: A solution of chalcones 1a-f (10 mmol) in dioxane (10 mL) and semicarbazide
(10 mmol) in sodium acetate/ acetic acid buffer solution [30]. The reaction mixture was stirred at
room temperature for 24 hours. The separated solid was filtered off, washed with water, dried and
recrystallized from methanol to give 3a-f. Melting points, IR and NMR data: see Tables 1 and 2.
Method B: A solution of the appropriate pyrazoline 5a-f (10 mmol), dioxane (10 mL) and sodium
hypochlorite (5 mL, 5%) was heated over a boiling water bath until effervescence occurs; heating was
continued for a further 10 minutes. The reaction mixture was allowed to reach ambient temperature
and the separated solid was filtered, washed with water, dried and recrystallized from methanol to give
the corresponding pyrazoles 3a-f. The physical properties and all the spectral data were identical with
those prepared by method A.
3.5. General Procedure for Preparation of 3-Cyclopropyl-5-(p-substituted-phenyl)-pyrazole-1-
(N-acetyl)-carboxamides 4a-f
Method A: A mixture of the appropriate semicarbazone 2a-f (10 mmol) and acetic anhydride
(15 mL) was heated under reflux for three hours. After the reaction mixture attained 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 with sodium bicarbonate, followed by water, dried over
anhydrous sodium sulphate and evaporated to give the corresponding pyrazoles 4a-f as needles.
Melting points, elemental analyses, IR and NMR data: see Tables 1 and 2.

Molecules 2011, 16
7743
Method B: A mixture of pyrazoles 3a-f (10 mmol) in acetic anhydride (5 mL) was heated under
reflux for 30 minutes. The reaction mixture was treated as mentioned in method A to give the N–acetyl
derivatives 4a-f.
3.6. General Procedure for Preparation of 4,5-Dihydro-3-cyclopropyl-5-(p-substituted-phenyl)-
pyrazole-1-carboxamides 5a-f
A solution of chalcones 1a-f (10 mmol) in dioxane (10 mL) was refluxed with the appropriate
semicarbazide hydrochloride (10 mmol) in glacial acetic acid (1 mL) for 4 hours, then the
reaction mixture was treated as mentioned for 2a-f. Melting points and spectral data are listed in
Tables 1 and 2.
3.7. Determination of Antimicrobial Activity
All the synthesized heterocyclic compounds were tested against four different microorganisms:
Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans. The agar
well-diffusion method was applied for the determination of inhibition zones and minimum inhibitory
concentrations (MICs). 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, 1 mg/mL)
was added to the respective wells. DMSO served as negative control, and the standard antimicrobial
drugs rifampicin (5 μg/disc) and ampicillin (10 μg/disc) were used as positive controls. Triplicate
plates of 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 Vernier Caliper (precision 0.1 mm). The
growth inhibition was calculated with reference to the positive control.
4. Conclusions
This work describes different methods for the synthesis of new heterocyclic pyrazole derivatives.
The antimicrobial activity of these compounds was evaluated against Gram-positive, Gram-negative
bacteria and fungi. Most of the compounds showed moderate antimicrobial activity.
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