Design and synthesis of new 1,2,3-triazole-pyrazole hybrids as antimicrobial agents

Article abstract of DOI:10.1134/S1070363217100280

In the present study, a series of novel 1,2,3-triazoles derivatives (4a–4c) were synthesized by the 1,3-dipolar cycloaddition (click-reaction) of 1-phenyl-3-[2-(prop-2-yn-1-yloxy)phenyl substituted]-1H-pyrazole-4-carbaldehyade (3a–3c) with various aryl az

Full text of DOI:10.1134/S1070363217100280

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 10, pp. 2454–2461. © Pleiades Publishing, Ltd., 2017.
Design and Synthesis of New 1,2,3-Triazole-pyrazole Hybrids
as Antimicrobial Agents1
S. Pervarama, D. Ashokb*, B. A. Raob, M. Sarasijac, and C. V. R. Reddya
a Department of Chemistry, Jawaharlal Nehru Technological University, Hyderabad, Telangana, 500085 India
b Green and Medicinal Chemistry Laboratory, Department of Chemistry,
Osmania University, Hyderabad, Telangana, 500007 India
*е-mail: ashokdou@gmail.com
c Department of Chemistry, Satavahana University, Karimnagar, Telangana, 505001 India
Received June 29, 2017
Abstract—In the present study, a series of novel 1,2,3-triazoles derivatives (4a–4c) were synthesized by the
1,3-dipolar cycloaddition (click-reaction) of 1-phenyl-3-[2-(prop-2-yn-1-yloxy)phenyl substituted]-1H-
pyrazole-4-carbaldehyade (3a–3c) with various aryl azides in the presence of sodium ascorbate and copper
sulphate with high yields. The required precursors 3a–3c were synthesized by the reaction of 1-(2-hydroxy
phenyl substituted)ethanones (1a–1c) with propargyl bromide via 1-[2-(prop-2-yn-1-yloxy)phenyl substituted]
ethanone (2a–2c), followed by reaction with phenyl hydrazine. The newly synthesized 1,2,3-triazole-pyrazole
derivatives were characterized by analytical and spectral data. All synthesized compounds were evaluated in
vitro for their antibacterial and antifungal activity. The most active compounds 4a5–4a7 demonstrated a broad
spectrum of antibacterial activity against all strains used for testing. Compounds (4a4, 4b1, 4c1, 4c2)
demonstrated significant antifungal activity at the concentration of 10 μg/mL.
Keywords: 1,2,3-triazoles, pyrazole, Knorr pyrazole synthesis, Click reaction, antimicrobial activity
DOI: 10.1134/S1070363217100280
1,2,3-Triazole and its derivatives demonstrate
diverse biological activities such as antitubercular [1],
anti-HIV [2], antifungal [3], antibacterial [4], and
anticancer [5], play significant role in organic
synthesis [6], and have many other valuable properties
[7–9]. Pyrazoles constitute another important pharmaco-
phores group with diverse biological activities [10–
20]. 1,2,3-Triazoles as active linker units can connect
two pharmacophores to give an original bifunctional
drugs [21]. Recently the strategy employing a
combination of two different active fragments in one
molecule has emerged [22]. According to it each drug
moiety is designed to bind separately to two different
biological targets.
components, 1,2,3-triazole and pyrazole, and tested its
potential antibacterial and antifungal effects.
RESULTS AND DISCUSSION
Synthetic approach to the target compounds 4a–4c
is depicted in Scheme 1. Approach to 1,2,3-triazole
derivatives containing pyrazole moiety was based on
the Knorr pyrazole synthesis [26]. The starting
compounds 1-[2-(prop-2-yn-1-yloxy)phenyl substituted]
ethanone (2a–2c) were prepared in the nucleophilic
substitution reaction of a 1-(2-hydroxyphenyl sub-
stituted) ethanone (1a–1c) with propargyl bromide in
the presence of K2CO3. Reaction of 2a–2c with phenyl
hydrazine in the presence of POCl3–DMF by
Vilsmeier Haack reaction afforded the pyrazole moiety
3a–3c. The compounds 4a–4c were prepared using
CuSO4·5H2O–sodium ascorbate in the solvent system
t-BuOH–H2O under conventional conditions in high
yields. In all cases, the reactions proceeded efficiently
at ambient temperatures.
In our earlier studies, we focused on the design and
synthesis of pyrazole derivatives bearing 1,2,3-triazole
scaffold as potential antimicrobial agents [23] and
pyrazoline-based bis 1,2,3-triazole scaffolds [24].
Synthesized 1,2,3-triazole derivatives were tested for
their antimicrobial activity [25]. In the current study
we synthesized a molecular system that combined two
All analytical and spectral data accumulated for
compounds 3, 4 were in accord with their structures.
1 The text was submitted by the authors in English.
2454

DESIGN AND SYNTHESIS OF NEW 1,2,3-TRIAZOLE-PYRAZOLE HYBRIDS
2455
Scheme 1. Synthesis of compounds 4a1-4c2.
R
R
R
O
H
Br
NH2
NH
O
K2CO3, acetone,
reflux, 24 h
N
POCl3, DMF,
−5°C to
room temperature, 24 h
N
O
O
OH
O
1a−1c
2a−2c
3a−3c
R
O
H
N3
R1
O
N
N
N
.
CuSO4 5H2O,
Sodium ascarbate
tert-butanol−water (2 : 1)
room temperature, 24 h
N N
4a−4c
R1
1a: R = H; 1b: R = CH3; 1c: R = Cl; 2a: R = H; 2b: R = CH3; 2c: R = Cl; 3a: R = H; 3b: R = CH3; 3c: R = Cl. 4a1: R = H;
R1 = phenyl; 4a2: R = H; R1 = 3-chlorophenyl; 4a3: R = H; R1 = 4-bromophenyl; 4a4: R = H; R1 = 3,5-dimethylphenyl; 4a5:
R = H; R1 = 4-methoxyphenyl; 4a6: R = H; R1 = 4-phenylcarboxylic acid; 4a7: R = H; R1 = CH2OH (methyl alcohol); 4b1:
R = CH3; R1 = phenyl; 4b2: R = CH3; R1 = 3-chlorophenyl; 4c1: R = Cl; R1 = phenyl; 4c2: R = Cl; R1 = 3-chlorophenyl.
Antibacterial activity. Antibacterial activity of
compounds 4a1–4a7, 4b1, 4b2, 4c1, 4c2 has been
assayed. The compounds in concentration range from 1
to 100 µg/mL were used against gram positive and
gram negative clinically important pathogens. Zones of
inhibition were determined according to the Muller–
Hinton agar method. Inhibitory effects of compounds
4a1–4a7, 4b1, 4b2, 4c1, 4c2 are presented in Fig. 1.
vitro at the concentration of 10 μg/mL in a well against
Aspergillus niger and Aspergillus flavus. Inhibitory
effects of compounds 4a1–4a7, 4b1, 4b2, 4c1, 4c2
against these organisms are presented in Fig. 2. The
zones of inhibition indicated that most of compounds
exhibited antifungal activity against the tested fungi.
The compounds 4a6, 4b1, 4b2, 4c2 in case of A. niger,
and 4a3, 4a5, 4b1, 4b2 in case of A. flavus,
demonstrated substantial zones of inhibition in
comparison with nystatin.
The tested compounds (4a1, 4a2, 4a5, 4a6, 4a7, 4c2)
demonstrated high antibacterial activity against all
tested bacteria (Table 1).
Minimum inhibitory concentration activity of fungal
stains. The minimum inhibitory activity of compounds
4a1–4a7, 4b1, 4b2, 4c1, 4c2 was determined against
Aspergillus niger and Aspergillus flavus (Table 2). The
compounds 4b1, 4c2 exhibited the most potent
antifungal activity against the tested fungi.
Minimum inhibitory activity of bacteria stains. The
minimum inhibitory concentration (MIC, μg/mL) of
synthesized compounds 4a1-4a7, 4b1, 4b2, 4c1, 4c2 and
ciprofloxacin was determined against antibiotic
susceptible strains of both Gram positive and Gram
negative bacteria. Among tested compounds 4a1, 4a3
demonstrated lower MIC values against both Gram
positive and Gram negative bacteria strains.
EXPERIMENTAL
All solvents and reagents were obtained commercially
and used as received unless noted otherwise. Melting
points were determined in open capillary tubes. Purity
of the compounds was tested by TLC on silica gel 60
Antifungal activity. Antifungal activity of
compounds 4a1–4a7, 4b1, 4b2, 4c1, 4c2 was assayed in
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 10 2017

2456
PERVARAM et al.
4a1
4a2
4a3
4a4
4a7
4b1
4b2
4c1
4a5
4a6
4c2
Fig. 1. Antibacterial activity of Gram positive and Gram negative starins.
F254 (Merck), the spots were visualized under UV light.
IR spectra were recorded (KBr discs) on a Perkin-
spectrometer in DMSO-d6 and CDCl3 using TMS as an
internal standard. Mass spectra were measured on a
GCMS-QP 1000 EX mass spectrometer. All reactions
were carried out under the atmosphere of Ar.
1
Elmer 1800 spectrophotometer. H and 13C NMR
spectra were measured on a Varian VNMRS-400
Table 1. Minimum inhibitory activity of Gram positive and Gram negative activitya
MIC, µg/mL
Compound
Escherichia
coli
Klebsiella
pneumoniae
Pseudomonas Staphylococcus
Streptococcus
pyogenes
aeruginosa
11.50±0.430
20.50±0.270
18.50±0.980
10.00±0.940
10.50±0.042
8.50±0.031
7.50±0.068
9.50±0.048
11.50±0.082
14.50±0.057
11.00±0.073
8.08±0.790
aureus
4a1
9.5±0.91
8.5±0.32
10.5±0.42
11.5±0.51
6.5±0.09
5.5±0.11
7.5±0.33
13.5±0.31
20.5±1.03
12.5±0.03
9.5±0.16
8.2±4.08
10.5±1.760
15.5±0.720
17.5±0.450
19.5±0.070
10.0±0.920
9.5±0.082
8.50±0.210
13.50±0.710
20.50±0.044
8.50±0.0510
7.50±0.820
7.50±0.640
10.50±0.036
11.00±0.100
10.50±0.019
9.50±0.660
11.50±0.710
8.12±0.750
15.5±0.82
11.5±0.58
13.5±0.42
9.5±0.031
9.5±0.29
4a2
4a3
4a4
4a5
4a6
6.5±0.99
4a7
17.5±0.210
14.5±0.290
13.5±0.170
12.5±0.077
10.5±0.310
4.5±1.340
10.5±0.32
25.0±0.72
22.5±0.33
13.5±0.36
15.0±0.61
9.5±0.11
4b1
4b2
4c1
4c2
Ciprofloxacin
a
Micro organism were inoculated in nutrient broth with varying concentrations of synthesized compounds and incubated with Escherichia
coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 10 2017

DESIGN AND SYNTHESIS OF NEW 1,2,3-TRIAZOLE-PYRAZOLE HYBRIDS
Synthesis of 1-[2-(prop-2-yn-1-yloxy)phenyl sub-
2457
stituted] ethanone (2a–2c). To a solution of hydroxy
acetophenone (0.01 mol) in acetone was added an-
hydrous potassium carbonate (0.015 mol) followed by
propargyl bromide (0.013 mol). The resulting mixture
was refluxed at 56°C for 8–12 h (TLC), then cooled
down to room temperature. Potassium carbonate was
filtered off and the filtrate was distilled under reduced
pressure leading to pure brown liquid product which
solidified readily. The products were obtained in 90–
95% of yields.
4a1
4a2
4a3
4a4
4a7
4b1
4b2
4c1
Synthesis of 1-phenyl-3-[2-(prop-2-yn-1-yloxy)-
phenyl substituted]-1H-pyrazole-4-carbaldehyade
(3a–3c). To a mixture of 1-[2-(prop-2-yn-1-yloxy)-
phenyl substituted] ethanone (2a–2c) (0.01 mol) and
phenyl hydrazine (0.01 mol) in methanol was added
acetic acid (0.0005 mol) and the mixture was refluxed
for 1 h. Upon completion of the reaction (TLC), the
mixture was poured into water, extracted with EtOAc
(twice, 40 mL) and dried over Na2SO4. The solvent
was evaporated. Meanwhile, DMF was loaded into
another round bottom flask and cooled to 0°C, then
POCl3 (0.02 mol) was added dropwise. The mixture
was stirred for 15 minutes, then the brown syrup was
added to the above reaction mass and it was stirred at
room temperature for 24 h. Upon consumption of the
starting compound 2a–2c (TLC), the reaction mixture
was treated with cold water, the precipitate filtered off
and used in the further step without additional
purification. Yield 80–85%.
4a5
4a6
4c2
Fig. 2. Antifungal activity of Aspergillus niger and Aspergillus
flavus.
7.71 d.d (1H, Ar-H, J = 1.6, 7.6 Hz). 13C NMR
spectrum, δC, ppm: 31.8, 56.2, 76.1, 77.9, 113.1, 121.6,
129.1, 130.4, 133.4, 156.7, 199.5. Found, %: C 75.79;
H 5.74. C11H10O2. Calculated, %: C 75.84; H 5.79.
Table 2. Minimum inhibitory concentration activity of
synthesized compounds against Aspergillus niger and
Aspergillus flavus
MIC, µg/mL
Synthesis of 3-{2-[(1-methyl-1H-1,2,3-triazol-4-
yl)methoxy]phenyl}-1-phenyl-1H-pyrazole-4-carbal-
dehyde (4a–4c). A round bottomed flask was loaded
with 1-phenyl-3-[2-(prop-2-yn-1-yloxy)phenyl
substituted]-1H-pyrazole-4-carbaldehyade (3a–3c)
(0.01 mol) and azide compound (0.01 mol). A mixture
of copper (II) sulfate pentahydrate (0.0005 mol) and
sodium ascorbate (0.0015 mol) dissolved in t-BuOH–
H2O (2 : 1) was added. The reaction mixture was
stirred for 15–20 h (TLC), then it was poured into ice
cold water. The precipitate was filtered off as white to
pale brown pure solid product.
Concentration,
Compound
Aspergillus
niger
Aspergillus
flavus
µg/mL
4a1
4a2
10
10
10
10
10
10
10
10
10
10
10
50
15.5±0.15
17.5±2.32
9.5±2.18
11.5±1.97
8.5±0.92
12.5±1.22
12.0±1.03
6.5±1.99a
8.5±1.42
14.5±1.06
5.5±1.32a
5.50±0.18
11.5±0.93
10.0±0.42
12.5±0.22
15.5±0.63
9.0±0.83
4a3
4a4
4a5
4a6
18.5±0.72
11.0±0.52
9.5±0.91a
10.5±0.89
8.5±0.63a
7.5±0.82a
7.80±0.67
4a7
4b1
1-[2-(Prop-2-yn-1-yloxy)phenyl] ethanone (2a).
Yield 90%, mp 47–49°C. IR spectrum, ν, cm–1: 3292
(C≡C–H), 2121 (C≡C), 1673 (C=O). 1H NMR
spectrum, δ, ppm: 2.52 t (1H, C≡C–H, J = 2.4 Hz),
2.61 s (3H, COCH3), 4.78 d (2H, O–CH2, J = 2.4 Hz),
7.00–7.05 m (2H, Ar-H), 7.42–7.46 m (1H, Ar-H),
4b2
4c1
4c2
Nystatin
a
Indicates statistically significant compared with Nystatin (p ≤ 0.05).
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PERVARAM et al.
1-Phenyl-3-[2-(prop-2-yn-1-yloxy)phenyl]-1H-
m (3H, Ar-H), 7.18 d (1H, Ar-H, J = 8.4 Hz), 7.35–
7.51 m (7H, Ar-H), 7.61 d.d (1H, Ar-H, J = 1.2,
pyrazole-4-carbaldehyade (3a). Yield 85%, mp 84–
86°C. IR spectrum, ν, cm–1: 3297 (C≡C), 2859 (H–
7.6 Hz), 7.75 d (2H, Ar-H, J = 7.6 Hz), 8.42 s (1H,
1
13
C=O), 2109 (C≡C), 1676 (C=O). H NMR spectrum,
H
pyrazole), 9.74 s (1H, H–C=O). C NMR spectrum, δC,
δ, ppm: 2.50 t (1H, C≡C–H, J = 2.4 Hz), 4.71 d (2H,
O–CH2, J = 2.4 Hz), 7.13–7.17 m (2H, Ar-H), 7.36 t
(1H, Ar-H, J = 7.6 Hz), 7.44 d (1H, Ar-H, J = 1.6 Hz),
7.48 t (2H, Ar-H, J = 8 Hz), 7.63 d.d (1H, Ar-H, J =
ppm: 53.4, 62.8, 112.8, 119.6, 120.9, 121.8, 122.7,
122.8, 123.2, 127.8, 128.8, 129.6, 129.7, 131, 131.4,
132.2, 133.4, 139, 151.9, 155.5, 186.5. Found, %: C
66.69; H 3.90; N 13.65. C26H20BrN5O2. Calculated, %:
C 60.71; H 3.92; N 13.62.
1.6, 7.6 Hz), 7.77 d (2H, Ar-H, J = 7.6 Hz), 8.51 s (1H,
13
H
pyrazole), 9.84 s (1H, H–C=O). C NMR spectrum, δC,
3-{2-[(1-(3,5-Dimethylbenzyl)-1H-1,2,3-triazol-4-
yl)methoxy]phenyl}-1-phenyl-1H-pyrazole-4-
carbal-dehyde (4a4). Yield 77%, mp 124-126°C. IR
ppm: 56, 76.1, 77.9, 112.8, 119.6, 121.1, 122, 123.3,
127.7, 129, 129.6, 130.7, 131.5, 139.1, 151.7, 154.8,
186.6. Found, %: C 75.44; H 4.63; N 9.32.
C19H14N2O2. Calculated, %: C 75.48; H 4.67; N 9.27.
1
spectrum, ν, cm–1: 2852 (H–C=O), 1671 (C=O). H
NMR spectrum, δ, ppm: 2.27 s (6H, 2CH3), 5.23 s (2H,
CH2), 5.37 s (2H, CH2), 6.84 s (2H, Ar-H), 6.94 s (1H,
Ar-H), 7.12 t (1H, Ar-H, J = 7.2 Hz), 7.20 d (1H,
Ar-H, J = 8.0 Hz), 7.35–7.50 m (5H, Ar-H), 7.60 d
(1H, J = 6.8 Hz), 7.74 d (2H, Ar-H, J = 8.0 Hz), 8.42 s
(1H, Hpyrazole), 9.75 s (1H, H–C=O). 13C NMR spec-
trum, δC, ppm: 21.1, 54.1, 62.8, 112.9, 119.6, 120.9,
121.7, 122.8, 123.2, 125.8, 127.7, 128.8, 129.6, 130.2,
130.9, 131.4, 134.2, 138.7, 139.1, 151.9, 155.6, 186.5.
Found, %: C 72.50; H 5.42; N 15.15. C28H25N5O2.
Calculated, %: C 72.55; H 5.44; N 15.11.
3-{2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy]-
phenyl}-1-phenyl-1H-pyrazole-4-carbaldehyde (4a1).
Yield 80%, mp 99–101°C. IR spectrum, ν, cm–1: 2852
1
(H–C=O), 1672 (C=O). H NMR spectrum, δ, ppm:
5.24 s (2H, CH2), 5.47 s (2H, CH2), 7.12 t (1H, Ar-H,
J = 7.6 Hz), 7.19–7.23 m (3H, Ar-H), 7.33–7.51 m
(8H, Ar-H), 7.61 d.d (1H, Ar-H, J = 1.6, 7.6 Hz), 7.75
d (2H, Ar-H, J = 7.6 Hz), 8.42 s (1H, Hpyrazole), 9.75 s
(1H, H–C=O). 13C NMR spectrum, δC, ppm: 53.4,
62.8, 112.8, 119.6, 120.9, 122.9, 123.2, 126.1, 127.7,
128, 128.9, 129.6, 130.4, 130.9, 131.4, 134.9, 136.4,
139.1, 144.3, 151.9, 155.5, 186.5. Found, %: C 71.69;
H 4.83; N 16.11. C26H21N5O2. Calculated, %: C 71.71;
H 4.86; N 16.08.
3-{2-[(1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-
yl)methoxy]phenyl}-1-phenyl-1H-pyrazole-4-car-
baldehyde (4a5). Yield 82%, mp 149–151°C. IR
1
spectrum, ν, cm–1: 2853 (H–C=O), 1682 (C=O). H
3-{2-[(1-(3-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy]phenyl}-1-phenyl-1H-pyrazole-4-carbalde-
hyde (4a2). Yield 81%, mp 102–104°C. IR spectrum,
ν, cm–1: 2855 (H–C=O), 1671 (C=O). 1H NMR
spectrum, δ, ppm: 5.25 s (2H, CH2), 5.44 s (2H, CH2),
7.09–7.15 m (2H, Ar-H), 7.18–7.22 m (2H, Ar-H),
7.29 d (2H, Ar-H, J = 7.2 Hz ), 7.38 t (1H, Ar-H, J =
7.6 Hz), 7.44 s (1H, Ar-H ), 7.45–7.52 m (3H, Ar-H),
7.62 d.d (1H, Ar-H, J = 1.2, 7.2 Hz), 7.75 d (2H, J =
7.6 Hz), 8.45 s (1H, Hpyrazole), 9.76 s (1H, H–C=O). 13C
NMR spectrum, δC, ppm: 51.9, 61.5, 113, 119.1, 120.6,
121, 122.9, 124.7, 126.4, 127.4, 127.6, 128, 129.6,
130.6, 130.7, 131, 131.02, 133.2, 138.3, 138.7, 142.7,
150.7, 155.5, 185.3. Found, %: C 66.40; H 4.27; N
14.95. C26H20ClN5O2. Calculated, %: C 66.45; H 4.29;
N 14.90.
NMR spectrum, δ, ppm: 3.72 s (3H, O–CH3), 5.18 s
(2H, CH2), 5.48 s (2H, CH2), 6.90 d (2H, Ar-H, J =
8.8 Hz), 7.11 t (1H, Ar-H, J = 7.6 Hz), 7.24 d (2H,
Ar-H, J = 8.8 Hz), 7.36–7.42 m (2H, Ar-H), 7.48 d
(2H, Ar-H, J = 7.6 Hz), 7.54 d (2H, Ar-H, J = 7.6 Hz),
7.95 d (2H, Ar-H, J = 7.6 Hz), 8.02 s (1H, Ar-H), 9.11
s (1H, Hpyrazole), 9.71 s (1H, H–C=O). 13C NMR spec-
trum, δC, ppm: 52.3, 55.1, 61.6, 112.9, 114, 119.1,
120.6, 120.9, 122.9, 124.1, 127.4, 127.7, 129.4, 129.6,
130.7, 130.9, 131, 138.7, 142.5, 150.7, 155.6, 159,
185.3. Found, %: C 69.63; H 4.97; N 15.08.
C27H23N5O3. Calculated, %: C 69.66; H 4.98; N 15.04.
4-{[4-([2-(4-Formyl-1-phenyl-1H-pyrazol-3-yl)-
phenoxy]methyl)-1H-1,2,3-triazol-1-yl]methyl}benzoic
acid (4a6). Yield 81%, mp 139–141°C. IR spectrum, ν,
cm–1: 2852 (H–C=O), 1671 (C=O). 1H NMR spectrum,
δ, ppm: 5.20 s (2H, CH2), 5.66 s (2H, CH2), 7.11 t (1H,
Ar-H, J = 7.2 Hz), 7.37–7.39 m (4H, Ar-H), 7.48–7.54
m (4H, Ar-H), 7.94 d (4H, Ar-H, J = 7.2 Hz), 8.14 s
(1H, Ar-H), 9.11 s (1H, Hpyrazole), 9.70 s (1H, H–C=O),
12.96 s (1H, COOH). 13C NMR spectrum, δC, ppm:
3-{2-[(1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy]phenyl}-1-phenyl-1H-pyrazole-4-carbalde-
hyde (4a3). Yield 82%, mp 144-146°C. IR spectrum, ν,
cm–1: 2856 (H–C=O), 1674 (C=O). 1H NMR spectrum,
δ, ppm: 5.22 s (2H, CH2), 5.45 s (2H, CH2), 7.08–7.14
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 10 2017

DESIGN AND SYNTHESIS OF NEW 1,2,3-TRIAZOLE-PYRAZOLE HYBRIDS
2459
1
52.2, 61.4, 112.9, 119, 120.5, 120.9, 122.8, 124.8,
127.3, 128.1, 129.5, 130.6, 130.9, 131.3, 133.2, 138.6,
140.5, 142.8, 150.6, 155.4, 169.1 185.2. Found, %: C
67.60; H 4.37; N 14.62. C27H21N5O3. Calculated, %: C
67.63; H 4.41; N 14.61.
2850 (H–C=O), 1670 (C=O). H NMR spectrum, δ,
ppm: 2.35 s (3H, CH3), 5.19 s (2H, CH2), 5.46 s (2H,
CH2), 7.08 d (1H, Ar-H, J = 8.4 Hz), 7.21–7.24 m (3H,
Ar-H), 7.32–7.42 m (6H, Ar-H), 7.49 t (2H, Ar-H, J =
8.4), 7.74 d (2H, Ar-H, J = 8.0 Hz), 8.41 s (1H,
13
H
pyrazole), 9.74 s (1H, H–C=O). C NMR spectrum, δC,
3-{2-[(1-(2-Hydroxyethyl)-1H-1,2,3-triazol-4-yl)-
methoxy]phenyl}-1-phenyl-1H-pyrazole-4-carbalde-
hyde (4a7). Yield 79%, mp 125–127°C. IR spectrum,
ppm: 20.4, 54.1, 63, 113.1, 119.6, 120.6, 122.7, 123.2,
127.7, 128, 128.6, 128.8, 129, 129.6, 131.2, 131.4,
131.8, 134.5, 139.1, 144.3, 152.1, 153.5, 186.6. Found,
%: C 72.10; H 5.12; N 15.62. C27H23N5O2. Calculated,
%: C 72.14; H 5.16; N 15.58.
1
ν, cm–1: 3390 (OH), 2853 (H–C=O), 1678 (C=O). H
NMR spectrum, δ, ppm: 3.73 q (2H, O–CH2 J = 5.6 Hz),
4.36 t (2H, N–CH2, J = 5.6 Hz), 4.99 t (1H, OH,
J = 5.6 Hz), 5.19 s (2H, O–CH2), 7.11 t (1H, Ar-H, J =
7.6 Hz), 7.38 s (1H, Ar-H), 7.41 d (1H, Ar-H, J =
7.6 Hz), 7.48–7.56 m (4H, Ar-H), 7.95 d (2H, Ar-H,
J = 8.4 Hz), 8.01 s (1H, Ar-H), 9.12 s (1H, Hpyrazole),
9.73 s (1H, H–C=O). 13C NMR spectrum, δC, ppm:
52.1, 59.8, 61.6, 113, 119.1, 120.6, 121, 123, 124.8,
127.5, 129.6, 130.8, 131.1, 131.2, 138.7, 142.1, 150.8,
155.6, 185.5. Found, %: C 64.75; H 4.90; N 17.99.
C21H19N5O3. Calculated, %: C 64.77; H 4.92; N 17.98.
3-{2-[(1-(3-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy]-5-methylphenyl}-1-phenyl-1H-pyrazole-4-
carbaldehyde (4b2). Yield 81%, mp 111–113°C. IR
spectrum, ν, cm–1: 2841 (H–C=O), 1678 (C=O). H
1
NMR spectrum, δ, ppm: 2.31 s (3H, CH3), 5.16 s (2H,
CH2), 5.67 s (2H, CH2), 7.12 d (1H, Ar-H, J = 7.2 Hz),
7.24–7.30 m (2H, Ar-H), 7.34–7.42 m (4H, Ar-H),
7.48–7.56 m (3H, Ar-H), 7.95 d (2H, Ar-H, J =
8.0 Hz), 8.03 s (1H, Ar-H), 9.09 s (1H, Hpyrazole), 9.69 s
(1H, H–C=O). 13C NMR spectrum, δC, ppm: 19.9,
50.5, 61.7, 113, 119.1, 120.4, 122.9, 124.8, 127.4,
127.6, 129.4, 129.5, 129.8, 130.1, 130.2, 130.8, 130.9,
131.3, 132.4, 133.1, 138.6, 142.7, 150.8, 153.4, 185.3.
Found, %: C 67.00; H 4.55; N 14.52. C27H22ClN5O2.
Calculated, %: C 67.01; H 4.58; N 14.47.
1-[5-Methyl-2-(prop-2-yn-1-yloxy)phenyl]ethanone
(2b). Yield 93%, mp 49–51°C. IR spectrum, ν, cm–1:
1
3259 (C≡C–H), 2130 (C≡C), 1652 (C=O). H NMR
spectrum, δ, ppm: 2.25 s (3H, Ar–CH3), 2.52 s (3H,
COCH3), 3.60 t (1H, C≡C–H, J = 2.4), 4.90 d (2H, O-
CH2 J = 2.4 Hz), 7.12 d (1H, Ar-H, J = 8.4 Hz), 7.34
d.d (1H, Ar-H, J = 2.4, 8.4 Hz), 7.37 d (1H, Ar-H, J =
1-[5-Chloro-2-(prop-2-yn-1-yloxy)phenyl]ethanone
(2c). Yield 92%, mp 51–53°C. IR spectrum, ν, cm–1:
3234 (C≡C–H), 2124 (C≡C), 1678 (C=O). H NMR
spectrum, δ, ppm: 2.56 t (1H, C≡C–H, J = 2.8), 2.60 s
(3H, O=CCH3), 4.78 d (2H, O–CH2 J = 2.8 Hz), 7.01 d
(1H, Ar-H, J = 8.8 Hz), 7.39 d.d (1H, Ar-H, J = 2.8,
8.8 Hz), 7.68 d (1H, Ar-H, J = 2.8 Hz). 13C NMR
spectrum, δC, ppm: 31.8, 56.5, 76.5, 77.3, 114.7, 127,
130, 130.1, 132.9, 155.1, 198. Found, %: C 63.29; H
4.30. C11H9ClO2. Calculated, %: C 63.32; H 4.35.
13
2.0 Hz). C NMR spectrum, δC, ppm: 19.8, 31.5, 56.2,
1
78.4, 78.8, 113.9, 128.3, 129.6, 130.2, 133.8, 154.3,
198.6. Found, %: C 76.55; H 6.40. C12H12O2.
Calculated, %: C 76.57; H 6.43.
3-[5-Methyl-2-(prop-2-yn-1-yloxy)phenyl]-1-phenyl-
1H-pyrazole-4-carbaldehyde (3b). Yield 81%, mp
89–91°C. IR spectrum, ν, cm–1: 3307 (C≡C–H), 2864
1
(H–C=O), 2111 (C≡C), 1677 (C=O). H NMR spec-
trum, δ, ppm: 2.37 s (3H, Ar–CH3), 2.48 s (1H, C≡C–H),
4.68 d (2H, O–CH2, J = 1.6), 7.06 d (1H, Ar-H, J =
8.4 Hz), 7.26 t (1H, Ar-H, J = 2.4 Hz), 7.37 t (1H,
Ar-H, J = 7.6 Hz), 7.45 s (1H, Ar-H), 7.49 d (2H,
Ar-H, J = 8.0 Hz), 7.77 d (2H, Ar-H, J = 8.0 Hz), 8.50
s (1H, Hpyrazole), 9.84 s (1H, H–C=O). 13C NMR spec-
trum, δC, ppm: 20.4, 56.2, 75.9, 78.1, 112.9, 119.7,
120.9, 123.3, 127.7, 129, 129.6, 131.1, 131.5, 131.9,
139.2, 151.9, 152.7, 186.7. Found, %: C 75.90; H 5.09;
N 8.89 C20H16N2O2. Calculated, %: C 75.93; H 5.10; N
8.86.
3-[5-Chloro-2-(prop-2-yn-1-yloxy)phenyl]-1-phenyl-
1H-pyrazole-4-carbaldehyde (3c). Yield 84%, mp
94–96°C. IR spectrum, ν, cm–1: 3309 (C≡C–H), 2859
1
(H–C=O), 2111 (C≡C), 1684 (C=O). H NMR spec-
trum, δ, ppm: 2.51 t (1H, C≡C–H, J = 2.4 Hz), 4.69 d
(2H, O–CH2, J = 2.4), 7.10 d (1H, Ar-H, J = 9.2 Hz),
7.36 d (1H, Ar-H, J = 7.2 Hz), 7.40 d.d (1H, Ar-H, J =
2.8, 9.2 Hz), 7.49 t (2H, Ar-H, J = 7.6 Hz), 7.63 d (1H,
Ar-H, J = 2.8 Hz), 7.76 d (2H, Ar-H, J = 8.0 Hz), 8.50
13
s (1H, Hpyrazole), 9.83 s (1H, H–C=O). C NMR spec-
3-{2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy]-5-
methylphenyl}-1-phenyl-1H-pyrazole-4-carbaldehyde
(4b1). Yield 78%, mp 109–111°C. IR spectrum, ν, cm–1:
trum, δC, ppm: 56.4, 76.5, 77.5, 114.2, 119.6, 122.9,
123.4, 127.1, 127.9, 129.4, 129.6, 130.2, 131.2, 139,
150.1, 153.4, 185.9. Found, %: C 67.74; H 3.88; N
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 10 2017

2460
PERVARAM et al.
8.36. C19H13ClN2O2. Calculated, %: C 67.76; H 3.89;
N 8.32.
compounds were inoculated into the wells and the
plates were incubated at 37°C for 24 h. Each test was
carried out in triplicate with controls. Microbial growth
was determined by measuring the diameter of
inhibition zone. The minimum inhibitory concentration
was determined using the tube dilution techniques
[27, 28]. Various concentrations of each compound
were prepared using single dilution method. The least
concentration of each compound that did not permit
any visible growth or turbidity of the inoculated test
organisms in broth culture was taken as the minimum
inhibitory concentration in each case. Control
experiments with each compound and a tube with no
compound were also performed.
3-{2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy]-5-
chlorophenyl}-1-phenyl-1H-pyrazole-4-carbaldehyde
(4c1). Yield 82%, mp 114–116°C. IR spectrum, ν, cm–1:
1
2847 (H–C=O), 1673 (C=O). H NMR spectrum, δ,
ppm: 5.23 s (2H, CH2), 5.46 s (2H, CH2), 7.15 d (1H,
Ar-H, J = 8.8 Hz), 7.24–7.26 m (2H, Ar-H), 7.34–7.40
m (6H, Ar-H), 7.50 t (2H, Ar-H, J = 7.2 Hz), 7.60 s
(1H, Ar-H), 7.74 d (2H, Ar-H, J = 7.6 Hz), 8.41 s (1H,
13
H
pyrazole), 9.74 s (1H, H–C=O). C NMR spectrum, δC,
ppm: 54.2, 63, 114.3, 119.6, 122.6, 122.9, 123.2,
126.8, 127.9, 128.1, 128.7, 129.1, 129.2, 129.7, 130.5,
131.1, 134.4, 139, 143.6, 150.4, 154.2, 185.9. Found,
%: C 66.44; H 4.26; N 14.95. C26H20ClN5O2.
Calculated, %: C 66.45; H 4.29; N 14.90.
Antifungal activity. Antifungal activity was studied
by the well plate or disc diffusion method [29, 30].
Fungal suspension (2×105) was streaked on the potato
dextrose agar (PDA) medium. Then, wells were loaded
with different concentrations of synthesized com-
pounds. Similarly, each plate was loaded with a sterile
disc and tetracycline as a positive control. All plates
were incubated at 28°C for 24–48 h. The zones of
growth inhibition were measured after 48 h. Sensitivity
of the fungal species to each compound was deter-
mined by measuring the sizes of inhibition zones. The
MIC was determined by the broth micro dilution
method using 96-well micro-plates [29, 30]. Each
sample (1.0 mg) was dissolved in DMSO (1 mL) to
obtain 1000 μg/mL stock solution. Nystatin was used
as a positive control. Plates were incubated at 37°C for
24 h.
3-{5-Chloro-2-[(1-(3-chlorobenzyl)-1H-1,2,3-tri-
azol-4-yl)methoxy]phenyl}-1-phenyl-1H-pyrazole-4-
carbaldehyde (4c2). Yield 79%, mp 119–121°C. IR
1
spectrum, ν, cm–1: 2854 (H–C=O), 1673 (C=O). H
NMR spectrum, δ, ppm: 5.22 s (2H, CH2), 5.68 s (2H,
CH2), 7.12 d (1H, Ar-H, J = 6.8 Hz), 7.35–7.43 m (4H,
Ar-H), 7.50–7.55 m (5H, Ar-H), 7.96 d (2H, Ar-H, J =
7.6 Hz), 8.09 s (1H, Ar-H), 9.16 s (1H, Hpyrazole), 9.72 s
(1H, H–C=O). 13C NMR spectrum, δC, ppm: 50.6,
61.9, 114.9, 119.2, 122.6, 123, 124.7, 125.2, 127.6,
127.7, 129.6, 129.7, 130.2, 130.3, 131.6, 132.5, 133.2,
138.6, 142.3, 149.1, 154.5, 185.2. Found, %: C 61.89;
H 3.79; N 13.93. C26H19Cl2N5O2. Calculated, %: C
61.91; H 3.80; N 13.89.
Antibacterial activity. Synthesized compounds have
been assayed for their antimicrobial activity against
different bacteria. The entire organisms were collected
from Department of Microbiology, Osmania University,
Hyderabad. Seven bacterial strains Escherichia coli
ATCC 25922, Klebsiella pneumoniae ATCC 15380,
Pseudomonas aeruginosa ATCC 12454, Staphylo-
coccus aureus ATCC 25923, and Streptococcus
pyogenes ATCC 35552 were used in the study.
Microbial cultures were stored at –20°C in micro-
centrifuge tubes having 40% sterile glycerol. Syn-
thesized compounds inhibitory activity was tested
according to the “well plate or disc diffusion
method” [27, 28]. The wells were created in Mueller
Hinton solid agar medium with well puncture10,
Trypton soy agar or Nutrient agar. The media was pre-
inoculated with test organisms. The standard inoculum
size was of (1–2)×108 CFU/mL of bacteria for
inoculating diffusion plates13 which was equal to
McFarland 0.5 turbidity standard. After that all tested
CONCLUSIONS
Herein, we present the synthesis of a new series of
1,2,3-triazole-pyrazole hybrids 4a1–4a7, 4b1, 4b2, 4c1,
and 4c2 using a two step synthetic route in which a
substituted 1,2,3-triazole ring was constructed in the
final step via the click reaction protocol. All target
compounds were characterized by IR, H and 13C
1
NMR, and MS spectral data and elemental analysis.
The in vitro antibacterial and antifungal activity
screening data accumulated for the synthesized com-
pounds demonstrated promising antibacterial and anti-
fungal activity.
ACKNOWLEDGMENTS
The authors are thankful to the Head, Department
of Chemistry, JNTU-H and Osmania University,
Hyderabad for the valuable support.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 10 2017

DESIGN AND SYNTHESIS OF NEW 1,2,3-TRIAZOLE-PYRAZOLE HYBRIDS
2461
and Mello, C.F., Eur. J. Pharmacol., 2002, vol. 451,
p. 141. doi org/10.1016/S0014-2999(02)02225-2
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