Ultrasound-Mediated Synthesis of Novel 1,2,3-Triazole-Based Pyrazole and Pyrimidine Derivatives as Antimicrobial Agents

Article abstract of DOI:10.1002/jhet.2935

In the development of novel antimicrobial agents, we synthesized novel 1,2,3-triazole-based pyrazole and pyrimidine derivatives 6(a–f) and 7(a–f) by ultrasound-assisted method. The synthesized compounds were characterized by IR, ¹H NMR, ¹³

Full text of DOI:10.1002/jhet.2935

Month 2017
Ultrasound-Mediated Synthesis of Novel 1,2,3-Triazole-Based Pyrazole
and Pyrimidine Derivatives as Antimicrobial Agents
a
Vidya S. Dofe,
Aniket P. Sarkate,b Zarina M. Shaikh,c and Charansingh H. Gilla
*
aDepartment of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India
bDepartment of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India
cDepartment of Microbiology, Maulana Azad College of Arts, Science and Commerce, Aurangabad 431 001, India
*
E-mail: vidya.dofe84@gmail.com
Received February 20, 2017
DOI 10.1002/jhet.2935
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
In the development of novel antimicrobial agents, we synthesized novel 1,2,3-triazole-based pyrazole and
pyrimidine derivatives 6(a–f) and 7(a–f) by ultrasound-assisted method. The synthesized compounds were
characterized by IR, 1H NMR, 13C NMR, MS, and elemental analysis. All compounds were assessed
in vitro for their efficacy as antimicrobial agents against four bacteria (Staphylococcus aureus, Bacillus
subtilis, Escherichia coli, and Pseudomonas aeruginosa) and two fungi (Candida albicans and Aspergillus
niger). In particular, compounds 6a, 6e, 7a, 7c, and 7e exhibited highly potent antimicrobial activity.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
active drugs carrying pyrazole substituents. Triazole
nucleus is an important pharmacophore that appears
extensively in various types of pharmaceutical agents and
bioactive molecules, such as anti-HIV [6], antitubercular
[7], anti-inflammatory, anticancer [8], antimicrobial [9],
anticonvulsant [10], antimalarial [11], analgesic [12],
antiviral [13], antidiabetic [14], and antimycobacterial
[15]. The biological activity of these compounds is
enhanced probably due to their high aromatic stabilization,
high dipole moment, and high bonding capacity. On the
other hand, pyrimidines occupy a distinct and unique
place in medicinal chemistry due to their presence in
several biologically active compounds [16]. Pyrimidine
derivatives are of interest due to their pharmacological
Microbial infections are major problems around the
world. There is a need for development of new
antimicrobial agents which will be more selective, potent,
and less toxic compared to the existing drugs to treat
these life-threatening invasive infections [1].
Heterocycles containing an azole ring system are found to
exhibit a wide spectrum of biological activities, including
antibacterial and antifungal properties. Pyrazole
derivatives have showed significant biological activities,
such as antimicrobial [2], antianalgesic [3], anti-
inflammatory [4], and anticancer activities [5]. This gave a
great force to the search for potential pharmacologically
© 2017 Wiley Periodicals, Inc.

V. S. Dofe, A. P. Sarkate, Z. M. Shaikh, and C. H. Gill
Vol 000
properties such as antitumor [17], antifilarial [18], antiviral
[19], antifungal [20], antibacterial [21], anti-inflammatory
[22], analgesic [23], anti-HIV [24], antiprotozoal [25],
antihypertensive [26] activity.
A survey of literatures showed that ultrasound-
accelerated chemical reactions have attracted much
attention during the past few years. Ultrasound irradiation
has been considered as a green and efficient technique
used as an alternative energy source for organic reactions
[27,28]. Keeping in view the importance of greener
protocol, we designed and synthesized 1,2,3-triazole-based
pyrazole and pyrimidine derivatives under ultrasound
irradiation and evaluated for antimicrobial activity.
(Scheme 3). Moreover, these reactions were performed
under ultrasound irradiation to afford substituted 2-(4-((1-
benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-(4-
fluorophenyl)-1H-pyrazol-3-yl)phenol 6(a–f) and 5-
((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-6-(4-
fluorophenyl)-4-(2-hydroxyphenyl)pyrimidine-2(1H)-
thione 7(a–f).
The synthesized compounds 6a and 7a were confirmed
1
by IR, MS, H NMR, 13C NMR, and elemental analysis.
In the mass spectrum of 6a, the [M + H]+ observed at
442.1632. In the 1H NMR spectrum of compound 6a,
the two methylene groups attached to nitrogen and
oxygen showed singlets at δ 4.81 and 5.51 ppm,
respectively, and proton of triazole ring showed singlet
at δ 7.95 ppm. In addition to this, hydroxy proton
showed singlet at δ 10.91 ppm and the pyrazole proton
showed singlet at δ 13.44 ppm. In the 13C NMR
spectrum of compound 6a, the signal at 52.8 and
66.3 ppm indicates the presence of methylene carbon
attached to the nitrogen of the triazole ring and oxygen to
the phenyl ring, respectively. In the mass spectrum of 7a,
the [M + H]+ observed at 486.53. In the 1H NMR spectrum
of compound 7a, the two methylene groups attached to
nitrogen and oxygen showed singlets at δ 4.66 and
5.38 ppm, respectively, and proton of triazole ring showed
singlet at δ 7.99 ppm. In addition to this, hydroxy proton
showed singlet at δ 10.11 ppm and the pyrazole proton
showed singlet at δ 11.68 ppm. In the 13C NMR spectrum
of compound 7a, the signal at 52.7 and 63.6 ppm indicates
RESULTS AND DISCUSSION
Chemistry.
The key starting material, 3-((1-benzyl-
1H-1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-
chromen-4-one 5(a–f), was synthesized in our previous
report [29] (Scheme 1). We have synthesized novel
triazole-based pyrazole derivatives 6(a–f) and triazole-
based pyrimidine derivatives 7(a–f) under conventional
method as well as ultrasound irradiation method.
The compounds 5(a–f) have been treated with hydrazine
hydrate in ethanol at reflux condition to furnish the desired
product 6(a–f) (Scheme 2). The compounds 5(a–f) have
been treated with thiourea in ethanol by using KOH at
reflux condition to furnish the desired product 7(a–f)
Scheme 1. Synthesis of triazole derivatives 5(a–f).
Scheme 2. Synthesis of triazole-based pyrazole derivatives 6(a–f).
Journal of Heterocyclic Chemistry
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Pyrazole and Pyrimidine as Antimicrobial Agents
Scheme 3. Synthesis of triazole-based pyrimidine derivatives 7(a–f).
Table 1
Ultrasound-promoted synthesis of pyrazole and pyrimidine derivatives 6(a–f) and 7(a–f).
Conventional method
Ultrasound method
Comp.
R1
R2
R3
M. P. (°C)
Yielda (%)
Time (min)
Yielda (%)
Time (min)
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
H
H
CH3
H
Cl
H
H
H
CH3
H
Cl
H
H
H
H
H
H
CH3
H
H
H
H
H
CH3
H
Cl
H
CH3
Cl
Cl
H
Cl
H
186–188
180–182
208–210
152–154
182–184
187–189
170–172
288–290
105–107
85–87
60
65
61
69
72
71
69
71
68
72
77
79
360
310
320
330
290
310
225
195
215
210
190
205
85
86
89
92
96
90
89
91
87
94
93
91
51
48
54
54
43
45
21
18
27
24
15
18
CH3
Cl
Cl
238–240
200–202
aIsolated yields.
Table 2
the presence of methylene carbon attached to the nitrogen of
the triazole ring and oxygen to the phenyl ring, respectively.
Furthermore, the signal at 199.8 ppm indicates the presence
of pyrimidine carbon. Similarly, all other derivatives 6(b–f)
and 7(b–f) was satisfactory in good conformity with the
spectroscopic properties (Table 1).
Antimicrobial screening data of the compounds 6(a–f) and 7(a–f).
Antimicrobial activitya (μg/mL)
Antifungal
activity
Antibacterial activity
Antimicrobial activity. In the screening assay studies, all
the compounds were evaluated for antibacterial activity
against Gram-positive bacteria viz. Staphylococcus aureus
(NCIM 2079) and Bacillus subtilis (NCIM 2920) and
Gram-negative bacteria Escherichia coli (NCIM 2065) and
Pseudomonas aeruginosa (NCIM 2200) and antifungal
activity against Candida albicans (NCIM 3471) and
Aspergillus niger (NCIM 596) (Table 2). The minimum
inhibitory concentration (MIC) values were determined by
microbroth dilution method. The result of antibacterial
screening was compared with the standard antibacterial
drug Chloramphenicol, and antibacterial screening was
compared with the standard antibacterial drug Clotrimazole.
Dimethylsulfoxide (DMSO) was used as solvent control.
From the antimicrobial screening of newly synthesized
compounds, compound 7f showed equipotent activity
against S. aureus and compounds 6d and 7a showed
equipotent activity against E. coli and compounds 6a and
7f showed equipotent activity against P. aeruginosa
compared with Chloramphenicol MIC 50 μg/mL.
Entry
Sa
Bs
Ec
Pa
Ca
An
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
12.5
200
25
25
25
150
25
100
12.5
100
75
12.5
100
125
50
50
175
25
100
50
125
12.5
50
25
75
100
50
75
75
50
175
25
150
25
75
50
200
100
100
75
125
75
150
75
175
75
50
50
–
25
50
75
75
50
50
25
75
50
75
50
75
–
50
150
125
50
12.5
25
50
125
50
100
25
25
–
25
50
Chloramphenicol 50
Clotrimazole
25
–
50
–
–
50
Sa, Staphylococcus aureus; Bs, Bacillus subtilis; Ec, Escherichia coli; Pa,
Pseudomonas aeruginosa; Ca, Candida albicans; An, Aspergillus niger.
aMinimum inhibitory concentration (μg/mL) against the pathological
strains based on microbroth dilution method.
Compound 7a showed equipotent activity against B.
subtilis compared with Chloramphenicol MIC 25 μg/mL.
Compound 6a has no substituent, and 7c has methyl
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V. S. Dofe, A. P. Sarkate, Z. M. Shaikh, and C. H. Gill
Vol 000
group with MIC 12.5 μg/mL and showed potent activity
against S. aureus. Compounds 6a and 7e with MIC
12.5 μg/mL exhibited potent activity against B. subtilis.
Compounds 6a, 7c, and 7e with MIC 25 μg/mL exhibited
potent activity against E. coli.
Compounds 6b, 6e, 7c, and 7e showed equipotent activity
with Clotrimazole MIC 50 μg/mL against C. albicans.
Compounds 6f, 7e, and 7f showed equipotent activity with
Clotrimazole MIC 25 μg/mL against A. niger. Compounds
6a and 7a has no substituent and showed potent activity
with MIC 25 μg/mL against C. albicans. Compound 6e
has dichloro substituent and exhibited highly potent
antifungal activity against A. niger with MIC 12.5 μg/mL.
General procedure for the synthesis of 2-(4-((1-benzyl-1H-
1,2,3-triazol-4-yl)methoxy)-5-(4-fluorophenyl)-1H-pyrazol-3-
yl)phenols 6(a–f). Conventional method.
Hydrazine
hydrate (1.0 mmol) was added to a solution of 3-((1-
benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-
4H-chromen-4-ones 5(a–f) (1.0 mmol) in ethanol (10 mL).
The reaction mixture was heated for 5–6 h. After
completion of the reaction (monitored by TLC), 10 mL
cold water was added and the product was filtered, dried
under vacuum, and crystallized from ethanol.
Non conventional method.
Hydrazine hydrate
(1.0 mmol) was added to a solution of 3-((1-benzyl-1H-
1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-
4-ones 5(a–f) (1 mmol) in ethanol (10 mL). The reaction
mixture was irradiated under ultrasonication for 40–55 min
at 65°C. After completion of reaction (monitored by TLC),
10 mL cold water was added and the product was filtered,
CONCLUSIONS
dried under vacuum, and crystallized from ethanol.
Ultrasonic irradiation was used to promote the synthesis
of triazole-based pyrazole and pyrimidine derivatives 6
(a–f) and 7(a–f) in good yields with more purity in short
reaction time as compared to the conventional method.
The synthesized compounds were evaluated for
antimicrobial activity. It can be concluded that the
compounds 6a, 6e, 7a, 7c, and 7e were identified as
highly potent antimicrobial agents.
2-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-(4-fluorophenyl)-
1H-pyrazol-3-yl)phenol (6a).
IR (KBr, cmÀ1): 3655, 3126,
3036. 1H NMR (400 MHz, CDCl3, δH ppm): 4.81 (s, 2H,
NCH2), 5.51 (s, 2H, OCH2), 6.88–6.94 (m, 2H, ArH),
6.99 (d, 1H, J = 8.1 Hz, ArH), 7.16–7.22 (m, 4H, ArH),
7.27 (t, 1H, J = 9.0 Hz, ArH), 7.31–7.33 (m, 2H, ArH),
7.35 (s, 1H, ArH), 7.85–7.89 (m, 1H, ArH), 7.95 (s, 1H,
triazole-H), 8.04–8.05 (m, 1H, ArH), 10.91 (s, 1H, OH),
13.44 (brs, 1H, NH). 13C NMR (100 MHz, CDCl3, δC
ppm): 52.8, 66.3, 115.2, 115.6, 115.9, 116.3, 119.1,
124.3, 124.7, 126.5, 127.7, 128.0, 128.6, 128.7, 129.0,
129.1, 129.1, 129.2, 131.9, 135.6, 142.2, 154.3, 155.3,
160.6, 163.1. LCMS Anal. Calcd. for C25H20FN5O2
[M + H]+: 442.1679. Found: 442.1632. Anal. calcd. for
C25H20FN5O2: C, 68.02; H, 4.57; N, 15.86. Found: C,
EXPERIMENTAL
Material and methods. All the solvents and reagents
used in synthesis were obtained from commercial sources
and were used without further purification. Melting points
were recorded by the open tube capillary method and are
uncorrected. The purity of compounds and completion of
the reaction was checked by thin-layer chromatography
(TLC). Infrared spectra were recorded on Carry 600 Series
(Agilent, Santa Clara, CA) FT-IR spectrophotometer by
68.08; H, 4.47; N, 15.82.
2-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-(4-fluorophenyl)-
1H-pyrazol-3-yl)-4-chlorophenol (6b). IR (KBr, cmÀ1): 3680,
1
3136, 3087. H NMR (400 MHz, CDCl3, δH ppm): 4.85
(s, 2H, NCH2), 5.49 (s, 2H, OCH2), 6.89 (d, 1H,
J = 8.4 Hz, ArH), 7.13 (dd, 2H, J = 2.4, 8.6 Hz, ArH),
7.19–7.23 (m, 3H, ArH), 7.29–7.32 (m, 3H, ArH), 7.86
(s, 2H, ArH), 7.92 (s, 1H, triazole-H), 7.97 (s, 1H, ArH),
10.95 (s, 1H, OH), 13.51 (s, 1H, NH). 13C NMR
(100 MHz, CDCl3, δC ppm): 53.0, 66.4, 115.6, 115.8,
117.6, 117.7, 123.0, 124.1, 125.6, 127.7, 128.0, 128.1,
128.5, 132.0, 132.3, 135.2, 135.3, 136.5, 136.6, 140.2,
142.1, 153.9, 154.0, 160.7, 163.2. ESI-MS Anal. Calcd.
for C25H19ClFN5O2 [M + H]+: 476.13. Found: 476.06.
Anal. calcd. for C25H19ClFN5O2: C, 63.09; H, 4.02; N,
1
using KBr pellets. H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on Bruker AVANCE II
400 NMR spectrometer (Japan) in CDCl3/ DMSO-d6
solution. Tetramethylsilane was used as an internal
standard. Chemical shift values are given in ppm relative
to TMS as internal reference and the coupling constant (J)
in hertz. The splitting pattern abbreviations are assigned as
singlet (s), doublet (d), triplet (t), broad singlet (brs),
doublet of doublets (dd), and multiplet (m). Mass spectra
were recorded on a WATERS, Q-TOF micro mass
(Milford, MA, United States) equipped with an Electron
Spin Impact (ESI) Source. Elemental analysis was
performed on a Perkin-Elmer EAL-240 elemental analyzer
(Germany). For ultrasonic irradiation, Bandelin Sonorex
(Berlin, Germany) (frequency 40 MHz, power 100 W)
ultrasound bath was used, and the reaction flask was
located in the ultrasonic bath containing water.
14.72. Found: C, 63.01; H, 3.91; N, 14.70.
2-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-(4-fluorophenyl)-
1H-pyrazol-3-yl)-6-methylphenol (6c). IR (KBr, cmÀ1): 3629,
1
3139, 3032. H NMR (400 MHz, CDCl3, δH ppm): 2.51
(s, 3H, CH3), 4.85 (s, 2H, NCH2), 5.48 (s, 2H, OCH2),
6.80–6.84 (m, 3H, ArH), 7.18–7.24 (m, 3H, ArH), 7.26–
7.29 (m, 3H, ArH), 7.86–7.88 (m, 2H, ArH), 7.91 (s, 1H,
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triazole-H), 7.96–7.98 (m, 1H, ArH), 10.94 (s, 1H, OH),
13.49 (s, 1H, NH). 13C NMR (100 MHz, CDCl3, δC
ppm): 15.3, 52.9, 66.3, 115.5, 115.9, 117.4, 117.8, 122.7,
123.8, 124.9, 127.5, 128.0, 128.6, 128.9, 132.3, 132.6,
134.6, 135.4, 136.3, 136.7, 139.6, 141.6, 154.7, 154.9,
161.3, 163.6. ESI-MS Anal. Calcd. for C26H22FN5O2
[M + H]+: 456.18. Found: 456.22. Anal. calcd. for
C26H22FN5O2: C, 68.56; H, 4.87; N, 15.38. Found: C,
68.65; H, 4.97; N, 15.32.
General procedure for the synthesis of 5-((1-benzyl-1H-1,2,3-
triazol-4-yl)methoxy)-6-(4-fluorophenyl)-4-(2-hydroxyphenyl)
pyrimidine-2(1H)-thiones 7(a–f). Conventional method.
Thiourea (1.5 mmol) was added to a mixture of
substituted 3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2-
(4-fluorophenyl)-4H-chromen-4-ones 5(a–f) (1.0 mmol)
and KOH (1.5 mmol) in ethanol (10 mL), and the reaction
mixture was heated for 3–4 h. After completion of the
reaction (monitored by TLC), reaction mass was cooled to
the room temperature and poured on crushed ice, and
acidified with Conc. HCl to get yellow solid. The solid
was filtered off and crystallized from ethanol.
2-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-(4-fluorophenyl)-
1H-pyrazol-3-yl)-4-methylphenol (6d).
IR (KBr, cmÀ1):
3628, 3136, 3032. 1H NMR (400 MHz, CDCl3, δH ppm):
2.47 (s, 3H, CH3), 4.85 (s, 2H, NCH2), 5.50 (s, 2H,
OCH2), 6.81–6.83 (m, 2H, ArH), 7.20–7.23 (m, 3H,
ArH), 7.26–7.31 (m, 4H, ArH), 7.88–7.89 (m, 1H, ArH),
7.91 (s, 1H, triazole-H), 7.94–7.97 (m, 2H, ArH), 10.92
(s, 1H, OH), 13.51 (s, 1H, NH). 13C NMR (100 MHz,
CDCl3, δC ppm): 20.4, 52.8, 66.1, 115.5, 115.9, 117.6,
117.9, 123.0, 123.4, 125.2, 127.9, 128.4, 128.7, 129.3,
131.9, 132.4, 134.7, 135.0, 135.8, 136.5, 139.2, 140.9,
154.2, 155.1, 161.2, 163.8. ESI-MS Anal. Calcd. for
C26H22FN5O2 [M + H]+: 456.18. Found: 456.14. Anal.
calcd. for C26H22FN5O2: C, 68.56; H, 4.87; N, 15.38.
Found: C, 68.53; H, 4.76; N, 15.35.
Non conventional method.
Thiourea (1.5 mmol) was
added To a mixture of substituted 3-((1-benzyl-1H-1,2,3-
triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-4-
ones 5(a–f) (1.0 mmol) and KOH (1.5 mmol) in ethanol
(10 mL), and the reaction mass was irradiated under
ultrasonication at 65°C. After completion of the reaction
(monitored by TLC), reaction mass was cooled to the
room temperature and poured on crushed ice, and
acidified with Conc. HCl to get yellow solid. The solid
was filtered off and crystallized from ethanol.
5-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-6-(4-fluorophenyl)-4-
(2-hydroxyphenyl)pyrimidine-2(1H)-thione (7a).
IR (KBr,
cmÀ1): 3914, 3660, 3070, 1603. 1H NMR (400 MHz,
CDCl3, δH ppm): 4.66 (s, 2H, NCH2), 5.38 (s, 2H, OCH2),
6.96–7.01 (m, 9H, ArH), 7.54 (dd, 1H, J = 1.5, 8.1 Hz,
ArH), 7.76 (dd, 3H, J = 5.5, 8.8 Hz, ArH), 7.99 (s, 1H,
triazole-H), 10.11 (brs, 1H, OH), 11.68 (s, 1H, NH). 13C
NMR (100 MHz, CDCl3, δC ppm): 52.7, 63.6, 115.3, 115.5,
117.5, 118.9, 119.2, 120.1, 121.7, 124.3, 124.4, 127.9, 127.9,
128.1, 128.2, 128.7, 129.7, 131.7, 135.5, 141.8, 144.0, 146.8,
155.7, 159.6, 160.8, 199.8. ESI-MS Anal. Calcd. for
C26H20FN5O2S [M + H]+: 486.14. Found: 486.53. Anal.
calcd. for C26H20FN5O2S: C, 64.32; H, 4.15; N, 14.42; S,
6.60. Found: C, 64.38; H, 4.17; N, 14.47, S, 6.56.
2-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-(4-fluorophenyl)-
1H-pyrazol-3-yl)-4,6-dichlorophenol (6e).
IR (KBr, cmÀ1):
3629, 3136, 3064. 1H NMR (400 MHz, CDCl3, δH ppm):
4.83 (s, 2H, NCH2), 5.45 (s, 2H, OCH2), 7.18 (d, 2H,
J = 2.4 Hz, ArH), 7.21–7.25 (m, 2H, ArH), 7.28–7.31
(m, 3H, ArH), 7.83–7.86 (m, 2H, ArH), 7.90 (s, 1H,
triazole-H), 7.92–7.94 (m, 2H, ArH), 10.91 (s, 1H, OH),
13.55 (s, 1H, NH). 13C NMR (100 MHz, CDCl3, δC
ppm): 53.3, 66.5, 115.3, 115.9, 117.7, 117.9, 123.2,
123.3, 126.4, 127.9, 128.2, 128.6, 129.0, 131.8, 132.4,
135.2, 135.6, 136.1, 136.3, 139.7, 142.3, 153.6, 154.4,
160.4, 163.7. ESI-MS Anal. Calcd. for C25H18Cl2FN5O2
[M + H]+: 510.09. Found: 510.12. Anal. calcd. for
C25H18Cl2FN5O2: C, 58.84; H, 3.56; N, 13.72. Found:
C, 58.76; H, 3.64; N, 13.85.
5-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(5-chloro-2-
hydroxyphenyl)-6-(4-fluorophenyl)pyrimidine-2(1H)-thione
(7b). IR (KBr, cmÀ1): 3917, 3670, 3071, 1639. 1H NMR
(400 MHz, CDCl3, δH ppm): 4.54 (s, 2H, NCH2), 5.38 (s,
2H, OCH2), 6.87 (d, 1H, ArH), 7.54 (dd, 1H, J = 8.8 Hz,
ArH), 7.12 (s, 1H, ArH), 7.14 (s, 1H, ArH), 7.16 (d, 1H,
J = 2.2 Hz, ArH), 7.21 (dd, 1H, J = 2.6, 8.8 Hz, ArH),
7.29–7.30 (m, 3H, ArH), 7.41 (s, 1H, ArH), 7.51 (d, 1H,
J = 2.6 Hz, ArH), 8.02 (dd, 2H, J = 5.5, 8.8 Hz, ArH),
8.08 (s, 1H, triazole-H), 10.69 (s, 1H, OH), 10.73 (s, 1H,
NH). 13C NMR (100 MHz, CDCl3, δC ppm): 52.9, 65.9,
115.1, 115.3, 118.2, 122.0, 122.6, 124.0, 127.8, 128.1,
128.5, 129.5, 130.5, 130.6, 131.1, 131.6, 131.7, 134.9,
141.6, 146.3, 155.1, 158.4, 159.3, 161.0, 162.3, 194.7.
ESI-MS Anal. Calcd. for C26H19ClFN5O2S [M + H]+:
2-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-(4-fluorophenyl)-
1H-pyrazol-3-yl)-4-chloro-5-methylphenol (6f). IR (KBr, cmÀ1):
3680, 3136, 3087. 1H NMR (400 MHz, CDCl3, δH ppm):
2.46 (s, 3H, CH3), 4.82 (s, 2H, NCH2), 5.47 (s, 2H,
OCH2), 6.83 (s, 1H, ArH), 7.15–7.18 (m, 2H, ArH),
7.21–7.25 (m, 3H, ArH), 7.30–7.34 (m, 4H, ArH), 7.96
(s, 1H, triazole-H), 8.16 (s, 1H, ArH), 10.94 (s, 1H, OH),
13.50 (s, 1H, NH). 13C NMR (100 MHz, CDCl3, δC
ppm): 20.3, 53.1, 66.5, 115.4, 115.6, 117.7, 117.8, 123.3,
124.5, 124.9, 127.5, 127.9, 128.4, 128.6, 131.9, 132.2,
135.4, 135.7, 137.0, 137.3, 140.3, 142.5, 152.9, 154.6,
160.8, 163.5. ESI-MS Anal. Calcd. for C26H21ClFN5O2
[M + H]+: 490.14. Found: 490.07. Anal. calcd. for
C26H21ClFN5O2: C, 63.74; H, 4.32; N, 14.29. Found: C,
63.62; H, 4.27; N, 14.25.
520.10.
Found:
520.20.
Anal.
calcd.
for
C26H19ClFN5O2S: C, 60.06; H, 3.68; N, 13.47; S, 6.17.
Found: C, 60.11; H, 3.72; N, 13.42; S, 6.23.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. S. Dofe, A. P. Sarkate, Z. M. Shaikh, and C. H. Gill
Vol 000
5-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-6-(4-fluorophenyl)-4-
115.8, 115.9, 117.3, 117.6, 124.5, 124.6, 124.8, 127.9,
128.5, 128.7, 128.9, 132.3, 132.6, 135.9, 136.0, 137.4,
137.6, 141.8, 143.4, 152.6, 155.0, 161.2, 164.3, 190.2.
ESI-MS Anal. Calcd. for C27H21ClFN5O2S [M + H]+:
(2-hydroxy-3-methylphenyl)pyrimidine-2(1H)-thione (7c).
IR
(KBr, cmÀ1): 3981, 3629, 3064, 1625. 1H NMR
(400 MHz, CDCl3, δH ppm): 2.56 (s, 3H, CH3), 4.74 (s,
2H, NCH2), 5.52 (s, 2H, OCH2), 6.71–6.76 (m, 3H,
ArH), 7.21–7.25 (m, 4H, ArH), 7.32–7.35 (m, 2H, ArH),
7.79–7.82 (m, 2H, ArH), 7.94–7.96 (m, 1H, ArH), 8.02
(s, 1H, triazole-H), 10.87 (s, 1H, OH), 11.57 (s, 1H,
NH). 13C NMR (100 MHz, CDCl3, δC ppm): 16.1, 53.3,
65.9, 115.7, 115.9, 117.9, 118.0, 123.1, 123.9, 125.9,
127.9, 128.2, 128.9, 129.5, 132.7, 133.1, 134.9, 135.8,
137.1, 137.5, 140.4, 142.2, 155.3, 155.6, 161.6, 164.5,
196.3. ESI-MS Anal. Calcd. for C27H22FN5O2S
[M + H]+: 500.16. Found: 500.11. Anal. calcd. for
C27H22FN5O2S: C, 64.91; H, 4.44; N, 14.02; S, 6.42.
534.12.
Found:
534.08.
Anal.
calcd.
for
C27H21ClFN5O2S: C, 60.73; H, 3.96; N, 13.11; S, 6.00.
Found: C, 59.68; H, 3.92; N, 13.08; S, 6.04.
Antimicrobial activity. In vitro antibacterial activity of
the synthesized compounds was tested against Gram-
positive bacteria viz. Staphylococcus aureus (NCIM
2079) and Bacillus subtilis (NCIM 2920) and Gram-
negative bacteria Escherichia coli (NCIM 2065) and
Pseudomonas aeruginosa (NCIM 2200). The compounds
were also screened for antifungal activity against
Candida albicans (NCIM 3471) and Aspergillus niger
(NCIM 596). Compounds were diluted in DMSO with
1 μg/mL concentrations for bioassay. Microbroth dilution
method [30] used to determined in vitro MIC of
compounds in 96-well microtiter plates. National
Committee for Clinical Laboratory Standards defined the
method against a panel of human pathogenic strains. Test
compounds were serially double diluted in growth
medium. Plates were incubated at 30°C for fungi and
37°C for bacteria for 24 h. All experiments were carried
out in triplicates, and mean values are represented.
Found: C, 64.86; H, 4.38; N, 13.96; S, 6.38.
5-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-6-(4-fluorophenyl)-4-
(2-hydroxy-5-methylphenyl)pyrimidine-2(1H)-thione (7d).
IR
1
(KBr, cmÀ1): 3905, 3628, 3099, 1618. H NMR (400 MHz,
CDCl3, δH ppm): 2.55 (s, 3H, CH3), 4.82 (s, 2H, NCH2),
5.43 (s, 2H, OCH2), 6.70–6.74 (m, 3H, ArH), 7.27–7.30 (m,
2H, ArH), 7.35–7.38 (m, 3H, ArH), 7.92–7.98 (m, 2H, ArH),
8.08 (s, 1H, triazole-H), 8.16–8.18 (m, 2H, ArH), 10.95 (s,
1H, OH), 11.62 (s, 1H, NH). 13C NMR (100 MHz, CDCl3,
δC ppm): 21.1, 52.2, 65.2, 114.8, 115.0, 116.7, 116.9, 123.2,
123.6, 125.9, 128.4, 128.8, 128.9, 129.6, 132.5, 132.8, 134.6,
135.3, 136.3, 136.7, 139.9, 141.6, 153.5, 155.4, 161.8, 164.5,
194.6. ESI-MS Anal. Calcd. for C27H22FN5O2S [M + H]+:
500.16. Found: 500.09. Anal. calcd. for C27H22FN5O2S: C,
64.91; H, 4.44; N, 14.02; S, 6.42. Found: C, 64.94; H, 4.42;
Acknowledgments. Author V.S.D. is very much grateful to the
Council of Scientific and Industrial Research (CSIR), New Delhi,
India, for providing Senior Research Fellowship and Sophisticated
Analytical Instrumentation Facility (SAIF), Panjab University,
Chandigarh, for providing spectral data. We are thankful to Head,
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad, Maharashtra, for providing laboratory
facility. We are also thankful to the Department of Microbiology,
Maulana Azad College of Arts, Science and Commerce,
Aurangabad, for providing biological activities.
N, 14.01; S, 6.35.
5-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(3,5-dichloro-
2-hydroxyphenyl)-6-(4-fluorophenyl)pyrimidine-2(1H)-thione
1
(7e). IR (KBr, cmÀ1): 3981, 3734, 3069, 1682. H NMR
(400 MHz, CDCl3, δH ppm): 4.62 (s, 2H, NCH2), 5.35 (s,
2H, OCH2), 7.26 (d, 2H, J = 2.4 Hz, ArH), 7.35–7.38 (m,
2H, ArH), 7.49–7.51 (m, 3H, ArH), 7.98–8.01 (m, 2H,
ArH), 8.13 (s, 1H, triazole-H), 8.16–8.19 (m, 2H, ArH),
10.74 (s, 1H, OH), 11.23 (s, 1H, NH). 13C NMR (100 MHz,
CDCl3, δC ppm): 51.4, 68.1, 115.6, 115.7, 118.1, 118.3,
123.7, 123.9, 127.4, 127.7, 128.8, 128.9, 130.1, 132.2,
132.7, 135.7, 136.0, 136.2, 136.9, 140.3, 144.0, 154.5,
154.8, 160.7, 164.2, 191.5. ESI-MS Anal. Calcd. for
C26H18Cl2FN5O2S [M + H]+: 554.06. Found: 554.12. Anal.
calcd. for C26H18Cl2FN5O2S: C, 56.32; H, 3.27; N, 12.63;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet