Synthesis, Characterization, and Antimicrobial Activity of a Series of 2-(5-Phenyl-1,3,4-oxadiazol-2-yl)-N-[(1-aryl-1H-1,2,3-triazol-4-yl)methyl]anilines Using Click Chemistry

Article abstract of DOI:10.1134/S1070363218070228

series of new triazolyl derived 1,3,4-oxadiazoles 7a–7l is synthesized with high yields by coppercatalyzed alkyne–azide cycloaddition reaction between a variety of substituted aryl/alkyl azides and 2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline. Structures of intermediates and the final compounds are confirmed by FTIR, ¹H and ¹³C NMR, and Mass spectra. The synthesized compounds demonstrate moderate antibacterial activity and potent antifungal activity against the tested strains.

Full text of DOI:10.1134/S1070363218070228

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 7, pp. 1488–1494. © Pleiades Publishing, Ltd., 2018.
Synthesis, Characterization, and Antimicrobial Activity
of a Series of 2-(5-Phenyl-1,3,4-oxadiazol-2-yl)-N-[(1-aryl-1H-
1
1
,2,3-triazol-4-yl)methyl]anilines Using Click Chemistry
a
a
b
a
a
N. Venkatagiri , T. Krishna , P. Thirupathi , K. Bhavani , and C. K. Reddy *
a
Department of Chemistry, Osmania University, Hyderabad, Telangana, 500007 India
*
e-mail: krreddych@gmail.com
b
Department of Chemistry, Loyola Academy Degree & PG College, Secunderabad, Telangana, 500010 India
Received July 27, 2017
Abstract—A series of new triazolyl derived 1,3,4-oxadiazoles 7a–7l is synthesized with high yields by copper-
catalyzed alkyne–azide cycloaddition reaction between a variety of substituted aryl/alkyl azides and 2-(5-
phenyl-1,3,4-oxadiazol-2-yl)aniline. Structures of intermediates and the final compounds are confirmed by FT-
1
13
IR, H and C NMR, and Mass spectra. The synthesized compounds demonstrate moderate antibacterial
activity and potent antifungal activity against the tested strains.
Keywords: triazolyloxadiazoles, 1,2,3-triazole, 1,3,4-oxadiazole, click reaction, microorganisms, antibacterial
activity, antifungal activity
DOI: 10.1134/S1070363218070228
INTRODUCTION
RESULTS AND DISCUSSION
Synthesis and properties of 1,3,4-oxadiazoles
attracted close attention [1,2] due to their important
biological activities such as anti-inflammatory [3],
anticonvulsant [4, 5], analgesic [6], antibacterial [7],
and anticancer [8]. 1,3,4-Oxadiazoles are structural
blocks of some drugs, for example, Raltegravir, Tiodazosin,
Furamizole, and Nesapidil.
Synthetic approach to the target compounds is
presented in Scheme 1.
2
,5-Diphenyl-1,3,4-oxadiazole 4 according to the
developed earlier method [19]. 2-(5-Phenyl-1,3,4-
oxadiazol-2-yl)-N-(prop-2-yn-1-yl)aniline 5 was syn-
thesized by the reaction of the intermediate 4 with
propargyl bromide in the presence of K CO . Forma-
2
3
1
13
tion of compound 5 was confirmed by IR, H and C
NMR spectra. Optimization of the following step of
synthesis of the target compounds was performed for
1
,2,3-Triazoles and their derivatives demonstrated a
wide spectrum of biological activities such as antiviral
[
[
9], antibacterial [10], antifungal [10], antiprotozoal
11], antioxidant [12], anti-inflammatory [13], and
2
1
-{5-phenyl-1,3,4-oxadiazol-2-yl)-N-[(1-(p-tolyl)-1H-
,2,3-triazol-4-yl]methyl}aniline 7a. Reaction of
anticancer [14]. Some of the well-known drugs contain
compound 5 with the phenylazide 6a, prepared in situ,
was carried out by using different molar percentages of
CuSO ·5H O and sodium ascorbate under click reaction
1
,2,3-triazole moiety [15, 16].
4
2
Over recent years interesting antibacterial mole-
cules combining 1,2,3-triazole and substituted 1,3,4-
oxadiazole demonstrated promising biological potential
conditions. The optimized conditions of synthesis of
7
a were determined to be 2 mol % of CuSO ·5H O,
4 2
1
0 mol % of sodium ascorbate and DMF–H O (1 : 1)
2
[17, 18].
media. Formation of compound 7a was confirmed by
–
1
disappearance of IR bands at 2112 and 3261 cm of
The presented above information inspired us to
study synthesis and biological activity of the title
compounds containing both 1,3,4-oxadiazoles and
the C≡C–H group characteristic for compound 5 and
1
13
supported by H and C NMR, and mass spectra.
1
,2,3-triazoles building blocks.
The optimized conditions were used in synthesis of
the other triazole derivatives 7b–7l. The products with
the electron donating substituents on phenyl moiety
were formed with higher yields than those containing
1
The text was submitted by the authors in English.
1
488

SYNTHESIS, CHARACTERIZATION, AND ANTIMICROBIAL ACTIVITY
1489
Scheme 1. Synthesis of 2-(5-phenyl-1,3,4-oxadiazol-2-yl)-N-[(1-aryl-1H-1,2,3-triazol-4-yl)methyl]anilines.
O
O
O
O
O
O
N
H
O
.
NH
NH NH2 H O
2
2
OEt
NHNH2
N
Ethanol, reflux,
h, 85%
H
Ethanol, reflux,
6
2
h, 90%
NH2
1
2
3
POCl , reflux,
3
3
h, 50%
N
O
N
N
O
N
Br
N
N
N −R
3
6
a−6l
O
.
K CO , acetone,
2 3
reflux,4 h, 87%
NH
2% CuSO4 5H O
2
NH
10% Na ascarbate
NH2
DMF, H O (1 : 1)
1−1.5 h,
room temperature
4
2
R
N
N
N
7
a−7l
5
R = p-tolyl (7a), phenyl (7b), o-anisyl (7c), m-nitrophenyl (7d), p-fluorophenyl (7e), p-chlorophenyl (7f), 4-methoxy-2-nitro-
phenyl (7g), m-chlorophenyl (7h), o-tolyl (7i), o-2-(4-phenyl-1,3,4-oxadiazolyl-2-yl)phenyl (7j), benzyl (7k), cyclohexyl (7l).
electron withdrawing substituent’s (7a 90%, 7d 71%).
The reaction with the bulky azide gave the cor-
responding product 7j with lower yield (70%).
strated high activity against Aspergillus niger with the
zone of inhibition in the range of that of the standard
(Ketoconazole), whereas against Trichoderma viride
most of compounds 7b–7e, 7h–7j, 7l, and 4 exhibited
activity higher than Ketoconazole. According to the
accumulated data, the synthesized compounds have
some potential as antifungal agents.
Biological evaluation. Antibacterial activity. The
synthesized compounds 7a–7l and the intermediate 4
were evaluated for in vitro antibacterial activity against
two Gram-positive and two Gram-negative bacterial
strains at concentrations 1.0 and 2.0 mg/mL by means
of disc diffusion method (Table 1). Among the tested
compounds only compound 4 exhibited high anti-
bacterial activity against all tested strains with the zone
of inhibition comparable with that of the standards NX
EXPERIMENTAL
All reagents were purchased from commercial
sources and used without purification. All solvents
1
were dried and distilled prior to their usage. H NMR
(
norfloxacin) and OF (ofloxacin). The synthesized
13
(
400 MHz) and C NMR (101 MHz) spectra were
compounds 7a–7l exhibited moderate antibacterial
activity against the tested strains. Compounds 7a–7l
with different substituents on the triazole ring demon-
strated nearly the same antibacterial effect demonstrating
no structure activity relationship. Various concentra-
tions of the compounds 7a–7l (1 mg/mL and 2 mg/mL)
did not influence on their antibacterial activity.
measured on a Bruker Biospin Avance-III spectro-
meters in CDCl using TMS as the internal standard.
3
Column chromatography was carried out using silica
gel, 60–120 mesh (Merck). The reaction progress was
monitored by TLC with silica gel 60-F254 plates and
visualized under UV light. Mass spectra were
+
measured in the ESI (ES ) mode.
Antifungal activity. The in vitro antifungal activity
of synthesized compounds was evaluated against two
fungal strains (Aspergillus niger and Trichoderma
viride) (Table 2). Compounds 7d, 7h, and 7i demon-
Preparation of benzohydrazide (2). A mixture of
ethyl benzoate (6.6 mmol, 1 g) with 98% hydrazine
mono hydrate (7.2 mmol, 0.35 mL) was refluxed for
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VENKATAGIRI et al.
Table 1. Antibacterial activity of compounds 4 and 7a–7l
Zone of inhibition, mm
gram positive bacteria
gram negative bacteria
Pseudomonas aeruginosa Escherichia coli
concentration, mg/mL
Compound
Bacillus subtilis
Staphylococcus aureus
1
2
1
2
1
2
1
2
4
7
7
7
7
7
7
7
7
7
7
7
7
4.5
2.5
2.5
4.5
2.5
2.5
2.5
2.5
2.5
3.0
2.5
2.5
2.5
8.0
4.5
2.5
4.5
2.5
2.5
2.5
2.5
2.5
4.5
2.5
2.5
3.0
3.0
8.0
6.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
6.0
6.0
2.5
2.5
2.5
2.5
3.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5.0
3.0
2.5
2.5
4.0
2.5
2.5
2.5
3.0
2.5
2.5
4.5
2.5
2.5
-
5.0
2.5
2.5
2.5
2.5
2.5
4.5
2.5
2.5
3.5
3.0
3.0
2.5
5.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
a
b
c
d
e
f
g
h
i
j
k
l
Ofloxacin
Norfloxacin
9.0
6.0
8.0
8.0
1
5 min. Ethanol (60 mL) was added to the mixture and
4.2 Hz), 7.49–7.62 m (3H, Ar-H), 7.87 d.d (1H, Ar-H,
refluxing continued for 6 h. After completion of the
reaction (TLC monitoring) ethanol was evaporated
under reduced pressure, benzoyl hydrazine was filtered
off and recrystallized from water. Yield 85%.
J = 7.9, 1.3 Hz), 8.15 d.t (2H, Ar-H, J = 8.5, 3.7 Hz).
C NMR spectrum, δ, ppm: 105.73, 116.24, 116.81,
1
3
123.89, 126.93, 129.09, 131.66, 132.53, 147.14, 162.78,
164.64. Found, %: C 70.90; H 4.72; N 17.75.
C H N O. Calculated, %: C 70.87; H 4.67; N 17.71.
1
4
11
3
Preparation of 2-amino-N'-benzoylbenzohydrazide
+
LC-MS: 238.1 [M + H] .
(
3). A mixture of isatoic anhydride (1 g, 7.34 mmol)
with benzoyl hydrazine 2 (1.2 g, 7.34 mmol) in ethanol
was refluxed for 2 h. The precipitated product was
filtered off and recrystallized from benzene. Yield
Synthesis of 2-(5-phenyl-1,3,4-oxadiazol-2-yl)-N-
prop-2-yn-1-yl)aniline (5). Propargyl bromide
4mmol, 0.32 mL, 80% in toluene) was added to a
(
(
9
0%, mp 190–191°C.
mixture of 2-(5-phenyl-1,3,4-oxdiazole-2-yl)aniline (4
mmol, 1 g) with K CO (8 mmol) in acetone. The
Preparation of 2-(5-phenyl-1,3,4-oxadiazole-2-yl)-
2
3
aniline (4). A mixture of 2-amino-N'-benzoylbenzo-
mixture was refluxed for 3 h. The reaction was
monitored by TLC using ethyl acetate–hexane mixture
(1 : 3) as an eluent. The solvent was removed under
reduced pressure and the resulting mixture was poured
in ice cold water. The precipitate formed was filtered
off, dried, and the product was purified column
chromatography packed with silica gel using ethyl
acetate and hexane (1 : 4) as an eluent. Colourless
hydrazide 3 (1 g, 4 mmol) with POCl (4 mL) was
3
refluxed for 3 h. The resulting solution was poured
onto crushed ice and neutralized with aqueous ammonia.
The precipitated product was purified by recrys-
tallization from petroleum ether. Yield 50%, mp 151–
–
l
1
52°C. IR spectrum, ν, cm : 1255 (C–N), 1319 (N–N),
1
442–1533 (C=Carom), 1610 (C=N), 3415, 3327 (NH2).
1
–l
H NMR spectrum, δ, ppm: 5.91 s (2H, NH ), 6.76–
solid, yield 87%, mp 204–205°C. IR spectrum, ν, cm :
2
6
.86 m (2H, Ar-H), 7.30 d.d (1H, Ar-H, J = 11.2,
1240 (C–N), 1311 (N–N), 1446–1585 (C=Carom), 1610
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SYNTHESIS, CHARACTERIZATION, AND ANTIMICROBIAL ACTIVITY
1491
(
(
C=N), 2112 (C≡C), 2918, 2848 (=C–H), 3261
≡C–H), 3329 (N–H secondary). H NMR spectrum, δ,
Table 2. Antifungal activity of compounds 4 and 7a–7l
1
(
concentration 1 mg/mL)
Compound
ppm: 2.25 t (1H, ≡C–H, J = 2.510 Hz). 4.16 d.d (2H,
CH , J = 5.772, 2.510 Hz), 6.94 s (1H, Ar-H), 6.85 s
(
t (1H, NH, J = 5.772 Hz), 7.95 s (1H, Ar-H), 8.16 s
(
8
1
Found, %: C 74.14; H 4.83; N 15.23. C H N O.
Calculated, %: C 74.17; H 4.76; N 15.26. LC- MS:
2
Zone of inhibition, mm
2
Aspergillus niger Trichoderma viride
1H, Ar-H), 7.43 s (1H, Ar-H), 7.56 s (3H, Ar-H), 7.91
4
3.0
2.5
2.5
2.5
5.5
2.5
2.5
4.0
5.5
5.0
3.0
4.0
3.0
6.0
5.5
2.5
6.1
6.0
5.5
6.0
3.0
2.5
4.0
6.5
5.0
2.5
6.6
4.0
1
3
2H,Ar-H). C NMR spectrum, δ, ppm: 32.65, 71.29,
7a
0.31, 106.34, 111.56, 116.48, 123.81, 126.97, 128.18,
29.10, 131.73, 132.88, 146.47, 162.78, 164.57.
7
7
7
b
c
1
7
13
3
d
+
76.1 [M + H] .
7e
7f
Synthesis of substituted azides (6a–6l). To a dilute
HCl solution of a substituted amine (1 equiv.)
maintained at 0–5°C, a solution of sodium nitrite
(
sodium azide (1.5 equiv.) was slowly added at the
same temperature. The mixture was stirred for about
2
completion (TLC), the corresponding product was
extracted 3 times with ethyl acetate, the organic layers
combined, washed with brine solution, dried over
anhydrous Na SO , and concentrated under reduced
7
7
7
g
h
i
1.5 equiv.) was added drop wise and then a solution of
7j
–3 h at room temperature. After the reaction
7
7
k
l
Ketoconazole
2
4
pressure [15]. No further purification was required for
the next step.
6
7
.83 m (1H, Ar-H), 6.94 d (1H, Ar-H, J = 8.4 Hz),
.27–7.30 m (1H, Ar-H), 7.35–7.40 m (2H, Ar-H),
Synthesis of 2-(5-phenyl-1,3,4-oxadiazole-2-yl)-N-
(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]anilines
7a–7l). To the mixture of 2-(5-phenyl-1,3,4-oxadiazol-
-yl)-N-(prop-2-yn-1-yl)aniline (100 mg, 8 mmol)
with DMF and water (1 : 1) stirred under the atmo-
7.53–7.61 m (5H, Ar-H), 7.89 s (1H, triazole-H), 7.94
[
(
2
d.d (1H, Ar-H, J = 7.9, 1.5 Hz), 8.13–8.17 m (3H,
1
3
Ar-H). C NMR spectrum, δ, ppm: 20.89, 39.02,
105.73, 111.38, 116.10, 120.01, 120.24, 123.51, 126.74,
128.09, 129.02, 130.04, 131.69, 132.94, 134.56, 134.95,
138.66, 146.80, 162.57, 164.51. Found, %: C 70.64; H
sphere of N , copper sulphate pentahydrate (2 mol %)
2
and sodium ascorbate (10 mol %) were added. After
min, in situ a prepared azide 6a–6l (10 mmol) was
4.80; N 20.52. C24
4.94; N 20.58. LC-MS: 409.1 [M + H] .
H N O. Calculated, %: C 70.57; H
20 6
+
5
added. The reaction mixture was stirred for 30 min at
room temperature (TLC monitoring using ethyl acetate–
hexane (1 : 1) mixture as an eluent). After completion
of the reaction, the mixture was poured into ice cold
water and extracted with ethyl acetate (10×3 mL). The
combined organic layers were dried over anhydrous
sodium sulphate and the solvent was evaporated under
reduced pressure to obtained the corresponding crude
product. The product was purified by column chromato-
graphy using EtOAc–hexane (1 : 2) as an eluent.
2
-(5-Phenyl-1,3,4-oxadiazol-2-yl)-N-[(1-phenyl-
1
H-1,2,3-triazol-4-yl)methyl]aniline (7b). Colourless
solid, yield 81%, mp 152–153°C. IR spectrum, ν, cm :
041 (=C–O), 1257 (C–N), 1321 (N–N), 1438–1585
C=Carom), 1610 (C=N), 2918, 2848 (=C–H), 3315
N–H secondary). H NMR spectrum, δ, ppm: 4.82 d
–l
1
(
(
(
(
1
2H, CH , J = 5.7 Hz), 6.78–6.85 m (1H, Ar-H), 6.94 d
1H, Ar-H, J = 8.3 Hz), 7.35–7.40 m (1H, Ar-H), 7.42
2
d.d.d (1H, Ar-H, J = 6.2, 3.2, 1.4 Hz), 7.47–7.58 m
5H, Ar-H), 7.69–7.71 m (1H, Ar-H), 7.72 s (1H,
triazole-H,), 7.94 d.d (2H, Ar-H, J = 8.3, 1.9 Hz), 8.14–
8.17 m (3H, Ar-H). C NMR spectrum, δ, ppm: 39.43,
105.69, 111.63, 116.24, 120.58, 123.78, 126.97, 128.21,
128.71, 129.14, 129.70, 131.80, 133.12, 140.26, 140.68,
147.02, 147.26, 162.82, 164.75. Found, %: C 70.03; H
4.67; N 21.34. C H N O. Calculated, %: C 70.04; H
(
2
-(5-Phenyl-1,3,4-oxadiazol-2-yl)-N-{[1-(p-tolyl)-
H-1,2,3-triazol-4-yl]methyl}aniline (7a). Pale
yellow solid, yield 90%, mp 131–132°C. IR spectrum,
13
1
–
l
ν, cm : 1045(=C–O), 1257 (C–N), 1328 (N–N), 1440–
1
3
2
583 (C=Carom), 1614 (C=N), 2846, 2916 (=C–H),
309 (N–H secondary). H NMR spectrum, δ, ppm:
1
2
3
18
6
+
.40 s (3H, CH ), 4.81 d (2H, CH , J = 5.7 Hz), 6.79–
4.60; N 21.31. LC-MS: 395.1 [M + H] .
3
2
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VENKATAGIRI et al.
N-[(1-(2-Methoxyphenyl)-1H-1,2,3-triazol-4-yl]-
methyl)-2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (7c).
39.38, 105.99, 111.57, 131.82, 129.14, 116.29, 116.54,
116.77, 120.07, 122.49, 122.58, 123.74, 126.96, 128.22,
133.12, 133.37, 146.96, 147.40, 161.15, 162.82, 163.63,
164.73. Found, %: C 66.95; H 4.19; N 20.41.
C H FN O. Calculated, %: C 66.98; H 4.15; N 20.38.
Pale yellow solid, yield 83%, mp 129–130°C. IR
–
l
spectrum, ν, cm : 1045 (=C–O), 1257 (C–N), 1327
(
(
N–N), 1438–1581 (C=Carom), 1612 (C=N), 2848, 2918
23
17
6
1
+
=C–H), 3317(N–H secondary). H NMR spectrum, δ,
LC-MS: 413.1 [M + H] .
ppm: 3.86 s (3H, OCH ), 4.82 d (2H, CH , J = 5.6 Hz),
3
2
N-{[1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl]-
methyl}-2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (7f).
Light brown solid, yield 85%, mp 159–160°C. IR spec-
6
8
.80 t (1H, Ar-H, J = 7.5 Hz), 6.97 d (1H, Ar-H, J =
.4 Hz), 7.05 d (1H, Ar-H, J = 8.3 Hz,), 7.09 t (1H,
Ar-H, J = 7.7 Hz ), 7.37–7.42 m (2H, Ar-H), 7.50–7.58
m (3H, Ar-H), 7.78 d.d (1H, Ar-H, J = 7.9, 1.6 Hz),
–l
trum, ν, cm : 1045 (=C-O), 1259 (C–N), 1327 (N–N),
1
3
4
6
1
438–1583 (C=Carom), 1614 (C=N), 2848, 2916 (=C–H),
309 (N–H secondary). H NMR spectrum, δ, ppm:
.82 d (2H, Ar-H, J = 5.6 Hz), 6.82 t (1H, J = 7.5 Hz),
.92 d (1H, Ar-H, J = 8.4 Hz), 7.38 d.d (1H, Ar-H, J =
2.1, 5.0 Hz), 7.45–7.49 m (2H, Ar-H), 7.54–7.59 m
7
.93 d.d (1H, Ar-H, J = 7.9, 1.4 Hz), 8.07 s (1H,
1
1
3
triazole-H), 8.12–8.16 m (3H, Ar-H). C NMR
spectrum, δ, ppm: 38.70, 55.41, 105.26, 111.05, 111.80,
1
1
1
1
1
15.56, 120.52, 123.09, 123.52, 124.75, 125.64, 126.29,
27.67, 128.58, 129.62, 131.23, 132.44, 144.68, 146.47,
50.58, 162.11, 164.09. Found, %: C 67.95; H 4.83; N
9.72. C H N O . Calculated, %: C 67.91; H 4.75; N
(
3H, Ar-H), 7.65–7.69 m (2H, Ar-H), 7.91 s (1H,
triazole-H), 7.95 d.d (1H, Ar-H, J = 7.9, 1.5 Hz). 8.13–
.19 m (3H, Ar-H). C NMR spectrum, δ, ppm: 39.37,
06.02, 111.57, 116.33, 119.79, 121.69, 123.73, 126.97,
28.24, 129.15, 129.88, 131.83, 133.13, 134.47, 135.55,
46.94, 147.56, 162.84, 164.72. Found, %: C 64.38; H
13
24
20
6
2
8
1
1
1
4
+
9.80. LC-MS: 425.1 [M + H] .
N-{[1-(3-Nitrophenyl)-1H-1,2,3-triazol-4-yl]-
methyl}-2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (7d).
.05; N 19.67. C H ClN O. Calculated, %: C 64.41;
Pale yellow solid, yield 71%, mp 208–209°C. IR spec-
23 17
6
+
–
l
H 4.00; N 19.60. LC-MS: 429.1 [M + H] .
trum, ν, cm : 1049 (=C–O), 1259(C–N), 1321 (N–N),
342 (N–O), 1529 (NO ), 1442–1583 (C=Carom), 1614
1
2
N-{[1-(4-Methoxy-2-nitrophenyl)-1H-1,2,3-tri-
azol-4-yl]methyl}-2-(5-phenyl-1,3,4-oxadiazol-2-yl)-
aniline (7g). Pale yellow solid, yield 78%, mp 169–
(
C=N), 2848, 2918 (=C–H), 3296 (N–H secondary).
1
H NMR spectrum, δ, ppm: 4.85 d (2H, CH , J =
2
–l
4
.9 Hz), 6.84 t (1H, Ar-H, J = 7.5 Hz), 6.91 d (1H,
1
70°C. IR spectrum, ν, cm : 1045 (=C–O), 1257 (C–N),
Ar-H, J = 8.2 Hz), 7.26 s (2H, Ar-H), 7.38 d (1H,
Ar-H, J = 7.4 Hz), 7.73 t (1H, Ar-H, J = 7.9 Hz), 7.96
d (1H, Ar-H, J = 7.3 Hz), 8.04 s (1H, Ar-H), 8.12–8.27
m (5H, Ar-H), 8.28–8. 30 d (1H, Ar-H, J = 8.031 Hz),
1
327 (N–N), 1514 (N–O), 1531 (NO ), 1440–1583
2
(
(
(
C=Carom), 1614 (C=N), 2846, 2913 (=C–H), 3310
N–H secondary). H NMR spectrum, δ, ppm: 3.94 s
3H, OCH ), 4.83 d (2H, CH , J = 5.6 Hz), 6.80–6.85
1
3
2
1
3
8.58 s (1H, triazole-H), CNMR spectrum, δ, ppm:
38.57, 105.67, 112.06, 115.16, 116.48, 122.23, 123.50,
123.66, 126.49, 127.19, 128.80, 129.90, 131.98, 132.52,
133.61, 137.65, 146.90, 146.98, 148.98, 162.64, 164.60.
m (1H, Ar-H), 6.93 d (1H, Ar-H, J = 8.4 Hz), 7.23 d.d
1H, Ar-H, J = 8.8, 2.8 Hz), 7.43–7.38 m (1H, Ar-H),
.49 d (1H, Ar-H, J = 8.8 Hz), 7.51–7.59 m (4H,
Ar-H), 7.76 s (1H, triazole-H), 7.93 d.d (1H, Ar-H, J =
(
7
13
Found, %: C 62.81; H 3.94; N 22.32. C H N O .
2
3
17
7
3
7.9, 1.5 Hz), 8.11–8.17 m (3H, Ar-H). C NMR spect-
rum, δ, ppm: 39.40, 56.38, 105.52, 111.70, 116.31,
Calculated, %: C 62.87; H 3.90; N 22.31. LC-MS:
+
4
40.1 [M + H] .
119.27, 123.21, 123.76, 123.87, 126.96, 128.19, 129.13,
129.46, 131.78, 133.12, 133.15, 146.80, 146.97, 160.79,
162.79, 164.74. Found, %: C 61.44; H 4.09; N 20.85.
N-{[1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl]-
methyl}-2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (7e).
C H N O . Calculated, %: C 61.40; H 4.08; N 20.89.
LC-MS: 470 [M + H] .
24
19
7
4
Colourless solid, yield 80%, mp 188–189°C. IR spec-
+
–
l
trum, ν, cm : 1047 (=C–O), 1226 (C–N), 1332 (N–N),
1
3
4
7
444–1585 (C=Carom), 1610 (C=N), 2846, 2916 (=C–H),
323 (N–H secondary). H NMR spectrum, δ, ppm:
N-{[1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl]-
methyl}-2-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (7h).
Pale yellow solid, yield 80%, mp 166–167°C. IR spec-
1
.81 d (2H, CH , J = 5.6 Hz), 6.82 t (1H, Ar-H, J =
2
–
l
.5 Hz), 6.93 d (1H, Ar-H, J = 8.5 Hz), 7.19 t (2H,
trum, ν, cm : 1041 (=C–O), 1263 (C–N), 1321 (N–N),
Ar-H, J = 8.5 Hz), 7.38 t (1H, Ar-H, J = 7.4 Hz), 7.56
d (3H, Ar-H, J = 6.6 Hz), 7.64–7.74 m (2H, Ar-H),
1446–1587 (C=Carom), 1608 (C=N), 2848, 2918
(=C–H), 3319 (N–H secondary). H NMR spectrum
1
7
8
.89 s (1H, triazole-H), 7.94 d (1H, Ar-H, J = 6.9 Hz),
.11–8.19 m (3H, Ar-H). C NMR spectrum, δ, ppm:
(400 MHz, CDCl ), δ, ppm: 4.82 d (2H, CH , J =
5.7 Hz), 6.82 t (1H, Ar-H, J = 7.4 Hz), 6.91 d (1H,
3
2
13
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 7 2018

SYNTHESIS, CHARACTERIZATION, AND ANTIMICROBIAL ACTIVITY
1493
–
l
Ar-H, J = 8.5 Hz), 7.40 m (3H, Ar-H), 7.56 d.d (3H,
Ar-H, J = 9.3, 3.1 Hz), 7.61 d.d (1H, Ar-H, J = 5.5,
solid, yield 75%, mp 169–170°C. IR spectrum, ν, cm :
1049 (=C–O), 1261 (C–N), 1338 (N–N), 1440-1583
(C=Carom), 1610 (C=N), 2916, 2846 (=C–H), 3309
4
.0 Hz), 7.76 t (1H, Ar-H, J = 1.8 Hz), 7.92 s (1H,
1
triazole-H), 7.95 d.d (1H,J = 7.9, 1.3 Hz), 8.13–8.19 m
(N–H secondary). H NMR spectrum, δ, ppm: 4.71 d
(2H, CH , J = 5.019 Hz), 5.50 s (2H, CH ), 6.79 t (1H,
13
(
3H, Ar-H). C NMR spectrum, δ, ppm: 39.35, 106.05,
2
2
1
1
1
6
6
11.55, 116.35, 118.49, 119.83, 120.77, 123.74, 126.97,
28.25, 128.77, 129.14, 130.77, 131.81, 133.13, 135.54,
37.89, 146.91, 147.61, 162.84, 164.72. Found, %: C
4.37; H 4.06; N 19.55. C H ClN O. Calculated, %: C
J = 7.3 Hz), 6.87 d (1H, Ar-H, J = 8.4 Hz), 7.24 s (2H,
Ar-H), 7.34 s (4H, Ar-H), 7.43 s (1H, triazole-H), 7.56
s (3H, Ar-H), 7.91d (1H, Ar-H, J = 7.6 Hz), 8.04 t (1H,
Ar-H, J = 5.019 Hz), 8.14 d(2H, Ar-H, J = 5.8 Hz). C
NMR spectrum, δ, ppm: 39.47, 54.19, 105.86, 111.62,
13
23
17
6
+
4.41; H 4.00; N 19.60. LC-MS: 429 [M + H] .
-(5-Phenyl-1,3,4-oxadiazol-2-yl)-N-{[1-(3-
methylphenyl)-1H-1,2,3-triazol-4-yl]methyl}aniline
7i). Pale yellow solid, yield 82%, mp 138–139°C. IR
116.07, 121.65, 123.78, 126.94, 127.96, 128.14, 128.68,
129.09, 129.12, 131.76, 133.01, 134.66, 146.86, 147.03,
162.74, 164.70. Found, %: C 70.64; H 5.01; N 20.50.
2
(
–l
C H N O. Calculated, %: C 70.57; H 4.94; N 20.58.
24 20 6
spectrum, ν, cm : 1060 (=C–O), 1257 (C–N), 1327 (N–N),
+
LC-MS: 409 [M + H] .
1440–1585 (C=Carom), 1610 (C=N), 2848, 2916 (=C–H),
1
3
2
6
7
7
1
309 (N–H secondary). H NMR spectrum, δ, ppm:
N-[(1-Cyclohexyl-1H-1,2,3-triazol-4-yl)methyl]-2-
.19 s (3H, CH ), 4.84 d (2H, CH , J = 5.7 Hz), 6.78–
3
2
(
5-phenyl-1,3,4-oxadiazol-2-yl)aniline (7l). Color-
.84 m (1H, Ar-H), 6.95 d (1H, Ar-H, J = 8.4 Hz),
.28–7.42 m (5H, Ar-H), 7.51–7.58 m (3H, Ar-H),
.69 s (1H, triazole-H), 7.93 d.d (1H, Ar-H, J = 7.9,
less solid, yield 74%, mp 171–172°C. IR spectrum, ν,
–
l
cm : 1051 (=C–O), 1259 (C–N), 1328 (N–N), 1444–
1
3
1583 (C=Carom), 1610 (C=N), 2856, 2922 (=C–H),
.5 Hz), 8.12–8.18 m (3H, Ar-H). C NMR spectrum,
1
3
1
307 (N–H secondary). H NMR spectrum, δ, ppm:
δ, ppm: 17.89, 39.47, 105.97, 111.64, 116.20, 123.27,
.19–1.34 m (2H, CH2 cyclohexyl), 1.36–1.51 m (2H,
123.76, 126.02, 126.78, 126.95, 128.22, 129.12, 129.80,
131.42, 131.78, 133.05, 133.69, 136.54, 146.27, 147.05,
162.79, 164.73. Found, %: C 70.59; H 5.01; N 20.52.
CH2 cyclohexyl), 1.73 qd (2H, CH2 cyclohexyl, J = 12.5,
.5 Hz), 1.86–1.95 m (2H, CH2 cyclohexyl), 2.19 d.d (2H,
CH2 cyclohexyl, J = 13.0, 2.5 Hz), 4.40 t.t (1H, CH2 cyclohexyl
J = 11.8, 3.8 Hz), 4.72 d (2H, CH , J = 5.624 Hz), 6.77–
3
,
C H N O. Calculated, %: C 70.57; H 4.94; N 20.58.
LC-MS: 409 [M + H] .
24
20
6
+
2
6
7
7
1
.83 m (1H, Ar-H), 6.91 d (1H, Ar-H, J = 8.5 Hz),
.33–7.40 m (1H, Ar-H), 7.49 s (1H, triazole-H), 7.51–
.60 m (3H, Ar-H), 7.92 d.d (1H, Ar-H, J = 7.9,
2
-(5-Phenyl-1,3,4-oxadiazol-2-yl)-N-{[1-[2-(5-
phenyl-1,3,4-oxadiazol-2-yl)phenyl]-1H-1,2,3-tri-
azol-4-yl]methyl}aniline (7j). Yellowish solid, yield
7
.5 Hz), 8.05 t (1H, Ar-NH, J = 5.624 Hz), 8.12–8.18
–
l
0%, mp 176–177°C. IR spectrum, ν, cm : 1082
13
m (2H, Ar-H). C NMR spectrum, δ, ppm: 25.11,
(
(
(
(
=C–O), 1263 (C–N), 1367 (N–N), 1446–1585
C=Carom), 1612 (C=N), 2846, 2916 (=C–H), 3323
N–H secondary). H NMR spectrum, δ, ppm: 4.84 d
2H, CH , J = 5.6 Hz), 6.76 t (1H, Ar-H, J = 7.5 Hz),
2
1
1
6
6
5.16, 33.50, 39.57, 60.18, 111.63, 116.00, 119.28,
22.59, 123.84, 126.96, 128.14, 129.11, 131.73, 133.05,
45.83, 147.19, 162.75, 164.78. Found, %: C 69.10; H
.02; N 20.92. C H N O. Calculated, %: C 68.98; H
1
2
2
3
24
6
6
7
5
.84 d (1H, Ar-H, J = 8.3 Hz), 7.19 t (1H, Ar-H, J =
.8 Hz), 7.50 m (6H, Ar-H), 7.61 d.d (1H, Ar-H, J =
.8, 3.3 Hz), 7.72 d.d (2H, Ar-H, J = 5.9, 3.4 Hz), 7.78
+
.04; N 20.99. LC-MS: 401 [M + H] .
Biological assay. Antibacterial activity. Four types
of bacteria [Pseudomonas aeruginosa (Gram-negative),
Escherichia coli (Gram-negative), Bacillus subtilis
s (1H, triazole-H), 7.82–7.86 m (2H, Ar-H), 7.89 d
(
(
1H, J = 7.8 Hz), 8.10–8.17 m (3H, Ar-H), 8.34 d.d
1H, Ar-H, J = 5.9, 3.4 Hz). C NMR spectrum, δ,
1
3
(
Gram-positive) and Staphylococcus aureus (Gram-
ppm: 39.37,105.95, 111.43, 116.27, 121.04, 123.29,
positive)] were obtained from Microbial Type Culture
Collection–MTCC. LB broth media was prepared,
autoclaved and incubated overnight at 37°C in a shaker
for bacterial growth. From this culture media, 0.3 mL
of bacterial culture was taken and inoculated by using
spreader on freshly prepared autoclaved agar plates,
petri dishes. Sample discs (5 mm) with samples
dissolved in DMSO (concentrations 1 and 2 mg/mL)
were kept on microbial plate along with positive
123.73, 124.03, 126.90, 126.93, 128.14, 128.20, 129.08,
129.12, 130.44, 130.75, 131.78, 131.99, 132.39, 133.02,
135.05, 146.71, 146.90, 161.73, 162.73, 164.63, 165.09.
Found, %: C 69.15; H 4.10; N 20.78. C H N O .
Calculated, %: C 69.13; H 4.12; N 20.81. LC-MS:
5
3
1
22
8
2
+
39.1 [M + H] .
N-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-2-(5-
phenyl-1,3,4-oxadiazol-2-yl)aniline (7k). Colourless
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 7 2018

1
494
VENKATAGIRI et al.
controls NX (norfloxacin) for Staphylococcus,
Pseudomonas and OF (ofloxacin) for Bacillus and
E.coli. The plates were incubated overnight at 37°C in
a BOD incubator. The zones of inhibition were
measured using measuring scale.
3. Palaska, E.,Sahin, G., Kelicen, P., Tugbadurlu, N., and
Altinok, G., IL Farmaco, 2002, vol. 57, p. 101. doi
1
0.1016/S0014-827X(01)01176-4
4
. Dogan, H., Daran, A., Rollas, S., Sener, G., Uysal, M.K.,
and Gulen, D., Bioorg. Med. Chem., 2002, vol. 10,
p. 2893. doi 10.1016/S0968-0896(02)00143-8
Antifungal activity. Two types of fungal strain
Aspergillus niger and Trichoderma viride were
obtained from Microbial Type Culture Collection–
MTCC. The cultures were incubated in an autoclaved
PDB media for 3–4 days at 30°C in a shaker for fungal
growth. From the culture media 20 µL of fungal
culture was taken and inoculated using inoculation
loop on freshly prepared autoclaved PDA plates, petri
dishes. 5 mm Sample discs (5 mm) with samples
dissolved in DMSO solvent (concentration 1 mg/mL)
were stored on microbial plate along with the standard
control Ketoconazole. The plates were incubated for
5. Jain. N., Kashaw. S.K., Agrawal, R.K., Gupta. A., and
Soni, A., Med. Chem. Res., 2011, vol. 20, p. 1696. doi
1
0.1007/s00044-010-9496-x
6
7
. Almasirad, A., Shafiee, A., Abdollahi, M., Noeparast, A.,
Shahrokhinejad, N., Vousooghi, N., Abbas Tabatabai, S.,
and Khorasani, R., Med. Chem. Res., 2011, vol. 20,
p. 435. doi 10.1007/s00044-010-9335-0
. Brown, P., Best, D.J., Broom, N.J.P., Cassels, R.,
Bhanlon, P.J., Mitchell, T.J., Osborne, N.F., and
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8. Shalini, B., Vivek. A., Jagadish, S., and Partha Pratim, R.,
Eur. J. Med. Chem., 2015, vol. 97, p. 124. doi 10.1016/
j.ejmech.2015.04.051
4
–5 days at 30°C in a BOD incubator. The radial
9
. He, Y.-W., Dong, C.-Z., Zhao, J.-Y., Ma, L.-L., Li, Y.-H.,
and Aisa, H.A., Eur. J. Med. Chem., 2014, vol. 76,
p. 245. doi 10.1016/j.ejmech.2014.02.029
growth of the fungal colonies (zone of inhibition) was
measured using measuring scale.
CONCLUSIONS
10. (a) Kaushik, C.P., Lal, K., Kumar, A., and Kumar, S.,
Med. Chem. Res., 2014, vol. 23, p. 2995. doi
Synthesis of a series of 1,2,3-triazolyl-1,3,4-oxa-
diazoles with high yields using click chemistry has
been developed. The synthesized compounds along
with the compound 4 were evaluated for their
antimicrobial activity. Among the tested compounds,
1
0.10.1007/s00044-013-0882-z. (b) Darandale, S.N.,
Mulla, N.A., Pansare, D.N., Sangshetti, J.N., and
Shinde, D.B., Eur. J. Med. Chem., 2013, vol. 65, p. 527.
doi 10.1016/j.ejmech.2013.04.045
1
1
1
1. Dürüst, Y., Karakuş, H., Kaiser, M., and Tasdemir, D.,
Eur. J. Med. Chem., 2012, vol. 48, p. 296. doi 10.1016/
j.ejmech.2011.12.028
2. Mady, M.F., Awad, G.E.A., and Jorgensen, K.B., Eur.
J. Med. Chem., 2014, vol. 84, p. 433. doi 10.1016/
j.ejmech.2014.07.042
3. Abuo-Rahma, G.E.-D.A.A., Abdel-Aziz, M., Farag, N.A.,
and Kaoud, T.S., Eur. J. Med. Chem., 2014, vol. 83,
p. 398. doi 10.1016/j.ejmech.2014.06.049
7
d, 7h, and 7i demonstrated very high antifungal
activity against tested strains of fungi. Few compounds
were found to be selective for a fungal strain (7b, 7c,
7
e, 7j, 7l, 4). The compound 4 demonstrated high
antibacterial activity.
ACKNOWLEDGMENTS
One of the authors (N. Venkatagiri) is thankful to
the UGC-New Delhi, India for financial support in the
form of UGC-SRF and Head of Department of
Chemistry, Osmania University, Hyderabad, India for
providing laboratory facilities and CFRD, O. U,
Hyderabad, India for providing spectral data.
14. Wenjuan, Z., Zhi, Li., Meng, Z., Feng, Wu., Xueyan,
Hou, Hao, Luo, Hao, Liu, et al., Bioorg. Med. Chem.
Lett., 2014, vol. 24, no. 3, p. 799. doi 10.1016/
j.bmcl.2013.12.095
1
5. Subhashini, N.J.P., Sranvathi, Ch., Sravanthi, K., and
Shivaraj, Russ. J. Gen. Chem., 2016, vol. 86, no. 6,
p. 1405. doi 10.1134/S107036321606027X
CONFLICT OF INTERESTS
No conflict of interest was declared by the authors.
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