Synthesis and Antibacterial Activity of Some {6-[(1H-1,2,3-Triazol-4-yl)methoxy]-3-methylbenzofuran-2-yl}(4-bromophenyl)methanone Derivatives

Article abstract of DOI:10.1134/S1070363218040254

A series of novel benzofuran?1,2,3-triazole hybrid heterocyclic molecules were synthesized using a click chemistry approach. The structure of the synthesized compounds was assessed by IR and NMR spectroscopy and mass spectrometry. The products showed moderate to high activity against gram-positive and gram-negative bacteria.

Full text of DOI:10.1134/S1070363218040254

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 4, pp. 789–796. © Pleiades Publishing, Ltd., 2018.
Synthesis and Antibacterial Activity of Some
{
6-[(1H-1,2,3-Triazol-4-yl)methoxy]-3-methylbenzofuran-
1
2-yl}(4-bromophenyl)methanone Derivatives
a
b
a
a
b
A. Kishore Kumar *, V. Sunitha , P. Shankaraiah , M. Siddhartha , and P. Jalapathi
a
Department of Humanities and Sciences, Vardhaman College of Engineering,
Shamshabad, Hyderabad, Telangana, 501218 India
*
e-mail: kishoreangajala@gmail.com
b
Department of Chemistry, University College of Science, Osmania University,
Saifabad, Hyderabad, Telangana, 500004 India
Received December 30, 2017
Abstract—A series of novel benzofuran−1,2,3-triazole hybrid heterocyclic molecules were synthesized using a
click chemistry approach. The structure of the synthesized compounds was assessed by IR and NMR
spectroscopy and mass spectrometry. The products showed moderate to high activity against gram-positive and
gram-negative bacteria.
Keywords: benzofuran, 1,2,3-triazoles, click chemistry, antibacterial activity
DOI: 10.1134/S1070363218040254
INTRODUCTION
binding affinity to receptors. 1,2,3-Triazoles possess a
remarkable metabolic stability, and they were used as
amide surrogates in various bioactive compounds [22].
Benzofurans belong to one of the most studied
structural units in both synthetic and medicinal
chemistry. They are known to be present in many
natural products and have found application as agro-
chemicals [1], hypnotics [2], cosmetics [3], and
pharmaceuticals [4–6]. Benzofuran derivatives possess
diverse pharmacological and biological activities,
including antibacterial [7], antifungal [8], anti-
inflammatory [9], anti-HIV [10], antitubercular [11],
antidiabetic [12], antidepressant, anticonvulsant [13],
and analgesic effects. Benzofuran is a promising pharma-
cophore for drug discovery, and a large number of
synthetic methodologies for its derivatives have been
developed.
In a continuation of our previous work [7], we
synthesized a series of novel hybrid molecules which
contain a benzofuran and a 1,2,3-triazole moieties. The
purpose of this study was to explore the antibacterial
activity of benzofuran-1,2,3-triazole hybrids 7a–7m,
with the aim to develop novel potent antimicrobial
agents.
RESULTS AND DISCUSSION
(
4-Bromophenyl){3-methyl-6-[1H-1,2,3-triazol-4-
yl)methoxy]benzofuran-2-yl}me-thanones 7a–7m were
synthesized by a 4-step protocol using known
procedures [7]. Resorcinol (1) was reacted with acetic
In recent years, the chemistry of triazoles has
received considerable attention due to their synthetic
and biological importance. The triazole nucleus is
incorporated into a wide range of therapeutically
interesting antibacterial [14], antifungal [15], anti-
inflammatory [14], antiviral [16], antitubercular [17],
anticancer [18], and cytotoxic [19] drug candidates.
acid in the presence of freshly fused ZnCl to obtain 1-
2
(2,4-dihydroxyphenyl)ethanone (2) in a 70% yield.
The selective O-alkylation of compound 2 with pro-
pargyl bromide in the presence of K
CO in dry
2
3
acetone under N for 8 h under reflux gave 1-(2-
2
hydroxy-4-(prop-2-yn-1-yloxy)phenyl)ethanone (3) in
1
,4-Disubstituted 1,2,3-triazoles have been recently
a 90% yield. The structureof the product was con-
firmed by the H NMR spectrum, which showed a
1
employed as amide mimics [20, 21], with a higher
characteristic singlet at δ 12.6 ppm and two doublets at
δ 4.71 and 2.53 ppm assignable to a chelated phenolic
1
The text was submitted by the authors in English.
7
89

7
90
KISHORE KUMAR et al.
Scheme 1.
Me
Me
Br
AcOH, ZnCl2
O
O
o
1
20−140 C
K CO , acetone
reflux, 8 h
HO
OH
30 min
HO
OH
2
3
O
OH
1
2 (70%)
3 (90%)
Br
K CO , acetone
2
3
room temperature, 20 h
O
Br
4
Br
Br
R
N N
Me
O
Me
N3
R
N
6
a−6m
.
CuSO4 5H O
sodium ascorbate
t-BuOH + H O (1 : 1),
2
O
O
O
O
O
2
7a−7m
room temperature
5 (95%)
Me
Me
Me
Me
R =
(7a),
(7b),
(
7c),
(7d),
(7e),
3
5
9
O N
2
Cl
(7j),
Cl
(
7f),
(7g),
(7h),
(7i),
Cl
(
7k),
NO2
(
7l),
(7m).
OMe
hydrogen of the o-OH group, O–CH –, and ≡CH,
pound 5, the carbonyl, O-CH , –C≡, and ≡CH carbons
2
2
respectively. (4-Bromophenyl)[3-methyl-6-(prop-2-yn-
appeared at δC 184.0, 56.2, 76.2, and 77.9 ppm,
respectively. The presence of the ν(C=O) band at
1
-yloxy)benzofuran-2-yl]methanone (5) was easily
–
1
prepared by the base-mediated reaction of compound 3
with 2-bromo-1-(4-bromophenyl)ethanone (4) for 20 h.
1664 cm and the absence of the ν(OH) band at
–
1
3422 cm provides evidence for the formation of
compound 5. Aliphatic and aromatic azide
intermediates 6a–6m were synthesized by published
protocol [23]. The target benzofuran–1,2,3-triazole
hybrid heterocycles 7a–7m (see Scheme 1) were
synthesized by the cycloaddition of compound 5 to
azides 6a–6m and characterized by means of IR and
1
The structure of compound 5 was confirmed by the H
NMR spectrum, which showed a three-proton singlet
at δ 2.63 ppm suggesting the presence of the methyl
group and a two-proton doublet at δ 4.78 and a one-
proton triplet at δ 2.57 ppm assignable for the O–CH
and ≡CH groups. In the C NMR spectrum of com-
2
1
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

SYNTHESIS AND ANTIBACTERIAL ACTIVITY
Antibacterial activity of compounds 7a–7m
791
Zone of inhibition, mm
gram-positive bacteria
gram-negative bacteria
Concentration,
µg/mL
Comp. no.
7
a
75
18
21
16
10
10
12
09
12
19
21
12
15
08
11
27
31
25
27
26
27
24
26
20
22
29
32
27
30
19
21
17
19
09
12
08
11
20
22
10
13
18
20
14
17
10
13
09
11
17
19
11
13
20
23
18
21
10
13
08
10
21
24
12
15
7
16
18
14
17
11
14
08
11
17
19
13
15
7
18
20
16
19
09
11
07
09
19
21
10
13
06
09
26
29
24
26
25
28
23
26
20
22
28
32
27
30
21
18
21
16
19
10
12
08
10
19
20
09
11
09
09
27
30
26
28
27
30
25
27
19
21
29
32
29
31
1
00
23
7
b
75
19
1
00
22
7
c
75
10
1
00
13
7
d
75
07
1
00
09
7
e
75
22
1
00
24
7
f
75
09
1
00
11
7
g
75
No activity No activity
No activity No activity
No activity
1
00
09
29
32
28
30
29
31
28
31
22
24
30
33
31
34
10
27
30
25
27
26
29
24
26
18
20
20
35
28
31
No activity
7
h
75
28
32
28
30
28
31
26
28
21
23
31
34
31
33
28
32
27
29
28
30
26
29
19
21
31
33
30
33
30
33
29
30
29
31
28
30
22
25
31
34
31
33
1
00
7
i
75
1
00
7
j
75
1
00
7
k
75
1
00
7
l
75
1
00
7
m
75
1
00
Gentamycin
75
1
00
NMR spectroscopy and mass spectrometry. The
presence of a 1,2,3-triazole fragment in the synthesized
compounds is confirmed by the observation of a
singlet signal between δ 7.59–7.65 ppm in their H
NMR spectra.
The synthesized benzofuran-based 1,4-disubstituted
1,2,3-triazoles 7a–7m were tested for their anti-
bacterial activity in two concentrations (75 and 100 μg/mL)
against four gram-positive bacteria (Micrococcus
luteus, Methcillin-resistant Staphylococcus aureus,
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

7
92
KISHORE KUMAR et al.
Bacillus subtilis, and Bacillus cereus) and four gram-
negative bacteria (Pseudomonas aeruginosa,
concentrated under reduced pressure. The crude
product was purified by column chromatography,
eluent 10% ethyl acetate in ether. Yield 70%, reddish
brown needles, mp 142–144°C [7].
Klebsiella pneumoniae, Escherichia coli and Proteus
vulgaris) using Gentamycin sulfate as standard drug.
The test compounds all displayed potent to moderate
inhibitory effects on the growth of the test bacterial
strains (see table). Compounds 7h–7m showed the
highest activity. It was interesting to note that the
compounds with strong electron-donor (MeO), weak
electron-acceptor (Cl), and strong electron electron-
Synthesis of 1-[2-hydroxy-4-(prop-2-yn-1-yloxy)-
phenyl]ethanone (3). A solution of propargyl bromide
(
2.34 g, 0.019 mol) in toluene was added dropwise to a
well-stirred mixture of a 25 mL solution of 1-(2,4-
dihydroxyphenyl)ethanone (2) (3 g, 0.019 mol) in dry
acetone and K CO (2.72 g, 0.019 mol), and the
2
3
acceptor (NO ) groups in the phenyl substituent in the
2
reaction mixture was refluxed for about 8 h. Progress
of the reaction was monitored by TLC. After comple-
tion of the reaction, the reaction mixture was cooled
down to room temperature, and excess acetone was
evaporated under reduced pressure. The residue was
diluted with water (50 mL) and extracted with ethyl
acetate (3×50 mL). The combined organic layers were
washed with brine (2×25 mL). The organic layer was
dried over anhydrous Na SO , filtered, and concen-
triazole ring proved to be more potent antibacterial
agents compared with the compounds with aliphatic
substituents in the triazole ring.
EXPERIMENTAL
The melting points were measured in open
capillaries and are uncorrected. The IR spectra were
recorded on a Perkin–Elmer 337 grating IR spectro-
photometer for solid samples pelleted in KBr. The
NMR spectra were obtained on Bruker AV-400 and
2
4
trated in vacuo. The crude product was purified by
column chromatography, eluent 5% ethyl acetate in
petroleum ether. Yield 92%, white solid, mp 196–198°C.
AV-300 NMR spectrometers for CDCl solutions. The
3
–
1
1
chemical shifts were measured in ppm against internal
TMS. CHN analysis was obtained on Perkin Elmer
Model 2400 CHNS elemental analyzer. Electron Spray
Ionization (ESI) mass spectra were recorded on a
QSTARXL hybrid MS system (Applied Bio Systems)
under electro spray ionization. Thin layer chromato-
graphy was carried out on Merck TLC silica gel 60
F254 plates. The spots were visualized in UV light at
IR spectrum, ν, cm : 3411, 2357, 1640. H NMR
spectrum (300 MHz, δ, ppm: 12.6 s (1H), 7.63 d.d (J =
7.05 and 2.3 Hz, 1H), 6.46–6.43 m (2H), 4.71 d (J =
2.3 Hz, 2H), 2.55 s (3H), 2.53 d (J = 2.28 Hz, 1H).
+
ESI+ mass spectrum: m/z 191.1 [M + 1] .
Synthesis of (4-bromophenyl)[3-methyl-6-(prop-
2
-yn-1-yloxy)benzofuran-2-yl]methanone (5). A mix-
ture of 1-[2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl]-
ethanone (3) (2 g, 0.010 mol), 2-bromo-1-(4-bromo-
phenyl)ethanone (4) (2.89 g, 0.010) (Sigma-Aldrich,
2
54 nm or, alternatively, by staining with aqueous
basic potassium permanganate. Column chromato-
graphy was performed on a Merck silica gel 60A (100–
9
8%), and K CO (2.90 g, 0.021 mol) was stirred in
2 3
2
00 mesh). Commercially available reagents were used
acetone (20 mL) at room temperature for 20 h.
Progress of the reaction was monitored by TLC. After
completion of the reaction, the precipitate that formed
was filtered off and washed with acetone (2 × 15 mL),
and washings were combined. The solution was con-
centrated, and the residue was purified by column
chromatography, eluent 10% ethyl acetate in petro-
leum ether. Yield 95%, white solid, mp 178–180°C. IR
as supplied, and all solvents were distilled before use.
All reactions were performed in an oven-dried
glassware.
Synthesis of 1-(2,4-dihydroxyphenyl)ethanone (2).
Acetic acid (3 g, 0.05 mol) was added to anhydrous
ZnCl (6.8 g, 0.05 mol), the mixture was heated at
2
1
20°C for 30 min and then resorcinol (5.5 g, 0.05 mol)
–
1
1
was added. The reaction mixture was heated at 140°C
for 30 min with TLC monitoring of the degree of
conversion. After completion of the reaction, the
reaction mixture was allowed to warm up to room
temperature, poured into an ice-cold water (100 mL),
and extracted with ethyl acetate (3×50 mL). The
combined organic layers were washed with 20% HCl
spectrum, ν, cm : 1665 (C=O). H NMR spectrum
(300 MHz), δ, ppm: 7.99–7.94 m (2H), 7.69–7.65 m
(2H), 7.62–7.58 m (1H), 7.12 d (J = 2.16 Hz, 1H),
7.04 d.d (J = 8.68 and 2.22 Hz, 1H), 4.78 d (J =
2.41 Hz, 2H), 2.63 s (3H), 2.57 t (J = 2.39 Hz, 1H).
1
3
C NMR spectrum, δ , ppm: 184.0, 159.0, 155.3,
C
148.0, 136.7, 131.5, 131.2, 128.2, 127.4, 123.3, 122.1,
114.2, 96.8, 77.9, 76.2, 56.2, 10.2. ESI+ mass
(
50 mL) and saturated NaHCO (25 mL). The organic
3
+
layer was dried over anhydrous Na SO , filtered, and
spectrum: m/z 369 [M + H] .
2
4
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

SYNTHESIS AND ANTIBACTERIAL ACTIVITY
793
Synthesis of (4-bromophenyl){3-methyl-6-[1H-
,2,3-triazol-4-yl)methoxy]benzofuran-2-yl}methanone
(4-Bromophenyl){3-methyl-6-[1-octyl-1H-1,2,3-
triazol-4-yl)methoxy]benzofuran-2-yl}(4-bromo-
phenyl)methanone (7c). Yield 95%, white solid, mp
1
derivatives (general procedure). (4-Bromophenyl)[3-
methyl-6-(prop-2-yn-1-yloxy)benzofuran-2-yl]metha-
none (5) (100 mg, 0.271 mmol) was dissolved in 5 mL
of 50% aqueous t-BuOH, and CuSO ·5H O (5 mol %),
–
1
1
210–212°C. IR spectrum, ν, cm : 1664 (C=O). H
NMR spectrum (400 MHz), δ, ppm: 8.02–7.95 m (2H),
7.79–7.64 m (3H), 7.66–7.54 m (1H), 7.15 d (J =
2.17 Hz, 1H), 7.07 d.d (J = 8.67, 2.23 Hz, 1H), 5.25 s
(2H), 4.36 t (J = 6.46 Hz, 2H), 2.65 s (3H), 2.01–1.82
4
2
sodium ascorbate (10 mol %), and azide (0.45 mmol)
were added to the solution. The reaction mixture was
stirred for 1 h at room temperature. After complete
conversion of starting materials into products, as
indicated by TLC, the reaction mixture was diluted
with water (25 mL) and extracted with ethyl acetate
1
3
m (2H), 1.37–1.16 m (10H), 0.98-0.77 m (3H).
C
NMR spectrum, δ , ppm: 185.0, 159.6, 155.8, 149.0,
C
144.0, 137.9, 132.5, 129.8, 128.3, 127.4, 123.5, 122.8,
122.1, 113.0, 97.4, 62.6, 50.7, 31.8, 30.4, 29.3, 28.7,
26.5, 22.8, 14.3, 10.1. ESI+ mass spectrum: m/z 524
(
3 × 25 mL). The combined organic layers were
+
washed with brine (2 × 25 mL), dried over anhydrous
Na SO , filtered, and concentrated in vacuo. The crude
[M + H] . Calculated, %. C 61.83; H 5.77; N 8.01.
2
4
C H BrN O . Found, %. C 61.30; H 5.29; N 7.81.
27 30
3
3
product was purified by column chromatography
eluent ethyl acetate–petroleum ether, 30-50%) to
afford the corresponding (4-bromophenyl){3-methyl-
-[1H-1,2,3-triazol-4-yl)methoxy]benzofuran-2-yl}-
methanone derivative.
(
4-Bromophenyl){6-[1-dodecyl-1H-1,2,3-triazol-
-yl)methoxy]-3-methyl-benzofuran-2-yl}methanone
7d). Yield 90%, white solid, mp 225–227°C. IR
(
4
(
6
–1
1
spectrum, ν, cm : 1667 (C=O). H NMR spectrum
(
(
(
400 MHz), δ, ppm: 8.12–8.04 m (2H), 7.62–7.47 m
4H), 7.17 s (1H), 7.05 d (J = 8.67 Hz, 1H), 5.28 s
2H), 4.36 t (J = 7.18 Hz, 2H), 2.64 s (3H), 2.05–1.83
m (2H), 1.39–1.26 m (18H), 0.99-0.86 m (3H).
NMR spectrum, δ , ppm: 185.1, 159.8, 155.7, 147.9,
44.0, 137.9, 132.5, 129.6, 128.4, 126.0, 122.9, 122.5,
22.0, 114.1, 96.7, 62.6, 51.3, 33.8, 31.9, 30.4, 29.0,
7.0, 26.6, 24.6, 22.6, 20.2, 17.3, 14.0, 10.0. ESI+
mass spectrum: m/z 580 [M + H] . Calculated, %. C
4.13; H 6.60; N 7.24. C H BrN O . Found, %. C
(
4-Bromophenyl){6-[1-butyl-1H-1,2,3-triazol-4-
yl)methoxy]-3-methyl-benzofuran-2-yl}methanone
7a). Yield 85%, white solid, mp 192–194°C. IR
1
3
C
(
–
1
1
spectrum, ν, cm : 1661 (C=O). H NMR spectrum
C
1
1
2
(
(
400 MHz), δ, ppm: 7.98–7.94 m (2H), 7.76–7.64 m
3H), 7.62–7.57 m (1H), 7.13 d (J = 2.15 Hz, 1H),
7
.05 d.d (J = 8.69, 2.23 Hz, 1H), 5.25 s (2H), 4.36 d
+
(
1
J = 8.43 Hz, 2H), 2.64 s (3H), 1.97–1.88 m (2H), 1.38–
.28 m (2H), 0.96-0.88 m (3H). C NMR spectrum,
1
3
6
6
31 38 3 3
3.81; H 6.47; N 7.06.
4-Bromophenyl){6-[1-cyclopentyl-1H-1,2,3-tri-
δC, ppm: 185.3, 159.7, 155.6, 148.4, 143.6, 138.1,
1
9
32.4, 129.7, 128.4, 127.5, 123.2, 122.7, 122.0, 114.2,
(
7.1, 62.7, 50.4, 30.1, 22.2, 13.7, 10.1. ESI+ mass
azol-4-yl)methoxy]-3-methyl-benzofuran-2-yl}metha-
none (7e). Yield 88%, white solid, mp 188–190°C. IR
spectrum, ν, cm : 1668 (C=O). H NMR spectrum
400 MHz), δ, ppm: 8.08 d (J = 7.27 Hz, 2H), 7.71 s
1H), 7.67–7.49 m (3H), 7.17 s (1H), 7.06 d.d (J =
.66, 1.73 Hz, 1H), 5.28 s (2H), 5.03–4.90 m (1H),
.65 s (3H), 2.34-2.22 m (2H), 2.15-2.02 m (2H), 1.99–
1.88 m (2H), 1.84–1.72 m (2H). C NMR spectrum, δ ,
ppm: 185.6, 160.1, 156.0, 148.7, 143.5, 138.1, 132.3,
30.1, 128.0, 127.7, 122.9, 122.0, 121.4, 114.1, 96.8,
+
spectrum: m/z 468 [M + H] . Calculated, %. C 58.98;
–
1
1
H 4.73; N 8.97. C H BrN O . Found, %. C 58.28; H
23
22
3
3
4
.28; N 8.47.
4-Bromophenyl){6-[1-hexyl-1H-1,2,3-triazol-4-
yl)methoxy]-3-methyl-benzofuran-2-yl}methanone
7b). Yield 96%, white solid, mp 201–203°C. IR spec-
(
(
(
8
2
(
13
–
1
1
C
trum, ν, cm : 1666 (C=O). H NMR spectrum
(
(
400 MHz), δ, ppm: 8.01–7.96 m (2H), 7.78–7.65 m
3H), 7.65–7.56 m (1H), 7.15 d (J = 2.17 Hz, 1H),
1
6
4
2.5, 62.1, 33.4, 24.1, 10.3. ESI+ mass spectrum: m/z
80 [M + H] . Calculated, %. C 60.01; H 4.62; N 8.75.
C H BrN O . Found, %. C 59.82; H 4.55; N 8.70.
24 22 3 3
7
.06 d.d (J = 8.68, 2.22 Hz, 1H), 5.27 s (2H), 4.39 t
+
(
1
J = 6.51 Hz, 2H), 2.66 s (3H), 2.08–1.99 m (2H), 1.40–
.27 m (4H), 0.98-0.87 m (5H). C NMR spectrum,
1
3
δC, ppm: 185.0, 159.6, 155.8, 149.0, 144.0, 137.9,
(4-Bromophenyl){6-[1-cyclohexyl-1H-1,2,3-tri-
132.5, 129.8, 128.3, 127.4, 123.5, 122.8, 122.1, 113.0,
azol-4-yl)methoxy]-3-methyl-benzofuran-2-yl}metha-
9
7.4, 62.9, 51.5, 32.0, 30.2, 26.5, 22.4, 13.5, 10.2. ESI+
none (7f). Yield 94%, white solid, mp 204-206°C. IR
+
–1
1
mass spectrum: m/z 496 [M + H] . Calculated, %. C
6
6
spectrum, ν, cm : 1659 (C=O). H NMR spectrum
(400 MHz), δ, ppm: 8.09–8.00 d (J = 6.44 Hz, 2H),
7.67 s (1H), 7.63–7.43 m (3H), 7.15 s (1H), 7.03 d
0.49; H 5.28; N 8.47. C H BrN O . Found, %. C
25 26 3 3
0.01; H 5.03; N 8.15.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

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94
KISHORE KUMAR et al.
(
(
1
J = 7.70 Hz, 1H), 5.25 s (2H), 4.44 s (1H), 2.59 s
3H), 2.23 d (J = 9.66 Hz, 2H), 1.93–1.87 m (2H),
(4-Bromophenyl)(6-{1-(4-chlorophenyl)-1H-1,2,3-
triazol-4-yl]methoxy}-3-methylbenzofuran-2-yl)-
methanone (7j). Yield 88%, white solid, mp 235–237°C.
.76–1.70 m (3H), 1.46–1.42 m (2H), 1.27–1.23 m
1
3
–1
1
(
1H). C NMR spectrum, δ , ppm: 185.7, 160.1,
IR spectrum, ν, cm : 1669 (C=O). H NMR spectrum
(400 MHz), δ, ppm: 8.15–8.03 m (3H), 7.71 d (J =
8.83 Hz, 2H), 7.66–7.58 m (2H), 7.58–7.47 m (4H),
7.19 d (J = 2.00 Hz, 1H), 7.09–7.05 m (1H), 5.39 s
C
1
1
2
55.8, 148.4, 143.3, 137.9, 132.6, 130.1, 128.5, 127.8,
23.3, 122.1, 120.8, 114.2, 96.6, 62.7, 60.4, 33.4, 25.3,
+
5.2, 10.3. ESI+ mass spectrum: m/z 494 [M + H] .
1
3
Calculated, %. C 60.74; H 4.89; N 8.50. C H BrN O .
(2H), 2.63 s (3H). C NMR spectrum, δ , ppm 185.4,
25
24
3
3
C
Found, %. C 60.58; H 4.81; N 8.12.
159.6, 155.7, 148.4, 144.7, 138.1, 135.5, 135.0, 132.5,
1
1
30.2, 129.8, 128.5, 127.7, 123.4, 122.1, 121.8, 121.1,
(
4-Bromophenyl){3-methyl-6-[1-phenyl-1H-1,2,3-
14.1, 96.7, 62.5, 10.1. ESI+ mass spectrum: m/z 522
triazol-4-yl)methoxy]benzofuran-2-yl}(4-bromo-
phenyl)methanone (7g). Yield 88%, white solid, mp
+
[
M + H] . Calculated, %. C 57.44; H 3.28; N 8.04.
–
1
1
C H BrClN O . Found, %. C 57.34; H 3.20; N 7.95.
25 17 3 3
1
77–179°C. IR spectrum, ν, cm : 1669 (C=O). H
NMR spectrum (400 MHz), δ, ppm: 8.14–8.09 m (3H),
.80–7.75 m (2H), 7.64–7.60 m (2H), 7.54–7.53 m
3H), 7.49–7.46 m (1H), 7.21 d (J = 2.13 Hz, 1H),
.09 d.d (J = 8.68, 2.21 Hz, 1H), 5.40 s (2H), 2.65 s
3H). C NMR spectrum, δ , ppm: 185.4, 159.7, 155.6,
48.4, 144.4, 138.1, 137.0, 132.4, 130.1, 129.7, 129.1,
28.4, 127.6, 123.4, 122.1, 121.3, 120.8, 114.1, 97.0,
2.7, 10.3. ESI+ mass spectrum: m/z 488 [M + H] .
(4-Bromophenyl)(3-methyl-6-{[1-(3-nitrophenyl)-
7
(
7
(
1
1
6
1H-1,2,3-triazol-4-yl]methoxy}benzofuran-2-yl)-
methanone (7k). Yield 84%, white solid, mp 245–
–
1
1
247°C. IR spectrum, ν, cm : 1655 (C=O). H NMR
spectrum (400 MHz), δ, ppm: 8.61 s (1H), 8.34–8.25
m (2H), 8.24–8.15 m (1H), 8.06 d (J = 7.45 Hz, 2H),
7.77 t (J = 8.17 Hz, 1H), 7.63–7.42 m (4H), 7.15 s
(1H), 7.05 d (J = 8.3 Hz, 1H), 5.34 s (2H), 2.56 s (3H).
13
C
+
1
3
Calculated, %. C 61.49; H 3.72; N 8.60. C H BrN O .
C NMR spectrum, δ , ppm: 185.5, 160.1, 155.6,
25
18
3
3
C
Found, %. C 61.26; H 3.66; N 8.54.
148.9, 148.5, 149.0, 138.1, 137.6, 132.5, 131.2, 129.7,
1
1
28.2, 127.5, 126.0, 123.4, 123.4, 122.3, 121.2, 115.3,
(
4-Bromophenyl)(6-{1-(2-chlorophenyl)-1H-1,2,3-
14.0, 96.8, 62.4, 10.3. ESI+ mass spectrum: m/z 533
triazol-4-yl]methoxy}-3-methylbenzofuran-2-yl)-
methanone (7h). Yield 82%, white solid, mp 217–
19°C. IR spectrum, ν, cm : 1656 (C=O). H NMR
+
[
M + H] . Calculated, %. C 56.30; H 3.21; N 10.51.
–
1
1
C H BrN O . Found, %. C 56.10; H 3.21; N 10.44.
25 17 4 5
2
spectrum (400 MHz), δ, ppm: 8.10 s (1H), 8.06 d (J =
(4-Bromophenyl)(3-methyl-6-{[1-(4-nitrophenyl)-
7
1
2
1
1
1
.17 Hz, 2H), 7.68–7.44 m (7H), 7.21 d (J = 2.10 Hz,
H), 7.09 d.d (J = 8.70, 2.10 Hz, 1H), 5.37 s (2H),
1H-1,2,3-triazol-4-yl]methoxy}benzofuran-2-yl)-
methanone (7l). Yield 90%, white solid, mp 261–263°C.
IR spectrum, ν, cm : 1660 (C=O). H NMR spectrum
(400 MHz, δ, ppm: 8.43 d (J = 8.88 Hz, 2H), 8.24 s
(1H), 8.10–7.94 m (3H), 7.66–7.58 m (2H), 7.57–7.50
1
3
–1
1
.62 s (3H). C NMR spectrum, δ , ppm: 185.5,
C
59.8, 155.6, 148.2, 143.5, 138.1, 134.6, 132.4, 131.3,
31.0, 129.8, 128.7, 128.4, 128.1, 128.1, 127.6, 124.9,
23.5, 121.8, 113.9, 97.0, 62.5, 10.3. ESI+ mass
m (2H), 7.19 s (1H), 7.09 d (J = 8.55 Hz, 1H), 5.39 s
+
13
spectrum: m/z 522 [M + H] . Calculated, %. C 57.44;
(2H), 2.61 s (3H). C NMR spectrum, δ , ppm: 185.5,
C
H 3.28; N 8.04. C H BrClN O . Found, %. C 57.34;
H 3.20; N 7.96.
159.8, 155.7, 148.9, 147.4, 145.5, 141.1, 138.1, 132.5,
130.1, 128.4, 127.7, 125.7, 123.7, 122.4, 121.0, 120.4,
2
5
17
3
3
1
13.9, 96.9, 62.3, 10.2. ESI+ mass spectrum: m/z 533
(
4-Bromophenyl)(6-{1-(3-chlorophenyl)-1H-1,2,3-
+
[
M + H] . Calculated, %. C 56.30; H 3.21; N 10.51.
triazol-4-yl]methoxy}-3-methylbenzofuran-2-yl)-
methanone (7i). Yield 80%, white solid, mp 230–232°C.
IR spectrum, ν, cm : 1668 (C=O). H NMR spectrum
400 MHz), δ, ppm: 8.13–7.97 m (3H), 7.79 s (1H),
C H BrN O . Found, %. C 56.12; H 3.21; N 10.42.
2
5
17
4
5
–1
1
(4-Bromophenyl)(6-{[1-(2-methoxyphenyl)-1H-
(
1,2,3-triazol-4-yl]methoxy}-3-methylbenzofuran-2-
7
.71–7.38 m (6H), 7.15 s (1H), 7.04 d (J = 8.29 Hz,
yl)methanone (7m). Yield 85%, white solid, mp 230–
13
–1
1
1H), 5.34 s (2H), 2.60 s (3H). C NMR spectrum, δ ,
232°C. IR spectrum, ν, cm : 1664 (C=O). H NMR
spectrum (400 MHz), δ, ppm: 8.27 s (1H), 8.14–8.07
m (2H), 7.81 d.d (J = 7.77, 1.61 Hz, 1H), 7.66–7.50 m
(3H), 7.49–7.41 m (1H), 7.22 d (J = 2.10 Hz, 1H),
7.17–7.07 m (3H), 5.38 s (2H), 3.89 s (3H), 2.63 s
C
ppm: 185.5, 160.1, 155.6, 148.4, 138.1, 137.9, 135.8,
132.5, 131.0, 129.7, 129.6, 129.1, 128.3, 127.5, 123.4,
122.1, 121.3, 120.7, 118.5, 114.1, 96.8, 62.4, 10.3. ESI+
+
mass spectrum: m/z 522 [M + H] . Calculated, %. C
13
57.44; H 3.28; N 8.04. C H BrClN O . Found, %. C
(3H). C NMR spectrum, δ , ppm: 185.3, 160.1, 155.6,
25
17
3
3
C
5
7.34; H 3.21; N 7.94.
151.2, 148.5, 143.0, 138.2, 132.5, 130.8, 130.1, 128.5,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

SYNTHESIS AND ANTIBACTERIAL ACTIVITY
795
1
1
5
27.8, 126.3, 125.6, 124.9, 123.7, 122.1, 121.4, 114.4,
nones 7a–7m were synthesized in good yields using a
click chemistry approach and characterized by different
spectroscopic techniques. The synthesized molecules
all showed an excellent antibacterial activity. The
highest activities were found in compounds 7m, 7h–7l.
These results positively encouraged us for further
developing novel bioactive agents.
12.7, 97.1, 62.8, 56.1, 10.3. ESI+ mass spectrum: m/z
+
18 [M + H] . Calculated, %. C 60.24; H 3.89; N 8.11.
C H BrN O . Found, %. C 60.96; H 3.68; N 8.02.
26
20
3
4
Antibacterial activity testing. Bacterial Strains.
The gram-positive strains Micrococcus luteus (ATCC
0240), methicillin-resistant Staphylococcus aureus
MRSA, NCTC 13616), Bacillus subtilis (ATCC
633), and Bacillus cereus (ATCC 14579) and the
gram-negative strains Pseudomonas aeruginosa
ATCC 27853), Klebsiella pneumoniae (ATCC
3816), Escherichia coli (ATCC 8739) and Proteus
1
(
6
ACKNOWLEDGMENTS
A. Kishore Kumar is grateful to the Head of the
Department, Freshman Engineering, IQAC and
Principal Vardhaman College of Engineering,
Hyderabad, Telangana, India for support.
(
4
vulgaris (ATCC 13315) were purchased from the
American Type Culture Collection. Methicillin-
resistant Staphylococcus aureus was purchased from
the Public Health England Culture Collections. All
bacterial strains stored at ‒80°C were streaked on
Luria‒Bertani (LB) agar plates (Hi-media Labora-
tories, Mumbai, India) and incubated at 37°C for 20–
REFERENCES
1
2
3
4
5
. Keay, B. and Dibble, P., Comprehensive Heterocyclic
Chemistry, New York: Pergamon, 1996, vol. 2, p. 413.
. Nasef, A., El-Naem, S., and El Shabrawy, O., Egypt. J.
Pharm. Sci., 1992, vol. 33, p. 463.
. Taufel, A., Mol. Nutr. Food Res., 1996, vol. 40, no. 5,
p. 289.
. Powers, L.J., J. Med. Chem., 1976, vol. 19, no. 1, p. 57.
doi 10.1021/jm00223a013
. Nagahara, T., Yokoyama, Y., Inamura, K., Katakura, S.-I.,
Komoriya, S., Yamaguchi, H., Hara, T., and Iwamoto, M.,
J. Med. Chem., 1994, vol. 37, no. 8, p. 1200. doi
2
4 h. A few isolated colonies were selected from each
plate and suspended in 5 mL of LB broth in a sterile
culture vessel. The vessel was plugged with cotton and
incubated with gentle shaking (140 rpm) at 37°C for
2
0 h.
Preparation of inocula. Following the protocol of
the Kirby–Bauer disk diffusion assay [24], four to five
well-isolated colonies of the same morphological type
were picked with an inoculating loop, transferred into
1
0.1021/jm00034a018
6
7
. Gubin, J., de Vogelaer, H., Inion, H., Houben, C.,
Lucchetti, J., Mahaux, J., Rosseels, G., Peiren, M., and
Clinet, M., J. Med. Chem., 1993, vol. 36, no. 10,
p. 1425. doi 10.1021/jm00062a015
. Sunitha, V., Kumar, A.K., Shankar, B., Kumar, A.A.,
Krishna, T., Lincoln, C.A., and Pochampalli, J., Russ. J.
Gen. Chem., 2017, vol. 87, no. 2, p. 322. doi 10.1134/
S1070363217020281
5
mL of nutrient broth, and incubated at 37°C for 24 h
until a slight visible turbidity appeared. The turbidity
of the actively growing broth cultures was then
adjusted with broth to a density equivalent to that of a
0
.5 McFarland standard, and the resulting suspensions
were used as the initial inocula in the assay.
Antibacterial assay. The initial inocula of the test
organisms, 100 µL, were swabbed over the surface of
the agar media (20 mL) in Petri dishes and let to be
absorbed for 15 min. Wells, 8 mm in diameter, were
made with a sterile cork borer in the seeded agar
plates. Solutions of the test compounds in DMSO
8. Gündoğdu-Karaburun, N., Benkli, K., Tunali, Y.,
Uçucu, Ü., and Demirayak, Ş., Eur. J. Med. Chem.,
2006, vol. 41, no. 5, p. 651. doi 10.1016/j.ejmech.2005.12.013
9
. Khan, M. W., Alam, M. J., Rashid, M., and Chowdhury, R.,
Bioorg. Med. Chem., 2005, vol. 13, no. 16, p. 4796. doi
1
0.1016/j.bmc.2005.05.009
1
1
0. Rida, S.M., El-Hawash, S.A., Fahmy, H.T., Hazzaa, A.A.,
and El-Meligy, M.M., Arch. Pharm. Res., 2006, vol. 29,
no. 10, p. 826.
(
100 µL; c 75 and 100 mg/mL) were then loaded into
the wells and incubated in air at 37°C for 24 h. The
inhibition zone diameter was measured with a zone
reader (HiAntibiotic Zone Scale). The positive control
was the standard drug Gentamycin.
1. Manna, K. and Agrawal, Y.K., Eur. J. Med. Chem.,
2
010, vol. 45, no. 9, p. 3831. doi 10.1016/
j.ejmech.2010.05.035
CONCLUSIONS
12. Reddy, K.A., Lohray, B., Bhushan, V., Bajji, A.,
Reddy, K.V., Reddy, P.R., Krishna, T.H., Rao, I.N.,
Jajoo, H.K., and Rao, N.M., J. Med. Chem., 1999,
vol. 42, no. 11, p. 1927. doi 10.1021/jm980549x
A series of novel (4-bromophenyl){3-methyl-6-[1H-
,2,3-triazol-4-yl)methoxy]benzofuran-2-yl}metha-
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

7
1
96
KISHORE KUMAR et al.
3. Patel, H.J., Sarra, J., Caruso, F., Rossi, M., Doshi, U.,
and Stephani, R.A., Bioorg. Med. Chem. Lett., 2006,
vol. 16, no. 17, p. 4644. doi 10.1016/j.bmcl.2006.05.102
4. Angajala, K K., Vianala, S., Macha, R., Raghavender, M.,
Thupurani, M.K., and Pathi, P., SpringerPlus, 2016,
vol. 5, no. 1, p. 423. doi 10.1186/s40064-016-2052-5
19. da Silva, G.D., da Silva, M.G., Souza, E.M., Barison, A.,
Simões, S.C., Varotti, F.P., Barbosa, L.A., Viana, G.H.,
and Villar, J.A., Molecules, 2012, vol. 17, no. 9,
p. 10331. doi 10.3390/molecules170910331
1
1
2
0. Valverde, I.E., Bauman, A., Kluba, C.A., Vomstein, S.,
Walter, M.A., and Mindt, T.L., Angew. Chem. Int. Ed.,
2013, vol. 52, no. 34, p. 8957. doi 10.1002/
anie.201303108
5. Kumar, A.K., Sunitha, V., Shankar, B., Krishna, T.M.,
Lincoln, C.A., and Jalapathi, P., Russ. J. Gen. Chem.,
2
017, vol. 87, no. 9, p. 2011. doi 10.1134/
2
2
2
2
1. Kim, S., Cho, M., Lee, T., Lee, S., Min, H.-Y., and Lee, S.K.,
Bioorg. Med. Chem. Lett., 2007, vol. 17, no. 16,
p. 4584. doi 10.1016/j.bmcl.2007.05.086
S1070363217090171
1
6. Das, K., Bauman, J.D., Rim, A.S., Dharia, C., Clark Jr., A.D.,
Camarasa, M.-J., Balzarini, J., and Arnold, E., J. Med.
Chem., 2011, vol. 54, no. 8, p. 2727. doi 10.1021/
jm101536x
7. Wang, X.-L., Wan, K., and Zhou, C.-H., Eur. J. Med.
Chem., 2010, vol. 45, no. 10, p. 4631. doi 10.1016/
j.ejmech.2010.07.031
2. Agalave, S.G., Maujan, S.R., and Pore, V.S., Chem.
Asian J., 2011, vol. 6, no. 10, p. 2696. doi 10.1002/
asia.201100432
1
1
3. Kumar, D., Khare, G., Kidwai, S., Tyagi, A.K., Singh, R.,
and Rawat, D.S., Eur. J. Med. Chem., 2014, vol. 81,
p. 301. doi 10.1016/j.ejmech.2014.05.005
8. Ju, R., Wu, D., Guo, L., Li, J., Ye, C., and Zhang, D.,
4. Bauer, A., Am. J. Clin. Pathol., 1966, vol. 45, p. 493.
Eur. J. Cancer., 2012, vol. 48, no. 7, p. 1085. doi
1
doi 10.1093/ajcp/45.4_ts.493
0.1016/j.ejca.2011.06.050
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