Synthesis and Antibacterial Evaluation of Benzofuran Based 3,5-Disubstituted Isoxazoles

Article abstract of DOI:10.1134/S1070363218120319

A series of novel benzofuran-isoxazole 7a–7j hybrid heterocyclic molecules are synthesized. The structures of compounds 7a–7j are assessed by IR, NMR, MASS spectroscopy and elemental analysis. The target compounds 7a–7j are screened for their antibacterial activity and demonstrated excellent to moderate activity against gram-positive and gram-negative bacteria.

Full text of DOI:10.1134/S1070363218120319

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 12, pp. 2669–2674. © Pleiades Publishing, Ltd., 2018.
Synthesis and Antibacterial Evaluation of Benzofuran
1
Based 3,5-Disubstituted Isoxazoles
a
b
c
c
a
V. Sunitha , A. Kishore Kumar , Ch. Abraham Lincoln , P. Jalapathi *, and V. Gopal Reddy
a
Department of Chemistry, University College of Science, Osmania University,
Saifabad, Hyderabad, Telangana, 500004 India
b
Department of Humanities and Sciences, Vardhaman College of Engineering,
Shamshabad, Hyderabad, Telangana, 501218 India
c
Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana, 500007 India
*
e-mail: pochampalli.ou.chemi@gmail.com
Received October 27, 2018
Revised December 11, 2018
Accepted December 11, 2018
Abstract—A series of novel benzofuran-isoxazole 7a–7j hybrid heterocyclic molecules are synthesized. The
structures of compounds 7a–7j are assessed by IR, NMR, MASS spectroscopy and elemental analysis. The
target compounds 7a–7j are screened for their antibacterial activity and demonstrated excellent to moderate
activity against gram-positive and gram-negative bacteria.
Keywords: Benzofuran, isoxazole, antibacterial activity
DOI: 10.1134/S1070363218120319
Benzofuran derivatives demonstrate a wide range
of pharmacologically valuable properties [1-4], and are
determined be active antibacterial [5], antifungal [6],
and anti-inflammatory [7] agents. Combination of
benzofuran derivatives with some other heterocyclic
compounds promoted their activity against multidrug-
resistant bacteria [8], which was more potent than the
activity of the individual heterocyclic compounds.
Synthetic and some naturally occurring isoxazole
derivatives exhibit distinctive action as neurotoxins
benzofuran-2-yl](phenyl)methanone 4 and aldoximes
6a–6j. Compound 4 was synthesized from 1,3-dixyd-
roxybenzene 1 via alkyne 2 as presented in our prior
publication [13].
The synthesis is based on a 1,3-dipolar cyclo-
addition of generated in situ aldoximes 6a–6j to
terminal alkyne (4), which led to the corresponding
3
,5-disubstituted isoxazoles 7a–7j. The structures of
the newly synthesized target molecules were
characterized by IR, NMR and MASS spectral data.
[9–11] and GABA related activity [11, 12].
Antibacterial activity. The synthesized benzofuran
based isoxazoles 7a–7j were screened for their
antibacterial activity in concentrations of 75 and
100 μg/mL against four gram positive bacteria vize
Micrococcus luteus, Methicillin-resistant Staphylococcus
aureus, Bacillus subtilis, and Bacillus cereus, and four
gram negative bacteria vize Pseudomonas aeruginosa,
Klebsiella pneumoniae, Escherichia coli, and Proteus
vulgaris using Gentamicin sulfate as a standard drug.
The accumulated data indicated that all tested
compounds exhibited good inhibitory effects on the
growth of the tested bacterial strains (Table 1). Among
those the compounds 7a, 7b, 7d, 7g, and 7h were
determined to be highly active according to the
inhibition zones (see the table). It is noteworthy that
Based on the above information, particularly on the
potential antimicrobial activity of benzofurans and
isoxazoles, we synthesized a diverse series of novel
benzofuran-isoxazole derivatives 7a–7j and tested
their antibacterial activity.
RESULTS AND DISCUSSION
Benzofuran based 3,5-disubstituted isoxazoles 7a–
j were synthesized by a 4-step protocol (Scheme 1).
The key intermediates used in the synthesis of the target
molecules were [3-methyl-6-(prop-2-yn-1-yloxy)-
7
1
The text was submitted by the authors in English.
2
669

2
670
SUNITHA et al.
Scheme 1. Synthesis of [6-(isoxazol-5-ylmethoxy)-3-methylbenzofuran-2-yl](phenyl)methanone derivatives 7a–7j.
O
Me
Me
Br
Br
Ph
O
O
O
O
3
K CO , acetone
reflux, 8 h
2
3
HO
OH
O
OH
O
9
2%
1
2
4
O
NaOAc, MeOH
NOH
H
DMF, NCS, DBU
.
0oC−room temperature
NH OH HCl
R
H
2
R
room temperature,
3 h
5
a−6j
6a−6j
N
O
R
O
O
O
7
a−7j
)Ph (7b), 4-(Cl)Ph (7c), 4-(OMe)Ph (7d), 2-(Cl)Ph (7e), Ph (7f), 3,4-(OMe)Ph (7g), 3-(OMe)Ph
7h), 4-(Me)Ph (7i), 3-(Cl)Ph (7j).
2 2
R = 3-(NO )Ph (7a), 4-(NO
(
the compounds with strong electron withdrawing
substituents on the phenyl ring attached to isoxazole
promoted the antibacterial activity of the compounds.
The compounds 7c, 7e, 7f, 7i, and 7j exhibited mild
antibacterial activity against the tested bacterial strains.
Synthesis of aldoximes 6a–6j. To a solutions of an
aldehyde 5a–5j (1 eq..) in methanol was added
hydroxylamine hydrochloride (1 eq.) followed by
sodium acetate (1.5 eq.). The resulting reaction
mixture was stirred at room temperature for 3 h. After
completion of the process (TLC), the reaction mixture
was quenched by adding crushed ice, and the
precipitate formed was filtered off, washed with
hexane and dried to afford the corresponding
substituted aldoximes 6a–6j.
EXPERIMENTAL
Commercially available reagents were used as
supplied, and all solvents were distilled before use. All
reactions were performed in an oven-dried glassware.
Melting points were measured in open capillaries and
are uncorrected. IR spectra were recorded on a
Perkin−Elmer 337 grating spectrophotometer for solid
samples pelleted in KBr. NMR spectra were measured
on a Bruker AV-400 and AV-300 NMR spectrometers
Synthesis of benzofuran based 3,5-disubstituted
isoxazoles (7a–7j). To a solution of one of benz-
aldehyde oximes 6a–6j (1 eq.) in DMF at room
temperature N-chlorosuccinamide (1 eq.) was added.
The resulting mixture was stirred at room temperature
for 30 min and then cooled down to 0°C. The catalytic
amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
(0.2 eq.) was slowly added to the reaction mixture.
This was followed by addition of 1 eq. of compound 4
[13]. The resulting reaction mixture was stirred for 4 h
at room temperature. After total consumption of the
starting compounds, as indicated by TLC, ice-cold
water was added to the reaction mixture. The
precipitate formed was filtered off, washed with water
and cold MeOH to give the corresponding pure
product 7a–7j.
using CDCl as a solvent and TMS as a standard. CHN
3
analysis was carried out on a Perkin Elmer Model
2
400 CHNS elemental analyzer. ESI mass spectra
were measured on a QSTARXL hybrid MS system
Applied Bio Systems) under electro spray ionization.
(
TLC was carried out on Merck silica gel 60 F254
plates. The spots were visualized under UV light at
2
54 nm or by potassium permanganate. Column
chromatography was performed on a Merck silica gel
0A (100–200 mesh).
6
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 12 2018

SYNTHESIS AND ANTIBACTERIAL EVALUATION OF BENZOFURAN
2671
a
Antibacterial activity of the compounds 7a–7j
Zone of inhibition (mm)
gram +ve
gram –ve
Compound
7
7
a
75
00
75
00
75
00
75
00
75
00
75
00
75
00
75
00
75
00
75
00
75
00
31
33
32
35
08
11
26
29
18
21
15
18
28
31
22
25
13
16
–
28
31
28
32
–
26
29
26
28
–
27
30
27
30
07
09
28
31
23
26
13
16
28
31
27
30
13
16
09
11
31
34
26
29
26
29
07
10
26
29
18
21
12
14
27
30
23
26
11
14
–
27
29
33
28
31
–
28
1
31
26
29
06
09
24
28
18
21
12
15
28
31
20
23
12
15
–
31
27
30
07
09
26
29
20
22
14
17
29
32
23
26
14
16
–
b
1
7
c
1
–
–
–
7
d
28
31
21
24
14
17
29
32
26
29
14
16
05
08
31
33
27
30
20
23
12
15
26
29
24
27
12
15
–
24
27
23
26
15
18
30
33
26
29
15
17
07
10
31
33
1
7
e
1
7
f
1
7
7
g
1
h
1
7
i
1
7
j
1
–
–
–
–
–
Zentamicin
27
30
30
33
28
31
27
30
29
31
1
a
(
–) no activity.
{
3-Methyl-6-([3-(3-nitrophenyl)isoxazol-5-yl]-
137.6, 132.4, 129.9 (2C), 128.6 (2C), 127.6, 125.9, 123.6,
123.4, 123.3, 122.1, 122.0, 114.2, 97.4, 61.5, 10.5. MS:
m/z: 455 [M + H] . Found, %: C 68.48; H 3.71; N 5.92.
methoxy)benzofuran-2-yl}(phenyl)methanone (7a).
Yellow solid, yield 90%, mp 139–141°C. IR spectrum,
ν, cm : 1654 (C=O). H NMR spectrum, δ, ppm: 8.37–
+
–1
1
C H N O . Calculated, %: C 68.72; H 3.99; N 6.16.
26
18
2
6
8
2
.22 m (2H), 8.21–8.12 m (1H), 8.03 d (J = 7.43 Hz,
H), 7.72 t (J = 8.16 Hz, 1H), 7.62–7.47 m (4H), 7.13
{3-Methyl-6-([3-(4-nitrophenyl)isoxazol-5-yl]-
methoxy)benzofuran-2-yl}(phenyl)methanone (7b).
s (1H), 7.04 d (J = 8.27 Hz, 1H), 6.88 s (1H), 5.38 s
1
3
(
2H), 2.58 s (3H). C NMR spectrum, δ , ppm: 185.5,
Yellow solid, yield 83%, mp 144–146°C. IR spectrum,
C
–
1
1
1
67.9, 159.2, 158.5, 155.6, 148.7, 148.4, 145.2, 138.1,
ν, cm : 1659 (C=O). H NMR spectrum, δ, ppm: 8.40
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 12 2018

2
672
SUNITHA et al.
70.11; H 3.87; N 2.97. C H ClNO . Calculated, %: C
d (J = 8.79 Hz, 2H), 8.11–7.7 m (2H), 7.63–7.58 m
2
6
18
4
(
2H), 7.57–7.48 m (2H), 7.18 s (1H), 7.05 d (J = 8.46
70.35; H 4.09; N 3.16.
13
Hz, 1H), 6.86 s (1H), 5.39 s (2H), 2.58 s (3H).
NMR spectrum, δ , ppm: 185.5, 167.7, 159.2, 158.5,
1
(
C
{
3-Methyl-6-[(3-phenylisoxazol-5-yl)methoxy]-
C
benzofuran-2-yl}(phenyl)methanone (7f). Light yellow
55.5, 148.5, 147.5, 145.4, 138.6, 137.8, 132.4, 128.0
–1
solid, yield 90%, mp 89–91°C. IR spectrum, ν, cm :
2C), 128.4 (2C), 127.6, 125.7 (2C), 123.6, 120.6 (2C),
1
1
651 (C=O). H NMR spectrum, δ, ppm: 8.10–8.06 m
+
1
22.1, 114.2, 97.4, 61.8, 10.5. MS: m/z: 455 [M + H] .
(
2H), 7.78–7.74 m (2H), 7.63–7.59 m (2H), 7.56–7.52
m (4H), 7.48–7.44 m (1H), 7.21 d (J = 2.11 Hz, 1H),
.09 d.d (J = 8.66, 2.16 Hz, 1H), 6.94 s (1H), 5.39 s
Found, %: C 68.48; H 3.71; N 5.92. C H N O .
Calculated, %: C 68.72; H 3.99; N 6.16.
2
6
18
2
6
7
(
1
3
2H), 2.62 s (3H). C NMR spectrum, δ , ppm: 185.3,
{6-([3-(4-Chlorophenyl)isoxazol-5-yl]methoxy)-3-
C
1
1
1
1
4
4
67.7, 159.3, 158.2, 155.8, 148.4, 145.5, 138.3, 136.3,
32.5, 129.9 (2C), 129.5 (2C), 128.4 (2C), 127.3,
26.7, 123.4, 122.3, 120.5 (2C), 113.9, 97.5, 61.5,
methylbenzofuran-2-yl}(phenyl)methanone (7c).
White solid, yield 85%, mp 75–77°C. IR spectrum, ν,
–
1
1
cm : 1653 (C=O). H NMR spectrum, δ, ppm: 8.14–
+
0.3. MS: m/z: 410 [M + H] . Found, %: C 76.02; H
8
7
.04 m (2H), 7.76–7.68 s (2H), 7.63–7.48 s (6H), 7.20–
.17 m (1H), 7.05–7.02 m (1H), 6.94 s (1H), 5.38 s
.41; N 3.19.C H NO . Calculated, %: C 76.27; H
26 19
4
1
3
.68; N 3.42.
6-([3-(3,4-Dimethoxyphenyl)isoxazol-5-yl]meth-
oxy)-3-methylbenzofuran-2-yl}(phenyl)methanone
7g). Light yellow solid, yield 82%, mp 78–80°C. IR
(
2H), 2.62 s (3H). C NMR spectrum, δ , ppm: 185.5,
C
1
1
1
1
3
4
67.9, 159.2, 158.2, 155.6, 148.5, 145.5, 138.4, 136.1,
34.5, 132.4, 130.1 (2C), 129.9 (2C), 128.7 (2C),
27.4, 123.6, 122.1, 121.7 (2C), 114.1, 97.1, 61.5,
{
(
+
0.3. MS: m/z: 444 [M + H] . Found, %: C 70.11; H
–1
1
spectrum, ν, cm : 1643 (C=O). H NMR spectrum, δ,
ppm: 8.07–8.02 m (2H), 7.71–7.64 m (3H), 7.60–7.54
m (2H), 7.41–7.36 m (2H), 7.17 d (J = 2.17 Hz, 1H),
.87; N 2.97. C H ClNO . Calculate, %: C 70.35; H
2
6
18
4
.09; N 3.16.
7
.07 d.d (J = 8.54, 2.14 Hz, 1H), 6.96 s (1H), 5.38 s
{
6-([3-(4-Methoxyphenyl)isoxazol-5-yl]methoxy)-
1
3
(
2H), 3.87 s (3H), 3.83 s (3H), 2.61 s (3H). C NMR
3
-methylbenzofuran-2-yl}(phenyl)methanone (7d).
Light yellow solid, yield 89%, mp 65–67°C. IR
spectrum, δ , ppm: 185.6, 168.2, 160.1, 157.8, 156.1,
148.9, 145.1, 137.8, 134.2, 137.0, 132.6, 130.7, 129.5
C
–
1
1
spectrum, ν, cm : 1657 (C=O). H NMR spectrum, δ,
ppm: 8.07 d.d (J = 5.24, 3.21 Hz, 2H), 7.79 d.d (J =
.88, 1.54 Hz, 1H), 7.64–7.56 m (1H), 7.57–7.48 m
2H), 7.46–7.38 m (2H), 7.28–7.24 m (1H), 7.22–7.18
m (1H), 7.14–7.06 m (2H), 6.86 s (1H), 5.37 s (2H),
(
2C), 129.1, 128.2 (2C), 127.1, 126.3, 122.9, 122.3,
1
4
21.6, 120.7, 114.3, 97.8, 61.4, 61.2, 10.2. MS: m/z:
7
(
+
70 [M + H] . Found, %: C 71.38; H 4.68; N 2.60.
C H NO . Calculated, %: C 71.63; H 4.94; N 2.98.
2
8
23
6
13
3
1
1
1
6
7
7
.86 s (3H), 2.60 s (3H). C NMR spectrum, δ , ppm:
C
{6-([3-(3-Methoxyphenyl)isoxazol-5-yl]methoxy)-
-methylbenzofuran-2-yl}(phenyl)methanone (7h).
Light yellow solid, yield 86%, mp 74–76°C. IR
85.6, 167.8, 160.2, 159.1, 158.4, 156.7, 155.7, 148.3,
38.3, 129.8 (2C), 128.5 (2C), 128.3 (2C), 127.9,
27.5, 124.0, 122.2, 122.0, 114.1, 114.0 (2C), 97.1,
1.7, 56.2, 10.4. MS: m/z: 440 [M + H] . Found, %: C
3.53; H 4.60; N 3.00. C H NO . Calculate, %: C
3
–
1
1
spectrum, ν, cm : 1649 (C=O). H NMR spectrum, δ,
ppm: 8.10–8.05 m (2H), 7.81–7.77 m (1H), 7.67–7.59
m (1H), 7.55–7.47 m (2H), 7.45–7.37 m (2H), 7.30–
+
2
7
21
5
3.79; H 4.82; N 3.19.
7
.25 m (1H), 7.21 d (J = 2.04 Hz, 1H), 7.16–7.09 m
(
(
2H), 6.87 s (1H), 5.38 s (2H), 3.85 s (3H), 2.61 s
{
6-([3-(2-Chlorophenyl)isoxazol-5-yl]methoxy)-3-
1
3
3H). C NMR spectrum, δ , ppm: 185.9, 167.6,
C
methylbenzofuran-2-yl}(phenyl)methanone (7e).
Light yellow solid, yield 88%, mp 82–84°C. IR
spectrum, ν, cm : 1655 (C=O). H NMR spectrum, δ,
ppm: 8.09 d (J = 7.16 Hz, 2H), 7.67–7.56 m (4H), 7.55–
.49 m (2H), 7.48–7.42 m (2H), 7.18 d (J = 2.03 Hz,
H), 7.07 d.d (J = 8.67, 2.09 Hz, 1H), 6.85 s (1H),
.39 s (2H), 2.60 s (3H). C NMR spectrum, δ , ppm:
85.5, 167.6, 159.2, 158.6, 155.8, 148.5, 145.4, 143.3,
38.4, 132.5, 129.8 (2C), 128.6, 128.4 (2C), 128.0,
27.8, 127.6, 125.0, 127.5, 123.5, 122.1, 114.0, 97.4,
1
59.8, 158.9, 158.1, 157.1, 155.3, 147.8, 138.1, 134.4,
130.9, 129.6, 128.6, 128.1 (2C), 127.8, 127.2, 124.2,
22.9, 122.1, 114.3, 114.1 (2C), 97.2, 61.6, 56.6, 10.5.
–
1
1
1
+
MS: m/z: 440 [M + H] . Found, %: C 73.53; H 4.60; N
3
3.19.
7
1
5
1
1
1
6
.00. C H NO . Calculated, %: C 73.79; H 4.82; N
27 21 5
13
C
{3-Methyl-6-([3-(p-tolyl)isoxazol-5-yl]methoxy)-
benzofuran-2-yl}(phenyl)methanone (7i). White solid,
yield 91%, mp 60–62°C. IR spectrum, ν, cm : 1650
–
1
+
1
1.5, 10.3. MS: m/z: 444 [M + H] . Found, %: C
(C=O). H NMR spectrum, δ, ppm: 8.06–8.02 m (2H),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 12 2018

SYNTHESIS AND ANTIBACTERIAL EVALUATION OF BENZOFURAN
2673
7
7
.79–7.72 s (2H), 7.60–7.47 s (6H), 7.22–7.18 m (1H),
.07–7.01 m (1H), 6.91 s (1H), 5.37 s (2H), 2.63 s
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 (100 µL; c 75 and
100 mg/mL) were then loaded into the wells and
incubated in the air at 37°C for 24 h. The inhibition
zone diameters were measured with a zone reader
(HiAntibiotic Zone Scale). The positive control was
the standard drug Gentamicin.
1
3
(
3H), 2.33 s (3H). C NMR spectrum, δ , ppm: 186.5,
C
1
1
1
2
7
7
67.9, 159.2, 158.2, 155.6, 148.5, 145.5, 138.4, 136.1,
34.5, 132.4, 130.1 (2C), 129.9 (2C), 128.7 (2C),
27.4, 123.6, 122.1, 121.7 (2C), 114.1, 97.1, 61.5,
+
1.7, 10.3. MS: m/z: 424 [M + H] . Found, %: C
6.32; H 4.81; N 3.09. C H NO . Calculated, %: C
2
7
21
4
6.58; H 5.00; N 3.31.
6-([3-(3-Chlorophenyl)isoxazol-5-yl]methoxy)-3-
methylbenzofuran-2-yl}(phenyl)methanone (7j). White
CONCLUSIONS
{
A new series of benzofuran-isoxazole hybrids 7a–
–
1
solid, yield 94%, mp 88–90°C. IR spectrum, ν, cm :
1
7
j is synthesized in high yields and characterized by
1
639 (C=O). H NMR spectrum, δ, ppm: 8.16–7.97 m
the spectroscopic techniques. The synthesized
compounds demonstrate significant to excellent
antibacterial activity against tested bacterial strains.
The highest activity was determined for compounds
(
(
3H), 7.67–7.28 m (7H), 7.17 s (1H), 7.08-6.99 m
1H), 6.89 s (1H), 5.36 s (2H), 2.58 s (3H). MS: m/z:
+
4
44 [M + H] . Found, %: C 70.11; H 3.87; N 2.97.
C H ClNO . Calculated, %: C 70.35; H 4.09; N 3.16.
2
6
18
4
7
a, 7b, 7d, 7g, and 7h.
ACKNOWLEDGMENTS
V. Sunitha thanks the Head of the Department,
Antibacterial activity. Gram +ve strains Micrococcus
luteus (ATCC 10240), methicillin-resistant Staphylococcus
aureus (MRSA, NCTC 13616), Bacillus subtilis
(
ATCC 6633), and Bacillus cereus (ATCC 14579),
and gram –ve strains Pseudomonas aeruginosa (ATCC
7853), Klebsiella pneumoniae (ATCC 43816),
Escherichia coli (ATCC 8739), and Proteus vulgaris
ATCC 13315) were purchased from the American
Type Culture Collection. Methicillin-resistant
UCS, Osmania University, Saifabad, Hyderabad, India
and Central Facilities for Research and Development,
Osmania University, Hyderabad, India for providing
analytical support.
2
(
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
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(
LB) agar plates (Hi-media Laboratories, Mumbai,
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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
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0 h.
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Following the protocol of the Kirby–Bauer disk
diffusion assay [14], four to five well-isolated colonies
of the same morphological type were picked with an
inoculating loop, transferred into 5 mL of nutrient
broth, and incubated at 37°C for 24 h until a slight
visible turbidity appeared. Turbidity of the actively
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