Synthesis of isoxazoles via 1,3-dipolar cycloaddition reactions: Pharmacological screening for their antioxidant and antimicrobial activities

Article abstract of DOI:10.14233/ajchem.2017.20781

In the present study, we report the synthesis of series of novel substituted isoxazoles via 1,3-dipolar cycloaddition reaction. Nitrile oxides generated by the catalytic dehydrogenation of aldoximes by chloramine-T, were trapped in situ by 4-(furan-2-yl)b

Full text of DOI:10.14233/ajchem.2017.20781

Asian Journal of Chemistry; Vol. 29, No. 12 (2017), 2660-2664
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20781
Synthesis of Isoxazoles via 1,3-Dipolar Cycloaddition Reactions:
Pharmacological Screening for Their Antioxidant and Antimicrobial Activities
*
DEVIRAMMANAHALLI MAHADEVASWAMY LOKESHWARI and KARIYAPPA AJAY KUMAR
Department of Chemistry, Yuvaraja’s College, Mysuru-570 005, India
*Corresponding author: E-mail: ajaykumar@ycm.uni-mysore.ac.in
Received: 15 May 2017;
Accepted: 28 July 2017;
Published online: 30 October 2017;
AJC-18611
In the present study, we report the synthesis of series of novel substituted isoxazoles via 1,3-dipolar cycloaddition reaction. Nitrile oxides
generated by the catalytic dehydrogenation of aldoximes by chloramine-T, were trapped in situ by 4-(furan-2-yl)but-3-en-2-one to obtain
an isomeric mixture of isoxazoles. The structure of the new isoxazoles were elucidated by spectral and elemental analyses. The synthesized
isoxazoles have been screened in vitro for their DPPH radical scavenging abilities and antimicrobial activities. Amongst the synthesized
series, compound 1-(3-(4-chlorophenyl)-4-(furan-2-yl)-4,5-dihydroisoxazol-5-yl)ethanone (4f) exhibited excellent radical scavenging
and antimicrobial susceptibilities.
Keywords: Antimicrobial, Antioxidant, Cycloaddition, Dipolar, Radical scavenging.
herein report the synthesis of new isoxazole derivatives by 1,3-
dipolar cycloaddition reactions and in vitro evaluation results
of their antimicrobial and antioxidant activities.
INTRODUCTION
Oxidative stress on a cell due to high concentration of
ROS can lead to a variety of disorders including cancer,
neurodegenerative disorder, atherosclerosis and aging [1]. An
interest in antioxidant activity of small molecules, to prevent
the deleterious effects caused by free radicals is attracting the
attention of the wider research community. Free radicals are
arising due to the oxidative stress resulting from an imbalance
between free radical generation and their quenching [2]. Five
membered heterocycles are important class of compounds in
bioorganic chemistry, among them isoxazoles occupies a prime
position due to their versatile synthetic and biological appli-
cations [3]. The efforts have been made to the development of
general and versatile synthetic methodologies for the synthesis
of isoxazoline. However, the classical method employed for
the synthesis of isoxazoline involves 1,3-dipolar cycloaddition
reactions of nitrile oxides to alkenes [4-6]. Rai et al. [7] develo-
ped new method for generating nitrile oxides involving oxidative
dehydrogenation of aldoximes using oxidants such as chlora-
mine-T and mercuric acetate.
EXPERIMENTAL
Melting points were determined by an open capillary tube
method and are uncorrected. Purity of the compounds was
checked on thin layer chromatography (TLC). 1H NMR and
13C NMR spectra were recorded on Agilent-NMR 400 M Hz
and 100 M Hz spectrometer respectively. The solvent CDCl3
with TMS as an internal standard was used to record the
spectra. The chemical shifts are expressed in δ ppm. Mass
spectra were obtained on ESI/APCI-Hybrid Quadrupole,
Synapt G2 HDMS ACQUITY UPLC model spectrometer.
Elemental analysis was obtained on a Thermo Finnigan Flash
EA 1112 CHN analyzer.
Initially, the precursor aromatic aldoximes 2(a-g) were
prepared by reacting aromatic aldehydes 1(a-g) with hydroxyl-
amine hydrochloride in the presence of sodium acetate in
ethanol as a solvent. Then, the reaction of 4-(furan-2-yl)but-
3-en-2-one (3) as dipolarophile moiety with aldoximes 2(a-g)
and chloramine-T in ethyl alcohol under reflux conditions
produced a mixture of 3-aryl-1-(4-(furan-2-yl)-4,5-dihydro-
isoxazol-5-yl)ethanones 4(a-g) (major product) and 3-aryl-1-
(5-(furan-2-yl)-4,5-dihydroisoxazol-5-yl)ethanones 5(a-g)
(minor product). Chloramine-T (CAT) served as an effective
catalytic dehydrogenating agent for the conversion of
Isoxazoles and their derivatives are known to exhibit broad
spectrum of biological activities, such as anticancer [8], antiarthritic
[9], antimicrobial [10], antinociceptive [11], selective agonists
at human cloned dopamine D4 receptors [12], antioxidant [13],
GABAA antagonist [14] and COX-2 inhibitor [15] properties.
With these observations in the back-ground and in search of
new potent antimicrobial and antioxidant small molecules, we

Vol. 29, No. 12 (2017)
Synthesis of Isoxazoles via 1,3-Dipolar Cycloaddition Reactions 2661
aldoximes to nitrile oxides [16], also effective aziridination
agent for alkenes [17]. Oxidative dehydrogenation of aldoximes
2(a-g) by chloramine-T afforded nitrile oxides, which was in situ
trapped by 4-(furan-2-yl)but-3-en-2-one (3) to obtain isormeric
mixture of products (Fig. 1).
yield. 1H NMR (CDCl3; δ ppm): 2.136 (s, 3H, CH3), 3.658 (d,
1H, J = 7.2 Hz, 4-H), 4.452 (d, 1H, J = 7.0 Hz, 5-H), 6.102-
13
6.387 (m, 2H, Ar-H), 7.481-7.782 (m, 6H, Ar-H); C NMR
(CDCl3; δ ppm): 24.32 (1C, CH3), 30.60 (1C, 4-C), 84.34 (1C,
5-C), 105.10 (1C), 110.12 (1C), 128.30 (1C), 128.36 (1C),
128.60 (1C), 128.65 (1C), 131.40 (1C), 136.80 (1C), 141.56
(1C), 151.70 (1C), 162.80 (1C, 3-C), 203.86 (1C, C=O). MS
(m/z): 255.09 (M+, 100); Anal. Calcd. for C15H13NO3 (%): C,
70.58; H, 5.13; N, 5.49; Found: C, 70.44; H, 5.02; N, 5.36.
1-[4-(Furan-2-yl)-3-(4-methoxyphenyl)-4,5-dihydro-
isoxazol-5-yl]ethanone (4b): 4-(Furan-2-yl)but-3-en-2-one
(3) (5 mmol) and 4-methoxybenzaldehye oxime (2b) (5 mol),
CHO
a) R1= H, R2= H;
b) R1= H, R2= OCH3;
c) R1= OCH3, R2= OCH3;
R1
d) R1= H, R2= CH3;
e) R1= H, R2= F;
f) R1= H, R2= Cl;
g) R1= H, R2= NO2.
R2
1(a-g)
NH2OH.HCl
CH3COONa/
C2H5OH
1
as pale yellow oil in 66 % yield. H NMR (CDCl3; δ ppm):
2.140 (s, 3H, CH3), 3.665 (d, 1H, J = 7.4 Hz, 4-H), 3.842 (s,
3H, OCH3), 4.446 (d, 1H, J = 7.1 Hz, 5-H), 6.113-6.356 (m,
2H, Ar-H), 7.184-7.756 (m, 5H, Ar-H); 13C NMR (CDCl3; δ
ppm): 24.50 (1C, CH3), 30.45 (1C, 4-C), 55.45 (1C), 84.55
(1C, 5-C), 105.34 (1C), 110.65 (1C), 115.32 (1C), 115.40 (1C),
126.30 (1C), 128.68 (1C), 128.74 (1C), 141.52 (1C), 151.48
(1C), 159.85 (1C), 163.12 (1C, 3-C), 203.60 (1C, C=O). MS
(m/z): 285.10 (M+, 100); Anal. Calcd. for C16H15NO4 (%): C,
67.36; H, 5.30; N, 4.91; Found: C, 67.25; H, 5.12; N, 4.76.
1-[3-(3,4-Dimethoxyphenyl)-4-(furan-2-yl)-4,5-dihydro-
isoxazol-5-yl]ethanone (4c): 4-(Furan-2-yl)but-3-en-2-one (3)
(5 mmol) and 3,4-dimethoxybenzaldehye oxime (2c) (5 mol),
as pale yellow oil in 74 % yield. 1H NMR (CDCl3; δ ppm):
2.202 (s, 3H, CH3), 3.640 (d, 1H, J = 7.7 Hz, 4-H), 3.852 (s,
6H, CH3), 4.458 (d, 1H, J = 7.5 Hz, 5-H), 6.121-6.370 (m,
2H, Ar-H), 7.320-7.774 (m, 4H, Ar-H); 13C NMR (CDCl3; δ
ppm): 24.80 (1C, CH3), 30.68 (1C, 4-C), 55.86 (1C, OCH3),
55.90 (1C, OCH3), 84.95 (1C, 5-C), 105.43 (1C), 110.22 (1C),
112.66 (1C), 115.31 (1C), 120.35 (1C), 121.55 (1C), 141.40 (1C),
148.45 (1C), 151.60 (1C), 152.82 (1C), 162.22 (1C, 3-C),
203.90 (1C, C=O). MS (m/z): 315.11 (M+, 100); Anal. Calcd.
for C17H17NO5 (%): C, 64.75; H, 5.43; N, 4.44; Found: C, 64.57;
H, 5.33; N, 4.31.
CH=N-OH
CH3
O
R1
R2
O
2(a-g)
3
CAT/EtOH
reflux, 3 h.
COCH3
COCH3
O
O
O
R1
R2
O
N
N
R2
5(a-g)
20-30%
4(a-g)
65-75%
R1
Fig. 1. Schematic diagram for the synthesis route for isoxazole derivatives
Synthesis of oximes 2(a-g):A solution of colourless phenyl
hydrazine hydrochloride (0.5 g) and crystallized sodium acetate
(0.8 g) in distilled water (10 mL) was mixed with solution of
aldehydes 3(a-g) (0.5 g) in ethyl alcohol. The mixture was then
warmed for 5-10 min and cooled in ice water. The crystals formed
were filtered, washed with a little cold water and recrystallized
from ethanol.
1-[4-(Furan-2-yl)-3-(p-tolyl)-4,5-dihydroisoxazol-5-yl]-
ethanone (4d): 4-(Furan-2-yl)but-3-en-2-one (3) (5 mmol) and
4-methyl benzaldehye oxime (2d) (5 mol), as pale yellow oil
in 70 % yield. 1H NMR (CDCl3; δ ppm): 2.190 (s, 3H, CH3),
2.324 (s, 3H, CH3), 3.660 (d, 1H, J = 7.0 Hz, 4-H), 4.455 (d,
1H, J = 7.6 Hz, 5-H), 6.185-6.345 (m, 2H,Ar-H), 7.455-7.795
General procedure for synthesis of isoxazoles 4(a-g),
5(a-g). A mixture of aldoximes 2(a-g) (5 mmol), 4-(furan-2-
yl)but-3-en-2-one (3) (5 mmol) and chloramine-T trihydrate
(7.5 mmol) was refluxed on a water bath for 3-4 h. The progress
of the reaction was monitored by TLC.After completion of the
reaction, the salts formed were filtered off and the solvent was
evaporated in vacuum. The residual mass was extracted into
ether (1 × 25 mL), washed successively with water (3 × 20 mL),
5 % sodium hydroxide (2 × 10 mL), brine solution (1 × 15 mL)
and dried over anhydrous sodium sulphate. Evaporation of
the solvent afforded crude oil, which gave one major spot corres-
ponding to the products 3-aryl-1-(4-(furan-2-yl)-4,5-dihydro-
isoxazol-5-yl)ethanones 4(a-g) and a minor spot corresponding
to the product 3-aryl-1-(5-(furan-2-yl)-4,5-dihydroisoxazol-
5-yl)ethanones 5(a-g) in TLC. The products were separated
by HPLC.
13
(m, 5H, Ar-H); C NMR (CDCl3; δ ppm): 21.30 (1C, CH3),
24.50 (1C, CH3), 30.36 (1C, 4-C), 84.08 (1C, 5-C), 105.62
(1C), 110.98 (1C), 1278.80 (1C), 127.86 (1C), 129.12 (1C),
129.16 (1C), 131.74 (1C), 141.50 (1C), 142.56 (1C), 151.44
(1C), 161.88 (1C, 3-C), 203.77 (1C, C=O). MS (m/z): 269.11
(M+, 100);Anal. calcd. for C16H15NO3 (%): C, 71.36; H, 5.61;
N, 5.20; Found: C, 71.25; H, 5.50; N, 5.08.
1-[3-(4-Fluorophenyl)-4-(furan-2-yl)-4,5-dihydroiso-
xazol-5-yl]ethanone (4e): 4-(Furan-2-yl)but-3-en-2-one (3)
(5 mmol) and 4-fluorobenzaldehye oxime (2e) (5 mol), as pale
yellow oil in 65 % yield. 1H NMR (CDCl3; δ ppm): 2.210 (s,
3H, CH3), 3.685 (d, 1H, J = 7.9 Hz, 4-H), 4.474 (d, 1H, J =
6.9 Hz, 5-H), 6.130-6.342 (m, 2H, Ar-H), 7.526-7.780 (m,
5H, Ar-H); 13C NMR (CDCl3; δ ppm): 24.51 (1C, CH3), 30.74
(1C, 4-C), 84.12 (1C, 5-C), 105.90 (1C), 111.10 (1C), 114.33
(1C), 114.38 (1C), 128.88 (1C), 128.95 (1C), 130.48 (1C),
1-[4-(Furan-2-yl)-3-phenyl-4,5-dihydroisoxazol-5-
yl]ethanone (4a): 4-(Furan-2-yl)but-3-en-2-one (3) (5 mmol)
and benzaldehyde oxime (2a) (5 mol) as pale yellow oil in 68 %

2662 Lokeshwari et al.
Asian J. Chem.
141.32 (1C), 151.55 (1C), 162.44 (1C, 3-C), 166.80 (1C),
203.20 (1C, C=O). MS (m/z): 273.08 (M+, 100); Anal. Calcd.
for C15H12NO3F (%): C, 65.93; H, 4.43; N, 5.13; Found: C,
65.81; H, 4.31; N, 5.04.
different aliquots of test samples (25, 50, 75 and 100 µg/mL)
in methanol. The mixture was shaken vigorously and allowed
to stand for 20 min at room temperature. The absorbance was
read against blank at 517 nm in an ELICO SL-159 UV-visible
spectrophotometer. Radical scavenging potential was calcu-
lated as a percentage (I %) of DPPH decolouration using the
equation:
1-[3-(4-Chlorophenyl)-4-(furan-2-yl)-4,5-dihydroiso-
xazol-5-yl]ethanone (4f): 4-(Furan-2-yl)but-3-en-2-one (3)
(5 mmol) and 4-chlorobenzaldehye oxime (2f) (5 mol), as pale
yellow oil in 73 % yield 1H NMR (CDCl3; δ ppm): 2.155 (s,
3H, CH3), 3.639 (d, 1H, J = 7.8 Hz, 4-H), 4.456 (d, 1H, J =
7.1 Hz, 5-H), 6.100-6.341 (m, 2H, Ar-H), 7.5301-7.793 (m,
5H, Ar-H); 13C NMR (CDCl3; δ ppm): 24.40 (1C, CH3), 30.55
(1C, 4-C), 84.71 (1C, 5-C), 105.44 (1C), 110.78 (1C), 128.24
(1C), 128.31 (1C), 128.92 (1C), 128.97 (1C), 131.88 (1C),
136.41 (1C), 141.35 (1C), 151.67 (1C), 162.97 (1C, 3-C),
203.66 (1C, C=O). MS (m/z): 291.05 (M+2, 33), 289.05 (M+,
100);Anal. Calcd. for C15H12NO3Cl (%): C, 62.19; H, 4.17; N,
4.83; Found: C, 62.10; H, 4.03; N, 4.70.
A0 − A
I (%) =
1 ×100
A0
A0 is the absorbance of the control without test compounds;
A1 is the absorbance of test compounds.
Antimicrobial activity: Antimicrobial activities of the
synthesized compounds were determined as minimum inhi-
bitory concentrations (MIC’s) by serial dilution method [19].
The nutrient broth, which contains logarithmic serially two-
fold diluted amount of compounds 4(a-g) and control was
inoculated with approximately 5 × 105 c.f.u of actively dividing
bacteria cells. The cultures were incubated for 24 h at 37 °C
for bacterial and 72 h at 37 °C for fungal stains and the growth
was monitored visually. The tests were conducted in triplicates
against bacterial pathogens Escherichia coli, Pseudomonas
aeruginosa, Staphylococcus aureus; and against fungal stains
Aspergillus nigar, Aspergillus flavus and Candila albicans.
Ciprofloxacin and nystatin were used as positive controls
against bacterial and fungal species, respectively; methanol
was used as solvent control.
1-[4-(Furan-2-yl)-3-(4-nitrophenyl)-4,5-dihydroisoxazol-
5-yl]ethanone (4g): 4-(Furan-2-yl)but-3-en-2-one (3) (5 mmol)
and 4-nitrobenzaldehye oxime (2g) (5 mol), as pale yellow oil
in 65 % yield. 1H NMR (CDCl3; δ ppm): 2.148 (s, 3H, CH3),
3.647 (d, 1H, J = 7.7 Hz, 4-H), 4.450 (d, 1H, J = 7.4 Hz, 5-H),
6.108-6.378 (m, 2H, Ar-H), 7.654-7.995 (m, 5H, Ar-H); 13C
NMR (CDCl3; δ ppm): 24.80 (1C, CH3), 30.32 (1C, 4-C), 84.70
(1C, 5-C), 106.02 (1C), 110.33 (1C), 127.30 (1C), 127.36 (1C),
127.84 (1C), 127.90 (1C), 140.55 (1C), 141.20 (1C), 151.14
(1C), 151.54 (1C), 163.12 (1C, 3-C), 204.22 (1C, C=O). MS
(m/z): 300.07 (M+, 100); Anal. Calcd. for C15H12N2O5 (%): C,
60.00; H, 4.03; N, 9.33; Found: C, 59.90; H, 3.87; N, 9.20.
1-[5-(Furan-2-yl)-3-(4-methoxyphenyl)-4,5-dihydro-
isoxazol-4-yl]ethanone (5b): 4-(Furan-2-yl)but-3-en-2-one (3)
(5 mmol) and 4-methoxybenzaldehye oxime (2b) (5 mol), as
pale yellow oil in 26 % yield. 1H NMR (CDCl3; δ ppm): 2.320
(s, 3H, CH3), 2.690 (d, 1H, J = 7.0 Hz, 4-H), 3.840 (s, 3H, OCH3),
4.980 (d, 1H, J = 7.5 Hz, 5-H), 6.322-6.484 (m, 2H, Ar-H),
7.382-7.886 (m, 5H, Ar-H); 13C NMR (CDCl3; δ ppm): 27.98
(1C, CH3), 47.65 (1C, 4-C), 55.84 (1C, OCH3), 65.30 (1C, 5-C),
110.02 (1C), 110.55 (1C), 114.36 (1C), 114.40 (1C), 120.64
(1C), 120.70 (1C), 121.86 (1C), 140.80 (1C), 151.56 (1C),
152.84 (1C, 3-C), 161.75 (1C), 203.50 (1C, C=O). MS (m/z):
285.04 (M+, 100); Anal. Calcd. for C16H15NO4 (%): C, 67.36;
H, 5.30; N, 4.91; Found: C, 67.22; H, 5.22; N, 4.79.
RESULTS AND DISCUSSION
1H NMR, 13C NMR, Mass spectra and elemental analysis
provided the structural proof of the compounds 4(a-g) and
5(a-g). Nitrile oxides generated in situ by the catalytic dehydro-
genation of aldoximes 2(a-g) with chloramine-T were trapped
in situ by 4-(furan-2-yl)but-3-en-2-one 3 to obtain an isomeric
mixture of isoxazoles 4(a-g) and 5(a-g). Compound 1-(4-(furan-
2-yl)-3-(4-methoxyphenyl)-4,5-dihydroisoxazol-5-yl)ethanone
1
(4b) in its H NMR spectrum, showed a singlets for three
protons each at δ 2.140 and δ 3.842 ppm due to CH3 and OCH3
protons. The 4-H resonates as doublet at δ 3.665 (J = 7.4 Hz)
ppm; while the 5-H appears as doublet at δ 4.446 (J = 7.1 Hz)
ppm. Multiplets appear at δ 6.113-6.356 ppm for two protons
and at δ 7.184-7.756 ppm for five protons were unambiguously
assigned to aromatic protons. In the 13C NMR spectrum, the
carbons of newly formed isoxazole ring 4-C, 5-C and 3-C
coupled at δ 30.45, 84.55 and 163.12 ppm, respectively. Signals
appeared at δ 24.50, 55.45 and 203.60 ppm were due to CH3,
OCH3 and C=O carbons.Aromatic carbons showed the signals
at δ 105.34, 110.65, 115.32, 115.40, 126.30, 128.68, 128.74,
141.52, 151.48 and 159.85 ppm. Compound, 4b showed a
base peak at m/z: 285.08 correspond to its molecular mass.
All synthesized series of compounds 4(a-g) showed similar
and consistent pattern signals in their respective spectra and
gave satisfactorily elemental analyses data with theoretically
calculated values confirms their structures. Coupling constants
(J) of 4-H and 5-H (J = 6.8-7.9 Hz) of compounds 4(a-g) suggests
that dipolar cycloaddition took place in cis fashion.
1-[3-(4-Fluorophenyl)-5-(furan-2-yl)-4,5-dihydroisoxazol-
4-yl]ethanone (5e): 4-(Furan-2-yl)but-3-en-2-one (3) (5 mmol)
and 4-fluorobenzaldehye oxime (2e) (5 mol), as pale yellow oil
in 24 % yield. 1H NMR (CDCl3; δ ppm): 2.323 (s, 3H, CH3),
2.688 (d, 1H, J = 7.7 Hz, 4-H), 4.992 (d, 1H, J = 7.5 Hz, 5-H),
6.302-6.390 (m, 2H, Ar-H), 7.568-7.980 (m, 5H, Ar-H); 13C
NMR (CDCl3; δ ppm): 27.80 (1C, CH3), 46.65 (1C, 4-C), 64.86
(1C, 5-C), 109.16 (1C), 110.24 (1C), 116.33 (1C), 116.38 (1C),
124.45 (1C), 129.66 (1C), 129.69 (1C), 141.52 (1C), 152.85
(1C), 154.54 (1C, 3-C), 163.81 (1C), 203.10 (1C, C=O). MS
(m/z): 273.02 (M+, 100); Anal. Calcd. for C15H12FNO3 (%):
C, 65.93; H, 4.43; N, 5.13; Found: C, 65.86; H, 4.27; N, 5.02.
DPPH radical scavenging assay: 1,1-Diphenylpicryl-
hydrazyl (DPPH) radical scavenging ability of synthesized
compounds 4(a-g) was performed by Blois method [18]. 1 mL
of DPPH solution (0.1 mM in 95 % methanol) was mixed with
Since, isomeric compounds 5(a-g) were obtained as minor
products, the characterization was done only for few com-

Vol. 29, No. 12 (2017)
Synthesis of Isoxazoles via 1,3-Dipolar Cycloaddition Reactions 2663
pounds. Compound 1-[5-(furan-2-yl)-3-(4-methoxyphenyl)-
4,5-dihydroisoxazol-4-yl]ethanone (5b) showed a singlets for
three protons each at δ 2.320 and δ 3.840 ppm due to CH3 and
OCH3 protons. The 4-H resonates as doublet at δ 2.690 (J =
7.0 Hz) ppm; while the 5-H appears as doublet at δ 4.980 (J =
7.5 Hz) ppm. Multiplets appear at δ 6.322-6.484 ppm for two
and at δ 7.382-7.886 ppm for five protons were due toaromatic
protons. The carbons of newly formed isoxazole ring 4-C, 5-
C and 3-C coupled at δ 47.65, 65.30 and 152.84 ppm, respec-
tively. Signals appeared at δ 27.98, 55.84 and 203.50 ppm
were due to CH3, OCH3 and C=O carbons. Compound, 5b
showed a base peak at m/z: 285.04 correspond to its molecular
mass. Similar and consistent pattern signals and satisfactorily
elemental analyses data provides the structure proof of 5(a-g).
The DPPH radical scavenging experiments were performed
in triplicate; the results were expressed as a mean standard
deviation (SD) and were summarized in Table-1.
dihydroisoxazol-5-yl]ethanone (4b), 1-[3-(3,4-dimethoxy-
phenyl)-4-(furan-2-yl)-4,5-dihydroisoxazol-5-yl]ethanone
(4c) and 1-[4-(furan-2-yl)-3-(p-tolyl)-4,5-dihydroisoxazol-5-
yl]ethanone (4d) showed moderate radical scavenging abilities.
From the results, it was observed that the presence of an electron
donating groups (OCH3, CH3) groups as aromatic ring substit-
utions retarded the DPPH radical scavenging ability; while
electron withdrawing groups and electronegative atoms as
substitutions enhanced the DPPH radical scavenging ability
of the synthesized series of compounds.
The antimicrobial screening tests were performed in tripli-
cate and the results were taken as a mean standard deviation
(SD) and are summarized in Table-2.
Preliminary antimicrobial evaluation results showed that,
amongst the series, compound 4f showed excellent inhibition
potential against all the tested organisms. Compounds 4a and
4e found good against S. aureus, E. coli, A. niger and C. albicans:
moderately active against E. coli and A. niger; less active
against P. aeruginosa and A. flavus organisms. Compounds
4b, 4c and 4d found promisingly active against S. aureus
moderately active against E. coli and A. niger; less active
against P. aeruginosa, A. flavus and C. albicans organisms.
Compound 4g showed lesser inhibition ability against all the
tested organisms, which might be attributed to the presence of
strong electron withdrawing nitro substitution in the aromatic
ring.
TABLE-1
DPPH RADICAL SCAVENGING ACTIVITY OF THE
SYNTHESIZED ISOXAZOLE DERIVATIVES 4(a-g)
Radical scavenging (%)*
Compd.
25 µg/mL
16.76 0.20
20.10 0.44
19.90 0.80
20.55 0.76
15.65 0.54
14.11 0.32
16.10 0.30
15.08 0.89
50 µg/mL
18.43 0.45
25.18 0.51
24.36 0.63
26.40 0.54
18.80 0.12
16.20 0.80
18.15 0.76
17.87 0.89
75 µg/mL
22.14 0.70
29.10 0.66
28.75 0.81
32.84 0.45
22.05 0.32
20.10 0.50
22.75 0.50
21.98 0.31
100 µg/mL
25.15 0.55
39.20 0.75
40.61 0.90
39.20 0.38
24.35 0.85
22.26 0.70
24.70 0.55
24.25 0.22
4a
4b
4c
4d
4e
Conclusion
4f
4g
AA
In the present study, the synthesis of isomeric mixture of
isoxazoles via 1,3-dipolar cycloaddition reactions is reported.
In vitro pharmacological evaluation results showed that, among
the synthesized series, compounds 4a, 4e, 4g and 4f act as a
potential DPPH radical scavengers, in particular compound
4f which showed the ability which is greater than the standard
ascorbic acid. The in vitro antimicrobial activity results of new
isoxazolines reveals that the compounds 4a, 4e and 4f may
become a potential antifungal and antibacterial drug candi-
dates.
*Values are mean SD of three replicates; AA = Ascorbic acid
(positive control)
Preliminary studies revealed that, the synthesized new
pyrazole derivatives exhibited moderate to excellent DPPH
radical scavenging abilities.Amongst the series, 1-[3-(4-chloro-
phenyl)-4-(furan-2-yl)-4,5-dihydroisoxazol-5-yl]ethanone (4f)
showed excellent activity which is more than the standard
ascorbic acid. Compounds 1-[4-(furan-2-yl)-3-phenyl-4,5-
dihydroisoxazol-5-yl]ethanone (4a), 1-[3-(4-fluorophenyl)-4-
(furan-2-yl)-4,5-dihydroisoxazol-5-yl]ethanone (4e) and 1-[4-
(furan-2-yl)-3-(4-nitrophenyl)-4,5-dihydroisoxazol-5-
yl]ethanone (4g) have showed good radical scavenging abilities.
Compounds 1-[4-(furan-2-yl)-3-(4-methoxyphenyl)-4,5-
ACKNOWLEDGEMENTS
The authors are grateful to IOE Instrumentation Facility,
Vijnana Bhavana, University of Mysore, Mysuru, India for spectral
analysis.
TABLE-2
MINIMUM INHIBITORY CONCENTRATION (MIC’s) OF COMPOUNDS 4(a-g) (µg/mL*)
Compound
S. aureus
25.0 0.30
25.0 0.35
25.0 0.65
25.0 0.30
25.0 0.40
25.0 0.40
75.0 0.46
25.0 0.40
–
E. coli
P. aeruginosa
50.0 0.65
75.0 0.65
75.0 0.40
75.0 0.76
75.0 0.55
12.5 0.30
50.0 0.30
12.5 0.50
–
A. niger
25.0 0.50
50.0 0.51
37.5 0.65
50.0 0.50
25.0 0.30
25.0 0.50
75.0 0.50
–
A. flavus
75.0 0.50
87.5 0.86
75.0 0.30
87.5 0.70
87.5 0.90
25.0 0.60
75.0 0.60
–
C. albicans
50.0 0.30
87.5 0.35
87.5 0.51
87.5 0.44
50.0 0.75
50.0 0.60
75.0 0.50
–
25.0 0.25
50.0 0.85
50.0 0.51
50.0 0.45
25.0 0.40
25.0 0.45
75.0 0.30
25.0 0.60
4a
4b
4c
4d
4e
4f
4g
Ciproa
Nystb
–
25.0 0.45
25.0 0.35
50.0 0.90
a
b
*Values are mean SD of three replicates; Ciproafloxacin-positive control against bacteria species; Nystatin-positive control against fungi
species.

2664 Lokeshwari et al.
Asian J. Chem.
11. M.P. Giovannoni, C. Vergelli, C. Ghelardini, N. Galeotti, A. Bartolini
and V. Dal Piaz, J. Med. Chem., 46, 1055 (2003);
https://doi.org/10.1021/jm021057u.
REFERENCES
1. B.P. Bandgar, L.K. Adsul, H.V. Chavan, S.S. Jalde, S.N. Shringare, R.
Shaikh, R.J. Meshram, R.N. Gacche and V. Masand, Bioorg. Med.
Chem. Lett., 22, 5839 (2012);
12. M. Rowley, H.B. Broughton, I. Collins, R. Baker, F. Emms, R. Marwood,
S. Patel, S. Patel, C.I. Ragan, S.B. Freedman and P.D. Leeson, J. Med.
Chem., 39, 1943 (1996);
https://doi.org/10.1016/j.bmcl.2012.07.080.
https://doi.org/10.1021/jm960072u.
13. K.A. Kumar, D.M. Lokeshwari and G.V. Kumar, Int. J. Pharm. Sci. Drug
Res., 4, 236 (2012).
2. K.R. Raghavendra, N. Renuka, V.H. Kameshwar, B. Srinivasan, K. Ajay
Kumar and S. Shashikanth, Bioorg. Med. Chem. Lett., 26, 3621 (2016);
https://doi.org/10.1016/j.bmcl.2016.06.005.
14. B. Frølund, A.T. Jørgensen, L. Tagmose, T.B. Stensbøl, H.T. Vestergaard,
C. Engblom, U. Kristiansen, C. Sanchez, P. Krogsgaard-Larsen and T.
Liljefors, J. Med. Chem., 45, 2454 (2002);
3. K.A. Kumar, M. Govindaraju, N. Renuka and G.V. Kumar, J. Chem.
Pharm. Res., 7, 250 (2015).
4. K.A. Kumar, M. Govindaraju and G.V. Kumar, Indian J. Heterocycl.
Chem., 20, 183 (2010).
https://doi.org/10.1021/jm020027o.
15. J.J. Talley, D.L. Brown, J.S. Carter, M.J. Graneto, C.M. Koboldt, J.L.
Masferrer, W.E. Perkins, R.S. Rogers, A.F. Shaffer, Y.Y. Zhang, B.S.
Zweifel and K. Seibert, J. Med. Chem., 43, 775 (2000);
https://doi.org/10.1021/jm990577v.
5. K.A. Kumar, M. Govindaraju, P. Jayaroopa and G.V. Kumar, Int. J. Pharm.
Chem. Biol. Sci., 3, 91 (2013).
6. P. Jayaroopa, G.V. Kumar, N. Renuka and K.A. Kumar, IOSR J. Appl.
Chem., 1, 20 (2012);
https://doi.org/10.9790/5736-0142023.
16. K.A. Kumar, K.M.L. Rai, K.B. Umesha and K.R. Prasad, Indian J. Chem.,
40B, 269 (2001).
7. K.M.L. Rai, N. Linganna, A. Hassner and C. Anjanamurthy, Org. Prep.
Proced. Int., 24, 91 (1992);
https://doi.org/10.1080/00304949209356711.
17. K.A. Kumar, K.M.L. Rai and K.B. Umesha, Tetrahedron, 57, 6993
(2001);
https://doi.org/10.1016/S0040-4020(01)00612-3.
18. N. Renuka, H.K.Vivek, G. Pavithra and K.A. Kumar, Russ. J. Bioorgan.
Chem., 43, 197 (2017);
8. W.-T. Li, D.-R. Hwang, C.-P. Chen, C.-W. Shen, C.-L. Huang, T.-W. Chen,
C.-H. Lin, Y.-L. Chang, Y.-Y. Chang, Y.-K. Lo, H.-Y. Tseng, C.-C. Lin,
J.-S. Song, H.-C. Chen, S.-J. Chen, S.-H. Wu and C.-T. Chen, J. Med.
Chem., 46, 1706 (2003);
https://doi.org/10.1134/S106816201702011X.
19. D.K. Achutha, P. Mallappa, L.K. Neratur and A.K. Kariyappa, Chem.
Data Coll., 2, 17 (2016);
https://doi.org/10.1021/jm020471r.
9. J.W. Patterson, P.S. Cheung and M.J. Ernest, J. Med. Chem., 35, 507
(1992);
https://doi.org/10.1021/jm00081a011.
https://doi.org/10.1016/j.cdc.2016.06.003.
10. K.A. Kumar, K.M.L. Rai and K.B. Umesha, J. Chem. Res. (S), 2001,
436 (2001);
https://doi.org/10.3184/030823401103168389.