Synthesis of some novel substituted phenylisoxazol phenoxy 2-methylpropanoic acids and there in vivo hypolipidemic activity

Article abstract of DOI:10.1007/s00044-015-1498-2

The novel series of phenylisoxazol phenoxy 2-methylpropanoic acid derivatives were synthesized and evaluated for their in vivo hypolipidemic activity by triton WR-1339-induced hyperlipidemia in rats. The newly synthesized compounds 5a and 5i showed significant decrease in the serum TCH, TG, LDL and VLDL along with an increase in serum HDL levels as compared to standard drug Fenofibrate. The treated groups also showed significant decrease in the atherogenic index, TC:HDL risk ratios compared to cholesterol-induced hyperlipidemic control group. These molecules indeed have the potential to be developed as antihypolipidemic molecules.

Full text of DOI:10.1007/s00044-015-1498-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1498-2
ORIGINAL RESEARCH
Synthesis of some novel substituted phenylisoxazol phenoxy
2-methylpropanoic acids and there in vivo hypolipidemic activity
Santosh N. Mokale1 Pritam N. Dube1 Manjusha C. Nevase1
•
•
•
Nikhil S. Sakle1 Vishakha R. Shelke1 Swati A. Bhavale1
Afreen Begum1
•
•
•
Received: 12 February 2015 / Accepted: 21 December 2015
Ó Springer Science+Business Media New York 2015
Abstract The novel series of phenylisoxazol phenoxy
2-methylpropanoic acid derivatives were synthesized and
evaluated for their in vivo hypolipidemic activity by triton
WR-1339-induced hyperlipidemia in rats. The newly syn-
thesized compounds 5a and 5i showed significant decrease
in the serum TCH, TG, LDL and VLDL along with an
increase in serum HDL levels as compared to standard drug
Fenofibrate. The treated groups also showed significant
decrease in the atherogenic index, TC:HDL risk ratios
compared to cholesterol-induced hyperlipidemic control
group. These molecules indeed have the potential to be
developed as antihypolipidemic molecules.
blood vessels if the quantity of HDL is high; this reduces
the normal blood flow (Howland and Mycek, 2006; Sae-tan
et al., 2011).
Fibrates are phenoxy-2-methyl propanoic acid deriva-
tives (Mokale et al., 2012a). Fibrates affect lipid metabo-
lism as agonists of enzyme peroxisome proliferator-
activated receptor alpha (PPAR-a) by lowering TG, LDL
and by increasing HDL cholesterol level (Bitzur et al.,
2009; Mokale et al., 2012b).
It was observed that phenoxy-2-methyl propanoic acid
pharmacophore has been frequently used in synthesis of
hypolipidemic agents (Fig. 1). Phenoxy-2-methyl propa-
noic acid pharmacophore has been coupled with many
heterocyclic nuclei which exhibit potent antihyperlipi-
demic activity, such as pyrimidine, thiazole, isoxazole,
oxadiazole, indole, benzisoxazole, piperidine and mor-
pholine (Vogel, 2008; Mokale et al., 2010). In view of this,
we have attempted the synthesis of phenoxy-2-methyl
propanoic acid pharmacophore containing isoxazole
derivative as an antihyperlipidemic agent (Fig. 2).
Keywords Hyperlipidemia Á Phenoxy propanoic acid Á
Isoxazole Á Atherogenic index
Introduction
Hyperlipidemia is abnormally high levels of fats in the
blood like cholesterol and triglycerides. It has been cate-
gorized as one of the greatest risk factors contributing to
coronary heart disease. It results from aberrations in lipid
metabolism or plasma lipid transport or a disorder in the
synthesis and degradation of plasma lipoproteins (Mokale
et al., 2011). Saturated fat in diet can increase the pro-
duction of VLDL, resulting in the formation of large
amounts of LDL which may adhere to the walls of the
Result and discussion
Chemistry
Synthesis of the final derivatives is shown in Scheme 1.
The proposed derivatives were synthesized in three steps,
1
and their structures have been verified by IR, H-NMR,
13C-NMR and LC–MS spectroscopy. The final compounds
5a–j, i.e., substituted phenylisoxazol phenoxy 2-methyl-
propanoic acid derivatives, were synthesized by using
substituted acetophenones and 4-hydroxyl benzaldehyde or
substituted benzaldehydes and 4-hydroxyl acetophenone
starting material as outlined in Scheme 1. The substituted
& Santosh N. Mokale
santoshmokale@rediffmail.com
1
Y. B. Chavan College of Pharmacy, Dr. Rafiq Zakaria
Campus, Aurangabad 431001, India
123

Med Chem Res
O
O
O
O
OH
O
O
O
N
H
O
Cl
O
Cl
O
1. Clofibrate
2. Fenofibrate
3. Benzafibrate
Fig. 1 Pharmacophore of phenoxy-2-methyl propanoic acid derivatives
O
Conclusion
10
Lipophilic tail
O
13
9
11
14
12
OH
19
20
4
In conclusion, we have designed, synthesized and evalu-
ated substituted phenylisoxazol phenoxy 2-methyl-
propanoic acid derivatives for their hypolipidemic activity.
All the synthesized compounds possess hypolipidemic
activity. Among these, 5a and 5i were found to be the most
active when compared with standard. The hypolipidemic
activity results revealed that phenoxy propanoic acid
pharmacophore with isoxazole ring as spacer is important
for hypolipidemic activity. The results suggest that these
compounds constitute a new prototype of lipid lowering
agents; further experimental and mechanistic studies are,
however, required to advance this series in preclinical
development.
5
18
8
6
R
Pharmacophore
3
7
15
1
O
17
N
16
2
Heterocyclic
linker
Fig. 2 Designed pharmacophore of phenoxy-2-methyl propanoic
acid derivatives (5a–j)
hydroxy chalcones (3a–j) were synthesized by using sub-
stituted benzaldehydes and 4-hydroxyl acetophenone or
substituted acetophenones and 4-hydroxyl benzaldehyde in
the presence of aq. alkali. The substituted isoxazole phe-
nols (4a–j) were synthesized by cyclization of substituted
hydroxy chalcones with hydroxylamine HCl. In this reac-
tion, cyclization takes place due to removal of a water
molecule to form substituted isoxazole phenols. The final
derivatives were obtained by condensing 2-chloro-2-
methyl propanoic acid with substituted isoxazole phenols
(5a–j, Table 1). The purity of these compounds was
ascertained by TLC and spectral analysis.
Experimental
General information
Melting points were determined on scientific melting point
apparatus in open capillaries and were uncorrected. FT-IR
spectra were recorded on JASCO FT-IR 4000 using KBr
powder. 1H and 13C NMR spectra were recorded on a
Bruker Avance II 400 NMR spectrometer with TMS as
internal standard and DMSO as a solvent. Mass spectra
were recorded on a Varian Inc, 410 Prostar Binary LC with
500 MS IT PDA Detectors. All the reagents and solvents
used were of analytical grade which are found in pure
form.
Hypolipidemic activity
The hypolipidemic activity of the synthesized compounds
was studied in the triton-induced hyperlipidemic rats
(Vogel, 2008; Sashidhara et al., 2013). In study, feeding
rats with triton for 24 h exhibited abnormalities in lipid
metabolism as evidenced from the significant elevation of
plasma TC, TG, LDL, AI and reduction in HDL levels
when compared with normal rats. The results obtained
were compared with group II (positive control). The
obtained data revealed that the treatment with compounds
5a and 5i significantly reduced the serum levels of
cholesterol, TG and LDL associated with simultaneous
significant increase in HDL-C levels as compared with
positive control (Table 1). It shows that unsubstituted
phenyl groups have more potent activity as compared to
other derivatives. Decrease in atherogenic index (Table 2)
in rats indicates that the compounds are potent
antiatherogenic activity which decreases the cardiovascular
risk.
HPLC analyses were performed using Jasco LC-NET II/
ADC pumps gradient-controlled HPLC system equipped
with a Jasco system controller (PU-2080 Plus) and UV–Vis
detector (UV-2075 Plus) utilizing Jasco BORWIN soft-
ware. A sample volume of 10 lL was injected into a
reverse-phase C18 column (4.6 9 250 mm) with a gradient
elution of 50–100 % of B in A for 15 min followed by
100–50 % of B in A for 15 min at a flow rate of 1.0 mL/
min. UV detection was performed at 254 nm. The mobile
phase A consisted of double distilled water with 20 mM
ammonium formate (AF), and B was 90 % ACN in water
123

Med Chem Res
Scheme 1 Synthesis of
designed compounds (5a–j)
O
O
2
H
R
R
CH3
1
H
O
N
H
O
H
O
a
O
OH
O
H
/
l
o
O
n
E
a
O
H
t
h
h
t
a
n
o
E
/
O
H
H
3C
O
l
O
a
N
R
O
H
O
O
O
H
O
R
O
O
R
R
O
3c
H
O
3b
a
3
H
3d-j
OHNH HCl/
OHNH2.HCl/
KOH
.
KOH2
OHNH HCl/
KOH
OHNH HCl/
.
2
.
2
KOH
OH
R
R
R
O
N
O
N
O
N
H
O
O
O
H
O
N
H
O
4b
Br
R
a
4
c
4
4d-j
Br
Br
Br
K2CO3
K2CO3
K2CO3
R
K2CO3
O
O
O
O
HO
H
O
H
HO
O
R
R
N
O
R
O
N
O
N
O
N
O
O
O
O
O
O
O
O
H
O
5b
H
O
5a
H
O
5c
O
HO
5d-j
with 20 mM AF. Compound purities are described as
percentages (%).
into the reaction mixture and it was acidified by dil. HCl.
The crude product obtained was filtered and recrystallized
by ethanol.
General procedure for the synthesis of substituted
hydroxy chalcones (Jeong et al., 2004)
General procedure for synthesis of substituted
isoxazole phenols
In a 250-ml conical flask, substituted benzaldehydes
(0.01 mol) and of 4-hydroxyl acetophenone (0.01 mol) or
substituted acetophenone (0.01 mol) and 4-hydroxyl ben-
zaldehyde (0.01 mol) were placed in 40 ml of ethanol. To
the above reaction mixture, 15 ml of 40 % sodium
hydroxide solution was added. Then the resultant solution
was stirred for 2 h. After stirring, the reaction mixture was
kept aside for 48 h. On next day, crushed ice was added
In a 250 ml RBF with a reflux condenser, chalcone
(0.01 mol) and a solution of KOH (0.02 mol) in 50 ml of
methanol and hydroxylamine HCl were placed. Then
resultant solution was refluxed in water bath for 12 h. After
compilation of reaction, the hot solution was acidified with
conc. HCl. The solid obtained was filtered off, washed with
water dried and recrystallized by ethanol.
123

Med Chem Res
CH:HDL
Table 1 Data of total lipid profile (TC, TG, LDL, VLDL and CH:HDL) of synthesized compounds
Groups
R
TC
TG
LDL
VLDL
Normal control
Positive control
Fenofibrate
5a
–
–
–
68.2 1.6
104 1.4
202 1.42#
104 1.8a
42 1.5
20.8 1.0
40.4 1.6#
20.8 1.7a
21.7 1.5a
1.62 1.56
9.7 1.34@
1.88 1.21b
1.51 1.01b
165.5 1.3#
75.6 1.8a
62.5 1.1a
16.9 0.98#
40.1 2.3a
41 1.2a
108.5 1.9a
5b
5c
5d
61.5 0.50a
119.5 1.5a
116 1.7a
102 1.2a
36 2.1a
23.9 1.2a
23.2 1.5a
20.4 1.1a
1.70 0.97b
2.26 0.69b
1.61 1.72b
77 1.1a
34 2.1a
F
60.5 0.60a
37.5 1.9a
OCH3
5e
5f
58 1.7a
107 1.7a
35 2.4a
21.4 1.3a
1.65 0.11b
OCH3
OCH3
OCH3
61 0.70a
111.5 1.8a
37 2.2a
22.3 1.1a
1.64 0.79b
Cl
5g
5h
66 1.7a
115 1.8a
36 2.2a
23 0.9a
1.83 1.66b
Cl
O
Cl
83 0.90a
128 1.6a
36 2.0a
25.6 1.7a
2.30 0.87b
5i
5j
77.7 1.5a
138 1.3a
120 1.2a
39 1.8a
27.6 0.9a
1.99 1.01b
1.88 1.11b
68 1.4a
36 1.9a
24 0.8a
Cl
Values are in mean SEM; number of animals in each group = 6
#
c
p \ 0.001 versus normal; @ p \ 0.001 versus normal; a p \ 0.001 versus untreated; b p \ 0.01 versus untreated; p \ 0.05 versus untreated
123

Med Chem Res
129.7 (Ar–C), 128.1 (Ar–C), 125.6 (Ar–C), 119.8 (Ar–C),
116.5 (C10, Ar–C), 99.2 (C4), 88.6 (C13), 25.2 (CH3); MS:
m/z of C19H17NO4 = 324.10 [M ? 1].
Table 2 Atherogenic index for target compounds
Groups
Atherogenic index
% Protection
Normal control
0.62
8.79
0.89
0.52
0.71
1.26
0.61
0.66
0.65
0.83
1.31
0.99
0.89
–
2-(4-(5-(4-fluorophenyl)isoxazole-3-yl)phenoxy)-2-methyl-
propanoic acid (5c) %Yield—65.54; Melting Point—
173 °C; Rf (ethyl acetate/n-hexane 1:4 v/v) = 0.54, and
100 % purity by HPLC. IR (KBr, cm-1): 3310 (O–H),
Positive control
–
Fenofibrate
89.87
94.08
91.92
85.67
93.06
92.49
92.61
90.56
85.1
5a
5b
5c
5d
5e
5f
1
1741 (C=O), 1273 (O–N), 1136 (C–N), 1097 (C–O); H
NMR (DMSO, 400 MHz): d = 11.0 (s, 1H, –OH), 7.1-7.7
(s, 8H, Ar–H), 6.7 (s, 1H, isoxazole), 1.5 (s, 3H, –CH3), 1.6
(s, 3H, –CH3); 13C NMR (DMSO, 100 MHz): d = 180.6
(C14, C=O), 171.4 (C5, ArC–O), 162.9 (C3, C=N), 161.2
(C18, C–F), 149.5 (C9), 130.7 (C7), 128.2 (C11), 125.4
(C16), 125.3 (C20), 122.3 (C15), 112.2 (C17), 108.2 (C8),
97.6 (C4), 89.2 (C13), 22.9 (CH3); MS: m/z of C19H16-
FNO4 = 343.10 [M ? 2].
5g
5h
5i
88.74
89.87
5j
2-(4-(3-(2-methoxyphenyl)isoxazole-5-yl)phenoxy)-2-methyl-
propanoic acid (5d) % Yield—68.31; Melting Point—
176 °C; Rf (ethyl acetate/n-hexane 1:4 v/v) = 0.62, and
100 % purity by HPLC. IR (KBr, cm-1): 3310 (O–H),
General procedure for synthesis of phenylisoxazol
phenoxy 2-methylpropanoic acid derivatives
(Nagaraj and Reddy, 2008)
1
1709 (C=O), 1291 (O–N), 1124 (C–N), 1148 (C–O); H
NMR (DMSO, 400 MHz): d = 10.8 (s, 1H, –OH), 8.2–7.2
(m, 8H, Ar–H), 6.6 (s, 1H, isoxazole), 3.7 (s, 3H, –OCH3),
1.4 (s, 3H, –CH3), 1.5 (s, 3H, –CH3); 13C NMR (DMSO,
100 MHz): d = 178.4 (C14, C=O), 170.2 (C5, ArC–O),
162.3 (C3, C=N), 155.7 (C16), 144.9 (C9), 128.7 (C20),
127.2 (C18), 124.1 (C7), 121.3 (C11), 113.8 (C17), 109.4
(C6), 98.3 (C4), 89.1 (C13), 56.5 (OCH3), 25.2 (CH3); MS:
m/z of C20H19NO5 = 354.2 [M ? 1].
In a 250 ml RBF with a reflux condenser, substituted
isoxazole phenols (0.01 mol), 2-bromo-2-methyl propionic
acid (0.01 mol) and K2CO3 (0.03 mol) in 25 ml acetone
were placed. Then resultant solution refluxed in water bath
for 12 h. After compilation of reaction, the hot solution
was acidified with conc. HCl. The solid obtained was fil-
tered off, washed with water dried and recrystallized by
ethanol.
2-(4-(3-(3,4,5-trimethoxyphenyl)isoxazole-5-yl)phenoxy)-2-
methylpropanoic acid (5e) %Yield—66.58; Melting
Point—156 °C; Rf (ethyl acetate/n-hexane 1:4 v/v) = 0.66,
and 100 % purity by HPLC. IR (KBr, cm-1): 3224 (O–H),
2-(2-methoxy-4-(5-phenylisoxazol-3-yl)phenoxy)-2-methyl-
propanoic acid (5a) % Yield—68.60; Melting Point—
168 °C; Rf (ethyl acetate/n-hexane 1:4 v/v) = 0.52, and
100 % purity by HPLC. IR (KBr, cm-1): 3220 (O–H), 1716
1
1
1719 (C=O), 1278 (O–N), 1127 (C–N), 1149 (C–O); H
(C=O), 1280 (O–N), 1124 (C–N), 1144 (C–O); H NMR
NMR (DMSO, 400 MHz): d = 10.9 (s, 1H, –OH), 6.8–7.6
(m, 6H, Ar–H), 6.7 (s, 1H, isoxazole), 3.7–3.8 (s, 9H, 3(–
OCH3)), 1.5 (s, 6H, 2(–CH3)); 13C NMR (DMSO,
100 MHz): d = 179.0 (C14, C=O), 169.8 (C5, ArC–O),
162.5 (C3, C=N), 158.6 (C9), 156.3 (C17), 153.7 (C19),
140.6 (C18), 128.4 (C7), 124.3 (C11), 118.1 (C8), 111.3
(C10), 100.7 (C16), 98.5 (C4), 89.4 (C13), 60.1 (OCH3), 56.4
(OCH3), 25.3 (CH3); MS: m/z of C22H23NO7 = 414.4
[M ? 1].
(DMSO, 400 MHz): d = 10 (s, 1H, –OH), 8.2–7.0 (m, 8H,
Ar–H), 6.8 (s, 1H, isoxazole), 4 (s, 3H, –OCH3), 1.4 (s, 3H, –
CH3), 1.5 (s, 3H, –CH3); 13C NMR (DMSO, 100 MHz):
d = 179.3 (C14, C=O), 165.1 (C3), 163.3 (C5), 151.4 (C8),
142.7 (C9), 133.9 (C15), 128.8 (C17), 128.3 (C19), 126.7 (C7),
122.9 (C18), 115.6 (C10), 101.3 (C4), 91.2 (C13), 53.9
(OCH3), 25.5 (CH3); MS: m/z of C20H19NO5 = 354.15
[M ? 1].
2-(2-(5-phenylisoxazol-3-yl)phenoxy)-2-methylpropanoic
acid (5b) % Yield—63.52; Melting Point—171 °C; Rf
(ethyl acetate/n-hexane 1:4 v/v) = 0.60, and 100 % purity
by HPLC. IR (KBr, cm-1): 3234 (O–H), 1728 (C=O), 1291
(O–N), 1117 (C–N), 1139 (C–O); 1H NMR (DMSO,
400 MHz): d = 11.1 (s, 1H, –OH), 8.0–7.1 (m, 9H, Ar–H),
6.7 (s, 1H, isoxazole), 1.6 (s, 6H, (–CH3)2); 13C NMR
(DMSO, 100 MHz): d = 181.2 (C14, C=O), 171.8 (C=N),
162.8 (C5, ArC–O), 154.3 (C9, ArC–O), 130.7 (Ar–C),
2-(4-(3-(2-chlorophenyl)isoxazole-5-yl)phenoxy)-2-methyl-
propanoic acid (5f) % Yield—70.20; Melting Point—
170 °C; Rf (ethyl acetate/n-hexane 1:4 v/v) = 0.52, and
100 % purity by HPLC. IR (KBr, cm-1): 3231 (O–H),
1
1722 (C=O), 1293 (O–N), 1152 (C–N), 1125 (C–O); H
NMR (DMSO, 400 MHz): d = 11.1 (s, 1H, –OH), 7.0–7.8
(m, 8H, Ar–H), 6.8 (s, 1H, isoxazole), 1.6 (s, 3H, –CH3),
1.5 (s, 3H, –CH3); 13C NMR (DMSO, 100 MHz):
123

Med Chem Res
d = 178.8 (C14, C=O), 166.4 (C5, ArC–O), 159.3 (C3,
C=N), 155.2 (C9), 141.2 (C16), 133.5 (C17), 129.6 (C7),
127.7 (C11), 124.1 (C20), 114.2 (C8), 109.6 (C10), 101.3
(C4), 88.9 (C13), 25.4 (CH3); MS: m/z of C19H16-
ClNO4 = 359.2 [M ? 2].
C=N), 157.6 (C9), 141.2 (C18), 133.8 (C19), 130.4 (C17),
128.2 (C7), 127.4 (C11), 122.8 (C20), 116.0 (C8), 115.1
(C10), 100.2 (C4), 89.7 (C14), 24.3 (CH3); MS: m/z of
C19H16ClNO4 = 359.1 [M ? 2].
Hypolipidemic activity
2-(4-(3-(2,6-dichlorophenyl)isoxazole-5-yl)phenoxy)-2-methyl-
propanoic acid (5g) % Yield—69.20; Melting Point—
161 °C; Rf (ethyl acetate/n-hexane 1:4 v/v) = 0.56, and
100 % purity by HPLC. IR (KBr, cm-1): 3222 (O–H),
Albino Wistar rats of either sex (200–250 g) were kept in a
room with controlled temperature (25–26 °C), humidity
(60–80 %) and 12/12-h light/dark cycle under hygienic con-
ditions. Animals were acclimatized for 1 week before starting
the experiment with free access to the normal diet and water.
The hypolipidemic activity of the synthesized com-
pounds was studied in the triton-induced hyperlipidemic
rats for 7 days by oral administration of the drug and
compounds. Hyperlipidemia was developed by intraperi-
toneal administration of triton WR-1339 (Sigma-Aldrich,
USA) at a dose of 400 mg/kg to all animals except the
control. The compounds were suspended in Tween 80 and
administered orally at a dose 250 mg/kg. Animals of nor-
mal control and positive control group (triton) were given
vehicle only. Fenofibrate (250 mg/kg) was used as standard
for the comparison hypolipidemic activity.
1
1734 (C=O), 1279 (O–N), 1174 (C–N), 1143 (C–O); H
NMR (DMSO, 400 MHz): d = 10.7 (s, 1H, –OH), 7.1–8.0
(m, 7H, Ar–H), 6.8 (s, 1H, isoxazole), 1.6 (s, 3H, –CH3),
1.5 (s, 3H, –CH3); 13C NMR (DMSO, 100 MHz):
d = 179.4 (C14, C=O), 167.2 (C5, ArC–O), 161.1 (C3,
C=N), 156.3 (C9), 142.1 (C20), 140.8 (C16), 132.7 (C17),
130.4 (C18), 128.6 (C19), 124.9 (C7), 115.2 (C8), 108.7
(C10), 100.3 (C4), 89.5 (C13), 26.1 (CH3); MS: m/z of
C19H15Cl2NO4 = 394.3 [M ? 2].
2-(4-(3-(furan-2-yl)isoxazole-5-yl)phenoxy)-2-methylpropanoic
acid (5h) % Yield—66.82; Melting Point—168 °C; Rf
(ethyl acetate/n-hexane 1:4 v/v) = 0.60, and 100 % purity
by HPLC. IR (KBr, cm-1): 3312 (O–H), 1714 (C=O), 1282
(O–N), 1125 (C–N), 1112 (C–O); 1H NMR (DMSO,
400 MHz): d = 11.1 (s, 1H, –OH), 7.1–7.8 (m, 7H, Ar–H),
6.6 (s, 1H, isoxazole), 1.5 (s, 6H, 2(–CH3)); 13C NMR
(DMSO, 100 MHz): d = 179.8 (C14, C=O), 169.7 (C5,
ArC–O), 161.4 (C3, C=N), 157.6 (C9), 150.2 (C15), 142.9
(C17), 126.3 (C7), 118.5 (C8), 112.9 (C18), 108.3 (C19), 99.2
(C4), 89.5 (C13), 25.2 (CH3); MS: m/z of
C17H15NO5 = 314.3 [M ? 1].
Biochemical analysis
The serum was assayed for total cholesterol (TC), triglyc-
erides (TG) and high-density lipoprotein (HDL). The LDL
and VLDL were calculated by using Friedwald formula
(Table 1). The atherogenic index (AI) was calculated as
(AI = (TC - HDL)/HDL, Table 2) (Hamauzu et al., 2011).
2-(4-(3-phenylisoxazol-5-yl)phenoxy)-2-methylpropanoic
acid (5i) % Yield—67.63; Melting Point—169 °C; Rf
(ethyl acetate/n-hexane 1:4 v/v) = 0.48, and 100 % purity
by HPLC. IR (KBr, cm-1): 3217 (O–H), 1761 (C=O), 1259
(O–N), 1007 (C–N), 1121 (C–O); 1H NMR (DMSO,
400 MHz): d = 11.0 (s, 1H, –OH), 7.1–7.9 (m, 9H, Ar–H),
6.8 (s, 1H, isoxazole), 1.6 (s, 3H, –CH3), 1.5 (s, 3H, –CH3);
13C NMR (DMSO, 100 MHz): d = 179.5 (C14, C=O),
169.7 (C5, ArC–O), 162.3 (C3, C=N), 155.2 (C9), 131.2
(C18), 129.8 (C17), 127.6 (C20), 123.3 (C7), 114.1 (C8),
108.5 (C10), 104.7 (C4), 88.9 (C13), 25.1 (CH3); MS: m/z of
C19H17NO4 = 324.1 [M ? 1].
Statistical evaluation
Data obtained in the test were compared against the control
group by using the one-way analysis of variance method and
followed by a post hoc Dunnett’s test. For all statistical
analyses, alpha was set to 0.05. Statistical analysis was per-
formed using the SPSS 16 software package. Results were
presented as mean standard error mean (Mean SEM).
Acknowledgments The authors are thankful to the Mrs. Fatima
Rafiq Zakaria, Chairman, Maulana Azad Educational Trust, Aur-
angabad 431001(MS), India, for providing the laboratory facility.
2-(4-(3-(4-chlorophenyl)isoxazole-5-yl)phenoxy)-2-methyl-
propanoic acid (5j) % Yield—68.72; Melting Point—
175 °C; Rf (ethyl acetate/n-hexane 1:4 v/v) = 0.62, and
100 % purity by HPLC. IR (KBr, cm-1): 3215 (O–H),
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