Synthesis and hypolipidemic activity of novel 2-(4-(2-substituted aminothiazole-4-yl) phenoxy) acetic acid derivatives

Article abstract of DOI:10.1016/j.ejmech.2010.03.043

A novel series of aminotihazole compounds possessing phenoxy acetic acid moiety were synthesized. The synthesized compounds were evaluated for their hypolipidemic activity by using high fat diet induced hyperlipidemia in Sprague-Dawley rats.

Full text of DOI:10.1016/j.ejmech.2010.03.043

European Journal of Medicinal Chemistry 45 (2010) 3096e3100
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and hypolipidemic activity of novel 2-(4-(2-substituted
aminothiazole-4-yl) phenoxy) acetic acid derivatives
,
Santosh N. Mokale a, Priyanka T. Sanap b, Devanand B. Shinde b
*
a Y. B. Chavan College of Pharmacy, Aurangabad (MS), India
b Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada, University, Aurangabad 431004 (MS), India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of aminotihazole compounds possessing phenoxy acetic acid moiety were synthesized.
The synthesized compounds were evaluated for their hypolipidemic activity by using high fat diet
induced hyperlipidemia in Sprague-Dawley rats.
Received 10 February 2010
Received in revised form
27 March 2010
Accepted 29 March 2010
Available online 3 April 2010
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
Hypolipidemic
Aminothiazole
Phenoxy acetic acid
1. Introduction
2-(4-acetylphenoxy) acetic acid (2, Table 1) was synthesized by
using 2-chloroacetic acid condensed with 1-(4-hydroxyphenyl)
Hyperlipidemia is an elevation of lipids in the bloodstream and
these lipids include fats, fatty acids, cholesterol, cholesterol esters,
phospholipids, and triglycerides [1]. Fibrates in dyslipidemic
patients, improve the plasma lipid profile by lowering TG, and to
lesser extent, LDL cholesterol levels and by increasing HDL
cholesterol level [2].
ethanone(1). Itwasundergoascyclizationwiththioureausingiodine
in DMF resulting in the formation of 2-(4-(2-aminothiazol-4-yl)
phenoxy)aceticacid(3, Table1). Thecompounds4a-4hwasprepared
by treating compound 3 with different substituted halide (Table 1).
3. Hypolipidemic activity
Phenoxy acetic acid pharmacophore has been used in many
compounds which exhibit anti-hyperlipidemic activity, which was
attached with various types of heterocycles such as thiazole [3e6],
oxazole [7e9], oxadiazole [10], indole [11], benzisoxazole [12],
piperidine [13] etc.
Many synthetic drugs are available to treat hyperlipidemia but
are associated with multiple side effects. So, there is need to
develop newer synthetic hypolipidemic agents with fewer or no
side effects. From the literature survey, it was found that large
number of compounds was synthesized using phenoxy acetic acid
as pharmacophore which shows good hypolipidemic activity [14].
The hypolipidemic activity of the synthesized compounds was
studied in the high fat diet induced hyperlipidemic rats for 30 days
by oral administration of the drug and compounds [15]. The results
were compared with that obtained by the Group II (positive
control). The obtained results revealed that feeding rats with high
fat diet for 30 days significantly elevated the serum level of total
cholesterol, triglycerides, LDL when compared with normal control
rats. Moreover, induction of hyperlipidemia significantly decreased
serum HDL level that of normal control rats. The obtained data
revealed that the tested compounds produced variable effects on
the serum levels of Cholesterol, TG, and LDL, as compared with
Group II (positive control).
2. Chemistry
4. Results and discussion
The compound 3 i.e. 2-(4-(2-aminothiazol-4-yl) phenoxy) acetic
acid was synthesized by using 1-(4-hydroxyphenyl) ethanone (1) as
starting material as outlined in Scheme 1.
4.1. Chemistry
Melting points were determined on scientific melting point
* Corresponding author. Tel.: þ912402403307.
E-mail address: dbssantosh06@rediffmail.com (D.B. Shinde).
apparatus in open capillaries and were uncorrected. 1H NMR
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.03.043

S.N. Mokale et al. / European Journal of Medicinal Chemistry 45 (2010) 3096e3100
3097
O
OH
O
350
300
250
200
150
100
50
O
OH
O
OH
a
b
0
N
O
CH3
O
CH3
1
2
S
NH2
3
Treatment
Fig. 1. Effect of the test compounds and Fenofibrate on change in body weight.
c
O
OH
20
15
10
5
4a-4h
O
4a R=-CO-CH2-CH3
4b R=-CO-CH3
4c R=-CO-C6H5
4d R=-CO-CH2-Cl
4e R=-CH2-C6H5
4f R=-CH2-CO-C6H5, 4-Cl
4g R=-CH2-CO-C6H5, 4-NO2
4h R=-CH2-CO-C6H5, 4-NH2
0
N
S
NHR
4
Treatment
(a) 2-Chloro acetic acid, NaOH, H2O; (b) Thiourea, Iodine, DMF; (c) R-X, DMF
Fig. 2. Effect of the test compounds and Fenofibrate on body circumference.
Scheme 1. 2-(4-(2-substituted aminothiazole-4-yl) phenoxy) acetic acid derivatives.
Group XI (test group e standard group) and respective vehicle
(10 ml/kg), test compounds (50 mg/kg) and standard drug
(250 mg/kg) was administered for last 7 days. The various param-
eters like body weight, body circumference and locomotor activity
were recorded every 5th day.
spectra were recorded on a BRUKER AVANCE II 400 spectrometer
(400 MHz) with TMS as internal standard and DMSO as a solvent.
Mass spectra were recorded on Time of flight mass spectrometer.
FT-IR spectra were recorded on JASCO FT-IR 4000 using KBr
powder.
On 31st day, 2 ml blood was withdrawn by retro-orbital method
and total lipid profile Cholesterol, triglycerides, LDL, HDL, and VLDL
was determined. The group II (positive control) results were
compared with group I (normal control) using student ‘t’ test while
group III to group XI were compared with group II using ANOVA
followed by Dunnett’s test. The change in body weight (Fig. 1), body
circumference (Fig. 2), and locomotor activity (Fig. 3) for the
compounds and that of standard were shown in Table 2. The total
lipid i.e. HDL (Fig. 4), Cholesterol (Fig. 5), Triglycerides (Fig. 6), LDL
(Fig. 7), VLDL (Fig. 8) for the compounds and that of standard were
shown in Table 3.
4.2. Hypolipidemic activity
Sprague-Dawley rats (120e150 g) of either sex were used for the
activity. Fenofibrate (250 mg/kg) was used as standard for the
comparison hypolipidemic activity. Normal diet was made avail-
able for 30 days to Group I (normal control) and vehicle (10 ml/kg)
was administered for last 7 days. High fat diet was made available
for 30 days to Group II (positive control) and from Group III to
Table 1
250
200
150
100
50
Experimental data of synthesized compounds 2e4h.
Compound
Molecular formula
Molecular
Weight
Melting
Point
% Yield
2
3
C10H10O4
194
250
306
292
354
326
340
402
413
383
184
251
155
162
180
149
110
105
121
140
49.48
61.2
C11H10N2O3S
C14H14N2O4S
C13H12N2O4S
0
4a
4b
4c
4d
4e
4f
58.76
61.58
56.44
59.06
52.29
55.85
52.05
51.69
C
18H14N2O4S
C13 H11ClN2O4S
C18 H16N2O3S
C19H15ClN2O4S
C19H15N3O6S
C19H17N3O4S
Tre atme nt
4g
4h
Fig. 3. Effect of the test compounds and Fenofibrate on locomotor activity.

3098
S.N. Mokale et al. / European Journal of Medicinal Chemistry 45 (2010) 3096e3100
Table 2
160
140
120
100
80
Data of body weight, body circumference & locomotor activity.
Compound Parameter
Body weight (gm)
Body circumference Locomotor activity
60
40
(cm)
(5 minutes)
20
Normal
control
Positive
control
Fenofibrate 229.666 ꢀ 9.475***
196.666 ꢀ 3.323
12.033 ꢀ 0.3442
213.166 ꢀ 8.946
0
295.333 ꢀ 12.582*** 15.483 ꢀ 0.4909**
148.5 ꢀ 8.85***
9.5 ꢀ 0.3194***
10.483 ꢀ 0.453***
12.516 ꢀ 0.600*
13.1 ꢀ 0.658ns
9.5 ꢀ 0.319***
216.666 ꢀ 9.017***
210.5 ꢀ 9.323**
217 ꢀ 10.86 ns
4a
4b
4c
4d
4e
4f
224.166 ꢀ 3.754**
250.833 ꢀ 3.683*
239.666 ꢀ 4.566**
230.666 ꢀ 3.783***
248.500 ꢀ 4.537ns
220.500 ꢀ 1.688*
258.166 ꢀ 3.825ns
237.333 ꢀ 6.443**
Treatment
206.833 ꢀ 9.659***
215 ꢀ 13.269**
Fig. 6. Effect of the tested compounds and Fenofibrate on Triglycerides level.
13.066 ꢀ 0.814ns
12.35 ꢀ 0.699*
12.85 ꢀ 0.793ns
12 ꢀ 0.617**
194.833 ꢀ 8.811*
201.833 ꢀ 10.543*
193.666 ꢀ 10.39ns
204.166 ꢀ 9.81*
4g
4h
60
50
40
30
20
10
0
The results were expressed as Mean ꢀ SEM. The data were analyzed using One-way
Analysis of Variance (ANOVA) followed by Tukey test. (n ¼ 5 rats per group;
***P < 0.001, **P < 0.01, *P < 0.05, ns e non significant) Values are average of 5
readings.
40
35
30
25
20
15
10
5
Treatment
Fig. 7. Effect of the tested compounds and Fenofibrate on LDL level.
0
body circumference as compared to aliphatic substituent (4a, 4b,
4d). The presence of C¼O spacer (4a, 4b, 4c) was more effective
than -CH2-C¼O (4h) between amino group and aliphatic or
aromatic substituent.
Treatment
Fig. 4. Effect of the tested compounds and Fenofibrate on HDL level.
5. Conclusion
4.3. Structure activity relationship
In this investigation the high fat diet fed for 30 days significantly
increased the body weight in positive control as compared to
normal diet group where as last 07 days treatment of given
compound has shown reduced body weight by compound 4d fol-
lowed by compounds 4a, 4c and 4h. In case of body circumference,
compounds 4a and 4d were most effective followed by 4h. The
locomotor activity measured has shown significant increase with
compound 4c, followed by 4a and 4d.
The synthesized compounds show good hypolipidemic activity
by increasing the HDL levels that of normal and positive control.
Aliphatic substitution on amino group with one or two carbon
chain show significant increase in HDL level and locomotor activity,
reduced in body weight and significant reduction in body circum-
ference. The presence of terminal chlorine (4d) increases
antihyperlipedemic activity more effectively. Compound with
aromatic substitution (4e, 4f, 4g) generally having less HDL and
locomotorincreasing capacity and no reduction in body weight and
From pathological investigation, the SAR data has revealed that
compounds 4a, 4b, 4c, 4d, and 4h have higher antihyperlipidmeic
30
25
20
15
10
5
140
120
100
80
60
40
0
20
0
Treatment
Tre atme nt
Fig. 5. Effect of the tested compounds and Fenofibrate on Cholesterol level.
Fig. 8. Effect of the tested compounds and Fenofibrate on VLDL level.

S.N. Mokale et al. / European Journal of Medicinal Chemistry 45 (2010) 3096e3100
3099
Table 3
Data of total lipid profile (CH, TG, LDL, HDL & VLDL).
Compound
Parameter in mg/dl
CH
TG
75.6 ꢀ 2.06
LDL
HDL
VLDL
Normal control
Positive control
Fenofibrate
4a
4b
4c
4d
4e
4f
72.6 ꢀ 0.86
128.8 ꢀ 1.20***
83.2 ꢀ 1.03**
86.6 ꢀ 2.13**
104.0 ꢀ 2.51*
89.2 ꢀ 2.20**
92.0 ꢀ 2.21*
32.6 ꢀ 1.28
33.6 ꢀ 1.50
15.2 ꢀ ꢀ 0.86
26.2 ꢀ 1.20**
17.4 ꢀ 1.03**
21 ꢀ 1.14*
142.4 ꢀ 1.53***
91.6 ꢀ 2.31**
103.6 ꢀ 2.65**
107.6 ꢀ 2.37*
114.6 ꢀ 2.24*
118.4 ꢀ 1.03*
140.2 ꢀ 1.46ns
136.6 ꢀ 2.01ns
122.8 ꢀ 1.98*
110.4 ꢀ 1.43*
51.8 ꢀ 2.03**
37.2 ꢀ 1.15*
33.0 ꢀ 1.64**
51.4 ꢀ 1.80ns
34.2 ꢀ 1.35**
34.8 ꢀ 1.93**
53.8 ꢀ 2.41ns
50.0 ꢀ 1.41ns
43.2 ꢀ 1.56*
36.8 ꢀ 1.28*
18.6 ꢀ 1.36**
28.4 ꢀ 1.43*
30.4 ꢀ 1.63**
31.8 ꢀ 1.71**
28.4 ꢀ 1.36*
34.4 ꢀ 1.20**
20.2 ꢀ 1.24ns
18.6 ꢀ 1.20ns
24.6 ꢀ 1.50*
27.0 ꢀ 1.14*
22.6 ꢀ 1.36ns
25 ꢀ 1.64ns
28 ꢀ 1.14ns
22.4 ꢀ 0.92ns
27.2 ꢀ 1.42ns
20.2 ꢀ 1.28*
26.2 ꢀ 1.35ns
122.2 ꢀ 2.47ns
119.2 ꢀ 2.41ns
106.8 ꢀ 1.68*
77.6 ꢀ 1.63**
4g
4h
Standard dose 250 mg/kg, Test compound 50mg/kg. PC (Positive control) was compared with control. Drug treated compared with PC. The data were analyzed using One-way
Analysis of Variance (ANOVA) followed by Dunnett’s Test. (n ¼ 5 rats per group; ***P < 0.001, **P < 0.01, *P < 0.05, ns e non significant.) Values are average of 5 readings.
effect and caused appropriate modulation in HDL levels. Overall,
compounds 4d and 4h were potential compounds for obesity
associated hyperlipidemia.
d
¼ 11.8 (s, 1H), 8.4 (s, 1H), 6e8.5 (m, 5H), 3.4 (s, 2H),, 2.53 (q, 2H),
1.20 (t, 3H); MS (TOF, 1.99 e4): m/z ¼ 306.
6.3.2. 2-(4-(2-acetamidothiazol-4-yl) phenoxy) acetic acid (4b)
IR (KBr): 3500, 3228, 3000, 2927, 1705, 1682, 1535, 1516, 1509,
6. Experimental
1422, 1324, 1165, 938, 819 cmꢁ1 1H NMR (400 MHz, DMSO):
;
d
¼ 11.9 (s, 1H), 8.1 (s, 1H),6e8.5 (m, 5H), 3.1(s, 2H),, 2.1 (s, 3H); MS
6.1. Synthesis 2-(4-acetylphenoxy) acetic acid (2) [16]
(TOF, 1.99 e4): m/z ¼ 292.
A solution of sodium hydroxide (8.8 g, 0.22 moles) and chloro-
acetic acid (11.35 g, 0.24 moles, 20% excess) in 110 ml distilled water
was added to (13.6 g, 0.2 moles) 4-hydroxy acetophenone and the
resultant solution was refluxed on an oil bath for 8.5 hrs. At regular
intervals, the pH was measured and kept in the 8e9 range by the
further addition of aqueous sodium hydroxide solution as neces-
sary. The hot reaction mixture was acidified with an excess of
concentrated hydrochloric acid and the white solid filtered off,
washed with water and dried. This product was dissolved in 5%
aqueous sodium carbonate solution and washed several times with
ethyl acetate. The aqueous layer was then acidified with hydro-
chloric acid and the solid filtered off, washed with water and dried.
This material was crystallized from ethyl acetate to get compound
2. Melting Point: ꢁ184 ꢂC (Ref. 183e185ꢂ C.).
6.3.3. 2-(4-(2-benzamidothiazol-4-yl) phenoxy) acetic acid (4c)
IR (KBr): 3542, 3214, 3010,1709,1653,1546,1512,1476,1219,1108,
935, 822 cmꢁ1
;
1H NMR (400 MHz, DMSO):
d
¼ 12.3 (s, 1H), 7.12
(s, 1H), 6e8.5 (m, 10H), 3.3 (s, 2H); MS (TOF, 1.99 e4): m/z ¼ 354.
6.3.4. 2-(4-(2-(2-chloroacetamido) thiazol-4-yl) phenoxy) acetic
acid (4d)
1H NMR (400 MHz, DMSO):
(m, 5H), 4.2 (s, 2H), 3.1(s, 2H); MS (TOF, 1.99 e4): m/z ¼ 326.
d
¼ 11.9 (s, 1H), 8.1 (s, 1H), 6e8.5
6.3.5. 2-(4-(2-(benzyl amino) thiazol-4-yl) phenoxy) acetic acid (4e)
1H NMR (400 MHz, DMSO):
(s, 1H), 3.3 (s, 2H), 2.6 (d, 2H); MS (TOF, 1.99 e4): m/z ¼ 340.
d
¼ 12.2 (s, 1H), 6e8.5 (m, 10H), 4.62
6.3.6. 2-(4-(2-(2-(4-chlorophenyl)-2-oxoethylamino) thiazol-4-yl)
phenoxy) acetic acid (4f)
6.2. 2-(4-(2-aminothiazol-4-yl) phenoxy) acetic acid (3) [17]
1H NMR (400 MHz, DMSO):
d
¼ 12.24 (s, 1H), 6e8.5 (m, 9H), 4.6
Thiourea (30.4 g, 0.4 mole) and I2 (50.8 g, 0.2 mole) were trit-
urated and mixed with 2-(4-acetylphenoxy) acetic acid (38.8 g, 0.2
mole) in DMF. The mixture was heated on water bath with occa-
sional stirring for 18 hrs. The heated solution was poured in water;
the precipitate was filtered off. Crystallization was carried out by
using ethanol. Melting Point: ꢁ251 ꢂC.
(s, 1H), 3.07 (s, 2H), 2.5 (d, 2H); MS (TOF, 1.99 e4): m/z ¼ 402.
6.3.7. 2-(4-(2-(2-(4-nitrophenyl)-2-oxoethylamino) thiazol-4-yl)
phenoxy) acetic acid (4g)
1H NMR (400 MHz, DMSO):
(s, 1H), 3.03 (s, 2H), 2.5 (d, 2H); MS (TOF, 1.99 e4): m/z ¼ 413.
d
¼ 12.2 (s, 1H), 6e8.5 (m, 9H), 4.7
IR (KBr): 3512, 3430, 3045, 1722, 1629, 1525, 1510, 1224, 1195,
932 cmꢁ1
6e8.5 (m, 5H), 4.6 (s, 2H).
;
1H NMR (400 MHz, DMSO):
d
¼ 12.3 (s, 1H), 7.4 (s, 2H),
6.3.8. 2-(4-(2-(2-(4-aminophenyl)-2-oxoethylamino) thiazol-4-yl)
phenoxy) acetic acid (4h)
1H NMR (400 MHz, DMSO):
(s, 1H), 3.07 (s, 2H), 2.5 (d, 2H), MS (TOF, 1.99 e4): m/z ¼ 383.
d
¼ 12.24 (s, 1H), 6e8.5 (m, 11H), 4.6
6.3. General procedure for synthesis of 2-(4-(2-
substitutedaminothiazol-4-yl) phenoxy) acetic acid (4a-4h)
To a solution of 2-(4-(2-aminothiazol-4-yl) phenoxy) acetic acid
(5 g, 0.02 mole) in DMF, substituted halide (0.04 mole) was added
and reaction mixture was heated for 3 hrs. The completion of
reaction was monitored by TLC. The resultant solution was poured
into the water. The solid obtained was filtered and recrystallized
from ethanol to obtained desired compounds 4a-4h.
Acknowledgement
The authors thankful to the Head, Department of Chemical
Technology, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad 431004 (MS), India for providing the laboratory facility.
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IR (KBr): 3500, 3219, 3000, 2916,1716,1679, 1561, 1510, 1456,
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