S. N. Mokale et al. / Bioorg. Med. Chem. Lett. 21 (2011) 682–685
685
Table 3
Data of blood sugar level
6.1. Synthesis of 2-(4-acetyl-2-substituted phenoxy)-2-methyl propanoic acid (2):
In 500 ml of RBF, provide with reflux condenser placed 4-hydroxy
acetophenone (0.01 mol), 2-bromo-2-methyl propanoic acid (0.01 mol) and
K2CO3 (0.03 mol) in 25 ml of distilled ethanol. Then resultant solution was
refluxed in water bath. After 1 h, pH of the solution had dropped to 7, and
further 1 g of K2CO3 was added. Refluxing was continued for a 12 h. The hot
solution was acidified with concd HCl. The product was extracted with diethyl
ether. Ether layer was washed with 50 ml of saturated solution of Sodium
Bicarbonate. The aqueous layer was acidified with dil HCl acid. White colored
solid was filtered off, washed with water dried and recrystallized by hot water
to get the desired compounds (2). Mp 102 °C, % yield 65%.
6.2. Synthesis of 2-(4-(2-aminothiazol-4-yl) phenoxy)-2-methyl propanoic acid
(3). Method A: Thiourea (0.4 mol) and I2 (0.2 mol) were triturated and mixed
with 2-(4-acetylphenoxy)-2-methyl propanoic acid (0.2 mol) in DMF. The
mixture was heated on water bath with occasional stirring for 18 h. The heated
solution was poured in water and the precipitate was filtered off.
Crystallization was carried out by using ethanol. Mp 182 °C, % yield 45%.
Method B [14]: A mixture of 2-(4-acetylphenoxy)-2-methyl propanoic acid
(5 mmol), N-bromosuccinimide (5.5 mmol) in PEG-400 (15 ml) was stirred for
Compound
Blood sugar (mg/dl)
Normal control
Positive control
Fenofibrate
4a
4b
4c
4d
4e
4f
57.83 0.6009
106.3 0.6666a
70.5 0.7638a
81.5 0.7638a
72.33 1.706a
74.5 0.7638a
74.33 0.9888a
66.67 1.282a
75.17 0 .601a
Test compound = 250 mg/kg.
Reference standard, Fenofibrate = 250 mg/kg.
The results are expressed as mean SEM. The data is analyzed
using One-way Analysis of Variance (ANOVA) followed by
Tukey’s test.
6 h at rt. The formation of
a-bromoketone was monitored by TLC. After
completion of the bromination, thiourea (5 mmol) was added and the reaction
mass further stirred for 1 h and the progress of the reaction was monitored by
TLC. After the completion of the reaction mixture was added in 20 ml of
distilled water. The solid obtained was filtered and recrystallized from ethanol.
Mp 182 °C, % yield 90%.
(n = 6).
a
P <0.001.
P <0.01.
P <0.05.
b
c
d
Non significant.
6.3. Synthesis of2-(4-(2-substituted aminothiazole-4-yl) phenoxy)-2-methyl
propanoic acid (4a–4f): To a solution of 2-(4-(2-aminothiazol-4-yl) phenoxy)-
2-methyl propanoic acid (0.02 mol) in dry benzene
a cooled solution of
substituted halides (0.04 mol) in dry benzene was added drop wise. The
reaction mixture was refluxed in a water bath at 80 °C for 3 h. Benzene and
excess substituted halides were removed by distillation. The crude product
was dried and crystallized.
further structural modification is planned to increase the antihy-
perlipidemic and antihyperglycemic activities.
6.3.1. 2-(4-(2-Acetamidothiazol-4-yl) phenoxy)-2-methylpropanoic acid (4a): 1H
NMR (400 MHz, DMSO): d = 11.9 (s, 1H), 9.1 (s, 1H), 6–8.5 (m, 5H), 2.2 (s, 3H),
1.5 (s, 6H); MS (TOF, 1.99 e4): m/z = 320; C15H16N2O4S (320.364); requires
(Found): C, 56.24 (56.12); H, 5.03 (4.9); N, 8.74 (8.64).
Acknowledgments
The authors thankful to the Mrs. Fatima Rafiq Zakaria Chairman
Maulana Azad Educational Trust and Dr. M. H. G. Dehghan,
Principal, Y. B. Chavan college of Pharmacy, Dr. Rafiq Zakaria
Campus, Aurangabad 431001(MS), India for providing the labora-
tory facility.
6.3.2. 2-(4-(2-(2-Chloroacetamido) thiazol-4-yl) phenoxy)-2-methylpropanoic
acid (4b): 1H NMR (400 MHz, DMSO): d = 12.1 (s, 1H), 9.3 (s, 1H), 6–8.8 (m,
5H), 4.2 (s, 2H), 1.5 (s, 6H); MS (TOF, 1.99 e4): m/z = 354; C15H15ClN2O4S
(354.8); requires (Found): C, 50.78 (50.68); H, 4.26 (4.2); N, 7.90 (7.64).
6.3.3. 2-(4-(2-Benzamidothiazol-4-yl) phenoxy)-2-methylpropanoic acid (4c): 1H
NMR (400 MHz, DMSO): d = 11.5 (s, 1H), 9.1 (s, 1H), 6.8–8.8 (m, 10H), 1.49 (s,
6H); MS (TOF, 1.99 e4): m/z = 382; C20H18N2O4S (382.43); requires (Found): C,
62.81 (62.78); H, 4.74 (4.6); N, 7.33 (7.24).
6.3.4.2-(4-(2-(2-(4-Chlorophenyl)-2-oxoethylamino) thiazol-4-yl) phenoxy)-2-
methyl propanoic acid (4d): 1H NMR (400 MHz, DMSO): d = 11.0 (s, 1H), 6.9–
7.88 (m, 9H), 4.55 (s, 1H), 4.01(s, 1H); 1.58 (s, 6H); MS (TOF, 1.99 e4): m/
z = 430; C21H19ClN2O4S (430.90); requires (Found): C, 58.53 (58.48); H, 4.44
(4.41); N, 6.50 (6.44).
References and notes
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6.3.5. 2-(4-(2-(3-Chloro-3-oxopropanamido) thiazol-4-yl) phenoxy)-2-methyl-
propanoic acid (4e): 1H NMR (400 MHz, DMSO): d = 11.0 (s, 1H), 6.9–7.88 (m,
9H), 4.55 (s, 1H), 4.01 (s, 1H), 1.58 (s, 6H); MS (TOF, 1.99 e4): m/z = 382;
C16H15ClN2O5S (382.81); requires (Found): C, 50.20 (50.18); H, 3.95 (3.91); N,
7.32 (7.28).
6.3.6. 2-(4-(2-(2-Chloro-2-oxoacetamido) thiazol-4-yl) phenoxy)-2-methyl-
propanoic acid (4f): 1H NMR (400 MHz, DMSO): d = 11.2 (s, 1H), 9.15 (s, IH),
6.9–7.88 (m, 5H), 1.55 (s, 6H); MS (TOF, 1.99 e4): m/z = 368; C15H13ClN2O5S
(368.79); requires (Found): C, 48.85 (48.78); H, 3.55 (3.50); N, 7.60 (7.58).
Pharmacological activity: Sprague–Dawley rats (120–150 g) of either sex were
divided into nine groups of six animals and they were numbered individually.
Normal diet was made available for 30 days to Group I. High fat diet was made
available for 23 days to Group II and vehicle was administered for last 7 days.
Also high fat diet was made available for 23 days to Group III–IX and test
compounds 4a–f (250 mg/kg) and standard drug, Fenofibrate (250 mg/kg) was
administered for last 7 days respectively. On 31st day, 2 ml blood was
withdrawn by retro orbital method and total lipid profile was determined by
standard method (Table 2). Along with lipid profile blood sugar level was also
determined (Table 3).
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16. General: melting points were determined on scientific melting point apparatus
in open capillaries and were uncorrected. 1H NMR 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.