Microwave-assisted synthesis, hypolipidemic and hypoglycemic activity of some novel 2-(4-(2-amino-6-(4-substituted phenyl)-pyrimidin-4-yl)-phenoxy)-2- methyl propanoic acid derivatives

Article abstract of DOI:10.1002/ardp.201000229

A novel series of aminopyrimidines containing the phenoxy isobutyric acid group as a pharmacophore was synthesized using conventional and microwave assisted methods of synthesis. The compounds were synthesized in good yields (70-89%) by the microwave-assisted one-pot protocol in much shorter reaction times. The synthesized compounds were evaluated for their hypolipidemic and hypoglycemic activity by high-fat diet-induced hyperlipidemia and hyperglycemia in male Sprague-Dawley rats. The present investigation showed significant antihyperlipidemic and antihyperglycemic activity for all compounds of the series when compared with the standard drug. Structure-activity relationship (SAR) for the series were developed by comparing total lipid profile data of synthesized compounds with fenofibrate as standard drug. A novel series of aminopyrimidines containing the phenoxy isobutyric acid group as a pharmacophore was synthesized using conventional and microwave-assisted methods of synthesis. The synthesized compounds were evaluated for their hypolipidemic and hypoglycemic activities on high-fat diet-induced hyperlipidemia and hyperglycemia in male Sprague-Dawley rats. Copyright

Full text of DOI:10.1002/ardp.201000229

22
Arch. Pharm. Chem. Life Sci. 2012, 345, 22–27
Full Paper
Microwave-Assisted Synthesis, Hypolipidemic and
Hypoglycemic Activity of Some Novel 2-(4-(2-Amino-6-
(4-substituted phenyl)-pyrimidin-4-yl)-phenoxy)-2-methyl
Propanoic Acid Derivatives
Santosh N. Mokale1, Rupali D. Elgire1, Nikhil S. Sakle1, and Devanand B. Shinde2
1 Dr. Rafiq Zakaria Campus, Y. B. Chavan College of Pharmacy, Aurangabad, India
2 Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, India
A novel series of aminopyrimidines containing the phenoxy isobutyric acid group as a
pharmacophore was synthesized using conventional and microwave assisted methods of synthesis.
The compounds were synthesized in good yields (70–89%) by the microwave-assisted one-pot protocol
in much shorter reaction times. The synthesized compounds were evaluated for their hypolipidemic
and hypoglycemic activity by high-fat diet-induced hyperlipidemia and hyperglycemia in male
Sprague-Dawley rats. The present investigation showed significant antihyperlipidemic and
antihyperglycemic activity for all compounds of the series when compared with the standard
drug. Structure-activity relationship (SAR) for the series were developed by comparing total lipid
profile data of synthesized compounds with fenofibrate as standard drug.
Keywords: Hypolipidemic / Microwave assisted synthesis / Phenoxy isobutyric acid / Pyrimidine
Received: August 9, 2010; Revised: September 29, 2010; Accepted: October 8, 2010
DOI 10.1002/ardp.201000229
Introduction
(PPAR-a) by lowering TG, LDL and by increasing HDL choles-
terol level.
The major cause of death in the western world is vascular
disease, of which the most prevalent form is atherosclerotic
heart disease. Many causative factors of this disease are recog-
nized (e.g. smoking, stress, diet). Atherosclerotic diseases can
be treated through medication or surgery. Hyperlipidemia is
the most prevalent indicator for susceptibility to atheroscler-
otic heart disease, it is a term used to describe elevated
plasma levels of the lipids that are usually in the form of
lipoproteins [1].
It was observed that phenoxy isobutyric acid pharmaco-
phores have been frequently used in the synthesis of hypo-
lipidemic agents [3–8]. Phenoxy isobutyric acid moiety was
frequently coupled with heterocyclic nucleus such as
benzoxazole [3], pyrimidine [9], thiazole [10], trifluorome-
thane sulfonamide [11], thiadiazole [12] and morpholine
[13] to have more potent antihyperlipidemic agent.
In view of this, we have attempted the synthesis of
aminopyrimidine containing phenoxy isobutyric acid
pharmacophore (Fig. 2) with improved antihyperlipidemic
activity.
Hyperlipidemia mainly increases the level of total choles-
terol (TC), triglycerides (TG), very low-density lipoprotein
(VLDL) and low-density lipoprotein (LDL) along with decrease
in high-density lipoprotein (HDL) [2].
We report herein the synthesis of 2-(4-(2-amino-6-(4-substi-
tuted phenyl)-pyrimidin-4-yl)-phenoxy)-2-methyl propanoic
acid under conventional heating and microwave-assisted sol-
vent-free synthesis. The conventional procedures involved a
solvent and heating condition which was not efficient, giving
lower yields and requiring longer period of time for com-
pletion of reaction (24 h). But microwave synthesis could
proceed within 5–7 min with higher yield.
Fibrates (Fig. 1) affect lipid metabolism as agonists of
enzyme peroxisome proliferator activated receptor alpha
Correspondence: Santosh N. Mokale, Dr. Rafiq Zakaria Campus, Y. B.
Chavan College of Pharmacy, Aurangabad, India.
E-mail: santoshmokale@rediffmail.com
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Arch. Pharm. Chem. Life Sci. 2012, 345, 22–27
Microwave Assisted Synthesis of Novel Pharmacophore-Containing Aminopyrimidines
23
Figure 1. Structures of some known fibrates.
Figure 2. General structure of the target compound.
Results and discussion
Chemistry
The final compounds 2-(4-(2-amino-6-(4-substituted phenyl)
pyrimidin-4-yl)-phenoxy)-2-methyl propanoic acid (4a–4f)
were synthesized from the commercially available 1-(4-
hydroxyphenyl) ethanone (1, Scheme 1). 1-(4-Hydroxyphenyl)
ethanone (1) was subjected to nucleophilic substitution
reaction with 2-bromo-2-methyl propanoic acid in alkaline
condition to give 2-(4-acetyl phenoxy)-2-methyl propanoic
acid (2, Scheme 1, Table 1). 2-(4-Acetyl-phenoxy)-2-methyl
propanoic acid (2) was subjected to Claisen-Schmidt reaction
with substituted benzaldehyde in alkaline condition to give
the corresponding substituted chalcones (3a–f, Scheme 1,
Table 1).
2-(4-(2-Amino-6-(4-substituted phenyl) pyrimidin-4-yl) phe-
noxy)-2-methyl propanoic acid compounds (4a–f, Scheme 1,
Table 2) were prepared by cyclocondensation of substituted
chalcones (3a–f) with guanidine HCl salt in alkaline con-
ditions. These derivatives were synthesized by conventional
as well as microwave-assisted methods. The comparison
between the two methods is given in Table 3.
Scheme 1. General synthetic route for the synthesis of the
compounds.
Pharmacological activity
The hypolipidemic and hypoglycemic activities of the syn-
thesized compounds were studied in the high-fat diet-
induced hyperlipidemic rats for 30 days by oral adminis-
tration of the drug and compounds and the lipid profile
was determined using Autoanalyser [14]. The results were
compared with 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, VLDL, LDL and blood sugar when compared
with normal control rats. Moreover, induction of hyper-
lipidemia significantly decreased serum HDL level compared
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S. N. Mokale et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 22–27
Table 1. Experimental data of synthesized compounds 2–3f.
Compound
Melting
point (8C)
Molecular
formula
Molecular
weight
2
102
170
200
180
185
158
175
C12 H14 O4
C19H17ClO4
C19H16Cl2O4
C19H18O5
222.18
345.32
379.21
326.29
326.29
328.34
310.32
3a
3b
3c
3d
3e
3f
C
19H18O5
C19H17FO4
C19H18O4
Figure 3. Structure highlighting important pharmacophores of the
target compound.
to that of normal control rats. The obtained data revealed
that the tested compounds produced variable effects on the
serum levels of TC, TG, VLDL, LDL and HDL as compared with
Group II (positive control).
Structure-activity relationship (Fig. 3)
1.
2.
3.
All fibrates are analogues of phenoxy isobutyric acid
which is very important for hypolipidemic activity. So,
we have used phenoxy isobutyric acid as a pharmacophore
in the present series.
The hyperlipidemia is a complex condition based upon
alteration in concentration of individual components, of
which TC, TG, VLDL, LDL and HDL are most important.
The pathological investigation revealed that compounds
4a and 4e are potential compounds for hyperlipidemia and
cause significant HDL and LDL level modulation.
In case of hypoglycemic activity, high-fat diet fed for
30 days significantly increased sugar level in rats and
compounds have shown significant decrease in blood
sugar level after 7 days treatment. Significant glucose
lowering activity has been shown by compounds 4d, 4e
and 4a.
Literature reveals that use of spacer in between phenoxy
isobutyric acid and lipophilic tail increases the activity. So,
we have used aminopyrimidine heterocycle as spacer
which shows promising activity.
Substitution on aminopyrimidine with 4-substituted phe-
nyl ring (lipophilic tail) influences hypolipidemic activity.
a.
4-Substituted phenyl with electron withdrawing group
showing highest activity. Activity decreases in follow-
ing order (4e > 4a > 4f) F > Cl > H.
b.
Substitution with electron donating group (-OH) on
phenyl ring decreases the hypolipidemic activity (4c, 4d).
Table 2. Experimental data of synthesized compounds 2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-4-yl)-phenoxy)-2-methyl
propanoic acid (4a–4f).
Compound
R
R0
Molecular formula
Molecular weight
Melting point (8C)
4a
4b
4c
4d
4e
4f
-Cl
-Cl
-OH
-H
-F
-H
-H
-Cl
-H
-OH
-H
C20H18ClN3O3
C20H17Cl2N3O3
C20H19N3O4
C20H19N3O4
C20H18FN3O3
C20H19N3O3
383
418
365
365
367
349
280
220
234
240
260
295
-H
Table 3. Comparative data of synthesized compounds (4a–4f) using conventional and microwave assisted synthetic methods.
Compound
Time required
% Yield
Microwave-assisted method
Conventional method
Microwave-assisted method
Conventional method
4a
4b
4c
4d
4e
4f
24 Hrs
24 Hrs
24 Hrs
24 Hrs
24 Hrs
24 Hrs
7 min
7 min
5 min
5 min
5 min
7 min
58
67
49
60
55
65
80
75
70
83
86
89
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Arch. Pharm. Chem. Life Sci. 2012, 345, 22–27
Microwave Assisted Synthesis of Novel Pharmacophore-Containing Aminopyrimidines
25
Conclusion
General procedure for preparation of compounds 3a–3f
Into a 250-mL conical flask were placed 2-(4-acetyl-2-substituted
phenoxy)-2-methyl propanoic acid (0.01 mol), substituted benzal-
dehyde (0.01 mol) in 40 mL of ethanol and 15 mL of 40% sodium
hydroxide solution. Then the reaction mixture was kept aside for
48 h. On the next day crushed ice was added in reaction mixture
and it was acidified by dil. HCl. The crude product obtained was
filtered and recrystallized by ethanol to get the desired product
(3a–f).
Novel 2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-4-yl)
phenoxy)-2-methyl propanoic acid derivatives were synthes-
ized by two method, conventional (solvent phase) and
microwave-assisted (solid phase), and their hypolipidemic
and hypoglycemic activities were screened in the high-fat
diet-induced hyperlipidemic rats for 30 days. The present
investigation showed significant antihyperlipidemic and
antihyperglycemic activity to all compounds of the series
when compared with standard drug. Among the synthesized
compounds 4e was found to be the most active hypolipidemic
agent affording significant effects on the serum levels of
TC, TG, LDL and HDL as compared with Group II (positive
control) and seems to be a good candidate for developing
hypolipidemic agent.
General procedure for preparation of compounds 4a–4f
Method A: Solvent phase synthesis (conventional method)
The reaction mixture of 2-(4-(3-(4-substituted phenyl)-3-oxoprop-
1-enyl)-phenoxy)-2-methyl propanoic acid (0.01 mol), guanidine
hydrochloride (0.03 mol), sodium hydroxide (0.02 mol) and
30 mL of ethanol was refluxed for 12 h in a water bath. The
reaction was monitored on TLC and heating was continued till
single spot. The reaction mixture was poured in 50 mL of 10%
cold hydrochloric acid solution, the precipitate was filtered
washed with water until free from acid, dried and recrystallized
from methanol to get desired product (4a–f).
On the other hand compounds from the series also showed
capacity to lower the plasma glucose level associated with
hyperlipidemia.
Hence the present series could be developed as a novel class
of antihyperlipidemic and antihyperglycemic agents. However,
further structural modification is planned to increase the
antihyperlipidemic and antihyperglycemic activities.
Method B: Solid phase synthesis (microwave method)
Mixture of chalcone (0.01 mol), guanidine HCl (0.01 mol) and
NaOH pellets (0.5 mol) was finely powdered by pestle-mortar.
This reaction mixture was irradiated at 320 W for 5–7 min in
oven. The reaction was monitored on TLC and heating was
continued till single spot. Distilled water was added to remove
excess alkali, filtered, dried. The derivatives were recrystallized
from ethanol to get desired product (4a–f).
Experimental
General
The compounds were synthesized by conventional (solvent
phase) and microwave-assisted (solid phase) methods using
Catalyst Systems Cata Scientific Microwave. Melting points of
the synthesized compounds were determined on scientific melt-
ing 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 a time of
flight mass spectrometer.
2-(4-(2-Amino-6-(4-chlorophenyl) pyrimidin-4-yl)
phenoxy)-2-methylpropanoic acid (4a)
IR (KBr): 3558, 3514, 3034, 2983, 1726, 1658, 1596, 1806, 1394,
1281, 1048, 1105, 944, 584 cmꢀ1
;
1H NMR (400 MHz, DMSO): d ¼ 11 (s, 1H), 8.56 (s, 2H), 7.06–7.96
(m, 9H), 1.5 (s, 6H); MS (TOF, 1.99 e4): m/z ¼ 383;
C20H18 Cl N3 O3 (383); requires (Found): C, 62.58 (62.48); H, 4.73
(4.6); N, 10.95 (10.84).
The total lipid profile and blood sugar level was determined by
Autoanalyser using cholesterol, triglycerides, HDL and glucose
assay kit (Agappe Diagnostics).
2-(4-(2-Amino-6-(2,4-dichlorophenyl) pyrimidin-4-yl)
phenoxy)-2-methylpropanoic acid (4b)
IR (KBr): 3548, 3511, 3044, 2973, 1736, 1648, 1576, 1390, 1271,
Chemistry
Synthesis of 2-(4-acetyl phenoxy)-2-methyl propanoic
acid 2
1038, 1115, 954, 587 cmꢀ1
;
1H NMR (400 MHz, DMSO): d ¼ 11.1 (s, 1H), 6.88 (s, 2H),
7.05–8.03 (m, 8H), 1.53 (s, 6H); MS (TOF, 1.99 e4): m/z ¼ 417;
C20H17Cl2N3O3 (418); requires (Found): C, 57.43 (57.41); H, 4.10
(4.08); N, 10.05 (10.00).
In 500 ml of RBF provided with reflux condenser were placed
4-hydroxy acetophenone (0.01 mol), 2-bromo-2-methyl propa-
noic acid (0.01 mol) in 25 mL of distilled ethanol and K2CO3
(0.03 mol). Then the resultant solution was refluxed in a
water bath. After 1 h, pH of the solution was dropped to 7,
and further 1 g of K2CO3 was added. Refluxing was continued
for 12 h. The hot solution was acidified with conc. HCl.
The product was extracted with diethyl ether. Ethereal layer
was washed with 50 mL of saturated solution of sodium
bicarbonate. The aqueous layer was acidified with dil. HCl.
White colored solid was filtered off, washed with water,
dried and recrystallized by hot water to get the desired com-
pounds 2.
2-(4-(2-Amino-6-(4-hydroxyphenyl) pyrimidin-4-yl)
phenoxy)-2-methylpropanoic acid (4c)
IR (KBr): 3663, 3544, 3488, 2815, 1716, 1683, 1685, 1636, 1413,
1278, 1253, 925 cmꢀ1;
1H NMR (400 MHz, DMSO): d ¼ 10.9 (s, 1H), 6.98 (s, 2H),
6.07–8.08 (m, 9H), 5.35 (s, 1H), 1.58 (s, 6H);
MS (TOF, 1.99 e4): m/z ¼ 365;
C20H19N3O4 (365); requires (Found): C, 65.73 (65.61); H, 5.24
(5.18); N, 11.50 (11.35).
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S. N. Mokale et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 22–27
Table 4. Data of total lipid profile (CH, TG, LDL, VLDL and HDL).
Compound
Parameter in mg/dL
VLDL
CH
TG
LDL
HDL
Normal control
Positive control
Fenofibrate
4a
4b
4c
4d
4e
4f
72.17 ꢁ 0.601
121.5 ꢁ 1.335a
105.2 ꢁ 1.939a
93.17 ꢁ 1.537a
103.3 ꢁ 2.186a
107.3 ꢁ 1.687a
113 ꢁ 1.054d
75.17 ꢁ 0.601
135 ꢁ 1.592a
73.17 ꢁ 0.945a
77.67 ꢁ 1.647a
82.5 ꢁ 0.7638a
76.67 ꢁ 0.882a
77.5 ꢁ 1.784a
76.33 ꢁ 1.856a
78.17 ꢁ 2.358a
15.03 ꢁ 0.120
27 ꢁ 0.3183a
14.67 ꢁ 0.261a
15.53 ꢁ 0.329a
16.5 ꢁ 0.152a
15.33 ꢁ 0.176a
15.5 ꢁ 0.356a
15.27 ꢁ 0.371a
15.87 ꢁ 0.548a
23.13 ꢁ 1.179
75.5 ꢁ 1.24a
55.33 ꢁ 2.90a
45.15 ꢁ 0.70a
55.25 ꢁ 1.48a
58.42 ꢁ 2.33a
53.07 ꢁ 1.98a
45.48 ꢁ 2.56a
59.98 ꢁ 2.28 a
34.5 ꢁ 0.7638
19 ꢁ 0.5774a
33.5 ꢁ 0.7638a
33.5 ꢁ 0.7638a
33 ꢁ 1.065a
32.67 ꢁ 0.8819a
32.5 ꢁ 0.7638a
33.83 ꢁ 0.9458a
32.83 ꢁ 0.6009a
93.33 ꢁ 1.783a
109.5 ꢁ 1.478a
a) Test compound ¼ 250 mg/kg
b) Reference standard, fenofibrate ¼ 250 mg/kg
c) The results are expressed as mean ꢁ SEM. The data is analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s test.
a
b
c
d
(n ¼ 6), P <0.001, P <0.01, P <0.05, non significant.
Table 5. Data of blood sugar level.
2-(4-(2-Amino-6-(2-hydroxyphenyl) pyrimidin-4-yl)
phenoxy)-2-methylpropanoic acid (4d)
IR (KBr): 3654, 3564, 3478, 2839, 1700, 1687, 1672, 1656, 1423,
Compound
Blood sugar (mg/dL)
1280, 1263, 923 cmꢀ1
;
Normal control
Positive control
Fenofibrate
4a
4b
4c
4d
4e
4f
57.83 ꢁ 0.6009
106.3 ꢁ 0.6666 a
70.5 ꢁ 0.7638 a
70.17 ꢁ 0.601 a
72.67 ꢁ 0.882 a
71.67 ꢁ 1.542 a
66.67 ꢁ 1.282 a
68 ꢁ 0.574 a
1H NMR (400 MHz, DMSO): d ¼ 11.2 (s, 1H), 6.99 (s, 2H),
6.9–8.18 (m, 9H), 5.4 (s, 1H), 1.54 (s, 6H); MS (TOF, 1.99 e4):
m/z ¼ 365;
C20H19N3O4 (365); requires (Found): C, 65.73 (65.66); H, 5.24
(5.20); N, 11.50 (11.45).
2-(4-(2-Amino-6-(4-fluorophenyl) pyrimidin-4-yl) phenoxy)-
2-methylpropanoic acid (4e)
IR (KBr): 3570, 3512, 3034, 2981, 1716, 1681, 1596, 1634, 1450,
71.17 ꢁ 2.088 a
a) Test compound ¼ 250 mg/kg
1299, 1230, 1088, 1108 cmꢀ1
;
b) Reference standard, fenofibrate ¼ 250 mg/kg
1H NMR (400 MHz, DMSO): d ¼ 11.1 (s, 1H), 6.96 (s, 2H),
7.06–8.15 (m, 9H), 1.52 (s, 6H); MS (TOF, 1.99 e4): m/z ¼ 367;
C20H18FN3O3 (367); requires (Found): C, 65.39 (65.26); H, 4.94
(4.88); N, 11.44 (11.35).
c) The results are expressed as mean ꢁ SEM. The data is analyzed
using one-way analysis of variance (ANOVA) followed by Tukey’s
a
b
c
d
test. (n ¼ 6), P <0.001, P <0.01, P <0.05, non significant.
2-(4-(2-Amino-6-phenyl pyrimidin-4-yl) phenoxy)-2-
methylpropanoic acid (4f)
IR (KBr): 3575, 3458, 3022, 1907, 1719, 1658, 1612, 1398, 1332,
The authors are grateful to the Mrs. Fatima Rafiq Zakaria Chairman,
Maulana Azad Educational Trust and Principal, Y. B. Chavan college of
Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad -431001(MS), India for
providing the laboratory facility.
1243, 939 cmꢀ1
;
1H NMR (400 MHz, DMSO): d ¼ 11.01 (s, 1H), 8.67 (s, 2H),
7.2–8.0 (m, 10H), 1.53 (s, 6H); MS (TOF, 1.99 e4): m/z ¼ 349;
C20H19N3O3 (349); requires (Found): C, 68.75 (68.66); H, 5.48
(5.38); N, 12.03 (11.99).
The authors have declared no conflict of interest.
Pharmacological activity
Male Sprague Dawley rats (120–150g) were divided into 9 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. 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 respect-
ively. On 31st day, 2 mL blood was withdrawn by retroorbital
method and total lipid profile was determined by standared
method (Table 4). Along with lipid profile blood sugar level
was also determined (Table 5).
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27
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