Synthesis and Hypolipidemic Activity of Novel 2-(4-(2-Amino-6-(4-Substituted Phenyl) Pyrimidin-4-yl)-2-Substituted Phenoxy) Acetic Acid Derivatives

Article abstract of DOI:10.1111/j.1747-0285.2012.01319.x

A novel series of 2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-4-yl)-2-substituted phenoxy) acetic acid derivatives were efficiently synthesized. The synthesized compounds were evaluated for their in vivo hypolipidemic activity, using high-fat-diet-induced hyperlipidemia in rats. Some of these compounds showed significant antihyperlipidemic activity.

Full text of DOI:10.1111/j.1747-0285.2012.01319.x

ª 2012 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2012.01319.x
Chem Biol Drug Des 2012; 79: 548–552
Research Article
Synthesis and Hypolipidemic Activity of Novel 2-
(4-(2-Amino-6-(4-Substituted Phenyl) Pyrimidin-4-
yl)-2-Substituted Phenoxy) Acetic Acid
Derivatives
Santosh N. Mokale1,*, Maheshwari T.
(10), indole (11), benzothiophene (12), benzisoxazole (13), and
oxadiazole (14), which exhibited potent antihyperlipidemic activity.
Shete1, Sameer I. Shaikh1 and
Devanand B. Shinde2
From the literature survey, it is observed that no efforts have been
made for developments of a molecular scaffold containing these
1Department of Pharmaceutical Chemistry, Dr Rafiq Zakaria Campus,
two important cores, that is, 2-amino-pyrimidin ring and phenoxy
acetic acid group. In view of this, we have attempted the synthesis
of novel series of 2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-4-
yl)-2-substituted phenoxy) acetic acids (Figure 1) for possible antihy-
perlipidemic activity.
Y. B. Chavan College of Pharmacy, Aurangabad, Maharashtra, India
2Department of Chemical Technology, Dr Babasaheb Ambedkar
Marathwada University, Aurangabad 431001, Maharashtra, India
*Corresponding author: Santosh N. Mokale,
santoshmokale@rediffmail.com
A
novel series of 2-(4-(2-amino-6-(4-substituted
phenyl) pyrimidin-4-yl)-2-substituted phenoxy) ace-
tic acid derivatives were efficiently synthesized.
The synthesized compounds were evaluated for
their in vivo hypolipidemic activity, using high-fat-
diet-induced hyperlipidemia in rats. Some of these
compounds showed significant antihyperlipidemic
activity.
Experimental
Physical measurement
Melting points were determined on scientific melting point appara-
tus in open capillaries and reported uncorrected. H NMR spectra
were recorded on
1
a BRUKER AVANCE II 400 spectrometer
(400 MHz) with TMS as internal standard and DMSO as a solvent.
Mass spectra were recorded on Waters Micro-mass Q-TOF Micro.
FT-IR spectra were recorded on JASCO FT-IR 4000 using KBr pow-
der. Elemental analysis was conducted on Perkin Elmer (San Jose,
CA, USA) Elemental Analyzer [2400 (CHN) Elemental Analyzer].
Key words: acetic acid, antihyperlipidemic, high-fat diet, phenoxy
acetic acid, pyrimidine
Received 10 February 2011, revised 30 September 2011 and accepted
for publication 24 December 2011
Cardiovascular diseases (CVD) are the leading cause of death and
disability for both men and women worldwide. The relationship
between CVD and disorders of cholesterol metabolism is well
established (1). CVD are caused by narrowing of artery that supplies
nutrients and oxygen to the heart. The main reason for this narrow-
ing of artery is atherosclerosis. Atherogenic dyslipidemia is charac-
terized by an abnormal circulating lipid profile including low level of
high-density lipoprotein (HDL), elevated level of low-density lipopro-
tein (LDL), and elevated triglycerides (TG) often found in patient
who are obese and having type 2 diabetes or the metabolic syn-
drome.
Synthesis of 2-(4-formyl-2-substituted phenoxy)
acetic acid (2a–b)
Into 250 mL of RBF 4-hydroxy benzaldehyde or 4-hydroxy-3-methoxy
benzaldehyde (1a or 1b, 0.21 mol), sodium hydroxide (0.44 mol),
monochloroacetic acid (0.24 mol), and 150 mL of distilled water
Fibrates in dyslipidemic patients improve the plasma lipid profile by
lowering TG and LDL levels and by increasing HDL level (2,3).
It was observed that phenoxy acetic acid pharmacophore has been
frequently used in the synthesis of hypolipidemic agent (4–6). Phen-
oxy acetic acid moiety was frequently coupled with heterocyclic
nucleus such as pyrimidine (7), piperidine (8), pyridine (9), oxazole
Figure 1: General structure of 2-(4-(2-amino-6-(4-substituted
phenyl) pyrimidin-4-yl)-2-substituted phenoxy) acetic acids.
548

Synthesis and Hypolipidemic Activity
were added. The resultant solution was refluxed in oil bath. After
1 h of refluxing, pH of the solution was dropped to 7, and further
1 g of sodium hydroxide was added. After 2 h refluxing, another
1 g of sodium hydroxide was added. Refluxing was continued for
an additional 2 h. The hot solution was acidified with conc. HCl
and crystallization took place on cooling. The solid was filtered off,
washed with water, dried, and recrystallized by hot water to get
the desired compounds (2a–b).
1H), 4.7 (s, 2H): MS (TOF, 1.99 e4): m ⁄ z = 338 [M+H]+; C18H15N3O4
(337); requires (Found): C, 64.09 (64.0) H, 4.48 (4.38); N, 12.46
(12.44).
2-(4-(2-amino-6-(4-chlorophenyl) pyrimidin-4-yl)-
2-methoxyphenoxy) acetic acid (4d)
Yield: 59.582%; mp: 147 ꢀC; IR (KBr): 3578, 3504, 3025, 1724, 1680,
1636, 1633, 1398, 1318, 1242, 924, 580 ⁄ cm; 1H NMR (400 MHz,
DMSO): d = 10.4 (s, 1H), 8–7.9 (m, 3H), 7.2–7.6 (m, 5H), 5.7 (s, 2H),
4.7 (s, 2H), 3.2 (s, 3H): MS (TOF, 1.99 e4): m ⁄ z = 386 [M+H]+;
C19H16ClN3O4 (385); requires (Found): C, 59.15 (59.05) H, 4.18 (4.08);
N, 10.89 (10.74).
2-(4-(3-(4-substitutedphenyl)-3-oxoprop-1-enyl)-
2-substituted phenoxy) acetic acid (3a–j)
Into a 250-mL conical flask, 2-(4-formyl-2-substituted phenoxy) ace-
tic acid (0.01 mol) (2a–b), substituted acetophenone (0.01 mol) in
40 mL of ethanol, and 15 mL of 40% sodium hydroxide were added
successively. Then, the reaction mixture was kept aside for 48 h.
Then, the reaction mixture was poured into crushed ice and acidi-
fied by diluted HCl. The crude product obtained was filtered and re-
crystallized by ethanol to get desired product (3a–j).
2-(4-(2-amino-6-(4-methoxyphenyl) pyrimidin-4-
yl)-2-methoxyphenoxy) acetic acid (4e)
Yield: 52.2%; mp: 155 ꢀC; IR (KBr): 3578, 3504, 3007, 3025, 1724,
1
1680, 1636, 1633, 1398, 1318, 1242, 924 ⁄ cm; H NMR (400 MHz,
DMSO): d = 10.2 (s, 1H), 8–7.9 (m, 3H), 7.2–7.6 (m, 5H),, 5.6 (s, 2
H), 4.4 (s, 2H), 3.2 (s, 6H): MS (TOF, 1.99 e4): m ⁄ z = 382 [M+H]+;
C20H19N3O5 (381); requires (Found): C, 62.99 (62.95) H, 5.02 (4.98);
N, 11.02 (10.97).
2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-
4-yl)-2-substituted phenoxy) acetic acid (4a–j)
Into 250 mL of RBF 2-(4-(3-(4-substituted phenyl)-3-oxoprop-1-enyl)-
2-substituted phenoxy) acetic acid (3a–j) (0.01 mol), guanidine HCl
(0.03 mol) and sodium hydroxide (0.02 mol) in 30 mL of ethanol
was refluxed for 12 h in water bath. The reaction was monitored
on TLC, and heating was continued until the starting materials were
consumed. The reaction mixture was poured into 50 mL of 10%
cold hydrochloric acid solution, and the resultant precipitate was fil-
tered, washed with water until free from acid, dried, and recrystal-
lized from methanol to get desired product (4a–j).
2-(4-(2-amino-6-(4-hydroxyphenyl) pyrimidin-4-
yl)-2-methoxyphenoxy) acetic acid (4f)
Yield: 51.49%; mp: 132 ꢀC; IR (KBr): 3663, 3580, 3506, 3007, 2823,
1720, 1681, 1668, 1600, 1433, 1309, 1252, 924 ⁄ cm; 1H NMR
(400 MHz, DMSO): d = 10.1 (s, 1H), 8–7.9 (m, 3H), 7.2–7.6 (m, 5H),
6.7 (s, 2H), 5.6 (s, 1H), 4.7 (s, 2H), 3.2 (s, 3H). MS (TOF, 1.99 e4):
m ⁄ z = 368 [M+H]+; C19H17N3O5 (367); requires (Found): C, 62.12
(62.05) H, 4.66 (4.58); N, 11.44 (11.37).
2-(4-(2-amino-6-(4-chlorophenyl) pyrimidin-4-yl)
phenoxy) acetic acid (4a)
2-(4-(2-amino-6-phenylpyrimidin-4-yl) phenoxy)
acetic acid (4g)
Yield: 61.42%; mp: 180 ꢀC; IR (KBr): 3554, 3490, 2829, 1706, 1693,
1682, 1646, 1433, 1288, 1273, 915, 585 ⁄ cm; 1H NMR (400 MHz,
DMSO): d = 10.2 (s, 1H), 8–7.9 (m, 3H), 7.2–7.6 (m, 6H), 5.7 (s, 2H),
4.5 (s, 2H): MS (TOF, 1.99 e4): m ⁄ z = 356 [M+H]+; C18H14ClN3O3 (355);
requires (Found): C, 60.77 (60.68); H, 3.97 (3.85); N, 11.81 (11.74).
Yield: 51.12%; mp: 142 ꢀC; IR (KBr): 3575, 3458, 3022, 1907, 1719,
1
1658, 1612, 1398, 1332, 1243, 939 ⁄ cm; H NMR (400 MHz, DMSO):
d = 10.0 (s, 1H), 8–7.9 (m, 3H), 7.2–7.6 (m, 7H),5.8 (s, 2 H), 4.6 (s,
2H): MS (TOF, 1.99 e4): m ⁄ z = 322 [M+H]+; C18H15N3O3 (321);
requires (Found): C, 67.28 (62.15) H, 4.71 (4.68); N, 13.08 (13.01).
2-(4-(2-amino-6-(4-methoxyphenyl) pyrimidin-4-
yl) phenoxy) acetic acid (4b)
2-(4-(2-amino-6-(4-fluorophenyl) pyrimidin-4-yl)
phenoxy) acetic acid (4h)
Yield: 61.42%; mp: 180 ꢀC; IR (KBr): 3554, 3490, 3007, 2829, 1706,
1
1693, 1682, 1646, 1433, 1288, 1273, 915 ⁄ cm; H NMR (400 MHz,
Yield: 47.5 %; mp: 135 ꢀC; IR (KBr): 3663, 3580, 3506, 2823, 1720,
1681, 1668, 1600, 1433, 1309, 1252, 1105, 924 ⁄ cm; 61H NMR
(400 MHz, DMSO): d = 10.4 (s, 1H), 8–7.9 (m, 3H), 7.2–7.6 (m, 5H),
5.8 (s, 2H), 4.3 (s, 2h): MS (TOF, 1.99 e4): m ⁄ z = 340 [M+H]+;
C18H14FN3O3 (339); requires (Found): C, 63.71 (63.65) H, 4.16 (4.08);
N, 12.38 (12.31).
DMSO): d = 10.3 (s, 1H), 8–7.9 (m, 3H), 7.2–7.6 (m, 6H), 5.7 (s, 2H),
4.7 (s, 2H), 3.2 (s, 3H): MS (TOF, 1.99 e4): m ⁄ z = 352 [M+H]+;
C19H17N3O4 (351); requires (Found): C, 64.95 (64.88); H, 4.88 (4.80);
N, 11.96 (11.84).
2-(4-(2-amino-6-(4-hydroxyphenyl) pyrimidin-4-
yl) phenoxy) acetic acid (4c)
2-(4-(2-amino-6-phenylpyrimidin-4-yl)-2-
methoxyphenoxy) acetic acid (4i)
Yield: 64.89%; mp: 134 ꢀC; IR (KBr): 3554, 3490, 2829, 1706, 1693,
1
1682, 1646, 1433, 1288, 1273, 915 ⁄ cm; H NMR (400 MHz, DMSO):
Yield: 51.42%; mp: 148 ꢀC; IR (KBr): 3578, 3504, 3025, 3012, 1724,
1
d = 10.1 (s, 1H), 8–7.9 (m, 3H), 7.2–7.6 (m, 6H), 6.7 (s, 2H), 5.6 (s,
Chem Biol Drug Des 2012; 79: 548–552
1680, 1636, 1633, 1398, 1318, 1242, 924 ⁄ cm; H NMR (400 MHz,
549

Mokale et al.
DMSO):d = 10.5 (s, 1H), 8–7.9 (m, 3H), 7.2–7.6 (m, 6H), 5.8 (s, 2H),
4.6 (s, 2H), 3.2 (s, 3H): MS (TOF, 1.99 e4): m ⁄ z = 352 [M+H]+;
C19H17N3O4 (351); requires (Found): C, 64.95 (64.85) H, 4.88 (4.78);
N, 11.96 (11.91).
Autoanalyser (Micro lab 200, Merck, Germany) and Agappe diagnos-
tics kits (Agappe Diagnostics Ltd, Kerala, India) (15–17).
Results and Discussion
2-(4-(2-amino-6-(4-fluorophenyl) pyrimidin-4-yl)-
2-methoxyphenoxy) acetic acid (4j)
Chemistry
The target compounds 2-(4-(2-amino-6-(4-substituted phenyl)
pyrimidin-4-yl)-2-substituted phenoxy) acetic acid derivatives were
synthesized from the commercially available 4-hydroxy benzaldehyde
or 4-hydroxy-3-substituted benzaldehyde (1a or 1b, Scheme 1).
4-hydroxy benzaldehyde or 4-hydroxy-3-substituted benzaldehyde (1a
or 1b) was subjected to nucleophilic substitution reaction with mono-
chloroacetic acid in alkaline condition to give 2-(4-formyl-2-substi-
tuted phenoxy) acetic acids (2a–b, Table 1). 2-(4-formyl-2-substituted
phenoxy) acetic acids were subjected to Claisen–Schmidt reaction
with substituted acetophenone in alkaline condition to give the corre-
sponding substituted chalcones (3a–j, Table 1).
Yield: 48.64%; mp: 115 ꢀC; IR (KBr): 3578, 3504, 3025, 3009, 1724,
1680, 1636, 1633, 1398, 1318, 1242, 1115, 924 ⁄ cm; 1H NMR
(400 MHz, DMSO):d = 10.4 (s, 1H), 8–7.9 (m, 3H), 7.2–7.6 (m, 5H),
5.5 (s, 2H), 4.5 (s, 2H), 3.2 (s, 3H): MS (TOF, 1.99 e4): m ⁄ z = 370
[M+H]+; C19H16FN3O4 (369); requires (Found): C, 61.79 (61.75) H,
4.37 (4.28); N, 11.38 (11.31).
In vivo hypolipidemic activity
Sprague–Dawley rats (120–150 g) of either sex were divided into
13 groups of five animals each and 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 also made available
for 23 days to groups III–XIII. The test compounds 4a–j (50 mg ⁄ kg)
and standard drug Fenofibrate (250 mg ⁄ kg) was administered for
last 7 days, respectively. Standard drug and test compounds were
prepared as aqueous suspension in carboxy methyl cellulose (CMC)
and administered orally. On 31st day, 2 mL of blood was withdrawn
by retro-orbital method, and total lipid profile was determined using
The target compounds 2-(4-(2-amino-6-(4-substituted phenyl) pyrimi-
din-4-yl)-2-substituted phenoxy) acetic acids (4a–j) were prepared
by cyclocondensation of substituted chalcones (3a–j) with guani-
dine HCl salt in alkaline conditions.
In vivo hypolipidemic activity
The in vivo hypolipidemic activity results revealed that feeding rats
with high-fat diet for 30 days significantly elevated the serum level
Scheme 1: Synthetic scheme
for the present series.
550
Chem Biol Drug Des 2012; 79: 548–552

Synthesis and Hypolipidemic Activity
Table 1: Experimental data of synthesized compounds 2a–3j
Molecular
formula
Molecular
weight
Melting
point ꢀC
Percentage
yield
Compound
2a
2b
3a
3b
3c
3d
3e
3f
C9H8O4
180.16
210.18
316.74
312.32
298.29
346.76
342.34
328.32
282.29
300.28
330.31
312.32
202–204
185–187
280–282
240–242
220–222
245–247
213–215
228–230
210–212
218–220
208–210
232–234
44.21
41.7
C10H10O5
C17H13ClO4
C18H16O5
C17H14O5
C18H15ClO5
C19H18O6
C18H16O6
C17H14O4
C17H13FO4
C18H16O5
C18H15FO5
79.11
76.92
68.96
73.23
79.41
68.75
75.0
70.23
73.71
71.87
Figure 2: Effects of pharmacophore on hypolipidemic activity.
3g
3h
3i
• Substitution on phenoxy acetic acid (ring A) has influence on the
hypolipidemic activity.
3j
• Unsubstituted phenoxy acetic acid (R-H) showed maximum hyp-
olipidemic activity (4a, 4b, 4c, 4g, and 4h).
of total cholesterol (CH), TG and 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 vari-
able effects on the serum levels of CH, TG, LDL and HDL when
compared with group II (positive control) (Table 2). Among the syn-
thesized compounds, 4c, 4h, 4f, and 4b were found to be the
most active hypolipidemic agents.
• Substituted phenoxy acetic acid (R-OCH3) showed lesser hypo-
lipidemic activity (4i, 4d, 4j, 4f, and 4e).
• Substitution of amino-pyrimidin (ring C) influences hypolipidemic
activity.
• 4-substituted phenyl ring with electron-withdrawing group
showed highest activity. (4a, 4d, 4h, and 4j)
• Substitution with (-OH) on phenyl ring retains the activity (4c
and 4f), but further substitution on it leads to decrease in the
activity (4b and 4e).
Structure–activity relationship (Figure 2)
• We have used phenoxy acetic acid (ring A) as a pharmacophore
in present series.
Conclusion
• Literature reveals that the use of spacer in between phenoxy
acid and lipophilic tail increases the activity (18). So, we have
used 2-amino-pyrimidin heterocycle (ring B) as spacer and lipo-
philic tail (ring C), which show promising activity.
Novel 2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-4-yl)-2-substi-
tuted phenoxy) acetic acid derivatives were prepared and structur-
ally characterized using spectroscopic techniques and their in vivo
Table 2: Data of total lipid profile (CH, TG, LDL, HDL, and VLDL)
Parameter in mg ⁄ dL
Compound
CH
TG
LDL
VLDL
HDL
Normal control
72.6 € 1.36
75.6 € 2.06
32.6 € 1.28
15.2 € 0.86
33.6 € 1.50
Positive control
Fenofibrate
128.8 € 3.37***
83.2 € 1.46***
105 € 1.30**
120.8 € 1.06NS
86.8 € 2.13**
96.6 € 1.56**
121.6 € 1.72NS
110 € 1.0**
142.4 € 1.53***
91.6 € 2.31***
120.4 € 2.01**
125.6 € 1.72**
118.4 € 1.20**
140.2 € 1.15NS
131.6 € 1.07*
122.6 € 1.36**
140 € 1.37NS
51.8 € 2.03**
37.2 € 1.15**
33.3 € 1.50**
49.0 € 1.51NS
25.2 € 1.15***
27.8 € 0.86**
53.6 € 1.80NS
44.8 € 1.65*
50.2 € 1.15NS
47.2 € 0.86NS
38.8 € 1.20**
43 € 0.89*
26.2 € 1.20**
17.4 € 1.03**
24 € 0.89NS
23.4 € 1.20NS
24.6 € 0.92NS
26 € 0.7NS
18.6 € 1.36***
28.4 € 1.43**
27.4 € 0.92***
29.4 € 0.92**
37.2 € 1.49**
25.8 € 1.49**
20.2 € 1.28NS
29.6 € 1.70**
21.2 € 1.59NS
34.2 € 0.86**
19.4 € 0.87NS
24.2 € 1.15**
4a
4b
4c
4d
4e
4f
29.4 € 1.5NS
23.8 € 1.06NS
25.4 € 1.2NS
20.6 € 1.36**
25.6 € 1.20NS
20.6 € 0.92**
4g
4h
4i
125.4 € 1.96NS
102 € 2.29**
119.6 € 2.29NS
118.4 € 1.43*
110.2 € 1.65**
135.68 € 1.63*
131 € 1.64*
4j
Dose of fenofibrate 250 mg ⁄ kg and test compound (4a–j) 50 mg ⁄ kg. Positive control (PC) was compared with control. Drug treated compared with PC. The
results are expressed as mean € SEM. The data were analyzed using one-way analysis of variance (ANOVA) followed by Dunnett's Test. n = 5 rats per group;
***p < 0.001, **p < 0.01, *p < 0.05; NS, non significant.
Chem Biol Drug Des 2012; 79: 548–552
551

Mokale et al.
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4c, 4h, 4f, and 4b were found to be the most active hypolipidem-
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LDL, and HDL as compared with group II (positive control).
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Maulana Azad Educational Trust, and Principal, Y.B. Chavan College
of Pharmacy, Dr Rafiq Zakaria Campus, Aurangabad, 431 001 (M.S.),
India, for providing the laboratory facility.
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