3-Aryl-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy]-phenyl}-acrylic acid alkyl ester: Synthesis and antihyperglycemic evaluation

Article abstract of DOI:10.1007/s00044-010-9369-3

A number of 2,4-thiazolidinedione derivatives of aryl-substituted cinnamic acid were synthesized and studied for their antihyperglycemic activity in neonatal streptozotocin- induced diabeticWistermale rats. Substitution of the aryl ring resulted in higher activity. 3-(2,4-Dimethoxyphenyl)- 2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy]-phenyl}- acrylic acid methyl ester (Thz7), was found to be most active compound in this series which showed that disubstitutions on aryl ring by electron releasing groups were found suitable for promising antihyperglycemic activity. Increase in the ester carbon chain length decreased the activity.

Full text of DOI:10.1007/s00044-010-9369-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:678–686
DOI 10.1007/s00044-010-9369-3
ORIGINAL RESEARCH
3-Aryl-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy]-phenyl}-
acrylic acid alkyl ester: synthesis and antihyperglycemic
evaluation
•
Ashwani Kumar Amit Chawla Sandeep Jain
•
•
•
Parvin Kumar Sunil Kumar
Received: 16 December 2009 / Accepted: 5 May 2010 / Published online: 5 June 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A number of 2,4-thiazolidinedione derivatives of
aryl-substituted cinnamic acid were synthesized and studied
for their antihyperglycemic activity in neonatal streptozoto-
cin-induced diabetic Wister male rats. Substitution of the aryl
ring resulted in higher activity. 3-(2,4-Dimethoxyphenyl)-
2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy]-phenyl}-
acrylic acid methyl ester (Thz7), was found to be most active
compound in this series which showed that disubstitutions on
aryl ring by electron releasing groups were found suitable for
promising antihyperglycemic activity. Increase in the ester
carbon chain length decreased the activity.
complications include vision damage due to retinopathy,
renal failure due to nephropathy, loss of sensation or pain
due to neuropathy-accelerated atherosclerosis, and pre-
mature cardiovascular mortality (Susman and Helseth,
1997).
Type 2 diabetes is usually first treated by attempts to
change physical activity (generally an increase is desired),
the diet (generally to decrease carbohydrate intake) and
weight loss (Luna and Mark, 2001). The usual next step, if
necessary, is treatment with oral antidiabetic drugs (John
et al., 2003; Hardman et al., 2007). There are different
classes of anti-diabetic drugs, and their selection depends
on the nature of the diabetes, age and situation of the
person, as well as other factors. Currently available thera-
pies for type 2 diabetes include insulin and various oral
agents: sulfonylureas; alpha-glucosidase inhibitors, such as
acarbose; biguanides; thiazolidinediones like troglitazone,
rosiglitazone, and pioglitazone (Berger et al., 1996), which
act by improving peripheral insulin sensitivity. Repaglinide
is a recently launched non-sulfonylurea insulin secreta-
gogue that works via a similar mechanism to sulfonylurea
drugs (Zhang and Moller, 2000). When oral medications
fail, insulin therapy will be necessary to maintain normal or
near normal glucose levels (Liu et al., 2001).
Keywords 2,4-Thiazolidinedione Á PPARc Á
Antihyperglycemic activity Á Neonatal streptozotocin-
induced diabetic rats
Introduction
Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder
characterized by hyperglycemia and/or insulin resistance. It
is one of the most chronic metabolic disorders associated
with co-morbidities, such as obesity, hypertension, hyper-
lipidemia, and cardiovascular disease, which taken toge-
ther, constitute the ‘‘metabolic syndrome’’ (Staels and
Fruchart, 2005; Bjork et al., 2003). T2DM chronic
However, current therapies to reduce plasma glucose
levels have inherent problems, including poor compliance,
ineffectiveness, and occurrence of hypoglycemic episodes
with insulin and the sulfonylureas (Hara et al., 2006).
Therefore, there is a need for more effective, orally active
agents, particularly Thiazolidinediones (TZDs) that nor-
malize both glucose and insulin levels (Adisakwattana
et al., 2005). Thiazolidinedione (TZD) also known as
‘‘glitazone’’, are a unique new class of oral antidiabetic
agents that exert direct effects on the mechanism of insulin
resistance (Imoto et al., 2002). Chemically, the members of
A. Kumar (&) Á A. Chawla Á S. Jain Á S. Kumar
Drug Discovery and Research Laboratory, Department
of Pharmaceutical Sciences, Guru Jambheshwar University
of Science and Technology, Hisar 125 001, India
e-mail: ashwanijangra@ymail.com
P. Kumar
Department of Chemistry, Guru Nanak Khalsa College,
Yamunanagar 135 001, India
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Med Chem Res (2011) 20:678–686
679
Thiazolidinediones do not stimulate the secretion of
insulin but rather enhance the effects of circulating insulin
by improving insulin sensitivity in muscle and adipose
tissue and by inhibiting hepatic gluconeogenesis. Thiazo-
lidinediones (TZDs) work by stimulating certain peroxi-
some proliferator-activated receptor c (PPARc) in the
nucleus of the cells (Koyama et al., 2003). Peroxisome
proliferator-activated receptors (PPARs) are ligand-acti-
vated transcription factors that belong to the nuclear hor-
mone receptor superfamily. The normal ligands for these
receptors are free fatty acids (FFAs) and eicosanoids.
Thiazolidinedione activate transcription by binding to the
PPARc i.e. also a transcription factor and, when activated,
binds to another transcription factor known as the retinoid
X receptor (RXR) (Brooks et al., 2001). The PPAR/RXR
complex can be activated by ligands of either receptors and
the simultaneous binding of both ligands is more efficient.
When these two proteins are complexed, a specific set of
genes becomes activated and this active form of the
receptor then binds to the PPRE and initiate transcription of
insulin sensitive genes (Mannucci et al., 2008). Activation
of insulin-responsive genes enhances the production of
mRNAs of insulin dependent enzymes that regulate car-
bohydrate and lipid metabolism (Feige et al., 2006).
Fig. 1 Structures of some glitazones
Chemistry
A general strategy for the synthesis of thiazolidine-2,4-
diones is shown in Scheme 1. Perkin condensation (Lee
et al., 2005) of aryl aldehyde 1 with 4-hydroxyphenyl
acetic acid 2 in the presence of acetic anhydride and tri-
ethylamine yielded 3-Aryl-2-(4-hydroxyphenyl)-acrylic
acid 3. Esterification of this substituted acid followed by
condensation with 4-fluorobenzaldehyde in the presence of
this class are derivatives of the parent compound thiazo-
lidinedione. Three thiazolidinediones have been used in
clinical practice: Troglitazone, Rosiglitazone and Pioglit-
azone as shown in Fig. 1. However, the first of these agents
to be introduced (troglitazone) has been withdrawn from
use because it was associated with severe hepatic toxicity
(Evans, 1988; Cantello et al., 1994).
Scheme 1 Reagents and
conditions: a acetic
anhydride.Et3N, 6 h, 130°C,
b ROH.H2SO4, 15 h, reflux,
c 4-fluorobenzaldehyde, NaH,
DMF. 18 h, 80°C,
d 2,4-thiazolidinedione,
piperidine. benzoic acid,
toluene. 5 h reflux, e PD/C
(10%), AcOH-HCOONH4,
15 h, 125°c
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Med Chem Res (2011) 20:678–686
sodium hydride in dimethyl formamide at 80°C for 18 h
i.p.) freshly diluted in citrate buffer (0.1 mol, sodium cit-
rate, pH 4.5). After 21 days, male rats were selected and
were kept in groups of six in each cage. Male rats (9 weeks
old) with fasting PGL of C200 mg/dl were considered as
diabetic and selected for further pharmacological study.
Blood samples were collected from retro-orbital sinus
(Henke et al., 1999).
yielded
3-Aryl-2-[4-(4-formylphenoxy)-phenyl]-acrylic
acid alkyl ester 5. Knovenagel condensation (Prabhakar
et al., 1998; Duendar et al., 2006) of this ester with 2,4-
thiazolidinedione in the presence of piperidinium benzoate
followed by hydrogenation using 10% Pd/C (3.52 g) in
glacial acetic acid gave a good yield of final compound
3-Aryl-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-
phenyl}-acrylic acid alkyl ester 7 (Thz1–24).
Dose selection and administration of synthesized
compounds
A major challenge was selective hydrogenation of one
of the double bond. Hydrogenation with 10% palladium on
carbon as catalyst yielded mixture of products (Bhat et al.,
2004], and the separation of desired compound (7) from
this mixture was possible only by reverse-phase chroma-
tography on C-18 silica. This problem was overcome by
using ammonium formate as hydrogen donor in the pres-
ence of palladium catalyst produced minimal amounts of
other products, and isolation of desired compounds in high
purity was possible by repeated crystallization from
methanol (Ebdrup et al., 2003; Acton et al., 2005; Chitti-
boyina et al., 2006).
The animals were kept under fasting state for 2 h before
and 2 h after drug administration (Nomura et al., 1999).
The effective dose to reduce plasma glucose level was
determined using results of dose selection experiment. All
compounds were given orally to 9 weeks old male rats,
suspended in 0.25% carboxy methyl cellulose (CMC). Two
compounds (Thz4 and Thz15) were selected randomly for
dose selection study, in which four different doses (15, 20,
25, and 30 lmol/kg) were tested at interval of 3, 7, 10,
and 15 days. Plasma glucose level (PGL) (mg/dl) was
measured by commercial supplied biological kit—Erba
Glucose Kit (GOD-POD Method) using Chem 5 Plus-V2
Auto-analyzer (Erba Mannhein Germany).
Pharmacology
On the basis of this study, 25 lmol/kg dose was found
most effective and this dose of all compounds was given
for 15 days. Rosiglitazone (25 lmol/kg) as a reference and
CMC (0.25% w/v) as a control were also given for 15 days
(Dundar et al., 2008; Kuhn et al., 2006). Blood samples
were collected from fasting animals under mild ether
anesthesia from retro-orbital sinus, after 15 days of con-
tinuous dosing. The plasma glucose level was determined
by enzymatic method using glucose kit and autoanalyzer.
Antidiabetic compounds of the thiazolidinedione class,
increase peripheral tissue sensitivity to insulin via PPARc
receptor activation. Neonatal streptozotocin diabetic Wistar
male rats (commonly used animal model of NIDDM), were
used to assess the plasma glucose lowering activity of
synthesized compounds and rosiglitazone was used as
reference drug in this study (Adisakwattana et al., 2005).
Experimental animals
Data analysis
Wistar rats (2–4 days old pups with mother) were pur-
chased from Disease Free Small Animal House, Chaudhary
Charan Singh Haryana Agriculture University (CCSHAU),
Hisar (Haryana). These mothers were housed separately
one in a single cage with pups under laboratory conditions
with alternating light and dark cycle of 12 h each. The
animals had free access to food and water. All experi-
mental procedures were approved by Institutional Animals
Ethics Committee (IAEC) and animals care was taken as
per the guidelines of Committee for the Purpose of Control
and Supervision of Experiments on Animals (CPCSEA),
India.
All the results were expressed as mean standard error
mean (SEM). The data of all the groups were analyzed
using one-way ANOVA followed by Dunnett’s t-test
(Madhavan et al., 2002) using the software SPSS 7.5.
Results and discussion
Physicochemical characteristics of the synthesized 2,4-
thiazolidinedione derivatives are presented in Table 1. The
synthesized compounds were screened for in vivo antihy-
perglycemic activity by using streptozotocin-induced neo-
natal diabetic rats model of type 2 diabetes. Rosiglitazone
(25 lmol/kg) was used as a reference drug and reduced
plasma glucose level up to 56.73%. The effective dose of
synthesized compounds was determined by dose selection
study which has been shown in Table 2. The effective dose
Induction of experimental neonatal streptozotocin
diabetes
For induction of experimental diabetes, Wistar rats (5 days
old pups) were injected with streptozotocin (90 mg/Kg,
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Med Chem Res (2011) 20:678–686
681
Table 1 Physicochemical characteristics of synthesized 3-Aryl-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy]-phenyl}-acrylic acid alkyl
esters
COOR
Ar
O
O
NH
O
S
Compounds
–Ar
–R
Molecular formula
C26H21NO5S
Molecular weight (g)
459.51
M.P. (°C)
Rf
% yield
48.51
Thz1
–CH3
134–136
0.55
Thz2
Thz3
Thz4
Thz5
Thz6
Thz7
–C2H5
–C3H7
–CH3
C27H23NO5S
C28H25NO5S
C27H23NO6S
C28H25NO6S
C29H27NO6S
C28H25NO7S
473.54
487.57
489.54
503.57
517.59
519.57
141–143
149–151
117–119
127–129
121–123
112–114
0.62
0.51a
0.57
0.49
0.58
0.64
34.10
52.09
38.34
42.80
29.21
47.40
MeO
–C2H5
–C3H7
–CH3
MeO
MeO
OMe
OMe
OMe
MeO
MeO
Thz8
–C2H5
–C3H7
–CH3
C29H27NO7S
C30H29NO7S
C28H25NO7S
C29H27NO7S
C30H29NO7S
533.59
547.62
519.57
533.59
547.62
128–130
123–125
92–94
0.71
0.59
0.65
0.56
0.47a
41.70
33.28
54.08
46.90
53.45
Thz9
MeO
MeO
Thz10
Thz11
Thz12
MeO
MeO
MeO
MeO
MeO
–C2H5
97–99
–C3H7
103–105
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Med Chem Res (2011) 20:678–686
Table 1 continued
Compounds
–Ar
–R
Molecular formula
C28H25NO7S
Molecular weight (g)
519.57
M.P. (°C)
Rf
% yield
32.58
Thz13
–CH3
99–101
0.54
MeO
MeO
MeO
OMe
OMe
OMe
Thz14
Thz15
–C2H5
C29H27NO7S
533.59
547.62
111–113
106–108
0.42
0.45
27.17
41.52
–C3H7
C30H29NO7S
Thz16
Thz17
Thz18
Thz19
Thz20
Thz21
Thz22
Thz23
Thz24
–CH3
C26H21NO6S
C27H23NO6S
C28H25NO7S
C26H20N2O7S
C27H22N2O7S
C28H24N2O7S
C26H20BrNO5S
C27H22BrNO5S
C28H24BrNO5S
475.51
489.54
503.57
504.51
518.54
532.56
538.41
552.44
566.46
90–92
96–98
0.72
0.67
0.74
0.46
0.37
0.41
0.61
0.48a
0.32a
25.36
37.49
34.64
39.60
57.26
42.81
52.57
35.20
38.40
HO
–C2H5
–C3H7
–CH3
HO
HO
105–107
101–103
114–116
109–111
139–141
147–149
154–156
O2N
O2N
O2N
Br
–C2H5
–C3H7
–CH3
–C2H5
Br
–C3H7
Br
a
TLC mobile phase—toluene:chloroform (1:2), Ethyl acetate:benzene (1:2)
Table 2 Dose selection study: effect of different doses on % PGL reduction
Dose (lmol/kg)
%PGL reduction in days (Thz4)
%PGL reduction in days (Thz15)
3
7
10
15
3
7
10
15
15
20
25
30
2.12
3.42
6.38
7.15
5.39
4.94
9.28
9.86
8.27
10.26
11.73
16.30
15.82
8.38
11.49
14.56
21.34
20.87
15.53
17.26
25.53
24.68
18.47
21.76
37.24
35.47
9.51
11.34
11.17
10.91
18.06
19.42
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Med Chem Res (2011) 20:678–686
683
groups between the interaction of compounds and target
site.
Table 3 Antihyperglycemic activity of thiazolidinedione derivatives
Compounds %PGL reduction Compounds
%PGL reduction
Thz1
Thz2
Thz3
Thz4
Thz5
Thz6
Thz7
Thz8
Thz9
Thz10
Thz11
Thz12
Thz13
10.74 2.23a
9.80 2.58a
8.60 3.64
Thz14
Thz15
Thz16
Thz17
Thz18
Thz19
Thz20
Thz21
Thz22
Thz23
Thz24
36.53 2.95b
37.24 4.39b
18.81 3.02b
18.16 2.07b
17.48 2.92b
13.26 1.93a
13.40 2.75a
12.45 2.39a
15.58 2.5b
13.63 2.74a
13.42 3.01a
Experimental
16.30 3.44a
14.61 2.58a
13.00 2.64a
46.13 4.96b
46.03 3.08b
45.91 4.51b
38.11 3.67b
37.15 4.06b
35.85 3.29b
37.05 3.6b
All reactions were monitored by thin layer chromatography
(TLC) using silica gel G (Spectrochem Pvt. Ltd., Mumbai).
The plates were developed by exposing to iodine chamber.
Melting points (m.p.) were determined by decibel melting
point apparatus and were uncorrected. Structures of the
selected newly synthesized 2,4-thiazolidinedione deriva-
tives have been ascertained on the basis of their consistent
IR and 1H NMR spectral assignments. The IR spectra were
recorded on Perkin Elmer IR spectrophotometer using KBr
pellets. Proton nuclear magnetic resonance spectra (1H
NMR) were recorded on Brucker Avance II 400 NMR
spectrophotometer using DMSO as solvent and TMS as
internal standard and reported as chemical shift in d values
(ppm). C, H, N- analysis has been performed with Carlo
Arba 1106 CHN analyzer.
Rosiglitazone 56.73 3.09b
Control
0.433 1.17
a
One-way ANOVA followed by Dunnett’s test. P \ 0.05 and
b
P \ 0.01
Values are presented as mean S.E.M. (n = 6)
was found 25 lmol/kg which was given to all experimental
diabetic rats. The results of antihyperglycemic activity of
synthesized derivatives are given in Table 3. The following
pattern of hypoglycemic activity of the synthesized com-
pounds was observed.
General procedure for the synthesis of 3-Aryl-2-{4-[4-
(2,4-dioxothiazolidin-5-ylmethyl)phenoxy]-phenyl}-
acrylic acid alkyl ester (Thz1–24)
Compounds Thz1–3 has no substitution on aryl ring and
has minimal activity (9–11% PGL reduction) among all
synthesized compounds. Substitution of aryl ring by elec-
tron-withdrawing or electron-donating groups increases the
activity. Compounds Thz4–6 having mono methoxy sub-
stitution on aryl ring, were found more active (13–16%
PGL reduction) than unsubstituted compounds, but were
found less active than compounds having dimethoxy sub-
stitution (Thz7–15) on aryl ring. The substitution on aryl
ring by electron-releasing group may be responsible for
their higher activity, which is further evidenced by higher
activities of hydroxy-substituted derivatives (Thz16–18)
than nitro (Thz19–21) and bromo- (Thz22–24) substituted
derivatives.
3-Aryl-2-(4-hydroxyphenyl)–acrylic acid (3)
To a mixture of aryl aldehyde (10 g, 0.06 mol) and
4-hydroxyphenylacetic acid (9.14 g, 0.06 mol) in a conical
flask, acetic anhydride (20 ml, 0.212 mol) and triethyl-
amine (8.4 ml, 0.06 mol) were added. The resulting mix-
ture was heated at 130–140°C for 6 h with continuous
stirring. Then, it was cooled to room temperature. Con-
centrated HCl (20 ml) was added to the reaction mixture
slowly over 30 min, while keeping the temperature of the
mixture between 20–30°C. The resulting precipitate was
filtered and washed with water to give crude product (3)
that was recrystallized from methanol–water (4:1) and
dried at 40°C.
Compound Thz7 exhibited highest antihyperglycemic
activity within all synthesized compounds, which reduced
PGL up to 46.13% in diabetic rats. Chemically compound
Thz7 is 3-(2,4-dimethoxyphenyl)-2-{4-[4-(2,4-thiazolidin-
5-ylmethyl)phenoxy]-phenyl}-acrylic acid methyl ester.
Compound Thz7 was found most active among all other
dimethoxy-substituted compounds, which indicates that
dimethoxy substitutions at ortho and para position on
aryl ring can enhance the binding of molecules with the
target (receptor). In all compounds methyl ester have
higher activity than ethyl and propyl ester, which means
that heavy carbon chain ester decreases the activity. This
may be due to hindrance developed by heavy ester
3-Aryl-2-(4-hydroxyphenyl)–acrylic acid alkyl ester (4)
Alkylalcohol (60 ml) was added to the completely dried
compound 3 (8.55 g, 0.028 mol) in RBF. Concentrated
sulfuric acid (2 ml) was added to the above suspension and
the reaction mixture was refluxed for 15 h under nitrogen.
The resulting mixture was filtered and residue was taken in
ethyl acetate (60 ml) in separating funnel and washed
sequentially with water (2 9 20 ml), saturated aqueous
NaHCO3 (2 9 20 ml) and brine (2 9 20 ml). The organic
layer was passed through anhydrous magnesium sulfate to
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Med Chem Res (2011) 20:678–686
remove any traces of water and filtered. Then, the solvent
was evaporated to dryness at water bath and compound 4
was obtained.
COOCH3), 7.06–7.31 (m, 8H, ArH–O–ArH), 7.35–7.58
(m, 5H, ArH), 7.04–7.12 (s, 1H, CH of Ar–CH=C\), 8.26
(s, 1H, NH), 3.64–3.72 (d, 2H, CH2 of Ar–CH2–Thz); IR
(KBr pellets): cm-1 1706.6 (C=O str., ketonic), 1734.1
(C=O str., COOCH3), 3029.1 (C–H str., aromatic), 2835.3
(C–H str., aliphatic), 3214.0 (NH str.), 1268.4 (Ar–O–SAr
str.), 1494.2 (C=C str., aromatic). Anal. Calcd for
C26H21NO5S: C, 67.96; H, 4.61; N, 3.05. Found: C, 67.89;
H, 4.67 N, 3.15.
3-Aryl-2-[4-(4-formylphenoxy)-phenyl]-acrylic acid alkyl
ester (5)
Compound 4 (8.66 g, 0.027 mol) was taken in a conical
flask and dissolved in dry DMF (32 ml). Sodium hydride
(1.2 g, 0.03 mol) was added to the above solution. Then,
4-fluorobenzaldehyde (3.7 ml, 0.034 mol) was added to the
resulting orange solution. The resulting solution was heated
at 80°C for 18 h with continuous stirring. The reaction
mixture was cooled to room temperature, diluted with ethyl
acetate (60 ml) and washed first with water (3 9 20 ml)
and then with brine (1 9 20 ml). The organic layer was
passed through anhydrous sodium sulfate, filtered and
solvent was evaporated. The residue was suspended in
methanol (60 ml) and then filtered to get compound 5
which was dried at 40°C.
Analytical data for compound Thz4: mp (°C)—118;
1
Yield—38.34%; H NMR (DMSO): d 1.34–1.57 (s, 3H,
COOCH3), 3.75–4.0 (s, 3H, OCH3), 7.2–7.9 (m, 12H, Ar–
H), 7.00 (s, 1H, CH of Ar–CH=C\), 8.5 (s, 1H, NH), 3.59
(d, 2H, CH2 of Ar–CH2–Thz); IR (KBr pellets): cm-1
1694.7 (C=O str., ketonic), 1734.1 (C=O str., COOCH3),
3030.1 (C–H str., aromatic), 2835.3 (C–H str., aliphatic),
3214.0 (NH str.), 1286.7 (Ar–O–Ar str.), 1507.6 (C=C str.,
aromatic). Anal. Calcd for C27H23NO6S: C, 66.24; H, 4.74;
N, 2.86. Found: C, 66.89; H, 4.88 N, 3.05.
Analytical data for compound Thz8: mp (°C)—129;
1
Yield—41.70%; H NMR (DMSO): d 1.14–1.18 (d, 5H,
COOC2H5), 3.75–3.95 (s, 6H, OCH3), 7.14–7.51 (m, 8H,
ArH–O–ArH), 6.7–6.76 (m, 3H, ArH) 6.9–6.96 (s, 1H, CH
of Ar–CH=C\), 8.21 (s, 1H, NH), 3.58 (d, 2H, CH2 of Ar–
CH2–Thz); IR (KBr pellets): cm-1 1673.0 (C=O str.,
ketonic), 1731.8 (C=O str., COOC2H5), 2941.0 (C–H str.,
aromatic), 2832.3 (C–H str., aliphatic), 3143.1 (NH str.),
1284.4 (Ar–O–Ar str.), 1461.8 (C = C str., aromatic).
Anal. Calcd for C29H27NO7S: C, 65.28; H, 5.10; N, 2.62.
Found: C, 65.59; H, 4.87 N, 2.78.
3-Aryl-2-{4-[4-(2,4-dioxothiazolidin-5-ylidenmethyl)-
phenoxy]-phenyl}-acrylic acid alkyl ester (6)
To a suspension of 5 (7.04 g, 0.016 mol) in anhydrous
toluene (50 ml), 2,4-thiazolidinedione (1.97 g, 0.017 mol),
benzoic acid (2.68 g, 0.022 mol), and piperidine (2.14 g,
0.025 mol) were added sequentially with continuous stir-
ring. The resulting mixture was taken in a RBF and
refluxed for 5 h. After refluxing, the reaction mixture was
cooled to room temperature and the resulting compound
was filtered and washed with water. The residue so
obtained was recrystallized in a mixture of methanol–die-
thyl ether (1:1, 60 ml). The compound 6 was obtained and
dried in oven at 40°C.
Analytical data for compound Thz11: mp (°C)—98;
1
Yield—46.90 %; H NMR (DMSO): d 1.14–1.18 (d, 5H,
COOC2H5), 3.92–3.94 (s, 6H, OCH3), 7.22–7.38 (m, 11H,
ArH), 7.14 (s, 1H, CH of Ar–CH=C\), 8.22 (s,1H, NH),
3.72 (d, 2H, CH2 of Ar–CH2–Thz); IR (KBr pellets): cm-1
1706.6 (C=O str., ketonic), 1734.1 (C=O str., COOC2H5),
3053.8 (C–H str., aromatic), 2835.3 (C–H str., aliphatic),
3214.0 (NH str.), 1265.3 (Ar–O–Ar str.), 1449.6 (C=C str.,
aromatic). Anal. Calcd for C29H27NO7S: C, 65.28; H, 5.10;
N, 2.62. Found: C, 65.61; H, 4.97 N, 2.71.
3-Aryl-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy]-
phenyl}-acrylic acid alkyl ester (7)
Analytical data for compound Thz13: mp (oC)—100;
To a solution of 6 (7.04 g, 0.013 mol) in glacial acetic acid
(120 ml) in a conical flask, ammonium formate (47.06 g,
0.74 mol) was added and stirred for 30 min. Slurry of Pd
on carbon (10%, dry, 3.52 g) in glacial acetic acid (5.8 ml)
was added to the flask and heated at 125°C for 15 h with
continuous stirring. The resulting mixture was filtered and
the filtrate was poured slowly into water (140 ml) with
vigorous stirring and the solid that separated, was filtered
and dried. The resulting solid was recrystallized in a
mixture of methanol and ethanol (2:1) to yield compound
7.
1
Yield—32.58%; H NMR (DMSO): d 1.14–1.18 (s, 3H,
COOCH3), 3.72–3.98 (s, 6H, OCH3), 7.13–7.34 (m, 11H,
ArH), 7.0–7.06 (s, 1H, CH of Ar–CH=C\), 8.22 (s, 1H,
NH), 3.64 (d, 2H, CH2 of Ar–CH2–Thz); IR (KBr pellets):
cm-1 1701.6 (C=O str., ketonic), 1737.7 (C=O str.,
COOCH3), 3028.8 (C–H str., aromatic), 2835.8 (C–H str.,
aliphatic), 3143.1 (NH str.), 1273.0 (Ar–O–Ar str.), 1454.0
(C=C str., aromatic). Anal. Calcd for C28H25NO7S: C,
64.73; H, 4.85; N, 2.70. Found: C, 65.19; H, 4.87 N, 2.88.
Analytical data for compound Thz16: mp (oC)—91;
1
Analytical data for compound Thz1: mp (°C)—135;
Yield—25.36%; H NMR (DMSO): d 1.13–1.32 (s, 3H,
COOCH3), 7.17–7.49 (m, 12H, ArH), 7.79–7.82 (s, 1H, CH
1
Yield—48.51%; H NMR (DMSO): d 1.06–1.13 (s, 3H,
123

Med Chem Res (2011) 20:678–686
685
novel thiazolidinedione derivatives. Bioorg Med Chem 12:5857–
5864
of Ar–CH=C\), 4.0 (s, 1H, OH), 8.3 (s, 1H, NH), 3.66–
3.77 (d, 2H, CH2 of Ar–CH2–Thz).; IR (KBr pellets): cm-1
1693.9 (C=O str., ketonic), 1751.0 (C=O str., COOCH3),
3034.6 (C–H str., aromatic), 2835.8 (C–H str., aliphatic),
3028.8 (OH str.), 3143.1 (NH str.), 1215.7 (Ar–O–Ar str.),
1485.9 (C=C str., aromatic). Anal. Calcd for C26H21NO6S:
C, 65.67; H, 4.45; N, 2.95. Found: C, 65.44; H, 4.35 N,
3.06.
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Analytical data for compound Thz19: mp (oC)—102;
1
Cantello BC, Cawthorne MA, Cottam GP, Duff PT, Haigh D, Hindley
9
Yield—39.60%; H NMR (DMSO): d 1.33 (s, 3H, CO-
RM, Lister CA, Smith SA, Thurlby PL (1994) [[x-(Hetero-
cyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent an-
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OCH3), 7.16–7.32 (m, 4H, ArH), 7.34–7.52 (m, 8H, ArH–
O–ArH), 7.83 (s, 1H, CH of Ar–CH=C\), 8.18 (s, 1H,
NH), 3.66 (d, 2H, CH2 of Ar–CH2–Thz); IR (KBr pellets):
cm-1 1697.8 (C=O str., ketonic), 1734.1 (C=O str., CO-
OCH3), 3047.6 (C–H str., aromatic), 2835.8 (C–H str.,
aliphatic), 1525.3 (NO2 str.), 3143.1 (NH str.), 1257.8 (Ar–
O–Ar str.), 1505.9 (C=C str., aromatic). Anal. Calcd for
C26H20N2O7S: C, 61.90; H, 4.00; N, 5.55. Found: C, 61.76;
H, 4.32 N, 5.15.
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Analytical data for compound Thz23: mp (°C)—148;
1
Yield—35.20%; H NMR (DMSO): d 1.17–1.31 (d, 5H,
COOC2H5), 7.35–7.50 (m, 4H, ArH), 7.15–7.32 (m, 8H,
ArH–O–ArH), 7.82 (s, 1H, CH of Ar–CH=C\), 8.2 (s, 1H,
NH), 3.65 (d, 2H, CH2 of Ar–CH2–Thz); IR (KBr pellets):
cm-1 1678.9 (C=O str., ketonic), 1734.1 (C=O str.,
COOC2H5), 3032.3 (C–H str., aromatic), 2835.3 (C–H str.,
aliphatic), 698.5 (Br str.), 3214.0 (NH str.), 1254.2 (Ar–O–
Ar str.), 1485.1 (C=C str., aromatic). Anal. Calcd for
C27H22NO5SBr: C, 58.7; H, 4.01; N, 2.54. Found: C, 58.43;
H, 4.27 N, 2.78.
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Acknowledgments Authors are thankful to Dr. Munish Ahuja,
Department of Pharmaceutical Sciences, GJUST, Hisar for providing
necessary information and encouragement. Authors are thankful to
Prof. Milind Parle, Chairman, Department of Pharmaceutical Sci-
ences, GJUST, Hisar, India, for providing research facilities.
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