Synthesis and evaluation of the hypoglycemic and hypolipidemic activity of novel 5-benzylidene-2,4-thiazolidinedione analogs in a type-2 diabetes model

Article abstract of DOI:10.1007/s00044-010-9359-5

This article reports synthesis and evaluation of two novel thiazolidinedione ring containing molecules namely (Z)-5-(2-(4-((2,4- dioxothiazolidin-5-ylidene)methyl)- phenoxy)acetyl)-2-hydroxybenzamide (4) and (Z)-2-(4-((2, 4-dioxothiazolidin-5-ylidene)meth

Full text of DOI:10.1007/s00044-010-9359-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:642–647
DOI 10.1007/s00044-010-9359-5
ORIGINAL RESEARCH
Synthesis and evaluation of the hypoglycemic and hypolipidemic
activity of novel 5-benzylidene-2,4-thiazolidinedione analogs
in a type-2 diabetes model
•
Sonali Mehendale-Munj Rumi Ghosh
•
C. S. Ramaa
Received: 19 November 2009 / Accepted: 3 May 2010 / Published online: 30 May 2010
Ó Springer Science+Business Media, LLC 2010
Abstract This article reports synthesis and evaluation of
two novel thiazolidinedione ring containing molecules
namely (Z)-5-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-
phenoxy)acetyl)-2-hydroxybenzamide (4) and (Z)-2-(4-((2,
4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-N-(5-nitro-
thiazol-2-yl)acetamide (7). The new chemical entities were
tested for hypoglycemic activity and for their total choles-
terol (CHL) and triglyceride (TG) lowering effect in high-fat
diet (HFD) fed Sprague–Dawley rats. The synthesized
molecules showed significant reduction in blood glucose,
CHL, and TG levels after 14 days of treatment.
Lohray, 2007) Clinically, patients can be classified as
having either type 1 (insulin-dependent diabetes mellitus or
IDDM) or type 2 (non-insulin-dependent diabetes mellitus
or NIDDM). The early stage of type-2 diabetes can be
managed by diet and exercise. However, in addition to this
insulin or oral hypoglycemic agents (OHAs), either alone
or in combination are needed for good control over blood
glucose. Clinically, insulin and its analogs, sulfonylureas,
biguanides, and TZD class of drugs are widely used.
Among these drugs, TZDs were found to be superior as
they avoid hypoglycemia and act as insulin sensitizers
(Skyler, 2004).
Keywords Type-2 diabetes Á 5-Benzylidene-
2,4-thiazolidinedione Á Knoevenagel condensation Á
Hypoglycemic activity Á Streptozotocin
In the late 1990s, the TZD class of drugs was developed,
of which troglitazone was the first candidate to be mar-
keted. However, due to hepatotoxic events it was then
voluntarily withdrawn (Williams and Lemke, 2005). The
search was further continued and resulted in discovery of
two molecules namely rosiglitazone and pioglitazone.
These two are potent analogs giving optimum plasma
glucose lowering profile. Both the drugs act as agonists
upon binding to PPARc which preferentially bind to DNA,
activating transcription of a wide variety of metabolic
regulators. These regulators increase expression of a
number of genes involved in regulation of glucose and lipid
metabolism (Williams and Lemke, 2005).
Introduction
Diabetes mellitus is a group of syndromes characterized by
hyperglycemia. The World Health Organization (WHO)
has designated diabetes mellitus as an epidemic, although it
is a non-infectious disease. Nearly 2.3% of the world’s
population is estimated to be suffering from this disease,
with an increasing trend of 4–5% every year. (Lohray and
Food Drug and Administration has ordered new safety
labels for pioglitazone and rosiglitazone (FDA Safety alerts
for drugs, 2007). This is because recent papers have shown
serious toxicity profile for these drugs, particularly for
rosiglitazone (Scheen, 2001). Moreover, some papers claim
that rosiglitazone is associated with hepatic failure (For-
man et al., 2000). It has also been proven that rosiglitazone
is associated with genotoxicity in rats (Bedir et al., 2006),
data indicating that the rosiglitazone is able to induce
primary DNA damage in rats, with greater damage being
S. Mehendale-Munj Á C. S. Ramaa (&)
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s
College of Pharmacy, Sector-8, C. B. D. Belapur, Navi Mumbai
400 614, India
e-mail: sinha_ramaa@hotmail.com
R. Ghosh
Department of Pharmacology, Bharati Vidyapeeth’s College
of Pharmacy, Sector-8, C. B. D. Belapur, Navi Mumbai 400 614,
India
123

Med Chem Res (2011) 20:642–647
643
detected in liver cells than lymphocytes. The reports show
that these drugs are associated with congestive heart failure
and pulmonary edema (Kenned, 2003).
TZD in the presence of bases like piperidinium benzoate
(Lohray et al., 1998). As an alternative and more convenient
route, we first synthesized 2 as a common intermediate.
Compound 4, having carbonyl carbon in the form of ketone
in the linker chain, was synthesized by condensing 3 and
Knoevenagel product 2 at room temperature (Scheme 1)
(Reddy et al., 1999). For compound 7, the intermediate 6
was obtained by a base-mediated bromoacetylation of 2-
nitrothiazole. This bromoacetylated product was further
condensed with 2 (Scheme 2) (Sengpracha, 2005).
The mechanism for toxicity profile of these drugs is still
unclear. From previous reports, we can infer that molecular
modifications, apart from pharmacophore TZD, are respon-
sible for its toxicity (Williams and Lemke, 2005). Thus, there
is much more scope for development in this area. Therefore,
in the present work, we have designed two novel molecules
by modifying the non-pharmacophoric elements.
Biological evaluation
Materials and methods
Materials
Chemistry
Streptozotocin was purchased from Sigma-Aldrich, USA.
Pioglitazone hydrochloride was obtained from Cipla Ltd.,
India as a gift sample. The animal feed ingredients were of
veterinary grade.
Antidiabetic TZDs are generally prepared by Knoevenagel
condensation, in which aryl aldehydes are refluxed with
Animals
Male Sprague–Dawley rats with an average body weight of
190 10 g were selected for the study. Animals were
housed in polypropylene cages at an ambient temperature
of 25 2°C and 45–55% relative humidity with standard
12-h light and dark cycle. They had free access to feed and
water. Animals were examined properly for infection and
metabolic disorders. The guidelines of committee for the
purpose of control and supervision of experiments on
animals (CPCSEA), Govt. of India were followed and prior
permission was sought from the institutional animal ethics
committee for conducting the study.
Scheme 1
Experimental Design
Sprague–Dawley rats were randomly divided into seven
groups with six animals each. Group 1 served as a normal
control and received vehicle 1% Na-CMC (2 ml kg-1
,
p.o.). Groups 2 and 3 served as drug control. Groups 4 and
5 comprised diabetic rats to which compounds 4 and 7
were administered in dose of 20 mg/kg/day, respectively,
for 14 days. Group 6 served as standard and received
pioglitazone hydrochloride, equivalent to 10 mg/kg/day of
piogliatazone for 14 days.
Development of HFD-fed and STZ-treated type-2 diabetic
rats
All groups were given HFD for a period of 2 weeks
(Shrinivasan et al., 2005). Composition of this diet was
58% fat, 25% protein, and 17% carbohydrate as percentage
of total Kcal.
Scheme 2
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Med Chem Res (2011) 20:642–647
Collection of blood and analytical methods
Results
For blood glucose estimations, rats were given mild ether
anesthesia followed by collection of blood from the retro
orbital plexus. Blood was collected in sodium fluoride
anticoagulant containing vials and glucose was analyzed by
glucose oxidase method. For triglycerides (TG) and cho-
lesterol (CHL) analysis, blood was collected in plain tubes
to obtain serum and estimation was carried out using
standard biochemistry kits.
Design of novel molecules
Every molecule has a typical group or groups of atoms that
interact with a receptor. This group of atoms which is
responsible for interaction, through various bondings, is
known as pharmacophore and plays a vital role in eluci-
dating pharmacological response. Structural elements other
than pharmacophore usually account for non-receptor
events like pharmacokinetics, toxicity, etc.
Biological activity
Thus, in our work, we retained the pharmacophore
(Sohda et al., 1982), i.e., TZD ring and made the changes
in lipophilic group to develop new congeners with better
efficacy and less toxicity. The general structure of the TZD
class of molecules (Fig. 1) can be depicted as follows:
The present work includes modification at three stages
We carried out acute toxicity studies for compounds 4 and
7 before testing hypoglycemic activity of both the com-
pounds. We tried different doses upto 500 mg/kg. Hypo-
glycemic and hypolipidemic activities were carried out
using a combination of high-fat diet (HFD) and low dose of
STZ-treated male Sprague–Dawley rats. The animals were
fed HFD for a period of 2 weeks. After 2 weeks of dietary
manipulation, rats were injected intraperitoneally (i.p.)
with low dose of STZ (35 mg/kg), while respective control
rats were given vehicle 1% Na-CMC (2 ml/kg, p.o.). Blood
glucose (BG) was estimated just before study, 1 week after
STZ injection and at the end of 14 days treatment. Rats
with non-fasting plasma glucose level more than
250 mg dl-1 were considered diabetic and 42 rats were
selected for further pharmacological studies. For hypolip-
idemic activity, CHL and TG estimations were carried out
prior to study, after 2 weeks of HFD and at the end of drug
treatment.
1. Novel lipophilic moiety in A part.
2. Introduction of carbonyl carbon in B part.
3. Unsaturation in D part.
Tanis et al. (1996) have synthesized the putative ketone
metabolite of pioglitazone (Fig. 2) and have described its
potential as a pioglitazone antihyperglycemic congener
with somewhat greater potency and a better metabolic
profile. Based on these findings, we designed compound 4,
which incorporates a carbonyl carbon as ketone in the
linker chain.
We further extended our work and introduced carbonyl
carbon as an amide linkage for compound 7 considering its
simpler metabolic pathway.
Diabetic rats were randomly divided into four groups,
i.e., from group 4 to 7. The diabetic rats were either treated
with test compound (20 mg/kg once daily for 14 days) or
with pioglitazone hydrochloride (equivalent to 10 mg/kg of
pioglitazone once daily for 14 days).
It has been reported that both p-alkoxybenzyl and p-
alkoxybenzylidene moieties were effective as linkers
between benzene and TZD ring (Memose et al., 1991). We
prepared benzylidene TZD analogues and evaluated them
for biological activity.
Fig. 1 Generalized structure of
TZD class
Fig. 2 Pioglitazone and its
putative metabolite
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645
Synthesis of 5-(2-(4-((2,4-dioxothiazolidin-5-
Experimental section
ylidene)methyl)phenoxy)acetyl)-2-hydroxybenzamide
1H NMR and 13C NMR spectra were recorded in DMSO-d6
on Varian 300 MHz instrument using TMS as internal
standard. Chemical shift values are reported in d, ppm.
Elementary analyses were performed on FLASH EA 1112
series (Thermo finnigan, Italy) CHNS analyzer. Mass
spectra were recorded on Waters Quattro Premier XE
Micromass in positive ion mode. All reactions as well as
column chromatography were followed by TLC using
Merck pre-coated silica gel 60 F254 plates and spots were
visualized by observing in UV cabinet under short UV. IR
spectra were recorded on FTIR-8400S instrument with KBr
pellets and only the principal absorption levels (cm-1) have
been listed. All reagents were used as received unless
otherwise stated.
(4)
A mixture of Knoevenagel product (2) and anhydrous
K2CO3 (1.55 g, 11 mmol) in DMF (7 ml) was stirred for
30 min.
5-(2-Bromoacetyl)-2-hydroxybenzamide
(3)
(3.5 g, 13 mmol) was added to above mixture and reaction
was stirred at room temperature for further 4 h. Water
(50 ml) was added and mixture was stirred at room tem-
perature for 1 h, extracted with ethyl acetate (3 9 20 ml).
Combined organic layer was dried over anhydrous Na2SO4
and concentrated in vacuo to give title compound. Yield:
84%; Rf:: 0.45 (6:1, chloroform/ ethanol); IR (KBr, cm-1):
3390 (OH stretching), 1737 and 1672 (C=O stretching
vibrations of cyclic imides), 1211 (C–O stretching), 1093;
1H NMR: (300 MHz, DMSO-d6) d (ppm): 5 (s, 2H, CO–
CH2–O), 6.32 (d, 1H, J = 9 Hz, aromatic), 6.94 (d, 2H,
J = 8.7 Hz, aromatic), 7.54 (d, 2H, J = 8.7 Hz, aromatic),
7.6 (d, 1H, J = 8.7 Hz, aromatic), 7.88 (s, 1H, aromatic),
8.42 (s, 1H, benzylidene proton), 10.6 (bs, 1H, phenolic
OH); 13C NMR: (300 MHz, DMSO-d6) d (ppm): 172.8
(C=O), 167.4 (C=O), 165.7 (C=O), 160.2, 145.8, 136.7,
133.7, 132.7, 127.4, 123.9, 116.8, 116.5, 46.2; MS (ESI?)
m/z (rel. intensity): 407 (M ? H, 100%); Anal. Calc. for
C15H10N4O6S2, %: C, 44.33; H, 2.48; N, 13.79. Found, %:
C, 43.95; H, 2.42; N, 13.48.
Synthesis of the Knoevenagel product: 5-(4-
hydroxybenzylidenethiazolidine-2,4-dione) (2)
A solution of p-hydroxy benzaldehyde (5 g, 40 mmol)
and 2,4- TZD (4.8 g, 40 mmol) with catalytic quantity of
piperidinium benzoate was refluxed in toluene with con-
tinuous removal of water using Dean–Stark apparatus for
4 h. The reaction mixture was cooled to 25°C and solid
separated was collected by filtration. Yield: 93%; Rf:: 0.70
(6:1, chloroform/ ethanol); IR (KBr, cm-1): 1718 and
1683 (C=O stretching vibrations of cyclic imides), 1510
(NH bending), 1338, 1213 (C–O stretching); 1H NMR
(DMSO-d6) d (ppm): 6.9 (d, 2H, J = 8.4 Hz, aromatic),
7.44 (d, 2H, J = 8.4 Hz, aromatic), 7.67 (s, 1H, benzyl-
idene proton).
Synthesis of 2-(4-((2,4-dioxothiazolidin-5-
ylidene)methyl)phenoxy)-N-(5-nitrothiazol-
2-yl)acetamide (7)
The title compound was prepared from Knoevenagel
product (2) (1.7 g, 7 mmol), 2-bromo-N-(5-nitrothiazole-2-
yl)acetamide (6) (2 g, 7 mmol), anhydrous K2CO3 (1.55 g,
11 mmol) in DMF (7 ml) by a procedure analogous to that
described for the preparation of 5-(2-(4-((2,4-dioxothiazo-
lidin-5-ylidene)methyl)phenoxy)acetyl)-2-hydroxyben-
zamide (4). Yield: 50%; Rf:: 0.60 (4:1, chloroform/
ethanol); IR (KBr, cm-1): 3382 (NH stretching), 1716 and
1664 (C=O stretching vibrations of cyclic imides), 1575;
1H NMR (300 MHz, DMSO-d6) d (ppm): 4.71 (s, 2H, CO–
CH2–O), 6.94 (d, 2H, J = 8.7 Hz, aromatic), 7.54 (d, 2H,
J = 8.4 Hz, aromatic), 7.90 (s, 1H, benzylidene proton),
8.66 (s, 1H, aromatic), 10.44 (s, 1H, NH of linker), 13.60
(bs, 1H, NH of TZD ring). 13C NMR: (300 MHz, DMSO-
d6) d (ppm): 188.2 (C=O), 170.4 (C=O), 169.6 (C=O),
167.3 (C=O), 165.6, 160.6, 134.2, 133.0, 131.8, 131.2,
127.0, 123.6, 122.5, 121.9, 119.6, 116.6, 116.2, 116.0,
47.2; MS (ESI?) m/z (rel. intensity): 399 (M ? H, 100%);
Anal. Calc. for C19H13N2O6S, %: C, 57.28; H, 3.54; N,
7.03. Found, %: C, 56.97; H, 3.26; N, 7.12.
Synthesis of 2-bromo-N-(5-nitrothiazole-2-yl)
acetamide (6)
5-Nitrothiazole-2-amine (3 g, 20 mmol) and anhydrous
K2CO3 (4.85 g, 35 mmol) were taken in 20 ml of
dichloromethane (DCM). Reaction mixture was cooled
between 2 and 5°C and to this bromoacetyl bromide
(2.7 ml, 30 mmol) in DCM (20 ml), was added dropwise.
Reaction was stirred overnight at room temperature.
Water was added to the reaction mixture and organic
layer was separated. Organic layer was passed through
anhydrous Na2SO4 and subsequently distilled out. Shiny
yellow colored needle-shaped crystals were collected.
Yield: 82%; Rf:: 0.65 (20:1, chloroform/ ethanol); IR
(KBr, cm-1): 1687 (C=O stretching), 1350 (Aromatic C-
1
NO2 stretching), 497 (C-Br stretching); H NMR (CDCl3)
d (ppm): 4.4 (s, 2H, CH2-Br), 8.36 (s, 1H, aromatic),
10.07 (bs, 1H, NH).
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Med Chem Res (2011) 20:642–647
Statistics
Table 1 Composition of HFD
Ingredients
Diet (g/kg)
The results were calculated with help of GraphPad InStat
using one-way ANOVA and Dunetts’ test and are expres-
sed as mean SEM. The percent reduction was calculated
using the equation (Lohray et al., 2001): [1 - (TT/OT)/
(TC/OC)] 9 100, where TT is test day treated, OT is zero
day treated, TC is test day control, and OC is zero day
control.
Powdered normal feed diet
Lard
365
310
250
10
Casein
Cholesterol
Vitamin and mineral mix
DL-Methionine
Yeast powder
Sodium chloride
60
03
01
01
Discussion
We have used HFD fed, low dose STZ model, as it
perfectly mimics the insulin resistance in humans char-
acterized by obesity, mild hyperglycemia, and hypercho-
lesterolemia. Hypoglycemic activity for compounds 4
and 7, carried out for 14 days in STZ-induced HFD fed
rats, gave 64 and 56 % reduction in blood glucose when
compared to vehicle control. It is pertinent to mention that
an efficient control of TG and CHL levels in type-2 dia-
betic patients has shown beneficial effects in diabetes-
related complications especially atherosclerosis and car-
diovascular diseases. Thus, the drugs which control both
TG and CHL would be more suitable candidates for further
development for the treatment of type-2 diabetes (Lohray
et al., 1999). In our study, both the compounds, 4 and 7,
were evaluated for its TG and CHL lowering activity. TG,
CHL data were, however, not used in concluding results,
since observed TG, CHL lowering effect of pioglitazone
hydrochloride were not reported in clinical trials (Sauer-
berg et al., 2002).
Table 2 Body weight in grams—before and after HFD
Normal rats
HFD rats
1–10
188.8 3.18
190.5 3.37
197 3.59
214 4.76
228 8.30
232 7.42
232 8.73
230 6.29
11–20
21–30
31–40
41–50
197.3 4.72
194.2 4.11
Table 3 Cholesterol levels mg/dl—before and after 2 weeks of HFD
Normal rats
HFD rats
1–10
59.2 3.77
58.2 3.82
56.9 2.915
53.2 2.95
54.5 3.17
183.4 4.49
187.7 4.35
178.1 5.08
183.8 6.13
180.9 5.21
11–20
21–30
31–40
41–50
Both the test compounds 4 and 7 gave significant blood
glucose reduction. Thus, introduction of carbonyl carbon in
the form of ketone and amide, in linker chain, may serve as
a useful strategy in drug design in the area of antidiabetic
TZDs. Both the compounds are expected to show a better
metabolic profile due to ketone and amide functional
groups, thus reducing the chances of toxicity. In our syn-
thetic scheme, we made Knoevenagel product separately as
a common intermediate and combined it with lipophilic
group. The same strategy could be further extended to
combinatorial synthesis, wherein addition of only one
component, i.e., different lipophilic groups would be nee-
ded (Table 1, 2, 3, 4, 5).
Table 4 Triglyceride levels mg/dl—after 2 weeks of HFD
Normal rats
HFD rats
1–10
84 3.30
67.5 4.32
73.9 5.74
82.6 3.04
70.5 4.01
157.6 7.20
152.8 5.91
173.1 4.14
150.6 4.72
162.8 5.90
11–20
21–30
31–40
41–50
and hypolipidemic activity in STZ-induced diabetic animal
model. Compounds 4 and 7 showed 64 and 56% blood
glucose lowering activity, respectively, relative to vehicle
control group. They could serve as lead molecules for
molecular modifications to get improved activity and tox-
icity profile.
Conclusion
Two new chemical entities belonging to the series of
benzylidene thiazolidinedione were synthesized and char-
acterized. Molecules were then screened for antidiabetic
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647
Table 5 In vivo efficacy in HFD-fed male Sprague–Dawley rats after oral treatment for 14 days
Compound No.
BGa % max reduction
TGb % max reduction
CHLc % max reduction
4
64.43 1.26N.S.
56.08 2.04N.S.
51.57 3.15**
74.18 4.64*
78.11 1.46**
78.38 1.80*
89.70 0.77**
92.46 0.54**
86.83 3.24**
7
Pioglitazone hydrochloride
Male Sprague–Dawley rats (n = 6) were treated once a day by oral gavage for 14 days. Compounds 4 and 7 were tested at dose of 20 mg/kg/day;
pioglitazone hydrochloride at 10 mg/kg/day. ‘‘% max reduction’’ is the maximum achieved reduction relative to vehicle control group SEM
N.S. non significant
a
Blood glucose after 14 days treatment
b
Triglycerides after 14 days treatment
c
Cholesterol after 14 days treatment
* P \ 0.05, ** P \ 0.01
Acknowledgements This work was supported by University Grant
(University of Mumbai). We are thankful to The Director - Board of
College and University Development, University of Mumbai. We are
also thankful to Cipla Ltd.and Shreenath Chemicals Ltd. for providing
gift samples.
Memose K, Hatanaka C, Satoru O, Sohda T (1991) Studies on
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Reddy AK, Lohray BB, Bhushan V, Bajji AC, Reddy KV, Reddy PR,
Krishna HT, Rao NI, Jajoo HK, Rao NVSM, Chakrabarti R,
Dileepkumar T, Rajagopalan R (1999) Novel antidiabetic and
hypolipidemic agents. 3. Benzofuran-containing thiazolidinedi-
ones. J Med Chem 42:1927–1940
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