Synthesis, glucose uptake activity and structure-activity relationships of some novel glitazones incorporated with glycine, aromatic and alicyclic amine moieties via two carbon acyl linker

Article abstract of DOI:10.1016/j.ejmech.2010.12.019

Three series of novel glitazones were designed and prepared by using appropriate synthetic schemes to incorporate glycine, aromatic and alicyclic amines via two carbon linker. Compounds were synthesized both under conventional and microwave methods. Nineteen out of twenty four synthesized compounds were evaluated for their in vitro glucose uptake activity using isolated rat hemi-diaphragm. Compounds, 6, 9a, 13a, 13b, 13c, 13f and 13h exhibited significant glucose uptake activity. Illustration about their synthesis and in vitro glucose uptake activity is described along with the structure-activity relationships.

Full text of DOI:10.1016/j.ejmech.2010.12.019

European Journal of Medicinal Chemistry 46 (2011) 835e844
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, glucose uptake activity and structureeactivity relationships of some
novel glitazones incorporated with glycine, aromatic and alicyclic amine moieties
via two carbon acyl linker
,
a
a
a
a
B.R. Prashantha Kumar a , Mukesh Soni , S. Santhosh Kumar , Kuldeep Singh , Mohan Patil ,
*
R.B. Nasir Baig b, Laxmi Adhikary c
a Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Rocklands, Ootacamund 643 001, India
b Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
c Department of Bioanalytical Division, Biocon Ltd., Bangalore 560 100, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Three series of novel glitazones were designed and prepared by using appropriate synthetic schemes to
incorporate glycine, aromatic and alicyclic amines via two carbon linker. Compounds were synthesized
both under conventional and microwave methods. Nineteen out of twenty four synthesized compounds
were evaluated for their in vitro glucose uptake activity using isolated rat hemi-diaphragm. Compounds,
6, 9a, 13a, 13b, 13c, 13f and 13h exhibited significant glucose uptake activity. Illustration about their
synthesis and in vitro glucose uptake activity is described along with the structureeactivity relationships.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Received 31 August 2010
Received in revised form
17 November 2010
Accepted 15 December 2010
Available online 23 December 2010
Keywords:
Glitazones
Thiazolidinediones
Glucose uptake activity
Antidiabetic activity
1. Introduction
Thiazolidine-2,4-diones (TZD’s) have become a pharmacologi-
cally important class of heterocyclic compounds since their intro-
Type 2 diabetes is a non-insulin dependent type of diabetes
mellitus (NIDDM) characterized by high blood glucose levels due to
impaired insulin action [1]. Insulin resistance in skeletal muscle,
adipose tissue and liver is an important distinctive feature of
NIDDM and is also a contributing factor in atherosclerosis, hyper-
tension, lipid disorders and polycystic ovarian syndrome [2].
Increasingly, there is an evidence to suggest that the presence of
insulin resistance increases cardiovascular risk in patients with
type 2 diabetes [3,4] and this metabolic syndrome is now recog-
nized as a major risk factor for coronary heart diseases [5]. Several
studies have shown that decreasing the insulin resistance is an
ultimate need for the NIDDM [6e8]. Among the oral hypoglyce-
mics, sulfonylureas are the most commonly used but they have
a tendency to induce serious hypoglycemia [9]. However, the non-
sulfonylureas do not increase insulin secretion or cause serious
hypoglycemia rather they enhance the insulin action which is much
required and this has led to the evolution of glitazones as insulin
sensitizers [10].
duction in the form of glitazones into clinical use for the treatment
of type 2 diabetes [11,12]. TZDs are known to be selective agonists of
peroxisome proliferator-activated receptor-
g (PPAR-g), thereby
increasing insulin sensitivity at adipose, muscle and hepatic tissues
[13,14]. Reports also claim that, TZDs are known to normalize
elevated blood glucose, lipid, and insulin levels in rodent models.
Some studies have indicated that the TZDs have an impact on
different elements of carbohydrate metabolism, thereby may delay
or prevent the progression of atherosclerotic disease in patients
with type 2 diabetes [13,15e17].
The TZDs are known to exert beneficial effects on lipid abnor-
malities, endothelial function, hemostasis and inflammation [18].
TZDs are also known to lower blood pressure thus reduce chances
of heart failure and microalbuminuria in patients with type 2 dia-
betes [19]. TZDs are known to cause weight gain, hepatotoxicity and
fluid retention [20], these side effects are more common during
combination therapy with sulfonylureas or insulin [20,21]. Fluid
retention associated with TZDs may result in mild to moderate
dose-related edema and the incidence of edema increases in
combination with insulin therapy [22,23]. Therefore, TZDs are not
recommended for use in class III or IV heart failure patients at New
* Corresponding author. Tel.: þ91 4232443393x223; fax: þ91 4232447135.
E-mail address: prashantha@jsscpooty.org (B.R.P. Kumar).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.12.019

836
B.R.P. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 835e844
H
H
N
O
N
O
O
b
a
HN
O
Cl
OH
S
S
1
O
O
H
N
O
d
c
H2N
Cl
OC2H5
H2N
OC2H5
OH
O
3
2
H
S
H
H
e
S
f
O
O
O
NH
NK
H3CO
O
H3CO
H3CO
H3CO
O
g
4
5
3
O
H
O
N
OC2H5
4
3N
5
2
1
O
S
O
6
Scheme 1. Reaction protocol for the synthesis of glycine incorporated glitazone (6). Reagents and conditions: (a) Water, thiourea, stirred at 0e5 ꢀC, 20 min (b) Conc. HCl, reflux,
10e12 h. (c) Ethanol, SOCl2, stirred at 0e5 ꢀC for 5e6 h and reflux for 1 h; (d) CHCl3, triethyl amine, chloroacetyl chloride, 0e5 ꢀC, stirred, 12e15 h; (e) Dry toluene, TZD 1, piperidine,
acetic acid, reflux at 110 ꢀC, 10e14 h (MW at 700 W for 20e30 min); (f) C2H5OH, KOH, stirred, 1 h; (g) DMF, 3, stirred with reflux, 96 h.
York Heart Association, USA [22,23]. Troglitazone, the first mar-
keted TZD was recalled from the market because of its increased
risk of hepatotoxicity [24]. However, drugs such as rosiglitazone
and pioglitazone are still in the market with a regular monitoring
[25,26]. In light of these beneficial and risk factors associated with
the glitazones, herein, we have made an attempt to design,
synthesize and evaluate some novel glitazones with structural
diversity for their possible antidiabetic activity.
Scheme 1. First, the basic nucleus thiazolidinedione 1 was
obtained by reacting equimolar amounts of thiourea and
chloroacetic acid. The C-terminal of glycine was blocked by
converting it to the ethyl ester 2 rather the methyl ester. As the
ethyl ester will release a relatively safer ethyl alcohol after its
hydrolysis during first pass metabolism in the body. After that, N-
terminal was extended by acylation reaction with chloroacetyl
chloride (a two carbon acyl linker) to obtain 3 [28]. Simulta-
neously, the TZD was subjected to the Knoevenagel condensation
with an anisaldehyde to obtain corresponding 5-benzylidene
thiazolidine-2,4-dione 4. The acidic NH group of TZD ring of
compound 4 was deprotonated by transforming it to the potas-
sium salt 5. Later, the chloride terminal of 3 was coupled to the
compound 5 to get the final compound 6 with a poor yield of 17%.
Due to the poor yield, this synthetic route lacks its scope to
generate diverse glitazones containing natural substrates like
amino acids and thus needs an alternative strategy.
2. Chemistry
Glitazones are known to have adverse side effects by
producing toxic metabolites in the body after their metabolism
[27]. As there are no reports so far about glitazones which are
incorporated with natural substrates like amino acids, therefore,
we have made an attempt to incorporate glycine (a simple,
natural and polar amino acid) in glitazone structure according to
H
O
H
N
a
b
H
N
R
R
NH2
R
Cl
O
8
7
O
O
c
H
S
X
H
N
R
NH
O
O
O
9a-l
Scheme 2. Reaction protocol for the synthesis of compounds 9ael. Reagents and conditions: (a) CHCl3, triethyl amine, chloroacetyl chloride, stirred at 0e5 ꢀC, 2 h; (b) Dry acetone,
4-hydroxybenzalaldehyde, anhydrous K2CO3, stirred at rt, 72 h; (c) Dry toluene, thiazolidinedione or rhodanine, piperidine, acetic acid, reflux at 110 ꢀC for 10e14 h or MW at 700 W
for 20e30 min.

B.R.P. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 835e844
837
From our previous studies, we have learned that glitazones
3. Pharmacology
normally need to possess a polar thiazolidinedione ring system as
their head followed by benzyloxy moiety as their trunk which in
turn connected to the hydrophobic tail via a two carbon acyl linker
for exhibiting better antidiabetic activity [28]. Therefore, we adop-
ted Scheme 2 to synthesize twelve new compounds (9ael). The tail
part was first designed and synthesized by connecting various
aromatic/alicyclic amines to the two carbon acyl linker. The acylated
amines 7 were then connected to the hydroxyl group of p-hydroxy
benzaldehyde to obtain 8. The motive for us to select p-hydroxy
benzaldehyde here was, in the past we had found some similar kind
of glitazones containing vanillin as part of their trunk with potential
antidiabetic activity [29]. The hydrophobic trunk was connected to
the hydrophobic tail via two carbon acyl linker and later aldehyde
functional was condensed on to the head group which may be
a thiazolidinedione 1 or its bioisostere rhodanine (Fig. 1) to obtain
compounds 9ael by Knoevenagel condensation reaction.
Compounds 13aek were synthesized according to Scheme 3.
These glitazones are structurally similar to compound 6, however,
polar glycine part of the structure is replaced with hydrophobic
aniline. Aniline was acylated with two acyl carbon linker to form 2-
chloro-N-phenylacetamide 10 [28,29]. The potassium salt of thia-
zolidinedione 11 was coupled to the halide terminal of 10 to get
2-(2,4-dioxothiazolidin-3-yl)-N-phenylacetamide 12. In the final
step, compound 12 was subjected to the Knoevenagel condensation
with various aryl aldehydes to get compounds 13aek.
3.1. Glucose uptake activity
Antidiabetic activity of the compounds 6, 9a, 9b, 9gel, 13aei
and 13k were evaluated by measuring glucose uptake using in vitro
rat hemi-diaphragm model according to the standard procedure
reported by Walaas and Chattopadhyay [30,31]. The institutional
animal ethics committee (IAEC) of JSS College of Pharmacy
approved the proposal. Rat diaphragm was selected because stri-
ated muscle is quantitatively the most important tissue for glucose
disposal in the body [32e34]. Insulin stimulates glucose uptake by
causing translocation of the transporters from an intracellular site
to the plasma membrane. In muscles, two types of glucose trans-
porter iso-forms are expressed, namely, GLUT1 and GLUT4. The
latter is quantitatively more abundant in adult rat muscle and is
distributed in intracellular compartments of basal state, from here
it will be rapidly translocated to the plasma membrane in response
to the insulin. Glucose uptake was measured in mg/dl/45 min at the
dose of 1 mg and 2 mg both in the absence and presence of insulin
in triplicates. The results are expressed as mean ꢂ standard error of
mean (SEM) and are shown in Table 2.
3.2. Statistics
Statistical comparisons between the groups were performed on
all the four sets using one-way ANOVA and Dunnet’s multiple
comparison post-test on graphPad Prism 4.0 software for Windows
(San Diego, California, USA).
Knoevenagel condensation reactions were performed both
under microwave and conventional methods using toluene as the
hydrophobic solvent. Microwave method showed better results in
terms of reaction time and yields when compared to the conven-
tional method (Table 1).
4. Results and discussion
Structures of all the synthesized compounds were confirmed by
IR, 1H NMR, 13C NMR and Mass spectral analyses. IR spectrum of all
the final compounds, showed characteristic peaks for NeH
stretching in the range of 3000e3400 cmꢁ1 and C]O stretching in
the range of 1685e1740 cmꢁ1 to confirm the presence of thiazoli-
dinedione or rhodanine ring system. 1H NMR showed a character-
In continuation with our earlier work on glitazones and with
certain rationale some novel glitazones have been designed
manually, synthesized, analyzed and evaluated for their glucose
uptake activity. The results in Table 2 indicate that, most of the
compounds exhibit glucose uptake activity ranging from good to
moderate and from moderate to weak. The results also indicate that
increasing concentration of test compound beyond 1 mg did not
produce any significant increase in the glucose uptake by the dia-
phragm both in presence and absence of insulin.
Comparatively, compounds exhibited good glucose uptake
activity in presence of insulin proving that they are insulin sensi-
tizers. It is quite evident, therefore, that this class of compounds
tend to sensitize the tissue cells to take up the insulin which later
leads to the glucose utilization by the cells [35e37]. Compounds
13a, 13b, 13c, 6, 9a, 13f and 13h exhibited significant glucose uptake
activity amongst the compounds screened. However, rosiglitazone,
a standard drug exhibited highest glucose uptake activity indi-
cating its supremacy over the title compounds. Compounds 13d,
13g, 9j, 9b and 9i have exhibited moderate glucose uptake activity.
Whereas, rest of the compounds exhibited weak glucose uptake
activity. Compound 13e alone failed to show any glucose uptake
activity both in presence and absence of insulin.
The structureeactivity relationships for the screened compounds
are asfollows. 5-Benzylidene-1,3-thiazolidine ring system is found to
be the pharmacophore structural part as all most all the compounds
possessed this substructure. Figs. 2 and 3 represent energy mini-
mized and aligned structures of glitazones from the present and
previous study, respectively [29]. Glitazones with polar thiazolidine-
2,4-dione as their head group produced good activity when
compared to their corresponding bioisoteres, 2-thioxo-thiazolidine-
4-ones 9b, 9d, 9f, 9h, 9j and 9k. Compound 13a, structurally con-
taining 4-methoxy benzylidene ring connected to 12 showed
maximum glucose uptake activity amongst all the compounds
istic broad singlet peak in the range of 12.5e13.9
d ppm to confirm
the presence of NH proton of thiazolidinedione or rhodanine
scaffolds in compounds 9ael. This large deshielding effect on NH
proton is attributed to the presence of electron withdrawing
carbonyl groups. The compounds obtained according to Schemes 2
and 3 (13aek), showed a characteristic peak for CH2 between 4.5
and 4.8 d ppm. In principle two geometrical isomers, namely, E and
Z are possible for all the Knoevenagel condensed products.
However, all the compounds exhibit only the Z configuration as
expected from our previous studies because in 1H NMR spectra,
peak for ]CH was found unusually between 7.7 and 8.2
NMR spectra showed signal for ]CH in Knoevenagel condensed
products at about 132 ppm. The reason for this deshielding is
d C
ppm. 13
d
attributed to the cis position of the carbonyl function of highly
electronegative TZD or 2-thioxo-thiazolidine-4-one ring to the ]
CH and hence the Z configuration. Cis positioning is due to the high
degree of thermodynamic stability of these compounds because of
the intramolecular hydrogen bond that can be formed between the
hydrogen atom of ]CH and the oxygen atom in TZD or 2-thioxo-
thiazolidine-4-one [29].
S
S
NH
O
Fig. 1. Structure of 2-thioxo-thiazolidine-4-one or rhodanine.

838
B.R.P. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 835e844
O
H
N
NH2
O
a
c
11
, b
Cl
S
N
O
N
H
10
O
12
d
H
N
K
N
O
O
O
O
O
H
S
S
11
N
1
4
3N
2
5
1
S
O
O
R
13a-k
Scheme 3. Reaction protocol for the synthesis of compounds 13aek. Reagents and conditions: (a) CHCl3, triethyl amine, chloroacetyl chloride, 0e5 ꢀC, stirred for 2 h; (b) DMF, 11,
stirred with reflux, 90 h; (c) C2H5OH, KOH, stirred, 1 h; (d) Dry toluene, substituted aldehydes, piperidine, acetic acid, reflux at 110 ꢀC for 10e14 h or MW at 700 W for 20e30 min.
reported. Compound 6, with similar substitution at the 5th position
of TZD ring and ethyl ester of glycine connected to the 3rd position of
TZDexhibits glucose uptake activitycloser to that of 13a. Compounds
belonging to the same series 13b, 13c, 13f and 13h with other
hydrophobic groups as their tail also produced significant glucose
uptake activity. Decreasing ring size from six membered benzene to
the five membered furan (13i) found to reduce the activity. Electron
donating hydroxyl group at ortho position over the benzylidene ring
in compound 13c showed good activity. However, surprisingly,
combination of hydroxyl group and methoxy groups at meta and
para positions in compound 13k reduced glucose uptake activity.
Compound 13e, alone from this series failed to produce any glucose
uptake activity with o-chloro benzene as its hydrophobic tail.
Compound 9a, with aniline as its tail alone produced significant
glucose uptake activity from its series of compounds having
hydrophobic tails connected to the 5-benzylidene structure via
a two carbon acyl linker. Rest of the compounds from this series
produced moderate glucose uptake activity (9b, 9gel).
6.1. Chemistry
6.1.1. Synthesis of thiazolidine-2,4-dione (1)
Equimolar amounts of chloroacetic acid (0.6 M) and thiourea
(0.6 M) were dissolved each in 60 ml of water separately and mixed
slowly at 0e5 ꢀC and stirred for 20 min to form a white precipitate
of 2-imino-thiazolidine-4-one. Conc. HCl (60 ml) was added and
refluxed for about 10e12 h. Reaction was monitored through TLC
(Chloroform: Methanol, 9:1). Reaction mixture was allowed to cool
to form white solid crystals, washed with water and dried. White
crystals, yield 79%, m.p. 123e125 ꢀC; IR (KBr) nmax in cmꢁ1: 3132
(NeH), 1739 (C]O), 1734 (C]O); 1H NMR (DMSO-d6, 400 MHz)
d
ppm: 4.42 (s, 2H, CH2), 12.54 (bs, 1H, NH).
6.1.2. Synthesis of ethyl-2-aminoacetate (2)
To a suspension of glycine (0.04 M) in 40 ml of ethanol on an ice
bath, thionyl chloride (0.16 M) was added drop wise for about
45 min at 0e5 ꢀC and later refluxed for 1 h. Reaction was monitored
through TLC by staining the plates with Ninhydrin reagent. The
excess of ethanol was distilled off by adding 50 ml of toluene and
the residue obtained was dried to get white crystals of 2.
5. Conclusion
New glitazones have been manually designed, synthesized and
evaluated for their glucose uptake activity using rat hemi-dia-
phragm. Among the glitazones investigated, compounds 13a, 13b,
13c, 6,13f and 13h have exhibited significant glucose uptake activity.
Compound 13a happens to be the most potent of all the glitazones
reported here. These results indicate a need for the agonistic study of
6.1.3. Synthesis of ethyl 2-(2-chloroacetamido) acetate (3)
An equimolar solution of ethyl-2-aminoacetate 2 (0.2 M) and
triethyl amine (0.2 M) in dry chloroform (50 ml) was stirred at
0e5 ꢀC. Chloroacetyl chloride (0.21 M) was added drop wise for
a period of about 30e45 min and later stirred for 24e30 h. The
reaction was monitored through TLC by staining the plates with
Ninhydrin reagent. After completion of the reaction, solvent was
distilled off. The solid obtained was washed with NaHCO3, later
with water and dried over anhydrous Na2SO4. White crystalline
solid, yield 35%; m.p. 45e50 ꢀC; IR (KBr) nmax in cmꢁ1: 3269 (NeH),
1739 (C]O), 1649 (C]O), 717 (CeCl); 1H NMR (DMSO-d6,
these compounds toward PPAR-
g and PPAR-a receptors followed by
in vivo studies to prove their potency and efficacy.
6. Experimental protocols
All the synthetic work was done by procuring required labora-
tory and analytical grade chemicals, reagents and solvents. Solvents
were purified and dried according to the standard procedures.
Microwave assisted synthesis was performed using scientific
microwave system CATA R from Catalyst Systems (Pune, India). The
melting points of the synthesized compounds were determined
using VeegoVMP-1 apparatus and are uncorrected. The IR spectra
were recorded on Shimadzu FT-IR spectrometer using KBR pellet
technique and are expressed in cmꢁ1. 1H NMR and 13C NMR spectra
were recorded on AV-III 400 and 500 MHz spectrometer using
DMSO-d6 as solvent and TMS as internal standard. Mass spectra
were recorded using PerkineElmer-high resolution mass spec-
trometer (HRMS) under electro spray ionization technique using
time of flight mass analyzer. Auto analyzer (Merck-Microlab 200)
was used for the estimation of glucose.
500 MHz)
d ppm: 1.30 (t, 3H, CH3), 3.85 (s, 2H, CH2), 4.10 (q, 2H,
CH2), 4.19 (s, 2H, CH2), 8.70 (bs, 1H, NH).
6.1.4. Procedure for the Knoevenagel condensation reaction 4
To a suspension of thiazolidinedione 1 (0.01 M) in dry toluene,
anisaldehyde (0.01 M), catalytic amounts of piperidine (0.0005 M),
acetic acid (0.0005 M) and 4e5 dried molecular sieves were added.
Under conventional method, the reaction mixture was stirred for
about 5 min and refluxed at 110 ꢀC with occasional stirring for
10e14 h. Under microwave method, reaction mixture was stirred
for about 5 min and then irradiated with microwaves at 700 W
power for about 20e30 min. The reaction was monitored through
TLC. The reaction mixture was allowed to cool, precipitate obtained
was filtered and recrystallized with aqueous ethanol.

B.R.P. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 835e844
839
Table 1
Structures of the synthesized glitazones and comparative data for the Knoevenagel condensation reaction under microwave and conventional methods.
Comp
R1
S
N
R
X
4
9a-l
Ethyl 2-acetamidoacetate
H
O
R1
13a-k N-Phenylacetamide
Comp
R
X
Reaction Time
MW(min)
Yield (%)
MW
Conv(h)
10
Conv
H3CO
6
O
20
19
17
9a
9b
O
S
25
20
10
10
85
88
70
72
O
O
NH
9c
9d
O
S
25
20
12
10
80
82
68
69
O
O
O
NH
9e
9f
O
S
30
30
13
13
65
60
50
50
O
NH
9g
9h
O
S
32
30
14
14
55
53
52
50
O
O
NH
9i
9j
O
S
30
30
10
10
75
78
70
71
O
O
H3CO
H3C
NH
9k
9l
O
S
30
30
11
13
65
68
50
50
O
O
NH
H3CO
Cl
13a
13b
O
O
28
30
10
14
79
80
70
75
Cl
OH
13c
13d
O
O
30
35
10
13
78
68
73
55
(continued on next page)

840
B.R.P. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 835e844
Table 1 (continued )
Comp
R
X
Reaction Time
MW(min)
Yield (%)
MW
Conv(h)
14
Conv
58
Cl
13e
13f
O
O
25
25
65
68
Cl
13
60
Cl
13g
13h
O
O
25
20
12
10
65
78
55
75
13i
13j
O
O
O
30
31
10
12
80
40
72
35
O2N
HO
13k
O
30
10
74
68
O
6.1.5. Procedure for the synthesis of the potassium salt of 5-arylidene-
thiazolidine-2,4-diones 5
To a suspension of 5-arylidene-2,4-thiazolidinedione 4 (0.25 M)
in 50 ml of ethanol, potassium hydroxide (15.4 g, 0.275 M) was
added and stirred at room temperature for about 1 h and warmed
on steam water bath for 10 min. The solid potassium salt of TZD was
collected by filtration and dried under vacuum.
Table 2
Glucose uptake activity of the synthesized glitazones at two different dose levels
both in absence and presence of insulin.
S. No. Comp Glucose uptake (mg/dl/45 min)
No insulin
1 mg
With insulin
1 mg
6.1.6. Procedure for the synthesis of (Z)-ethyl-2-(2-(5(4-methoxyben-
zylidene)-2,4-dioxothiazolidin-3-yl)acetamido)acetate (6)
2 mg
2 mg
To a suspension of the potassium salt of 5-arylidene-2,4-thia-
zolidinediones (0.02 M) in 50 ml of DMF, compound 3 was added
slowly with stirring. Reaction mixture was refluxed with continued
stirring for about 96 h. Reaction was monitored through TLC. After
completion, reaction mixture was poured into ice cold water
(500 ml), formed solid product was collected after filtration. The
resultant solid 6 was recrystallized using methanol. White amor-
1
2
3
4
5
6
7
8
6
18.28 ꢂ 1.30** 18.79 ꢂ 0.42** 41.50 ꢂ 4.42** 43.07 ꢂ 2.36**
18.46 ꢂ 2.16** 18.50 ꢂ 2.22** 41.16 ꢂ 1.30** 42.69 ꢂ 1.25**
16.16 ꢂ 1.47** 16.33 ꢂ 1.66** 34.66 ꢂ 1.66** 35.33 ꢂ 2.49**
9a
9b
9g
9h
9i
9j
9k
9l
15.82 ꢂ 3.60* 15.00 ꢂ 3.36
14.50 ꢂ 1.42 15.66 ꢂ 1.33
29.00 ꢂ 1.36** 29.80 ꢂ 1.30**
28.83 ꢂ 0.30* 28.50 ꢂ 1.52*
16.66 ꢂ 1.55** 16.83 ꢂ 2.60** 34.16 ꢂ 1.47** 35.66 ꢂ 2.42**
16.91 ꢂ 1.67** 17.01 ꢂ 0.90** 35.00 ꢂ 1.77** 37.09 ꢂ 0.36**
16.00 ꢂ 1.73** 16.16 ꢂ 1.30** 33.83 ꢂ 2.47** 33.50 ꢂ 1.50**
phous solid, yield 17%; m.p. 238e240 ꢀC; IR (KBr) nmax in cmꢁ1
3296 (NeH), 3061 (ArCeH), 2953 (AliCeH), 1739 (C]O), 1681 (C]
O), 1180 (ester CeO); 1H NMR (DMSO-d6, 500 MHz)
ppm: 1.21 (t,
:
9
15.33 ꢂ 0.49
16.56 ꢂ 1.30** 33.79 ꢂ 1.30** 34.16 ꢂ 0.47**
10
11
12
13
14
15
16
17
18
19
20
13a
13b
13c
18.71 ꢂ 2.36** 19.66 ꢂ 1.42** 42.16 ꢂ 1.40** 43.90 ꢂ 0.42**
18.33 ꢂ 1.33** 18.50 ꢂ 2.42** 41.93 ꢂ 2.49** 42.44 ꢂ 1.30**
18.00 ꢂ 0.36** 18.33 ꢂ 1.21** 41.85 ꢂ 0.40** 42.26 ꢂ 1.33**
d
3H, CH3), 3.83 (s, 3H, CH3), 3.88 (q, 2H, CH2), 4.13 (d, 2H, CH2), 4.32
(s, 2H, CH2), 7.11 (d, 2H, AreH), 7.60 (d, 2H, AreH), 7.95 (s,1H, ]CH),
8.70 (bs, 1H, NH); HRMS (ES-TOF) m/z found 411.1079 (M þ Na),
calculated 411.0895 (M þ Na).
13d 15.00 ꢂ 1.36
16.16 ꢂ 1.30** 36.16 ꢂ 1.47** 36.66 ꢂ 1.33**
13e
13f
13g
13.81 ꢂ 0.30
14.03 ꢂ 1.60
26.03 ꢂ 1.49
27.16 ꢂ 0.47
17.83 ꢂ 0.30** 17.63 ꢂ 4.30** 39.00 ꢂ 1.36** 40.500 ꢂ 0.42**
16.83 ꢂ 1.24** 16.90 ꢂ 1.36** 36.03 ꢂ 1.47** 36.66 ꢂ 1.61**
13h 17.72 ꢂ 2.30** 18.00 ꢂ 1.25** 38.30 ꢂ 3.49** 39.00 ꢂ 0.25**
13i
13k 15.50 ꢂ 1.50
Std
19.00 ꢂ 2.73** 20.36 ꢂ 1.70** 48.34 ꢂ 4.49** 50.33 ꢂ 5.29**
15.66 ꢂ 1.55
15.86 ꢂ 1.30* 32.16 ꢂ 0.70** 32.29 ꢂ 3.55**
6.1.7. Procedure for the acylation of substituted amines (7)
Acylated amines 7 were prepared by following the procedure
described for the preparation of compound 3 by taking corre-
sponding substituted amine as a substrate.
16.96 ꢂ 1.47** 28.50 ꢂ 1.34* 30.83 ꢂ 1.65**
Group 1(Tyrode): 14.166 ꢂ 0.477; Group 2 (Insulin): 26.51 ꢂ 1.522*; **p < 0.01,
*p < 0.05, Std: Rosiglitazone; Values are mean ꢂ SEM; n ¼ 3.

B.R.P. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 835e844
841
6.1.9.2. (Z)-2-(4-((4-Oxo-2-thioxothiazolidin-5-ylidine)methyl)phe-
noxy)-N-phenylacetamide (9b). Yellowish amorphous solid, yield
72%; m.p. 225e228 ꢀC; IR (KBr) nmax in cmꢁ1: 3365 (NeH), 3053
(NeH), 1712 (C]O), 1651 (C]O), 1197 (C]S), 1170 (ester CeO). 1H
NMR (DMSO-d6, 500 MHz)
d ppm: 4.86 (s, 2H, CH2), 7.08 (t, 1H,
AreH), 7.17 (d, 2H, AreH), 7.33 (t, 2H, AreH), 7.62 (m, 4H, AreH),
7.60 (s, 1H, C]CH), 10.52 (bs, 1H, NH), 13.70 (bs, 1H, rhodanine NH).
HRMS (ES-TOF) m/z found 393.0369 (M þ Na), calculated 393.0401
(M þ Na).
6.1.9.3. (Z)-N-Benzyl-2-(4-((2,4-dioxothiazolidin-5-ylidine)methyl)
phenoxy)acetamide (9c). White amorphous solid, yield 68%; m.p.
230e233 ꢀC; IR (KBr) nmax in cmꢁ1: 3342 (NeH), 3111 (NeH), 1739
(C]O), 1689 (C]O), 1182 (ester CeO). 1H NMR (DMSO-d6,
500 MHz) d ppm: 4.43 (d, 2H, CH2), 4.57 (s, 2H, CH2), 7.1e7.4 (m, 5H,
AreH), 7.60 (d, 2H, AreH), 7.87 (d, 2H, AreH), 7.95 (bt, 1H, NH), 8.74
(s, 1H, ]CH), 12.50 (bs, 1H, thiazolidinedione NH); HRMS (ES-TOF)
m/z found 391.08101 (M þ Na), calculated 391.08216 (M þ Na).
Fig. 2. Glitazones of the present study after energy minimization and alignment using
Sybyl 6.7.
6.1.8. General procedure for connecting various acylated amines to
the p-hydroxy benzaldehyde (8)
6.1.9.4. (Z)-N-Benzyl-2-(4-((4-oxo-2-thioxothiazolidin-5-ylidine)
methyl)phenoxy)acetamide (9d). Yellowish amorphous solid, yield
69%; m.p. 235e238 ꢀC; IR (KBr) nmax in cmꢁ1: 3385 (NeH), 3061
(NeH), 1724 (C]O), 1662 (C]O), 1195 (C]S), 1165 (ester CeO);
To a solution of acylated amine 7 (0.02 M) in dry acetone,
4-hydroxy benzaldehyde (0.022 M), and triturated anhydrous
K2CO3 (0.021 M) were added and stirred at 30e34 ꢀC for about
40e48 h. The reaction was monitored by TLC (pet ether:ethyl
acetate:methanol, 7:2:1). Subsequently the reaction mixture was
poured into water, extracted with 3 ꢃ 20 ml of ethyl acetate,
washed with 5% aqueous NaOH and saturated NaCl solutions. The
organic layer was evaporated and residue collected was purified
from column chromatography using 5% ethyl acetate in pet ether as
solvent over silica gel.
1H NMR (DMSO-d6, 500 MHz)
d ppm: 3.64 (d, 2H, CH2), 4.55 (s, 2H,
CH2), 7.10e7.90 (m, 9H, AreH), 7.70 (s, 1H, ]CH), 7.95 (d, 1H, NH),
13.70 (bs, 1H, rhodanine NH); HRMS (ES-TOF) m/z found 407.0633
(M þ Na), calculated 407.0582 (M þ Na).
6.1.9.5. (Z)-N-Cyclohexyl-2-(4-((2,4-dioxothiazolidin-5-ylidine)
methyl)phenoxy)acetamide (9e). Pale greenish amorphous solid,
m.p. 190e193 ꢀC; IR (KBr) nmax in cmꢁ1: 3294 (NeH), 3061 (NeH),
1737 (C]O), 1685 (C]O), 1178 (ester CeO); 1H NMR (DMSO-d6,
6.1.9. General procedure for the Knoevenagel condensation
reactions (9ael)
500 MHz) d ppm: 1.25 (m, 4H, 2CH2), 1.57 (m, 2H, CH2), 1.71 (m, 4H,
2CH2), 3.34 (m, 1H, CH), 4.53 (s, 2H, CH2), 7.09 (d, 2H, AreH), 7.56
(d, 2H, AreH), 7.74(s, 1H, ]CH), 7.95(d, 1H, NH), 12.47(bs, 1H, thia-
zolidinedione NH); HRMS (ES-TOF) m/z found 383.1325 (M þ Na),
calculated 383.1204(M þ Na).
Compounds 9ael were prepared by following the procedure for
Knoevenagel condensation reaction as described for the synthesis
of compound 4.
6.1.9.1. (Z)-2-(4-((2,4-Dioxothiazolidin-5-ylidine)methyl)phenoxy)-
N-phenylacetamide (9a). Pale brown amorphous solid, yield 70%;
m.p. 218e221 ꢀC; IR (KBr) nmax in cmꢁ1: 3387 (NeH), 3144 (NeH),
1739 (C]O), 1685 (C]O), 1176 (ester CeO); 1H NMR (DMSO-d6,
6.1.9.6. (Z)-N-Cyclohexyl-2-(4-((4-oxo-2-thioxothiazolidin-5-ylidine)
methyl)phenoxy)acetamide (9f). Yellowish amorphous solid, yield
50%; m.p. 205e209 ꢀC; IR (KBr) nmax in cmꢁ1: 3402 (NeH), 3034
(NeH), 1707(C]O), 1654 (C]O), 1195 (C]S), 1172 (ester CeO); 1H
500 MHz)
d ppm: 4.82 (s, 2H, CH2), 7.08 (t, 1H, AreH), 7.17 (m, 2H,
NMR (DMSO-d6, 500 MHz)
d ppm: 1.21 (m, 4H, 2CH2), 1.57 (m, 2H,
AreH), 7.33 (t, 2H, AreH), 7.58 (d, 2H, AreH), 7.58 (d, 2H, AreH), 7.71
(s, 1H, ]CH), 10.54 (s, 1H, NH), 12.57 (bs, 1H, thiazolidinedione NH);
CH2),1.70 (m, 4H, 2CH2), 3.34 (m,1H, CH), 4.53 (s, 2H, CH2), 7.06e7.11
(m, 2H, AreH), 7.56e7.61(m, 2H, AreH), 7.91 (s, 1H, ]CH), 13.7 (bs,
1H, rhodanine NH); HRMS (ES-TOF) m/z found 399.0986 (M þ Na),
calculated 399.1077 (M þ Na).
13C NMR (DMSO-d6, 125 MHz)
d ppm: 67.52 (CH2), 115.65 (]C),
116.05, 120.16, 121.22, 124.22, 126.56, 129.22, 130.58, 130.60, 132.21,
132.47, 138.78, 160.00 (aromatic carbons), 132.12 (]CH), 166.48
(C]O), 167.91 (C]O), 168.43 (C]O); HRMS (ES-TOF) m/z found
377.0981 (M þ Na), calculated 377.0586 (M þ Na).
6.1.9.7. (Z)-N-(2,6-Diethylphenyl)-2-(4-((2,4-dioxothiazolidin-5-yli-
dine)methyl)phenoxy)acetamide (9g). White amorphous solid, yield
50%; m.p. 229e233 ꢀC; IR (KBr) nmax in cmꢁ1: 3201 (NeH), 3037
(NeH),1741 (C]O),1691 (C]O),1178 (ester CeO); 1H NMR (DMSO-
d6, 400 MHz)
d ppm: 1.22 (m, 6H, 2CH3), 2.50 (m, 4H, 2CH2), 4.53
(s, 2H, CH2), 7.09 (d, 2H, AreH), 7.61 (d, 2H, AreH), 7.69 (d, 2H,
AreH), 7.78 (s, 1H, ]CH), 7.99 (t, 1H, AreH), 12.53 (bs, 1H, thiazoli-
dinedione NH); HRMS (ES-TOF) m/z found 433.1287 (M þ Na),
calculated 433.1308 (M þ Na).
6.1.9.8. (Z)-N-(2,6-Diethylphenyl)-2-(4-((4-oxo-2-thioxothiazolidin-
5-ylidine)methyl)phenoxy)-acetamide (9h). Yellowish amorphous
solid, yield 52%; m.p. 242e245 ꢀC; IR (KBr) nmax in cmꢁ1: 3225
(NeH), 3037 (NeH), 1714 (C]O), 1651 (C]O), 1197 (C]S), 1176
(ester CeO); 1H NMR (DMSO-d6, 400 MHz)
d ppm: 1.22 (m, 6H,
2CH3), 2.53 (m, 4H, 2CH2), 4.81 (s, 2H, CH2), 7.09 (d, 2H, AreH), 7.61
(d, 2H, AreH), 7.69(d, 2H, AreH), 7.78(s, 1H, ]CH), 7.99 (t, 1H,
Fig. 3. Glitazones of our previous study after energy minimization and alignment
using Sybyl 6.7 [29].

842
B.R.P. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 835e844
AreH), 9.55 (s, 1H, NH), 13.68 (bs, 1H, rhodanine NH). HRMS (ES-
TOF) m/z found 449.1009 (M þ Na), calculated 449.1088 (M þ Na).
6.1.13.1. (Z)-2-(5-(4-Methoxybenzylidine)-2,4-dioxothiazolidin-3-
yl)-N-phenylacetamide (13a). Pale brown amorphous solid, yield
70%; m.p. 201e204 ꢀC; IR (KBr) nmax in cmꢁ1: 3300 (NeH), 2929
(CeH), 1741 (C]O), 1685 (C]O), 1180 (ether CeO); 1H NMR
6.1.9.9. (Z)-2-(4-((4-Oxo-2-thioxothiazolidin-5-ylidine)methyl)phe-
noxy)-N-(4-methoxyphenyl)-acetamide (9i). Pale brownish amor-
(DMSO-d6, 500 MHz) d ppm: 3.84 (s, 3H, CH3), 4.51 (s, 2H, CH2), 7.08
phous solid, yield 50%; m.p. 245e247 ꢀC; IR (KBr) nmax in cmꢁ1
:
(t, 1H, AreH), 7.14 (m, 4H, AreH), 7.33 (t, 2H, AreH), 7.64 (d, 2H,
3389 (NeH), 3126 (NeH), 3026 (Methoxy OCH3), 1737 (C]O), 1683
AreH), 7.95 (s, 1H, ]CH), 10.39 (s, 1H, NH); 13C NMR (DMSO-d6,
(C]O),1186 (ester CeO); 1H NMR (DMSO-d6, 400 MHz)
d
ppm: 3.70
125 MHz) d ppm: 44.45 (CH2), 56.02 (OCH3), 118.16 (]C), 124.16
(s, 3H, CH3), 4.75 (s, 2H, CH2), 6.90 (d, 2H, AreH), 7.25 (d, 1H, AreH),
7.05 (d, 1H, AreH), 7.15 (d, 2H, AreH), 7.51 (d, 1H, AreH), 7.19 (d, 1H,
AreH), 7.75 (s,1H, ]CH), 10.0 (s, 1H, NH), 12.5 (bs, 1H, thiazolidi-
nedione NH); HRMS (ES-TOF) m/z found 407.0401 (M þ Na),
calculated 407.0518 (M þ Na).
(]CH), 115.51, 115.53, 119.63, 119.65, 125.81, 129.34, 129.36, 132.85,
132.87, 134.07, 138.87, 161.79 (aromatic carbons), 164.31 (C]O),
165.89 (C]O), 167.68 (C]O); HRMS (ES-TOF) m/z found 391.0694
(M þ Na), calculated 391.0797 (M þ Na).
6.1.13.2. (Z)-2-(5-(2,4-Dichlorobenzylidine)-2,4-dioxothiazolidin-3-
yl)-N-phenylacetamide (13b). Pale yellow amorphous solid, yield
75%; m.p. 211e213 ꢀC; IR (KBr) nmax in cmꢁ1: 3261 (NeH), 1743
(C]O), 1701 (C]O), 1656 (C]O); 1H NMR (DMSO-d6, 400 MHz)
6.1.9.10. (Z)-N-(4-Methoxyphenyl)-2-(4-((4-oxo-2-thioxothiazolidin-
5-ylidine)methyl)phenoxy)-acetamide (9j). Yellowish amorphous
solid, yield 71%; m.p. 250e253 ꢀC; IR (KBr) nmax in cmꢁ1: 3398
(NeH), 3134 (NeH), 2999 (Methoxy OCeH), 1734 (C]O), 1687 (C]
O), 1182 (C]S), 1172 (ester CeO); 1H NMR (DMSO-d6, 400 MHz)
d
ppm: 4.50 (s, 2H, CH2), 7.07 (t, 1H, AreH), 7.33 (t, 1H, AreH), 7.55
(d, 2H, AreH), 7.65 (d, 2H, AreH), 7.81 (s, 1H, AreH), 8.10 (s, 1H, ]
CH),10.42 (s,1H, NH). HRMS (ES-TOF) m/z found 428.0018 (M þ Na),
calculated 427.9991 (M þ Na).
d
ppm: 3.75 (s, 3H, CH3), 4.82 (s, 2H, CH2), 6.91 (d, 2H, AreH), 7.25
(d, 2H, AreH), 7.05 (d, 2H, AreH), 7.15 (d, 2H, AreH), 7.21 (s,1H, ]
CH) 10.0 (s, 1H, NH), 13.7 (bs, 1H, rhodanine NH). HRMS (ES-TOF) m/
z found 423.0486 (M þ Na), calculated 423.0459 (M þ Na).
6.1.13.3. (Z)-2-(5-(2-Hydroxybenzylidine)-2,4-dioxothiazolidin-3-
yl)-N-phenylacetamide (13c). Yellow amorphous solid, yield 73%;
m.p. 235e238 ꢀC; IR (KBr) nmax in cmꢁ1: 3292 (Phenol OeH), 3055
(NeH), 1732 (C]O), 1676 (C]O), 1662 (C]O); 1H NMR (DMSO-d6,
6.1.9.11. (Z)-2-(4-((2,4-Dioxothiazolidin-5-ylidine)methyl)phenoxy)-
N-p-tolylacetamide (9k). Paleyellowish amorphous solid, yield 50%;
m.p. 235e238 ꢀC; IR (KBr) nmax in cmꢁ1: 3350 (NeH), 3064 (NeH),
1714 (C]O), 1697 (C]O), 1182 (ester CeO); 1H NMR (DMSO-d6,
400 MHz) d ppm: 2.9 (s,1H, OH), 4.5 (s, 2H, CH2), 6.97 (m, 2H, AreH),
7.06 (m,1H, AreH), 7.31 (m, 2H, AreH), 7.39(m,1H, AreH), 7.54 (t, 2H,
AreH), 7.88 (s, 1H, AreH), 8.25 (s, 1H, ]CH), 10.4 (s, 1H, NH); HRMS
(ES-TOF)m/zfound377.0583(Mþ Na), calculated377.0679(Mþ Na).
400 MHz)
d ppm: 2.54 (s, 3H, CH3), 4.50 (s, 2H, CH2), 7.04e7.15
(m, 4H, AreH), 7.39 (s, 1H, ]CH), 7.41e7.52 (m,4H, AreH), 9.90
(s,1H, NH),12.52 (bs,1H, thiazolidinedione NH); HRMS (ES-TOF) m/z
found 391.0699 (M þ Na), calculated 391.0715 (M þ Na).
6.1.13.4. (Z)-2(2,4-Dioxo-5-(3-phenylallylidene)thiazolidin-3-yl)-N-
phenylacetamide (13d). Yellow amorphous solid, yield 55%; m.p.
197e200 ꢀC; IR (KBr) nmax in cmꢁ1: 3325 (NH), 1741 (C]O), 1689
6.1.9.12. (Z)-2-(4-((4-Oxo-2-thioxothiazolidin-5-ylidine)methyl)phe-
noxy)-N-p-tolylacetamide (9l). Pale brownish amorphous solid,
yield 50%; m.p. 239e242 ꢀC; IR (KBr) nmax in cmꢁ1: 3284 (NeH),
3036 (NeH),1685 (C]O),1664 (C]O),1199 (C]S),1176 (ester CeO).
(C]O), 1666 (C]O); 1H NMR (DMSO-d6, 400 MHz)
d ppm: 4.55
(s, 2H, CH2), 7.15 (d, 1H, ]CH), 7.21 (d, 1H, ]CH), 7.61 (s, 1H, ]CH),
7.65e7.65 (m, 10H, AreH), 10.50 (s, 1H, NH). HRMS (ES-TOF) m/z
found 387.0754 (M þ Na), calculated 387.0807 (M þ Na).
1H NMR (DMSO-d6, 400 MHz)
d ppm: 2.50 (s, 3H, CH3), 4.51 (s, 2H,
CH2), 7.04e7.20 (m, 4H, AreH) 7.39 (s, 1H, ]CH), 7.42e7.68 (m, 4H,
AreH), 9.91 (s,1H, NH),13.70 (bs,1H, rhodanineNH). HRMS (ES-TOF)
m/z found 407.0691 (M þ Na), calculated 407.0714 (M þ Na).
6.1.13.5. (Z)-2-(5-(2-Chlorobenzylidine)-2,4-dioxothiazolidin-3-yl)-
N-phenylacetamide (13e). Pale yellow amorphous solid, yield 58%;
m.p. 202e205 ꢀC; IR (KBr) nmax in cmꢁ1: 3273 (NeH), 1753 (C]O),
6.1.10. Synthesis of 2-chloro-N-phenylacetamide (10)
1703 (C]O), 1666 (C]O); 1H NMR (DMSO-d6, 400 MHz)
d ppm:
The compound 10 was prepared following the procedure
described for the preparation of compound 3 by taking aniline.
4.54 (s, 2H, CH2), 7.07 (t, 1H, AreH), 7.33 (t, 2H, AreH), 7.55 (d, 2H,
AreH), 7.65 (d, 2H, AreH), 7.88 (t, 2H, AreH), 8.11 (s, 1H, ]CH),
10.44 (s, 1H, NH); 13C NMR (DMSO-d6, 100 MHz)
d ppm: 44.01
6.1.11. Synthesis of potassium salt of thiazolidine-2,4-dione (11)
Compound 11 was prepared following the procedure for the
preparation of 5 by taking thiazolidine-2,4-dione.
(CH2), 124.78 (]C), 128.67 (]CH), 119.12, 119.14, 123.67, 128.14,
128.94, 128.99, 130.35, 130.83, 132.14, 132.16, 134.45, 138.31 (ArC),
163.60 (C]O), 164.85 (C]O), 166.79 (C]O). HRMS (ES-TOF) m/z
found 395.0321 (M þ Na), calculated 395.0298 (M þ Na).
6.1.12. 2-(2,4-Dioxothiazolidin-4-yl)-N-phenylacetamide (12)
Compound 12 was prepared as per the procedure followed for
synthesis of compound 6 by taking 11 in place of potassium salt of
5-arylidene-2,4-thiazolidinediones and 8 in place of 3. White
amorphous solid, yield 55%; IR (KBr) nmax in cmꢁ1: 3259 (Amide
NH), 1763 (ring C]O), 1685 (Amide C]O); 1H NMR (DMSO-d6,
6.1.13.6. (Z)-2-(5-(3-Chlorobenzylidine)-2,4-dioxothiazolidin-3-yl)-
N-phenylacetamide (13f). White amorphous solid, yield 60%; m.p.
207e210 ꢀC; IR (KBr) nmax in cmꢁ1: 3265 (NeH), 1753 (C]O), 1697
(C]O), 1670 (C]O); 1H NMR (DMSO-d6, 400 MHz)
d ppm: 4.50
(s, 2H, CH2), 7.12 (t,1H, AreH), 7.32 (t, 2H, AreH), 7.54 (d, 2H, AreH),
7.50e7.59 (m, 3H, AreH), 7.75 (s, 1H, AreH), 7.90 (s,1H, ]CH), 10.41
(s, 1H, NH); HRMS (ES-TOF) m/z found 395.0330 (M þ Na), calcu-
lated 395.0298 (M þ Na).
500 MHz)
d ppm: 4.33 (s, 2H, CH2), 4.34 (s, 2H, CH2), 7.07 (t, 1H,
AreH), 7.32 (t, 2H, AreH), 7.54 (d, 2H, AreH), 10.31 (s, 1H, NH).
6.1.13. General procedure for the Knoevenagel condensation of 2-
(2,4-dioxothiazolidin-4-yl)-N-phenylacetamide 12 with various
aldehydes (13aek)
Compounds 13aek were prepared by following the procedure
for Knoevenagel condensation reaction described above for the
synthesis of compound 6.
6.1.13.7. (Z)-2-(5-(4-Chlorobenzylidine)-2,4-dioxothiazolidin-3-yl)-
N-phenylacetamide (13g). Brown amorphous solid, yield 55%; m.p.
206e208 ꢀC; IR (KBr) nmax in cmꢁ1: 3279 (NeH), 1745 (C]O), 1697
(C]O), 1666 (C]O); 1H NMR (DMSO-d6, 400 MHz)
d
ppm: 4.52
(s, 2H, CH2), 7.07 (t,1H, AreH), 7.33 (t, 2H, AreH), 7.55 (d, 2H, AreH),

B.R.P. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 835e844
843
7.65 (d, 2H, AreH), 7.88 (d, 2H, AreH), 7.88 (s, 1H, ]CH), 10.4 (s, 1H,
NH). HRMS (ES-TOF) m/z found 395.0326 (M þ Na), calculated
395.0298 (M þ Na).
water ad libitum, and fasted overnight. The animals were killed by
decapitation under ether anaesthesia and diaphragms were taken
out swiftly avoiding trauma and divided into two halves and weight
was noted. The hemi-diaphragms were then rinsed in cold Tyrode
solution (without glucose) to remove any blood clots and quickly
transferred to the respective wells. The plates were closed with the
lids and incubated for 45 min at 21 ꢀC with shaking at 60 cycles
per min. Following the incubation, the glucose content of the
incubated wells was measured by GOD/POD enzymatic method
using Merckotest glucose kit.
6.1.13.8. (Z)-2-(5-(Benzylidine)-2,4-dioxothiazolidin-3-yl)-N-phenyl-
acetamide (13h). White amorphous solid, yield 75%; m.p.
202e205 ꢀC; IR (KBr) nmax in cmꢁ1: 3275 (NeH), 1749 (C]O), 1697
(C]O), 1662 (C]O); 1H NMR (DMSO-d6, 400 MHz)
d ppm: 4.52
(s, 2H, CH2), 7.07 (t,1H, AreH), 7.32 (t, 2H, AreH), 7.54 (m, 5H, AreH),
7.67 (d, 2H, AreH), 7.90 (s,1H, ]CH),10.4 (s,1H, NH); HRMS (ES-TOF)
m/z found 361.0561 (M þ Na), calculated 361.0759 (M þ Na).
Acknowledgment
6.1.13.9. (Z)-2-(5-(Furan-2-ylmethylene)-2,4-dioxothiazolidin-3-yl)-
N-phenylacetamide (13i). Pale orange amorphous solid, yield 72%;
m.p. 213e216 ꢀC; IR (KBr) nmax in cmꢁ1: 3275 (NeH), 1741 (C]O),
Prashantha Kumar and Mukesh Soni would like to thank all the
staff members of department of pharmacology, JSS College of
Pharmacy, Ootacamund, for the help rendered during pharma-
cology experiments.
1693 (C]O), 1664 (C]O); 1H NMR (DMSO-d6, 400 MHz)
d ppm:
4.51 (s, 2H, CH2), 6.79 (d, 1H, AreH), 7.04 (t, 1H, AreH), 7.18 (d, 2H,
AreH), 7.32 (t, 1H, AreH), 7.56 (t, 2H, AreH), 7.82 (s, 1H, ]CH), 8.14
(d,1H, AreH), 10.4 (s, 1H, NH); HRMS (ES-TOF) m/z found 351.0491
(M þ Na), calculated 351.0380 (M þ Na).
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O), 1682 (C]O); 1H NMR (DMSO-d6, 400 MHz)
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CH2), 7.24 (t, 1H, AreH), 7.43 (t, 2H, AreH), 7.61 (d, 2H, AreH),
7.69e7.78 (m, 3H, AreH), 7.90 (s, 1H, ]CH), 7.80 (s,1H, AreH),10.52
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6.1.13.11. (Z)-2-(5-(3-Hydroxy-4-methoxybenzylidine)-2,4-dioxo-
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6.95 (d, 2H, AreH), 7.07 (t, 1H, AreH), 7.15 (t, 1H, AreH), 7.26 (s, 1H,
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m
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