Synthesis, hypoglycemic and hypolipidemic activities of novel thiazolidinedione derivatives containing thiazole/triazole/oxadiazole ring

Article abstract of DOI:10.1016/j.ejmech.2012.04.015

Novel thiazolidinedione derivatives were synthesized by incorporating pharmacologically significant heterocycles viz, substituted thiazole, triazole, and oxadiazole moieties linked to the central phenyl ring via heteroatomlinkage with one/two carbon spacer as the structural analogs of Pioglitazone by employing multistep synthetic protocols. Structures of all the newly synthesized intermediates and target molecules were established by analytical and spectral data. These newly synthesized compounds were screened for their invivo hypoglycemic and hypolipidemic activities in male wistar rats. Some of the synthesized compounds demonstrated good activity.

Full text of DOI:10.1016/j.ejmech.2012.04.015

European Journal of Medicinal Chemistry 53 (2012) 308e315
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, hypoglycemic and hypolipidemic activities of novel thiazolidinedione
derivatives containing thiazole/triazole/oxadiazole ring
A.K. Mohammed Iqbal a, Ashraf Y. Khan a, Mallikarjun B. Kalashetti a, Ningaraddi S. Belavagi a,
,
Young-Dae Gong b, Imitiyaz Ahmed M. Khazi a
*
a Department of Chemistry, Karnatak University, Pavate Nagar, Dharwad, Karnataka 580003, India
b Center for Innovative Drug Library Research, Science College, Dongguk University, Seoul, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel thiazolidinedione derivatives were synthesized by incorporating pharmacologically significant
heterocycles viz, substituted thiazole, triazole, and oxadiazole moieties linked to the central phenyl ring
via heteroatomlinkage with one/two carbon spacer as the structural analogs of Pioglitazone by
employing multistep synthetic protocols. Structures of all the newly synthesized intermediates and
target molecules were established by analytical and spectral data. These newly synthesized compounds
were screened for their invivo hypoglycemic and hypolipidemic activities in male wistar rats. Some of the
synthesized compounds demonstrated good activity.
Received 17 December 2011
Received in revised form
5 April 2012
Accepted 12 April 2012
Available online 21 April 2012
Keywords:
Ó 2012 Elsevier Masson SAS. All rights reserved.
Thiazolidinediones
Pioglitazone analogs
Hypoglycemic activity
Hypolipidemic activity
1. Introduction
least side effects. Our strategies to accomplish these goals were
to pursue modifications in the composition and nature of the
Thiazolidinediones are synthetic, high-affinity ligands of
peroxisome proliferator activated receptor-gamma (PPAR ), which
are members of a super family of nuclear receptors that include
steroid, retinoid, and thyroid hormone receptors [1e3]. These
receptors play a pivotal role in regulating the expression of a large
number of genes involved in lipid metabolism and energy balance
linker that joins the central phenyl ring and the lipophilic tail,
we replaced the 5-ethyl-pyridine moiety of Pioglitazone with
pharmacologically important substituted thiazole, triazole and
oxadiazole which were connected to the central phenyl ring via
oxymethyl and thioethyloxy linkage with one/two carbon
spacer.
g
[4]. It has been shown that PPAR
g located in nucleus is able to
increase the insulin sensitivity, promote the differentiation of lip-
ocytes, and retard the occurrence of complications.
2. Results and discussion
Pioglitazone (Fig. 1) was identified as the first high-affinity
2.1. Chemistry
ligand for peroxisome proliferator-activated receptor
g (PPARg)
[5,6]. Thiazolidinedione compounds are predicted to be prom-
ising compounds, capable of ameliorating non-insulin-
dependent diabetes mellitus (NIDDM) by improving insulin
resistance without inducing hypoglycemia. However these drugs
are found to have undesirable side effects including weight gain
and edema [7,8]. These observations prompted us to undertake
the synthesis of structural analogs of Pioglitazone with a hope of
getting compounds with improved hypoglycemic activity and
The general strategy for the synthesis of target molecules is
shown in Schemes 1 and 2. The required starting material, 4-
chloromethyl-2-methyl/phenyl thiazoles 2(aeb) were prepared in
good yields from the reaction of thioacetamide/thiobenzamide and
1,3-dichloroacetone (Scheme 1) [9,10]. This on coupling with p-
hydroxybenzaldehyde in presence of anhydrous potassium
carbonate in dry acetone furnished the intermediate 4-(2-methyl/
phenyl-thiazol-4-ylmethoxy)-benzaldehyde 3(aeb). The structure
of these intermediates 3(aeb) were confirmed by their IR spectra,
which exhibited
and 1210 cmꢀ1 respectively. The 1H NMR spectra of these
compounds displayed characteristic aldehydic proton at 10.00
nC]O, nC] and nCeO bands around 1680, 1610
N
* Corresponding author. Tel.: þ91 836 2215286; fax: þ91 836 2771275.
E-mail addresses: drimkorgchem@gmail.com, dr_imk@yahoo.com (I.A.M. Khazi).
d
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.04.015

A.K. Mohammed Iqbal et al. / European Journal of Medicinal Chemistry 53 (2012) 308e315
309
showed the vinylic proton around
resonated at expected regions. The absence of aldehydic proton also
confirmed the formation of these compounds.
d
7.70 and the other protons
O
NH
The configuration of the title compounds were established
S
based on 1H NMR analysis (olefinic CeH around
d 7.70e7.90)
N
O
[18,19], theoretical calculations [20e23] and thermodynamic
stability [24,25]. All these observation support the Z configuration.
Hence the Z configuration was confirmed for the thiazolidinedione
derivatives.
O
Fig. 1. Pioglitazone.
and rest of the protons resonated in the expected region. The
reaction of 3(aeb) with thiazolidine-2,4-dione in toluene with
catalytic amount of piperidine-acetate afforded the target molecule
4(aeb) . The structures of thus obtained thiazolidine-2,4-dione
derivatives (4 aeb) were ascertained by their spectral and analyt-
ical data. The IR spectra of these compounds showed the presence
2.2. Hypoglycemic and hypolipidemic activities
All the synthesized thiazolidinedione analogs were screened
invivo for their plasma glucose (PG) and triglyceride (TG) lowering
activities in alloxan induced diabetic male wistar rats after oral
treatment for 15 days with different doses. Acute toxicity studies
were performed and doses were fixed. Pioglitazone was used as
a standard drug for comparison. The hypoglycemic and hypolipi-
demic effects after oral administration of all the synthesized
compounds in alloxan-induced model are summarized in terms of
percentage reduction of PG and TG levels, obtained from samples of
blood collected on final day of treatment.
of nC
along with nNeH, nC
NMR spectra displayed the absence of aldehyde proton and the
presence of vinylic proton around 7.80, confirming the formation
]
O for two carbonyl groups around 1730 cmꢀ1 and 1695 cmꢀ1
N and nCeO in their respective regions. The 1H
]
d
of condensed product. These compounds 3(aeb) and 4(aeb) were
further confirmed by their 13C NMR and mass spectra.
Substituted 2-mercaptotriazoles (5) and 2-mercaptooxadiazole
(6) required for the synthesis of second class of compounds
depicted in Scheme 2 were synthesized according to the literature
methods [11e16]. Synthon 7, which provided the bromoethyloxy
part of the target molecule, was prepared by condensation of
dibromoethane with p-hydroxybenzaldehde in DMF with potas-
sium carbonate [17].
The base catalyzed nucleophilic substitution reaction of bro-
moethyloxybenzaldehyde 7 with 2-mercaptotriazoles (5) and 2-
mercaptooxadiazoles (6) at room temperature yielded compound
8(aeh) and 9(aed) respectively. The intermediate 8 and 9 were
With our objective focused on improving insulin sensitivity to
decrease the PG and TG level, initially we introduced methyl/
phenyl substituted thiazole ring linked to the central phenyl ring
via oxymethyl linkage with one carbon spacer 4(aeb) which does
not shown impressive results (Table 1).
Further we introduce the triazole and oxadiazole ring linked to
the central phenyl ring via thioethyloxy linkage with two carbon
spacer. We began our optimization work by exploring the SAR at
the C-5 position of the triazole and oxadiazole. Introduction of
benzyl moiety and introduction of both electron-donating and
withdrawing groups at para and ortho position of the aromatic ring
does not show any significant hypoglycemic and hypolipidemic
activities. Further with introduction of methoxy group at para
position of phenyl ring present at C-5 position of triazole ring
(10h) caused a significant increase in insulin sensitivity. Similarly
introduction of 3-pyridyl ring (11c) and 4-pyridyl ring (11d) at C-5
position of the oxadiazole ring displayed increased insulin
sensitivity.
confirmed by their IR spectra where, aldehyde nC
around 1680 cmꢀ1 and the 1H NMR spectra displayed the aldehydic
proton around 9.7, along with the tripletetriplet pattern for
eCH2CH2e group i; e 3.67(t, 2H, SCH2) and 4.37(t, 2H,
]
O
appeared
d
d
d
OCH2).These intermediate 8 and 9 when refluxed with thiazoli-
dine-2,4-dione in toluene, along with catalytic amount of piperi-
dine acetate results in the formation of the target molecules 10,11in
good yields. They displayed the bands in the IR spectra for carbonyl
group of thiazolidinedione around 1735 cmꢀ1 and 1690 cmꢀ1, for
derivatives 8, nNeH was observed around 3100 cmꢀ1. The 1H NMR
Hence the results after 15 days of treatment (Tables 1e3)
revealed that incorporation of thioethyloxy linkage with two
carbon spacer connecting to triazole derivative (10h) and
Cl
N
NH2
O
i,ii
R
Cl
Cl
R
S
S
2(a-b)
1 (a-b)
OH
iii
CHO
O
N
S
R
N
CHO
R
iv
O
NH
O
S
S
O
4(a-b)
4(a-b): R = methyl (a), phenyl (b)
3(a-b)
Scheme 1. Synthesis of 5-[4-(2-methyl/phenyl-thiazol-4-ylmethoxy)-benzylidine]-thiazol idine-2,4-dione 4(aeb).

310
A.K. Mohammed Iqbal et al. / European Journal of Medicinal Chemistry 53 (2012) 308e315
N
N
O
i
N
N
O
Br
R1
S
X
SH
R1
X
CHO
CHO
5; X = NH
6; X = O
7
8; X = NH
9; X = O
ii
N
N
O
O
NH
R1
S
X
O
S
10; X = NH
11; X = O
10(a-h): X = NH; R1 = phenyl(a), benzyl(b), p-Me-phenyl(c), p-NO2-phenyl(d), o-NO2 –
phenyl(e), p-Cl-Phenyl(f), p-Br-phenyl(g), p-OMe-phenyl(h).
11(a-d): X = O; R1 = phenyl (a), benzyl (b), 3-pyridyl(c), 4-pyridyl (d).
Scheme 2. Synthesis of 5-(4-{2-[(5-aryl-4H-1,2,4-triazol-3-yl)thio]ethoxy}benzy lidene)-1,3-thiazolidine-2,4-dione 10(aeh) and 5-(4-{2-[(5-aryl-1,3,4-oxadiazol-2-yl)thio]ethoxy}
benzylidene)-1,3-thiazolidine-2,4dione 11(aed).
oxadiazole derivative (11c,11d) displayed good activities than the
compounds having either thioethyloxy linkage connected to tri-
azole/oxadiazole or oxymethyl linkage with one carbon spacer
connected to thiazole.
hyperglcaemia and cardiovascular complication. Hence it’s
concluded that incorporation of thioethyloxy linkage connecting to
triazole and oxadiazole may leads to development of novel potent
drug candidate.
3. Conclusions
4. Experimental
In this paper we have reported the design and synthesis of novel
thiazole, triazole and oxadiazole containing thiazolidinedione
derivatives. These compounds were screened for their invivo
hypoglycemic and hypolipidemic activities which show interesting
insulin sensitizing properties. Compound 10h, 11c and 11d dis-
played comparable hypoglycemic and hypolipidemic efficacy that
of standard. It is important to notice that 10h, 11c and 11d
significantly decreases plasma glucose and also lowers the
triglyceride level, which is preferable for treatment of both
4.1. Chemistry e general aspects
Melting points were determined in open capillaries and are
uncorrected. The IR spectra were recorded on Nicolet Impact 410
FTIR spectrophotometer using KBr pellets. 1H and 13C NMR were
recorded on Bruker 300-MHz and 75-MHz FT NMR spectrometer in
CDCl3, C6D6 and TFA with TMS as internal standard. Mass spectra
were recorded on Finnigan MAT (Model MAT8200) spectrometer
and elemental analyses were carried out using Heraus CHN rapid
Table 1
Plasma glucose and triglyceride level at various drug doses of 4(aeb).
O
N
R
O
NH
S
S
O
5-[4-(2-methyl/phenyl-thiazol-4-ylmethoxy)-benzylidine]-thiazolidine-2,4-dione.
Compound
R
% Decrease in plasma glucose (PG) and triglyceride (TG) level at various doses (mg/kg body weight)
3 mg
10 mg
30 mg
100 mg
Pioglitazone
e
TG
PG
TG
PG
41.60 ꢁ 2.25
47.02 ꢁ 14.39
18.62 ꢁ 0.43
10.42 ꢁ 4.23
47.25 ꢁ 5.50
35.25 ꢁ 20.42
19.20 ꢁ 2.01
10.64 ꢁ 1.18
64.59 ꢁ 5.42
40.96 ꢁ 17.59
26.40 ꢁ 1.97
14.73 ꢁ 3.75
75.43 ꢁ 3.40
45.89 ꢁ 2.24
38.92 ꢁ 1.46
22.87 ꢁ 1.73
4a
CH3
4b
TG
PG
25.24 ꢁ 0.65
17.75 ꢁ 1.85
21.69 ꢁ 1.73
20.36 ꢁ 1.20
40.26 ꢁ 1.10
22.64 ꢁ 4.05
53.96 ꢁ 0.66
29.73 ꢁ 1.39
Each value represents the mean ꢁ SEM (n ¼ 6). Percentage reduction was calculated according to the formula: [(PG in controlꢀPG in treated)/PG in control] ꢂ 100; [(TG in
controlꢀTG in treated)/TG in control] ꢂ 100.

A.K. Mohammed Iqbal et al. / European Journal of Medicinal Chemistry 53 (2012) 308e315
311
Table 2
Plasma glucose and triglyceride level at various drug doses of 10(aeh).
N
N
O
O
NH
R1
S
N
H
O
S
5-(4-{2-[(5-aryl-4H-1,2,4-triazol-3-yl)thio]ethoxy}benzylidene)-1,3-thiazolidine-2,4-dione.
Compounds
Pioglitazone
R1
% Decrease in plasma glucose (PG) and triglyceride (TG) level at various doses (mg/kg body weight)
3 mg
10 mg
30 mg
100 mg
e
TG
PG
41.60 ꢁ 2.25
47.02 ꢁ 14.39
47.25 ꢁ 5.50
35.25 ꢁ 20.42
64.59 ꢁ 5.42
40.96 ꢁ 17.59
75.43 ꢁ 3.40
45.89 ꢁ 2.24
10a
10b
10c
TG
PG
18.62 ꢁ 0.43
10.42 ꢁ 4.23
19.20 ꢁ 2.01
10.64 ꢁ 1.18
26.40 ꢁ 1.97
14.73 ꢁ 3.75
38.92 ꢁ 1.46
22.87 ꢁ 1.73
TG
PG
22.45 ꢁ 0.55
18.28 ꢁ 1.68
22.81 ꢁ 1.08
19.36 ꢁ 2.81
38.25 ꢁ 2.78
28.54 ꢁ 3.08
41.87 ꢁ 3.54
34.38 ꢁ 1.56
TG
PG
25.24 ꢁ 0.65
16.87 ꢁ 1.01
21.69 ꢁ 1.73
20.36 ꢁ 1.20
40.26 ꢁ 1.10
22.64 ꢁ 4.05
53.96 ꢁ 0.66
29.73 ꢁ 1.39
10d
10e
10f
TG
PG
14.12 ꢁ 2.06
11.92 ꢁ 1.04
15.32 ꢁ 1.82
13.85 ꢁ 0.92
18.56 ꢁ 1.82
16.02 ꢁ 3.08
22.08 ꢁ 2.18
18.04 ꢁ 1.28
O2N
NO2
TG
PG
19.84 ꢁ 1.24
14.58 ꢁ 0.85
20.91 ꢁ 1.05
15.28 ꢁ 1.37
38.64 ꢁ 1.83
20.14 ꢁ 2.12
49.12 ꢁ 1.56
26.84 ꢁ 1.98
TG
PG
23.85 ꢁ 0.52
16.04 ꢁ 0.57
24. 56 ꢁ 2.26
19.63 ꢁ 1.58
32.92 ꢁ 1.42
23.68 ꢁ 2.05
41.56 ꢁ 1.08
28.85 ꢁ 1.28
Cl
10g
10h
TG
PG
28.35 ꢁ 1.64
13.15 ꢁ 3.28
26.87 ꢁ 0.82
20.43 ꢁ 1.58
39.45 ꢁ 2.07
19.52 ꢁ 2.47
45.68 ꢁ 3.12
28.51 ꢁ 1.83
Br
TG
PG
43.14 ꢁ 2.10
41.28 ꢁ 2.06
42.63 ꢁ 3.21
33.62 ꢁ 2.13
59.46 ꢁ 3.82
40.04 ꢁ 1.84
71.24 ꢁ 1.30
43.42 ꢁ 0.50
MeO
Each value represents the mean ꢁ SEM (n ¼ 6). Percentage reduction was calculated according to the formula: [(PG in controlꢀPG in treated)/PG in control] ꢂ 100; [(TG in
controlꢀTG in treated)/TG in control] ꢂ 100.
analyzer. Thin layer chromatography (TLC) was performed on silica
gel plates (60 F254; Merck). Column chromatography was per-
formed using silica gel (100e200 mesh size; Merck).
anhydrous potassium carbonate for 6e7 h monitored by TLC. The
solid (K2CO3) was removed by filtration. Excess of solvent was
removed under reduced pressure and the concentrated mass was
kept for 5 h to afford pale yellow solid in moderate yield. It was
purified by column chromatography with ethyl acetateehexane
(30:70v/v to 50:50v/v).
4.1.1. Preparation of 4-chloromethyl-2-methyl/phenyl thiazole
2(aeb)
It was prepared in good yield from equimolar mixture of thio-
acetamide/thiobenzamide and 1,3-dichloroacetone according to
previously described method [9,10].
4.1.2.1. 4-(2-Methyl-thiazol-4-ylmethoxy)-benzaldehyde (3a). Yield
66%; Pale yellow granules (chloroform þ pet ether); m.p. 92e94 ꢃC;
IR (KBr)
CDCl3) d: 2.73(s, 3H, CH3), 5.26(s, 2H, CH2), 6.84(s, 1H, H5, thiazole),
y
cmꢀ1: 3044, 1675, 1608, 1535, 1208; 1H NMR (300 MHz,
4.1.2. General procedure for preparation of 4-(2-methyl/phenyl-
thiazol-4-ylmethoxy)-benzaldehyde 3(a,b)
A mixture of 2(aeb) (0.001 mol) and p-hydroxybenzaldehyde
(1.22 g, 0.001 mol) was refluxed in dry acetone in presence of
6.93(d, J ¼ 7.3 Hz, 2H, H3, H5, AreH), 7.68(d, J ¼ 7.3 Hz, 2H, H2, H6,
AreH), 9.94(s, 1H, CHO); Anal calcd. for C12H11NO2S, %: C, 61.78; H,
4.75; N, 6.00; Found, %: C, 62.05; H, 4.87; N, 5.86.

312
A.K. Mohammed Iqbal et al. / European Journal of Medicinal Chemistry 53 (2012) 308e315
Table 3
Plasma glucose and triglyceride level at various drug doses of 11(aed).
N
N
O
O
NH
R1
S
O
O
S
5-(4-{2-[(5-Aryl-1,3,4-oxadiazol-2-yl)thio]ethoxy}benzylidene)-1,3-thiazolidine-2,4dione.
Compounds
Pioglitazone
R1
% Decrease in plasma glucose (PG) and triglyceride (TG) level at various doses (mg/kg body weight)
3 mg
10 mg
30 mg
100 mg
e
TG
PG
41.60 ꢁ 2.25
47.02 ꢁ 14.39
47.25 ꢁ 5.50
35.25 ꢁ 20.42
64.59 ꢁ 5.42
40.96 ꢁ 17.59
75.43 ꢁ 3.40
45.89 ꢁ 2.24
11a
11b
TG
PG
21.56 ꢁ 0.52
11.62 ꢁ 2.24
22.18 ꢁ 3.24
14.64 ꢁ 0.38
24.05 ꢁ 1.97
16.13 ꢁ 3.75
33.12 ꢁ 1.46
20.08 ꢁ 2.52
TG
PG
18.52 ꢁ 1.26
14.23 ꢁ 3.05
20.54 ꢁ 0.88
16.82 ꢁ 2.04
28.02 ꢁ 1.92
19.08 ꢁ 2.14
34.56 ꢁ 1.62
23.08 ꢁ 1.68
11c
11d
TG
PG
40.66 ꢁ 2.15
24.35 ꢁ 1.14
45.10 ꢁ 1.62
33.16 ꢁ 1.08
60.78 ꢁ 2.27
39.34 ꢁ 0.90
72.32 ꢁ 4.27
50.09 ꢁ 0.85
N
TG
PG
40.15 ꢁ 2.10
23.46 ꢁ 0.65
42.17 ꢁ 3.90
32.62 ꢁ 2.16
58.48 ꢁ 1.82
40.00 ꢁ 1.86
69.72 ꢁ 3.21
43.42 ꢁ 0.55
N
Each value represents the mean ꢁ SEM (n ¼ 6). Percentage reduction was calculated according to the formula: [(PG in controlꢀPG in treated)/PG in control] ꢂ 100; [(TG in
controlꢀTG in treated)/TG in control] ꢂ 100.
4.1.2.2. 4-(2-Phenyl-thiazol-4-ylmethoxy)-benzaldehyde (3b). Yield
73%; yellow granules (chloroform þ pet ether); m.p.106e108 ꢃC; IR
C20H14N2O3S2, %: C, 60.90; H, 3.58; N, 7.10; Found, %: C, 60.72; H,
3.62; N, 6.96.
(KBr)
y
cmꢀ1: 3048, 1682, 1613, 1548, 1212; 1H NMR (300 MHz,
CDCl3)
d
: 5.35(s, 2H, CH2), 6.98(d, J ¼ 8.04 Hz, 2H, AreH), 7.24(s, 1H,
4.1.4. Preparation of 3-aryl-1,2,4-triazolin-5-thiones (5aeh)
The required 3-aryl-1,2,4-triazolin-5-thiones were prepared by
treating corresponding properly substituted thiosemicarbazide
with aqueous sodium hydroxide under reflux according to previ-
ously described method [11e13].
H5, thiazole), 7.46e7.97(m, 7H, AreH), 9.91(s, 1H, CHO). Anal calcd.
for C17H13N O2S, %: C, 69.13; H, 4.44; N, 4.74; Found, %: C, 69.28; H,
4.38; N, 4.82.
4.1.3. General procedure for preparation of 5-[4-(2-methyl/phenyl-
thiazol-4-ylmethoxy)-benzylidine]-thiazol idine-2,4-dione 4(aeb)
A mixture of 4-(2-methyl/phenyl-thiazol-4-ylmethoxy)benzal-
dehyde 3(aeb). (0.001 mol) and 1,3-thiazolidine-2,4-dione (0.11 g,
0.001 mol) was refluxed in toluene (25 mL) with catalytic amount
of piperidine-acetate for 2e3 h. The yellow solid that separated was
collected by filtration, washed with hot toluene, benzene and
methanol successively. The products were recrystallized from
dimethylformamide.
4.1.5. Preparation of p-(2-bromoethyloxy)benzaldehyde (7)
It was prepared by condensation of dibromoethane with p-
hydroxybenzaldehde in DMF with potassium carbonate according
to previously described method [17].
4.1.6. General procedure for preparation of 4-{2-[(5-aryl-4H-1,2,4-
triazol-3-yl)thio]ethoxy}benzaldehyde (8aeh)
To a solution of 5-aryl-2,4-dihydro-3H-1,2,4-triazole-3-thione
5/5-aryl-1,3,4-oxadiazole-2(3H)-thione
thylformamide (10 mL) was added potassium hydroxide
(0.012 mol) and stirred for 20 min. solution of p-(2-
6 (0.01 mol) in dime-
4.1.3.1. 5-[4-(2-Methyl-thiazol-4-ylmethoxy)-benzylidene]-thiazoli-
dine-2,4-dione (4a). Yield 86%; pale yellow solid (DMF); m.p.
A
252e254 ꢃC; IR (KBr)
y
cmꢀ1: 3182, 2962, 1732, 1696, 1617, 1554,
bromoethyloxy)benzaldehyde (0.01 mol) in DMF (8 mL) was then
added and the reaction mixture was stirred at room temperature
for 4 h (monitored by TLC). The mixture was then poured into water
and extracted with chloroform (3ꢂ30 mL). The combined extracts
were washed with water, dried over anhydrous sodium sulfate and
solvent was removed under diminished pressure. The residue thus
obtained was purified by column chromatography through silica
using a mixture of hexane and ethyl acetate in required ratios, to
obtain the title compounds.
1191; 1H NMR (300 MHz, CDCl3þTFA)
d: 2.77(s, 3H, CH3), 5.31 (s,
2H, OCH2), 6.95e7.13(m, 3H, H5, thiazole; H3, H5, AreH), 7.67(d,
J ¼ 7.3 Hz, H2, H6, AreH), 7.75(s, 1H, vinylic proton); Anal calcd. for
C15H12N2O3S2, %: C, 54.20; H, 3.64; N, 8.43; Found, %: C, 54.46; H,
3.75; N, 8.25, Mass, m/z (%) Mþ1, 333 (100).
4.1.3.2. 5-[4-(2-Phenyl-thiazol-4-ylmethoxy)-benzylidene]-thiazoli-
dine-2,4-dione (4b). Yield 91%; pale yellow granules (DMF); m.p.
268e272 ꢃC; IR (KBr)
y
cmꢀ1: 3172, 2972, 1729, 1695, 1619, 1553,
1188; 1H NMR (300 MHz, CDCl3þTFA)
d
: 5.42(s, 2H, CH2), 7.07(d,
4.1.6.1. 4-{2-[(5-Phenyl-4H-1,2,4-triazol-3-yl)thio]ethoxy}benzalde-
J ¼ 8.87 Hz, 2H, AreH), 7.11e7.76(m, 9H, H5, thiazole; AreH;
hyde (8a). Yield 66%; colorless crystalline solid (chloroform); m.p.
vinylic proton); MS (ESI): 417.03 (M þ Na); Anal. calcd. for
94e96 ꢃC; IR (KBr)
y
cmꢀ1, 3201, 2846, 1670, 1599; 1H NMR

A.K. Mohammed Iqbal et al. / European Journal of Medicinal Chemistry 53 (2012) 308e315
313
(300 MHz, CDCl3)
d
: 3.55 (t, J ¼ 6.3 Hz, 2H, SCH2), 4.40 (t, J ¼ 6.3 Hz,
AreH), 7.86 (d, J ¼ 8.4 Hz, 2H, H200, H600, AreH), 9.75 (s, 1H, CHO);
Anal. calcd. for C18H17N3O3S, %: C, 60.83; H, 4.82; N, 11.82; Found, %:
C, 60.75; H, 4.76; N, 11.70.
2H, OCH2), 7.05 (d, J ¼ 8.1 Hz, 2H, H300, H500, AreH), 7.43 (m, 3H, H30,
H40, H50, AreH), 7.78 (d, J ¼ 8.1 Hz, 2H, H20, H60, AreH), 7.98 (m, 2H,
H200, H600, AreH), 12.40 (s, br, 1H, NH, D2O exchangeable), 9.84 (s,
1H, CHO); Anal. calcd. for C17H15N3O2S, %: C, 62.75; H, 4.65; N,
12.91; Found, %: C, 62.63; H, 4.79; N, 13.18.
4.1.7. Preparation of 5-(4-{2-[(5-aryl-4H-1,2,4-triazol-3-yl)thio]
ethoxy}benzy lidene)-1,3-thiazolidine-2,4-dione (10aeh)
The title compounds were prepared by procedure describe
similar to 4(aeb).
4.1.6.2. 4-{2-[(5-Benzyl-4H-1,2,4-triazol-3-yl)thio]ethoxy}benzalde-
hyde (8b). Yield 64% colorless crystalline solid (chloroform); m.p.
84e86 ꢃC; IR (KBr)
y
cmꢀ1 3137, 2800, 1694, 1602; 1H NMR
4.1.7.1. 5-(4-{2-[(5-Phenyl-4H-1,2,4-triazol-3-yl)thio]ethoxy}benzyli-
(300 MHz, CDCl3)
d
: 3.45 (t, J ¼ 6.6 Hz, 2H, SCH2), 4.15 (s, 2H, CH2),
dene)-1,3-thiazolidine-2,4-dione (10a). Yield 89%; pale yellow solid
4.33 (t, J ¼ 6.6 Hz, 2H, OCH2), 6.99 (d, J ¼ 8.4 Hz, 2H, H300, H500, Ar-
H), 7.23 (s, 5H, Ar-H), 7.76 (d, J ¼ 8.4 Hz, 2H, H200, H600, Ar-H), 9.80 (s,
1H, CHO); Anal. cacd. for C18 H17 N3 O2 S, %: C, 63.70; H, 5.05; N,
12.38; Found, %: C, 63.55; H, 5.10; N, 12.45.
(DMF); m.p. 208e210 ꢃC; IR (KBr) cmꢀ1 3249, 1751, 1692, 1594; 1H
y
NMR (300 MHz, C6D6þTFA) : 3.24 (t, J ¼ 5.1 Hz, 2H, SCH2), 3.94 (t,
d
J ¼ 5.1 Hz, 2H, OCH2), 6.78 (d, J ¼ 8.4 Hz, 2H, H300, H500, AreH),
7.22e7.30 (m, 5H, AreH), 7.61 (d, J ¼ 8.4 Hz, 2H, H200, H600, AreH),
7.73 (s, 1H, vinylic proton); 13C NMR (75 MHz, C6D6þTFA)
d: 32.1
4.1.6.3. 4-(2-{[5-(4-Methylphenyl)-4H-1,2,4-triazol-3-yl]thio}ethoxy)
(SCH2), 66.4 (OCH2), 109.2, 113.2, 115.61, 116.8, 119.3, 120.6, 126.3,
127.2, 130.1, 133.2, 134.9, 160.7, 169.7(C]O, C4, thiazolidine) and
172.1(C]O, C2, thiazolidine); Anal. calcd. for C20H16N4O3S2, %: C,
56.59; H, 3.80; N, 13.20; Found, %: C, 56.52; H, 3.73; N, 13.25; Mass,
m/z (%) Mþ1, 425 (100).
benzaldehyde
(8c). Yield
72%;
colorless
needles
y
(3:1
chloroform þ benzene); m.p. 108e110 ꢃC; IR (KBr)
cmꢀ1 3158,
2877, 1700,1599; 1H NMR (300 MHz, CDCl3)
d: 2.41 (s, 3H, CH3), 3.67
(t, J ¼ 5.7 Hz, 2H, SCH2), 4.42 (t, J ¼ 5.7 Hz, 2H, OCH2), 7.01 (d,
J ¼ 8.4 Hz, 2H, H30, H50, AreH), 7.37 (d, J ¼ 8.1 Hz, 2H, H300, H500,
AreH), 7.77 (d, J ¼ 8.4 Hz, 2H, H20, H60, AreH), 7.85 (d, J ¼ 8.1 Hz, 2H,
H200, H600, AreH), 9.74 (s,1H, CHO); Anal. calcd. for C18H17N3O2S, %: C,
63.70; H, 5.05; N, 12.38; Found, %: C, 63.99; H, 5.12; N, 12.93.
4.1.7.2. 5-(4-{2-[(5-Benzyl-4H-1,2,4-triazol-3-yl)thio]ethoxy}benzy-
lidene)-1,3-thiazolidine-2,4-dione (10b). Yield 90%; pale yellow
solid (DMF); m.p. 282e284 ꢃC; IR(KBr)
y
cmꢀ1 3125, 1737, 1691,
1593; 1H NMR (300 MHz, C6D6þTFA)
: 3.07 (t, J ¼ 5.1 Hz, 2H,
d
4.1.6.4. 4-(2-{[5-(4-Nitrophenyl)-4H-1,2,4-triazol-3-yl]thio}ethoxy)
SCH2), 3.77 (t, J ¼ 5.1 Hz, 2H, OCH2), 4.07 (s, 2H, CH2), 6.65 (d,
benzaldehyde (8d). Yield 65%; yellow color solid (chloroform);
J ¼ 8.4 Hz, 2H, H300, H500, AreH), 7.18e7.60 (m, 7H, AreH), 7.71 (s,
m.p. 156e59 ꢃC; IR (KBr)
y
cmꢀ1, 2827, 1697, 1601; 1H NMR
1H, vinylic proton); 13C NMR (75 MHz, C6D6þTFA)
d: 30.7 (SCH2),
(300 MHz, CDCl3)
d
: 3.75 (t, J ¼ 6 Hz, 2H, SCH2), 4.51 (t, J ¼ 6 Hz,
31.8 (CH2), 66.2 (OCH2), 109.2, 113.0, 115.5, 116.8, 120.5, 126.2,
129.3, 129.9, 130.2, 133.2, 154.8, 169.5 (C]O, C4, thiazolidine) and
172.1 (C]O, C2, thiazolidine); Anal. calcd. for C21H18N4O3S2, %: C,
57.52; H, 4.14; N, 12.78; Found, %: C, 57.45; H, 4.09; N, 12.84.
2H, OCH2), 7.06e7.87 (m, 8H, AreH), 9.89 (s, 1H, CHO); Anal. calcd.
for C17H14N4O4S, %: C, 55.13; H, 3.7; N, 15; Found, % : C, 55.26; H,
3.8; N, 14.8.
4.1.6.5. 4-(2-{[5-(2-Nitrophenyl)-4H-1,2,4-triazol-3-yl]thio}ethoxy)
4.1.7.3. 5-[4-(2-{[5-(4-Methylphenyl)-4H-1,2,4-triazol-3-yl]thio}ethoxy)
benzaldehyde (8e). Yield 72%; yellow color solid (chloroform);
benzylidene]-1,3-thiazolidine-2,4-dione (10c). Yield 93%; pale yellow
m.p. 148e54 ꢃC; IR (KBr)
y
cmꢀ1 2827, 1697, 1601; 1H NMR
granules (DMF); m.p. 218e220 ꢃC; IR (KBr) cmꢀ1 3245, 1754, 1692,
y
(300 MHz, CDCl3)
d
: 3.75 (t, J ¼ 6 Hz, 2H, SCH2), 4.51 (t, J ¼ 6 Hz,
1593; 1H NMR (300 MHz, C6D6þTFA)
d: 2.27 (s, 3H, CH3), 3.33 (t,
2H, OCH2), 7.00e7.85 (m, 8H, AreH), 9.89 (s, 1H, CHO); Anal. calcd.
for C17H14N4O4S, %: C, 55.13; H, 3.7; N, 15; Found, %: C, 55.26; H,
3.8; N, 14.8.
J ¼ 5.1 Hz, 2H, SCH2), 4.04 (t, J ¼ 5.1 Hz, 2H, OCH2), 6.85 (d, J ¼ 8.7 Hz,
2H, H30, H50, AreH), 7.25 (d, J ¼ 8.1 Hz, 2H, H300, H500, AreH), 7.29 (d,
J ¼ 8.7 Hz, 2H, H20, H60, AreH), 7.56 (d, J ¼ 8.1 Hz, 2H, H200, H600, AreH),
7.79 (s, 1H, vinylic proton); 13C NMR (75 MHz, C6D6þTFA)
d: 20.8 (CH3),
4.1.6.6. 4-(2-{[5-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl]thio}ethoxy)
benzaldehyde (8f). Yield 70%; yellow color crystalline solid (chlo-
31.9 (SCH2), 66.3 (OCH2), 109.2, 113.0, 115.6, 116.7, 120.5, 127.2, 130.9,
133.3, 138.4, 147.2, 154.3, 160.9, 169.6 (C]O, C4, thiazolidine) and 172.5
(C]O, C2, thiazolidine); Anal. calcd. for C21H18N4O3S2, %: C, 57.52; H,
4.14; N, 12.78; Found, %: C, 57.61; H, 4.05; N, 13.14.
roform); m.p. 124e29 ꢃC; IR (KBr)
y
cmꢀ1, 3201, 2846, 1670, 1599;
1H NMR (300 MHz, CDCl3)
d
: 3.55 (t, J ¼ 6.3 Hz, 2H, SCH2), 4.40 (t,
J ¼ 6.3 Hz, 2H, OCH2), 7.05e7.85(m, 8H, AreH), 12.40 (s, br 1H, NH,
D2O exchangeable), 9.84 (s, 1H, CHO); Anal. calcd. for
C17H14N3O2SCl, %: C, 62.96; H, 4.32; N, 12.96; Found, %: C, 63.20; H,
4.29; N, 13.08.
4.1.7.4. 5-[4-(2-{[5-(4-Nitro-phenyl)-4H-1,2,4-triazol-3-yl]thio}
ethoxy)benzylidene]-1,3-thiazolidine-2,4-dione (10d). Yield 80%;
pale yellow solid (DMF); m.p. 197e199 ꢃC; IR (KBr)
y
cmꢀ1 3143,
1738, 1686, 1588; 1H NMR (300 MHz, CDCl3)
SCH2), 4.02 (t, J ¼ 6 Hz, 2H, OCH2), 6.82e7.86(m, 8H, AreH), 7.76 (s,
1H, vinylic proton); 13C NMR (75 MHz, CDCl3)
: 32.0 (SCH2), 65.8
d: 3.33 (t, J ¼ 6 Hz, 2H,
4.1.6.7. 4-(2-{[5-(4-Bromophenyl)-4H-1,2,4-triazol-3-yl]thio}ethoxy)
benzaldehyde (8g). Yield 65%; yellow color solid (chloroform); m.p.
d
134-39 ꢃC; IR (KBr)
y
cmꢀ1 2827, 1697, 1601; 1H NMR (300 MHz,
(OCH2),109.4,113.1,115.5,116.9,118.1,119.7,120.7,126.1,129.7,113.3,
134.7, 138.1, 169.6 (C]O, C4, thiazolidine) and 172.0 (C]O, C2,
thiazolidine); Anal. calcd. for C20H15N5O5S2, %: C, 51.17; H, 3.19; N,
14.92; Found, %: C, 52.14; H, 3.42; N, 15.32.
CDCl3)
d
: 3.75 (t, J ¼ 6 Hz, 2H, SCH2), 4.51 (t, J ¼ 6 Hz, 2H, OCH2),
7.06e7.90(m, 8H, AreH), 9.89 (s, 1H, CHO); Anal. calcd. for
C17H14N3O2SBr, %: C, 56.64; H, 3.84; N, 11.53; Found, %: C, 57.20; H,
4.04; N, 12.42.
4.1.7.5. 5-[4-(2-{[5-(2-Nitro-phenyl)-4H-1,2,4-triazol-3-yl]thio}ethoxy)
4.1.6.8. 4-(2-{[5-(4-Metoxyphenyl)-4H-1,2,4-triazol-3-yl]thio}ethoxy)
benzylidene]-1,3-thiazolidine-2,4-dione (10e). Yield 72%; pale yellow
benzaldehyde (8h). Yield 70%; colorless needles (chloroform); m.p.
color solid (DMF); m.p. 229e32 ꢃC; IR (KBr) cmꢀ1 3143, 1738, 1686,
y
133e135 ꢃC; IR (KBr)
y
cmꢀ1, 3142, 1701, 1598; 1H NMR (300 MHz,
1588; 1H NMR (300 MHz, CDCl3)
J ¼ 6 Hz, 2H, OCH2), 6.82e7.70 (m, 8H, AreH), 7.76 (s, 1H, vinylic
proton); 13C NMR (75 MHz, CDCl3)
: 32.0 (SCH2), 65.8 (OCH2), 109.4,
113.1, 115.5, 116.9, 118.1, 119.7, 120.7, 126.1, 129.7, 113.3, 134.7, 138.1,
d: 3.33 (t, J ¼ 6 Hz, 2H, SCH2), 4.02 (t,
CDCl3)
d
: 3.64 (t, J ¼ 5.7 Hz, 2H, SCH2), 3.87 (s, 3H, OCH3), 4.41 (t,
J ¼ 5.7 Hz, 2H, OCH2), 7.01 (d, J ¼ 8.4 Hz, 2H, H30, H50, AreH), 7.01 (d,
d
J ¼ 8.4 Hz, 2H, H300, H500, AreH), 7.86 (d, J ¼ 8.4 Hz, 2H, H20, H60,

314
A.K. Mohammed Iqbal et al. / European Journal of Medicinal Chemistry 53 (2012) 308e315
169.6 (C]O, C4, thiazolidine) and 172.0 (C]O, C2, thiazolidine); Anal.
calcd. for C20H15N5O5S2, %: C, 51.17; H, 3.19; N, 14.92; Found, %: C,
51.97; H, 4.08; N, 15.12.
(m, 9H, AreH), 9.87 (s, 1H, CHO); Anal. calcd. for C18H16N2O3S:
C, 63.51%; H, 4.74%; N, 8.23%; Found: C, 63.75%; H, 4.71%; N,
8.28%.
4.1.7.6. 5-[4-(2-{[5-(4-Chloro-phenyl)-4H-1,2,4-triazol-3-yl]thio}et-
4.1.9.3. 4-{2-[(5-Pyridin-3-yl-1,3,4-oxadiazol-2-yl)thio]ethoxy}benz-
hoxy)benzylidene]-1,3-thiazolidine-2,4-dione (10f). Yield 89%; pale
aldehyde (9c). Yield 71%; colorless solid (2:1 chloroform þ ethyl
yellow solid (DMF); m.p. 186e188 ꢃC; IR (KBr)
y
cmꢀ1 3249, 1751,
acetate); m.p. 62e64 ꢃC; IR (KBr) cmꢀ1 2485, 1698, 1601; 1H NMR
y
1692, 1594; 1H NMR (300 MHz, CDCl3)
d
: 3.24 (t, J ¼ 5.1 Hz, 2H,
(300 MHz, CDCl3)
d: 3.72 (t, J ¼ 6 Hz, 2H, SCH2), 4.50 (t, J ¼ 6 Hz, 2H,
SCH2), 3.94 (t, J ¼ 5.1 Hz, 2H, OCH2), 6.78e7.70 (m, 8H, AreH), 7.73
OCH2), 7.30 (d, J ¼ 8.4 Hz, 2H, H300, H500, AreH), 7.45 (dd,
JH4H5 ¼ 8.1 Hz, JH5H6 ¼ 8.5 Hz, 1H, H50, pyridine), 7.52 (d, J ¼ 8.4 Hz,
2H, H200, H600, AreH), 8.25 (d, J ¼ 8.1 Hz, 1H, H40, pyridine), 8.75 (d,
J ¼ 8.5 Hz, 1H, H60, pyridine), 9.19 (s, 1H, H20, pyridine), 9.87(s, 1H,
CHO); Anal. calcd. for C16H13N3O2S2, %: C, 55.96; H, 3.82, N, 12.24;
Found, %: C, 55.92; H, 3.79, N, 12.86.
(s, 1H, vinylic proton); 13C NMR (75 MHz, C6D6þTFA)
d: 32.1
(SCH2), 66.4 (OCH2), 109.2, 113.2, 115.61, 116.8, 119.3, 120.6, 126.3,
127.2, 130.1, 133.2, 134.9, 160.7, 169.7(C]O, C4, thiazolidine) and
172.1(C]O, C2, thiazolidine); Anal. calcd. for C20 H15N4O3S2Cl, %: C,
56.20; H, 3.5; N, 13.11; Found, %: C, 56.62; H, 3.92; N, 12.98.
4.1.7.7. 5-[4-(2-{[5-(4-Bromo-phenyl)-4H-1,2,4-triazol-3-yl]thio}et-
4.1.9.4. 4-{2-[(5-Pyridin-4-yl-1,3,4-oxadiazol-2-yl)thio]ethoxy}benz-
hoxy)benzylidene]-1,3-thiazolidine-2,4-dione (10g). Yield 72%; pale
aldehyde (9d). Yield 68%; colorless solid (1:1 hexaneeethyl
yellow color solid (DMF); m.p. 232e235 ꢃC; IR (KBr)
y
cmꢀ1 3143,
acetate); m.p. 66e68 ꢃC; IR (KBr) cmꢀ1 2844, 1692, 1600; 1H
y
1738, 1686, 1588; 1H NMR (300 MHz, CDCl3)
d
: 3.33 (t, J ¼ 6 Hz, 2H,
NMR (300 MHz, CDCl3)
d: 3.77 (t, J ¼ 6 Hz, 2H, SCH2), 4.50 (t,
SCH2), 4.02 (t, J ¼ 6 Hz, 2H, OCH2), 6.82e7.75 (m, 8H, AreH), 7.76 (s,
J ¼ 6 Hz, 2H, OCH2), 7.02(d, J ¼ 8.7 Hz, 2H, H300, H500, AreH), 7.82 (d,
J ¼ 8.7 Hz, 2H, H30, H50, pyridine), 7.85(d, J ¼ 8.7 Hz, 2H, H200, H600,
AreH), 8.81 (d, J ¼ 8.7 Hz, 2H, H20, H60, pyridine), 9.86 (s, 1H, CHO);
Anal. calcd. for C16H13N3O2S2, %: C, 55.96; H, 3.82, N, 12.24; Found,
%: C, 55.91; H, 3.89, N, 12.39.
1H, vinylic proton); 13C NMR (75 MHz, CDCl3þTFA)
d: 32.0 (SCH2),
65.8 (OCH2), 109.4, 113.1, 115.5, 116.9, 118.1, 119.7, 120.7, 126.1, 129.7,
113.3, 134.7, 138.1, 169.6 (C]O, C4, thiazolidine) and 172.0 (C]O,
C2, thiazolidine); Anal. calcd. for C20H15N4O3S2Br, %: C, 51.83; H,
3.23; N, 12.09; Found, %: C, 52.1; H, 3.46; N, 11.96.
4.1.10. 5-(4-{2-[(5-Aryl-1,3,4-oxadiazol-2-yl)thio]ethoxy}
benzylidene)-1,3-thiazolidine-2,4-dione (11aed)
The title compounds were prepared by procedure describe
similar to 4(aeb).
4.1.7.8. 5-[4-(2-{[5-(4-Methoxyphenyl)-4H-1,2,4-triazol-3-yl]thio}et-
hoxy)benzylidene]-1,3-thiazolidine-2,4-dione (10h). Yield 93%; pale
yellow solid (DMF); m.p. 226e228 ꢃC; IR (KBr) cmꢀ1 3131, 1740,
y
1686, 1596; 1H NMR (300 MHz, C6D6þTFA)
: 3.34 (t, J ¼ 5.1 Hz, 2H,
d
SCH2), 3.60 (s, 3H, OCH3), 4.06 (t, J ¼ 5.1 Hz, 2H, OCH2), 6.86 (d,
J ¼ 8.4 Hz, 2H, H30, H50, Ar-H), 7.00 (d, J ¼ 8.7 Hz, 2H, H300, H500, Ar-
H), 7.29 (d, J ¼ 8.4 Hz, 2H, H20, H60, Ar-H), 7.64 (d, J ¼ 8.7 Hz, 2H, H200,
H600, phenyl), 7.79 (s, 1H, vinylic proton); 13C NMR (75 MHz,
4.1.10.1. 5-(4-{2-[(5-Phenyl-1,3,4-oxadiazol-2-yl)thio]ethoxy}benzy-
lidene)-1,3-thiazolidine-2,4-dione (11a). Yield 91%; pale yellow
solid (DMF); m.p. 202e214 ꢃC; IR (KBr)
y
cmꢀ1 3143, 1738, 1686,
1588; 1H NMR (300 MHz, CDCl3þTFA)
: 3.33 (t, J ¼ 6 Hz, 2H, SCH2),
d
C6D6þTFA)
d
: 31.8 (OCH3), 55.3 (SCH2), 66.2 (OCH2), 109.3, 113.0,
4.02 (t, J ¼ 6 Hz, 2H, OCH2), 6.82 (d, J ¼ 9 Hz, 2H, H300, H500, AreH),
115.6, 115.8, 116.8, 120.6, 129.4, 133.3, 138.4, 153.8, 160.5, 165.1, 169.6
(C]O, C4, thiazolidine) and 172.7 (C]O, C2, thiazolidine); Anal.
calcd. for C21H18N4O4S2, %: C, 55.49; H, 3.99; N, 12.33; Found, %: C,
55.71; H, 4.31; N, 12.61; Mass, m/z (%) Mþ1, 455 (100).
7.29e7.32 (m, 5H, AreH), 7.73 (d, J ¼ 9 Hz, 2H, H200, H600, AreH),
7.76 (s, 1H, vinylic proton); 13C NMR (75 MHz, CDCl3þTFA)
d:
32.0 (SCH2), 65.8 (OCH2), 109.4,113.1, 115.5, 116.9, 118.1,119.7, 120.7,
126.1, 129.7, 113.3, 134.7, 138.1, 169.6 (C]O, C4, thiazolidine) and
172.0 (C]O, C2, thiazolidine); Anal. calcd. for C20H15N3O4S2, %: C,
56.46; H, 3.55; N, 9.88. Found, %: C, 56.25; H, 3.47; N, 10.00.
4.1.8. Preparation of 5-aryl-1,3,4-oxadiazole-2(3H)-thione 6(aed)
The required 5-aryl-1,3,4-oxadiazole-2(3H)-thione were
prepared by refluxing Acid hydrazide in ethanolic potassium
hydroxide solution and carbon disulfide according to previously
described method [14e16].
4.1.10.2. 5-(4-{2-[(5-Benzyl-1,3,4-thiadiazol-2-yl)thio]ethoxy}benzy-
lidene)-1,3-thiazolidine-2,4-dione (11b). Yield 77%; pale yellow
solid (DMF); m.p. 258e260 ꢃC; IR (KBr)
1592; 1H NMR (300 MHz, CDCl3 þ TFA)
y
cmꢀ1 3147, 1736, 1697,
d
: 3.71 (t, J ¼ 5.4 Hz, 2H,
4.1.9. Preparation of 4-{2[(5-aryl-1,3,4eoxadiazol-2-yl)thio]
ethoxy}benzaldehyde (9aed)
The title compounds were prepared by procedure describe
similar to 8(aeh).
SCH2), 4.39 (t, J ¼ 5.4 Hz, 2H, OCH2), 4.48 (s, 2H, CH2), 6.94e7.56 (m,
9H, AreH), 7.97 (s, 1H, vinylic proton); Anal. calcd. for
C21H17N3O4S2, %: C, 57.39; H, 3.90; N, 9.56; Found, %: C, 57.65; H,
3.77; N, 9.64, Mass, m/z (%) Mþ1, 456 (100).
4.1.9.1. 4-{2-[(5-Phenyl-1,3,4-oxadiazol-2-yl)thio]ethoxy}benzalde-
4.1.10.3. 5-(4-{2-[(5-Pyridin-3-yl-1,3,4-oxadiazol-2-yl)thio]ethoxy}
hyde (9a). Yield 65%; colorless solid (1:1 hexaneeethyl acetate);
benzylidene)-1,3-thiazoli dine-2,4-dione (11c). Yield 89%; pale
m.p. 78e80 ꢃC; IR (KBr)
y
cmꢀ1 2827, 1697, 1601; 1H NMR
yellow granules (DMF); m.p. 246e248 ꢃC; IR (KBr)
y
cmꢀ1 3153,
: 3.83 (t,
(300 MHz, CDCl3)
d
: 3.75 (t, J ¼ 6 Hz, 2H, SCH2), 4.51 (t, J ¼ 6 Hz,
1736, 1701, 1597; 1H NMR (300 MHz, CDCl3þTFA)
d
2H, OCH2), 7.06 (d, J ¼ 8.7 Hz, 2H, H300, H500, AreH), 7.53 (m, 3H,
H30, H40, H50, AreH), 7.86 (d, J ¼ 8.7 Hz, 2H, H20, H60, AreH), 8.02
(m, 2H, H200, H600, AreH), 9.89 (s, 1H, CHO); Anal. calcd. for
C17H14N2O2S2, %: C, 59.63; H, 4.12; N, 8.18; Found, %: C, 59.89; H,
4.05; N, 8.62.
J ¼ 5.1 Hz, 2H, SCH2), 4.99 (t, J ¼ 5.1 Hz, 2H, OCH2), 7.04 (d,
J ¼ 8.7 Hz, 2H, H300, H500, AreH), 7.47 (d, J ¼ 8.7 Hz, 2H, H200, H600,
AreH), 7.91 (s, 1H, vinylic proton), 8.29 (dd, JH4H5 ¼ 6 Hz,
JH5H6 ¼ 6.3 Hz, 1H, H50, pyridine), 9.16 (d, J ¼ 6 Hz, 1H, H40,
pyridine), 9.19 (d, J ¼ 6 Hz, 1H, H60, pyridine), 9.56 (s, 1H, H20,
pyridine); 13C NMR (75 MHz, CDCl3þTFA)
d: 32.2 (SCH2), 66.0
4.1.9.2. 4-{2-[(5-Benzyl-1,3,4-oxadiazole-2-yl)thio]ethoxy}benzalde-
(OCH2), 109.1, 112.9, 115.8, 116.6, 118.3, 124.1, 126.2, 133.4, 138.2,
140.2, 144.2, 144.5, 169.7 (C]O, C4, thiazolidine) and 171.6 (C]O,
C2, thiazolidine); Anal. calcd. for C19 H14N4O4S2, %: C, 53.51; H,
3.31; N, 13.14; Found, %: C, 53.39; H, 3.39; N, 13.51.
hyde (9b). Yield 65% colorless semisolid; IR (CCl4)
1693, 1600; 1H NMR (300 MHz, CDCl3)
: 3.69 (t, J ¼ 6.3 Hz, 2H,
SCH2), 4.39 (t, J ¼ 6.3 Hz, 2H, OCH2), 4.41(s, 2H, CH2), 6.97e8.01
y
cmꢀ1 2830,
d

A.K. Mohammed Iqbal et al. / European Journal of Medicinal Chemistry 53 (2012) 308e315
315
4.1.10.4. 5-(4-{2-[(5-Pyridin-4-yl-1,3,4-oxadiazol-2-yl)thio]ethoxy}
benzylidene)-1,3-thiazoli dine-2,4-dione (11d). Yield 92%; yellow
[F.No: 36-138/2009 (SR)] and to the University Science Instruments
Centre, Karnatak University, Dharwad, for providing the spectral
data.
solid(DMF); m.p. 268e270 ꢃC; IR(KBr)
y
cmꢀ1 3142, 1738, 1686,
1589; 1H NMR (300 MHz, CDCl3)
d
: 3.87 (t, J ¼ 5.7 Hz, 2H, SCH2),
4.51 (t, J ¼ 5.7 Hz, 2H, OCH2), 7.05 (d, J ¼ 8.1 Hz, 2H, H300, H500,
AreH), 7.49 (d, J ¼ 8.1 Hz, 2H, H200, H600, AreH), 7.92 (s, 1H, vinylic
proton), 8.62 (d, J ¼ 5.1 Hz, 2H, H30, H50, pyridine), 9.10 (d,
J ¼ 5.1 Hz, 2H, H20, H60, pyridine); 13C NMR (75 M Hz, CDCl3þTFA)
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4.2.1. Hypoglycemic and hypolipidemic activities
Male Wistar rats weighing 150e200 g were used for this study
[26]. All animals were maintained under 12 h light and 12 h dark
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Institute of Nutrition, India) and water ad libitum. The experiments
were designed and conducted in accordance with the guidelines of
institutional animal’s ethics committee. The acclimatized animals
were kept fasting for 24 h with water ad libitum and alloxan
monohydrate (120 mg/kg i.p.) in normal saline was then adminis-
tered. Serum glucose level was checked after 72 h. Animals with
serum glucose levels >250 mg/dl were considered diabetic and
were used for the study. The animals were divided in to two groups
of six animals each. Group I animal was termed as control or
untreated and group II animals was termed as treated. Group II
animals were administered with compounds to be screened for
euglycemic effect. The suspension of the compound was prepared
in water with 1% carboxy methyl cellulose (CMC) as suspending
agent. All the test compounds were orally administered at different
doses (3, 10, 30, 100 mg/kg) for 15 days. Pioglitazone was used as
standard drug. On the final day the blood samples were collected
from the tail vein. Plasma was separated from whole blood of each
group by centrifugation. Plasma glucose (PG) and triglyceride (TG)
levels were estimated using commercial kits [27e29].
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Acknowledgments
The authors thanks Karnatak University, Dharwad, University
[29] C.S. Frings, T.W. Fendley, R.T. Dunn, C.A. Queen, Clin. Chem. 18 (1972)
Grants Commission (UGC), New Delhi, India, for financial support
673e674.