Synthesis, biological evaluation and molecular modeling studies of some novel thiazolidinediones with triazole ring

Article abstract of DOI:10.1016/j.ejmech.2013.10.005

A new series of thiazolidinedione derivatives were synthesized and evaluated for in vitro α-glucosidase inhibition and anticancer activities. Compounds 3d, 3e and 3j showed potential α-glucosidase inhibition with IC₅₀ values ranging between 0.1 and 0.3 μg/ml whereas compounds 3i, 3j and 3k have showed better anticancer activity towards human cancer cell lines IMR-32 (neuroblastoma), Hep-G2 (hepatoma) and MCF-7 (breast). Molecular docking studies revealed compounds 3d, 3e and 3j are potent inhibitors of α-glucosidase and also showed compliance with standard parameters of drug likeness.

Full text of DOI:10.1016/j.ejmech.2013.10.005

European Journal of Medicinal Chemistry 70 (2013) 308e314
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, biological evaluation and molecular modeling studies of
some novel thiazolidinediones with triazole ring
Yakaiah Chinthala a, Anand Kumar Domatti b, Alam Sarfaraz c, Shailendra Pratap Singh b,
,
Niranjan Kumar Arigari a, Namita Gupta c, Srinivas K.V.N. Satya a, Jonnala Kotesh Kumar a
,
*
Feroz Khan c, Ashok K. Tiwari b, Grover Paramjit b
a Natural Product Chemistry, CSIR-Central Institute of Medicinal and Aromatic Plants-Research Centre, Boduppal, Hyderabad 500092, A.P., India
b CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, A.P., India
c Metabolic & Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Kukrail Picnic Spot Road, Lucknow 226015, U.P., India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of thiazolidinedione derivatives were synthesized and evaluated for in vitro a-glucosidase
Received 8 May 2013
Received in revised form
24 September 2013
Accepted 3 October 2013
Available online 10 October 2013
inhibition and anticancer activities. Compounds 3d, 3e and 3j showed potential
a-glucosidase inhibition
with IC50 values ranging between 0.1 and 0.3 g/ml whereas compounds 3i, 3j and 3k have showed
m
better anticancer activity towards human cancer cell lines IMR-32 (neuroblastoma), Hep-G2 (hepatoma)
and MCF-7 (breast). Molecular docking studies revealed compounds 3d, 3e and 3j are potent inhibitors of
a-glucosidase and also showed compliance with standard parameters of drug likeness.
Ó 2013 Elsevier Masson SAS. All rights reserved.
Keywords:
Thiazolidinediones
1,2,3-Triazoles
Anticancer activity
a
-Glucosidase inhibition
Molecular modeling study
1. Introduction
stimulate PPAR-g (Peroxisome Proliferator Activated Receptor
gamma) receptor, they also have showed other significant biolog-
ical activities, such as antimicrobial [4], analgesic [5], anti-
inflammatory [6] and anticancer [7] etc. Similarly, nitrogenous
compounds like 1,2,3-triazole also played an important role in
agrochemical and pharmaceuticals such as anti-HIV [8,9], anti-
bacterial [10], antiviral [11], antiproliferative [12], insecticidal [13]
and fungicidal [14].
The diverse biological potencies of both pharmacophores
prompted us to synthesize the title compounds with a presumption
that their incorporation in a single structural entity could produce
novel compounds with significant antidiabetic as well as anticancer
properties. One of the therapeutic approaches for treating diabetes
Thiazolidinediones (TZDs), also known as glitazones, are a class
of insulin sensitizing drugs includes ciglitazone, pioglitazone, tro-
glitazone and rosiglitazone (Fig. 1) etc. TZDs were initially
discovered by Takeda Pharmaceuticals, Japan, in 1975 and the lead
substance ciglitazone was synthesized in 1980. Although ciglita-
zone improved gycaemic control in animal models of insulin
resistance, but toxicity prevented trials in humans. Rosiglitazone
and pioglitazone are currently approved for use for type 2 diabetes
under the trade names AvandiaÔ and ActosÔ respectively whereas
troglitazone (RezulinÔ), the first of the glitazones approved by the
U.S.FDA, was recently withdrawn from the market due to hepa-
totoxicity [1]. Apart from their known antidiabetic activity, the
ability of TZDs to contribute to cancer therapy has been evidenced
by in vitro and in vivo studies [2,3]. While TZDs are known to
is the inhibition of the enzyme a-glucosidase which delays carbo-
hydrate digestion, causing a reduction in the rate of glucose ab-
sorption and consequently blunting the postprandial blood glucose
and insulin levels [15]. This paper consists of synthesis of novel
TZD’s tagged with 1,2,3-triazoles and evaluation of their antidia-
betic and anticancer activity profiles. Finally, molecules that
* Corresponding author. Tel.: þ91 40 27201131.
E-mail addresses: koteshkumarj@yahoo.com, koteshnpp@yahoo.co.in (J. Kotesh
Kumar).
showed potential
a-glucosidase inhibition were subjected to
docking studies using molecular modeling tools.
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.10.005

Y. Chinthala et al. / European Journal of Medicinal Chemistry 70 (2013) 308e314
309
2.3.
a
-Glucosidase inhibition
S
O
O
O
N
H
O
O
O
S
Intestinal
a
-glucosidase inhibitory activity was determined as
NH
HO
per earlier reported methods [17,18]. Rat intestinal acetone powder
in normal saline (100:1; w/v) was sonicated properly and the su-
O
pernatant was used as a source of crude intestinal
after centrifugation. In brief, 10 L of test samples (5 mg/mL DMSO
solution) were reconstituted in 100 L of 100 mM-phosphate buffer
(pH 6.8) in 96-well microplate and incubated with 50
glucosidase (0.76 U/Ml in same buffer) or crude intestinal
glucosidase for 5 min before 50
-D-glucopyranoside prepared in same buffer) was added. Release
of p-nitrophenol was measured at 405 nm spectrophotometrically
(SpectraMAx Plus384, Molecular Devices Corporation, Sunnyvale, CA,
USA) 5 min after incubation with substrate. Individual blanks for
test samples were prepared to correct back-ground absorbance
a-glucosidase
Ciglitazone
O
Troglitazone
O
m
m
mL yeast
a
a
-
-
O
O
S
S
N
N
HN
m
L substrate (5 mM, p-nitrophenyl-
HN
N
a
O
O
Pioglitazone
Rosiglitazone
Fig. 1. Structures of some thiazolidinedione drugs.
where substrate was replaced with 50
contained 10 L DMSO in place of test samples. Acarbose was taken
as standard reference for -glucosidase inhibition. All the samples
were studied in triplicate. Percentage of enzyme inhibition was
calculated as (1 ꢀ B/A) ꢁ 100 where A represents absorbance of
control without test samples, and B represents absorbance in
presence of test samples. All the tests were run in duplicate. IC50
values were calculated applying suitable regression analysis from
the mean inhibitory values. As shown in Table 1, among all the
mL of buffer. Control sample
2. Results and discussion
m
a
2.1. Chemistry
A series of 5-(benzo-[1,3]-dioxol-5-ylmethylene)-3-((1-phenyl-
1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2,4-diones 3ae3k were
synthesized in three steps (Scheme 1). In the first step, 5-(benzo-
[1,3]-dioxol-5-ylmethylene)-2,4-Thiazolidinedione 1 was prepared
by attempting Knoevenagel condensation reaction between piper-
onal and 2,4-thiazolidinedione under reflux conditions in the
presence of piperidine as catalyst. In the second step, compound 1
was condensed with propargyl bromide in the presence of K2CO3 in
dry acetone under reflux for 4e5 h to obtain intermediate 2 which
was common to all derivatives being synthesized. In the final step,
intermediate 2 was condensed with various aromatic azides under
click chemistry reaction conditions in presence of copper iodide
and dry THF at room temperature for 10e12 h to result in novel
TZD’s 3ae3k in quantitative yields. All the derivatives were char-
acterized by 1H NMR, IR and ESI-MS spectra. Compounds 3ae3k
showed IR absorption bands ranging from 3132 to 3000 cmꢀ1 for
aromatic CeH stretching, 2960e2900 cmꢀ1 for aliphatic CeH
stretching’s. There were also absorptions due to C]C, C]N
stretchings at 1580e1570 and 1505e1480 cmꢀ1 respectively. In 1H
synthesized derivatives, compounds 3d (IC50 0.1
0.3 g/ml) and 3j (IC50 0.3 g/ml) have shown much better
glucosidase enzyme inhibitory activity than the standard Acarbose
(IC50 12.5 g/ml). Comparing the -glucosidase inhibitory activity of
compounds 3ae3i with a substituted benzene ring, it was observed
that the presence of NO2 group at ortho (3d, IC50 0.1 g/ml) and
Isopropyl group at para-positions (3e, IC50 0.3 g/ml) showed most
potent inhibitory activity than chloro (3c, IC50 40 g/ml) at ortho,
flouro (3a, >100 g/ml) and methyl (3f, 75.5 g/ml) at para posi-
mg/ml), 3e (IC50
m
m
a-
m
a
m
m
m
m
m
tions resulted in dramatically less potential compounds. Similarly,
substitution of 1-phenyl ethyl moiety at 3 position of triazole ring
(3j, IC50 0.1
mg/ml) showed potential enzyme inhibition activity
than aliphatic n-hexyl (3k IC50 > 100 mg/ml) substitution.
3. Molecular docking studies
NMR spectra, the presence of singlet resonances at
d 5.5e6.0 ppm
and 6.0e6.5 ppm were attributed to the methylene protons
attached to nitrogen and oxygen atoms respectively whereas the
corresponding carbon resonances in the 13C NMR spectra were
observed at 36.8 and 102.3 ppm respectively. Rest all the protons
and carbons resonated at expected regions.
Exploration of mechanism of action and molecular interaction of
compound 3d, 3e and 3j was performed through molecular docking
studies using AutoDock Vina software [19]. Oral bioavailability and
drug likeness parameters screening was performed by evaluating
topological polar surface area (TPSA) and Lipinski’s rule of five [20].
The toxicity risk assessment at high doses or long term use was
performed through OSIRIS program. To study the molecular inter-
2.2. Anticancer activity
action of compounds, crystallographic data of human intestinal
glucosidase (EC ¼ 3.2.1.20) (PDB:3L4Y) was retrieved from Protein
Data Bank [21]. Retrieved crystal structure of -glucosidase was
cleaned and hydrogen atoms were added. All the heteroatoms were
removed before docking study. The chemical samples used in the
molecular docking studies were compounds 3d, 3e, 3j and Acarbose
(Fig. 2). The 2D structures were sketched using ChemDraw-ultra-
v8.0 followed by 3D structure conversion and energy minimiza-
tion by ChemBioOffice modeling software (Cambridgesoft, UK).
a-
Anti-cancer activity of the synthesized thiazolidinedione de-
rivatives was evaluated in in vitro mode using 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
assay [16] on the human cancer cell lines IMR 32 (neuroblastoma),
HepG2 (Human hematoma) and MCF-7 (Human breast adenocar-
cinoma). The assay was dependent on the reduction of tetrazolium
salt by the mitochondrial dehydrogenase of viable cells to form a
blue formazan product dissolved in DMSO and measured at
570 nm. The results of cytotoxic activity in vitro were expressed as
a
the IC50
(
m
g/ml) and doxorubicin was used as positive control
3.1. Exploration of interacting amino acid residues through
molecular docking studies
(Table 1). The structural diversity in all the derivatives was intro-
duced by varying substitution at 3 position of the triazole ring
while keeping the thiazolidinedione moiety intact. As shown in
Table 1, most of the compounds were moderately active but,
Results of molecular docking on human intestinal
a-glucosidase
(Table and Fig. 3) showed that compound 3e (docking
2
compound 3j showed better inhibition against HepG2 (IC50 31
ml) and MCF-7 (IC50 30 g/ml) cell lines respectively.
mg/
score ꢀ7.9 kcal/mol and two hydrogen bonds with ARG-647, ASP-
m
649) has similar binding affinity as compared to standard drug

310
Y. Chinthala et al. / European Journal of Medicinal Chemistry 70 (2013) 308e314
Step 1: Synthesis of 1 (Knoevenagel condensation)
H
H
O
O
O
O
Piperidene
O
O
NH
NH
S
S
Toluene,4h, Reflux
O
O
O
1
piperonal
thiazolidine-2,4-dione
5-(benzo[1,3]dioxol-5-ylmethylene)
thiazolidine-2,4-dione
Step 2: Synthesis of 2 (propargylation)
H
O
H
O
O
O
K2CO3, Dry acetone
O
O
Br
NH
S
N
4-5 h, Reflux
S
O
1
O
2
5-(benzo[1,3]dioxol-5-
ylmethylene)thiazolidine-2,4-
dione
5-(benzo[1,3]dioxol-5-ylmethylene)
-3-(prop-2-ynyl)thiazolidine-2,4-dione
Step 3: Synthesis of thiazolidine-2,4-dione-1,2,3-triazole derivatives
H
O
H
O
O
O
N3
O
O
Dry THF, CuI
RT, 10-12 hr
N
N
S
S
R
+
O
N
N
O
R
N
2
3a-i
3a. R=4-F
R=4-Cl
H
3f.
R=4-CH3
R=3,4-F2
O
O
O
3b.
N
S
3g.
O
N
N
3c. R=2-Cl
N
3h. R=3-F,4-Cl
3j
R=2-NO2
3d.
3e.
H
O
R=2-OCH3,5-CH3
3i.
R=4-Isopropyl
O
N
S
O
O
N
N
3k
N
Scheme 1.
Acarbose (docking score ꢀ7.9 kcal/mol and eleven hydrogen bonds
bioavailability. The excretion process that eliminates the compound
from the human body also depends on Log P as well as the mo-
lecular weight. Large molecular weight drugs generally have poor
absorption pattern due to the presence of polar groups. Moreover,
when the TPSA was calculated as a chemical descriptor for passive
molecular transport through membranes, results showed lower
TPSA value than Acarbose, thus indicates better intestinal absorp-
tion of compounds 3d, 3e and 3j (refer Table 1 in Supplementary
material).
with ARG-653, ARG-647, TYR-733, ASP-759, GLU-767) within the
ꢀ
4 A of selection radius. On the other hand compound 3d (docking
score ꢀ8.8 kcal/mol and five hydrogen bonds with GLU-658, ARG-
647, ARG-653) and 3j (docking score ꢀ8.3 kcal/mol and three
hydrogen bonds with ARG-647, GLU-658) showed slightly higher
binding affinity than Acarbose.
To analyze oral bioavailability and drug likeness compliance of
compounds 3d, 3e and 3j with standard parameters, chemical de-
scriptors of pharmacokinetic properties were calculated. Log P
value which is a measure of lipophilicity and is the ratio of the
solubility of the compound in octanol compared to its solubility in
water was calculated. Log P and molecular weight of compounds
3d, 3e and 3j were within the standard range limit as per Lipinski’s
rule of five and comparable with Acarbose, thus indicating high oral
3.2. Toxicity risk assessment screening
Toxicity risk assessment screening showed that compounds 3d,
3e and 3j have risk of mutagenicity on prolonged usage whereas
compound 3d exhibited risk of tumorogenicity and medium risk of

Y. Chinthala et al. / European Journal of Medicinal Chemistry 70 (2013) 308e314
311
Table 1
Anticancer and
recorded on a VG Micromass model 7070H instrument. All the re-
actions were monitored on silica gel precoated TLC plates of Merck
and spots were visualized with UV light. Silica gel (100e200 mesh)
used for column chromatography was procured from Merck.
a
-glucosidase inhibitory activity of compound 3ae3k.
-Glucosidase Anticancer activity
Compound
a
inhibition
IC50 mg/ml
IMR 32
IC50 g/ml
HepG2
IC50 mg/ml
MCF-7
IC50 mg/ml
m
5.1.1. Synthesis of 5-(benzo[1,3]dioxol-5-ylmethylene)thiazolidine-
2,4-dione 1 general procedure
3a
3b
3c
3d
3e
3f
3g
3h
>100
33.6
40.0
0.1
>100
>100
>100
>100
97.52
>100
>100
>100
52.58
52.64
77.58
e
>100
>100
>100
>100
66
>100
>100
>100
45
96.21
>100
87
>100
78
>100
>100
>100
34
A mixture of Piperonal (40 mmol) and thiazolidine-2,4-dione
(40 mmol) with catalytic quantity of piperidine was refluxed in
toluene with continuous removal of water using dean stark appa-
ratus for 4 h. The reaction mixture was cooled to 25 ꢂC to obtain a
pale yellow solid. The solid was recrystallized from water to get
compound 1, 5-(benzo [1,3]dioxol-5-ylmethylene) thiazolidine-
2,4-dione.
0.3
75.5
>100
>100
>100
0.3
>100
12.5
e
3i
3j
3k
31
67
30
43
5.1.2. Synthesis of 5-(benzo[1,3]dioxol-5-ylmethylene)-3-(prop-2-
ynyl)-thiazolidine-2,4-dione 2 general procedure
Acarbose
Doxorubicine
e
e
0.80
0.60
0.87
Compound 1 (23.60 mmol) along with potassium carbonate
(22 mmol) was dissolved in 10 ml of dry Acetone and later prop-
argyl bromide (23 mmol) was added slowly while stirring. The
reaction mixture was refluxed for 4 h and then extracted with ethyl
acetate to afford crude 5-(benzo[1,3]dioxol-5-ylmethylene)-3-
(prop-2-ynyl)-thiazolidine-2,4-dione 2. This crude residue was
purified by column chromatography over silica gel (100e200 mesh)
in 15% ethyl acetate in hexane to get compound 2 in pure state.
Yellow solid, yield: 93%, m.p.199-201 ꢂC, 1H NMR (CDCl3, 300 MHz)
reproductive or developmental toxicity. Compound 3e has showed
risk of irritation but no risk of tumorogenecity. Compound 3j
showed no risk of tumorogenicity; irritation and reproductive
toxicity (refer Table 2 in Supplementary material).
4. Conclusion
Synthesis of a series of novel hybrid molecules, 3ae3k, con-
sisting of biologically important pharmacophores 2,4-
thiazolidinediones tagged with 1,2,3-triazoles showed potential
d
2.291 (s,1H), 4.52 (s, 2H), 6.08 (s, 2H), 6.91e6.94 (d, 1H, J ¼ 8.1 Hz),
7.06e7.09 (d, 1H, J ¼ 8.1 Hz), 7.86 (s, 1H); 13C NMR (CDCl3,75 MHz)
d
ppm: 31.03, 72.55, 76.57, 102.39, 109.52, 118.91, 127.22, 127.71,
antidiabetic properties. a-Glucosidase enzyme inhibition in in vitro
129.09, 134.94, 149.03, 150.38, 165.56, 167.15; ESI-MS (m/z): 288.0
(M þ 1) observed for C14H9NO4S.
screening revealed compounds 3d, 3e and 3j were highly potential
than the standard Acarbose. These inhibitory results were further
optimized by molecular docking studies. Docking studies showed
5.1.3. Synthesis of thiazolidine-2,4-dione triazole derivatives 3ae
3k general procedure
compounds 3d, 3e and 3j have high binding affinity with the a-
glucosidase due to the presence of conserved binding site amino
acid residues e.g., LEU-640, ARG-647, ASP-649, ARG-653, PRO-676,
GLY-766, GLU-767, thus indicating their high stability along with
activity potentials similar to control Acarbose.
Compound 2 (1.0 mmol) was dissolved in dry THF (10 ml) and
catalytic amount of Copper iodide was added. To this, substituted
aromatic azides (1.0 mmol) in dry THF were added slowly while
stirring at room temperature under nitrogen atmosphere for 12 h.
Later, the solvent was removed under reduced pressure and the
residue was diluted with distilled water and extracted thrice with
dichloromethane. The combined organic layers were dried over
anhydrous Na2SO4 and concentrated to get the final product 3ae3k.
The crude products were purified by column chromatography with
ethyl acetate in hexane.
5. Experimental
5.1. Chemistry
Melting points of all the compounds was recorded on Casia-
Siamia (VMP-AM) melting point apparatus and uncorrected. IR
spectra were recorded on a PerkineElmer FT-IR 240-C spectrom-
eter using KBr optics. NMR spectra were recorded on Burker Avance
300 MHz in CDCl3 and DMSO-d6 using TMS as internal standard.
Electron impact (EI) and chemical ionization mass spectra were
5.1.4. 5-(Benzo[1,3]dioxol-5-ylmethylene)-3-((1-(4-fluorophenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione 3a
Yellow solid, yield: 85%, m.p.199e201 ꢂC, IR (KBr) cmꢀ1 3156,
2920, 1733, 1683, 1518, 1488. 1H NMR (CDCl3, 300 MHz)
d (ppm):
OH
HO
OH
H
H
O
O
O
O
N
H
O
OH
O
HO
O
O
O
O
N
O
N
S
S
O
HO
HO
O
S
N
N
N
N
N
N
O
O
OH
OH
O
O
N
N
H3C
OH
N
NH
OH
NO2
HO
OH
3e
3d
3j
Acarbose
Fig. 2. Structures of most potential a-glucosidase enzyme inhibitors.

312
Y. Chinthala et al. / European Journal of Medicinal Chemistry 70 (2013) 308e314
Table 2
Binding site residues detected during docking studies of compounds 3d, 3e, 3j and Acarbose on
a
-glucosidase.
Conserved binding site residues
ꢀ
Compound
Interacting amino acid residues (within 4 A binding site)
3d
THR-269, GLU-271, GLN-272, GLN-275, TYR-636, THR-639, LEU-640, ARG-647,
ASP-649, ARG-653, GLU-658, PRO-676, TYR-733, ILE-734, GLY-766, GLU-767
THR-269, GLU-271, LEU-640, ARG-647, ASP-649, ARG-653, HIS-657, GLU-658,
TYR-660, PRO-676, GLY-732, TYR-733, LYS-765, GLY-766, GLU-767
THR-269, GLU-271, TYR-636, THR-639, LEU-640, ARG-647, ASP-649, ARG-653,
HIS-657, GLU-658, TYR-660, PRO-676, TYR-733, LYS-765, GLY-766, GLU-767
Tyr-636, THR-639, LEU-640, ARG-643, ARG-647, ASP-649, ARG-653, GLU-658,
PRO-676, GLY-732, TYR-737, ILE-734, PRO-736, ASP-759, GLU-763, ALA-764,
LYS-765, GLY-766, GLU-767
LEU-640, ARG-647, ASP-649, ARG-653, PRO-676, GLY-766, GLU-767
LEU-640, ARG-647, ASP-649, ARG-653, PRO-676, GLY-766, GLU-767
LEU-640, ARG-647, ASP-649, ARG-653, PRO-676, GLY-766, GLU-767
LEU-640, ARG-647, ASP-649, ARG-653, PRO-676, GLY-766, GLU-767
3e
3j
Acarbose
5.14 (s, 2H), 6.07 (s, 2H), 6.91 (d, 1H, J ¼ 8.1 Hz), 6.07 (s, 1H), 7.07 (d,
1H, J ¼ 8.1 Hz), 7.22 (1H, d, J ¼ 8.85 Hz), 7.28 (s, 1H), 7.73e7.69 (m,
7.86 (s, 1H), 8.09 (s, 1H). 13C NMR (CDCl3, 75 MHz)
d (ppm):
168.12, 167.43, 166.22, 150.35, 149.05, 143.50, 138.11, 136.03,
134.90, 131.22, 129.38, 127.77, 127.18, 122.32, 121.96, 121.28, 119.01,
110.62, 109.53, 102.36, 36.84. ESI-MS (m/z) 441 (M þ 1) observed
for C20H13ClN4O4S.
2H) 7.85 (s, 1H), 8.04 (s, 1H). 13C NMR (CDCl3,75 MHz):
d (ppm) 36.8,
102.3, 109.5, 116.9, 117.2, 119.11, 122.1, 123.0, 123.1, 127.1, 127.7, 133.6,
134.8, 142.8, 149.0, 150.35, 161.2, 164.5, 166.2, 167.8. ESI-MS (m/z)
425 (M þ 1) observed for C20H13FN4O4S.
5.1.6. 5-(Benzo[1,3]dioxol-5-ylmethylene)-3-((1-(2-chlorophenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione 3c
5.1.5. 5-(Benzo[1,3]dioxol-5-ylmethylene)-3-((1-(4-chlorophenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione 3b
Yellow solid, yield: 83%, m.p.179e180 ꢂC, 1H NMR (CDCl3,
Yellow solid, yield: 85%, m.p. 180e182 ꢂC, 1H NMR (CDCl3,
300 MHz) d (ppm): 5.15 (s, 2H), 6.05 (s, 2H), 6.89 (d, 1H,
300 MHz)
d
(ppm): 5.15 (s, 2H), 6.08 (s, 2H), 6.92 (d, 1H,
J ¼ 8.120 Hz), 6.97 (s, 1H), 7.04 (d, 1H, J ¼ 8.120 Hz), 7.42e7.46 (m,
2H) 7.55e7.61 (m, 2H) 7.83 (s, 1H), 8.08 (s, 1H). ESI-MS (m/z) 441
(M þ 1) observed for C20H13ClN4O4S.
J ¼ 8.100 Hz), 6.99 (s, 1H), 7.07 (d, 1H, J ¼ 8.471 Hz), 7.29 (s, 1H),
7,45 (d, 2H, J ¼ 7.912 Hz), 7.15 (d, 1H, J ¼ 7.535 Hz), 7.79 (s, 1H),
Fig. 3. Molecular insight of compounds 3d, 3e, 3j and Acarbose docked on human intestinal a-glucosidase.

Y. Chinthala et al. / European Journal of Medicinal Chemistry 70 (2013) 308e314
313
5.1.7. 5-(Benzo[1,3]dioxol-5-ylmethylene)-3-((1-(2-nitrophenyl)-
5.1.14. 5-(Benzo[1,3]dioxol-5-ylmethylene)-3-((1-octyl-1H-1,2,3-
1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione 3d
triazol-4-yl)methyl)thiazolidine-2,4-dione 3k
Yellow solid, yield: 83%, m.p. 202e205 ꢂC, IR (KBr) cmꢀ1 3155,
Yellow solid, yield: 81%, m.p. 95e98 ꢂC, 1H NMR (CDCl3,
2923, 1733, 1675, 1585, 1456. 1H NMR (CDCl3, 300 MHz)
d
(ppm):
300 MHz) d (ppm): 0.84e0.89 (t, 3H),1.25e1.30 (s, 6H), 1.85e1.90 (t,
5.13 (s, 2H), 6.04 (s, 2H), 6.89 (d, 1H, J ¼ 9.042 Hz), 7.60 (d, 1H,
J ¼ 7.15 Hz), 7.71 (d,1H, J ¼ 7.535 Hz), 7.77 (d,1H, J ¼ 8.66 Hz), 7.83 (s,
1H), 7.97 (s, 1H), 8.08 (d, 1H, J ¼ 8.66 Hz). ESI-MS (m/z) 452 (M þ 1)
observed for C20H13N5O6S.
2H), 4.28e4.33 (t, 2H), 5.03 (s, 2H), 6.05 (s, 2H), 6.88e6.91 (d, 1H,
J ¼ 8.12 Hz), 6.96 (s,1H), 7.02e7.05 (d, 1H, J ¼ 8.12 Hz), 7.60 (s, 1H),
7.81 (s, 1H). ESI-MS 415 (m/z) (M þ 1) observed for C20H22N4O4S.
Acknowledgments
5.1.8. 5-(Benzo[1,3]dioxol-5-ylmethylene)-3-((1-(4-
isopropylphenyl)-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-
dione 3e
Authors thank Director, CSIR-CIMAP, Lucknow, India, and SIC,
CSIR-CIMAP-RC, Hyderabad, India for their constant encourage-
ment and support. Author Yakaiah thanks CSIR-New Delhi for
granting Senior Research Fellowship. Also, Author Sarfaraj thank
‘Council of Science and Technology, Uttar Pradesh’ (CST, UP),
Lucknow for the award of fellowship.
Yellow solid, yield: 79%, m.p. 142e146 ꢂC, 1H NMR (CDCl3,
300 MHz) d (ppm): 1.29 (s, 6H), 2.93e3.02 (m, 1H), 5.12 (s, 2H), 6.05
(s, 2H), 6.88e6.91 (d, 1H, J ¼ 8.30 Hz), 6.97 (s, 1H), 7.03e7.06 (d, 1H,
J ¼ 8.3 Hz), 7.33e7.36 (d, 2H, J ¼ 8.3 Hz), 7.59e7.62 (d, 2H,
J ¼ 9.0 Hz), 7.83 (s, 1H), 8.02 (s, 1H). ESI-MS (m/z) 449 (M þ 1)
observed for C23H20N4O4S.
Appendix A. Supplementary data
5.1.9. 5-(Benzo[1,3]dioxol-5-ylmethylene)-3-((1-p-tolyl-1H-1,2,3-
triazol-4-yl)methyl)thiazolidine-2,4-dione 3f
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.10.005.
Yellow solid, yield: 79%, m.p.155e158 ꢂC, 1H NMR (CDCl3,
300 MHz) d (ppm): 1.28 (s, 3H), 5.16 (s, 2H), 6.08 (s, 2H), 6.92 (d, 1H,
J ¼ 8.10 Hz), 6.99 (s, 1H), 7.08 (d, 1H, J ¼ 7.53 Hz), 7.64 (d, 1H,
J ¼ 7.91 Hz) 7.73e7.81 (m, 2H), 7.86 (s, 1H), 8.00 (s, 1H), 8.11 (d, 1H,
J ¼ 7.91 Hz). ESI-MS (m/z) 421 (M þ 1) observed for C21H16N4O4S.
References
[1] J.P. Ye, Challenges in drug discovery for thiazolidinedione substitute, Acta
Pharm. Sin. B 1 (2011) 137e142.
[2] C. Blanquicett, J. Roman, C.M. Hart, Thiazolidinediones as anti-cancer agents,
Cancer Ther. 6 (A) (2008) 25e34.
[3] P. Vijay, T. Kalpana, M.M. Sonali, R. Mohan, C.S. Ramaa, Synthesis and primary
cytotoxicity evaluation of new 5-benzylidene-2,4-thiazolidinedione de-
rivatives, Eur. J. Med. Chem. 45 (2010) 4539e4544.
[4] X.F. Liu, C.J. Zheng, L.P. Sun, X.K. Liu, H.R. Piao, Synthesis of new chalcone
derivatives bearing 2,4-thiazolidinedione and benzoic acid moieties as po-
tential antibacterial agents, Eur. J. Med. Chem. 46 (2011) 3469e3473.
[5] A. Garg, P. Chawla, D. Panjvani, S.A. Saraf, Synthesis of some novel 5-
substituted arylidine 2,4-thiazolidinediones as bioactive agents, Int. J.
Pharm. Sci. Nanotechnol. 4 (2011) 1373e1378.
[6] V.S. Jain, D.K. Vora, C.S. Ramaa, Thiazolidine-2,4-diones: progress towards
multifarious applications, Bioorg. Med. Chem. 21 (2013) 1599e1620.
[7] A. Galli, E. Ceni, T. Mello, S. Polvani, M. Tarocchi, F. Buccoliero, F. Lisi, L. Cioni,
B. Ottanelli, V. Foresta, G. Mastrobuoni, G. Moneti, G. Pieraccini, C. Surrenti,
S. Milani, Thiazolidinediones inhibit hepatocarcinogensis in hepatitis B virus-
5.1.10. 5-(Benzo[1,3]dioxol-5-ylmethylene)-3-((1-(3,4-
difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione
3g
Yellow solid, yield: 85%, m.p.182e184 ꢂC, 1H NMR (CDCl3,
300 MHz)
d
(ppm): 5.11 (s, 2H), 6.05 (s, 2H), 6.90 (d, 1H, J ¼ 8.477),
6.96 (s, 1H), 7.05 (s, 1H), 7.30 (d,1H, J ¼ 11.86 Hz), 7.58e7.64 (m, 2H),
7.85 (d, 1H, J ¼ 2.63 Hz) 7.83 (s, 1H) 8.02 (s, 1H). ESI-MS (m/z) 443
(M þ 1) observed for C20H12F2N4O4S.
5.1.11. 5-(Benzo[1,3]dioxol-5-ylmethylene)-3-((1-(4-chloro-3-
fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione
3h
Yellow solid, yield: 80%, m.p.174e175 ꢂC, IR (KBr) cmꢀ1: 3156,
transgenic mice by peroxisome proliferator-activated receptor g-independent
regulation of nucleophosmin, Hepatology 52 (2010) 493e505.
2926, 1736, 1685, 1588, 1451. 1H NMR (CDCl3, 300 MHz)
d (ppm):
[8] M. Whiting, J.C. Tripp, Y.C. Lin, W. Lindstrom, A.J. Olson, J.H. Elder,
K.B. Sharpless, V.V. Fokin, Rapid discovery and structure activity profiling of
novel inhibitors of human immunodeficiency virus type 1 protease enabled by
the copper(I) catalyzed synthesis of 1,2,3,-triazoles and their further func-
tionalization, J. Med. Chem. 49 (2006) 7697e7710.
[9] M.J. Giffin, H. Heaslet, A. Brik, Y.C. Lin, G. Cauvi, C.H. Wong, D.E. McRee,
J.H. Elder, C.D. Stout, B.E. Torbett, A copper(I)-catalyzed 1,2,3-triazole azide-
alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1
protease variant, J. Med. Chem. 51 (2008) 6263e6270.
[10] H. Bektas, N. Karaali, D. Sahin, A. Demirbas, S.A. Karaoglu, N. Demirbas, Syn-
thesis and antimicrobial activities of some new 1,2,3-triazole derivatives,
Molecules 15 (2010) 2427e2438.
[11] G.P. Dorota, B. Jan, E.G. Iwona, Design, synthesis, antiviral and cytostatic
evaluation of novel isoxazolidine nucleotide analogues with a 1,2,3-triazole
linker, Eur. J. Med. Chem. 47 (2012) 501e509.
[12] S.G. Agalave, S.R. Maujan, V.S. Pore, Click chemistry: 1,2,3-triazoles as phar-
macophores, Chem. Asian J. 6 (2011) 2696e2718.
[13] I.K. Boddy, G.G. Briggs, R.P. Harrison, T.H. Jones, M.J. O’Mahony, I.D. Marlow,
B.G. Roberts, R.J. Willis, R. Bardsley, J. Reid, The synthesis and insecticidal
activity of a series of 2-aryl-1,2,3-triazoles, Pest Manage. Sci. 48 (1996) 189e
196.
[14] N.G. Aher, V.S. Pore, N.N. Mishra, A. Kumar, P.K. Shukla, A. Sharma, M.K. Bhat,
Synthesis and antifungal activity of 1,2,3-triazole containing fluconazole an-
alogues, Bioorg. Med. Chem. Lett. 19 (2009) 759e763.
[15] S.A. Ross, E.A. Gulve, M. Wang, Chemistry and biochemistry of type 2 diabetes,
Chem. Rev. 104 (2004) 1255e1282.
5.14 (s, 2H) 6.08 (s, 2H), 6.92 (d, 1H, J ¼ 8.10 Hz), 6.98 (s, 1H), 7.07 (d,
1H, J ¼ 8.10 Hz),7.33 (d,1H, J ¼ 8.28 Hz), 7.61e76 (m,1H), 7.83 (d,1H,
J ¼ 2.637 Hz), 7.85 (s, 1H), 8.06 (s, 1H). ESI-MS (m/z) 459 (M þ 1)
observed for C20H12ClFN4O4S.
5.1.12. 5-(Benzo[1,3]dioxol-5-ylmethylene)-3-((1-(2-methoxy-4-
methylphenyl)-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione
3i
Yellow solid, yield: 82%, m.p. 200e205 ꢂC, 1H NMR (CDCl3,
300 MHz)
d (ppm): 1.25 (s, 3H), 2.414 (s, 3H), 5.12 (s, 2H), 6.04 (s,
2H), 6.88e6.91 (d, 1H, J ¼ 8.12 Hz), 6.97 (s, 1H), 7.03e7.06 (d, 1H,
J ¼ 9.63 Hz), 7.28e7.31 (d, 2H, J ¼ 8.3 Hz), 7.56e7.59 (d, 2H,
J ¼ 8.3 Hz), 7.83 (s, 1H), 8.01 (s, 1H). ESI-MS (m/z) 451 (M þ 1)
observed for C22H18N4O5S.
5.1.13. 5-(Benzo[1,3]dioxol-5-ylmethylene)-3-((1-phenethyl-1H-
1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione 3j
Yellow solid, yield: 86%, m.p. 166e165 ꢂC, IR (KBr) cmꢀ1: 3122,
2924, 1744, 1684, 1591, 1506. 1H NMR (CDCl3, 300 MHz)
d (ppm):
3.44e3.49 (t, 2H), 4.81e4.86 (t, 2H), 5.27 (s, 2H), 6.35 (s, 2H), 7.18e
7.20 (d, 1H, J ¼ 8.12 Hz), 7.32e7.37 (m, 3H), 7.50e7.59 (m, 4H) 7.62
(s, 1H), 8.01 (s, 1H). ESI-MS (m/z) 435 (M þ 1) observed for
[16] T. Mossman, Rapid colorimetric assay for cellular growth and survival:
application to proliferation and cytotoxicity assays, J. Immunol. Methods 65
(1983) 55e63.
[17] K.S. Babu, A.K. Tiwari, P.V. Srinivas, A.Z. Ali, B.C. Raju, J.M. Rao, Yeast and
C
22H18N4O4S.
mammalian
a-glucosidase inhibitory constituents from Himalayan rhubarb

314
Y. Chinthala et al. / European Journal of Medicinal Chemistry 70 (2013) 308e314
Rheum emodi Wall. Ex Meisson, Bioorg. Med. Chem. Lett. 14 (2004) 3841e
3845.
[18] G.J. McDougall, F. Shpiro, P. Dobson, P. Smith, A. Blake, D. Stewart, Different
[20] D.K. Yadav, A. Meena, A. Srivastava, D. Chanda, F. Khan, S.K. Chattopadhyay,
Development of QSAR model for immunomodulatory activity of natural
coumarinolignoids, Drug Des. Dev. Ther. 4 (2010) 173e186.
polyphenolic components of soft fruits inhibit
J. Agric. Food Chem. 53 (2005) 2760e2766.
a
-amylase and
a
-glucosidase,
[21] L. Sim, K. Jayakanthan, S. Mohan, R. Nasi, B.D. Johnston, B.M. Pinto, D.R. Rose,
New glucosidase inhibitors from an ayurvedic herbal treatment for type 2
diabetes: structures and inhibition of human intestinal maltase-
glucoamylase with compounds from Salacia reticulate, Biochemistry 49
(2010) 443e451.
[19] O. Trott, A.J. Olson, AutoDock Vina: improving the speed and accuracy of
docking with new scoring function, efficient optimization and multi-
threading, J. Comput. Chem. 31 (2010) 455e461.
a