Multicomponent domino process for the synthesis of some novel 5-(arylidene)-3-((1-aryl-1H-1,2,3-triazol-4-yl)methyl)-thiazolidine-2,4-diones using PEG-400 as an efficient reaction medium and their antimicrobial evaluation

Article abstract of DOI:10.1016/j.cclet.2014.09.006

A series of novel thiazolidinedione-triazole hybrids were synthesized by one pot reaction between thiazolidine-2,4-dione, substituted aryl aldehydes, propargyl bromide and substituted aryl azides using piperidine, CuSO₄·5H₂O and sodi

Full text of DOI:10.1016/j.cclet.2014.09.006

G Model
CCLET 3087 1–5
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
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Original article
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Multicomponent domino process for the synthesis of some novel
5-(arylidene)-3-((1-aryl-1H-1,2,3-triazol-4-yl)methyl)
thiazolidine-2,4-diones using PEG-400 as an efficient reaction medium
and their antimicrobial evaluation
a
a
a,
b
b
7
Q1 Jayant Sindhu , Harjinder Singh , J.M. Khurana *, Chetan Sharma , K.R. Aneja
a
8
9
Department of Chemistry, Delhi University, Delhi 110007, India
b
Department of Microbiology, Kurukshetra University, Kurukshetra, India
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of novel thiazolidinedione–triazole hybrids were synthesized by one pot reaction between
thiazolidine-2,4-dione, substituted aryl aldehydes, propargyl bromide and substituted aryl azides using
Received 23 April 2014
Received in revised form 20 July 2014
Accepted 31 July 2014
Available online xxx
piperidine, CuSO
4
Á5H
2
O and sodium ascorbate as catalysts in PEG-400 as a highly efficient and green
media. These thiazolidinedione–triazole hybrids were subjected to in vitro antibacterial activity against
four strains namely, Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and
antifungal activity against two fungal strains namely, Aspergillus niger and Aspergillus flavus.
ß 2014 J.M. Khurana. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
Multicomponent
Antibacterial
Antifungal
1
,2,3-Triazoles thiazolidine-2,4-diones
1
1
0
1
1. Introduction
reaction media would be an added advantage for organic synthesis 30
as it reduces environmental burden. Over the years, polyethylene 31
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25
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The focus on the discovery and optimization of novel
antimicrobial agents which are active against resistant strains is
an active area of research [1]. The development of new synthetic
methods leading to hybrid structures, which consist of different
biologically active moieties in a single molecule, has attracted
much attention. The heterocyclic pharmacophores are selected on
the basis of their known bio profiles, so that the successive hybrid
molecules may exhibit synergistic or additive pharmacological
activities [2,3].
Multicomponent reactions (MCRs) approach has played an
important role in modern drug discovery by introducing structural
complexity and diversity and also offers various advantages like
atom economy and high efficiency over conventional linear-type
syntheses [4–6]. The role of click chemistry is also very significant in
modern drug discovery. Biologically important compounds contain-
ing more than one pharmacophore have been developed by many
researchers in a single step by combining MCRs with click reactions
[7,8]. Deploying non-toxic, bio-degradable and bio-compatible
glycol (PEG-400) and modified polyethylene glycol derivatives have 32
become more popular alternate reaction media, due to their 33
interesting properties like non-toxicity, bio-compatibility, and 34
bio-degradability when compared to other ‘neoteric solvents’ such 35
as ionic liquids, super-critical fluids, and micellar systems [9]. Sev- 36
eral reactions like substitution reactions [10], oxidation and 37
reduction reactions [11], Heck reaction [12], asymmetric dihydrox- 38
ylation[13], couplingreaction[14], Wackerreaction[15], andpartial 39
reductions of alkynes [16] were reported using PEG-400.
40
5-Arylidenethiazolidine-2,4-diones have been found to exhibit 41
several pharmacological activities such as antidiabetic [17], 42
antioxidant [18], cardiotonic [19], anti-inflammatory [20], anti- 43
cancer [21] and also inhibits several targets such as HCV protease 44
[22],
b-lactamase [23], JNK-stimulating phosphatase-1 (JSP-1) 45
[24], aldose reductase inhibitor [25], tyrosine phosphatases 46
inhibitor [26], antimicrobial and antihyperglycemic agents 47
[27]. In addition, 5-arylidenethiazolidine-2,4-diones have sub- 48
stantial anti-proliferative effect on vascular smooth muscle [28] 49
and also act as selective inhibitors of the PIM-1, PIM-2, and PIM-3 50
protein kinases [29]. 1,2,3-Triazole and its derivatives have also 51
attracted the attention of organic and medicinal chemists due to 52
their numerous biological activities such as anti-tubercular [30], 53
*
Corresponding author.
E-mail address: jmkhurana@chemistry.du.ac.in (J.M. Khurana).
http://dx.doi.org/10.1016/j.cclet.2014.09.006
001-8417/ß 2014 J.M. Khurana. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
1
Please cite this article in press as: J. Sindhu, et al., Multicomponent domino process for the synthesis of some novel 5-(arylidene)-3-((1-
aryl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-diones using PEG-400 as an efficient reaction medium and their antimicrobial
evaluation, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.006

G Model
CCLET 3087 1–5
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J. Sindhu et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
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3
anti-HIV [31], antifungal [32], antibacterial [33], anticancer
activities [34], GABA [35] and glycosidase inhibitors [36]. The
enhanced biological activities shown by 1,2,3-triazole ring are
probably due to high dipole moment, hydrogen bonding capability,
rigidity and stability under in vivo conditions [37].
1,2,3-Triazoles are extremely stable under basic and acid
hydrolysis and also in reductive and oxidative conditions
[38,39]. Moreover, 1,2,3-triazoles are also incorporated as linker
between two pharmacophores to give bifunctional drugs [40]. It
by filtration at pump and washed with water. The product so
obtained, was purified by using flash column chromatography over
104
105
106
107
108
109
110
111
112
113
114
115
116
117
silica gel (230–400 mesh) to afford pure product 5a. Off-white solid;
1
mp: 2038C; H NMR (400 MHz, CDCl
3
):
d
H
8.00 (s, 1H, Ar–H), 7.87 (s,
1H, C 55 C–H), 7.56–7.54 (s, 2H, Ar–H), 7.37–7.35 (m, 2H, Ar–H),
7.27–7.23 (m, 4H, Ar–H), 5.10 (s, 2H, N–CH ), 2.38 (s, 3H, CH ), 2.37
167.6, 165.8, 141.4, 139.0,
2
3
1
3
3 3
(s, 3H, CH ); C NMR (100 MHz, CDCl ): d
134.5, 130.3, 130.1, 129.9, 121.5, 120.5, 119.8, 36.4, 21.5, 21.0; IR
À1
(KBr, cm ):
n
max 1745, 1684, 1599, 1336, 1238, 1136, 1044. MS (ESI)
+
was also found that N–CH
2
bridge has been used for synthesizing
m/zcalcd. forC21
18 4 2
H N O S:390.1150HR-MS(ESI):391.1225[M +1].
complex molecules containing two active pharmacophores [41].
In view of the biological importance of 1,2,3-triazoles and
5-arylidenethiazolidine-2,4-diones, and in continuation of our
interest in the development of medicinally important heterocycles
[42], we decided to explore the synthesis of hybrid heterocycles
comprising 1,2,3-triazoles and 5-arylidenethiazolidine-2,4-dione
substructures. Such a strategy would provide access to a rapid
synthesis of 1H-1,2,3-triazole tethered 5-arylidenethiazolidine-
2,4-dione molecular conjugates which are otherwise accessible
through multistep synthesis.
By similar procedure, 5b–5p were synthesized and
a
1
13
characterized using H NMR, C NMR, IR and mass. Spectral data
for all other compounds and the procedure for antimicrobial
screening were included in Supporting information.
3. Result and discussion
118
119
3.1. Chemistry
The present manuscript reports the synthesis of targeted
120
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124
125
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127
128
129
130
131
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133
134
135
136
137
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139
140
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142
143
144
145
146
147
148
149
150
151
152
5
-(arylidene)-3-((1-aryl-1H-1,2,3-triazol-4-yl)methyl)thiazoli-
7
4
2. Experimental
dine-2,4-diones, by a multicomponent domino process. Firstly,
Knoevenagel condensation of thiazolidine-2,4-dione and aro-
matic aldehydes using piperidine as catalyst in PEG-400 at
120 8C resulted in the formation of 5-(arylidene)thiazolidine-
2,4-dione (3), which further reacts with propargyl bromide and
7
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7
7
8
8
8
8
8
8
8
8
8
8
9
9
9
9
9
9
9
9
9
9
1
1
1
1
5
Structures of all of the compounds were identified by their
spectral data. Silica gel 60 F254 (Precoated aluminium plates) from
Merck were used to monitor reaction progress. Melting points
were determined on Buchi Melting Point M-560 apparatus and are
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
00
01
02
03
1-azido-4-methylbenzene (4a) in presence of CuSO
4
Á5H
2
O and
uncorrected. IR (KBr) spectra were recorded on Perkin Elmer FTIR
sodium ascorbate as catalysts in the same pot resulting in
the formation of 5-(arylidene)-3-((1-aryl-1H-1,2,3-triazol-4-
yl)methyl)thiazolidine-2,4-diones (5) (Scheme 1).
À1
spectrophotometer and the values are expressed as
n
max cm . The
1
13
H NMR and C NMR spectra were recorded on Jeol JNM ECX-400P
at 400 MHz and 100 MHz respectively. Mass spectra were recorded
at Bruker Micro TOF Q – II. The chemical shift values are recorded
on d scale and the coupling constants (J) are in Hertz. The aryl
azides used in the synthesis of compounds (5a–5p) were prepared
from aromatic amines by reported procedure [43].
General procedureforthe synthesis of 5-(4-methylbenzylidene)-
3-((1-(4-tolyl)-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione
(5a): a mixture of thiazolidine-2,4-dione (1.0equiv.), 4-methylben-
zaldehyde (1.0equiv.), piperidine (1.0 equiv.) and 5 mL of PEG-400
was placed in a 50 mL round-bottomed flask and the contents
were stirred magnetically in an oil-bath maintained at 120 8C until
5-(4-methylbenzylidene)thiazolidine-2,4-dione (3) was formed
(3–4 h), which was monitored by TLC using ethyl acetate–petroleum
ether, (30:70, v/v) as eluent. Then, propargyl bromide (1.0equiv.),
4-methylphenyl azide (1.0equiv.) (4) were added to the above
To search the optimal reaction conditions for the synthesis of 5,
firstly Knoevenagel condensation of thiazolidine-2,4-dione
(1.0 equiv.) and 4-methylbenzaldehyde (1.0 equiv.) was carried
out in refluxing ethanol using piperidine (1.0 equiv.) as base
[27]. The reaction was completed after 6 h as monitored by TLC
(ethyl acetate: petroleum ether, 40:60, v/v). Propargyl bromide
(1.0 equiv.) and 1-azido-4-methylbenzene (1.0 equiv.) (4) were
then added to the same pot followed by addition of aq. CuSO
4
Á5H
2
O
(10 mol%) and aq. sodium ascorbate (20 mol%). The reaction was
not complete even after 12 h but yielded 50% of 5a after workup
(Table 1, entry 1).
1
13
The formation of 5a was confirmed by H NMR and C NMR. A
1
singlet at
proton on the C-5 carbon of triazole ring. Similarly a singlet at
7.87 for 1 proton is assigned to the exocyclic double bond. A singlet
at 5.10 confirms the presence of N–CH group and two singlets at
2.37 and 2.38 are assigned to three protons each for two methyl
d 8.00 for 1 proton in the H NMR spectra is assigned to
d
reaction mixture followed by an aqueous solution of CuSO
4 2
Á5H O
d
2
(10 mol%) and aqueous solution of sodium ascorbate (20 mol%). The
reaction mixture was further heated at 120 8C for 60 min. The
progress of the reaction was monitored by TLC (ethyl acetate-
petroleum ether, 40:60, v/v). After completion of the reaction, the
reaction mixture was allowed to cool at room temperature and was
quenched with water (ꢀ5 mL). The precipitate formed was collected
d
1
3
groups attached to the phenyl ring.
C
NMR also shows
36.4 for
methylene carbon attached to nitrogen of thiazolidinedione ring
and at 21.5 and 21.0 for carbons of two methyl groups,
respectively. To improve the efficacy, the reaction was then
characteristic peaks at d 119.8 for C-5 of triazole ring, d
d
Scheme 1. Synthesis of 5-(arylidene)-3-((1-aryl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-diones (5a–5p) using domino process.
Please cite this article in press as: J. Sindhu, et al., Multicomponent domino process for the synthesis of some novel 5-(arylidene)-3-((1-
aryl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-diones using PEG-400 as an efficient reaction medium and their antimicrobial
evaluation, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.006

G Model
CCLET 3087 1–5
J. Sindhu et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
Table 1
a
Optimization table for the synthesis of 5a starting using domino process
o
Entry
Solvent
Time (h)
Temp ( C)
Base (1 equiv.)
Yield (%)
b
1
2
3
4
5
6
7
Ethanol
Methanol
DMF
12
12
6
Reflux
Reflux
100
Piperidine
Piperidine
Piperidine
Piperidine
50
b
48
c
No rxn
PEG-400
PEG-400
PEG-600
PEG-400
6
100
82
c
6
100
K
2
CO
3
No rxn
6
100
Piperidine
Piperidine
78
90
5
120
a
Reaction was performed using thiazolidine-2,4-dione (1.1equiv.) (1), 4-methyl-
benzaldehyde (1.0equiv.) (2a), propargyl bromide (1.0equiv.) and 1-azido-4-methyl-
benzene (1.0equiv.) (4);
b
Incomplete reaction;
c
Intermediate compound 3a was not formed during the reaction.
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
attempted in other solvents like methanol, DMF, PEG-400 and
PEG-600 (Table 1, entries 2–7). The highest yield of 5a (90%) was
obtained when the reaction was carried out in PEG-400 at 120 8C
(Table 1, entry 7). Thiazolidine-2,4-dione (1.0 equiv.), 4-methyl-
benzaldehyde (1.0 equiv.) and piperidine (1.0 equiv.) as base were
reacted in PEG-400 at 120 8C. After completion of reaction as
evident from TLC (ethyl acetate:petroleum ether, 40:60, v/v) after
4 h, propargyl bromide (1.0 equiv.) and 1-azido-4-methylbenzene
(1.0 equiv.) (4) were then added to the same pot followed by
addition of aq. CuSO
(20 mol%). The reaction was completed after 60 min and results in
the formation of 5a in 90% yield.
4
Á5H
2
O (10 mol%) and aq. sodium ascorbate
Fig. 1. Crystal structure of compound 5m by single crystal X-ray diffraction study.
Subsequently, reactions of thiazolidine-2,4-dione and other
aromatic aldehydes containing electron withdrawing and electron
releasing substituents were carried out in PEG-400 using piperi-
dine as base followed by addition of propargyl bromide, aryl azides,
by single crystal X-ray diffraction study of 5m which confirmed the 181
regioselectivity of the product (Fig. 1).
182
183
184
4
aq. CuSO and aq. sodium ascorbate in the same pot at 120 8C. All
the reactions were complete in less than 80 min and gave
the desired products 5-(arylidene)-3-((1-aryl-1H-1,2,3-triazol-
4-yl)methyl)thiazolidine-2,4-diones (5a–5p) in high yields
(Table 2, Scheme 1).
3.2. Biological screening
3.2.1. Antibacterial activity
A total of 16 chemical compounds were screened for their 185
antibacterial and antifungal activity. Tested chemical compounds 186
possessed variable antibacterial activity against Gram-positive 187
(Staphylococcus aureus, Bacillus subtilis) bacteria. However, they did 188
not exhibit any activity against Gram-negative (Escherichia coli and 189
Pseudomonas aeruginosa) bacteria. Positive controls produced 190
significantly sized inhibition zones against the tested bacteria 191
and fungi. However, negative controls did not show observable 192
inhibitory effect against any of the test organisms as shown in 193
1
13
All the novel compounds were characterized by H NMR,
C
NMR, IR and ESI–MS/HRMS. The formation of triazole ring was
confirmed by the resonance of H-5 of the triazole ring in the
1
aromatic region in the H NMR spectra. The structures were further
13
supported by the C NMR spectra, which confirmed the C-skeleton
of triazole derivatives 5a–5p. ESI–MS/HRMS of all compounds
+
+
showed [M +Na] and [M +1]. The structure was finally established
Table 3.
194
Compounds 5a–5p showed zone of inhibition ranging between 195
Table 2
13.3 mm and 22.3 mm against the Gram-positive bacteria. On the 196
Synthesis of 5-(arylidene)-3-((1-aryl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-
2
,4-diones (5a–5p) using multicomponent domino reaction.
basis of zone of inhibition produced against the test bacterium, five 197
compounds namely, 5g, 5h, 5i, 5k and 5o were found to be most 198
active against S. aureus and B. subtilis with zone of inhibition 199
ranging between 18.3 mm and 22.3 mm, respectively. Compound 200
1
2
3
a
o
Compd.
R
R
R
Yield (%)
Time (min)
Mp ( C)
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
Me
Me
Me
Me
Me
Br
Me
F
H
H
H
Cl
Cl
H
Cl
Cl
Cl
H
H
H
H
Cl
H
Cl
90
88
92
86
88
88
86
84
90
92
88
84
88
86
90
88
60
70
80
75
70
60
70
75
75
80
70
60
70
75
80
70
204
208
186
212
193
234
197
228
207
222
246
236
272
184
193
174
5h shows more than 80% inhibition of bacterial growth. However 201
OMe
F
d
e
f
other tested compounds showed moderate antibacterial activity 202
(Table 3). Minimum inhibitory concentration (MIC) of all 203
compounds 5a–5p was measured against Gram-positive bacteria, 204
as shown in Table 3. The MIC of chemical compounds ranged 205
H
Me
H
g
h
i
Br
Br
F
between 32 and 256
compounds 5f, 5g, 5i, 5k were found to be best as they exhibited 207
the MIC of 64 g/mL against S. aureus and B. subtilis whereas 5h 208
was found to be best against S. aureus and B. subtilis with lowest 209
MIC of 32 g/mL (Table 3). Presence of electron withdrawing 210
mg/mL against Gram-positive bacteria. Four 206
NO
2
NO
2
NO
2
F
F
j
OMe
F
k
l
m
Me
F
m
n
o
p
OMe
OMe
OMe
OMe
m
F
OMe
H
substituent on the phenyl ring attached to the exocyclic double 211
bond enhances the activity of compounds. The enhanced activity of 212
5h is due to substitution of three halogen substituents on both the 213
a
Time required for completion of reaction after addition of propargyl bromide
(1.0 equiv.) and substituted aryl azides (1.0 equiv.)
phenyl rings.
214
Please cite this article in press as: J. Sindhu, et al., Multicomponent domino process for the synthesis of some novel 5-(arylidene)-3-((1-
aryl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-diones using PEG-400 as an efficient reaction medium and their antimicrobial
evaluation, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.006

G Model
CCLET 3087 1–5
4
J. Sindhu et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
Table 3
Antibacterial activity of compounds 5a-5p.
a
Compd.
Diameter of growth of inhibition zone (mm)
Minimum inhibitory
concentration (MIC) (in
mg/mL)
S. aureus
B. subtilis
E. coli
P. aeruginosa
S. aureus
B. subtilis
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
14.6
15.6
13.3
16.6
15.3
18.3
19.6
21.6
19.3
17.6
18.6
15.6
16.0
16.3
18.6
15.3
16.0
26.6
15.3
16.3
15.6
18.3
17.6
19.6
20.6
22.3
20.6
18.3
19.3
16.3
17.3
17.6
19.3
16.6
17.6
24.0
–
–
256
256
256
128
256
64
128
128
128
128
128
64
–
–
–
–
d
e
f
–
–
–
–
–
–
g
h
i
–
–
64
64
–
–
32
32
–
–
64
64
j
–
–
64
64
k
l
–
–
64
64
–
–
128
256
128
64
128
128
128
64
m
n
o
p
–
–
–
–
–
–
–
–
128
128
6.25
128
128
6.25
b
q
–
–
Ciprofloxacin
25.0
22.0
–
, no activity;
a
Values, including diameter of the well (8 mm), are means of three replicates.
b
5
q: 5-(4-bromobenzylidene)thiazolidine-2,4-dione.
Table 4
Antifungal activity of compounds 5a–5p through poisoned food method.
Compd.
Mycelial growth inhibition (%)
Compd.
Mycelial growth inhibition (%)
Aspergillus niger
Aspergillus flavus
Aspergillus niger
Aspergillus flavus
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
35.5
35.5
37.7
47.7
33.3
48.8
37.7
35.5
41.1
41.1
38.8
43.3
51.1
36.6
53.3
42.2
43.3
43.3
5j
33.3
38.8
33.3
45.5
48.8
53.3
41.1
34.5
81.1
37.7
41.1
37.7
47.7
52.2
55.5
45.5
39.7
77.7
5k
5l
5m
5n
5o
g
h
i
5p
5q
Fluconazole
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
3.2.2. Antifungal activity
developing thiadiazolidine-2–4-dione based derivatives as promis-
ing antibacterial agents.
239
240
All the 16 compounds 5a–5p were also tested for their in
vitro antifungal activity against two fungal strains, namely,
Aspergillus niger and Aspergillus flavus species through poisoned
food method. Standard drug fluconazole was used for compari-
son of antifungal activity shown by the compounds and results
were recorded as percentage (%) of mycelial growth inhibition. It
can be inferred from Table 4 that all the compounds 5a–5p
showed variable antifungal activity against two pathogens. It
can be inferred by comparison of the results that seven
compounds namely 5d , 5f, 5i, 5m, 5n, 5o, and 5p showed high
antifungal activity with >50% inhibition of mycelial growth
against the two fungi in comparison with the standard drug.
Other compounds also showed good antifungal activities as
summarized in Table 4.
Uncited references
Q2 241
[44–48].
242
Acknowledgment
243
JS and HS thank UGC, New Delhi, India for the grant of Junior Q3 244
and Senior Research Fellowships.
Q4 245
Appendix A. Supplementary data
246
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at http://dx.doi.org/10.1016/j.cclet.2014.09.006.
247
248
2
30
4. Conclusion
231
232
233
234
235
236
237
238
The present study offers an efficient and convenient multicom-
ponent domino process for the synthesis of (Z)-5-(arylidene)-3-((1-
aryl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-diones (5a–5p).
Among all the tested chemical compounds, compound 5h showed
good antibacterial and 5o showed good antifungal activity. The
hybrid molecule shows good antimicrobial activities as compared to
their thiazolidinedione substructure used for the synthesis of new
antimicrobials. Hence this study has widened the scope of
References
249
[
1] F.L. Gouveia, R.M.B. De Oliveira, T.B. De Oliveira, et al., Synthesis, antimicrobial
and cytotoxic activities of some 5-arylidene-4-thioxo-thiazolidine-2-ones, Eur. J.
Med. Chem. 44 (2009) 2038–2043.
250
251
252
253
254
255
256
257
[2] E.M. Guantai, K. Ncokazi, T.J. Egan, et al., Design, synthesis and in vitro antima-
larial evaluation of triazole-linked chalcone and dienone hybrid compounds,
Bioorg. Med. Chem. 18 (2010) 8243–8256.
[3] C.A. Fraga, Drug hybridization strategies: before or after lead identification?
Expert Opin. Drug Discov. 4 (2009) 605–609.
Please cite this article in press as: J. Sindhu, et al., Multicomponent domino process for the synthesis of some novel 5-(arylidene)-3-((1-
aryl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-diones using PEG-400 as an efficient reaction medium and their antimicrobial
evaluation, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.006

G Model
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2
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2
2
2
2
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2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
00
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
[4] J.E. Biggs-Houck, A. Younai, J.T. Shaw, Recent advances in multicomponent reac-
tions for diversity-oriented synthesis, Curr. Opin. Chem. Biol. 14 (2010) 371–382.
[5] L.A. Marcaurelle, M.A. Foley, The evolving role of molecular diversity in drug
discovery, Curr. Opin. Chem. Biol. 14 (2010) 285–288.
[6] N. Dahan-Farkas, C. Langley, A.L. Rousseau, et al., 6-Substituted imidazo[1,
2-a]pyridines: synthesis and biological activity against colon cancer cell lines
HT-29 and Caco-2, Eur. J. Med. Chem. 46 (2011) 4573–4583.
[25] S.V. Sambasivarao, L.K. Soni, A.K. Gupta, P. Hanumantharao, Quantitative struc- 344
ture-activity analysis of 5-arylidene-2,4-thiazolidinediones as aldose reductase 345
inhibitors, Bioorg. Med. Chem. Lett. 16 (2006) 512–520.
346
[26] R. Maccari, P. Paoli, R. Ottana, et al., 5-Arylidene-2,4-thiazolidinediones as 347
inhibitors of protein tyrosine phosphatases, Bioorg. Med. Chem. 15 (2007) 348
5137–5149.
349
[27] V.R. Avupati, R.P. Yejella, A. Akula, et al., Synthesis, characterization and bio- 350
logical evaluation of some novel 2,4-thiazolidinediones as potential cytotoxic, 351
antimicrobial and antihyperglycemic agents, Bioorg. Med. Chem. Lett. 22 (2012) 352
Q5 [7] (a) D.J. Ram o´ n, M. Yus, Asymmetric multicomponent reactions (AMCRs): the new
frontier, Angew. Chem. Int. Ed. Engl. 44 (2005) 1602–1634;
(b) C. Hulme, V. Gore, Multi-component reactions: emerging chemistry in drug
discovery ‘from xylocain to crixivan’, Curr. Med. Chem. 10 (2003) 51–80;
(c) P. Salehi, D.I. MaGee, M. Dabiri, L. Torkian, J. Donahue, Combining click-
multicomponent reaction: one-pot synthesis of triazolyl methoxy-phenyl inda-
zolo[2,1-b] phthalazine-trione derivatives, Mol. Divers. 16 (2012) 231–240;
(d) P. Salehi, M. Dabiri, M. Koohshari, S.K. Movahed, M. Bararjanian, One-pot
synthesis of 1,2,3-triazole linked dihydropyrimidinones via Huisgen 1,3-dipolar/
Biginelli cycloaddition, Mol. Divers. 15 (2011) 833–837;
(e) F.R. Charati, Efficient synthesis of functionalized hydroindoles via catalyst-
free multicomponent reactions of ninhydrin in water, Chin. Chem. Lett. 25 (2014)
169–171;
(f) Z. Hossaini, F.R. Charati, M.E. Moghadam, F.M. Kochaksaraee, Expeditious
solvent-free synthesis of 1, 3-thiazolanes via multicomponent reactions, Chin.
Chem. Lett. 25 (2014) 794–796.
6442–6450.
353
[28] J.D. Peuler, S.M. Phare, A.R. Lannussi, M.J. Hoderek, Differential inhibitory effects 354
of antidiabetic drugs on arterial smooth muscle cell proliferation, Am. J. Hyper- 355
tens. 9 (1996) 188–192.
356
[29] L.A. Dakin, M.H. Block, H. Chen, et al., Discovery of novel benzylidene-1,3- 357
thiazolidine-2,4-diones as potent and selective inhibitors of the PIM-1, PIM-2, 358
and PIM-3 protein kinases, Bioorg. Med. Chem. Lett. 22 (2012) 4599–4604.
359
[30] C. Gill, G. Jadhav, M. Shaikh, et al., Clubbed [1–3] triazoles by fluorine benzimid- 360
azole: a novel approach to H37Rv inhibitors as a potential treatment for tuber- 361
culosis, Bioorg. Med. Chem. Lett. 18 (2008) 6244–6247.
362
[31] F. de, C. da Silva, M.C.B.V. de Souza, I.I.P. Frugulhetti, et al., Synthesis, HIV-RT 363
inhibitory activity and SAR of 1-benzyl-1H-1, 2,3-triazole derivatives of carbo- 364
hydrates, Eur. J. Med. Chem. 44 (2009) 373–383.
365
[32] N.G. Aher, V.S. Pore, N.N. Mishra, et al., Synthesis and antifungal activity of 1,2,3- 366
triazole containing fluconazole analogues, Bioorg. Med. Chem. Lett. 19 (2009) 367
[8] (a) J. Sindhu, H. Singh, J.M. Khurana, C. Sharma, K.R. Aneja, Multicomponent
synthesis of novel 2-aryl-5-((1-aryl-1H-1,2,3-triazol-4-yl)methylthio)-1,3,4-oxa-
diazoles using CuI as catalyst and their antimicrobial evaluation, Aust. J. Chem. 66
(2013) 710–717;
759–763.
368
[33] B.S. Holla, M. Mahalinga, M.S. Karthikeyan, et al., Synthesis, characterization and 369
antimicrobial activity of some substituted 1,2,3-triazoles, Eur. J. Med. Chem. 40 370
(b) H. Singh, J. Sindhu, J.M. Khurana, C. Sharma, K.R. Aneja, A facile eco-friendly
one-pot five-component synthesis of novel 1,2,3-triazole-linked pentasubstituted
1,4-dihydropyridines and their biological and photophysical studies, Aust. J.
Chem. 66 (2013) 1088–1096;
(c) J. Sindhu, H. Singh, J.M. Khurana, A green, multicomponent, regio- and stereo-
selective 1,3-dipolar cycloaddition of azides and azomethine ylides generated
in situ with bifunctional dipolarophiles using PEG-400, Mol. Divers. 18 (2014)
345–355.
(2005) 1173–1178.
371
[34] M.S. Alam, J. Huang, F. Ozoe, F. Matsumura, Y. Ozoe, Synthesis, 3D-QSAR, 372
and docking studies of 1-phenyl-1H-1,2,3-triazoles as selective antagonists for 373
beta3 over alpha1beta2gamma2 GABA receptors, Bioorg. Med. Chem. 15 (2007) 374
5090–5104.
375
[35] R. P e´ rion, V. Ferri e` res, M.I. Garc ı´ a-Moreno, et al., 1,2,3-Triazoles and related 376
glycoconjugates as new glycosidase inhibitors, Tetrahedron 61 (2005) 377
9118–9128.
378
[9] J. Chen, S.K. Spear, J.G. Huddleston, R.D. Rogers, Polyethylene glycol and solutions
of polyethylene glycol as green reaction media, Green Chem. 7 (2005) 64–82.
[10] P. Ferravoschi, A. Fiecchi, P. Grisenti, E. Santaniello, S. Trave, Polyethylene
glycols as solvents for anionic activation: synthesis of thioacetates by means
of potassium thioacetate in polyethylene glycol 400, Synth. Commun. 17 (1987)
1569–1575.
[11] J.R. Blanton, The selective reduction of aldehydes using polyethylene glycol–
sodium borohydride derivatives as phase transfer reagents, Synth. Commun. 27
(1997) 2093–2102.
[36] A. Kamal, N. Shankaraiah, V. Devaiah, et al., Synthesis of 1,2,3-triazole-linked 379
pyrrolobenzodiazepine conjugates employing ‘click’ chemistry: DNA-binding 380
affinity and anticancer activity, Bioorg. Med. Chem. Lett. 18 (2008) 1468–1473. 381
[37] H.C. Kolb, K.B. Sharpless, The growing impact of click chemistry on drug discovery, 382
Drug Discov. Today 8 (2003) 1128–1137.
383
[38] N.S. Vatmurge, B.G. Hazra, V.S. Pore, et al., Deshpande, Synthesis and antimicro- 384
bial activity of beta-lactam-bile acid conjugates linked via triazole, Bioorg. Med. 385
Chem. Lett. 18 (2008) 2043–2047.
[39] M. Whiting, J. Muldoon, Y.C. Lin, et al., Inhibitors of HIV-1 protease by using in Situ 387
click chemistry, Angew. Chem. Int. Ed. 45 (2006) 1435–1439.
386
[12] S. Chandrasekhar, Ch. Narsihmulu, S.S. Sultana, N.R.K. Reddy, Poly(ethylene
glycol) (PEG) as a reusable solvent medium for organic synthesis, application
in the Heck reaction, Org. Lett. 4 (2002) 4399–4401.
388
[40] (a) J. Zhang, H. Zhang, W.X. Cai, et al., ‘Click’ D(1) receptor agonists with a 5- 389
HT(1A) receptor pharmacophore producing D(2) receptor activity, Bioorg. Med. 390
[13] S. Chandrasekhar, Ch. Narsihmulu, S.S. Sultana, N.R.K. Reddy, Osmium tetroxide in
poly(ethylene glycol) (PEG): a recyclable reaction medium for rapid asymmetric
dihydroxylation under sharpless conditions, Chem. Commun. (2003) 1716–1717.
[14] (a) V.V. Namboodiri, R.S. Varma, Microwave-accelerated Suzuki cross-coupling
reaction in polyethylene glycol (PEG), Green Chem. 3 (2001) 146–148;
(b) S. Gaddam, H.R. Kasireddy, K. Konkala, R. Katla, N.Y.V. Durga, Synthesis of
N-substituted-2-aminobenzothiazoles using nano copper oxide as a recyclable
catalyst under ligand-free conditions, in reusable PEG-400 medium, Chin. Chem.
Lett. 5 (2014) 732–736.
Chem. 17 (2009) 4873–4880;
391
(b) R. Jagasia, J.M. Holub, M. Bollinger, K. Kirshenbaum, M.G. Finn, Peptide 392
cyclization and cyclodimerization by Cu(I)-mediated azide-alkyne cycloaddition, 393
J. Org. Chem. 74 (2009) 2964–2974.
394
[41] K. Kumar, S. Sagar, L. Esau, M. Kaur, V. Kumar, Synthesis of novel 1H-1,2,3-triazole 395
tethered C-5 substituted uracil-isatin conjugates and their cytotoxic evaluation, 396
Eur. J. Med. Chem. 58 (2012) 153–159.
[42] (a) H. Singh, J. Sindhu, J.M. Khurana, Efficient, green and regioselective synthesis 398
of 1,4,5-trisubstituted-1,2,3-triazoles in ionic liquid [bmim]BF and in task- 399
specific basic ionic liquid [bmim]OH, J. Iran. Chem. Soc. 10 (2013) 883–888;
397
4
[15] A. Haimov, R. Neumann, Polyethylene glycol as a non-ionic liquid solvent for
polyoxometalate catalyzed aerobic oxidation, Chem. Commun. (2002) 876–877.
400
(b) H. Singh, J. Sindhu, J.M. Khurana, Synthesis of biologically as well as industri- 401
ally important 1,4,5-trisubstituted-1,2,3-triazoles using a highly efficient, green 402
[16] S. Chandrasekhar, Ch. Narsihmulu, G. Chandrasekhar, T. Shyamsundar, Pd/CaCO
3
in liquid poly(ethylene glycol) (PEG): an easy and efficient recycle system for
partial reduction of alkynes to cis-olefins under a hydrogen atmosphere, Tetra-
hedron Lett. 45 (2004) 2421–2423.
and recyclable DBU–H
2
O catalytic system, RSC Adv. 3 (2013) 22360–22366;
403
(c) H. Singh, J. Sindhu, J.M. Khurana, C. Sharma, K.R. Aneja, Ultrasound promoted 404
one pot synthesis of novel fluorescent triazolyl spirocyclic oxindoles using DBU 405
based task specific ionic liquids and their antimicrobial activity, Eur. J. Med. Chem. 406
[17] S.R. Pattana, P. Kekareb, A. Patilc, A. Nikaljec, B.S. Kitturd, Studies on the synthesis
of novel 2,4-thiazolidinedione derivatives with antidiabetic activity, Iran. J.
Pharm. Sci. 5 (2009) 225–230.
[18] R. Ottan a` , R. Maccari, M. Giglio, et al., Identification of 5-arylidene-4-thiazolidi-
none derivatives endowed with dual activity as aldose reductase inhibitors and
antioxidant agents for the treatment of diabetic complications, Eur. J. Med. Chem.
46 (2011) 2797–2806.
[19] A. Andreani, M. Rambaldi, A. Locatelli, et al., Synthesis of lactams with potential
cardiotonic activity, Eur. J. Med. Chem. 28 (1993) 825–829.
[20] C.D. Barros, A.A. Amato, T.B. Oliveira, et al., Synthesis and anti-inflammatory
activity of new arylidene-thiazolidine-2,4-diones as PPARgamma ligands, Bioorg.
Med. Chem. 18 (2010) 3805–3811.
[21] Z. Beharry, M. Zemskova, S. Mahajan, et al., Novel benzylidene-thiazolidine-2,
4-diones inhibit Pim protein kinase activity and induce cell cycle arrest in
leukemia and prostate cancer cells, Mol. Cancer Ther. 8 (2009) 1473–1483.
[22] W.T. Sing, C.L. Lee, S.L. Yeo, S.P. Lim, M.M. Sim, Arylalkylidene rhodanine with
bulky and hydrophobic functional group as selective HCV NS3 protease inhibitor,
Bioorg. Med. Chem. Lett. 11 (2001) 91–94.
[23] E.B. Grant, D. Guiadeen, E.Z. Baum, et al., The synthesis and SAR of rhodanines
as novel class C beta-lactamase inhibitors, Bioorg. Med. Chem. Lett. 10 (2000)
2179–2182.
77 (2014) 145–154;
407
(d) H. Singh, S. Kumari, J.M. Khurana, A new green approach for the synthesis of 12- 408
aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-one derivatives using task specific 409
acidic ionic liquid[NMP]H
j.cclet.2014.05.014.
2
PO
4
, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/ 410
411
[43] N.D. Obushak, N.T. Pokhodylo, N.I. Pidlypnyi, V.S. Matiichuk, Synthesis of 1,2,4- 412
and 1,3,4-oxadiazoles from 1-aryl-5-methyl-1H-1,2,3-triazole-4-carbonyl chlor- 413
ides, Russ. J. Org. Chem. 44 (2008) 1522–1527.
414
[44] K.R. Aneja, C. Sharma, R. Joshi, Fungal infection of the ear: a common problem in 415
the North Eastern part of Haryana, Int. J. Pediatr. Otorhinolaryngol. 74 (2010) 416
604–607.
417
[45] I. Ahmad, A.Z. Beg, Antimicrobial and phytochemical studies on 45 Indian me- 418
dicinal plants against multi-drug resistant human pathogens, J. Ethnopharmacol. 419
74 (2001) 113–123.
[46] J.M. Andrews, Determination of minimum inhibitory concentrations, J. Antimi- 421
crob. Chemother. 48 (2001) 5–16.
420
422
[47] National Committee for Clinical Laboratory Standards, Method for Dilution 423
Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically; Approved 424
Standards, Villanova, PA, fifth ed., 2000.
425
[48] S.K.S. Al-Burtamani, M.O. Fatope, R.G. Marwah, A.K. Onifade, S.H. Al-Saidi, Chem- 426
ical composition, antibacterial and antifungal activities of the essential oil of 427
Haplophyllum tuberculatum from Oman, J. Ethnopharmocol. 96 (2005) 107–112. 428
[24] N.S. Cutshall, C. O’Day, M. Prezhdo, Rhodanine derivatives as inhibitors of JSP-1,
Bioorg. Med. Chem. Lett. 15 (2005) 3374–3379.
3
43
Please cite this article in press as: J. Sindhu, et al., Multicomponent domino process for the synthesis of some novel 5-(arylidene)-3-((1-
aryl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-diones using PEG-400 as an efficient reaction medium and their antimicrobial
evaluation, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.006