New thiazolidinyl analogs containing pyridine ring: Synthesis, biological evaluation and QSAR studies

Article abstract of DOI:10.1007/s00044-012-0149-0

A series of pyridine derivatives of thiazolidin-4-ones (4a-4o) has been synthesized. Structures of these compounds were established on the basis of elemental analysis, IR, ¹H NMR, ¹³C NMR, and Mass spectral data. All the synthesized compounds have been evaluated for their anti-inflammatory and analgesic effects. The results showed that compound 2-[4-methylphenylimino]-5-(1H-pyridin-2-ylmethylidene)-1,3-thiazolidin-4-one (4d), 2-(2,4-dinitro-phenylhydrazinylidine)-5-(1H-pyridin-2-yl-methylidene)-1,3- thiazolidin-4-one (4h), and 2-[3-nitro-phenylimino]-5-(1H-pyridin-2-yl- methylidene)-1,3-thiazolidin-4-one (4j) exhibited good anti-inflammatory and analgesic activity. Compound 4h was found to be the most active compound of the series with an interesting dual anti-inflammatory and analgesic activity. Docking simulation was performed to position synthesized compounds into the active site of COX-2. The relationships of energy-based docking score with analgesic and anti-inflammatory activities were also investigated by linear regression method. The QSAR models with R ² of 0.621 and 0.740 were developed for analgesic and anti-inflammatory activities, respectively.

Full text of DOI:10.1007/s00044-012-0149-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0149-0
ORIGINAL RESEARCH
New thiazolidinyl analogs containing pyridine ring: synthesis,
biological evaluation and QSAR studies
•
Reetu Ranga Vikas Sharma Vipin Kumar
•
Received: 29 November 2011 / Accepted: 8 June 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A series of pyridine derivatives of thiazolidin-
4-ones (4a–4o) has been synthesized. Structures of these
compounds were established on the basis of elemental
of inflammation and pain by inhibiting the formation of
important biological mediators called Eicosanoids. COX-2 is
an inducible isoform that leads to inflammation. Inflammation
is a multi-factorial process which reflects the response of
organism to various stimuli and is related to many disorders
such as arthritis, asthma, and psoriasis (Bennamane et al.,
2011). Classical non-steroidal anti-inflammatory drugs
(NSAIDs), such as aspirin, ibuprofen, diclofenac, and flurbi-
profen, non-selectivelyinhibitbothformsofCOXwithgastric
and renal side effects. The selective inhibition of COX-2 will
provide a new generation of NSAIDs with significantly
reduced side effects. Diclofenac (C14H11Cl2NO2) possesses
wide spectrum of biological activities like anti-inflammatory,
analgesic, platelet aggregation, lysosomal enzymes, and car-
bohydrate metabolism(Brogden etal., 1980). Various dosage
forms of diclofenac such as tablets, emulsions, suppositories,
and injection have been prepared and characterized (Lamas
et al., 2010; Varshika et al., 2009; Ramadan, 2012).
1
analysis, IR, H NMR, 13C NMR, and Mass spectral data.
All the synthesized compounds have been evaluated for
their anti-inflammatory and analgesic effects. The results
showed that compound 2-[4-methylphenylimino]-5-(1H-
pyridin-2-ylmethylidene)-1,3-thiazolidin-4-one (4d), 2-(2,
4-dinitro-phenylhydrazinylidine)-5-(1H-pyridin-2-yl-methyl-
idene)-1,3-thiazolidin-4-one (4h), and 2-[3-nitro-phenylimi-
no]-5-(1H-pyridin-2-yl-methylidene)-1,3-thiazolidin-4-one
(4j) exhibited good anti-inflammatory and analgesic
activity. Compound 4h was found to be the most active
compound of the series with an interesting dual anti-
inflammatory and analgesic activity. Docking simulation
was performed to position synthesized compounds into the
active site of COX-2. The relationships of energy-based
docking score with analgesic and anti-inflammatory activi-
ties were also investigated by linear regression method. The
QSAR models with R2 of 0.621 and 0.740 were developed
for analgesic and anti-inflammatory activities, respectively.
Cl
HO
O
HN
Keywords Analgesic activity ꢀ Anti-inflammatory ꢀ
COX-2 inhibitors ꢀ Docking ꢀ QSAR
Cl
Diclofenac
Introduction
Heterocyclic moieties, like indoles, thiazolidine-4-ones,
pyrazoles, piperazines, pyridines, etc., have always got
considerable attention due to their numerous pharmacolog-
ical activities (Marson, 2011; Sharma et al., 2010). Thiaz-
olidin-4-one ring has attracted profound interest for their
wide range of pharmacological activities, such as anticon-
vulsant (Siddiqui et al., 2010), antimicrobial (Rajanarendar
et al., 2011), anti-inflammatory (Zacher et al., 2008), and
Pharmacological inhibition of cyclooxygenase (COX)
enzyme (EC 1.14.99.1) can provide relief from the symptoms
R. Ranga ꢀ V. Sharma ꢀ V. Kumar (&)
Institute of Pharmaceutical Sciences, Kurukshetra University,
Kurukshetra, 136119 Haryana, India
e-mail: vipbhardwaj@rediffmail.com
123

Med Chem Res
O
H
N
N
H
N
NH4SCN
N.N DMF
Ar
Pyridine aldehyde
Piperidine
N
HN
Ar-NH2
Ar
Cl
O
S
ClCOCH2Cl
S
O
N
Ar
1a - 1o
4a - 4o
3a - 3o
2a - 2o
Scheme 1 Synthetic scheme
analgesic (Sharma et al., 2010) activities. A number of
thiazolidin-4-one derivatives have been reported to possess
diversified activities (Rawal et al., 2007; Rawal et al., 2005;
Murugesan et al. 2009; Sharma et al., 2011; Raghubir et al.,
2011).
and piperidine in ethanol afforded the corresponding 2-(a-
rylimino)-5-(pyridine-2-ylmethylidene)-1,3-thiazolidin-4-ones
(4a–4o).
The structures of the synthesized compounds were con-
1
firmed by elemental analysis, IR, H-NMR, 13C-NMR, and
Furthermore, heterocyclic ring pyridine plays an important
role in antidiabetic activity of some drugs like pioglitazone,
rosiglitazone (Hosni and Abdulla, 2008). Compounds pos-
sessing pyridine ring also exhibits activities like anti-inflam-
matory, analgesic, antimicrobial (Ramesh et al., 2008),
antithyroid (Lagorce et al., 1993), antiviral and anti-HIV
(Balzarini et al., 2005). In view of these, it was thought
of interest to combine the both pharmacophoric moieties,
i.e., thiazolidine-4-one and pyridine ring. A series of 2-(aryl-
imino)-5-(pyridine-2-yl-methylidene)-1,3-thiazolidine-4-
ones (4a–4o) were synthesized and evaluated for their
potential as analgesic and anti-inflammatory agents. Docking
simulations were performed by X-ray crystallographic struc-
ture of the COX-2 (PDB ID 3HS5) in complex with arachi-
donic acid as an inhibitor to explore the binding modes of all
the synthesized compounds at the active site. In addition, we
have made an attempt to integrate the power of QSAR and
molecular docking by means of docking-generated energy-
based score as a descriptor for building QSAR models. By this
strategy, the informationregarding bindingmodeof ligands in
the active site was accumulated which would in turn assist the
accurate prediction of biological activity.
Mass spectral studies. The general IR spectral characters of
some of the representative compounds 3a–3o, i.e., 3a, 3b, and
3e showed absorption bands ranging from 3,124 to
3,140 cm-1 for N–H and 1,690–1,720 cm-1 for C=O
stretching of thiazolidinone ring. In the IR spectra of com-
pounds 4a–4o, the N–H and C=O stretching bands of thia-
zolidinone ring were observed in the range 3,031–3,140 and
1,666–1,723 cm-1, respectively. The presence of the N–H
stretching band in the IR spectra of 4a–4o provided evidence
that the bond between pyridine aldehyde and compounds 3a–
3o was formed at the 5-position of the thiazolidinone ring
rather than at the 3-position. The absence of absorption band
due to CH2 of thiazolidinone and the presence of band in the
range 1,615–1,640 cm-1 because of C=C absorption in the IR
spectra of compounds 4a–4o again provides confirmatory
evidence for bond formation at 5-position of the thiazolidi-
none ring rather than at the 3-position.
1
The H NMR of 3a, 3b and 3e chosen as prototypes
showed single N–H resonances in the d 12.41–12.55 ppm
region and singlet at d 4.23–4.35 ppm due to CH2 protons
of thiazolidinone ring. The singlet at d 12.21–12.82 ppm
due to N–H of thiazolidinone ring in the 1H NMR spectrum
of 4a–4o showed that the nitrogen still had a proton, which
further supported the substitution at the 5-position. In
addition, the absence of signal due to CH2 protons of
thiazolidinone ring and the presence of singlet at d
Results and discussion
1
Chemistry
6.78–7.95 ppm because of C=CH proton in the H NMR
spectrum of 4a–4o confirms the replacement of proton
from 5th position of compounds 3a–3o with pyridine-2-yl-
methylidene group.
The synthesis of compounds 2-chloro-N-arylacetamide
were carried out by reaction of appropriate substituted
aromatic amine (1a–1o) with chloro-acetyl-chloride in
presence of DMF by earlier reported method by Geronikaki
et al., ( 2007). The synthetic route of the compounds is
outlined in Scheme 1. On reaction with ammonium thio-
cyanate in ethanol, 2-chloro-N-arylacetamide (2a–2o)
yielded corresponding 2-(arylimino)-1,3-thiazolidin-4-ones
(3a–3o). Reacting these 3a–3o with pyridine-aldehyde
Electron impact mass spectra of 3a, 3b, and 3e showed
an accurate molecular ion peak at m/z 192.62, 226.62, and
210.62, respectively, which confirmed their molecular
weights. Similarly, the EIMS displayed accurate molecular
ion peak at m/z 281, 315.24, 295.24, 295, 299, 296, 326,
386, 311, 326.64, 360.64, 309.64, 315.64, 295.24, and 360
for title compounds 4a–4o, respectively.
123

Med Chem Res
Pharmacological evaluation
molecules and previously investigated thiazolidin-4-ones
derivatives strongly support the hypothesis that these
compounds could act through the inhibition of Cyclooxy-
genase-2 (COX-2) enzyme. In the present work, docking
simulations were performed on all the synthesized com-
pounds 4a–4o by X-ray crystallographic structure of the
COX-2 (PDB code 3HS5) in complex with arachidonic
acid as an inhibitor to explore the binding modes and
biomolecular interactions of these compounds at the active
site by means of GLIDE.
All the synthesized compounds 4a–4o have been evaluated
for their anti-inflammatory and analgesic activities. The
evaluation of anti-inflammatory activity was carried out by
the method of Joseph et al., ( 2009) by carrageenan-
induced paw edema test. The results are summarized in
Table 1. Compounds 4a–4o at 10 mg/kg body weight p.o.
exhibited 26.17, 34.78, 39.67, 43.83, 34.67, 39.67, 34.78,
56.52, 39.13, 43.48, 39.67, 39.67, 26.17, 30.43, and
30.43 % anti-inflammatory activity, respectively, whereas
diclofenac exhibited 43.48 % anti-inflammatory activity at
10 mg/kg body weight p.o. The results indicate that all the
synthesized compounds are active as anti-inflammatory
agent. Compound 4b, 4c, 4e, 4f, 4g, 4i, 4k, 4l, 4n, and 4o
exhibited good anti-inflammatory activity, i.e., more than
30 % inhibition of inflammation, compound 4d and 4j
exhibited anti-inflammatory activity comparable to that
exhibited by diclofenac, while compound 4h showed anti-
inflammatory activity better than diclofenac.
Glide searches for favorable interactions between ligand
molecules and a receptor molecule. The combination of
position and orientation of a ligand relative to the receptor
along with its conformation is referred to as a ligand pose.
Final scoring is then carried out on the energy-minimized
poses.
All the synthesized thiazolidinone compounds 4a–4o
and diclofenac were embedded in the binding pocket
formed by the amino acid SER53, THR212, GLU86,
PHE210, and LEU294 of COX-2. The results of docking
analysis, i.e., docking scores (glide score) and conforma-
tional energy of the docked pose for compounds 4a–4o are
depicted in Table 2.
The compounds 4a–4o were evaluated for analgesic
activity by acetic acid-induced writhing model (Kumar
et al., 2007) and results are summarized in Table 1.
Compounds 4a–4o at 50 mg/kg body weight p.o. exhibited
29.17, 41.67, 52.34, 43.17, 45.63, 46.16, 36.74, 68.74,
42.44, 62.34, 37.42, 51.45, 36.24, 43.56, and 28.67 %
analgesic activity whereas diclofenac exhibited 60.23 %
analgesic activity at 50 mg/kg body weight p.o. A look at
Table 1 indicates that all the compounds exhibited anal-
gesic activity. Compounds 4b, 4c, 4d, 4e, 4f, 4i, 4l, and 4n
exhibited good analgesic activity, i.e., more than 40 %
inhibition of writhing while compound 4j and 4h showed
analgesic activity better than diclofenac.
All the synthesized derivatives of thiazolidin-4-ones
interact actively with the COX-2 and forms hydrogen
bonds with COX-2 except compound 4a. The oxo group
present at fourth position of thiazolidinone moiety of
compound 4i, 4j, and 4l forms a hydrogen bond (distance
˚
2.756, 2.583, and 1.765 A, respectively) with the residue
THR212. Similarly, the oxygen of the ortho nitro group in
phenyl ring of compound 4h forms a hydrogen bond with
˚
the THR212 residue with a bond distance of 2.485 A. The
oxygen of the para nitro group in phenyl ring of compound
˚
4k forms a hydrogen bond (distance of 1.824 A) with the
THR212 residue bond (Fig. 1).
The compound 4h, having nitro group at position 2 and 4
of phenyl ring, was found to be the most active compound of
the series with an interesting dual anti-inflammatory and
analgesic activity. However, no direct correlation could be
justified between the nature of functionality and the phar-
macological activity of the compounds.
As shown in Table 3, compound 4h exhibited highest
value of docking score, i.e., -9.63, which was found to be
comparable to that of diclofenac (-10.31), which indicates
energetically favored binding of 4h with COX-2. This is in
accordance with the observation that compound 4h was
found to be the most active compound of the series with an
interesting dual anti-inflammatory and analgesic activity.
Similarly, the compounds 4c, 4d, 4f, 4i, 4j, 4k, and 4l
exhibited good value of docking score (more than -6)
indicating energetically favorable binding of these com-
pounds with COX-2.
Molecular docking studies
Docking is a method which predicts the preferred orien-
tation of one molecule to a second when bound to each
other to form a stable complex. Docking of a ligand is
typically achieved by generating a number of orientation
(or poses) of a ligand within the active sites, and scoring of
poses to identify one or more that closely approximate the
bioactive conformation determined by X-ray crystallogra-
phy (Still et al., 1990).
Quantitative structure activity relationship (QSAR)
studies
Despite the fact that pharmacological mechanism of
action was not determined for the synthesized compounds,
our results based upon the similarity between these
In recent years, in silico techniques like QSAR and molecular
docking are gaining high popularity in the drug discovery
123

Med Chem Res
Table 1 Anti-inflammatory and analgesic activity of compounds 4a–4o
Comp.
Ar
Anti-inflammatory activity
Analgesic activity
Edema (DT)*
(mm) SEM
Activity (%) at
120 min
Mean no of
writhing SEM
Inhibition
(%)
NH
4a
4b
4c
4d
4e
4f
0.17 0.003
0.15 0.009
0.14 .006
0.13 0.007
0.15 0.01
0.14 0.01
0.15 0.006
0.10 0.014
0.14 0.006
26.17
21.10 0.69
18.17 0.22
14.50 0.26
17.29 0.27
17.29 0.27
16.38 0.22
19.32 0.36
9.35 0.28
17.48 0.31
29.17
41.67
52.34
43.17
43.17
46.16
36.74
68.74
42.44
NH
34.78
39.67
43.83
34.67
39.67
34.78
56.52
39.13
Cl
H
C
NH
3
NH
H
F
C
3
NH
NH
NH
NH
NH
NO
4g
4h
4i
2
NH
NH
O
H
N
NO
2
2
NH
CO
3
NH
4j
0.13 0.005
0.14 0.01
43.48
39.67
11.71 0.12
19.50 0.42
62.34
37.42
NO
N
2
NH
4k
O
Cl
2
CH
3
4l
0.14 0.003
39.67
15.29 0.38
51.45
NH
CH
3
NH
4m
4n
0.17 0.01
26.17
30.43
19.53 0.42
17.55 0.58
36.24
43.56
Cl
NH
0.16 0.006
CH
3
123

Med Chem Res
Table 1 continued
Comp.
Ar
Anti-inflammatory activity
Analgesic activity
Edema (DT)*
(mm) SEM
Activity (%) at
120 min
Mean no of
writhing SEM
Inhibition
(%)
NH
Br
4o
0.16 0.005
0.13 0.002
30.43
22.17 0.42
10.40 0.14
28.67
Diclo-fenac sodium
–
43.48
60.23
Values are mean SEM from 6 animals in each group, p \ 0.05, * p \ 0.01, compared to control
(Schneider and Fechner, 2005). Both these methodologies
allow the identification of probable lead candidates expedi-
tiously before chemical synthesis and characterization,
thereby, making the process more cost effective (Muegge
and Oloff, 2006; Willet, 2006). Keeping in view the impor-
tance of docking and performance of QSAR, we integrated
both approaches by docking-generated energy-based score as
descriptor for QSAR modeling. The major benefit presumed
by this integration would be an additional validation of the
docking results by prediction of their bioactivity values by
means of QSAR models. Hence, in the present work, the
relationships of docking score (Table 2) with the experi-
mentally observed analgesic and anti-inflammatory activities
(Table 1) of compounds 4a–4o were also investigated.
For proposing statistically significant models, QSAR
models were generated by the technique of linear regres-
sion. All the regression analysis was performed by means
of SPSS software. Predictive ability of the proposed
models was evaluated by leave-one-out cross validation
method (Dureja et al., 2007). The criterion of squared
correlation coefficient of the prediction was used to access
the quality of the predictive ability of model.
Linear regression analysis has indicated that statistically
significant results are obtained by docking-generated
energy-based score, i.e., docking score (glide score) as
descriptor. Linear regression yielded the following models
for analgesic and anti-inflammatory activities:
Analgesic activity ðpercentage inhibition of writhingÞ
¼ ꢁ8:114 ðglide scoreÞ ꢁ 4:868
n ¼ 15; R2 ¼ 0:614; Ra2dj ¼ 0:584;
F ¼ 20:663; R2ðCVÞ ¼ 0:622; PRESS ¼ 655:9;
R2pred ¼ 0:613; Q ¼ 0:086
ð1Þ
Table 3 Experimentally observed and predicted activities of com-
pounds 4a–4o
Table 2 Ligand receptor interaction data of compounds 4a–4o
Compound Anti-inflammatory activity
Analgesic activity
Compound
No. of
H-bond
Glide
score
Conformational
energy (kJ/mole)
Observed
activity
Predicted
activity
Observed Predicted
activity
activity
4a
0
1
1
1
2
1
1
1
1
1
1
1
1
1
1
1
-5.17
-5.53
-6.12
-6.28
-5.72
-6.03
-5.52
-9.63
-6.07
-6.23
-6.22
-6.18
-5.78
-5.61
-4.96
-10.31
-21.55
-31.59
-35.03
-34.88
-21.11
-33.36
-32.58
-35.80
-25.43
-35.78
-29.50
-29.48
-18.59
-32.80
-23.70
-37.40
4b
4a
4b
4c
4d
4e
4f
26.17
34.78
39.67
43.83
34.67
39.67
34.78
56.52
39.13
43.48
39.67
39.67
26.17
30.43
30.43
31.64
33.89
37.58
38.59
35.08
37.02
33.83
59.55
37.27
38.27
38.21
37.96
35.46
34.39
30.32
29.17
41.67
52.34
43.17
43.17
46.16
36.74
68.74
42.44
62.34
37.42
51.45
36.24
43.56
28.67
37.08
40
4c
4d
44.79
46.09
41.54
44.06
39.92
73.27
44.38
45.68
45.68
45.28
42.03
40.65
35.38
4e
4f
4g
4h
4g
4h
4i
4i
4j
4k
4j
4l
4k
4l
4m
4n
4m
4n
4o
4o
Diclofenac
123

Med Chem Res
Fig. 1 Binding mode of compound 4h, 4i, and 4k showing H-bonding interaction (in yellow color) with the COX-2 (PDB code 3HS5)
Anti-inflammatory activity ðpercentage inhibition of oedemaÞ
¼ ꢁ6:259 ðglide scoreÞ ꢁ 0:721
Conclusion
n ¼ 15; R2 ¼ 0:741; Ra2dj ¼ 0:721;
In the present studies, a series of 2-(aryl-imino)-5-(pyridine-
2-yl-methylidene)-1,3-thiazolidine-4-ones (4a–4o) was
synthesized successfully in convenient steps in 45–93 %
yields and evaluated for their potential as analgesic and anti-
inflammatory agents. All the synthesised compounds
exhibited anti-inflammatory and analgesic activities in vivo.
Compound 2-[4-methylphenylimino]-5-(1H-pyridin-2-yl-
methylidene)-1,3-thiazolidin-4-one (4d), 2-(2,4-dinitro-
phenylhydrazinylidine)-5-(1H-pyridin-2-yl-methylidene)-1,
3-thiazolidin-4-one (4h) and 2-[3-nitro-phenylimino]-5-(1H-
pyridin-2-yl-methylidene)-1,3-thiazolidin-4-one (4j) exhib-
ited pronounced anti-inflammatoryactivitycomparable to the
reference standard diclofenac. Compounds 4h and 4j also
showed more analgesic activity as compared to that of dic-
lofenac. SAR studies led to the conclusions that compounds
containing Br and Cl at phenyl ring are consistently more
potent and the alkyl group in phenyl ring led to the decrease in
inhibitory activity if present at ortho and meta position. NO2
group at ortho and para position of phenyl ring increases the
activity; but, when it is at meta position, it decreased the
activity. In addition, molecular docking studies were carried
out to position all the synthesized compounds 4a–4o and
diclofenac into the active site of COX-2. All the compounds
interact actively with the COX-2 and form hydrogen bonds
with COX-2 except compound 4a. Compound 4h exhibited
the highest value of docking score, which indicates energet-
ically favored binding of 4h with COX-2. This is in accor-
dance with the observation that compound 4h was also found
to be the most active compound of the series with an inter-
esting dual anti-inflammatory and analgesic activity.
F ¼ 37:098; R2ðCVÞ ¼ 0:744; PRESS ¼ 217:4;
R2pred ¼ 0:74; Q ¼ 0:181
ð2Þ
The model 1 could explain 58.4 % of variance (adjusted
coefficient of variation). The leave-one-out predicted
variance was found to be 62.2 %. When this model was
applied for the prediction of analgesic activity, the
R2pred was found to be 61.3 %. Similarly, model 2 could
explain 72.1 % of variance. The leave-one-out predicted
variance was found to be 74.4 %, while the model 2 was
applied for prediction of anti-inflammatory activity, the
R2pred was found to be 74 %.
In order to investigate the predictive power of the pro-
posed models, we calculated Pogliani’s quality factor (Q).
The Pogliani’s quality factor (Q) is defined as the ratio of
the model represented by correlation coefficient to that of
the standard error of estimation (R2/SE) (Nikolic et al.,
1998). The value of Pogliani’s quality factor Q is the
largest for model 2, indicating that it has highest predictive
power as compared to model 1.
In order to confirm our results, we have estimated
analgesic and anti-inflammatory activity by means of
model 1 and 2, respectively, and compared them with the
experimentally observed activities. Such a comparison is
shown in the Table 3 and Fig. 2. The predicted analgesic
and anti-inflammatory activity by leave-one-out procedure
exhibited a correlation of 0.621 and 0.740 (n = 15) with
reported analgesic activity and anti-inflammatory activity
using model 1 and 2, respectively (Fig. 2). For a reliable
model, the squared predictive correlation coefficient should
be[0.60 (Dureja et al., 2007; Wold S, 1991). The results
of this study reveal that the proposed QSAR models 1 and
2 can be used for the prediction of analgesic and anti-
inflammatory activities, respectively.
Keeping in view the importance of docking and better
performance of QSAR, we integrated both approaches
by means of docking-generated energy-based score as
descriptor for QSAR modeling. The statistically significant
QSAR models with R2 of 0.621 and 0.740 were
developed. Investigations reveal significant correlation of
123

Med Chem Res
Fig. 2 Relation between observed and predicted analgesic (a) and anti-inflammatory (b) activity of compounds 4a–4o
anti-inflammatory and analgesic activities with docking-
generated energy-based score. QSAR models were gener-
ated by the technique of linear regressions. Leave-one-out
cross validation methods were used to validate the reli-
ability of model. All the proposed models possess good
statistical significance. We believe that the derived QSAR
models will be of interest and significance for the strategic
design of more potent thiazolidin-4-ones as analgesic and
anti-inflammatory agents. The statistically significant cor-
relation between docking score and experimentally
observed biological activity emphasizes on the usefulness
of docking and QSAR methodology.
refluxed for 2 h and cooled to room temperature. The solid
mass so obtained was filtered, washed with water, dried,
and purified by recrystallization from ethanol to obtain
2-chloro-N-arylacetamides 2a–2o.
Synthesis of 2-(arylimino)-1,3-thiazolidin-4-ones (3a–3o)
The mixture of 2-chloro-N-arylacetamide (2a–2o) (0.05 mol)
and ammonium thiocyanate (0.1 mol) in ethanol (50 ml) was
refluxed for 1 h and left overnight. Solid thus obtained was
separated by filtration and recrystallized from ethanol to give
the corresponding 2-(arylimino)-1,3-thiazolidin-4-ones 3a–3o.
2-(Phenylimino)-1,3-thiazolidin-4-one (3a) m.p.: 198–201;
% yield: 73; IR (KBr) cm-1: 3140 (N–H of thiazolidin-4-
one), 3047 (C–H str. of aromatic), 1690 (C=O of thiaz-
Materials and methods
1
olidin-4-one), 1589 (C=N); H NMR, d ppm (DMSO-d6):
Chemistry
12.55 (1H, s, NH of thiazolidin-4-one), 7.23–7.94 (m, 9H,
Ar), 4.23 (2H, s, CH2); EI-MS m/z: 192.62 M?; Anal.
Calcd. for C9H8N2OS (192.23): C, 35.97; H, 2.66; N, 9.33.
Found: C, 35.91; H, 2.52; N, 9.14.
All the chemicals and solvents employed in the present study
were procured from Merck AG (Mumbai, India), SD Fines
(Mumbai, India), and Qualigens (Navi Mumbai, India).
Melting points were determined on a Lab India MR-VIS
visualmeltingrangeapparatusandareuncorrected.Elemental
analysis was performed on Flash 2000 CHN–S–O– analyzer
(Thermo Fisher). The IR spectra were obtained on a Perkin
Elmer IR spectrophotometer (Navi Mumbai, India) using
potassium bromide disk. NMR spectra (Massachusetts, USA)
were recorded using a Bruker 400 spectrometer (Fallanden,
Switzerland) and chemical shifts are expressed as d (ppm)
with tetramethylsilane as an internal standard. Mass spectra
were recorded on Waters Q-TOF micro mass spectrometer
(Manchester, UK) by electron spray ionization method.
2-(4-Chlorophenylimino)-1,3-thiazolidin-4-one (3b) m.p.:
221–223; % yield: 59; IR (KBr) cm-1: 3134 (N–H of
lactam), 3037 (C–H str. of aromatic), 1697 (C=O of
1
thiazolidin-4-one), 1575 cm-1 (C=N); H NMR, d ppm,
(DMSO-d6): 12.51(1H, s, NH– thiazolidinone), 7.23–7.94
(m, 9H, Ar), 4.45 (2H, s, –CH2). EI-MS: m/z 226.62 M?;
Anal. Calcd. for C9H7ClN2OS (226.68): C, 35.96; H, 2.32;
N, 9.30. Found: C, 35.64; H, 2.46; N, 9.54.
2-(4-Fluorophenylimino)-1,3-thiazolidin-4-one (3e) m.p.:
238–239; % yield: 69; IR (KBr) cm-1: 3124 (N–H of
lactam), 3045 (C–H str. of aromatic), 1714 (C=O of thia-
1
zolidinone), 1575 cm-1 (C=N) H NMR, d ppm, (DMSO-
Synthesis of 2-chloro-N-arylacetamide (2a–2o)
d6): 12.41(1H, s, NH– thiazolidinone), 7.13–7.74 (m, 9H,
Ar), 4.35 (2H, s, –CH2). EI-MS: m/z 210.62 M?; Anal.
Calcd. for C9H7FN2OS (210.22): C, 35.74; H, 2.37; N,
9.34. Found: C, 35.64; H, 2.42; N, 9.44.
To a solution of aromatic amine (0.01 mol) in DMF
(30 ml), chloro acetyl chloride (0.01 mol) was added drop
wise with constant stirring. The reaction mixture was
123

Med Chem Res
Synthesis of 2-(arylimino)-5-(pyridin-2-yl-methylidene)-
1,3-thiazolidine-4-one (4a–4o)
2[4-Fluorophenylimino]-5-(1H-pyridin-2-ylmethylidene)-
1,3-thiazolidin-4-one (4e) m.p. 276–278; % yield: 45; IR
(KBr) cm-1: 3074 (N–H of lactam), 3045 (C–H str. of
aromatic), 1666 (C=O of thiazolidinone), 1622 (C=C aro-
The mixture of 2-(arylimino)-1,3-thiazolidin-4-one (3a–3o)
(0.01 mol), pyridine aldehyde (0.01 mol), and piperidine
(few drops) was refluxed for 24 h. The mixture was then
cooled and poured on to crushed ice. The solid thus obtained
was separated by filtration and purified by recrystallized
from rectified spirit to give corresponding 2-(arylimino)-5-
(pyridin-2-yl-methylidene)-1,3-thiazolidine-4-one (4a–4o).
1
matic), 1582 cm-1 (C=N). H NMR, d ppm, (DMSO-d6):
12.23 (1H, s, NH, thiazolidinone), 7.14 (1H, s, =CH),
6.82–7.44 (m, 10H, Ar). EI-MS: m/z 299 M?; Anal. Calcd.
for C15H10FN3OS (299.32): C, 44.41; H, 2.51; N, 10.17.
Found: C, 44.12; H, 2.14; N, 10.74.
2-(Phenylhydrazinylidine)-5-(1H-pyridin-2-ylmethylidene)-
1,3-thiazolidin-4-one (4f) m.p. 2263–266; % yield: 93; IR
(KBr) cm-1: 3138 (N–H of CONH), 3057 (C–H str. of
aromatic), 1694 (C=O of thiazolidinone), 1644 (C=C aro-
5-(1H-pyridin-2-ylmethylidene)-2-(phenylimino)-1,3-thiaz-
olidin-4-one (4a) (m.p.: 265–267; % yield: 60; IR (KBr)
cm-1: 3140 (N–H of lactam), 3047 (C–H str. of aromatic),
1702 (C=O of thiazolidinone), 1625 (C=C aromatic),
1
matic), 1589 cm-1(C=N). H NMR, d ppm, (DMSO-d6):
1
1589 cm-1 (C=N). H NMR, d ppm, (DMSO-d6): 12.55
12.21 (1H, s, NH, thiazolidinone), 6.95 (1H, s, =CH),
6.98–7.94 (m, Ar, 10H), 10.2 (IH, S, NH). EI-MS: m/z 296
M?; Anal. Calcd. for C15H12N4OS (296.34): C, 52.36; H,
2.95; N, 13.70. Found: C, 52.12; H, 2.64; N, 13.74.
(1H, s, NH, thiazolidinone), 6.9 (1H, s, =CH), 7.23–7.94
(m, 9H, Ar). EI-MS: m/z 281 M?; Anal. Calcd. for
C15H11N3OS (281.33): C, 44.91; H, 2.71; N, 10.34. Found:
C, 44.34; H, 2.56; N, 10.74.
2[2-Nitrophenylimino]-5-(1H-pyridine-2-ylmethylidene)-
1,3-thiazolidin-4-one (4g) m.p.: 282–285; % yield: 79;
IR (KBr) cm-1: 3036 (N–H of lactam), 3047 (C–H str. of
aromatic), 1714 (C=O of thiazolidinone), 1605 (C=C aro-
2[4-Chlorophenylimino]-5-(1H-pyridin-2-ylmethylidene)-
1,3-thiazolidin-4-one (4b) m.p.: 232–235; % yield: 61;
IR (KBr) cm-1: 3138 (N–H of lactam), 3057 (C–H str. of
aromatic), 1723 (C=O of thiazolidinone), 1632 (C=C aro-
1
matic), 1598 (C=N), 1513, 1340 cm-1 (NO2). H NMR, d
1
matic), 1592 cm-1 (C=N), 114 cm-1. H NMR, d ppm,
ppm, (DMSO-d6): 12.35 (1H, s, NH, thiazolidinone), 6.95
(1H, s, =CH), 6.98–7.94 (m, 8H, Ar). EI-MS: m/z 326 M?;
Anal. Calcd. for C15H10N4O3S (326.32): C, 52.46; H, 2.61;
N, 13.70. Found: C, 52.12; H, 2.64; N, 13.74.
(DMSO-d6): 12.82 (1H, s, NH, thiazolidinone), 7.25 (1H,
s, C=CH), 6.98–7.54 (m, 8H, Ar). EI-MS: m/z 315.24 M?;
Anal. Calcd. for C15H10ClN3OS (315.77): C, 44.34; H,
2.62; N, 10.14. Found: C, 44.64; H, 2.56; N, 10.74.
2-(2,4-Dinitrophenylhydrazinylidine)-5-(1H-pyridin-2-yl-
methylidene)-1,3-thiazolidin-4-one (4h) m.p.: 255–257;
% yield: 84; (KBr) cm-1: 3138 (N–H of CONH), 3057 (C–
H str. of aromatic), 1694 (C=O of thiazolidinone), 1644
(C=C aromatic), 1589 cm-1 (C=N). 1H NMR, d ppm,
(DMSO-d6): 12.21 (1H, s, NH, thiazolidinone), 6.95 (1H,
s, =CH), 6.98–7.94 (m, Ar, 7H), 10.2 (IH, s, NH). 13C
NMR d ppm, (DMSO-d6): 118.4, 120.1, 120.4, 122.7,
128.6, 131.0, 132.6, 133.7, 137.0, 148.9, 149.7, 149.9,
153.4, 144.5, 167.8. EI-MS: m/z 386 M?; Anal. Calcd. for
C15H10N6O5S (386.34): C, 52.56; H, 2.71; N, 20.70.
Found: C, 52.12; H, 2.64; N, 20.74.
2[3-Methylphenylimino]-5-(1H-pyridine-2-ylmethylidene)-
1,3-thiazolidin-4-one (4c) m.p.: 251–253; % yield: 62; IR
(KBr) cm-1: 3138 (N–H of lactam), 3057 (C–H str. of aro-
matic), 1712 (C=O of thiazolidinone), 1624 (C= aromatic),
1
1592 cm-1 (C=N). H NMR, d ppm, (DMSO-d6): 12.25
(1H, s, NH, thiazolidinone), 6.9 (1H, s, =CH), 6.98–7.94 (m,
8H, Ar), 2.37 (3H, s, CH3). EI-MS: m/z 295.24 M?; Anal.
Calcd. for C16H13N3OS (295.35): C, 52.17; H, 3.25; N,
10.17. Found: C, 52.64; H, 3.06; N, 10.74.
2[4-Methylphenylimino]-5-(1H-pyridin-2-ylmethylidene)-
1,3-thiazolidin-4-one (4d) m.p.: 229–231; % yield: 72; IR
(KBr) cm-1: 3082 (N–H of lactam), 3127 (C–H str. of aro-
matic), 1697 (C=O of thiazolidinone), 1636 (C=C aromatic),
2[4-Methoxyphenylimino]-5-(1H-pyridin-2-ylmethylidene)-
1,3-thiazolidin-4-one (4i) m.p.: 242–244; % yield: 53; IR
(KBr) cm-1: 3110 (N–H of lactam), 3042 (C–H str. of
aromatic), 1690 (C=O of thiazolidinone), 1643 (C=C aro-
1
1605 cm-1 (C=N). H NMR, d ppm, (DMSO-d6): 12.25
(1H, s, NH, thiazolidinone), 6.78 (1H, s, =CH), 6.98–7.94
(m, 8H, Ar), 2.37 (3H, s, CH3). 13C NMR d ppm, (DMSO-
d6): 24.3, 121.0, 122.2, 122.4, 122.7, 130.4, 130.9, 132.0,
133.8, 136.9, 137.0, 146.0, 148.9, 154.9, 168.5. EI-MS:
m/z 295 M?; Anal. Calcd. for C16H13N3OS (295.35): C,
52.34; H, 3.17; N, 10.36. Found: C, 52.64; H, 3.06; N, 10.75.
1
matic), 1590 cm-1 (C=N). H NMR, d ppm, (DMSO-d6):
12.25 (1H, s, NH, thiazolidinone), 6.97 (1H, s, =CH),
6.98–7.94 (m, 8H, Ar). EI-MS: m/z 311 M?; Anal. Calcd.
for C16H13N3O2S (311.35): C, 52.36; H, 3.21; N, 10.19.
Found: C, 52.12; H, 3.64; N, 10.74.
123

Med Chem Res
2[3-Nitrophenylimino]-5-(1H-pyridin-2-ylmethylidene)-
1,3-thiazolidin-4-one (4j) m.p.: 279–281; % yield: 67;
IR (KBr) cm-1: 3080 (N–H of lactam), 3047 (C–H str. of
aromatic), 1713 (C=O of thiazolidinone), 1622 (C=C aro-
matic), 1592 (C=N), 1513, 1340 cm-1 (NO2).1H NMR, d
ppm, (DMSO-d6): 12.55 (1H, s, NH, thiazolidinone), 6.95
(1H, s, =CH), 7.2–8.44 (m, 8H, Ar). 13C NMR d ppm,
(DMSO-d6): 118.1, 119.5, 122.1, 122.4, 123.1, 124.4, 128.0,
135.4, 137.1, 139.3, 147.6, 148.4, 154.2, 154.7, 164.8.
EI-MS: m/z 326.64 M?; Anal. Calcd. for C15H10N4O3S
(326.32): C, 44.36; H, 2.51; N, 13.65. Found: C, 44.12; H,
2.64; N, 13.74.
2[4-Bromophenylimino]-5-(1H-pyridin-2-ylmethylidene)-
1,3-thiazolidin-4-one (4o) m.p.: 281–283; % yield: 45; IR
(KBr) cm-1: 3108 (N–H of lactam), 3127 (C–H str. of
aromatic), 1716 (C=O of thiazolidinone), 1632 (C=C aro-
1
matic), 1592 cm-1 (C=N). H NMR, d ppm, (DMSO-d6):
12.35 (1H, s, NH, thiazolidinone), 6.8 (1H, s, =CH),
6.98–7.94 (m, 8H, Ar). EI-MS: m/z 360 M?; Anal. Calcd.
for C15H10BrN3OS (360.22): C, 43.36; H, 2.51; N, 10.41.
Found: C, 43.62; H, 2.34; N, 10.54.
Pharmacological evaluation
2[2-Chloro,4-nitrophenylimino]-5-(1H-pyridin-2-ylmethy-
lidene)-1,3-thiazolidin-4-one (4k) m.p.: 286–288;
Wistar rats weighing 180–250 g and Swiss albino mice
weighing 25–30 g were housed in a room maintained under
controlled room temperature of 22 2 °C with a relative
humidity 60–70 % and provided with food and water
ad libitum. All the experimental procedures and protocols
used in the study were reviewed by the Institutional Animal
Ethics Committee (Registration No. 563/02/a/CPCSEA) and
were in accordance with the guidelines of the CPCSEA,
Ministry of Forests and Environment, Government of India.
The animals were deprived of food for 24 h before experi-
mentation, but allowed free access to water throughout.
%
yield: 47; IR (KBr) cm-1: 3048 (N–H of lactam), 3057
(C–H str. of aromatic), 1687 (C=O of thiazolidinone), 1618
1
(C=C aromatic), 1589 (C=N), 1513, 1340 cm-1 (NO2). H
NMR, d ppm, (DMSO-d6): 12.55 (1H, s, NH, thiazolidi-
none), 7.95 (1H, s, =CH), 7.5–8.4 (m, 7H, Ar). EI-MS:
m/z 360.64 M?; Anal. Calcd. for C15H9ClN4O3S (360.77):
C, 43.96; H, 2.21; N, 13.65. Found: C, 43.12; H, 2.34; N,
13.74.
2[2,6-Dimethylphenylimino]-5-(1H-pyridine-2-ylmethylid-
ene)-1,3-thiazolidin-4-one (4l) m.p.: 222–225; % yield:
57; IR (KBr) cm-1: 3031 (N–H of lactam), 3037 (C–H str.
of aromatic), 1697 (C=O of thiazolidinone), 1635 (C=C
Anti-inflammatory activity
The anti-inflammatory activity of the synthesised com-
pounds by the carrageenan-induced paw edema test was
studied according to the method by Joseph et al., (2009). The
animals were divided into different groups consisting of six
rats each. The control group received normal saline: tween
80 (95:5), the standard group received the standard drug
diclofenac sodium 10 mg/kg body weight and the test groups
received the synthesised compounds at a dose of 10 mg/kg
body weight. Thirty minutes after the administration of the
test and standard drugs, 0.01 ml of 1 % w/v carrageenan
suspension in normal saline was injected into the left hind
paw (plantar region) of all the animals. The paw volume, up
to the tibiotarsal articulation, was measured using a ple-
thysmometer (Model 7140, Ugo Basile, Italy). The per-
centage protection of oedema (inhibition of inflammation)
was calculated according to the formula, percentage anti-
inflammatory activity = 100 9 (1 - Vt/Vc) where Vt and
Vc are the volumes of oedema for the test compounds and
control groups, respectively. It is pertinent to mention here
that maximum activity was obtained at 120 min, and thus the
percentage inhibition was calculated at 120 min.
1
aromatic), 1603 cm-1 (C=N). H NMR, d ppm, (DMSO-
d6): 12.35 (1H, s, NH, thiazolidinone), 6.95 (1H, s, =CH),
6.98–7.94 (m, 7H, Ar), 2.35 (6H, s, CH3). EI-MS: m/z
309.64 M?; Anal. Calcd. for C17H15N3OS (309.38): C,
50.96; H, 3.71; N, 10.65. Found: C, 50.12; H, 3.34; N, 10.74.
2[2-Chlorophenylimino]-5-(1H-pyridin-2-ylmethylidene)-
1,3-thiazolidin-4-one (4m) m.p.: 261–263; % yield: 73;
IR (KBr) cm-1: 3078 (N–H of lactam), 3035 (C–H str. of
aromatic), 1716 (C=O of thiazolidinone), 1638 (C=C aro-
1
matic), 1589 cm-1 (C=N). H NMR, d ppm, (DMSO-d6):
12.55 (1H, s, NH, thiazolidinone), 6.9 (1H, s, =CH),
6.98–7.94 (m, 8H, Ar). EI-MS: m/z 315.64 M?; Anal.
Calcd. for C15H10ClN3OS (315.77): C, 43.96; H, 2.51; N,
10.25. Found: C, 43.62; H, 2.34; N, 10.54.
2[2-Methylphenylimino]-5-(1H-pyridin-2-ylmethylidene)-
1,3-thiazolidin-4-one (4n) m.p.: 232–235; % yield: 64;
IR (KBr) cm-1: 3138 (N–H of lactam), 3057 (C–H str. of
aromatic), 1698 (C=O of thiazolidinone), 1632 (C=C aro-
1
matic), 1592 cm-1 (C=N). H NMR, d ppm, (DMSO-d6):
12.55 (1H, s, NH, thiazolidinone), 6.8 (1H, s, =CH),
6.98–7.94 (m, 8H), 2.37 (6H, s, CH3). EI-MS: m/z 295.24
M?; Anal. Calcd. for C16H13N3OS (295.35): C, 52.36; H,
3.31; N, 10.51. Found: C, 52.62; H, 3.34; N, 10.54.
Analgesic activity
The analgesic activity was measured against chemical
stimuli. For analgesic activity, the animals were divided into
123

Med Chem Res
groups consisting of six mice each. The control group
received normal saline: tween 80 (95:5). The standard group
received diclofenac 50 mg/kg body weight and the test
groups received the synthetic compounds at a dose of 50 mg/
kg body weight. Thirty minutes later, nociception was
induced by an intraperitoneal (IP) injection of acetic acid
(1 %), 0.1 ml/10 g. The numbers of stretching or writhing
movements were recorded from 5 to 15 min. The percentage
protection was calculated by the following formula:
Percentage protection = 100 - (No. of writhes in test/
No. of writhes in control) 9 100.
the hydrogen bond network by reorienting hydroxyl group,
water molecules, and amide groups, and selecting appro-
priate states and orientation of the rings in the residues. The
final step in the protein preparation process was to refine
the structure with a restrained minimization. Their task was
˚
initiated in the Impref minimization with the 0.3 A RMSD
for the OPLS_2005 force field.
Ligand docking
Glide, Version 5.6, (2010) searches for favorable interac-
tions between ligand molecules and the receptor protein.
Grids were generated to define the binding site of the
protein and generated the electrostatic grid. No constraints
were included in the grid files. The shape and properties of
the receptor were represented on a grid by several different
sets of field, which provide progressively more accurate
scoring of the ligand poses. For receptors that adopt more
than one conformation on binding, grids were prepared for
each conformation to insure that possible actives were not
missed. Ligand molecule was picked so that it can be
excluded from the grid generation with van der Waals
radius scaling 1.00 and partial charge cutoff of 0.25. The
compounds were docked by means of Glide with standard
settings in standard precision (SP) mode.
Molecular docking studies
Ligand preparation
The chemical structures of all the compounds were drawn
in maestro and geometrically refined by means of LigPrep,
Version 2.4, (2010) module. The simplest use of LigPrep
produces a single, low-energy, 3D structure with correct
chiralities for each successfully proposed input structure.
Chiralities and original states of ionization were retained.
Tautomers and conformations were generated by Monte
Carlo (MCMM) method as implemented in MacroModel
Version 9.8, (2010) by means of OPLS-2005 force field.
All the conformers were subsequently minimized by trun-
cated Newton conjugate gradient (TNCG) minimization up
to 500 iterations. For each molecule, a set of conformers
with a maximum energy difference of 30 kcal/mol relative
to the global energy minimum conformer was retained. The
conformational searches were done for aqueous solution
using the generalized born/solvent accessible surface (GB/
SA) continuum solvation model (Schneider and Fechner,
2005).
Quantitative structure activity relationship studies
QSAR models were generated by the technique of linear
regressions. All the regression analyses were performed by
means of SPSS software. Regression analysis by the
method of maximum R2 was used for proposing statisti-
cally significant models. Predictive ability of the proposed
models was evaluated by leave-one-out cross validation
methods (Dureja et al., 2007). The criteria of squared
correlation coefficient of the predictions were used for the
quality of the predictive ability of model.
Protein preparation
Conflict of interest The authors declare that they have no com-
peting interests.
The COX-2 (PDB code 3HS5) X-ray structure was acces-
sed from the protein data bank. A typical PDB structure file
consists only of heavy atoms, can contain waters, cofactors,
and metal ions, and can be multimeric. The structure
generally has no information on bond orders, formal atomic
charges, and generally unassigned ionization and tauto-
meric states. Thus, the protein structures were prepared by
the protein preparation wizard in Maestro. In this step,
bond orders were assigned, all hydrogens in the structure
were added, and the bonds to metals were deleted and the
formal charge on the metal & the neighboring atoms, that
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