Synthesis, biological activity, and docking study of novel isatin coupled thiazolidin-4-one derivatives as anticonvulsants

Article abstract of DOI:10.1002/ardp.201500020

A series of 2-(substituted-phenyl)-3-(2-oxoindolin-3-ylidene)amino)-thiazolidin-4-one derivatives were designed and synthesized under microwave irradiation, using an eco-friendly, efficient, microwave-assisted synthetic protocol that involves cyclocondensation of 3-substituted benzylidine-hydrazono-indolin-2-one 3a-j with thioglycolic acid in dimethyl formamide (DMF) as solvent and anhydrous zinc chloride as a catalyst, keeping in view the structural requirement of the pharmacophore. The intermediate compounds 3a-j were obtained by condensation of the hydrazone of indoline-2,3-dione with aromatic aldehydes. The synthesized derivatives were evaluated for CNS depressant activity and anticonvulsant activity in mice using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (sc-PTZ) induced seizure tests. All the derivatives showed good CNS depressant activity and showed protection in the MES test, indicative of their ability to inhibit the seizure spread. A histopathological study was performed to evaluate liver toxicity caused by the synthesized compounds. The compounds were nontoxic. A computational study was performed, in which log P values were calculated experimentally. Virtual screening was performed by molecular docking of the designed compounds into the ATP binding sites of the NMDA and AMPA receptors, to predict if these compounds have analogous binding modes.

Full text of DOI:10.1002/ardp.201500020

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Arch. Pharm. Chem. Life Sci. 2015, 348, 1–13
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Full Paper
Synthesis, Biological Activity, and Docking Study of Novel Isatin
Coupled Thiazolidin-4-one Derivatives as Anticonvulsants
Anna P. Nikalje1, Altamash Ansari1, Sanjay Bari2, and Vinod Ugale2
1
Department of Pharmaceutical Chemistry, Y. B. Chavan College of Pharmacy, Aurangabad,
Maharashtra, India
2
Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmacy, Shirpur (Dhule),
Maharashtra, India
A series of 2-(substituted-phenyl)-3-(2-oxoindolin-3-ylidene)amino)-thiazolidin-4-one derivatives were
designed and synthesized under microwave irradiation, using an eco-friendly, efficient, microwave-
assistedsyntheticprotocolthatinvolvescyclocondensationof3-substitutedbenzylidine-hydrazono-indolin-
2-one 3a–j with thioglycolic acid in dimethyl formamide (DMF) as solvent and anhydrous zinc chloride as a
catalyst, keeping in view the structural requirement of the pharmacophore. The intermediate compounds
3a–j were obtained by condensation of the hydrazone of indoline-2,3-dione with aromatic aldehydes. The
synthesized derivatives were evaluated for CNS depressant activity and anticonvulsant activity in mice using
themaximalelectroshockseizure(MES)andsubcutaneouspentylenetetrazole(sc-PTZ)inducedseizuretests.
AllthederivativesshowedgoodCNSdepressantactivityandshowedprotectionintheMEStest,indicativeof
their ability to inhibit the seizure spread. A histopathological study was performed to evaluate liver toxicity
caused by the synthesized compounds. The compounds were nontoxic. A computational study was
performed, in which log P values were calculated experimentally. Virtual screening was performed by
moleculardockingofthedesignedcompoundsintotheATPbindingsitesoftheNMDAandAMPAreceptors,
to predict if these compounds have analogous binding modes.
Keywords: Anticonvulsants / Indoline-2,3-dione / MES test / Molecular docking / PTZ-induced seizure
Received: January 16, 2015; Revised: February 28, 2015; Accepted: March 6, 2015
DOI 10.1002/ardp.201500020
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
megaloblastic anemia and lifelong medication may be
required [2–4]. Therefore, there is continuous need for the
Introduction
Epilepsy is a very common neurological affliction in men
characterized by temporary high neuronal discharges result-
ing in uncontrolled seizure and affected millions of people
worldwide [1]. Moreover, the recent drug therapy is full with
adverse side effects such as gastrointestinal disturbances,
drowsiness, ataxia, hirsutism, gingival hyperplasia, and
search and development of more effective and reliable
anticonvulsant drugs. As the literature survey reveals that
indoline-2,3-dione (isatin) derivatives have exhibited potent
CNS depressant and anticonvulsant activities in many research
papers [5, 6] as well as the Schiff base with 4-thiazol-
idinone derivatives possess remarkable anticonvulsant activi-
ty [7–9] and in continuation of our earlier efforts [10–14] for
search of novel anticonvulsant agents. In the present work our
objective was to develop novel hybrid heterocyclic molecule
having indoline-2,3-dione moiety coupled with thiazolidi-
none nucleus having appropriate pharmacophors with the
hope to get novel compounds with significant and potential
anticonvulsant activity and minimal toxic side effects. Thus,
novel 2-(substituted-phenyl)-3-(2-oxoindolin-3-ylidene)amino)-
Correspondence: Dr. Anna P. Nikalje, Department of Pharma-
ceutical Chemistry, Y. B. Chavan College of Pharmacy, Dr. Rafiq
Zakaria Campus, Rauza Bagh, P.B. No. 33, Aurangabad, Maha-
rashtra 431001, India.
E-mail: annapratimanikalje@gmail.com
Fax: þ91 0240-2381129
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thiazolidin-4-one derivatives, having optimum log P values,
were designed and synthesized, which show similar mode of
action on neuronal sodium channels as phenytoin. All
the synthesized derivatives have essential pharmacophoric
elements that are necessary for anticonvulsant activity as
suggested by Nadeem et al. [15], which are shown in
Fig. 1. The anticonvulsant drugs require basic groups like
neurotransmitter which normally acts at that receptor [17,
18]. Hence, we have also tried to dock the designed
compounds with the crystal structure of NMDA and AMPA
receptors to explore their binding mode. Computational
study was performed in which log P values were calculated
experimentally. Histopathological study of liver was per-
formed with the standard drug phenytoin and the synthe-
sized compound 4e, same compound 4e shows excellent
anticonvulsant activity, so as to compare the necrosis and
inflammation caused and to study hepatotoxicity.
–
–CH, –C O, –NH which could be responsible for interaction
–
with the active site of receptors of brain were a hydrophobic
unit (R), hydrogen donor (D) group [16]. Most of the
anticonvulsant drugs are acting by two basic receptors
mechanisms, AMPA and NMDA. The a-amino-3-hydroxy-
5-methyl-4-isoxazolepropionic acid receptor (AMPA) is a
non-NMDA-type ionotropic transmembrane receptor for
glutamate that mediates fast synaptic transmission in the
central nervous system. N-Methyl-D-aspartic acid (NMDA) is
an amino acid derivative that acts as a specific agonist at
the NMDA receptor mimicking the action of glutamate, the
Results and discussion
Chemistry
The synthesis of the title compounds 4a–j was carried out as
presented in Scheme 1. Thiazolidin-4-one ring was built up on
the indoline-2,3-dione by a series of reactions as follows: in
Figure 1. Structures of sodium channel modulators.
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Scheme 1. Synthetic protocol for the title compounds.
the first step, indoline-2,3-dione was refluxed with hydrazine
hydrate for 25 min in heating mental to give 3-hydrazonoin-
dolin-2-one 2; which was further refluxed with aromatic
aldehydes in absolute ethanol in the presence of catalytic
amount of piperidine to give 3-substituted benzylidine-
hydrazono-indolin-2-ones 3a–j. Final derivatives 2-(substitut-
ed-phenyl)-3-(2-oxoindolin-3-ylidene)amino)-thiazolidin-4-
ones 4a–j were obtained by cyclocondensation of 3a–j with
mercaptoacetic acid (thioglycolic acid) in dimethyl formamide
(DMF) as solvent and anhydrous zinc chloride, as a catalyst,
under microwave irradiation. The physicochemical param-
eters of the synthesized compounds are presented in Table 1.
cleaner, and greener, eco-friendly synthetic protocol [19, 20];
DMF is used as a solvent, instead of benzene, which is a
proven carcinogenic solvent used in conventional synthesis of
thiazolidinones. The conventional synthesis is carried out in
Dean–Stark apparatus and also requires removal of benzene–
water azotrope [21]. Thus, the microwave-assisted synthetic
protocol is efficient and eco-friendly. All the synthesized
compounds were evaluated for CNS depressant and anti-
convulsant activity and have shown promising CNS activity.
Anticonvulsant activity
All the synthesized compounds have shown protection
against MES test indicative of their ability to inhibit the
seizure spread. Test compounds 4d, 4e, 4f, 4i, and 4j have
shown better protection against MES at 100 mg/kg, after
30 min and compounds 4e, 4f, 4h, and 4i have shown
protection at dose level of 100 mg/kg at 30 min against PTZ-
induced seizure. The compounds 4e, 4f, and 4i have shown
excellent activity in both MES and PTZ models at same dose of
100 mg/kg. The activity data are presented in Table 2.
1
The data obtained from IR, mass, H NMR elemental analysis
confirmed the proposed structures.
A
series of novel 2-(substituted-phenyl)-3-(2-oxoindolin-
3-ylidene)amino)-thiazolidin-4-one derivatives 4a–j were
obtained under microwave irradiation in good yield and
required shorter reaction time. Microwave-assisted synthesis
oftitlecompoundswascarriedoutasitrequiresreducedreaction
time, giving increased reaction rate, yield enhancement,
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Table 1. The physicochemical parameters of the synthesized compounds 4a–j.
Code
Ar
Mol. weight
Yield (%)
M.P. (°C)
Log P value
Rf value
MW (min)
4a
323
86
132–134
1.92
0.45
0.62
0.42
18
4b
4c
357
339
89
87
139–140
149–151
2.91
1.93
20
19
4d
4e
353
383
82
80
124–126
179–181
1.94
1.98
0.68
0.72
20
22
4f
383
337
90
75
114–116
129–131
2.54
2.06
0.73
0.80
23
20
4g
4h
4i
369
369
383
72
74
91
139–141
159–161
119–121
2.04
2.28
2.52
0.50
0.69
0.88
20
22
24
4j
Solvent of recrystallization was ethanol; eluants used in TLC were petroleum benzene/methanol (0.5:4.5) for all compounds.
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Arch. Pharm. Chem. Life Sci. 2015, 348, 1–13
Isatin Coupled Thiazolidin-4-ones as Anticonvulsants
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Table 2. Anticonvulsant activity and mortality percentage of compounds 4a–j.
MES screen
Sc PTZ screen
mean ꢀ SEM onset of convulsion
mean ꢀ SEM
30 mg/kg 100 mg/kg
16.02 ꢀ 0.344
% Mortality R/D
Compounds
30 mg/kg
100 mg/kg
Control
Standard (phenytoin)
1/4
5/0
2/3
4/1
5/0
4/1
4/1
3/2
3/2
5/0
4/1
40.44 ꢀ 0.748**
12.21 ꢀ 0.152**
9.12 ꢀ 0.142**
15.36 ꢀ 0.160**
11.24 ꢀ 0.240**
13.26 ꢀ 0.169**
11.26 ꢀ 0.229**
12.38 ꢀ 0.193**
14.98 ꢀ 0.339**
10.1 ꢀ 0.114ns
12.04 ꢀ 0.242**
15.72 ꢀ 0.432**
55.48 ꢀ 0.462*
86.84 ꢀ 0.482
4a
4c
4d
4e
4f
4g
4h
4i
X
X
61.22 ꢀ 0.432**
52.36 ꢀ 0.297**
56.52 ꢀ 0.439**
71.46 ꢀ 0.460**
73.3 ꢀ 0.249**
63.45 ꢀ 0.564**
71.4 ꢀ 0.933**
77.56 ꢀ 0.729**
61.82 ꢀ 0.673**
15.67 ꢀ .0.130ns
43.25 ꢀ 0.439**
X
X
16.21 ꢀ .0.230**
17.35 ꢀ 0.168**
X
15.12 ꢀ 0.339**
14.09 ꢀ 0.159**
X
43.84 ꢀ 0.139**
52.92 ꢀ 0.339**
X
56.22 ꢀ 0.432**
64.22 ꢀ 0.729**
X
4j
A dose of 30 and 100 mg/kg of compound was administered and the protection measured after 30 min. The mean significant
results were calculated by GraphPad and one-way ANOVA method. R, recovery; D, death; X, not done.
*P < 0.05, **P < 0.01, ns ¼ non significant P > 0.05.
Behavioral study
4 h time period when compared to diazepam. The results of
these activities are shown in Tables 3 and 4 [22].
In the behavioral activity using actophotometer, the com-
pounds 4a, 4b, 4d, 4e, 4f, and 4g showed no behavioral
despair effect when compared to diazepam at 1 h, and
compounds 4c, 4h, 4i, and 4j have shown good CNS
depressant activity at 30 mg/kg at 1 h when compared with
standard (diazepam, 4 mg/kg). At 100 mg/kg, compounds 4c,
4e, 4f, 4h, and 4i have shown good CNS depressant activity.
The compounds 4c, 4e, 4h, 4i, and 4j at dose level 30 mg/kg
have shown excellent activity and compounds 4e, 4f, 4h, and
4i at dose level 100 mg/kg have shown decreased locomotor
activity in the 4 h interval but no despair was observed during
Muscle relaxant activity
All compounds in muscle relaxant activity have shown very
good result except 4b which has chloro group at 4-position.
The compounds 4a, 4c, 4e, 4f, 4h, 4i, and 4j have shown
activity at dose level 100 mg/kg.
Histopathological evaluation
Histopathological study of liver T.S. shows that the standard
drug phenytoin has caused necrosis and inflammation and is
Table 3. Behavioral study of the synthesized compounds 4a–j.
Activity score using actophotometer post-treatmenta)
1 h
4 h
Compounds
30 mg/kg
100 mg/kg
30 mg/kg
100 mg/kg
4a
4b
4c
4d
4e
4f
4g
4h
126.00 ꢀ 10.242**
182.00 ꢀ 1.095ns
107.20 ꢀ 12.114**
122.00 ꢀ 9.793**
120.20 ꢀ 1.772**
118.20 ꢀ 10.336**
133.20 ꢀ 3.043**
104.00 ꢀ 7.169**
110.60 ꢀ 9.304**
116.40 ꢀ 9.605**
133.60 ꢀ 1.400**
199.0 ꢀ 1.517ns
103.8 ꢀ 7.179**
118.2 ꢀ 10.336**
97.00 ꢀ 11.480**
87.00 ꢀ 1.703**
133.0 ꢀ 2.049**
62.01 ꢀ 1.612**
68.00 ꢀ 1.225**
120.0 ꢀ 2.121**
118.20 ꢀ 10.336**
202.40 ꢀ 3.709ns
85.80 ꢀ 0.860**
129.20 ꢀ 0.862**
107.20 ꢀ 12.11**
125.00 ꢀ 1.258**
149.20 ꢀ 2.354**
96.00 ꢀ 2.350**
114.80 ꢀ 12.944**
113.40 ꢀ 12.143**
139.0 ꢀ 1.000**
207.80 ꢀ 3.917ns
92.60 ꢀ 1.208**
159.0 ꢀ 2.049*
89.00 ꢀ 1.225**
80.60 ꢀ 0.509**
153.00 ꢀ 1.00**
57.00 ꢀ 0.707**
61.40 ꢀ 1.631**
127.40 ꢀ 0.9274**
4i
4j
Standardb)
Control
Diazepam 44.60 ꢀ 0.509**
224.2 ꢀ 20.038
Diazepam 67 ꢀ 0.3162**
224.2 ꢀ 20.038**
a)Each value represents the mean ꢀ SEM significantly different from the control at P < 0.05, NS denotes not significant at P < 0.05
(Student’s t-test).
b)The compound was tested at dose level of 4 mg/kg (oral).
*P < 0.05, **P < 0.01, ns ¼ non significant P > 0.05.
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Table 4. Locomotor activity of the synthesized compounds 4a–j.
% Decrease in locomotor activity
1 h
4 h
Compounds
30 mg/kg
100 mg/kg
30 mg/kg
100 mg/kg
4a
4b
4c
4d
4e
4f
4g
4h
51.1
86.34
54.32
91.8
47.75
20.10
41.10
32.46
49.96
43.15
26.14
59.01
68.80
61.16
80.59
25.93
86.55
86.38
88.42
86.55
79.40
90.81
88.12
81.27
30.76
49.96
39.24
51.66
40.26
32.50
69.53
63.07
65.11
86.6
90.44
88.10
85.32
92.83
92.15
90.12
4i
4j
Standard
Control
Diazepam 12.2 ꢀ 0.663**
Diazepam 10.4 ꢀ 0.509**
293.8 þ 1.828
The locomotor activity score was measured for 10 min.
Figure 2. Microscopical examination.
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Isatin Coupled Thiazolidin-4-ones as Anticonvulsants
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Table 5. Distance mapping between the structure elements R, D, and HBD
Compounds
R-HD
R-D
D-HBD
Phenytoin
Carbamazepine
Lamotrigine
Diazepam
3.58
5.09
6.44
4.79
6.04
3.77
4.87
3.41
4.82
4.75
2.21
4.06
4.45
1.49
5.01
Lead moiety of 4a–j
Distances calculated for 3D optimized structures using ACD freeware 3D viewer 8.04 versions.
hepatotoxic. Control, 0.5% Tween 80 has shown fatty changes
and necrosis, whereas liver of animals administered with
synthesized compound, 4e, has shown very less necrosis and
no inflammation, as shown in Fig. 2. Thus, the synthesized
compounds are less toxic than the standard drug.
4c, 4e, 4f, 4h, and 4i have shown dependence of biological
activityonlipophiliccharacterincongenericseries.Hence,these
compounds are showing excellent anticonvulsant activity.
Molecular docking methodology
In this study, we have used molecular docking tool, GLIDE
€
Computational parameters
(Schrodinger, Inc., USA) (2006) for automated flexible ligand
Distance mapping
docking of synthesized compounds with two established
epilepsy molecular targets namely NMDA receptor and AMPA
receptor. The low energy conformation of the ligands was
selected and docked into the grid generated from protein
structures using extra precision (XP) docking mode. The final
The present work involves the correlation of the structural
requirement of well-known and structurally different anti-
convulsant compounds with the title compounds. The
presence of at least one aryl (R) unit, one or two electron
donor (D) atoms, and a hydrogen bond acceptor/donor unit
(HBD) is structural requirement for anticonvulsant activity.
The essential structural features which could be responsible
for an interaction with the active site of voltage-gated sodium
channels were a hydrophobic unit (R), an electron donor (D)
group, and a hydrogen donor/acceptor (HBD) unit. Distance
mapping between the structure elements R, D, and HBD is
shown in Table 5.
Table 6. Experimental and theoretical log P values of
compounds 4a–j.
Experimental
Theoretical
log P combined value
Compounds
log P
4a
4b
4c
4d
4e
4f
4g
4h
4i
1.92
2.91
1.93
1.94
1.98
2.54
2.06
2.04
2.28
2.52
2.5
3.1
2.1
2.4
2.32
2.32
2.64
2.06
2.06
2.3
Log P determination
Several classes of CNS active compounds showed dependence
of biological activity on lipophilic character in a congeneric
series. Hansch and Leo found that blood–brain barrier
penetration is optimal when the log P values are in the
range of 1.5–2.7 with the mean value of 2.1 [23, 24]. From the
experimental log P determination, it was found that most of
the compounds are having log P values between 1.5 and 2.7,
which is requirement to cross the blood–brain barrier. All the
values are shown in Table 6. Most of the compounds like 4b,
4j
Theoretical log P combined was calculated by using Pallas
demo version 3112.
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Figure 3. Binding mode of phenytoin (A), compound 4h (B) and 4i (C) showing H-bond interaction with amino acid residues of NMDA
receptor (PDB: 1PBQ); binding mode of phenytoin (D), compound 4h (E) and 4i (F) showing H-bond interaction with amino acid
residues of AMPA receptor (PDB: 1FTL); dotted yellow bond showing H-bond interaction with site residue.
evaluation is done on the basis of docking score, glide energy
(kcal/mol), and probable hydrogen bonding interaction with
amino acid residues. We docked phenytoin into the active
site of both NMDA receptor (docking score ꢁ9.010283 and
3 H-bonds) and AMPA receptor (docking score ꢁ8.457558
and 1 H-bond) and then we replaced with our compounds to
compare the binding mode of both the ligand and the test
compounds. Compound 4h has exhibited good binding
properties with NMDA receptor (docking score ꢁ9.190447
and 3 H-bonds) and AMPA receptor (docking score ꢁ8.482894
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Table 7. Results of glide docking based on glide dock score, glide energy, and hydrogen bonding interaction of
synthesized compounds 4a–j with NMDA receptor.
Sr. no.
Docking score
Glide energy (kcal/mol)
H-bonding residues
4a
4b
4c
4d
4e
4f
4g
4h
ꢁ8.267906
ꢁ8.222225
ꢁ8.696813
ꢁ8.632272
ꢁ8.63082
ꢁ66.717638
ꢁ66.343933
ꢁ68.998742
ꢁ62.91166
ꢁ69.3503
GLY 93, PHE 92
GLY 93, PHE 92
GLY 93, PHE 92, GLN 13
GLY 93, PHE 92
GLY 93, PHE 92
GLY 93, PHE 92
GLY 93, PHE 92
ꢁ8.329504
ꢁ8.188746
ꢁ9.190447
ꢁ9.006918
ꢁ8.649542
ꢁ9.010283
ꢁ62.149948
ꢁ60.289785
ꢁ72.684925
ꢁ70.632847
ꢁ66.1017
GLY 93, PHE 92, GLN 13
GLY 93, PHE 92, SER 180
GLY 93, PHE 92
4i
4j
Phenytoin
ꢁ70.945541
ARG 131, THR 126
and 3 H-bonds). Compound 4i has shown prominent interac-
tion with amino acid residues of NMDA receptor (docking
score ꢁ9.006918 and 3 H-bonds) and AMPA receptor (docking
score ꢁ8.170842 and 3 H-bonds). The docking images are
given in Fig. 3. The purpose of docking study was to co-relate
the obtained activity data and explain the possible inter-
actions which might take place between the synthesized
derivatives 4a–j and epilepsy molecular targets. Results of
glide docking based on glide dock score, glide energy, and
hydrogen bonding interaction of synthesized compounds 4a–j
with NMDA receptor and AMPA receptor are shown in Tables
7 and 8.
agents. SAR study predicts that compounds like 4h and 4i have
shown promising activity. Compounds with smaller electron
donating, polar groups like –OH (4c), –OCH3 (4d), attached to
phenyl ring at para-position show significant activity in MES
screening model. Experimental calculation of log P values
suggests that compounds having log P values in the range 1.5–
2.5, have exhibited better activities than the compounds
having higher log P values. Compounds 4c, 4h, 4i, and 4j
have shown good CNS depressant activity at 30 mg/kg. The
synthesized derivative 4e having experimental log P value
of 1.98 has shown good protection against MES and PTZ
seizures and has shown less hepatotoxicity than the standard
drug phenytoin. Some of the synthesized derivatives like 4b,
having higher log P value, i.e., 4b, has exhibited lesser CNS
depressant and anticonvulsant activity. The results of docking
studies also support the postulation that our active com-
pounds may act on the epilepsy molecular targets through
hydrogen bonding. Thus, all the experimental observations of
biological activity, docking studies, log P calculations suggest
that the synthesized compounds 2-(substituted-phenyl)-3-(2-
oxoindolin-3-ylidene)amino)-thiazolidin-4-one are potential
anticonvulsants, cause CNS depression and muscle relaxation.
Conclusion
By using eco-friendly, efficient, microwave-assisted synthetic
protocol, 2-(substituted-phenyl)-3-(2-oxoindolin-3-ylidene)-
amino)-thiazolidin-4-one derivatives were synthesized in
good yield. These derivatives were evaluated for anticonvul-
sant and CNS depressant activity with the hope of getting
novel hybrid compounds serving as potential anticonvulsant
Table 8. Results of glide docking based on glide dock score, glide energy, and hydrogen bonding interaction of
synthesized compounds 4a–j with AMPA receptor.
Sr. no.
Docking score
Glide energy (kcal/mol)
H-bonding residues
4a
4b
4c
4d
4e
4f
4g
4h
ꢁ7.408415
ꢁ7.395962
ꢁ7.948836
ꢁ7.073684
ꢁ7.189234
ꢁ7.110536
ꢁ7.063207
ꢁ8.482894
ꢁ8.170842
ꢁ7.045262
ꢁ8.457558
ꢁ57.9229
ꢁ55.0516
ꢁ62.7822
ꢁ53.0707
ꢁ54.3548
ꢁ55.6056
ꢁ53.5356
ꢁ62.8598
ꢁ64.9968
ꢁ54.1236
ꢁ65.2977
PRO 89, THR 91
PRO 89, THR 91
PRO 89, THR 91, ARG 96
PRO 89, THR 91
PRO 89, THR 91
PRO 89, THR 91
PRO 89, THR 91
PRO 89, THR 91, ARG 96
PRO 89, THR 91, ARG 96
PRO 89, THR 91
4i
4j
Phenytoin
SER 142
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In conclusion, the compounds 4e, 4f, 4h, and 4i can be further
optimized and developed as lead molecules for future
investigations.
calcd. for C17H13N3O2S: C, 65.79; H, 4.55; N, 9.03; Found C,
65.77; H, 4.54; N, 9.01.
2-(4-Chlorophenyl)-3-((2-oxoindolin-3-ylidene)amino)-
thiazolidin-4-one (4b)
IR (KBr vmax in cmꢁ1): 3337 (N–H stretch), 3081 (C–H stretch
Experimental
–
Ar), 2890 (C–H stretching of CH ), 1665 (C O stretch), 1242
–
2
(C–S stretching), 720 (C–S bending); 1H NMR (DMSO-d6,
400 MHz) d ppm: 3.96 (s, 2H, –CH2 of thiazolidinone ring);
5.82 (s, 1H, –C–H of thiazolidinone ring); 7.1–7.8 (m, 8H,
J ¼ 1.25 Hz, Ar–H); 8.21 (s, 1H, J ¼ 1.5 Hz, –NH D2O exchange-
able); 13C NMR (DMSO-d2) d ppm: 35.2, 62.2, 117.6, 119.5,
124.6, 128.2, 128.3, 129.5, 130.2, 130.4, 131.0, 132.8, 133.2,
137.5, 141.2, 163.8, 172.1; MS m/z 357.12 (Mþ1); Anal. calcd.
for C17H12N3O2SCl: C, 65.79; H, 4.55; N, 9.03; Found C, 65.76; H,
4.55; N, 9.05.
Chemistry
The structures of the final compounds of the series 4a–j
were confirmed by the spectral data and elemental analysis.
Infrared (IR) was recorded for the compounds on JASCO FTIR
(PS 4000) using KBr pellet. All 1H NMR and 13C NMR spectra
were recorded on Bruker Advance II (400 MHz) instruments.
Chemical shifts are reported in parts per million (ppm) using
TMS as an internal standard. Elemental analyses (C, H, and N)
were undertaken with a Shimadzu’s FLASHEA112 analyzer
and all analyses were consistent with theoretical values
(within ꢀ0.5%) unless indicated otherwise.
2-(4-Hydroxyphenyl)-3-((2-oxoindolin-3-ylidene)amino)-
thiazolidin-4-one (4c)
General procedure for synthesis of 3-
IR (KBr vmax in cmꢁ1): 3495 (N–H stretch), 3261 (–OH stretch),
–
substituted benzylidine-hydrazono-indolin-2-ones 3a–j
Mixture of equimolar quantity of aromatic aldehyde
(0.015 mol) and hydrazone 2 (0.01 mol) was refluxed for 3–
6 h in the presence of 3–4 drops of piperidine as a catalyst in
absolute ethanol on heating mental. The completion of the
reaction was monitored by TLC. The reaction mixture was
filtered and washed with water and cooled. The crude
product was recrystallized from ethanol. The melting point
and yield were recorded.
3060 (C–H stretch Ar), 1712 (C O stretch), 724 (C–S stretching);
–
1H NMR (DMSO-d6, 400 MHz) d ppm: 4.23 (s, 2H, –CH2 of
thiazolidinone ring); 5.38 (s 1H –OH); 5.87 (s, 1H, –N–CH–Ar);
7.8–7.7 (m, 8H, J ¼ 1.25 Hz, Ar–H); 8.2 (s, 1H, J ¼ 7.5 Hz, –NH
D2O exchangeable); 13C NMR (DMSO-d2) d ppm: 35.9, 63.4,
115.8, 115.2, 117.7, 119.6, 124.6, 129.5, 130.2, 130.4, 131.0,
132.8, 133.2, 141.2, 156.9, 163.7, 172.1; MS m/z 339.01 (Mþ1);
Anal. calcd. for C17H13N3O3S: C, 60.17; H, 3.86; N, 12.38; Found
C, 60.25; H, 3.83; N, 12.40.
General procedure for synthesis of 2-(substituted-phenyl)-
3-(2-oxoindolin-3-ylidene)amino)-thiazolidin-4-ones 4a–j
Microwave method: Schiff’s base 3 (0.01 mol) in DMF (15 mL)
and thioglycolic acid (0.01 mol) was taken in a dry Erlenmeyer
flask. A pinch of anhydrous ZnCl2 as a catalyst was added to
the flask slowly. The reaction mixture was irradiated in
synthetic microwave oven for about 12–14 min at 700 W and
82°C. The completion of reaction was monitored by TLC. The
reaction mixture was poured in ice cold water with continu-
ous stirring. The obtained solid was filtered, washed with
water, and dried. The product was recrystallized from
ethanol. The melting point and yield of the product was
recorded. The structures of the synthesized final compounds
of the series 4a–j were confirmed by the spectral data and
elemental analysis as given below.
2-(4-Methoxyphenyl)-3-((2-oxoindolin-3-ylidene)amino)-
thiazolidin-4-one (4d)
IR (KBr vmax in cmꢁ1): 3320 (N–H stretch), 3110 (C–H stretch Ar),
–
1672 (C O stretch), 1242 (–OCH stretch), 722 (C–S stretching);
–
3
1H NMR (DMSO-d6, 400 MHz) d ppm: 3.23 (s, 3H of –OCH3); 4.23
(s, 2H, –CH2 of thiazolidinone ring); 5.97 (s, 1H, –N–CH–Ar);
6.8–7.5 (m, 9H, J ¼ 1.25 Hz, Ar–H); 8.2 (s, 1H, J ¼ 7.5 Hz, –NH
D2O exchangeable); 13C NMR (DMSO-d2) d ppm: 35.8, 55.3,
63.4, 114.2, 114.6, 117.3, 119.6, 124.6, 128.5, 130.2, 130.4,
131.0, 132.8, 133.2, 141.3, 159.0, 163.8, 172.4; MS m/z 353.2
(Mþ1); Anal. calcd. for C18H15N3O3S: C, 61.18; H, 4.28; N, 11.89;
Found C, 61.17; H, 4.25; N, 11.86.
2-(3,4-Dimethoxyphenyl)-3-((2-oxoindolin-3-ylidene)-
amino)-thiazolidin-4-one (4e)
IR (KBr vmax in cmꢁ1): 3360 (N–H stretch), 3045 (C–H stretch
–
3-((2-Oxoindolin-3-ylidene)amino)-2-phenylthiazolidin-4-
one (4a)
Ar), 2875 (–CH3 stretch), 1690 (C O stretch), 1242 (–OCH
–
3
stretch), 743 (C–S stretching); 1H NMR (DMSO-d6, 400 MHz) d
ppm: 3.98 (s, 6H of –OCH3); 4.01 (s, 2H, –CH2 of thiazolidinone
ring); 5.95 (s, 1H, –N–CH–Ar); 6.9–7.4 (m, 7H, J ¼ 1.25 Hz,
Ar–H); 8.0 (s, 1H, J ¼ 7.5 Hz, –NH D2O exchangeable); 13C NMR
(DMSO-d2) d ppm: 35.9, 63.9, 56.1, 56.3, 112.0, 113.5, 117.5,
119.5, 122.2, 124.2, 129.8, 131.2, 132.9, 133.6, 148.3, 149.2,
141.7, 168.2, 172.8; MS m/z 383.2 (Mþ1); Anal. calcd. for
IR (KBr vmax in cmꢁ1): 3369 (N–H stretch), 3130 (C–H stretch
–
Ar), 1630 (C O stretch), 1243 (C–S stretching), 596 (C–S
–
bending); 1H NMR (DMSO-d6, 400 MHz) d ppm: 4.23 (s, 2H,
–CH2 of thiazolidinone ring); 5.97 (s, 1H, –N–CH–Ar); 6.8–7.5
(m, 9H, J ¼ 1.25 Hz, Ar–H); 8.2 (s, 1H, J ¼ 7.5 Hz, –NH D2O
exchangeable); 13C NMR (DMSO-d2) d ppm: 34.9, 63.4, 117.6,
119.5, 124.5, 126.8, 126.9, 127.2, 128.6, 128.7, 129.5, 131.3,
133.2, 139.4, 141.4, 168.4, 171.2. MS m/z 323.12 (Mþ1); Anal.
C
19H17N3O4S: C, 59.52; H, 4.47; N, 10.96; Found C, 59.55; H,
4.46; N, 10.93.
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2-(2,4-Dimethoxyphenyl)-3-((2-oxoindolin-3-ylidene)-
amino)-thiazolidin-4-one (4f)
770 (C–S stretching); 1H NMR (DMSO-d6, 400 MHz) d ppm: 3.34
(s,6H of –OCH3); 4.02 (s, 2H, –CH2 of thiazolidinone ring); 5.12
(s, 1H, –N–CH–Ar); 6.8–7.8 (m, 7H, J ¼ 1.25 Hz, Ar–H); 8.00 (s,
1H, J ¼ 7.5 Hz, –NH D2O exchangeable); 13C NMR (DMSO-d2) d
ppm: 35.6, 57.9, 55.8, 60.3, 113.7, 117.5, 117.9, 119.8, 121.4,
124.5, 129.4, 131.5, 133.2, 145.6, 150.2, 141.2, 168.8, 172.9. MS
m/z 383.12 (Mþ1); Anal. calcd. for C19H17N3O4S: C, 59.52; H,
4.47; N, 10.96; Found C, 59.56; H, 4.45; N, 10.91.
IR (KBr vmax in cmꢁ1): 3415 (N–H stretch), 3057 (C–H stretch Ar),
–
2890 (–CH stretch), 1252 (–OCH stretch), 1720 (C O stretch),
–
3
3
718 (C–S stretching); 1H NMR (DMSO-d6, 400 MHz) d ppm: 3.38
(s,6H OF –OCH3); 4.23 (s, 2H, –CH2 of thiazolidinone ring); 5.97
(s, 1H, –N–CH–Ar); 7.2–7.9 (m, 7H, J ¼ 1.25 Hz, Ar–H); 8.02 (s,
1H, J ¼ 7.5 Hz, –NH D2O exchangeable); 13C NMR (DMSO-d2) d
ppm: 34.9, 52.9, 55.1, 56.8, 100.2, 106.8, 108.2, 116.5, 119.6,
124.2, 129.7, 159.2, 160.3, 130.5, 131.8, 133.7, 141.2, 168.2,
171.3; MS m/z 383.1 (Mþ1); Anal. calcd. for C19H17N3O4S: C,
59.52; H, 4.47; N, 10.96; Found C, 59.54; H, 4.48; N, 10.94.
Pharmacology
Male Swiss Albino mice (CF-1 strain, 20–30 g) were used as
experimental animals. Animals divided into each group of five
animals were housed and allowed free access to water and
food. A 12:12 h light/dark cycle was maintained throughout
the experimental studies. All the tested compounds were
administered in suspension made up to 0.5% Tween 80 in
0.9% sodium chloride solutions and are used for MES and sc-
PTZ study and 30% PEG for behavioral activity. Pentylenete-
trazole (80 mg/kg) dissolved in 0.9% sodium chloride solution
was administered in the posterior midline of the mice and the
onset and severity of convulsions were noted for control
group. The test group was administered with the selected
compounds 0.5 h prior to the administration of PTZ. The
statistical analyses were performed by one-way ANOVA
followed by Student’s t-test to evaluate the results using
GraphPad Prism software. All the values were expressed as
meanꢀ SEM. All the tests were performed in accordance with
guidelineslaidoutbytheInstitutionalAnimalEthicsCommittee
[25]. The approval of the Institutional Animal Ethics Committee
(CPCSEA number CPCSEA/IAEC/Pharm. Chem/12/2011-12/54) of
Y.B. Chavan college of Pharmacy, Aurangabad, Maharashtra,
India, was taken prior to the start of the experiments.
3-((2-Oxoindolin-3-ylidene)amino)-2-(p-tolyl)-thiazolidin-
4-one (4g)
IR(KBrvmaxincmꢁ1):3231(N–Hstretch),3010(C–HstretchAr),2895
1
–
(–CH stretch), 1692 (C O stretch), 752 (C–S stretching); H NMR
–
3
(DMSO-d6, 400MHz)dppm: 2.40 (s 3H of –CH3)4.02(s, 2H, –CH2 of
thiazolidinone ring); 5.98 (s, 1H, –N–CH–Ar); 6.8–7.8 (m, 8H,
J¼ 1.25 Hz, Ar–H); 8.15 (s, 1H, J¼ 7.5 Hz, –NH D2O exchangeable);
13C NMR (DMSO-d2) d ppm: 21.3, 35.1, 63.7, 117.7, 119.4, 124.2,
127.9, 128.6, 128.8, 128.9, 129.4, 131.1, 133.0, 136.7, 136.6, 141.4,
168.8, 172.2. MS m/z 337.2 (Mþ1); Anal. calcd. for C18H15N3O2S: C,
64.08; H, 4.48; N, 9.03; Found C, 64.12; H, 4.45; N, 9.00.
2-(4-Hydroxy-3-methoxyphenyl)-3-((2-oxoindolin-3-
ylidene)amino)-thiazolidin-4-one (4h)
IR (KBr vmax in cmꢁ1): 3419 (N–H stretch), 3209 (OH stretch), 3052
(C–H stretch Ar), 2880 (–CH3 stretch), 1250 (OCH3 stretch), 1690
1
–
(C Ostretch), 716(C–Sstretching); HNMR(DMSO-d ,400MHz)d
–
6
ppm: 3.23 (s 3H OF –OCH3); 4.30 (s, 2H, –CH2 of thiazolidinone
ring); 5.39 (s,1H –OH); 5.97 (s, 1H, –N–CH–Ar); 6.9–7.5 (m, 7H,
J¼ 1.25 Hz, Ar–H); 8.2 (s, 1H, J¼ 7.5 Hz, –NH D2O exchangeable);
13C NMR (DMSO-d2) d ppm: 35.9, 63.8, 56.1, 114.2, 115.6, 117.5,
119.4, 122.2, 124.3, 129.3, 131.5, 132.8, 133.2, 141.3, 147.1, 147.7,
168.9, 170.1. MSm/z 369.3 (Mþ1);Anal. calcd. forC18H15N3O4S: C,
58.53; H, 4.09; N, 11.38; Found C, 58.55; H, 4.40; N,11.36.
Anticonvulsant effects in the maximal electroshock seizure
(MES) test [26, 27]
All the test compounds and the standard drug phenytoin was
injected intraperitonially in a volume of 0.01 mL/g at a dose of
30 and 100 mg/kg. Seizures were elicited with a 60 Hz
alternating current of 50 mA intensity in mice. The current
was applied via corneal electrodes for 0.2 s. Protection against
the spread of MES-induced seizures was defined as the
abolition of the hind leg and tonic maximal extension
component of the seizure. At 30 min after the administration
of the compounds, the activities were evaluated in MES test.
The animals were observed closely for 5 min. The disappear-
ance of the hind limb extensor tonic convulsion was used as
positive criterion. The results of test compounds were
compared with the standard drug.
2-(3-Hydroxy-4-methoxyphenyl)-3-((2-oxoindolin-3-
ylidene)amino)-thiazolidin-4-one (4i)
IR (KBr vmax in cmꢁ1): 3300 (N–H stretch), 3202 (OH stretch),
–
3085 (C–H stretch Ar), 2890 (–CH stretch), 1687 (C O stretch),
–
3
1225 (OCH3 stretch), 722 (C–S stretching); 1H NMR (DMSO-d6,
400 MHz) d ppm: 3.34 (s 3H of –OCH3); 4.23 (s, 2H, –CH2 of
thiazolidinone ring); 4.79 (s,1H of –OH); 5.87 (s, 1H,
–N–CH–Ar); 7.3–7.7 (m, 7H, J ¼ 1.25 Hz, Ar–H); 8.2 (s, 1H,
J ¼ 7.5 Hz, –NH D2O exchangeable); 13C NMR (DMSO-d2) d
ppm: 35.7, 56.2, 63.8, 112.7, 115.4, 116.2, 119.5, 122.3, 124.4,
129.4, 133.1, 131.2, 132.9, 147.1, 149.5, 141.2, 168.5, 172.1. MS
m/z 369.2 (Mþ1); Anal. calcd. for C18H15N3O4S: C, 58.53; H,
4.09; N, 11.38; Found C, 58.57; H, 4.06; N, 11.32.
Sc-PTZ-induced seizures [28, 29]
All the test compounds and the standard drug phenytoin was
injected intraperitonially in a volume of 0.01 mL/g at a dose 30
and 100 mg/kg and at 30 min after the administration of
the test compounds, 85 mg/kg PTZ dissolved in saline was
administered subcutaneously. The animals were placed in
individual cages and observed for 30 min. The number of
2-(2,3-Dimethoxyphenyl)-3-((2-oxoindolin-3-ylidene)-
amino)-thiazolidin-4-one (4j)
IR (KBr vmax in cmꢁ1): 3350 (N–H stretch), 3040 (C–H stretch Ar),
–
2885 (–CH stretch), 1730 (C O stretch), 1233 (OCH stretch),
–
3
3
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clonic and tonic seizures as well as the number of deaths was
noted. The delay onset of convulsion was referred to be
anticonvulsant response. The results of test compounds were
compared with the standard drug.
procedure [33]. A total of 10 mL of octanol and 10 mL of
phosphate buffer were taken in glass stoppered graduated
tube and 5 mg of accurately weight test drug was added. The
mixture was then shaken with mechanical shaker for 24 h
at room temperature and then transferred to a separating
funnel and allowed to equilibrate for 6 h. The aqueous and
octanol phase were separated and the phases were filtered
though membrane filter and drug content in aqueous phase
was analysed by UV spectroscopy. Partition coefficient [34]
was calculated by using the formula PC ¼ (Ct ꢁ Ca)/Ca. PC ¼
partition coefficient Ct ¼ concentration of total drug. Ca ¼
concentration of drug in aqueous phase.
Behavioral screening
CNS depressant activity
The activity was measured on digital actophotometer with
the oral administration of drug in a volume 0.2 mL at dose of
30 and 100 mg/kg to mice. The standard drug diazepam was
injected at dose 4 mg/kg. The activity was assessed after 1 and
4 h of drug administration. The mice were placed in the box
and behaviour was noted for 10 min and the basal activity
scores for all the animals were recorded. The results of test
compounds were compared with the standard drug.
Molecular modeling
€
The molecular docking tool, GLIDE (Schrodinger Inc., USA;
2006) was used for ligand docking studies into the NMDA and
AMPA receptor binding pocket. The crystal structure of these
receptors was obtained from a protein data bank (PDB ID:
1PBQ and 1FTL) [35, 36]. The protein preparation was carried
out using “protein preparation wizard” in Maestro 9.0 in two
steps: preparation and refinement. After ensuring chemical
correctness, water molecules in the crystal structures were
deleted, and hydrogens were added, where they were
missing. Using the OPLS 2005, force field energy of crystal
structure was minimized [37]. Grids were defined centering
them on the ligand in the crystal structure using the default
box size. The ligands were built using Maestro build panel and
prepared by Ligprep 2.2 module, which produce the low-
energy conformer of ligand using OPLS 2005 force field.
Muscle relaxant activity
This activity was measured on rotarod. The treated mice were
placed on rotarod at intervals and the time of fall from the rod
was noted. A group of five mice was used for one compound
and average reading was taken. The activity score was noted
and based on these result percentage decrease in fall time was
calculated [30].
Evaluation of histopathology of mice liver
(T.S. of liver)
The synthesized compounds were evaluated for liver toxicity
upon Swiss Albino mice with reference to standard phenytoin,
300 mg/kg. The synthesized compounds of 4-thiazolidinone
derivatives 4e and 4i at 300 mg/kg were administered
intraperitoneally to animal. The mice liver was removed after
scarification of mice followed by the drug administration. The
liver was washed with Kreb’s solution and stored in 10%
formalin; the specimen was subjected to microscopic visuali-
zation; it was found that the liver of the animal treated with
standard resulted in hepatotoxicity. The liver treated with
standard has shown hepatotoxicity while the liver of animals
treated with synthesized compounds resulted in lesser
inflammation and has shown lesser hepatotoxicity [31].
The authors are grateful to Mrs. Fatma Rafiq Zakaria,
Chairman, Maulana Azad Education Trust and Principal for
encouragement and support. The authors are thankful to
Dr. S.J. Surana, Principal, R.C. Patel Institute of Pharmaceutical
Education and Research, Shirpur, for providing necessary
facility for in silico study.
The authors have declared no conflict of interest.
Computational parameters
Distance mapping
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pharmacophore when compared with other standard anti-
convulsants. A molecular model was suggested on the basis of
molecular dynamics distance estimation with the help of ACD/
chem. sketch/3-D viewer 8.04 version program [32].
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