Ultrasound-assisted synthesis, anticonvulsant activity, and docking study of indole-appended thiazolidin-4-ones

Article abstract of DOI:10.1002/ardp.201400148

Two series of novel indolyl thiazolidin-4-one derivatives 4a-j and 5a-j were obtained by an ecofriendly synthetic protocol by treating a mixture of Schiff's bases (0.01 mol) with thioglycolic acid or thiolactic acid (0.01 mol) and anhydrous zinc chloride

Full text of DOI:10.1002/ardp.201400148

756
Arch. Pharm. Chem. Life Sci. 2014, 347, 756–767
Full Paper
Ultrasound-Assisted Synthesis, Anticonvulsant Activity, and
Docking Study of Indole-Appended Thiazolidin-4-ones
Anna Pratima G. Nikalje1, Sameer I. Shaikh1, Abhineet Mulay1, Firoz A. K. Khan1,
Jaiprakash N. Sangshetti1, and Shoaib Shaikh2
1
Department of Pharmaceutical Chemistry, Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus,
Rauza Bagh, Aurangabad, Maharashtra, India
Wockhardt Research Centre, D-4, Chikalthana MIDC, Aurangabad, Maharashtra, India
2
Two series of novel indolyl thiazolidin-4-one derivatives 4a–j and 5a–j were obtained by an ecofriendly
synthetic protocol by treating a mixture of Schiff’s bases (0.01 mol) with thioglycolic acid or thiolactic
acid (0.01 mol) and anhydrous zinc chloride in catalytic amount in DMF as solvent under ultrasound
irradiation, using an ultrasound synthesizer with a synthetic solid probe. The structures of the
1
synthesized compounds were confirmed by IR, H NMR, 13C NMR, MS, and elemental analysis. The
anticonvulsant activity and neurotoxicity of the newly synthesized compounds were established
by MES and sc-PTZ model and by rotarod test, respectively, in vivo using mouse models. The
actophotometer was used for the screening of behavioral activity. The compounds exhibited promising
anticonvulsant activity; especially, the compounds showed maximum protection in the MES model at a
dose of 100 mg/kg. Further, docking studies of the synthesized compounds were performed against the
sodium channel receptor and showed good binding interactions with the receptor. A computational
study was carried out to highlight the pharmacophore distance mapping, log p determination, and
pharmacokinetic parameters.
Keywords: Anticonvulsant activity / Computational study / Docking study / Indolyl thiazolidin-4-ones / Ultrasound
irradiation
Received: April 19, 2014; Revised: May 24, 2014; Accepted: May 26, 2014
DOI 10.1002/ardp.201400148
Introduction
new drug development in AEDs is facilitated by the concept of
“the new wave of research in the epileptics” [6].
The characteristic event in epilepsy is the seizure, which is a
condition that results from a temporary electrical disturbance
in the brain due to an imbalance between excitatory and
inhibitory neurotransmitters [1, 2]. According to an epidemi-
ological survey, epilepsy affects more than 50 million people
across the globe [3]. About one-third of the population
develops refractory epilepsy to currently available antiepilep-
tic drug therapy [4, 5]. The recent developments in antiepi-
leptic agents have become more progressive and are affording
many research opportunities in medicinal chemistry. The
The search for new antiepileptic drugs with one or more
selective activity and low toxicity profile continues to be an
area of investigation in medicinal chemistry. There are
different pharmacophoric models that are applied for a
rational drug design process for new anticonvulsant drugs [7–
9]. Based on the above concept of drug design, we have
designed and synthesized new 3-(substituted)-2-(1H-indol-3-yl)-
thiazolidin-4-one by ultrasound irradiation.
Many researchers had investigated indole and thiazolidi-
none as potential anticonvulsant agents. Indole-containing
compounds are known to have a wide range of pharmacolog-
ical activities [10]. Researchers have reported that the indole
derivatives can be used for the treatment of epilepsy [11–24].
Ralitoline (Fig. 1) is the compound which possesses a
thiazolidinone moiety and is found to be effective in
preclinical anticonvulsant evaluation. The available literature
Correspondence: Dr. Anna Pratima G. Nikalje, Department of Pharma-
ceutical Chemistry, Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria
Campus, Rauza Bagh, P.B. No. 33, Aurangabad, Maharashtra 431001,
India.
E-mail: annapratimanikalje@gmail.com
Fax: þ91 0240 2381129
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Arch. Pharm. Chem. Life Sci. 2014, 347, 756–767
Ultrasound-Assisted Indolyl Thiazolidinones as Anticonvulsants
757
Figure 1. Pharmacophoric pattern of well-known anticonvulsants
and model compound with essential structure elements.
reveals that the thiazolidinone nucleus is a good candidate for
anticonvulsant activity. The mechanism involved in anticon-
vulsant activity of thiazolidinones is inhibition of oxidation of
the substrates of the tricarboxylic acid cycle such as pyruvate,
a-ketoglutarate, and citrate, and b-hydroxybutyrate [25–33].
Indole coupled with thiazolidinone derivatives has been
previously synthesized by conventional methods and evaluated
for anti-HIV, anticancer, and anti-tubercular activities [34].
However, to the best of our knowledge such compounds have
never been synthesized by ultrasound irradiation and also
have not been evaluated for anticonvulsant activity. Based on
these reported literature and as a part of our continuous
investigation in this area [35, 36] we thought to synthesize
indole-appended phenylthiazolidin-4-one derivatives with
enhanced CNS activities, which could be effectively used for
the treatment of epilepsy. The ultrasound-promoted eco-
friendly synthetic strategy was selected so as to get the desired
products in better yield and in shorter reaction times [37]. All
the synthesized compounds comprised essential pharmaco-
phoric elements that were necessary for good anticonvulsant
activity as suggested by Unverferth et al. [38] (Fig. 1). The
computational studies such as molecular docking, log p
determination, and pharmacokinetic parameters (ADME) were
carried out and the results suggested that the compounds
could be exploited as good anticonvulsant agents.
Scheme 1. Scheme of synthesis.
were irradiated under ultrasound to afford corresponding
coupled indolyl thiazolidin-4-one derivatives. The purity of
the synthesized compounds was checked by thin-layer
chromatography on silica gel G precoated plates (Merck)
and visualization of the developed chromatogram was
performed by staining with iodine and melting points were
determined in open capillary tubes on a Buchi 530 melting
point apparatus and are uncorrected. All the synthesized
compounds were characterized by their physical data (Table 1)
and spectral data.
The IR spectra of the Schiff’s bases (C N) showed stretching
vibration in the region of 1620–1530 cmꢀ1. The absence of
broad band of Schiff’s bases (C N) in the IR spectrum of
indolyl thiazolidin-4-one confirms the formation of the title
compounds. In 1H NMR spectrum of series 4a–j, the two
protons of CH2 of thiazolidinone ring (axial and equatorial)
couple each other and split the signal in a double doublet in
the region 3.90–4.00 d ppm. In 1H NMR, spectrum of series of
derivatives 5a–j exhibited quartet at (3.65 d ppm) due to
Results and discussion
Chemistry
The reaction sequence for the synthesis of the title
compounds 3-(substituted)-2-(1H-indol-3-yl)thiazolidin-4-one
4a–j and 3-(substituted)-2-(1H-indol-3-yl)methylthiazolidin-4-
one 5a–j is outlined in Scheme 1. 3-Formylindole 2 was
synthesized by Vilsmeier–Haack reaction, and by refluxing 2
with various aromatic amines in ethanol indolyl Schiff’s bases
were obtained. In this reaction, activated molecular sieves 3 Å
were used to obtain a better yield of the product and for the
reaction rate enhancement. Finally, equimolar quantities of
Schiff’s bases and thioglycolic acid/thiolactic acid in DMF as
solvent and catalytic amount of anhydrous zinc chloride,
–
–
–
–
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A. P. G. Nikalje et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 756–767
Table 1. Physical data of final synthesized compounds.
Comp.
Ar
Mol. formula
Mol. wt
m.p. (°C)
Yield (%)
4a
4bꢁ
4cꢁ
4d
4eꢁ
4f
4g
4h
4i
Phenyl
C17H14N2OS
C17H13ClN2OS
C17H13ClN2OS
C17H12Cl2N2OS
C17H13BrN2OS
C18H16N2OS
294.37
328.81
328.81
363.26
373.26
308.39
322.42
324.39
310.37
326.43
308.39
342.84
342.84
377.28
387.29
322.42
336.45
338.42
324.39
340.46
220–222
188–190
125–127
229–230
114–116
153–154
102–104
201–202
133–135
98–100
240–244
156–158
134–136
171–173
229–231
126–128
193–195
189–190
140–142
110–112
65
52
60
56
43
69
56
49
58
62
48
54
64
57
62
59
56
62
53
71
4-Cl-Phenyl
3-Cl-Phenyl
2,4-Cl-Phenyl
4-Br-Phenyl
4-CH3-Phenyl
2,4-CH3-Phenyl
4-OCH3-Phenyl
2-OH-Phenyl
2-SH-Phenyl
Phenyl
4-Cl-Phenyl
3-Cl-Phenyl
2,4-Cl-Phenyl
4-Br-Phenyl
4-CH3-Phenyl
2,4-CH3-Phenyl
4-OCH3-Phenyl
2-OH-Phenyl
2-SH-Phenyl
C19H18N2OS
C18H16N2O2S
C17H14N2O2S
C17H14N2OS2
C18H16N2OS
C18H15ClN2OS
C18H15ClN2OS
C18H14Cl2N2OS
C18H15BrN2OS
C19H18N2OS
4j
5a
5bꢁ
5cꢁ
5d
5eꢁ
5f
5g
5h
5i
C20H20N2OS
C19H18N2O2S
C18H16N2O2S
C18H16N2OS2
5j
Ethanol is used for re-crystallization; mobile phase for TLC is ethylacetate/n-hexane (7:3) and benzene/methanolꢁ (6:4).
neighboring methyl group on thiazolidinone ring and –CH of
thiazolidinone ring splits the methyl protons in a doublet at
1.38 d ppm, and in both the series, the presence of a sharp
singlet at 6.44 d ppm due to –CH of thiazolidinone ring
confirms the formation of the title compounds.
The reactions were performed using ultrasound synthesizer
with solid synthetic probe at a temperature of 90°C and at a
frequency of 20 Hz. All the products were obtained in 60- to
90-min time, whereas the conventional synthesis of thiazo-
lidinone using Dean-Stark apparatus requires 14–16 h for
completion of reaction [39]. The conventional method suffers
a major drawback as it involves use of benzene, which is a
carcinogenic, harmful solvent. Therefore, the present meth-
odology used for the synthesis of 3-(substituted)-2-(1H-indol-3-
yl)thiazolidin-4-one 4a–j and 3-(substituted)-2-(1H-indol-3-yl)-
methylthiazolidin-4-one 5a–j is very efficient, convenient, and
ecofriendly.
intervals. The compounds 5a, 5c, 5e, 5f, 5h, and 5i showed
protection at 0.5 h while compounds 5a, 5d, 5f, 5g, and 5i
showed protection at 4 h.
In sc-PTZ test (Table 2), among synthesized compounds in a
first series, compounds 4c, 4d, 4f, 4g, 4i, and 4j showed
protection at 0.5 h and 4f and 4i showed protection at 4 h
and the dose 100 mg/kg. The compounds 4f and 4i showed
protection in sc-PTZ test in both time intervals. Many
compounds of the series 5a–j were also found to be active
in sc-PTZ test. The compounds 5b, 5c, 5e, 5f, and 5h have
shown protection at 0.5 h and compounds 5c, 5e, 5i, and 5j
showed protection at 4 h. The compounds 5c and 5e have
shown protection at both time intervals at the dose of
100 mg/kg.
Neurotoxicity screening
In neurotoxicity screening, the compounds 4c, 4e, and 4j were
found to be nontoxic at a dose of 100 mg/kg while compounds
4d, 4f, and 4h were found to be toxic at the same dose after 4 h
(Table 2). In the series of compounds 5a–j, the compounds 5c,
5f, 5h, and 5i were non- toxic and the compounds 5b, 5e, and
5i were found to be toxic at the dose of 100 mg/kg.
Anticonvulsant activity
All the synthesized compounds were evaluated for their
anticonvulsant activity by MES and sc-PTZ model and have
shown best protection against MES test (Table 2). In MES test,
the anticonvulsant activity of the newly synthesized com-
pounds was carried out at 0.5 and 4 h at the dose of 100 mg/kg.
The compounds 4c, 4e, and 4i have shown best protection at
both time intervals. In MES test, the compounds 4b, 4c, 4e, 4f,
4i, and 4j showed protection at 0.5 h, while compounds 4a, 4c,
4e, 4g, and 4i showed protection at 4 h. In other series of 5a–j,
compounds 5f and 5i showed protection at both time
Behavioral activity
From the behavioral activity of synthesized compounds using
actophotometer, the compounds 4a, 4e, 4f, 4g, 4h, 4j, and 5c,
5d, 5h, 5i, 5j showed no behavioral despair effect when
compared to diazepam at 0.5 h. The compounds 4a, 4d and 5c,
5h, and 5j showed no behavioral despair effect when
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Arch. Pharm. Chem. Life Sci. 2014, 347, 756–767
Ultrasound-Assisted Indolyl Thiazolidinones as Anticonvulsants
759
Table 2. Anticonvulsant and neurotoxicity screening of
Table 3. Behavioral study of compounds using actophotometer.
compounds.
Activity score
Post-treatmenta)
Neurotoxicity
Control
(24 h before)
MES screen
sc PTZ screen
screen
Comp.
0.5 h
4 h
Comp.
0.5 h
4 h
0.5 h
4 h
4 h
4a
4b
4c
4d
4e
4f
4g
4h
4i
178.41 ꢂ 5.192
129.79 ꢂ 4.294
104.82 ꢂ 3.942
184.61 ꢂ 10.628
101.59 ꢂ 6.547
117.44 ꢂ 8.060
123.22 ꢂ 5.380
127.63 ꢂ 5.60
150.60 ꢂ 8.453
115.18 ꢂ 3.736
120.41 ꢂ 2.731
102.63 ꢂ 3.076
170.09 ꢂ 4.722
136.38 ꢂ 5.409
107.79 ꢂ 8.285
126.20 ꢂ 4.259
103.07 ꢂ 4.452
142.25 ꢂ 8.381
172.81 ꢂ 3.216
168.12 ꢂ 7.087
142.78 ꢂ 3.852ns 153.81 ꢂ 6.094
39.80 ꢂ 4.259
41.39 ꢂ 3.458
68.58 ꢂ 5.183
97.32 ꢂ 4.84ns
111.82 ꢂ 4.663
118.79 ꢂ 4.176
63.12 ꢂ 2.835
56.79 ꢂ 4.042
171.61 ꢂ 3.473
85.59 ꢂ 3.750
62.42 ꢂ 3.219
78.02 ꢂ 6.066
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
5a
–
100
–
–
–
–
X
X
100
100
–
–
100
–
100
100
–
Nontoxic
Toxic
Nontoxic
Toxic
X
Toxic
Nontoxic
X
–
100
100
–
100
–
–
100
100
–
100
–
92.75 ꢂ 4.913ns 120.81 ꢂ 5.152ns
100
–
47.12 ꢂ 1.789
63.09 ꢂ 3.633
79.58 ꢂ 4.517
–
–
4j
99.58 ꢂ 5.662ns
100
100
100
–
100
–
100
100
–
100
–
5a
5b
5c
5d
5e
5f
5g
5h
5i
84.40 ꢂ 4.479ns 116.14 ꢂ 321
78.18 ꢂ 2.596ns
133.78 ꢂ 3.201
110.34 ꢂ 4.632
83.12 ꢂ 4.461
64.36 ꢂ 2.182
147.17 ꢂ 4.283
117.59 ꢂ 2.874
73.55 ꢂ 3.544
–
–
X
5b
5c
5d
5e
100
–
100
100
–
–
Toxic
Nontoxic
X
Toxic
Nontoxic
X
Nontoxic
Nontoxic
Toxic
X
100
–
100
–
100
–
78.40 ꢂ 6.242ns 101.02 ꢂ 2.429
100
100
–
100
100
–
100
–
73.08 ꢂ 4.069ns
121.60 ꢂ 4.578
144.01 ꢂ 3.286
132.11 ꢂ 2.569
90.78 ꢂ 3.942
81.51 ꢂ 3.458
125.34 ꢂ 3.487
122.43 ꢂ 3.400
145.15 ꢂ 2.267
122.72 ꢂ 2.596
5f
100
100
–
5g
5h
5i
–
100
100
–
100
–
–
5j
100
–
100
100
X
Diazepamb) 214.60 ꢂ 2.839
5j
–
Phenytoin
100
100
X
a)
Each value represents the mean ꢂ SEM significantly different
from the control at p < 0.05; ns denotes not significant at p < 0.05
(Student’s t-test); locomotor activity score was measured for
10 min.
Dose 100 mg/kg of the compound was administered and the
protection and neurotoxicity were measured after 0.5 and 4 h.
The figures indicate the minimal dose required to cause
protection or neurotoxicity in 50% or more of the animals. The
dash (ꢀ) indicates the absence of anticonvulsant activity or
neurotoxicity. (X) denotes not tested.
b)
The compound was tested at dose level of 4 mg/kg (i.p.).
the sodium channel receptor. The various hydrophobic
interactions occurred between the thiazolidinone ring and
active side chain of LYS1495, LYS1496, TYR1498, ASN1499,
LYS1502, LYS1503, LEU1504, GLY1505, and SER1506. The
amino acid residues such as LYS1495, GLY1505, and SER1506
had formed hydrogen bonds with –NH group of indole
nucleus. The carbonyl group of thiazolidinone ring (4b, 4e,
4f, and 5e) and sulfur atom of thiazolidinone ring (4i and 5j)
had formed the hydrogen bonding with SER1506. The
substituents such as –CH3 and –OCH3 at 4th position of
phenyl ring showed hyrdrophobic interactions with amino
acid residues such as LYS1496, LYS1502, and LEU1504, thus
suggesting that the introduction of these lipophilic groups at
4th position of phenyl ring would show good interactions
with sodium channel receptors. The interactions of most
active compounds 4e, 4i, 5e, and 5f from both the series are
shown in Fig. 2 and revealed that the amino acids had formed
good hydrophobic and van der Waals interactions. On the
basis of this activity data (Table 2) and the docking results
(Table 4), it was found that the synthesized derivatives of both
the series 4a–j and 5a–j have potential to inhibit sodium
channel receptors.
compared to diazepam at 4 h (Table 3). All the other
compounds were found to decrease behavioral activity of
the animals at 100 mg/kg compared to diazepam.
Computational parameters
The docking study
In the present study, the synthesized derivatives were more
effective in the MES model than in sc-PTZ model, and the MES
test is known to be sensitive to sodium channel inhibitors,
which suggests that the synthesized compounds might be
inhibiting voltage-gated ion channels (particularly sodium
channels). Based on these results, we docked the compounds
against sodium channel receptor (PDB ID: 1BYY) [40] to
understand the binding interactions. The docking calculation
and hydrogen bond and hydrophobic bond interactions are
presented in Table 4. The interaction energy of the
compounds 4a–j and 5a–j and their anticonvulsant activity
(MES test) showed the corresponding results. The docking
results indicated that the thiazolidinone core of these
compounds was held in the active pocket by combination
of various hydrophobic and van der Waals interactions with
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A. P. G. Nikalje et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 756–767
Table 4. Molecular docking statistics of indolyl-thiazolidinones.
Binding energy
Entry
(kcal/mol)
Hydrogen bonds
Hydrophobic bonds
4a
4b
ꢀ55.35
ꢀ54.39
SER1506-NH of indole
ASN1499 and LEU1504-CH of thiazolidinone; LEU1504-CH2 of thiazolidinone
TYR1498, ASN1499, and LYS1502-CH of thiazolidinone; LYS1502-CH2 of
thiazolidinone
–
SER1506-O C of thiazolidinone
–
4c
4d
4e
4f
ꢀ56.72
ꢀ55.20
ꢀ70.64
ꢀ57.90
SER1506-NH of indole
LYS1495-NH of indole
TYR1498, ASN1499, and LYS1502-CH of thiazolidinone; LYS1502, LEU1504,
GLY1505, and SER1506-CH2 of thiazolidinone
ASN1499-CH of thiazolidinone; ASN1499, LYS1502, LEU1504, and SER1506-CH2
of thiazolidinone
TYR1498, ASN1499, and LYS1502-CH of thiazolidinone; TYR1498 and
LYS1502-CH2 of thiazolidinone
TYR1498, ASN1499, and LYS1502-CH of thiazolidinone; LYS1502-CH2 of
thiazolidinone; ASN1499 and LYS1502-CH3 of phenyl
ASN1499 and LEU1504-CH of thiazolidinone; LEU1504-CH2 of thiazolidinone
TYR1498, ASN1499, and LYS1502-CH of thiazolidinone; LYS1502, LEU1504,
GLY1505, and SER1506-CH2 of thiazolidinone; LYS1495 and LYS1496-CH3O of
phenyl
–
SER1506-O C of thiazolidinone
–
–
SER1506-O C of thiazolidinone
–
4g
4h
ꢀ58.18
ꢀ54.55
SER1506-NH of indole
–
4i
ꢀ64.01
ꢀ53.17
ꢀ54.74
ꢀ61.22
ꢀ56.79
ꢀ52.28
ꢀ65.95
ꢀ75.70
–
TYR1498 and SER1506-CH of thiazolidinone; TYR1498 and LYS1502-CH2 of
thiazolidinone
ASN1499-CH of thiazolidinone; ASN1499, LYS1502, LEU1504, GLY1505,
SER1506-CH2 of thiazolidinone
4j
LYS1495-NH of indole
5a
5b
5c
5d
5e
5f
GLY1505, and SER1506-NH of indole ASN1499 and LEU1505-CH of thiazolidinone; LEU1505-CH(CH)3 of
thiazolidinone; LEU1505-CH3 of thiazolidinone
–
–
–
ASN1499-CH of thiazolidinone; ASN1499, LEU1504, and SER1506-CH(CH)3 of
thiazolidinone; ASN1499 and LEU1504-CH3 of thiazolidinone
TYR1498 and SER1506-CH of thiazolidinone; TYR1498 and LYS1502-CH(CH)3 of
thiazolidinone; LYS1502-CH3 of thiazolidinone
ASN1499 and LEU1504-CH(CH)3 of thiazolidinone; LEU1504-CH3 of
thiazolidinone
TYR1498, ASN1499, and LYS1502-CH of thiazolidinone; TYR1498 and
LYS1502-CH(CH)3 of thiazolidinone; LYS1502-CH3 of thiazolidinone
ASN1499 and LEU1504-CH of thiazolidinone; LEU1504-CH(CH)3 of
thiazolidinone; LEU1504-CH3 of thiazolidinone
–
–
SER1506-O C of thiazolidinone
SER1506-NH of indole
5g
5h
ꢀ53.36
ꢀ51.20
SER1506-NH of indole
SER1506-NH of indole
ASN1499-CH of thiazolidinone; ASN1499 and LEU1504-CH3 of phenyl
ASN1499 and LEU1504-CH of thiazolidinone; ASN1499 and LEU1504-CH(CH)3
of thiazolidinone; LEU1504-CH3 of thiazolidinone
5i
5j
ꢀ65.58
ꢀ47.62
SER1506-S of thiazolidinone
SER1506-S of thiazolidinone
TYR1498-CH of thiazolidinone; TYR1498 and LYS1502-CH(CH)3 of
thiazolidinone; LYS1502-CH3 of thiazolidinone
TYR1498, ASN1499, and LYS1502-CH of thiazolidinone; ASN1499, LYS1505,
LYS1503, LEU1504, GLY1505, and SER1506-CH(CH)3 of thiazolidinone;
ASN1499, LYS1505, LYS1503, LEU1504, GLY1505, and SER1506-CH3 of
thiazolidinone
(ꢀ) Indicates no hydrogen bond interactions.
Distance mapping
CHARMm force fields and MM3 parametrization. Table 5
The present work involves the correlation of the structural
requirement of well-known and structurally different
anticonvulsant compounds with the title compounds. A
hydrophobic unit (R), an electron donor (D) group, and a
hydrogen donor/acceptor (HBD) unit are the essential
structural requirements that could be responsible for an
interaction with the active site of voltage-gated sodium
channels. In this study, we selected well-known and
structurally different compounds having anticonvulsant
activity, i.e., phenytoin, carbamazepine, lamotrigine, and
diazepam. The pharmacophore distance estimation was done
by mechanics calculation with the force fields based on
shows the distances between the various groups that are
essential for anticonvulsant activity. Herein, we evaluated the
synthesized compounds whether they satisfy the required
conditions of the derived pharmacophore model. Our
analyses of distance relationship showed that the synthesized
compounds fulfill the essential demands of pharmacophoric
model when they are compared to the average distance
requirement.
log p determination
The compounds with optimum lipophilicity, i.e., having log
p values near 2.0, pass blood–brain barrier (BBB) and can have
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Arch. Pharm. Chem. Life Sci. 2014, 347, 756–767
Ultrasound-Assisted Indolyl Thiazolidinones as Anticonvulsants
761
Figure 2. Docking images of compounds 4e, 4i, 5e, and 5f.
an effect on central nervous system. Here, we tried to correlate
the anticonvulsant activity of synthesized compounds with
calculated log p. The experimental log p values were deter-
mined by using octanol-phosphate buffer method. The
data are presented in Table 6. As observed some of
the experimental values were in good agreement with the
theoretical values.
parameters, it can be observed that all title compounds
exhibited a great %ABS ranging from 89.56 to 96.54% (Table 7).
From the synthesized compounds, only one compound 5d
violated only one of the Lipinski’s parameters. None of the
other compounds violated Lipinski’s parameters, making
them potentially promising agents for epilepsy therapy.
Structure–activity relationship (SAR)
Prediction of ADME properties
In this study, two series of indolyl phenylthiazolidin-4-ones
derivatives were investigated to determine the better activity
of pharmacophoric groups. These pharmacophoric groups
were selected from available literature and computational
study. The compounds having electron-donating lipophilic
groups such as –CH3, –OCH3, and polar –OH group at para
position of the phenyl ring were found to be effective
anticonvulsants. From the literature [41], bromide ion is
found to show an inhibitory effect on CNS; among the
A computational study for prediction of ADME properties of
the title compounds was performed. Topological polar surface
area (TPSA), i.e., surface belonging to polar atoms, is a
descriptor that was shown to correlate well with passive
molecular transport through membranes and, therefore,
allows prediction of transport properties of drugs in the
intestines and blood–brain barrier crossing. The percentage of
absorption (% ABS) was calculated using TPSA. From all these
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762
A. P. G. Nikalje et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 756–767
Table 5. Distance range between the essential structure Conclusion
elements R, D, and HBD.
Two series of indole-appended thiazolidinones were designed
and synthesized under ultrasound irradiation in good yield
and at a faster reaction rate. The synthesized derivatives were
evaluated for their anticonvulsant activity. The derivatives
exhibited promising activity in MES and sc-PTZ test. The
rotarod test was used for neurotoxicity evaluation and shows
significant results. The various computational parameters
studied include calculation of distance between pharmaco-
phores, prediction of ADME properties; logp calculation, and
docking studies. Among the two series of compounds
synthesized, the compounds having electron-donating lipo-
philic groups such as –CH3, OCH3, and polar electron-donating
–OH group exhibited significant anticonvulsant activity. The
docking study reveals that the compounds have good binding
interactions with the active site residues of sodium channel
receptor. The docking results indicated that the thiazolidinone
core of these compounds was held in the active pocket by
combination of hydrogen bonding and various hydrophobic,
van der Waals interactions with the sodium channel receptor.
Thus, the synthesized derivatives 3-(substituted)-2-(1H-indol-
3-yl)thiazolidin-4-one 4a–j and 3-(substituted)-2-(1H-indol-3-yl)-
methylthiazolidin-4-one 5a–j have been obtained in good
yield in an eco-friendly synthetic protocol, have exhibited
potential anticonvulsant activity, and can be developed as a
lead molecule.
Compounds
R–HBD
R–D
D–HBD
Phenytoin
3.58
6.44
5.09
4.79
5.08
3.77
3.41
4.87
4.82
4.65
2.21
4.45
4.06
1.49
5.20
Lamotrigine
Carbamazepine
Diazepam
Lead compounds
synthesized compounds, the derivative with p-bromo substit-
uent has shown significant anticonvulsant activity and
longest duration of action. MES test is known to be sensitive
to sodium channel inhibitors; from the data analysis and
docking study of the synthesized compounds, it was found
that the compounds act by inhibiting the sodium channels.
Table 6. Experimental and theoretical log p values of compounds.
Experimental
Experimental
Theoretical log p
(milog pa))
Compounds
log p
Chemistry
All reagents and solvents were used as obtained from the supplier
or recrystallized/redistilled unless otherwise noted. The ultrasound
sonicator, Sonics Vibra-cell (Model No. VCX 500), with synthetic
probe was used for synthesis of final title compounds. The progress
of the reaction was monitored by TLC, silica gel-G (Merck) coated
aluminum plates, visualized by iodine vapor. Infrared (IR) and
nuclear magnetic resonance (1H NMR and 13C NMR) spectra of the
synthesized compounds were recorded on JASCO FTIR (PS 4000)
using KBr pellets and Bruker Avance II (400 MHz) instruments,
respectively. 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 FLASHEA112 analyzer
and all analyses were consistent with theoretical values (within
ꢂ0.5%) unless indicated. The mass spectra were recorded on a
Waters MicroMass ZQ 2000 spectrometer.
Rule
4a
4b
4c
4d
4e
4f
4g
4h
4i
–
ꢃ5
3.12
3.94
3.84
4.25
4.01
3.23
3.75
2.91
2.85
3.08
3.15
4.24
3.89
4.92
4.48
3.86
3.81
3.19
3.65
3.75
3.467
4.145
4.121
4.751
4.276
3.916
4.292
3.524
3.2
4j
3.648
3.830
4.508
4.484
5.114
4.639
4.279
4.655
3.887
3.563
4.011
5a
5b
5c
5d
5e
5f
5g
5h
5i
General procedure for the synthesis of Schiff’s base
3-Formylindole 2 was synthesized from indole by Vilsmeier–
Haack reaction [42] and indolyl Schiff’s bases were obtained by
refluxing compound 2 with various substituted aromatic amines
in absolute ethanol as solvent [43]. Activated molecular sieves 3 Å
were employed in this reaction for the removal of water formed in
the reaction [44], which enhanced the yield and also enhanced
the reaction rate.
5j
a)
milog p, logarithm of compound partition coefficient between
n-octanol and water calculated as per Molinspiration online
property toolkit.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 756–767
Ultrasound-Assisted Indolyl Thiazolidinones as Anticonvulsants
763
Table 7. Pharmacokinetic parameters important for good oral bioavailability of the compounds.
TPSA
n-OHNH
donors
n-ON
acceptors
Lipinski’s
violations
Comp.
%ABS
(A2)
n-ROTB
MW
MV
Rule
4a
4b
4c
4d
4e
4f
4g
4h
4i
–
–
–
2
2
2
2
2
2
2
3
2
2
2
2
2
2
2
2
2
3
2
2
<500
294.37
–
<5
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1
1
1
2
1
<10
3
ꢃ1
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
0
96.54
96.54
96.54
96.54
96.54
96.54
96.54
93.35
89.56
96.54
96.54
96.54
96.54
96.54
96.54
96.54
96.54
93.35
89.56
96.54
36.1
36.1
36.1
36.1
36.1
36.1
36.1
45.33
56.32
36.1
36.1
36.1
36.1
36.1
36.1
36.1
36.1
45.33
56.32
36.1
257.11
270.64
270.64
284.18
274.99
273.69
290.23
282.65
265.13
274.77
273.70
287.23
287.23
300.77
291.58
290.26
306.46
299.24
281.71
291.36
328.81
328.81
363.26
373.26
308.39
322.42
324.39
310.37
326.43
308.39
342.84
342.84
377.28
387.29
322.42
336.45
338.42
324.39
340.46
3
3
3
3
3
3
4
4
3
3
3
3
3
3
3
3
4j
5a
5b
5c
5d
5e
5f
5g
5h
5i
4
4
3
5j
%ABS, percentage of absorption; TPSA, topological polar surface area; n-ROTB, number of rotatable bonds; MW, molecular weight; MV,
molecular volume; n-OHNH, number of hydrogen bond donors; n-ON, number of hydrogen bond acceptors.
General procedure for the synthesis of indolyl substituted
thiazolidinones 4a–j and 5a–j
(m, 8H, Ar ring), 7.20 (s, 1H, C2 of indole ring), 8.85 (s, 1H, NH of
indole); 13C NMR (100 MHz CDCl3, ppm): 33.2, 70.2, 111.1, 112.7,
118.1, 119.4, 121.7, 123.1, 126.1, 126.4, 129.7, 129.9, 132.8, 137.7,
140.7, 171.1, MS: m/z ¼ 328.7 (Mþ), 329.4 (Mþ1). Anal. calcd. for
In an 25 mL beaker, the mixture of Schiff’s bases (0.01 mol),
thioglycolic acid or thiolactic acid (0.01 mol), and anhydrous zinc
chloride in catalytic amount was taken in DMF (15 mL), as a
solvent. The reaction mixture was sonicated for about 60–90 min
at 90°C and at a frequency of 20 kHz using synthetic probe.
Completion of the reaction was monitored by TLC. After
completion of reaction, the mixture was poured into ice-cold
water. The solid product formed was filtered, dried, and
recrystallized from ethanol. The structures of the synthesized
final compounds of the series 4a–j and 5a–j were confirmed by the
spectral data and elemental analysis.
C
17H13ClN2OS: C, 62.10; H, 3.98; N, 8.52. Found: C, 62.13; H, 3.96;
N, 8.50.
3-(3-Chlorophenyl)-2-(1H-indol-3-yl)thiazolidin-4-one (4c)
IR (KBr, nmax, cmꢀ1): 3441–3285 (N–H indole), 3021 (C–H of aromatic
–
ring), 1770 (C O of thiazolidinone), 771 (C–S–C of thiazolidinone);
–
1H NMR (CDCl3, 400 MHz): 3.53–4.00 (dd, 2H, CH2 of thiazolidinone),
6.13 (s, 1H, CH of thiazolidinone), 6.90 (s, 1H, C2 of indole ring),
7.01–7.69 (m, 8H, Ar ring), 9.08 (s, 1H, NH of indole); 13C NMR
(100MHz CDCl3, ppm): 33.2, 70.1, 111.1, 112.5, 118.4, 119.8, 121.5,
123.1, 127.7, 130.6, 134.3, 135.6, 136.4, 144.6, 171.1, MS: m/z ¼ 328.7
(Mþ), 329.4 (Mþ1). Anal. calcd. for C17H13ClN2OS: C, 62.10; H, 3.98;
N, 8.52. Found: C, 62.09; H, 3.99; N, 8.50.
2-(1H-Indol-3-yl)-3-phenylthiazolidin-4-one (4a)
IR (KBr, nmax, cmꢀ1): 3425–3279 (N–H indole), 3042 (C–H of
–
aromatic ring), 1762 (C O of thiazolidinone), 784 (C–S–C of
–
thiazolidinone); 1H NMR (CDCl3, 400 MHz): 3.56–4.10 (dd, 2H, CH2
of thiazolidinone), 6.01 (s, 1H, CH of thiazolidinone), 6.99–7.76
(m, 9H, Ar ring), 7.09 (s, 1H, C2 of indole ring), 8.26 (s, 1H, NH of
indole); 13C NMR (100 MHz CDCl3, ppm): 33.6, 70.8, 111.2, 112.2,
118.6, 119.8, 121.7, 123.8, 127.4, 127.6, 128.1, 128.9, 136.7, 141.7,
171.6, MS: m/z ¼ 294.2 (Mþ). Anal. calcd. for C17H14N2OS: C, 69.36;
H, 4.79; N, 9.52. Found: C, 69.35; H, 4.81; N, 9.49.
3-(2,4-Dichlorophenyl)-2-(1H-indol-3-yl)thiazolidin-4-one
(4d)
IR (KBr, nmax, cmꢀ1): 3421–3265 (N–H indole), 3030 (C–H of
–
aromatic ring), 1754 (C O of thiazolidinone), 769 (C–S–C of
–
thiazolidinone); 1H NMR (CDCl3, 400 MHz): 3.52–4.23 (dd, 2H,
CH2 of thiazolidinone), 5.96 (s, 1H, CH of thiazolidinone), 6.86
(s, 1H, C2 of indole ring), 7.16–7.53 (m, 7H, Ar ring), 8.03 (s, 1H,
NH of indole); 13C NMR (100 MHz CDCl3, ppm): 33.5, 70.8, 111.7,
112.2, 118.4, 119.3, 121.7, 123.5, 127.7, 131.4, 131.6, 136.6,
138.4, 144.6, 172.1, MS: m/z ¼ 363.3 (Mþ1). Anal. calcd. for
C17H12Cl2N2OS: C, 56.21; H, 3.33; N, 7.71. Found: C, 56.23;
H, 3.32; N, 7.69.
3-(4-Chlorophenyl)-2-(1H-indol-3-yl)thiazolidin-4-one (4b)
IR (KBr, nmax, cmꢀ1): 3435–3262 (N–H indole), 3053 (C–H of
–
aromatic ring), 1752 (C O of thiazolidinone), 775 (C–S–C of
–
thiazolidinone); 1H NMR (CDCl3, 400 MHz): 3.85–4.02 (dd, 2H, CH2
of thiazolidinone), 6.24 (s, 1H, CH of thiazolidinone), 7.12–7.52
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A. P. G. Nikalje et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 756–767
3-(4-Bromophenyl)-2-(1H-indol-3-yl)thiazolidin-4-one (4e)
2-(1H-Indol-3-yl)-3-(2-mercaptophenyl)thiazolidin-4-one
IR (KBr, nmax, cmꢀ1): 3425–3252 (N–H indole), 3047 (C–H of
(4j)
IR (KBr, nmax, cmꢀ1): 3425–3279 (N–H indole), 3035 (C–H of
–
aromatic ring), 1724 (C O of thiazolidinone), 746 (C–S–C of
–
thiazolidinone); 1H NMR (CDCl3, 400 MHz): 3.82–3.99 (dd, 2H,
CH2 of thiazolidinone), 6.18 (s, 1H, CH of thiazolidinone),
7.10 (s, 1H, C2 of indole ring), 7.20–7.63 (m, 8H, Ar ring), 8.12
(s, 1H, NH of indole); 13C NMR (100 MHz CDCl3, ppm): 33.1, 70.9,
111.7, 112.1, 118.1, 119.2, 121.4, 123.5, 127.2, 131.4, 131.1, 136.2,
136.3, 140.4, 172.3, MS: m/z ¼ 373.6 (Mþ1). Anal. calcd. for
C17H13BrN2OS: C, 54.70; H, 3.51; N, 7.50. Found: C, 54.72; H, 3.49;
N, 7.51.
–
aromatic ring), 1736 (C O of thiazolidinone), 789 (C–S–C of
–
thiazolidinone); 1H NMR (CDCl3, 400 MHz): 3.23–3.99 (dd, 2H, CH2
of thiazolidinone), 3.51 (s, 1H, –SH), 5.99 (s, 1H, CH of
thiazolidinone), 7.15–7.89 (m, 8H, Ar ring), 7.42 (s, 1H, C2 of
indole ring), 9.12 (s, 1H, NH of indole); 13C NMR (100 MHz CDCl3,
ppm): 33.2, 70.5, 111.4, 112.8, 118.5, 119.8, 121.1, 123.5, 124.5,
124.8, 125.5, 125.8, 127.7, 136.5, 138.1, 171.7, MS: m/z ¼ 326.4
(Mþ1). Anal. calcd. for C17H14N2OS2: C, 62.55; H, 4.32; N, 8.58.
Found: C, 62.57; H, 4.35; N, 8.60.
2-(1H-Indol-3-yl)-3-p-tolylthiazolidin-4-one (4f)
IR (KBr, nmax, cmꢀ1): 3445–3285 (N–H indole), 3032 (C–H of
2-(1H-Indol-3-yl)-5-methyl-3-phenylthiazolidin-4-one (5a)
–
IR (KBr, nmax, cmꢀ1): 3430–3285 (N–H indole), 3039 (C–H of
aromatic ring), 1724 (C O of thiazolidinone), 768 (C–S–C of
–
thiazolidinone); 1H NMR (CDCl3, 400 MHz): 2.13 (s, 3H, methyl of
Ar ring), 3.85–4.02 (dd, 2H, CH2 of thiazolidinone), 6.43 (s, 1H, CH
of thiazolidinone), 7.11–7.72 (m, 8H, Ar ring), 7.24 (s, 1H, C2 of
indole ring), 7.98 (s, 1H, NH of indole); 13C NMR (100 MHz CDCl3,
ppm): 21.7, 33.7, 70.4, 111.1, 112.1, 118.4, 119.4, 121.4, 123.5,
127.2, 129.4, 133.1, 136.2, 138.3, 171.9, MS: m/z ¼ 308.6 (Mþ1).
Anal. calcd. for C18H16N2OS: C, 70.10; H, 5.23; N, 9.08. Found: C,
70.13; H, 5.22; N, 9.10.
–
aromatic ring), 2950 (C–H of methyl), 1725 (C O of thiazolidi-
–
1
none), 785 (C–S–C of thiazolidinone); H NMR (CDCl3, 400 MHz):
1.15 (d, 3H, methyl group attached to thiazolidinone), 3.78 (q, 1H,
–CH– of thiazolidinone bearing methyl group), 6.32 (s, 1H, CH of
–
thiazolidinone), 7.10–7.81 (m, 9H, Ar ring), 7.23 (s, 1H, CH of
–
indole ring), 9.02 (s, 1H, NH of indole); 13C NMR (100 MHz CDCl3,
ppm): 20.2, 42.5, 68.5, 111.4, 112.8, 118.5, 119.8, 121.1, 123.5,
124.5, 124.8, 125.5, 125.8, 127.7, 136.5, 138.1, 171.7, MS:
m/z ¼ 308.4 (Mþ1). Anal. calcd. for C18H16N2OS: C, 70.10; H,
5.23; N, 9.08. Found: C, 70.13; H, 5.25; N, 9.10.
3-(3,5-Dimethylphenyl)-2-(1H-indol-3-yl)thiazolidin-4-one
(4g)
IR (KBr, nmax, cmꢀ1): 3421–3285 (N–H indole), 3025 (C–H of
3-(4-Chlorophenyl)-2-(1H-indol-3-yl)-5-methylthiazolidin-
–
aromatic ring), 1758 (C O of thiazolidinone), 785 (C–S–C of
–
4-one (5b)
thiazolidinone); 1H NMR (CDCl3, 400 MHz): 2.29 (s, 6H, methyl of
Ar ring), 3.42–4.10 (dd, 2H, CH2 of thiazolidinone), 6.05 (s, 1H, CH
of thiazolidinone), 7.25–7.86 (m, 7H, Ar ring), 7.42 (s, 1H, C2 of
indole ring), 8.23 (s, 1H, NH of indole); 13C NMR (100 MHz CDCl3,
ppm): 21.2, 33.2, 70.4, 111.8, 112.3, 118.4, 118.6, 119.4, 121.5, 123,
126.2, 136.5, 138.1, 141.2, 171.2, MS: m/z ¼ 322.2 (Mþ1). Anal.
calcd. for C19H18N2OS: C, 70.78; H, 5.63; N, 8.69. Found: C, 70.80;
H, 5.61; N, 8.71.
IR (KBr, nmax, cmꢀ1): 3430–3285 (N–H indole), 3039 (C–H of aromatic
–
ring), 2950 (C–H of methyl), 1725 (C O of thiazolidinone), 785 (C–S–C
–
of thiazolidinone); 1H NMR (CDCl3, 400MHz): 1.53 (d, 3H, methyl
group attached to thiazolidinone), 3.34 (q, 1H, –CH– of thiazolidi-
none bearing methyl group), 6.82 (s, 1H, CH of thiazolidinone), 7.13–
7.53 (m, 8H, Ar ring), 7.15 (s, 1H, C2 of indole ring), 9.23 (s, 1H, NH of
indole); 13C NMR (100 MHz CDCl3, ppm): 20.3, 42.4, 68.8, 111.3, 112.7,
118.8, 119.1, 121, 123.2, 125.6, 127.5, 129.5, 133.5, 136.5, 139.8, 174.7,
MS: m/z¼ 342.5 (Mþ1). Anal. calcd. for C18H15ClN2OS, C, 63.06; H,
4.41; N, 8.17. Found: C, 63.08; H, 4.42; N, 8.15.
2-(1H-Indol-3-yl)-3-(4-methoxyphenyl)thiazolidin-4-one (4h)
IR (KBr, nmax, cmꢀ1): 3442–3290 (N–H indole), 3059 (C–H of
–
aromatic ring), 1745 (C O of thiazolidinone), 789 (C–S–C of
–
3-(3-Chlorophenyl)-2-(1H-indol-3-yl)-5-methylthiazolidin-
thiazolidinone); 1H NMR (CDCl3, 400 MHz): 2.29 (s, 3H, methyl of
Ar ring), 3.42–4.10 (dd, 2H, CH2 of thiazolidinone), 6.05 (s, 1H, CH
of thiazolidinone), 7.25–7.86 (m, 8H, Ar ring), 7.42 (s, 1H, C2 of
indole ring), 8.23 (s, 1H, NH of indole); 13C NMR (100 MHz CDCl3,
ppm): 33.2, 55.6, 70, 111.5, 112.3, 114.6, 118.9, 119.4, 121.6, 123,
127.2, 134.5, 158.6, 171.2, MS: m/z ¼ 324.2 (Mþ1). Anal. calcd. for
C18H16N2O2S: C, 66.64; H, 4.97; N, 8.64. Found: C, 66.62; H, 4.95;
N, 8.66.
4-one (5c)
IR (KBr, nmax, cmꢀ1): 3441–3295 (N–H indole), 3030 (C–H of
–
aromatic ring), 2950 (C–H of methyl), 1725 (C O of thiazolidi-
–
1
none), 785 (C–S–C of thiazolidinone); H NMR (CDCl3, 400 MHz):
1.33 (d, 3H, methyl group attached to thiazolidinone), 3.53 (q, 1H,
–CH– of thiazolidinone bearing methyl group), 6.02 (s, 1H, CH of
thiazolidinone), 7.21–7.65 (m, 8H, Ar ring), 7.23 (s, 1H, C2 of indole
ring), 9.74 (s, 1H, NH of indole); 13C NMR (100 MHz CDCl3, ppm):
20.8, 42.5, 68.3, 111.4, 112.4, 118.8, 119.8, 121.4, 123.2, 125.4,
127.5, 130.5, 134.5, 135.5, 144.8, 174.1, MS: m/z ¼ 342.7 (Mþ1).
Anal. calcd. for C18H15ClN2OS; C, 63.06; H, 4.41; N, 8.17. Found: C,
63.05; H, 4.43; N, 8.19.
3-(2-Hydroxyphenyl)-2-(1H-indol-3-yl)thiazolidin-4-one (4i)
IR (KBr, nmax, cmꢀ1): 3435–3275 (N–H indole), 3045 (C–H of
–
aromatic ring), 1726 (C O of thiazolidinone), 756 (C–S–C of
–
thiazolidinone); 1H NMR (CDCl3, 400 MHz): 3.50–4.01 (dd, 2H, CH2
of thiazolidinone), 4.89 (s, 1H, –OH), 5.91 (s, 1H, CH of
thiazolidinone), 7.01–7.95 (m, 8H, Ar ring), 7.13 (s, 1H, C2 of
indole ring), 9.05 (s, 1H, NH of indole); 13C NMR (100 MHz CDCl3,
ppm): 33.3, 71.5, 111.6, 112.5, 116.6, 118.9, 119.4, 121.4, 121.6,
123.5, 125.5, 127.2, 130.5, 136.6, 149.5, 171.2, MS: m/z ¼ 310.2
(Mþ1). Anal. calcd. for C17H14N2O2S: C, 65.79; H, 4.55; N, 9.03.
Found: C, 65.80; H, 4.56; N, 9.05.
3-(2,4-Dichlorophenyl)-2-(1H-indol-3-yl)-5-methylthiazolidin-
4-one (5d)
IR (KBr, nmax, cmꢀ1): 3420–3285 (N–H indole), 3032 (C–H of
–
aromatic ring), 2950 (C–H of methyl), 1752 (C O of thiazolidi-
–
1
none), 755 (C–S–C of thiazolidinone); H NMR (CDCl3, 400 MHz):
1.21 (d, 3H, methyl group attached to thiazolidinone), 3.46 (q, 1H,
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Arch. Pharm. Chem. Life Sci. 2014, 347, 756–767
Ultrasound-Assisted Indolyl Thiazolidinones as Anticonvulsants
765
–CH– of thiazolidinone bearing methyl group), 5.96 (s, 1H, CH of
thiazolidinone), 7.34–7.62 (m, 7H, Ar ring), 7.13 (s, 1H, C2 of indole
ring), 9.13 (s, 1H, NH of indole); 13C NMR (100 MHz CDCl3, ppm):
20.1, 42.7, 67.2, 111.4, 112.4, 118, 119.8, 121.4, 123.2, 124.4, 126.5,
130.6, 136.5, 136.5, 138.8, 174.8, MS: m/z ¼ 377.1 (Mþ1). Anal.
calcd. for C18H14Cl2N2OS; C, 57.30; H, 3.74; N, 7.42. Found: C,
57.28; H, 3.73; N, 7.44.
(m, 8H, Ar ring), 7.49 (s, 1H, C2 of indole ring), 9.13 (s, 1H, NH of
indole); 13C NMR (100 MHz CDCl3, ppm): 20.1, 42.1, 55.4, 68.4,
111.7, 112.7, 114.5, 118.4, 119.3, 121.6, 122.3, 123.5, 127.8, 134.4,
136.1, 158.5, 174, MS: m/z ¼ 338.5 (Mþ1). Anal. calcd. for
C19H18N2O2S; C, 67.43; H, 5.36; N, 8.28. Found: C, 67.40; H,
5.34; N, 8.30.
3-(2-Hydroxyphenyl)-2-(1H-indol-3-yl)-5-methylthiazolidin-
3-(4-Bromophenyl)-2-(1H-indol-3-yl)-5-methylthiazolidin-
4-one (5i)
IR (KBr, nmax, cmꢀ1): 3500 (O–H), 3456–3245 (N–H indole), 3057
4-one (5e)
IR (KBr, nmax, cmꢀ1): 3445–3295 (N–H indole), 3056 (C–H of
–
(C–H of aromatic ring), 2950 (C–H of methyl), 1728 (C O of
–
thiazolidinone), 755 (C–S–C of thiazolidinone); 1H NMR (CDCl3,
400 MHz): 1.23 (d, 3H, methyl group attached to thiazolidinone),
3.14 (q, 1H, –CH– of thiazolidinone bearing methyl group), 5.15 (s,
1H, OH of Ar ring), 6.39 (s, 1H, CH of thiazolidinone), 7.13–7.64 (m,
8H, Ar ring), 7.22 (s, 1H, C2 of indole ring), 8.53 (s, 1H, NH of
indole); 13C NMR (100 MHz CDCl3, ppm): 20.3, 42.2, 68.8, 111.7,
112.7, 116.3, 117.8, 118.5, 119.5, 121.6, 123.5, 125.7, 127.8, 130.8,
136.1, 149.5, 174.7, MS: m/z ¼ 324.7 (Mþ1). Anal. calcd. for
C18H16N2O2S; C, 66.64; H, 4.97; N, 8.64. Found: C, 66.65; H, 4.99; N,
8.62.
–
aromatic ring), 2950 (C–H of methyl), 1766 (C O of thiazolidi-
–
1
none), 785 (C–S–C of thiazolidinone); H NMR (CDCl3, 400 MHz):
1.24 (d, 3H, methyl group attached to thiazolidinone), 3.41 (q, 1H,
–CH– of thiazolidinone bearing methyl group), 5.96 (s, 1H, CH of
thiazolidinone), 7.24 (s, 1H, C2 of indole ring), 7.45–7.73 (m, 8H, Ar
ring), 8.25 (s, 1H, NH of indole); 13C NMR (100 MHz CDCl3, ppm):
20.7, 42.8, 68.2, 111.4, 112.4, 118.7, 119, 121.3, 123, 127.5, 131.6,
136.8, 136.4, 140.8, 174, MS: m/z ¼ 386.1 (Mþ1). Anal. calcd. for
C18H15BrN2OS; C, 55.82; H, 3.90; N, 7.23. Found: C, 55.84; H, 3.92;
N, 7.25.
2-(1H-Indol-3-yl)-3-(2-mercaptophenyl)-5-methylthiazolidin-
2-(1H-Indol-3-yl)-5-methyl-3-p-tolylthiazolidin-4-one (5f)
IR (KBr, nmax, cmꢀ1): 3421–3255 (N–H indole), 3045 (C–H of
4-one (5j)
IR (KBr, nmax, cmꢀ1): 3445–3290 (N–H indole), 3045 (C–H of
–
aromatic ring), 2950 (C–H of methyl), 1736 (C O of thiazoli-
–
dinone), 756 (C–S–C of thiazolidinone); 1H NMR (CDCl3,
400 MHz): 1.26 (d, 3H, methyl group attached to thiazolidi-
none), 2.53 (s, 3H, methyl of Ar ring), 3.39 (q, 1H, –CH– of
thiazolidinone bearing methyl group), 6.17 (s, 1H, CH of
thiazolidinone), 7.29–7.52 (m, 8H, Ar ring), 7.35 (s, 1H, C2 of
indole ring), 9.51 (s, 1H, NH of indole); 13C NMR (100 MHz CDCl3,
ppm): 20.2, 21.7, 42.6, 68.3, 111, 112.3, 118.4, 119.3, 121.6,
127.5, 129.6, 133.8, 136.4, 138.8, 174.4, MS: m/z ¼ 322.4 (Mþ1).
Anal. calcd. for C19H18N2OS; C, 70.78; H, 5.63; N, 8.69. Found: C,
70.76; H, 5.65; N, 8.71.
–
aromatic ring), 2950 (C–H of methyl), 1736 (C O of thiazolidi-
–
1
none), 785 (C–S–C of thiazolidinone); H NMR (CDCl3, 400 MHz):
1.57 (d, 3H, methyl group attached to thiazolidinone), 3.07 (s, 1H,
SH of Ar ring), 3.24 (q, 1H, –CH– of thiazolidinone bearing methyl
group), 6.23 (s, 1H, CH of thiazolidinone), 7.27–7.56 (m, 8H, Ar
ring), 7.16 (s, 1H, C2 of indole ring), 9.23 (s, 1H, NH of indole); 13
C
NMR (100 MHz CDCl3, ppm): 20.4, 42.7, 67.8, 111.7, 112.7, 118.5,
119.5, 121.6, 124.5, 125.5, 127.5, 129.4, 136.1, 138.5, 174.1, MS: m/
z ¼ 340.7 (Mþ1). Anal. calcd. for C18H16N2OS2; C, 63.50; H, 4.74; N,
8.23. Found: C, 63.52; H, 4.75; N, 8.24.
Pharmacology
3-(3,5-Dimethylphenyl)-2-(1H-indol-3-yl)-5-methylthiazolidin-
The compounds 3-(substituted)-2-(1H-indol-3-yl)thiazolidin-4-one
4a–j and 3-(substituted)-2-(1H-indol-3-yl)methylthiazolidin-4-one
5a–j were evaluated for anticonvulsant activity according to
anticonvulsant drug development (ADD) program protocol [45, 46].
All the synthesized compounds were evaluated for anticonvulsant
activity using MES and sc-PTZ model and behavioral activity. Male
Swiss albino mice (CF-1 strain, 20–30 g) were used as experimental
animals. They were housed in groups of five and allowed free access
to water and food. A 12h:12h light/dark cycle was maintained
throughout the experimental studies. For MES and sc-PTZ models
study, all the test compounds were administered in the form of
suspension made up to 0.5% Tween 80 in 0.9% sodium chloride
solutions. The approval of the Institutional Animal Ethics
Committee (CPCSEA/IAEC/Pharm. Chem.-20/2012-2013/78) of Y.B.
Chavan college of Pharmacy, Aurangabad (Maharashtra, India) was
taken prior to the start of the experiments.
4-one (5g)
IR (KBr, nmax, cmꢀ1): 3452–3295 (N–H indole), 3056 (C–H of
–
aromatic ring), 2950 (C–H of methyl), 1742 (C O of thiazoli-
–
dinone), 747 (C–S–C of thiazolidinone); 1H NMR (CDCl3,
400 MHz): 1.26 (d, 3H, methyl group attached to thiazolidi-
none), 2.43 (s, 6H, methyl of Ar ring), 3.47 (q, 1H, –CH– of
thiazolidinone bearing methyl group), 6.28 (s, 1H, CH of
thiazolidinone), 7.33–7.61 (m, 7H, Ar ring), 7.71 (s, 1H, C2 of
indole ring), 8.53 (s, 1H, NH of indole); 13C NMR (100 MHz
CDCl3, ppm): 20.4, 21.5, 42.1, 68.4, 111.4, 112.7, 118.4, 118.5,
119.3, 121.6, 127.3, 136.4, 138.1, 174.5, MS: m/z ¼ 336.4 (Mþ1).
Anal. calcd. for C20H20N2OS; C, 71.40; H, 5.99; N, 8.33. Found: C,
71.42; H, 5.98; N, 8.35.
2-(1H-Indol-3-yl)-3-(4-methoxyphenyl)-5-methylthiazolidin-
4-one (5h)
IR (KBr, nmax, cmꢀ1): 3445–3259 (N–H indole), 3033 (C–H of
Anticonvulsant activity
–
aromatic ring), 2950 (C–H of methyl), 1752 (C O of thiazolidi-
none), 779 (C–S–C of thiazolidinone); H NMR (CDCl3, 400 MHz):
1.41 (d, 3H, methyl group attached to thiazolidinone), 3.52 (s, 3H,
methoxy of Ar ring), 3.59 (q, 1H, –CH– of thiazolidinone bearing
methyl group), 5.96 (s, 1H, CH of thiazolidinone), 7.24–7.56
All the test compounds were administered intra-peritoneally
in a volume of 0.01 mL/g for mice at doses of 100 mg/kg.
Anticonvulsant activity was assessed after 30 min and 4 h of drug
administration. The preliminary anticonvulsants (MES and sc-
PTZ) evaluations were done using reported procedures.
–
1
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www.archpharm.com

766
A. P. G. Nikalje et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 756–767
Neurotoxicity screening
The authors are grateful to University Grant Commission, New Delhi
for the Major Research Project Grant No. 39-173-2010. The authors are
thankful to Mrs. Fatma Rafiq Zakaria Chairman, Maulana Azad
Educational Trust and Principal, Y.B. Chavan College of Pharmacy,
Dr. Rafiq Zakaria Campus, Aurangabad-431001 (M.S.) India for their
constant support.
Rotarod test was used to detect a neurological deficit inability of
the animal to maintain equilibrium on the rod for at least 1 min
in each of the three trials. The dose at which the animal fell off
the rod was determined. Animals were divided in groups of five
and trained to stay on an accelerating rotarod that rotates at
10 rpm. The rod diameter was 3.2 cm. Trained animals (able to
stay on the rotarod for at least two consecutive trials of 90 s each)
were given an i.p. injection of the test compounds at doses of
100 mg/kg.
The authors have declared no conflict of interest.
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