Design and synthesis of 2-(1, 3-dioxoisoindolin-2-yl)-N-(4-oxo-2- substitutedthiazolidin-3-yl) acetamide derivatives as potential anticonvulsant agents

Article abstract of DOI:10.1016/j.ejmech.2011.09.003

A series of 2-(1,3-dioxoisoindolin-2-yl)-N-(4-oxo-2-substitutedthiazolidin- 3-yl) acetamide derivatives were designed and synthesized using appropriate synthetic route, keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and CNS depressant activities in mice. The synthesized derivatives were examined in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (sc-PTZ) induced seizure and neurotoxicity screens and were also evaluated for behavioral activity. All the tested compounds showed protection against MES test indicative of their ability to inhibit the seizure spread.

Full text of DOI:10.1016/j.ejmech.2011.09.003

European Journal of Medicinal Chemistry 46 (2011) 5448e5455
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design and synthesis of 2-(1, 3-dioxoisoindolin-2-yl)-N-(4-oxo-2-
substitutedthiazolidin-3-yl) acetamide derivatives as potential
anticonvulsant agents
*
Anna Pratima G. Nikalje , Firoz Kalam Khan, Mangesh Ghodke
Department of Pharmaceutical Chemistry, Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Rauza Bagh, P.B. No. 33, Aurangabad, Maharashtra 431001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-(1,3-dioxoisoindolin-2-yl)-N-(4-oxo-2-substitutedthiazolidin-3-yl) acetamide derivatives
were designed and synthesized using appropriate synthetic route, keeping in view the structural
requirement of pharmacophore and evaluated for anticonvulsant activity and CNS depressant activities
in mice. The synthesized derivatives were examined in the maximal electroshock seizure (MES),
subcutaneous pentylenetetrazole (sc-PTZ) induced seizure and neurotoxicity screens and were also
evaluated for behavioral activity. All the tested compounds showed protection against MES test indic-
ative of their ability to inhibit the seizure spread.
Received 23 July 2011
Received in revised form
30 August 2011
Accepted 1 September 2011
Available online 8 September 2011
Keywords:
Ó 2011 Elsevier Masson SAS. All rights reserved.
Anticonvulsants
Behavioral activity
Neurotoxicity
Thiazolidinyl-acetamide
Microwave-assisted
1. Introduction
ized as antiepileptic drugs that shares similar mode of action on
neuronal sodium channels as phenytoin [7]. Our work also high-
Epilepsy, being one of the most common and serious neuro-
logical disorder is characterized by recurrent seizures which results
from a temporary electrical disturbance of the brain due to an
imbalance between excitatory and inhibitory neurotransmitters.
About one third of the patients do not respond well to current
multiple drug therapy [1,2]. Phenytoin, carbamazepine, lamo-
trigine, sulfamate and topiramate are recent antiepileptic drugs
which have been clinically effective against different types of
seizures [3].
The improvement in the treatment of epilepsy over the past
decade is mainly associated with the development of new anti-
epileptic drugs, taking advantage of the pharmacophoric require-
ment specifically on a single target [4e6]. In the present work, our
objective was to design and synthesize new compounds having
dioxoindolin moiety coupled with thiazolidinone nucleus via
amide linkage with the hope to get compounds with enhanced
bioactivity. Thus, novel, 2-(1,3-dioxoisoindolin-2-yl)-N-(4-oxo-2-
substitutedthiazolidin-3-yl) acetamide derivatives were synthes-
lights the distance mapping and matching of the synthesized
compounds with the help of the given model. All the synthesized
titled compounds comprised of the essential pharmacophoric
elements that are necessary for good anticonvulsant activity as
suggested by Unverferth et al. [8], which are indicated by rect-
angles in Fig. 1. 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 [9]. Micro-
wave assisted synthesis of title compounds was carried out as it
gives reduced pollution, reduced reaction time, increased reaction
rate; yield enhancement, cleaner and greener eco friendly
synthetic protocol [10].
2. Chemistry
The synthetic protocols employed for the synthesis of 2-(1,3-
dioxoisoindolin-2-yl)-N-(4-oxo-2-substitutedthiazolidin-3-yl)
ace-tamide derivatives 6(aep) are presented in Scheme 1. The
2-(1,3-dioxoisoindolin-2-yl) acetohydrazides were obtained via
reaction of 2-(1,3-dioxoisoindolin-2-yl) acetic acid with hydrazine
hydrate in presence of N,N0- dicyclohexyl carbodiimide (DCC).
* Corresponding author. Tel.: þ91 9823619992; fax: þ91 0240 2381129.
E-mail address: ana@k.st (A.P.G. Nikalje).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.09.003

A.P.G. Nikalje et al. / European Journal of Medicinal Chemistry 46 (2011) 5448e5455
5449
from IR, 1H NMR, Mass and elemental analysis data confirmed the
proposed structures.
3. Pharmacology
The new derivatives obtained by the above mentioned
procedure were undertaken for the anticonvulsant studies by the
anticonvulsant drug development (ADD) program protocol
[11,12]. The profile of anticonvulsant activity was established
after i.p. injections into mice and evaluated in the maximal
electroshock (MES), subcutaneous pentylenetetrazole (sc-PTZ)
and neurotoxicity screens, using doses of 30, 100 and 300 mg/kg
at 0.5 h and 4 h time intervals. These data are presented in
Table 2. The compounds were also evaluated for their CNS
behavioral activity in mice using actophotometer at dose level of
30 mg/kg at 0.5 h and 4 h time intervals. The results are pre-
sented in Table 3.
Fig. 1. Structures of sodium channel modulators. The essential structure elements for
the pharmacophore of Unverferth are indicated by rectangles.
The 2-(1,3-dioxoisoindolin-2-yl) acetohydrazide when reacted with
various substituted aromatic/heteryl aldehydes gave N-substituted
benzylidene/methylene-2-(1,3-dioxo isoindolin-2-yl) acetohy-
drazides 5(aep), which upon reaction with thioglycolic acid under
microwave irradiation in DMF for about 10e12 min (700 W), gave
2-(1,3-dioxoisoindolin-2-yl)-N-(4-oxo-2-substitutedthiazolidin-3-
yl) acetamide derivatives 6(aep). The purity of the synthesized
compounds was checked by TLC and melting points were deter-
mined in open capillary tubes on a Buchi 530 melting point appa-
ratus and are uncorrected. The assignments of the structures were
based on elemental and spectral data. The physical data of the
synthesized compounds are presented in Table 1. The data obtained
4. Computational parameter
The pharmacophore pattern studies in which distance between
the various groups postulated as essential for anticonvulsant
activity were done on the 3D optimized structures using ACD
freeware 3D viewer 8.04 version. The results are presented in
Table 4. Along with this C log P for synthesized compounds were
calculated by using Pallas demo version 3112 which was then
Scheme 1. Synthetic protocol for titled compounds.

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A.P.G. Nikalje et al. / European Journal of Medicinal Chemistry 46 (2011) 5448e5455
Table 1
Physical data 2-(1,3-Dioxoisoindolin-2-yl)-N-(4-oxo-2-substitutedthiazolidin-3-yl) acetamide derivatives 6(aep).
Compounds
Ar
Yield (%)
Melting point (o C)
Molecular formula (M.W.)
C19H15N3O4S (381)
Rf
6a
87
218e220
0.62
HO
6b
88
234e238
C19H15N3O5S (397)
0.61
6c
6d
6e
95
85
92
198e200
290e292
268e270
C19H15N3O5S (397)
C20H17N3O5S (411)
C20H17N3O6S (427)
0.65
0.66
0.55
OH
OCH3
OCH
3
OH
OCH3
6f
87
92
284e286
244e246
C21H19N3O6S (441)
C20H17N3O4S (395)
0.68
0.56
OCH3
6g
CH3
Cl
6h
6i
95
94
250e252
318e320
C19 H14ClN3O4S (415)
C19H13Cl2N3O4S (449)
0.65
0.64
Cl
Cl
Cl
6j
91
294e296
C19H13ClFN3O4S (433)
0.44
F
6k
6l
89
93
84
262e264
256e258
232e234
C21H20N4O4S (424)
C21H17N3O4S (407)
C17H13N3O5S (371)
0.59
0.43
0.46
N
6m
O
S
6n
6o
90
87
190e192
236e238
C17H13N3OS2 (387)
C18H14N4O4S (382)
0.54
0.55
N
6p
85
270e272
C21H16N4O4S (420)
0.62
N
H
Solvent of re crystallization was ethanol; Eluants used in TLC were petroleum benzene: methanol (8:2) for all compounds.

A.P.G. Nikalje et al. / European Journal of Medicinal Chemistry 46 (2011) 5448e5455
5451
Table 2
Anticonvulsant and neurotoxicity screening of compounds.
5.1. Anticonvulsant activity
All the tested compounds showed protection against MES test
indicative of their ability to inhibit the seizure spread. Compounds
6c, 6e and 6g showed protection against the MES model at 30 mg/kg
and compounds 6a, 6b, 6d, 6j, 6m and 6o showed protection at dose
level of 100 mg/kg while compounds 6f, 6h, 6k, 6l and 6p showed
protection at dose level of 300 mg/kg after 0.5 h. Compounds 6g and
6i showed protection against the MES model at 30 mg/kg and
compounds 6a, 6b, 6c, 6d, 6e, 6j and 6n showed protection at dose
level of 100 mg/kg whilecompounds 6f, 6h, 6k, 6l, 6o and 6p showed
protection at dose level of 300 mg/kg at 4 h. The compound 6g
showed activity both at 0.5 h and 4 h period at dose level of 30 mg/kg
indicating the compound to be more effective and long acting.
Similarly compound 6c and 6e were also found to be more effective
but short acting as 4 h protection requires the dose of 100 mg/kg. The
compounds 6a, 6b, 6d and 6j showed activity both at 0.5 h and 4 h
period at dose level of 100 mg/kg indicating that compounds are
effective and long acting. The compounds 6f, 6h, 6k, 6l and 6p
showed activity both at 0.5 h and 4 h period at dose level of 300 mg/
kg indicating that compounds are less potent and long acting. The
compounds 6i showed activity at dose level of 30 mg/kg and 6n
showed activity at dose level of 100 mg/kg only at 4 h indicating that
compounds have sustained release activity. The compound 6m
showed activity only at 0.5 h indicating that compound has rapid
onset and shorter duration of action.
Compounds
MES screen
Sc PTZ screen
Neurotoxicity
screen
0.5 h
4 h
0.5 h
4 h
0.5 h
4 h
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
100
100
30
100
30
100
100
100
100
100
300
30
100
e
300
e
30
100
300
300
e
30
100
300
300
e
e
e
e
e
300
100
100
300
100
300
300
300
e
300
300
300
e
300
30
e
e
e
e
300
e
300
30
300
300
e
e
100
300
300
e
e
100
300
300
100
e
100
300
300
e
e
e
e
e
e
e
e
e
100
300
300
30
e
e
e
100
e
100
300
30
e
e
e
300
ꢁ
e
e
e
Phenytoin
Sodium Valproate
ꢁ
100
e
100
e
ꢁ
ꢁ
300
e
a Doses of 30, 100 and 300 mg/kg of the compound were administered and the
protection and neurotoxicity 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 (ꢂ) indicates the absence of anticonvulsant activity or
neurotoxicity. ꢁ denotes not tested.
Most of the compounds were found to be active in the sc PTZ
test, a test used to identify compounds that elevate seizure
threshold. The Compounds 6a, 6f, 6g and 6i showed activity at
a dose of 100 mg/kg while, compounds 6e, 6h, 6j, 6k, 6l, and 6p
showed activity at dose of 300 mg/kg at 0.5 h. The Compounds 6i
showed activity at a dose of 100 mg/kg while 6a, 6e, 6f, 6g, 6j and
6k showed activity at dose of 300 mg/kg at 4 h. No compounds
were found active at dose level of 30 mg/kg. The compounds 6e, 6j
and 6k have shown activity at 300 mg/kg at 0.5 h and 4 h indicating
that these compounds have moderate activity. The compounds 6a,
6f and 6g were found to be potent with rapid onset and interme-
diate duration of action. The compounds 6b, 6c, 6d, 6m, 6n and 6o
showed absence of activity at all dose level while, compounds 6h, 6l
and 6p found to be active with short duration of action.
compared with the experimental log P data of these compounds.
The results are presented in Table 5.
5. Results and discussions
A
series of novel 2-(1,3-dioxoisoindolin-2-yl)-N-(4-oxo-2-
substitutedthiazolidin-3-yl) acetamide derivatives 6(aep) were
obtained under microwave irradiation in good yield and require
shorter reaction times, the solvent used in conventional synthesis
of thiazolidinones is benzene, which is carcinogenic and hence
avoided in present investigation. All the synthesized compounds
were evaluated for anticonvulsant activity and have shown prom-
ising anticonvulsant activities.
Table 3
Behavioral study of compounds using Actophotometer.
Compounds
Activity score using actophotometer
Control (24 h before)
% Decrease in locomotor activity
Post treatmenta
0.5 h
0.5 h
4 h
4 h
41.60 ꢀ 10.67
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
116.40 ꢀ 7.24
188.36 ꢀ 4.28
120.68 ꢀ 2.72
327.17 ꢀ 12.37
160.74 ꢀ 1.36
167.29 ꢀ 2.25
118.20 ꢀ 5.28
112.20 ꢀ 5.73
165.88 ꢀ 7.33
144.32 ꢀ 1.60
289.00 ꢀ 11.16
267.50 ꢀ 14.85
262.00 ꢀ 19.41NS
142.22 ꢀ 3.45
148.37 ꢀ 0.92
122.88 ꢀ 3.26
119.33 ꢀ 17.43
210.43 ꢀ 10.22
58.20 ꢀ 9.37
126.88 ꢀ 5.46
38.16 ꢀ 8.84
50.00(Y)
32.63(Y)
68.37(Y)
3.25(Y)
38.13(Y)
20.25(Y)
25.94(Y)
50.83(Y)
63.73(Y)
12.01(Y)
9.78(Y)
64.26(Y)
36.91(Y)
43.34(Y)
14.93(Y)
7.31(Y)
118.82 ꢀ 6.34
68.37 ꢀ 12.34
278.30 ꢀ 10.18
148.98 ꢀ 13.24
120.54 ꢀ 4.84
37.64 ꢀ 6.68
94.10 ꢀ 7.46
123.49 ꢀ 8.78
100.75 ꢀ 5.52
161.58 ꢀ 3.24
89.59 ꢀ 8.88
231.48 ꢀ 9.82
40.20 ꢀ 5.46
112.74 ꢀ 5.58
91.12 ꢀ 6.64
97.17 ꢀ 13.49
119.23 ꢀ 5.98
316.51 ꢀ 6.60
99.44 ꢀ 9.94
133.41 ꢀ 3.64
87.54 ꢀ 12.24
55.16 ꢀ 18.34NS
60.15 ꢀ 2.64
27.95(Y)
68.16(Y)
16.13(Y)
25.55(Y)
30.18(Y)
44.08(Y)
66.50(Y)
11.64(Y)
71.73(Y)
24.01(Y)
25.84(Y)
18.57(Y)
43.33(Y)
126.98 ꢀ 5.64
260.71 ꢀ 13.54NS
252.34 ꢀ 9.55
248.51 ꢀ 6.35
52.56 ꢀ 4.87
5.66(Y)
5.14(Y)
63.04(Y)
18.03(Y)
9.95(Y)
33.90(Y)
73.18(Y)
121.61 ꢀ 5.32
110.65 ꢀ 10.25
78.87 ꢀ 16.66
56.42 ꢀ 13.30
Phenytoin
Diazepamb
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), locomotor activity score
was measured for 10 min.
b
The compound was tested at dose level of 4 mg/kg (i. p.).

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Table 4
5.1.1. SAR
Distance range between the essential structure elements R, D & HBD.
As observed through data analysis, the compound with electron
releasing groups are highly effective but compound 6g with peCH3
substitution at aromatic ring was found to be most effective in both
the models and also possess long duration of action. Thus overall
conclusion suggests that the whole moiety can be interpreted as
the lead molecule from this data. In sc-PTZ induced seizers among
the tested compounds 6i, having dichloro phenyl substituent was
found to be highly effective having rapid onset and long duration of
action. When aromatic ring was replaced by heterocyclic rings like
furan, thiophene, pyridine and indol, the anticonvulsant activity
was altered in both the models and has exhibited less significant
effect. Compounds having eOCH3, eOH, substituents on aromatic
ring have shown better activity.
0
D
1
.
A
5
9
.
-
5
.
5
-5
2
.
3
0
A
H-D
0
R
A
6
2
0
.4
0
-6
.5
1
A
2.
-
4
.
2
H-A
Compounds
R-HD
R-D
D-HBD
Phenytoin
3.58
5.09
6.44
4.79
6.18
3.77
4.87
3.41
4.82
5.62
2.21
4.06
4.45
1.49
3.83
Carbamazepine
Lamotrigine
Diazepam
During the study most of the synthesized derivatives were more
effective in the MES test, and the MES test is known to be sensitive
to sodium channel inhibitors (e.g. Phenytoin), which suggested that
tested compounds may inhibit voltage-gated ion channels
(particularly sodium channels).
Lead moiety of 6(aep)
Distances calculated for 3D optimized structures using ACD freeware 3D viewer 8.04
version.
5.2. Computational parameter
In neurotoxicity screening, compounds 6e, 6f, 6g, 6j, 6k, 6l, 6m,
6o and 6p did not show neurotoxicity in the maximum administered
dose (300 mg/kg). The compounds 6a showed neurotoxicity at dose
30 mg/kg, while 6b showed neurotoxicity at dose 100 mg/kg. The
remaining compounds were found to be less neurotoxic as compared
to phenytoin.
5.2.1. Distance mapping
The present work involves the correlation of the structural
requirementof well known and structurally different anticonvulsant
compounds with the titled 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) are structural requirement for
anticonvulsant activity. The essential structural features which
could be responsible for an interactionwith 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. In
the present study, four well-known and structurally different
compounds with anticonvulsant activity i.e. phenytoin, carbamaz-
epine, lamotrigine and diazepam were selected. In an initial study,
calculations on the basis of molecular mechanics, with the force field
based on CHARMM parameterization [13] were performed to obtain
an overview on their minimum energy conformation. Table 4 shows
the distances between the various groups postulated as essential for
anticonvulsant action. Now it was interesting to evaluate whether
the synthesized compounds 2-(1,3-dioxoisoindolin-2-yl)-N-(4-oxo-
2-substitutedthiazolidin-3-yl) acetamide 6(aep) reflected the
conditions of the derived pharmacophore model. Our analysis of
the distance relationship showed that the titled compounds fulfill
the essential demands of pharmacophore when compared with
other standard anticonvulsants.
In behavioral activity using actophotometer, the compounds 6b,
6d, 6f, 6g, 6j, 6k, 6l, 6m, 6o and 6p showed no behavioral despair
effect when compared to phenytoin at 0.5 h. The compounds 6e, 6d,
6h and 6m showed no behavioral despair effect when compared to
phenytoin at 4 h. Compounds 6e and 6h showed decreased loco-
motor activity in the 0.5 h interval but no significant effect on
behavioral despair was observed during 4 h time period when
compared to phenytoin. All other compounds were found to
decrease behavioral activity of the animals when compared to
phenytoin. All compounds showed no behavioral despair effect
when compared to diazepam at 0.5 h. The compounds 6b, 6d, 6e, 6f,
6h, 6i, 6j, 6m, 6o and 6p showed no behavioral despair effect when
compared to diazepam at 4 h. All other compounds were found to
show decreasing behavioral activity of the animals when compared
to diazepam. From experimental Log P determination it was
observed that most of the compounds are having Log P values
between 1.5 and 2.7, sufficient value for crossing of BBB, therefore
these compounds are showing promising anticonvulsant activity.
Table 5
C log P for synthesized compounds.
5.2.2. Log P determination
Some of the active compounds showed dependence of biological
activity on lipophilic character in a congeneric series. For several
classes of CVS active substances, Hansch and Leo found that BBB
penetration is optimal when the log P values are in the range of
1.5e2.7, with the mean value of 2.1 [14,15]. In this study, we
attempted to correlate the anticonvulsant activity of congeners
with their combined calculated Log P value, CLOGP. As observed
some of the experimental values were in good agreement with the
theoretical values. Some of the compounds like 6a, 6c, 6d, 6g, 6i, 6k,
6n have shown dependence of biological activity on lipophilic
character in congeneric series.
Compounds
Experimental Log P
Theoretical Log
Pcombined value
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
2.23
1.46
2.40
1.97
1.31
2.78
2.97
3.21
2.54
3.79
2.84
3.65
1.13
2.15
1.25
1.59
1.62
1.23
1.23
1.49
1.10
1.37
2.11
2.18
2.73
2.33
1.90
2.13
0.23
1.60
0.28
1.16
6. Conclusion
By choosing proper experimental conditions we have been able
to synthesize 2-(1,3-dioxoisoindolin-2-yl)-N-(4-oxo-2-substitut-
edthiazolidin-3-yl) acetamide derivatives in good yields and
Theoretical Log Pcombined was calculated by using Pallas demo version 3112.

A.P.G. Nikalje et al. / European Journal of Medicinal Chemistry 46 (2011) 5448e5455
5453
investigate for anticonvulsant and CNS depressant activities with
the hope of discovering new structure leads serving as potential
anticonvulsant agents. SAR studies revealed the critical role of
peCH3 substituent on aryl group in the target compounds like 6g
that showed promising activity. Compounds 6c, 6e and 6g showed
significant activity in MES screen model. Compounds 6a, 6e, 6f and
6i have exhibited significant activity when compared with standard
in sc PTZ model. Some of the synthesized compounds exhibited
lesser CNS depression and neurotoxicity compared to clinically
effective drug. In conclusion compound 6g can be further opti-
mized and developed as a lead molecule.
thiazolidinone ring), 4.87 (s, 2H, eNeCH2), 5.95 (s,1H, eNeCHeAr),
6.94e7.79 (m, 9H, AreH), 8.61 (s, 1H, eCONH, D2O exchangeable);
MS m/z: 382 (Mþ1); Anal. Calcd. for C19H15N3O4S: C, 59.84; H, 3.93;
N, 11.02. Found: C, 59.86; H, 3.93; N, 11.01.
7.1.2.2. 2-(1, 3-dioxo-1,3-dihydro-isoindol-2-yl)-N-[2-(2-hydroxy-phe
nyl)-4-oxo-thiazolidin-3-yl] acetamide 6b. IR (KBr, nmax in cmꢂ1):
3450 (OH), 3335 (NeH of amide), 3152 (CeH of aromatic), 2876
(CeH of alkyl), 1770 C]O of thiazolidinone), 1725, 1718 C]O of
Phthalimide), 1640 C]O of amide), 1608 (C/C of aromatic), 1310
(CeN), 1288 (NeN), 716 (CeSeC); 1H NMR (DMSOd6, 400 MHz)
d
ppm: 3.85 (s, 2H, CH2 of thiazolidinone ring), 4.87 (s, 2H, eNeCH2),
7. Experimental protocols
5.42 (s, 1H, OH) 5.92 (s, 1H, eNeCHeAr), 6.94e7.79 (m, 8H, AreH),
8.64 (s, 1H, eCONH, D2O exchangeable); MS m/z: 398 (Mþ1); Anal.
Calcd. for C19H15N3O5S: C, 57.43; H, 3.77; N, 10.57. Found: C, 57.45; H,
3.78; N, 10.55.
7.1. Chemistry
All reagents and solvents were used as obtained from the
supplier or recrystallized/redistilled unless otherwise noted.
Infrared (IR) and proton nuclear magnetic resonance (1H NMR)
spectra were recorded for the compounds on JASCO FTIR (PS
4000) using KBr pallet and Brucker Advance II (400 MHz)
instruments, respectively. Chemical shifts are reported in parts per
million (ppm), using TMS as an internal standard. All exchange-
able protons were confirmed by the addition of D2O. Elemental
analyses (C, H, and N) were undertaken with a Shimadzu’s FLA-
SHEA112 analyzer and all analyses were consistent with theoret-
ical values (within ꢀ0.5%) unless indicated. The homogeneity of
the compounds was monitored by ascending thin layer chroma-
tography (TLC) on silica gel-G (Merck) coated aluminum plates,
visualized by iodine vapor.
7.1.2.3. 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-[2-(4-hydroxy-
phenyl)-4-oxo-thiazolidin-3-yl] acetamide 6c. IR (KBr, nmax in cmꢂ1):
3446 (OH), 3328 (NeH of amide), 3150 (CeH of aromatic), 2776
(CeH of alkyl), 1775 C]O of thiazolidinone), 1725, 1720 C]O of
Phthalimide), 1642 C]O of amide), 1610 (C/C of aromatic), 1315
(CeN), 1278 (NeN), 720 (CeSeC); 1H NMR (CDCl3, 400 MHz)
d
ppm: 3.80 (s, 2H, CH2 of thiazolidinone ring), 4.97 (s, 2H,
eNeCH2), 5.49 (s, 1H, OH) 5.90 (s, 1H, eNeCHeAr), 6.94e7.79 (m,
8H, AreH), 8.74 (s, 1H, eCONH, D2O exchangeable); MS m/z: 398
(Mþ1); Anal. Calcd. for C19H15N3O5S: C, 57.43; H, 3.77; N, 10.57.
Found: C, 57.44; H, 3.77; N, 10.56.
7.1.2.4. 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-[2-(4-methoxy-
phenyl)-4-oxo-thiazolidin-3-yl] acetamide 6d. IR (KBr, nmax in
cmꢂ1): 3335 (NeH of amide), 3012 (CeH of aromatic), 2886 (CeH of
alkyl), 1775 C]O of thiazolidinone), 1722, 1715 C]O of Phthali-
mide), 1660 C]O of amide), 1615 (C/C of aromatic), 1318 (CeN),
1270 (NeN), 1214 (OeCH3) 736 (CeSeC); 1H NMR (DMSOd6,
7.1.1. General procedure for the preparation of N-substituted
benzylidene/methylene-2-(1,3-dioxo isoindolin-2-yl)
acetohydrazides 5(aep)
2-(1,3-Dioxoisoindolin-2-yl) acetic acid (3) was obtained by the
reaction of phthalic acid anhydride (1) (0.05 mol) with glycine (2)
(0.05 mol) [16]. Equimolar quantities of 2-(1,3-dioxoisoindolin-2-
yl)acetic acid (3) (0.03 mol) and hydrazine hydrate (99%)
(0.03 mol) were condensed in the presence of DCC (0.03 mol) in
dichloromethane, by stirring at ice-cold conditions (0e3 ꢃC) for
6e8 h [17]. Equimolar quantities of 2-(1,3-dioxoisoindolin-2-yl)
acetohydrazide (4) (0.03 mol) and different substituted aromatic
aldehydes and heterocyclic aldehydes (0.03 mol) were refluxed in
ethanol for 6e8 h, in presence of glacial acetic acid (0.06 mol).
Products were recrystallized with ethanol. The other compounds
5(aep) were prepared similarly by treating with corresponding
aldehydes [18].
400 MHz)
d ppm: 3.85 (s, 3H, OeCH3), 4.03 (s, 2H, CH2 of thiazo-
lidinone ring), 4.87 (s, 2H, eNeCH2), 5.95 (s, 1H, eNeCHeAr),
6.94e7.79 (m, 8H, AreH), 8.61 (s, 1H, eCONH, D2O exchangeable);
MS m/z: 412 (Mþ1); Anal. Calcd. for C20H17N3O5S: C, 58.39; H, 4.13;
N, 10.21. Found: C, 58.40; H, 4.13; N, 10.20.
7.1.2.5. 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-[2-(4-hydroxy-3-
methoxy-phenyl)-4-oxo-thiazolidin-3-yl] acetamide 6e. IR (KBr, nmax
in cmꢂ1): 3457 (OH), 3345 (NeH of amide), 3152 (CeH of
aromatic), 2876 (CeH of alkyl), 1770 C]O of thiazolidinone), 1728,
1713 C]O of Phthalimide), 1640 C]O of amide), 1615 (C/C of
aromatic), 1313 (CeN), 1288 (NeN), 1215 (OeCH3), 716 (CeSeC);
1H NMR (DMSOd6, 400 MHz)
d ppm: 3.32 (s, 3H, OeCH3), 3.85 (s,
7.1.2. General procedure for the preparation of2-(1,3-dioxoisoindolin-
2-yl)-N-(4-oxo-2-substitutedthiazolidin-3-yl) acetamide derivatives
6(aep)
In an Erlenmeyer flask the mixture of compounds 5(aep)
(0.01 mol), thioglycolic acid (0.01 mol) and anhydrous zinc chloride
(0.004 mol) was taken in DMF (20 ml). The reaction mixture was
irradiated inside a synthetic microwave oven for about 10e12 min
(700 W). After completion of reaction, mixture was poured into ice-
cold water. The solid product formed was filtered, dried and
recrystallized from ethanol.
2H, CH2 of thiazolidinone ring), 4.87 (s, 2H, eNeCH2), 5.42 (s, 1H,
OH), 5.92 (s, 1H, eNeCHeAr), 6.94e7.79 (m, 7H, AreH), 8.64 (s,
1H, eCONH, D2O exchangeable); MS m/z: 428 (Mþ1); Anal. Calcd.
for C20H17N3O6S: C, 56.20; H, 3.98; N, 9.83. Found: C, 56.22; H,
3.94; N, 9.85.
7.1.2.6. N-[2-(3,4-dimethoxy-phenyl)-4-oxo-thiazolidin-3-yl]-2-(1,3-
dioxo-1,3-dihydro-isoindol-2-yl) acetamide 6f. IR (KBr, nmax in
cmꢂ1): 3349 (NeH of amide), 3150 (CeH of aromatic), 2896 (CeH of
alkyl), 1765 C]O of thiazolidinone), 1733, 1728 C]O of Phthali-
mide), 1644 C]O of amide), 1616 (C/C of aromatic), 1316 (CeN),
1298 (NeN), 1242, 1215 (OeCH3), 706 (CeSeC); 1H NMR (DMSOd6,
7.1.2.1. 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(4-oxo-2-phenyl-
thiazolidin-3-yl) acetamide 6a. IR (KBr, nmax in cmꢂ1): 3335 (NeH of
amide), 3012 (CeH of aromatic), 2886 (CeH of alkyl), 1770 C]O of
thiazolidinone), 1720, 1715 C]O of Phthalimide), 1680 C]O of
amide), 1605 (C/C of aromatic), 1315 (CeN), 1285 (NeN), 736
400 MHz)
d ppm: 3.32e3.45 (s, 6H, OeCH3), 3.83 (s, 2H, CH2 of
thiazolidinone ring), 4.80 (s, 2H, eNeCH2), 5.90 (s,1H, eNeCHeAr),
6.94e7.79 (m, 7H, AreH), 8.69 (s, 1H, eCONH, D2O exchangeable);
MS m/z: 442 (Mþ1); Anal. Calcd. for C21H19N3O6S: C, 57.14; H, 4.30;
N, 9.52. Found: C, 57.18; H, 4.29; N, 9.50.
(CeSeC); 1H NMR (DMSOd6, 400 MHz)
d ppm: 4.03 (s, 2H, CH2 of

5454
A.P.G. Nikalje et al. / European Journal of Medicinal Chemistry 46 (2011) 5448e5455
7.1.2.7. 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(4-oxo-2-p-tolyl-
thiazolidin-3-yl) acetamide 6g. IR (KBr, nmax in cmꢂ1): 3335 (NeH of
amide), 3110 (CeH of aromatic), 2956 (CeH3), 2883 (CeH of alkyl),
1785 C]O of thiazolidinone),1725,1720 C]O of Phthalimide),1705
C]O of amide), 1635 (C/C of aromatic), 1405 (CeN), 1280 (NeN),
1285 (NeN), 736 (CeSeC); 1H NMR (CDCl3, 400 MHz)
d ppm: 4.03
(s, 2H, CH2 of thiazolidinone ring), 4.87 (s, 2H, eNeCH2), 5.50e5.84
(m, 2H, CH ¼ CHeAr), 5.95 (s, 1H, eNeCHeAr), 6.94e7.79 (m, 9H,
AreH), 8.61 (s, 1H, eCONH, D2O exchangeable); MS m/z: 408
(Mþ1); Anal. Calcd. for C21H17N3O4S: C, 61.91; H, 4.17; N, 10.31.
Found: C, 61.94; H, 4.18; N, 10.28.
725 (CeSeC); 1H NMR (CDCl3, 400 MHz)
d ppm: 2.30 (s, 3H, CH3),
4.13 (s, 2H, CH2 of thiazolidinone ring), 4.55 (s, 2H, eNeCH2), 5.90
(s, 1H, eNeCHeAr), 6.94e7.79 (m, 8H, AreH), 8.68 (s, 1H, eCONH,
D2O exchangeable); MS m/z: 396 (Mþ1); Anal. Calcd. for
C20H17N3O4S: C, 60.75; H, 4.30; N, 10.63. Found: C, 60.90; H, 4.30; N,
10.61.
7.1.2.13. 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-(2-furan-2-yl-4-
oxo-thiazolidin-3-yl) acetamide 6m. IR (KBr, nmax in cmꢂ1): 3405
(NeH of amide), 3088 (CeH of aromatic), 2845 (CeH of alkyl), 1777
C]O of thiazolidinone), 1728, 1725 C]O of Phthalimide), 1681 C]O
of amide), 1655 (C/C of aromatic), 1315 (CeN), 1282 (NeN), 1256
7.1.2.8. N-[2-(4-chloro-phenyl)-4-oxo-thiazolidin-3-yl]-2-(1,3-dioxo-
1,3-dihydro-isoindol-2-yl) acetamide 6h. IR (KBr, nmax in cmꢂ1):
3545 (NeH of amide), 3152 (CeH of aromatic), 2876 (CeH of alkyl),
1755 C]O of thiazolidinone),1720, 1715 C]O of Phthalimide),1642
C]O of amide), 1626 (C/C of aromatic), 1320 (CeN), 1284 (NeN),
(CeOeC), 737 (CeSeC); 1H NMR (DMSOd6, 400 MHz)
d ppm: 3.62
(s, 2H, CH2 of thiazolidinone ring), 4.83 (s, 2H, eNeCH2), 5.95 (s, 1H,
eNeCHeAr), 7.0e7.94 (m, 7H, AreH), 8.08 (s, 1H, eCONH, D2O
exchangeable); MS m/z: 372 (Mþ1); Anal. Calcd. for C17H13N3O5S: C,
54.98; H, 3.50; N, 11.32. Found: C, 54.94; H, 3.48; N, 11.25.
825 (AreCl), 716 (CeSeC); 1H NMR (DMSOd6, 400 MHz)
d ppm:
3.97 (s, 2H, CH2 of thiazolidinone ring), 4.79 (s, 2H, eNeCH2), 5.89
(s, 1H, eNeCHeAr), 7.74e8.06 (m, 8H, AreH), 8.08 (s, 1H, eCONH,
D2O exchangeable); MS m/z: 416 (Mþ1); Anal. Calcd. for C19
H14ClN3O4S: C, 54.93; H, 3.37; N, 10.12. Found: C, 54.86; H, 3.33; N,
10.14.
7.1.2.14. 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-(4-oxo-2-
thiophen-2-yl-thiazolidin-3-yl) acetamide 6n. IR (KBr, nmax in cmꢂ1):
3325 (NeH of amide), 3108 (CeH of aromatic), 2852 (CeH of alkyl),
1780 C]O of thiazolidinone),1733, 1721 C]O of Phthalimide),1688
C]O of amide), 1659 (C/C of aromatic), 1311 (CeN), 1288 (NeN),
785, 737 (CeSeC); 1H NMR (DMSOd6, 400 MHz)
d ppm: 3.66 (s, 2H,
7.1.2.9. Ne[2-(2,4-dichloro-phenyl)-4-oxo-thiazolidin-3-yl]-2-(1,3-
dioxo-1,3-dihydro-isoindol-2-yl) acetamide 6i. IR (KBr, nmax in
cmꢂ1): 3545 (NeH of amide), 3159 (CeH of aromatic), 2873 (CeH of
alkyl), 1755 C]O of thiazolidinone), 1710, 1702 C]O of Phthali-
mide), 1645 C]O of amide), 1620 (C/C of aromatic), 1321 (CeN),
1280 (NeN), 855, 825 (AreCl), 695 (CeSeC); 1H NMR (DMSOd6,
CH2 of thiazolidinone ring), 4.82 (s, 2H, eNeCH2), 5.85 (s, 1H,
eNeCHeAr), 7.10e7.93 (m, 7H, AreH), 8.18 (s, 1H, eCONH, D2O
exchangeable); MS m/z: 388 (Mþ1); Anal. Calcd. for C17H13N3OS2:
C, 52.71; H, 3.35; N, 10.85. Found: C, 52.84; H, 3.38; N, 10.80.
7.1.2.15. 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-(4-oxo-2-pyrid-
in-3-yl-thiazolidin-3-yl) acetamide 6o. IR (KBr, nmax in cmꢂ1): 3349
(NeH of amide), 3112 (CeH of aromatic), 2850 (CeH of alkyl), 1774
C]O of thiazolidinone), 1730, 1723 C]O of Phthalimide), 1678 C]O
of amide), 1650 (C/C of aromatic), 1610 (C]N), 1301 (CeN), 1265
400 MHz)
d ppm: 3.90 (s, 2H, CH2 of thiazolidinone ring), 4.73 (s,
2H, eNeCH2), 5.59 (s, 1H, eNeCHeAr), 7.74e8.06 (m, 7H, AreH),
8.10 (s, 1H, eCONH, D2O exchangeable); MS m/z: 450 (Mþ1); Anal.
Calcd. for C19H13Cl2N3O4S: C, 50.77; H, 2.89; N, 9.35. Found: C,
50.80; H, 2.89; N, 9.37.
(NeN), 730 (CeSeC); 1H NMR (DMSOd6, 400 MHz)
d ppm: 3.15 (s,
2H, CH2 of thiazolidinone ring), 4.22 (s, 2H, eNeCH2), 5.13 (s, 1H,
eNeCHeAr), 7.12e7.90 (m, 8H, AreH), 8.13 (s, 1H, eCONH, D2O
exchangeable); MS m/z: 383 (Mþ1); Anal. Calcd. for C18H14N4O4S: C,
56.54; H, 3.66; N, 14.65. Found: C, 56.84; H, 3.68; N, 14.83.
7.1.2.10. N-[2-(2-chloro-6-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-2-
(1,3-dioxo-1,3-dihydro-isoindol-2-yl) acetamide 6j. IR (KBr, nmax in
cmꢂ1): 3540 (NeH of amide), 3059 (CeH of aromatic), 2875 (CeH
of alkyl), 1760 C]O of thiazolidinone), 1722, 1705 C]O of Phtha-
limide), 1643 C]O of amide), 1620 (C/C of aromatic), 1329 (AreF),
1311 (CeN), 1273 (NeN), 825 (AreCl), 693 (CeSeC); 1H NMR
7.1.2.16. 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-[2-(1H-indol-3-
yl)-4-oxo-thiazolidin-3-yl ] acetamide 6p. IR (KBr, nmax in cmꢂ1):
3406 (NeH of indole), 3289 (NeH of amide), 3155 (CeH of
aromatic), 2874 (CeH of alkyl), 1768 C]O of thiazolidinone), 1728,
1720 C]O of Phthalimide), 1689 C]O of amide), 1655 (C/C of
aromatic), 1305 (CeN), 1263 (NeN), 732 (CeSeC); 1H NMR
(DMSOd6, 400 MHz) d ppm: 3.91 (s, 2H, CH2 of thiazolidinone ring),
4.70 (s, 2H, eNeCH2), 5.49 (s, 1H, eNeCHeAr), 7.74e8.06 (m, 7H,
AreH), 8.54 (s, 1H, eCONH, D2O exchangeable); MS m/z: 434
(Mþ1); Anal. Calcd. for C19H13ClFN3O4S: C, 52.65; H, 3.00; N, 9.69.
Found: C, 52.69; H, 3.00; N, 9.67.
(DMSOd6, 400 MHz) d ppm: 3.67 (s, 2H, CH2 of thiazolidinone ring),
4.75 (s, 2H, eNeCH2), 5.48 (s, 1H, eNeCHeAr), 7.15e7.95 (m, 9H,
AreH), 8.18 (s, 1H, eCONH), 11.5 (b, 1H, NH of indole, D2O
exchangeable); MS m/z: 421 (Mþ1); Anal. Calcd. for C21H16N4O4S:
C, 60.00; H, 3.80; N, 13.33. Found: C, 60.09; H, 3.80; N, 13.35.
7.1.2.11. N-[2-(4-dimethylamino-phenyl)-4-oxo-thiazolidin-3-yl]-2-
(1,3-dioxo-1,3-dihydro- isoindol-2-yl) acetamide 6k. IR (KBr, nmax in
cmꢂ1): 3295 (NeH of amide), 3145 (CeH of aromatic), 2885 (CeH of
alkyl), 1755 C]O of thiazolidinone), 1733, 1725 C]O of Phthali-
mide), 1680 C]O of amide), 1615 (C/C of aromatic), 1308 (CeN),
1295 (NeN), 785 (CeSeC); 1H NMR (DMSOd6, 400 MHz)
d
ppm:
7.2. Pharmacology
1.50 (s, 6H, N(CH3)2), 4.24 (s, 2H, CH2 of thiazolidinone ring), 4.82 (s,
2H, eNeCH2), 5.90 (s, 1H, eNeCHeAr), 6.90e7.79 (m, 8H, AreH),
8.69 (s, 1H, eCONH, D2O exchangeable); MS m/z: 425 (Mþ1); Anal.
Calcd. for C21H20N4O4S: C, 59.43; H, 4.71; N, 15.09. Found: C, 59.45;
H, 4.70; N, 15.10.
Male Swiss albino mice (CF-1 strain, 20e30 g) were used as
experimental animals. All the test compounds were suspended in
0.5% methyl cellulose in the case of MES and sc PTZ induced seizure
models and 30% PEG 200 for behavioral activity at our lab. The
animals were maintained at an ambient temperature of 25 ꢀ 2 ꢃC,
in groups of five per cage under standard laboratory conditions,
receiving standard laboratory chow and water ad libitum. A 12 h:
12 h light/dark cycle was maintained throughout the experimental
studies. All the tests have been performed in accordance with the
guidelines laid out by the Institutional Animal Ethics Committee.
7.1.2.12. 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(4-oxo-2-styryl-
thiazolidin-3-yl) acetamide 6l. IR (KBr, nmax in cmꢂ1): 3335 (NeH of
amide), 3012 (CeH of aromatic), 2886 (CeH of alkyl), 1770 C]O of
thiazolidinone), 1720, 1715 C]O of Phthalimide), 1680 C]O of
amide), 1630 (CeH ¼ CHeAr), 1605 (C/C of aromatic), 1315 (CeN),

A.P.G. Nikalje et al. / European Journal of Medicinal Chemistry 46 (2011) 5448e5455
5455
7.2.1. Anticonvulsant screening
room temperature and then transferred to a separating funnel and
allowed to dynamic equilibrate for 6 h. The aqueous and octanol
phase were separated and filtered through membrane filter and
drug content in aqueous phase was analyzed by UV spectroscopy.
All the test compounds were administered intraperitoneally in
a volume of 0.01 mL/g for mice at doses of 30, 100 and 300 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.
Acknowledgments
7.2.2. Neurotoxicity screening
Authors are grateful to Mrs. Fatma Rafiq Zakaria Chairman,
Maulana Azad Education Trust and Dr. M. H. Dehghan, Principal, Y.B
Chavan College of Pharmacy, Aurangabad for encouragement and
support. The authors are thankful to Dr. Sayyed Ayyaz Ali, Assistant
Prof., Department of Pharmacology, for his guidance during the
pharmacological screening.
Rotarod test has been performed to detect the minimal motor
deficit in mice. Animals were divided into groups of 5 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 30, 100 and 300 mg/kg.
Neurological deficit was indicated by the 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.
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The partition coefficient between octanol and phosphate buffer
was determined at room temperature [21]. 10 mL of octanol and
10 mL phosphate buffer were taken in a glass stoppered graduated
tube and 5 mg of accurately weighed drug was added. The mixture
was then shaken with the help of mechanical shaker for 24 h at