Design, synthesis and pharmacological screening of potential anticonvulsant agents using hybrid approach

Article abstract of DOI:10.1016/j.ejmech.2009.09.014

A series of 9H, 10H, 3-[N- 4 methyl -2-benzamido thiophen 3-yl carbonyl amino [2-(2′-phenyl 1′- ethylenyl)] 10-(aryl) thiazolidino [4, 5-b] 1, 5 benzodiazepine [7a-7h] were designed and synthesized to meet the structural requirements essential for anticonvulsant activity. Anticonvulsant activity was determined after intra-peritoneal administration to mice by supramaximal electroshock seizures model and Isoniazide Hydrazone induced seizures model. Motor impairement was determined using actophotometer and rotarod apparatus. Among the synthesized compounds two [JG 7a and JG 7e] compounds exhibited significant anticonvulsant activity after intra-peritoneal administration. Active compounds carry hydroxy substitutent at 2-position and methoxy at 4-position in the phenyl ring at C₅ of benzodiazepine. In present we study conclude that small polar and electron rich groups contribute significantly for anticonvulsant activity while electronegative substitutents showed lesser contribution for anticonvulsant activity.

Full text of DOI:10.1016/j.ejmech.2009.09.014

European Journal of Medicinal Chemistry 45 (2010) 857–863
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and pharmacological screening of potential anticonvulsant
agents using hybrid approach
,
b
a
a
J.G. Ghogare a, S.V. Bhandari a , K.G. Bothara , A.R. Madgulkar , G.A. Parashar ,
*
B.G. Sonawane a, P.R. Inamdar a
a Department of Pharmaceutical Chemistry, A.I.S.S.M.S College of Pharmacy, Kennedy Road, Pune-411001, India
b Associate Dean, School of Pharmacy & Technology, NMIMS University, Shirpur , Dist.-Dhule , India
a r t i c l e i n f o
a b s t r a c t
A series of 9H, 10H, 3-[N- 4 methyl -2-benzamido thiophen 3-yl carbonyl amino [2-(20-phenyl 10-
ethylenyl)] 10-(aryl) thiazolidino [4, 5-b] 1, 5 benzodiazepine [7a–7h] were designed and synthesized to
meet the structural requirements essential for anticonvulsant activity. Anticonvulsant activity was
determined after intra-peritoneal administration to mice by supramaximal electroshock seizures model
and Isoniazide Hydrazone induced seizures model. Motor impairement was determined using acto-
photometer and rotarod apparatus. Among the synthesized compounds two [JG 7a and JG 7e]
compounds exhibited significant anticonvulsant activity after intra-peritoneal administration. Active
compounds carry hydroxy substitutent at 2-position and methoxy at 4-position in the phenyl ring at C5
of benzodiazepine. In present we study conclude that small polar and electron rich groups contribute
significantly for anticonvulsant activity while electronegative substitutents showed lesser contribution
for anticonvulsant activity.
Article history:
Received 30 June 2007
Received in revised form
28 July 2009
Accepted 10 September 2009
Available online 17 September 2009
Keywords:
Hybrid approach
Thiazolidinone
Anticonvulsant and locomotor activity
Thiophene
Benzodiazepine
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
(GABA) mediated synaptic inhibition [2]. GABA a primary neuro-
transmitter inhibitor of central nervous system, plays an important
The chemistry and pharmacological applications of condensed
diazepines are proved to be the fascinating field of investigation
during past few years. Derivatives of 1, 5 benzodiazepine are
reported to have tranquilizing, muscle relaxant, anti-convulsant,
and sedative actions [1]. Now a days many benzodiazepine deriv-
atives are widely used as daytime sedatives, tranquilizers, sleep
inducers, anesthetics, anticonvulsants, and muscle relaxants. The
use of this class of compound with therapeutic purposes is not only
confined to anxiety and stress conditions but also changes in the
structure of benzodiazepine can produce a host of different bio-
logical activity. Novel applications of this hybrid category of
compounds are continuously emerging [1]. Combined five atom
heterocycles and thiazolidinone ring system when fused with
benzodiazepine occupy a prominent place amongst drugs for
treatment of CNS disorders.
role in the arrest of convulsions. Many anticonvulsant drugs are
reported to act by increasing the GABA level in the brain [3].
Many reports are available on anticonvulsant activity of thia-
zolidine [4]. Thiophene ring is responsible for CNS depressant
action in general and anticonvulsant activity in particular but
literature is scarce on significant outcomes of its study. Due to
potential clinical applications of 1, 5 benzodiazepine, thiophene
and thiazolidine an attempt have been made to discover new, safe
and potent chemical entities for the treatment of epilepsy. The aim
of this study was to produce more active anticonvulsant drug than
currently available anticonvulsant agents without any side effects.
In this study combination of thiazolidine nucleus and benzodiaz-
epine was carried out using hybrid approach.
2. Results and discussion
The anticonvulsant activity of benzodiazepines can be corre-
lated to their ability to limit the sustained repetitive firing of
2.1. Chemistry
neurons, an effect mediated by enhancing
g-amino butyric acid
The synthetic route of compounds is outlined in Scheme 1. The
benzoylation of 2-amino 3-carboethoxy 4-methyl thiophene [1]
yielded 2-benzamido 3-carboethoxy- 4-methyl thiophene [2].
Hydrazination of compound [2] gave compound [3] which on
formation of Schiff’s base with a cinnamaldehyde yielded derivative
* Corresponding author. Department of Pharmaceutical Chemistry, A.I.S.S.M.S
College of Pharmacy, Near RTO, Kennedy Road, Pune-411001, Maharashtra, India.
E-mail address: drugdesign1@gmail.com (S.V. Bhandari).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.09.014

858
J.G. Ghogare et al. / European Journal of Medicinal Chemistry 45 (2010) 857–863
O
S
H2N
S
S
Pyridine,
Benzene
OC2H5
O
O
NH2NH2, H2O
reflux, 4 hr
H5C2O
H2NHN
NH
NH
O
O
C6H5COCl,
reflux at 60 0C, 1hr
[3]
[1]
[2]
C6H5CH=CH-CHO
ethanol, reflux, 2 hr
S
SHCH2COOH,
O
NH
O
N
-
N
NH
1,4 Dioxane
O
NH
12 hr reflux
S
NH
O
O
S
[5]
[4]
C2H5ONa,
OHC
-
6
8 hr
R
S
R
H2N
H
N
H2N
R
S
O
N
N
N
O
Xylene,
8 - 10 hr
O
S
NH
NH
NH
NH
S
O
O
[7a - 7f]
[6a - 6f]
Scheme I. Scheme I Synthetic route for compounds [7a–7f].
[4]. The compound [4] was further cyclized with mercptoacetic acid
in presence of anhydrous ZnCl2 to afford thiazolidinone derivative
[5], further compound [5] on treatment with different aromatic
aldehydes yielded [6a–6f]. This [6a–6f] series on further treatment
with O-phenylene diamine and xylene as solvent yielded 1, 5
benzodiazepines of compounds [7a–7f] respectively.
All above reactions were monitored by TLC using precoated TLC
plates. The absence of TLC spots for starting materials and
appearance of new TLC spots at different Rf values ensured the
completion of reaction. The TLC plates were visualized either by
iodine vapours or by observing in UV-visible chamber. Structures
and purity of anticipated compounds were characterized by
physical constant, FTIR spectral studies initially followed by 1H
NMR analysis. All the compounds were characterized by their
spectral and elemental analysis. The synthetic route is outlined in
Scheme-I.
and Fig. 2. The results of pharmacological studies of the synthesized
compounds of this series are reported in Table 1.
Spontaneous motor activity was measured using an actopho-
tometer and rotarod instruments. Each animal was placed in the
chamber for 1 min to get acclimatized and then activity was
measured for duration of 10 min. The compounds were tested at two
doses 10 mg/kg and 30 mg/kg intraperitoneally. Compounds having
thiazolidine ring at position 2 possess significant anticonvulsant
activity. Presence of 4-methoxy in aromatic ring at C5 of benzodi-
azepine (7e) ring have shown good anticonvulsant activity than 4-
fluro derivative against SMES model. Compound 7f i.e. 4-fluoro at
aromatic ring at C5 of benzodiazepine ring is less potent as compared
to 7e (-4-methoxy derivative) and 7d (dimethyl amino derivative) in
locomotor activity indicating requirement of small, electron rich
group at 4-position of aromatic ring at C5 of benzodiazepine and
requirement of thiazolidine at C2 of benzodiazepine ring. The
2.2. Pharmacology
The anticonvulsant activity of the synthesized compounds was
determined by evaluation of the ability of the compounds to protect
mice against convulsion induced by a lethal dose of isoniazide
hydrazone (INH) and electroshock models. Diazepam was consid-
ered as a reference standard for anticonvulsant effect in all the
models. The synthesized compounds, diazepam or vehicles were
administered 30 min before injection of INH 2.5 mg/kg or induction
of electroshock (42 mA and 0.2 s). The hind limb tonic extensions
were observed in supramaximal electroshock seizures (SMES)
model and reduction of seizure were observed in INH model,
30 min later. The compounds were tested at two doses 10 mg/kg
and 30 mg/kg intraperitoneally. Among the synthesized
compounds two [7a and 7e] were found to be more potent. The
graphical representations of compounds [7a–7f] are shown in Fig. 1
Fig. 1. Comparative locomotor activity of compounds JG7A-JG7H with diazepam using
actophotometer.

J.G. Ghogare et al. / European Journal of Medicinal Chemistry 45 (2010) 857–863
859
Table 2
Locomotor activity of compounds [7a–7f] using actophotometer and rotarod.
Group
Drug/test
compounds
Dose
(mg/kg)
Activity scorea
(0.5 h after)
Activity scorea
(fall of time)
1
2
3
4
5
6
7
8
Control
7a
7a
7b
7b
7c
7c
7d
7d
7e
7e
7f
–
323.33 ꢀ 2.689
54.33 ꢀ 2.155
52.33 ꢀ 2.261
51.66 ꢀ 2.217
59.66 ꢀ 2.261
57.67 ꢀ 2.217
55.50 ꢀ 2.261
51.00 ꢀ 2.082*
49.50 ꢀ 1.875*
48.50 ꢀ 1.875***
47.50 ꢀ 1.875***
64.68 ꢀ 2.472
62.83 ꢀ 2.472
46.33 ꢀ 2.445***
323.33 ꢀ 14.977
43.833 ꢀ 4.143*
42.607 ꢀ 3.989*
46.633 ꢀ 4.302
10
30
10
30
10
30
10
30
10
30
10
30
5
45.167 ꢀ 4.151***
49.00 ꢀ 4.619**
46.197 ꢀ 4.337
51.500 ꢀ 4.890*
50.750 ꢀ 4.802*
55.333 ꢀ 5.155*
53.00 ꢀ 5.007*
9
10
11
12
13
14
59.333 ꢀ 5.590***
56.833 ꢀ 5.288***
41.50 ꢀ 4.023***
Fig. 2. Comparative locomotor activity (fall of time) of compounds JG7A-JG7H with
diazepam using rotarod.
7f
Diazepam
a
pharmacological data of the synthesized compounds of this series is
shown in Table 2. The graphical representations of compounds [7a–
7f] are shown in Fig. 3 and Fig. 4.
Each score represents the mean ꢀ SEM of six mice, significantly different from
the control score. Data analyzed by one-way ANOVA followed by Student Newman
Keals Multiple Comparison test. n ¼ 6 animals in each group. [*p < 0.05, **p < 0.01,
***p < 0.001].
2.2.1. SMES model
The compounds when screened for their anticonvulsant
activity against (SMES) induced seizures, at 10 mg/kg and 30 mg/
kg body weight intraperitoneally, exhibited significant anticon-
vulsant activity. The characteristic feature of this series is presence
of thiazolidine nucleus which showed significant contribution to
anticonvulsant activity [5]. The results of the compounds 7b, 7f
showed poor anticonvulsant activity. Compounds 7a, 7c, 7d, 7e
were found to have significant anticonvulsant activity. This could
be due to presence of comparatively polar and electron rich
groups such as –OH, –Cl, –N–(CH3)2 and –OCH3. The compounds
7b and 7f were less potent in MES model and that might be due to
presence of comparatively less polar and electron withdrawing
groups.
seizure model was probably less predictive or the mechanism
through which these compounds reduced the firing of neurons was
different and therefore INH model yielded poor results for the same
set of compounds. Compounds [7a and 7e] have been found to be
equipotent with standard drug diazepam indicating presence of
optimum structural requirements.
In all considering the results of compounds of this series, it could
be concluded that all the nuclei viz. thiazolidine, thiophene and 1, 5
Benzodiazepine significantly contributed for the anticonvulsant
activity.
3. Conclusions
2.2.2. INH model
Considering the pharmacological results of all the newly
synthesized compounds, it can be concluded that: compounds
having thiazolidine ring at position 2 possesses significant anti-
convulsant activity. Presence of 4-methoxy group at aromatic ring
at C5 of benzodiazepine [7e] ring had shown good anticonvulsant
activity than 4-fluro [7f] derivative against MES model. Compound
[7f] was less potent as compared to 7e and 7d in locomotor activity
which indicated requirement of small, electron rich group at
4 position of aromatic ring at C5 of benzodiazepine and require-
ment of thiazolidine at C2 of benzodiazepine ring. The compounds
were found to be less potent anticonvulsant as compared to diaz-
epam in all models, indicating further investigations of structural
features required for anticonvulsant activity and probably the
pharmacokinetic profile of these drugs.
In INH model compounds [7a, 7c, 7d, 7e] were found to be
significantly active and more potent against INH induced convul-
sions while 7b and 7f were found to have poor activity.
2.2.3. Rota rod and actophotometer model
In case of locomotor activity the compounds [7a, 7c, 7d and 7e]
were more active than [7b and 7f]. This indicated INH induced
Table 1
Anticonvulsant activity of tested compounds [7a–7f] using SMES model and INH
induced seizures.
Group Drug/test
compounds
Dose (mg/kg) Duration of hind
limb extension
Reduction of
duration of
seizures (sec)
phase (sec)
1
2
3
4
5
6
7
8
Control
7a
7a
7b
7b
7c
7c
7d
7d
7e
7e
7f
–
24.514 ꢀ 0.5245
13.228 ꢀ 0.9674*
14.263 ꢀ 0.9436*
15.328 ꢀ 0.5226*
14.907 ꢀ 0.3916
34.12 ꢀ 0.7444
85.50 ꢀ 1.761**
87.667 ꢀ 1.211**
71.33 ꢀ 1.966*
78.833 ꢀ 1.169*
10
30
10
30
10
30
10
30
10
30
10
30
5
14.540 ꢀ 0.9780*** 81.833 ꢀ 1.169*
13.632 ꢀ 0.5490*** 83.33 ꢀ 0.7528*
13.355 ꢀ 0.8635*** 92.33 ꢀ 2.160***
13.000 ꢀ 0.9220*** 95.33 ꢀ 2.338***
15.328 ꢀ 0.5226*** 101.83 ꢀ 5.345***
14.907 ꢀ 0.3916*** 108.50 ꢀ 4.848***
9
10
11
12
13
14
16.442 ꢀ 0.5917
15.408 ꢀ 0.5578
69.833 ꢀ 1.472
74.00 ꢀ 0.8944
7f
Diazepam
8.500 ꢀ 0.5627*** 146.67 ꢀ 4.271***
Values are mean ꢀ SEM. Mice were pretreated with test compounds i.p. before the
induction of electroshock. Data analyzed by one-way ANOVA followed by Student
Newman Keals Multiple Comparison test. n ¼ 6 animals in each group. [p < 0.05*,
**p < 0.01, ***p < 0.001].
Fig. 3. Anticonvulsant activity (% reduction in extension of hind-limb) of compounds
JG7A-JG7H in comparison with diazepam using SMES model.

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J.G. Ghogare et al. / European Journal of Medicinal Chemistry 45 (2010) 857–863
Table 3
Physicochemical data for compounds [6a–6f].
Code no
‘R’
Molecular formula
Molecular weight
% Yield
Melting point (uncorrected)
Rf
7a
7b
7c
7d
7 e
7 f
-2- OH
-3-NO2
-2-Cl
-4-N, N (CH3)2
-4-(OCH3)
-4-F
C31H25N3S2O4
C31H24N4S2O5
C31H24N3S2O3Cl
C33H30N4S2O3
C32H27N3S2O4
567
596
585.5
594
581
569
71.57
73.92
76.23
82.84
66.67
80.65
181–182 ꢁ
197–198 ꢁ
135–136 ꢁ
134–135 ꢁ
163–164 ꢁ
209–210 ꢁ
C
C
C
C
C
C
0.745
0.846
0.723
0.501
0.788
0.342
C
31H24N3S2O3F
General structure of 9H, 10H, 3-[N(4-methyl 2-benzamido thiophen-3-yl)]carbonyl amino]2(2-phenyl 1- ethylenyl)10-(substituted aryl) thiazolidino [4,5-b] 1,5 benzodi-
azepine.
R
H
N
S
N
N
O
NH
NH
S
O
4. Experimental [23]
washed with 5% Na2CO3, followed by water. The produced mixture
was dried with anhydrous MgSO4. The benzene layer was separated
and concentrated to 1/3 rd volume and the resulting mixture was
stirred with n-hexane.
The yellow crystalline product [2] (Yield 79.14%, m.p.125–
126 ꢁC) separated was collected by filtration. IR (KBr): 3234(N–H
stretch of amine), 686 (C–S–C bond stretching), 1655 –C]O
stretching, 2976 (aromatic C–H stretch).
All the chemicals were analytical grade unless and otherwise
stated and procured from LOBA chemicals, Pune, India. Distilled
water was used for solution preparation of test compounds,
melting points were taken by using melting point apparatus and
were uncorrected. Elemental analysis was done by elemental vario
EL Z Carlo Erba 1108 elemental analyzer. IR spectra recorded on
JASCO-FTIR V430þ instrument using KBr pellet technique. 1H NMR
spectra were recorded by FT NMR Varian Mercury YH300 spec-
trophotometer. The protocol for the animal experiments performed
was approved by CPCSEA. Test compounds were prepared by
dissolving it in distilled water along with Tween 80.
4.1.2. 2-(Benzamido)-3-hydrazido 4-methyl thiophene- [8]
Compound [2] (0.02 mol) and 99% hydrazine hydrate were
mixed in 1:3 proportion. The mixture was refluxed for 10 min. To
this mixture ethanol was added till both the layers were miscible
and was refluxed for 4 h. The mixture was concentrated, allowed to
cool at room temperature, and then poured into ice-cold water.
The solid thus obtained was filtered, dried and recystallized
from ethanol to get compound [3] (Yield 76.46%.m.p., 150–151 ꢁC).
IR (KBr): 3325 (–NH stretch), 2919 (–CH3 stretch), 3216 (–NH–NH2
stretching).
4.1. Synthesis
4.1.1. [(Ethyl 2-(benzamido)-3 carboethoxy 4-methyl thiophene)]
[6,7]
Compound [1] (0.03 mol), pyridine (0.04 mol) and benzene
(0.04 mol), benzoyl chloride (0.03 mol) were taken in a round
bottom flask. The reaction mixture was refluxed at 60 ꢁC for 60 min.
The resultant reaction mixture was cooled, and poured into ice-cold
water. The benzene layer was separated and aqueous layer was
again extracted with benzene. The collected benzene extract was
4.1.3. 2-Benzamido-4-methyl-3-N-[40-phenylprop-10, 30dieneimino]
thiophen-3-carboxamide [9]
A mixture of compound [3] (0.01 mol) and cinnamaldehyde
(0.01 mol) and 2–3 drops of glacial acetic acid in ethanol was
refluxed for about 2 h. The solvent was removed under reduced
pressure to afford product [4] Schiff base.
The product was recrystallized using ethanol (Yield 88.37%, m.p.
239–240 ꢁC). IR (KBr): 3304 (N–H stretch), 1671 (–C]O stretch of
CONH), 1546 (C]N stretch), 696 (C–S–C bond stretching), 1576
(–N]N stretch).
4.1.4. 2-Benzamido-4-methyl-N-[20-(2-phenyl 1-ethylenyl)-
4-oxothiazolidin-3-yl] thiophene-3-carboxamide [10]
Schiff Base [4] (0.015 mol) was dissolved in sufficient quantity of
1, 4 dioxane (0.015 mol) and mercaptoacetic acid (0.015 mol) and
pinch of anhydrous ZnCl2 was added to it. The reaction mixture was
refluxed on water bath for 12 h. The solid obtained was triturated
with excess of 10% NaHCO3 solution.
Fig. 4. Anticonvulsant activity (% reduction in seizure) of compounds JG7A-JG7H in
comparison with diazepam using INH induced seizure.

J.G. Ghogare et al. / European Journal of Medicinal Chemistry 45 (2010) 857–863
861
Table 4
Physicochemical properties of compounds [7a–7f].
Code no.
R
Molecular formula
37H31N5S2O3
C37H30N6S2O4
C37H30N5S2O2 Cl
C39H36N6S2O2
C38H33N5S2O3
C37H30N5S2O2F
Molecular weight
% Yield
Melting point (uncorrected)
% C
% H
% N
7a
7b
7c
7d
7e
7f
-2-OH
-3-NO2
-2-Cl
-4-N (CH3)2
-4-(OCH3)
-4-F
C
657
686
675.5
684
671
658
33.18
31.94
85.06
50.00
84.26
67.09
110–111 ꢁ
218–219 ꢁ
220–221 ꢁ
C
C
C
66.073 (66.47)
64.983 (64.72)
66.748 (66.31)
70.271 (69.92)
68.126 (68.38)
68.364 (68.12)
5.472 (5.071)
5.258 (4.918)
5.372 (5.11)
6.564 (6.291)
5.417 (5.05)
5.475 (5.231)
11.943 (11.456)
12.854 (12.636)
9.461 (9.621)
12.616 (12.358)
10.435 (10.71)
12.163(12.44)
90–91 ꢁ
C
240–241 ꢁ
119–120 ꢁ
C
C
The precipitate obtained [5] was filtered and dried (Yield 71.68%,
m.p. 110–111 ꢁC). IR (KBr): 2978 (C–H bond stretch), 1724 (–C]O
stretch of CONH), 1536 (C]N stretch), 696 (C–S–C bond stretching),
1576 (–N]N stretch).
6f] were synthesized in a similar way. The details of results
obtained are listed in Table 3.
4.1.6. 9H, 10H, 3[N(4-methyl 2-benzamido thiophen-3-yl)]carbonyl
amino] 2(2-phenyl 1- ethylenyl) 10-(2-hydroxy phenyl) thiazolidino
[4,5-b] 1,5 benzodiazepine [12]
4.1.5. 2-Benzamido-4-methyl-N-[20-(2-pheny1 1-ethylenyl)-50
(2-hydroxy phenyl) methenyl-4-oxothiazolidin 3-yl] thiophene
3-carboxamide [11]
Compound [5], (0.002 mol) in presence of sodium ethoxide
(0.002 mol) was refluxed in 1, 4 dioxane (50 mL) for about 6–8 h
and then cooled. The reaction mixture was poured into ice-cold
water. The product precipitated out was filtered, dried and
recrystallised using methanol. The resulting compound [6a] (Yield
71.57%, m.p.181–182 ꢁC) collected by filtration. Compounds [6b to
A solution of compound [6a] was prepared (0.003 mol) in hot
xylene and a solution of o-phenylene diamine (0.003 mol) in xylene
was prepared separately. Both the solutions were mixed in small
proportions and refluxed for 6–10 h using Dean-stark apparatus.
Excess solvent was distilled off at reduced pressure to afford
product [7a].
The compound obtained had yield 33.18%. m.p.110–111 ꢁC.
Similarly compounds [7b–7f] were synthesized by reacting with
Table 5
Spectral data of compounds [7a–7f].
Compound
7a
IR(KBr) Vmax (cmꢂ1
)
NMR (CDCl3 þ DMSO)
d ppm
H
N
OH
2.26 (s,3H, –CH3), 7.164 (s,1H ,
a –CH of thiophene)
3231(N–H stretch of amine),3862(–OH bond stretch),
686(C–S–C bond stretching),1312(–NH bending of
thiazolidine ring), 1745(–C]O stretching) 1680
(–C]O stretching of CONH), 1298 (NH in plane)
S
7.252(s,1H, –CH of thiophene),8.175(s,1H, –NH of benzoyl),
b
N
7.807 (s,5H, Ar–H of benzoyl), 3.036 (d,1H, –CH of
thiazolidine), 2.574(t,2H,–CH]CH), 7.524 (s,5H,–C6H5 of
cinnamaldehyde), 2.630 (d, 1H, 9H of 1,5 BZD), 2.653 (t,1H,
–CH 10H of 1,5 BZD), 7.524 (s,4H, OPD), 7.501 (s,2H, Ar-H of
sallicyldehyde), 3.321(s,1H –OH)
N
O
NH
NH
NH
NH
S
O
O
O
7b
NO2
H
N
S
3351(–NH stretch), 2921(–CH3 stretch) , 2960(C–S–C,
cyclic S), 1622(C]C Ar conjugated), 1746(C]O stretching 7.297(s,1H,
of cyclic amide) 1674 (C]O stretching of primary amide) 4.3 (s,1H,–NO2)
1541 (NO2 stretching), 839 (–C–N stretching) , 1578
(–N–O stretch), 1285(–NH in a plane)
2.274 (s,3H, –CH3), 7.160 (s,1H ,
a –CH of thiophene)
N
b
–CH of thiophene),8.202(s,1H, –NH of benzoyl)
N
O
NH
S
7c
H
N
Cl
S
3340 (–NH stretch of amine), 3097(aromatic CH stretch), 2.241 (s,3H, -CH3), 7.153 (s,1H ,a –CH of thiophene)
2924 (–CH2 stretch) ,1666(–C]O stretch of -CONH),
1288(–N–H in plane, 695 (C–S–C stretching), 745
(C–Cl bond bending)
7.231(s,1H, b-CH of thiophene), 3.036 (d,1H, –CH of
thiazolidine), 2.574(t,2H,–CH]CH),3.8(s,1H, –Cl), 2.630
(d, 1H, 9H of 1,5 BZD), 2.653 (t,1H, –CH 10H of 1,5 BZD)
N
N
O
NH
S
(continued on next page)

862
Table 5 (continued)
J.G. Ghogare et al. / European Journal of Medicinal Chemistry 45 (2010) 857–863
Compound
7d
IR(KBr) Vmax (cmꢂ1
)
NMR (CDCl3 þ DMSO)
d ppm
N
H
N
3210 (N–H bond stretch), 2963 (C–S–C, cyclic S), 1360
(C–N stretching of ter. Amide), 1665 (–C]O stretch
of CONH), 1523 (C]N stretch), 818 (C–S–C bond
stretching), 1224(–CH3 stretch) 757(1,2 disubstitued
benzene)
2.273 (s,3H, –CH3), 7.189 (s,1H ,
a –CH of thiophene)
7.253(s,1H, –CH of thiophene),8.027(s,1H, –NH of benzoyl),
b
S
7.497 (s,5H, Ar–H of benzoyl),8.339(s,1H, –NH of CONH),
2.778(d,1H, –CH of thiazolidine)2.413 (d, 1H,–CH]CH),
2.660 (t,2H, –CH]CH), 7.524 (s,4H, OPD),1.266
N
N
O
NH
[s,6H, N(CH3)2
]
NH
S
O
7e
O
H
N
3162 (N–H bond stretch of amine), 1674 (–C]O stretch
of –CONH),1602 (–]CH aromatic stretch), 1543
(C]NH stretch),1259 (C–N stretching), 682 (C–S–C bond
stretching) 1157 (–C]O stretch of aralkyl ether)
7 7.252 (s,1H, b–CH of thiophene ,8.175(s,1H, –NH of
S
benzoyl), 7.807 (s,5H, Ar–H of benzoyl), 3.036 (d,1H, –CH of
thiazolidine), 2.574(t,2H,–CH]CH), 7.524 (s,5H,–C6H5 of
cinnamaldehyde), 2.630 (d, 1H, 9H of 1,5 BZD), 2.653
(t,1H, CH 10H of 1,5 BZD),3.711(s.4H, –OCH3)
N
N
O
NH
NH
S
O
7f
F
H
N
3361(N–H stretch of amine) , 3090 (aromatic CH stretch), 2.281 (s,3H, –CH3), 7.150(s,1H ,
a –CH of thiophene)
–CH of thiophene), ,8.175(s,1H, –NH of benzoyl),
7.807 (s,5H, Ar–H of benzoyl), 3.036 (d,1H, –CH of
thiazolidine), 2.574(t,2H,–CH]CH), 7.524 (s,5H,–C6H5 of
cinnamaldehyde), 2.630 (d, 1H, 9H of 1,5 BZD), 2.653 (t,1H,
–CH 10H of 1,5 BZD),4.312(s,1H, –F)
S
1676 (–C]O stretch of –CONH), 1603 (–C]CH stretching), 7.290(s,1H,
b
N
1225 (N-H in a plane), 743 (1,2 disubstitued benzene),
696 (C–S–C bond stretching), 1102 (C–F stretching)
N
O
NH
NH
S
O
respective aldehydes. The details of results obtained are listed in
Table 4. IR (KBr): 3351(–NH stretch), 2921 (–CH3 stretch), 2960 (C–
S–C, cyclic S), 1622 (C]CAr conjugated), 1746 (C]O stretching of
cyclic amide) 1674 (C]O stretching of primary amide) 1541 (NO2
stretching), 839 (–C–N stretching), 1578 (–N]O stretch), 1285
(–NH in a plane). All the data is analyzed by IR (KBr) and NMR,
resulting data is shown in Table 5.
injected intraperitoneally for ½ h before the supramaximal elec-
troshock. The protective index was defined as the abolition or
reduction of the hind limb tonic extension component of seizure.
The lesser time for which hind-limb tonic extension was observed,
more potent the compound as anticonvulsant.
4.2.2. INH induced seizures
INH induced seizures test was performed on Swiss albino mice
weighing 30–35 g. The mice were injected with test drug 10 and
30 mg/kg intraperitoneally. After 30 min, INH injection of dose
250 mg/kg was given intraperitoneally. The animals developed the
sequence of excitement, myoclonic jerks, clonic seizures, one or
more maximal seizures. Animals exhibiting these seizures pattern
were detected and divided into the groups of 6 animals each. The
standard drug used in this model was diazepam [15,16].
4.2. Anticonvulsant activity
4.2.1. SMES pattern test
The SMES pattern test was performed according to the method
of Tomon, et.al. [13] using Swiss albino mice of either sex, weighing
in the range 30–35 g. Mice were divided into groups of six animals
each and mice were treated with two doses of test drugs mainly
10 mg/kg and 30 mg/kg intraperitoneally. Similarly diazepam at
5 mg/kg was given to standard group. After 1 h mice were sub-
jected to the electroshock of 42 mA by electro-convulsiometer
through ear electrode for 0.2 s by a techno convulsiometer [14].
Animals which showed positive hind limb tonic extensor response
during pre-screening were selected and the test drugs were
4.3. Locomotor activity
4.3.1. Using actophotometer
Actophotometer was used to evaluate the locomotor activity
[17,18]. The Swiss albino mice weighing in range 30–35 g were

J.G. Ghogare et al. / European Journal of Medicinal Chemistry 45 (2010) 857–863
863
divided into six groups each consisting of six mice. One group
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Authors are grateful to the Head, Department of Sophisticated
Analytical Instrument Facilities, CDRI, Lucknow for performing
elemental analysis of newly synthesized compounds. We
acknowledge the support extended by National Chemical Labora-
tory, Pune for providing library facilities and University of Pune for
analyzing 1HNMR of newly synthesized compounds.