Synthesis and anticonvulsant and neurotoxicity evaluation of N 4-phthalimido phenyl (thio) semicarbazides

Article abstract of DOI:10.1016/j.ejps.2003.08.002

The phenyl (thio) semicarbazide derivatives of phthalimido pharmacophore were synthesized and evaluated for their anticonvulsant and neurotoxic properties. Initial anticonvulsant screening was performed using intraperitoneal (i.p.), maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (sc STY)-induced seizure threshold tests in mice. Compound 2c afforded protection in all the three screens. Compounds except 1d, 2a and 2d showed no neurotoxicity up to 300mg/kg. Compounds 1a, 1b, 2c, 2d, 2g and 2i were found to show oral MES activity. The compounds exhibited CNS depression and behavioral despair side effects, lesser than the conventional antiepileptic drugs.

Full text of DOI:10.1016/j.ejps.2003.08.002

European Journal of Pharmaceutical Sciences 20 (2003) 341–346
Synthesis and anticonvulsant and neurotoxicity evaluation of
N4-phthalimido phenyl (thio) semicarbazides
P. Yogeeswaria,∗, D. Srirama, V. Saraswata, J. Vaigunda Ragavendrana,
M. Mohan Kumara, S. Murugesana, R. Thirumurugana, J.P. Stablesb
a
Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani 333031, India
b
Preclinical Pharmacology Section, Epilepsy Branch, National Institute of Health, MD 20892, USA
Received 31 December 2002; received in revised form 22 July 2003; accepted 7 August 2003
Abstract
The phenyl (thio) semicarbazide derivatives of phthalimido pharmacophore were synthesized and evaluated for their anticonvulsant and
neurotoxic properties. Initial anticonvulsant screening was performed using intraperitoneal (i.p.), maximal electroshock-induced seizure
(MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (sc STY)-induced seizure threshold tests in mice. Compound
2c afforded protection in all the three screens. Compounds except 1d, 2a and 2d showed no neurotoxicity up to 300 mg/kg. Compounds 1a,
1b, 2c, 2d, 2g and 2i were found to show oral MES activity. The compounds exhibited CNS depression and behavioral despair side effects,
lesser than the conventional antiepileptic drugs.
© 2003 Published by Elsevier B.V.
Keywords: Phthalimides; Semicarbazides; Thiosemicarbazides; Anticonvulsants; CNS depressants
1. Introduction
N-phenyl pthalimide derivatives have emerged as potent anti-
convulsants (Vamecq et al., 1998, 2000).
In recent years, aryl semicarbazones (Dimmock et al.,
1993; Pandeya et al., 1999a, 2000; Puthucode et al., 1998)
and thiosemicarbazones (Dimmock et al., 1990; Karali and
Gursoy, 1994; Yogeeswari et al., 2002) have emerged as
structurally novel anticonvulsants. Aryl semicarbazides are
reported to display excellent anticonvulsant activity in mice
and rats compared to that of phenytoin (Andurkar et al.,
2001). The aryl semicarbazones were believed to interact
at locations on the putative binding site designated as aryl
binding site, a hydrogen bonding domain and an auxiliary
aryl binding site (Dimmock et al., 1995a). The aryl binding
site can be phenyl or other hydrophobic moieties with reten-
tion of the anticonvulsant activity (Dimmock et al., 1995b;
Pandeya et al., 2001). N-Phenyl phthalimide derivatives were
also found to possess anticonvulsant potency associated with
a phenytoin-like profile (Bailleux et al., 1994a, 1994b, 1995;
Poupaert et al., 1995). More recently a variety of substituted
In view of these data, we have undertaken the synthe-
sis and pharmacological evaluation of hybrids of aryl (thio)
semicarbazides and N-phenyl phthalimides (Fig. 1). In the
present work, synthesis of N4-phthalimido phenyl semicar-
bazide and thiosemicarbazide derivatives was accomplished.
The compounds were evaluated for their antiepileptic and
neurotoxic properties through the antiepileptic drug devel-
opment (ADD) program developed by the National Insti-
tute of Health (Kupferberg and Stables, 1998; Stables and
Kupferberg, 1997; White et al., 1995a, 1995b). The com-
pounds were also evaluated for other CNS activities.
2. Experimental
2.1. Chemistry
The melting points were determined in open capillary
tubes in a Thomas Hoover melting point apparatus and are
uncorrected. IR spectra were recorded as KBr pellets on
∗
Corresponding author. Tel.: +91-1596-244684;
fax: +91-1596-244183.
1
E-mail address: pyogie 2000@rediffmail.com (P. Yogeeswari).
a Jasco IR Report 100 Spectrophotometer. The H NMR
0928-0987/$ – see front matter © 2003 Published by Elsevier B.V.
doi:10.1016/j.ejps.2003.08.002

342
P. Yogeeswari et al. / European Journal of Pharmaceutical Sciences 20 (2003) 341–346
Fig. 1. Synthetic protocol of the target compounds.
spectra were taken on a Jeol Fx 90Q Fourier transform
NMR spectrometer. Chemical shifts (δ) are expressed in
ppm relative to tetramethylsilane (TMS) as an internal stan-
dard. Elemental analyses were realized on a Perkin-Elmer
model 240c analyzer and were within 0.4% of the the-
oretical values. The homogeneity of the compounds was
checked by TLC on silica gel.
sodium cyanate in the presence of glacial acetic acid. The
urea thus obtained was refluxed with equimolar amounts of
hydrazine hydrate and sodium hydroxide in ethanol as the
solvent.
2.1.2. Synthesis of aryl thiosemicarbazides
Aryl thiosemicarbazides were prepared from the respec-
tive anilines in a similar manner as reported earlier (Pandeya
et al., 1999c). Anilines on treatment with carbon disulphide
in the presence of potassium hydroxide in tetrahydrofuran
gave potassium salt of the corresponding dithiocarbamate,
which on reaction with hydrazine hydrate yielded the re-
spective thiosemicarbazide.
2.1.1. Synthesis of aryl semicarbazides
Aryl semicarbazides were prepared from the respec-
tive anilines according to the procedures reported earlier
(Pandeya et al., 1999b). Briefly aryl ureas were prepared
from anilines by reacting with equimolar quantities of
Table 1
Physical constants of the synthesized compounds
b
c
Compound
X
R
Yield (%)
Melting point (◦C)
Molecular formulaa
C9H7N3O3
Rf
Rm
1a
1b
1c
1d
1e
1f
1g
1h
2a
2b
2c
2d
2e
2f
2g
2h
2I
2j
2k
2l
O
O
O
O
O
O
O
O
S
S
S
S
S
S
S
S
S
S
S
S
S
–
2-Cl
4-Cl
4-NO2
4-OCH3
4-SO3H
4-NHCOCH3
4-N N–Ph
–
32
46
41
64
61
89
62
95
51
60
99
54
46
59
61
56
55
56
70
89
61
244
139
184
206
149
268
264
246
249
273
159
194
169
137
154
193
279
275
151
164
251
0.73
0.77
0.40
0.37
0.40
0.66
0.75
0.72
0.67
0.71
0.74
0.68
0.52
0.45
0.75
0.62
0.58
0.54
0.72
0.36
0.90
−0.44
−0.54
0.18
0.23
0.18
C15
C15
H
H
10N3O3Cl
10N3O3Cl
C
C
15H10N4O5
16H13N3O4
C15H11N3O6S
C17H14N4O4
C21H15N5O3
−0.29
−0.48
−0.42
−0.31
−0.40
−0.46
−0.33
−0.68
0.09
−0.48
−0.21
−0.14
−0.07
−0.42
0.25
=
C9H7N3O2S
2-Cl
4-Cl
C15H10N3O2SCl
C15H10N3O2SCl
C15H10N4O4S
C15H10N4O4S
C16H13N3O3S
C16H13N3O3S
C16H13N3O2S
C15H11N3O3S
2-NO2
4-NO2
2-OCH3
4-OCH3
4-CH3
4-OH
4-COOH
4-COOEt
4-SO2NH2
C
C
C
16H11N3O4S
18H15N3O4S
15H12N4O4S2
=
2m
4-N N–Ph
C21
H15N5O2S
−0.96
a
Elemental analyses for C, H, N were within 0.4% of the theoretical values.
b
Eluants used in TLC were petroleum ether:ethyl acetate (7:3) for all compounds except 1a, 1c, 1g, 1h, 2a, 2e, 2h and 2l for which chloroform:methanol
(9:1) was used.
c
Rm = log(1 − 1/Rf ).

P. Yogeeswari et al. / European Journal of Pharmaceutical Sciences 20 (2003) 341–346
343
2.1.3. General Method for the synthesis of N4-phthalimido
phenyl (thio) semicarbazides
2h (CDCl3): 2.30 (s, 3H, CH3), 6.75 (s, 1H, ArNH, D2O
exchangeable), 7.65–8.22 (m, 8H, ArH), 9.55 (s, 1H,
C3NH, D2O exchangeable).
The titled compounds were synthesized as per the re-
ported procedure for N-phenyl pthalimides (Hearn and
Lucas, 1984; Vamecq et al., 2000). An equimolar mixture
of the respective aryl (thio) semicarbazide and phthalic an-
hydride in acetic acid was stirred and heated under reflux
for 5 h. The product of this reaction was precipitated by
the addition of water, filtered, dried and recrystallized from
95% ethanol. The physical data of the titled compounds
are presented in Table 1. IR spectra (ν, cm−1) of some
representative compounds were as follows:
2.2. Pharmacological evaluation
The anticonvulsant evaluation was carried out using re-
ported procedures (Löscher and Schmidt, 1994; Krall et al.,
1978; Porter et al., 1984). Male albino mice (CF-1 strain,
18–25 g) and male albino rats (Sprague–Dawley, 100–150 g)
were used as experimental animals. The test compounds
were suspended in 0.5% methyl cellulose–water mixture or
in polyethylene glycol (PEG).
=
1c: 3500 (amino), 3300 (CONH), 1780–1720 (C O of
=
phthalimide), 1635, 1450 (phenyl), 1620 (C O), 1100
2.2.1. Anticonvulsant screening
(C–Cl).
In the preliminary screening, each compound was ad-
ministered as an i.p. injection at three dose levels (30,
100 and 300 mg/kg) and the anticonvulsant activity as-
sessed after 30 min and 4 h intervals of administration.
The anticonvulsant efficacy was evaluated by the max-
imal electroshock-induced seizure (MES), subcutaneous
pentylenetetrazole (scPTZ) and subcutaneous strychnine
(scSTY)-induced seizure threshold tests and the data are pre-
sented in Table 2. Some selected derivatives described in this
study were examined for oral activity in the rat MES screen
(Brodie, 1992) and the results are presented in Table 3.
=
1d: 3420 (amino), 3346 (CONH), 1765, 1705 (C O of
phthalimide), 1635, 1490 (phenyl), 1650 (C O), 1350
(nitro).
=
2h: 3426, 3340, 1633 (amino), 1780, 1711 (imide), 1500
1
=
(C S), 1660, 1470 (phenyl), H NMR (90 MHz, δ ppm)
spectra of some representative compounds were as fol-
lows:
1e (CDCl3): 3.65 (s, 3H, OCH3), 5.85 (s, 1H, ArNH,
D2O exchangeable), 7.7–8.4 (m, 8H, ArH), 8.77 (s, 1H,
CONH, D2O exchangeable).
Table 2
Anticonvulsant and neurotoxicity screening results of the titled compounds
Compound
Intraperitoneal injection in micea
MES screen
0.5 h
scPTZ screen
scSTY screenb
0.5 h
Toxicity screen
4 h
0.5 h
4 h
4 h
0.5 h
4 h
1b
1c
1d
1f
1g
2a
2c
2d
2e
2g
2I
2j
100
–
–
–
–
–
–
–
–
300
–
–
–
30
30
–
–
–
–
300
30
–
–
300
–
–
–
–
300
–
–
100
–
–
–
–
300
–
–
–
–
–
–
–
300
–
–
X
X
X
X
X
X
X
X
X
–
300
–
300
–
–
–
–
X
X
X
X
X
–
–
–
–
–
300
300
–
–
–
–
–
–
–
–
–
–
–
100
–
–
–
–
–
–
100
300
–
–
300
300c
–
d
–
300
–
300
–
–
–
–
–
300
30
100
–
–
30
X
300
300
300
300
–
300
–
300
X
X
X
X
X
e
2m
–
Phenytoinf
Carbamazepinef
Sodium valproatef
Ethosuximidef
Phenobarbitalf
–
100
100
–
–
100
100
300
300
30
–
100
30
a
Doses of 30, 100 and 300 mg/kg were administered. The figures in the table indicate the minimum dose whereby bioactivity was demonstrated in
half or more of the animal. The animals were examined 0.5 and 4 h after administration. The dash (–) indicates an absence of activity at maximum dose
administered (300 mg/kg) and ‘X’ mark indicates not tested.
b
Rats were used as experimental animals.
At 100 mg/kg, 1/6.
At 100 mg/kg, 1/4.
At 100 mg/kg after 2 h, 2/3 and at 30 mg/kg, 1/5.
c
d
e
f
Data from references (Dimmock et al., 1996; Porter et al., 1984; Flaherty et al., 1996).

344
P. Yogeeswari et al. / European Journal of Pharmaceutical Sciences 20 (2003) 341–346
Table 3
Table 5
Evaluation of selected compounds in the MES test after oral administration
(30 mg/kg) to rats
CNS depressant study on selected N4-pthalimido phenyl semicarbazides
in forced swim pool test
Compound
Oral administration to ratsa
Compounda
Immobility timeb (min)
0.25 h
0.5 h
1 h
2 h
4 h
Control
(24 h prior)
Post-treatment
(60 min after)
1a
1b
2c
2d
2g
2I
0
1
X
3
1
0
1
0
4
1
0
3
0
4
0
2
0
0
2
0
3
2
3
2
1
1
2
3
2
1
2
2
0
0
3
PEG
1a
1c
1d
1e
1f
1g
1h
136.3
132.8
127.4
137.3
133.5
132.2
143.9
128.3
138.4
125.8
135.3
6.3
8.4
7.3
8.1
4.3
2.2
8.1
7.7
7.3
8.9
9.7
l21.2
152.4
147.6
146.4
131.2
123.6
150.6
132.6
240.6
265.8
87.6
9.6
9.3
8.7
4.1
2.5 NS
2.6
5.1 NS
4.2 NS
4.l
Phaenytoin
a
The figures indicate the number of rats out of four, which were
protected. The mark ‘X’ indicates not tested.
Carbamazepine
Sodium valproate
Imipramine
4.3
4.6
a
2.2.2. Neurotoxicity screen
The compounds were tested at a dose of 30 mg/kg (i.p.).
Each value represents the mean S.E.M. of six rats significantly
b
Minimal motor impairment was measured in mice by the
rotarod test. The mice were trained to stay on an accelerat-
ing rotarod that rotates at 10 revolutions/min. The rod diam-
eter was 3.2 cm. Trained animals were given i.p. injection
of the test compounds in doses of 30, 100 and 300 mg/kg.
Neurotoxicity 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.
different from the control at P < 0.005, and NS, denotes not significant
at t99.5% (Student’s t-test).
2.2.3. Behavioral test
The titled compounds (30 mg/kg) were screened for their
behavioural effects using actophotometer (Boissier and
Simon, 1965). Albino mice were placed inside the actopho-
tometer after 30 min of drug injection. The behaviour of
animals inside the photocell was recorded as a digital score.
Increased scores suggest good behavioural activity. The
control animal was administered PEG. The observations are
tabulated (Table 4).
Table 4
Behavioral study on the titled compounds using actophotometer
Compounda
Scoreb (time span 5 min)
Control
1a
1b
1c
1d
1e
1f
1g
1h
2a
2b
2c
2d
2e
2f
2g
275
410
216
111
155
173
141
38
115
108
294
276
210
409
204
217
207
286
330
285
60
31.11∗∗
13.58∗∗
15.74∗∗
32.75∗∗
10.25∗∗
23.69∗∗
10.46∗∗
22.35∗∗
12.00∗∗
12.37∗∗
13.54∗
2.2.4. CNS depressant study
The forced swim pool method described earlier was fol-
lowed (Porsolt et al., 1978). Albino mice were placed in
a chamber (diameter: 45 cm; height: 20 cm) containing wa-
ter up to a height of 15 cm at 25 2 ◦C. Two swim ses-
sions were conducted, an initial 15 min pre-test, followed
by a 5 min test 24 h later. The animals were administered
an i.p. injection (30 mg/kg) of the test compounds after the
pre-test session. The period of immobility (passive floating
without struggling and making only those movements which
are necessary to keep its head above the surface of water)
during the 5 min test period were measured. The results are
presented in Table 5.
15.57∗N∗ S
16.15∗∗
22.32∗∗
20.33
10.22∗∗
10.12∗∗
24.44 NS
27.73∗∗
20.22 NS
6.32∗∗
2h
2I
2j
2l
3. Results and discussion
2m
Phenytoinc
Phenobarbitalc
Sodium valproatec
44
346
30
4.56∗∗
Initial anticonvulsant activity and neurotoxicity data for
the titled compounds are reported in Table 2 along with
the literature data on phenytoin, carbamazepine, sodium
valproate, phenobarbital and ethosuximide (Porter et al.,
1984; Dimmock et al., 1996; Flaherty et al., 1996). The
MES and subcutaneous pentylenetetrazole (scPTZ) tests
have become the most widely employed seizure models for
the early identification and high throughput screening of
7.22∗∗
3.66∗∗
a
The compounds were tested at a dose of 30 mg/kg (i.p.).
Each score represents the mean S.E.M. of six rats significantly
b
different from the control and NS, insignificant (Student’s t-test).
c
Tested at 5 mg/kg p.o. and for sodium valproate at 100 mg/kg p.o.
∗
∗∗P < 005.
P < 0.005.

P. Yogeeswari et al. / European Journal of Pharmaceutical Sciences 20 (2003) 341–346
345
investigational antiepileptic drugs. At the three doses (30,
100 and 300 mg/kg) tested, compounds 1a, 1e, 1h, 2b, 2f,
2h, 2k and 2l were found to be devoid of activity in both
MES and scPTZ tests and presented no neurotoxicity in
any of the doses administered. Compounds that exhibited
anti-MES activity include 1b, 1c, 1g, 2c, 2g and 2m show-
ing their ability to prevent seizure spread and the mecha-
nism may involve blockade of neuronal voltage-dependent
Na+ channels as exhibited by the N-phenyl phthalimides
(Vamecq et al., 2000). Among these 2c exhibited protec-
tion against all the screens with neurotoxicity. In the MES
screen, 2-chioro phenyl semicarbazide, 1b was more potent
than 4-chioro derivative, 1c but with thiosemicarbazides
it was the opposite. The nitro derivatives (1d, 2d and 2e)
were found to be ineffective in this screen. The 4-methoxy
phenyl thiosemicarbazide (2g) did show activity and the
semicarbazide analog did not. Similar results were obtained
with the 4-diazo compounds (1h and 2m). The compounds
1c, 1d, 1f, 2c and 2j showed anti-scPTZ activity indicat-
ing their ability to elevate seizure threshold. Compound
1f was more potent than sodium valproate and ethosux-
imide. In the PTZ screen, the 4-chloro phenyl compound
(1c and 2c) showed protection at 100 and 300 mg/kg but
the 2-chioro derivative (1b and 2b) did not show any pro-
tection. The 4-phenyl sulfonic acid (1f) derivative showed
more potency than other compounds. Among the thiosemi-
carbazide derivatives, compounds that showed protection
against subcutaneous strychnine induced seizure threshold
test (scSTY) include 2a, 2c–2e and 2i which indicate that
N4-pthalimido phenyl thio semicarbazides could also act
through inhibitory glycine receptors. In the neurotoxicity
screen, all the compounds except 2a and 2c were devoid of
toxicity at doses up to 300 mg/kg.
forced swim pool test and compared with Imipramine. The
present study showed an increase in the immobility time by
all the compounds (except 1e and 1f) but not as much as
the standard antiepileptic drugs carbamazepine and sodium
valproate, indicating lesser CNS depression effects than that
of conventional drugs.
In conclusion the present results have revealed that a num-
ber of phthalimido phenyl (thio) semicarbazides exhibit a
range of activities in anticonvulsant screens, with compound
1b showing anti-MES activity comparable with phenytoin.
References
Andurkar, S.V., Beguin, C., Stables, J.P., Kohn, H., 2001. J. Med. Chem.
44, 1475.
Bailleux, V., Vallee, L., Nuyts, J.P., Vamecq, J., 1994a. Biomed. Phar-
macother. 48, 95.
Bailleux, V., Vallee, L., Nuyts, J.P., Vamecq, J., 1994b. Chem. Pharm.
Bull. 42, 1817.
Bailleux, V., Vallee, L., Nuyts, J.P., Hamoir, G., Poupaert, J.H., Stables,
J.P., Vamecq, J., 1995. Epilepsia 36, 559.
Boissier, J.R., Simon, P., 1965. Arch. Int. Pharmacodyn. Ther. 158, 212.
Brodie, J.M., 1992. Lancet 339, 1397.
Dimmock, J.R., Jonnalagadda, S.S., Hussain, S., Tiwari, S., Quail, J.W.,
Reid, R.S., Delbaere, L.T.J., Prasad, L., 1990. Eur. J. Med. Chem.
25, 581.
Dimmock, J.R., Sidhu, K.K., Thayer, R.S., Mack, P., Duffy, M.J., Reid,
R.S., Quail, J.W., 1993. J. Med. Chem. 36, 2243.
Dimmock, J.R., Pandeya, S.N., Quail, J.W., Pugazhenthi, U., Allen, T.M.,
Kao, G.Y., Balzarini, J., De Clercq, E., 1995a. Eur. J. Med. Chem.
30, 303.
Dimmock, J.R., Vashishta, S.C., Stables, J.P., 1995b. Pharmazie 50, 823.
Dimmock, J.R., Puthucode, R.N., Smith, J.M., Hetherington, M., Quail,
J.W., Pugazhenthi, U., Lechler, T., Stables, J.P., 1996. J. Med. Chem.
39, 3984.
Some selected compounds (1a, 1b, 2c, 2d, 2g and 2i) were
examined for activity in the rat oral screen at 30 mg/kg dose
to study their activity profiles. The compounds which were
inactive or showed moderate activity in the mice i.p. screen
were selected randomly. The data are presented in Table 3.
Compound 2c did not show much activity as it had been
found with mice i.p. MES screen where at 300 mg/kg at 4 h
it showed 100% protection. The 2-chioro phenyl semicar-
bazide derivative (1b) afforded protection against seizures
with a peak time of activity at 0.5 h (100%) and 2 h (75%)
compared to phenytoin. It is found that these compounds
exhibit activity differences between mice and rats. The com-
pound 1b may undergo some oral activation in the gut to an
active metabolite. This needs some more experimentation
to confirm the hypothesis. There was no apparent toxicity
observed in rats at the dose level of 30 mg/kg.
Flaherty, P.T., Greenwood, T.D., Manhein, A.L., Wolfe, J.F., 1996. J.
Med. Chem. 39, 1509.
Hearn, M.J., Lucas, L.E., 1984. J. Het. Chem. 21, 615.
Karali, N., Gursoy, A., 1994. Farmaco 49, 819.
Krall, R.I., Penry, J.K., White, B.G., Kupferberg, H.J., Swinyard, E.A.,
1978. Epilepsia 19, 409.
Kupferberg, H.J., Stables, J.P., 1998. In: Stefan, H., Kramer, G., Mamoli,
B. (Eds.), Challenge Epilepsy—New Anticonvulsant Drugs. Blackwell,
Boston, p. 7.
Loscher, W., Schmidt, D., 1994. Epilepsy Res. 17, 95.
Pandeya, S.N., Ponnilavarasan, I., Pandey, A., Lakhan, R., Stables, J.P.,
1999a. Pharmazie 54, 923.
Pandeya, S.N., Aggarwal, N., Jain, J.S., 1999b. Pharmazie 54, 300.
Pandeya, S.N., Sriram, D., Nath, G., De Clercq, E., 1999c. Eur. J. Pharm.
Sci. 9, 25.
Pandeya, S.N., Yogeeswari, P., Stables, J.P., 2000. Eur. J. Med. Chem.
35, 879.
Pandeya, S.N., Sriram, D., Yogeeswari, P., Stables, J.P., 2001. Pharmazie
56, 875.
In the behavioral despair test the compounds except 1a,
2b, 2e, 2i and 2j showed decreased motor activity as in-
dicated by the actophotometer scores (Table 4). The com-
pounds with acetamido group (1g) showed the maximum
motor impairment with the lowest actophotometer score of
38 22.35. The N4-pthalimido phenylsemicarbazide deriva-
tives were studied for CNS depressant effect by Porsolt’s
Porsolt, R.D., Anton, G., Blanet, N., Jalfre, M., 1978. Eur. J. Pharmacol.
47, 379.
Porter, R.J., Cereghino, J.J., Gladding, G.D., Hersie, B.J., Kupferberg,
H.J., Scoville, B., White, B., 1984. Cleve. Clin. Q. 51, 293.
Poupaert, J.H., Hamoir, G., Barbeaux, P., Lambert, D., Henichart, J.P.,
1995. J. Pharm. Pharmacol. 47, 89.
Puthucode, R.N., Pugazhenthi, U., Quail, J.W., Stables, J.P., Dimmock,
J.R., 1998. Eur. J. Med. Chem. 33, 595.

346
P. Yogeeswari et al. / European Journal of Pharmaceutical Sciences 20 (2003) 341–346
Stables, J.P., Kupferberg, H.J., 1997. In: Avarzini, G., Tanganelli, P., Aroli,
M. (Eds.), Molecular And Cellular Targets Of Antiepileptic Drugs.
John Libber & Co. Ltd., London, p. 197.
White, H.S., Woodhead, J.H., Franklin, M.R., 1995a. In: Levy, R., Mattson,
R., Meidrum, B.S. (Eds.), Antiepileptic Drugs, 4th ed. Raven Press,
New York, p. 99.
Vamecq, J., Lambert, D., Poupaert, J.H., Masereel, B., Stables, J.P., 1998.
J. Med. Chem. 41, 3307.
White, H.S., Johnson, M., Wolf, H.H., Kupferberg, H.J., 1995b. Ital. J.
Sci. 16, 73.
Vamecq, J., Bac, P., Herrenknecht, C., Maurois, P., Delcourt, P., Stables,
J.P., 2000. J. Med. Chem. 43, 1311.
Yogeeswari, P., Sriram, D., Suniljit, L.R.J., Kumar, S.S., Stables, J.P.,
2002. Eur. J. Med. Chem. 37, 231.