Design, synthesis and biological evaluation of novel thiosemicarbazide analogues as potent anticonvulsant agents

Article abstract of DOI:10.1016/j.bioorg.2014.04.002

Novel thiosemicarbazide derivatives were synthesised and evaluated for their anticonvulsant activity and neurotoxicity. Anticonvulsant activity was done for grand mal and petit mal types of epilepsies by maximal electroshock (MES) and pentylenetetrazol (P

Full text of DOI:10.1016/j.bioorg.2014.04.002

Bioorganic Chemistry 54 (2014) 68–72
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Design, synthesis and biological evaluation of novel thiosemicarbazide
analogues as potent anticonvulsant agents
⇑
Reshma J. Nevagi , Avinash S. Dhake, Harsha I. Narkhede, Prabhjeet Kaur
Department of Pharmaceutical Chemistry, SMBT College of Pharmacy, Nandi Hills, Dhamangaon, Igatpuri, Nashik 422403, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 January 2014
Available online 22 April 2014
Novel thiosemicarbazide derivatives were synthesised and evaluated for their anticonvulsant activity and
neurotoxicity. Anticonvulsant activity was done for grand mal and petit mal types of epilepsies by
maximal electroshock (MES) and pentylenetetrazol (PTZ) induced convulsions methods respectively.
Rotarod test was done to determine neurotoxicity. Amongst synthesised compounds, N-(4-bromophe-
nyl)2-[(2-phenylhydrazinyl) carbonothioyl] hydrazinecarbothioamide (5e) is a broad-spectrum anticon-
vulsant agent since it was active in both (MES) and (PTZ) induced seizure models with no neurotoxicity
and N,N-(bis(chlorophenyl)hydrazine-1,2-dicarbothoamide (5g) acts as a selective agent for grand mal
epilepsy.
Keywords:
Epilepsy
Neurotoxicity
Grand mal
Petit mal
Ó 2014 Elsevier Inc. All rights reserved.
1. Introduction
[19,20]. A simple pictorial representation of pharmacophoric
model is as below [21]:
Epilepsy is a collective term that includes over 40 different
types of human seizure disorders. Approximately 1% of the world
population (50 million people worldwide) is afflicted with this
serious neurological disorder [1]. Epilepsy is a major neurological
disorder, characterised by periodic and unpredictable occurrence
of seizures, which take various forms depending on the part of
the brain affected [2]. Thiosemicarbazides have aroused consider-
able interest in chemistry and biology due to their antibacterial
[3], anti-malarial [4], anti-cancer [5], anti-HIV [6], anti-tubercular
[7], anti-viral [8], anti-tumor [9] and anti-protozoal [10] proper-
ties. Along with these activities, recent reports suggested that this
moiety also possess good anticonvulsant properties [11–13].
There have been several attempts to postulate a general
pharmacophore for the different anticonvulsant classes [14–17].
A 3 point pharmacophore model was proposed for anticonvulsants
acting through blocking of voltage-gated sodium Channel by
superimposing carbamazepine (CBZ), phenytoin (DPH), lamotri-
gine (LAM), zonisamide (ZON), and rufinamide (CGP). The common
structural features essential for the activity were at least one aryl
ring, one electron donor atom and a second donor atom in proxim-
ity to the NAH group, forming a hydrogen bond acceptor or donor
[18]. Later on, a new generalised 4-point pharmacophoric model
was proposed by studying structurally different compounds with
anticonvulsant activity with different mechanisms of action
According to pharmacophoric model, there are four structural
requirements for the anticonvulsant activity.
A. An aryl hydrophobic binding site with halo substituent pref-
erably in the para position.
B. A system containing 2 electron donor systems.
C. Hydrogen bonding domain exemplified by the presence of
ANHCO/ANHCS grouping.
D. Another hydrophilic–hydrophobic site controlling the phar-
macokinetic properties of the anticonvulsant.
1.1. Designed strategy for the molecules
According to published model (Fig. 1), we synthesised new
thiosemicarbazide analogues to explore their anticonvulsant prop-
erties. The target compounds (5a–h) possessed all the required
pharmacophoric elements (Fig. 2). The aryl ring substituted with
halo group can be referred to the aryl hydrophobic binding site
(A), the sulphur of thiosemicarbazide moiety can act as a two
electron donor system (B), AC(S)NHA grouping constitutes the
hydrogen bonding domain (C) and R1 represents hydrophilic–
hydrophobic site.
2. Materials and methods
⇑
Melting points were taken by open cup capillary method and
are uncorrected. IR spectra were taken on FTIR JASCO-4100 type
Corresponding author. Fax: +91 02553 202000.
E-mail address: rjnevagi@gmail.com (R.J. Nevagi).
http://dx.doi.org/10.1016/j.bioorg.2014.04.002
0045-2068/Ó 2014 Elsevier Inc. All rights reserved.

R.J. Nevagi et al. / Bioorganic Chemistry 54 (2014) 68–72
69
30 min. with stirring at room temperature (27–30 °C). The reaction
mixture was stirred for 8 h. To the reaction mixture, dimethyl sul-
phate (0.05 mole) was added dropwise with stirring at 0–5 °C and
stirred further for 5 h. After completion of the reaction confirmed
by TLC, ice-cold water was added to obtain the hydrazinecarbodi-
thioate product. The solid obtained was filtered through suction
pump, washed with water, dried and recrystallised from DMSO
to obtain the pure hydrazinecarbodithioate. The traces of DMSO
were removed by giving the ethyl acetate slurry wash to the
recrystallised compounds.
Fig. 1. Structural requirements for displaying Anticonvulsant activity.
3.2.1. Methyl 2-[(4-bromophenyl) carbamothioyl hydrazinecarbodi-
thioate (5a)
IR (KBr) c
max cmÀ1 3433, 3255 (ANH stretch), 1593 (ANH bend),
1534 (C@C stretch), 1073 (C@S), 502 (CABr); 1H NMR (DMSO-d6,
400 MHz) d 2.65 (s, 3H, ACH3), 3.67 (s, 1H, ANH), 7.55 (d,
J = 8.32 Hz, 2H, ArAH), 7.37 (d, J = 8.20 Hz, 2H, ArAH), 10.30 (s,
1H, ArANH); 13C NMR (DMSO-d6, 100 MHz) d 18.52, 126.59,
127.63, 128.39, 137.96, 178.35, 202.56; MS (EI): [M]+ 336.2.
3.2.2. Methyl 2-[(4-fluorophenyl) carbamothioyl hydrazinecarbodithio-
ate (5b)
IR (KBr) cmax cmÀ1 3459, 3260 (NH stretch), 1551 (NH bend),
1506 (C@C stretch), 1405 (CAF), 1207 (C@S); 1H NMR (DMSO-d6,
400 MHz) d 2.68 (s, 3H, ACH3), 3.75 (s, 1H, ANH), 7.56 (d,
J = 8.32 Hz, 2H, ArAH), 7.39 (d, J = 8.23 Hz, 2H, ArAH), 10.28 (s,
1H, ArANH); 13C NMR (DMSO-d6, 100 MHz) d 18.52, 113.75,
127.91, 133.46, 161.28, 178.35, 202.5; MS (EI): [M]+ 275.6.
Fig. 2. Target molecules. Where, A = Aryl hydrophobic binding site, D = electron
donor system, HD and HA = Hydrogen bonding domains, R1 = Hydrophilic–hydro-
phobic site.
A spectrophotometer using KBr pellet. Proton and Carbon nuclear
magnetic resonance (NMR) spectra were recorded using DMSO as
a solvent at ambient temperature using tetramethylsilane as an
internal standard on BRUKER AVANCE II 400 Spectrometer. Mass
spectra were recorded on Varian 410 Prostar Binary LC 500
instrument using THF as solvent. The chemicals used were of LR
grade and used without further purification. Thin layer chromatog-
raphy was performed on silica gel G and spots were visualised
under ultraviolet (UV) lamp.
3.3. General method for synthesis of hydrazinedithioamides (5c–5f)
To the solution of substituted thiosemicarbazide (4b, 4c)
(0.01 mole) in DMSO (20 ml), CS2 (0.01 mole) and the aqueous
solution of 2.0 M KOH (0.01 mole) were added and the reaction
mixture was stirred at 0–5 °C for 2 h to form corresponding potas-
sium salt of dithiocarbamate. To a stirred mixture, hydrazine
hydrate or phenylhydrazine (0.01 mole) was added, and stirring
was continued at 80 °C for several hours. After the completion of
the reaction was confirmed by TLC, crushed ice was added to
obtain the corresponding hydrazinedithioamide. The obtained
solid was then filtered, washed with cold water, dried and recrys-
tallised using DMSO. The traces of DMSO were removed by giving
the ethyl acetate slurry wash to the recrystallised compounds.
3. Experimental procedure
3.1. Synthesis of aryl thiosemicarbazides (4a–c)
Aryl thiosemicarbazides were prepared from the respective
anilines by 2 routes (Route A and B).
3.3.1. N-(4-bromophenyl)-2-(hydrazinylcarbonothioyl) hydrazinecar-
bothioamide (5c)
Route A was employed according to the procedure reported
earlier [22]. p-Chloro aniline on treatment with carbon disulphide
in the presence of sodium hydroxide and dimethyl sulphate gave
corresponding dithiocarbamate (3a), which was then isolated and
reacted with hydrazine hydrate to yield p-chlorophenyl thiosemi-
carbazide (4a).
Route B was employed according to the procedure reported
earlier [23]. Anilines on treatment with carbon disulphide in the
presence of ammonia, water and sodium chloroacetate gave
sodium acetate salt of the corresponding dithiocarbamate (3b,
3c), which on reaction with hydrazine hydrate yielded the respec-
tive thiosemicarbazide (4b, 4c).
IR (KBr) cmax cmÀ1 3443, 3293 (NH stretch), 1619, 1549 (NH
Bend), 1483 (C@C stretch), 1058 (C@S), 727 (CABr); 1H NMR
(DMSO-d6, 400 MHz) d 2.54–3.41 (s, 4H, 4XANH), 3.75 (s, 1H,
ANH), 7.52 (d, J = 8.76 Hz, 2H, ArAH), 7.30 (d, J = 8.76 Hz, 2H,
ArAH), 7.64 (s, 2H, NH2), 9.76 (s, 1H, ArANH); 13C NMR (DMSO-
d6, 100 MHz) d 126.59, 127.63, 128.39, 137.96, 178.35, 179.33;
MS (EI): [M]+ 320.2.
3.3.2. N-(4-fluorophenyl)-2-(hydrazinylcarbonothioyl) hydrazinecar-
bothioamide (5d)
IR (KBr) cmax cmÀ1 3423, 3236 (NH stretch), 1613, 1572 (NH
bend), 1506 (C@C stretch), 1327 (CAF), 1057 (C@S); 1H NMR
(DMSO-d6, 400 MHz) d 2.51–3.40 (s, 4H, 4XANH), 3.74 (s, 1H,
ANH), 7.52 (d, J = 8.76 Hz, 2H, ArAH), 7. 30 (d, J = 8.76 Hz, 2H,
ArAH), 7.63 (s, 2H, NH2), 9.78 (s, 1H, ArANH); 13C NMR (DMSO-
d6, 100 MHz) d 113.75, 127.91, 133.46, 161.28, 178.35, 179.33;
MS (EI): [M]+ 259.4.
3.2. General method for the synthesis of hydrazinecarbodithioates
(5a, 5b)
Substituted thiosemicarbazide (4b–c) (0.05 mole) was dis-
solved in 20 ml DMSO. To this reaction mixture, CS2 (0.05 mole)
and the aqueous solution of 2.0 M NaOH (6 ml) was added over

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R.J. Nevagi et al. / Bioorganic Chemistry 54 (2014) 68–72
3.3.3. N-(4-bromophenyl)2-[(2-phenylhydrazinyl) carbonothioyl]
hydrazine carbothioamide (5e)
3.5. Biological assay
IR (KBr) cmax cmÀ1 3243, 3180 (NH stretch), 1602, 1546 (NH
bend), 1496 (C@C stretch), 1076 (C@S), 617 (CABr); 1H NMR
(DMSO-d6, 400 MHz) d 7.33–7.46 (5H, m, ArAH), 7.51–7.59 (m,
4H, ArAH), 10.58, 10.04 (s, 3H, 3XANH), 10.65 (s, 2H, ArANH),
13C NMR (DMSO-d6, 100 MHz) d 112.88, 120.51, 126.59, 127.63,
128.39, 128.84, 137.96, 145.7, 178.35, 179.33; MS (EI): [M]+ 396.3.
The preliminary anticonvulsant evaluation was carried out by
MES and scPTZ methods using reported procedures [24]. Male
Swiss Albino mice weighing 20–40 g were used as the experimen-
tal animals. The animals were maintained at ambient temperature,
in a group of 5 per cage under the standard laboratory conditions,
receiving standard laboratory chow and water ad libitum. A 12 h
light and dark cycle was maintained throughout the experimental
studies. All the tests have been performed in accordance with the
guidelines laid by the Institutional Animal Ethics Committee (Ref.
No. 1329/AC/10/CPCSEA). The electroconvulsometer and rotarod
equipments used were of Omega scientific industries. Pentylen-
etetrazole (PTZ) was obtained by Sigma–Aldrich. The test
compounds were suspended in a mixture of 0.3% carboxymethyl-
cellulose and 0.2% dimethyl sulfoxide [25]. Phenytoin and Carbam-
azepine were used as reference drugs. The animals were divided
into three groups (control, standard and test) and each group com-
prised of five mice (n = 5). The control group received only mixture
of 0.3% carboxymethylcellulose and 0.2% dimethyl sulfoxide
suspension.
3.3.4. N-(4-fluorophenyl)2-[(2-phenylhydrazinyl) carbonothioyl]
hydrazinecarbothioamide (5f)
IR (KBr) cmax cmÀ1 3315, 3162 (NH stretch), 1637, 1528 (NH
bend, 1506 (C@C stretch), 1283 (CAF), 1071 (C@S); 1H NMR
(DMSO-d6, 400 MHz) d 7.34–7.48 (5H, m, ArAH), 7.53–7.60 (m,
4H, ArAH), 10.60, 10.06 (s, 3H, 3XANH), 10.67 (s, 2H, ArANH);
13C NMR (DMSO-d6, 100 MHz) d 113.75, 120.51, 127.91, 128.39,
128.8, 133.46, 145.17, 161.28, 178.35, 179.33; MS (EI): [M]+ 335.2.
3.4. General method for the synthesis of hydrazine-1,2-dicarbothioa-
mides (5g, 5h)
3.5.1. Anticonvulsant screening
In round bottom flask (RBF), methyl 4-chloro phenyl carbodi-
thioate 3a (0.01 mole) was dissolved in DMF. To this solution, 4-
chlorothiosemicarbazide 4a (0.01 mole) was added. The flask was
then attached to reflux condenser, and the temperature was main-
tained between 125–130 °C. After the completion of the reaction,
the flask was cooled in ice bath and ice-cold water was added to
the reaction mixture to obtain the product. The solid was filtered,
dried and recrystallised using DMF. The traces of DMF were
removed by giving the ethyl acetate slurry wash to the recrystal-
lised compound.
Some selected derivatives (5a–5e, 5g) were examined for anti-
convulsant activity. In the preliminary screening, each compound
was administered as an i.p. injection at three dose levels (30, 100
and 300 mg/kg) and the anticonvulsant activity assessed after
30 min and 4 h intervals of administration. The anticonvulsant
efficacy was evaluated by the maximal electroshock-induced
seizure (MES) [26], and pentylenetetrazole (PTZ) induced convul-
sions methods [27].
3.5.2. Neurotoxicity screen
Minimal motor impairment was measured in mice by the
rotarod test. The mice were trained to stay on an accelerating rota-
rod that rotates at 10 rpm. Doses used were 100 and 300 mg/kg.
Neurotoxicity was indicated by the inability of the animal to main-
tain equilibrium on the rod for at least one min in each of the three
trials.
3.4.1. N,N-bis (4-chlorophenyl)hydrazine-1,2-dicarbothioamide (5g)
IR (KBr) cmax cmÀ1 3209, 3175 (NH stretch), 1590 (NH bend),
1533 (C@C stretch), 1012 (C@S), 575 (CACl); 1H NMR (DMSO-d6,
400 MHz) d 2.79, 2.93 (s, 2H, 2XANH), 7.31–7.62 (8H, m, ArAH),
10.11–10.60 (s, 2H, ArANH); 13C NMR (DMSO-d6, 100 MHz) d
128.51, 130.23, 134.64, 136.82, 178.35; MS (EI): [M]+ 371.3.
4. Results and discussion
3.4.2. N-(4-chlorophenyl)-N-(4-fluorophenyl) hydrazine-1,2-dica-
rbothioamide (5h)
4.1. Chemistry
IR (KBr) c
max cmÀ1 3311, 3175 (ANH stretch), 1638 (ANH bend),
1533 (C@C stretch), 1089 (C@S), 1397 (CAF), 728 (CACl). 1H NMR
(DMSO-d6, 400 MHz) d 2.80, 2.94 (s, 2H, 2XANH), 7.33–7.64 (8H,
m, ArAH), 10.13–10.63 (s, 2H, ArANH), 1H NMR (DMSO-d6,
General route for the synthesis of the substituted thiosemicar-
bazide is shown in Scheme 1. Two similar methods were used to
synthesise the required thiosemicarbazides. In the first route (A),
p-chloro aniline treated with carbon disulphide in the presence
of sodium hydroxide and dimethyl sulphate gave corresponding
dithiocarbamate (3a), which was isolated and reacted with hydra-
zine hydrate to yield p-chlorophenyl thiosemicarbazide (4a). In the
second route (B), anilines on treatment with carbon disulphide in
the presence of ammonia water and sodium chloroacetate gave
sodium acetate salt of the corresponding dithiocarbamate (3b,
3c), which on treatment with hydrazine hydrate yielded the
respective thiosemicarbazide (4b, 4c).
Route B proved to be efficient in terms of time and yield
compared to Route A. The compounds were obtained in pure form
with the general yield of 50–80%. The time required was compar-
atively less as it was one pot synthesis. Route A required isolation
of dithiocarbamate intermediate whereas, in route B, direct hydra-
zinolysis of the salt formed therein was carried out.
400 MHz)
d 113.75, 127.91, 128.51, 130.23, 133.46, 133.51,
134.64, 136.82, 161.28, 178.35; MS (EI): [M]+ 354.8.
The physical data of all the synthesised compounds (5a–5h) is
represented in Table 1.
Table 1
Physical constants of titled compounds.
Compound
Molecular formulaa
Melting point (°C)
Rfb
Yield (%)
5a
5b
5c
5d
5e
5f
C9H10N3S3Br
C9H10N3S3F
C8H10N5S2Br
C8H10N5S2F
C14H14N5S2Br
C14H14N5S2F
C14H12N4S2Cl2
C14H12N4S2ClF
180
0.87
0.77
0.85
0.82
0.96
0.93
0.94
0.92
89
85
50
45
47.5
50
60
58
187
238(d)
175
227
239
208
5g
5h
233
The target compounds were synthesised by the reaction of aryl
thiosemicarbazide, carbon disulphide under basic condition with
hydrazine hydrate, phenyl hydrazine and phenyl carbodithioate
a
Elemental analyses for C, H, N were within 0.4% of the theoretical values.
Eluent used for TLC was benzene:ethyl acetate (8:2).
b

R.J. Nevagi et al. / Bioorganic Chemistry 54 (2014) 68–72
71
Scheme 1. Synthetic protocol for the titled compounds.
Table 2
Anticonvulsant and neurotoxicity screening results of the titled compounds.
Compound
MES screen
0.5 h
PTZ screen
0.5 h
Neurotoxicity screen
0.5 h
LogPa
4 h
4 h
4 h
5a
5b
5c
5d
5e
5g
–
–
–
100
–
100
30
30
–
–
–
–
100
100
30
100
–
–
–
–
–
–
–
100
300
–
–
–
100
–
–
–
–
300
–
–
100
100
300
100
–
300
–
–
100
300
2.849
2.204
0.660
0.015
3.566
3.716
–
Phenytoin
Carbamazepine
–
300
–
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).
a
LogP values were calculated by using molinspiration online services (http://www.molinspiration.com/cgi-bin/properties).
(according to the requirement of the final compound) [as shown in
the Scheme 1].
Three compounds 5d, 5e and 5g exhibited activity in the
preliminary MES screen, indicative of their ability to prevent sei-
zure spread. At the dose of 100 mg/kg, compounds 5d, 5g and 5e
showed protection in half or more of the tested mice. Compounds
5d and 5g showed rapid onset (0.5 h) with a shorter duration of
action. Compound 5g was found to be active even after four hours
indicative of its longer duration of action. Compound 5e showed
activity at 100 mg/kg as well as 300 mg/kg but only after four
hours indicating its slow onset of action.
In the PTZ test, a test used to identify compounds that elevate
seizures threshold, compounds 5a and 5e showed protection with
slow onset of action (4 h). Compound 5e has broad-spectrum anti-
convulsant activity as it is active in both MES and PTZ screens.
Therefore, we can say that, clinically, it is effective in both grand
mal and petit mal types of epilepsy. Compound 5d and 5g are
showed activity only in MES model. Therefore, they are selective
agents for the treatment of only grand mal epilepsy.
The spectroscopic data (IR, 1HNMR) and mass spectra were
consistent with the assigned structures. All the compounds
showed characteristic NH stretching and peak for C@S in IR
spectroscopy. The 1HNMR spectrum revealed that the ASCH3
showed
a singlet at d = 2.68 ppm. The different compounds
showed a singlet for the aromatic ANH proton (ArANH) in the
range of 9.76–10.65 ppm and the multiplet was observed in an
aromatic region 7.31–7.62 ppm. In 13C NMR spectrum, aromatic
carbons were observed in the region of 112.88–161.28 ppm.
The characteristics carbon for C@S was observed at 178.33 and
178.33 ppm. In mass spectrometry, compounds showed
characteristics molecular ion peak. All this data supported the
synthesis of the molecules.
4.2. Pharmacology
In the acute neurotoxicity screen, compounds 5e and 5g were
found to be devoid of any neurotoxicity at the highest dose admin-
istered (300 mg/kg). There was no distinction between anticonvul-
sant dose and neurotoxicity dose for the compound 5a. Rest of the
compounds 5b, 5c, 5d showed neurotoxicity at dose of 300 mg/kg.
Results are given in Table 2.
The data reveals that 66% of the compounds were active in the
MES screen as compared to 34% in the PTZ screen. Compound 5b
and 5c showed no activity in all the screenings.
Preliminary anticonvulsant evaluation of the synthesised novel
compounds was established by electrical and chemical tests. The
electrical test employed was maximal electroshock seizure (MES)
pattern test and chemical test was PTZ seizure threshold test. Rota-
rod test was used to determine the acute neurotoxicity. Male
Albino mice were divided into three groups (control, standard
and test) and each group comprised of five mice. The results of
MES and PTZ screening are reported in Table 2.

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R.J. Nevagi et al. / Bioorganic Chemistry 54 (2014) 68–72
The 100% protection was observed for the compounds 5e and
Authors also thank to Dr. V. Balsubramaniyan for his valuable guid-
ance, support and help for achieving success in this study.
5g, and 0% mice showed neurotoxicity. The compounds 5a showed
activity at the neurotoxic dose and compound 5d was active at
100 mg/kg, but it was found to be neurotoxic at higher dose
300 mg/kg.
Appendix A. Supplementary material
From this study, it was observed that the hydrophobic binding
site (A) and hydrophilic–hydrophobic site (R1) when incorporated
in the structure shows the different activity depending on their
structural properties (Fig. 2). The compounds having p-bromo
substitution on the aryl ring (5a, 5e) were observed to have good
anticonvulsant activity because of their bulkier bromine group
which increases lipophilicity of the molecule and also helps to
cross blood-brain barrier.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bioorg.2014.04.
002.
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5. Conclusion
Hydrazine-thioate and hydrazine-(carbo)-thioamide molecules
were synthesised. The present study identified compounds 5e
and 5g as lead molecules. Study demonstrated that the compound
5e possesses broad-spectrum anticonvulsant activity as indicated
by its effect in both PTZ and MES models with no neurotoxicity.
Compound 5g is active in MES model at 30 min and 4 h, has a
fast-moderate onset and long duration with no sign of neurotox-
icity. The R1 substitution with the phenylhydrazine or aniline
was found to be beneficial for the anticonvulsant activity. Our
study validated that the presence of a second aryl or phenyl ring
increases the anticonvulsant potential by attachment to the bind-
ing site using van der waals forces. The further modification at R1
with other substituted anilines would open up new horizons for
thiosemicarbazide analogues. It is interesting to note that long
chain enriched with AC(S) NHA functions as in compound 5g func-
tionality can serve as peptidomimetics in drug–receptor binding
and further development in this area will be clinically rewarding.
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Acknowledgments
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Authors are very grateful to SMBT College of Pharmacy, Nashik,
India, for providing financial support for completion of this study.