A New class of anticonvulsants possessing 6 hz psychomotor seizure test activity: 2-(1H-benzotriazol-1-yl)-N'-[substituted] acetohydrazides

Article abstract of DOI:10.2174/157340612800786606

A series of 2-(1H-Benzotriazol-1-yl)-N'-[substituted]acetohydrazides was designed and synthesized keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and neurotoxicity. The new compounds were characterized using FT-IR, ¹H NMR, mass spectral data and elemental analysis. The anticonvulsant activity of the titled compounds was assessed using the 6 Hz psychomotor seizure test. The neurotoxicity was assessed using the rotarod method. The most active compound of the series was N'-[4-(1,3-Benzodioxol-5-yloxy)benzylidene]-2-(1Hbenzotriazol-1-yl) acetohydrazide (BTA 9), which showed good activity with 75 % protection (3/4, 0.5 h) at a dose of 100 mg/kg in mice. None of the compounds exhibited neurotoxicity. A computational study was carried out for the calculation of pharmacophore pattern and prediction of pharmacokinetic properties. Titled compounds have also exhibited good binding properties with epilepsy molecular targets such as glutamate, GABA (A) delta, GABA (A) alpha-1 receptors and Na/H exchanger, in Lamarckian genetic algorithm based flexible docking studies.

Full text of DOI:10.2174/157340612800786606

Medicinal Chemistry, 2012, 8, 337-348
337
A New Class of Anticonvulsants Possessing 6 Hz Psychomotor Seizure Test
Activity: 2-(1H-Benzotriazol-1-yl)-N'-[Substituted] Acetohydrazides
Praveen Kumar* and Laxmi Tripathi
S. D. College of Pharmacy & Vocational Studies, Muzaffarnagar 251001 Uttar Pradesh, India
Abstract: A series of 2-(1H-Benzotriazol-1-yl)-N'-[substituted]acetohydrazides was designed and synthesized keeping in
view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and neurotoxicity. The new
compounds were characterized using FT-IR, 1H NMR, mass spectral data and elemental analysis. The anticonvulsant ac-
tivity of the titled compounds was assessed using the 6 Hz psychomotor seizure test. The neurotoxicity was assessed using
the rotarod method. The most active compound of the series was N'-[4-(1,3-Benzodioxol-5-yloxy)benzylidene]-2-(1H-
benzotriazol-1-yl)acetohydrazide (BTA 9), which showed good activity with 75 % protection (3/4, 0.5 h) at a dose of 100
mg/kg in mice. None of the compounds exhibited neurotoxicity. A computational study was carried out for the calculation
of pharmacophore pattern and prediction of pharmacokinetic properties. Titled compounds have also exhibited good bind-
ing properties with epilepsy molecular targets such as glutamate, GABA (A) delta, GABA (A) alpha-1 receptors and Na/H
exchanger, in Lamarckian genetic algorithm based flexible docking studies.
Keywords: Anticonvulsant, Benzotriazole, Computational study, Docking study, 6 Hz Psychomotor Seizure test,
Neurotoxicity.
INTRODUCTION
ity. In addition, the 4-(2-phenoxyphenyl)semicarbazones 5
(Fig. 1) were reported as potential anticonvulsants [13].
Epilepsy affects 1% of world’s population according to
the epidemiological studies. Current clinically available
drugs produce satisfactory seizure control in 60–70% of pa-
tients [1]. Several new anticonvulsants like oxacarbazepine,
vigabatrin, lamotrigine, gabapentin, topiramate, felbamate,
rufinamide and levetiracetam have been put in clinical prac-
tice. Despite familiarity with established antiepileptic drugs
and the introduction of these new agents in the past decade,
upto one third of epilepsy patients remain resistant to opti-
mum drug treatment [2]. These facts triggered the search for
newer more effective and less toxic anticonvulsants.
Continuing our studies on benzfused derivatives that are
attractive candidates as anticonvulsant agents [14], we de-
signed a new series of functionalized 2-(1H-Benzotriazol-1-
yl)-N'-[substituted]acetohydrazides compounds BTA 1-10,
exploring 1H-benzotriazole, as starting material. The rational
design of these new derivatives BTA 1-10, was planned by
molecular hybridization of substituted 1H-benzotriazole 7,
and 4-(aryloxy) phenyl semicarbazones 6 (Fig. 2).
Based on the literature review, we are the first to report
the synthesis and anticonvulsant activities of 2-(1H-Benzo-
triazol-1-yl)-N'-[substituted]acetohydrazides. Their chemical
Benzotriazole derivatives constitute an important class of
heterocyclic compounds and present a wide range of bioac-
tivities. Among the most important are: anticonvulsant [3-5],
CNS depressant [6], antimicrobial [7, 8], anticancer [9], an-
algesic and anti-inflammatory activity [10]. Several deriva-
tives of benzotriazole are reported as agonists of peroxisome
proliferator activated receptors [11]. Synthesis and biological
activity of 1H-benzotriazole analogs as inhibitors of the
NTpase / helicase and some related Flavivirade have been
extensively investigated [12].
1
structures were characterized using IR, H-NMR, MS and
elemental analysis techniques. All the synthesized titled
compounds comprised of the essential pharmacophoric ele-
ments (Fig. 3) that are necessary for good anticonvulsant
activity as suggested by Unverferth et al. [15]. In addition,
their anticonvulsant activity was evaluated by using 6 Hz
psychomotor seizure test in mice. The rotorod assay was
performed in mice to evaluate the neurotoxicity of the com-
pounds. Computational study was also carried out to high-
light the pharmacophore distance mapping, Log P calcula-
tion and prediction of pharmacokinetic parameters. In this
study, we have used AutoDock 4.0 along with its LGA algo-
rithm for automated flexible ligand docking of compounds
with six established epilepsy molecular targets and evaluated
the affinity and hydrogen bonding.
In the twenties, 1H-benzotriazole moiety containing
compounds such as benzotriazole and benzofuran-based het-
erocycles 1 & 2 [3], 1-(2-Amino phenyl)-2-[5-(2-benzo-
triazol-2-yl-ethyl)-tetrazol-2-yl]-ethanone 3 and 1-(4-Amino
phenyl)-2-[5-(2-benzotriazol-2-yl-ethyl)-tetrazol-2-yl]-etha-
none 4 [4] were reported as potential anticonvulsants. In fact,
these evidences suggest that the 1H-benzotriazole moiety,
possesses a pharmacophoric character for anticonvulsant activ
MATERIALS AND METHODS
Chemistry
*Address correspondence to this author at S. D. College of Pharmacy and
Vocational Studies, Bhopa Road, Muzaffarnagar, 251001, U.P., India;
Tel/Fax: 91 0131 2605158. E-mail: praveensha1977@rediffmail.com
All the chemicals and solvents, purchased from Merck
(India), Spectrochem (India), Himedia (India) and S. d. Fine
1875-6638/12 $58.00+.00
© 2012 Bentham Science Publishers

338 Medicinal Chemistry, 2012, Vol. 8, No. 3
Kumar and Tripathi
N
N
N
N
N
N
N
N
O
O
O
N
O
H2N
N
N
O
X
S
N
N
Y
R
(1)
(3)
(2)
N
N
N
O
R
O
N
C
H
O Ar
NH
NH
Ar
H2N
N
H
N
N
O
N
O
N
N
NH2
(4)
(5)
(6)
Fig. (1). Chemical structure of benzotriazole and benzofuran-based heterocycles 1 & 2
1-(2-Amino phenyl)-2-[5-(2-benzotriazol-2-yl-ethyl)-tetrazol-2-yl]-ethanone 3
1-(4-Amino phenyl)-2-[5-(2-benzotriazol-2-yl-ethyl)-tetrazol-2-yl]-ethanone 4
4-(2-phenoxyphenyl) semicarbazones 5, and 4-(aryloxy)phenyl semicarbazones 6
N
O
N
H2N
C
N
H
N
C
O
Ar
N
R
H
(6)
(7)
Molecular Hybridization
N
N
O
N
N
C
H
O
Ar
N
H
(BTA 1-10)
Fig. (2). Rational concept to new 2-(1H-Benzotriazol-1-yl)-N'-[substituted] acetohydrazides BTA 1-10.
were used without further purification. The compounds were
synthesised according to Scheme 1. The progress of reaction
was monitored by thin layer chromatography, performed on
a silica gel 60 F254 coated aluminium sheet. The melting
points were determined by using Thomas- Hoover melting
point apparatus and were uncorrected. The FT-IR spectra
were recorded on Perkin- Elmer Spectrum BX-II Spectro-
confirmed by the addition of D2O. The mass spectra were
recorded on a Waters Micromass ZQ 2000 mass spectrome-
ter. Elemental analysis (C, H, N) was undertaken with Perkin
Elmer Model 240C analyzer.
Synthesis of Ethyl 1H-benzotriazol-1-ylacetate (2): A
mixture of 1H-Benzotriazole (1) (0.1 mole), chloroethyl ace-
tate (0.1 mole) and potassium carbonate (3 g) was stirred in
dry acetone for 6 h. The solvent was removed under reduced
pressure and the solid mass obtained was extracted with
ether. The ether was removed under reduced pressure to get
needle shaped white crystals of compound (2). Yield: 86%;
1
photometer. The H-NMR spectra were recorded on Bruker
300 MHz High Resolution NMR spectrometer using TMS as
an internal standard. Chemical shifts were reported in ppm
(ꢀ) and signals were described as singlet (s), doublet (d),
triplet (t) and multiplet (m). All exchangeable protons were

A New Class of Anticonvulsants Possessing 6 Hz Psychomotor Seizure Test Activity
Medicinal Chemistry, 2012, Vol. 8, No. 3 339
D
D
CH3
A
D
H
N
H
HD
HA
OH
O
S
CH3
A
N
HD
N
N
H
A
S HA
HA
O
HD H2N
Gabapentin
Albutoin
Carbamazepine
HA
O
D
D
H
N
H
N
N
O
A
H
NH
HD
N
Cl
HD
H
C2H5
Cl
N
H
O
N
O
N
HA
Lamotrignine
N
O
D
CH3
H
HA
Mephobarbital
Phenytoin
HA
O
N
O
A
OH
H
HD
H3C
O
N
H
D
O
HA
D
HD
H
S
N
N
A
N
F
HA
O
H
H
N
H
H
Zonisamide
A
HD
Remacemide
Progabide
Cl
O
O
H3C
CH3
HA
O
N
D
A
N
HD
N
N
S
HA
N
HN
O
H
N
A
O
Cl
H
O
D
HD
Ralitoline
BTA 9
Fig. (3). Pharmacophoric pattern of well- known anticonvulsants and N'-[4-(1,3- Benzodioxol-5-yloxy)benzylidene]-2-(1H-benzotriazol-1-
yl)acetohydrazide BTA 9.
m.p.: 40°C; IR (KBr, cm–1) ꢀ: 1742 (C=O), 1464, 1237 (N-
Synthesis of 4-substituted benzaldehyde (6a-i): A mix-
1
ture of substituted phenol (4a-i) (37.4 mmol), 4-
fluorobenzaldehyde (5) (37.4 mmol) and potassium carbon-
ate (38.8 mmol) in N,N-dimethylformamide (30 mL) was
refluxed for 16-18 h under nitrogen. After cooling, the prod-
uct was extracted from the reaction mixture and purified by
chromatography. (6f) Yield: 70%; m.p.: 41°C; IR (KBr,
CH2); H NMR (CDCl3, 300 MHz) ꢁ in ppm: 1.30 (t, 3H,
CH3), 4.27 (q, 2H, COOCH2), 5.81 (s, 2H, N-CH2), 6.80-
7.94 (a set of signals, 4H, Ar-H); MS (m/z, %): 206.16 (M+
+ 1, 76.9); Anal. Calcd. for C10H11N3O2 (205.21): C, 58.53;
H, 5.40; N, 20.48. Found: C, 58.49; H, 5.41; N, 20.45.
1
cm–1) ꢀ: 1665 (C=O), 1240 (-O-); H NMR (CDCl3, 300
Synthesis of 2-(1H-Benzotriazol-1-yl)acetohydrazide
(3): Compound (2) (0.1 mole) and hydrazine hydrate (0.3
mole) in ethanol (50 mL) were stirred for 1h and then re-
fluxed for 2h. The excess of solvent was removed under re-
duced pressure and recrystallized from chloroform-hexane
(3:1) to yield white crystals of compound (3). Yield: 81%;
m.p.: 178°C; IR (KBr, cm–1) ꢀ: 3337 ( -NHNH2), 1672
MHz) ꢁ in ppm: 9.87 (s, 1H, -CHO), 6.23-7.87 (a set of sig-
nals, 8H, Ar-H); MS (m/z, %): 216.17 (M+ + 1, 67.2); Anal.
Calcd. for C13H9FO2 (216.21): C, 72.22; H, 4.20; O, 14.80.
Found: C, 72.19; H, 4.16; O, 14.77.
Synthesis of 2-(1H-Benzotriazol-1-yl)-N'-[substituted]
acetohydrazide (BTA 1-10): Equimolar quantities (0.01
mol) of 4-substituted benzaldehydes (6a-i)/ isatin (6j) and 2-
(1H-Benzotriazol-1-yl)acetohydrazide (3) were dissolved in
warm ethanol containing 0.5 ml of glacial acetic acid. The
reaction mixture was refluxed for 4-6 h and set aside. The
resultant solid was washed with ethanol and recrystallized
1
(C=O), 1461, 1232 (N-CH2); H NMR (CDCl3, 300 MHz) ꢁ
in ppm: 9.88 (s, 1H, NH), 5.81 (s, 2H, N-CH2), 4.68 (s, 2H,-
NH2), 6.83-7.91 (a set of signals, 4H, Ar-H); MS (m/z, %):
192.13 (M+ + 1, 71.1); Anal. Calcd. for C8H9N5O (191.19):
C, 50.26; H, 4.74; N, 36.63. Found: C, 50.21; H, 4.71; N,
36.65.

340 Medicinal Chemistry, 2012, Vol. 8, No. 3
Kumar and Tripathi
N
N
N
N
N
a
b
N
N
N
N
H
CH2COOC2H5
CH2CONHNH2
2
1
3
c
O
F
Ar
OH
+
Ar
CHO
CHO
4a-i
6a-i
5
O
N
O
Ar
OR
N
O
N
H
CHO
N
N
N
6j
6a-i
CH2CONHN
C
O
Ar
N
H
d
BTA 1-9
CH2CONHNH2
N
N
N
3
CH2CONHN
NH
BTA 10
O
BTA 1: Ar =
BTA 2: Ar =
F
BTA 6: Ar =
CH3
NO2
Cl
BTA 7: Ar =
BTA 8: Ar =
BTA 9: Ar =
CH3
Cl
BTA 3: Ar =
BTA 4: Ar =
BTA 5: Ar =
O
O
Br
Scheme 1. Synthesis of 2-(1H-Benzotriazol-1-yl)-N'-[substituted] acetohydrazides (BTA 1-10). Reagents and conditions: a)
ClCH2COOC2H5, K2CO3, Acetone, Stirring, 6h; b) NH2NH2.H2O, Ethanol, Reflux, 2h; c) K2CO3, DMF, Reflux, 16-18h; d) Ethanol, GAA,
Reflux, 4-6h.
from 90% ethanol. The physical, elemental analysis and
spectral data of the titled compounds (BTA 1-10) are given
below.
CH=N-), 9.582 (s, 1H, -NH-, D2O exchangeable); MS (m/z,
%): 417.14 (M+ + 1, 72.5); Anal. Calcd. for C21H16N6O4
(416.39): C, 60.57; H, 3.87; N, 20.18. Found: C, 60.56; H,
3.84; N, 20.19.
2-(1H-Benzotriazol-1-yl)-N'-(4-phenoxybenzylidene)
acetohydrazide (BTA 1): Yield: 73%; m.p.: 146°C; IR
(KBr, cm–1) ꢀ: 3217 (-NH-), 1684 (C=O), 1604 (-N=CH-),
2-(1H-Benzotriazol-1-yl)-N'-[4-(4-methylphenoxy)
benzylidene]acetohydrazide (BTA 3): Yield: 75%; m.p.:
155°C; IR (KBr, cm–1) ꢀ: 3216 (-NH-), 1681 (C=O), 1605 (-
N=CH-), 1481, 1261 (-N-CH2-), 1231 (-O-); 1H NMR
(CDCl3, 300 MHz) ꢁ in ppm: 2.353 (s, 3H, -CH3), 5.892 (s,
2H, N-CH2), 6.422-8.068 (a set of signals, 12H, Ar-H), 7.710
(s, 1H, -CH=N-), 9.580 (s, 1H, -NH-, D2O exchangeable);
MS (m/z, %): 386.17 (M+ + 1, 68.9); Anal. Calcd. for
C22H19N5O2 (385.42): C, 68.56; H, 4.97; N, 18.17. Found: C,
68.52; H, 4.95; N, 18.16.
1
1478, 1260 (-N-CH2-), 1229 (-O-); H NMR (CDCl3, 300
MHz) ꢁ in ppm: 5.894 (s, 2H, N-CH2), 6.420-8.07 (a set of
signals, 13H, Ar-H), 7.713 (s, 1H, -CH=N-), 9.586 (s, 1H, -
NH-, D2O exchangeable); MS (m/z, %): 372.16 (M+ + 1,
89.9); Anal. Calcd. for C21H17N5O2 (371.39): C, 67.91; H,
4.61; N, 18.86. Found: C, 67.90; H, 4.61; N, 18.85.
2-(1H-Benzotriazol-1-yl)-N'-[4-(4-nitrophenoxy)ben-
zylidene]acetohydrazide (BTA 2): Yield: 74%; m.p.:
138°C; IR (KBr, cm–1) ꢀ: 3218 (-NH-), 1686 (C=O), 1601 (-
N=CH-), 1525 ( N=O), 1478, 1261 (-N-CH2-), 1227 (-O-);
1H NMR (CDCl3, 300 MHz) ꢁ in ppm: 5.890 (s, 2H, N-CH2),
6.421-8.04 (a set of signals, 12H, Ar-H), 7.711 (s, 1H, -
2-(1H-Benzotriazol-1-yl)-N'-[4-(4-chlorophenoxy)ben-
zylidene]acetohydrazide (BTA 4): Yield: 76%; m.p.:
188°C; IR (KBr, cm–1) ꢀ: 3215 (-NH-), 1681 (C=O), 1603 (-
N=CH-), 1479, 1263 (-N-CH2-), 1231 (-O-); 1H NMR

A New Class of Anticonvulsants Possessing 6 Hz Psychomotor Seizure Test Activity
Medicinal Chemistry, 2012, Vol. 8, No. 3 341
(CDCl3, 300 MHz) ꢀ in ppm: 5.893 (s, 2H, N-CH2), 6.421-
8.067 (a set of signals, 12H, Ar-H), 7.711 (s, 1H, -CH=N-),
9.582 (s, 1H, -NH-, D2O exchangeable); MS (m/z, %):
406.12 (M+ + 1 for 35Cl, 100.00), 408.10 (M+ + 1 for 37Cl,
33.8); Anal. Calcd. for C21H16ClN5O2 (405.84): C, 62.15; H,
3.97; N, 17.26. Found: C, 62.13; H, 3.92; N, 17.23.
m.p.: 260°C; IR (KBr, cm–1) ꢁ: 3263 (-NH- of isatin), 3215
(-NH-), 1687 (C=O), 1601 (-N=C-), 1478, 1260 (-N-CH2-);
1H NMR (CDCl3, 300 MHz) ꢀ in ppm: 5.89 (s, 2H, N-CH2),
6.72-7.81 (a set of signals, 8H, Ar-H), 9.58 (s, 1H, -NH-,
D2O exchangeable), 12.83 (s, 1H, -NH of isatin, D2O ex-
changeable); MS (m/z, %): 321.12 (M+ + 1, 81.7); Anal.
Calcd. for C16H12N6O2 (320.31): C, 60.00; H, 3.78; N, 26.24.
Found: C, 59.9; H, 3.77; N, 26.22.
2-(1H-Benzotriazol-1-yl)-N'-[4-(4-bromophenoxy)ben-
zylidene]acetohydrazide (BTA 5): Yield: 78%; m.p.:
215°C; IR (KBr, cm–1) ꢁ: 3219 (-NH-), 1689 (C=O), 1607 (-
N=CH-), 1475, 1260 (-N-CH2-), 1232 (-O-); 1H NMR
(CDCl3, 300 MHz) ꢀ in ppm: 5.890 (s, 2H, N-CH2), 6.423-
8.07 (a set of signals, 12H, Ar-H), 7.715 (s, 1H, -CH=N-),
9.581 (s, 1H, -NH-, D2O exchangeable); MS (m/z, %):
452.10 (M+ + 1 for 81Br, 100.00), 450.07 (M+ + 1 for 79Br,
98.3); Anal. Calcd. for C21H16BrN5O2 (450.29): C, 56.01; H,
3.58; N, 15.55. Found: C, 56.0; H, 3.56; N, 15.53.
Pharmacology
The evaluation of anticonvulsant activity and neurotoxic-
ity was carried out by the Epilepsy Branch, National Institute
of Neurological Disorder and Stroke, National Institute of
Health, Bethesda, USA following the reported procedures.
Male albino mice (CF-1 strain, 18-25g) and male albino rats
(Sprague-Dawley, 100-150g) were used as experimental
animals. The synthesized derivatives were suspended in
0.5% methyl cellulose and the test compound is usually ma-
nipulated with a motar pestle to help in the preparation of
suspension. The titled compounds BTA 1-10 were subjected
to anticonvulsant screening by 6 Hz psychomotor seizure test
to identify the anticonvulsant activity of the compounds at
five different time points, i.e., 0.25 h, 0.5 h, 1.0 h, 2.0 h and
4.0 h after i.p. administration in mice at a dose of 100 mg/kg.
Neurotoxicity was observed by minimal motor impairment
which was measured by the rotorod (neurotoxicity) test.
2-(1H-Benzotriazol-1-yl)-N'-[4-(4-fluorophenoxy)ben-
zylidene]acetohydrazide (BTA 6): Yield: 74%; m.p.:
204°C; IR (KBr, cm–1) ꢁ: 3216 (-NH-), 1687 (C=O), 1602 (-
N=CH-), 1477, 1260 (-N-CH2-), 1233 (-O-); 1H NMR
(CDCl3, 300 MHz) ꢀ in ppm: 5.891 (s, 2H, N-CH2), 6.425-
8.076 (a set of signals, 12H, Ar-H), 7.710 (s, 1H, -CH=N-),
9.582 (s, 1H, -NH-, D2O exchangeable); MS (m/z, %):
390.16 (M+ + 1, 85.3); Anal. Calcd. for C21H16FN5O2
(389.38): C, 64.78; H, 4.14; N, 17.99. Found: C, 64.73; H,
4.12; N, 17.98.
2-(1H-Benzotriazol-1-yl)-N'-[4-(4-chloro-3-methyl-
phenoxy)benzylidene]acetohydrazide (BTA 7): Yield:
72%; m.p.: 195°C; IR (KBr, cm–1) ꢁ: 3217 (-NH-), 1687
(C=O), 1602 (-N=CH-), 1477, 1261 (-N-CH2-), 1231 (-O-);
1H NMR (CDCl3, 300 MHz) ꢀ in ppm: 2.351 (s, 3H, -CH3),
5.892 (s, 2H, N-CH2), 6.421-8.072 (a set of signals, 11H, Ar-
H), 7.7130(s, 1H, -CH=N-), 9.581 (s, 1H, -NH-, D2O ex-
changeable); MS (m/z, %): 420.12 (M+ + 1 for 35Cl, 100.00),
6 Hz Psychomotor Seizure Test
6 Hz psychomotor seizure or minimal clonic seizure test
was used to assess a compound’s efficacy against electrically
induced seizures but used a lower frequency (6 Hz) and
longer duration of stimulation (3s). Test compounds were
pre-administered to mice via i.p. injection. At varying times,
individual mice (four mice per time point) were challenged
with sufficient current delivered through corneal electrodes
to elicit a psychomotor seizure in 97% animals (32 mA for 3
s). The untreated mice would display seizure characterized
by a minimal clonic phase followed by stereotyped, automa-
tistic behaviors, described originally as being similar to the
aura of human patients with partial seizure. Animals not dis-
playing this behavior are considered to be protected [16, 17].
422.08 (M+
+ 1
for 37Cl, 34.7); Anal. Calcd. for
C22H18ClN5O2 (419.86): C, 62.93; H, 4.32; N, 16.68. Found:
C, 62.90; H, 4.28; N, 16.64.
2-(1H-Benzotriazol-1-yl)-N'-[4-(naphthalen-2-yloxy)
benzylidene]acetohydrazide (BTA 8): Yield: 77%; m.p.:
172°C; IR (KBr, cm–1) ꢁ: 3216 (-NH-), 1681 (C=O), 1601 (-
N=CH-), 1478, 1260 (-N-CH2-), 1233 (-O-), 836, 821 (ꢂ-
1
naphthyl); H NMR (CDCl3, 300 MHz) ꢀ in ppm: 5.895 (s,
2H, N-CH2), 6.412-8.05 (a set of signals, 15H, Ar-H), 7.709
(s, 1H, -CH=N-), 9.585 (s, 1H, -NH-, D2O exchangeable);
MS (m/z, %): 422.17 (M+ + 1, 63.5); Anal. Calcd. for
C25H19N5O2 (421.45): C, 71.25; H, 4.54; N, 16.62. Found: C,
71.21; H, 4.52; N, 16.59.
Neurotoxicity- Minimal Motor Impairment (MMI)
Minimal motor impairment was measured by the rotarod
(neurotoxicity) test. When a mouse is placed on a rod that
rotates at a speed of 6 rpm, the animal can maintain its equi-
librium for a long period of time. The compound was con-
sidered toxic if the treated animal fell off this rotating rod 3
times during 1 minute period. Mice were placed on the
elevated accelerating rod (rotarod, 3 cm in diameter)
beginning at 5 rpm/min for four trials per day for three
consecutive days. Each trial lasted a maximum of 10 min,
during which time the rotating rod underwent a linear
acceleration from 4 to 40 rpm over the first 5 min of the trial
and then remained at maximum speed for the remaining 5
min. Animals were scored for their latency (in seconds) to
fall (height = 20 cm) for each trial. Animals rested a
minimum of 10 min between trials to avoid fatigue.
N'-[4-(1,3-Benzodioxol-5-yloxy)benzylidene]-2-(1H-
benzotriazol-1-yl)acetohydrazide (BTA 9): Yield: 71%;
m.p.: 165°C; IR (KBr, cm–1) ꢁ: 3215 (-NH-), 1687 (C=O),
1
1602 (-N=CH-), 1480,1262 (-N-CH2-), 1228(-O-); H NMR
(CDCl3, 300 MHz) ꢀ in ppm: 5.892 (s, 2H, N-CH2), 5.989 (s,
2H, O-CH2), 6.521-8.09 (a set of signals, 11H, Ar-H), 7.711
(s, 1H, -CH=N-), 9.588 (s, 1H, -NH-, D2O exchangeable);
MS (m/z, %): 416.15 (M+ + 1, 65.3); Anal. Calcd. for
C22H17N5O4 (415.40): C, 63.61; H, 4.12; N, 16.86. Found: C,
63.60; H, 4.10; N, 16.84.
2-(1H-Benzotriazol-1-yl)-N'-[(3Z)-2-oxo-1,2-dihydro-
3H-indol-3-ylidene]acetohydrazide (BTA 10): Yield: 79%;

342 Medicinal Chemistry, 2012, Vol. 8, No. 3
Kumar and Tripathi
tions of 27,000, an elitism value of 1 and a number of active
torsion of 9 were used. AutoDock 4.0 was used to generate
both grid and docking parameter files (i.e., .gpf and .dpf
files) and docking affinity (Kcal/mol) and count of probable
H-bonds were determined.
Computational Studies
Distance Mapping
The pharmacophore pattern studies in which distance be-
tween the various groups postulated as essential for anticon-
vulsant activity were done on the 3D optimized structures
using ACD/3D viewer version 12.01 and Argus Lab 4.0
Mark A. Thompson Planaria Software LLC. In conforma-
tional analysis of the ten clinically effective, well known and
structurally different anticonvulsant drugs such as albutoin,
carbamazepine, gabapentin, lamotrigine, mephobarbital,
phenytoin, progabide, ralitoline, remacemide, zonisamide; a
molecular model was suggested on the basis of molecular
dynamics distance estimations [18].
RESULTS AND DISCUSSION
Synthesis and Characterization of BTA 1-10
The key intermediate 2-(1H-Benzotriazol-1-yl)aceto-
hydrazide 3 was synthesized by reacting 1H-Benzotriazole 1
with chloroethyl acetate and potassium carbonate in dry ace-
tone to yield ethyl 1H-benzotriazol-1-ylacetate 2, which was
refluxed with hydrazine hydrate in ethanol to afford the 3. A
mixture of substituted phenol 4a-i, 4-fluorobenzaldehyde 5
and potassium carbonate in N,N-dimethylformamide was
refluxed to afford 4-substituted benzaldehydes 6a-i. The IR
spectra of compound 3 showed peaks at 3337, 1672 and
1461, 1232 cm-1 indicating the presence of NH, C=O, N-CH2
group respectively. Its 1H NMR spectra showed a singlet at ꢁ
9.88 ppm due to NH group; a singlet at ꢁ 5.81 due to N-CH2;
a singlet at ꢁ 4.68 for NH2 and a multiplet at ꢁ 6.83-7.91 ppm
for aromatic (4H) protons. The absence of a triplet at ꢁ 1.30
for CH3 and a quartet at ꢁ 4.27 for COOCH2 of 2 confirms
the conversion of 2 to 3. Data from the elemental analyses
were found to be in conformity with the assigned structure.
Further the [M++1] peak recorded in the mass spectra is also
in agreement with the molecular weight of the compound.
The formation of 4-substituted benzaldehydes 6a-i from 4-
Calculation of Physicochemical Properties
A computational study of titled compounds was per-
formed for the prediction of ADME properties. Polar surface
area (TPSA) [19], miLog P, number of rotable bonds, mo-
lecular volume, number of hydrogen donor and acceptor
atoms and violations of Lipinski’s rule of five [20] were cal-
culated using Molinspiration online property calculation
toolkit [21]. Absorption (%ABS) was calculated by: %ABS
= 109-(0.345 ꢀ TPSA) [22].
Log P Determination
The partition coefficient between octanol and phosphate
buffer was determined at room temperature [23]. 10 mL of
octanol and 10 mL phosphate buffer were taken in a glass
stoppered graduated tube and 5 mg of accurately weighed
compound was added. The mixture was then shaken with the
help of a mechanical shaker for 24 h at room temperature
and then transferred to a separating funnel and allowed to
dynamically equilibrate for 6 h. The aqueous and octanol
phases were separated and filtered through membrane filter
and drug content in aqueous phase was analyzed by UV
spectroscopy. Theoretical miLog P for synthesized com-
pounds was then compared with the experimental Log P
data.
1
substituted phenols 4a-i was confirmed by its IR and H-
NMR spectral studies. The IR spectrum of 4-(4-fluoro-
phenoxy) benzaldehydes 6f showed bands at 1665, 3035 and
1240 cm-1 indicating the presence of C=O str, C-H str and
diaryl ether linkage (-O-). The absence of broad band of
phenolic -OH at 2900-3000 cm-1 confirms the conversion of
4-fluoro phenol 4f to 6f. In its 1H-NMR spectrum a singlet at
ꢁ 9.87 ppm indicates the presence of -CHO group, where as
the absence of a singlet around ꢁ 9.288 ppm for phenolic –
OH confirms the conversion of 4f to 6f.
The IR spectrum of the title compound BTA 9 showed
C=O str at 1687 cm-1, N-H str at 3215 cm-1, CH=N str at
1602 cm-1, N-CH2 str at 1480, 1262 cm-1 and diaryl ether
Docking Studies
Compound BTA 9 was selected as a ligand for docking
studies with six established epilepsy receptors namely
GABA(A) alpha-1, GABA(A) delta, glutamate, Na/H ex-
changer, Na channel and T-type calcium channel (Fig. 5).
These receptors are the most important molecular targets in
the design and discovery of successful antiepileptic drugs
[24]. In the present study, AutoDock 4.0 with its Lamarckian
genetic algorithm (LGA) was used for automated flexible
ligand docking of BTA 9 with above mentioned receptors
and affinity (Kcal/mol) and H-bond properties were evalu-
ated.
1
linkage (-O-) at 1228 cm-1. Its H-NMR spectrum showed a
singlet of imine (CH=N) proton at ꢁ 7.711 ppm; a singlet at ꢁ
5.892 ppm for N-CH2; a singlet at ꢁ 5.989 ppm for O-CH2; a
multiplet at ꢁ 6.521-8.09 for aromatic (11H) protons and –
NH proton resonated as a broad singlet at ꢁ 9.588 ppm that
was D2O exchangeable. The presence of CH=N str at 1602
cm-1 in IR spectrum and a singlet for imine (CH=N) proton at
ꢁ 7.711 ppm confirm the formation of BTA 9. The mass
spectrum of the compound showed [M++1] peak at 416.15
corresponding to their molecular formula and are in confor-
mity with the assigned structure. Elemental (C, H, N) analy-
ses satisfactorily confirmed elemental composition and pu-
rity of the synthesized compounds.
The grid maps were calculated using AutoGrid. In all
dockings, a grid map with 60 ꢀ 60 ꢀ 60 points, a grid spac-
ing of 0.375 A ° (roughly a quarter of the length of a carbon–
carbon single bond) were used, and the mps were centered
on the ligand binding site. For all dockings, 100 independent
run with, an initial population of random individuals with a
population size of 150 individuals, a maximum number of
2.5 ꢀ 106 energy evaluations, maximum number of genera-
Pharmacology
The newly synthesized 2-(1H-Benzotriazol-1-yl)-N'-
[substituted] acetohydrazides BTA 1-10 were subjected to
anticonvulsant screening by 6 Hz psychomotor seizure or

A New Class of Anticonvulsants Possessing 6 Hz Psychomotor Seizure Test Activity
Medicinal Chemistry, 2012, Vol. 8, No. 3 343
Table 1. 6 Hz psychomotor seizure test activity and neurotoxicity of BTA 1-10
Time (h) to Peak Effect (N/F)*
Dose
Compound
BTA 1
Test
(mg/kg)
0.25
0.5
1.0
2.0
4.0
6 Hz
TOX
6 Hz
TOX
6 Hz
TOX
6 Hz
TOX
6 Hz
TOX
6 Hz
TOX
6 Hz
TOX
6 Hz
TOX
6 Hz
TOX
6 Hz
TOX
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
0/4
0/4
0/4
0/4
0/4
0/4
1/4
0/4
0/4
0/4
0/4
0/4
1/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
1/4
0/4
0/4
0/4
1/4
0/4
1/4
0/4
2/4
0/4
0/4
0/4
1/4
0/4
2/4
0/4
3/4
0/4
1/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
2/4
0/4
1/4
0/4
1/4
0/4
0/4
0/4
1/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
ꢀ
BTA 2
BTA 3
BTA 4
BTA 5
BTA 6
BTA 7
BTA 8
BTA 9
BTA 10
0/4
0/4
0/4
0/4
0/4
0/4
0/4
*N/F= number of animals active or toxic over the number tested.
anticonvulsant compounds with the titled compounds. The
two- dimensional (2D) modeling on anticonvulsants has
identified that at least one aryl unit, one or two electron do-
nor atoms, and/or an NH group in a special spatial arrange-
ment are recommended for anticonvulsant activity. In the
present study, the 10 well-known and structurally different
compounds with anticonvulsant activity- albutoin, carba-
mazepine, gabapentin, lamotrigine, mephobarbital, pheny-
toin, progabide, ralitoline, remacemide and zonisamide (Fig.
3) with different mechanism of action, were selected so as to
propose a generalized pharmacophore model. The pharma-
cophore group’s distance estimation was done by molecular
mechanics calculation with the force fields based on both
CHARMm force fields and MM3 parametrization. In the
present work, energy minimization was performed on above
mentioned ten well known anticonvulsants and titled com-
pounds using Argus Lab 4.0. Distance between the various
structural components essential for activity was determine by
ACD/3D viewer version 12.01. The crucial structural com-
ponents that were included in the four-point pharmacophore
model (Fig. 4) were the aryl ring center or the lipophilic
group (A), an electron donor atom (D), a hydrogen bond
acceptor (HA), and a hydrogen bond donor (HD). An aver-
minimal clonic seizure test to identify their anticonvulsant
activity at five different time points, i.e., 0.25 h, 0.5 h, 1.0 h,
2.0 h and 4.0 h after i.p. administration in mice at a dose of
100 mg/kg. The results of screening at five different points
are summarized in Table 1. As observed from the results of
various tested 2-(1H-Benzotriazol-1-yl)-N'-[substituted] ace-
tohydrazides, compound BTA 9 was the most active one in
this series with 75 % protection (3/4, 0.5 h) at a dose of 100
mg/kg. At a dose of 100 mg/kg, compounds BTA 4, BTA 5
and BTA 8 showed 50% protection (2/4) at a time point of
1.0 h, 0.5 h and 0.5 h respectively. Other compounds showed
mild to moderate activity. These active compounds contain
1,3-benzodioxol-5-yl, 4-chlorophenyl, 4-bromophenyl and
naphthalen-2-yl substitution attached to basic molecular
structure. None of the compounds showed neurotoxicity in
the highest administered dose.
Computational Studies
Distance Mapping
The present work involves the correlation of the struc-
tural requirement of well known and structurally different

344 Medicinal Chemistry, 2012, Vol. 8, No. 3
Kumar and Tripathi
A- Hydrophobic Unit
D- Electron Donar Group
HA- Hydrogen Bond
Acceptor Unit
HD- Hydrogen Bond
Donar Unit
D
4.30
(3.01-5.38)
4.86
(2.43-6.79)
4.37
(2.52-6.72)
C
C
C
A
C
C
C
6.05
(3.78-9.51)
5.86
(2.72-9.23)
HA
2.54
(1.78-3.87)
HD
Fig. (4). Four-point 3D pharmacophore model for anticonvulsants derived by using MM3 and CHARMm parametrization (Argus Lab 4.0 and ACD/3D
viewer).
Table 2. Distance ranges between the essential structural elements A, D and HA – HDa
Compounds
A-HA
A-HD
A-D
HA-HD
HD-D
HA-D
Albutoin
Carbamazepine
Gabapentin
5.37
4.28
2.72
4.28
4.51
4.25
2.72
2.33
4.03
5.75
5.40
5.67
4.26
4.93
3.83
2.23
3.57
4.50
Lamotrigine
Mephobarbital
Phenytoin
5.30
7.42
4.54
2.42
4.94
4.25
3.78
5.50
4.81
2.34
4.63
5.23
6.20
4.01
4.35
2.63
3.88
5.17
Progabide
9.51
9.23
3.79
2.41
6.72
6.79
Ralitoline
8.30
5.55
4.56
2.75
2.52
4.85
Remacemide
Zonisamide
7.51
8.75
5.38
3.87
3.96
2.43
6.02
6.22
3.01
1.78
3.71
4.31
Mean±standard deviation
6.05 ± 1.87
5.86 ± 2.09
4.30 ± 0.64
2.54 ± 0.54
4.37 ± 1.19
2.37
4.86 ± 1.13
4.66
BTA 9
3.29
6.07
6.56
3.14
aDistances calculated for 3D optimized structures using MM3 and CHARMm parameterization (Argus Lab 4.0 and ACD/3D viewer).
age distance range for every point was obtained and com-
pared to the titled compounds. Now it may be interesting to
examine whether the titled compounds reflect the conditions
of the derived pharmacophore model. Our analyses of the
distance relationship showed that titled compounds did fulfill
the essential demands of the pharmacophore when compared
to the average distance requirement (Table 2).
molecular transport through membranes and, therefore, al-
lows prediction of transport properties of drugs in the intes-
tines and blood-brain barrier crossing [17]. The percentage
of absorption (%ABS) was calculated using TPSA. From all
these parameters, it can be observed that all titled com-
pounds exhibited a great %ABS ranging from 65.1 to 80.9%
(Table 3). Furthermore, except BTA 7 and BTA 8, none of
the compounds violated Lipinski’s parameters, making them
potentially promising agents for epilepsy therapy.
Prediction of ADME Properties
A computational study for the prediction of ADME prop-
erties of titled compounds was performed. Topological polar
surface area (TPSA), i.e., surface belonging to polar atoms,
is a descriptor that was shown to correlate well with passive
Log P Determination
Titled compounds showed dependence of biological ac-
tivity on lipophilic character in a congeneric series. In par-

A New Class of Anticonvulsants Possessing 6 Hz Psychomotor Seizure Test Activity
Medicinal Chemistry, 2012, Vol. 8, No. 3 345
Table 3. Pharmacokinetic parameters important for good oral bioavailability of compounds BTA 1-10a
Molecular
Volume
n-OHNH
Donors
n-OH
Lipinski’s
Violation
Compound
% ABS
TPSA (A2)
n-ROTB
MW
Acceptors
Rule
BTA 1
BTA 2
BTA 3
BTA 4
BTA 5
BTA 6
BTA 7
BTA 8
BTA 9
BTA 10
--
--
--
6
7
6
6
6
6
6
6
6
3
<500
371.4
--
<5
1
<10
7
ꢀ1
0
0
0
0
0
0
1
1
0
0
80.9
65.1
80.9
80.9
80.9
80.9
80.9
80.9
74.5
72.7
81.41
127.23
81.41
81.41
81.41
81.41
81.41
81.41
99.88
105.04
328.34
351.674
344.901
341.875
346.225
333.271
358.436
372.331
352.269
268.49
416.39
385.43
405.85
450.29
389.39
419.87
421.46
415.41
320.312
1
10
7
1
1
7
1
7
1
7
1
7
1
7
1
9
2
8
a %ABS, percentage of absorption; TPSA, topological polar surface area; n-ROTB, number of rotatable bonds; MW, molecular weight; MV, molecular volume; n-OHNH, number of
hydrogen bond donors; n-ON, number of hydrogen bond acceptors.
Table 4. Log P value for compounds BTA 1-10
Compounds
Experimental Log P
Theoretical Log P (miLog Pa)
Rule
BTA 1
BTA 2
BTA 3
BTA 4
BTA 5
BTA 6
BTA 7
BTA 8
BTA 9
BTA 10
--
ꢀ5
3.892
3.813
4.356
4.567
4.644
4.144
4.923
4.961
3.870
1.630
4.184
4.143
4.633
4.862
4.993
4.348
5.239
5.367
4.074
1.665
amiLog P, logarithm of compound partition coefficient between n-octanol and water calculated as per Molinspiration Online Property Toolkit.
ticular, for drugs acting on central nervous system to be po-
tent, they have to cross blood brain barrier (BBB), thus po-
tency has been correlated with optimum lipophilicity (Log P)
near 2. In this study, we attempted to correlate the anticon-
vulsant activity of congeners with their calculated Log P
value. The experimental Log P values were determined using
the octanol- phosphate buffer method. The data are presented
in Table 4. As observed some of the experimental values
were in good agreement with the theoretical values. All the
titled compounds showed lipophilic character.
compound BTA 9 with six established epilepsy molecular
targets namely GABA (A) alpha-1 receptor, GABA (A) delta
receptor, glutamate receptor, Na/ H exchanger, Na channel
receptor, T-type calcium channel receptor and evaluated
their affinity (Kcal/mol) and hydrogen bonding. The crystal-
lographic structure of receptors is shown in Fig. (5). BTA 9
has exhibited good binding properties with GABA (A) delta
receptor (Affinity value -6.3 Kcal/mol and 4 H-bonds),
GABA (A) alpha-1 receptor (Affinity value -5.5 Kcal/mol
and 1 H-bond), glutamate receptor (Affinity value -5.8
Kcal/mol and 1 H-bond) and Na/H exchanger (Affinity value
-5.7 Kcal/mol and 1 H-bond). The docking study results are
shown in Table 5 and Fig. (6). Docking study results shows
that the BTA 9 exhibited good binding properties with
Docking Studies
In this study, we have used AutoDock 4.0 along with its
LGA algorithm for automated flexible ligand docking of

346 Medicinal Chemistry, 2012, Vol. 8, No. 3
Kumar and Tripathi
Fig. (5). Crystallographic structure of (a) GABA(A) alpha-1 receptor, (b) GABA(A) delta receptor, (c) Glutamate receptor, (d) Na/H exchanger, (e) Na chan-
nel receptor, (f) T-type calcium channel receptor.
Table 5. Docking study results of compound BTA 9a
H- BindingLigand
Atom
H- Binding Receptor
Affinity
H-
Ligand
Receptor
Atom
bonds
(Kcal/mol)
Element
Type
Residue
Element
ID
Type
ID
GABA(A)
alpha-1
-5.5
-6.3
01
04
N
8
Acceptor
Ser299
O
185
Both
N
N
N
N
N
12
06
07
08
12
Donor
Acceptor
Acceptor
Acceptor
Donor
Tyr318
Tyr318
Tyr318
Tyr318
Leu469
O
O
O
O
O
400
400
400
400
250
Both
Both
GABA(A)
delta
Both
Both
BTA 9
Glutamate
-5.8
-5.7
-0.0
-0.0
01
01
00
00
Acceptor
Na/H ex-
changer
N
--
--
06
--
Acceptor
Phe253
N
--
--
96
--
Donor
Na Channel
--
--
--
--
--
--
T-type Cal-
cium
--
--
aAffinity and H-bonds calculations were determined by docking studies using Autodoc 4.0 software.
GABA (A) delta, GABA (A) alpha-1, glutamate receptor and
Na/H exchanger.
except BTA 7 and 8, none of the compounds violated Lipin-
ski’s parameters, making them potentially promising agent
for epilepsy therapy. Docking study results show that the
compounds exhibited good binding properties with GABA
(A) delta, GABA (A) alpha-1, glutamate receptor and Na/H
exchanger. The docking study data strongly support the as-
sumption that these receptors may be involved in observed
anticonvulsant activity of 2-(1H-Benzotriazol-1-yl)-N'-
[substituted]acetohydrazides. However, further studies need
to be carried out to ascertain the precise mechanism of action
of anticonvulsant activity of these molecules.
CONCLUSION
A series of 2-(1H-Benzotriazol-1-yl)-N'-[substituted] ace-
tohydrazide was designed, synthesized, and their anticonvul-
sant activity was evaluated after intraperitoneal administra-
tion in 6 Hz psychomotor seizure test. A computational study
was also carried out, including the calculation of pharma-
cophore pattern, prediction of pharmacokinetic properties
and docking studies. The compound BTA 9 displayed sig-
nificant protection and emerged as a lead in this series. Fur-
ther, compounds BTA 4, BTA 5 and BTA 8 came out as a
potential candidate for further investigation. Furthermore,
DISCLOSURE
Some part of information included in this chapter has
been previously published MEDICINAL CHEMISTRY RE-

A New Class of Anticonvulsants Possessing 6 Hz Psychomotor Seizure Test Activity
Medicinal Chemistry, 2012, Vol. 8, No. 3 347
Fig. (6). Docking images of BTA 9 with (a) GABA(A) alpha-1 receptor, (b) GABA(A) delta receptor, (c) Glutamate receptor, (d) Na/H
exchanger.
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The authors would like to express their gratitude to Dr.
James P. Stables, Preclinical Pharmacology Section, Epi-
lepsy Branch, National Institute of Health, USA for provid-
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drug development program. The authors are also thankful to
Dr. Birendra Shrivastava, School of Pharmaceutical Sci-
ences, Jaipur National University, Jaipur and Dr. S. N.
Pandeya, Dept. of Pharmacy, Saroj Institute of Technology
and Management, Lucknow for their valuable suggestions
during the research work. The authors also appreciate the
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Received: November 10, 2010
Revised: April 30, 2011
Accepted: July 27, 2011