Synthesis and characterization of some heterocyclic schiff bases: Potential anticonvulsant agents

Article abstract of DOI:10.1007/s00044-010-9441-z

A series of novel schiff bases of 3-aminomethyl pyridine have been synthesized through condensation reaction with substituted aryl aldehydes/ketones and/cyclic ketones. These schiff bases were screened for anticonvulsant activity. The chemical structures of synthesized compounds were confirmed by FT-IR, ¹H-NMR, spectroscopy, and elemental analysis. A number of compounds were observed to exhibit seizures protection after intraperitoneal administration at the dose 30 and 100 mg kg^-1 in various models employed. In MES screen we found five potent compounds i.e., (1_c) N-(2-chlorobenzylidene) (pyridin-3-yl) methanamine, (1 _f) 2-methoxy-4-{(pyridine-3-ylmethyl imino) methyl} phenol, (2 _a) N-(3phenylallylidene) (pyridin-3-yl) methanamine, (3b) 3-{1-(pyridin-3-ylmethylimino) ethyl} benzenamine, and (4_a) N-(diphenyl-methylene) (pyridin-3- yl) methanamine, emerged as most active compounds in series (ED₅₀) 11.70, 6.39, 11.70, 8.64, and 9.13 mg kg^-1 with high protective index (PI)>10. Four compounds (1 _e) 4-{(Pyridine-3-ylmethylmino) methyl}benzene-1,3-diol, (1 _g) N-(3,4,-dimethoxybenzylidene) (pyridin-3-yl)methanamine, (2 _b) N-{(1H-indol-3-yl)methylene}(pyridin-3-yl) methanamine, and (5) N-cyclohexylidene (pyridine-3-yl) methanamine) showed remarkable protection over clinically used drugs in sc.PTZ screen (ED₅₀) 6.44, 11.70, 6.47, and 14.16 with (PI>10). Compound (4_b) showed good anticonvulsant activity (ED50) 20.79, but with relatively higher neurotoxicity (PI, 0.57). Compound (l_e) was active in both sc.PTZ and in sc.STR seizures. Some selected compounds were subjected to oral MES screen (30 mg kg^-1) in rats, most of the compounds showed peak activity after 0.5 h of oral administration. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9441-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1091–1101
DOI 10.1007/s00044-010-9441-z
ORIGINAL RESEARCH
Synthesis and characterization of some heterocyclic schiff bases:
potential anticonvulsant agents
•
Shailendra Pandey R. S. Srivastava
Received: 13 April 2010 / Accepted: 15 September 2010 / Published online: 6 October 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series of novel schiff bases of 3-aminomethyl
pyridine have been synthesized through condensation reac-
tion with substituted aryl aldehydes/ketones and/cyclic
ketones. These schiff bases were screened for anticonvulsant
activity. The chemical structures of synthesized compounds
were confirmed by FT-IR, 1H-NMR, spectroscopy, and
elemental analysis. A number of compounds were observed
to exhibit seizures protection after intraperitoneal adminis-
tration at the dose 30 and 100 mg kg-1 in various models
employed. In MES screen we found five potent compounds
i.e., (1c) N-(2-chlorobenzylidene) (pyridin-3-yl) methan-
amine, (1f) 2-methoxy-4-{(pyridine-3-ylmethyl imino)
methyl} phenol, (2a) N-(3phenylallylidene) (pyridin-3-yl)
methanamine, (3b) 3-{1-(pyridin-3-ylmethylimino) ethyl}
benzenamine, and (4a) N-(diphenyl-methylene) (pyridin-3-
yl) methanamine, emerged as most active compounds in
series (ED50) 11.70, 6.39, 11.70, 8.64, and 9.13 mg kg-1
with high protective index (PI) [ 10. Four compounds (1e)
4-{(Pyridine-3-ylmethylmino) methyl}benzene-1,3-diol, (1g)
N-(3,4,-dimethoxybenzylidene) (pyridin-3-yl)methanamine,
(2b) N-{(1H-indol-3-yl)methylene}(pyridin-3-yl) methan-
amine, and (5) N-cyclohexylidene (pyridine-3-yl) methan-
amine) showed remarkable protection over clinically used
drugs in sc.PTZ screen (ED50) 6.44, 11.70, 6.47, and 14.16
with (PI [ 10). Compound (4b) showed good anticonvulsant
activity (ED50) 20.79, but with relatively higher neurotox-
icity (PI, 0.57). Compound (1e) was active in both sc.PTZ
and in sc.STR seizures. Some selected compounds were
subjected to oral MES screen (30 mg kg-1) in rats, most of
the compounds showed peak activity after 0.5 h of oral
administration.
Keywords Heterocyclic schiff bases Á
3-Aminomethyl pyridine Á Anticonvulsant activity Á
Neurotoxicity
Introduction
Epilepsy is one of the world’s oldest recognized chronic
neurological disorders, affecting more than 50 million
people world-wide (World Health Organization, 2001) of
all the age group (Hanneke et al., 2008). India is home of
around 20% of the global population living with epilepsy.
Latest survey indicates that approximately 0.5 million new
cases of epilepsy are diagnosed every year in India and
beside that majority of people cannot afford or access
appropriate medical care, due to high treatment cost (Bo-
`
nifacio et al., 2001; Krishnan et al., 2007). The estimated
treatment gap in developing countries like India is tre-
mendous, and is almost three times to the total number of
people with epilepsy in developed counties. Epilepsy is
characterized by recurrent seizures, which are physical
reactions to sudden, usually brief, excessive electrical dis-
charges in a group of neurons in the different parts of brain.
Complex physiological and biochemical events during
epileptic seizures provide insight into the molecular
mechanisms by which seizures might be controlled. Inhi-
bition of neuronal cation conductance via blockage of
voltage gated sodium channels is one of the proven mech-
anisms to regulate the seizures activity for many anticon-
vulsants like Phenytoin, Carbamazepine, Valproic acid etc.
Despite of strong antiepileptic capabilities many mar-
keted antiepileptic drugs i.e., Ethosuximide, Valproic acid,
S. Pandey (&) Á R. S. Srivastava
Pharmaceutical Chemistry Research Laboratory,
Department of Pharmaceutics, Institute of Technology,
Banaras Hindu University, Varanasi 221005, India
e-mail: spandey.rs.phe@itbhu.ac.in; pandey99itbhu@gmail.com
123

1092
Med Chem Res (2011) 20:1091–1101
Phenytoin, Carbamazepine, and Barbiturates, are also pro-
ducing many adverse effects such as ataxia, hepatotoxicity,
gingival (Brodie and Dichter, 1996) hyperplasia, and
megaloblastic anaemia (Noviasky et al., 2001). Moreover,
the treatment condition becomes worsen due to develop-
ment resistance in almost 20–30% patients by currently
used therapeutic agents. Thus, it is essential to investigate a
novel antiepileptic agent that is highly efficacious, safe in
terms of drug related toxicity that not only abolish the
occurrence of seizures but also lead to a self sustained life.
The pyridines derivatives became of recent importance
due to their wide biological and medicinal applicability.
Pyridines and its derivatives have already been reported with
anticonvulsant (Kaminski et al., 2006) (Narendar et al.,
2003), cardiotonic (Bekhit and Baraka, 2005), antihyper-
tensive (Ludden et al., 1979), b-adrenergic blocking (Fer-
rarinia et al., 2000) activities. Pyridine and amino-pyridines
are well known class of compounds for its potassium channel
blocking action. Various amino-alkyl pyridines have been
reported as excitatory amino acid inhibitors and N-methyl-D-
aspartic acid (NMDA)/r receptor antagonist and had been
evaluated as potent antiepileptic agent (Pankaja, 1991).
Substituted amino-pyridines have been used as chemical
intermediates in the production of various medicaments (i.e.,
Cyclopiroxolamine, Diphenpyramide, Methaqualone Pro-
piramfumarate, Pyrilamine, Triprolidine, Zomepirac etc.).
Some amino-methyl pyridine derivatives with significant
anticonvulsant activity (Inguva et al., 2003) and aminopyr-
idine derivatives of 2-carboxaldehyde thiosemicarbazone
have also been reported for their tumor-inhibitory action
(Cory et al., 1995). The dilemma in the use of 4-aminopyr-
idine is its side effects neurotoxicity (Johnson and Morgan,
2006) and cardiovascular abnormalities in humans (Pickett
and Enns, 1996). Schiff bases derived from various hetero-
cyclic compounds also have been reported to possess cyto-
toxic, anticonvulsant, antiproliferative, antimicrobial,
anticancer, and antifungal activities (Karthikeyan et al.,
2006). Our research group (Pandey and Srivastava, 2009)
had also explored and reported a series of some new schiff
bases from 2-aminomethylpyridine having anticonvulsant
action. In continuation of our previous exciting research
outcomes on 2-aminopyridine schiff bases, as well as by
considering excellent anticonvulsant potential of some schiff
bases, and amino alkyl-pyridine, we are now shifting our
research focus on 3-aminomethylpyridine schiff bases.
BARNSTEAD/ELECTROTHERMAL STUART-SMP10.
Spectroscopic data were recorded on SHIMADZU RF-
1501-UV Spectro-fluorophotometer, IR spectra were
recorded on KBr disks using SHIMADZU Infrared-spec-
1
trophotometer, FTIR-8400S, The H-NMR spectra’s were
measured by JEOL, AL300, FT-NMR Spectrophotometer
(300 MHz) at temperature 25°C, compounds were solub-
lized in DMSO-d6/CDCl3 solvents. All the chemical shifts
were reported in d (ppm) values using tetramethylsilane
(TMS) as internal standard. Perkin-Elmer model 240C
analyzer was used for C, H, N, elemental analyses. The
homogeneity of the compounds was monitored by
ascending thin layer chromatography (TLC) on silica gel-
G (0.2-mm thickness Merck, India) coated aluminium
plates, visualized in UV light. The log P values were
determined using Chem. Draw Ultra version 5.0software
(Chem. Draw Ultra version 8.0 is a program of cam-
bridge-soft corporation, USA). All the chemicals and
reagents were used of synthetic grade. The various sub-
stitutions (Table 1) were made on amino group of
3-aminomethylpyridine nucleus.
Synthesis of compounds
Procedure for synthesis of 3-aminomethyl pyridine
In a 250-ml conical flask 3-cyanopiridine (0.05 mol) was
dissolved in 20 ml absolute ethanol and kept for stirring on
magnetic stirrer at 90°C in liquid paraffin oil bath, to this
solution small freshly cut pieces (50–100 mg) of sodium
metal were dropped and a vigorous reduction process
starts, the progress of the reaction was monitored by TLC.
On completion of reaction the product was separated by
evaporation and fractionation.
General procedure for synthesis of schiff bases (1a–2b)
3-aminomethyl pyridine (0.05 mol.) was dissolved in suf-
ficient quantity of methanol in a 250-ml conical flask and
stirred at room temperature for 15 min until get a clear
solution. To this solution equimolar quantity (0.05 mol) of
each substituted aryl aldehydes (in methanol) were added
with few drops of concentrated hydrochloric acid (cata-
lyst), and reaction mixture was refluxed with stirring up to
12–18 h at 70°C on magnetic stirrer. The reaction progress
was monitored by thin layer chromatography (TLC). On
completion of reaction, solvent was evaporated to dryness
and compounds were obtained by precipitation on addition
of 10 ml ethyl acetate. For the recrystallization of the
synthesized compounds ethyl acetate and absolute metha-
nol were used in different proportions depending on the
nature of the compound.
Materials and methods
Chemistry
The melting points were determined in an open capillary
melting point apparatus and are uncorrected by using
123

Med Chem Res (2011) 20:1091–1101
1093
Table 1 Physical constants of the synthesized schiff bases
Compound
1a
R1
H
R2
Mol. for.
C13H12N2
Mol. weight
196.2
Log P
2.63
1b
H
H
C13H11N3O2
241.2
230.7
1.65a
2.62a
NO2
1c
C13H11N2Cl
Cl
1d
H
H
C13H11N2Cl
230.7
242.3
2.62a
2.00a
Cl
OCH3
OH
1e
C14H14N2O2
OH
OCH3
1f
H
H
C14H14N2O2
242.3
256.3
2.12
2.38
OCH3
1
C15H16N2O2
g
OCH3
OCH3
1h
H
H
C16H18N2O2
286.3
222.3
2.25
2.52
OCH3
OCH3
1i
C15H14N2
2a
H
H
C14H14N2O
226.27
235.3
2.51
2.17
O
2b
C15H13N3
N
H
3a
CH3
C14H14N2
210.3
2.2
123

1094
Med Chem Res (2011) 20:1091–1101
Table 1 continued
Compound
R1
R2
Mol. for.
C14H15N3
Mol. weight
225.3
Log P
NH2
3b
4a
CH3
1.4
C19H16N2
272.3
302.4
4.1
OH
4b
C20H18N2O
3.39
5
6
–
C12H16N2
C16H22N2
188.3
242.2
2.28
3.77
–
a
cLogP instead of log P calculated through Chem. Draw Ultra software
N-Benzylidene (pyridin-3-yl) methanamine (1a)
67.68; H, 4.81; N, 12.14. Found: C, 67.47; H, 4.62; N,
12.40.
Recrystallized in absolute ethanol, yield: 75.0%, m.p.:
260–262°C, Rf 0.76 chloroform:methanol (9:1) mixture,
Spectroscopic analysis: IR (cm-1, KBr): 1384 (C–N), 1435
N-(4-Chlorobenzylidene) (pyridin-3-yl) methanamine (1d)
1
(C=C), 1604 (C=N), 2997 (CH); H-NMR (DMSO-d6) d
Recrystallized in absolute ethanol; yield: 63.0%; m.p.:
245–247°C; Rf 0.70 chloroform:methanol (9:1) mixture; IR
(cm-1, KBr): 1384 (C–N), 1491, 1435 (C=C), 1606 (C=N),
3003 (CH); 1H-NMR(DMSO-d6) d [ppm]: 3.93 (s, 2H,
–CH2–), 7.39–7.83 (m, 4H, Ar-H), 8.58 (s, 1H, –CH=N–),
7.81–8.50 (d, 4H, Py-H); Anal. Calcd. for C13H11N2Cl: C,
67.68; H, 4.81; N, 12.14. Found: C, 67.89; H, 5.02; N, 12.51.
[ppm]: 2.50 (s, 2H, –CH2–), 7.42–7.94 (m, 5H, Ar-H), 7.97
(s, 1H, –CH=N–), 8.56–8.68 (d, 4H, Py-H); Anal. calcd. for
C13H12N2: C, 79.56; H, 6.16; N, 14.27. Found: C, 79.60; H,
6.20; N, 14.22.
N-(4-Nitrobenzylidene) (pyridin-3-yl) methanamine (1b)
Recrystallized in ethyl acetate:chloroform (9:1); yield:
69.3% m.p.: 168–170°C, Rf 0.61 chloroform:methanol
(9:1) mixture; IR (cm-1, KBr): 1384 (C–N), 1491, 1437
2-Methoxy-5-((pyridin-3-ylmethylimino)methyl)phenol (1e)
Recrystallized in ethyl acetate :chloroform(9:1); yield:
90.2%; m.p.: 256–258°C, Rf 0.74 chloroform:methanol
(9:1) mixture; IR (cm-1, KBr): 1369 (C–N), 1550, 1467
(C=C), 1602 (C=N), 2991 (CH), 3425-3444 (OH); 1H-
NMR(DMSO-d6) d [ppm]: 3.82 (s, 3H, –OCH3–)4.09 (s,
2H, –CH2–), 4.64 (s, 1H, –OH) 7.44–7.88 (m, 4H, Ar-H),
7.91 (s, 1H, –CH=N–), 8.21–8.66 (d, 4H, Py-H); Anal.
Calcd. for C14H14N2O2: C, 73.56; H, 5.70; N, 13.20.
Found: C, 73.25; H, 5.92; N, 13.69.
1
(C=C), 1606 (C=N), 2999 (CH); H-NMR(DMSO-d6) d
[ppm]: 3.42 (s, 2H, –CH2–), 7.44–8.00 (m, 4H, Ar-H), 7.97
(s, 1H, –CH=N–), 8.57–8.70 (d, 4H, Py-H); Anal. Calcd.
for C13H11N3O2: C, 64.72; H, 4.60; N, 13.26. Found: C,
64.57; H, 4.92; N, 13.56.
N-(2-Chlorobenzylidene) (pyridin-3-yl) methanamine (1c)
Recrystallized in absolute ethanol; yield: 85.4%; m.p.:
256–258°C; Rf 0.56 chloroform:methanol (9:1) mixture; IR
(cm-1, KBr): 1386 (C–N), 1489, 1435 (C=C), 1604 (C=N),
2962 (CH); 1H-NMR(DMSO-d6) d [ppm]: 4.07 (s, 2H,
–CH2–), 7.46–7.68 (m, 4H, Ar-H), 7.98 (s, 1H, –CH=N–),
7.62–8.66 (d, 4H, Py-H); Anal. Calcd. for C13H11N2Cl: C,
2-Methoxy-4-{(pyridine-3-ylmethylimino) methyl}phenol
(1f)
Recrystallized in ethyl acetate and chloroform (9:1); yield:
59.8%; m.p.: 159–161°C; Rf 0.68 chloroform:methanol
123

Med Chem Res (2011) 20:1091–1101
1095
(9:1) mixture; IR (cm-1, KBr): 1384 (C–N), 1489, 1435
(C=C), 1605 (C=N), 2995 (CH), 3368–3444 (OH); 1H-
NMR(DMSO-d6) d [ppm]: 2.50 (s, 2H, –CH2–), 3.80 (s,
3H, –OCH3–), 4.84 (s, 1H, –OH) 7.42–7.46 (m, 3H, Ar-H),
8.57 (s, 1H, –CH=N–), 7.95–8.68 (d, 4H, Py-H); Anal.
Calcd. for C14H14N2O2: C, 73.56; H, 5.70; N, 13.20.
Found: C, 73.11; H, 6.02; N, 13.33.
(E)-N-((1H-indol-3-yl)methylene)(pyridin-3-
yl)methanamine (2b)
Recrystallized in absolute ethanol solution; yield: 71.35%;
m.p.: 138–140°C; Rf 0.56 chloroform:methanol (9:1); IR
(cm-1, KBr): 1381 (C–N), 1575, 1448 (C=C), 1631 (C=N),
3128–2821 (CH), 3439 (NH); 1H-NMR(DMSO-d6) d
[ppm]: 7.35–7.44 (m, 4H, Ar-H), 7.78 (s, 1H, –CH=N–),
8.20–8.62 (d, 4H, Py-H), 11.51 (s, 1H, Indole NH) (D2O)
exchangeable; Anal. Calcd. for C15H13N3: C, 76.57; H,
5.57; N, 17.86. Found: C, 76.50; H, 5.59; N, 17.88.
N-(3,4,-Dimethoxybenzylidene) (pyridin-3-yl)
methanamine (1g)
Recrystallized in methanol; yield: 82.6%; m.p.:
160–162°C; Rf 0.56 chloroform:methanol (9:1) mixture; IR
(cm-1, KBr): 1114(C–O), 1386 (C–N), 1489, 1435 (C=C),
1602 (C=N), 2999 (CH); 1H-NMR(DMSO-d6) d [ppm]:
2.50 (s, 6H, –OCH3) 3.93 (s, 2H, –CH2–), 7.41–7.80 (m,
3H, Ar-H), 7.83 (s, 1H, –CH=N–), 8.52–8.59 (d, 4H, Py-
H); Anal. Calcd. for C15H16N2O2: C, 70.29; H, 6.29;
N,10.93. Found: C, 70.74; H, 6.17; N, 11.04.
General procedure for synthesis of schiff bases (3a–6)
For the preparation of schiff bases methanolic solution of
3-aminomethyl pyridine (0.05 mol.) was taken in 250-ml
conical flask, to this equimolar (0.05 mol) methanolic
solution of respective substituted aryl ketone/cyclic
ketones were added drop-wise with few drops of glacial
acetic acid to make the resulting reaction mixture slight
acidic. This reaction mixture was left for stirring for
12–15 h at temperature 60–80°C on magnetic stirrer. The
progress of reaction was monitored by thin layer chroma-
tography (TLC). After the completion of reaction almost
half of the solvent was evaporated and resulting solution
was kept for crystallization. The recrystallization was done
accordingly in appropriate solvent system.
N-(3,4,5-Trimethoxybenzylidene) (pyridin-3-yl)
methanamine (1h)
Recrystallized in ethylacetate:chloroform (8:2); yield:
66.4%; m.p.: 152–154°C; Rf 0.44 chloroform:methanol
(9:1); IR (cm-1, KBr): 1386 (C–N), 1487, 1431 (C=C),
1595 (C=N), 2997 (CH); 1H-NMR(DMSO-d6) d [ppm]:
3.70 (s, 9H, –OCH3) 4.08 (s, 2H, –CH2–), 7.76 (s, 2H, Ar-
H), 7.97 (s, 1H, –CH=N–), 8.16–8.69 (d, 4H, Py-H); Anal.
Calcd. for C16H18N2O2: C, 67.12; H, 6.34; N, 9.78. Found:
C, 67.48; H, 6.33; N, 9.65.
N-(1-Phenylethylidene) (pyridine-3-yl) methanamine (3a)
Recrystallized in absolute ethanol; yield: 52.4%; m.p.:
238–240°C; Rf 0.72 chloroform:methanol (9:1); IR (cm-1
KBr): 1384 (C–N), 1487, 1433 (C=C), 1602 (C=N), 2993
,
N-(-3-Phenylallylidene) (pyridine-3-yl) methanamine (1i)
1
(CH); H-NMR(DMSO-d6) d [ppm]: 2.50 (s, 2H, –CH2–),
7.42–7.94 (m, 5H, Ar-H), 7.97 (s, 1H, –CH=N–), 8.56–8.68
(d, 4H, Py-H); Anal. Calcd. for C14H14N2: C, 79.97; H,
6.71; N, 13.32. Found: C, 79.55; H, 6.45; N, 13.22.
Recrystallized in hot distilled water; yield: 42.8%; m.p.:
144–146°C; Rf 0.8 butanol:acetic acid:water (4:2:1); IR
(cm-1, KBr): 1184 (C–N), 1566, 1419 (C=C), 1643 (C=N),
2926 (CH); 1H-NMR(DMSO-d6) d [ppm]: 2.50 (s, 2H,
–CH2–), 7.42–7.94 (m, 5H, Ar-H), 7.97 (s, 1H, –CH=N–),
8.56–8.68 (d, 4H, Py-H); Anal. Calcd. for C15H14N2: C,
81.05; H, 6.35; N, 12.60. Found: C, 81.47; H, 6.04; N,
12.24.
3-(1-(Pyridin-3-ylmethylimino) ethyl) benzenamine (3b)
Recrystallized in absolute ethanol; yield: 73.3%; m.p.:
158–160°C; Rf 0.65 chloroform:methanol (9:1); IR (cm-1
KBr): 1384 (C–N), 1491, 1435 (C=C), 1603 (C=N), 2993
,
1
(CH), 3498 (NH); H-NMR(DMSO-d6) d [ppm]: 2.40 (s,
N-(2-Methoxybenzylidene) (pyridin-3-yl) methanamine (2a)
2H, –CH2–), 3.66 (s, Ar-NH2), 7.66–7.94 (m, 4H, Ar-H),
7.97 (s, 1H, –CH=N–), 8.36–8.56 (d, 4H, Py-H); Anal.
Calcd. for C14H15N3: C, 74.64; H, 6.71; N, 18.65. Found:
C, 74.32; H, 6.47; N, 18.11.
Recrystallized in ethyl acetate:chloroform (9:1); yield:
89.2%; m.p.: 160–162°C; Rf 0.55 chloroform:methanol
(9:1); IR (cm-1, KBr): 1386 (C–N), 1489, 1435 (C=C),
1602 (C=N), 2991 (CH); 1H-NMR(DMSO-d6) d [ppm]:
2.50 (s, 2H, –CH2–), 7.42–7.94 (m, 5H, Ar-H), 7.97 (s, 1H,
–CH=N–), 8.56–8.68 (d, 4H, Py-H); Anal. Calcd. for
C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C, 74.68;
H, 6.47; N, 12.12.
N-(Diphenylmethylene) (pyridin-3-yl) methanamine (4a)
Recrystallized in ethanol; yield: 64.2%; m.p.: 262–268°C;
Rf 0.80 chloroform:methanol (9:1); IR (cm-1, KBr): 1384
123

1096
Med Chem Res (2011) 20:1091–1101
(C–N), 1491, 1435 (C=C), 1602 (C=N), 2995 (CH), 3498
1
India) and water ad libitum. The experiments were con-
ducted according to the norms of committee for the purpose
of control the supervision of the experiments in Animals
(CPCSEA) New Delhi India, and Institutional Animal Eth-
ical Committee (IAEC). After 7 days of adaptation to lab-
oratory conditions, the animals were randomly assigned to
experimental groups (consisting of six animals). Each ani-
mal was used only once. The experiments were conducted
between 9:00 am and 4:00 pm. The test compounds were
dissolved in water and polyethylene glycol (PEG-200)
depending on their solubility. In Phase-I screening (Table 2)
each compound was administered at three dose levels {30,
100, and 300 mg kg-1 intraperitonealy (i.p.), six mice for
each dose} with anticonvulsant activity and neurotoxicity
assessed at 0.5 and 4 h intervals after administration. The
pharmacologic parameters estimated in phase-I screening
was quantified in phase-II screening (Table 3). For calcu-
lation of the ED50 and TD50 values, groups of ten mice were
given a range of intraperitoneal doses of the test drug until at
least three points were established in the range of 10–90%
seizure protection or minimal observed neurotoxicity. From
the plot of this data, the respective ED50 and TD50 values,
95% confidence intervals were then calculated by log-probit
method (Litchfield and Wilcoxon, 1949). Almost for all the
compounds, the time of peak anticonvulsant effect was
observed between 0.25 and l.0 h.
(NH); H-NMR(DMSO-d6) d [ppm]: 4.02 (s, 2H, –CH2–),
7.41–7.95 (m, 10H, Ar-H), 8.54–8.67 (d, 4H, Py-H); Anal.
Calcd. for C19H16N2: C, 83.79; H, 5.92; N, 10.29. Found:
C, 83.42; H, 5.66; N, 10.58.
(Z)-1,2-Diphenyl-2-(pyridin-3-ylmethylimino)ethanol (4b)
Recrystallized in ethanol; yield: 64.2%; m.p.: 132–134°C;
Rf 0.52 chloroform:methanol (9:1); IR (cm-1, KBr): 1267
(C–N), 1491, 1435 (C=C), 1676 (C=N), 2926 (CH), 3414
1
(OH); H-NMR(DMSO-d6) d [ppm]: 4.27 (s, 2H, –CH2–),
2.52 (s, 1H, –OH), 6.80–7.73 (m, 10H, Ar-H), 7.75–8.07
(d, 4H, Py-H); Anal. Calcd. for C20H18N2O: C, 79.44; H,
6.00; N, 9.26. Found: C, 79.65; H, 5.86; N, 9.18.
N-Cyclohexylidene (pyridine-3-yl) methanamine (5)
Recrystallized in absolute ethanol; yield: 78.8%; m.p.:
210–212°C; Rf 0.80 chloroform:methanol (9:1); IR (cm-1
KBr): 1116 (C–N), 1552, 1470 (C=C), 1603 (C=N), 2991
,
1
(CH); H-NMR(DMSO-d6) d [ppm]: 2.50 (s, 2H, –CH2–),
7.42–7.94 (m, 5H, Ar-H), 7.97 (s, 1H, –CH=N–), 8.56–8.68
(m, 4H, Py-H); Anal. Calcd. for C12H16N2: C, 76.55; H,
8.57; N, 14.88. Found: C, 76.58; H, 8.55; N, 14.83.
Pyridin-3-yl-N-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-
ylidene) methanamine (6)
Anticonvulsant screening
Recrystallized in ethyl acetate and absolute ethanol, yield
74.21%, mp 252–254°C; Rf 0.82 in chloroform:methanol
(9:1), IR (cm-1, KBr): 1122 (C–N), 1489, 1435 (C=C),
The anticonvulsant screening of the synthesized com-
pounds were under taken by the following the Anticon-
vulsant drug development protocol (Krall et al., 1978).
1
1595 (C=N), 2997 (CH); H-NMR(CDCl3) d [ppm]: 1.85
(s, 9H, CH3), 2.45 (s, 1H, –CH–), 2.87–2.88 (s, 6H, CH2),
4.82 (s, 2H, CH2) 7.69–7.89(d, 4H, Py-H); Anal. Calcd. for
C16H22N2: C, 79.29; H, 9.15; N, 11.56. Found: C, 79.31; H,
9.20; N, 11.49.
Maximal electro shock (MES) test
In the MES test (Kupferberg, 1989) seizures were elicited
with a 60 Hz alternating current of 50 mA intensity in
mice. The current was applied via ear electrodes for 0.2 s.
Abolition of the hind-leg tonic-extensor component of the
seizure indicated protection against the spread of MES-
induced seizures. The anticonvulsant activity of synthe-
sized compounds were determined as its median effective
doses (ED50, mg kg-1), the dose required to protect 50% of
the animals tested against MES-induced seizures. In the
MES test one can readily preselect compounds that are
effective in suppression of tonic–clonic seizures and to a
certain extent, of partial seizures with or without secondary
generalization in humans.
Pharmacology
Preliminary anticonvulsant screening of the synthesized
compounds were performed by three major convulsant
tests: maximal electro shock (MES), subcutaneous penty-
lenetetrazole (sc.PTZ) and subcutaneous strychnine
(sc.STR). These schiff bases were also evaluated for
neurotoxicity (rotorod method) in mice. Pharmacological
experiments were carried out on Swiss albino mice of
either sex weighing 20–30 g and Wistar rats weighing
100–150 g of either sex. The animals were obtained from
Central Animal House, Institute of Medical science, Ban-
aras Hindu University (Regd. No. 542/02/ab/CPCSEA).
The animals were randomly housed in polypropylene cages
with free access to standard pellets (Unilever Limited
Chemically induced seizures
The subcutaneous pentylenetetrazole (sc.PTZ) and strych-
nine (sc.STR) test involved subcutaneous injection of a
123

Med Chem Res (2011) 20:1091–1101
1097
Table 2 Phase-I preliminary anticonvulsant data of some compounds in mice (Test drug administered I.P.)
Compounds
Intraperitoneal injection in micea
MES screen
0.5
Sc PTZ screen
0.5
Sc STY screen
0.5
Toxicity screen
0.5 4
4
4
4
1a
1b
1c
1d
1e
1f
1g
1h
1i
100
100
30
30
–
–
100
30
100
100
30
100
–
100
100
100
300
30
300
–
100
–
100
–
100
30
100
30
30
–
100
–
300
–
300
100
300
300
–
–
100
100
30
–
–
–
30
–
30
–
–
100
–
300
100
30
30
–
30
–
100
300
30
–
100
–
30
–
–
–
–
–
100
300
100
–
100
300
100
–
2a
2b
3a
3b
4a
4b
5
30
–
–
–
–
300
100
30
30
30
–
30
30
–
300
–
100
–
30
30
30
30
–
30
–
100
–
100
–
100
–
30
–
–
30
300
30
30
–
100
–
–
30
30
–
–
30
100
–
–
6
–
–
–
–
300
–
a
Dose of 30, 100, and 300 mg kg-1 were administered, the figure in the table indicates the minimum dose where by bioactivity was
demonstrated in half or more of the mice
The animals were examined for 0.5 and 4.0 h after injection
The dash (–) indicates the absence of activity at maximum dose administered (300 mg kg-1
)
convulsant dose (CD97) 85 and 2, mg kg-1 in mice,
respectively (Dunham and Miya, 1957). After the dosing
the mice were subsequent placed separately into polypro-
pylene cages (25:15:10, cm) and were observed twice after
0.5 and 4 h for the occurrence of seizures. Elevation of the
pentylenetetrazole-induced seizure threshold was indicated
by the absence of clonic spasms for at least 5 s duration
over 0.5 h period with an accompanying loss of righting
reflex, following administration of the test compound. The
number of animals convulsing out of the total number of
mice tested was noted for each treatment condition.
50% of the animals tested). To evaluate each TD50 value,
various groups of animals (each group consisted of six
mice) injected with three doses of test compound and were
challenged with the rotorod test. Worth mentioning feature
of rotorod test is to gauge the impairment of motor per-
formance, ataxia and loss of skeletal muscular strength, and
acute neurotoxicity produced by drugs in preclinical
studies.
Protective index (PI)
Protective index was calculated by dividing a given TD50
value, evaluated in the rotorod test, by the respective ED50
values determined separately in the MES test and various
chemically induced seizures. The PI is considered an index
of the margin of safety and tolerability between anticon-
vulsant doses and doses of various synthesized compounds
exerting acute adverse effects (e.g., sedation, ataxia,
impairment of motor coordination, or other neurotoxic
manifestations) in preclinical studies.
Neurotoxicity screening
The rotorod test was executed to gauge the minimal motor
impairment in mice. The mice were trained to stay on
revolving rod of diameter 3.2 cm, and rotating at the speed
of 6 revolutions per min. The trained mice were given test
compounds intraperitoneal in dose 30, 100, and
300 mg kg-1 bodyweight. The neurotoxicity was mea-
sured by the inability of the animal to maintain equilibrium
on the revolving rod for at least 1 min in each of the three
trails. The adverse effects of synthesized compounds were
expressed as its TD50 values, (the doses at which synthe-
sized compounds shows impaired motor coordination in
Statistical analysis
ED50 and TD50 values of synthesized compounds from
various seizure models and rotorod test were calculated by
123

1098
Med Chem Res (2011) 20:1091–1101
Table 3 (Phase-II) Quantitative anticonvulsant activity data of some compounds in MES, sc.PTZ, and sc.PTZ induced seizures (mice i.p.)
Compound
MES
sc.PTZ
sc.STR
Neuro-toxicity TD50 Protection
index
(MES)
ED50 (mg kg-1) 95% Std.
confidence
ED50 (mg kg-1
95% confidence
)
Std.
ED50 (mg kg-1) 95% Std.
error confidence
(Slope
error
(Slope)
error
(Slope)
=TD50
ED50
/
1a
1b
1c
1d
1e
1f
53.02 (14.13–67.47) 1.44
61.36 (36.38–86.69) 2.11
11.7 (05.11–21.21) 0.84
53.02 (21.58–85.48) 1.44
53.02 (21.58–85.48) 1.44
6.39 (02.57–10.51) 1.13
–
–
–
–
–
–
–
–
62.44 (29.84–107.43) 1.38
22.25 (03.84–40.64) 1.07
111.5 (24.8–187.9)
[500
2.1
[10
93.64 (63.52–153.56) 4.22
201.7 (72.38–381)
124.8 (40.0–219.4)
175.7 (66.78–290.6)
17.27
2.35
6.44 (02.05–11.41) 0.81
14.24 (07.98–20.75) 2.25
3.31,
–
–
–
–
–
–
198.2 (79.44–339.9) 31
1
–
–
11.7 (05.11–21.21) 0.84
[500
[10
[10
g
1h
71.73 (44.79–105.41) 2.23
36.26 (05.68–75.68) 0.66
11.7 (05.11–21.21) 0.84
–
–
–
–
–
–
50.31 (21.05–80.79) 1.32
[500
84.85 (9.60–179.42)
1i
–
–
–
–
–
–
–
–
–
–
–
–
2.34
2a
175.7 (66.78–290.6) 15
2b
–
–
6.47 (01.76–12.00) 0.86
23.17 (15.43–40.16) 1.76
[500
[10
[10
3a
55.73 (23.91–95.41) 1.24
8.64 (03.88–13.33) 1.43
9.13 (01.59–21.46) 0.64
20.79 (12.82–37.16) 1.42
[500
3b
–
–
–
–
–
–
60.23 (6.67–123.8)
[500
6.97
[10
0.57
[10
5.45
4a
4b
105.87 (71.52–283.05) 2.45
11.86 (5.84–19.14)
[500
5
–
–
–
–
–
14.16 (07.34–25.66) 1.13
32.21 (04.33–48.77) 2.38
–
–
–
–
–
–
–
–
6
–
175.7 (66.78–290.6)
65.5 (52.5–72.1)
69 (62.8–72.9)
Phenytoina
Phenobarbitala 21.8 (15.0–25.5)
9.5.0 (08.1–10.4)
–
–
–
32.75
3.16
13.2 (05.87–15.9)
a
Data from Huseyin, et al. (1998)
The dash (–) indicates the absence of significant activity at maximum dose administered (300 mg kg-1
)
computer log-probit analysis (Litchfield and Wilcoxon,
1949).
azomethine proton is shifted to downfield due to deshiel-
ding effect. The chemical shift due to aromatic protons of
the benzene ring is observed at (8.00–6.80 ppm) region of
spectrum. The shape, the position, and the integration value
of these signals are visibly affected by the rate of exchange,
the relaxation time, the concentration of the solution, and
nature of the solvent used. From spectral analysis it can be
revealed that signal is shifted to lower field values by
strong electron-withdrawing substituent’s (–NO2, and –Cl),
and is shifted to higher fields with electron-donating sub-
stituent’s (–OCH3, and –OH). The signals due to (–OCH3)
substituent’s proton appear at d (3.70–3.93) in compounds
(1e, 1f, 1g, and 1h). The disappearance of signals of starting
material (singlet at d 11.60–12.10 due to proton of alde-
hyde –CH=O and singlet at d 9.6 of –NH) strongly cor-
roborates the proposed structures of the schiff bases.
Four aromatic protons of the pyridine ring in all the
schiff bases emerged as two doublets each of integration
value corresponding to two protons. These doublets
appeared at chemical shift (7.62–8.70 ppm) region in the
spectra. Spectral data revealed that, when there is a large
chemical shift difference between the two protons of each
set, the peaks appear as clear distinct doublets with a quite
wide separation, and when these protons are virtually in the
Results and discussions
The schiff bases from 3-aminomethyl pyridine with various
substituted aromatic aldehydes, ketones, and cyclic ketones
were synthesized according to reaction scheme (Fig. 1 and
Table 1). The characteristics signals (chemical-shifts) in
1H-NMR spectras of the investigated 3-aminomethyl pyr-
idine schiff bases (1a–6) were recorded in DMSO-d6/
CDCl3. A sharp singlet is observed at (8.58–7.76 ppm)
region of spectrum, is characteristics azomethine proton
peak of schiff bases. It is noteworthy that the downfield
chemical shift (d 8.58 ppm) corresponds to the azomethine
proton of the p-Cl and p-NO2 in their respective sub-
stituent’s, which has the highest electron affinity, while the
upfield value (d 7.76 ppm) due to tri-methoxy substituent
in compound (1h) with the highest electron donating power.
So it is concluded that resonating position of the azome-
thine proton is strongly affected by the electro-negativity of
the substituent’s group on adjoining benzene ring. As
electron affinity of the substituent’s group increases the
123

Med Chem Res (2011) 20:1091–1101
1099
Fig. 1 Reaction scheme
CN
NH2
C2H5OH/ Na
Reduction
N
N
3-AMP
l
3-Cyanopyridine
C
H
c
n
R2
o
C
/
C
H
O
R1
H
O
C
N
R1
C
N
N
Schiff base
(6)
R2
N
N
Schiff bases (1a-4b)
N
Schiff base (5)
same chemical environment, there is only a small chemical
shift difference and the peaks appeared as almost a quartet.
These schiff bases were also characterized by FT-IR spec-
tra’s and were found almost similar to each other. The very
strong and sharp peak at (1595–1640 cm-1) was charac-
teristics of azomethine m(C=N) stretching vibrations of the
schiff base. Infrared spectra (FT-IR) of starting material
(aldehydes/ketones)/(amine) demonstrates the characteristic
(C=O) stretching at (1757 cm-1) and a sharp peak (between
3320 and 3395 cm-1) due to (N–H) stretching respectably
were missing in synthesized compounds strongly supports
the proposed structures of schiff bases. The IR spectra of
anticonvulsant activity and neurotoxicity in the preliminary
evaluation (phase-I) the schiff bases were administered i.p.
at three doses level 30, 100, and 300 mg kg-1 (Table 2)
and the response were compared with the reference drugs
Phenytoin and Phenobarbital (Pandeya et al. 2000).
Neurotoxicity was determined by rotorod ataxia test (per-
formed to know the potential of motor impairment in co-
ordination of movement by the test compounds) in mice.
As a performance of the compounds in the preliminary
screening in MES test, 13 compounds (1a, 1b, 1c, 1d, 1e, 1f,
1h, 1i, 2a, 3a, 3b, 4a, and 4b,) were considered for advanced
phase-II screen in mice for quantification of their anti-
convulsant activity and neurotoxicity, while compounds
(1e, 1g, 2b, 3a, 5, 6) in (sc.PTZ) and (1a, 1b, 1c, 1e, 1h, 4b) in
(sc.STR) were chosen for quantitative evaluation (phase-
II). The median effective dose (ED50) and the median
neurotoxin dose (TD50) were determined in phase-II
screening (Table 3). The results were compared with ref-
erence drugs i.e., Phenytoin, and Phenobarbital. Some of
these derivatives demonstrate a high degree of protection
against MES-induced seizures, and little effective against
sc.PTZ and sc.STR induced seizures. Compound (1h)
shows the best protection against MES (ED50
6.39 mg kg-1 with PI [10). In the phase-II quantitative
evaluation of the test compounds (MES test), the ED50
values for some potent compounds (1c, 2a, 3b, 4a, and 4b)
were 11.7, 11.7, 8.64, 9.13 and 20.79 mg kg-1 with [PI[6
except (4b) 0.57] respectively, while ED50 and PI of the
reference drug phenytoin was reported as 9.5 mg kg-1
with PI 3.2 (Huseyin et al., 1998). Thus considering these
low values of ED50 and high PI is a marked indication of
the compounds of this series towards their potential as
being good anticonvulsant agents in future.
schiff bases display resonance bands at (1510–1470 cm-1
)
for aromatic C=C stretching. In addition a broad (O–H)
vibration at (3425–3444 cm-1), a strong band of phenolic
(C–O) stretching around (1270–1260 cm-1), for (C–N)
stretching (1120–1150 cm-1) and for aromatic (C–H)
stretching a band around (650–760 cm-1) were also
observed in the spectra’s. All these data were well in
accordance with those of reported schiff bases (Chiswell
et al., 1980, Pandeya et al., 1999, Bosque and Lopez, 1995).
In C, H, N elemental analyses all the elements were found
within 0.4% of the theoretical values.
These schiff bases were investigated for anticonvulsant
activity by the intraperitonealy (i.p.) administration using
three seizure models maximal electroshock seizure (MES)
test, subcutaneous pentylenetetrazole (Metrazole) seizure
threshold (sc.PTZ) and subcutaneous strychnine (sc.STR)
test in mice. These methods of seizure provocation con-
sistently elicit well characterized seizure phenomenon and
together they have shown sufficient to identify all the
compounds known to demonstrate anticonvulsant activity
in other tests (Porter et al., 1984). For the determination
123

1100
Med Chem Res (2011) 20:1091–1101
Most of the synthesized compounds showed protection
Table 4 Oral anticonvulsant evaluation of selected compounds in
MES test (dose 30 mg kg-1) in rats
against MES-induced seizures after 0.5 h of drug admin-
istration. Compounds (1c, 1f, 1i, 2a, 2b, 3b, 4a, 4b) were
active at dose 30 mg kg-1, while (1a, 1b, 1d, 1e, 1h, 3a)
were active at the dose 100 mg kg-1 after 0.5 h of drug
administration. Whereas, compounds (1a, 1c, 1e, 1f, 2a, 3a,
3b, 4a, 4b and 1b, 1d, 1h) showed seizures protection at dose
30 and 100 mg kg-1 after 4 h of drug administration,
respectively. These compounds exhibit their ability to
diminish the magnitude of tonic-clonic seizures in MES
test. Most of the compounds exhibit prolonged duration of
action (up to 4 h) at dose 30 and 100 mg kg-1 after drug
administration (i.p.). Whereas, six compounds (1c, 1f, 2a,
3b, 4a, 4b) showed rapid and longer duration of action in
MES screen.
Compound Response after time (h) in oral administration to rats
0.25
0.5
1
2
4
1a
1
0
3
1
1
3
0
4
3
1
3
3
3
1
1
1
3
1
1
4
0
2
4
1
4
4
4
4
3
2
4
2
3
4
2
1
4
3
4
3
4
3
3
2
4
2
4
4
3
0
4
4
3
2
4
3
4
2
4
4
4
4
4
0
4
3
3
3
2
3
1b
1c
1d
1e
1f
1h
1i
2a
3a
A good number of compounds (1e, 1g, 2b, 3a, 5, 6)
showed protection against (sc.PTZ) induced seizures after
0.5 h of drug administration. Compounds (1e, 1g, 2b, 3a, 5,
6) were active at 30 mg kg-1, while compound (1b)
showed protection at the dose 100 mg kg-1 after 0.5 h of
drug administration (i.p.). Whereas, compounds (1e, 1g, 2b,
3a, 5) at dose 30 mg kg-1 and compound (6) at dose
100 mg kg-1 showed seizure protection after 4 h of drug
administration in mice. Five compounds (1e, 1g, 2b, 3a, 5,)
3b
4a
4b
Phenytoin
This figure indicates that number of rats out of four, which were
protected in oral testing
are presented in (Table 4). Compounds (1c, 1f, 1i, 2a, 3b, 4a,
4b) emerged as the most active compounds (time to peak
effect\0.5 h). All the schiff bases tested afford significant
protection against seizures induces by MES model in rat
corroborating their potential utility as prototypic molecules
for suppression of tonic clonic seizures and to a certain
extant of partial seizures. The potency and spectrum of
activity of these schiff bases were comparable to that of
reference drugs.
showed rapid and longer duration of action at 30 mg kg-1
.
All the other compounds were inactive or less effective in
sc.PTZ screen. Six compounds were evaluated quantita-
tively in sc.PTZ induced seizures (phase-II) for their
respective ED50 and PI (Table 3), in this series only two
compounds (1e and 2b) showed (ED50 6.44, 6.47 with PI
[3) good protection over reference compounds, reflects
their potential for future anticonvulsant agent with good
margin of safety. Whereas, four compounds (1g,3a,5,and 6)
showed ED50 between 20 and 30 mg kg-1 with PI [5.
In case of strychnine induced seizures seven compounds
(1a, 1b, 1c, 1e, 1h, 3b, and 4b) showed protection at dose 30
to 100 mg kg-1 in phase-I screen. Compound (1e) showed
rapid and longer duration of action and was active at
30 mg kg-1 even after 4 h of drug administration. Com-
pound (1e) also showed best ED50 14.24 mg kg-1 with
good margin of safety (PI, 3.31). While three compounds
(1a, 1c, 4b) showed protection at dose 100 mg kg-1 after
0.5 h. Four compounds (1a, 1c, 1h, 3b) showed longer
duration of action and were found active after 4 h of drug
administration (i.p.). Only two compounds (1b, 1e,) were
active in all three MES, sc.PTZ, and sc.STR model, six
compounds (1a, 1c, 1d, 1f, 1h, 3b) were active in MES, and
sc.STR, induced seizures tests, and only compound (3a),
showed protection in both MES, and sc.PTZ induced
seizures.
In neurotoxicity screening only compound (4b) TD50
11.86, showed higher neurotoxicity at 30 mg kg-1 dose
and five compounds (1a, 1d, 1i, 2b, 4b) showed neurotox-
icity at 100 mg kg-1 whereas, some reference drugs also
exemplify neurotoxicity (TD50 of Phenytoin 65.5 and
Phenobarbital 69 mg kg-1) after 0.5 h of drug adminis-
tration (Huseyin et al., 1998). Only three compounds
showed (TD50 \ 100), remaining compounds showed
diminutive neurotoxic effects. While five compounds (1a,
1i, 2b, 3b, 4b,) of this series showed prolonged neurotoxicity
(up to 4 h).
Conclusion
In the conclusion, the schiff bases with various substituted
aromatic aldehydes and ketones showed better anticon-
vulsant activity and lower neurotoxicity in MES screen
then the benchmark reference drugs. The unique feature of
this series compounds is that some compounds are capable
of blocking seizures in both the MES and sc.PTZ, or in
Selected schiff bases were also evaluated orally in rats at
dose 30 mg kg-1 for their anticonvulsant activity and to
calculate time to peak effect in MES screen and the data
123

Med Chem Res (2011) 20:1091–1101
1101
and 2(3H)-benzothiazolone derivatives.
1138–1145
Inguva R, Ramaiah S, Nithyanantham M, Navaneetharaman A,
Vedachalam G, Thomas LJ (2003) Pharmacological evaluation
of some new 6-amino/methyl pyridine derivatives. Chem Pharm
Bull 51:162–170
J
Med Chem 41:
MES and sc.STR test model where as many clinically
effective drugs, including Primidone and Vigabatrin are not
capable of blocking seizures in both the MES and sc.PTZ
model (Swinyard, 1969) and only a few standard anticon-
vulsants demonstrate such a wide spectrum of anticonvul-
Johnson NC, Morgan MW (2006) An unusual case of 4-aminopyr-
idine toxicity. J Emerg Med 30:175–177
Kaminski K, Obniska J, Zagorska A, Maciag D (2006) Synthesis,
physicochemical and anticonvulsant properties of new N-(Pyr-
idine-2-yl) derivatives of 2-azaspiro[4.4]nonane and [4.5]dec-
ane-1, 3-dione Part II. Arch Pharm 339:255–261
Karthikeyan MS, Prasad DJ, Poojary B, Bhat KS, Hollaa BS,
Kumarib NS (2006) Synthesis and biological activity of schiff
and mannich bases bearing 2, 4-dichloro-5-fluorophenyl moiety.
Bioorg Med Chem 147:7482–7489
¨
sant activity in these threshold models (Loscher et al.,
1991). Schiff bases synthesized from cyclic ketones and
substituted aromatic ketones also showed fair activities
against seizures induces by sc.STR, while these schiff
bases were found less active in sc.PTZ-induced seizures
model. The exact molecular mechanism through with these
compound acts is still to be explored.
Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA (1978)
Antiepileptic drug development: II. Anticonvulsant drug screen-
ing. Epilepsia 19:409–428
Krishnan A, Ritvik, Chowdhury D (2007) Cost of antiepileptic drugs
in India. Neurol Asia 12:42–43
Kupferberg HJ (1989) Antiepileptic drug development program: a
cooperative effort of government and industry. Epilepsia
30:51–56
Acknowledgments This research was supported by University
Grants Commission India, as one of the author Mr. Shailendra Pandey
deeply acknowledge them for providing Senior Research Fellowship.
We wish to thanks to Dr P.N. Singh of Department of Pharmacology,
IT-BHU, for his excellent assistance during pharmacological evalu-
ation. Author is also thankful to ALKALI METALS LTD for pro-
viding gift samples.
Litchfield JT, Wilcoxon FA (1949) A simplified method of evaluating
dose-effect experiments. J Pharmacol Exp Ther 96:99–133
¨
Loscher W, Fassbender CP, Nolting B (1991) The role of technical,
Conflict of interest None.
biological and pharmacological factors in the laboratory evalu-
ation of anticonvulsant drugs. II. Maximal electroshock seizure
models. Epilepsy Res 8:79–94
References
Ludden CT, Scriabine A, Ulm EH, Morgan G, Fisher MH, Ruyle WV
(1979) Antihypertensive activity of some novel pyridinylidene
arylurea derivatives in spontaneously hypertensive rats. Exper-
ientia 15:799–801
Bekhit AA, Baraka MA (2005) Novel milrinone analogs of pyridine-
3-carbonitrile derivatives as promising cardiotonic agents. Eur J
Med Chem 40:1405–1413
`
Narendar P, Parthiban J, Anbalagan N, Gunasekaran V, Leonard JT
(2003) Pharmacological evaluation of some new 2-substituted
pyridine derivatives. Biol Pharm Bull 26:182–187
Noviasky JA, Porsteinsson AP, Lee YH (2001) Second generation
anticonvulsant medications: Their use in children. J Sch Nurs
17:103–111
Pandey S, Srivastava RS (2009) Anticonvulsant activity of some
schiff bases synthesized from 2-aminopyridine. Pharmacolog-
yonline 2:1048–1074
Bonifacio MJ, Sheridan RD, Parada A, Cunha RA, Patmore L,
Soares-da-Silva P (2001) Interaction of the novel anticonvulsant,
BIA 2–093, with voltage-gated sodium channels: comparison
with carbamazepine. Epilepsia 42(5):600–608
Bosque R, Lopez C (1995) Schiff bases derived from aminomethyl-
ferrocene and their cyclopalladated derivatives. J Organomet
Chem 498:147–154
Brodie MJ, Dichter MA (1996) Antiepileptic drugs. N Engl J Med
334:168–175
Pandeya SN, Sriram D, Nath G, DeClercq E (1999) Synthesis,
antibacterial, antifungal and anti-HIV activities of schiff and
mannich bases derived from isatin derivatives and N-[4-(4’-
chlorophenyl)thiazol-2-yl]thiosemicarbazide. Eur J Pharm Sci
9:25–31
Pandeya SN, Yogeeswari P, Stables JP (2000) Synthesis and
anticonvulsant activity of 4-bromophenyl substituted aryl semi-
carbazones. Eur J Med Chem 35:879–886
Chiswell B, Crawford JP, O’reilly EJ (1980) Synthesis and complexes
of unsymmetrical ligands-part III-quadridentate ligands. Inorg
Chim Acta 40:223–228
Cory JG, Cory AH, Germana RF, Loricot A, Liut MC, Lint TS,
Sartorelli AC (1995) Structure-function relationships for a new
series of pyridine-2-carboxaldehyde thiosemicarbazones on
ribonucleotide reductase activity and tumor cell growth in
culture and in vivo. Adv Enzyme Regul 35:55–68
Pankaja KK (1991) University of Kentucky Research Foundation, US
patent 5648369
Pickett TA, Enns R (1996) A typical presentation of 4-aminopyridine
overdose. Ann Emerg Med 27:382–385
Porter RJ, Cereghino JJ, Gladding GD, Hessie BJ, Kupferberg HJ,
Scoville B, White BG (1984) Antiepileptic drug development
program. Cleve Clin Q 51:293–305
Swinyard EA (1969) Laboratory evaluation of antiepileptic drugs.
Epilepsia 10:107–119
Dunham MS, Miya TA (1957) A note on a simple apparatus for
detecting neurological deficit in rats and mice. J Am Pharm
Assoc Sci Edit 46:208–209
Ferrarinia PL, Moria C, Badawnehb M, Calderonec V, Grecoc R,
Maneraa C, Martinellia A, Nieric P, Saccomannia G (2000)
Synthesis and b-blocking activity of (R, S)-(E)-oximeethers of
2,3-dihydro-1,8-naphthyridine and 2,3-dihydrothiopyrano[2,3-
b]pyridine: potential antihypertensive agents—Part IX. Eur J
Med Chem 35:815–826
World Health Organization (2001) International classification of
functioning disability and health: ICF, Geneva
Hanneke MB, Marco M, Josemir WS (2008) The global burden and
stigma of epilepsy. Epilepsy Behav 12:540–546
Huseyin U, Kim VD, Silvia C, Santi S, James PS, Paul D et al (1998)
Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone
123