Synthesis, anticonvulsant and neurotoxic activity of some new 2,5-disubstituted-1,3,4-oxadiazoles

Article abstract of DOI:10.1007/s00044-010-9496-x

Two novel series 2a-2d (2Z)-N-[5-(4-substituted) phenyl-1,3,4-oxadiazol-2- yl]-2-[(2Z)-3,7-dimethylocta- 2,6-dien-1-ylidene]hydrazinecarboxamide and 1a-1d 5-(4-substituted)phenyl-N-[(1Z,2Z)-3,7-dimethylocta-2,6- dien-1-ylidene]-1,3,4- oxadiazol-2-amine have been synthesized and screened for their anticonvulsant and neurotoxic activity. After i.p. injection to mice at doses of 30, 100 and 300 mg/kg body weight 2,5-disubstituted-1,3,4- oxadiazole analogues were examined in the maximal electroshock induced seizures (MES) and subcutaneous metrazole (ScMET) induced seizure models in mice. Amongst all the compounds, 1a-1d and 2a-2d, one compound 1a exhibited activity at 100 mg/kg body weight at 0.5 and 4 h in ScMET, respectively. Compound 2b showed anticonvulsant activity at 100 mg/kg without activity in ScMET and neurotoxicity. The neurotoxicity was assessed by rotorod method, and all compounds (except 1a) were found to be safe at maximum administered dose. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9496-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1696–1703
DOI 10.1007/s00044-010-9496-x
ORIGINAL RESEARCH
Synthesis, anticonvulsant and neurotoxic activity of some new
2,5-disubstituted-1,3,4-oxadiazoles
•
Neha Jain Sushil K. Kashaw R. K. Agrawal
•
•
•
Anjali Gupta Abhishek Soni
Received: 27 February 2010 / Accepted: 29 October 2010 / Published online: 16 November 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Two novel series 2a–2d (2Z)-N-[5-(4-substi-
tuted)phenyl-1,3,4-oxadiazol-2-yl]-2-[(2Z)-3,7-dimethyl-
octa-2,6-dien-1-ylidene]hydrazinecarboxamide and 1a–1d
5-(4-substituted)phenyl-N-[(1Z,2Z)-3,7-dimethylocta-2,6-
dien-1-ylidene]-1,3,4-oxadiazol-2-amine have been syn-
thesized and screened for their anticonvulsant and neuro-
toxic activity. After i.p. injection to mice at doses of 30,
100 and 300 mg/kg body weight 2,5-disubstituted-1,3,4-
oxadiazole analogues were examined in the maximal
electroshock induced seizures (MES) and subcutaneous
metrazole (ScMET) induced seizure models in mice.
Amongst all the compounds, 1a–1d and 2a–2d, one com-
pound 1a exhibited activity at 100 mg/kg body weight at
0.5 and 4 h in ScMET, respectively. Compound 2b showed
anticonvulsant activity at 100 mg/kg without activity in
ScMET and neurotoxicity. The neurotoxicity was assessed
by rotorod method, and all compounds (except 1a) were
found to be safe at maximum administered dose.
of these people being in developing countries. It is usually
controlled, but not cured, with medication. However, over
30% of people with epilepsy do not have seizure control
even with the best available medications. There is currently
a need for improved agents for the treatment of seizures,
since currently available drugs are effective only in
60–80% of epileptic patients. Polytherapy with antiepi-
leptic drugs (AEDs) is necessary in clinical practice
because of the limited efficacy of monotherapy. In recent
years many new chemical entities (NCE) have been
designed that were structurally similar to many common
anticonvulsant containing dicarboximide functional group
(CONRCO). 2,5-Disubstituted-1,3,4-oxadiazole is a ver-
satile pharmacophore which exhibits wide variety of bio-
logical activities like hypnotic, sedative, anti-HIV, anti-
inflammatory, analgesic, anticonvulsant, antibacterial, hy-
poglycaemic, antioxidant, genotoxic, antifungal and
insecticidal activities (Havaldar and Patil, 2009; Mehta
et al., 2009; Nagalakshmi, 2008; Husaini et al., 2008;
George et al., 2008; Iqbal et al., 2006; Mishra et al., 2005;
Girges, 1994; Revanasiddappa and Subrahmanyam, 2009;
Maslat et al., 2002). Literature survey revealed that some
substituted semicarbazones also exhibit promising anti-
convulsant activity (Yogesswari et al., 2004a; b, 2005a, b).
With an aim to observe synergistic effect, some new 1,3,4-
oxadiazole analogues with semicarbazone side chain have
been synthesized and evaluated for anticonvulsant activity.
Pharmacophore model proposed by Dimmock et al.
(1995a, b, 2000) and other scientist for aryl semicarba-
zones (Yogeeswari et al., 2006; Agrawal and Mishra, 2005;
Verma et al., 2004) suggested the presence of an aryl
hydrophobic binding site (A), a hydrogen bonding domain
(HBD), an electron donor system (D) and another hydro-
phobic–hydrophilic binding site (R), where R controls the
pharmacokinetic properties of the anticonvulsant. Figure 1
Keywords 1,3,4-Oxadiazole Á Anticonvulsant activity Á
Neurotoxicity
Introduction
Epilepsy is a common chronic neurological disorder char-
acterized by recurrent unprovoked seizures. About 50
million people worldwide have epilepsy, with almost 90%
N. Jain Á S. K. Kashaw (&) Á R. K. Agrawal Á A. Gupta Á
A. Soni
Pharmaceutical Chemistry Division, Department of
Pharmaceutical Sciences, Dr. H. S. Gour University,
Sagar, MP 470003, India
e-mail: sushilkashaw@gmail.com
123

Med Chem Res (2011) 20:1696–1703
1697
represents the comparative pictorial representation of
this hypothesis (aryl semicarbazones), carbamazepine,
N-desmethyl diazepam, phenytoin and our designed
compounds.
threefold objectives: (i) Synthesis of 2,5-disubstituted-
1,3,4-oxadiazole derivatives with substituted aryl group
(R2) at fifth position; (ii) To observe the biological
effect of chain lengthening at second position; (iii)
Finally synthesis of hybrid compounds containing semi-
carbazone side chain at R1 position and 1,3,4-
oxadiazole.
With the mentioned hypothesis as background we
proposed to undertook the synthesis of 1,3,4-oxadiazole
derivatives with following template structure (Fig. 2) and
(Hydrogen bonding domain)
(Hydrogen bonding domain)
(Aryl hydrophobic
(Aryl hydrophobic
HBD
binding site) A
HBD
binding site)
A
O
H
O
H
N
N
NH
N
D
(Electron
donor site)
N
Cl
Br
R
D
(Electron
donor site)
Cl
Aryl semicarbazone
Desmethyl diazepam
(Aryl hydrophobic
D
(Electron
donor site)
(Aryl hydrophobic
binding site)
(Hydrogen bonding
A
binding site)
A
domain)
HBD
O
H
N
H
D
(Electron
donor site)
(Hydrogen bonding
NH
domain)
N
O
HBD
O
H
Phenytoin
Carbamazepine
(Hydrogen bonding
(Aryl hydrophobic
binding site)A
domain)
HBD
(Hydrophobic-hydrophilic
N
N
binding site )
O
R
(Aryl hydrophobic
binding site)A
N
O
H
N
N
NH
X
N
D
(Electron
donor site)
N
O
D
(Hydrophobic-hydrophilic
(Electron
binding site )
R
donor site)
X
(2a-2d)
(1a-1d)
Fig. 1 Comparative pictorial representation of the proposed hypothesis, previously reported compounds (aryl semicarbazones), N-desmethyl
diazepam, phenytoin, carbamazepine and our designed compounds (2a–2d and1a–1d)
123

1698
Med Chem Res (2011) 20:1696–1703
3
4
corresponding aromatic aldehydes in the presence of bro-
mine in glacial acetic acid (Rajak et al., 2007). Substituted
oxadiazole amines (1) were treated with sodium cyanate in
the presence of glacial acetic acid according to the known
urea method to yield substituted phenyl urea derivatives (2)
(Furniss et al., 2005b). These substituted phenyl urea
derivatives on condensation with hydrazine hydrate in
ethanol under alkaline conditions provided substituted aryl
semicarbazides (3) (Pandeya et al., 1999). Synthesis of the
target compounds was carried out according to the scheme
presented in the Fig. 3. Title compounds 1a–1d were
synthesized by refluxing (1) with citral in glacial acetic
acid and alcohol for 3 h (Pandeya et al., 2000). Whilst title
compounds 2a–2d were obtained by refluxing corre-
sponding semicarbazides with citral at acidic pH for 3 h
(Pandeya et al., 2000). The IR spectra showed the C=O str.
R1= Semicarbazone containing chain
R2= Aryl group
N
N
5
2
R2
R1
O
1
Fig. 2 Basic template of 2,5-disubstituted-1,3,4-oxadiazoles
Chemistry
The synthetic route is outlined in Fig. 3. Substituted
aryl semicarbazones were prepared according to the
method reported in the literature using semicarbazide
hydrochloride and substituted aldehydes in alcohol (Fur-
niss et al., 2005a). 2-Amino-5-aryl-1,3,4-oxadiazoles (1)
were prepared by cyclization of semicarbazones of the
H
O
H
CH3COONa
NH2
N
N
O
+
NH2NHCONH2.HCl
Semicarbazide
H
R
R
Substituted semicarbazones
Substituted aldehydes
CH3COONa
Br2,CH3COOH
N
N
N
N
O
NaOCN
NH2
O
NH2
N
O
H
CH3COOH
R
R
(1)
(2)
Substituted oxadiazole ureas
Substituted oxadiazole amines
NH2NH2.H2O
Reflux 4 h
CH
O
N
N
N
N
O
O
Citral
CH
N
NH2
N
O
N
H
N
N
O
H
H
H
Reflux 3 h
pH 4-5
R
(3)
R
N1-N4
Substituted oxadiazole semicarbazides
N
N
N
N
CH
O
NH2
O
CH
Citral
N
O
R
Reflux 3 h
pH 4-5
(1)
Substituted oxadiazole amines
R
(1a-1d)
Fig. 3 Scheme for synthesis of target compounds
123

Med Chem Res (2011) 20:1696–1703
1699
between 1,675 and 1,695 cm-1, C=N str of oxadiazole ring
between 1,585 and 1,600 cm-1. In 1HNMR spectra of
synthesized compounds, phenyl protons were observed
between 6.83 and 7.50 (d ppm) and oxadiazole urea pro-
tons were observed between 6 and 7 (d ppm). Thin layer
chromatography (TLC) was run throughout the reaction to
optimize the reaction for purity and completion.
Conclusion
Based upon the experimental results it may be concluded
that the synthesized new chemical entities showed potent
anticonvulsant activity. Only the most potent compound 1a
showed neurotoxicity, which may be due to relatively
better penetration of blood brain barrier and binding to
false protein. Activity of 1a and 2b is very much
comparable.
Pharmacology
Initial anticonvulsant evaluation of the target compounds
was undertaken by anticonvulsant drug development
(ADD) program, NIH protocol. The profile of anticonvul-
sant activity was established after i.p. injections by one
electrical and one chemical test. The electrical test
employed was the MES pattern test. The chemical test
employed was the subcutaneous metrazole seizure thresh-
old test. Minimal motor impairment was measured by the
rotorod (neurotoxicity, NT) test.
Experimental protocols
Chemistry
Melting points were determined in one end open capillary
tubes on a Buchi 530 melting point apparatus and are
uncorrected. Infrared (IR) spectrum was recorded on
Schimandzu and Perkin Elmer spectrophotometer in KBr
pellets. 1HNMR spectrum was recorded on Bruker Avance
spectrometer at 400 MHz using CDCl3 as the solvent.
Chemical shifts are reported in ppm using TMS as an
internal standard. The purity of the compounds was con-
firmed by thin layer chromatography using chloroform and
methanol (8:2) as mobile phase and on silica gel G-coated
plates as stationary phase. The spots were developed in
iodine chamber and visualized under ultraviolet lamp.
Results and discussion
Initial anticonvulsant activities of the synthesized com-
pounds are reported in Table 2, along with the data on
phenytoin and carbamazepine. In the prepared series 1a
was found to be active in the MES screen at both 0.5 and
4 h. 1b, 2a, 2c and 2d showed anticonvulsant activity at
300 mg at 4 h. Amongst all compounds (1a–1d and 2a–2d)
two compounds 1a and 2b exhibited activity at 100 mg/kg
at 0.5 and 4 h. 1a showed activity at 4 h also. Compound
1a was also active in the ScMET screen at 300 mg/kg at
both 0.5 and 4 h interval time, whilst 1b was active at
300 mg/kg only at 4 h. All compounds except 1a were
devoid of neurotoxicity.
Synthesis of arylsemicarbazone
A solution of aromatic aldehyde (0.2 mol) in warm alcohol
(250 ml) and a solution of semicarbazide (0.2 mol) and
sodium acetate (0.4 mol) in 50–60 ml of warm water were
mixed slowly with continuous stirring. The product sepa-
rated immediately on cooling. Product was recrystallized
by hot ethanol.
1a and 1b showed broad spectrum of anticonvulsant
activity, which is advantageous as compared to phenytoin.
Thus these could block both MES and ScMET models,
thereby suggesting that these could be of use in both clo-
nic-tonic (grand mal) seizures and absence (petit mal)
seizures. Compound with -Cl at para position is relatively
better than p-OMe and p-Me derivatives. This is also true
according to the literature, which suggested the presence of
halogen at para position for better anticonvulsant activity.
The most active compounds of the series 1a and 2b showed
the activity at lower dose level 100 mg/kg i.p. in MES
screen at 0.5 and 4 h interval time, respectively. The low
duration of the activity suggests that probably the metab-
olism rate of the compound is fast. Compounds with
observed activity at both 0.5 and 4 h indicate rapid onset of
action and long duration of activity.
Synthesis of 5-phenyl-1,3,4-oxadiazole-2-amine (1)
Substituted semicarbazone (0.15 mol) and sodium acetate
(0.3 mol) were dissolved in 300–350 ml of warm glacial
acetic acid with continuous stirring. Bromine (10.5 ml in
75 ml of glacial acetic acid) was added slowly to it.
Solution was stirred for an hour and then poured onto
crushed ice. The resulting solid was dried and recrystal-
lized from hot ethanol.
Synthesis of 5-(4-substituted)phenyl-1,3,4-oxadiazole-
2-yl-urea (2)
Oxadiazole amine (1) (0.1 mol) was dissolved in 10–50 ml
of glacial acetic acid and diluted to 100 ml with distilled
123

1700
Med Chem Res (2011) 20:1696–1703
water. Sometimes mixture was warmed to affect solubili-
zation. Sodium cyanate (0.1 mol) in 50 ml of warm water
was added to oxadiazole amine solution with stirring. It
was allowed to stand for half an hour and then cooled in ice
for 30 min. Obtained precipitate was filtered, dried and
recrystallized by hot ethanol.
other physical properties of synthesized compounds are
recorded in Table 1.
Synthesis of final compounds (1a–1d)
Oxadiazole amine (1) (0.02 mol) was dissolved in 50 ml of
alcohol. To this (0.01 mol) of citral was added and pH 4–5
was adjusted by glacial acetic acid. Mixture was refluxed
for 3 h. Obtained product was filtered and recrystallized by
hot ethanol. The yield, melting point and other physical
properties of synthesized compounds are recorded in
Table 1.
Synthesis of 5-(4-substituted)phenyl-1,3,4-oxadiazole-
2-yl-semicarbazide (3)
Substituted oxadiazole urea (2) (0.1 mol) was dissolved in
40–50 ml of ethanol. To this equimolar solution of
hydrazine hydrate (0.1 mol, 5 ml) was added and reaction
mixture was made alkaline by adding (0.1 mol, 4 g)
sodium hydroxide. Contents were refluxed for 4 h and kept
aside for some time. Obtained precipitate was filtered,
dried and recrystallized by hot ethanol.
1a IR (cm-1) 3119.20 (Ar C–H str), 1678.30 (Acyclic
C=N str), 1656.30 (C=C str in citral), 1596.60 (C=C
str in conjugated alkene in citral), 1487.10, 1444.90
(C=C skeletal vibration), 1282.80 (Ar C–N str),
1137.30 (C–O–C str in oxadiazole ring), 1HNMR
(400 MHz, d) 7.5 (d, 1H, N=CH), 7.22–7.48 (m, 5H,
ArH), 5.2 (t, 1H, C=CH), 4.8 (d, 1H, C=CH), 2.0 (q,
2H, CH2), 1.71 (s, 3H, CH3).
Synthesis of final compounds (2a–2d)
1b IR (cm-1) 3150, 3041 (Ar C–H str), 2992.40 (C–H str
in CH3), 1672.20 (acyclic C=N str), 1661.20 (C=C str
in citral), 1610.20 (C=N str in oxadiazole ring),
1592.40 (C=C str in conjugated alkene in citral),
1482.40, 1409 (C=C skeletal vibration), 1279.70 (Ar
Oxadiazole semicarbazide (3) (0.01 mol) was dissolved in
50 ml of alcohol. To this (0.01 mol) of citral was added
and pH was adjusted to 4–5 by glacial acetic acid. Mixture
was refluxed for 3 h. Obtained product was filtered and
recrystallized by hot ethanol. The yield, melting point and
Table 1 Physical data of synthesized compounds
N
N
N
N
O
CH
N
O
CH
N
N
N
H
O
H
1a-1d
R
2a-2d
R
S. no.
Code
–R
% Yield
MP (°C)
Molecular formula
Molecular weight
1
2
3
4
5
6
7
8
a
1a
1b
1c
1d
2a
2b
2c
2d
–H
40.20
36.33
12.50
27.72
70.21
19.10
68.29
63.49
239–241
181–183a
178–180
174–176
167–169
171–173a
118–120
160–162
C18H21N3O
C18H20ClN3O
C19H23N3O2
C19H23N3O
295.39
329.83
325.41
309.41
353.43
387.87
383.45
367.45
–Cl
–OCH3
–CH3
–H
C19H23N5O2
–Cl
C19H22N5O2Cl
C20H25N5O3
C20H25N5O2
–OCH3
–CH3
Melting point of the compound at their decomposition
123

Med Chem Res (2011) 20:1696–1703
1701
C–N str), 1140.70 (C–O–C str in oxadiazole ring),
1HNMR (400 MHz, d) 7.5 (d, 1H, N=CH), 7.33–7.42
(m, 4H, ArH), 5.2 (t, 1H, C=CH), 4.8 (d, 1H, C=CH),
2.0 (q, 2H, CH2), 1.71 (s, 3H, CH3).
CH3), 1725 (C–N str in 2° amide), 1691.53 (C=O str),
1666.55 (C=N str), 1589.40 (C=C str in conjugated
alkene in citral), 1125.83, 1050.11 (C–O–C str in
1
oxadiazole ring), HNMR (400 MHz, d) 7.5 (d, 1H,
1c IR (cm-1) 3137.50 (Ar C–H str), 1681.10 (Acyclic
C=N str), 1660.30 (C=C str in citral), 1629.30 (C=N
str in oxadiazole ring), 1608.30 (C=C str in conjugated
alkene in citral), 1502.4, 1461.10 (C=C skeletal
vibration), 1309.50 (Ar C–N str), 1113.90 (C–O–C
str in oxadiazole ring), 1257.60 (asym C–O–C str in
acyclic ether), 1021.90 (sym C–O–C str in acyclic
ether), 1HNMR (400 MHz, d) 7.5 (d, 1H, N=CH),
7.37–6.83 (m, 4H, ArH), 5.2 (t, 1H, C=CH), 4.8 (d,
1H, C=CH3), 3.73 (s, 3H, ArOCH3), 2.0 (q, 2H, CH2),
1.71 (s, 3H, CH3).
1d IR (cm-1) 3097.78, 3074.63 (Ar C–H str), 1675.20
(acyclic C=N str), 1658.80 (C=C str in citral), 1606.76
(C=N str in oxadiazole ring), 1583.51 (C=C str in
conjugated alkene in citral), 1504.53, 1421.58 (C=C
skeletal vibration), 1298.14, 1286.56 (Ar C–N str),
1126.47, 1118.75 (C–O–C str in oxadiazole ring),
1HNMR (400 MHz, d) 7.5 (d, 1H, N=CH), 7.12–7.36
(m, 4H, ArH), 5.20 (t, 1H, C=CH), 4.8 (d, 1H, C=CH),
2.0 (q, 2H, CH2), 1.71 (s, 3H, CH3).
2a IR (cm-1) 3443.20 (N–H str in 2° amide), 3090 (Ar
C–H str), 1730.20 (C–N str in 2° amide), 1690.70
(C=O str), 1665 (C=N str), 1638 (C=C str in
conjugated alkene in citral), 1413.50 (C=C skeletal
vibration), 1HNMR (400 MHz, d) 7.5 (d, 1H, N=CH),
7.22–7.48 (m, 5H, ArH), 6.0–7.0 (2s, 2H, NHCONH),
5.2 (t, 1H, C=CH), 4.8 (d, 1H, C=CH), 2.0 (q, 2H,
CH2), 1.71 (s, 3H, CH3).
2b IR (cm-1) 3459.70 (N–H str in 2° amide), 3030.10 (Ar
C–H str), 1737.70 (C–N str in 2° amide), 1680.20
(C=O str), 1660.90 (C=N str), 1630.90 (C=C str in
conjugated alkene in citral), 1416.20 (C=C skeletal
vibration), 1139.40 (C–O–C str in oxadiazole ring),
1HNMR (400 MHz, d) 7.5 (d, 1H, N=CH), 7.33–7.42
(m, 4H, ArH), 6.0–7.0 (2s, 2H, NHCONH), 5.2 (t, 1H,
C=CH), 4.8 (d, 1H, C=CH), 2.0 (q, 2H, CH2), 1.71 (s,
3H, CH3).
N=CH), 7.12–7.36 (m, 4H, ArH), 6.0–7.0 (2s, 2H,
NHCONH), 5.2 (t, 1H, C=CH), 4.8 (d, 1H, C=CH),
2.35 (s, 3H, ArCH3), 2.0 (q, 2H, CH2), 1.71 (s, 3H,
CH3).
Pharmacology
The new derivatives obtained from the reaction sequence
were injected intraperitoneally into mice and evaluated in
the maximal electroshock (MES), subcutaneous metrazole
(ScMET) and neurotoxicity screens, using doses of 30, 100
and 300 mg/kg at two different time intervals. These data
are presented in Table 2.
Anticonvulsant screening
Albino mice (18–25 g weight) of either sex were used for
this experiment. Food was withdrawn 12–15 h before the
commencement of the experiments, whilst water was
withdrawn immediately before the experiment. Maximum
seizures were induced by applications of electrical current
across the brain via corneal electrodes primed with normal
saline (0.9% NaCl). The stimulus parameters were 50 mA
AC in a pulse of 60 Hz for 0.2 s. After applying shock,
mice were observed for the type of convulsion produced,
and the hind limb extensor response was taken as the end
point. Animals showing positive hind limb extensor
response were used for testing drug substance. For ScMET
test, the test compounds were administrated i.p. to all
animals in a group. Pentylenetetrazole (85 mg/kg) was
injected subcutaneously, 30 min and 4 h after the admin-
istration of the compounds. The absence or presence of an
episode of clonic convulsion was taken as the end point.
Initially all the compounds were administered i.p. in a
volume of 0.01 ml/g body weight for mice at doses of 30,
100 and 300 mg/kg to one to four animals. Activity was
established using the MES and ScMET test (White et al.,
1995a, b). These data are presented in Table 2.
2c IR (cm-1) 3466.20 (N–H str in 2° amide), 1678.70
(C=O str), 1658.20 (C=N str), 1610.60 (C=C str in
conjugated alkene in citral), 1414.20 (C=C skeletal
vibration), 1181.10 (C–O–C str in oxadiazole ring),
1255.60 (asym C–O–C str in acyclic ether), 1021.40
(sym C–O–C str in acyclic ether), 1HNMR (400 MHz,
d) 7.5 (d, 1H, N=CH), 7.37–6.83 (m, 4H, ArH),
6.0–7.0 (2s, 2H, NHCONH), 5.2 (t, 1H, C=CH), 4.8
(d, 1H, C=CH3), 3.73 (s, 3H, ArOCH3), 2.0 (q, 2H,
CH2), 1.71 (s, 3H, CH3).
Neurotoxicity screen
Minimal motor impairment (Swinyard et al., 1961) was
measured in mice by the rotorod test. The mice were
trained to stay on an accelerating rotorod that rotated at six
revolutions per minute. The rod diameter was 3.2 cm.
Neurotoxicity was indicated by the inability of the animal
to maintain equilibrium on the rod for at least 1 min in
each of the three trials.
2d IR (cm-1) 3466.20 (N–H str in 2° amide), 3192.30,
3157.58 (Ar C–H str), 2989.76, 2900.32 (C–H str in
123

1702
Med Chem Res (2011) 20:1696–1703
Table 2 Anticonvulsant and neurotoxic activity of the synthesized compounds
N
N
N
N
O
CH
N
O
CH
N
N
N
H
O
H
1a-1d
2a-2d
R
R
Code
–R
Intraperitonial injection in mice (dose mg/kg)a
MES screen
0.5 h
ScMET screen
0.5 h
Neurotoxicity screen
0.5 h
4 h
4 h
4 h
J1
–H
30
–
100
300
–
300
–
300
300
–
300
–
300
–
J2
–Cl
J3
–OMe
–Me
–H
–
–
–
–
J4
–
–
–
–
–
–
N1
N2
N3
N4
–
300
–
–
–
–
–
–Cl
30
–
–
–
–
–
–OMe
–Me
300
300
30
–
–
–
–
–
–
–
–
–
Phenytoinb
Carbamazepineb
30
30
–
–
100
100
100
300
100
100
300
a
Doses of 30, 100 and 300 mg/kg were administered. The figure in the table indicates the minimum dose whereby bioactivity was demonstrated
in half or more of the animals (mice). The animals were examined 0.5 and 4 h after injections. (–) indicates an absence of activity at maximum
dose administered (300 mg/kg)
b
Reference drug
Acknowledgments The authors deeply appreciate the assistance of
Dr. J.P. Stables, Director, Antiepileptic Drug Development Program,
Epilepsy Branch, Preclinical Pharmacology Section, NIH, USA for
screening the compounds for anticonvulsant activity.
Furniss BS, Hannaford AJ, Smith PWG, Tatchell AR (2005b) Vogel’s
textbook of practical organic chemistry, 5th edn. Pearson
Education, New Delhi, p 964
George S, Parameswaran MK, Chakraborty AR, Ravi TK (2008)
Synthesis and evaluation of the biological activities of some 3-
{[5-(6-methyl-4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-yl)-
1,3,4-oxadiazol-2-yl]-imino}-1,3-dihydro-2H-indol-2-one deriv-
atives. Acta Pharm 58:119–129
References
Girges MM (1994) Synthesis and pharmacological evaluation of
novel series of sulfonate ester-containing 1,3,4-oxadiazole
derivatives with anticipated hypoglycemic activity. Arzneimitt-
elforschung 44:490–495
Havaldar FH, Patil AR (2009) Synthesis of biologically active 3-[4-
(4-substituted amino-4-yl-methyl-5-thione[1,3,4]-oxadiazole-2-
Agrawal N, Mishra P (2005) Synthesis and evaluation of 4-substituted
semicarbazones of levulinic acid for anticonvulsant activity.
J Zhejiang Univ Sci B 6:617–621
Dimmock JR, Pandeya SN, Quail JW, Pugazhenthi U, Allen TM, Kao
GY, Balzarini J, Clercq ED (1995a) Evaluation of the semicar-
bazones, thiosemicarbazones and bis-carbohydrazones of some
aryl alicycylic ketones for anticonvulsant and other biological
properties. Eur J Med Chem 30:303–314
yl-methoxy)-phenyl]-2-phenyl-3H-quinazolin-4-ones. Asian
Chem 21:5267–5272
J
Husaini A, Ahmad FJ, Ajmal M, Ahuja P (2008) Synthesis of 1-(4-
phenoxyphenyl)-3-[5-(substituted aryl)-1,3,4-oxadiazol-2-
Dimmock JR, Sidhu KK, Tumber SD, Basran SK, Chen MJ, Quail W,
Yang J, Rozas I, Weaver DF (1995b) Some aryl semicarbazones
yl]propan-1-ones as safer anti-inflammatory and analgesic
agents. J Serb Chem Soc 73:781–791
Iqbal R, Zareef M, Ahmed S, Zaidi JH, Arfan M, Shafique M,
Al-Masoudi NA (2006) Synthesis, antimicrobial and anti-HIV
activity of some novel benzenesulfonamides bearing 2,5-disub-
stituted-1,3,4-oxadiazoles. J Chin Chem Soc 53:689–696
possessing anticonvulsant activities. Eur
30:287–301
J
Med Chem
Dimmock JR, Vashishths SC, Stables JP (2000) Anticonvulsant
properties of various acetylhydrazones, oxamoylhydrazones and
semicarbazones derived from aromatic and unsaturated carbonyl
compounds. Eur J Med Chem 35:241–248
Maslat AO, Abussaud M, Tashtoush H, Al-Taalib
M (2002)
Furniss BS, Hannaford AJ, Smith PWG, Tatchell AR (2005a) Vogel’s
textbook of practical organic chemistry, 5th edn. Pearson
Education, New Delhi, p 1258
Synthesis, antibacterial, antifungal and genotoxic activity of
bis-1,3,4-oxadiazole derivatives. Pol J Pharmacol 54:55–59
123

Med Chem Res (2011) 20:1696–1703
1703
Mehta DK, Das R, Dua K (2009) Synthesis, antimicrobial and anti-
inflammatory activity of some new 1,3,4-oxadiazoles and 1,3,4-
oxadiazole-2-thione derivatives as mannich bases containing
furan moiety. Int J Chem Sci 7:225–234
White HS, Johnson M, Wolf HH, Kupferberg HJ (1995a) The early
identification of anticonvulsant activity: role of the maximal
electroshock and subcutaneous pentylenetetrazol seizure models.
Ital J Neurol Sci 16:73–77
Mishra AR, Singh DV, Mishra RM (2005) Synthesis and antifungal
activity of new 1,3,4-oxadiazolo[3,2-b]-s-triazine-5-ones and
their thiones analogues. Indian J Heterocycl Chem 14:289–292
Nagalakshmi G (2008) Synthesis, antimicrobial and anti-inflamma-
tory activity of 2,5-disubstituted-1,3,4-oxadiazoles. Indian J
Pharm Sci 70:49–55
Pandeya SN, Aggarwal N, Jain JS (1999) Evaluation of semicarba-
zones for anticonvulsant and sedative hypnotic properties.
Pharmazie 54:300–302
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
Rajak H, Mishra P, Kharya MD (2007) Synthesis of some novel
oxadiazole and oxadiazoline analogues for their anti-inflamma-
tory activity. Yakugaku Zasshi 127:1757–1764
White HS, Woodhead JH, Franklin MR (1995b) General principles:
experimental selection, quantification and evaluation of antiep-
ileptic drugs. In: Antiepileptic drugs. Raven Press, New York,
pp 99–110
Yogeeswari P, Sriram D, Thirumurugan R, Sunil Jit LR, Ragavendran
JV, Kavya R, Rakhra K, Saraswat V (2006) Synthesis of N4-
(2,4-dimethylphenyl) semicarbazones as 4-aminobutyrate ami-
notransferase inhibitors. Acta Pharm 56:259–272
Yogesswari P, Sriram D, Pandeya SN (2004a) 4-Sulphamoylphenyl
semicarbazones with anticonvulsant activity. IL Farm 59:
609–613
Yogesswari P, Thirumurugan R, Kavya R, Samuel JS, Stables JP,
Sriram D (2004b) Synthesis and anticonvulsant activity of 2-
methyl-3-chlorophenyl-substituted semicarbazones. Eur J Med
Chem 39:729–734
Revanasiddappa BC, Subrahmanyam EVS (2009) Chloramine-T
mediated synthesis of 1,3,4-oxadiazoles. Orient
25:707–710
Yogesswari P, Sriram D, Thirumurugan R, Raghavendran JV, Sudhan
K, Pavana RK, Stables JP (2005a) Discovery of N-(2,6-
dimethylphenyl)-substituted semicarbazones as anticonvulsants:
J Chem
Swinyard EA, Clark LD, Miyahara JT, Wolf HH (1961) Studies on
the mechanism of amphetamine toxicity in aggregated mice.
J Pharmacol Exp Ther 132:97–102
Verma M, Pandeya SN, Singh KN, Stables JP (2004) Anticonvulsant
activity of Schiff bases of isatin derivatives. Acta Pharm
54:49–56
hybrid pharmacophore-based design.
6202–6211
Yogesswari P, Sriram D, Veena V, Kavya R, Rakhaa K, Ragaven-
dram JV, Mehta S, Thirumurugan R, Stables JP (2005b)
Synthesis of aryl semicarbazones as potential anticonvulsant
agents. Biomed Pharmacother 59:51–55
J Med Chem 48:
123