A Novel Series of 2,5-Disubstituted 1,3,4-oxadiazoles: Synthesis and SAR Study for their Anticonvulsant Activity

Article abstract of DOI:10.1111/j.1747-0285.2010.01066.x

In search for a better anticonvulsant drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-oxadiazoles as anticonvulsant pharmacophore, a series of novel substituted semicarbazones were designed, synthesized, and evaluated for their anticonvulsant activity. The chemical structures of the synthesized molecules were confirmed by elemental and spectral (IR, ¹H NMR, ¹³C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure and subcutaneous pentylenetetrazole (scPTZ) models. Efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity.

Full text of DOI:10.1111/j.1747-0285.2010.01066.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2010.01066.x
Chem Biol Drug Des 2011; 77: 152–158
Research Letter
A Novel Series of 2,5-Disubstituted
1,3,4-oxadiazoles: Synthesis and SAR Study for
their Anticonvulsant Activity
Harish Rajak1,*, Pradeep Singour2, Murli
Dhar Kharya3 and Pradeep Mishra4
In the recent years, aryl semicarbazones have emerged as structur-
ally novel class of compounds with anticonvulsant activity (3–5).
Also, several investigations have revealed that 1,3,4-oxadiazole ana-
logs possess considerable anticonvulsant activity (6–8).
1SLT Institute of Pharmaceutical Sciences, Guru Ghasidas University,
Bilaspur 495 009, Chhattisgarh, India
2VNS Institute of Pharmacy, Neelbud, Bhopal 462 044, Madhya
The conformational investigation into the clinically active anticonvul-
Pradesh, India
sant drugs such as phenytoin, carbamazepine, lamotrigine, rufina-
mide, and phenobarbitone has resulted in the proposal of a general
model for anticonvulsant activity (9,10) (Figure 1). This semicarbaz-
one-based pharmacophore model consists of the following four
essential binding sites: (i) an aryl hydrophobic binding site (A) with
halo substituent, preferably at para position; (ii) a hydrogen binding
domain; (iii) an electron donor group (D) and (iv) another hydropho-
bic–hydrophilic site controlling the pharmacokinetic properties of the
anticonvulsant (C) (Figure 2). In earlier pharmacophore model stud-
ies, our research group confirmed that the presence of aryl group
(preferably halogen substituted) near the semicarbazone moiety is
one of the indispensable parameters for anticonvulsant activity (11).
3Department of Pharmaceutical Sciences, Dr H. S. Gour University,
Sagar 470 003, Madhya Pradesh, India
4GLA Institute of Pharmaceutical Sciences and Research, Mathura
281 406, Uttar Pradesh, India
*Corresponding author: Harish Rajak, harishdops@yahoo.co.in
In search for a better anticonvulsant drug and
the importance of semicarbazones and 2,5-
disubstituted 1,3,4-oxadiazoles as anticonvulsant
pharmacophore,
a series of novel substituted
semicarbazones were designed, synthesized, and
evaluated for their anticonvulsant activity. The
chemical structures of the synthesized molecules
were confirmed by elemental and spectral (IR, 1H
NMR, 13C NMR and MS) analysis. The anticonvul-
sant activities of the compounds were investi-
gated using maximal electroshock seizure and
subcutaneous pentylenetetrazole (scPTZ) models.
Efforts were also made to establish structure–
activity relationships among synthesized com-
pounds. The results of the present study validated
that the pharmacophore model with four binding
sites is essential for anticonvulsant activity.
Materials and Methods
All the chemicals and solvents employed in this study were
purchased from E-Merck (Darmstadt, Germany), Aldrich (Steinheim,
Germany), and Himedia (Mumbai, India). Melting points were deter-
mined by open capillary method and are uncorrected. Elemental
analysis was performed using an elemental analyzer Heraeus Carlo
Erba-1108, IR spectra were recorded on a Perkin Elmer IR spectro-
photometer (KBr disc) (Perkin Elmer, Beaconsfield, UK), NMR spectra
on a Bruker DRX-300 NMR spectrometer (DMSO-d6, TMS) (Bruker
Bioscience, Billerica, MA, USA), and the electrospray mass spectra
on a Micromass Quattro II triple-quadrupole mass spectrometer
(Methanol) (Micromass, Manchester, UK).
Key words: 1,3,4-oxadiazoles, anticonvulsant activity, semicarbazones
Received 26 February 2009, revised 24 October 2010 and accepted for
publication 22 November 2010
The title compounds were prepared using the synthetic strategy
described in Scheme 1. Methylsalicylate I on reaction with benzyl
chloride in alkaline hydromethanolic solution resulted in correspond-
ing 2-benzyloxy benzoic acid methyl ester II (12). 2-(Benzyloxy)ben-
zohydrazide III was synthesized from compound II on treatment
with hydrazine hydrate in methanol (13). Compound III was cyclized
to 2-amino-5-(2-benzyloxyphenyl)-1,3,4-oxadiazoles IV using cyano-
gen bromide in methanol in the presence of sodium bicarbonate
(14,15). Compound IV was treated with sodium cyanate in the
presence of glacial acetic acid to yield 1-{5-[2-(benzyloxy)phenyl]-1,
3,4-oxadiazol-2-yl}-urea V. N-{5-[2-(benzyloxy)phenyl]-1,3,4-oxadiazol-
Epilepsy is a chronic neurological disorder characterized by the
periodic sudden loss or impairment of consciousness, often fol-
lowed by convulsions. About 50 million people worldwide have epi-
lepsy, with almost 90% of these people being in developing
countries (1). Epilepsy also affects about 4% of individuals over
their lifetime. Despite the development of several new anticonvul-
sants, over 30% of people with epilepsy do not have seizure
control and others do so only at the expense of significant
dose-related toxicity and peculiar adverse effects (2). Thus, there is
an enormous need for the development of more effective and safer
antiepileptic drugs.
152

Anticonvulsant Activity of 1,3,4-oxadiazoles
D
D
H
N
H
N
N
A
O
A
Cl
H
N
Cl
H
N
H
N
N
H
HBD
HBD
A
O
Phenytoin
Lamotrigine
D
D
F
O
H3C
H
A
N
N
O
Figure 1: Commonly used anti-
convulsant drugs with their vital
structural features. (A) Hydropho-
bic aryl ring system, (HBD) hydro-
gen binding domain, (D) electron
donor moiety.
N
N
A
O
A
HBD
N
N
H
A
NH2
HBD
H2N
Carbamazepine
O
HBD
Phenobarbitone
Rufinamide
2-yl}-hydrazine carboxamide VI was prepared by reaction of com-
pound V with hydrazine hydrate in the presence of sodium hydrox-
ide. Title compounds 1–14 were prepared by reaction of the
appropriate aldehyde or ketone with compound VI.
ondary NH), 3317.9 (amide NH) and 1682.4 (C = O str of amide),
3431.7 (NH str of NH2); H NMR (300 MHz, DMSO-d6, TMS, d ppm):
1
5.3 (s, 2H, OCH2), 2.6 (d, 2H, NH2), 6.2 (t, 1H, NHNH2), 6.0 (s, 1H,
NHCO), 6.8–7.4 (m, 9H, ArH); ESMS (Methanol) m ⁄ z 325 (M+).
General procedure for synthesis of 1-{5-[2-
(benzyloxy)phenyl)]-1,3,4-oxadiazol-2-yl}-urea V
The appropriate 2-amino-5-(benzyloxy)phenyl-1,3,4-oxadiazoles IV
(0.01 mol) was dissolved in 10–30 mL of glacial acetic acid diluted
to 50 mL with distilled water. To this, equimolar (0.01 mol) quantity
of sodium cyanate in 20–30 mL of warm water was added with
stirring. The reaction mixture was allowed to stand for 3 h followed
by cooling on an ice bath. The precipitates obtained were collected
by filtration, washed with cold water, and recrystallized from 90%
aqueous ethanol.
General procedure for synthesis of N1-{5-[(2-
benzyloxy)phenyl]-1,3,4-oxadiazol-2-yl}-N4-(4-
substitutedbenzaldehyde)-semicarbazone 1-6,
N1-{5-[(2-benzyloxy)phenyl]-1,3,4-oxadiazol-2-yl}-
N4-[1-(4-substitutedphenyl)ethanone]-
semicarbazone 7–10 and N1-{5-[(2-
benzyloxy)phenyl]-1,3,4-oxadiazol-2-yl}-N4-[1-(4-
substitutedphenyl) (phenyl) methanone]-
semicarbazone 11–14
Equimolar quantities of VI (0.01 mol) and carbonyl compound
(0.01 mol) were dissolved in 20–30 mL of ethanol. To this, 5 mL of
water was added. Whenever the solution became turbid, the turbid-
ity was removed by adding ethanol. The pH of the reaction mixture
was adjusted between 4 and 5, by adding glacial acetic acid. The
reaction mixture was refluxed for a period of time ranging from 2
to 3 h. Thereafter, the reaction mixture was cooled on an ice bath,
and the crystallized product so obtained was filtered under vacuum.
The crude product was recrystallized from 90% aqueous ethanol.
Compound V
Yield 58%; MP (ꢀC) 172–173; IR (KBr), 3071.3 (Aromatic C-H),
1091.8 (C-O of oxadiazole nucleus), 1667.2 (C = N of oxadiazole),
3429.5 (secondary NH), 3319.7 (amide NH), 1685.3 (C = O str of
1
amide), 3432.8 (NH str of NH2); H NMR (300 MHz, DMSO-d6, TMS,
d ppm): 5.3 (s, 2H, OCH2), 6.8–7.4 (m, 9H, ArH), 6.3 (s, 2H, NH2),
5.9 (s, 1H, NH); ESMS (Methanol) m ⁄ z 310 (M+).
Compound 1
Yield: 56%; MP: 173–175 ꢀC; IR (per cm) (KBr) 3046.3 (Aromatic C-H
str), 1602.7 & 1503.9 (Aromatic C-C str), 1090.2 (C-O of 1,3,4-oxadiazole
nucleus), 1659.5 (C = N of 1,3,4-oxadiazole nucleus), 1685.2 (C = O
str of amide), 3429.5 (N-H str of amide), 1615.8 (C = N group), 822.6
General procedure for synthesis of N-{5-[2-
(benzyloxy)phenyl)]-1,3,4-oxadiazol-2-yl}-
hydrazinecarboxamide VI
Required quantity of V (0.01 mol) was dissolved in 30–40 mL of
ethanol. To this was added equimolar solution of hydrazine hydrate
in 5 mL of water. The reaction mixture was made alkaline by
adding 4 g of sodium hydroxide pellets. The contents were then
heated to reflux for 2–8 h, followed by cooling on an ice bath. The
product was filtered and recrystallized from 90% aqueous ethanol.
1
(C-H def disubstituted benzene ring); H NMR (300 MHz, DMSO-d6,
TMS, d ppm): 6.9–7.6 (m, 14H, ArH), 5.3 (OCH2), 6.2 (s, 1H, NHCONH),
9.5 (s, 1H, NHCONH), 6.8 (s, 1H, imine H); 13C-NMR (75 MHz, DMSO-
d6, TMS, d ppm): 127.4 (C-2¢ & C-6¢), 128.8 (C-3¢ & C-5¢), 127.6 (C-4¢),
140.8 (C-1¢), 78.4 (OCH2), 122.3 (C-1¢¢), 160.5 (C-2¢¢), 114.6 (C-3¢¢)
129.5 (C-4¢¢), 121.4 (C-5¢¢), 128.2 (C-6¢¢), 171.3 (C-2), 169.1 (C-5), 157.5
(NHCONHNCH), 154.8 (NHCONHNCH), 129.2 (C-2¢¢¢ & C-6¢¢¢), 128.4
(C-3¢¢¢ & C-5¢¢¢), 130.9 (C-4¢¢¢), 131.3 (C-1¢¢¢); ESMS (Methanol) m ⁄ z
413 (M+); Anal. Calcd for C23H19N5O3: C, 66.82; H, 4.63; N, 16.94.
Found: C, 67.15; H, 4.73; N, 16.79.
Compound VI
Yield 66%; MP (ꢀC) 198–199; IR (KBr), 3086.2 (Aromatic C-H), 1094.8
(C-O of oxadiazole nucleus), 1661.6 (C = N of oxadiazole), 3423.1 (sec-
Chem Biol Drug Des 2011; 77: 152–158
153

Rajak et al.
1682.9 (C = O str of amide), 3428.8 (N-H str of amide), 1607.2
(C = N group), 821.6 (C-H def disubstituted benzene ring), 1521.8 &
1354.5 (N = O str of Ar-NO2 group); H NMR (300 MHz, DMSO-d6,
O
C
N
N
D
1
R′′′′
N
H
N
H
C
N
O
TMS, d ppm): 7.0–8.2 (m, 13H, ArH), 5.2 (OCH2), 6.3 (s, 1H,
NHCONH), 9.6 (s, 1H, NHCONH), 6.8 (s, 1H, imine H); 13C-NMR
(75 MHz, DMSO-d6, TMS, d ppm): 127.3 (C-2¢ & C-6¢), 128.6 (C-3¢
& C-5¢), 127.5 (C-4¢), 140.7 (C-1¢), 78.3 (OCH2), 122.4 (C-1¢¢), 160.7
(C-2¢¢), 114.5 (C-3¢¢) 129.6 (C-4¢¢), 121.5 (C-5¢¢), 128.2 (C-6¢¢), 171.2
(C-2), 169.0 (C-5), 157.4 (NHCONHNCH), 154.7 (NHCONHNCH), 129.8
(C-2¢¢¢ & C-6¢¢¢), 123.6 (C-3¢¢¢ & C-5¢¢¢), 150.9 (C-4¢¢¢), 137.3 (C-1¢¢¢);
ESMS (Methanol) m ⁄ z 458 (M+); Anal. Calcd for C23H18N6O5: C,
60.26; H, 3.96; N, 18.33. Found: C, 60.19; H, 4.02; N, 18.45.
O
CH2
HBD
C
A
R′′′
Figure 2: Pharmacophoric structural features in title compounds:
(A) hydrophobic aryl ring system, (HBD) hydrogen binding domain,
(D) electron donor moiety, (C) distal aryl ring.
Compound 2
Yield: 67%; MP: 180–182 ꢀC; IR (per cm) (KBr) 3043.7 (Aromatic C-
H str), 1602.9 & 1505.4 (Aromatic C-C str), 1090.6 (C-O of 1,3,4-
oxadiazole nucleus), 1656.3 (C = N of 1,3,4-oxadiazole nucleus),
Compound 3
Yield: 56%; MP: 165–166 ꢀC; IR (per cm) (KBr) 3041.4 (Aromatic
C-H str), 1601.7 & 1504.9 (Aromatic C-C str), 1091.6 (C-O of
CONHNH2
COOCH3
COOCH3
OH
b
a
O
CH2
O
CH2
III
II
I
c
N
N
O
C
N
N
NH2
CH2
d
O
NH2
NH
CH2
O
O
O
IV
V
e
O
C
O
N
N
6′′
3′′
N
N
1′′
2′′
5′′
4′′
f
C
R′′′′
NH
CH2
N
N
O
NH
CH2
C
NH2
H
N
O
1′′′
H
6′′′
5′′′
2′′′
3′′′
O
1–14
O
VI
1′
6′
5′′
2′
3′
R′′′
4′′′
4′
Compound
Code
1
2
3
4
5
Compound
Code
6
7
8
9
10
Compound
Code
11
12
13
R′′′
R′′′′
R′′′
4-Cl
4-OH
4-OCH3
4-NO2
4-Cl
R′′′′
R′′′
R′′′′
H
4-NO2
4-OH
4-CH3
H
H
H
H
H
H
CH3
CH3
CH3
CH3
H
4-OH
4-NO2
C6H5
C6H5
C6H5
C6H5
14
4-OCH3
4-OCH3
Reaction conditions: (a) BzCl, KOH 10%; MeOH, rt, 6 h; (b) NH2NH2.H2O; MeOH, rt, 5 h; (c) BrCN, NaHCO3;
MeOH, rt, 3 h; (d) NaOCN, CH3COOH, rt, 3 h; (e) NH2NH2.H2O, NaOH, reflux 2-8 h; (f) Aldehydes or ketone,
CH3COONa, reflux, 2-3 h.
Scheme 1: Synthesis of 2,5-disubstituted-1,3,4-oxadiazole derivatives 1–14.
154
Chem Biol Drug Des 2011; 77: 152–158

Anticonvulsant Activity of 1,3,4-oxadiazoles
1
1,3,4-oxadiazole nucleus), 1664.0 (C = N of 1,3,4-oxadiazole
nucleus), 1681.7 (C = O str of amide), 3426.9 (N-H str of amide),
1614.5 (C = N group), 821.8 (C-H def disubstituted benzene ring),
3459.1 (O-H str of alcoholic group), 1155.4 (C-O str of alcoholic
group); 1H NMR (300 MHz, DMSO-d6, TMS, d ppm): 6.9–7.5 (m,
13H, ArH), 5.2 (OCH2), 6.3 (s, 1H, NHCONH), 9.7 (s, 1H, NHCONH),
6.7 (s, 1H, imine H), 5.2 (ArOH); 13C-NMR (75 MHz, DMSO-d6, TMS,
d ppm): 127.4 (C-2¢ & C-6¢), 128.6 (C-3¢ & C-5¢), 127.5 (C-4¢), 140.8
(C-1¢), 78.3 (OCH2), 122.3 (C-1¢¢), 160.8 (C-2¢¢), 114.7 (C-3¢¢) 129.6 (C-
4¢¢), 121.6 (C-5¢¢), 128.2 (C-6¢¢), 171.1 (C-2), 169.2 (C-5), 157.2
(NHCONHNCH), 154.6 (NHCONHNCH), 130.6 (C-2¢¢¢ & C-6¢¢¢), 115.8
(C-3¢¢¢ & C-5¢¢¢), 150.8 (C-4¢¢¢), 123.5 (C-1¢¢¢); ESMS (Methanol) m ⁄ z
429 (M+); Anal. Calcd for C23H19N5O4: C, 64.33; H, 4.46; N, 16.31.
Found: C, 64.47; H, 4.44; N, 16.48.
(C-Cl str); H NMR (300 MHz, DMSO-d6, TMS, d ppm): 7.0–7.6 (m,
13H, ArH), 5.2 (OCH2), 6.3 (s, 1H, NHCONH), 9.6 (s, 1H, NHCONH),
6.8 (s, 1H, imine H); 13C-NMR (75 MHz, DMSO-d6, TMS, d ppm):
127.3 (C-2¢ & C-6¢), 128.8 (C-3¢ & C-5¢), 127.4 (C-4¢), 140.8 (C-1¢),
78.3 (OCH2), 122.2 (C-1¢¢), 160.6 (C-2¢¢), 114.5 (C-3¢¢) 129.6 (C-4¢¢),
121.4 (C-5¢¢), 128.2 (C-6¢¢), 171.4 (C-2), 169.1 (C-5), 157.4 (NHCON-
HNCH), 154.7 (NHCONHNCH), 130.4 (C-2¢¢¢ & C-6¢¢¢), 129.2 (C-3¢¢¢ &
C-5¢¢¢), 136.2 (C-4¢¢¢), 129.4 (C-1¢¢¢); ESMS (Methanol) m ⁄ z 448 (M+);
Anal. Calcd for C23H18N5O3Cl: C, 61.68; H, 4.05; N, 15.64. Found: C,
61.60; H, 4.12; N, 15.58.
Compound 7
Yield: 62%; MP: 188–190 ꢀC; IR (per cm) (KBr) 3037.7 (Aromatic C-
H str), 1603.2 & 1506.8 (Aromatic C-C str), 1092.8 (C-O of 1,3,4-ox-
adiazole nucleus), 1659.4 (C = N of 1,3,4-oxadiazole nucleus),
1681.6 (C = O str of amide), 3421.6 (N-H str of amide), 1617.3
(C = N group), 822.5 (C-H def disubstituted benzene ring), 3451.4
Compound 4
Yield: 68%; MP: 171–173 ꢀC; IR (per cm) (KBr) 3042.7 (Aromatic C-H
str), 1601.7 & 1508.5 (Aromatic C-C str), 1089.3 (C-O of 1,3,4-oxadiaz-
ole nucleus), 1664.7 (C = N of 1,3,4-oxadiazole nucleus), 1675.2
(C = O str of amide), 2908.0 (aliphatic C-H str), 1443.3 (aliphatic C-H
def), 3422.7 (N-H str of amide), 1612.8 (C = N group), 819.6 (C-H def
1
(O-H str of alcoholic group), 1151.0 (C-O str of alcoholic group); H
NMR (300 MHz, DMSO-d6, TMS, d ppm): 6.8–7.5 (m, 13H, ArH), 5.2
(OCH2), 6.3 (s, 1H, NHCONH), 9.7 (s, 1H, NHCONH), 5.4 (ArOH), 1.1
(s, 3H, Carbimino CH3); 13C-NMR (75 MHz, DMSO-d6, TMS, d ppm):
127.3 (C-2¢ & C-6¢), 128.7 (C-3¢ & C-5¢), 127.5 (C-4¢), 140.8 (C-1¢),
78.4 (OCH2), 122.3 (C-1¢¢), 160.7 (C-2¢¢), 114.6 (C-3¢¢) 129.5 (C-4¢¢),
121.4 (C-5¢¢), 128.1 (C-6¢¢), 171.4 (C-2), 169.2 (C-5), 157.3 (NHCON-
HNCH), 154.7 (NHCONHNCH), 130.6 (C-2¢¢¢ & C-6¢¢¢), 115.6 (C-3¢¢¢ &
C-5¢¢¢), 159.7 (C-4¢¢¢), 123.6 (C-1¢¢¢), 12.3 (NHCONHNCCH3); ESMS
(Methanol) m ⁄ z 443 (M+); Anal. Calcd for C24H21N5O4: C, 65.00; H,
4.77; N, 15.79. Found: C, 65.15; H, 4.71; N, 15.84.
1
disubstituted benzene ring); H NMR (300 MHz, DMSO-d6, TMS, d
ppm): 7.0–7.5 (m, 13H, ArH), 5.2 (OCH2), 6.3 (s, 1H, NHCONH), 9.8 (s,
1H, NHCONH), 6.9 (s, 1H, imine H), 2.4 (ArOCH3); 13C-NMR (75 MHz,
DMSO-d6, TMS, d ppm): 127.4 (C-2¢ & C-6¢), 128.7 (C-3¢ & C-5¢), 127.6
(C-4¢), 140.8 (C-1¢), 78.4 (OCH2), 122.2 (C-1¢¢), 160.6 (C-2¢¢), 114.6 (C-
3¢¢) 129.7 (C-4¢¢), 121.5 (C-5¢¢), 128.3 (C-6¢¢), 171.3 (C-2), 169.2 (C-5),
157.3 (NHCONHNCH), 154.9 (NHCONHNCH), 129.9 (C-2¢¢¢ & C-6¢¢¢),
129.5 (C-3¢¢¢ & C-5¢¢¢), 140.2 (C-4¢¢¢), 128.3 (C-1¢¢¢), 21.2 (CH3C6H5);
ESMS (Methanol) m ⁄ z 427 (M+); Anal. Calcd for C24H21N5O3: C, 67.44;
H, 4.95; N, 16.38. Found: C, 67.28; H, 4.85; N, 16.31.
Compound 8
Yield: 64%; MP: 176–177 ꢀC; IR (per cm) (KBr) 3037.5 (Aromatic C-
H str), 1603.6 & 1509.3 (Aromatic C-C str), 1091.8 (C-O of 1,3,4-
oxadiazole nucleus), 1656.4 (C = N of 1,3,4-oxadiazole nucleus),
1679.3 (C = O str of amide), 3422.8 (N-H str of amide), 2906.9 (ali-
phatic C-H str), 1442.4 (aliphatic C-H def), 1614.1 (C = N group),
817.7 (C-H def disubstituted benzene ring), 3460.8 (O-H str of alco-
holic group), 1166.2 (C-O str of alcoholic group), 1262.9 (C-O of
Compound 5
Yield: 58%; MP: 202–204 ꢀC; IR (per cm) (KBr) 3040.5 (Aromatic C-H
str), 1602.6 & 1507.4 (Aromatic C-C str), 1094.2 (C-O of 1,3,4-ox-
adiazole nucleus), 1665.7 (C = N of 1,3,4-oxadiazole nucleus), 1681.2
(C = O str of amide), 3421.5 (N-H str of amide), 1613.7 (C = N
group), 827.5 (C-H def disubstituted benzene ring), 1256.3 (C-O of
1
OCH3 group); H NMR (300 MHz, DMSO-d6, TMS, d ppm): 6.8–7.5
1
OCH3 group); H NMR (300 MHz, DMSO-d6, TMS, d ppm): 6.9–7.5
(m, 13H, ArH), 5.3 (OCH2), 6.3 (s, 1H, NHCONH), 9.8 (s, 1H,
NHCONH), 1.1 (s, 3H, Carbimino CH3), 3.8 (ArOCH3); 13C-NMR
(75 MHz, DMSO-d6, TMS, d ppm): 127.2 (C-2¢ & C-6¢), 128.5 (C-3¢
& C-5¢), 127.6 (C-4¢), 140.8 (C-1¢), 78.2 (OCH2), 122.2 (C-1¢¢), 160.7
(C-2¢¢), 114.7 (C-3¢¢) 129.6 (C-4¢¢), 121.4 (C-5¢¢), 128.3 (C-6¢¢), 171.3
(C-2), 169.1 (C-5), 157.3 (NHCONHNCH), 154.7 (NHCONHNCCH3),
12.3 (NHCONHNCCH3), 129.9 (C-2¢¢¢ & C-6¢¢¢), 114.4 (C-3¢¢¢ & C-5¢¢¢),
164.6 (C-4¢¢¢), 123.3 (C-1¢¢¢), 56.1 (OCH3C6H5); ESMS (Methanol) m ⁄ z
457 (M+); Anal. Calcd for C25H23N5O4: C, 65.63; H, 5.07; N, 15.31.
Found: C, 65.54; H, 5.14; N, 15.37.
(m, 13H, ArH), 5.3 (OCH2), 6.4 (s, 1H, NHCONH), 9.7 (s, 1H, NHCONH),
6.7 (s, 1H, imine H), 3.8 (ArOCH3); 13C-NMR (75 MHz, DMSO-d6,
TMS, d ppm): 127.4 (C-2¢ & C-6¢), 128.8 (C-3¢ & C-5¢), 127.5 (C-4¢),
140.7 (C-1¢), 78.3 (OCH2), 122.3 (C-1¢¢), 160.5 (C-2¢¢), 114.7 (C-3¢¢)
129.6 (C-4¢¢), 121.4 (C-5¢¢), 128.1 (C-6¢¢), 171.4 (C-2), 169.2 (C-5),
157.3 (NHCONHNCH), 154.8 (NHCONHNCH), 130.0 (C-2¢¢¢ & C-6¢¢¢),
114.4 (C-3¢¢¢ & C-5¢¢¢), 164.5 (C-4¢¢¢), 123.5 (C-1¢¢¢), 56.2 (OCH3C6H5);
ESMS (Methanol) m ⁄ z 443 (M+); Anal. Calcd for C24H21N5O4: C,
65.00; H, 4.77; N, 15.79. Found: C, 65.16; H, 4.72; N, 15.88.
Compound 6
Compound 9
Yield: 63%; MP: 219–220 ꢀC; IR (per cm) (KBr) 3043.5 (Aromatic
C-H str), 1604.2 & 1506.2 (Aromatic C-C str), 1092.3 (C-O of 1,3,4-
oxadiazole nucleus), 1653.6 (C = N of 1,3,4-oxadiazole nucleus),
1691.5 (C = O str of amide), 3429.3 (N-H str of amide), 1618.3
(C = N group), 817.8 (C-H def disubstituted benzene ring), 719.8
Yield: 56%; MP: 214–215 ꢀC; IR (per cm) (KBr) 3041.7 (Aromatic C-
H str), 1601.5 & 1503.3 (Aromatic C-C str), 1091.0 (C-O of 1,3,4-
oxadiazole nucleus), 1653.8 (C = N of 1,3,4-oxadiazole nucleus),
1685.3 (C = O str of amide), 3429.3 (N-H str of amide), 2909.5 (ali-
phatic C-H str), 1445.8 (aliphatic C-H def), 1611.6 (C = N group),
Chem Biol Drug Des 2011; 77: 152–158
155

Rajak et al.
821.1 (C-H def disubstituted benzene ring), 3462.5 (O-H str of alco-
holic group), 1162.6 (C-O str of alcoholic group), 1526.9 & 1358.7
(N = O str of Ar-NO2 group); H NMR (300 MHz, DMSO-d6, TMS, d
1H, NHCONH), 5.4 (ArOH); 13C-NMR (75 MHz, DMSO-d6, TMS, d
ppm): 127.3 (C-2¢ & C-6¢), 128.6 (C-3¢ & C-5¢), 127.4 (C-4¢), 140.9 (C-
1¢), 78.2 (OCH2), 122.2 (C-1¢¢), 160.7 (C-2¢¢), 114.7 (C-3¢¢) 129.7 (C-4¢¢),
121.5 (C-5¢¢), 128.3 (C-6¢¢), 171.3 (C-2), 169.4 (C-5), 157.4 (NHCON-
HNCC6H5), 154.9 (NHCONHNCC6H5), 130.3 (C-2¢¢¢ & C-6¢¢¢), 115.7 (C-
3¢¢¢ & C-5¢¢¢), 159.8 (C-4¢¢¢), 123.9 (C-1¢¢¢), 129.1 (C-2¢¢¢¢ & C-6¢¢¢¢),
128.7 (C-3¢¢¢¢ & C-5¢¢¢¢), 130.8 (C-4¢¢¢¢), 131.3 (C-1¢¢¢¢); ESMS (Metha-
nol) m ⁄ z 506 (M+); Anal. Calcd for C29H23N5O4: C, 68.90; H, 4.59; N,
13.85. Found: C, 68.76; H, 4.51; N, 13.80.
1
ppm): 6.8–8.2 (m, 13H, ArH), 5.3 (OCH2), 6.3 (s, 1H, NHCONH), 9.8
(s, 1H, NHCONH), 1.1 (s, 3H, Carbimino CH3); 13C-NMR (75 MHz,
DMSO-d6, TMS, d ppm): 127.4 (C-2¢ & C-6¢), 128.4 (C-3¢ & C-5¢),
127.5 (C-4¢), 140.9 (C-1¢), 78.2 (OCH2), 122.3 (C-1¢¢), 160.6 (C-2¢¢),
114.8 (C-3¢¢) 129.6 (C-4¢¢), 121.5 (C-5¢¢), 128.2 (C-6¢¢), 171.2 (C-2),
169.3 (C-5), 157.3 (NHCONHNCH), 154.8 (NHCONHNCCH3), 12.3
(NHCONHNCCH3), 129.8 (C-2¢¢¢ & C-6¢¢¢), 123.6 (C-3¢¢¢ & C-5¢¢¢),
150.8 (C-4¢¢¢), 137.5 (C-1¢¢¢); ESMS (Methanol) m ⁄ z 472 (M+); Anal.
Calcd for C24H20N6O5: C, 61.01; H, 4.27; N, 17.79. Found: C, 61.21;
H, 4.33; N, 17.68.
Compound 13
Yield: 66%; MP: 226–227 ꢀC; IR (per cm) (KBr) 3042.6 (Aromatic C-H
str), 1603.7 & 1507.9 (Aromatic C-C str), 1091.4 (C-O of 1,3,4-oxadiaz-
ole nucleus), 1657.3 (C = N of 1,3,4-oxadiazole nucleus), 1684.2
(C = O str of amide), 3425.7 (N-H str of amide), 1612.7 (C = N group),
826.2 (C-H def disubstituted benzene ring), 3460.6 (O-H str of alco-
holic group), 1162.8 (C-O str of alcoholic group), 1259.3 (C-O of OCH3
Compound 10
Yield: 58%; MP: 182–184 ꢀC; IR (per cm) (KBr) 3040.8 (Aromatic C-H
str), 1602.9 & 1503.6 (Aromatic C-C str), 1682.3 (C = O str of amide),
3429.7 (N-H str of amide), 2911.8 (aliphatic C-H str), 1444.6 (aliphatic
C-H def), 1621.5 (C = N group), 826.1 (C-H def disubstituted benzene
1
group); H NMR (300 MHz, DMSO-d6, TMS, d ppm): 6.8–8.4 (m, 18H,
ArH), 5.2 (OCH2), 6.3 (s, 1H, NHCONH), 9.7 (s, 1H, NHCONH); 13C-NMR
(75 MHz, DMSO-d6, TMS, d ppm): 127.4 (C-2¢ & C-6¢), 128.6 (C-3¢ &
C-5¢), 127.5 (C-4¢), 140.8 (C-1¢), 78.3 (OCH2), 122.3 (C-1¢¢), 160.7 (C-2¢¢),
114.8 (C-3¢¢) 129.7 (C-4¢¢), 121.4 (C-5¢¢), 128.2 (C-6¢¢), 171.2 (C-2),
169.5 (C-5), 157.3 (NHCONHNCC6H5), 154.7 (NHCONHNCC6H5), 130.0
(C-2¢¢¢ & C-6¢¢¢), 123.8 (C-3¢¢¢ & C-5¢¢¢), 150.8 (C-4¢¢¢), 137.5 (C-1¢¢¢),
129.2 (C-2¢¢¢¢ & C-6¢¢¢¢), 128.7 (C-3¢¢¢¢ & C-5¢¢¢¢), 130.9 (C-4¢¢¢¢), 131.3
(C-1¢¢¢¢); ESMS (Methanol) m ⁄ z 534 (M+); Anal. Calcd for C29H22N6O5:
C, 65.16; H, 4.15; N, 15.72. Found: C, 65.34; H, 4.22; N, 15.63.
1
ring) 719.8 (C-Cl str); H NMR (300 MHz, DMSO-d6, TMS, d ppm):
6.8–7.6 (m, 13H, ArH), 5.3 (OCH2), 6.4 (s, 1H, NHCONH), 9.7 (s, 1H,
NHCONH); 13C-NMR (75 MHz, DMSO-d6, TMS, d ppm): 127.3 (C-2¢ &
C-6¢), 128.7 (C-3¢ & C-5¢), 127.5 (C-4¢), 140.9 (C-1¢), 78.3 (OCH2),
122.3 (C-1¢¢), 160.6 (C-2¢¢), 114.7 (C-3¢¢) 129.5 (C-4¢¢), 121.4 (C-5¢¢),
128.1 (C-6¢¢), 171.2 (C-2), 169.3 (C-5), 157.4 (NHCONHNCH), 154.6
(NHCONHNCCH3), 12.2 (NHCONHNCCH3), 130.6 (C-2¢¢¢ & C-6¢¢¢),
129.2 (C-3¢¢¢ & C-5¢¢¢), 136.3 (C-4¢¢¢), 129.5 (C-1¢¢¢); ESMS (Methanol)
m ⁄ z 462 (M+); Anal. Calcd for C24H20N5O3Cl: C, 62.41; H, 4.36; N,
15.16. Found: C, 62.31; H, 4.43; N, 15.32.
Compound 14
Yield: 57%; MP: 240–242 ꢀC; IR (per cm) (KBr) 3041.8 (Aromatic C-H
str), 1601.7 & 1504.8 (Aromatic C-C str), 1091.5 (C-O of 1,3,4-
oxadiazole nucleus), 1660.2 (C = N of 1,3,4-oxadiazole nucleus),
1681.5 (C = O str of amide), 3421.4 (N-H str of amide), 1613.0 (C = N
group), 821.5 (C-H def disubstituted benzene ring), 3457.7 (O-H str of
alcoholic group), 1161.0 (C-O str of alcoholic group), 1259.6 (C-O of
Compound 11
Yield: 59%; MP: 220–221 ꢀC; IR (per cm) (KBr) 3041.6 (Aromatic C-
H str), 1601.3 & 1502.9 (Aromatic C-C str), 1672.7 (C = O str of
amide), 3431.9 (N-H str of amide), 1629.4 (C = N group), 709.5 &
1
766.7 (C-H def monosubstituted benzene ring); H NMR (300 MHz,
1
DMSO-d6, TMS, d ppm): 6.8–7.8 (m, 19H, ArH), 5.2 (OCH2), 6.3 (s,
1H, NHCONH), 9.7 (s, 1H, NHCONH); 13C-NMR (75 MHz, DMSO-d6,
TMS, d ppm): 127.3 (C-2¢ & C-6¢), 128.4 (C-3¢ & C-5¢), 127.5 (C-4¢),
140.8 (C-1¢), 78.3 (OCH2), 122.3 (C-1¢¢), 160.8 (C-2¢¢), 114.8 (C-3¢¢)
129.6 (C-4¢¢), 121.5 (C-5¢¢), 128.2 (C-6¢¢), 171.2 (C-2), 169.4 (C-5),
157.3 (NHCONHNCC6H5), 154.8 (NHCONHNCC6H5), 129.2 (C-2¢¢¢ &
C-6¢¢¢), 128.5 (C-3¢¢¢ & C-5¢¢¢), 130.7 (C-4¢¢¢), 131.3 (C-1¢¢¢), 129.2 (C-
2¢¢¢¢¢ & C-6¢¢¢¢), 128.5 (C-3¢¢¢¢ & C-5¢¢¢¢), 130.7 (C-4¢¢¢¢), 131.3 (C-
1¢¢¢¢); ESMS (Methanol) m ⁄ z 489 (M+); Anal. Calcd for C29H23N5O3:
C, 71.15; H, 4.74; N, 14.31. Found: C, 71.15; H, 4.79; N, 14.25.
OCH3 group); H NMR (300 MHz, DMSO-d6, TMS, d ppm): 6.9–7.8
(m, 18H, ArH), 5.2 (OCH2), 6.3 (s, 1H, NHCONH), 9.7 (s, 1H, NHCONH),
3.8 (ArOCH3); 13C-NMR (75 MHz, DMSO-d6, TMS, d ppm): 127.4 (C-2¢
& C-6¢), 128.5 (C-3¢ & C-5¢), 127.5 (C-4¢), 140.9 (C-1¢), 78.3 (OCH2),
122.3 (C-1¢¢), 160.8 (C-2¢¢), 114.8 (C-3¢¢) 129.6 (C-4¢¢), 121.4 (C-5¢¢),
128.1 (C-6¢¢), 171.3 (C-2), 169.3 (C-5), 157.4 (NHCONHNCC6H5), 154.7
(NHCONHNCC6H5), 130.2 (C-2¢¢¢ & C-6¢¢¢), 114.4 (C-3¢¢¢ & C-5¢¢¢),
164.5 (C-4¢¢¢), 123.7 (C-1¢¢¢), 129.2 (C-2¢¢¢¢ & C-6¢¢¢¢), 128.8 (C-3¢¢¢¢ &
C-5¢¢¢¢), 130.9 (C-4¢¢¢¢), 131.2 (C-1¢¢¢¢), 56.2 (OCH3C6H5); ESMS (Metha-
nol) m ⁄ z 520 (M+); Anal. Calcd for C30H25N5O4: C, 69.35; H, 4.85; N,
13.48. Found: C, 69.45; H, 4.77; N, 13.42.
Compound 12
The structures of the compounds were confirmed on the basis of
1
Yield: 60%; MP: 212–214 ꢀC; IR (per cm) (KBr) 3047.5 (Aromatic C-H
str), 1601.9 & 1504.4 (Aromatic C-C str), 1088.1 (C-O of 1,3,4-ox-
adiazole nucleus), 1659.0 (C = N of 1,3,4-oxadiazole nucleus), 1686.2
(C = O str of amide), 3426.5 (N-H str of amide), 1613.8 (C = N
group), 821.8 (C-H def disubstituted benzene ring), 3461.8 (O-H str of
alcoholic group), 1165.2 (C-O str of alcoholic group), 1526.3 & 1357.9
elemental analysis, IR, H-NMR, 13C-NMR, and mass spectroscopy.
The anticonvulsant screening (16,17) was performed using male
albino mice (swiss, 18–25 g) and rats (wistar 100–150 g). The anti-
convulsant activity of the test compounds was evaluated by two
models, namely maximal electroshock seizure (MES) and subcutane-
ous pentylenetetrazole (scPTZ) models. The MES test identifies
those compounds that stop seizure spread, and it is used to
1
(N = O str of Ar-NO2 group); H NMR (300 MHz, DMSO-d6, TMS, d
ppm): 6.8–7.6 (m, 18H, ArH), 5.2 (OCH2), 6.3 (s, 1H, NHCONH), 9.7 (s,
156
Chem Biol Drug Des 2011; 77: 152–158

Anticonvulsant Activity of 1,3,4-oxadiazoles
evaluate drug effectiveness in tonic-clonic (grand mal) type of epi-
lepsy. The scPTZ seizure test primarily detects compounds that ele-
vate seizure threshold. The scPTZ-induced convulsion is not typical
of absence epilepsy but clonic in nature. Phenytoin, carbamazepine
and sodium valproate were used as the standard drugs for the com-
parison. Acute neurological toxicity was determined in the rotorod
test (18). Procedures employed for the evaluation of anticonvulsant
activity and neurotoxicity were reviewed and approved by the Uni-
versity Animal Ethical Committee.
Table 1: Anticonvulsant activity and minimal motor impairment
of 2,5-disubstituted 1,3,4-thiadiazoles
Intraperitoneal injection in micea
sc PTZ
MES screening
screening
NT screening
Compound
0.5 h
4.0 h
0.5 h
4.0 h
0.5 h
4.0 h
1
–
–
–
–
300
300
–
–
–
–
–
–
–
300
–
–
–
300
300
–
2
3
4
–
–
–
–
Maximal electroshock seizure (MES test)
5
–
–
–
–
–
–
The maximal seizure usually consists of a short period of tonic
extension of the hind limbs and a final clonic episode. The MESs
were elicited with a 60-cycle altering current of 50 mA intensity
delivered for 0.25 seconds via ear clip electrodes. After 30 min and
4 h of drug administration, electroshock was applied via corneal
electrodes. The vanishing of the hind limb tonic extensor component
of convulsion was considered as positive criteria.
6
–
100
–
–
–
–
300
–
–
–
–
–
–
–
–
–
–
–
300
300
–
300
–
–
–
300
–
300
–
100
–
–
300
–
–
7
300
300
300
–
300
300
300
300
30
300
100
–
–
–
–
300
–
100
300
–
8
9
10
11
12
–
100
100
–
30
30
300
13
14
–
300
100
100
–
Phenytoin
Carbamazepine
Na valproate
–
100
300
Subcutaneous pentylenetetrazole (scPTZ)
seizure threshold test
100
–
It was performed by administering PTZ dissolved in 0.9% sodium
chloride solution in the posterior midline of the animals. A minimal
time of 30 min subsequent to administration of PTZ was employed
for seizure detection. Protection was indicated as there was a fail-
ure to notice any episode of clonic convulsions of at least 5 sec-
onds duration during this time period.
a30, 100, and 300 mg ⁄ kg of doses were administered i.p. in mice. The data
of the table indicate the minimal dose whereby biological activity was dem-
onstrated in half or more of the mice. The activity was measured after 0.5
and 4.0 h of dose administration of test compounds. The sign – (dash) rep-
resents an absence of activity at maximum dose administered (300 mg ⁄ kg).
MES, maximal electroshock seizure; NT, Neurotoxicity.
Neurotoxicity screening
Table 2: Anticonvulsant evaluation of compounds after oral
administration in rats
Minimal motor impairment (neurotoxicity) was evaluated in mice by
the rotorod test. The mice were trained to stopover an accelerating
rotorod of diameter 3.2 cm that rotates at six revolutions per min.
Only those animals that had proven their competence to remain on
the revolving rod for at least 1 min were considered for the test.
Previously trained mice were given test compounds i.p. in doses of
30, 100, and 300 mg ⁄ kg. The mice were placed on the rotating rod
30 min after i.p. administration. Neurotoxicity was indicated by the
failure of the animals to maintain equilibrium on the rod for at
least 1 min in each of the three trials.
Oral administration in ratsa
MES screening
NT screening
Compound 0.25 h 0.5 h 1 h 2 h 4 h 0.25 h 0.5 h 1 h 2 h 4 h
7
9
0
0
0
0
1
0
0
0
0
0
0
1
0
1
1
0
1
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
1
0
1
0
0
12
13
aThe compounds were administered in a dose of 30 mg ⁄ kg. The data in
table indicate the number of rats out of four, which were protected.
MES, maximal electroshock seizure; NT, Neurotoxicity.
Result and Discussion
All the compounds were screened for their anticonvulsant potential
through MES and scPTZ models in doses of 30, 100, and
300 mg ⁄ kg by intraperitoneal (i.p.) injection. The data indicate that
64% of the compounds were active in the MES screening when
compared to 28% in the scPTZ test. Thus, the compounds exhibited
some MES selectivity. The majority of the compounds showed activ-
ity after 4 h, indicating that the synthesized compounds were slow-
acting anticonvulsants (Tables 1 and 2).
overview of synthesized compounds, it has been found that com-
pounds bearing the groups like hydroxy or nitro on distant phenyl
ring present on right-hand side of molecules possess high potency
in MES and scPTZ tests. Conversely, replacement of these groups
with methoxy and chloro groups on the distant phenyl ring has
resulted in compounds with decrease in anticonvulsant activity. On
comparison of results, it has been found that antiepileptic activity
of test compounds changes on varying p-substituted group on aryl
moiety as follows: hydroxy > nitro > chloro > methoxy group.
Replacement of the proton on the carbimino carbon atom by methyl
group i.e., 7–10 or phenyl ring i.e., 11–14 has demonstrated vari-
ation in activity because of increase in the dimension of the group
A variety of title compounds were synthesized using various substi-
tutions i.e., hydroxy, nitro, methoxy, and chloro groups around the
phenyl ring on the right-hand side of the molecules. On critical
Chem Biol Drug Des 2011; 77: 152–158
157

Rajak et al.
at this position of the molecule. The increase in the anticonvulsant
activity with phenyl substitution i.e., compounds 11–14 might be
because of additional van der Waals-London forces bonding to the
binding site. Compounds with phenyl ring were found to possess
considerably more activity in comparison with methyl group.
activity against three animal models of seizures: synthesis and
pharmacological evaluation. Bioorg Med Chem Lett;14:3106–3112.
4. Dimmock J.R., Puthucode R.N., Smith J.M., Hetherington M.,
Quail J.W., Pugazhenthi U., Lechler T. (1996) (Aryloxy)aryl semic-
arbazones and related compounds: a novel class of anticonvul-
sant agents possessing high activity in the maximal electroshock
screen. J Med Chem;39:3984–3997.
5. Siddiqui N., Rana A., Khan S.A., Bhat M.A., Haque S.E. (2007)
Synthesis of benzothiazole semicarbazones as novel anticonvul-
sants-the role of hydrophobic domain. Bioorg Med Chem
Lett;17:4178–4182.
6. Omar A.M.M.E., Aboulwafa O.M. (1984) Synthesis and anticon-
vulsant properties of a novel series of 2-substituted amino-
5-aryl-1,3,4-oxadiazole derivatives. J Heterocycl Chem;21:1415–
1418.
7. Zarghi A., Faizi M., Shafaghi B., Ahadian A., Khojastehpoor H.R.,
Zangaheh V., Tabatabai S.A., Shafiee A. (2005) Design
and synthesis of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-
oxadiazoles as benzodiazepine receptor agonists. Bioorg Med
Chem Lett;15:3126–3129.
In the present study, we have designed and synthesized the title
compounds keeping in mind that a number of clinically active anti-
convulsants possess a nitrogen hetero atomic system with one or
two phenyl rings and at least one carbonyl group in their structure.
The structure of the title compounds fulfilled all the pharmacophore
structural requirements i.e., presence of 5-[2-(benzyloxy)phenyl]-
1,3,4-oxadiazol-2-yl moiety as hydrophobic portion, N as electron
donor system, and another hydrophobic distal aryl ring responsible
for metabolism. In the present study, N1-{5-[(2-benzyloxy)phenyl]-
1,3,4-oxadiazol-2-yl}-N4-[1-(4-hydroxyphenyl) (phenyl) methanone]-
semicarbazone 12 came out as the most active compound, showing
considerable activity in MES (at 100 mg ⁄ kg after 0.5 h and at
300 mg ⁄ kg after 4.0 h) and subcutaneous pentylenetetrazole model
(at 300 mg ⁄ kg after 4.0 h) without any neurotoxicity (up to
300 mg ⁄ kg after 4.0 h). The results obtained showed that the
majority of the compounds exhibited anticonvulsant activity. Thus,
the results confirmed that four pharmacophore elements in semicar-
bazones are vital for their anticonvulsant activity.
8. Almasirad A., Tabatabai S.A., Faizi M., Kebriaeizadeh A., Mehra-
bai N., Dalvandi A., Shafiee A. (2004) Synthesis and anticonvul-
sant activity of new 2-substituted-5-[2-(2-fluorophenoxy)phenyl]-
1,3,4-oxadiazoles and 1,2,4-triazoles. Bioorg Med Chem
Lett;14:6057–6059.
9. Pandeya S.N., Ponnilavarasan I., Pandey A., Lakhan R., Stables
J.P. (1999) Evaluation of p-nitrophenyl substituted semicarbaz-
ones for anticonvulsant properties. Pharmazie;54:923–925.
10. Wong M.G., Dejina J.A., Andrews P.R. (1986) Conformational
Conclusion
A series of novel substituted semicarbazones containing 1,3,4-
oxadiazole nucleus were synthesized to meet structural require-
ments essential for anticonvulsant activity. The structure–activity
relationship studies indicate that anticonvulsant activity changes on
varying p-substituted group on aryl moiety in the following manner:
hydroxy > nitro > chloro > methoxy group. While anticonvulsant
activity changes on varying the substitution attached to carbimino
carbon atom as follows: C6H5 > CH3 > H. Our results supported that
the pharmacophore model with four structural features is vital for
anticonvulsant activity. These new data might be expedient in the
future development of semicarbazones as novel anticonvulsants.
analysis of clinically active anticonvulsant drugs.
Chem;29:562–571.
J Med
11. Aggarwal N., Mishra P. (2004) Synthesis of 4-aryl substituted
semicarbazones of some terpenes as novel anticonvulsants. J
Pharm Pharmaceut Sci;7:260–264.
12. Bown D.H., Bradshaw J.S. (1980) Photoalkylation of s-triazol-
o[4,3-b]pyridazine with alcohols and glycols. J Org Chem;45:
2320–2324.
13. Firoozi F., Javidnia K., Kamal M., Fooladi A., Foroumadi A., Sha-
fiee A. (1995) Syntheses of substituted 1-methyl-2-(1,3,4-thia-
diazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-
4-nitropyrroles. J Heterocycl Chem;32:123–128.
14. Goswami B.H., Sarmah Kataky J.C., Baruah J.N. (1984) Synthesis
and antibacterial activity of 1-(2,4-dichlorobenzoyl)-4-substituted
thiosemicarbazides, 1,2,4-triazoles and their methyl derivatives. J
Heterocycl Chem;21:1225–1229.
15. Zarghi A., Tabatabai S.A., Faizi M., Ahadian A., Navabi P.,
Zanganeh V., Shafiee A. (2005) Synthesis and anticonvulsant
activity of new 2-substituted-5-(2-benzyloxyphenyl)-1,3,4-oxadiz-
oles. Bioorg Med Chem Lett;15:1863–1865.
Acknowledgement
The help rendered by SAIF, CDRI, Lucknow, for elemental and spec-
tral analysis is gratefully acknowledged.
References
16. Krall R.L., Penry J.K., White B.G., Kupferberg H.J., Swinyard E.A.
(1978) Anticonvulsant drug development: anticonvulsant drug
screening. Epilepsia;19:409–428.
17. Porter R.J., Hessie B.J., Cereghino J.J., Gladding G.D., Kupfer-
berg H.J., Scoville B., White B.G. (1985) Advances in the clinical
development of antiepileptic drugs. Fed Proc;44:2645–2649.
18. Vogel H.G. (2002) Drug Discovery and Evaluation – Pharmacologi-
cal Assays. Germany: Springer, Heidelberg, Germany.
1. Fisher R., Boas W.V.E., Blume W., Elger C., Genton P., Lee P.,
Engel J. (2005) Epileptic seizures and epilepsy: definitions pro-
posed by the International League Against Epilepsy (ILAE) and
the International Bureau for Epilepsy (IBE). Epilepsia;46:470–472.
2. Brown T.R., Holmes G.L. (2001) Primary care: epilepsy. N Engl J
Med;344:1145–1151.
3. Thirumurugan R., Sriram D., Saxena A., Stables J.P., Yogeeswari P.
(2006) 2,4-Dimethoxyphenylsemicarbazones with anticonvulsant
158
Chem Biol Drug Des 2011; 77: 152–158