Synthesis of novel 2,5-disubstituted 1,3,4-thiadiazoles for their potential anticonvulsant activity: Pharmacophoric model studies

Article abstract of DOI:10.1002/ardp.200800213

A series of novel N¹-[5-(4-substituted phenyl)-1,3,4-thiadiazol- 2-yl]-N⁴-(4-substituted benzaldehyde)-semicarbazone 1-12, N ¹-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N ⁴-[1-(4-substituted phenyl)-ethanone]-semicarbazone 13-16, and N1-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N4-[1-(4-substituted phenyl) (phenyl) methanone]-semicarbazone 17-20 were synthesized for their anticonvulsant activity. The chemical structures of the compounds were proved by elemental and spectral (IR, ¹H-NMR, ¹³C-NMR, and MS) analysis. The anticonvulsant potential of the compounds was investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models. Compound 19 was found to possess significant anticonvulsant activity in both the models employed for anticonvulsant evaluation. Compounds 8, 13, 15, and 16 also demonstrated a marked anticonvulsant property. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity. The efforts were also made to establish structure-activity relationships among the synthesized compounds.

Full text of DOI:10.1002/ardp.200800213

Arch. Pharm. Chem. Life Sci. 2009, 342, 453–461
H. Rajak et al.
453
Full Paper
Synthesis of Novel 2,5-Disubstituted 1,3,4-Thiadiazoles for
Their Potential Anticonvulsant Activity: Pharmacophoric
Model Studies
Harish Rajak1, Ravitas Deshmukh1, Navneet Aggarwal2, Sushil Kashaw3, Murli Dhar Kharya3,
and Pradeep Mishra4
1 Medicinal Chemistry Division, SLT Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur,
(CG), India
2 Lachoo Memorial College of Science & Technology, Pharmacy Wing, Jodhpur, (Raj), India
3 Natural Product Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour University,
Sagar (MP), India
4 GLA Institute of Pharmaceutical Research, Mathura (UP), India
A series of novel N1-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N4-(4-substituted benzaldehyde)-
semicarbazone 1–12, N1-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N4-[1-(4-substituted phenyl)-
ethanone]-semicarbazone 13-16, and N1-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N4-[1-(4-sub-
stituted phenyl) (phenyl) methanone]-semicarbazone 17–20 were synthesized for their anticon-
vulsant activity. The chemical structures of the compounds were proved by elemental and spec-
tral (IR, 1H-NMR, 13C-NMR, and MS) analysis. The anticonvulsant potential of the compounds was
investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole
(scPTZ) models. Compound 19 was found to possess significant anticonvulsant activity in both
the models employed for anticonvulsant evaluation. Compounds 8, 13, 15, and 16 also demon-
strated a marked anticonvulsant property. The results of the present study validated that the
pharmacophore model with four binding sites is essential for anticonvulsant activity. The efforts
were also made to establish structure-activity relationships among the synthesized compounds.
Keywords: Anticonvulsant activity / Semicarbazones / 1,3,4-Thiadiazoles /
Received: November 23, 2008; accepted: March 16, 2009
DOI 10.1002/ardp.200800213
treatment of epilepsy remains still inadequate. About
one third of patients do not respond well to the existing
anticonvulsant drugs and others do so only at the
expense of significant dose-related toxicity and peculiar
adverse effects that range in harshness from minimal
brain impairment to death from aplastic anaemia or hep-
atic failure [3]. Thus, there is an enormous need for the
development of novel anticonvulsant drugs with lower
toxicities and fewer side effects.
In the recent years, aryl semicarbazones have emerged
as structurally novel class of compounds with anticonvul-
sant activity [4–8]. They have been found to act by block-
ing the voltage-gated sodium ion channels [5, 7, 9].
On going through the structures of clinically estab-
lished drugs, it can be determined that the anticonvul-
sant properties have been shown by a diversity of hydra-
Introduction
Epilepsy is one of the most frequent neurological disor-
ders involving episodes of irregular electrical discharge
in the brain; it is also characterized by the periodic sud-
den loss or impairment of consciousness, often followed
by convulsions. Approximately 50 million people world-
wide suffer from epilepsy, making this condition the sec-
ond leading neurological disorder [1]. Epilepsy affects
about 4% of the individuals over their lifetime [2]. Despite
the development of several new anticonvulsants, the
Correspondence: Harish Rajak, Medicinal Chemistry Division, Institute
of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur -495
009 (CG) India.
E-mail: harishdops@yahoo.co.in
Fax: +91 758 226-0148
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454
H. Rajak et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 453–461
Figure 1. Pharmacophoric structural features in the title com-
pounds: (A) hydrophobic aryl ring system, (HBD) hydrogen-bind-
ing domain, (D) electron-donor moiety, (C) distal aryl ring.
zones (=N-NH-), amides (-CONH2), and carbamides (-NHCO-
NH-). Thus the key prerequisite was to look for a molecule
that might combine all the above structures in one; the
semicarbazido (-NH-NH-CO-NH2) group is well intentional
one of them [6, 10].
The conformational exploration of the clinically active
anticonvulsant drugs such as Phenytoin, Carbamaze-
pine, Lamotrigine, Rufinamide, and Phenobarbitone has
resulted in the proposal of a general model for anticon-
vulsant activity [11, 12]. This pharmacophore model
based on the semicarbazones comprises of following four
essential binding sites: (i) An aryl hydrophobic binding
site (A) with halo substituent preferably at the para posi-
tion; (ii) a hydrogen-bonding domain (HBD); (iii) an elec-
tron-donor group (D); and (iv) another hydrophobic-
hydrophilic site controlling the pharmacokinetic proper-
ties of the anticonvulsant (C).
The pharmacophoric elements playing a vital role at
the binding site are a lipophilic aryl ring and a hydrogen-
binding semicarbazone moiety [7, 13]. The presence of a
second aryl ring (distal aryl ring) increases the anticon-
vulsant potential by attachment to the binding site using
van der Waal's forces. Substitutions in the aryl ring by
halogens have been found to enhance the potency in the
MES screen [6, 14] (Fig. 1). In earlier studies on the phar-
macophoric model, our research group confirmed that
the presence of an aryl group (preferably halogen-substi-
tuted) near the semicarbazone moiety is one of the essen-
tial parameter for anticonvulsant activity [15].
On the other hand, numerous studies have been per-
formed with the aim of exploring anticonvulsant proper-
ties of 1,3,4-thiadiazole analogues. Those studies found
that 1,3,4-thiadiazole analogues possess comparable anti-
convulsant activity in comparison to the respective
standard drugs employed. [16–19].
Reaction conditions: a) H2NNHCSNH2 6 HCl, CH3COONa; b) FeCl3; c) NaCNO,
CH3COOH; d) NH2NH2 6 H2O, EtOH, NaOH; e) Aldehydes or ketones, CH3COONa,
EtOH.
Scheme 1. Synthesis of 2,5-disubstituted-1,3,4-thiadiazole
derivatives.
stituted benzaldehyde)-semicarbazone 1-12, N1-[5-(4-sub-
stituted phenyl)-1,3,4-thiadiazol-2-yl]-N4-[1-(4-substituted
phenyl)ethanone]-semicarbazone 13-16, and N1-[5-(4-sub-
stituted phenyl)-1,3,4-thiadiazol-2-yl]-N4-[1-(4-substituted
phenyl) (phenyl) methanone]-semicarbazone 17-20. The
present work is the only one of its kind reporting anti-
convulsant activity in structures containing semicarba-
zone moiety and 1,3,4-thiadiazole nucleus together.
The search for better anticonvulsant drug and the
importance of semicarbazones and 2,5-disubstituted
1,3,4-thiadiazoles as anticonvulsant pharmacophore
encouraged us to carry out the synthesis of some novel
N1-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N4-(4-sub-
Result and discussion
Chemistry
The title compounds were prepared using the synthetic
strategy described in Scheme 1. The first step of the syn-
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Arch. Pharm. Chem. Life Sci. 2009, 342, 453–461
Anticonvulsant Activity of Novel 1,3,4-Thiadiazoles
455
Table 1. Physical data of the synthesized thiadiazoles.
Compound
R
R9
R99
Mol. formula (Mol. Wt.)
M.P. (8C)
Yield (%)
C, H, N analysis (%) found
(calculated)
1
2
Cl
H
H
C16H12N5OSCl (357.81)
C16H11N6O3SCl (402.81)
C16H12N5O2SCl (373.81)
C17H14N5OSCl (371.84)
C17H14N5O2SCl (387.84)
C16H11N5OSCl2 (392.26)
C16H13N5O2S (339.37)
C16H12N6O4S (384.36)
C16H13N5O3S (355.37)
C17H15N5O2S (353.39)
C17H15N5O3S (369.39)
C16H12N5O2SCl (373.81)
C17H15N5O3S (369.39)
C18H17N5O3S (383.42)
C17H14N6O4S (398.39)
C17H14N5O2SCl (387.84)
C22H17N5O2S (415.46)
C22H17N5O3S (431.46)
C22H16N6O4S (460.46)
C23H19N5O3S (445.49)
226
179
194
218
238
214
205
173
219
188
241
227
186
254
169
182
158
195
168
237
65
68
59
62
55
65
64
66
60
62
56
64
61
65
64
57
63
58
61
64
53.62 (53.71), 3.33 (3.38),
19.61 (19.57)
47.61 (47.71), 2.79 (2.75),
20.74 (20.86)
51.53 (51.41), 3.37 (3.24),
19.65 (18.73)
54.89 (54.91), 3.84 (3.79),
18.91 (18.83)
52.73 (52.65), 3.51 (3.64),
17.95 (18.06)
48.87 (48.99), 3.89 (2.83),
17.74 (17.85)
59.75 (56.63), 3.92 (3.86),
20.70 (20.64)
50.14 (50.01), 3.21 (3.15),
21.97 (21.86)
54.16 (54.08), 3.72 (3.69),
19.77 (19.71)
57.65 (57.78), 4.36 (4.28),
19.89 (19.82)
55.38 (55.27), 4.13 (4.09),
19.05 (18.96)
51.49 (51.41), 3.31 (3.24),
18.66 (18.73)
55.35 (55.27), 4.11 (4.09),
18.86 (18.96)
56.47 (56.38), 4.58 (4.47),
18.35 (18.27)
51.32 (51.25), 3.62 (3.54),
21.18 (21.09)
54.76 (52.65), 3.85 (3.64),
18.73 (18.06)
Cl
H
4-NO2
4-OH
4-CH3
4-OCH3
4-Cl
3
Cl
H
4
Cl
H
5
Cl
H
6
Cl
H
7
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
H
8
H
4-NO2
4-OH
4-CH3
4-OCH3
4-Cl
9
H
10
11
12
13
14
15
16
17
18
19
20
H
H
H
CH3
CH3
CH3
CH3
C6H5
C6H5
C6H5
C6H5
OH
4-OCH3
4-NO2
4-Cl
H
63.69 (63.60), 4.03 (4.12),
16.75 (16.86)
61.33 (61.24), 4.03 (3.97),
16.36 (16.23)
57.47 (57.38), 3.53 (3.50),
18.17 (18.25)
62.16 (62.01), 4.38 (4.30),
15.66 (15.72)
4-OH
4-NO2
4-OCH3
thetic strategy involves preparation of 4-substituted ben- carboxamide Va–b was prepared by reaction of 1-[5-(4-
zaldehyde thiosemicarbazones IIa–b by reaction of thio- substituted phenyl)-1,3,4-thiadiazol-2-yl]-urea IVa–b with
semicarbazide hydrochloride with different aromatic hydrazine hydrate in the presence of sodium hydroxide.
aldehydes Ia–b. 4-Substituted benzaldehyde thiosemi- The title compounds 1–20 were prepared by reaction of
carbazones IIa–b were cyclized to 2-amino-5-aryl-1,3,4- the appropriate aldehyde or ketone with 1-[5-(4-substi-
thiadiazoles IIIa–b by ferric chloride. 2-Amino-5-aryl- tuted phenyl)-1,3,4-thiadiazol-2-yl]-hydrazine carboxa-
1,3,4-thiadiazoles IIIa–b were treated with sodium cyan- mide Va–b.
ate in the presence of glacial acetic acid, to yield 1-[5-(4-
substituted phenyl)-1,3,4-thiadiazol-2-yl]-urea IVa–b. 1-[5- and elemental analysis (percentage C, H, and N analysis)
(4-Substituted phenyl)-1,3,4-thiadiazol-2-yl]-hydrazine found are presented in Table 1. The structures of the title
The yield of the final compounds, their melting points,
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456
H. Rajak et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 453–461
Table 2. Anticonvulsant activity and minimal motor impairment
of 2,5-disubstituted 1,3,4-thiadiazoles.
dence for the presence of aromatic C–H bonds. The pres-
ence of aromatic C–C bonds was confirmed by the pres-
ence of an absorption band around 1605 and 1503 cm– 1
.
Compound
Intraperitoneal injection in micea)
MES Screening scPTZ Screening NT Screening
The IR data also confirm the presence of specific func-
tional groups present in the final synthesized com-
pounds. In13C-NMR spectra, C-2 and C-5 of the thiadiazole
nucleus were seen around 164 and 157 ppm, respec-
tively. The chemical shift of all other carbons of the final
compounds was seen as expected. The 1H-NMR and mass
spectra of title compounds were in conformity with the
assigned structure. The mass spectra of these compounds
showed molecular ion peaks corresponding to their
molecular formula.
0.5 h
4.0 h
0.5 h
4.0 h
0.5 h
4.0 h
1
2
3
–
100
–
300
300
–
–
–
–
–
–
–
–
–
–
300
300
–
4
5
6
7
–
–
100
–
300
–
300
–
–
300
–
–
–
–
–
–
300
100
–
100
300
–
–
–
8
9
10
11
12
13
14
15
16
17
18
19
100
–
–
–
–
300
–
100
300
-
100
100
–
300
300
–
300
–
300
300
–
–
300
–
–
–
300
–
–
–
–
–
100
–
300
300
–
–
–
–
–
–
–
–
100
100
–
–
300
300
–
300
–
100
–
–
Anticonvulsant activity
All the compounds were screened for their anticonvul-
sant potential through maximal electroshock seizure
(MES) and subcutaneous pentylenetrtrazole (scPTZ) mod-
els in doses of 30, 100, 300 mg/kg by intraperitoneal (i.p.)
injection. The data indicate that 75% of the compounds
were active in the MES screening as compared to 40% 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
are slow acting anticonvulsants. Compounds 8, 13, 15,
and 16 did not show neurotoxicity at the highest admin-
istered dose and exhibited significant anticonvulsant
properties. The most active compound 19 demonstrated
anticonvulsant activity comparable to carbamzepine and
was also devoid of neurotoxicity. Compound 3 and 7
were found inactive although devoid of neurotoxicity
(Tables 2 and 3).
–
–
–
300
100
–
–
–
100
–
–
100
300
300
300
300
–
300
–
–
300
–
–
300
300
100
300
30
100
100
–
20
–
Phenytoin
Carbamazepine 30
Na valproate
30
100
300
–
100
–
300
a)
30, 100, and 300 mg/kg of doses were administered i.p. in
mice. The data in the table indicates the minimal dose
whereby biological activity was demonstrated in half or
more of the mice. The activity was measured after 0.5 and
4.0 h of dose administration of the test compounds. The sign
– (dash) represents the absence of activity at the maximum
dose administered (300 mg/kg).
compounds were elucidated on the basis of elemental
analysis, IR,1H-NMR, 13C-NMR, and mass spectral data.
IR data of synthesized thiadiazole analogues clearly
show a C=N stretching band around 164 cm– 1 and C–S
absorption band around 740 cm– 1 which indicates ring
closure of 1,3,4-thiadiazole ring. All the final compounds
have a strong absorption around 3045 cm– 1 which is evi-
In general, compounds bearing groups like nitro or
hydroxy on a distant phenyl ring showed high potency in
MES and scPTZ tests. Whereas replacement of these
groups with methoxy and chloro groups on the distant
phenyl ring has resulted in compounds with decrease in
anticonvulsant activity.
Table 3. Anticonvulsant evaluation of compounds after oral administration in rats.
Compound
Oral administration in ratsa)
MES Screening
NT Screening
0.25 h
0.5 h
1 h
2 h
4 h
0.25 h
0.5 h
1 h
2 h
4 h
8
13
15
16
19
0
0
1
0
0
0
0
1
0
0
1
0
0
0
0
0
2
0
1
1
1
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
1
0
0
1
0
a)
The compounds were administered in a dose of 30 mg/kg. The data in the table indicate the number of rats out of four, which
were protected.
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Arch. Pharm. Chem. Life Sci. 2009, 342, 453–461
Anticonvulsant Activity of Novel 1,3,4-Thiadiazoles
457
Replacement of the proton on the carbimino carbon One of author, Ravitas Deshmukh is thankful to AICTE New
atom by methyl group i. e., 13 to 16 or phenyl ring i. e., 17 Delhi, India for awarding a Junior Research Fellowship and
to 20 has demonstrated variation in activity due to financial assistance. The help rendered by SAIF, CDRI Lucknow
increase in the dimension of the group at this position of for spectral and elemental analysis is gratefully acknowledged.
the molecule. Compounds with a phenyl ring were found We extend sincere thanks to Dr. Chhabra, Dean, Chhattisgarh
to possess considerable activity in comparison to methyl Institute of Medical Sciences (CIMS), Bilaspur for helpful con-
group. The increase in the anticonvulsant activity with a versations regarding in-vivo studies.
phenyl substitution might be due to additional van-der-
Waals bonding to the binding site.
The authors have declared no conflict of interest.
In the present studies, we have designed and synthe-
sized the title compounds with keeping two major facts
in mind. Firstly, a number of clinically active anticonvul-
sants possess a nitrogen hetero atomic system with one
or two phenyl rings and at least one carbonyl group in
their structure. Secondly, several investigations con-
cluded that at least one aryl group, one or two-electron
donor atom, and / or an NH group in a special spatial
arrangement appears to be vital for anticonvulsant activ-
ity [20]. Our earlier work confirmed the requirements of
these structural features i. e., substituted semicarbazones
of lipophilic carbonyl molecules yielded compounds
with excellent anticonvulsant activity [21].
The structure of the title compounds fulfilled all the
pharmacophoric structural requirements, i.e., the pres-
ence of a [5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]
moiety as hydrophobic portion, N as an electron-donor
system, and another hydrophobic distal aryl ring respon-
sible for metabolism. Compounds in which semicarba-
zones attached to 1,3,4-thiadiazole ring were designed
and synthesized to meet structural requirements essen-
tial for anticonvulsant activity. The results obtained
showed that the majority of the compounds exhibited
anticonvulsant activity. Thus, the results validated the
four binding site hypothesis for semicarbazones. In the
present study, 4-nitrophenyl-substituted semicarbazone
came out as the most active compound, showing a broad
spectrum of activity without any neurotoxicity. The
results confirmed that the pharmacophoric model ele-
ments are necessary for the anticonvulsant activity,
which may account for bioactivity of majority of com-
pounds.
Experimental
Chemistry
All the chemicals and solvents used in this study were purchased
from E-Merck (Darmstadt, Germany), Aldrich (Steinheim, Ger-
many), and Himedia (Mumbai, India). Melting points were deter-
mined by open capillary method and are uncorrected. Elemental
analysis was done using an elemental analyzer Heraeus Carlo
Erba-1108, IR spectra were recorded on a Perkin Elmer IR spec-
trophotometer (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).
General procedure for synthesis of 4-substituted
benzaldehyde thiosemicarbazones IIa–b
Required thiosemicarbazones were synthesized according to the
reported method [19].
Compound IIa; Yield: 83%; m.p.: 207–2088C.
Compound IIb; Yield: 76%; m.p.: 230–2318C.
General procedure for synthesis of 2-amino-5-aryl-1,3,4-
thiadiazoles IIIa–b
Required 2-amino-5-aryl-1,3,4-thiadiazole were synthesized
according to the reported method [19].
Compound IIIa; Yield: 75%; m.p.: 226–2278C.
Copmpound IIIb; Yield: 72%; m.p.: 248–2498C.
General procedure for synthesis of 1-[5-(4-substituted
phenyl)-1,3,4-thiadiazol-2-yl]-urea IVa–b
The appropriate 2-amino-5-aryl-1,3,4-thiadiazoles III (0.01 mol)
was dissolved in 10-30 mL of glacial acetic acid diluted to 50 mL
with distilled water. In some cases the mixture was warmed to
dissolve III. To this an 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 several hours fol-
lowed while cooling on an ice bath. The precipitates obtained
were collected by filtration, washed with cold water, and were
recrystallized from 90% aqueous ethanol.
In conclusion, the present studies indicate that some
of the compounds possess marked anticonvulsant activ-
ity as shown by MES and scPTZ models in comparison
with the standard drug. In the neutotoxicity studies
some of the active compounds were devoid of toxicity.
Our results validated that the pharmacophore model
with four binding sites is essential for anticonvulsant
activity. These new data might be beneficial in the future
for the development of semicarbazones as novel anticon-
vulsants.
Compound IVa
Yield: 67%; m.p.: 158–1598C; IR (cm– 1) (KBr): 3080.4 (aromatic C-
H), 735.1 (C-S of thiadiazole nucleus), 1642.8 (C=N of thiadiazole),
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Arch. Pharm. Chem. Life Sci. 2009, 342, 453–461
3424.0 (secondary NH), 3322.6 (amide NH), 1683.8 (C=O str of
amide), 718.6 (C-Cl str), 832.7 (C-H def disubstituted benzene).
Compound 1
IR (cm– 1) (KBr): 3038.5 (aromatic C-H str), 1603.7 & 1506.1 (aro-
matic C-C str), 746.1 (C-S of 1,3,4-thiadiazole nucleus), 1640.7
(C=N of 1,3,4-thiadiazole nucleus), 1688.5 (C=O str of amide),
3434.6 (N-H str of amide), 1617.4 (C=N group), 822.8 (C-H def dis-
ubstituted benzene ring), 721.4 (C-Cl str); 1H-NMR d (ppm)
(DMSO-d6, TMS): 7.3–7.6 (m, 9H, ArH), 9.3 (s, 1H, NHCONH), 9.6 (s,
1H, NHCONH), 6.9 (s, 1H, imine H); 13C-NMR d (ppm) (DMSO-d6,
TMS): 128.4 (C-29 & C-69), 129.4 (C-39 & C-59), 133.9 (C-49), 134.7 (C-
19), 164.4 (C-2), 156.7 (C-5), 157.3 (NHCONHNCH), 154.8
(NHCONHNCH), 129.1 (C-299 & C-699), 128.5 (C-399 & C-599), 130.9 (C-
499), 131.3 (C-199); ESMS (methanol) m/z: 358 [M+].
Compond IVb
Yield: 63%; m.p.: 176–1778C; IR (cm– 1) (KBr): 3081.6 (aromatic C-
H), 743.7 (C-S of thiadiazole nucleus), 1644.8 (C=N of thiadiazole),
3422.7 (secondary NH), 3322.5 (amide NH) and 1682.9 (C=O str of
amide), 826.2 (C-H def disubstituted benzene), 3458.1 (O-H str of
alcoholic group), 1162.5 (C-O str of alcoholic group).
General procedure for synthesis of 1-[5-(4-substituted
phenyl)-1,3,4-thiadiazol-2-yl]-hydrazine carboxamide
Va–b
Required quantity of 1-[5-(4-substituted phenyl)-1,3,4-thiadiazol-
2-yl]-urea IV (0.01 mol) was dissolved in 30–40 mL of ethanol. To
this was added an equimolar solution of hydrazine hydrate in
5 mL of water. The reaction mixture was made alkaline by add-
ing 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 [22].
Compound 2
IR (cm– 1) (KBr): 3043.9 (aromatic C-H str), 1602.5 & 1503.8 (aro-
matic C-C str), 743.3 (C-S of 1,3,4-thiadiazole nucleus), 1642.0
(C=N of 1,3,4-thiadiazole nucleus), 1681.5 (C=O str of amide),
3422.5 (N-H str of amide), 1602.7 (C=N group), 822.7 (C-H def dis-
ubstituted benzene ring), 713.8 (C-Cl str), 1522.4 & 1355.3 ( N=O
str of Ar-NO2 group);1H-NMR d (ppm) (DMSO-d6, TMS): 7.3–8.2 (m,
8H, ArH), 9.1 (s, 1H, NHCONH), 9.8 (s, 1H, NHCONH), 6.9 (s, 1H,
imine H); 13C-NMR d (ppm) (DMSO-d6, TMS): 128.5 (C-29 & C-69),
129.4 (C-39 & C-59), 133.7 (C-49), 134.7 (C-19), 164.0 (C-2), 156.5 (C-5),
157.4 (NHCONHNCH), 154.7 (NHCONHNCH), 129.9 (C-299 & C-699),
123.8 (C-399 & C-599), 150.9 (C-499), 137.2 (C-199); ESMS (methanol) m/
z: 403 [M+].
Compound Va
Yield: 66%; m.p.: 173–1748C; IR (cm– 1) (KBr): 3063.8 (aromatic C-
H), 741.9 (C-S of thiadiazole nucleus), 1644.8 (C=N of thiadiazole),
3423.7 (secondary NH), 3317.4 (amide NH), 1685.9 (C=O str of
amide), 716.5 (C-Cl str), 832.0 (C-H def disubstituted benzene).
Compound 3
IR (cm-1) (KBr): 3043.7 (aromatic C-H str), 1601.4 & 1506.2 (aro-
matic C-C str), 742.8 (C-S of 1,3,4-thiadiazole nucleus), 1643.6
(C=N of 1,3,4-thiadiazole nucleus), 1673.8 (C=O str of amide),
3428.7 (N-H str of amide), 1616.3 (C=N group), 826.7 (C-H def dis-
ubstituted benzene ring), 719.4 (C-Cl str), 3453.0 (O-H str of alco-
holic group), 1153.8 (C-O str of alcoholic group); 1H-NMR d (ppm)
(DMSO-d6, TMS): 7.3–7.6 (m, 8H, ArH), 9.2 (s, 1H, NHCONH), 9.8 (s,
1H, NHCONH), 6.8 (s, 1H, imine H), 5.3 (ArOH); 13C-NMR d (ppm)
(DMSO-d6, TMS): 128.5 (C-29 & C-69), 129.3 (C-39 & C-59), 133.9 (C-49),
134.7 (C-19), 164.1 (C-2), 156.8 (C-5), 157.3 (NHCONHNCH), 154.8
(NHCONHNCH), 130.5 (C-299 & C-699), 115.8 (C-399 & C-599), 159.7 (C-
499), 123.9 (C-199); ESMS (methanol) m/z: 374 [M+].
Compound Vb
Yield: 57%; m.p.: 181–1838C; IR (cm– 1) (KBr): 3080.7 (aromatic C-
H), 744.9 (C-S of thiadiazole nucleus), 1644.1 (C=N of thiadiazole),
3428.3 (secondary NH), 3317.8 (amide NH) and 1687.4 (C=O str of
amide), 827.1 (C-H def disubstituted benzene), 3452.8 (O-H str of
alcoholic group), 1168.0 (C-O str of alcoholic group).
General procedure for synthesis of N1-[5-(4-substituted
phenyl)-1,3,4-thiadiazol-2-yl]-N4-(4-substituted
Compound 4
IR (cm– 1) (KBr): 3047.3 (aromatic C-H str), 1605.2 & 1506.2 (aro-
matic C-C str), 746.3 (C-S of 1,3,4-thiadiazole nucleus), 1646.8
(C=N of 1,3,4-thiadiazole nucleus), 1678.7 (C=O str of amide),
2904.4 (aliphatic C-H str), 1442.0 (aliphatic C-H def), 3426.4 (N-H
str of amide), 1616.9 (C=N group), 815.8 (C-H def disubstituted
benzaldehyde)-semicarbazone 1-12, N1-[5-(4-substituted
phenyl)-1,3,4-thiadiazol-2-yl]-N4-[1-(4-substituted
phenyl)ethanone]-semicarbazone 13–16 and N1-[5-(4-
substituted phenyl)-1,3,4-thiadiazol-2-yl]-N4-[1-(4-
substituted phenyl) (phenyl) methanone]-semicarbazone
1
benzene ring), 728.2 (C-Cl str); H-NMR d (ppm) (DMSO-d6, TMS):
7.3-7.6 (m, 8H, ArH), 9.3 (s, 1H, NHCONH), 9.8 (s, 1H, NHCONH),
6.7 (s, 1H, imine H), 2.5 (ArOCH3); 13C-NMR d (ppm) (DMSO-d6,
TMS): 128.4 (C-29 & C-69), 129.5 (C-39 & C-59), 133.7 (C-49), 134.7 (C-
19), 164.3 (C-2), 156.6 (C-5), 157.2 (NHCONHNCH), 154.9
(NHCONHNCH), 128.8 (C-299 & C-699), 129.3 (C-399 & C-599), 140.2 (C-
499), 128.1 (C-199), 21.0 (CH3C6H5); ESMS (methanol) m/z: 372 [M+].
17–20
Equimolar quantities of 1-[5-(4-substituted phenyl)-1,3,4-thiadia-
zol-2-yl]-hydrazine carboxamide V (0.01 mol) and carbonyl com-
pound (0.01 mol) were dissolved in 20–30 mL of ethanol. To
this, 5 mL of water was added. The turbidity, if appeared, was
removed by adding ethanol with adequate stirring of the reac-
tion mixture. The pH of the reaction mixture was adjusted
between 4 and 5, by adding glacial acetic acid. The reaction mix-
ture was refluxed for a period of time ranging from 2–3 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 etha-
nol.
Compound 5
IR (cm– 1) (KBr): 3047.4 (aromatic C-H str), 1606.9 & 1504.9 (aro-
matic C-C str), 742.9 (C-S of 1,3,4-thiadiazole nucleus), 1647.1
(C=N of 1,3,4-thiadiazole nucleus), 1676.0 (C=O str of amide),
3422.4 (N-H str of amide), 1613.7 (C=N group), 828.3 (C-H def dis-
ubstituted benzene ring), 718.4 (C-Cl str), 1252.1 (C-O of OCH3
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Anticonvulsant Activity of Novel 1,3,4-Thiadiazoles
459
group);1H-NMR d (ppm) (DMSO-d6, TMS): 7.3–7.6 (m, 8H, ArH), 9.2
(s, 1H, NHCONH), 9.8 (s, 1H, NHCONH), 6.8 (s, 1H, imine H), 3.8
(ArOCH3); 13C-NMR d (ppm) (DMSO-d6, TMS): 128.3 (C-29 & C-69),
129.3 (C-39 & C-59), 133.9 (C-49), 134.6 (C-19), 164.1 (C-2), 156.8 (C-5),
157.4 (NHCONHNCH), 154.7 (NHCONHNCH), 130.2 (C-299 & C-699),
114.2 (C-399 & C-599), 164.3 (C-499), 123.6 (C-199), 56.2 (OCH3C6H5);
ESMS (methanol) m/z: 388 [M+].
(NHCONHNCH), 130.4 (C-299 & C-699), 115.7 (C-399 & C-599), 159.8 (C-
499), 123.8 (C-199); ESMS (methanol) m/z: 355 [M+].
Compound 10
IR (cm– 1) (KBr): 3046.8 (aromatic C-H str), 1607.2 & 1504.1 (aro-
matic C-C str), 740.3 (C-S of 1,3,4-thiadiazole nucleus), 1643.7
(C=N of 1,3,4-thiadiazole nucleus), 1674.1 (C=O str of amide),
3427.2 (N-H str of amide), 2904.2 (aliphatic C-H str), 1440.2 (ali-
phatic C-H def), 1616.3 (C=N group), 821.9 (C-H def disubstituted
benzene ring), 3446.9 (O-H str of alcoholic group), 1159.7 (C-O str
of alcoholic group); 1H-NMR d (ppm) (DMSO-d6, TMS): 6.8–7.6 (m,
8H, ArH), 9.1 (s, 1H, NHCONH), 9.7 (s, 1H, NHCONH), 6.8 (s, 1H,
imine H), 5.3 (ArOH), 2.4 (ArCH3); 13C-NMR d (ppm) (DMSO-d6,
TMS): 128.5 (C-29 & C-69), 116.4 (C-39 & C-59), 157.5 (C-49), 129.3 (C-
1'), 164.6 (C-2), 156.9 (C-5), 157.4 (NHCONHNCH), 154.5
(NHCONHNCH), 128.9 (C-299 & C-699), 129.4 (C-399 & C-599), 140.2 (C-
499), 128.4 (C-199) 21.0 (CH3C6H5); ESMS (methanol) m/z: 353 [M+].
Compound 6
IR (cm– 1) (KBr): 3044.1 (aromatic C-H str), 1604.7 & 1503.2 (aro-
matic C-C str), 748.7 (C-S of 1,3,4-thiadiazole nucleus), 1648.3
(C=N of 1,3,4-thiadiazole nucleus), 1695.2 (C=O str of amide),
3426.0 (N-H str of amide), 1614.4 (C=N group), 817.3 (C-H def dis-
ubstituted benzene ring), 715.5 (C-Cl str).; 1H-NMR d (ppm)
(DMSO-d6, TMS): 7.3–7.6 (m, 8H, ArH), 9.2 (s, 1H, NHCONH), 9.7 (s,
1H, NHCONH), 6.9 (s, 1H, imine H); 13C-NMR d (ppm) (DMSO-d6,
TMS): 128.5 (C-29 & C-69), 129.3 (C-39 & C-59), 133.7 (C-49), 134.7 (C-
19), 164.1 (C-2), 156.7 (C-5), 157.3 (NHCONHNCH), 154.7
(NHCONHNCH), 130.2 (C-299 & C-699), 129.1 (C-399 & C-599), 136.2 (C-
499), 129.4 (C-199); ESMS (methanol) m/z: 392 [M+].
Compound 11
IR (cm– 1) (KBr): 3039.3 (aromatic C-H str), 1605.7 & 1503.5 (aro-
matic C-C str), 743.6 (C-S of 1,3,4-thiadiazole nucleus), 1645.9
(C=N of 1,3,4-thiadiazole nucleus), 1679.2 (C=O str of amide),
3420.2 (N-H str of amide), 1614.8 (C=N group), 822.9 (C-H def dis-
ubstituted benzene ring), 716.4 (C-Cl str), 3457.0 (O-H str of alco-
holic group), 1261.8 (C-O of OCH3 group), 1166.2 (C-O str of alco-
holic group); 1H-NMR d (ppm) (DMSO-d6, TMS): 7.3–7.6 (m, 8H,
ArH), 9.2 (s, 1H, NHCONH), 9.6 (s, 1H, NHCONH), 6.8 (s, 1H, imine
H), 5.3 (ArOH), 3.9 (ArOCH3); 13C-NMR d (ppm) (DMSO-d6, TMS):
128.5 (C-29 & C-69), 116.2 (C-39 & C-59), 157.2 (C-49), 129.1 (C-19),
164.4 (C-2), 156.7 (C-5), 157.3 (NHCONHNCH), 154.6
(NHCONHNCH), 130.2 (C-299 & C-699), 114.4 (C-399 & C-599), 164.6 (C-
499), 123.5 (C-199), 56.1 (OCH3C6H5); ESMS (methanol) m/z: 369 [M+].
Compound 7
IR (cm– 1) (KBr): 3042.8 (aromatic C-H str), 1605.3 & 1502.6 (aro-
matic C-C str), 741.6 (C-S of 1,3,4-thiadiazole nucleus), 1648.9
(C=N of 1,3,4-thiadiazole nucleus), 1685.9 (C=O str of amide),
3421.6 (N-H str of amide), 1611.8 (C=N group), 826.9 (C-H def dis-
ubstituted benzene ring), 3454.2 (O-H str of alcoholic group),
1
1158.2 (C-O str of alcoholic group); H-NMR d (ppm) (DMSO-d6,
TMS): 6.8–7.6 (m, 9H, ArH), 9.3 (s, 1H, NHCONH), 9.5 (s, 1H,
NHCONH), 6.9 (s, 1H, imine H), 5.4 (ArOH); 13C-NMR d (ppm)
(DMSO-d6, TMS): 128.4 (C-29 & C-69), 116.4 (C-39 & C-59), 157.5 (C-49),
129.2 (C-19), 164.3 (C-2), 156.6 (C-5), 157.2 (NHCONHNCH), 154.8
(NHCONHNCH), 129.2 (C-299 & C-699), 128.7 (C-399 & C-599), 130.8 (C-
499), 131.3 (C-199); ESMS (methanol) m/z: 339 [M+].
Compound 12
IR (cm– 1) (KBr): 3037.2 (aromatic C-H str), 1605.3 & 1502.9 (aro-
matic C-C str), 750.4 (C-S of 1,3,4-thiadiazole nucleus), 1639.7
(C=N of 1,3,4-thiadiazole nucleus), 1690.9 (C=O str of amide),
3420.5 (N-H str of amide), 2903.8 (aliphatic C-H str), 1440.1 (ali-
phatic C-H def), 1601.9 (C=N group), 822.6 (C-H def disubstituted
benzene ring), 3451.7 (O-H str of alcoholic group), 1162.8 (C-O str
of alcoholic group), 717.0 (C-Cl str); 1H-NMR d (ppm) (DMSO-d6,
TMS): 6.9–7.6 (m, 8H, ArH), 9.2 (s, 1H, NHCONH), 9.8 (s, 1H,
NHCONH), 6.7 (s, 1H, imine H), 5.4 (ArOH); 13C-NMR d (ppm)
(DMSO-d6, TMS): 128.4 (C-29 & C-69), 116.4 (C-39 & C-59), 157.5 (C-49),
129.3 (C-19), 164.0 (C-2), 156.6 (C-5), 157.2 (NHCONHNCH), 154.8
(NHCONHNCH), 130.5 (C-299 & C-699), 129.1 (C-399 & C-599), 136.2 (C-
499), 129.5 (C-199); ESMS (methanol) m/z: 373 [M+].
Compound 8
IR (cm– 1) (KBr): 3035.8 (aromatic C-H str), 1604.1 & 1506.7 (aro-
matic C-C str), 740.3 (C-S of 1,3,4-thiadiazole nucleus), 1647.4
(C=N of 1,3,4-thiadiazole nucleus), 1680.7 (C=O str of amide),
3423.0 (N-H str of amide), 1616.2 (C=N group), 823.9 (C-H def dis-
ubstituted benzene ring), 3447.3 (O-H str of alcoholic group),
1145.1 (C-O str of alcoholic group), 1524.7 & 1351.0 (N=O str of
Ar-NO2 group); 1H-NMR d (ppm) (DMSO-d6, TMS): 6.8–8.2 (m, 8H,
ArH), 9.1 (s, 1H, NHCONH), 9.7 (s, 1H, NHCONH), 6.8 (s, 1H, imine
H), 5.4 (ArOH); 13C-NMR d (ppm) (DMSO-d6, TMS): 128.5 (C-2k & C-
69), 116.3 (C-39 & C-59), 157.5 (C-49), 129.2 (C-19), 164.5 (C-2), 156.7 (C-
5), 157.3 (NHCONHNCH), 154.8 (NHCONHNCH), 129.8 (C-299 & C-
699), 123.8 (C-399 & C-599), 150.9 (C-499), 137.4 (C-199); ESMS (methanol)
m/z: 384 [M+].
Compound 13
IR (cm– 1) (KBr): 3043.6 (aromatic C-H str), 1604.2 & 1505.8 (aro-
matic C-C str), 747.9 (C-S of 1,3,4-thiadiazole nucleus), 1643.3
(C=N of 1,3,4-thiadiazole nucleus), 1687.9 (C=O str of amide),
3424.7 (N-H str of amide), 1609.3 (C=N group), 828.5 (C-H def dis-
ubstituted benzene ring), 3450.3 (O-H str of alcoholic group),
Compound 9
IR (cm– 1) (KBr): 3038.2 (aromatic C-H str), 1604.1 & 1505.9 (aro-
matic C-C str), 745.6 (C-S of 1,3,4-thiadiazole nucleus), 1643.8
(C=N of 1,3,4-thiadiazole nucleus), 1672.7 (C=O str of amide),
3423.9 (N-H str of amide), 1614.8 (C=N group), 824.0 (C-H def dis-
ubstituted benzene ring), 3453.6 (O-H str of alcoholic group),
1
1148.9 (C-O str of alcoholic group); H-NMR d (ppm) (DMSO-d6,
1
1158.1 (C-O str of alcoholic group); H-NMR d (ppm) (DMSO-d6,
TMS): 6.9–7.5 (m, 8H, ArH), 9.2 (s, 1H, NHCONH), 9.7 (s, 1H,
NHCONH), 5.5 (ArOH), 1.1 (s, 3H, carbimino CH3); 13C-NMR d
(ppm) (DMSO-d6, TMS): 128.5 (C-29 & C-69), 116.3 (C-39 & C-59), 157.3
(C-49), 129.2 (C-19), 164.2 (C-2), 156.8 (C-5), 157.2 (NHCONHNCH),
155.6 (NHCONHNCH), 130.3 (C-299 & C-699), 115.8 (C-399 & C-599),
TMS): 6.8–7.6 (m, 8H, ArH), 9.3 (s, 1H, NHCONH), 9.8 (s, 1H,
NHCONH), 6.9 (s, 1H, imine H), 5.4 (ArOH); 13C-NMR d (ppm)
(DMSO-d6, TMS): 128.5 (C-29 & C-69), 116.3 (C-39 & C-59), 157.5 (C-4'),
129.2 (C-19), 164.2 (C-2), 156.8 (C-5), 157.3 (NHCONHNCH), 154.6
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460
H. Rajak et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 453–461
159.7 (C-499), 123.8 (C-199), 11.4 (NHCONHNCCH3); ESMS (methanol)
m/z: 369 [M+].
156.8 (C-5), 157.5 (NHCONHNCH), 155.6 (NHCONHNCH), 129.2 (C-
299 & C-699), 128.7 (C-399 & C-599), 130.9 (C-499), 131.5 (C-199), 129.2 (C-
2999 & C-6999), 128.7 (C-3999 & C-5999), 130.9 (C-4999), 131.5 (C-1999); ESMS
(methanol) m/z: 415 [M+].
Compound 14
IR (cm– 1) (KBr): 3046.1 (aromatic C-H str), 1607.2 & 1504.8 (aro-
matic C-C str), 738.6 (C-S of 1,3,4-thiadiazole nucleus), 1648.3
(C=N of 1,3,4-thiadiazole nucleus), 1688.5 (C=O str of amide),
3428.7 (N-H str of amide), 2909.0 (aliphatic C-H str), 1447.9 (ali-
phatic C-H def), 1616.5 (C=N group), 817.3 (C-H def disubstituted
benzene ring), 3461.5 (O-H str of alcoholic group), 1168.4 (C-O str
of alcoholic group), 1269.2 (C-O of OCH3 group); 1H-NMR d (ppm)
(DMSO-d6, TMS): 6.8–7.5 (m, 8H, ArH), 9.4 (s, 1H, NHCONH), 9.8 (s,
1H, NHCONH), 5.4 (ArOH), 1.1 (s, 3H, Carbimino CH3), 3.8
(ArOCH3); 13C-NMR d (ppm) (DMSO-d6, TMS): 128.5 (C-29 & C-69),
116.3 (C-39 & C-59), 157.5 (C-49), 129.2 (C-19), 164.3 (C-2), 156.8 (C-5),
157.2 (NHCONHNCH), 155.7 (NHCONHNCH), 130.1 (C-299 & C-699),
114.2 (C-399 & C-599), 164.4 (C-499), 123.5 (C-199), 11.4 (NHNCHCH3),
56.1 (OCH3C6H5); ESMS (methanol) m/z: 383 [M+].
Compound 18
IR (cm– 1) (KBr): 3049.2 (aromatic C-H str), 1605.2 & 1501.9 (aro-
matic C-C str), 743.7 (C-S of 1,3,4-thiadiazole nucleus), 1640.5
(C=N of 1,3,4-thiadiazole nucleus), 1683.8 (C=O str of amide),
3439.2 (N-H str of amide), 1618.8 (C=N group), 824.4 (C-H def dis-
ubstituted benzene ring), 3468.6 (O-H str of alcoholic group),
1
1159.4 (C-O str of alcoholic group); H-NMR d (ppm) (DMSO-d6,
TMS): 6.8–7.9 (m, 13H, ArH), 9.2 (s, 1H, NHCONH), 9.8 (s, 1H,
NHCONH), 5.4 (ArOH); 13C-NMR d (ppm) (DMSO-d6, TMS): 128.4 (C-
29 & C-69), 116.3 (C-39 & C-59), 157.5 (C-49), 129.2 (C-19), 164.0 (C-2),
156.6 (C-5), 157.3 (NHCONHNCH), 155.5 (NHCONHNCH), 130.2 (C-
299 & C-699), 115.8 (C-399 & C-599), 159.8 (C-499), 123.7 (C-199), 129.1 (C-
2999 & C-6999), 128.6 (C-3999 & C-5999), 130.7 (C-4999), 131.4 (C-1999); ESMS
(methanol) m/z: 431 [M+].
Compound 15
IR (cm– 1) (KBr): 3042.3 (aromatic C-H str), 1601.7 & 1504.2 (aro-
matic C-C str), 744.8 (C-S of 1,3,4-thiadiazole nucleus), 1647.9
(C=N of 1,3,4-thiadiazole nucleus), 1686.3 (C=O str of amide),
3429.3 (N-H str of amide), 2909.1 (aliphatic C-H str), 1445.2 (ali-
phatic C-H def), 1614.8 (C=N group), 827.2 (C-H def disubstituted
benzene ring), 3469.4 (O-H str of alcoholic group), 1160.3 (C-O str
of alcoholic group), 1529.1 & 1357.0 ( N=O str of Ar-NO2 group);
1H-NMR d (ppm) (DMSO-d6, TMS): 6.9–8.2 (m, 8H, ArH), 9.2 (s, 1H,
NHCONH), 9.8 (s, 1H, NHCONH), 5.4 (ArOH), 1.1 (s, 3H, carbimino
CH3); 13C-NMR d (ppm) (DMSO-d6, TMS): 128.4 (C-29 & C-69), 116.4
(C-39 & C-59), 157.3 (C-49), 129.3 (C-19), 164.1 (C-2), 156.8 (C-5), 157.4
(NHCONHNCH), 155.7 (NHCONHNCH), 129.9 (C-299 & C-699), 123.8
(C-399 & C-599), 150.6 (C-499), 137.5 (C-199), 11.4 (NHNCHCH3); ESMS
(methanol) m/z: 398 [M+].
Compound 19
IR (cm– 1) (KBr): 3041.7 (aromatic C-H str), 1603.7 & 1509.3 (aro-
matic C-C str), 759.2 (C-S of 1,3,4-thiadiazole nucleus), 1646.1
(C=N of 1,3,4-thiadiazole nucleus), 1683.8 (C=O str of amide),
3423.6 (N-H str of amide), 1617.5 (C=N group), 824.5 (C-H def di-
substituted benzene ring), 3463.8 (O-H str of alcoholic group),
1160.4 (C-O str of alcoholic group), 1522.7 & 1352.0 ( N=O str of
Ar-NO2 group); 1H-NMR d (ppm) (DMSO-d6, TMS): 6.8–7.9 (m, 13H,
ArH), 9.2 (s, 1H, NHCONH), 9.7 (s, 1H, NHCONH), 5.3 (ArOH); 13C-
NMR d (ppm) (DMSO-d6, TMS): 128.5 (C-29 & C-69), 116.4 (C-39 & C-
59), 157.5 (C-49), 129.3 (C-19), 164.2 (C-2), 156.8 (C-5), 157.4
(NHCONHNCH), 155.7 (NHCONHNCH), 130.0 (C-299 & C-699), 123.6
(C-399 & C-599), 150.8 (C-499), 137.6 (C-199), 129.1 (C-2999 & C-6999), 128.7
(C-3999 & C-5999), 130.9 (C-4999), 131.4 (C-1999); ESMS (methanol) m/z:
460 [M+].
Compound 16
IR (cm– 1) (KBr): 3042.7 (aromatic C-H str), 1603.6 & 1509.2 (aro-
matic C-C str), 745.2 (C-S of 1,3,4-thiadiazole nucleus), 1642.7
(C=N of 1,3,4-thiadiazole nucleus), 1680.6 (C=O str of amide),
3429.2 (N-H str of amide), 2902.8 (aliphatic C-H str), 1440.2 (ali-
phatic C-H def), 1616.5 (C=N group), 823.8 (C-H def disubstituted
benzene ring), 3462.7 (O-H str of alcoholic group), 1166.2 (C-O str
Compound 20
IR (cm– 1) (KBr): 3047.3 (aromatic C-H str), 1606.2 & 1503.8 (aro-
matic C-C str), 744.9 (C-S of 1,3,4-thiadiazole nucleus), 1643.8
(C=N of 1,3,4-thiadiazole nucleus), 1686.2 (C=O str of amide),
3427.3 (N-H str of amide), 1615.1 (C=N group), 823.8 (C-H def dis-
ubstituted benzene ring), 3459.5 (O-H str of alcoholic group),
1167.9 (C-O str of alcoholic group), 1254.7 (C-O of OCH3 group);
1H-NMR d (ppm) (DMSO-d6, TMS): 6.8–7.9 (m, 13H, ArH), 9.2 (s,
1H, NHCONH), 9.8 (s, 1H, NHCONH), 5.3 (ArOH), 3.8 (ArOCH3); 13C-
NMR d (ppm) (DMSO-d6, TMS): 128.4 (C-29 & C-69), 116.5 (C-39 & C-
59), 157.5 (C-49), 129.3 (C-19), 164.1 (C-2), 156.9 (C-5), 157.3
(NHCONHNCH), 174.5 (NHCONHNCH), 130.2 (C-299 & C-699), 114.3
(C-399 & C-599), 164.6 (C-499), 123.6 (C-199), 129.1 (C-2999 & C-6999), 128.8
(C-3999 & C-5999), 130.9 (C-4999), 131.4 (C-1999), 56.2 (OCH3C6H5); ESMS
(methanol) m/z: 446 [M+].
1
of alcoholic group), 715.9 (C-Cl str); H-NMR d (ppm) (DMSO-d6,
TMS): 6.9–8.2 (m, 8H, ArH), 9.3 (s, 1H, NHCONH), 9.8 (s, 1H,
NHCONH), 5.3 (ArOH), 1.2 (s, 3H, carbimino CH3); 13C-NMR d
(ppm) (DMSO-d6, TMS): 128.5 (C-29 & C-69), 116.4 (C-39 & C-59), 157.6
(C-49), 129.3 (C-19), 164.4 (C-2), 156.9 (C-5), 157.4 (NHCONHNCH),
155.5 (NHCONHNCH), 130.3 (C-299 & C-699), 129.3 (C-399 & C-599),
136.2 (C-499), 129.4 (C-199), 11.3 (NHNCHCH3); ESMS (methanol) m/z:
388 [M+].
Compound 17
IR (cm– 1) (KBr) 3039.3 (aromatic C-H str), 1602.7 & 1503.8 (aro-
matic C-C str), 748.2 (C-S of 1,3,4-thiadiazole nucleus), 1641.1
(C=N of 1,3,4-thiadiazole nucleus), 1674.3 (C=O str of amide),
3428.2 (N-H str of amide), 1625.3 (C=N group), 821.9 (C-H def dis-
ubstituted benzene ring), 3443.9 (O-H str of alcoholic group),
Pharmacology
The anticonvulsant screening [23–25] was performed using
male albino mice (swiss, 18–25 g) and rat (wistar, 100–150 g).
The test compounds were suspended in 0.5% methyl cellulose/
water mixture. All the animals were acclimatized for a week
before use. The animals were maintained in colony cages under
a 12 h-light-and-12 h-dark cycle and were fed on standard labora-
tory diet and water ad libitum. The animals were kept at a tem-
perature of 228C (l38C) and at a relative humidity between 50 to
1
1165.9 (C-O str of alcoholic group); H-NMR d (ppm) (DMSO-d6,
TMS): 6.8– –7.9 (m, 14H, ArH), 9.2 (s, 1H, NHCONH), 9.7 (s, 1H,
NHCONH), 5.4 (ArOH); 13C-NMR d (ppm) (DMSO-d6, TMS): 128.5 (C-
29 & C-69), 116.3 (C-39 & C-59), 157.6 (C-49), 129.1 (C-19), 164.0 (C-2),
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2009, 342, 453–461
Anticonvulsant Activity of Novel 1,3,4-Thiadiazoles
461
60%. Initially all the test compounds were administered intra-
peritoneal (i.p.) at doses of 30, 100, and 300 mg/kg to one to four
mice. The anticonvulsant activity of the test compounds were
evaluated by two models namely, MES and scPTZ models. Pheny-
toin, carbamazepine, and sodium valproate were used as the
standard drugs for the comparison. The acute neurological tox-
icity was determined in the rotorod test. Procedures employed
for evaluation of anticonvulsant activity and neurotoxicity were
reviewed and approved by the University Animal Ethical Com-
mittee.
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The maximal electroshock seizure were elicited with a 60 cycle
altering current of 50 mA intensity delivered for 0.25 s via ear
clip electrodes. The maximal seizure usually consists of a short
period of tonic extension of the hind limbs and a final clonic epi-
sode. After 30 min and 4 h of drug administration, electroshocks
were applied via corneal electrodes. Disappearance of the hind
limb tonic extensor component of convulsion was considered as
positive criteria.
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J. R. Dimmock, Eur. J. Med. Chem. 1998, 33, 595–607.
The scPTZ test 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 administra-
tion of PTZ was used for seizure detection. Protection was
referred to as the failure to observe an episode of clonic convul-
sions of at least 5 s duration during this time period.
[14] S. N. Pandeya, H. Manjula, J. P. Stables, Pharmazie 2001, 56,
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Neurotoxicity screening
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The rotorod test was conducted to evaluate neurotoxicity. Mini-
mal motor impairment was measured in mice by the rotorod
test. The mice were trained to stay on an accelerating rotorod
with a diameter of 3.2 cm that rotates at six revolutions per min.
Only those animals which have demonstrated their capability 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. 30 min after i.p. adminis-
tration the mice are placed on the rotating rod. Neurotoxicity
was indicated by the failure of the animal to sustain equilibrium
on the rod for at least 1 min in each of three trials [26].
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i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com