New hydrazides and thiosemicarbazides derived from ethylenedioxythiophene as potential anticonvulsants

Article abstract of DOI:10.1080/10426500903051831

A series of ethyl 7-({2-[(substituted)carbonyl]hydrazino}carbonyl)-2,3- dihydrothieno [3,4-b][1,4]dioxine-5-carboxylates (5-13) and ethyl 7-{[({2-[(substituted)carbonyl]hydra-zino}carbonothioyl)amino]carbonyl}-2, 3-dihydrothieno[3,4-b][1,4]dioxine-5-carboxy-lates (15-20) were synthesized in good yield by condensing ethyl-7-(chlorocarbonyl)-2,3-dihydrothieno[3,4-b][1,4] dioxine-5-carboxylate (4) with suitable hydrazides. The newly synthesized compounds were characterized using FTIR, 1H NMR, 13C NMR, mass spectroscopy, and elemental analyses. The anticonvulsant activity of all the title compounds was investigated against maximal electroshock-induced seizures (MES) and pentylenetetrazole (PTZ)-induced convulsion models. None of the compounds showed toxicity at the maximum dose of 2000 mg/kg. Almost all the compounds showed protection in flexion and extension stage against induced convulsion. Among them, naphthyloxy-substituted derivatives exhibited very good response against induced seizures. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

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New Hydrazides and Thiosemicarbazides
Derived from Ethylenedioxythiophene as
Potential Anticonvulsants
Ravi Kulandasamy a , Airody Vasudeva Adhikari a , Ashok Taranalli b &
Thimmaiah Venkataswamy b
a Department of Chemistry , National Institute of Technology
Karnataka , Surathkal, Mangalore, India
b Department of Pharmacology , KLE College of Pharmacy , Belgaum,
India
Published online: 02 Jul 2010.
To cite this article: Ravi Kulandasamy , Airody Vasudeva Adhikari , Ashok Taranalli & Thimmaiah
Venkataswamy (2010) New Hydrazides and Thiosemicarbazides Derived from Ethylenedioxythiophene
as Potential Anticonvulsants, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:7,
1358-1368, DOI: 10.1080/10426500903051831
To link to this article: http://dx.doi.org/10.1080/10426500903051831
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Phosphorus, Sulfur, and Silicon, 185:1358–1368, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903051831
NEW HYDRAZIDES AND THIOSEMICARBAZIDES
DERIVED FROM ETHYLENEDIOXYTHIOPHENE AS
POTENTIAL ANTICONVULSANTS
Ravi Kulandasamy,1 Airody Vasudeva Adhikari,1
Ashok Taranalli,2 and Thimmaiah Venkataswamy2
1Department of Chemistry, National Institute of Technology Karnataka, Surathkal,
Mangalore, India
2Department of Pharmacology, KLE College of Pharmacy, Belgaum, India
A
series of ethyl 7-({2-[(substituted)carbonyl]hydrazino}carbonyl)-2,3-dihydrothieno
[3,4-b][1,4]dioxine-5-carboxylates (5–13) and ethyl 7-{[({2-[(substituted)carbonyl]hydra-
zino}carbonothioyl)amino]carbonyl}-2,3-dihydrothieno[3,4-b][1,4]dioxine-5-carboxy-lates
(15–20) were synthesized in good yield by condensing ethyl-7-(chlorocarbonyl)-2,3-
dihydrothieno[3,4-b][1,4]dioxine-5-carboxylate (4) with suitable hydrazides. The newly
synthesized compounds were characterized using FTIR, 1H NMR, 13C NMR, mass spec-
troscopy, and elemental analyses. The anticonvulsant activity of all the title compounds was
investigated against maximal electroshock-induced seizures (MES) and pentylenetetrazole
(PTZ)-induced convulsion models. None of the compounds showed toxicity at the maximum
dose of 2000 mg/kg. Almost all the compounds showed protection in flexion and extension
stage against induced convulsion. Among them, naphthyloxy-substituted derivatives
exhibited very good response against induced seizures.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Anticonvulsant; hydrazide; MES; PTZ; thiophene; thiosemicarbazide
INTRODUCTION
Epilepsy is one of the most common neurological disorders of the brain, due to a sud-
den burst of abnormal electrical discharges. It has been reported that the number of people
suffering from epilepsy is increasing day by day in the world.1 Until recently, physicians
have had relatively limited antiepileptic drugs (AEDs) to treat patients with seizure disor-
ders. Among the various active drugs available in the commercial scene, phenobarbitone,
phenytoin, ethosuximide, tiagabin, etizolam, phethenylate sodium, clonazepam, stiripen-
tol, and topiramate are noteworthy. Close observation of their structures reveals that their
enhanced activity is due to the presence of active functional groups like dicarboxamide,
Received 28 December 2008; accepted 19 May 2009.
The authors are thankful to the Head, SAIF, CDRI, Lucknow, India, and the Chairman, NMRRC, IISc,
Bangalore, India, for providing mass, 1H NMR, and 13C NMR spectral data.
Address correspondence to Airody Vasudeva Adhikari, Department of Chemistry, National Institute of Tech-
nology Karnataka, Surathkal, Mangalore 575025, India. E-mail: avchem@nitk.ac.in; avadhikari123@yahoo.co.in
1358

NEW HYDRAZIDES AND THIOSEMICARBAZIDES
1359
imide, and dioxole attached to potent base moieties such as thiophene, phenyl, and ben-
zodiazepine. Some of the conventional drugs2 were found to be toxic due to the presence
of a cyclic dicarboxamide ring in their structure. Moreover, they have wide diversity of
their effects, which has disrupted the attempt to correlate their activity with structures.
Consequently, a search for new antiepileptic compounds with more selectivity and minimal
toxicity has gained much importance in recent years.
Various thiophene derivatives have been reported to possess different types of CNS
activities such as analgesic,3 anti-inflammatory,4 antipsychotic,5 antidepressant,6 and anti-
convulsant7–9 properties. It has been well documented that the thiophene moiety is an im-
portant pharmacophore in active anticonvulsants such as tiagabine,7 etizolam,8 and sodium
phethenylate,9 which belong to different classes of antiepileptic agents (Figure 1). In these
molecules, the biological activity is mainly attributed to the presence of a hydrophobic
S
S
CH3
N
O
N
S
Cl
CH3
N
Na
HN
N
H3C
S
N
N
O
H3C
HOOC
sodium phethenylate
etizolam
tiagabine
HN
H
N
R
COOMe
COOEt
N
O
N
NH
F
H3C
O
O
COOEt
R
pyrrole
ethyl
loflazepate
enaminone
OH
O
O
CH
O
3
COOEt
O
O
O
N
R
O
CH
3
H C
NH
3
N
O
N
NH CH3
stiripentol
F
ester derivatives
R1
NH2
H2N
benzodiazepines
O
H3C
N
O
O
HN
O
NH
CH3
OH
NH
O
O
H3C
CH3
CH3
ameltolide
O
amide derivatives
SB-204269
H2N
Figure 1 Structures of well-known active antiepileptic agents.

1360
R. KULANDASAMY ET AL.
aryl-binding site, hydrogen bonding domain, and electron donor group, which are the es-
sential requirements10 for the molecules to show potential activity. Further, it has been
noticed that the CNS active drug ethyl loflazepate11 showed anticonvulsant activity. Here,
the drug molecule contains an ester group as an important pharmacophore. This has been
confirmed by the observation that 1-substituted-2-aryl derivatives12 containing an ester in
their structures displayed better activity than the other substituted derivatives. Also, Ed-
dington et al.13 reported that enaminones (Figure 1) containing an ester group showed
superior activity compared to the unsubstituted molecules, while Unverferth et al. showed
that with the introduction of an ester group in the pyrrole,14 derivatives enhanced their
activity considerably.
According to the literature, the dioxole group acts as an important bioactive moiety
in the active drugs, stiripentol15 and topiramate16 (Figur 1). It is interesting to note that
compounds containing a cyclic ether in their structure17–19 exhibited moderate activity.
On the other hand, there are a number of reports on antiepileptic studies of substituted
aromatic amides20,21 (Figure 1). It has been observed that they are capable of forming
hydrogen bonding with the receptor sites during their action, which may be the main rea-
son for their increased activity. On similar lines, hydrazides and thiosemicarbazides are
expected to show good activity, as they are structurally similar to amides and are capable
of forming H-bonding. Keeping this in view, it was thought to be of interest to design
new thiophene derivatives (4–13 and 15–20) containing a hydrazide or thiosemicarbazide
group at position 2, a bioactive ester group at position 5, and an electron-releasing cyclic
ether group at positions 3 and 4 of the active thiophene ring. Figure 2 shows the newly
designed molecule, which contains all the required pharmacophoric elements. It is hoped
that combination of these active pharmacophores in the synthetic design would lead to
better anticonvulsants with least neurotoxicity. In the present article, we report the synthe-
sis, characterization, and anticonvulsant activities by MES and PTZ models of hitherto
unknown ethyl 7-({2-[(substituted)carbonyl]hydrazino}carbonyl)-2,3-dihydrothieno[3,4-
b][1,4]dioxine-5-carboxylate (5–13) and ethyl 7-{[({2-[(substituted)carbonyl]hydrazino}
carbonothioyl)amino]carbonyl}-2,3-dihydrothieno[3,4-b][1,4]dioxine-5-carboxylate (15–
20) derivatives.
Dioxole
Amide
Ester
O
O
NH
R
EtOOC
S
O
Thiophene
Figure 2 Structure of the newly designed target molecule.

NEW HYDRAZIDES AND THIOSEMICARBAZIDES
1361
RESULTS AND DISCUSSION
The reaction sequences employed for the synthesis of the title compounds, viz. ethyl
7-({2-[(substituted)carbonyl]hydrazino}carbonyl)-2,3-dihydrothieno[3,4-b][1,4]dioxine-
5-carboxylates (5–13) and ethyl 7-{[({2-[(substituted)carbonyl]hydrazino}carbonothio-
yl)amino]carbonyl}-2,3-dihydrothieno[3,4-b][1,4]dioxine-5-carboxylates (15–20) are
shown in Scheme 1.
HO
OH
EtOOC
COOEt
S
1
A
O
O
O
O
B
EtOOC
EtOOC
EtOOC
COOH
S
3
EtOOC
COOEt
S
2
C
O
O
O
O
O
D
R1
NH
NH
COOEt
S
COCl
O
S
5-13
4
E
O
O
O
O
O
R
NH
F
NH
NH
O
COOEt
S
S
CONCS
S
15-20
14
Scheme 1 Synthesis of new hydrazides and thiosemicarbazides. A: Dibromoethane, K2CO3, DMF B: 1M
ethanolic NaOH/H+ C: SOCl2, 5 h reflux, D: methylene dichloride, pyridine, hydrazide, E: NH4SCN, methylene
dichloride, PEG 600, and F: hydrazide.
The key intermediate carboxylic acid, 3 was synthesized by controlled hydrolysis of
ethylenedioxythiophene diester (2). In this reaction, temperature and solvent ratio played
an important role in obtaining a satisfactory yield. The acid 3 was converted to its acid
chloride (4) by refluxing with thionyl chloride for 5 h. The final compounds 5–13 were

1362
R. KULANDASAMY ET AL.
synthesized by treating the acid chloride with corresponding hydrazide in the presence of
pyridine.
In another route, acid chloride (3) was treated with ammonium thiocyanate in the
presence of phase transfer catalyst, polyethylene glycol (PEG)-600, in order to obtain the
intermediate 14. This product 14 was directly used for the next step without purification, as
it is unstable. They were conveniently converted to final compounds 15–20 by condensing
different hydrazides with the intermediate 14.
The structural assignments to new compounds were based on their elemental analysis
1
and spectral (FTIR, H and 13C NMR, and mass) data. The physical and characterization
data of all the newly synthesized compounds are summarized in Tables I and II.
The IR spectrum of hydrazide (5) showed the absorption band at 3287 cm−1, due to
NH stretching of amide group. Further, the carbonyl stretching of the amide and ester
groups appeared at 1660 and 1713 cm−1, respectively. Here, the carbonyl frequency of amide
was observed in the lower region than the ester carbonyl group, which is due to resonance.
In the 1H NMR spectrum of 5, the appearance of sharp peaks at δ 1.35 (triplet) and 4.28
(quartet) showed the presence of a CH3CH2O group. The protons of the ethylenedioxy
group resonated as a singlet at δ 4.46 ppm. The two singlets observed at δ 9.55 and 10.77
were due to a NHNH proton of hydrazide. The 13C NMR spectrum of compound
5 showed signals at δ 14 and 60.7 due to an OCH2CH3 group and peaks at 64.5 ppm
belonging to OCH2CH2O of ethylenedioxy thiophene. The peaks at 110.0, 114.6, 117.7,
129.9, 131.7, 138.8, 141.6, and 144.8 represent the thiophene and ethylenedioxy thiophene
carbon. Ester and amide carbonyl carbons were observed at 159.3 and 160.1, respectively.
Formation of the compound 5 from its precursor was further confirmed by its mass spectrum.
In its mass spectrum, the compound displayed a molecular ion peak at m/z 461 (M+ 20%),
which is in agreement with the molecular formula C15H13BrN2O6S2. The peaks at m/z
383, 327, 281, 221, and 155 were due to the fragmentation of the molecular ion with the
elimination of simple molecules. The scheme of the mass fragmentation pattern is shown
in the Figure S1 (available online in the Supplemental Materials). The other compounds in
the series also followed the same type of fragmentation pattern in their mass spectra.
Formation of thiosemicarbazides 15–20 from the respective acid chloride (4) was
evidenced by their FTIR, 1H NMR, and mass spectral data. The IR spectrum of compound
15 showed sharp bands at 3332, 1672, 1146, and 1699 cm−1 due to >NH, >C O (amide),
>C S, and >C O (ester), respectively. Furthermore, the 1H NMR spectrum displayed a
sharp triplet at δ 1.25 and quartet at 4.28 due to CH3 and CH2 protons of ester linkage,
respectively. The appearance of three broad singlets at δ 10.00, 11.27, and 11.67 was
attributed to the presence of three different NH protons. Finally, in its mass spectrum,
its molecular ion peak appeared at m/z 520 (M+ 100%), which is in agreement with the
molecular formula C16H14BrN3O6S3. The peaks at m/z 488, 443, 358, 307, 241, and 190
were due to the fragmentation of its molecular ion. The mass fragmentation pattern of
compound 15 is shown in the Figure S2 (Supplemental Materials). Similar fragmentation
patterns were observed for the other thiosemicarbazides (16–20).
ANTICONVULSANT ACTIVITIES
The results of the anticonvulsant activity of the newly synthesized final compounds
against MES and PTZ models have been summarized, along with the data for standard
drugs phenytoin and diazepam, in Tables S1 and S2 (Supplemental Materials).

1363

1364

NEW HYDRAZIDES AND THIOSEMICARBAZIDES
1365
CONCLUSION
The present study highlights the design, synthesis, and characterization of various
hydrazides and thiosemicarbazides derived from ethylenedioxythiophene and their anticon-
vulsant profile in the traditional animal models. The results show that thiophene hydrazides
substituted with heteroaromatic systems exhibit better activity than the other compounds.
Methyl substitution at the distal ring resulted in very good activity in flexion and recovery
phases while the bromo derivative displayed good activity in extension, clonus, and stupor
stages. Of the two series of pharmacophoric hybrids, the hydrazides were found to be more
active than the thiosemicarbazide derivatives. Among them, naphthyloxy-substituted com-
pounds possess significant activity in both convulsion-induced models. From the results, it
can be concluded that ethylenedioxythiophene moiety acts as an active pharmacophore in
combating induced convulsions, as it is hydrophobic in nature and less toxic.
EXPERIMENTAL
All the chemicals and the solvents, purchased from Aldrich and Merck, were used
without further purification. The purity of the compounds was confirmed by thin layer
chromatography, performed on a silica gel 60 F254–coated aluminum sheet. Melting points
were determined on open capillaries using a Stuart SMP3 (Bibby Sterlin Ltd., UK) ap-
paratus and are uncorrected. FTIR spectra were recorded on a Nicolet Avatar 330 FTIR
spectrophotometer. The 1H and 13C NMR spectra were recorded on Varian 400 MHz NMR
spectrophotometers using TMS as an internal standard. Chemical shifts were reported in
ppm (δ), and signals were described as singlet (s), doublet (d), triplet (t), quartet (q), broad
(br), and multiplet (m). The coupling constant (J) values are expressed in Hz. The FAB
mass spectra were recorded on a JEOL SX 102/DA-6000 spectrophotometer/data system
using argon/xenon (6 kV, 10 mA) FAB gas, at 70 eV. Elemental analysis was carried out
using Flash EA 1112 series, CHNSO Analyser (Thermo).
Compound 2 was synthesized from diethyl-3,4-dihydroxythiophene-2,5-dicarboxy
late following the reported procedure.22
7-(Ethoxycarbonyl)-2,3-dihydrothieno[3,4-b][1,4]dioxine-5-carboxylic
Acid (3)
A mixture of diethyl-2,3-dihydrothieno[3,4-b][1,4]dioxine-5,7-dicarboxylate (2) (1
g, 3.5 mmol) dissolved in absolute ethanol (20 mL) and alcoholic sodium hydroxide (20
mL, 3.5 mmol) was refluxed for 5 h. It was then concentrated to one-third of its total
volume under vacuum. The concentrate was diluted with water (50 mL) and stirred for 2
h at 60◦C. The reaction mixture was cooled to 5–10◦C. The unreacted starting material
that separated was removed by filtration. The filtrate was then acidified with conc. HCl.
The separated product was filtered and recrystallized using methanol to give 3 with yield
1
78%. Mp: 239–240◦C. IR: (br) 2500–3000 cm−1 (-OH), 1687 cm−1 (>C O). H NMR
(DMSO d6 300 MHz) δ (ppm): 1.26 (t, 3H, CH3 ester, J = 7.2), 4.23 (q, 2H, CH2-ester,
J = 7.2), 4.34 (s, 4H, OCH2CH2O ), 13.27 [br, 1H, -OH (D2O exangeable)]. 13C NMR
(DMSO d6 300 MHz) δ (ppm): 14.0 ( CH3), 60.8 ( OCH2 ), 65.9 ( OCH2 ), 110.0
(C3-thiophene), 112.1 (C4-thiophene), 144.6 (C2-thiophene), 145.1 (C5-thiophene), 160.1
( CO-ester), 161.9 ( CO-acid). MS (m/z,%): 258 (M+, 70), 230 (50), 213 (100), 169 (40)
and 142 (10).

1366
R. KULANDASAMY ET AL.
Ethyl-7-(chlorocarbonyl)-2,3-dihydrothieno[3,4-b][1,4]dioxine-5-
carboxylate (4)
A mixture of 7-(ethoxycarbonyl)-2,3-dihydrothieno[3,4-b] [1,4]dioxine-5-carboxylic
acid (3) (0.5 g, 1.9 mmol) and thionyl chloride (15 mL) was refluxed for 5 h. Excess thionyl
chloride was removed from the reaction mixture. The residual off-white solid was extracted
with methylene dichloride (50 mL), and the organic layer was washed with saturated sodium
bicarbonate solution (25 mL). After drying the organic layer with anhydrous sodium sulfate,
the solvent was removed under vacuum to give 0.4 g (yield 75%) of the product 4. This
was used for the next step without further purification.
General Procedure for the Synthesis of Hydrazides 5–13
To a clear solution of acid chloride 4 (0.5 g, 1.8 mmol) in N-methyl pyrrolidinone
(10 mL) containing pyridine (0.1 mL) as a catalyst, an equimolar quantity of the respective
hydrazide was added while stirring. The stirring was continued at 50◦C for 12 h. The reaction
mixture was then quenched with ice-cold water (100 mL). The product was separated by
filtration and recrystallized from the appropriate solvent. The physical and characterization
data of compounds 5–13 are given in Table I. The spectral data of some of the synthesized
compounds are as follows:
Ethyl-7-({2-[(5-bromo-2-thienyl)carbonyl]hydrazino}carbonyl)-2,3-dihy-
drothieno[3,4-b] [1,4]dioxine-5-carboxylate (5). IR: 3287 cm−1 (>NH), 1660
cm−1 (>C O amide) and 1713 cm−1 (>C O ester). 1H NMR (DMSO d6 400
MHz) δ (ppm): 1.35 (t, 3H, CH3 ester, J = 7.0), 4.28 (q, 2H, CH2 ester, J =
6.9), 4.46 (s, 4H, OCH2CH2O ), 7.32 (d, 1H, C4-thiophene, J = 3.8), 7.68 (d, 1H,
C3-thiophene, J = 3.8), 9.55 (s, 1H, >CONH), 10.77 (s, 1H, >CONH-). 13C NMR
(CDCl3, 400MHz) δ (ppm): 14.0 ( CH3), 60.7 ( OCH2 ester), 64.5 ( OCH2CH2O ),
110.0 (C3-EDOTthiophene), 114.6 (C4-EDOTthiophene), 117.7 (C2-thiophene), 129.9
(C3-thiophene), 131.7 (C4-thiophene), 138.8 (C5-thiophene), 141.6 (C2-EDOTthiophene),
144.8 (C5-EDOTthiophene), 159.3 ( CONH ), 160.1 (ester). MS (m/z,%): 461 (M+,
20), 383 (10), 355 (20), 327 (50), 281 (80), 221 (70).
Ethyl-7-{[2-(phenoxyacetyl)hydrazino]carbonyl}-2,3-dihydrothieno[3,4-
b][1,4]dioxine-5-carboxylate (9). IR: 3184 cm−1 (>NH), 1625 cm−1 (>C O amide)
1
and 1702 cm−1 (>C O ester). H NMR (DMSO d6 400 MHz) δ (ppm): 1.25 (t, 3H,
CH3 ester, J = 7.0), 4.23 (q, 2H, CH2-ester, J = 7.0), 4.41 (s, 4H, OCH2CH2O ),
4.61 (s, 2H, OCH2 ), 6.99–7.30 (m, 5H, aromatic), 9.38 (s, 1H, CONH ) and 10.40
(s, 1H, CONH ). MS (m/z,%): 407 (M+, 70), 391 (20), 241 (60), 165 (10).
Ethyl-7-({2-[(quinolin-8-yloxy)acetyl]hydrazino}carbonyl)-2,3-dihydro-
thieno[3,4-b][1,4] dioxine-5-carboxylate (12). IR: 3205 cm−1 (>NH), 1652 cm−1
(>C O amide) and 1707 cm−1 (>C O ester). 1H NMR (DMSO d6 400 MHz) δ (ppm):
1.25 (t, 3H, CH3 ester, J = 7.0), 4.25 (q, 2H, CH2 ester, J = 7.0), 4.42 (s, 4H,
OCH2CH2O ), 4.89 (s, 2H, OCH2 ), 7.30 (d, 1H, C2-aromatic, J = 7.4), 7.50 (m,
3H, C3, C4, C6-aromatic), 8.36 (d, 1H, C5-aromatic, J = 7.3), 8.88 (d, 1H, C7-aromatic,
J = 2.6), 9.48 (s, 1H, >CONH-) and 10.68 (s, 1H, >CONH-). MS (m/z,%): 458 (M+1,
100), 241 (10), 214 (10), 203 (5).
General Procedure for the Preparation of Semicarbazides 15–20
To a clear solution acid chloride 4 (0.5 g, 1.8 mmol) in methylene dichloride (25 mL),
ammonium thiocyanate powder (0.0027 mol) and PEG-600 (0.1 g) as PTC were added.

NEW HYDRAZIDES AND THIOSEMICARBAZIDES
1367
After stirring the reaction mixture for 2 h at room temperature, the corresponding acid
hydrazide (1.8 mmol) was added, and the reaction mixture was further stirred for 4 h at room
temperature. Then, water (25 mL) was added to the well-stirred mixture and the resulting
slurry was filtered, washed with water, dried, and finally recrystallized from the appropriate
solvent to obtain the title compounds (15–20). The physical and characterization data of
compounds 15–20 are tabulated in Table II. The spectral data of some of the synthesized
compounds are as follows:
Ethyl-7-{[({2-[(5-bromo-2-thienyl)carbonyl]hydrazino}carbonothioyl)-
amino]carbonyl}-2,3-dihydrothieno[3,4-b][1,4]dioxine-5-carboxylate (15). IR:
3332 cm−1 (>NH), 1672 cm−1 (>C O amide), 1146 cm−1 (>C S) and 1699 cm−1
1
(>C O ester). H NMR (DMSO d6 400 MHz) δ (ppm): 1.25 (t, 3H, CH3 ester, J =
7.0), 4.28 (q, 2H, CH2 ester, J = 7.0), 4.47 (s, 2H, CH2 ), 4.59 (s, 2H, CH2 ),
7.34 (d, 1H, C4-thiophene, J = 3.8), 7.72 (d, 1H, C3-thiophene, J = 3.9), 10.00 (s, 1H, -
NHNHCS), 11.27 (s, 1H, CONH ), 11.67 (s, 1H, -CSNHCO-). MS (m/z,%): 522 (M+2,
100), 520 (M+, 100), 488 (10), 443 (20), 359 (5), 307 (50), 300 (10), 241 (5), 212 (5).
Ethyl-7-({[(2-benzoylhydrazino)carbonothioyl]amino}carbonyl)-2,3-
dihydrothieno[3,4-b] [1,4]dioxine-5-carboxylate (16). IR: 3355 cm−1 (>NH), 1661
1
cm−1 (>C O amide), 1153 cm−1 (>C S) and 1710 cm−1 (>C O ester). H NMR
(DMSO d6 400 MHz) δ (ppm): 1.27 (t, 3H, CH3 ester, J = 7.0), 4.29 (q, 2H, CH2
ester, J = 7.0), 4.47 (s, 2H, CH2 , J = 1.84), 4.60 (s, 2H, CH2 , J = 2.1), 7.49—7.94
(m, 5H, aromatic), 10.00 (s, 1H, NHNHCS ), 11.18 (s, 1H, CONH ), 11.79 (s, 1H,
-CSNHCO-). MS (m/z,%): 436 (M+, 90), 391 (5), 258 (5), 241 (50), 214 (5), 136 (80).
Ethyl-7-{[({2-[(quinolin-8-yloxy)acetyl]hydrazino}carbonothioyl)amino]-
carbonyl}-2,3-dihydrothieno[3,4-b][1,4]dioxine-5-carboxylate (17). IR: 3424
cm−1 (>NH), 1666 cm−1 (>C O amide), 1152 cm−1 (>C S) and 1709 cm−1 (>C O
ester). 1H NMR (DMSO d6 400 MHz) δ (ppm): 1.25 (t, 3H, CH3 ester, J = 7), 4.27 (q,
2H, CH2 ester, J = 7.1), 4.46 (s, 2H, CH2 ), 4.65 (s, 2H, CH2 ), 4.95 (s, 2H,
OCH2 ), 7.34 (d, 1H, C2-aromatic, J = 7.5), 7.50—7.62 (m, 3H, C3, C4, C6-aromatic),
8.38 (d, 1H, C5-aromatic, J = 7.6), 8.90 (d, 1H, C7-aromatic, J = 2.6), 9.99 (s, 1H,
NHNHCS ), 11.53 (s, 1H, CONH ), 12.05 (s, 1H, CSNHCO). MS (m/z,%): 517
(M+, 80), 460 (10), 371 (10), 241 (40), 202 (5), 186 (60).
PHARMACOLOGY
The evaluation of anticonvulsant activity of the title compounds was carried out
using MES and PTZ models. Their toxicity studies were performed based on Organization
for Economic Co-Operation and Development (OECD) guidelines 423. The details of
evaluation procedures23–24 are as placed in the Supplemental Materials (available online).
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