Synthesis of novel spiro(indolone-3,2′-[1,3,4]thiadiazol)-2-ones and evaluation of their antidepressant and anticonvulsant activities

Article abstract of DOI:10.1002/jhet.687

The reaction of 3-(dicyanomethylene)-2-indolone in a solution of ethanol/piperidine with 4-substituted thiosemicarbazides forms the derivatives of 5′-(substituted amino)-3′H-spiro(indoline-3,2′-[1,3,4] thiadiazol-2-one. Rationales for these conversions involving the nucleophilic addition on the dicyanomethylene carbon atom are presented. The prepared compounds were evaluated each for antidepressant activity using tail suspension behavioral despair test and anticonvulsant activity against pentylenetetrazol induced seizures in mice.

Full text of DOI:10.1002/jhet.687

1050
Synthesis of Novel Spiro(indolone-3,20-[1,3,4]thiadiazol)-2-ones
and Evaluation of Their Antidepressant and Anticonvulsant
Activities
Vol 48
Alaa A. Hassan,a* Fathy F. Abdel-Latif,a Ahmed M. Nour El-Din,a
b
Mohamed Abdel-Aziz, Sara M. Mostafa, and Stefan Brase
a
c
¨
aChemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt
bDepartment of Medicinal Chemistry, Faculty of Pharmacy, El-Minia University,
El-Minia 61519, Egypt
cInstitute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6,
Karlsruhe 76131, Germany
*E-mail: alaahassan2001@yahoo.com
Received May 25, 2010
DOI 10.1002/jhet.687
Published online 13 May 2011 in Wiley Online Library (wileyonlinelibrary.com).
The reaction of 3-(dicyanomethylene)-2-indolone in a solution of ethanol/piperidine with 4-substituted
thiosemicarbazides forms the derivatives of 50-(substituted amino)-30H–spiro(indoline-3,20-[1,3,4]thiadia-
zol-2-one. Rationales for these conversions involving the nucleophilic addition on the dicyanomethylene
carbon atom are presented. The prepared compounds were evaluated each for antidepressant activity
using tail suspension behavioral despair test and anticonvulsant activity against pentylenetetrazol
induced seizures in mice.
J. Heterocyclic Chem., 48, 1050 (2011).
INTRODUCTION
N4-substituted isatin-3-thiosemicarbazones were intro-
duced as urease inhibitors [30,31]. Pharmacophore de-
velopment for isatin-b-thiosemicarbazones with selective
activity toward multidrug-resistant cells has been
reported [32]. A novel and a efficient procedure for the
synthesis of thiosemicarbazones has been achieved via a
multicomponents and catalyst-free reaction of phenyl or
p- chlorophenyl isothiocyanate, hydrazine, and alde-
hydes or ketones [33]. Besides, thiosemicarbazones are
versatile building blocks in the synthesis of densely sub-
stituted heterocycles [34–40]. It has been reported ear-
lier that, isatin-3-thiosemicarbazones were cyclized to
5H-as-triazino[5,6-b]indole-3-thiones in aqueous K2CO3
[41–43]. 3-(Dicyanomethylene)-2-indolone (2), [44]
which is a ylidene malononitrile, reacted with N,N0-dia-
rylaceta-midines to give spiro[2,3-dihydroindol-3,40-
(pyridine)-50-carbonitriles [45]. An efficient transforma-
tion of substituted carbohydrazides with 2 into spiro(in-
doline-3,20-oxadiazol)-2-ones and acylpyrazoloindoles
has been reported [46]. Recently, we have reported that
the reaction of acylthiosemicarbazides 1a–d with 2
afforded substituted pyrroloindenohydrazide 3a–d and
Antidepressants and anticonvulsants are among the
most widely utilized drugs for the treatment of central
nervous system (CNS) disorders [1–4]. The 1,3,4-thia-
diazole core is found to be the active part of several bio-
logically active compounds, including antibacterial [5–
8], antifungal [7,8], antitubercular [9–11], analgesic
[12], anti-inflammatory [7,8,13], antidepressant [14], and
leishmanicidal agents [15]. Isatin is an endogenous com-
pound isolated, and reported to possess a wide range of
central nervous system activities [16–18]. Isatin has
been identified as a selective inhibitor of monoamine
oxidaze B (MAOB), with IC50 values of about 5 lM
[16,19], it is also considered an endogenous marker of
stress and anxiety [20]. Several studies show that isatin
exhibits anxiogenic effects at doses of 10–20 mg/kg
[21], in contrast to sedative and anticonvulsant effects at
doses of 80–200 mg/kg [22]. Furthermore, isatin deriva-
tives are reported to show a variety of biological activ-
ities like antibacterial [23], antifungal [24], anti-HIV
[25] anticonvulsant [26], antineoplastic [27,28], and
DNA gyrase inhibitors [29]. In addition, a number of
C
V
2011 HeteroCorporation

September 2011 Synthesis of Novel Spiro(indolone-3,20-[1,3,4]thiadiazol)-2-ones and Evaluation
of Their Antidepressant and Anticonvulsant Activities
1051
Scheme 1
the presence of an allyl group which appeared as three
multiplets centered at 4.31, 5.28, and 6.0 ppm due to
allyl-CH2N, allyl-CH2¼¼ and allyl-CH¼¼, respectively.
The presence of the allyl group was also proved by the
13C-DEPT-NMR spectrum, exhibiting positive signals at
133.78 (allyl-CH¼¼) and negative signals at 47.12, 116.34
due to (allyl-CH2N and (allyl ACH2¼¼), respectively. The
IR and 13C-NMR spectra of 8a–f confirmed the disappear-
ance of a thione group, respectively. Instead, signals at
110.10–109.86 (spiro-C-3¼¼C-20), 162.22–162.86 (C-50),
and 177.18–175.93 ppm (indolone–CO) could be
observed, in addition to the aromatic carbons.
In 8d, mass spectrometry and elemental analysis
proved the molecular formula as C15H10F2N4SO. The IR
spectrum revealed absorption bands at u ¼ 3350–3190,
1710, and 1625 cm–1 assigned to NH, CO, and C¼¼N
stretching, respectively. Distinctive 13C-NMR signals of
8d appeared at dc ¼ 176.12 (indolone-CO), 161.18 for
(3,5-diflorophenyl), 162.87 (C-50), 110.08 (C-3¼C-20),
124.86, 125.71, 125.92, 128.26, 129.66, 129.91 (Ar-
CH), and 132.66, 141.75, 143.26 (Ar-C) ppm. The ana-
lytical data of compound 8a–f also match those of other
isomers of products 7, 9, and10 (Scheme 2).
thiazolo[5,4-b]indolylidene hydrazide derivatives 4a–d
[47] (Scheme 1). Encouraged by the above-mentioned
results, the present work describes the chemical behav-
ior of 4-substituted thiosemicarbazides 5a–f towards
dicyano-methyleneindolone 2. The isolated compounds
8a–e were evaluated each for antidepressant activity
using tail suspension behavioral despair test [48] and
anticonvulsant activity against pentylenetetrazol (PTZ)
induced seizures in mice [49].
The alternative structures 7 and 9 were ruled out on
1
the basis of H-NMR and 13C-NMR spectra. Therefore,
we will concentrate on the interplay between the forma-
tion of the products 8 and the alternative structures 10.
A priori possible isomer structure 10 was ruled out on
RESULTS AND DISCUSSION
1
the basis of H-NMR and disappearance of the thiosemi-
Chemistry. Heating equimolar amounts of 5a–f with
3-(dicyanomethylene)-2-indolone (2) in ethanol/piperi-
dine under reflux resulted in pink coloration of the solu-
tion, which later turned into reddish brown precipitates
from 8a–f. The structures of 8a–f were delineated from
their spectroscopic properties and molecular composi-
tions. The products 8a–f, obtained from 5a–f, were
found to be formed by reacting one molecule of 5a–f
and one molecule of 2 via loss of a molecule of malono-
nitrile. The molecular ions in their EI-mass spectra con-
firm the molecular masses and the molecular composi-
tions. Furthermore, the common features of the fragmen-
tation patterns supported the assigned structures. The
EI-mass spectra of 8a–f are characterized by molecular
ions of high intensity and the loss of 28 a.m.u (dinitro-
gen or carbonyl group) followed by the loss of 119
a.m.u (most likely PhN¼¼C¼¼O) and RN¼¼C¼¼S from
the molecular ion. The IR spectra of 8a–f showed
absorption bands characteristic for NH groups at 3430–
3350, 3250–3190, strong carbonyl group at 1710–1695
carbazide-N2-H proton. Moreover, the fact that the in
the structures 10, the NH-thiadiazole in position 3 in
not adjacent to C¼¼N double bond should result in
1
considerable lowering of the dH value [30] in H-NMR
spectra which was not the case of 8a–f. Based on
these observations the formation of isomers 10 was
excluded.
Nucleophilic attacks of the terminal NH2 of 5a–f on
C-3 of 2 with elimination of malononitrile from adduct
6 gives rise to indolone 7. Intramolecular attack of the
thione sulfur atom on C-3 of 7 leads to the formation of
spiroindoline-3,20-[1,3,4]thiadiazolone derivatives 8a–f.
The alternative option, namely nucleophilic attack of R-
NH-group on C-3 of 7, is not observed, since a product
of structure 9 instead of 8a–f was not found.
PHARMACOLOGY
Antidepressant activity. The synthesized compounds
8a–e were screened for antidepressant activity using tail
suspension behavioral despair test [48]. This test is used
effectively in predicting the activity of a wide variety of
antidepressants such as MAO inhibitors and tricyclic
antidepressants [48]. Results of the antidepressant
1
and C¼¼N at 1625–1620 cmꢀ1. The H-NMR spectrum
of 8c clearly showed the presence of three different
broad signals with the ratio 1:1:1 at 12.82, 9.75, and
7.65 ppm due to thiadiazole-NH, indole-NH, and allyl-
1
NH, respectively. The H-NMR of 8c clearly indicated
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
A. A. Hassan, F. F. Abdel-Latif, A. M. N. El-Din, M. Abdel-Aziz, S. M. Mostafa, and S. Brase
1052
Vol 48
Scheme 2
PTZ induced seizures in mice [49]. The results of these
experiments are listed in Fig. 1 and were determined
using the following formula [50].
% of protection ¼
no:of convulsions of controlꢀno:of convulsions of treated
no: of convulsions of control
ꢁ 100
Compounds 8a, 8b, and 8d exhibited the most protec-
tive class of the tested compounds against clonic seiz-
ures induced by ip injection of PTZ. They induced
87.78, 73.33, and 67.03% protection, respectively, at a
dose level of 20 mg kgꢀ1
.
Compound 8a showed a markedly protective effect
nearly equal to phenobarbital sodium at a dose level of
30 mg kgꢀ1 and better than phenytoin sodium at a dose
level of 30 mg kgꢀ1. Compound 8b exhibits a remark-
able protective effect close to phenobarbital sodium at a
dose level of 30 mg kgꢀ1 and better than phenytoin so-
dium at a dose level of 30 mg kgꢀ1. Compound 8d
exhibited a good protective effect compared with pheno-
barbital sodium at a dose level of 30 mg kgꢀ1 and better
than phenytoin sodium at a dose level of 30 mg kgꢀ1
.
Compound 8e exhibited a moderate protection against
clonic seizures induced by ip injection of PTZ at a dose
level of 20 mg kgꢀ1, it induced 47.03%. Compound 8c
exhibited a weak protection against clonic seizures
induced by ip injection of PTZ at a dose level of 20 mg
kgꢀ1. The results are illustrated in Fig. 1.
Table 1
Antidepressant activities of the tested compounds 8a–e compared to
imipramine.
Antidepressant activities
Duration of
immobility (s)
(mean 6 S.E.M.)
Change from
control (%)
Compoundsa
activity of the tested compounds and reference drugs are
given in Table 1.
8a
8b
8c
8d
55.10 6 6.64
66.98 6 5.33
64.55 6 6.44
53.21 6 4.45
116.60 6 4.50
132.00 6 3.60
243.30 6 8.00
ꢀ77.35
ꢀ72.47
ꢀ72.64
ꢀ78.13
ꢀ52.07
ꢀ45.75
–
Compounds 8d and 8a exhibit remarkable antidepres-
sant activity compared with imipramine: their activities
are nearly equal 2.5 times the activity of imipramine.
Compounds 8c and 8b significantly reduced the duration
of immobility times to 64.55 and 66.98 s, respectively,
compared with 132.00 s reduction of the duration of
immobility for imipramine at 10 mg kgꢀ1 dose level.
Compounds 8c and 8b induced remarkable antidepres-
sant activity compared with imipramine, their activities
are nearly equal twice the activity of imipramine. Com-
pounds 8c and 8b significantly
8e
Imipramine
Control
Values represent the mean 6 S.E.M. (n ¼ 6)
a Tested compounds and imipramine were tested at 10 mg.kgꢀ1 dose
level, ip. reduced the duration of immobility times to 64.55 and 66.98
s, respectively, compared with 132.00 s reduction for imipramine at 10
mg kgꢀ1 dose level. Compound 8e exhibits antidepressant activity,
nearly equaling 1.13 times the activity of imipramine. Compound 8e
significantly reduced the duration of immobility times to 116.60 s
compared with 132.00 s reduction for imipramine at 10 mg kgꢀ1 dose
level.
Anticonvulsant activity. The synthesized compounds
8a–e were evaluated for anticonvulsant activity against
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011 Synthesis of Novel Spiro(indolone-3,20-[1,3,4]thiadiazol)-2-ones and Evaluation
of Their Antidepressant and Anticonvulsant Activities
1053
proper isothiocyanate according to published procedures in lit-
erature: 4-phenyl-thiosemicarbazide (5a) [51,52], 4-benzylthio-
semicarbazide (5b) [33,34], 4-allylthiosemicarbazide (5c)
[53,54], 4-(3,5-difluoro-phenyl)thiosemicarbazide (5d) [55], 4-
[4-(trifluoromethyl)-phenyl]thiosemicarbazide (5e) [55], 4-(4-
fluorophenyl)thio-semicarbazide (5f) [56]. 3-(Dicyanomethy-
lene)-2-indolone 2 was prepared according to Fatiadi [44].
Reaction of 4-substituted thiosemicarbazides (5a–f) with 3-
(dicyanomethylene)-2-indolone (2). Thiosemicarbazides (5a–f)
(1.0 mmol) were dissolved in 20 mL absolute ethanol with
two drops of piperidine and added to the indolone (2) (1
mmol) in 25 mL absolute ethanol, the mixture was heated
under reflux for 3h (for run 5a), 4h (for runs 5b,c), 7h (for
runs 5e,f), and 5h (for run 5d) cooled to room temperature.
Yellowish brown crystals from compounds 8a–f were precipi-
tated, filtered, and washed with a small amount of cold ethanol
and recrystallized from listed solvents.
50-(Phenylamino)-30H-spiro(indoline-3,20-[1,3,4]-thiadiaz-
ole)-2-one (8a). This compound was obtained as yellowish
brown crystals (acetonitrile), mp 220–222; IR (KBr) u: NH
3390–3210, CO 1695, C¼¼N 1625, Ar-C¼¼C 1600 cmꢀ1
;
1H-
Figure 1. Anticonvulsant activity of compounds 8a–e expressed as
mean 6 S.E.M. compared with Phenobarbital sodium and phenytoin
sodium at a dose level of 30 mg kgꢀ1. Compounds were tested at 20
mg kgꢀ1 dose level, ip. Values represent the mean 6 S.E.M. (n ¼ 6).
NMR (DMSO-d6); d 6.90–7.70 (m, 9H, Ar-H), 8.60 (br, 1H,
NHPh), 9.45 (br, 1H, indolone-NH), 12.85 (br, 1H, thiadia-
zole-NH); 13C-NMR (DMSO-d6):
d
110.10 (C-3¼¼C-20),
124.32, 125.31, 126.50, 128.21, 128.95, 131.65 (Ar-CH),
137.53, 137.84, 141.14 (Ar-C), 162.58 (C-50), 175.93 (CO);
MS: m/z 296 (Mþ, 51), 268 (100), 203 (6), 179 (9), 161 (10),
150 (14), 104 (12), 93 (18), 77 (15). Anal. calcd. for
C15H12N4OS: C, 60.79; H, 4.08; N, 18.91; S, 10.82. Found: C,
60.94; H, 3.98; N, 19.06; S, 10.94.
CONCLUSION
The presented synthesis provides insight into the reac-
tions between the electron donating 4-substituted thiosemi-
carbazides 5a–f and a suitable electron acceptor, 2 in our
case. Spiroindoline-3,20-[1,3,4]thiadiazolones 8a–f are
formed from 5a–f and 2 (in presence of a base such as pi-
peridine). The results reported here-in supplement the rich
chemistry of 3-(dicyanomethylene)-2-indolone 2.
The results indicated that all of the tested compounds
induced remarkable antidepressant activity compared with
imipramine at 10 mg kgꢀ1 dose level. Moreover, com-
pounds 8a, 8b, and 8d represented the most protective
class of the tested compounds against clonic seizures
induced by ip injection of PTZ, their effect nearly close
to that of phenobarbital sodium at a dose level of 30 mg
kgꢀ1. Therefore, these compounds appear to be promising
for their antidepressant and anticonvulsant activities.
50-(Benzylamino)-30H-spiro(indoline-3,20-[1,3,4]thiadiazole)-
2-one (8b). This compound was obtained as yellowish brown
crystals (acetonitrile), mp 200–202; IR (KBr) u: NH 3430–
3250, CO 1705, C¼¼N 1620, Ar-C¼¼C 1605 cmꢀ1
;
1H-NMR
(DMSO-d6); d 4.90 (S, 2H, CH2Ph), 7.05–7.55 (m, 9H, Ar-H),
7.75 (br, 1H, NH-CH2Ph), 9.70 (br, 1H, indolone-NH), 12.76
(br, 1H, thiadiazole-NH); 13C-NMR (DMSO-d6): d 48.67
(CH2), 109.86 (C-3¼¼C-20), 127.56, 128.23, 128.67, 128.95,
129.16, 131.25 (Ar-CH), 132.21, 133.35, þ143.14 (Ar-C),
162.61 (C-50), 173.36 (CO); MS: m/z 310 (M , 67), 282 (24),
164 (43), 149 (90), 118 (26), 106 (71), 91 (100), 77 (21).
Anal. calcd. for C16H14N4OS: C, 61.92; H, 4.55; N, 18.05; S,
10.33. Found: C, 62.06; H, 4.39; N, 17.89; S, 10.51.
50-(Allylamino)-30H-spiro(indoline-3,20-[1,3,4]thiadiazole)-2-
one (8c). This compound was obtained as yellowish brown crys-
tals (ethanol), mp 190–192; IR (KBr) u: NH 3390–3220, CO
1
1705, C¼¼N 1620, Ar-C¼¼C 1600 cmꢀ1; H-NMR (DMSO-d6);
d 4.31 (m, 2H, allyl-CH2N), 5.28 (m, 2H, allyl-CH2¼¼), 6.0 (m,
1H, allyl-CH¼¼), 7.08–7.53 (m, 4H, Ar-H), 7.65 (br, 1H, NH-
allyl), 9.75 (br, 1H, indolone-NH), 12.82 (br, 1H, thiadiazole-
NH); 13C-NMR (DMSO-d6): d 47.12 (allyl-CH2-N), 110.08 (C-
3¼¼C-20), 116.34 (allyl-CH2¼¼), 129.15, 129.76, 128.67, 128.95,
129.16, 131.25 (Ar-CH), 133.78 (allyl-CH¼¼), 136.85, 137.22,
142.81 (Ar-C), 162.22 (C-50), 176.62 (CO); MS: m/z 260 (Mþ,
23), 232 (21), 161 (18), 147 (46), 113 (51), 91 (100). Anal.
calcd. for C12H12N4OS: C, 55.37; H, 4.65; N, 21.52; S, 12.32.
Found: C, 55.22; H, 4.76; N, 21.39; S, 12.48.
50-(3,5-Difluorophenylamino)-30H-spiro(indoline-3,20[1,3,4]-
thiadiazole)-2-one (8d). This compound was obtained as pale
yellowish-brownish crystals (acetonitrile), mp 260–262; IR
(KBr) u: NH 3350–3190, CO 1710, C¼¼N 1625, Ar-C¼¼C
EXPERIMENTAL
Chemistry. Melting points (uncorrected) were determined in
open glass capillaries on a Gallenkamp melting point apparatus.
The IR spectra were recorded with a Shimadzu 408 (potassium
bromide disks). The 400 MHz 1H and 100 MHz 13C-NMR spectra
were recorded on a Bruker AM 400 spectrometer with tetramethyl-
silane as the internal standard, br ¼ broad, s ¼ singlet, m ¼ mul-
tiplet. The 13C signals were assigned on the basis of DEPT 135/90
spectra. The mass spectra (70 eV, electron impact mode) were
recorded on a Finnigan MAT instrument. Elemental analyses were
carried out at the microanalytical center, Cairo University, Egypt.
Starting materials. 4-Substituted thiosemicarbazides (5a–f)
were synthesized by the reaction of hydrazine hydrate with the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A. A. Hassan, F. F. Abdel-Latif, A. M. N. El-Din, M. Abdel-Aziz, S. M. Mostafa, and S. Brase
1054
Vol 48
1
1605 cmꢀ1; H-NMR (DMSO-d6); d 7.02–7.88 (m, 7H, Ar-H),
9.91 (br, 1H, indolone-NH), 10.18 (br, 1H, NH-C6H3-F2),
12.86 (br, 1H, thiadiazole-NH); 13C-NMR (DMSO-d6): d
110.08 (C-3¼¼C-20), 124.86, 125.71, 125.92, 128.26, 129.66,
129.91 (Ar-CH), 132.66, 141.75, 143.26 (Ar-C), 16þ1.18 (Ar-C-
F), 162.87 (C-50), 176.12 (CO); MS: m/z 332 (M , 52), 304
(100), 178 (11), 150 (18), 104 (26), 77 (19). Anal. calcd. for
C15H10F2N4OS: C, 54.21; H, 3.03; N, 16.86; S, 9.65. Found:
C, 54.06; H, 2.91; N, 17.05; S, 9.83.
animals were similarly treated with CMC solution (0.5%
w/v in water). One hour later, the mice were suspended
by the tail to the edge of a shelf 80 cm above the floor.
The tail was secured to the shelf by adhesive tape
placed approximately 1 cm from the tip of the tail. The
duration of the immobility was recorded for a period of
6 min. Mice were considered immobile only when they
hung passively and completely motionless.
50-[(4-Trifluoromethyl)(phenylamino)-30H-spiro-(indoline-
3,20-[1,3,4]thiadiazol)]-2-one (8e). This compound was
obtained as pale yellowish brown crystals (acetonitrile), mp
248–250; IR (KBr) u: NH 3390–3210, CO 1695, C¼¼N 1625,
Anticonvulsant activity. The synthesized compounds
8a–e were evaluated for anticonvulsant activity against
PTZ induced seizures in mice [49]. On the testing day,
mice were assigned into different groups (n ¼ 6 for
each group). The tested compounds were dissolved in
CMC solution (0.5% w/v in water) and administered to
animals at a dose of (20 mg kgꢀ1) ip at a volume of 0.5
mL per 100 g body weight. After1 h, the administration
of the tested compound, mice were injected PTZ (80 mg
kgꢀ1) as a 0.5% solution ip that produces clonic seizures
lasting for a period of at least 5 s in greater than 95%
of animals tested. The animals were observed for 30
min, failed to observe even a threshold seizure (a single
episode of clonic spasms of at least 5 s duration was
defined as protection). Animals devoid of generalized
convulsions were considered to be protected, and the
results were represented as percentage protection [50].
Standard drug used was phenobarbital sodium and phe-
Ar-C¼¼C 1605 cmꢀ1
;
1H-NMR (DMSO-d6); d 6.95–7.90 (m,
8H, Ar-H), 9.92 (br, 1H, indolone-NH), 10.18 (br, 1H, NH-
Ph), 12.91 (br, 1H, thiadiazole-NH); 13C-NMR (DMSO-d6): d
110.02 (C-3¼¼C-20), 123.88 (C-F3), 125.96, 126.18, 127.74,
128.65, 129.26 (Ar-CH), 131.66, 132.74, 142.83, 143.11 (Ar-
C), 162.28 (C-50), 177.18 (CO); MS: m/z 364 (Mþ, 56), 336
(100), 218 (8), 203 (17), 178 (21), 150 (33), 104 (35), 77 (21).
Anal. calcd. for C16H11F3N4OS: C, 52.74; H, 3.04; N, 15.38;
S, 8.80. Found: C, 52.92; H, 2.89; N, 15.21; S, 9.02.
50-(4-Fluorophenylamino)-30H-spiro(indoline-3,20-[1,3,4]-
thiadiazole)-2-one (8f). This compound was obtained as pale
yellowish brown crystals (methanol), mp 236–238; IR (KBr)
u: NH 3385–3215, CO 1695, C¼¼N 1620, Ar-C¼¼C 1605
cmꢀ1; H-NMR (DMSO-d6); d 6.95–7.78 (m, 8H, Ar-H), 9.83
1
(br, 1H, NH, indolone-NH), 10.26 (br, 1H, NH-C6H4-F), 12.76
(br, 1H, thiadiazole-NH); 13C-NMR (DMSO-d6): d 109.92 (C-
3¼¼C-20), 125.24, 126.63, 128.55, 129.15, 129.76, 131.25 (Ar-
CH), 132.16, 135.77, 142.66 (Ar-C), 16þ0.65 (Ar-C-F), 162.71
(C-50), 176.53 (CO); MS: m/z 314 (M , 22), 266 (27), 152
(11), 110 (26), 91 (100). Anal. calcd. for C15H11FN4OS: C,
57.31; H, 3.53; N, 17.82; S, 10.20. Found: C, 57.47; H, 3.39;
N, 18.03; S, 10.36.
nytoin sodium at a dose level of 30 mg kgꢀ1
.
Statistical analysis. Results are expressed as mean 6
S.E.M.; n represents the number of animals. Data
obtained from pharmacological experiments were ana-
lyzed by one-way analysis of variance. A P-value of
less than 0.05 was considered statistically significant.
PHARMACOLOGY
Acknowledgments. A. A. Hassan is indebted to the A. v.
Humboldt-Foundation for the donation of the Shimadzu
408 IR spectrophotometer. The authors are gratefully to
the Pharmacology Department, Faculty of Pharmacy,
Minia University for their valuable help in measuring the
antidepressant and anticonvulsant activities.
Adult male albino Swiss-Webster mice (22 6 2 g)
were obtained from the animal house, Cairo. The mice
were housed in a quiet and temperature and humidity-
controlled room (22 6 3ꢂC and 60 6 5%, respectively)
in which a 12 h light/dark cycle was maintained (08.00–
20.00 h light). The animals were acclimated to their
environment for at least 2 days before the experiments
and were allowed free access to food and water before
being tested.
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