1
From
Dr. Ashok Kumar
Prof-cum-druggist,
Department of Pharmacology
L.L.R.M. Medical College, Meerut
(U.P.) 250004 (India)
To,
Executive Editor
Shahrah-e-Dr. Salimuzzaman Siddiqui
Pakistan Journal of Scientific and Industrial Research,
Scientific Information Centre, PCSIR Laboratories Campus,
Karachi-75280, Pakistan.
Dear Sir,
I am herewith online submitting the paper entitled, “Synthesis of
substituted indole derivatives as anticonvulsant agents’’ for publication to your esteemed
journal. I shall be kind enough you can acknowledge the receipt of the paper either by e-mail,
or by post.
Thanking you.
Yours Sincerely
(Ashok Kumar)
ashokraj.kumar744@gmail.com
2
Synthesis of substituted indole derivatives as anticonvulsant agents
Hemlata Kaur, Sunil Kumar and Ashok Kumar*
Medicinal Chemistry Division, Department of Pharmacology,
L.L.R.M. Medical College, Meerut 250004, U.P. India.
Abstract
A series 3-[6’-{2’’-(Substituted phenyl-4’’-oxothiazolidin-3’’-yl)-s-triazol-3’-yl [5’, 4’-b]
[1’,3’,4’]thiadiazole]methylindoles
and
3-[6’-{2”-(4”-substituedphenyl-3”-chloro-2”-
oxoazetidin-1”-yl)-s-triazol-3’-yl [5’,4’-b] [1’,3’,4’] thiadiazole] methyl indoles were designed,
synthesized and tested for anticonvulsant activity. All compounds were screened in vitro
anticonvulsant activity against maximal electroshock seizure induced convulsions and tested
for their acute toxicity. Structures of all the compounds of this series have been established
by elemental and spectral (IR, 1H-NMR and Mass) analysis. Out of these nineteen
compounds the most active compound was 3-[6’-(2”- (4-methoxyphenyl)-4”-oxothiazolidin3’-yl)-s-triazol-3’-yl [5’,4’-b][1’,3’,4’] thiadiazole] methyl indole 12. Interestingly this
compounds exhibits more potent and equipotent anticonvulsant activity than standard drug
phenytoin sodium and lamotrigine respectively and less toxicity.
Keywords: Benzylidene triazolyl-thiadiazolyl indoles, Triazolyl-thiadiazolyl azetidinonyl
indoles, Triazolyl-thiadiazolyl thiazolidinonyl indoles, Anticonvulsant activity, acute
toxicity.
Introduction
Indole derivatives substituted by different heterocyclic moieties at 1, 2 and specially at 3-
*Corresponding author: Mobile: +919917053074
E-mail address: ashokraj.kumar744 (A. Kumar)
Fax: +91 121 2760888
3
positions have been reported to exhibit anticonvulsant (Archana et al 2003; George et al
2008) antipsychotic (Bajaj et al. 2003) and Antifungal (Young et al. 2003) properties. Several
of these heterocyclic substituted indoles showed a high level of protection against maximal
electroshock induced seizure (MES) induced convulsions in animal models. Triazoles
(Almasirad et al. 2004; Jin et al., 2006) and thiadiazoles (Chapleo et al. 1988; Dogan et al.,
2002) have been observed to exhibit anticonvulsant properties in experimentally induced
convulsions. Similarly, substituted azetidinones (Srivastava et al. 2002; Rajasekaran A. and
Murugesan S. 2005) and thiazalidinones (Archana et al. 2003; Agarwal et al. 2006) have
been found to showed anticonvulsant effect in various experimental models. However, these
compounds have not been in clinical use as they possess either less activity or more side
effects. Incorporating these moieties at 3rd position of indole nucleus might be thought to
yield more potent anticonvulsant compound as substitution on 3rd position further results in
protection against convulsions. Thus the substitution by these moieties may be synergistic.
The present project is therefore aimed at synthesizing such compounds.
Chemistry
The target indole derivatives were synthesized in scheme 1. The reaction of indole with ethyl
chloro acetate in methanol afforded the Ethyl-2-(1H-indol-3’-yl) acetate 1 in high yield
(90%). The Ethyl-2-(1H-indol-3’-yl) acetate was converted into 3-(2’-hydrazinoacetyl)
indole 2 by using hydrazine hydrate in absolute ethanol in high yield (85%). 3-(4’-Amino-5’mercapto-1’, 2’, 4’ triazol-3’-yl) methyl indole 3 were prepared by the reaction of 3-(2’hydrazinoacetyl) indole 2 with carbon disulphide and KOH and cyclisation of hydrazine
hydrate (72%). Compound 3 on reaction with cyanogens bromide furnished 3-(6'-Amino-striazol-3'-yl [5', 4’-b] [1', 3’, 4’] thiadiazole) methylindole 4 (70%). The reaction mixture of
compound 4 in methanol and glacial acetic acid were added to various substituted aromatic
aldehydes
to
obtained
3-[(6’-(Substituted
benzylidenylimino)-5-triazol-3’-yl[5’,4’-b]
[1’,3’,4’] thiadiazole] methylindoles 5-9 (59-72%) . Compounds 5-9 undergo cycloaddition
4
reaction with thioglycolic acid in presence of pinch of anhydrous zinc chloride in methanol to
furnish
3-[6'-{2”-(Substituted
phenyl-4"-oxothiazolidin-3"yl)}-s-triazol-3'-yl
[5',
4’-b]
[1',3',4'] thiadiazole] methylindoles 10-14 (60-72%). 3-[6’-{2”-(4”-substituedphenyl-3”chloro-2”-oxoazetidin-1”-yl)}-s-triazol-3’-yl [5’,4’-b] [1’,3’,4’] thiadiazole] methyl indoles 1519 were synthesized by the reaction mixture of compounds 5-9 and chloroacetyl chloride in
presence of tri ethyl amine (68-75%). The purity of synthesized compounds was determined
by thin layer chromatography using several systems of different polarity.
Material and Methods
The melting points of the compounds were determined in open capillaries with the help of
thermonic melting point apparatus and were uncorrected. The homogeneity of all the newly
synthesized compounds was routinely checked by thin layer chromatography. Elemental
analysis (C, H, N) of all the compounds were determined by Perkin-Elmer 2400 elemental
analyses and results were found within  0.4% of theoretical values. Infra-red (IR) spectra
were recorded in KBr on Perkin Elmer-spectrum RX-I, spectrometer and max was recorded
in cm-1. 1H NMR spectra were recorded by Bruker AC-300 F instrument using a mixture of
CDCl3 and DMSOd6 as solvent and tetramethyl silane (TMS) as internal reference standard.
All chemical shift values were recorded as  (ppm). Mass spectra were determined on VG70-S instrument. Elemental and spectral analyses of the compounds were obtained from
Sophisticated, Analytical, Instrumentation facility Chandigarh, Punjab, India.
Procedure for preparation of Ethyl-2-(1H-indol-3’-yl) acetate (1)
Dissolve the indole (1.0 mol) in methanol and ethyl chloro acetate (1.0 mol) was added
dropwise in presence K2CO3 (5 gm) in the mixture with stirring. The resulted mixture was
refluxed for 10 hours and the reaction mixture poured into ice cold water and neutralized
with dil HCl. The semisolid thus obtained was washed several times with water and left in
water for 72 hours. The crystals formed were filtered, washed thoroughly with water and
5
dried. The completion of the reaction was mentioned on T.L.C. by using silica Gel G coated
plates by using ethyl acetate and petroleum ether (1:1) as the eluent and observed in UV light
and Ethyl-2-(1H-indol-3’-yl) acetate was obtained. Yield: 90%; mp: 42 ºC. IR (KBr) : 
(cm–1) 1123 (C-O), 1580 (C ... C of aromatic ring), 1676 (C=O), 2900 (C-H aliphatic), 3015
(C-H aromatic stretching), 3320 (N-H stretching); 1H-NMR:  (ppm)  2.33 (t, 3H, C3-CH2COOCH2CH3), 4.71 (q, 2H, C3-CH2-COOCH2CH3), 5.50 (s, 2H, C3-CH2.COOCH2CH3)
7.02-6.35 (m, 5H, Ar-H), 8.90 (brs, 1H, NH of indole exchangeable with D2O). Mass M+ at
m/z 203. Anal. Calcd for C12H13NO2 : C, 70.94; H, 6.40; N, 6.90; Found: C, 70.75; H, 6.28;
N, 6.82.
Procedure for preparation of 3-(2’-Hydrazinoacetyl) indole (2).
To a solution of Ethyl-2-(1H-indol-3’-yl) acetate 1 (0.2 mol) in absolute ethanol (99%),
hydrazine hydrate (0.2 mol) were added and the reaction mixture was refluxed for 12 hours.
The excess of solvent was distilled off and reaction mixture was cooled, poured onto crushed
ice and filtered off. The separated solid was recrystallized from ethanol-water to furnish
compound 2. Yield: 85%; mp: 50 ºC. IR (KBr):  (cm–1) 1269 (N-N stretching), 1580
(C=N), 1590 (C ... C of aromatic ring), 3148 (C-H aromatic stretching) 1665 (C=O), 3342
(NH2), 3314 (N-H stretching); 1H-NMR:  (ppm).
5.52 (s, 2H, C3-CH2-CONH.NH2
exchangeable with D2O), 7.00-6.40 (m, 5H, Ar-H ), 8.94 (brs, 1H NH of indole exchangeable
with D2O) 9.26 (brs, 3H, C3-CH2CO-NH. NH2 exchangeable with D2O). Mass, M+ at m/z
189. Anal. Calcd for C10H11N3O: C, 63. 49, H, 5.82; N, 22.22; Found : C, 63.32 H, 6.01, N,
22.46.
Procedure for preparation of 3-(4'-Amino-5-mercapto-1', 2', 4'-triazolyl-3'-yl) methyl
indole (3).
To a methanolic solution of 3-(2’-Hydrazinoacetyl) indole 2 (0.1 mol), KOH (0.1 mol) and
carbon disulphide (0.1 mol) were added slowly with constant stirring. The reaction mixture
6
was refluxed with excess of hydrazine hydrate for 4 hours. The reaction mixture was cooled,
poured into ice water and neutralized with dil. HCl. Product thus obtained was filtered,
washed with water dried and recrystallized from aqueous methanol to give compound 3.
Yield: 72%; mp: 66 ºC. IR (KBr) :  (cm–1) 1295 (N-N stretching), 1603 (C ... C of aromatic
ring), 1580 (C=N), 2710 (S-H), 3142 (C-H aromatic stretching), 3332 (N-H stretching), 3344
(NH2); 1H-NMR:  (ppm) 5.75 (hump, 2H, NH2 exchangeable with D2O), 6.25 (s, 2H, C3CH2 6.98-6.30 (m, 5H, Ar-H), 8.93 (brs, 1H, NH of indole exchangeable with D2O), 11.43
(brs, 1H, SH exchangeable with (D2O). Mass, M+ at m/z 245. Anal. calcd. for C11H11N5S : C,
53.88; H, 4.49; N, 28.57; Found : C, 53.84; H, 4.44; N, 28.34.
Procedure for preparation of 3-[6'-{2” - Amino-s-triazol-3'-yl [5', 4’-b] [1', 3’, 4’]
thiadiazole) methylindole (4)
Compound 3 (0.05 mol) was dissolved in absolute ethanol (35 ml). To the solution obtained
cyanogen bromide (0.05 mol) was added and the resulting reaction mixture was refluxed for
8 hours on a steam bath. Concentration of the mixture to one fourth of its volume left a
residue, which was diluted with saturated solution of sodium acetate. The precipitated solid
was filtered, dried and recrystallized from ethanol to afford compound 4. Yield: 70%; mp:
138 ºC. IR (KBr):  (cm–1) 671 (C-S-C), 1296 (N-N stretching), 1610 (C ... C of aromatic
ring) 1585 (C=N), 3143 (C-H aromatic stretching), 3321 (N-H stretching) 3340 (NH2) ; 1HNMR:  (ppm) 5.70 (hump 2H, NH2 exchangeable with D2O), 6.24 (s, 2H, C3-CH2), 7.056.40 (m, 5H, Ar-H) 8.91 (brs, 1H, NH of indole exchangeable with D2O). Mass, M+ at m/z
270. Anal. Calcd for C12H10N6S : C, 53.33; H, 3.70; N, 31.11; Found C, 53.47; H, 3.62; N,
31.34.
General procedure for the preparation of 3-[(6'{2”-Substitutedbenzylidenylamino)-striazol-3'-yl [5', 4'-b] [1', 3’, 4’ thiadiazole] methyl indoles (5-9)
7
Compound 4 (0.04 mol), benzaldehyde (0.04 mol) and glacial acetic acid (2 ml) were
refluxed in methanol (60 ml) for about 8 hours. The solvent was distilled off at reduced
pressure and the solid mass thus obtained was recrystallized from benzene to afford
compound 5. Yield: 72%; mp: 190 ºC. IR (KBr):  (cm–1) 672 (C-S-C), 1298 (N-N
stretching), 1611 (C ... C of aromatic ring), 1586 (C=N), 3142 (C-H aromatic stretching) ; 1HNMR:  (ppm) 6.25 (s, 2H, C3-CH2), 7.83-6.38 (m, 10H, Ar-H), 8.62 (s, 1H, =CH-Ar), 8.92
(brs, 1H, NH of indole exchangeable with D2O). Mass, M+ at m/z 358. Anal. Calcd. for
C19H14N6S : C, 63.69; H, 3.91; N, 23.46; Found : C, 63.78 ; H, 3.74; N, 23.32.
3-[6'{2”-(4-Hydroxy benzylidenyl amino)-s-triazol-3'-yl [5',4'-b] [1',3',4' thiadiazole]
methyl indole (6).
Yield: 68%; (Ethanol) mp: 142 ºC. IR (KBr)  (cm–1) 674 (C-S-C), 1299 (N-N stretching),
1613 (C ... C of aromatic ring). 1583 (C=N), 3144 (C-H aromatic stretching) 3440 (OH
stretching); 1H-NMR:  (ppm) 6.28 (s, 2H, C3-CH2), 7.99-6.38 (m, 9H, Ar-H), 8.62 (s, 1H,
=CH-Ar), 11.17 (s, 1H, OH), 8.92 (brs, 1H, NH of indole exchangeable with D2O) Mass, M+
at m/z 374. Anal. Calcd. for C19H14N6OS :C, 60.96; H, 3.74; N, 22.46; Found : C, 60.74 ; H,
3.84; N, 22.38.
3-[6'{2”-(4- Methoxybenzylidenylamino-s-triazol -3'-yl[5',4'-b] [1',3',4' thiadiazole]
methyl indole (7)
Yield: 70%; (Acetone) mp: 145 ºC. IR (KBr)  (cm–1) 676 (C-S-C), 1295 (N-N stretching)
1612 (C ... C of aromatic ring) 1587 (C=N), 3148 (C-H aromatic stretching), 1225 (OCH3);
1
H-NMR:  (ppm) 6.30 (s, 2H, C3-CH2), 8.10-6.38, (m, 9H, Ar-H) 8.63 (s, 1H, =CH-Ar),
3.38 (s, 3H, OCH3), 8.92 (brs, 1H, NH of indole exchangeable with D2O) Mass, M+ at m/z
388. Anal. Calcd. for C20H16N6OS : C, 61.86; H, 4.12; N, 21.65; Found : C, 61.57 ; H, 4.03;
N, 21.79.
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3-[6'{2”- (4- Hydroxy-3-methoxy benzylidenylamino)-s-triazol -3'-yl[5',4'-b] [1',3',4'
thiadiazole] methyl indole (8)
Yield: 59%; (Benzene) mp: 130 ºC. IR (KBr)  (cm–1) 673 (C-S-C), 1297 (N-N stretching)
1615 (C ... C of aromatic ring) 1586 (C=N), 3149 (C-H aromatic stretching) 3439 (OH
stretching), 1223 (OCH3); 1H-NMR:  (ppm) 6.25 (s, 2H, C3-CH2), 8.11-6.39 (m, 8H, Ar-H),
8.64 (s, 1H, = CH-Ar), 3.39 (s, 3H, OCH3), 11.20 (s, 1H, OH) 8.93 (brs, 1H, NH of indole
exchangeable with D2O). Mass, M+ at m/z 404. Anal. Calcd. for C20H16N6O2S : C, 59.40; H,
3.96; N, 20.79; Found : C, 59.7 ; H, 3.74; N, 20.72.
3-[6'{2”-(4-NN' Dimethyl amino benzylidenylamino)-s- triazol -3'-yl[5',4'-b] [1',3',4'
thiadiazole] methyl indole (9)
Yield: 65%; (Methanol) mp: 100 ºC. IR (KBr)  (cm–1) 671 (C-S-C), 1298 (N-N stretching),
1615 (C ... C of aromatic ring) 1588 (C=N), 3145 (C-H aromatic stretching); 1H-NMR: 
(ppm) 6.29 (s, 2H-C3-CH2), 8.13-6.38 (m, 9H, Ar-H), 8.65 (s, 1H-CH-Ar), 1.50 (s, 6H, N
(CH3)2), 8.92 (brs 1H, NH of indole exchangeable with D2O); Mass, M+ at m/z 401. Anal.
Calcd. for C21H19N7S : C, 62.84; H, 4.74; N, 24.44; Found: C, 62.74 ; H, 4.86; N, 24.12.
General
procedure
for
the
preparation
of
3-[6'-{2"-(Substitutedphenyl-4"-
oxothiazolidin-3"yl)-s-triazol-3'-yl [5', 4'-b] [1',3',4'] thiadiazole] methylindoles (1014)
A mixture of compound 5 (0.008 mol) and thioglycolic acid (0.008 mol) in methanol (100
ml) in the presence of anhydrous ZnCl2 (a pinch) was kept for four days at room
temperature and the mixture was refluxed for 10 hours on water bath, excess solvent was
distilled off, poured into ice-cold water, filtered and finally recrystallized from methanol to
furnish compounds 10. Yield: 60%; mp: 160 ºC. IR (KBr) (cm–1) 673 (C-S-C), 1294 (NN stretching), 1614 (C ... C of aromatic ring) 1590 (C=N), 1760 (C=O of --thialactum
9
ring), 3143 (C-H aromatic stretching) ;
1
H-NMR:  (ppm) 3.90 (s, 2H, CH2 of
thiazolidinone ring), 5.65 (s, 1H, CH-Ar), 6.23 (s, 2H, C3-CH2), 7.92-6.32 (m 10H, Ar-H),
8.90 (brs, 1H, NH of indole exchangeable with D2O). Mass, M+ at m/z 432. Anal. Calcd. for
C21H16N6OS2 : C, 58.33; H, 3.70; N, 1944; Found : C, 58.45; H, 3.85; N, 19.32.
3-[6'-{2"-(4-Hydroxy phenyl-4"-oxothiazolidin-3"-yl)}-s-triazol-3'-yl [5',4'-b] [1',3',4']
thiadiazole] methylindole (11)
Yield: 65%; (Benzene) mp: 157 ºC. IR (KBr)  (cm–1) 674 (C-S-C), 1296 (N-N stretching)
1613 (C ... C of aromatic ring), 1587 (C=N), 1761 (C=O of -thialactum ring), 3144 (C-H
aromatic stretching) 3445 (OH stretching); 1H-NMR:  (ppm) 3.93 (s, 2H, CH2 of
thiazolidinone ring), 5.66 (s, 1H, CH-Ar), 6.24 (s, 2H, C3-CH2), 7.94-6.33 (m, 9H, Ar-H),
11.18 (s, 1H, OH), 8.89 (brs 1H, NH of indole exchangeable with D2O). Mass, M+ at m/z
448. Anal. Calcd. for C21H16N6O2S2 : C, 56.25; H, 3.37 ; N, 18.85; Found : C, 56.04; H, 3.42;
N, 18.82.
3-[6'-{2"-(4-Methoxyphenyl-4"-oxothiazolidin-3"-yl)} -s-triazol-3'-yl [5',4'-b] [1',3',4']
thiadiazole] methylindole (12)
Yield: 64%; (Acetone) mp: 162 ºC. IR (KBr)  (cm–1) 675 (C-S-C), 1298 (N-N stretching),
16.15 (C ... C of aromatic ring), 3146 (C-H aromatic stretching), 1227 (OCH3) 1585 (C=N),
1765 (C=O of -thialactum ring); 1H-NMR:  (ppm) 3.97 (s, 2H, CH2 of thiazolidinone ring),
5.68 (s, 1H, CH-Ar), 6.27 (s, 2H, C3-CH2), 7.91-6.33 (m, 9H, Ar-H), 8.95 (brs, 1H, NH of
indole exchangeable with D2O), 3.37 (s, 3H, OCH3). Mass, M+ at m/z 462. Anal.calcd. for
C22H18N6O2S2; C, 57.14; H, 3.90; N, 18.18; Found: C, 57.03, H, 3.75; N, 18.43.
3-[6'-{2"-(4-Hydroxy-3-methoxyphenyl-4"-oxothiazolidin-3"-yl)}-s-triazol -3'-yl [5',4'b] [1',3',4'] thiadiazole] methylindoles (13)
Yield: 72%; (Ethanol) mp: 140 ºC. IR (KBr)  (cm–1) 677 (C-S-C), 1299 (N-N stretching),
1616 (C ... C of aromatic ring), 1586 (C=N), 1764 (C=O of -thialactum ring), 3145 (C-H
10
aromatic stretching), 3440 (OH stretching), 1227 (OCH3) ; 1H-NMR:  (ppm) 3.94 (s, 2H,
CH2 of thiazolidinone ring), 5.66 (s, 1H CH-Ar) 6.29 (s, 2H C3-CH2), 7.93-6.32 (m, 8H, ArH) 3.40 (s, 3H, OCH3), 11.23 (s, 1H, OH), 8.94 (brs 1H, NH of indole exchangeable with
D2O). Mass, M+ at m/z 478. Anal. calcd. for C22H18N6O3S2 : C, 55.23; H, 3.76; N, 17.57;
Found : C, 55.57 ; H, 3.43; N, 17.24.
3-[6'-{2"-(4-NN'Dimethylamino phenyl-4"-oxothiazolidin-3"-yl)}-s-triazol -3'-yl [5',4'b] [1',3',4'] thiadiazole] methylindole (14)
Yield: 68%; (Methanol) mp: 150 ºC. IR (KBr) (cm–1) 678 (C-S-C), 1298 (N-N stretching),
1617 (C ... C of aromatic ring), 1589 (C=N), 1765 (C=O of -thialactum ring), 3143 (C-H
aromatic stretching) ; 1H-NMR:  (ppm) 3.97 (s, 2H, CH2 of thiazolidinone ring), 5.67 (s, 1H
CH-Ar) 6.30 (s, 2H C3-CH2), 7.92-6.32 (m, 9H, CH-Ar), 8.95 (brs 1H, NH, of indole
exchangeable with D2O), 1.54 (s, 6H, N (CH3)2). Mass, M+ at m/z 475. Anal. Calcd. for
C23H21N7OS2 : C, 58.10; H, 4.42; N, 20.63; Found : C, 58.02 ; H, 4.63; N, 20.45.
General procedure for the preparation of 3-[6'-(Substitutedphenyl-3"-chloro-2"oxoazetidin-1"-yl)}-s-triazol-3'-yl [5', 4'-b] [1',3',4'] thiadiazole] methyl indole (15-19)
In ethanolic solution of compounds 5 (0.008 mol), chloro acetyl chloride (0.008 mol) was
added drop by drop at 0-5 0C temperature in presence of few drops of triethylamine. The
reaction mixture was kept at room temperature for 6-8 hours, refluxed for 8 hours excess of
solvent was distilled off and poured onto crushed ice. The solid thus obtained was filtered
and finally recrystallized from methanol to give compound 15. Yield: 70%; mp: 175 ºC. IR
(KBr)  (cm–1) 672 (C-S-C), 1295 (N-N stretching), 1619 (C ... C of aromatic ring), 1585
(C=N), 1735 (C=O, of -thialactum ring), 3153 (C-H aromatic stretching); 1H-NMR: 
(ppm) 4.22 (d, 1H, CHCl), 5.66 (d, 1H, CH-Ar), 6.24 (s, 2H bridge-CH2) 7.85-6.35 (m, 10 H,
Ar-H), 8.94 (brs, 1H, NH of indole exchangeable with D2O). Mass, M+ at m/z 434. Anal.
11
Calcd. for C21H15N6OSCl : C, 58.00; H, 3.45; N, 19.33; Found : C, 58.25 ; H, 3.45; N, 19.45;
19.147.
3-[6’-{2"-{4"-(4-Hydroxyphenyl-3"-chrolo-2"-oxoazetidin-1"yl)}-s-triazol -3'-yl [5',4'b] [1',3',4'] thiadiazole] methylindole (16)
Yield: 71%; (Benzene) mp: 169 ºC. IR (KBr) (cm–1) 673 (C-S-C), 1296 (N-N stretching),
1611 (C ... C of aromatic ring), 1588 (C=N), 1736 (C=O of -thialactum ring), 3147 (C-H
aromatic stretching), 3443 (OH stretching); 1H-NMR:  (ppm) 4.24 (d, 1H, CHCl), 5.67 (d,
1H, CH-Ar), 6.28 (s, 2H bridge-CH2), 7.86-6.35 (m, 9H, Ar-H), 8.95 (brs, 1H, NH of indole
exchangeable with D2O), 11.19 (s, 1H, OH) Mass, M+ at m/z 450. Anal. Calcd. for
C21H15N6O2SCl : C, 55.94, H, 3.33; N, 18.64; Found C, 56.06; H, 3.38; N, 18.78.
3-[6’-{2"-{4"-(4-Methoxyphenyl-3"-chrolo-2"-oxoazetidin-1"yl)}-s-triazol-3’-yl [5’, 4’b] [1’, 3’, 4’] thiadiazole] methyl indole (17)
Yield: 72%; (DMF-Water) mp: 182 ºC. IR (KBr) (cm–1) 674 (C-S-C), 1297 (N-N
stretching), 1620 (C ... C of aromatic ring), 1589 (C=N), 1737 (C=O of -thialactum ring),
3155 (C-H aromatic stretching), 1229 (OCH3 aromatic); 1H-NMR:  (ppm) 4.25 (d, 1H,
CHCl), 5.66 (d, 1H, CH-Ar), 6.25 (s, 2H bridge-CH2), 3.38 (s, 3H, OCH3), 7.85-6.34 (m, 9H,
Ar-H), 8.97 (brs, 1H, NH of indole exchangeable with D2O). Mass, M+ at m/z 464. Anal.
Calcd. for C22H17N6O2SCl : C, 56.84, H, 3.66; N, 18.08; Found C, 56.90; H, 3.48; N, 18.09.
3-[6'-{2"-{4"-(4-hydroxy-3 methoxy phenyl-3"-chrolo-2"-oxoazetidin-1"yl)}-s-triazol3’-yl [5’, 4’-b] [1’, 3’, 4’] thiadiazole] methyl indoles (18)
Yield: 75%; (Acetone) mp: 152 ºC. IR (KBr)  (cm–1) 676 (C-S-C), 1297 (N-N stretching),
1623 (C ... C of aromatic ring), 1583 (C=N), 1738 (C=O of -thialactum ring), 3154 (C-H
aromatic stretching), 1228 (OCH3), 3441 (OH stretching); 1H-NMR:  (ppm) 4.23 (d, 1H,
CHCl), 5.66 (d, 1H, CH-Ar), 6.23 (s, 2H bridge-CH2), 7.79-6.33 (m, 8H, Ar–H), 8.95 (brs,
12
1H, NH of indole exchangeable with D2O), 3.39 (s, 3H, OCH3), 11.14 (s, 1H, OH). Mass,
M+ at m/z 480. Anal. Calcd. for C22H17N6O3SCl : C, 54.94; H, 3.54; N, 17.48; Found : C,
54.74, H, 3.46; N, 17.72.
3-[6'-{2"-{4"-(4-NN'-Dimethyl phenyl-3"-chloro-2"-oxoazetidin-1"yl)}-s-triazol -3’-yl
[5’, 4’-b] [1’, 3’, 4’] thiadiazole] methyl indole (19)
Yield: 68%. (Methanol) mp: 172 ºC. IR (KBr)  (cm–1) 675 (C-S-C), 1297 (N-N
stretching), 1622 (C ... C of aromatic ring), 1584 (C=N), 1738 (C=O of -thialactum ring),
3157 (C-H aromatic stretching) ; 1H-NMR:  (ppm) 4.22 (d, 1H, CHCl), 5.67 (d, 1H, CHAr), 6.23 (s, 2H bridge-CH2) 7.72-6.34 (m, 9H, Ar–H), 8.94 (brs, 1H, NH of indole
exchangeable with D2O), 1.70 (s, 6H N (CH3)2) Mass, M+ at m/z 477. Anal. Calcd. for
C23H20N7OSCl : C, 57.80; H, 4.19; N, 20.52 ; Found : C, 57.72, H, 4.29; N, 20.34.
Biological Methods
All the compounds 1-19 were tested for anticonvulsant activity. Anticonvulsant activity was
determined by supra maximal electro shock seizure pattern test (SMES).The effect of
unknown compounds was compared with the standard drugs and propylene glycol treated
group served as control. The statistical evaluation of observations was done by using
appropriate statistical tests. Compounds 1-19 were also screened for their approximate lethal
dose (ALD50).
Supramaximal electroshock seizure pattern test (SMES): This activity was performed by
following the method of Toman et al. (1946) in albino rats. Rats of either sex weighing 100120 gm were divided into groups of ten animals each. The test drugs and phenytoin sodiumreference drug was administrated i.p. route in rats. After 1 hour they were subjected to a
shock of 150 mA by convulsiometer through ear electrodes for 0.2 seconds and the presence
or absence of extensor response was noted. Animals in which extensor response was
abolished were taken as protected rats.
13
Approximate lethal dose (ALD50): The LD50 was determined in Albino rats weighing 100120 gm of either sex by the method of Smith (1960). The test compounds were administered
i.p. route in one group and the same volume of propylene glycol in another group of animals
consisting six rats in graded doses. Discuss the study, the animals were allowed to take food
and water adlibidum. After 24 hours of drug administration percent mortality in each group
was observed. From the data obtained ALD50 was calculated.
Biological Discussion
All the newly synthesized compounds studied for their anticonvulsant activity. The
pharmacological data of all the compounds of this series have been reported in Table 1. The
compounds were screened for their anticonvulsant activity against maximal electroshock
induced seizure at the dose of 30 mgkg-1 i.p. Compounds 1-19 showed significant
anticonvulsant activity. The characteristic feature of this series is the presence of a triazole
ring fused with thiadiazole ring at the 3rd position of methyl indole moiety, which was further
substituted with iminosubstituted benzylidenyl group at the 6th position of fused thiadiazoletriazole ring. The compounds 1-4 exhibited moderate anticonvulsant activity varying from 20
to 30%. In the next step compounds i.e. componds 5-9, an increase in anticonvulsant activity
(varying between 40 to 60%) was noticed. Most active compounds of this step is compound 7
(having a substitution of 4-methoxy at phenyl ring) exhibited maximum anticonvulsant
response (60%) in comparison to the compounds 5, 6, 8 and 9 which elicited 50%, 40% 50%
and 50% protection against maximal electroshock induced seizures (MES). Further in the
next step compounds, 10-14, which is characterized by the presence of 5-membered
heterocyclic thiazolidinone moiety, compound 12 have shown most potent anticonvulsant
activity (90%) which was more potent and equipotent than reference drug phenytoin sodium
and lamotrigine respectively at the dose of 30 mg/kg i.p. On the other side, compounds 1519, substituted with four membered heterocyclic azetidinone moiety have shown varying
degree (60-80%) of anticonvulsant activity. Compound 17, 18 and 19 showed better response
14
i.e. 80%, 70% and 70%, respectively in comparison to the compound 15 and 16 which have
shown 60% inhibition of protection. Therefore, considering the compounds of this series, it
may be concluded that compounds 12 and 17 were tested at three graded doses i.e. 7.5 15 and
30 mgkg-1 i.p. Compound 12 have shown most potent response at the dose 30 mg/kg i.p. (i.e.
90%). Compound 17 elicited maximum response (80%) in comparison to the other
substituted azetidinones. This compound showed 80% anticonvulsant response which was
equipotent to reference drug phenytoin sodium. The newly synthesized compounds were also
tested for approximate lethal dose ALD50 and were found to exhibit a higher value of ALD50
i.e. more than 1000mg/kg i.p. except compound 12 which exhibited ALD50 of more than
1600 mg/kg i.p. (maximum dose tested) thus indicating the safer nature of the compounds.
From the results obtain in this study the following conclusion can be drawn:
1. Fused triazole-thiadiazole indoles derivatives exhibit a mild to moderate
anticonvulsant activity.
2. Cyclisation of this fused triazole-thiadiazole indoles into thiazolidinone and
azetidinone derivatives enhance the anticonvulsant property.
2. Presence of 4-Hydroxy-3-methoxyphenyl as a substituent elicits a remarkable
increase in anticonvulsant activity.
Acknowledgements
Authors are thankful to SAIF Punjab University Chandigarh for elemental and spectral
analysis. One of author Ankita Agarwal, JRF is also thankful for financial assistance to
U.G.C. New Delhi for carrying out this work.
References
Agarwal, A., Lata, S., Saxena, K.K., Srivastava, V.K. and Kumar A. 2006; Synthesis and
anticonvulsant activity of some potential thiazolidinonyl 2-oxo/thiobarbituric acids. Eur.
J. Med. Chem. 41: pp 1223- 1229.
15
Almasirad A., Tabatabai S.A., Faizi M., Kebriacezadch A., Mehrabi N.,Dalvandi A.
Shafiee, A. 2004; Synthesis and anticonvulsant activity of new 2-Substituted-5-[2- (2fluorophen--oxy) phenyl]-1,3,4-oxadiazoles 1,2,4-triazoles, Bioorg. Med. Chem,
14: pp 6057-6059.
Archana., Rani P.; Bajaj K.; Srivastava V.K.; Chandra R.; Kumar A.2003; Synthesis
of Newer indolyl/phenothiazinyl Substituted-2-oxo’thiobarbituric acid derivarives
as Potent anticonvulsant agents, Arzneim Forsch/Drug Research. 53: pp 301- 306.
Archana, Srivastava V.K., Kumar A. 2003; Synthesis of newer indolyl thiadiazoles and their
thiazolidinones and formazans as potent anticonvulsant agents, Indian J., Pharm. Sci. 65:
pp 358-362.
Bajaj K. , Srivastava, V.K. , Lata. S., Chandra R. and Kumar A. 2003; Synthesis of some
new benzothia/oxazepinyl indoles as an antipsychotic agents. Indian J. Chem. 42B:
1723-1728.
Chapleo C.B., Myers P.L., Smith A.C.B., Stilling M.R.,Tulloch I.F., Walter D.S. 1988;
Substituted 1,3,4-Thiadiazoles with Anticonvulsant Activity.4.Amidines, J. Med.
Chem., 31: pp 7-11.
Dogan H.N., Duran A, Rollas S., Sener G, Uysal M.K., Gulen D. 2002; Synthesis of new 2,5Disubstitutes-1,3,4-thiadiazoles and preliminary evaluation of anticonvulsant and
antimicrobial activities, Bio.Med.Chem. 10: pp 2893-2898.
George S., Parameswaran M.K., Chakrabotry A.R., Ravi T.K. 2008. Synthesis and
evaluation of the biological activities of some 3{[5-(6-methyl-4-aryl-2-oxo-1,2,3,4tetrahydropyrimidin-5-yl)-1,2,4-oxadiazol-2-yl]-imino}-1,3- dihydro-2H-indol-2one derivatives, Acta Pharm. 58: pp 119-129.
Jin H.G., Sun X.Y., Chai K.Y; Piao H.R.; Quan S.Z., 2006; Anticonvulsant and toxicity
evaluation of some 7-alkoxy-4,5-dihydro-[1,2,4] triazolo [4,3-a] quinoline-1(2H)-
16
ones, Bioorg. Med. Chem., 20: pp 6868-6873.
Rajasekaran A., Murugesan S., 2005; Synthesis and characterization of some novel
azetidinone derivatives as antibacterial and anticonvulsant agents, Journal of pharmacy
& Biosources, 2 (2): pp 262-268.
Smith, Q.E. 1960.
Pharmacological screening tests progress in medicinal chemistry,
Butterworth, London, 1: pp 1-33.
Srivastava S.K, Srivastava S., Srivastava S.D., 2002; Synthesis of New 1,2,4-triazolothiadiazoles and its 2-oxoazetidines as antimicrobial, anticonvulsant and antiinflammatory agents, Indian J. Chem. 41B: pp 2357-2363.
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17
Table 1. Anticonvulsant activity of compounds 1-19.
Compo
und No.
R
Dose (mg/kg
i.p. )
Anticonvulsant activity (SMESc)
No. of animals
exhibiting convulsions
ALD50 (mg/kg i.p.)
% seizure
protection
0.5 ml
10
0
Phenytoin
7.5
8
20*
sodiumb
15
5
50*
30
2
7.5
8
80***
20*
15
5
50**
30
1
30
8
P.G.a
Lamotri
gineb
90***
20*
> 1000
20*
> 1000
7
30*
> 1000
30
7
30*
> 1000
H
30
5
50**
> 1000
4-OH
30
6
40*
> 1000
6.
4-OCH3
30
4
60**
> 1000
7.
4-OH, 3-OCH3
30
5
50**
> 1000
8.
4-N(CH3)2
30
5
50**
> 1000
9.
3
> 1000
H
30
70**
10.
4
> 1000
4-OH
30
60**
11.
7
> 1000
4-OCH3
7.5
30*
12.
15
4
60**
> 1000
30
1
90***
> 1600
30
3
70**
> 1000
30
4
60**
> 1000
30
4
60**
> 1000
30
4
60**
> 1000
7.5
5
50**
> 1000
15
6
40**
> 1000
30
2
80***
> 1000
1.
-
2.
-
30
8
3.
-
30
4.
-
5.
13.
4-OH, 3-OCH3
14.
4-N(CH3)2
15.
H
16.
4-OH
17.
4-OCH3
18.
4-OH, 4-OCH3
30
3
70**
> 1000
19.
4-N(CH3)2
30
3
70**
> 1000
*P<0.05; **P<0.01; ***P<0.001
a
P.G.= Propylene glycol standard for control group.
b
Phenytoin Sodium=reference drug for anticonvulsant activity.
c
Supramaximal electroshock seizure pattern test.
18
O
O
Cl
O
O
N
H
N
H
(1)
NH2.NH 2.H2 O
H
N
NH2
O
R = H,
N
H
4-OH,
4-OCH3,
(2)
4-OH, 3-OC H3 ,
4-N(CH 3)2
1. C S2/KOH
2. NH2.NH 2.H2 O
N
N
SH
N
NH 2
N
H
(3)
CNBr
N N
S
N
N
NH2
(4)
N
H
R
CHO / gl CH 3C OOH
N
N
N
N
S
N
N
H
R
(5-9)
N
1. HSCH2COOH
1. ClCH2 COCl
2. Anhy. ZnCl 2
2. Et3N
N N
N
R
R
N
S
N
N
N
N
N
H
S
N
H
S
O
O
(15-19)
(10-14)
SCHEME-1
N
Cl