Synthesis and pharmacological investigation of 2-(4-dimethylaminophenyl)-3, 5-disubstituted thiazolidin-4-ones as anticonvulsants

Article abstract of DOI:10.1002/ardp.201200126

A new series of 2-(4-dimethylaminophenyl)-3-substituted thiazolidin-4-one-5-yl-acetyl acetamides/benzamides were synthesized by the nucleophilic substitution of 3-substituted-2-(4-dimethylaminophenyl)- thiazolidin-4-one-5-yl-acetylchloride with acetamide and benzamide. The starting material 3-substituted-2-(4-dimethylaminophenyl)-thiazolidin-4-one-5-yl- acetylchloride was synthesized from 3-substituted-2-(4-dimethylaminophenyl)- thiazolidin-4-one-5-yl-acetic acid, which in turn was prepared by one-pot reaction of amino component, p-dimethylamino benzaldehyde and mercapto succinic acid. The title compounds were investigated for their anticonvulsant activities; among the test compounds, compound 2-(4-dimethylaminophenyl)-3-phenylamino- thiazolidine-4-one-5-yl-acetylbenzamide (14) emerged as the most active compound of the series and as moderately more potent than the reference standard diazepam. Copyright

Full text of DOI:10.1002/ardp.201200126

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–7
1
Full Paper
Synthesis and Pharmacological Investigation of
2-(4-Dimethylaminophenyl)-3,5-disubstituted
thiazolidin-4-ones as Anticonvulsants
Manavalan Senthilraja1 and Veerachamy Alagarsamy2
1 Department of Pharmaceutical Chemistry, J.K.K. Nattraja College of Pharmacy, Komarapalayam,
Tamilnadu, India
2 Medicinal Chemistry Research Laboratory, MNR College of Pharmacy, Sangareddy, Gr. Hyderabad,
Andhra Pradesh, India
A new series of 2-(4-dimethylaminophenyl)-3-substituted thiazolidin-4-one-5yl-acetyl acetamides/
benzamides were synthesized by the nucleophilic substitution of 3-substituted-2-(4-dimethyl-
aminophenyl)-thiazolidin-4-one-5yl-acetylchloride with acetamide and benzamide. The starting
material 3-substituted-2-(4-dimethylaminophenyl)-thiazolidin-4-one-5yl-acetylchloride was synthesized
from 3-substituted-2-(4-dimethylaminophenyl)-thiazolidin-4-one-5yl-acetic acid, which in turn was
prepared by one-pot reaction of amino component, p-dimethylamino benzaldehyde and mercapto
succinic acid. The title compounds were investigated for their anticonvulsant activities; among
the test compounds, compound 2-(4-dimethylamino phenyl)-3-phenylamino-thiazolidine-4-one-5yl-
acetylbenzamide (14) emerged as the most active compound of the series and as moderately more
potent than the reference standard diazepam.
Keywords: Anticonvulsant activity / Diazepam / Thiazolidinone
Received: March 29, 2012; Revised: May 19, 2012; Accepted: June 19, 2012
DOI 10.1002/ardp.201200126
Introduction
explored as possible anticonvulsant agents. Thiazolidin-4-
ones belong to an important class of heterocyclic compounds
containing sulfur and nitrogen atoms and received much
attention of medicinal chemists due to their potential bio-
logical activities [4–6]. Thiazolidin-4-ones with 2,3 substitution
are reported to possess significant hypoglycaemic [7], anti-
inflammatory [8], cholerectic, anti-HIV [9, 10], diuretic, immu-
nosuppresant, anti-psychotic, and anticonvulsant activities
[11–13]. Among the biological activities exhibited by thiazoli-
dinones, the anticonvulsant activities of 2,3-disubstituted thia-
zolidinones are interesting [14, 15]. Prompted by these reports
of thiazolidinone derivatives as potent anticonvulsant agents,
we aimed at preparing a series of 2,3-disubstituted-thiazolidin-
4-one-5yl-acetyl acetamides/benzamides.
Epilepsy is a disorder characterized by paroxysmal, excessive,
and hypersynchronous discharges of large numbers of
neurons and affects at least 50 million people worldwide
[1]. Epilepsy is the second most common chronic neurological
condition reported by neurologists [2]. Despite the optimal
use of available anti-epileptic drugs (AEDs), many patients
with epilepsy fail to experience seizure control and others do
so only at the expense of significant toxic side effects [3]. The
limitations with the conventional AEDs highlighted the need
for developing newer agents for epilepsies and therefore new,
less toxic, and more effective drugs are required.
As a part of our ongoing new drug development program
of AED, 2,3-disubstituted thiazolidin-4-ones have been
Results and discussion
Chemistry
Correspondence: Veerachamy Alagarsamy, Medicinal Chemistry
Research Laboratory, MNR College of Pharmacy, Sangareddy 502 294,
Gr. Hyderabad, Andhra Pradesh, India.
E-mail: drvalagarsamy@gmail.com
Fax: þ91 8455-230 555
The synthetic route depicted in Scheme 1 outlines the
chemistry part of the present work. The key intermediates
3-substituted-2-(4-dimethylamino phenyl)-thiazolidin-4-one-
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

2
M. Senthilraja and V. Alagarsamy
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–7
CH
N(CH3)2
R
N
ZnCl2
C2H5OH
R-NH2
OHC
N(CH3)2
+
HS
CH
COOH
+
S
O
CH2COOH
Tetrahydrofuran
_
CH2COOH
1 5
SOCl2
C6H6
CH
N(CH3)2
R
N
CH
N(CH3)2
R
N
CH3CONH2
C2H5OH
S
S
O
O
CH2CONHCOCH3
CH2COCl
_
_
16
20
6 10
C6H5CONH2
C2H5OH
CNH2
CNH2
R =
HNOC
3, 8, 13, 18
N
S
O
CH
N(CH3)2
R
N
1, 6, 11, 16
2, 7, 12, 17
S
O
O2N
HN
CH2CONHCOC6H5
HN
NO2
_
11 15
4, 9, 14, 19
5, 10, 15, 20
Scheme 1. Synthesis of 2-(4-dimethylaminophenyl)-3-substituted thiazolidin-4-one-5yl-acetyl acetamides/benzamides.
5-yl acetic acid (1–5) were obtained by the cyclocondensation
of 4-dimethylamino benzaldehyde, substituted amines, and
mercaptosuccinic acid in the presence of tetrahydrofuran (1–
5). The compounds 1–5 were then chlorinated with thionyl
chloride with vigorous stirring and refluxing to afford 6–10.
The compounds 6–10 obtained were then reacted with acet-
amide and benzamide to afford the title compounds 2-(4-
dimethylamino phenyl)-3-phenylamino-thiazolidine-4-one-
5yl-acetyl acetamide/benzamide (11–20). The desired prod-
ucts were obtained in excellent yields and purity, the struc-
tures of all the new compounds were confirmed by IR spectra,
which show a peak in the region of 3600–3500 cmꢀ1 for
hydroxy (OH) stretching, an intense peak in the region of
3400–3200 cmꢀ1 for NH stretching, 1690–1730 cmꢀ1 for car-
Pharmacology
All the synthesized compounds were evaluated for their anti-
epileptic effects using male albino Swiss mice (18–25 g). The
primary qualitative evaluations were performed in mice by
maximal electroshock seizure test (MES). Acute neurological
toxicity induced by the compounds in mice was assessed
through standardized rotorod test. In the initial screening,
candidate compounds were screened for their anti-epileptic
potential through MES models in mice at a dose level of 20,
40, 60, 80, and 100 mg/kg by intraperitoneal (i.p.) route and
the groups of mice were tested at 1 h post administration of
the test candidate. Compounds found to be active in these
seizure challenges are generally regarded to be significantly
useful candidates in the treatment of partial, generalized, and
even absence seizures. The data regarding the anti-epileptic
screening of all the compounds are reported in Table 1.
All the synthesized compounds were evaluated for anti-
convulsant activity and have shown promising anticonvul-
sant activities. All the tested compounds showed protection
against MES test indicative of their ability to inhibit the
seizure spread. From the results it was found that the key
intermediate 3-substituted-2-(4-dimethylamino phenyl)-thiazoli-
bonyl group (C O). 1HNMR (CDCl3) spectra of 2,3-disubsti-
–
–
tuted-thiazolidin-4-one-5yl-acetyl
acetamides/benzamides
(1–20) show multiplet in the range of d 6.80–8.30 ppm owing
to aromatic protons. A singlet shows at d 2.30–2.80 ppm,
4.00–5.00 ppm, and 9.90–11.0 ppm due to CH3, NH2, and
NH groups, respectively. Further elemental analysis (C, H,
and N) and molecular ions recorded in the mass spectra
confirmed the assigned structures.
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–7
3,5-Disubstituted Thiazolidin-4-ones as Anticonvulsants
3
Table 1. Anticonvulsant activity (duration in s) of compounds 1–5 and 11–20.
Compound no.
Flexion
Extension
Convulsion
Stupor
Death
% Protection
Control
Diazepam
1
2
3
3.22 ꢁ 0.412
22.39 ꢁ 2.650
1.70 ꢁ 0.359
10.34 ꢁ 0.952
3.56 ꢁ 1.351
90.99 ꢁ 5.158
2/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
–
2.01 ꢁ 0.320ꢂ
2.90 ꢁ 0.563
76.67 ꢁ 3.739
50.45
30.60
30.32
33.34
43.22
42.20
38.42
44.03
43.41
66.44
63.69
31.40
33.96
36.47
48.05
46.54
5.24 ꢁ 1.445ꢂꢂ
5.44 ꢁ 1.255ꢂꢂ
4.68 ꢁ 0.562
9.22 ꢁ 1.486ꢂꢂ
9.12 ꢁ 1.786ꢂꢂ
7.55 ꢁ 1.023
68.17 ꢁ 8.638ns
69.53 ꢁ 7.746ns
73.50 ꢁ 2.564ꢂꢂ
70.17 ꢁ 7.520ꢂꢂ
72.17 ꢁ 2.733ꢂꢂ
71.17 ꢁ 8.338ns
70.83 ꢁ 7.546ꢂ
72.50 ꢁ 2.764ns
61.17 ꢁ 7.420ꢂꢂꢂ
65.17 ꢁ 2.533ꢂꢂꢂ
74.17 ꢁ 8.538ns
70.83 ꢁ 7.846ns
77.50 ꢁ 2.964ꢂꢂ
71.17 ꢁ 7.120ꢂꢂ
79.17 ꢁ 2.833ꢂꢂ
2.89 ꢁ 0.595ꢂꢂꢂ
2.96 ꢁ 0.858
4
5
2.82 ꢁ 0.458ꢂꢂ
2.85 ꢁ 0.638ꢂꢂꢂ
2.59 ꢁ 0.493
3.56 ꢁ 0.262ꢂꢂ
3.68 ꢁ 0.362ꢂꢂ
2.26 ꢁ 1.315ꢂꢂꢂ
2.25 ꢁ 1.445
4.81 ꢁ 0.945ꢂꢂ
4.85 ꢁ 0.953ꢂꢂ
8.12 ꢁ 1.656ꢂꢂ
7.25 ꢁ 1.586
11
12
13
14
15
16
17
18
19
20
2.12 ꢁ 0.495ꢂꢂ
2.46 ꢁ 0.558ꢂ
1.65 ꢁ 0.658ꢂꢂꢂ
1.75 ꢁ 0.658ꢂꢂꢂꢂ
2.49 ꢁ 0.493ꢂꢂ
2.34 ꢁ 0.295
1.85 ꢁ 0.812ꢂꢂ
1.21 ꢁ 0.522ꢂꢂꢂ
1.47 ꢁ 0.462ꢂꢂꢂ
2.94 ꢁ 1.345ꢂꢂ
2.90 ꢁ 1.123ꢂ
2.01 ꢁ 0.862ꢂ
1.88 ꢁ 0.562ꢂꢂꢂ
1.94 ꢁ 0.248ꢂꢂꢂ
6.41 ꢁ 1.143ꢂꢂ
1.17 ꢁ 1.123ꢂꢂꢂ
1.31 ꢁ 1.123ꢂꢂꢂ
9.82 ꢁ 1.686ꢂꢂ
9.26 ꢁ 1.752
2.90 ꢁ 0.558ꢂꢂꢂ
2.70 ꢁ 0.658ꢂꢂꢂ
2.77 ꢁ 0.274ꢂꢂꢂ
8.55 ꢁ 1.123ꢂꢂ
3.75 ꢁ 1.023ꢂꢂꢂ
3.88 ꢁ 0.239ꢂꢂꢂ
ꢂAll the valuꢂeꢂs are expressed as mean ꢁ SEM (n ¼ 6).
ꢂꢂꢂ
ns
p < 0.05;
significantly different from control group.
p < 0.01;
p < 0.001 versus control (one-way ANOVA followed by Dunnett’s test);
not significant; values are
din-4-one-5-yl acetic acid (1–5) was found to exhibit less anti-
convulsant activity than the title compounds (11–20) and the
reference diazepam. Within the title compounds synthesized,
benzamide derivatives (11–15) showed better activity than the
corresponding acetamide analogs (16–20). In addition, it was
found that substitution present in N-3 of the title compound
also influences the pharmacological effects. Among various
substituents tested at the N-3 position of thiazolidinones, com-
pounds possessing substituted phenyl derivative (14–15 and 19–
20) exhibited significant anticonvulsant activity, which was
found to be more than rest of substituents tested. When the
aromatic ring was replaced by aliphatic substituents (such as
CONH2, CSNH2) or heterocyclic ring systems this resulted in less
anticonvulsant activity.
were synthesized by the nucleophilic substitution of 3-sub-
stituted-2-(4-dimethylaminophenyl)-thiazolidin-4-one-5yl-ace-
tylchloride by acetamide/benzamide. All the compounds
were tested for their anticonvulsant activity by MES method
in mice. In the present study, benzamide derivatives (11–15)
showed better activity than the corresponding acetamide ana-
logs (16–20). The benzamide derivatives possessing a substituted
phenyl derivative (14 and 15) exhibited significantly higher anti-
convulsant activity than the rest of the compounds. Among the
entire tested compounds, 2-(4-dimethylamino phenyl)-3-phenyl-
amino-thiazolidine-4-one-5yl-acetylbenzamide (14) emerged as
the most active compound and it was found moderately more
potent than the reference standard diazepam.
In the present study, the anticonvulsant activity was
enhanced by introducing a substituted phenyl amino group
(14–15 and 19–20) moiety at the N-3 position by keeping a
dimethylamino phenyl substituent at C-2 of the 4-thiazolidi-
none ring. Among the test compounds, compound 2-(4-dime-
thylamino phenyl)-3-thioamido-thiazolidine-4-one-5-acetamide
(14) emerged as the most active compound (66.44%) of the series
and as moderately more potent than the reference standard
diazepam.
Experimental
Chemistry
Melting points were taken in open capillaries on a Thomas
Hoover melting point apparatus and are uncorrected. The
IR spectra were recorded in film or in potassium bromide disks
on a Bruker 398 spectrometer. The 1H spectra were recorded on a
DPX-500 MHz Bruker FT-NMR spectrometer. The chemical shifts
were reported as parts per million (d ppm) tetramethylsilane
(TMS) as an internal standard. Mass spectra were obtained on
a JEOL-SX-102 instrument using fast atom bombardment (FAB
positive). Elemental analysis was performed on a Perkin-Elmer
240 C, H, N analyzer and values were within the acceptable limits
of the calculated values. The progress of the reaction was moni-
tored on readymade silica gel plates (Merck) using chloroform/
benzene (8:2) as solvent system. Iodine chamber was used as
Conclusion
In summary, a new series of 2-(4-dimethylaminophenyl)-
3-substituted thiazolidin-4-one-5yl-acetylbenzamides (1–20)
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

4
M. Senthilraja and V. Alagarsamy
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–7
detecting agent. Spectral data (IR, NMR, and mass spectra) con-
firmed the structures of the synthesized compounds and the
purity of these compounds was ascertained by microanalysis.
Elemental (C, H, and N) analysis indicated that the calculated and
observed values were within the acceptable limits (ꢁ0.4%). All
chemicals and reagents were obtained from Aldrich (USA) and
were used without further purification.
for C19H21N3O3S: C, 61.44; H, 5.70; N, 11.35; Found: C, 61.22;
H, 5.72; N, 11.39.
2-(4-Dimethylaminophenyl)-3-(2, 4-dinitrophenylamino)-
thiazolidin-4-one-5-yl-aceticacid (5)
Yield: 91%; mp 198–1998C; IR (KBr) cmꢀ1: 3506 (OH), 3319 (NH),
–
3081 (Ar–CH), 2983 (CH –CH), 1696 (C O), 1539 and 1312 (NO );
–
3
2
1HNMR (CDCl3) d (ppm): 2.74 (s, 6H, N(CH3)2), 2.95 (t, 2H, CH2),
3.88 (t, 1H, COCH), 5.64 (s, 1H, NCH), 6.49 (d, J ¼ 7.5 Hz, 2H,
Ar–H), 6.89 (d, J ¼ 8.0 Hz, 2H, Ar–H), 7.10–7.12 (m, 1H, Ar–H),
8.51–8.53 (m, 1H, Ar–H), 9.02–9.03 (m, 1H, Ar–H), 10.16 (br s, 1H,
NH), 11.03 (s, 1H, OH), MS (m/z) 461 [Mþ]; Anal. Calcd.
for C19H19N5O7S: C, 49.45; H, 4.15; N, 15.18; Found: C, 49.64;
H, 4.13; N, 15.13.
General procedure for synthesis of 2-(4-dimethylaminophenyl)-
3-substituted thiazolidin-4-one-5-yl acetic acid (1–5)
A solution of alkyl/aryl amines (0.01 mol) in ethanol (20 mL) and
p-dimethylamino benzaldehyde (0.01 mol) were taken in 100 mL
round bottom flask. To this mercapto succinic acid (0.01 mol) in
ethanol (10 mL) was added. The solution was added to tetrahy-
drofuran (20 mL) and zinc chloride (0.5 g) with vigorous stirring
and refluxed for 10 h. The reaction mixture was then poured
into ice water. The solid obtained was filtered, washed with water
and dried. The residue was recrystallized from methanol.
General procedure for synthesis of 2,3-disubstituted
thiazolidin-4-one-5-yl acetyl chlorides (6–10)
A solution of 2,3-disubstituted thiazolidin-4-one-5-yl acetic acid
(1–5) (0.01 mol) was dissolved in benzene (20 mL). To this thionyl
chloride (10 mL) was added slowly with vigorous stirring and
refluxed for 4 h. The resulting solution was then poured into ice
water. The solid obtained was filtered, washed with water, and
dried. The residue was recrystallized from methanol.
2-(3-Carbamoyl-2-(4-(dimethylamino)phenyl)-4-
oxothiazolidin-5-yl)acetic acid (1)
Yield 91%, mp 176–1788C; IR (KBr) cmꢀ1: 3506 (OH), 3310 (NH),
3085 (Ar–CH), 2948 (CH –CH), 1696 (C O); 1H NMR (CDCl3)
–
–
3
d (ppm): 2.72 (s, 6H, N(CH3)2), 2.98 (t, 2H, CH2), 3.75 (t, 1H,
COCH), 4.87 (s, 2H, NH2), 5.74 (s, 1H, NCH), 6.83 (d, J ¼ 8.0 Hz,
2H, Ar–H), 6.90 (d, J ¼ 7.5 Hz, 2H, Ar–H), 10.91 (s, 1H, OH).
MS (m/z): 323 [Mþ]; Anal. Calcd. for C14H17N3O4S: C, 52.00;
H, 5.30; N, 12.99; Found: C, 52.19; H, 5.28; N, 12.96.
3-Carbamoyl-2-(4-dimethylaminophenyl)-thiazolidin-4-
one-5-yl-acetylchloride (6)
Yield: 74%, mp 216–2188C; IR (KBr) cmꢀ1: 3360 (NH), 3073
–
(Ar–CH), 2957 (CH –CH), 1716 (C O), 718 (C–Cl); NMR (CDCl ):
–
3
3
d (ppm): 2.75 (s, 6H, N(CH3)2), 3.29 (d, 2H, CH2), 3.85 (t, 1H, COCH),
4.91 (br s, 2H, NH2), 5.46 (s, 1H, NCH), 6.83 (d, J ¼ 8.0 Hz, 2H,
Ar–H), 6.90 (d, J ¼ 7.5 Hz, 2H, Ar–H). MS (m/z): 343 [Mþ2]; Anal.
Calcd. for C14H16ClN3O3S: C, 49.19; H, 4.72; N, 12.29; Found: C,
49.37; H, 4.71; N, 12.24.
2-(4-Dimethylamino phenyl)-3-thiocarbamoyl thiazolidin-4-
one-5-yl-aceticacid (2)
Yield 93%, mp 189–1918C; IR (KBr) cmꢀ1: 3523 (OH), 3340 (NH),
3067 (Ar–CH), 2954 (CH –CH), 1710 (C O), 1210 (C S); 1H NMR
–
–
–
–
3
(CDCl3) d (ppm): 2.75 (s, 6H, N(CH3)2), 2.86 (t, 2H, CH2), 3.82 (t, 1H,
COCH), 4.59 (s, 2H, NH2), 5.63 (s, 1H, NCH), 6.85 (d, J ¼ 8.0 Hz, 2H,
Ar–H), 6.93 (d, J ¼ 7.5 Hz, 2H, Ar–H), 10.84 (s, 1H, OH). MS (m/z)
339 (Mþ); Anal. Calcd. for C14H17N3O3S2: C, 49.54; H, 5.05;
N, 12.38; Found: C, 49.69; H, 5.04; N, 12.34.
2-(4-Dimethylamino phenyl)- 3-thiocarbamoyl thiazolidin-
4-one-5-yl-acetylchloride (7)
Yield: 80%, mp 164–1668C; IR (KBr) cmꢀ1: 3288 (NH2), 3059
–
–
–
(Ar–CH), 2962 (CH –CH), 1714 (C O), 1200 (C S), 711 (C–Cl);
–
3
NMR (CDCl3) d (ppm): 2.75 (s, 6H, N(CH3)2), 3.29 (d, 2H, CH2),
3.97 (t, 1H, COCH), 4.27 (br s, 2H, NH2), 5.48 (s, 1H, NCH), 6.85 (d,
J ¼ 8.0 Hz, 2H, Ar–H), 6.93 (d, J ¼ 7.5 Hz, 2H, Ar–H). MS (m/z): 359
[Mþ2]; Anal. Calcd. for C14H16ClN3O2S2: C, 46.99; H, 4.51; N,
11.74. Found: C, 46.83; H, 4.53; N, 11.78.
2-(4-Dimethylaminophenyl)-3-isonicotinamido-thiazolidin-
4-one-5yl-acetic acid (3)
Yield: 88%, mp 193–1958C; IR (KBr) cmꢀ1: 3535 (OH), 3332 (NH),
3081 (Ar–CH), 2946 (CH –CH), 1716 (C O); 1H NMR (CDCl3)
–
–
3
d (ppm): 2.76 (s, 6H, N(CH3)2), 2.95 (t, 2H, CH2), 3.72 (t, 1H,
COCH), 5.49 (s, 1H, NCH), 6.55 (d, J ¼ 8.0 Hz, 2H, Ar–H), 6.86
(d, J ¼ 7.5 Hz, 2H, Ar–H), 8.01 (d, J ¼ 7.5 Hz, 2H, Ar–H), 9.04
(d, J ¼ 8.0 Hz, 2H, Ar–H), 9.73 (s, 1H, NH), 10.69 (s, 1H, OH).
MS (m/z): 400 [Mþ]; Anal. Calcd. for C19H20N4O4S: C, 56.99;
H, 5.03; N, 13.99; Found: C, 57.20; H, 5.01; N, 13.94.
2-(4-Dimethylaminophenyl)-3-isonicotinamido-thiazolidin-
4-one-5-yl-acetylchloride (8)
Yield: 86%, mp 231–2328C; IR (KBr) cmꢀ1: 3315 (NH), 3094
–
(Ar–CH), 2964 (CH –CH), 1713 (C O), 717 (C–Cl); NMR (CDCl ):
–
3
3
d (ppm): 2.77 (s, 6H, N(CH3)2), 3.52 (d, 2H, CH2), 3.99 (t, 1H, COCH),
5.63 (s, 1H, NCH), 6.55 (d, J ¼ 8.0 Hz, 2H, Ar–H), 6.88
(d, J ¼ 7.5 Hz, 2H, Ar–H), 8.03 (d, J ¼ 7.5 Hz, 2H, Ar–H), 9.05
(d, J ¼ 8.0 Hz, 2H, Ar–H), 10.03 (s, 1H, NH). MS (m/z): 420
[Mþ2]; Anal. Calcd. for C19H19ClN4O3S: C, 54.47; H, 4.57;
N, 13.37. Found: C, 54.31; H, 4.58; N, 13.42.
2-(4-Dimethylamino phenyl)-3-phenylamino-thiazolidine-
4-one-5yl-acetic acid (4)
Yield: 93%, mp. 180–1828C; IR (KBr) cmꢀ1: 3508 (OH), 3273 (NH),
3094 (Ar–CH), 2968 (CH –CH), 1710 (C O); 1H NMR (CDCl3)
–
–
3
d (ppm): 2.74 (s, 6H, N(CH3)2), 3.01 (t, 2H, CH2), 3.88 (t, 1H,
COCH), 5.81 (s, 1H, NCH), 6.45 (d, J ¼ 7.5 Hz, 2H, Ar–H), 6.64
(d, J ¼ 8.0 Hz, 2H, Ar–H), 6.67–6.69 (m, 1H, Ar–H), 6.91
(d, J ¼ 8.0 Hz, 2H, Ar–H), 7.25 (d, J ¼ 7.5 Hz, 2H, Ar–H), 9.68
(s, 1H, NH), 11.21 (s, 1H, OH). MS (m/z): 371 [Mþ]; Anal. Calcd.
2-(4-Dimethylamino phenyl)-3-phenylamino-thiazolidin-4-
one-5-yl-acetylchloride (9)
Yield: 82%, mp 210–2128C; IR (KBr) cmꢀ1: 3338 (NH), 3075
–
(Ar–CH), 2958 (CH –CH), 1707 (C O), 719 (C–Cl). NMR (CDCl ) d
–
3
3
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–7
3,5-Disubstituted Thiazolidin-4-ones as Anticonvulsants
5
(ppm): 2.76 (s, 6H, N(CH3)2), 3.47 (d, 2H, CH2), 4.02 (t, 1H, COCH),
5.56 (s, 1H, NCH), 6.42 (d, J ¼ 7.5 Hz, 2H, Ar–H), 6.61
(d, J ¼ 8.0 Hz, 2H, Ar–H), 6.65–6.67 (m, 1H, Ar–H), 6.93
(d, J ¼ 8.0 Hz, 2H, Ar–H), 7.24 (d, J ¼ 7.5 Hz, 2H, Ar–H),
9.96 (br s, 1H, NH). MS (m/z): 391 [Mþ2]; Anal. Calcd.
for C19H20ClN3O2S: C, 58.52; H, 5.17; N, 10.77. Found: C, 58.67;
H, 5.15; N, 10.73.
(d, J ¼ 8.0 Hz, 2H, Ar–H), 10.27 (br s, 1H, NH), 10.39 (br s, 1H,
NH). MS (m/z): 503 [Mþ]; Anal. Calcd. for C26H25N5O4S: C, 62.01; H,
5.00; N, 13.90. Found: C, 62.27, H, 4.98, N, 13.86.
2-(4-Dimethylamino phenyl)-3-phenylamino-thiazolidine-
4-one-5yl-acetylbenzamide (14)
Yield: 84%, mp 245–2478C; IR (KBr) cmꢀ1: 3370 (NH), 3091
(Ar–CH), 2966 (CH –CH), 1712 (C O). 1H NMR (CDCl3) d (ppm):
–
–
3
2-(2-(4-(Dimethylamino)phenyl)-3-(2,4-dinitrophenylamino)-
4-oxothiazolidin-5-yl)acetyl chloride (10)
2.78 (s, 6H, N(CH3)2), 3.21 (t, 2H, CH2), 3.83 (t, 1H, COCH), 5.46
(s, 1H, NCH), 6.45 (d, J ¼ 8.0 Hz, 2H, Ar–H), 6.69 (d, J ¼ 8.0 Hz, 2H,
Ar–H), 6.71–6.73 (m, 1H, Ar–H), 6.90 (d, J ¼ 8.0 Hz, 2H, Ar–H),
7.24 (d, J ¼ 8.0 Hz, 2H, Ar–H), 7.48 (d, J ¼ 8.0 Hz, 2H, Ar–H), 7.53–
7.54 (m, 1H, Ar–H), 7.98 (d, J ¼ 8.0 Hz, 2H, Ar–H), 10.22 (br s, 1H,
NH), 10.75 (br s, 1H, NH). MS (m/z): 474 [Mþ]. Anal. Calcd.
for C26H26N4O3S: C, 65.80; H, 5.52; N, 11.81. Found: C, 65.56;
H, 5.54; N, 11.85.
Yield: 78%, mp 177–1788C; IR (KBr) cmꢀ1: 3300 (NH), 3079
–
(Ar–CH), 2952 (CH –CH), 1720 (C O), 1533 and 1319 (NO ); 715
–
3
2
(C–Cl); NMR (CDCl3) d (ppm): 2.73 (s, 6H, N(CH3)2), 3.22 (d, 2H,
CH2), 3.96 (t, 1H, COCH), 5.36 (s, 1H, NCH), 6.45 (d, J ¼ 7.5 Hz, 2H,
Ar–H), 6.84 (d, J ¼ 8.0 Hz, 2H, Ar–H), 7.09–7.10 (m, 1H, Ar–H),
8.49–8.51 (m, 1H, Ar–H), 9.00–9.01 (m, 1H, Ar–H), 10.03 (br s, 1H,
NH); MS (m/z): 481 [Mþ2]; Anal. Calcd. for C19H18ClN5O6S: C,
47.54; H, 3.78; N, 14.59. Found: C, 47.71; H, 3.77; N, 14.63.
N-(2-(2-(4-(Dimethylamino)phenyl)-3-(2,4-dinitrophenylamino)-
4-oxothiazolidin-5-yl)acetyl)benzamide (15)
Yield: 84%; mp 252–2548C; IR (KBr), cmꢀ1: 3342 (NH), 3090
General procedure for synthesis of 2,3-disubstituted
–
thiazolidin-4-one-5yl-acetyl benzamides (11–15)
2,3-Disubstituted thiazolidin-4-one-5-yl acetylchloride (6–10)
(0.01 mol) was dissolved in ethanol (10 mL). To this benzamide
(1.21 g, 0.01 mol) was added with vigorous stirring and reflux for
6 h. The resulting solution was poured into ice water. The solid
obtained was filtered, washed with water, and dried. The residue
was recrystallized from methanol.
(Ar–CH), 2975 (CH –CH), 1707 (C O), 1534 and 1318 (NO ).
–
3
2
1H NMR (CDCl3) d (ppm): 2.75 (s, 6H, N(CH3)2), 3.48 (t, 2H, CH2),
4.03 (t, 1H, COCH), 5.39 (s, 1H, NCH), 6.40 (d, J ¼ 8.0 Hz, 2H,
Ar–H), 6.86 (d, J ¼ 8.0 Hz, 2H, Ar–H), 7.15–7.16 (m, 1H, Ar–H),
7.48 (d, J ¼ 8.0 Hz, 2H, Ar–H), 7.53–7.55 (m, 1H, Ar–H), 7.98
(d, J ¼ 8.0 Hz, 2H, Ar–H), 8.49–8.51 (m, 1H, Ar–H), 9.01–9.03
(m, 1H, Ar–H), 10.01 (br s, 1H, NH), 10.53 (br s, 1H, NH).
MS (m/z): 564 (Mþ). Anal. Calcd. for C26H24N6O7S: C, 55.31;
H, 4.28; N, 14.89. Found: C, 55.51; H, 4.27; N, 14.84.
5-(2-Benzamido-2-oxoethyl)-2-(4-(dimethylamino)phenyl)-
4-oxothiazolidine-3-carboxamide (11)
Yield: 80%, mp 195–1968C; IR (KBr) cmꢀ1: 3305 (NH), 3082
General procedure for synthesis of 2,3-disubstituted
thiazolidin-4-one-5yl-acetyl acetamides (16–20)
(Ar–CH), 2960 (CH –CH), 1717 (C O). 1HNMR (CDCl3) d (ppm):
–
–
3
2.76 (s, 6H, N(CH3)2), 3.24 (t, 2H, CH2), 3.90 (t, 1H, COCH), 4.67
(br s, 2H, NH2), 5.35 (s, 1H, NCH), 6.43 (d, J ¼ 7.5 Hz, 2H, Ar–H),
6.77 (d, J ¼ 8.0 Hz, 2H, Ar–H), 7.43–7.75 (m, 1H, Ar–H), 7.55
(d, J ¼ 8.0 Hz, 2H, Ar–H), 7.95 (d, J ¼ 7.5 Hz, 2H, Ar–H), 10.20
(br s, 1H, NH); MS (m/z): 426 [Mþ]; Anal. Calcd. for C21H22N4O4S: C,
59.14; H, 5.20; N, 13.14. Found: C, 58.95; H, 5.22; N, 13.19.
2,3-Disubstituted thiazolidin-4-one-5-yl acetylchloride (6–10)
(0.01 mol) was dissolved in ethanol (10 mL). To this acetamide
(0.59 g, 0.01 mol) was added with vigorous stirring and reflux for
7 h. The resulting solution was poured into ice water. The solid
obtained was filtered, washed with water, and dried. The residue
was recrystallized from methanol.
N-(2-(3-Carbamothioyl-2-(4-(dimethylamino)phenyl)-4-
oxothiazolidin-5-yl)acetyl)benzamide (12)
5-(2-Acetamido-2-oxoethyl)-2-(4-(dimethylamino)phenyl)-
4-oxothiazolidine-3-carboxamide (16)
Yield: 82%, mp 220–2228C; IR (KBr) cmꢀ1: 3371 (NH), 3084
Yield 86%, mp 232–2338C; IR (KBr) cmꢀ1: 3310 (NH), 3073
(Ar–CH), 2965 (CH3–CH), 1706 (C O), 1205 (C S). 1HNMR
(Ar–CH), 2954 (CH –CH), 1710 (C O). 1HNMR (CDCl3): 2.35
–
–
–
–
–
–
3
(CDCl3) d (ppm): 2.52 (s, 6H, N(CH3)2), 3.38 (t, 2H, CH2), 3.81
(t, 1H, COCH), 4.39 (s, 2H, NH2), 5.51 (s, 1H, NCH), 6.55
(d, J ¼ 7.5 Hz, 2H, Ar–H), 6.81 (d, J ¼ 7.5 Hz, 2H, Ar–H),
7.44 (m, 1H, Ar–H), 7.61 (d, J ¼ 7.5 Hz, 2H, Ar–H), 8.11
(d, J ¼ 8.0 Hz, 2H, Ar–H), 10.42 (s, 1H, NH). MS (m/z) 442 [Mþ];
Anal. Calcd. for C21H22N4O3S2: C, 56.99%; H, 5.01%, N, 12.66%.
Found: C, 57.12%, H, 4.99%, N, 12.62.
(s, 3H, CH3), 2.72 (s, 6H, N(CH3)2), 3.47 (d, 2H, CH2), 3.96 (t, 1H,
COCH), 4.71 (s, 2H, NH2), 5.26 (s, 1H, NCH), 6.85 (d, J ¼ 8.0 Hz, 2H,
Ar–H), 6.89 (d, J ¼ 8.0 Hz, 2H, Ar–H), 10.30 (br s, 1H, NH); MS (m/z)
364 [Mþ]; Anal. Calcd. for C16H20N4O4S: C, 52.73; H, 5.53; N, 15.37.
Found: C, 52.91; H, 5.55; N, 15.31.
5-(2-Acetamido-2-oxoethyl)-2-(4-(dimethylamino)phenyl)-
4-oxothiazolidine-3-thiocarboxamide (17)
Yield 73%, mp 195–1978C; IR (KBr) cmꢀ1: 3370 (NH), 3079
2-(4-Dimethylaminophenyl)-3-isonicotinamido-thiazolidin-
4-one-5-yl-acetylbenzamide (13)
(Ar–CH), 2966 (CH3–CH), 1710 (C O), 1200 (C S). 1HNMR
–
–
–
–
Yield: 85%, mp 185–1868C; IR (KBr) cmꢀ1: 3320 (NH), 3068
(CDCl3) d (ppm): 2.38 (s, 3H, CH3), 2.73 (s, 6H, N(CH3)2), 3.27
(t, 2H, CH2), 3.90 (s, 1H, COCH), 4.52 (s, 2H, NH2), 5.33 (s, 1H,
NCH), 6.87 (d, J ¼ 8.0 Hz, 2H, Ar–H), 6.91 (d, J ¼ 8.0 Hz, 2H,
Ar–H), 10.08 (br s, 1H, NH). MS (m/z) 380 [Mþ]; Anal. Calcd.
for C16H20N4O3S2: C, 50.51; H, 5.30, N, 14.73. Found: C, 50.68,
H, 5.28, N, 14.69.
(Ar–CH), 2950 (CH –CH), 1714 (C O). 1H NMR d (CDCl3) (ppm):
–
–
3
2.78 (s, 6H, N(CH3)2), 3.25 (t, 2H, CH2), 3.92 (t, 1H, COCH), 5.38
(s, 1H, NCH), 6.50 (d, J ¼ 7.5 Hz, 2H, Ar–H), 6.80 (d, J ¼ 8.0 Hz, 2H,
Ar–H), 7.45 (d, J ¼ 7.5 Hz, 2H, Ar–H), 7.53 (m, 1H, Ar–H), 7.99
(d, J ¼ 7.5 Hz, 2H, Ar–H), 8.03 (d, J ¼ 8.0 Hz, 2H, Ar–H), 9.02
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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6
M. Senthilraja and V. Alagarsamy
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–7
Kerala) weighing 20–25 g were kept under hygienic conditions
and on standard laboratory diet (diet composition A. O. A. C
vitamin mix. 1%, mineral mix. 4%, sucrose 20%, cellulose 0.2%,
5% pure casein 10.5%, starch 54.3%) and water was provided
ad libitum. Mice were divided into groups of six animals each.
The test groups received the tested compounds intraperitoneally
at a dose of 10 mg/kg body weight. The standard group received
diazepam in a dose of 10 mg/kg. One hour after the injection,
electroshock was applied via ear-lip electrodes and generated by
a stimulator (Ugo Basile ECT Unit, Pulse generator 57800-001,
delivering an alternating 50 Hz current), the stimulus duration
was 0.2 s and the end point was tonic hind limb extension. The
maximum electroshock was determined. Then, % protection as
well as % potency was calculated according to the following
equations:
2-(4-Dimethylaminophenyl)-3-isonicotinamido-thiazolidin-
4-one-5-yl-acetyl acetamide (18)
Yield 77%, mp 205–2078C; IR (KBr) cmꢀ1: 3310 (NH), 3068
(Ar–CH), 2956 (CH –CH), 1705 (C O); 1H NMR d (CDCl3) (ppm):
–
–
3
2.72 (s, 3H, CH3), 2.97 (s, 6H, N(CH3)2), 3.36 (t, 2H, CH2), 3.99 (t, 1H,
COCH), 5.71 (s, 1H, NCH), 6.56 (d, J ¼ 8.0 Hz, 2H, Ar–H), 6.89
(d, J ¼ 7.5 Hz, 2H, Ar–H), 8.02 (d, J ¼ 7.5 Hz, 2H, Ar–H),
9.04 (d, J ¼ 8.0 Hz, 2H, Ar–H), 7.05–8.12 (m, 8H, Ar–H), 10.06
(br s, 1H, NH), 10.33 (br s, 1H, NH). MS (m/z) 441 [Mþ]; Anal. Calcd.
for C21H23N5O4S: C, 57.13; H, 5.25; N, 15.86. Found: C, 56.96,
H, 5.27, N, 15.92.
2-(4-Dimethylamino phenyl)-3-phenylamino-thiazolidin-4-
one-5-yl-acetyl acetamide (19)
Yield 84%, mp 225–2278C; IR (KBr) cmꢀ1: 3362 (NH), 3068
(Ar–CH), 2962 (CH –CH), 1710 (C O). 1HNMR (CDCl3) d (ppm):
–
–
3
% Protection of a compound
2.34 (s, 3H, CH3), 2.79 (s, 6H, N(CH3)2), 3.25 (t, 2H, CH2), 4.07 (t, 1H,
COCH), 5.94 (s, 1H, NCH), 6.45 (d, J ¼ 7.5 Hz, 2H, Ar–H), 6.65
(d, J ¼ 8.0 Hz, 2H, Ar–H), 6.67–6.68 (m, 1H, Ar–H), 6.94
(d, J ¼ 8.0 Hz, 2H, Ar–H), 7.26 (d, J ¼ 7.5 Hz, 2H, Ar–H), 10.23
(br s, 1H, NH), 10.51 (br s, 1H, NH). MS (m/z): 412 (Mþ). Anal. Calcd.
for C21H24N4O3S : C, 61.14; H, 5.86; N, 13.58. Found: C, 61.36;
H, 5.84; N, 13.54.
ðMCT of the compound ꢀ MCT of the controlÞ
¼
ꢃ 100
MCT of the control
MCT of the compound
MCT of the reference drug
% Potency of a compound ¼
ꢃ 100
where MCT means mean convulsion threshold. The results are
presented in Table 1, showing the mean convulsion threshold
and percentage protection for both the newly synthesized com-
pounds and the standard diazepam.
2-(4-Dimethylaminophenyl)-3-(2,4-dinitrophenylamino)
thiazolidin-4-one-5-yl-acetyl acetamide (20)
Yield 81%, mp 232–2348C; IR (KBr) cmꢀ1: 3320 (NH), 3060
–
(Ar–CH), 2957 (CH –CH), 1710 (C O), 1515 and 1316 (NO ).
–
3
2
1H NMR (CDCl3) d (ppm): 2.36 (s, 3H, CH3), 2.75 (s, 6H,
N(CH3)2), 3.23 (t, 2H, CH2), 3.95 (t, 1H, COCH), 5.88 (s, 1H,
NCH), 6.46 (d, J ¼ 7.5 Hz, 2H, Ar–H), 6.82 (d, J ¼ 8.0 Hz, 2H,
Ar–H), 7.08–7.09 (m, 1H, Ar–H), 8.5–8.53 (m, 1H, Ar–H),
9.01–9.03 (m, 1H, Ar–H), 10.16 (br s, 1H, NH), 10.54 (br s, 1H,
NH). MS (m/z): 502 [Mþ]. Anal. Calcd. for C21H22N6O7S: C, 50.19;
H, 4.41; N, 16.72. Found: C, 50.01; H, 4.42; N, 16.78.
Statistical analysis
All values are expressed as mean ꢁ SEM. Data were analyzed by
non-parametric ANOVA followed by Dunnett’s multiple compari-
son tests, and other data was evaluated using GraphPad PRISM
software. A p-value of <0.05 was considered as significantly
different.
The authors have declared no conflict of interest.
Acute toxicity studies
Acute toxicity study was performed for all the synthesized com-
pounds to ascertain safe dose by acute oral toxic class method
of Organization of Economic Co-operation and Development,
as per 423 guidelines (OECD). The experimental protocol was
duly approved by the institutional animal ethical committee
(IAEC, F. No.25/559/2010-AWD) constituted by the Committee
for the Purpose of Control and Supervision of Experimental
Animals (CPCSEA), Ministry of Environment and Forest, New
Delhi, India.
All the compounds tested for acute toxicity studies were also
observed for gross behavioral changes in mice, continuously for
5 h at 1-h intervals after administration of the compounds. There
after the observations were recorded intermittently for 24 h
and compared with that of the control group. In the behavioral
profile, the animals were observed for changes in their awareness
and mood.
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