Synthesis and pharmacological screening of some novel anti-hypertensive agents possessing 5-Benzylidene-2-(phenylimino)-thiazolidin-4-one ring

Article abstract of DOI:10.1016/j.ejmech.2014.02.048

In the present study, fourteen derivatives comprising of 5-benzylidene-2-(phenylimino)-thiazolidin-4-one moiety were synthesized. The structures of synthesized compounds were established by elemental analysis, IR, ¹H NMR, ¹³C NMR and mass spectral data and tested for electrocardiographic, antiarrhythmic and antihypertensive activities. Compound 11 was found to be most potent in this series. The pharmacological results suggested that, the antiarrhythmic effects of these compounds were related to their Ca⁺⁺ ion channel antagonistic properties, which are believed to be due to the presence of 5-benzilidine-2-(phenylimino)-thiazolidin-4-one moiety. The antihypertensive effect of β-blocker side chain is enhanced by the presence of less bulky aliphatic and heterocyclic tertiary amines.

Full text of DOI:10.1016/j.ejmech.2014.02.048

European Journal of Medicinal Chemistry 76 (2014) 580e588
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and pharmacological screening of some novel anti-
hypertensive agents possessing 5-Benzylidene-2-(phenylimino)-
thiazolidin-4-one ring
,
c
c
Chetan M. Bhalgat a, Pooja V. Darda b , Kailash G. Bothara , Shashikant V. Bhandari ,
*
Jotsna Gandhi d, B. Ramesh a
a Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, B.G. Nagara 571448, Nagamangala (tq), Mandya (dist), Karnataka,
India
b Department of Pharmaceutical Chemistry, SCSSS’S Sitabai Thite College of Pharmacy, Shirur, 412210 Pune, Maharashtra, India
c Department of Pharmaceutical Chemistry, (PG Wing), A.I.S.S.M.S. College of Pharmacy, Pune 411 001, Maharashtra, India
d Department of Pharmacognosy, Ashokrao Mane College of Pharmacy, Peth Vadgaon 416 112, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present study, fourteen derivatives comprising of 5-benzylidene-2-(phenylimino)-thiazolidin-4-
one moiety were synthesized. The structures of synthesized compounds were established by
elemental analysis, IR, 1H NMR, 13C NMR and mass spectral data and tested for electrocardiographic,
antiarrhythmic and antihypertensive activities. Compound 11 was found to be most potent in this series.
The pharmacological results suggested that, the antiarrhythmic effects of these compounds were related
to their Caþþ ion channel antagonistic properties, which are believed to be due to the presence of 5-
Received 24 August 2013
Received in revised form
13 February 2014
Accepted 17 February 2014
Available online 19 February 2014
benzilidine-2-(phenylimino)-thiazolidin-4-one moiety. The antihypertensive effect of
chain is enhanced by the presence of less bulky aliphatic and heterocyclic tertiary amines.
Ó 2014 Elsevier Masson SAS. All rights reserved.
b-blocker side
Keywords:
Thiazolidinone
Propanolamine
Hybrid
Antihypertensive
Antiarrhythmic
1. Introduction
molecules often consist of different pharmacophores, which are
linked to each other via spacers [2].
In past twenty years, cardiovascular diseases have become the
world’s leading cause of death. Most of the currently used antihy-
pertensive agents could not be used in single drug therapy due to
their toxicity and side effects. Multiple drug therapy makes the
regime complicated and less successful. One of the most important
goals of organic and medicinal chemistry is to design and synthe-
size the molecules having therapeutic value. In this regard, het-
erocyclic compounds have proven to be versatile support structures
that offer a high degree of structural diversity [1].
Combination drug therapy is used now a day, to limit the side
effects of the therapeutic agents, used alone in the treatment of
certain diseases, with complex and heterogenous pathogenesis.
This can be achieved by concomitant administration of two or more
single active drugs or by designing hybrid molecules. These hybrid
In the long-term treatment of hypertension, there is no single
antihypertensive drug which can normalize the elevated blood
pressure in all patients.
important role in the regulation of the autonomic nervous system
and -blockers have proven to be useful in the pharmacotherapy of
b-Adrenoceptors are known to play an
b
serious and widespread cardiovascular diseases [3,4].
A research group in the People’s Republic of China noted that a
compound, changrolin, was effective as an antiarrhythmic agent
during the clinical trials for examining the antimalarial properties
of Febrifugine derivatives. Stout and his research group studied the
structure of changrolin for its dissimilarity with currently marketed
antiarrhythmics [5e9]. Other studies were also carried out with
regard to the biological structure activity relationships [5,10,11].
Considering the above mentioned facts, we took 2-arylimino-5-
arylidene-4-thiazolidinones rings as
a structural requirement
to show cardiovascular effects. We changed the pyrrolidin-one [12]
ring to substituted thiazolidinone ring and synthesized some
5-benzilidine-2-(phenylimino)-thiazolidin-4-one derivatives (5e
18) as pharmacodynamic hybrids. These novel hybrids were
* Corresponding author.
E-mail addresses: chetanbhalgat2004@gmail.com (C.M. Bhalgat), darda.pooja@
gmail.com (P.V. Darda).
http://dx.doi.org/10.1016/j.ejmech.2014.02.048
0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved.

C.M. Bhalgat et al. / European Journal of Medicinal Chemistry 76 (2014) 580e588
581
characterized by spectral data and elemental analysis, and then
tested for in vivo electrocardiographic, antiarrhythmic and anti-
hypertensive activity on normotensive and hypertensive rats.
presence of fused sodium acetate in ethanol (95%) [14]. The reaction
of 2 with benzaldehyde in presence of fused sodium acetate in
ethanol gave good yield of 5-benzylidene-2-(phenylimino)-thia-
zolidin-4-one (3). The aim of next step was to introduce reactive
2,3-epoxypropyl moiety at the 3rd position of thiazolidin-4-one.
2. Result and discussions
Compound
3 was reacted with epichlorhydrine to give 5-
benzylidene-2-(phenylimino)-3-(oxiran-2-ylmethyl)-thiazolidin-
4-one (4) [15e17]. The syrupy residue and the hydrochloric salt of
the compound 4 were used immediately in the next step. In the
following step, the epoxy bridge was cleaved with secondary
amines (diethyl amine, diphenyl amine, di-n-propyl amine, di-n-
butyl amine, morpholine, piperidine, piperazine, 4-methyl
piperazine, 4-isopropylpiperazine, 4-benzylpiperazine, 4-phenyl
piperazine, 4-cyclohexylpiperazine, pyrrolidine, azacyclonol)
to obtain 5-benzylidene-3-(2-hydroxy-3-(substituted)propyl)-2-
(phenylimino)-thiazolidin-4-ones (5e18) (Scheme 1).
2.1. Chemistry
In the present work, the title compounds were synthesized by a
four step reaction. The starting material i.e. Phenyl thiourea (1), was
prepared according to the method reported by Malawska et al. [13],
using ammonium thiocyanate and benzoyl chloride. This process
was optimized in the presence of dry acetone. The acetone was
dried for at least 48 h over anhydrous calcium sulfate and distilled
just before it was used. 2-Phenyliminothiazolidin-4-one (2) was
prepared by heating phenyl thiourea and ethylchloroacetate in
S
Ethanol (95%)
Ethanol (95%)
HN
NH2
N
N
fused CH3COONa
fused CH3COONa
Benzaldehyde
Reflux 7 h
HN
O
S
ClCH2COOC2H5
Reflux 3.5 h
HN
O
S
1
2
3
Ethanol
Reflux
Epichlorhydrine
Caustic soda solution
N
N
S
O
R
O
5-
6-
7-
8-
(C2H5)2N-
(C6H5)2N-
(CH3CH2CH2)2N-
4
(CH3CH2CH2CH2)2N-
Secondary amine
RH
NaHCO3, Ethanol
Reflux 15-17 h
9-
Morpholine
10-
11-
12-
13-
14-
15-
16-
17-
18-
Piperidine
Piperazine
4-Methylpiperazine
4-isopropylpiperazine
4-Benzylpiperazine
4-Phenylpiperazine
4-cyclohexylpiperazine
Pyrrolidine
N
OH
S
N
R
O
Azacyclonol
5-18
Scheme 1. Schematic representation of synthesis of compounds, 5e18.

582
C.M. Bhalgat et al. / European Journal of Medicinal Chemistry 76 (2014) 580e588
2.2. Spectral elucidation
compounds showed peaks at Mþ, M þ 1 and M þ 2 corresponding
to their molecular formula, which confirmed their chemical struc-
ture. All the compounds gave C, H, N and S analysis within ꢁ1.9% of
the theoretical values. The IR, 1H NMR, 13C NMR, mass spectra and
elemental analysis supported the structure of the various synthe-
sized compounds.
The structures assigned to the title compounds were substan-
tiated by their analytical and other spectral data. The IR spectra of
all the synthesized compounds (5e18) showed characteristic sig-
nals at 3757e3541 cmꢀ1 for OeH, 3176e3031 cmꢀ1 for aromatic Ce
H, 2978e2823 cmꢀ1 for aliphatic CeH, 2646e2387 cmꢀ1 for CeS,
1798e1635 cmꢀ1 for C]O, 1626e1498 cmꢀ1 for C]N and 1383e
1305 cmꢀ1 for t-amine CeN. Similarly 1H NMR spectra of all the
synthesized compounds (5e18) showed peaks in the range of
2.3. Pharmacology
In the present study, various pharmacological tests were carried
out to assess the effects of the compounds on normal electrocar-
diogram (ECG). The antiarrhythmic and hypotensive assay of the
synthesized compounds were also carried out. The effect on ECG
intervals and the heart rate were determined for all the compounds
at the dose of 40 mg/kg ip and compared against standard
d
d
d
4.51e5.24 for OH,
2.87e3.46 for 1st CH2 of propanolamine,
d
2.37e3.34 for 3rd CH2 of propanolamine,
4.05e4.62 for CHeOH,
d
6.83e7.68 for benzylidine, d 7.19e7.98 for bezylimino and d 7.42e
8.12 for eC]CH. Additionally, 13C NMR spectra also supported the
structures of synthesized compounds. The mass spectrum of all the
Table 1
Effects of an intraperitoneal injection of the investigated compounds (40 mg/kg ip) on ECG intervals in anaesthetized Wistar rats.
Compound
Parameters
Time of observation
0 min
15 min
30 min
45 min
60 min
Control
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
PeQ (ms)
QRS (ms)
QeT (ms)
52.4 ꢁ 0.927
19.6 ꢁ 1.142
78.8 ꢁ 1.030
50.6 ꢁ 0.780
20.3 ꢁ 0.519
76.3 ꢁ 1.707
52.0 ꢁ 1.393
18.4 ꢁ 1.030
80.4 ꢁ 1.170
50.6 ꢁ 1.581
20.3 ꢁ 1.062
70.2 ꢁ 1.030
49.4 ꢁ 1.563
22.8 ꢁ 0.653
72.5 ꢁ 0.894
53.5 ꢁ 1.707
20.4 ꢁ 0.346
67.0 ꢁ 1.049
49.9 ꢁ 0.487
23.4 ꢁ 0.567
74.3 ꢁ 0.963
52.2 ꢁ 0.232
20.2 ꢁ 0.843
72.7 ꢁ 1.050
54.3 ꢁ 0.288
20.8 ꢁ 0.874
80.2 ꢁ 0.362
53.0 ꢁ 1.693
22.4 ꢁ 1.030
74.5 ꢁ 0.963
53.5 ꢁ 1.581
23.3 ꢁ 1.062
76.0 ꢁ 1.049
49.8 ꢁ 0.587
23.4 ꢁ 0.567
74.3 ꢁ 0.963
52.4 ꢁ 1.563
21.8 ꢁ 1053
73.5 ꢁ 0.894
51.2 ꢁ 0.235
20.0 ꢁ 0.883
72.8 ꢁ 1.090
50.2 ꢁ 1.281c
20.5 ꢁ 1.112
70.6 ꢁ 1.030
49.8 ꢁ 1.063
22.4 ꢁ 0.663
72.9 ꢁ 0.894c
52.2 ꢁ 1.158
18.9 ꢁ 1.563
79.4 ꢁ 1.270
51.6 ꢁ 1.020
24.2 ꢁ 0.275
85.8 ꢁ 0.727
52.2 ꢁ 1.265
19.4 ꢁ 0.927
81.4 ꢁ 0.997
51.2 ꢁ 1.020
21.2 ꢁ 1.158
71.5 ꢁ 0.921
49.7 ꢁ 0.654
23.2 ꢁ 0.832
72.9 ꢁ 1.143
55.0 ꢁ 1.043
21.6 ꢁ 0.875
67.9 ꢁ 1.020
50.2 ꢁ 0.832
23.2 ꢁ 0.436
74.9 ꢁ 0.986
51.7 ꢁ 1.012
21.5 ꢁ 0.781
72.9 ꢁ 0.443
54.7 ꢁ 0.612
21.6 ꢁ 0.637
80.6 ꢁ 0.973
53.2 ꢁ 1.265
22.6 ꢁ 0.927
74.8 ꢁ 0.986
53.9 ꢁ 1.020
23.7 ꢁ 1.158
76.2 ꢁ 1.020
50.4 ꢁ 0.932
23.2 ꢁ 0.436
74.9 ꢁ 0.986
52.7 ꢁ 1.050
22.2 ꢁ 0.882
73.9 ꢁ 1.143
51.7 ꢁ 1.112
21.4 ꢁ 1.081
72.9 ꢁ 0.943
51.6 ꢁ 0.982
21.3 ꢁ 0.958
71.2 ꢁ 0.927
50.1 ꢁ 0.634
23.1 ꢁ 0.832
73.4 ꢁ 1.143
51.6 ꢁ 0.927
19.9 ꢁ 1.393
78.3 ꢁ 0.860a
52.9 ꢁ 0.422
26.1 ꢁ 0.913
88.3 ꢁ 0.894
53.8 ꢁ 1.393
21.2 ꢁ 1.030
83.2 ꢁ 1.270
54.1 ꢁ 0.422
22.1 ꢁ 1.030
72.3 ꢁ 0.832
51.3 ꢁ 0.275
23.8 ꢁ 0.774
73.4 ꢁ 1.066
56.1 ꢁ 1.348
22.0 ꢁ 0.321
68.9 ꢁ 0.727
50.9 ꢁ 0.356
23.8 ꢁ 0.556
73.2 ꢁ 0.237
51.9 ꢁ 0.857
21.9 ꢁ 0.638
73.3 ꢁ 0.936
56.4 ꢁ 1.860
23.8 ꢁ 0.549a
81.8 ꢁ 0.459
54.4 ꢁ 1.393
23.2 ꢁ 1.030
75.2 ꢁ 0.237
54.1 ꢁ 0.422
24.1 ꢁ 0.730
76.6 ꢁ 0.727
50.9 ꢁ 0.356
23.8 ꢁ 0.556
73.2 ꢁ 0.237
53.3 ꢁ 1.205
23.5 ꢁ 0.974c
74.2 ꢁ 1.066
52.3 ꢁ 0.859
21.9 ꢁ 0.658
73.3 ꢁ 1.036
54.3 ꢁ 0.522
22.5 ꢁ 1.040
72.6 ꢁ 0.862
51.3 ꢁ 0.275
23.8 ꢁ 0.774
74.3 ꢁ 1.066
52.5 ꢁ 0.780
20.2 ꢁ 1.348
78.8 ꢁ 0.927
54.4 ꢁ 1.020
27.6 ꢁ 1.066
91.3 ꢁ 1.398
54.2 ꢁ 1.020
20.6 ꢁ 0.860
84.8 ꢁ 0.860a
53.4 ꢁ 0.780
21.6 ꢁ 0.863
71.3 ꢁ 1.142
52.4 ꢁ 0.913
24.1 ꢁ 1.026
74.9 ꢁ 0.864
57.3 ꢁ 1.288
22.4 ꢁ 0.582
68.4 ꢁ 0.753
51.3 ꢁ 0.954
23.1 ꢁ 0.387
74.3 ꢁ 0.852
50.6 ꢁ 0.245
22.8 ꢁ 0.583a
72.3 ꢁ 0.633
56.9 ꢁ 0.887
23.7 ꢁ 0.584a
82.4 ꢁ 0.565a
54.9 ꢁ 1.020
23.6 ꢁ 0.860
75.3 ꢁ 0.852
55.2 ꢁ 0.780
24.6 ꢁ 0.863
77.1 ꢁ 0.753
51.3 ꢁ 0.954
23.1 ꢁ 0.387
74.3 ꢁ 0.852
53.9 ꢁ 0.973
24.1 ꢁ 1.026
74.9 ꢁ 0.764
50.6 ꢁ 1.245
22.8 ꢁ 0.783a
72.7 ꢁ 0.332
53.3 ꢁ 1.280
21.1 ꢁ 0.866
71.5 ꢁ 1.155
52.4 ꢁ 0.991
24.2 ꢁ 1.956
74.9 ꢁ 1.064
52.9 ꢁ 0.924
19.3 ꢁ 0.873
79.7 ꢁ 0.965b
54.6 ꢁ 0.780
28.2 ꢁ 1.364
90.6 ꢁ 1.288
55.6 ꢁ 1.364
21.4 ꢁ 0.927
86.4 ꢁ 0.965b
52.6 ꢁ 0.519
20.4 ꢁ 0.924
70.7 ꢁ 0.475
50.2 ꢁ 0.873
22.5 ꢁ 0.728
72.7 ꢁ 0.243
54.3 ꢁ 1.398
22.6 ꢁ 0.763
66.4 ꢁ 0.854
52.7 ꢁ 0.396a
23.7 ꢁ 0.283
74.2 ꢁ 0.642
51.5 ꢁ 0.942
22.6 ꢁ 0.632
71.8 ꢁ 0.363
55.1 ꢁ 0.653
22.4 ꢁ 0.875
82.1 ꢁ 0.357
55.6 ꢁ 1.364
24.0 ꢁ 0.927
75.6 ꢁ 0.642
55.6 ꢁ 0.519
24.8 ꢁ 0.924
77.4 ꢁ 0.854
52.7 ꢁ 0.394a
23.7 ꢁ 0.283
74.2 ꢁ 0.642
54.2 ꢁ 1.073
24.7 ꢁ 0.728
75.0 ꢁ 0.243
51.3 ꢁ 1.042
22.6 ꢁ 0.652
71.2 ꢁ 0.363
52.8 ꢁ 0.619
20.6 ꢁ 0.964
70.9 ꢁ 0.575
50.2 ꢁ 0.782
22.5 ꢁ 0.758
72.7 ꢁ 0.243
Quinidine
5
6
7
8
9
10
11
12
13
14
15
16
17
18
The data are the means of five experiments ꢁ S.E.M. Statistical analyses were performed using a one-way ANOVA followed by Dunnett’s test.
a
P < 0.05.
P < 0.01.
P < 0.001.
b
c

C.M. Bhalgat et al. / European Journal of Medicinal Chemistry 76 (2014) 580e588
583
Table 2
Responses (MAP) versus time (min), following the administration of the compounds (40 mg/kg ip) in normotensive rats.
Compound
Mean arterial pressure (MAP) in mm Hg
0 min
15 min
30 min
45 min
60 min
Control
Propranolol
5
6
7
8
9
10
11
12
13
14
15
16
17
18
94.21 ꢁ 2.065
92.56 ꢁ 1.543c
91.39 ꢁ 1.923
94.09 ꢁ 1.402
95.41 ꢁ 1.672
95.56 ꢁ 1.962
92.99 ꢁ 2.065a
94.65 ꢁ 0.743
92.33 ꢁ 1.045
91.93 ꢁ 1.623
92.09 ꢁ 1.452
95.09 ꢁ 1.756
94.56 ꢁ 1.962
93.99 ꢁ 2.065
93.02 ꢁ 1.043a
91.39 ꢁ 1.045
93.81 ꢁ 1.543
79.43 ꢁ 1.213
79.23 ꢁ 1.182b
87.32 ꢁ 1.013b
91.10 ꢁ 1.198d
84.43 ꢁ 1.986b
82.61 ꢁ 2.045b
82.63 ꢁ 1.065b
78.76 ꢁ 0.472b
79.37 ꢁ 1.152b
79.32 ꢁ 1.213b
92.10 ꢁ 1.098d
86.43 ꢁ 1.986b
85.61 ꢁ 2.045b
84.63 ꢁ 1.265b
76.73 ꢁ 1.472b
94.68 ꢁ 1.213
62.96 ꢁ 0.962
68.93 ꢁ 1.161b
85.08 ꢁ 0.631b
79.16 ꢁ 0.993b
77.87 ꢁ 0.923b
73.87 ꢁ 1.973b
72.76 ꢁ 0.865b
62.26 ꢁ 0.732b
63.43 ꢁ 1.161b
62.08 ꢁ 0.931b
78.19 ꢁ 1.093b
76.84 ꢁ 0.923b
77.84 ꢁ 1.973b
74.76 ꢁ 0.865b
70.26 ꢁ 0.732b
94.83 ꢁ 0.943
65.87 ꢁ 1.003
63.51 ꢁ 1.061b
85.43 ꢁ 1.002b
72.37 ꢁ 0.965b
80.16 ꢁ 0.943b
62.69 ꢁ 1.165b
64.69 ꢁ 0.647b
62.53 ꢁ 0.531b
64.51 ꢁ 1.221b
65.43 ꢁ 1.602b
72.57 ꢁ 0.965b
79.26 ꢁ 0.943b
64.01 ꢁ 1.165b
69.69 ꢁ 0.647b
64.53 ꢁ 0.531b
95.07 ꢁ 1.973
70.21 ꢁ 0.991c
73.31 ꢁ 1.172b
90.27 ꢁ 1.021d
88.98 ꢁ 1.045b
90.59 ꢁ 0.805d
71.43 ꢁ 0.973b
76.12 ꢁ 0.283b
70.27 ꢁ 0.632b
74.63 ꢁ 1.072b
76.27 ꢁ 1.021b
85.44 ꢁ 1.145b
83.55 ꢁ 0.805d
75.43 ꢁ 0.973b
73.12 ꢁ 0.283b
71.94 ꢁ 0.632b
The data are the mead of five experiments ꢁ S.E.M. Statistical analyses were performed using a one-way ANOVA followed by Dunnett’s test.
a
P < 0.05.
P < 0.01.
P < 0.001.
P > 0.05.
b
c
d
(Quinidine). Electrocardiographic experiments showed that the
compounds 11, 12, 5, 10, 13 and 9 at the dose of 40 mg/kg, signifi-
cantly decreased the number of cardiac beats per minute. The
compound 9 prolonged the PeQ interval, QRS complex by com-
pounds 11, 12, 10, 13 and QeT interval by compound 5 (Table 1).
Compounds 5e18 were suspended in 0.5% methylcellulose and
an intraperitoneal dose of 40 mg/kg was administered. Blood
pressure lowering effect in normotensive rats of the compounds 13,
11, 12, 15, 8 and 6 reached their maximum in about 30 min after
dosing and those of compounds 9, 5,16,18,10,17, 7 and 14 lasted for
45 min. Propranolol of dose 10 mg/kg, produced significant
reduction in blood pressure within 30 min after dosing in normo-
tensive rats (Table 2). Blood pressure lowering effect in hyperten-
sive rats of the compounds 10, 17, 15, 8 and 14 reached their
maximum in about 30 min after dosing and those of compounds 5,
9, 11, 12, 18, 16, 13, 7 and 6 lasted for 45 min. Propranolol of dose
10 mg/kg, produced significant reduction in blood pressure within
45 min after dosing in hypertensive rats (Table 3). Heart rates of
thiopental-anesthetized normotensive Wistar rats were recorded.
Heart rate (in beats per min) was recorded at 15 min intervals (0,15,
30, 45, 60 min) after administration of the compounds (Table 4).
Further, all the compounds were tested for antiarrhythmic activity
in barium chloride induced arrhythmia. All the experimental ani-
mals were given intravenous injections of barium chloride in high
dose (32 mg/kg), which results in sinus bradycardia, rapid ven-
tricular extrasystoles, ventricular tachycardia and ventricular
fibrillation (100%), leading to the death of all animals. Among the
synthesized compounds, 11, 12, 13, 18, 5 and 9, were more effective
in barium chloride induced arrhythmia test. Compounds 16, 14, 15,
17, 10, 7, 8 and 6 exhibited weak antiarrhythmic properties after
administration, leading to slight increase in the appearance time of
arrhythmia and mortality (Table 5). The lowest activity was
Table 3
Responses (MAP) versus time (min), following the administration of the compounds (40 mg/kg ip) in hypertensive rats.
Compound
Mean arterial pressure (MAP) in mm Hg
0 min
15 min
30 min
45 min
60 min
Control
Propranolol
5
6
7
8
9
10
11
12
13
14
15
16
17
18
194.08 ꢁ 1.962
195.12 ꢁ 1.065b
194.43 ꢁ 1.043
194.26 ꢁ 1.265
193.57 ꢁ 0.965
195.08 ꢁ 1.002c
195.43 ꢁ 1.161
194.76 ꢁ 1.213
196.63 ꢁ 1.923
196.43 ꢁ 0.531
193.37 ꢁ 1.472
194.51 ꢁ 0.923
194.87 ꢁ 1.003
195.99 ꢁ 1.172
196.10 ꢁ 0.283
193.69 ꢁ 0.923
195.68 ꢁ 1.623
171.73 ꢁ 0.865b
172.98 ꢁ 0.931b
183.55 ꢁ 1.543
184.76 ꢁ 1.198
171.43 ꢁ 1.973
175.31 ꢁ 1.045
165.33 ꢁ 2.045c
176.65 ꢁ 1.623
182.76 ꢁ 1.093
185.53 ꢁ 1.072
179.02 ꢁ 1.182
180.43 ꢁ 1.021
185.69 ꢁ 0.965
165.01 ꢁ 0.805
176.43 ꢁ 0.973
194.72 ꢁ 1.002
148.53 ꢁ 1.165b
161.27 ꢁ 1.161b
169.59 ꢁ 0.805
170.10 ꢁ 0.865
159.69 ꢁ 0.943
168.61 ꢁ 2.065
134.16 ꢁ 1.986
153.16 ꢁ 0.632
157.99 ꢁ 1.065d
161.56 ꢁ 0.647
160.63 ꢁ 1.045
146.27 ꢁ 1.986
151.12 ꢁ 1.402
148.37 ꢁ 1.962
139.21 ꢁ 2.045
193.96 ꢁ 0.865
120.32 ꢁ 2.065
119.43 ꢁ 0.531b
159.27 ꢁ 0.732
153.26 ꢁ 0.631
163.37 ꢁ 1.973
131.61 ꢁ 1.452d
145.87 ꢁ 0.943
128.32 ꢁ 1.221
134.44 ꢁ 0.647
146.51 ꢁ 1.756
166.41 ꢁ 1.602
156.09 ꢁ 1.061
138.63 ꢁ 1.672
149.39 ꢁ 1.021a
135.96 ꢁ 1.013
195.11 ꢁ 0.531
152.26 ꢁ 0.991
159.87 ꢁ 1.172b
169.93 ꢁ 0.632
172.23 ꢁ 0.973
182.09 ꢁ 1.165
154.93 ꢁ 0.993
166.84 ꢁ 1.165
159.08 ꢁ 0.283
162.19 ꢁ 1.962
160.84 ꢁ 1.145
179.51 ꢁ 0.732
182.32 ꢁ 1.098
158.39 ꢁ 0.962
177.56 ꢁ 1.152
162.87 ꢁ 1.161
The data are the mead of five experiments ꢁ S.E.M. Statistical analyses were performed using a one-way ANOVA followed by Dunnett’s test.
a
P < 0.05.
P < 0.01.
P < 0.001.
P > 0.05.
b
c
d

584
C.M. Bhalgat et al. / European Journal of Medicinal Chemistry 76 (2014) 580e588
Table 4
Heart rate (beats per min) versus time (min), following the administration of the compounds (40 mg/kg ip).
Compound
Heart rate (beats per min)
0 min
15 min
30 min
45 min
60 min
Control
Quinidine
5
6
7
8
9
10
11
12
13
14
15
16
17
18
316.62 ꢁ 9.643
311.8 ꢁ 8.248
319.65 ꢁ 9.876
316.34 ꢁ 9.247
329.62 ꢁ 9.135
309.12 ꢁ 9.325
315.15 ꢁ 9.643
308.43 ꢁ 9.369
302.12 ꢁ 9.221
305.65 ꢁ 9.213
310.34 ꢁ 6.256
333.62 ꢁ 9.135
318.34 ꢁ 9.247
324.13 ꢁ 9.213
318.73 ꢁ 9.134c
332.05 ꢁ 9.521
313.93 ꢁ 9.912
285.16 ꢁ 9.533
312.24 ꢁ 9.235
305.46 ꢁ 9.325
319.34 ꢁ 9.639
297.25 ꢁ 9.634
304.65 ꢁ 9.912
297.54 ꢁ 9.607
292.46 ꢁ 9.442
290.24 ꢁ 9.235
298.46 ꢁ 9.533
312.34 ꢁ 9.423
309.46 ꢁ 9.325
312.65 ꢁ 7.132
298.54 ꢁ 9.034
310.46 ꢁ 9.142
317.68 ꢁ 7.631
246.18 ꢁ 8.248
274.66 ꢁ 9.256b
292.41 ꢁ 9.246
289.52 ꢁ 9.618a
276.46 ꢁ 9.554
293.54 ꢁ 9.164a
268.74 ꢁ 9.213a
259.31 ꢁ 9.122b
256.32 ꢁ 9.018b
272.41 ꢁ 8.248
283.52 ꢁ 9.638a
295.41 ꢁ 9.246
289.54 ꢁ 8.164a
256.85 ꢁ 9.343a
279.31 ꢁ 9.567b
316.82 ꢁ 8.452
261.63 ꢁ 7.943
309.56 ꢁ 8.216
289.26 ꢁ 8.241
305.32 ꢁ 8.218
283.50 ꢁ 8.452
294.42 ꢁ 7.934a
274.15 ꢁ 8.463a
269.73 ꢁ 7.631a
283.56 ꢁ 6.216
253.26 ꢁ 8.641
298.21 ꢁ 8.432
287.25 ꢁ 8.241
294.42 ꢁ 7.766a
287.15 ꢁ 8.645a
295.73 ꢁ 7.564a
314.96 ꢁ 9.442
286.32 ꢁ 8.641
312.28 ꢁ 7.345
302.92 ꢁ 7.943
312.43 ꢁ 7.842
301.69 ꢁ 7.476
308.42 ꢁ 7.763
303.32 ꢁ 7.151
298.12 ꢁ 7.287
302.28 ꢁ 7.675c
302.92 ꢁ 7.943
312.21 ꢁ 7.842
301.92 ꢁ 7.932
303.42 ꢁ 7.432
309.32 ꢁ 7.751
302.12 ꢁ 7.678
The data are the means of five experiments ꢁ S.E.M. Statistical analyses were performed using a one-way ANOVA followed by Dunnett’s test.
a
P < 0.05.
P < 0.01.
P < 0.001.
b
c
demonstrated by the compound 6, in all the experimental animals,
3.2. Induction of hypertension in normotensive rats
followed by their death.
The deoxycortisone acetate (DOCA, 20 mg/kg sc in olive oil) was
administered twice a week for 4 weeks to induce hypertension in
rats. Drinking water was replaced by 1% w/v NaCl solution [18].
Blood pressure started to rise after one week and the systolic value
reached between 160 and 180 mm Hg after 4 weeks.
3. Pharmacology
3.1. Animals
All the animals (Wistar rats, weighing in the range 250e300 g)
were housed in standard cages, under standard ambient condi-
tions; temperature (25 ꢁ 2 ꢂC) and relative humidity of 50 ꢁ 5%. A
12 h light: 12 h dark cycle was maintained. All the animals were
allowed to have free access to water and standard pelletized food.
All the experimental procedures and protocols used in these
studies were reviewed and approved by the Institutional Animal
Ethical Committee (IAEC) of A.I.S.S.M.S. College of Pharmacy, Pune,
constituted in accordance with the guidelines of Committee for the
Purpose of Control and Supervision of Experiments on Animals
(CPCSEA), Government of India.
3.3. Preparation of test compounds
Test compounds were suspended in 0.5% aqueous solution of
methylcellulose. Test compounds were administered intraperito-
neally (ip).
3.4. In vivo pharmacological screening
3.4.1. Influence on blood pressure [19,20]
Influence on blood pressure was analyzed in adult normotensive
and hypertensive Wistar rats (250e300 g) under thiopental sodium
anesthesia (60 mg/kg ip). The right carotid artery was exposed and
cannulated with polyethylene tube filled with small volumes of
heparin solution (20 IU/mL, in physiological saline) for the mea-
surement of mean arterial pressure of rats. The heparin solution
was injected in the arterial catheter at 30 min intervals, to avoid
possible blood coagulation. The catheter (PE-50) was connected to
the blood pressure transducer and the transducer was connected
with the Four Channel Data Acquisition System (BIOPAC System,
Inc., MP35). One hour after the surgical protocol, mean arterial
pressure values were measured at 0, 15, 30, 45 and 60 min after
administration of the standard and test compounds. The test
compounds (40 mg/kg) and standard (propranolol, 10 mg/kg) were
administered intraperitoneally and thereafter the blood pressure
measurement was continued for 60 min.
Table 5
Prophylactic antiarrhythmic activity in anaesthetized rats.
Compound
Appearance time of arrhythmia (sec)
Mortality time (sec)
Control
Quinidine
5
6
7
8
9
10
11
12
13
14
15
16
17
18
129.4 ꢁ 4.373c
394.8 ꢁ 3.576
343.1 ꢁ 2.187c
234.8 ꢁ 1.584
266.1 ꢁ 1.865
265.4 ꢁ 1.524c
313.5 ꢁ 2.875
279.3 ꢁ 1.653
379.7 ꢁ 3.143b
349.7 ꢁ 3.183c
354.8 ꢁ 3.184
296.9 ꢁ 2.865c
285.4 ꢁ 1.875a
297.5 ꢁ 2.735
285.3 ꢁ 2.653
323.4 ꢁ 2.143
682.8 ꢁ 9.656
1281.8 ꢁ 14.363c
1142.4 ꢁ 8.453
768.5 ꢁ 11.736
938.4 ꢁ 6.360
786.2 ꢁ 13.425
1089.8 ꢁ 11.120
886.9 ꢁ 9.886c
1380.5 ꢁ 10.152a
1276.0 ꢁ 7.184
1213.7 ꢁ 6.875
986.7 ꢁ 16.889c
964.4 ꢁ 14.323
944.9 ꢁ 12.698
918.8 ꢁ 14.578
1162.1 ꢁ 18.572b
3.4.2. Influence on normal electrocardiogram [12,19]
Electrocardiogram recording is an essential tool for the evalua-
tion of antiarrhythmic drugs. Similar to the heart rate, the elec-
trocardiogram differs for various species. Electrocardiographic
investigations were carried out with the application of subcu-
taneous needle electrodes to the flexor aspect of limbs of rat and
connected with the SS2L electrode transducer, which was
The data are the means of five experiments ꢁ S.E.M. Statistical analyses were per-
formed using a one-way ANOVA followed by Dunnett’s test.
a
P < 0.05.
P < 0.01.
P < 0.001.
b
c

C.M. Bhalgat et al. / European Journal of Medicinal Chemistry 76 (2014) 580e588
585
connected with the Four Channel Data Acquisition System (BIOPAC
System, Inc, MP 35) with the respective ECG transducer. Physio-
logical ECG recordings were taken from Wistar rats (250e300 g),
anaesthetized with thiopental sodium (60 mg/kg ip) followed by
injection of the compounds under investigation. Test compounds
(40 mg/kg) and standard (Quinidine, 15 mg/kg) were administered
intraperitoneally. ECG parameters were collected at 0, 15, 30, 45
and 60 min of administration of the compounds.
respectively. The pharmacological results suggested that the anþtiþ-
arrhythmic effects of these compounds were related to their Ca
ion channel antagonistic and antioxidant properties. These Caþþ
ion channel antagonistic and antioxidant properties may be due to
the presence of the 5-benzilidine-2-(phenylimino)-thiazolidin-4
one moieties. Further the antihypertensive effect of
b blocker side
chain is enhanced by the presence of less bulky aliphatic and het-
erocyclic secondary amines in the tested compounds.
The activity of the compounds, 5e18, was promising enough to
continue further experiments. From the detailed analysis of phar-
macological activities of the synthesized compounds, we have
concluded that the rationale basis for the designed hybrid mole-
cules containing multiple pharmacophore has proven to be prom-
ising at least in these preliminary in vivo pharmacological
screening models.
3.4.3. Influence on heart rate [12,19]
Heart rate recordings were taken from Wistar rats (250e300 g)
by applying subcutaneous needle electrodes to the flexor aspect of
the limbs of rats, connected with the SS2L electrode transducer
which was in connection with the Four Channel Data Acquisition
System (BIOPAC System, Inc., MP 35) with the respective ECG
transducer. Rats were anaesthetized with thiopental sodium
(60 mg/kg ip) and the test compounds were then injected. Test
compounds (40 mg/kg) and standard (Quinidine, 15 mg/kg) were
administered intraperitoneally. Heart rate (in beats per min) was
recorded at 0, 15, 30, 45 and 60 min after administration of the
compounds.
4.1. Scope for further research
The most potent compounds will be subjected to following
studies:
1. Acute and chronic toxicity studies
2. Pharmacokinetic profile
3.4.4. Antiarrhythmic activity [12,19]
The synthesized title compounds (5e18) were examined in vivo,
for prophylactic antiarrhythmic action in animal models of heart
rhythm disturbances, caused by intravenous injection of barium
chloride. Increase in appearance time of arrhythmia and increase in
mortality time after administration of arrhythmogen (barium
chloride) depicts the ability of a compound to act as a potential
antiarrhythmic agent. Barium chloride acts by decreasing the out-
ward potassium currents.
3. Mechanism of action
4. Possibility of metabolic activation and if yes, mechanism of
degradation of the compounds etc.
Latter if the results are found to be promising, then further
decision on starting clinical studies will be taken.
5. Experimental section
3.4.4.1. Barium chloride-induced arrhythmia. The arrhythmia was
evoked in rats anaesthetized with thiopental sodium (60 mg/kg ip)
by iv injection of barium chloride (32 mg/kg, in a volume of 1 mL/
kg). Test compounds (40 mg/kg) and standard (Quinidine, 15 mg/
kg) administered intraperitoneally, 60 min prior to arrhythmogen
administration. Overdose of barium chloride induces progressive
increase in disturbance of cardiac rhythm, which is associated with
premature ventricular beats, ventricular tachycardia, ventricular
fibrillation and leading to death within 2e5 min. Increase in
appearance time of arrhythmia and increase in mortality time after
barium chloride administration were accepted as a criterion for
antiarrhythmic effect of the compounds.
Unless otherwise noted, materials were obtained from com-
mercial suppliers and used without further purification. Melting
points were determined by Digital Melting Point Apparatus [Veego
(Model-VMP-D)] and are uncorrected. All reactions were monitored
by thin-layer chromatography on 0.25 mm silica gel (60GF-254)
plates, by using benzene: methanol in the ratio of [9:1] as mobile
phase and visualized in UV light. FT-IR spectra of the powdered
compounds were recorded using KBr on a SHIMADZU FT-IR 8400S
spectrometer using diffuse reflectance attachment and reported in
cmꢀ1. The 1H NMR, 13C NMR spectra were recorded on a Varian
Mercury YH500 (500 MHz FT NMR) spectrophotometer using TMS
as an internal reference (chemical shift represented in d ppm). Mass
spectra were recorded on GCeMS QP5050A System (bench top
quadruple mass spectrophotometer). Elemental analyses were
performed for C, H, N and S using instrument FLASHEA 1112 series.
3.5. Statistical analyses
The data is expressed as mean ꢁ SEM. The statistical significance
was calculated using a one-way ANOVA test. Differences were
considered significant when p < 0.05. All statistical calculations
were performed using evaluation version of Graph PadÒ Prism 3.0
(USA) statistical software.
6. Material and methods
6.1. Synthesis of phenyl thiourea (1)
The phenyl thiourea was prepared as per reported method. M.p.:
4. Conclusions
151e153 ꢂC; yield: 57.84% (solid); Rf value: 0.72; FTIR (KBr) cmꢀ1
3325 (NeH), 2970 (CeH), 1221 (C]S).
:
In present study, we have described simple and efficient pro-
tocol for the synthesis of 5-benzilidine-2-(phenylimino)-thiazoli-
din-4-one derivatives (5e18) with good yields. The screening of
hypotensive and antiarrhythmic activities of the title compounds
(5e18) has led to the identification of several potent cardiovascular
agents. The results from this study indicate that the compounds 11,
9, 18, 17, 5, 12, 16, 10 and 13 at given concentration were effective
hypotensive agents.
6.2. Synthesis of 2-phenyliminothiazolidin-4-one (2)
Phenyl thiourea (16 g, 0.08 mol) was dissolved in 33 mL ethanol
(95%). The resulting solution was refluxed with fused sodium ace-
tate (8.63 g, 0.105 mol) and ethylchloroacetate (2.94 g, 11.30 mL,
0.106 mol) for 3.5 h. The mixture was then poured into 250 mL of
water. The mixture was then poured into 250 mL of water. The
crystalline product obtained was filtered and dried. The compound
was recrystallized using ethanol (95%). M.p.: 172e174 ꢂC; yield:
Compounds 11 and 5 were the most potent antihypertensive
agents in the series for normotensive and hypertensive rats

586
C.M. Bhalgat et al. / European Journal of Medicinal Chemistry 76 (2014) 580e588
71.12% (solid); Rf value: 0.62; FTIR (KBr) cmꢀ1: 3410 (NeH), 2970
(CeH), 1742 (C]O), 1610 (C]N); 1H NMR (300 MHz, CDCl3, ppm):
166.78; MS: m/z 409.4 (Mþ), 410.4 (Mþ1), 411.4 (Mþ2). %Anal.
Calcd. for C23H27N3O2S: C, 65.45; H, 6.65; N, 10.26; S, 7.83. Found C,
65.39; H, 6.62; N, 10.08; S, 7.72.
d
3.21 (s, 2H, CH2), 6.98e7.34 (m, 5H, phenyl), 8.82 (s, 1H, NH); MS:
m/z 192 (Mþ), 193 (Mþ1), 194 (Mþ2).
6.5.1.2. 5-Benzylidene-3-(3-(diphenylamino)-2-hydroxypropyl)-2-
(phenlimino)-thiazolidin-4-one (6). M.p.: 285e287 ꢂC; yield: 57.40%
(solid); Rf value: 0.63; FTIR (KBr) cmꢀ1: 3592 (OeH), 3141 (Ar CeH),
2956 (Aliphatic CeH), 2387 (CeS), 1734 (C]O),1626 (C]N),1383 (t
6.3. Synthesis of 5-benzyliden-2-(phenylimino)-thiazolidin-4-one
(3)
Benzaldehyde (2.12 g, 0.02 mol), 2-phenyliminothiazolidin-4-
one (2, 3.84 g, 0.02 mol) and fused sodium acetate (5.44 g,
0.04 mol) were taken in 15 mL of absolute ethanol. The resultant
mixture was refluxed for 7 h. The hot mixture was then poured into
50 mL of water and kept overnight. The precipitate obtained was
filtered and washed with sufficient water (30e40 mL) to remove
unreacted aldehyde and then dried. The product was recrystallized
using ethanol (95%). M.p.: 220e222 ꢂC; yield: 80.20% (solid); Rf
value: 0.63; FTIR (KBr) cmꢀ1: 3442 (NeH), 3018 (Ar CeH), 1716 (C]
amine CeN); 1H NMR (400 MHz, CDCl3, ppm):
d 2.98e3.08 (d, 4H,
1st CH2 of propanolamine), 3.23e3.34 (d, 2H, 3rd CH2 of prop-
anolamine), 4.56e4.62 (m, 1H, CHeOH), 4.92 (s, 1H, OH), 6.49e6.57
(d, 4H, o-Position of Sub. Phenyl ring), 6.64e6.78 (d, 2H, p-position
of Sub. phenyl ring), 7.07e7.12 (t, 4H, m-Position of Sub. Phenyl
ring), 7.20e7.35 (m, 5H, benzylidine), 7.38e7.43 (m, 5H, benzyli-
mino), 7.62 (s, 1H, eC]CH); 13C NMR (400 MHz, CDCl3, ppm):
d
40.38, 62.31, 66.38, 113.92, 117.81, 119.87, 121.68, 124.77, 126.13,
127.71, 128.43, 129.65, 131.13, 134.61, 140.69, 148.66, 149.81, 163.22,
168.73; MS: m/z 505.6 (Mþ), 506.6 (M þ 1), 507.6 (M þ 2). %Anal.
Calcd. for C31H27N3O2S: C, 73.64; H, 5.83; N, 8.31; S, 6.34. Found: C,
73.24; H, 5.72; N, 8.23; S, 6.26.
O), 1620 (C]N); 1H NMR (300 MHz, CDCl3, ppm):
10H, phenyl and benzylidene), 7.82 (s, 1H, C]CH), 8.21 (s, 1H, NH);
MS: m/z 280 (Mþ), 281 (Mþ1), 282 (Mþ2).
d 6.99e7.60 (m,
6.4. Synthesis of 5-benzylidene-2-(phenylimino)-3-(oxiran-2-
ylmethyl)-thiazolidin-4-one (4)
6.5.1.3. 5-Benzylidene-3-(3-(dipropylamino)-2-hydroxypropyl)-2-
(phenylimino)-thiazolidin-4-one (7). M.p.: 247e250 ꢂC; yield:
70.50% (solid); Rf value: 0.55; FTIR (KBr) cmꢀ1: 3564 (OeH), 3058
(Ar CeH), 2896 (Aliphatic CeH), 2646 (CeS), 1498 (C]N), 1635 (C]
A solution of epichlorhydrin (0.64 mL, 0.75 g, 0.0081 mol) in
10 mL of ethanol was heated to 65e70 ꢂC. This solution was then
added in a drop wise manner over a period of 1e2 h in the sus-
pension of compound 3 (2.27 g, 0.0081 mol) in ethanol (30 mL)
maintaining the reaction temperature at around 70 ꢂC. The solution
was then heated for 1e3 h to gentle reflux (75e80 ꢂC) and cooled to
60 ꢂC. The reflux time was monitored using TLC. Caustic soda so-
lution (10% alcoholic) was added until it was distinctly alkaline to
thymolphthalein paper. The reaction mixture was concentrated to
40% of the initial volume. The precipitated sodium chloride was
filtered off and the filtrate was evaporated to dryness at 100 ꢂC in
vacuo. The resultant syrup like residue was used immediately in the
next step.
O), 1358 (t-amine CeN); 1H NMR (400 MHz, CDCl3, ppm):
d 0.98e
1.02 (t, 6H, CH3 of 2ꢂ amine), 1.45e1.57 (m, 4H, 2nd CH2 of 2ꢂ
amine), 2.13e2.17 (t, 4H, 1st CH2 of 2ꢂ amine), 2.37e2.43 (t, 2H, 3rd
CH2 of propanolamine), 2.87e3.12 (d, 2H, 1st CH2 of propanol-
amine), 4.12e4.20 (m, 1H, CHeOH), 4.62 (s, 1H, OH), 7.08e7.20 (m,
5H, benzylidine), 7.34e7.39 (m, 5H, benzylimino), 7.52 (s, 1H, eC]
CH); 13C NMR (400 MHz, CDCl3, ppm):
d 10.86, 19.32, 38.89, 54.18,
56.09, 66.12, 112.18, 122.32, 125.78, 126.81, 127.69, 128.78, 131.17,
137.78, 140.17, 151.21, 161.41, 167.88; MS: m/z 437.4 (Mþ), 438.4
(M þ 1), 439.4 (M þ 2). %Anal. Calcd. for C25H31N3O2S: C, 68.62; H,
7.14; N, 9.60; S, 7.33. Found C, 68.54; H, 7.02; N, 9.46; S, 7.29.
6.5.1.4. 5-Benzylidene-3-(3-(dibutylamino)-2-hydroxypropyl)-2-
(phenylimino)-thiazolidin-4-one (8). M.p.: 257e259 ꢂC; yield:
62.50% (solid); Rf value: 0.61; FTIR (KBr) cmꢀ1: 3685 (OeH), 3094
(Ar CeH), 2923 (aliphatic CeH), 2598 (CeS), 1798 (C]O), 1531 (C]
6.5. General procedure for the synthesis of 5-benzylidene-3-(2-
hydroxy-3-(substituted)propyl)-2-(phenylimino)-thiazolidin-4-
ones (5e18)
N), 1374 (t-amine CeN); 1H NMR (400 MHz, DMSO, ppm):
d 1.03e
Compound 4 (2.70 g, 0.0081 mol) and secondary amines
(0.0081 mol) were dissolved in ethanol (30 mL), to which sodium
bicarbonate (0.68 g, 0.0081 mol) was added. The reaction mixture
was refluxed for 15e17 h, which was further concentrated to
remove excess of alcohol. Cold water was added to the above so-
lution with vigorous stirring. The precipitated product obtained
was filtered, washed with water and recrystallized from ethanol to
yield respective derivatives, 5e18.
1.14 (t, 6H, CH3 of 2ꢂ amine),1.20e1.31 (m, 4H, 3rd CH2 of 2ꢂ amine),
1.45e1.52 (m, 2H, 2nd CH2 of 2ꢂ amine), 2.54e2.63 (t, 2H, 1st CH2 of
2ꢂ amine), 2.74e2.97 (d, 2H, 3rd CH2 of propanolamine), 3.21e3.27
(d, 2H, 1st CH2 of propanolamine), 4.05e4.12 (m, 1H CHeOH), 4.51
(s, 1H, OH), 7.01e7.15 (m, 5H, benzylidine), 7.25e7.32 (m, 5H, ben-
zylimino), 7.49 (s, 1H, eC]CH); 13C NMR (400 MHz, DMSO, ppm):
d
14.18, 22.17, 29.38, 40.16, 55.68, 59.63, 67.22,113.12,124.28,126.16,
127.18, 127.93, 129.03, 131.23, 136.18, 143.41, 153.12, 162.55, 168.78;
MS: m/z 465.7 (Mþ), 466.7 (M þ 1), 467.7 (M þ 2). %Anal. Calcd. for
6.5.1. Characterization data of 5-benzylidene-3-(2-hydroxy-3-
(substituted)propyl)-2-(phenylimino)- thiazolidin-4-ones (5e18)
6.5.1.1. 5-Benzylidene-3-(3-(diethylamino)-2-hydroxypropyl)-2-
(phenylimino)-thiazolidin-4-one (5). M.p.: 243e245 ꢂC; yield:
63.90% (solid); Rf value: 0.59; FTIR (KBr) cmꢀ1: 3541 (OeH), 3498
(NeH), 3031 (Ar CeH), 2823 (aliphatic CeH), 2546 (CeS), 1683 (C]
O), 1597 (C]N), 1359 (t-amine CeN); 1H NMR (400 MHz, DMSO,
C27H35N3O2S: C, 69.64; H, 7.58; N, 9.02; S, 6.89. Found: C, 69.43; H,
7.52; N, 8.85; S, 6.79.
6.5.1.5. 5-Benzylidene-3-(2-hydroxy-3-morpholinopropyl)-2-(phe-
nylimino)-thiazolidin-4-one (9). M.p.: 275e277 ꢂC; yield: 52.70%
(solid); Rf value: 0.68; FTIR (KBr) cmꢀ1: 3749 (OeH), 3106 (Ar CeH),
2864 (Aliphatic CeH), 2638 (CeS), 1798 (C]O), 1531 (C]N), 1287
(Cyclic CeO), 1325 (t-amine CeN); 1H NMR (400 MHz, CDCl3, ppm):
ppm): d
1.12e1.20 (t, 6H, CH3 of 2ꢂ amine), 2.65e2.71 (m, 4H, CH2 of
2ꢂ amine), 2.88e2.98 (d, 2H, 3rd CH2 of propanolamine), 3.09e3.12
(d, 2H, 1st CH2 of propanolamine), 4.32e4.46 (m, 1H, H of CHeOH),
4.83 (s, 1H, OH), 7.14e7.20 (m, 5H, benzylidine), 7.30e7.34 (m, 5H,
bezylimino), 7.42 (s, 1H, eC]CH); 13C NMR (400 MHz, DMSO,
d 2.37e2.38 (t, 4H, CH2eNeCH2 of morpholine), 2.67e2.85 (d, 2H,
3rd CH2 of propanolamine), 3.18e3.23 (d, 2H, 1st CH2 of prop-
anolamine), 3.64e3.72 (t, 4H, CH2eOeCH2 of Morpholine), 4.15e
4.20 (m, 1H, CHeOH), 4.82 (s, 1H, OH), 7.03e7.18 (m, 5H, benzyli-
dine), 7.20e7.29 (m, 5H, benzylimino), 7.54 (s, 1H, eC]CH); 13C
ppm):
d 12.98, 39.11, 48.16, 55.89, 64.19, 111.21, 119.31, 124.89,
126.62, 127.98, 129.06, 129.69, 130.22, 135.55, 139.32, 151.18, 157.69,
NMR (400 MHz, CDCl3, ppm):
d 38.78, 53.16, 55.31, 64.79, 66.62,

C.M. Bhalgat et al. / European Journal of Medicinal Chemistry 76 (2014) 580e588
587
115.18, 121.22, 124.38, 126.79, 127.38, 128.41, 131.17, 136.16, 139.89,
151.18, 160.66, 167.22; MS: m/z 423.4 (Mþ), 424.4 (M þ 1), 425.4
(M þ 2). %Anal. Calcd. for C23H25N3O3S: C, 65.23; H, 5.95; N, 9.92; S,
7.57. Found C, 65.14; H, 5.87; N, 9.75; S, 7.49.
1H, eC]CH); 13C NMR (400 MHz, CDCl3, ppm):
d
20.89, 41.38,
49.48, 50.14, 53.46, 56.87, 67.51, 118.47, 124.20, 128.02, 128.73,
129.52, 130.33, 131.40, 137.11, 144.29, 152.45, 163.82, 168.05; MS: m/
z 464.6 (Mþ), 465.6 (M þ 1), 466.6 (M þ 2). %Anal. Calcd. for
C26H32N4O2S: C, 67.21; H, 6.94; N, 12.06; S, 6.90. Found: C, 66.93; H,
6.5.1.6. 5-Benzylidene-3-(2-hydroxy-3-(piperidin-1-yl)propyl)-2-
(phenylimino)-thiazolidin-4-one (10). M.p.: 268e270 ꢂC; yield:
65.20% (solid); Rf value: 0.66; FTIR (KBr) cmꢀ1: 3757 (OeH), 3123
(Ar CeH), 2995 (cycloalkane CeH), 2916 (aliphatic CeH), 2638 (Ce
S), 1798(C]O), 1531 (C]N), 1342 (t-amine CeN); 1H NMR
7.03; N, 12.09; S, 6.92.
6.5.1.10. 5-Benzylidene-3-(2-hydroxy-3-(4-benzylpiperazin-1-yl)
propyl)-2-(phenylimino)-thiazolidin-4-one (14). M.p.: 285e287 ꢂC;
yield: 61.20% (solid); Rf value: 0.70; FTIR (KBr) cmꢀ1: 3703 (OeH),
3105 (Ar CeH), 3043 (cycloalkane CeH), 2978 (aliphatic CeH), 2605
(CeS), 1724 (C]O), 1583 (C]N), 1318 (t-amine CeN); 1H NMR
(400 MHz, CDCl3, ppm): d 1.62e1.69 (t, 6H, CH2 of CH2eCH2eCH2 of
piperidine), 2.21e2.28 (t, 4H, CH2 of CH2eNeCH2 of piperidine),
2.43e2.56 (d, 2H, 3rd CH2 of propanolamine), 2.93e2.98 (d, 2H, 1st
CH2 of propanolamine), 4.18e4.21 (m, 1H CHeOH), 4.93 (s, 1H, OH),
7.04e7.23 (m, 5H, benzylidine), 7.29e7.34 (m, 5H, benzylimino),
(400 MHz, CDCl3, ppm):
d 2.52e2.67 (t, 8H, CH2 of CH2eNeCH2 of
piperizine), 2.84e2.99 (d, 2H, 3rd CH2 of propanolamine), 3.22e
3.31 (d, 2H, 1st CH2 of propanolamine), 3.71 (s, 2H, eCH2 of benzyl),
4.09e4.23 (m, 1H CHeOH), 4.93 (s, 1H, OH), 7.16e7.33 (m, 5H,
benzyl), 7.51e7.68 (m, 5H, benzylidine), 7.83e7.96 (m, 5H, benzy-
limino), 8.12 (s, 1H, eC]CH); 13C NMR (400 MHz, CDCl3, ppm):
7.58 (s, 1H, eC]CH); 13C NMR (400 MHz, CDCl3, ppm):
d 24.36,
43.18, 55.38, 57.73, 63.38, 111.39, 119.89, 124.82, 126.12, 127.88,
128.16, 129.93, 134.18, 138.77, 144.16, 155.42, 161.16; MS: m/z 421.4
(Mþ), 422.4 (M þ 1); 423.4 (M þ 2). %Anal. Calcd. for C23H25N3O3S:
C, 68.38; H, 6.46; N, 9.97; S, 7.61. Found: C, 67.97; H, 6.34; N, 9.81; S,
7.48.
d
43.26, 51.87, 54.42, 58.11, 62.04, 68.18, 113.14, 121.67, 126.89,
127.64, 128.88, 129.54, 129.97, 130.38, 131.11, 131.82, 137.14, 138.19,
144.31, 152.31, 162.32, 167.13; MS: m/z 512.8 (Mþ), 513.7 (M þ 1),
514.7 (M þ 2). %Anal. Calcd. for C23H26N4O2S: C, 70.28; H, 6.29; N,
10.93; S, 6.25. Found: C, 70.52; H, 6.31; N, 10.89; S, 6.21.
6.5.1.7. 5-Benzylidene-3-(2-hydroxy-3-(piperazin-1-yl)propyl)-2-
(phenylimino)-thiazolidin-4-one (11). M.p.: 290e292 ꢂC, yield:
63.80% (solid), Rf value: 0.64. FTIR (KBr) cmꢀ1: 3649 (OeH), 3338
(NeH), 3146 (Ar CeH), 2990 (cycloalkane CeH), 2964 (aliphatic Ce
H), 2597 (CeS), 1764 (C]O), 1536 (C]N), 1310 (t-amine CeN); 1H
6.5.1.11. 5-Benzylidene-3-(2-hydroxy-3-(4-phenylpiperazin-1-yl)pro-
pyl)-2-(phenylimino)-thiazolidin-4-one (15). M.p.: 256e258 ꢂC;
yield: 55.30% (solid); Rf value: 0.71; FTIR (KBr) cmꢀ1: 3666 (OeH),
3165 (Ar CeH), 2978 (cycloalkane CeH), 2942 (aliphatic CeH), 2588
(CeS), 1734 (C]O), 1556 (C]N), 1312 (t-amine CeN); 1H NMR
NMR (400 MHz, CDCl3, ppm): d 1.90 (s, 1H, eNH), 2.23e2.28 (t, 4H,
CH2 of CH2eNeCH2 of piperizine), 2.46e2.52 (d, 2H, 3rd CH2 of
propanolamine), 2.68e2.73 (t, 4H, CH2 of CH2eNHeCH2 of piper-
izine), 2.98e3.25 (d, 2H, 1st CH2 of propanolamine), 4.23e4.36 (m,
1H CHeOH), 5.08 (s, 1H, OH), 7.05e7.13 (m, 5H, benzylidine), 7.19e
7.25 (m, 5H, benzylimino), 7.49 (s,1H, eC]CH); 13C NMR (400 MHz,
(400 MHz, CDCl3, ppm):
d 2.54e2.62 (t, 4H, CH2 of CH2eNeCH2 of
piperizine), 2.71e2.76 (d, 2H, 3rd CH2 of propanolamine), 3.08e
3.20 (d, 2H, 1st CH2 of propanolamine), 3.53e3.65 (t, 4H, CH2 of
CH2eN(Ph)eCH2 of piperizine), 4.06e4.16 (m, 1H CHeOH), 5.18 (s,
1H, OH), 6.85e7.02 (m, 5H, N-Ph), 7.11e7.23 (m, 5H, benzylidine),
7.38e7.51 (m, 5H, benzylimino), 7.78 (s, 1H, eC]CH); 13C NMR
CDCl3, ppm):
d 37.66, 43.12, 53.68, 56.52, 62.38, 113.18, 117.17,
124.22, 125.16, 126.03, 126.96, 128.05, 131.14, 137.54, 143.25, 154.18,
161.33; MS: m/z 422.6 (Mþ), 423.6 (M þ 1), 424.5 (M þ 2). %Anal.
Calcd. for C23H26N4O2S: C, 65.38; H, 6.20; N, 13.26; S, 7.59. Found: C,
65.12; H, 6.11; N, 13.09; S, 7.47.
(400 MHz, CDCl3, ppm):
d 44.38, 51.47, 54.54, 57.69, 68.12, 112.67,
115.21, 119.12, 124.16, 127.38, 128.82, 129.52, 130.21, 130.93, 132.55,
138.72, 146.09, 150.37, 152.05, 162.26, 169.11; MS: m/z 498.5 (Mþ),
499.5 (M þ 1), 500.5 (M þ 2). %Anal. Calcd. for C29H30N4O2S: C,
69.85; H, 6.06; N, 11.24; S, 6.43. Found: C, 70.12; H, 6.01; N, 11.28; S,
6.48.
6.5.1.8. 5-Benzylidene-3-(2-hydroxy-3-(4-methylpiperazin-1-yl)pro-
pyl)-2-(phenylimino)-thiazolidin-4-one (12). M.p.: 281e283 ꢂC;
yield: 59.80% (solid); Rf value: 0.68; FTIR (KBr) cmꢀ1: 3664 (OeH),
3098 (Ar CeH), 2983 (cycloalkane CeH), 2973 (aliphatic CeH), 2591
(CeS), 1771 (C]O), 1567 (C]N), 1309 (t-amine CeN); 1H NMR
6.5.1.12. 5-Benzylidene-3-(3-(4-cyclohexylpiperazin-1-yl)-2-
hydroxypropyl)-2-(phenylimino)-thiazolidin-4-one (16). M.p.: 302e
305 ꢂC; yield: 59.70% (solid); Rf value: 0.71; FTIR (KBr) cmꢀ1: 3661
(OeH), 3123 (Ar CeH), 3014 (cycloalkane CeH), 2971 (aliphatic Ce
H), 2602 (CeS), 1768 (C]O), 1611 (C]N), 1305 (t-amine CeN); 1H
(400 MHz, CDCl3, ppm):
d 2.16 (s, 3H, eCH3), 2.36e2.47 (t, 8H, CH2
of CH2eNeCH2 of piperizine), 2.76e2.84 (d, 2H, 3rd CH2 of prop-
anolamine), 3.09e3.12 (d, 2H, 1st CH2 of propanolamine), 4.11e4.21
(m, 1H CHeOH), 5.24 (s, 1H, OH), 6.83e7.04 (m, 5H, benzylidine),
7.23e7.36 (m, 5H, benzylimino), 7.68 (s, 1H, eC]CH); 13C NMR
NMR (400 MHz, CDCl3, ppm):
d 1.38e1.45 (m, 2H, eCH2 of cyclo-
hexyl), 1.54e1.61 (m, 4H, eCH2 of cyclohexyl), 1.78e1.85 (m, 4H, e
CH2 of cyclohexyl), 2.58e2.66 (t, 8H, CH2 of piperizine), 2.89e2.96
(m, 1H, eCH of cyclohexyl), 3.09e3.15 (d, 2H, 3rd CH2 of prop-
anolamine), 3.38e3.46 (d, 2H, 1st CH2 of propanolamine), 4.47e
4.55 (m, 1H CHeOH), 5.12 (s, 1H, OH), 7.19e7.32 (m, 5H, benzyli-
dine), 7.45e7.61 (m, 5H, benzylimino), 7.93 (s, 1H, eC]CH); 13C
(400 MHz, CDCl3, ppm):
d 42.38, 44.48, 52.39, 54.48, 56.99, 67.18,
116.38, 124.33, 127.12, 128.89, 129.65, 130.41, 132.03, 136.64, 144.78,
149.22, 162.39, 167.12; MS: m/z 436.3 (Mþ), 437.3 (M þ 1), 438.3
(M þ 2). %Anal. Calcd. for C2H28N4O2S: C, 66.03; H, 6.46; N, 12.83; S,
7.34. Found: C, 65.87; H, 6.40; N, 12.88; S, 7.32.
NMR (400 MHz, CDCl3, ppm):
d 24.38, 27.00, 33.11, 42.10, 50.54,
6.5.1.9. 5-Benzylidene-3-(2-hydroxy-3-(4-isopropylpiperazin-1-yl)
propyl)-2-(phenylimino)-thiazolidin-4-one (13). M.p.: 276e278 ꢂC;
yield: 67.20% (solid); Rf value: 0.64; FTIR (KBr) cmꢀ1: 3578 (OeH),
3176 (Ar CeH), 2964 (cycloalkane CeH), 2924 (aliphatic CeH), 2581
(CeS), 1752 (C]O), 1593 (C]N), 1318 (t-amine CeN); 1H NMR
53.21, 55.84, 64.38, 112.56, 119.23, 124.05, 125.85, 127.02, 127.85,
129.19, 137.34, 143.16, 151.37, 160.88, 168.06; MS: m/z 504.3 (Mþ),
505.3 (M þ 1), 506.3 (M þ 2). %Anal. Calcd. for C29H36N4O2S: C,
69.02; H, 7.19; N, 11.10; S, 6.35. Found: C, 69.16; H, 7.23; N, 11.14; S,
6.31.
(400 MHz, CDCl3, ppm):
d 1.19e1.28 (d, 6H, e(CH3)2), 2.42e2.49 (t,
8H, CH2 of piperizine), 2.81e2.96 (d, 2H, 3rd CH2 of propanol-
amine), 3.09 (m, 1H, CH of isopropyl), 3.21e3.29 (d, 2H, 1st CH2 of
propanolamine), 4.31e4.38 (m, 1H CHeOH), 4.89 (s, 1H, OH), 6.94e
7.17 (m, 5H, benzylidine), 7.48e7.57 (m, 5H, benzylimino), 7.85 (s,
6.5.1.13. 5-Benzylidene-3-(2-hydroxy-3-(pyrrolidin-1-yl)propyl)-2-
(phenylimino)-thiazolidin-4-one (17). M.p.: 263e265 ꢂC; yield:
58.35% (solid); Rf value: 0.67; FTIR (KBr) cmꢀ1: 3618 (OeH), 3153
(Ar CeH), 2998 (cycloalkane CeH), 2943 (aliphatic CeH), 2583 (Ce

588
C.M. Bhalgat et al. / European Journal of Medicinal Chemistry 76 (2014) 580e588
S), 1749 (C]O), 1571 (C]N), 1316 (t-amine CeN); 1H NMR
(400 MHz, CDCl3, ppm): 1.64e1.73 (m, 4H, CH2 of CH2eCH2 of
Hyderabad and National Chemical Laboratories (NCL), Pune for
providing facilities for spectral studies of the compounds. The au-
thors report no declarations of interest.
d
pyrrolidine), 2.19e2.23 (t, 4H, CH2 of CH2eNeCH2 of pyrrolidine),
2.39e2.44 (d, 2H, 3rd CH2 of propanolamine), 3.08e3.18 (d, 2H, 1st
CH2 of propanolamine), 3.98e4.09 (m, 1H CHeOH), 4.55 (s, 1H, OH),
6.95e7.12 (m, 5H, benzylidine), 7.23e7.36 (m, 5H, benzylimino),
References
7.71 (s, 1H, eC]CH); 13C NMR (400 MHz, CDCl3, ppm):
d 24.38,
[1] R.M. Nieto, A. Coelho, A. Martínez, A. Stefanachi, E. Sotelo, E. Raviña, Chemical
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39.13, 52.78, 57.17, 65.18, 111.39, 118.22, 123.41, 124.35, 126.66,
127.42, 128.08, 129.12, 133.16, 141.18, 148.33, 157.81, 162.22; MS: m/z
407.5 (Mþ), 408.4 (M þ 1), 409.4 (M þ 2). %Anal. Calcd. for
C
23H25N3O2S: C, 67.79; H, 6.18; N, 10.31; S, 7.87. Found: C, 67.61; H,
6.14; N, 10.36; S, 7.92.
[5] A.M. Velázquez, L. Martínez, V. Abrego, M.A. Balboa, L.A. Torres, B. Camacho,
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[8] D.M. Stout, W.L. Matier, C. Barcelon-Yang, R.D. Reynolds, B.S. Brown, Journal of
Medicinal Chemistry 28 (1985) 295e298.
6.5.1.14. 5-Benzylidene-3-(2-hydroxy-3-(4-(hydroxydiphenylmethyl)
piperidin-1-yl)propyl)-2-(phenylimino)-thiazolidin-4-one
(18).
M.p.: 249e252 ꢂC; yield: 62.80% (solid); Rf value: 0.59; FTIR (KBr)
cmꢀ1: 3592 (OeH), 3043 (Ar CeH), 2992 (cycloalkane CeH), 2956
(aliphatic CeH), 2588 (CeS), 1731 (C]O), 1605 (C]N), 1314 (t-
amine CeN); 1H NMR (400 MHz, CDCl3, ppm):
d 1.66e1.75 (t, 4H,
CH2 of CH2e(CH)eCH2 of piperidine), 2.16e2.32 (t, 4H, CH2 of CH2e
NeCH2 of piperidine), 2.46e2.62 (m, 1H, CH of piperidine), 2.68e
2.81 (d, 2H, 3rd CH2 of propanolamine), 2.95e3.08 (d, 2H,1st CH2 of
propanolamine), 4.13e4.19 (m, 1H CHeOH), 5.11 (s, 1H, OH), 5.39 (s,
1H, OH), 6.91e7.28 (m, 10H, C-(Ph)2), 7.49e7.56 (m, 5H, benzyli-
dine), 7.81e7.98 (m, 5H, benzylimino), 8.09 (s, 1H, eC]CH); 13C
[9] M.L. Glowka, R.L. Dargie, P.W. Codding, Journal of Medicinal Chemistry 34
(1991) 2678e2684.
[10] Y.L. Zeng, Y.F. Wang, J. Li, J.M. Xu, M. Wang, H.F. Qiu, European Journal of
Pharmacology 183 (1990) 1849.
[11] D. Dai, Journal of Molecular and Cellular Cardiology 22 (1990) S74.
[12] B. Malawska, K. Kulig, B. Filipek, J. Sapa, D. Maciag, M. Zygmunt, L. Antkiewicz-
Michaluk, European Journal of Medicinal Chemistry 37 (2002) 183e195.
[13] R.L. Frank, P.V. Smith, Organic Syntheses 3 (1955) 735.
[14] M.K. Rout, G.N. Mahapatra, Journal of the American Chemical Society 77
(1955) 2427e2428.
NMR (400 MHz, CDCl3, ppm):
d 22.41, 43.19, 47.52, 55.09, 57.89,
67.36, 87.31, 114.21, 123.44, 127.85, 128.46, 128.93, 129.67, 130.08,
130.55, 130.89, 132.32, 136.63, 143.48, 147.21, 149.54, 159.16, 164.33;
MS: m/z 603.9 (Mþ), 604.9 (M þ 1), 605.9 (M þ 2). %Anal. Calcd. for
[15] O. Stallmann, U.S. Patent 1977253, Oct 16, 1934.
[16] B.S. Furniss, A.J. Hannaford, P.W. Smith, A.R. Tatchell, Vogel’s Textbook of
Practical Organic Chemistry, fifth ed., ELBS Publication, 1994, pp. 908e973.
[17] S.V. Bhandari, K.G. Bothara, A.A. Patil, T.S. Chitre, A.P. Sarkate, S.T. Gore,
S.C. Dangre, C.V. Khachane, Bioorganic & Medicinal Chemistry 17 (2009) 390e
400.
C
37H37N3O3S: C, 73.60; H, 6.18; N, 6.96; S, 5.31. Found: C, 73.32; H,
6.11; N, 7.01; S, 5.26.
[18] C.S. Bockman, W.B. Jeffries, W.A. Pettinger, P.W. Abel, American Journal of
Physiology 262 (1992) 1752e1758.
Acknowledgments and declaration of interest
[19] T. Dylag, M. Zygmunt, D. Maciag, J. Handzlik, M. Bednarski, B. Filipek,
ꢀ
K. Kiec - Kononowicz, European Journal of Medicinal Chemistry 39 (2004)
The authors are thankful to The Principal, Sri Adichunchanagiri
College of Pharmacy, for providing infrastructure facilities. The
authors also wish to thank IISC, Bangalore, Suven Life Sciences,
1013e1027.
[20] P.L. Ferrarini, C. Mori, V. Calderone, L. Calzolari, P. Nieri, G. Saccomanni,
E. Martinotti, European Journal of Medicinal Chemistry 34 (1999) 505e513.