Studies on the synthetic and structural aspects of benzosuberones bearing 2, 4-thiazolidenone moiety as potential anti-cancer agents

Article abstract of DOI:10.1016/j.ejmech.2013.10.078

Novel representative of the important group of biologically active benzosuberones bearing 2, 4-thiazolidenone moiety was synthesized as potential anticancer agents (6a-j). These compounds were synthesized in good yields from Knoevenagel condensation of co

Full text of DOI:10.1016/j.ejmech.2013.10.078

European Journal of Medicinal Chemistry 71 (2014) 91e97
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Studies on the synthetic and structural aspects of benzosuberones
bearing 2, 4-thiazolidenone moiety as potential anti-cancer agents
,
a
a
b
Lingaiah Nagarapu a , Bandi Yadagiri , Rajashaker Bantu , C. Ganesh Kumar ,
*
Sujitha Pombala b, Jagadesh Nanubolu c
a Organic Chemistry Division II, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, Andhra Pradesh, India
b Centre for Medicinal Chemistry & Pharmacology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
c Centre for X-Ray Crystallography, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel representative of the important group of biologically active benzosuberones bearing 2, 4-
thiazolidenone moiety was synthesized as potential anticancer agents (6aej). These compounds were
synthesized in good yields from Knoevenagel condensation of compounds 2aeb with thiazolidenone
derivatives 3aee in the presence of sodium acetate and glacial acetic acid. The in vitro cytotoxicity of
these compounds was evaluated against different human cancer cell lines (A549, HeLa, MDA-MB-231,
MCF-7) and normal cell line, HEK293. Compound 6a exhibited promising cytotoxicity with IC50 values
Received 10 September 2013
Received in revised form
29 October 2013
Accepted 31 October 2013
Available online 8 November 2013
ranging from 2.98 to 13.34
231, while compound 6g showed potent cytotoxicity against human breast adenocarcinoma cell line
(MCF-7, IC50 value of 1.91 M).
mM against all the tested cancer cell lines, HeLa, A549, MCF-7 and MDA-MB-
Keywords:
Benzosuberone
2, 4-Thiazolidenone
Knoevenagel condensation
Vilsmeier Haack Arnold reaction
Cytotoxicity
m
Ó 2013 Published by Elsevier Masson SAS.
1. Introduction
thiazolidenone derivatives has gained immense interest and
proven promising for oncology. Since the two heterocyclic moieties,
benzosuberone and thiazolidenone, constitute two active phar-
macophores that are highly active against tumour cell lines and
microbes. In view of this fact, these two moieties were combined to
obtain synthons which would plausibly have a synergistic effect on
their biological properties. The reported significance of such syn-
thons generated the interest among medicinal chemists in the
recent years to exploit this valuable structure in the design and
synthesis of new benzosuberone derivatives bearing 2, 4-
thiazolidenone moieties.
Benzosuberone derivatives possess potential bacteriostatic,
anti-inflammatory, anti-pyretic, anti-ulcer, CNS-depressant, CNS-
stimulant and anti-convulsant activities. Some of the derivatives
are also known for anti-tumor activity in murine P388 cell line tests
[1]. Tricyclic antidepressants containing dibenzosuberone moieties
mostly effect the autonomic and central nervous systems, and
traditional anti-depressants, like amitriptyline [2], imipramine [3]
and noxiptiline [4] which continue to be used as first-line drugs
in treating depressive disorders.
Thiazolidenone templates are a privileged structure fragments
in modern medicinal chemistry considering its broad spectrum and
affinity for various bio-targets of this class of heterocyclic com-
pounds. Thiazolidenone derivatives are well known class of bio-
logical active substances that became basic for the whole number of
innovative medicinal agents, such as hypoglycaemic thiazolide-
nones (pioglitazone and its analogues) [5], aldose reductase in-
hibitors (Epalrestat) [6]. In the recent years, research on
In continuation to our on-going research programme [7e13] to
discover and develop tumour growth inhibitors and apoptotic in-
ducers as potential new anti-cancer agents, we designed and syn-
thesized novel benzosuberone bearing 2, 4-thiazolidenone
moieties having cytotoxic properties. Analysis of the structuree
activity relationships (SARs) identified the benzosuberone de-
rivatives with thiazolidine-2, 4-dione nucleus as being essential for
this promising activity, and the substitution at the head group of
the benzosuberone ring when condensed with 3-(2-oxo-2-
phenylethyl)thiazolidine-2, 4-dione moiety (3aee) increases the
cytotoxicity against human breast cancer cell lines like MDA-MB-
231 and MCF-7 more efficiently, when compared to the isolated
fragments, 3aee, 8a and 8b. Among the intermediate fragments,
* Corresponding author. Tel.: þ91 40 27191509, þ91 40 27191510, þ91 40
27191511; fax: þ91 40 27193382.
E-mail address: lnagarapuiict@yahoo.com (L. Nagarapu).
0223-5234/$ e see front matter Ó 2013 Published by Elsevier Masson SAS.
http://dx.doi.org/10.1016/j.ejmech.2013.10.078

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L. Nagarapu et al. / European Journal of Medicinal Chemistry 71 (2014) 91e97
O
Br
O
NH
+
S
O
4
5a-e
R1
K2CO3, TBAI
DMF, rt, 2h, 79-84%
Cl
O
R1
CHO
+
O
R
R
R
R
POCl3, DMF
N
S
0oC-80oC, 4h, 84-87%
O
3a-e
2a-b
O
1a
b
R = H
R = CH3
3
a
R1 = H
3b R1 = CH3
3c R1 = OCH3
3d R1 = Cl
AcONa,
AcOH,
reflux,
12h,64-75%
3e R1 = Br
R1
O
N
Cl
R
R
S
O
O
Tail group
Head group
6a-j
6f
6g
6h
6i
6
a
R = CH3
R = CH3
R = CH3
R = CH3
R = CH3
R1 = H
R = H
R1 = H
R1 = CH3
R1 = OCH3
R1 = Cl
6b R = H
6c R = H
6d R = H
6e R = H
R1 = CH3
R1 = OCH3
R1 = Cl
6j
R1 = Br
R1 = Br
Scheme 1. Synthesis of compounds 6aej.
only 8b showed cytotoxicity against A549, HeLa, and MDA-MB-231
cell lines. The compounds 6a and 6g showed promising cytotoxicity
compounds 2aeb with thiazolidine-2, 4-dione 4 gave the desired
compounds 8aeb with yields of only 24% (Scheme 2).
against MCF-7 with IC50 values of 5.31 and 1.9 mM, respectively.
2.2. Synthesis of (Z)-9-chloro-6,7-dihydro-5H-benzo[7]annulene-
8-carbaldehydes
2. Chemistry
The compounds 2aeb were synthesized by Vilsmeier Haack
Arnold reaction [14] of substituted benzosuberones 1aeb in pres-
ence of POCl3, dimethylformamide with 84e87% yield. The struc-
tures of all the synthesized compounds were confirmed by spectral
data analysis (FTIR, 1H NMR, 13C NMR and ESI-MS). In the 1H NMR
2.1. Synthesis of (Z)-5-(((Z)-9-chloro-6,7-dihydro-5H-benzo[7]
annulen-8-yl)methylene)-3-(2-oxo-2-phenylethyl)thiazolidine-2, 4-
dione
The synthetic route of target compounds was obtained in
Scheme 1. A series of target compounds 6aej were synthesized by
Knoevenagel condensation of compounds 2aeb with thiazolide-
none derivatives (3aee) in glacial acetic acid, in the presence of
sodium acetate. The yields were in the range of 64e75% (Scheme 1).
The structures of all the synthesized compounds were confirmed by
spectral data (FTIR, 1H NMR, 13C NMR and ESI-MS). The target model
compound 6b was evident from the appearance of [M þ H]þ peak at
m/z 438 in the mass spectrum (ESI), eC]O stretching at 1682 cmꢀ1
in IR and the appearance of characteristic methine proton as singlet
spectra, the presence of characteristic singlet at
d 10.36 ppm rep-
resenting one proton provided evidence for the formation of car-
baldehyde 2b. The required starting compounds were synthesized
from Fridel-Craft’s acylation of aromatic hydrocarbons with glutaric
anhydride furnishing aryl butyric acids which on Clemmenson
reduction followed by cyclization with excess polyphosphoric acid
gave substituted benzosuberones 1aeb (Scheme 1).
2.3. Synthesis of 3-(2-oxo-2-phenylethyl)thiazolidine-2, 4-dione
at
d
8.37 in 1H NMR. The structure of the product 6b was further
confirmed by X-ray crystallographic analysis. In another route, the
The synthetic procedure of the thiazolidenone derivatives 3aee
synthesis of target compounds by Knoevenagel condensation of
is shown in Scheme 1. Due to the labile hydrogen atom at the 3-

L. Nagarapu et al. / European Journal of Medicinal Chemistry 71 (2014) 91e97
93
O
Cl
Cl
O
CHO
NH
R
R
R
R
AcONa, AcOH,
S
NH
+
S
O
Reflux, 12 h, 24%
O
4
8a R = H
2a R = H
8b R = CH3
2b R = CH3
K2CO3, TBAI
DMF, rt, 2 h, 27%
O
Br
O
N
Cl
R
R
S
O
O
6a R = H
6f R = CH3
Scheme 2. Synthesis of compounds 8aeb, 6a and 6f.
position, the thiazolidine-2, 4-dione was N-alkylated with appro-
priate phenacyl bromides 5aee in alkaline medium. Thiazolidine-2,
4-dione and phenacyl bromide derivatives were stirred in dime-
thylformamide as a solvent in the presence of K2CO3 and TBAI at
room temperature. The yields obtained were higher than the earlier
reported procedures [15].
Methods using SHELXS97 [18] and refinement was carried out by
full-matrix least-squares technique using SHELXL97. Anisotropic
displacement parameters were included for all non-hydrogen
atoms. All H atoms were positioned geometrically and treated as
ꢀ
riding on their parent C atoms, with CeH distances of 0.93e0.97 A,
and with Uiso(H) ¼ 1.2Ueq (C) or 1.5Ueq for methyl atoms.
Crystal data for AN40 6b: C24H20ClNO3S, M ¼ 437.92, colourless
3. Pharmacology
block, 0.31 ꢂ 0.24 ꢂ 0.13 mm3, monoclinic, space group P21/n (No.
ꢀ
14),
b
a
¼
10.7446(7),
b
¼
16.8271(11),
c
¼
12.1712(8) A,
3
ꢀ
¼ 104.4560(10) , V ¼ 2130.9(2) A , Z ¼ 4, Dc ¼ 1.365 g/cm3,
ꢃ
3.1. In vitro cytotoxicity assay
ꢀ
F000 ¼ 912, CCD area detector, MoK
a
radiation,,
l
¼ 0.71073 A,
Cytotoxicity of all the synthesized compounds was determined
on the basis of measurement of in vitro growth inhibition of tumour
cell lines in 96 well plates by cell-mediated reduction of tetrazo-
lium salt to water insoluble formazan crystals using doxorubicin as
a standard. The cytotoxicity as assessed against a panel of four
different human tumour cell lines: A549 derived from human
alveolar adenocarcinoma epithelial cells (ATCC No. CCL-185), HeLa
derived from human cervical cancer cells (ATCC No. CCL-2), MDA-
MB-231 derived from human breast adenocarcinoma cells (ATCC
No. HTB26), MCF7 derived from human breast adenocarcinoma
cells (ATCC No. HTB22) and HEK293 (normal human embryonic
kidney cell line) using the MTT assays [16]. The IC50 values (50%
inhibitory concentration) were calculated from the plotted absor-
T ¼ 293(2)K, 2qmax ¼ 50.0ꢃ, 20,229 reflections collected, 3752
unique (Rint
¼
0.0250). Final GooF
¼
1.044, R1
¼
0.0372,
(I)
wR2 ¼ 0.0958, R indices based on 3063 reflections with I > 2
s
(refinement on F2), 272 parameters,
m
¼ 0.303 mm-1. CCDC 934532
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge Crystallographic Data
Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44(0)
1223 336 033; email: deposit@ccdc.cam.ac.uk] (Fig. 1).
The synthetic strategy to prepare the target compounds 6aej
and fragments 8aeb is illustrated in Schemes 1 and 2. Initially,
when compounds 2aeb were reacted with thiazolidine-2, 4-dione
4 in the presence of sodium acetate and acetic acid at 120 ꢃC, 8aeb
was obtained in 20e24% yield (Scheme 2). The yield obtained by
the combination strategy was unsatisfactory to us and hence we
planned to alter the route that would help us to increase the yield
and we were successful in our idea when the synthesis was carried
out as shown in Scheme 1. Thiazolidine-2, 4-dione 4 was taken as a
starting material and it was condensed with phenacyl bromides
5aee to result in compounds 3aee, which was further condensed
with compounds 2aeb to give our desired compounds 6aej, the
yield was found to be 75%. The change in the synthetic route of the
final compounds 6aej helped us to increase the yield by more than
55%.
bance data for the doseeresponse curves. IC50 values (in mM) are
indicated as mean ꢁ SD of three independent experiments.
4. Results and discussion
4.1. X-ray crystallography and spectral studies
4.1.1. Crystallographic data for AN40 6b
X-ray crystallographic data for the compound were collected at
room temperature using a Bruker Smart Apex CCD diffractometer
ꢀ
with graphite monochromated MoK
a
radiation (
l
¼ 0.71073 A)
with
u
-scan method. Preliminary lattice parameters and orienta-
tion matrices were obtained from four sets of frames. Unit cell di-
mensions were determined using 6655 reflections for AN40 6b
data. Integration and scaling of intensity data was accomplished
using SAINT program [17]. The structures were solved by Direct
4.2. Effects of the compounds on the viability of human cancer cells
The newly synthesized benzosuberone bearing 2, 4-
thiazolidenone moieties 6aej as potential anticancer agents were

94
L. Nagarapu et al. / European Journal of Medicinal Chemistry 71 (2014) 91e97
Fig. 1. The molecular structure of 6b AN40 with the atom-numbering scheme. Displacement ellipsoids are drawn at 30% probability level and H atoms are shown as small spheres of
arbitrary radius.
further evaluated for their in vitro cytotoxicity against alveolar
adenocarcinoma (A549), cervical cancer (HeLa), breast adenocar-
cinoma (MDA-MB-231, MCF-7), and normal human embryonic
kidney (HEK293) cell lines using the standard MTT assay. From the
data reported in Table 1, most of the prepared compounds
possessed significant cytotoxicity effect on all the tested cell lines
and potencies of some the compounds were comparable to the
standard doxorubicin, the most widely used drug for the treatment
of tumors. Among the tested ten target compounds, 6g showed
most potent activity against MCF-7 cell line with IC50 value of
only 8b showed significant activity against alveolar adenocarci-
noma (A549), cervical cancer (HeLa), breast adenocarcinoma
(MDA-MB-231) cell lines. While, the intermediate compounds, 3a,
3b and 3e, showed moderate cytotoxicity against A549 cell line. The
intermediate compound 3d was active against normal cell line,
HEK293, however, the final compound did not exhibit any cyto-
toxicity against the normal HEK293 cell line. The SAR study
revealed that the substitution at head group of benzosuberone ring
played an important role in imparting the cytotoxicity to the
compound. For example, compound 8b bearing methyl substituent
at head group of benzosuberone showed cytotoxicity against
alveolar adenocarcinoma (A549), breast adenocarcinoma (MDA-
MB-231) and cervical cancer (HeLa) cell lines with IC50 values of
1.91
MDA-MB-231 and HeLa cells lines with IC50 values of 5.84 and
7.89 M, respectively. In contrast, 6d showed no significant cyto-
mM, whereas 6b and 6f showed promising activity against
m
toxicity against all the tested cancer cell lines. Generally speaking,
the compounds without substituents at head group, and with
substituents at tail group of benzosuberone exhibited significant
cytotoxicity against alveolar adenocarcinoma (A549), breast
adenocarcinoma (MDA-MB-231 and MCF-7) cell lines.
5.39, 5.79 and 5.89 mM, respectively. Later, we investigated the ef-
fect of electron donating group at the head group of benzosuberone
and electron with-drawing as well as electron donating groups at
the tail group of the compounds 6aej, it was observed that com-
pound 6g with p-methyl (at tail group) was very active against
Based on the in vitro cytotoxicity results shown in Table 2, it was
noticed that of the fragments 8ae8b, obtained by the combination
of benzosuberone 2aeb with 2, 4-thiazolidenone 4 (Scheme 2),
MCF-7 cell line (IC50 value ¼ 1.91
mM). The results indicated that the
compounds 8a and 3c, d were found to be less active as compared
to the target compounds.
Table 1
IC50 values of the tested compounds 6aej against four human tumor cell lines and normal cell line (HEK293).
R1
O
Cl
N
R
R
S
O
O
6 a-j
a
Compounds
IC50 in
m
M
HEK293
A549
HeLa
MDA-MB-231
MCF-7
6a
6b
6c
6d
6e
6f
6g
6h
4.89 0.02
>100
5.44 0.02
>100
5.75 0.03
>100
>100
2.98 0.02
>100
>100
>100
>100
13.34 ꢁ 0.02
5.84 0.03
>100
>100
>100
5.31 0.03
>100
8.95 0.03
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
51.71 ꢁ 0.04
7.89 0.02
>100
>100
>100
13.39 ꢁ 0.04
7.89 0.03
>100
>100
0.91 0.19
1.91 0.03
>100
9.85 0.03
36.79 ꢁ 0.05
1.07 0.02
>100
17.89 ꢁ 0.04
6i
6j
3.49 0.03
9.69 0.03
0.459 0.01
>100
>100
0.509 0.01
Doxorubicinb
a
Data presented is the mean ꢁ SD value of three independent determinations.
b
Positive control.

L. Nagarapu et al. / European Journal of Medicinal Chemistry 71 (2014) 91e97
95
Table 2
IC50 values of the tested compounds 3aee, 8a and 8b, against four human tumor cell lines and normal cell line (HEK293).
O
R1
O
Cl
NH
O
R
R
S
N
S
O
O
8a-b
3a-e
Compounds
IC50 (in
A549
m
M)a
HEK293
HeLa
MDA-MB-231
MCF-7
3a
3b
3c
14.1 0.09
17.03 0.19
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
3d
3e
8a
>100
22.7 0.87
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
14.0 0.11
>100
>100
8b
5.39 0.02
0.459 0.01
5.89 0.03
0.509 0.01
5.79 0.03
0.91 0.02
>100
1.07 0.02
>100
>100
Doxorubicinb
a
Data presented is the mean ꢁ SD value of three independent determinations.
b
Positive control.
5. Conclusions
designated as s (singlet), d (doublet), t (triplet), q (quartet), br
(broad), m (multiplet, for unresolved lines), etc. Infrared (IR)
spectra were recorded on a Perkin Elmer FT-IR 400 spectrometer;
data is reported in wavenumbers (cmꢀ1). Mass spectra were
recorded on Agilent Technologies 1100 Series (Agilent Chem-
istation Software). ESI mass spectra were obtained by using ESI-
QTOF mass spectrometry.
A series of novel benzosuberone bearing 2, 4-thiazolidenone
moieties as potential anticancer agents have been synthesized
and evaluated for their in vitro cytotoxicity against A549, HeeLa,
MDA-MB-231 and MCF-7 cell lines. All the compounds showed
promising activity at micromolar level against all the four tested
cell lines (except 6d). The in vitro anticancer activity of the com-
pounds showed that alkyl-, methoxy-substituted compounds were
more active than halo-substituted. Among all these derivatives,
compounds 6f and 6b displayed the selective cytotoxicity against
6.2. General method for the synthesis of compounds (6aej and 8ae
b)
HeLa (IC50 value
value ¼ 5.84 M) cell lines and compound 6g showed most potent
cytotoxicity against MCF-7 (IC50 value ¼ 1.19 M). Moreover, the
¼
7.89
mM) and MDA-MB-231 (IC50
The substituted 3-(2-oxo-2-phenylethyl) thiazolidine-2, 4-dione
derivatives (0.42 mmol) dissolved in acetic acid (1.0 mL), sodium
acetate (0.51 mmol) and substituted 2aeb (0.42 mmol) were added
within 15 min duration. The reaction mixture was subjected to
reflux conditions during the time indicated for each compound.
When the reaction was complete, TLC analysis was performed, the
reaction mixture was diluted with H2O (10 mL) and extracted with
ethyl acetate (3 ꢂ 10 mL). The combined ethyl acetate extracts were
washed with H2O (2 ꢂ 20 mL), the organic phase dried over Na2SO4.
The solvent was then evaporated under reduced pressure and the
residue purified by column chromatography (SiO2, hexane/EtOAc).
m
m
synthetic route was simplified which increased the total yield and
also enabled to obtain similar or superior anti-cancer results. The
novel structures determined in this study represents a new series of
analogues with effective anti-cancer activities. Further studies will
be focused on the mechanistic studies to determine the targets of
action at pathway level.
6. Experimental protocols
6.1. Chemistry
6.2.1. (Z)-5-((9-chloro-6,7-dihydro-5H-benzo[7]annulen-8-yl)
methylene)-3-(2-oxo-2-phenyl ethyl)thiazolidine-2, 4-dione(6a)
Colourless solid in a yield of 64%, mp 179 ꢃC, IR (KBr, v cmꢀ1):
2947, 1748, 1691, 1579, 1405, 1379, 1230, 1148, 921, 756, 1H NMR
All commercial reagents and solvents were used as received
without further purification unless specified and reaction solvents
were distilled before use. The reactions were monitored and Rf
value was determined using analytical thin layer chromatography
(TLC) with Merck Silica gel 60 and F254 precoated plates (0.25 mm
thickness). Spot on the TLC plates were visualized using ultraviolet
light (254 nm). Column chromatography was performed with
Merck silica gel 60 (100e200 mesh). Melting points were deter-
mined in capillaries and are uncorrected. 1H NMR spectra were
recorded on Bruker DRX-300, Varian 400 and Varian-500 NMR
spectrometers. 13C NMR spectra’s were recorded on Bruker DRX-75.
(300 MHz, CDCl3):
d
2.19e2.30 (m, 4H, 2CH2), 2.64 (t, J ¼ 5.9, 6.5 Hz,
2H, CH3), 5.18 (s, 2H, CH2), 7.19e7.28 (m, 2H, AreH), 7.32e7.38 (m,
2H, AreH), 7.54 (t, J ¼ 7.6,7.7 Hz, 2H, AreH), 7.63e7.69 (m, 2H, Are
H), 8.00 (d, J ¼ 7.4 Hz, 2H, AreH), 8.37 (s, 1H, C]CH), 13C NMR
(75 MHz, CDCl3):
d 14.1, 30.1, 31.8, 31.5, 27.0, 29.6, 33.6, 47.4, 134.1,
131.8, 129.0,128.7, 121.5, 128.1, 126.6, 129.8, 132.5, 140.1, 138.1, 140.5,
167.2, 166.0, 189.7, MSeMS (ESI): m/z ¼ 424 [M þ H]þ.
6.2.2. (Z)-5-((9-chloro-6,7-dihydro-5H-benzo[7]annulen-8-yl)
methylene)-3-(2-oxo-2-(p-tolyl) ethyl)thiazolidine-2, 4-dione (6b)
Colourless solid in a yield of 68%, mp 147 ꢃC, IR (KBr, v cmꢀ1):
2933, 2857, 1734, 1682, 1590, 1403, 1381, 1230, 1096, 818, 776, 1H
Proton chemical shifts are reported in ppm (
tetramethylsilane (TMS, 0.00) or with the solvent reference
relative to TMS employed as the internal standards (CDCl3,
7.26 ppm; DMSO-d6 d 2.54) and multiplicities of NMR signals are
d) relative to internal
d
d
NMR (300 MHz, CDCl3): d 2.20e2.31 (m, 4H, 2CH2), 4.25 (s, 3H,

96
L. Nagarapu et al. / European Journal of Medicinal Chemistry 71 (2014) 91e97
CH3), 2.64 (t, J ¼ 6.2, 6.4 Hz, 2H, CH2), 5.15 (s, 2H, CH2), 7.28e7.38
(m, 4H, AreH), 7.66e7.38 (d, J ¼ 7.1 Hz, 2H, AreH), 7.89 (d, J ¼ 8.1,
CH2), 6.96 (s, 1H, AreH), 7.29 (d, J ¼ 8.3 Hz, 2H, AreH), 7.37 (s, 1H,
AreH), 7.88 (d, J ¼ 7.9 Hz, 2H, AreH), 8.31 (s, 1H, C]CH), 13C NMR
2H, AreH), 8.36 (s, 1H, C]CH), 13C NMR (75 MHz, CDCl3):
d
27.1,
(75 MHz, CDCl3): d 22.6, 14.0, 19.6, 19.3, 21.7, 31.1, 27.1, 29.6, 33.7,
29.8, 31.7, 33.6, 31.5, 29.9, 29.6, 33.8, 43.3, 131.6, 131.8, 132.6, 129.8,
129.5, 128.7, 128.4, 128.1, 126.8, 126.6, 128.9, 132.3, 140.5, 145.1,
189.2, ESI-MS: m/z ¼ 438 [M þ H]þ.
47.3, 139.0, 135.5, 132.7, 131.6, 130.0, 121.0, 129.7, 129.5, 128.2, 131.3,
134.9, 138.0, 140.7, 145.1, 166.0, 189.3, ESI-MS: m/z ¼ 466 [M þ H] þ
.
6.2.8. (Z)-5-((9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzo[7]
annulen-8-yl)methylene)-3-(2-(4-methoxyphenyl)-2-oxoethyl)
thiazolidine-2, 4-dione (6h)
6.2.3. (Z)-5-((9-chloro-6,7-dihydro-5H-benzo[7]annulen-8-yl)
methylene)-3-(2-(4-methoxyphenyl)-2-oxoethyl)thiazolidine-2, 4-
dione (6c)
Pale solid in a yield of 72%, mp 177 ꢃC, IR (KBr, v cmꢀ1): 2921,
Colourless solid in a yield of 66%, mp 192 ꢃC, IR (KBr, v cmꢀ1):
1739, 1683, 1600, 1575, 1408, 1383, 1242, 1172, 1148, 1016, 831, 1H
2935, 1732, 1682, 1595, 1403, 1381, 1238, 1167, 1148, 839, 774, 1H
NMR (300 MHz, CDCl3):
d 2.16e2.37 (m, 4H, 2CH2), 2.30 (s, 6H,
NMR (75 MHz, CDCl3):
d
2.19e2.34 (m, 4H, 2CH2), 2.65 (t, J ¼ 6.0,
2CH3), 2.56 (t, J ¼ 6.4, 6.7 Hz, 2H, CH2), 3.90 (s, 3H, OCH3), 5.13 (s,
2H, CH2), 6.99e7.02 (m, 3H, AreH), 7.41 (s, 1H, AreH), 7.97 (d,
J ¼ 9.0 Hz, 2H, AreH), 8.36 (s, 1H, C]CH), 13C NMR (75 MHz,
6.7 Hz, 2H, CH2), 3.91 (s, 3H, OCH3), 5.14 (s, 2H, CH2), 6.99 (d,
J ¼ 9.0 Hz, 2H, AreH), 7.31e7.38 (m, 2H, AreH), 7.62e7.68 (m, 2H,
AreH), 7.98 (d, J ¼ 9.0 Hz, 2H, AreH), 8.37 (s, 1H, C]CH), 13C NMR
CDCl3):
d 14.0, 19.3, 22.6, 27.1, 29.6, 31.0, 33.6, 47.0, 55.5, 114.0,
(300 MHz, CDCl3):
d
26.9, 33.6, 31.5, 47.1, 55.5, 96.1, 132.4, 130. 114.0,
121.0, 127.1, 130.0, 129.7, 130.4, 131.3, 132.6, 134.9, 135.6, 138.0,
129.8,127.1,121.6,126.6,126.4,128.8,131.9,140.0,135.8,138.1,140.5,
139.0, 140.0, 164.2, 166.1, 167.3, 188.1, ESI-MS: m/z
¼
482
166.1, 164.2, 175.5, 104.6, ESI-MS: m/z ¼ 477 [M þ Na]þ.
[M þ H]þ.
6.2.4. (Z)-5-((9-chloro-6,7-dihydro-5H-benzo[7]annulen-8-yl)
methylene)-3-(2-(4-chlorophenyl)-2-oxoethyl)thiazolidine-2, 4-
dione (6d)
6.2.9. (Z)-5-((9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzo[7]
annulen-8-yl)methylene)-3-(2-(4-chlorophenyl)-2-oxoethyl)
thiazolidine-2, 4-dione (6i)
Yellow solid in a yield of 66%, mp 169 ꢃC, IR (KBr, v cmꢀ1): 2924,
Yellow solid in a yield of 71%, mp 160 ꢃC, IR (KBr, v cmꢀ1): 2922,
1742, 1688, 1588, 1572, 1406, 1375, 1224, 114, 1089, 926, 1H NMR
1735, 1689, 1383, 1086, 834, 1H NMR (300 MHz, CDCl3):
d 2.18e2.27
(300 MHz, CDCl3):
d
2.21e2.39 (m, 4H, 2CH2), 2.64 (t, J ¼ 5.5, 6.3 Hz,
(m, 4H, 2CH2), 2.29 (s, 6H, 2CH3), 2.57 (t, J ¼ 6.0, 4.9 Hz, 2H, CH2),
5.13 (s, 2H, CH2), 7.01 (s, 1H, AreH), 7.41(s, 1H, AreH), 7.51 (d,
J ¼ 8.4 Hz, 2H, AreH), 7.94 (d, J ¼ 8.6 Hz, 2H, AreH), 8.37 (s, 1H, C]
2H, CH2), 5.13 (s, 2H, CH2), 7.31e7.38 (m, 2H, AreH), 7.51(d,
J ¼ 7.9 Hz, 2H, AreH), 7.65 (d, J ¼ 7.1 Hz, 2H, AreH), 7.94 (d,
J ¼ 8.7 Hz, 2H, AreH), 8.37 (s, 1H, C]CH), 13C NMR (75 MHz, CDCl3):
CH), 13C NMR (75 MHz, CDCl3):
d 19.7,19.3, 31.0, 29.5, 27.1, 29.6, 33.7,
d
31.5, 27.0, 29.6, 33.6, 47.2, 140.8, 132.6, 132.4, 129.9, 129.5, 121.4,
47.2, 41.0, 41.1, 139.0, 135.5, 132.9, 131.3, 130.0, 129.7, 129.4, 129.2,
132.4, 134.9, 138.0, 140.7, 167.2, 165.9, 188.7, ESI-MS: m/z ¼ 486
[M þ H]þ.
128.7, 126.6, 129.2, 131.8, 140.2, 131.8, 140.2, 138.1, 140.5, 167.1, 165.9,
188.7, ESI-MS: m/z ¼ 458 [M þ H].
6.2.5. (Z)-3-(2-(4-bromophenyl)-2-oxoethyl)-5-((9-chloro-6,7-
dihydro-5H-benzo[7]annulen-8-yl)methylene)thiazolidine-2, 4-
dione (6e)
6.2.10. (Z)-3-(2-(4-bromophenyl)-2-oxoethyl)-5-((9-chloro-2,3-
dimethyl-6,7-dihydro-5H-benzo[7] annulen-8-yl)methylene)
thiazolidine-2, 4-dione (6j)
Yellow solid in a yield of 69%, mp 170 ꢃC, IR (KBr, v cmꢀ1): 2938,
Yellow solid in a yield of 71%, mp 159 ꢃC, IR (KBr, v cmꢀ1): 2919,
1741, 1694, 1682, 1585, 1414, 1381, 1224, 1149, 1009, 919, 833, 1H
2850, 1736, 1697, 1686, 1578, 1371, 1227, 1149, 1005, 839, 1H NMR
NMR (300 MHz, CDCl3):
d
2.19e2.38 (m, 4H, 2CH2), 2.56e2.74 (m,
(300 MHz, CDCl3): d 2.16e2.28 (m, 4H, 2CH2), 2.29 (s, 6H, 2CH3),
2H, CH2), 5.12 (s, 2H, CH2), 7.28e7.47 (m, 2H, AreH),7.68 (d,
J ¼ 9.0 Hz, 2H, AreH), 7.86 (d, J ¼ 8.3 Hz, 2H, AreH), 8.37 (s, 1H, C]
2.57 (t, J ¼ 6.6, 6.6 Hz, 2H, CH2), 5.12 (s, 2H, CH2), 7.01 (s, 1H, AreH),
7.41 (s, 1H, AreH), 7.67 (d, J ¼ 8.8 Hz, 2H, AreH) 7.86 (d, J ¼ 8.8 Hz,
CH), 13C NMR (75 MHz, CDCl3):
d
31.0, 14.0, 19.6,19.3, 27.1, 29.6, 33.7,
2H, AreH) 8.37 (s, 1H, C]CH), 13C NMR (75 MHz, CDCl3):
d 31.8,
47.2, 139.1, 135.5, 132.9, 131.2, 120.7, 130.0, 129.7, 129.5, 132.2,þ134.9,
31.0, 14.0, 19.6, 19.3, 22.6, 27.1, 29.6, 33.7, 47.2, 139.1, 135.5, 132.9,
132.9, 131.3, 120.7, 130.0, 129.0, 132.2, 134.9, 138.0, 141.0, 167.3,
165.9, 188.9, ESI-MS: m/z ¼ 530 [M þ H]þ.
138.0, 141.0, 167.3, 165.9, 188.9, ESI-MS: m/z ¼ 502 [M þ H]
.
6.2.6. (Z)-5-((9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzo[7]
annulen-8-yl)methylene)-3-(2-oxo-2-phenylethyl)thiazolidine-2, 4-
dion (6f)
6.2.11. (Z)-5-(((Z)-9-chloro-6,7-dihydro-5H-benzo[7]annulen-8-yl)
methylene)thiazolidine-2, 4-dione (8a)
Pale yellow solid in a yield of 75%, mp 165 ꢃC, IR (KBr, v cmꢀ1):
Yellow solid in a yield of 27%, mp 192e194 ꢃC, IR (KBr, v cmꢀ1):
2919, 2851, 1735, 1693, 1575, 1405, 1374, 1230, 1149, 1008, 865, 1H
3028, 3020, 2935, 3772, 1749, 1696, 1556, 1329, 612, 1H NMR
NMR (500 MHz, CDCl3):
d
2.21e2.28 (m, 4H, 2CH2), 2.3 (s, 6H,
(300 MHz, CDCl3):
2H, CH2), 7.32e7.38 (m, 2H, AreH), 7.65 (d, J ¼ 8.2 Hz, 2H, AreH),
8.28 (s, 1H, ]CH), 8.61 (s, 1H, NH), 13C NMR (75 MHz, CDCl3):
26.9,
d
2.20e2.24 (m, 4H, 2 CH2), 2.62 (t, J ¼ 6.7, 6.8 Hz,
2CH3), 2.57 (t, J ¼ 6.9, 7.4 Hz, 2H, CH2), 5.12 (s, 2H, CH2), 6.81 (s, 1H,
AreH), 6.96 (s, 1H, AreH), 7.38 (s, 1H, AreH), 7.51 (t, J ¼ 7.9 Hz, 2H,
AreH), 8.00 (d, J ¼ 8.4 Hz, 2H, AreH), 8.32 (s, 1H, C]CH), 13C NMR
d
29.6, 31.1, 33.7, 122.4, 126.7, 132.5, 128.8, 129.9, 131.7, 128.9, 129.9,
(75 MHz, CDCl3):
d
14.0, 19.6, 22.6, 24.6, 27.6, 27.6, 27.2, 29.3, 29.2,
131.7, 138.1140.5, 166.5, ESI-MS: m/z ¼ 306 [M þ H]þ.
29.0, 29.6, 31.0, 47.4, 128.1, 128.9, 129.7, 131.3, 132.8, 134.1, 134.9,
135.6, 138.1, 139.0, 166.1, 189.8, ESI-MS: m/z ¼ 452 [M þ H]þ.
6.2.12. (Z)-5-(((Z)-9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzo[7]
annulen-8-yl)methylene)thiazo lidine-2, 4-dione (8b)
6.2.7. (Z)-5-((9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzo[7]
annulen-8-yl)methylene)-3-(2-oxo-2-(p-tolyl)ethyl)thiazolidine-2,
4-dione (6g)
Yellow solid in a yield of 24%, mp 219e221 ꢃC, IR (KBr, v cmꢀ1):
3171, 3020, 2922, 2853, 1749, 1695, 1567, 1329, 1160, 652, 1H NMR
(300 MHz, CDCl3):
d 2.15e2.23 (m, 4H, 2 CH2), 2.29 (s, 6H, 2 CH3),
Pale yellow solid in a yield of 74%, mp 199 ꢃC, IR (KBr, v cmꢀ1):
2.53 (t, J ¼ 5.6, 7.4 Hz, CH2), 6.96 (s, 1H, C]CH), 7.34 (s, 1H, Ar-H),
2923, 2853, 1733, 1693, 1574, 1403, 1372, 1236, 1149, 1005, 800, 1H
7.55 (s, 1H, Ar-H), 8.09 (s, 1H, NH), 13C NMR (75 MHz, CDCl3):
NMR (300 MHz, CDCl3):
2CH3), 2.45 (s, 3H, CH3), 2.56 (t, J ¼ 6.4, 6.7 Hz, 2H, CH2), 5.09 (s, 2H,
d
2.18e2.28 (m, 4H, 2CH2), 2.29 (s, 6H,
d 19.7, 19.3, 31.0, 27.0, 29.6, 33.7, 131.1, 141.2, 134.6, 130.2, 135.5,
130.0, 129.7, 132.7, 138.0, 139.1, 166.7, ESI-MS: m/z ¼ 334 [M þ H]þ.

L. Nagarapu et al. / European Journal of Medicinal Chemistry 71 (2014) 91e97
97
6.3. General procedures for the synthesis of compounds (2aeb)
6.4.3. 3-(2-(4-Methoxyphenyl)-2-oxoethyl)thiazolidine-2, 4-
dione(3c)
Phosphorus oxychloride (8.3 mmol) was added to a round bot-
tom flask containing N,N-dimethylformamide (12.1 mmol) in an ice
bath at 0 ꢃC and stirred for 10 min, benzosuberone (6.2 mmol) was
added and stirred for 15 min. The ice bath was replaced and stirred
for an additional 3 h at 80 ꢃC. The reaction mixture was poured on
crushed ice and stirred for 10 min and neutralized with 20% sodium
bicarbonate solution. After extraction with diethyl ether
(3 ꢂ 100 mL), the combined organic extracts were washed with
brine solution (2 ꢂ 50 mL) and water (3 ꢂ 100 mL). The organic
layer was dried over Na2SO4 and concentrated on reduced pressure
to yield a red liquid. The product was purified by column chro-
matography (hexane/EtOAc).
Colourless solid in a yield of 89%, mp 99e102 ꢃC, IR (KBr, v
cmꢀ1): 2936, 2843, 1749, 1683, 1599, 1412, 1236, 1173, 833, 997, 1H
NMR (300 MHz, CDCl3):
(s, 2H, CH2), 6.97 (d, J ¼ 9.0 Hz, 2H, AreH), 7.94 (d, J ¼ 8.3 Hz, 2H,
AreH), 13C NMR (75 MHz, CDCl3):
33.9, 47.0, 55.7, 114.0, 114.5,
d 3.89 (s, 3H, OCH3), 4.90 (s, 2H, CH2), 5.00
d
127.0, 130.3, 130.9, 164.2, 171.4, 171.0, 187.9, ESI-MS: m/z ¼ 266
[M þ H]þ.
6.4.4. 3-(2-(4-Chlorophenyl)-2-oxoethyl)thiazolidine-2, 4-dione
(3d)
Yellow solid in a yield of 82%, mp 120e123 ꢃC, IR (KBr, v cmꢀ1):
2991, 2940, 1754, 1677, 1586, 1404, 1379, 1230, 1156, 985, 838, 1
H
NMR (300 MHz, CDCl3): d 4.11 (s, 2H, CH2), 5.00 (s, 2H, CH2), 7.49 (d,
6.3.1. 5-Chloro-8,9-dihydro-7H-benzocycloheptene-6-
Carbaldehyde (2a)
J ¼ 9.0 Hz, 2H, AreH), 7.90 (d, J ¼ 8.3 Hz, 2H, AreH), 13C NMR
(75 MHz, CDCl3):
d
33.9, 47.2, 129.4, 129.9, 129.2, þ129.3, 140.7, 141.9,
Brown liquid in a yield of 84%, IR (NEAT, v cmꢀ1): 2936, 2860,
171.3, 170.9, 188.6, ESI-MS: m/z ¼ 292 [M þ Na]
.
1671, 1580,1448, 1262, 919, 750, 1H NMR (300 MHz, CDCl3):
d 2.11e
2.25 (m, 4H, 2CH2), 2.62 (t, J ¼ 6.4, 6.9 Hz, 2H, CH2), 2.60 (t, J ¼ 6.4,
6.6 Hz, 2H, CH2), 7.19e7.27 (m, 1H, AreH), 7.28e7.37 (m, 2H, AreH),
5.90e7.68 (m, 1H, AreH), 10.36 (s, 1H, CHO), 13C NMR (75 MHz,
6.4.5. 3-(2-(4-Bromophenyl)-2-oxoethyl)thiazolidine-2, 4-
dione(3e)
Brown solid in a yield of 84%, mp 125e128 ꢃC, IR (KBr, v cmꢀ1):
CDCl3):
d 22.5, 32.0, 33.8, 96.2, 126.5, 126.7, 128.4, 128.8, 129.0,
2990, 2941, 1754, 1689, 1583, 1404, 1155, 985, 1H NMR (300 MHz,
130.5, 140.7, 189.3, ESI-MS: m/z ¼ 207 [M þ H]þ, 229 [M þ Na]þ.
CDCl3):
d
4.11 (s, 2H, CH2), 5.00 (s, 2H, CH2), 7.66 (d, J ¼ 9.0 Hz, 2H,
AreH), 7.82 (d, J ¼ 6.0 Hz, 2H, AreH), 13C NMR (75 MHz, CDCl3):
6.3.2. 5-Chloro-2,3-dimethyl-8,9-dihydro-7H-benzocycloheptene-
6-carbaldehyde(2b)
d 33.9, 47.2, 132.7, 29.5, 132.2, 132.8, 131.4, 129.5, 171.3, 170.9, 188.8,
ESI-MS: m/z ¼ 314 [M þ H]þ.
Brown liquid in a yield of 87%, IR (KBr, v cmꢀ1): 2932, 1670, 1582,
1447, 1266, 749, 1H NMR (300 MHz, CDCl3):
d 2.07e2.12 (m, 2H,
Acknowledgements
CH2), 2.21 (t, J ¼ 6.4, 3.5 Hz, 2H, CH2), 2.29 (s, 3H, CH3), 2.30 (s, 3H,
CH3), 2.50 (t, J ¼ 6.6, 7.1 Hz, 2H, CH2), 6.69 (s, 1H, AreH), 7.38 (s, 1H,
The authors gratefully acknowledge the fellowships awarded to
BY and SP by Council of Scientific and Industrial Research (CSIR),
New Delhi and the financial support from DST-SERB/EMEQ-078/
2013.
AreH), 10.33 (s, 1H, CHO), 13C NMR (75 MHz, CDCl3):
d 19.3, 19.6,
22.6, 31.3, 33.7, 129.3, 130.2, 134.9, 135.0, 135.8, 138.5, 139.7, 147.8,
190.2, ESI-MS: m/z ¼ 235 [M þ Na]þ.
6.4. General procedures for the synthesis of compounds (3aee)
Appendix A. Supplementary data
A
mixture of the thiazolidine-2, 4-dione (5 mmol), 2-
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.10.078.
bromoacetophenone (5 mmol), potassium carbonate (5 mmol)
and tetrabutylammoniumiodide in N,N-dimethylformamide
(30 mL) was stirred at room temperature. Stirring was continued
at room temperature until the disappearance of the starting
material (2e3 h, TLC analyses). After completion of the reaction,
the reaction mixture was poured on crushed ice and stirred for
10 min and extracted into diethyl ether (3 ꢂ 100 mL). The organic
layer was dried over Na2SO4 and concentrated on reduced
pressure to yield a desired product. The crude product was
recrystallized from ethanol.
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6.4.1. 3-(2-Oxo-2-phenylethyl)thiazolidine-2, 4-dione(3a)
Pale yellow solid in a yield of 88%, mp 93e96 ꢃC, IR (KBr, v cmꢀ1):
2926, 2852, 1689, 1542, 1292, 1225, 758, 1H NMR (300 MHz, CDCl3):
d
3.71 (t, 2H, CH2), 4.68 (d, J ¼ 4.5 Hz, 2H, CH2), 7.48 (t, J ¼ 6.7, 8.3 Hz,
2H, AreH), 7.60 (t, J ¼ 7.5, 6.7 Hz, 1H, AreH), 7.97 (d, J ¼ 7.5 Hz, 2H,
AreH); 13C NMR (75 MHz, CDCl3):
d 29.6, 47.8, 52.4, 130.0, 128.8,
128.3, 127.8, 134.0, 133.3, 156.9, 194.0, ESI-MS: m/z ¼ 236 [M þ H]þ.
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G. Subhashini, Bioorg. Med. Chem. Lett. 18 (2008) 1167.
6.4.2. 3-(2-Oxo-2-p-tolylethyl)thiazolidine-2, 4-dione (3b)
Pale yellow solid in a yield of 79%, mp 161e163 ꢃC, IR (KBr, v
cmꢀ1): 2987, 2933, 1746, 1681, 1604, 1383, 1238, 1005, 817, 512, 1H
[12] L. Nagarapu, N.V. Rao, Heterocyclic Commun. 6 (2001) 535.
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NMR (300 MHz, CDCl3):
d 2.44 (s, 3H, CH3), 4.07 (s, 2H, CH2), 4.95 (s,
2H, CH2), 7.27 (d, J ¼ 8.3 Hz, 2H, AreH), 7.85 (d, J ¼ 7.5 Hz, 2H, Are
H), 13C NMR (75 MHz, CDCl3):
d 21.7, 33.7, 47.2, 128.4, 128.9, 129.4,
130.1, 131.6, 145.2, 171.3, 170.1, 189.1, ESI-MS: m/z ¼ 250 [M þ H]þ,
272 [M þ Na]þ.