Synthesis and anticancer activity of novel nonfused bicyclic thiazolidinone derivatives

Article abstract of DOI:10.1080/10426500802247563

A series of new 2-{4-oxo-2-[(4-oxothiazolidin-2-ylidene)-hydrazono]- thiazolidin-5-yl}-N-arylacetamides (4a-e), 5-(2-oxo-2-aryl-ethyl)-2-[(4- oxothiazolidin-2-ylidene)-hydrazono]-thiazolidine-4-ones (5a-d), 2-(4-oxo-2-[(2-oxothiazolidin-4-ylidene)-hydrazo

Full text of DOI:10.1080/10426500802247563

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Synthesis and Anticancer
Activity of Novel Nonfused
Bicyclic Thiazolidinone
Derivatives
Dmytro Havrylyuk a , Borys Zimenkovsky a & Roman
Lesyk a
a Department of Pharmaceutical, Organic and
Bioorganic Chemistry, Danylo Halytsky Lviv National
Medical University, Lviv, Ukraine
Version of record first published: 19 Feb 2009.
To cite this article: Dmytro Havrylyuk , Borys Zimenkovsky & Roman Lesyk (2009):
Synthesis and Anticancer Activity of Novel Nonfused Bicyclic Thiazolidinone
Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 184:3, 638-650
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Phosphorus, Sulfur, and Silicon, 184:638–650, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802247563
Synthesis and Anticancer Activity of Novel Nonfused
Bicyclic Thiazolidinone Derivatives
Dmytro Havrylyuk, Borys Zimenkovsky,
and Roman Lesyk
Department of Pharmaceutical, Organic and Bioorganic Chemistry,
Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
A series of new 2-{4-oxo-2-[(4-oxothiazolidin-2-ylidene)-hydrazono]-thiazolidin-5-
yl}-N-arylacetamides (4a–e), 5-(2-oxo-2-aryl-ethyl)-2-[(4-oxothiazolidin-2-ylidene)-
hydrazono]-thiazolidine-4-ones (5a–d), 2-4-oxo-2-[(2-oxothiazolidin-4-ylidene)-
hydrazono]-thiazolidin-5-yl-N-arylacetamides (7a–e), and 5-(2-oxo-2-aryl-ethyl)-
2-[(2-oxothiazolidin-4-ylidene)-hydrazono]-thiazolidine-4-ones (8a–d) have been
synthesized starting from 2-thioxothiazolidin-4-one and 4-thioxothiazolidin-2-
one through a multistep reaction sequence. 2-Thioxothiazolidin-4-one was alky-
lated via the intermediate formation of the triethylammonium salt 1 by ethyl
chloroacetate. Compound 2 and 4-thioxothiazolidin-2-one reacted with thiosemi-
carbazides to give the 1-(4-thiazolidinone-2-ylidene)-4-R-thiosemicarbazones (3a,b)
and 1-(2-thiazolidinone-4-ylidene)thiosemicarbazones (6a,b), respectively. Follow-
ing [2+3]-cyclization of thiazolidinone-substituted thiosemicarbazones (3a,b and
6a,b) with N-arylmaleimides and aroylacrylic acids as equivalents of dielec-
trophilic synthon [C2]2+, novel non-fused bicyclic thiazolidinones (4a–e, 5a–d,
7a–e, 8a–d) were synthesized. The structures of the new compounds (4a–e, 5a–
d, 7a–e, 8a–d) were established on the basis of their elemental analysis and
1H NMR and mass spectral data. Eight of the synthesized compounds were
tested, and three of them displayed different levels of antitumor activity. The most
efficient antitumor agent—2-{4-oxo-3-furylmethyl-2-[(4-oxothiazolidin-2-ylidene)-
hydrazono]-thiazolidin-5-yl}-N-4-chlorophenylacetamide (4d) was found to be ac-
tive against leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and
breast cancer cell lines with mean lgGI50 and lgTGI values of –5.35 and –4.78,
respectively.
Keywords Anticancer activity; [2+3]-cyclization; thiazolidinones
Received 23 February 2008; accepted 4 June 2008.
We are grateful to Dr. V. L. Narayanan from Drug Synthesis and Chemistry Branch,
National Cancer Institute, Bethesda, Maryland, USA, for in vitro evaluation of anticancer
activity.
Address correspondence to Roman Lesyk, Department of Pharmaceutical, Organic
and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska
69, Lviv 79010, Ukraine. E-mail: dr r lesyk@org.lviv.net
638

Nonfused Bicyclic Thiazolidinone Derivatives
639
INTRODUCTION
Thiazolidinone derivatives are a traditionally known class of biolog-
ically active compounds. In recent years, a large number of inno-
vative drugs containing the thiazolidinone moiety have been devel-
oped, including hypoglycemic thiazolidinediones (pioglitazone and its
analogs), dual COX-2/5-LOX inhibitors (darbufelon), new generation di-
uretics (etozolin), etc.1 Using modern technologies such as virtual and
high-throughput screening, combinatorial chemistry, and molecular
modeling, it was established that 4-thiazolidinones possess a high
affinity to the PPAR-receptors family and are selective inhibitors of
UDP-MurNAc/L-Ala ligase.2–6 As a consequence, a series of poten-
tial anti-inflammatory, hypoglycemic, cardiovascular, and antimicro-
bial agents at different stages of clinical studies were created. Ad-
vanced studies of PPARγ-receptors stimulated the concept that PPARγ
agonists, including thiazolidinediones, have therapeutic potential in
treatment of some cancer types. Moreover, binding inhibitors of anti-
apoptic proteins Bcl-XL and BH37 which promote normalization of nat-
ural cell death and inhibitors of TNF-α binding to TNFRc-1,8 as well as
inhibitors of translation initiation, which cause cell cycle arrest in G1
phase via partial depletion of intercellular Ca2+ stores, were identified
among 4-thiazolidinones.9 In this article, we enlarge the database of
anticancer thiazolidinones and report on the synthesis of a series of
novel nonfused bicyclic thiazolidinones.
RESULTS AND DISCUSSION
The general methods for the synthesis of the new bicyclic nonfused
thiazolidinones are depicted in Schemes 1 and 2. As starting reagents,
several thiazolidinone-substituted thiosemicarbazones were used.
Following a procedure from the literature, we prepared 1-(4-
thiazolidinon-2-ylidene)thiosemicarbazones 3 by prolonged heating
of equimolar amounts of 2-thioxo-4-thiazolidinone (rhodanine) and
thiosemicarabazide in ethanol.10 In order to improve this method
and enhance the reactivity of rhodanine, the latter was alkylated
via the intermediate formation of the triethylammonium salt 1 by
ethyl chloroacetate in refluxing acetone, as reported.11 On reac-
tion of the resulting 2-carbethoxymethylthio-2-thiazolin-4-one 2 with
thiosemicarbazide or 4-(2-furylmethyl)thiosemicarbazide in reflux-
ing ethanol, the 1-(4-thiazolidinon-2-ylidene)-4-R-thiosemicarbazones
(3a, b) were obtained (Scheme 1). The isomeric 1-(2-thiazolidinon-4-
ylidene)thiosemicarbazones (6a, b) were synthesized by the reaction

640
D. Havrylyuk et al.
SCHEME 1
of 4-thioxo-2-thiazolidinone (isorhodanine) with the same thiosemicar-
bazides in refluxing ethanol (Scheme 2).
In order to prepare the bicyclic thiazolidinones, we followed a route
to the 4-thiazolidinone moiety, which is based on the [2+3]-cyclization
of thiazolidinone-substituted thiosemicarbazones with equivalents of
the dielectrophilic synthon [C2].2+ We studied the interaction of
the above-mentioned binucleophiles with N-arylmaleimides and aroy-
lacrylic acids. As a result, a group of new isomeric bicyclic thiazolidi-
nones have been synthesized for a detailed elaboration of a structure–
anticancer activity relationship (Schemes 1 and 2).
The [2+3]-cyclization of the thiazolidinone-substituted thiosemicar-
bazone with one equivalent of the dielectrophilic synthon [C2]2+ con-
sists of two steps: 1) addition of the thiosemicarbazone isoform to
the double bond of the N-arylmaleimide or aroylacrylic acid, and 2) a
spontaneous cyclization of intermediate to form the thiazolidine ring
(Scheme 3).
The characteristic data of the new nonfused bicyclic thiazolidinones
are given in the Experimental section. The analytical and spectral data
(1H NMR, EI-MS) confirm the structure and the purity of the synthe-
sized compounds.

Nonfused Bicyclic Thiazolidinone Derivatives
641
SCHEME 2
1
In the H NMR spectra of synthesized compounds, the protons of
the CH2-CH moiety show the characteristic pattern of an AMX spin
system.12 The chemical shifts of the protons HA, HM, and HX were
determined to δ = 2.85–3.61, δ = 3.13–4.05, and δ = 4.25–4.44, respec-
tively, with coupling constants JAM = 16.7–18.9, JAX = 8.4–10.8, and
JMX = 2.4–4.4 Hz. The protons of the methylene group in 4–5 and 7–8
appear at δ = 3.72–4.32. The 1H NMR spectra of the nonfused bicyclic
thiazolidinones show singlets at δ = 10.12–10.48, δ = 11.32–11.76, and
δ = 11.69–11.80 corresponding to the NH protons. The signals of the
protons of the furyl fragment in 4c–4e, 5c–5d, 7c–7e, and 8c–8d ap-
pear at δ = 6.31–6.34, δ = 6.39–6.45, and δ = 7.22–7.45. In the 1H NMR
SCHEME 3

642
D. Havrylyuk et al.
TABLE I Anticancer Screening Data of 60 Cancer Cell Line Assays in
Concentration 10−5
M
60 cell lines assay in 1 dose 10−5M conc.
The most
sensitive cell
line
Growth% of the Active (selected
most sensitive for 5-dose 60
sensitive cell line cell line assays)
Mean
growth%
Range of
growth%
4d
14.45
–62.88 to 62.81 SK-MEL-5
(Melanoma)
–62.88
A
7d
7e
88.08
102.11
32.82 to 127.32 SR (Leukemia)
69.49 to 147.39 UO-31 (Renal
cancer)
32.82
69.49
N
N
8b
8c
102.98
99.03
14.68 to 133.49 UACC-257
(Melanoma)
74.50 to 123.67 HOP-92
(Non-small cell
14.68
74.50
N
N
lung cancer)
8d
96.69
34.93 to 154.34 CAKI-1 (Renal
cancer)
34.93
N
spectra of 7c–7e and 8c–8d, the protons of the CH2-CH moiety show
three multiplets at δ = 2.85–3.61, δ = 3.13–4.05, and δ = 4.25–4.44. For
the NH protons of the thiazolidinone ring, two singlets at δ = 11.32–
11.38 and δ = 11.52–11.75, and for the amide protons of 7c–7e two
signals at δ = 10.12–10.31 are observed. This can be explained by the
presence of syn/anti isomers of these derivatives.
Evaluation of the Anticancer Activity In Vitro
The activity of some of the new nonfused bicyclic thiazolidinones (4d,
7d, 7c, 8b–8d) at a single concentration of 10−5 M against 57 cancer
cell lines was evaluated. The human tumor cell lines were derived from
nine different cancer types: leukemia, melanoma, lung, colon, CNS,
ovarian, renal, prostate, and breast cancers. Primary anticancer as-
says were performed according to the US NCI protocol, and described
elsewhere.13–16 The compounds were added at a single concentration,
and the cell culture was incubated for 48 h. End point determinations
were made with a protein binding dye, sulforhodamine B (SRB). The
results for each compound are reported as the percent growth of treated
cells when compared to untreated control cells. Compound 4d showed
considerable activity and was selected for an advanced assay against
full panel (57 cell lines) at five concentrations. On the other hand,
the isomer 7d showed only moderate cytotoxicity. The results of this
screening are presented in Table I.

Nonfused Bicyclic Thiazolidinone Derivatives
643
Finally, compound 4d, as well as compounds 4b and 7a without pre-
liminary screening, were tested in vitro against a full panel of about 60
tumor cell lines. The human tumor cell lines were derived from nine
different cancer types: leukemia, melanoma, lung, colon, CNS, ovar-
ian, renal, prostate, and breast cancers and used at tenfold dilutions of
five concentrations (100 µM, 10 µM, 1 µM, 0.1 µM, and 0.01 µM).13–16
The percentage of growth was evaluated spectrophotometrically ver-
sus control cells not treated with test agents. A 48-h continuous drug
exposure protocol followed, and SRB (sulforodamine B) protein assay
was used to estimate cell viability or growth. Based on the cytotoxicity
assays, three antitumor activity dose–response parameters were calcu-
lated for each experimental agent against each cell line: GI50—molar
concentration of the compound that inhibits 50% net cell growth, TGI—
molar concentration of the compound leading to total inhibition, and
LC50—molar concentration of the compound leading to 50% net cell
death. Compounds having values of –4.00 and less were declared to be
active. Values were calculated for each of these parameters if the level
of activity was reached; however, if the effect was not reached or was
exceeded, the value was expressed as greater or less than the maximum
or minimum concentration tested. Furthermore, mean graph midpoints
(MG MID) were calculated for each of the parameters, giving an aver-
age activity parameter over all cell lines for each compound. For the
calculation of the MG MID, insensitive cell lines are included with the
highest concentration tested. The results of five concentrations’ full
panel screening are summarized in Table II.
TABLE II Summary of Anticancer Screening Data at 60 Cancer
Cell Lines Dose–Dependent Assay
Log GI50
Log TGI
Log LC50
Na N1b Range MG MID N2b Range MG MID N3b Range MG MID
4b 57
5
–5.41 to
–4.00
–4.05
–5.35
–4.04
1
–4.80 to
–4.00
–4.01
–4.78
–4.01
0
–
–4.00
–4.29
–4.00
4d 56 56 –5.94 to
55 –5.42 to
–4.00
1
50 –4.81 to
–4.00
0
–4.36
–5.61 to
–4.00
7a 57
2
–4.55 to
–4.00
–
aN – Number of human tumor cell lines tested at the 2nd stage assay.
bN1, N2, N3 – Number of sensitive cell lines, against which the compound
possessed considerable growth inhibition according to the mentioned parameter
(Parameter Log < –4.00).

644
D. Havrylyuk et al.
FIGURE 1 Anticancer selectivity pattern of the most active compounds 4b,
4d, and 7a.
Compound 4d showed the highest cytotoxicity and was active against
all tested human tumour cell lines (Table II). Interestingly, the isomeric
compound 7d is inactive to most of the tested cancer cell lines. Selectiv-
ity pattern analysis of cell lines by disease origin can definitely affirm
selective action of compound 4b on melanoma cell lines and of com-
pound 7a on leukemia (Figure 1). These compounds appeared to be the
most active against selected individual cell lines with logGI50 varying
from –5.61 to –5.41 (Table III). Compound 4b was found to be a highly
active growth inhibitor of the melanoma cell line M14 (logGI50 = –5.41),
and compound 7b showed significant activity against the leukemia cell
line CCRF-CEM (logGI50 = –5.61).
EXPERIMENTAL
The starting compounds 2-thioxo-4-thiazolidinone,17 4-thioxo-2-
thiazolidinone,18 and 2-carbethoxymethylthio-2-thiazolin-4-one11 were
obtained according to methods described previously.
ꢀꢀ
Melting points were measured in open capillary tubes on a BUCHI
B-545 melting point apparatus and are uncorrected. The elemen-
tal analyses (C, H, N) were performed using a Perkin-Elmer 2400
CHN analyzer and were within 0.4% of the theoretical values. The
1H-NMR spectra were recorded on Varian Gemini spectrometer at

Nonfused Bicyclic Thiazolidinone Derivatives
645
TABLE III The Most Sensitive to the Synthesized Compounds
Individual Tumor Cell Lines (log GI50 ≤ –5.40)
Compound
Disease
Cell line
logGI50
logTGI
4b
4d
Melanoma
Leukemia
Leukemia
Leukemia
Leukemia
M14
CCRF-CEM
HL-60(TB)
K-562
RPMI-8226
NCI-H460
NCI-H522
COLO 205
HCT-116
HCT-15
HT29
KM 12
SW-620
SF-295
SF-539
SNB-75
MALME-3M
M14
SK-MEL-28
SK-MEL-5
UACC-62
OVCAR-3
OVCAR-4
A498
RXF 393
MCF7
MDA-MB-435
T-47D
–5.41
–5.49
–5.68
–5.50
–5.58
–5.47
–5.45
–5.44
–5.41
–5.74
–5.62
–5.60
–5.42
–5.59
–5.58
–5.75
–5.44
–5.43
–5.41
–5.56
–5.46
–5.49
–5.49
–5.44
–5.66
–5.58
–5.94
–5.48
–5.61
–4.80
–4.95
–5.28
–4.90
–5.07
–4.92
–4.81
–4.90
–4.80
–5.44
–5.14
–4.80
–4.87
–4.98
–5.03
–5.19
–4.79
–4.82
–4.66
–4.87
–4.80
–4.88
–4.74
–4.82
–5.07
–4.84
–5.42
–4.77
–4.55
NSC lung cancer
NSC lung cancer
Colon cancer
Colon cancer
Colon cancer
Colon cancer
Colon cancer
Colon cancer
CNS cancer
CNS cancer
CNS cancer
Melanoma
Melanoma
Melanoma
Melanoma
Melanoma
Ovarian cancer
Ovarian cancer
Renal cancer
Renal cancer
Breast cancer
Breast cancer
Breast cancer
Leukemia
7a
CCRF-CEM
300 MHz using a mixture of DMSO-d6 + CCl4 as a solvent and TMS
as an internal standard. Chemical shifts are reported in ppm. EI-MS
were obtained on Varian 1200 L instrument.
Synthesis of 1-(4-Thiazolidinone-2-ylidene)-4-
R-thiosemicarbazones (3a, b)
A mixture of 2-carbethoxymethylthio-2-thiazolin-4-one (20 mmol) and
thiosemicarbazide or 4-(2-furylmethyl)thiosemicarbazide (20 mmol)
were refluxed for 0.5 h in 150 mL of ethanol. After cooling to room
temperature, a light violet powder precipitated, which was filtered off,

646
D. Havrylyuk et al.
washed with 50 mL of methanol, and recrystallized from a DMF:ethanol
mixture (1:2).
3a: Violet crystals; yield 2.85 g (75%); mp 198–199◦C (lit. 196–
197◦C10); Anal. Calcd. for C4H6N4OS2: C, 25.25; H, 3.18; N, 29.45%.
Found: C, 25.40; H, 3.30; N, 29.50%.
3b: Violet crystals; yield 4.23 g (78%); mp 184–185◦C; Anal. Calcd.
for C9H10N4O2S2: C, 39.99; H, 3.73; N, 20.73%. Found: C, 40.12; H, 3.85;
N, 20.61%.
Synthesis of 1-(2-Thiazolidinon-4-ylidene)-4-
R-thiosemicarbazones (6a, b)
To a solution of 4-thioxothiazolidin-2-one (20 mmol) in ethanol
(150 mL), thiosemicarbazide (20 mmol) in water (20 mL) or 4-(2-
furylmethyl)thiosemicarbazide (20 mmol) in ethanol (20 mL) was
added. The reaction mixture was refluxed for 0.5 h. After cooling to
room temperature, a light brown powder precipitated, which was fil-
tered off, washed with 50 mL of methanol, and recrystallized from a
DMF:ethanol mixture (1:2).
6a: Brown crystals; yield 2.75 g (72%); mp 191–192◦C (lit. 192◦C 19);
Anal. Calcd. for C4H6N4OS2: C, 25.25; H, 3.18; N, 29.45%. Found: C,
25.12; H, 3.32; N, 29.31%.
6b: Brown crystals; yield 3.47 g (64%); mp 171–172◦C; Anal. Calcd.
for C9H10N4O2S2: C, 39.99; H, 3.73; N, 20.73%. Found: C, 39.86; H, 3.61;
N, 20.84%.
Synthesis of 2-4-Oxo-2-[(4-oxothiazolidin-2-ylidene)-
hydrazono]-thiazolidin-5-yl-N-arylacetamides (4a–e),
5-(2-Oxo-2-aryl-ethyl)-2-[(4-oxothiazolidin-2-ylidene)-
hydrazono]-thiazolidin-4-ones (5a–d),
2-{4-Oxo-2-[(2-oxothiazolidin-4-ylidene)-hydrazono]-
thiazolidin-5-yl}-N-arylacetamides (7a–e), and
5-(2-Oxo-2-aryl-ethyl)-2-[(2-oxothiazolidin-4-ylidene)-
hydrazono]-thiazolidin-4-ones (8a–d): General
Procedure
A mixture of the appropriate thiazolidinone-substituted thiosemicar-
bazone (3a, b, 6a, b) (5 mmol) and the respective N-arylmaleimide (5
mmol) or β-aroylacrylic acid (5 mmol) was refluxed for 1 h in 10 mL of
acetic acid. After cooling to room temperature, the precipitated powder
was filtered off, washed with 10 mL of water and 10 mL of methanol,
and recrystallized from a DMF:ethanol mixture (1:2).

Nonfused Bicyclic Thiazolidinone Derivatives
647
4a: Pink crystals; yield 1.52 g (69%); mp >240◦C; 1H NMR (300 MHz,
DMSO-d6+ CCl4): δ = 2.88 (dd, J = 18.0, 9.8 Hz, 1H), 3.13 (dd, J = 18.0,
2.9 Hz, 1H), 3.77 (s, 2H), 4.28 (dd, J = 9.8, 2.9 Hz, 1H), 7.39 (d, J = 8.8
Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 10.19 (s, 1H), 11.76 (s, 1H), 11.80 (s,
1H); Anal. Calcd. for C14H12B3àrN5O3S2: C, 38.02; H, 2.73; N, 15.83%.
Found: C, 38.20; H, 2.60; N, 15.90%.
1
4b: Pink crystals; yield 1.41 g (65%); mp 278–280◦C; H NMR (300
MHz, DMSO-d6+ CCl4): δ = 1.31 (t, J = 6.9 Hz, 3H), 2.98 (dd, J = 17.8,
10.0 Hz, 1H), 3.22 (dd, J = 17.8, 3.4 Hz, 1H), 3.86 (s, 2H), 4.28 (q, J =
6.9 Hz, 2H), 4.29 (dd, J = 10.0, 3.4 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H),
7.91 (d, J = 8.8 Hz, 2H), 10.48 (s, 1H), 11.74 (s, 1H), 11.82 (s, 1H); EI-
MS (m/z): 435 (M+); Anal. Calcd. for C17H17N5O5S2: C, 46.89; H, 3.93;
N, 16.08%. Found: C, 46.70; H, 3.80; N, 15.90%.
4c: Pink crystals; yield 1.77 g (68%); mp >240◦C; 1H NMR (300 MHz,
DMSO-d6+ CCl4): δ = 2.85 (dd, J = 17.0, 10.2 Hz, 1H), 3.28 (dd, J =
17.0, 3.2 Hz, 1H), 3.74 (s, 2H), 4.39 (dd, J = 10.2, 3.2 Hz, 1H), 4.88
(s, 2H) 6.32 (br s, 1H), 6.42 (br s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.42
(br s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 10.12 (s, 1H), 11.75 (s, 1H); EI-MS
(m/z): 523 (M+); Anal. Calcd. for C19H16BrN5O4S2: C, 43.69; H, 3.09; N,
13.41%. Found: C, 43.58; H, 2.95; N, 13.54%.
4d: Pink crystals; yield 1.33 g (55%); mp >240◦C; 1H NMR (300 MHz,
DMSO-d6+ CCl4): δ = 2.85 (dd, J = 16.8, 10.1 Hz, 1H), 3.26 (dd, J =
16.8, 3.1 Hz, 1H), 3.72 (s, 2H), 4.37 (dd, J = 10.1, 3.1 Hz, 1H), 4,89 (s,
2H), 6.33 (br s, 1H), 6.45 (br s, 1H), 7.22 (d, J = 8.6 Hz, 2H), 7.42 (br s,
1H), 7.56 (d, J = 8.6 Hz, 2H), 10.13 (s, 1H), 11.73 (s, 1H); Anal. Calcd.
for C19H16ClN5O4S2: C, 47.75; H, 3.37; N, 14.65%. Found: C, 47.63; H,
3.51; N, 14.77%.
4e: Pink crystals; yield 1.57 g (61%); mp >240◦C; 1H NMR (300
MHz, DMSO-d6+ CCl4): δ = 1.33 (t, J = 7.0 Hz, 3H), 2.88 (dd, J = 16.7,
9.9 Hz, 1H), 3.29 (dd, J = 16.7, 3.3 Hz, 1H), 3.75 (s, 2H), 4.27 (q, J =
7.0 Hz, 2H), 4.41 (dd, J = 9.9, 3.3 Hz, 1H), 4,87 (s, 2H), 6.33 (br s, 1H),
6.43 (br s, 1H), 7.42 (br s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.87 (d, J = 8.6
Hz, 2H), 10.33 (s, 1H), 11.75 (s, 1H); Anal. Calcd. for C22H21N5O6S2: C,
51.25; H, 4.11; N, 13.58%. Found: C, 51.17; H, 4.23; N, 13.71%.
5a: Pink crystals; yield 1.20 g (64%); mp >250◦C; 1H NMR (300 MHz,
DMSO-d6+ CCl4): δ = 2,32 (s, 6H), 3.48 (dd, J = 18.6, 10.8 Hz, 1H), 3.86
(dd, J = 18.6, 2.9 Hz, 1H), 3.89 (s, 2H), 4.25 (dd, J = 10.8, 2.9 Hz, 1H),
7.22 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 11.65 (s,
1H), 11.73 (s, 1H); Anal. Calcd. For C16H16N4O3S2: C, 51.05; H, 4.28;
N, 14.88%. Found: C, 51.18; H, 4.31; N, 14.76%.
5b: Pink crystals; yield 1.30 g (71%); mp >250◦C; 1H NMR (300 MHz,
DMSO-d6+ CCl4): δ = 3.55 (dd, J = 18.8, 10.4 Hz, 1H), 3.73 (s, 2H), 3.92

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(dd, J = 18.8, 2.8 Hz, 1H), 4.28 (dd, J = 10.4, 2.8 Hz, 1H), 7.23 (t, J =
8.5 Hz, 2H), 8.06 (m, 1H), 11.66 (s, 1H), 11.75 (s, 1H); Anal. Calcd. for
C14H11FN4O3S2: C, 45.89; H, 3.03; N, 15.29%. Found: C, 45.98; H, 3.21;
N, 15.41%.
5c: Pink crystals; yield 1.36 g (59%); mp >240◦C; 1H NMR (300 MHz,
DMSO-d6+ CCl4): δ = 3.61 (dd, J = 18.8, 9.9 Hz, 1H), 3.75 (s, 2H), 3.99
(dd, J = 18.8, 2.6 Hz, 1H), 4.44 (dd, J = 9.9, 2.6 Hz, 1H), 4.88 (s, 2H),
6.34 (br s, 1H), 6.44 (br s, 1H), 7.45 (br s, 1H), 7.50 (d, J = 8.4 Hz, 2H),
7.98 (d, J = 8.4 Hz, 2H), 11.75 (s, 1H); EI-MS (m/z): 462 (M+); Anal.
Calcd. for C19H15ClN4O4S2: C, 49.30; H, 3.27; N, 12.10%. Found: C,
49.45; H, 3.61; N, 11.95%.
5d: Pink crystals; yield 1.44
g
(63%); mp >240◦C; 1H
NMR (300 MHz, DMSO-d6+ CCl4): δ = 2.32 (s, 6H), 3.55 (dd, J = 18.7,
10.3 Hz, 1H), 3.75 (s, 2H), 3.93 (dd, J = 18.7, 2.4 Hz, 1H), 4.42 (dd,
J = 10.3, 2.4 Hz, 1H), 4.87 (s, 2H), 6.32 (br s, 1H), 6.44 (br s, 1H), 7.24
(d, J = 7.4 Hz, 1H), 7.45 (br s, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.73 (s,
1H), 11.74 (s, 1H); Anal. Calcd. For C21H20N4O4S2: C, 55.25; H, 4.42;
N, 12.27%. Found: C, 55.11; H, 4.57; N, 12.39%.
7a: White crystals; yield 1.31 g (66%); mp 236–238◦C; 1H NMR (300
MHz, DMSO-d6+ CCl4): δ = 2.85 (dd, J = 17.4, 10.6 Hz, 1H), 3.18 (dd,
J = 17.4, 4.4 Hz, 1H), 4.27 (dd, J = 10.6, 4.4 Hz, 1H), 4.31 (s, 2H), 7.28
(d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 10.21 (s, 1H), 11.50 (s,
1H), 11.74 (s, 1H); Anal. Calcd. for C14H12ClN5O3S2: C, 42.26; H, 3.04;
N, 17.60%. Found: C, 42.12; H, 2.91; N, 17.71%.
7b: White crystals; yield 1.57 g (72%); mp 210–212◦C; 1H NMR (300
MHz, DMSO-d6+ CCl4): δ = 1.33 (t, J = 7.1 Hz, 3H), 2.86 (dd, J = 17.6,
10.8 Hz, 1H), 3.17 (dd, J = 17.6, 4.3 Hz, 1H), 4.32 (s, 2H), 4.25 (q, J =
7.0 Hz, 2H), 4.28 (dd, J = 10.8, 4.3 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H),
7.88 (d, J = 8.8 Hz, 2H), 10.44 (s, 1H), 11.51 (s, 1H), 11.75 (s, 1H); Anal.
Calcd. for C17H17N5O5S5: C, 46.89; H, 3.93; N, 16.08%. Found: C, 47.01;
H, 3.82; N, 16.19%.
1
7c: White crystals; yield 1.80 g (69%); mp >250◦C; H NMR (300
MHz, DMSO-d6+ CCl4): δ = 2.86 (m, 1H), 3.28 (m, 1H), 4.18 (s, 1H),
4.28 (s, 1H), 4.33 (m, 1H), 4.87 (s, 1H), 6.32 (br s, 1H), 6.39 (d, J =
13.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.43 (br s, 1H), 7.51 (d, J = 8.0
Hz, 2H), 10.12 (d, J = 10.7 Hz 1H), 11.32 (s, 1H), 11.52 (s, 1H); EI-MS
(m/z): 522 (M+); Anal. Calcd. for C19H16BrN5O4S2: C, 43.69; H, 3.09; N,
13.41%. Found: C, 43.82; H, 3.24; N, 13.27%.
1
7d: White crystals; yield 1.34 g (56%); mp >250◦C; H NMR (300
MHz, DMSO-d6+ CCl4): δ = 2.85 (m, 1H), 3.27 (m, 1H), 4.17 (s, 1H),
4.29 (s, 1H), 4.35 (m, 1H), 4.87 (s, 1H), 6.31 (br s, 1H), 6.42 (d, J =
14.1 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.42 (br s, 1H), 7.56 (d, J =

Nonfused Bicyclic Thiazolidinone Derivatives
649
8.4 Hz, 2H), 10.13 (d, J = 12.8 Hz, 1H), 11.73 (s, 1H); Anal. Calcd. for
C19H16ClN5O4S2: C, 47.75; H, 3.37; N, 14.65%. Found: C, 47.88; H, 3.29;
N, 14.52%.
7e: White crystals; yield 1.60 g (62%); mp 222–223◦C; 1H NMR (300
MHz, DMSO-d6+ CCl4): δ = 1.35 (t, J = 7.4 Hz, 3H), 2.86 (m, 1H), 3.25
(m, 1H), 4.18 (s, 1H), 4.25(s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 4.38 (m, 1H),
4,89 (s, 1H), 6.33 (br s, 1H), 6.40 (d, J = 14.2 Hz, 1H), 7.43 (br s, 1H),
7.66 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 10.31 (d, J = 10.9
Hz, 1H), 11.32 (s, 1H), 11.52 (s, 1H); Anal. Calcd. for C22H21N5O6S2: C,
51.25; H, 4.11; N, 13.58%. Found: C, 51.39; H, 4.25; N, 13.46%.
1
8a: White crystals; yield 0.93 g (54%); mp >240◦C; H NMR (300
MHz, DMSO-d6+ CCl4): δ = 3.54 (dd, J = 18.8, 10.2 Hz, 1H), 3.93 (dd,
J = 18.8, 2.9 Hz, 1H), 4.28 (dd, J = 10.2, 2.9 Hz, 1H), 4.30 (s, 2H), 7.50
(t, J = 7.6 Hz, 2H), 7.61 (t, J = 6.9 Hz, 1H), 7.97 (d, J = 7.5 Hz, 2H),
11.42 (s, 1H), 11.70 (s, 1H). EI-MS (m/z): 349 (M+). Anal. Calcd. for
C14H12N4O3S2: C, 48.26; H, 3.47; N, 16.08%. Found: C, 48.38; H, 3.61;
N, 15.95%.
1
8b: White crystals; yield 1.16 g (62%); mp >240◦C; H NMR (300
MHz, DMSO-d6+ CCl4): δ = 2,32 (s, 6˝), 3.49 (dd, J = 18.9, 10.5 Hz,
1H), 3.88 (dd, J = 18.9, 4.4 Hz, 1H), 4.26 (dd, J = 10.5, 4.4 Hz, 1H),
4.28 (s, 2H), 7.22 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.73
(s, 1H), 11.42 (s, 1H), 11.69 (s, 1H); Anal. Calcd. for C16H16N4O3S2: C,
51.05; H, 4.28; N, 14.88%. Found: C, 50.99; H, 4.17; N, 14.98%.
8c: White crystals; yield 1.35 g (63%); mp 222–224◦C; 1H NMR (300
MHz, DMSO-d6+ CCl4): δ = 3.61 (m, 1H), 4.05 (m, 1H), 4.23 (d, J = 8.6
Hz, 1H), 4.32 (s, 1H), 4.44 (m, 1H), 4.88 (s, 1H), 6.34 (br s, 1H), 6.43
(d, J = 13.5 Hz, 1H), 7.42 (br s, 1H), 7.51 (t, J = 6.7 Hz, 2H), 7.62 (t,
J = 6.7 Hz, 1H), 7.97 (d, J = 7.2 Hz, 2H), 11.38 (s, 1H), 11.56 (s, 1H);
Anal. Calcd. For C19H16N4O4S2: C, 53.26; H, 3.76; N, 13.08%. Found:
C, 53.38; H, 3.64; N, 13.15%.
8d: White crystals; yield 1.20 g (52%); mp 217–218◦C; 1H NMR (300
MHz, DMSO-d6+ CCl4): δ = 3.59 (m, 1H), 3.99 (m, 1H), 4.19 (d, J = 8.4
Hz, 1H), 4.31 (s, 1H), 4.43 (m, 1H), 4.89 (s, 1H), 6.34 (br s, 1H), 6.39
(d, J = 13.7 Hz, 1H), 7.44 (br s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.98 (d,
J = 8.4 Hz, 2H), 11.37 (s, 1H), 11.75 (s, 1H); EI-MS (m/z): 462 (M+);
Anal. Calcd. for C19H15ClN4O4S2: C, 49.30; H, 3.27; N, 12.10%. Found:
C, 49.18; H, 3.19; N, 12.22%.
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