Synthesis, Single Crystal X-Ray, and Anticancer Activity of Some New Thiophene and 1,3-Thiazolidine Derivatives

Article abstract of DOI:10.1134/S1070363217120374

New series of thiophenes 6a–6e and 1,3-thiazolidines 13a–13f and 15a–15e were synthesized starting from 2-(4-methoxybenzoyl)-3-(phenylamino)-3-thioxopropanoate 3. The reaction of 3 with 1-aryl-2-bromoethanones 4a–4e yielded thiophenes 6a–6e. The X-ray single crystal analysis data accumulated for 6c and its structural features can be extended to the analogues 6a, 6b and 6d, 6e. Treatment of 3 with ethyl 2-bromoacetate afforded 1,3-thiazolidinone 11 which upon treatment with aldehydes 12a-f or isatins 14a–4e gave 5-arylidene derivatives 13a–13f and 4-oxo-5(-2-oxoindolin)-3-ylidenes 15a–15e, respectively. The newly synthesized compounds were tested in vitro for their anti-cancer activity against two cell lines (HepG-2 and MCF-7) using MTT assay. Most of these compounds demonstrated a significant anticancer activity compared with that of doxorubicin. Isatin derivative 15a was the most potent compound against HepG-2 cancer cells whereas p-MeO substituted benzylidine 13b showed the highest anticancer activity against MCF-7 cancer cells. The fluoro substituted isatin 15d showed anticancer activity more potent than doxorubicin against both HepG-2 and MCF-7 cancer cells, respectively.

Full text of DOI:10.1134/S1070363217120374

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 12, pp. 2951–2960. © Pleiades Publishing, Ltd., 2017.
Synthesis, Single Crystal X-Ray, and Anticancer Activity
of Some New Thiophene and 1,3-Thiazolidine Derivatives1
U. Fathya*, R. S. Gouharb, H. M. Awadc, and H. A. Abdel-Aziza
a Applied Organic Chemistry Department, National Research Centre, Dokki, Giza, 12622 Egypt
*e-mail: usamafathy2000@yahoo.com
b Therapeutic Chemistry Department, National Research Centre, Dokki, Giza, 12622 Egypt
c Tanning Materials and Leather Technology Department, National Research Centre, Dokki, Giza, 12622 Egypt
Received September 26, 2017
Abstract―New series of thiophenes 6a–6e and 1,3-thiazolidines 13a–13f and 15a–15e were synthesized
starting from 2-(4-methoxybenzoyl)-3-(phenylamino)-3-thioxopropanoate 3. The reaction of 3 with 1-aryl-2-
bromoethanones 4a–4e yielded thiophenes 6a–6e. The X-ray single crystal analysis data accumulated for 6c
and its structural features can be extended to the analogues 6a, 6b and 6d, 6e. Treatment of 3 with ethyl 2-
bromoacetate afforded 1,3-thiazolidinone 11 which upon treatment with aldehydes 12a-f or isatins 14a–4e gave
5-arylidene derivatives 13a–13f and 4-oxo-5(-2-oxoindolin)-3-ylidenes 15a–15e, respectively. The newly
synthesized compounds were tested in vitro for their anti-cancer activity against two cell lines (HepG-2 and
MCF-7) using MTT assay. Most of these compounds demonstrated a significant anticancer activity compared
with that of doxorubicin. Isatin derivative 15a was the most potent compound against HepG-2 cancer cells
whereas p-MeO substituted benzylidine 13b showed the highest anticancer activity against MCF-7 cancer cells.
The fluoro substituted isatin 15d showed anticancer activity more potent than doxorubicin against both HepG-2
and MCF-7 cancer cells, respectively.
Keywords thiophene, 1,3-thiazolidine, isatin, single crystal X-ray diffraction, anticancer
DOI: 10.1134/S1070363217120374
INTRODUCTION
anticancer agents [11–16]. Tiazofurin (3) (Fig. 1),
inhibits IMP dehydrogenase, is a potential 1,3-thiazole-
based anticancer drug [17, 18]. 1,3-Thiazole-based
dasatinib (4) (Fig. 1) is a tyrosine kinase inhibitor used
for treatment of leukemia and advanced prostate
cancer [19].
Thiophene-based derivatives have shown numerous
biological activities such as analgesic [1], anti-
inflammatory [2], antifungal [3] and antibacterial
activities [4]. Thiophene-based compounds showed a
promising antitumor activity [5–6]. For example, a
series of functionalized thiophenes with general
structure 1 [7] (Fig. 1) exhibited antiproliferative effect
against human cells of cervical adenocarcinoma
(HeLa), human pancreatic adenocarcinoma (PANC1)
and mice fibroblasts (3T3) in concentrations of 5, 10,
25 and 50 µM. Methyl 4-(4-amidoaryl)-3-methoxy-
thiophene-2-carboxylate 2 [8] (Fig. 1) exhibited
potential anticancer activity with IC50 = 2.22 µM
against MCF-7 and 0.72 µM against HepG2 cell lines.
Isatin (1H-indole-2,3-dione) has been emerged as
an interesting moiety in the developing of several
anticancer agents [20–26]. Indirubin (5) (Fig. 1) has
potential inhibitory action against CDK-2 (IC50
=
1.0 µM) [27]. Sunitinib (6, Sutent®; Fig. 1) is an active
isatin derivative that acts as an inhibitor for multi-
targeted tyrosine kinase used for the management of
gastrointestinal stromal tumors and metastatic renal-
cell carcinoma [28, 29].
Some 1,3-thiazole derivatives have been reported to
be efficient in treatment of allergies [9], bacterial
infection [10] and inflammation [11], and also potent
Based on the above and in continuation of our
studies in the synthesis of new heterocycles as
potential anticancer agents [30–35], herein we present
synthesis of a new series of thiophenes 6a–6e and 1,3-
thiazole derivatives 13a–13f and 15a–15e, and evalua-
1 The text was submitted by the authors in English.
2951

2952
FATHY et al.
O
H2N
OH
N
Ar
O
R
NC
O
O
S
Ar
R1
N
S
S
OH
O
HO
Tiazofurin 3
1
2
O
R
O
N
NH
O
N
N
H
N
F
R
Br
N
H
Ar
N
O
S
H
O
N
H
N
H
Dasatinib 4
Indirubin 5
Sunitinib 6
O
Ph
O
Ph
O
R
O
O
O
O
N
O
N
O
Ar
S
S
O
O
Ph
O
N
H
O
S
O
NH
Ar
O
6a−6e
16a−16e
14a−14f
Fig. 1. The structure of compounds 1–6, the newly synthesized thiophenes 6a–6e and 1,3-thiazole derivatives 14a–14f and
16a–16e.
tion of their activity against human liver carcinoma
(HepG-2) and human breast adenocarcinoma (MCF-7).
yielded, in each case, a single product (TLC) with two
possible structures (Scheme1). There were two possible
routes to the reaction product via dehydration with
formation of either thiophene derivatives 6a–6e (route
a) [38–40] or 1,3-thiazoles 7a–7e (route b) [41–43].
1H NMR spectra of the isolated compounds
demonstrated the characteristic signal of NH in the
region 10.28–10.37 ppm and disappearance of the
singlet of the methylene group which supported forma-
tion of thiophenes 6a–6e. X-Ray single crystal analysis
of compound 6c supported the absolute confirmation
of thiophenes 6a–6e (Fig. 2). Therefore, the previous
reaction proceeded via “route a.” Crystallographic data
for the structure 6c has been deposited at the
Cambridge Crystallographic Data Center and allocated
with the deposition numbers: CCDC 1538956.
RESULTS AND DISCUSSION
The present study targeted the synthesis of novel thio-
phene and 1,3-thiazolidine derivatives (Schemes 1, 2)
for testing their anticancer activity against HepG-2 and
MCF-7 cell lines.
Ethyl 3-(4-methoxyphenyl)-3-oxopropanoate 1 was
prepared according to the developed earkier
procedures [36, 37]. The reaction of compound 1 with
phenyl isothiocyanate in the presence of KOH in DMF
media gave the non-isolable intermediate potassium
salt 2, which upon treatment with diluted HCl led to
the corresponding ethyl 2-(4-methoxybenzoyl)-3-
(phenylamino)-3-thioxopropanoate 3, the structure of
which was confirmed by 1H and 13C NMR spectrum.
Reaction of compound 3 with ethyl 2-bromoacetate
(8) in ethanol, in the presence of TEA, afforded 1,3-
Reaction of compound 3 with 1-aryl-2-bromo-
ethanones 4a–4e in ethanol, in the presence of TEA,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017

SYNTHESIS, SINGLE CRYSTAL X-RAY, AND ANTICANCER ACTIVITY
2953
Scheme 1. Synthesis of ethyl 5-aryl-4-(4-methoxyphenyl)-2-(phenylamino)thiophene-3-carboxylates (6a–6e).
O
O
O
O
Ph-NCS /KOH
HCl
O
O
Ph
O
KS
N
H
O
1
2
O
S
O
O
O
O
Br
O
Ar
O
4a−4e
Ph
O
N
H
Ph
a
TEA
O
HS
N
H
O
b
3
Ar
5a−5e
−H2O
a
b
×
O
O
O
N
O
O
O
Ph
O
Ph
O
S
N
S
H
Ar
Ar
6a−6e
7a−7e
Ar = Ph (a), 4-MeC6H4 (b), 4-ClC6H4 (c), 4-FC6H4 (d), 4-BrC6H4 (e).
1
thiazolidinone 11 proceeded via “route b.” H NMR
spectrum of compound 11 displayed the presence of a
singlet of methylene protons of 1,3-thiazolidinone
moiety at 4.04 ppm. 13C NMR of 11 showed three
signals of three C=O at 158.69 ppm (C1 of
propanoate), 165.55 ppm (C4 of 1,3-thiazolidinone)
and 188.42 (C3 of propanoate) in addition to the signal
of C5 (CH2) of 1,3-thiazolidinone at 31.18 ppm.
oxoindolin)-3-ylidenes 15a–15e. 1H NMR spectra of
compounds 15a-f demnstrated the presence of NH of
isatin as a singlet in the range of 11.20–11.85 ppm.
Anti-tumor activity. The newly synthesized com-
pounds 3, 6a–6e, 11, 13a–13f and 15a–15e (18 com-
pounds), were tested in vitro for anti-tumor activity
against HepG-2 and MCF-7 human carcinoma cell
lines using the MTT assay. The IC50 values of all
tested compounds are presented in the table. The
activity of these compounds against two carcinoma
cells were compared with that of Doxorubicin® (see
the table). According to the accumulated data all
compounds demonstrated dose-dependent anticancer
activities against both cancer cells.
Treatment of compound 11 by aldehydes 12a–12f
in the presence of pipridine led to 5-arylidene
respective derivatives 13a–13f. 1H NMR spectra of
compounds 13a–13f exhibited the presence of a singlet
of Ar–CH=C< at δ 7.75 ppm. Treatment of 1,3-
thizolidinone 11 with isatin dervatives 14a–4e in
glacial acetic acid and in the presences of anhydrous
sodium acetate afforded the corresponding 4-oxo-5-(2-
In general, the response of MCF-7 cancer cells was
higher than that of HepG-2 cancer cells against the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017

2954
FATHY et al.
Scheme 2. Synthesis of 1,3-thiazolidinones.
O
O
O
O
O
O
Br
Ph
O
O
S
N
H
O
a
8
O
Ph
b
O
HS
N
H
3
O
9
a
b
×
−EtOH
−H2O
O
O
S
O
N
O
O
O
Ph
O
O
Ph
N
S
H
O
O
11
10
O
R
O
N
Ar CHO
H
14a−14e
12a−12f
AcOH/AcONa
Ph
O
O
R
Ph
O
O
O
O
O
N
O
N
S
Ar
O
S
O
NH
O
15a−15e
13a−13f
15: R = H (a), Br (b), Cl (c), F (d), NO2 (e). 16: Ar = Ph (a), 4-MeOC6H4 (b), 4-ClC6H4 (c), 4-FC6H4 (d), 4-(CH3)2NC6H4 (e),
2,4-diClC6H4 (f).
newly synthesized compounds. From Structure
Activity Relationship (SAR) point of view, the
anticancer activity of 1,3-thiazolidinones 13a–13f and
15a–15e was higher than that of thiophenes 6a–6e.
The unsubstituted at C5 of isatin, ethyl 3-(4-methoxy-
phenyl)-3-oxo-2-[4-oxo-5-(2-oxoindolin-3-ylidene)-3-
phenylthiazolidin-2-ylidene] propanoate (15a), was the
most potent against HepG-2 cancer cells whereas p-
MeO substituted benzylidine, ethyl 2-[5-(4-meth-
oxybenzylidene)-4-oxo-3-phenylthiazolidin-2-ylidene]-
3-(4-methoxyphenyl)-3-oxopropanoate (13b) demon-
strated the highest anticancer activity against MCF-7
cancer cells. The fluoro substituted at C5 of isatin,
ethyl 2-[5-(5-fluoro-2-oxoindolin-3-ylidene)-4-oxo-3-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017

SYNTHESIS, SINGLE CRYSTAL X-RAY, AND ANTICANCER ACTIVITY
O15
2955
Cl2
C16
C24
phenylthiazolidin-2-ylidene]-3-(4-methoxyphenyl)-3-
C14
oxopropanoate (15d), showed anticancer activity
exhibited higher activity than doxorubicin.
C20
S1
C30
C23
C22
C11
C29
C18
C19
C8
EXPERIMENTAL
C13 C21
N7
C31
C34
C4
C10
C32
C9
O3
Melting points were uncorrected and measured on
an Electro-thermal IA 9100 apparatus (Shimadzu,
Japan). Microanalytical data were accumulated on a
Vario El-Mentar apparatus (Shimadzu, Japan),
National Research Centre, Cairo, Egypt. IR spectra
were recorded (as KBr pellets) on a Perkin-Elmer 1650
Spectrophotometer, National Research Centre, Cairo,
Egypt. NMR spectra were measured on a JEOL-Ex-
300 MHz in DMSO-d6 using TMS as an internal
reference (Faculty of Science, Cairo University, Cairo,
Egypt). Mass spectra were measured on a Shimadzu
GCMS-QP-1000EX mass spectrometer at 70 eV
(Cairo University, Cairo, Egypt). X-Ray single crystal
data were accumulated on a maXus difractometer
(Bruker Nonius, Delft & MacScience, Japan).
C25
C17
C27
C28
O12
C33
O5
C6
C26
Fig. 2. X-Ray single crystal structure of ethyl 5-(4-chloro-
benzoyl)-4-(4-methoxyphenyl)-2-(phenylamino)thiophene-
3-carboxylate (6c).
Synthesis of ethyl 5-aryl-4-(4-methoxyphenyl)-2-
(phenylamino)thiophene-3-carboxylates (6a–6e). To
a mixture of ethyl 2-(4-methoxybenzoyl)-3-(phenyl-
The anticancer IC50 values of the nineteen compounds using
MTT assay against two cancer types
Ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (1).
The compound was synthesized according to the
earlier reported method [36, 37] by the reaction of 4-
methoxy acetophenone and diethyl carbonate in the
presence of sodium hydride.
IC50, µg/mL
Comp. no.
HepG-2
MCF-7
3
6a
56.56±2.9
69.46 ± 3.2
80.67 ± 4.6
73.52 ± 4.2
81.61 ± 3.0
79.03 ± 2.7
77.48 ± 3.1
74.30 ± 4.2
70.65 ± 2.6
69.15 ± 1.9
83.09 ± 5.1
77.46 ± 4.2
83.69 ± 2.8
74.88 ± 3.0
72.01 ± 1.8
71.19 ± 2.4
72.45 ± 4.1
71.69 ± 2.9
71.34 ± 2.1
74.28 ± 4.2
84.45 ± 3.1
75.72 ± 4.2
91.30 ± 2.5
110.00 ± 5.1
84.68 ± 4.3
86.57 ± 3.6
62.20 ± 2.9
65.93 ± 3.1
63.71 ± 3.2
68.71 ± 4.3
81.71 ± 5.3
67.13 ± 3.2
55.39 ± 3.2
72.67 ± 3.2
65.57 ± 2.1
56.574 ± 3.2
63.13 ± 2.7
57.76 ± 2.1
Ethyl 2-(4-methoxybenzoyl)-3-(phenylamino)-3-
thioxopropanoate (3). A mixture of ethyl 3-(4-
methoxyphenyl)-3-oxopropanoate (1) (2.22 g, 10 mmol)
with KOH (0.61 g, 1.1 mmol) was dissolved in DMF
(25 mL) and stirred for 30 min, then phenyl
isothiocyanate 2 (1.5 g, 1.1 mmol) was added. After
strring for 12 h at room temperature it was poured into
crushed ice and neutralized by 1 N HCl. The
precipitated product was filtered off, washed with cold
water, dried, and recrystallized from ethanol. Yield
91%, mp 98–100°C. IR spectrum, ν, cm–1: 3181 (NH),
1737 (C=O), 1678 (C=O). 1H NMR spectrum, δ, ppm:
1.17 t (J = 7 Hz, 3H, OCH2CH3), 3.85 s (3H, OCH3),
4.15 q (J = 7 Hz, 2H, OCH2CH3), 6.03 s (1H, CH–
C=S), 7.07 d (J = 9 Hz, 2H [o], OMeC6H4), 7.26 t (J =
9 Hz, 1H [p], PhH), 7.40 t (J = 9 Hz, 2H [m], PhH),
7.79 d (J = 9 Hz, 2H [o], PhH), 7.90 d (J = 9 Hz, 2H
[o], OMeC6H4), 11.85 s (1H, D2O-exchangeable, NH).
13C NMR spectrum, δ, ppm: 13.81 (CH3), 55.56
(OCH3), 61.25 (CH2), 68.07 (CH), 114.10 (2C), 122.87
(2C), 126.27, 128.60 (2C), 128.80, 130.52 (2C),
139.17(C1 of Ph), 163.40 (C4 of OMeC6H4), 166.05
(C=O), 188.43 (C=O), 191.58 (C=S). MS, m/z: 358
[M]+. C19H19NO4S.
6b
6c
6d
6e
11
13a
13b
13c
13d
13e
13f
15a
15b
15c
15d
15e
Doxorubicin
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FATHY et al.
amino)-3-thioxopropanoate (3) (1 mmol) and 2-bromo-
1-phenylethanone dervatives (0.357 g, 1 mmol) in
absolute ethanol (25 mL) was added triethylamine
(0.2 mL). The reaction mixture was refluxed for 1 h
and then cooled down to room temperature. The
precipitate was filtered off, dried and washed with
ethanol. The crude product was recrystallized from
EtOH giving compounds 6a–6e, respectively.
90%, mp 130°C. IR spectrum, ν, cm–1: 3430 (NH),
1734 (C=O), 1655 (C=O). 1H NMR spectrum, δ, ppm:
0.80 t (J = 7 Hz, 3H, OCH2CH3), 3.65 s (3H, OCH3),
3.95 q (J = 7 Hz, 2H,OCH2CH3), 6.58 d (J = 9 Hz, 2H
[m], OMeC6H4), 6.61–7.28 m ( 9H, 5H of Ph + 2H of
OMeC6H4 + 2H of FArH), 7.48 d (J = 9 Hz, 2H [o],
ArH), 10.32 s (1H, D2O-exchangeable, NH). MS, m/z:
476 [M]+. C27H22FNO4S.
Ethyl 5-(4-bromobenzoyl)-4-(4-methoxyphenyl)-
2-(phenylamino)thiophene-3-carboxylate (6e). Yield
86%, mp 150–152°C. IR spectrum, ν, cm–1: 3430
(NH), 1735 (C=O), 1660 (C=O). 1H NMR spectrum, δ,
ppm: 0.79 t (J = 7 Hz, 3H, OCH2CH3), 3.67 s (3H,
OCH3), 3.92 q (J = 7 Hz, 2H, OCH2CH3), 6.55 d (J =
9 Hz, 2H [m], OMeC6H4), 6.89 t (J = 9 Hz, 1H [p],
Ph), 7.05 t (J = 9 Hz, 2H, m-Ph), 7.08–7.27 m (6H, 2H
[o], PhH + 2H [m], BrPhH + 2H [o], OMeC6H4), 7.49
d (J = 9Hz, 2H [o], Br-ArH ), 10.37 s (1H, D2O-ex-
changeable, NH). MS, m/z: 537 [M]+. C27H22BrNO4S.
Ethyl 5-benzoyl-4-(4-methoxyphenyl)-2-(phenyl-
amino)thiophene-3-carboxylate (6a). Yield 85%, mp
135–137°C. IR spectrum, ν, cm–1: 3423 (NH), 1716
(C=O), 1654 (C=O). 1H NMR spectrum, δ, ppm: 0.80 t
(J = 7 Hz, 3H, OCH2CH3), 3.63 s (3H, OCH3),3.99 q
(J = 7 Hz, 2H, OCH2CH3), 6.55 d (J = 9 Hz, 2H [m],
OMeC6H4), 6.93–7.27 m (10H, 2H [o], OMeC6H4 +
5H of Ph + 3H of Ar), 7.50 d (J = 9 Hz, 2H [o], ArH),
10.30 s (1H, D2O-exchangeable, NH). MS, m/z: 458
[M]+. C27H23NO4S.
Ethyl 4-(4-methoxyphenyl)-5-(4-methylbenzoyl)-
2-(phenylamino)thiophene-3-carboxylate (6b). Yield
82%, mp 137–138°C. IR spectrum, ν, cm−1: 3430
(NH), 1730 (C=O), 1650 (C=O). 1H NMR spectrum, δ,
ppm: 0.80 t (J = 7 Hz, 3H, OCH2CH3), 2.20 s (3H,
CH3), 3.65 s (3H, OCH3), 3.92 q (J = 7 Hz, 2H,
OCH2CH3), 6.58 d (J = 9 Hz, 2H [m], OMeC6H4), 6.89
t (J = 9 Hz, 1H [p], PhH), 6.92 t (J = 9 Hz, 2H [m],
PhH), 7.14 d (J = 9 Hz, 2H [m], ArH), 7.21–7.24 m
(4H, 2H [o], PhH + 2H [o], OMeC6H4), 7.47 d (J =
9 Hz, 2H [o], ArH), 10.28 s (1H, D2O-exchangeable,
NH). MS, m/z: 472 [M]+. C28H25NO4S.
Synthesis of ethyl 3-(4-methoxyphenyl)-3-oxo-2-
(4-oxo-3-phenylthiazolidin-2-ylidene) propanoate
(11). To a mixture of ethyl 2-(4-methoxybenzoyl)-3-
(phenylamino)-3-thioxopropanoate (3) (3.57 g, 10 mmol)
and ethyl 2-bromoacetate (9) (1.67 g, 10 mmol) in
absolute ethanol (25 mL), TEA (0.2 mL) was added.
The reaction mixture was refluxed for 4 h, then cooled
down to room temperature. The precipitate was filtered
off, dried and washed with ethanol. The crude product
was recrystallized from EtOH to give the compound
11. Yield 65%, mp 179°C. IR spectrum, ν, cm−1: 1723–
1
1689 (3C=O). H NMR spectrum, δ, ppm: 0.88 t (J =
Ethyl 5-(4-chlorobenzoyl)-4-(4-methoxyphenyl)-
2-(phenylamino)thiophene-3-carboxylate (6c). Yield
93%, mp 140°C. IR spectrum, ν, cm–1: 3435 (NH),
1735 (C=O), 1650 (C=O). 1H NMR spectrum, δ, ppm:
0.79 t (J = 7 Hz, 3H, OCH2CH3), 3.66 s (3H, OCH3),
3.97 q (J = 7 Hz, 2H, OCH2CH3), 6.55 d (J = 9 Hz, 2H
[m], OMeC6H4), 6.89 t (J = 9 Hz, 1H [p], Ph), 7.06–
7.27 m (8H, 4H of PhH + 4H of ClC6H4 + OMeC6H4),
7.49 d (J = 9Hz, 2H [o], ClArH), 10.37 s (1H, D2O-
exchangeable, NH). 13C NMR spectrum, δ, ppm: 13.29
(CH3), 55.09 (OCH3), 59.76 (CH2), 109.54, 112.31
(2C), 120.61, 121.20, 121.34 (2C), 125.24, 127.26,
127.30 (2C), 129.65 (2C), 129.72 (2C), 131.18, 134.80,
137.25, 139.73 (C1 of Ph), 147.93 (C4 of thiophene),
158.84 (C=O of ester), 163.18 (C4 of OMeC6H4),
164.92 (C2 of thiophene), 187.64 (C=O of ClAr). MS,
m/z: 492 [M]+. C27H22ClNO4S.
7 Hz, 3H, OCH2CH3), 3.81 s (3H, OCH3), 4.0 q (J =
7 Hz, 2H, OCH2CH3), 4.04 s (2H, CH2 of 1,3-thiazol-
idinone), 6.82–7.35 m ( 7H, 2H [m] OMeC6H4 + 5H
Ph), 7.35(d, J = 9 Hz, 2H [o], OMeC6H4). 13C NMR
spectrum, δ, ppm: 13.88 (CH3 of ester), 31.18 (C5 of
1,3-thiazolidinone (CH2)), 55.42 (OCH3), 59.90 (CH2
of ester), 104.69 (C2 of propanoate), 113.15 (C3 and C5
of MeOC6H4), 128.02, 128.19 (2C), 128.87, 129.75,
129.91, 130.66 (2C), 134.75 (C1 of Ph), 158.69 (C1 of
propanoate), 162.96 (C4 of MeOC6H4), 165.55 (C4,
C=O of 1,3-thiazolidinone), 173.35 (C2 of 1,3-thiazol-
idinone), 188.42 (C3 of propanoate). MS, m/z: 398 [M]+.
C21H19NO5S.
Synthesis of aryylidene-5-(4-methoxyphenyl)-2,4-
dihydro-3H-pyrazol-3-one (13a–13f). To a mixture
of compound 11 (0.397g, 1 mmol) and the appropriate
aldehyde (12a–12e) (1 mmol) in absolute ethanol
(25 mL), piperidine (0.2 mL) was added. The reaction
mixture was refluxed for 1 h, then cooled down to
Ethyl 5-(4-fluorobenzoyl)-4-(4-methoxyphenyl)-
2-(phenylamino)thiophene-3-carboxylate (6d). Yield
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SYNTHESIS, SINGLE CRYSTAL X-RAY, AND ANTICANCER ACTIVITY
2957
room temperature. The precipitate was filtered off,
dried and washed with ethanol. The crude product was
recrystallized from EtOH to afford the respective
compounds 13a–13f.
2H, OCH2CH3), 6.83 d [J = 9 Hz, 2H [m]
N(Me)2C6H4}, 6.89–7.14 m (7H, 2H [m] OMeC6H4 +
5H PhH), 7.36 d {J = 9 Hz, 2H [o] N(Me)2C6H4}, 7.58–
7.62 m (3H, 1H, –CH=C< + 2H [o] OMeC6H4). MS,
m/z: 529 [M]+. C30H28N2O5S.
Ethyl 2-(-5-benzylidene-4-oxo-3-phenylthiazol-
idin-2-ylidene)-3-(4-methoxyphenyl)-3-oxopro-
panoate (13a). Yield 83%, mp 215°C. IR spectrum, ν,
cm−1: 1725–1671 (3C=O). 1H NMR spectrum, δ, ppm:
0.92 t (J = 7 Hz, 3H, OCH2CH3), 3.82 s (3H, OCH3),
4.02 q (J = 7 Hz, 2H, OCH2CH3), 6.84–7.65 m (12H,
2H [m] OMeC6H4 + 5H PhH + 5H Ar), 7.74 s (1H,
–CH=C<), 7.77 d (J = 9 Hz, 2H [o] OMeC6H4). MS,
m/z: 486 [M]+. C28H23NO5S.
Ethyl 2-[-5-(2,4-dichlorobenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene]-3-(4-methoxyphenyl)-3-
oxopropanoate (13f). Yield 86%, mp 230°C. IR
spectrum, ν, cm−1: 1716–1662 (3C=O). 1H NMR spec-
trum, δ, ppm: 0.91 t (J = 7 Hz, 3H, OCH2CH3), 3.82 s
(3H, OCH3), 4.01 q (J = 7 Hz, 2H,OCH2CH3), 6.84 d
(J = 9 Hz, 2H [m] OMeC6H4), 7.00–7.18 m (7H, 2H
[m] 2,4-ClC6H4 + 5H PhH), 7.36 d (J = 9 Hz, 2H [o]
2,4-ClC6H4), 7.74–7.88 m (3H, 1H, –CH=C<+ 2H [o]
OMeC6H4). MS, m/z: 555 [M]+. C28H21Cl2NO5S.
Ethyl 2-[-5-(4-methoxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene]-3-(4-methoxyphenyl)-3-
oxopropanoate (13b). Yield 85%, mp 205°C. IR
spectrum, ν, cm−1: 1720–1670 (3C=O). 1H NMR
spectrum, δ, ppm: 0.92 t (J = 7 Hz, 3H, OCH2CH3),
3.82 s (3H, OCH3), 3.86 s (3H, OCH3), 4.04 q (J =
7 Hz, 2H,OCH2CH3), 6.84 d (J = 9 Hz, 2H [m]
OMeC6H4), 6.86–7.20 m (7H, 2H [m] OMeC6H4 + 5H
PhH), 7.36 d (J = 9 Hz, 2H [o] OMeC6H4), 7.71 s (1H,
–CH=C<), 7.74 d (J = 9 Hz, 2H [o] OMeC6H4). MS,
m/z: 516 [M]+. (C29H25NO6S).
Synthesis of ethyl 3-(4-methoxyphenyl)-3-oxo-2-
[4-oxo-5-(2-oxoindolin-3-ylidene)-3-phenylthiazol-
idin-2-ylidene]propanoate derivatives (15a–15e). To
a mixture of compound 11 (0.397g, 1 mmol) and the
appropriate isatin (1 mmol) in glacial acetic acid
(25 mL), anhydrous sodium acetate (0.25 g, 3 mmol)
was added. The reaction mixture was refluxed for 4 h
and then cooled down to room temperature. The pre-
cipitate was filtered off, dried and washed with
ethanol. The crude product was recrystallized
from EtOH/DMF to afford the respective compounds
15a–15e.
Ethyl 2[-5-(4-chlorobenzylidene)-4-oxo-3-phenyl-
thiazolidin-2-ylidene]-3-(4-methoxyphenyl)-3-oxo-
propanoate (13c). Yield 85%, mp 202°C. IR spec-
trum, ν, cm−1: 1725-1665 (3C=O). 1H NMR spectrum,
δ, ppm: 0.92 t (J = 7 Hz, 3H, OCH2CH3), 3.83 s (3H,
OCH3), 4.01 q (J = 7 Hz, 2H, OCH2CH3), 6.82 d (J =
9 Hz, 2H [m] OMeC6H4), 6.86–7.50 m (9H, 4H ClC6H4 +
5H PhH), 7.74 s (1H, –CH=C<), 7.80 d (J = 9 Hz, 2H
[o] OMeC6H4). MS, m/z: 520 [M]+. C28H22ClNO5S.
Ethyl 3-(4-methoxyphenyl)-3-oxo-2-[4-oxo-5-(2-
oxoindolin-3-ylidene)-3-phenylthiazolidin-2-yl-
idene]propanoate (15a). Yield 80%, mp ˃300°C. IR
spectrum, ν, cm−1: 3211 (NH), 1697–1658 (4C=O). 1H
NMR spectrum, δ, ppm: 0.92 t (J = 7 Hz, 3H, OCH2CH3),
3.82 s (3H, OCH3), 4.01 q (J = 7 Hz, 2H, OCH2CH3),
6.84–7.40 m (12H, 4H [o, m], OMeC6H4 + 3H isatin +
5H PhH), 8.65 d (J = 2 Hz, 1H of C4 isatin), 11.19 s
(1H, D2O-exchangeable, NH). MS, m/z: 527 [M]+.
C29H22N2O6S.
Ethyl 2-[-5-(4-fluorobenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene]-3-(4-methoxyphenyl)-3-
oxopropanoate (13d). Yield 81%, mp 190°C. IR
spectrum, ν, cm−1: 1718–1668 (3C=O). 1H NMR spec-
trum, δ, ppm: 0.92 t (J = 7 Hz, 3H, OCH2CH3), 3.82 s
(3H, OCH3), 4.02 q (J = 7 Hz, 2H,OCH2CH3), 6.84 d
(J = 9 Hz, 2H [m] OMeC6H4), 6.86–7.16 m (7H, 2H
[m] FC6H4 + 5H [p], PhH), 7.37 d (J = 9 Hz, 2H [o]
FC6H4), 7.75 s ( 1H, –CH=C<), 7.80 m (2H, 2H [o]
OMeC6H4). MS, m/z 504 [M]+. C28H22FNO5S.
Ethyl 2-[-5-(5-bromo-2-oxoindolin-3-ylidene)-4-
oxo-3-phenylthiazolidin-2-ylidene]-3-(4-methoxy-
phenyl)-3-oxopropanoate (15b). Yield 83%, mp
˃300°C. IR spectrum, ν, cm−1: 3420 (NH), 1690–1665
(4C=O). 1H NMR spectrum, δ, ppm: 0.93 t (J = 7 Hz,
3H, OCH2CH3), 3.83 s (3H, OCH3), 4.03 q (J = 7 Hz,
2H, OCH2CH3), 6.85–7.37 m (4H, 2H [m], OMeC6H4 +
1H of C7 isatin + 1H [p], PhH), 7.48 m (5H, 4H PhH +
1H of C6 isatin), 7.50 d (J = 9 Hz, 2H [o], OMeC6H4),
8.82 d (J = 2 Hz, 1H of C4 isatin), 11.30 s (1H, D2O-
exchangeable, NH). MS, m/z: 604 [M]+. C29H21BrN2O6S.
Ethyl 2-[-5-(4-(dimethylamino)benzylidene)-4-oxo-
3-phenylthiazolidin-2-ylidene]-3-(4-methoxyphenyl)-
3-oxopropanoate (13e). Yield 86%, mp 200°C. IR
spectrum, ν, cm−1: 1720–1662 (3C=O). 1H NMR spec-
trum, δ, ppm: 0.92 t (J = 7 Hz, 3H, OCH2CH3), 3.05 s
[6H, N(CH3)2], 3.82 s (3H, OCH3), 4.05 q (J = 7 Hz,
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FATHY et al.
Ethyl 2-[-5-(5-chloro-2-oxoindolin-3-ylidene)-4-
different concentrations in DMSO of each tested
compound or Doxorubicin® (positive control) for 48 h
in a serum free medium prior to the MTT assay. After
incubation, media were carefully removed, 40 µL of
MTT (2.5 mg/mL) were added to each well and then
incubated for the additional 4 h. Purple formazan dye
crystals were solubilized by addition of 200 µL of
DMSO. Absorbance was measured at 590 nm using a
SpectraMax® Paradigm® Multi-Mode microplate
reader. Relative cell viability was expressed as the
mean percentage of viable cells compared to the
untreated control cells.
oxo-3-phenylthiazolidin-2-ylidene]-3-(4-methoxy-
phenyl)-3-oxopropanoate (15c). Yield 80%, mp
˃300°C. IR spectrum, ν, cm−1: 3390 (NH), 1680–1669
(4C=O). 1H NMR spectrum, δ, ppm: 0.93 t (J = 7 Hz,
3H, OCH2CH3), 3.83 s (3H, OCH3), 4.05 q (J = 7 Hz,
2H, OCH2CH3), 6.84–7.42 m (11H, 4H [o, m],
OMeC6H4 + 2H of isatin + 5H PhH), 8.66 d (J = 2 Hz,
1H of C4 isatin), 11.27 s (1H, D2O-exchangeable, NH);
MS, m/z: 561 [M]+. C29H21ClN2O6S.
Ethyl 2-[-5-(5-fluoro-2-oxoindolin-3-ylidene)-4-
oxo-3-phenylthiazolidin-2-ylidene]-3-(4-methoxy-
phenyl)-3-oxopropanoate (15d). Yield 80%, mp
˃300°C. IR spectrum, ν, cm−1: 3425 (NH), 1693–1672
(4C=O). 1H NMR spectrum, δ, ppm: 0.93 t (J = 7 Hz,
3H, OCH2CH3), cm−1: 3.82 s (3H, OCH3), 4.06 q (J =
7 Hz, 2H, OCH2CH3), 6.85–7.50 m (11H, 4H [o, m],
OMeC6H4+ 2H of isatin + 5H PhH), 8.71 d (J = 2 Hz,
1H of C4 isatin), 11.30 s (1H, D2O-exchangeable, NH).
MS, m/z: 545 [M]+. C29H21FN2O6S.
Statistical analysis. All experiments were
conducted in triplicate and repeated on three different
days. All values were represented as mean ± SD. IC50s
were determined by probit analysis using SPSS
software program (SPSS Inc., Chicago, IL).
CONCLUSIONS
New thiophenes and 1,3-thiazolidinones were
synthesized and evaluated for their anticancer activity
against HepG-2 and MCF–7. Several compounds
revealed high anticancer activity. The un-substituted at
C5 of isatin 15a was the most potent compound against
HepG-2 cancer cells, whereas p-MeO substituted
benzylidine 13b showed the highest anticancer activity
against MCF-7 cancer cells. The fluoro substituted at
C5 of isatin 15d was more potent than doxorubicin
against both HepG-2 and MCF-7 cancer cells.
Ethyl 3-(4-methoxyphenyl)-2-[5-(5-nitro-2-
oxoindolin-3-ylidene)-4-oxo-3-phenylthiazolidin-2-
ylidene]-3-oxopropanoate (15e). Yield 80%, mp
˃300°C. IR spectrum, ν, cm−1:3 288 (NH), 1696–1658
(4C=O). 1H NMR spectrum, δ, ppm: 0.94 t (J = 7 Hz,
3H, OCH2CH3), 3.83 s (3H, OCH3), 4.05 q (J = 7 Hz,
2H, OCH2CH3), 6.85 d (2H, 2H [m], OMeC6H4), 7.07–
7.21 m (7H, 2H [o], OMeC6H4 + 5H PhH), 7.39 d (J =
8.5 Hz, 1H of C7 isatin), 8.23 d.d (J = 2.5, J = 8.5 Hz,
1H of C6 isatin), 9.55 d (J = 2.5 Hz, 1H of C4 isatin),
11.86 s (1H, D2O-exchangeable, NH). MS, m/z: 572
[M]+. C29H21N3O8S.
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