Design, synthesis and biological evaluation of novel 4-thiazolidinones containing indolin-2-one moiety as potential antitumor agent

Article abstract of DOI:10.1016/j.ejmech.2011.05.017

A series of novel 4-thiazolidinone and indolin-2-one hybrid derivatives 5a-5s and 10a-10s have been designed and synthesized and their cytotoxic activities were evaluated in vitro against three human cancer cell lines including HT-29 (human colon cancer),

Full text of DOI:10.1016/j.ejmech.2011.05.017

European Journal of Medicinal Chemistry 46 (2011) 3509e3518
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and biological evaluation of novel 4-thiazolidinones containing
indolin-2-one moiety as potential antitumor agent
*
Shuobing Wang, Yanfang Zhao, Guogang Zhang, Yingxiang Lv, Ning Zhang, Ping Gong
Key Laboratory of Original New Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District 110016, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 4-thiazolidinone and indolin-2-one hybrid derivatives 5ae5s and 10ae10s have been
designed and synthesized and their cytotoxic activities were evaluated in vitro against three human
cancer cell lines including HT-29 (human colon cancer), H460 (human lung cancer), MDA-MB-231
(human breast cancer) by MTT assay. Several potent target compounds (5m, 5p, 5s, 10a, 10ce10g,
10m, 10p) were further evaluated against one cancer cell line SMMC-7721 (human liver cancer) and one
normal cell line WI-38 (human fetal lung fibroblasts). Most of the prepared compounds exhibited
significant antitumor activities against different human cancer cell lines. Compound 10c
Received 11 February 2011
Received in revised form
6 May 2011
Accepted 8 May 2011
Available online 13 May 2011
Keywords:
(IC50 ¼ 0.025
(IC50 ¼ 1.3 M, 2.7
line, respectively.
m
M, 0.075
m
M, 0.77
m
M, 1.95
m
M) was 52, 36, 4.8 and 3.3 times more active than Sunitinib
4-thiazolidinone
Indolin-2-one
Synthesis
m
m
M, 3.7
m
M, 6.47
m
M) against HT-29, H460, MDA-MB-231 and SMMC-7721 cancer cell
Ó 2011 Elsevier Masson SAS. All rights reserved.
Cytotoxic activities
1. Introduction
gastrointestinal stromal tumors (GIST) (Fig.1) [19]. BIBF 1120, a triple
angiokinase inhibitor reported by Boehringer, is currently in phase III
clinical trials in non-small cell lung cancer (Fig. 1) [20]. Indirubin, an
active ingredient of a traditional Chinese medicine recipe, has been
applied to treat chronic myelocytic leukemia (Fig. 1) [21].
The aforementioned compounds have inspired us to attach
substituted indolin-2-one to the 5-benzylidene-4-thiazolidinone
scafford, and the combination of two privileged structures in one
molecule leads to drug-like molecules. To our knowledge there are
hardly any studies about introduction of indolin-2-one group at the
2-position of the 4-thiazolidinone ring so far. Thus, indolin-2-one
group was introduced at the 2-position of the 4-thiazolidinone
ring and a basic side chain was introduced at the 3-position of
the 4-thiazolidinone ring, in order to improve the solubility and
bioavailability of these structures.
4-Thiazolidinone derivatives are an important group of hetero-
cyclic compounds possessing a variety of biological effects [1],
including antitumor [2e4], anti-inflammatory [5], antimicrobial [6],
antiviral [7], anticonvulsant [8], antifungal [9], antibacterial [10]
activities and so on. Among them, 5-benzylidene-4-thiazolidinone
derivatives have been reported to show marked antitumor activities
with different biotargets and mechanism, such as phosphatase of
a regenerating liver (PRL-3) [11], Sphingosine Kinase (SK) [12], JNK-
stimulating phosphatase-1 (JSP-1) [13] and nonmembrane protein
tyrosine phosphatase (SHP-2) [14]. Moreover, 5-benzylidene-4-
thiazolidinone derivatives exhibited potent antitumor activities
against non-small cell lung cancer cell line H460, paclitaxel-resistant
H460taxR, human colon cancer cell line HT-29 and human breast
cancer cell line MDA-MB-231 (Fig. 1) [15e17].
Here, we report the newly synthesized target compounds
(Fig.1) and their cytotoxic activities against HT-29, H460, MDA-MB-
231 and SMMC-7721 human cancer cell lines.
The indolin-2-one ring system belongs to the privileged structure
in modern medicinal chemistry, particularly in discovery of new
antitumor and antiangiogenic agents. Various kinase inhibitors
containing indolin-2-one moiety have been intensively studied for
2. Chemistry
the inhibition of VEGFR, c-Kit, FLT3, PDGFR-a/b, and CSF-1-R [18].
Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, inter-
fering with tumor blood vessel formation, is approved by the FDA for
the treatment of advanced renal cell carcinoma (RCC) and
The preparation of target compounds 5ae5s and 10ae10s was
described in Scheme 1. The indolin-2-ones 11ae11f were synthe-
sized from appropriate anilines according to the reported proce-
dures [22,23].
The 5-benzylidene-3-substitutedrhodanine intermediates 3ae3h
and 8ae8f were synthesized by reaction of the primary amine 1 or 6
and carbon disulfide under basic conditions followed by ring closure
* Corresponding author. Tel./fax: þ86 24 2398 6429.
E-mail address: gongpinggp@126.com (P. Gong).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.05.017

3510
S. Wang et al. / European Journal of Medicinal Chemistry 46 (2011) 3509e3518
O
N
N
H
O
O
N
H
N
N
HN
O
N
N
S
N
H
S
O
Selective cytotoxic activities
against H460 and H460taxR
Sunitinib
Inhibition of the HT29 cell line
O
N
N
N
R= (CH2)3N(CH2CH3)2
(CH2)2N(CH3)2
O
O
R
N
X
NH
O
S
NH
O
X= Alkyloxy, Fluorine, Hydroxy
Y= Alkyl, Halide
Y
O
O
N
H
N
H
N
H
Target compounds
O
BIBF1120
Indirubin
Fig. 1. Structures of 4-thiazolidinones, indolin-2-ones and target compounds.
with chloroacetic acid and subsequent the intermediate 2 or 7 was
subjected to Knoevenagel condensation with suitable benzaldehydes
in refluxing ethanol (Scheme 1).
The Knoevenagel condensation reaction of 2 or 7 with benzal-
dehydes provided only the Z isomer, as determined by the chemical
shift of the methine proton in 3ae3h and 8ae8f ranging from 7.70
to 8.00 ppm as a singlet. The exclusive formation of the thermo-
dynamically stable Z-isomers is in agreement with which was re-
ported for similar structures in literature [24,25]. This downfield
movement of methine proton in 3ae3h and 8ae8f was due to the
deshielding effect of the adjacent carbonyl group at the 4-position.
The S-Ethylation of 3ae3h and 8ae8f with boron trifluoride diethyl
O
O
O
a, b, c
d
e
N
N
N
N
S
X
X
NH2
N
N
N
O
S
S
BF4
S
S
S
1
3a-3h
2
4a-4h
X
dioxymethylene
3g, 4g X= 3, 4-
3a, 4a X= 4-hydroxy
3b, 4b X= 4-methoxy
X
O
N
Y
3h, 4h X= 3, 4, 5-trimethoxy
N
S
f
S
N
3c, 4c X= 3, 4-difluoro
3d, 4d X= 2, 4-difluoro
3e, 4e X= 2, 4-dimethoxy
3f, 4f X= 2, 5-dimethoxy
+
N
Y
O
O
Y
O
N
N
H
N
H
11a-11f
H
5a-5s (2Z,5Z)
5a-5s (2E,5Z)
O
N
O
O
N
N
e
d
a, b, c
N
NH2
N
X
X
N
N
S
S
S
S
7
BF4
9a-9f
S
8a-8f
S
6
X
N
O
8a, 9a X= 3, 4-dioxymethylene
difluoro
X
O
8b, 9b X=3, 4-
N
S
N
S
f
8c, 9c X=2, 4-difluoro
8d, 9d X= 3, 4, 5-trimethoxy
8e, 9e X=4-hydroxy
N
+
Y
O
Y
O
Y
O
N
N
H
N
H
H
8f, 9f X=2-hydroxy
11a-11f
10a-10s (2Z,5Z)
10a-10s (2E,5Z)
Scheme 1. Reagents and conditions: (a) CS2, Et3N, Et2O, 25 ꢀC, 0.5 h; (b) ClCH2COOH, K2CO3, MeOH, H2O, 25 ꢀC, 7e8 h; (c) concd.H2SO4, pH ¼ 4.0, 35e40 ꢀC,12 h; (d) Benzaldehyde,
piperidine, EtOH, reflux 3e4 h; (e) BF3.Et2O, HC(OEt)3, 1,4-dioxane, 80 ꢀC; (f) Et3N, CH3CN, 25 ꢀC, 4 h.

S. Wang et al. / European Journal of Medicinal Chemistry 46 (2011) 3509e3518
3511
etherate and triethyl orthoformate produced thiazolinium salts
4ae4h and 9ae9f, which were condensed with indolin-2-ones
11ae11f in the presence of triethylamine to form target
compounds 5ae5s and 10ae10s.
(c) The 3-(diethylamino)propyl group at the 3-position of 4-
thiazolidinone ring was favorable for increasing antitumor
potency (10f vs 5h, 10g vs 5i, 10i vs 5k). (d) The position of
substituents in the phenyl ring appears to have significant effect
on cytotoxic activity. When comparing compounds with different
electron-donating group in the phenyl ring, it could clearly be seen
that 4-OH, 4-OMe or 3,4-dioxymethylene group in the phenyl ring
(5ae5g, 5pe5r) were favorable for a good antitumor potency,
whereas a drop of potency could be observed for compounds with
2,5-dimethoxybenzylidenegroup (5ne5o)or2-hydroxybenzylidene
group (10qe10s). Furthermore, compounds with fluorine in the
phenyl ring were less active, confirming that the electron-
withdrawing group in the phenyl ring may be unfavorable.
Compounds 10f and 10g possessed good potency may be due to the
longer basic side chain and fluoroindolin-2-one group. (e)
Compounds with 3,4-dioxymethylene group in the phenyl ring dis-
played less toxicity against normal cell line WI-38 (10c vs 10f, 10c vs
10m,10d vs 10g). Moreover, compound 10c was less toxic for normal
cell line WI-38, when compared to HT-29 and H460 cancer cell lines.
The selective index (IC50 normal cell/IC50 cancer cell) for HT-29 and
H460 cancer cell lines was 279 and 93, respectively. These data
demonstrated that the tumor cells were more sensitive than the
normal cells.
Due to the exocyclic double bond at 2-position of 4-thiazolidinone
ring, 5ae5s and 10ae10s existed as inseparable mixture of 2Z, 5Z and
2E, 5Z isomers. The tow isomers were assigned on the basis of NOESY
experiment. For the representative compound 5g or 10c, the NOESY
effect was observed between the proton of a-methylene and the
proton in 4-position of the indolin-2-one ring in 2Z, 5Z isomer (see
Supplementary information), whereas the 2E, 5Z isomer didn’t show
this effect (Fig. 2). The downfield shift of a-methylene proton in 2E, 5Z
isomer was presumably due to the deshielding effect of the carbonyl
group at the 2-position of the indolin-2-one ring (Fig. 2). 2Z, 5Z/2E, 5Z
ratios were determined using the corresponding integrals of a-
methylene proton in the 1H NMR spectra as shown in Table 1.
3. Biological evaluation
Compounds 5ae5s and 10ae10s were evaluated as mixtures of
both isomers for their cytotoxic activities against HT-29 (human
colon cancer), H460 (humanlung cancer) and MDA-MB-231 (human
breast cancer) cancer cell lines together with reference Sunitinib by
MTTassay. In addition, several potent target compounds (5m, 5p, 5s,
10a, 10ce10g, 10m, 10p) were further evaluated against one cancer
cell line SMMC-7721 (human liver cancer) and one normal cell line
WI-38 (human fetal lung fibroblasts). The results expressed as IC50
were summarized in Table 1. The IC50 values are the average of at
least three independent experiments.
As illustrated in Table 1, most of the synthesized compounds
showed moderate to excellent cytotoxic activities against different
cancer cell lines in submicromolar range. Compound 10c possessed
the highest potency against all four cancer cell lines, while
compounds 5j, 5m, 5q, 10d and 10g, indicated significant selectivity
toward HT-29 cancer cell line. Compounds 10h, 10j and 10le10o
exhibited selectivity on H460 cancer cell line.
The initial structure-activity relationships could be drawn from
the pharmacological data: (a) Compound (5ae5f) bearing different
substituted indolin-2-one showed greater cytotoxic activities than
the parent intermediate 3a against all the cancer cell lines,
therefore a substituted indolin-2-one ring is a necessary moiety
for these compounds to possess potent cytotoxic activities. (b)
Smaller electron-withdrawing fluorine atom at 5-position of the
indolin-2-one ring was more favorable, as compound 10c was
more potent than 10a, 10b, 10d, 10e against all the cancer cell lines.
4. Conclusion
In summary, a series of 4-thiazolidinones with indolin-2-one
fragment were designed and synthesized. The cytotoxic activities
of synthesized compounds were evaluated against four human
cancer cell lines (HT-29, H460, MDA-MB-231 and SMMC-7721).
Most of the prepared compounds displayed moderate to excellent
cytotoxic activities against one or more cancer cell lines. In partic-
ular, compound 10c showed potent antitumor activity against all
four cancer cell lines. In addition, compound 10c exerted markedly
weaker effects on WI-38 normal cell line than on HT-29 and H460
cancer cell lines. From the preliminary SAR studies, it revealed that
introduction of 5-fluoroindolinone or 6-fluoroindolinone group at
2-position of the 4-thiazolidinone scaffold could enhance their
antitumoractivities. Compound 10c exhibited interesting antitumor
activity and selective index in comparison to the other investigated
compounds. This compound appeared as promising and interesting
lead, endowed of potential antitumor activity. Further studies are in
progress in our laboratories and will be reported upon in the future.
5. Experimental protocols
5.1. Chemistry
O
O
4.34
a
N
H
O
N
4.84
a
Melting points were obtained on a Büchi Melting Point B-540
apparatus (Büchi Labortechnik, Flawil, Switzerland) and were
uncorrected. Mass spectra (MS) were taken in ESI mode on Agilent
1100 LC-MS (Agilent, Palo Alto, CA, USA). 1H NMR and 13C NMR
spectra were recorded on Bruker ARX-300, 300 MHz or Bruker ARX-
600, 600 MHz spectrometers (Bruker Bioscience, Billerica, MA USA)
with TMS as an internal standard. (2Z, 5Z)/(2E, 5Z) ratios were
determined by integration of the corresponding peaks in the 1H
NMR spectra. IR spectra (KBr disks) were recorded on a Bruker IFS55
instrument (Bruker). Elemental analysis was determined on a Carlo-
Erba 1106 Elemental analysis instrument (Carlo Erba, Milan, Italy).
All chemicals were obtained from commercial suppliers and used
without purification. TLC analysis was carried out on silica gel plates
GF254 (Qindao Haiyang Chemical, China). Indolin-2-ones 11ae11f
were synthesized in accordance with literature procedures [22,23].
The detailed experimental data of precursors (2, 7, 3ae3h and
8ae8f) are presented in Supplementary information.
S
H
S
O
N
NOESY
N
O
O
N
F
N
H
F
Deshielding effect
H
5g (2E,5Z)
5g (2Z,5Z)
O
O
O
N
4.28
a
O
O
4.63
a
H
N
S
O
S
N
NOESY
H
N
F
F
O
O
N
H
N
H
Deshielding effect
10c (2Z,5Z)
10c (2E,5Z)
Fig. 2. Key NOESY of 5g (2Z,5Z) and 10c (2Z,5Z) and deshielding effect of carbonyl
group in 5g (2E,5Z) and 10c (2E,5Z).

3512
S. Wang et al. / European Journal of Medicinal Chemistry 46 (2011) 3509e3518
Table 1
Structure and cytotoxic activities of target compounds against HT-29, H460, MDA-MB-231, SMMC-7721 cancer cell lines and WI-38 normal cell line in vitro.
X
X
O
X
N
O
X
N
O
O
N
S
N
S
S
N
S
N
N
N
Y
O
Y
O
Y
O
Y
O
N
H
N
N
H
N
H
H
5a-5s (2Z,5Z)
5a-5s (2E,5Z)
10a-10s (2Z,5Z)
10a-10s (2E,5Z)
Compd.
Ratioa
X
Y
IC50
(
m
M)bꢁ SD
HTꢂ29c
H460c
MDA-MBꢂ231c
SMMCꢂ7721c
WIꢂ38c
3a
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
e
4-hydroxy
4-hydroxy
4-hydroxy
4-hydroxy
4-hydroxy
4-hydroxy
4-hydroxy
e
59.67 ꢁ 4.21
1.39 ꢁ 0.14
2.29 ꢁ 0.06
1.48 ꢁ 0.29
2.27 ꢁ 0.25
2.46 ꢁ 0.35
1.92 ꢁ 0.11
2.30 ꢁ 0.30
3.09 ꢁ 0.25
12.06 ꢁ 0.9
7.43 ꢁ 0.78
6.46 ꢁ 0.27
1.53 ꢁ 0.24
0.868 ꢁ 0.41
4.45 ꢁ 0.14
96 ꢁ 6
46.13 ꢁ 3.12
0.98 ꢁ 0.15
1.77 ꢁ 0.075
1.27 ꢁ 0.38
1.43 ꢁ 0.18
2.03 ꢁ 0.32
1.11 ꢁ 0.19
2.2 ꢁ 0.36
84.2 ꢁ 4.51
4.28 ꢁ 0.26
1.32 ꢁ 0.11
4.20 ꢁ 0.98
3.45 ꢁ 0.25
3.25 ꢁ 0.41
2.52 ꢁ 0.26
2.09 ꢁ 0.13
9.48 ꢁ 0.54
25 ꢁ 3
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
67/33
86/14
72/28
69/31
74/26
78/22
69/31
76/24
64/36
80/20
54/46
80/20
71/29
74/26
88/12
60/40
52/48
92/8
72/28
65/35
60/40
77/23
24/76
81/19
47/53
12/88
80/20
80/20
82/18
67/33
37/63
77/23
75/25
70/30
47/53
40/60
44/56
45/55
H
5-CH3
5-F
6-F
5-Cl
5-Br
6-F
5-F
6-F
5-CH3
6-F
5-Cl
6-F
6-F
H
H
5-CH3
6-F
5-F
H
5-CH3
5-F
6-F
5-Cl
5-F
6-F
4-methoxy
3,4-difluoro
3,4-difluoro
3,4-difluoro
2,4-difluoro
2,4-dimethoxy
2,4-dimethoxy
2,5-dimethoxy
2,5-dimethoxy
3,4-dioxymethylene
3,4-dioxymethylene
3,4-dioxymethylene
3,4,5-trimethoxy
3,4-dioxymethylene
3,4-dioxymethylene
3,4-dioxymethylene
3,4-dioxymethylene
3,4-dioxymethylene
3,4-difluoro
3,4-difluoro
2,4-difluoro
2,4-difluoro
2,4-difluoro
3,4,5-trimethoxy
3,4,5-trimethoxy
3,4,5-trimethoxy
3,4,5-trimethoxy
3,4,5-trimethoxy
4-hydroxy
44.7 ꢁ 5.03
6.4 ꢁ 0.53
59.67 ꢁ 4.51
3.20 ꢁ 0.11
10.6 ꢁ 1.61
20.53 ꢁ 3.16
7.15 ꢁ 0.41
63.7 ꢁ 5.51
0.82 ꢁ 0.095
4.03 ꢁ 0.10
2.81 ꢁ 0.12
1.70 ꢁ 0.26
1.02 ꢁ 0.20
1.86 ꢁ 0.22
0.075 ꢁ 0.025
1.91 ꢁ 0.54
1.00 ꢁ 0.10
1.30 ꢁ 0.26
1.12 ꢁ 0.15
5.47 ꢁ 0.76
2.33 ꢁ 0.42
6.10 ꢁ 0.36
1.67 ꢁ 0.34
2.67 ꢁ 0.50
0.78 ꢁ 0.11
1.41 ꢁ 0.29
2.99 ꢁ 0.36
0.26 ꢁ 0.13
NA
NA
8.44 ꢁ 0.29
3.83 ꢁ 0.76
4.83 ꢁ 0.98
14.53 ꢁ 0.41
21 ꢁ 5.57
3.23 ꢁ 0.35
8.10 ꢁ 0.16
2.42 ꢁ 0.14
1.90 ꢁ 0.61
1.12 ꢁ 0.18
3.1 ꢁ 0.26
0.77 ꢁ 0.21
4.13 ꢁ 0.61
3.13 ꢁ 0.61
1.22 ꢁ 0.33
2.9 ꢁ 1.39
NA
ND
ND
6.81 ꢁ 0.27
3.01 ꢁ 0.28
ND
ND
ND
ND
0.70 ꢁ 0.17
1.03 ꢁ 0.18
1.36 ꢁ 0.08
2.53 ꢁ 0.31
0.91 ꢁ 0.27
2.11 ꢁ 0.28
0.025 ꢁ 0.008
0.19 ꢁ 0.04
0.437 ꢁ 0.10
0.64 ꢁ 0.12
0.028 ꢁ 0.009
NA
2.74 ꢁ 0.27
1.77 ꢁ 0.20
5q
5r
5s
ND
ND
ND
ND
6.06 ꢁ 0.40
3.41 ꢁ 0.20
ND
1.95 ꢁ 0.23
4.02 ꢁ 0.18
3.12 ꢁ 0.27
3.07 ꢁ 0.51
5.33 ꢁ 0.42
ND
ND
ND
ND
ND
8.10 ꢁ 0.39
3.93 ꢁ 0.29
ND
6.98 ꢁ 0.26
8.30 ꢁ 0.32
3.32 ꢁ 0.15
4.30 ꢁ 0.35
4.45 ꢁ 0.30
ND
ND
ND
ND
ND
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
10s
H
6-F
5-Cl
H
5-CH3
5-F
1.52 ꢁ 0.17
2.10 ꢁ 0.12
NA
NA
1.97 ꢁ 0.31
NA
NA
NA
NA
2.39 ꢁ 0.26
NA
NA
NA
NA
2.21 ꢁ 0.18
2.02 ꢁ 0.13
6-F
ND
ND
5-Cl
5-CH3
H
5-CH3
5-Br
ND
ND
0.77 ꢁ 0.40
1.81 ꢁ 0.46
5.09 ꢁ 0.33
5.75 ꢁ 0.52
2-hydroxy
2-hydroxy
2-hydroxy
NA
NA
ND
ND
8.07 ꢁ 0.83
18.07 ꢁ 0.90
1.30 ꢁ 0.12
11.33 ꢁ 2.31
51.67 ꢁ 5.69
2.70 ꢁ 0.26
15.93 ꢁ 2.00
19.93 ꢁ 1.79
3.70 ꢁ 0.33
ND
ND
6.47 ꢁ 0.25
ND
ND
8.56 ꢁ 0.35
Sunitinibd
NA: Compound showing IC50 value >200 mM.
ND: not determined.
a
Ratio ¼ (2Z, 5Z):(2E, 5Z).
b
IC50: concentration of the compound (mM) producing 50% cell growth inhibition after 72 h of drug exposure, as determined by the MTT assay. Each experiment was run at
least three times, and the results are presented as average values ꢁ standard deviation.
c
HT-29, human colon cancer cell line; H460, non-small-cell lung cancer cell line; MDA-MB-231, human breast cancer cell line; SMMC-7721, human liver cancer cell line;
WI-38, human fetal lung fibroblasts.
d
Used as a positive control.
5.2. General procedure for the synthesis of 3-substituted-2-thioxo-
4-thiazolidinone (2, 7)
exothermic reactions resulted in the dithiocarbamates salt of
a white or slightly yellow crystalline solid. The precipitate was
separated, dried and immediately used, without any additional
purification, as starting material for the following reactions. The
appropriate dithiocarbamates salt was dissolved in water (200 ml)
and methanol (50 ml). A prepared solution of chloroacetic acid
(9.4 g, 0.1 mol) and K2CO3 (6.9 g, 0.05 mol) in water (40 ml) was
The corresponding primary amine (1 or 6) (0.1 mol) was dis-
solved in dry diethylether (200 ml). After addition of triethylamine
(10.2 g, 0.1 mol), a solution of CS2 (7.7 g, 0.1 mol) in diethylether
(50 ml) was added dropwise with stirring. After a short time, the

S. Wang et al. / European Journal of Medicinal Chemistry 46 (2011) 3509e3518
3513
added and stirring was continued at 25 ꢀC for 7e8 h. Then the
5.4.3. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(4-hydroxyben-
reaction mixture was acidified with dilute H2SO4 until pH 4.0 and
stirred at 35e40 ꢀC for 12 h. The cyclized product (2, 7) was
extracted with ethyl acetate, dried over anhydrous sodium sulfate
and evaporated under vacuum and the residue was purified by
recrystallization with ethanol to obtain intermediate (2, 7).
zylidene)-4-oxo-2-thiazolidinylidene)-5-fluoroindolin-2-one (5c)
Yield: 50%. ESI-MS: m/z, 426.4 [M þ H]þ. IR (KBr) cmꢂ1: 3427.9,
1671.6, 1580.3, 1511.6, 1478.7, 1386.0, 1334.7, 1290.1, 1208.3, 1172.7,
1153.1, 1136.6, 1013.4. 1H NMR (300 MHz, DMSO-d6)
d: 2.04 (s,
0.72 ꢃ 6H, 2 ꢃ CH3), 2.07 (s, 0.28 ꢃ 6H, 2 ꢃ CH3), 2.40e2.49 (m, 2H,
CH2), 4.34 (t, 0.72 ꢃ 2H, J ¼ 6.6 Hz, CH2), 4.87 (t, 0.28 ꢃ 2H,
J ¼ 6.9 Hz, CH2), 6.83e7.66 (m, 7H, arom), 7.69 (s, 0.72 ꢃ 1H, CH),
7.81 (s, 0.28 ꢃ 1H, CH), 10.36 (s, 1H, OH), 10.65 (s, 0.28 ꢃ 1H, NH),
10.87 (s, 0.72 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 72:28. 13C NMR
5.3. General procedure for the synthesis of 3-substituted-5-benzylid-
ene-2-thioxo-4-thiazolidinones (3ae3h, 8ae8f)
(75 MHz, DMSO-d6) d: 169.7, 168.3, 159.9, 151.6, 135.4, 133.2, 133.0,
A mixture of intermediate (2 or 7) (0.01 mol), appropriate
benzaldehyde (0.011 mol) and piperidine (0.01 mol) was refluxed
for 3e4 h in ethanol (10 ml) and cooled to room temperature to give
in a crystalline product. The solid was filtered under suction. The
crude products were then purified by recrystallization with ethanol
to obtain intermediate (3ae3h, 8ae8f).
132.4, 124.9, 121.6, 117.9, 116.7, 116.6, 110.5, 110.1, 100.9, 55.7, 45.3,
45.0. Anal. Calcd for C22H20FN3O3S (%):C, 62.10; H, 4.74; N, 9.88.
Found (%): C, 62.15; H, 4.78; N, 9.93.
5.4.4. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(4-hydroxybe-
nzylidene)-4-oxo-2-thiazolidinylidene)-6-fluoroindolin-2-one (5d)
Yield: 53%. ESI-MS: m/z, 426.4 [M þ H]þ. IR (KBr) cmꢂ1: 3145.0,
1687.5, 1660.9, 1629.0, 1582.5, 1525.4, 1512.8, 1464.3, 1435.7, 1360.1,
1320.4, 1282.1, 1206.3, 1168.3, 1131.0, 1098.7, 1015.5. 1H NMR (300 MHz,
5.4. General procedure for the synthesis of final compounds 5ae5s
and 10ae10s
DMSO-d6)
d
: 2.01 (s, 0.69 ꢃ 6H, 2 ꢃ CH3), 2.09 (s, 0.31 ꢃ 6H, 2 ꢃ CH3),
To
a
solution of 3-substituted-5-benzylidene-2-thioxo-4-
2.42e2.49 (m, 2H, CH2), 4.34 (t, 0.69 ꢃ 2H, J ¼ 6.6 Hz, CH2), 4.85 (t,
0.31 ꢃ2H, J ¼ 7.2 Hz, CH2), 6.72e7.78 (m, 8H, CH and arom),10.36 (s,1H,
OH), 10.80 (s, 0.31 ꢃ1H, NH), 11.01 (s, 0.69 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z)
thiazolidinone (3ae3h, 8ae8f) (0.003 mol) in 1,4-dioxane (15 ml)
was added HC(OEt)3 (2 ml) and BF3$Et2O (2 ml). The reaction mixture
was heated to 80 ꢀC and stirring was continued at the same temper-
ature for 4 h. The resulting 2-ethylthio-3-substituted-5-benzylidene-
4-thiazolium fluoroborate (4ae4h, 9ae9f) was precipitated, filtered
off, and dried without any additional purification, as starting material
for the following reactions. To a mixture of thiazolium fluoroborate
(4ae4h, 9ae9f) (0.003 mol) and indolin-2-one (11ae11f) (0.003 mol)
in acetonitrile (15 ml) was added triethylamine (0.91 g, 0.009 mol)
dropwise at 25 ꢀC, and the mixture was stirred for 4 h at the same
temperature. The orange precipitate was collected and washed with
ethyl acetate (8 ml). The crude product thus obtained was recrystal-
lized from methanol or acetone to give compound (5ae5s,10ae10s).
ratio (%) 69:31.13C NMR (75 MHz, DMSO-d6)
d: 169.9,168.4,159.7,149.5,
140.8,132.8,131.8,124.9,124.4,124.3,118.0,117.1,116.5,114.7,107.3,107.0,
100.5, 55.6, 45.3, 45.2. Anal. Calcd for C22H20FN3O3S (%):C, 62.10; H, 4.74;
N, 9.88. Found (%): C, 62.17; H, 4.80; N, 9.96.
5.4.5. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(4-hydroxybe-
nzylidene)-4-oxo-2-thiazolidinylidene)-5-chloroindolin-2-one (5e)
Yield: 55%. ESI-MS: m/z, 442.1 [M þ H]þ. IR (KBr) cmꢂ1: 3423.5,
3116.2, 2827.9, 1703.6, 1664.9, 1591.7, 1526.8, 1465.4, 1444.6, 1384.2,
1344.3, 1315.3, 1284.7, 1251.7, 1206.0, 1167.0, 1138.7, 1099.8, 1030.4.
1H NMR (300 MHz, DMSO-d6)
d
: 2.07 (s, 6H, 2 ꢃ CH3), 2.39e2.49
(m, 2H, CH2), 4.31 (t, 0.74 ꢃ 2H, J ¼ 6.9 Hz, CH2), 4.84 (t, 0.26 ꢃ 2H,
J ¼ 6.9 Hz, CH2), 6.90e7.66 (m, 7H, arom), 7.68 (s, 0.74 ꢃ 1H, CH),
7.82 (s, 0.26 ꢃ 1H, CH), 10.38 (s, 1H, OH), 10.78 (s, 0.26 ꢃ 1H, NH),
10.98 (s, 0.74 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 74:26. 13C NMR
5.4.1. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(4-hydroxyben-
zylidene)-4-oxo-2-thiazolidinylidene)indolin-2-one (5a)
Yield: 55%. ESI-MS: m/z, 408.1 [M þ H]þ. IR (KBr) cmꢂ1: 3444.3,
1696.2, 1671.2, 1612.9, 1582.8, 1514.1, 1464.2, 1364.7, 1348.3, 1315.2,
(75 MHz, DMSO-d6) d: 169.3, 168.2, 159.9, 151.8, 137.7, 132.9, 132.5,
1290.6,1229.7,1208.7,1173.7,1137.9.1H NMR (300 MHz, DMSO-d6)
d:
126.0, 125.1, 124.8, 122.4, 122.1, 117.7, 116.5, 110.8, 100.0, 55.7, 45.3,
45.0. Anal. Calcd for C22H20ClN3O3S (%):C, 59.79; H, 4.56; N, 9.51.
Found (%): C, 59.83; H, 4.70; N, 9.56.
1.98 (s, 0.67 ꢃ 6H, 2 ꢃ CH3), 2.07 (s, 0.33 ꢃ 6H, 2 ꢃ CH3), 2.41e2.49
(m, 2H, CH2), 4.36 (t, 0.67 ꢃ 2H, J ¼ 6.6 Hz, CH2), 4.87 (t, 0.33 ꢃ 2H,
J ¼ 6.6 Hz, CH2), 6.98e7.76 (m, 9H, CH and arom), 10.36 (s, 1H, OH),
10.65 (s, 0.33 ꢃ 1H, NH), 10.85 (s, 0.67 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z)
5.4.6. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(4-hydroxybe-
nzylidene)-4-oxo-2-thiazolidinylidene)-5-bromoindolin-2-one (5f)
Yield: 57%. ESI-MS: m/z, 486.0 [M þ H]þ. IR (KBr) cmꢂ1: 3416.5,
3114.8, 2825.8, 1701.7, 1663.4, 1591.1, 1518.7, 1465.0, 1444.3, 1384.2,
1343.4, 1314.4, 1283.6, 1247.3, 1204.9, 1165.8, 1137.2, 1099.1, 1027.4.
ratio (%) 67:33. 13C NMR (75 MHz, DMSO-d6)
d: 169.6, 168.6, 159.8,
149.6,139.3,132.8,131.7,126.8,125.0,123.2,121.0,120.6,118.2,116.5,
109.8, 101.5, 55.7, 45.4, 45.3. Anal. Calcd for C22H21N3O3S (%): C,
64.85; H, 5.19; N, 10.31. Found (%): C, 65.89; H, 5.21; N, 10.35.
1H NMR (300 MHz, DMSO-d6)
d
: 2.08 (s, 6H, 2 ꢃ CH3), 2.40e2.49
5.4.2. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(4-hydroxybenz-
ylidene)-4-oxo-2-thiazolidinylidene)-5-methylindolin-2-one (5b)
Yield: 52%. ESI-MS: m/z, 422.2 [M þ H]þ. IR (KBr) cmꢂ1: 3330.5,
2947.2, 2826.7, 1682.6, 1644.2, 1584.8, 1516.1, 1484.1, 1448.5, 1384.9,
1357.4, 1329.8, 1315.3, 1286.1, 1252.2, 1208.6, 1171.8, 1150.3, 1130.8,
(m, 2H, CH2), 4.30 (t, 0.78 ꢃ 2H, J ¼ 6.6 Hz, CH2), 4.83 (t, 0.22 ꢃ 2H,
J ¼ 7.2 Hz, CH2), 6.86e7.82 (m, 8H, CH and arom), 10.38 (s, 1H, OH),
10.79 (s, 0.22 ꢃ 1H, NH), 10.99 (s, 0.78 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z)
ratio (%) 78:22. 13C NMR (75 MHz, DMSO-d6)
d: 169.3, 168.3, 160.0,
151.9, 138.1, 133.0, 132.6, 129.0, 125.1, 124.9, 122.7, 117.8, 116.6, 112.9,
111.4, 100.0, 55.8, 45.4, 45.2. Anal. Calcd for C22H20BrN3O3S (%):C,
54.33; H, 4.14; N, 8.64. Found (%): C, 54.40; H, 4.20; N, 8.70.
1100.2, 1044.1. 1H NMR (300 MHz, DMSO-d6)
d
: 2.04 (s, 0.86 ꢃ 6H,
2 ꢃ CH3), 2.17 (s, 0.14 ꢃ 6H, 2 ꢃ CH3), 2.32 (s, 0.86 ꢃ 3H, CH3), 2.40
(s, 0.14 ꢃ 3H, CH3), 2.42e2.48 (m, 2H, CH2), 4.37 (t, 0.86 ꢃ 2H,
J ¼ 6.6 Hz, CH2), 4.86 (t, 0.14 ꢃ 2H, J ¼ 6.9 Hz, CH2), 6.82e7.78 (m,
8H, CH and arom), 10.35 (s, 1H, OH), 10.55 (s, 0.14 ꢃ 1H, NH), 10.75
(s, 0.86 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 86:14. 13C NMR
5.4.7. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(4-methoxybe-
nzylidene)-4-oxo-2-thiazolidinylidene)-6-fluoroindolin-2-one (5g)
Yield: 62%. ESI-MS: m/z, 440.1 [M þ H]þ. IR (KBr) cmꢂ1: 3426.9,
3127.4, 2978.4, 2825.2, 2775.0, 1705.0, 1675.7, 1623.6, 1593.8, 1566.9,
1524.1, 1510.1, 1464.3, 1419.1, 1393.7, 1363.2, 1320.2, 1259.9, 1232.0,
1211.1,1163.6,1135.5,1099.4,1060.1,1033.3.1HNMR(600MHz,DMSO-
(75 MHz, DMSO-d6) d: 169.7, 168.6, 159.7, 149.2, 137.1, 132.8, 131.5,
129.8, 127.3, 125.0, 123.7, 120.7, 118.4, 116.5, 109.5, 101.6, 55.8, 45.3,
45.0, 21.1. Anal. Calcd for C23H23N3O3S (%):C, 65.54; H, 5.50; N, 9.97.
Found (%): C, 65.60; H, 5.52; N, 10.01.
d6)
d: 2.02 (s, 0.69 ꢃ 6H, 2 ꢃ CH3), 2.12 (s, 0.31 ꢃ 6H, 2 ꢃ CH3), 2.43 (t,

3514
S. Wang et al. / European Journal of Medicinal Chemistry 46 (2011) 3509e3518
0.69 ꢃ 2H, J ¼ 6.6 Hz, CH2), 2.48 (t, 0.31 ꢃ 2H, J ¼ 6.0 Hz, CH2), 3.85 (s,
0.69 ꢃ 3H, CH3), 3.86 (s, 0.31 ꢃ 3H, CH3), 4.35 (t, 0.69 ꢃ 2H, J ¼ 6.6 Hz,
CH2), 4.85 (t, 0.31 ꢃ 2H, J ¼ 6.0 Hz, CH2), 6.70 (dd, 0.31 ꢃ 1H, J ¼ 9.0,
2.4 Hz, arom), 6.72 (dd, 0.69 ꢃ1H, J ¼ 9.0, 2.4 Hz, arom), 6.79e6.82 (m,
0.69 ꢃ 1H, arom), 6.85e6.88 (m, 0.31 ꢃ 1H, arom), 7.15e7.17 (m, 2H,
arom), 7.51 (dd, 0.69 ꢃ 1H, J ¼ 8.4, 6.4 Hz, arom), 7.66 (d, 0.69 ꢃ 2H,
J¼ 12.0Hz, arom), 7.70(s,0.69ꢃ1H, CH), 7.73 (d, 0.31 ꢃ2H, J¼ 12.0 Hz,
arom), 7.78 (dd, 0.31 ꢃ1H, J ¼ 9.0, 5.4Hz, arom), 7.82(s, 0.31 ꢃ1H, CH),
10.79 (s, 0.31 ꢃ1H, NH),11.00 (s, 0.69 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio
0.46 ꢃ 6H, 2 ꢃ CH3), 2.41e2.48 (m, 2H, CH2), 4.34 (t, 0.54 ꢃ 2H,
J ¼ 6.0 Hz, CH2), 4.83 (t, 0.46 ꢃ 2H, J ¼ 6.0 Hz, CH2), 6.69e6.88 (m,
2H, arom), 7.34e7.88 (m, 5H, CH and arom), 10.86 (s, 0.46 ꢃ 1H,
NH), 11.07 (s, 0.54 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 54:46. Anal.
Calcd for C22H18F3N3O2S (%):C, 59.32; H, 4.07; N, 9.43. Found (%): C,
59.36; H, 4.11; N, 9.32.
5.4.12. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(2,4-dimethoxy-
benzylidene)-4-oxo-2-thiazolidinylidene)-5-chloroindolin-2-one (5l)
Yield: 52%. ESI-MS: m/z, 486.1 [M þ H]þ. IR (KBr) cmꢂ1: 3428.8,
2938.4, 2830.2, 1702.1, 1670.5, 1615.1, 1585.0, 1523.3, 1492.8, 1465.7,
1418.7, 1385.7, 1360.5, 1317.1, 1298.6, 1263.5, 1222.9, 1178.2, 1154.3,
(%) 69:31. 13C NMR (75 MHz, DMSO-d6)
d: 169.9, 168.4, 160.9, 149.3,
140.9, 132.5, 131.3, 126.5, 124.7, 124.6, 119.4, 117.2, 116.0, 115.1, 107.5,
107.2, 100.8, 55.7, 55.6, 45.2, 44.8. Anal. Calcd for C23H22FN3O3S (%):C,
62.85; H, 5.05; N, 9.56. Found (%): C, 62.90; H, 5.02; N, 9.46.
1137.9, 1044.0. 1H NMR (300 MHz, DMSO-d6)
d
: 2.01 (s, 0.80 ꢃ 6H,
2 ꢃ CH3), 2.08 (s, 0.20 ꢃ 6H, 2 ꢃ CH3), 2.43 (t, 2H, J ¼ 6.3 Hz, CH2),
3.80 (s, 0.80 ꢃ 3H, CH3), 3.81 (s, 0.20 ꢃ 3H, CH3), 3.87 (s, 0.80 ꢃ 3H,
CH3), 3.89 (s, 0.20 ꢃ 3H, CH3), 4.38 (t, 0.80 ꢃ 2H, J ¼ 6.3 Hz, CH2),
4.87 (t, 0.20 ꢃ 2H, J ¼ 6.3 Hz, CH2), 6.88e7.22 (m, 5H, arom), 7.51 (d,
0.80 ꢃ 1H, J ¼ 6.0 Hz, arom), 7.68 (d, 0.20 ꢃ 1H, J ¼ 6.0 Hz, arom),
7.91 (s, 0.80 ꢃ 1H, CH), 7.98 (s, 0.20 ꢃ 1H, CH), 10.66 (s, 0.20 ꢃ 1H,
NH), 10.84 (s, 0.80 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 80:20. 13C
5.4.8. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(3,4-difluorob-
enzylidene)-4-oxo-2-thiazolidinylidene)-5-fluoroindolin-2-one (5h)
Yield: 53%. ESI-MS: m/z, 446.4 [M þ H]þ. IR (KBr) cmꢂ1: 3442.7,
3157.6, 3046.9, 2868.5, 2831.2,1670.9,1592.3,1518.9,1478.5,1459.0,
1371.5, 1324.1, 1300.2, 1211.8, 1192.2, 1168.3, 1137.7, 1116.2, 1030.5,
1016.0. 1H NMR (300 MHz, DMSO-d6)
d
: 2.05 (s, 0.76 ꢃ 6H, 2 ꢃ CH3),
2.08 (s, 0.24 ꢃ 6H, 2 ꢃ CH3), 2.39e2.49 (m, 2H, CH2), 4.33 (t,
0.76 ꢃ 2H, J ¼ 6.3 Hz, CH2), 4.86 (t, 0.24 ꢃ 2H, J ¼ 5.7 Hz, CH2),
6.83e6.91 (m, 1H, arom), 7.01e7.07 (m, 1H, arom), 7.42e7.94 (m,
5H, CH and arom), 10.71 (s, 0.24 ꢃ 1H, NH), 10.92 (s, 0.76 ꢃ 1H, NH).
NMR (75 MHz, DMSO-d6) d: 169.6, 168.3, 153.2, 152.6, 149.0, 139.5,
127.1, 125.0, 123.4, 123.1, 122.9, 121.1, 120.5, 116.5, 114.7, 113.0, 109.9,
102.1, 56.4, 55.7, 55.6, 45.3, 44.9. Anal. Calcd for C24H24ClN3O4S
(%):C, 59.31; H, 4.98; N, 8.65. Found (%): C, 59.35; H, 4.52; N, 8.55.
(2Z, 5Z)/(2E, 5Z) ratio (%) 76:24. 13C NMR (75 MHz, DMSO-d6)
d:
169.7, 167.8, 158.4, 156.9, 150.1, 135.8, 129.2, 123.8, 121.2, 121.1, 119.6,
119.5, 118.9, 118.7, 113.5, 113.3, 110.7, 110.5, 110.4, 110.3, 102.0, 55.5,
45.2, 45.1. Anal. Calcd for C22H18F3N3O2S (%):C, 59.32; H, 4.07; N,
9.43. Found (%): C, 59.38; H, 4.03; N, 9.40.
5.4.13. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(2,4-dimethoxy-
benzylidene)-4-oxo-2-thiazolidinylidene)-6-fluoroindolin-2-one (5m)
Yield: 50%. ESI-MS: m/z, 470.2 [M þ H]þ. IR (KBr) cmꢂ1: 3430.3,
2944.4, 2832.3, 1701.3, 1676.3, 1610.9, 1586.2, 1531.1, 1493.8, 1466.6,
1430.5,1384.6,1370.9,1330.8,1284.8,1264.6,1224.9,1203.4,1169.0,
5.4.9. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(3,4-difluorob-
enzylidene)-4-oxo-2-thiazolidinylidene)-6-fluoroindolin-2-one (5i)
Yield: 50%. ESI-MS: m/z, 446.4 [M þ H]þ. IR (KBr) cmꢂ1: 3443.8,
3132.4, 2829.7, 2778.1, 1697.4, 1677.8, 1627.9, 1603.2, 1516.5, 1457.4,
1327.3, 1299.7, 1281.3, 1207.6, 1168.5, 1135.4, 1112.1, 1057.9. 1H NMR
1143.0, 1043.9, 1009.5. 1H NMR (300 MHz, DMSO-d6)
d: 2.09 (s,
0.71 ꢃ 6H, 2 ꢃ CH3), 2.13 (s, 0.29 ꢃ 6H, 2 ꢃ CH3), 2.43e2.49 (m, 2H,
CH2), 3.80 (s, 0.71 ꢃ 3H, CH3), 3.85 (s, 0.29 ꢃ 3H, CH3), 3.86 (s,
0.71 ꢃ 3H, CH3), 3.91 (s, 0.29 ꢃ 3H, CH3), 4.30 (t, 0.71 ꢃ 2H,
J ¼ 6.6 Hz, CH2), 4.86 (t, 0.29 ꢃ 2H, J ¼ 6.9 Hz, CH2), 6.83e7.36 (m,
5H, arom), 7.73 (s, 0.71 ꢃ 1H, arom), 7.80 (s, 0.29 ꢃ 1H, arom), 7.92
(s, 0.71 ꢃ 1H, CH), 7.98 (s, 0.29 ꢃ 1H, CH), 10.80 (s, 0.29 ꢃ 1H, NH),
10.98 (s, 0.71 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 71:29. 13C NMR
(300 MHz, DMSO-d6)
d
: 2.01 (s, 0.64 ꢃ 6H, 2 ꢃ CH3), 2.07 (s,
0.36 ꢃ 6H, 2 ꢃ CH3), 2.39e2.49 (m, 2H, CH2), 4.35 (t, 0.64 ꢃ 2H,
J ¼ 6.0 Hz, CH2), 4.84 (t, 0.36 ꢃ 2H, J ¼ 6.0 Hz, CH2), 6.69e6.87 (m,
2H, arom), 7.55e7.86 (m, 5H, CH and arom), 10.85 (s, 0.36 ꢃ 1H,
NH), 11.07 (s, 0.64 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 64:36. Anal.
Calcd for C22H18F3N3O2S (%):C, 59.32; H, 4.07; N, 9.43. Found (%): C,
59.40; H, 4.10; N, 9.36.
(75 MHz, DMSO-d6) d: 169.3, 168.1, 153.2, 152.7, 151.2, 138.4, 129.3,
125.9, 125.3, 122.9, 122.5, 122.4, 116.8, 114.7, 113.8, 113.5, 113.1, 111.5,
100.6, 56.4, 55.8, 55.7, 45.2, 44.6. Anal. Calcd for C24H24FN3O4S
(%):C, 61.39; H, 5.15; N, 8.95. Found (%): C, 61.35; H, 5.02; N, 8.82.
5.4.10. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(3,4-difluorob-
enzylidene)-4-oxo-2-thiazolidinylidene)-5-methylindolin-2-one (5j)
Yield: 52%. ESI-MS: m/z, 442.5 [M þ H]þ. IR (KBr) cmꢂ1: 3421.1,
2920.9, 2823.9,1700.0, 1675.1,1605.9, 1535.4,1518.4, 1484.5, 1432.0,
1384.7, 1329.5, 1300.8, 1279.3, 1251.7, 1208.7, 1168.4, 1146.8, 1040.4.
5.4.14. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(2,5-dimethoxy-
benzylidene)-4-oxo-2-thiazolidinylidene)-6-fluoroindolin-2-one (5n)
Yield: 46%. ESI-MS: m/z, 470.2 [M þ H]þ. IR (KBr) cmꢂ1: 3421.1,
3124.4, 2960.6, 2831.3, 2773.5, 1699.3, 1673.9, 1626.2, 1599.1, 1524.1,
1495.5, 1462.2, 1385.7, 1359.8, 1322.2, 1294.0, 1265.4, 1225.0, 1176.1,
1H NMR (300 MHz, DMSO-d6)
d
: 2.05 (s, 0.80 ꢃ 6H, 2 ꢃ CH3), 2.08 (s,
1139.4, 1097.8, 1045.0, 1025.3. 1H NMR (300 MHz, DMSO-d6)
d: 2.00
0.20 ꢃ 6H, 2 ꢃ CH3), 2.32 (s, 0.80 ꢃ 3H, CH3), 2.38 (s, 0.20 ꢃ 3H,
CH3), 2.45e2.49 (m, 2H, CH2), 4.36 (t, 0.80 ꢃ 2H, J ¼ 6.3 Hz, CH2),
4.86 (t, 0.20 ꢃ 2H, J ¼ 6.0 Hz, CH2), 6.74e6.82 (m, 1H, arom),
6.98e7.02 (m, 1H, arom), 7.52e7.90 (m, 5H, CH and arom), 10.58 (s,
0.20 ꢃ 1H, NH), 10.79 (s, 0.80 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%)
(s, 0.74 ꢃ 6H, 2 ꢃ CH3), 2.09 (s, 0.26 ꢃ 6H, 2 ꢃ CH3), 2.34e2.49 (m,
2H, CH2), 3.79 (s, 3H, CH3), 3.85 (s, 3H, CH3), 4.33 (t, 0.74 ꢃ 2H,
J ¼ 6.3 Hz, CH2), 4.83 (t, 0.26 ꢃ 2H, J ¼ 6.6 Hz, CH2), 6.74e7.66 (m,
6H, arom), 7.90 (s, 0.74 ꢃ 1H, CH), 7.96 (s, 0.26 ꢃ 1H, CH), 10.82 (s,
0.26 ꢃ 1H, NH), 11.00 (s, 0.74 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%)
80:20. 13C NMR (75 MHz, DMSO-d6)
d
: 169.7, 168.1, 147.8, 137.4,
74:26. 13C NMR (75 MHz, DMSO-d6)
d: 169.9, 168.2, 153.3, 153.2,
130.0, 128.4, 127.9, 127.2, 124.2, 124.1, 120.4, 119.5, 119.4, 118.9, 118.7,
109.7, 102.8, 55.6, 45.2, 45.0, 21.0. Anal. Calcd for C23H21F2N3O2S
(%):C, 62.57; H, 4.79; N, 9.52. Found (%): C, 62.51; H, 4.83; N, 9.56.
152.6, 148.9, 125.2, 124.8, 123.0, 122.7, 122.4, 117.1, 116.6, 114.7, 113.1,
107.5, 107.2, 101.2, 56.4, 55.8, 55.6, 45.2, 44.8. Anal. Calcd for
C24H24FN3O4S (%):C, 61.39; H, 5.15; N, 8.95. Found (%): C, 61.34; H,
5.08; N, 8.89.
5.4.11. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(2,4-difluorob-
enzylidene)-4-oxo-2-thiazolidinylidene)-6-fluoroindolin-2-one (5k)
Yield: 56%. ESI-MS: m/z, 446.1 [M þ H]þ. IR (KBr) cmꢂ1: 3134.7,
2824.6, 2775.7, 1708.3, 1682.1, 1606.1, 1537.3, 1498.7, 1459.8, 1433.2,
1340.1, 1313.5, 1276.1, 1189.6, 1137.6, 1105.1, 1083.0, 1001.9. 1H NMR
5.4.15. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(2,5-dimethoxy-
benzylidene)-4-oxo-2-thiazolidinylidene)indolin-2-one (5o)
Yield: 44%. ESI-MS: m/z, 452.2 [M þ H]þ. IR (KBr) cmꢂ1: 3427.8,
2940.8, 2831.0, 1677.6, 1614.7, 1584.8, 1526.9, 1493.0, 1465.2, 1386.0,
1361.2, 1317.8, 1295.9, 1265.4, 1223.8, 1179.7, 1154.9, 1139.5, 1098.9,
(300 MHz, DMSO-d6)
d: 2.02 (s, 0.54 ꢃ 6H, 2 ꢃ CH3), 2.08 (s,

S. Wang et al. / European Journal of Medicinal Chemistry 46 (2011) 3509e3518
3515
1044.3. 1H NMR (300 MHz, DMSO-d6)
d
: 2.07 (s, 6H, 2 ꢃ CH3),
1431.9, 1321.5, 1243.0, 1214.0, 1188.4, 1134.2, 1015.9. 1H NMR
(300 MHz, DMSO-d6)
: 2.06 (s, 0.72 ꢃ 6H, 2 ꢃ CH3), 2.10 (s,
2.34e2.49 (m, 2H, CH2), 3.80 (s, 0.88 ꢃ 3H, CH3), 3.81 (s, 0.12 ꢃ 3H,
CH3), 3.87 (s, 0.88 ꢃ 3H, CH3), 3.89 (s, 0.12 ꢃ 3H, CH3), 4.40 (t,
0.88 ꢃ 2H, J ¼ 6.0 Hz, CH2), 4.87 (t, 0.12 ꢃ 2H, J ¼ 6.0 Hz, CH2),
6.88e7.72 (m, 7H, arom), 7.91 (s, 0.88 ꢃ 1H, CH), 7.98 (s, 0.12 ꢃ 1H,
CH), 10.70 (s, 0.12 ꢃ 1H, NH), 10.85 (s, 0.88 ꢃ 1H, NH). (2Z, 5Z)/(2E,
d
0.28 ꢃ 6H, 2 ꢃ CH3), 2.41e2.49 (m, 2H, CH2), 3.76 (s, 6H, CH3), 3.87
(s, 0.72 ꢃ 3H, CH3), 3.90 (s, 0.28 ꢃ 3H, CH3), 4.33 (t, 0.72 ꢃ 2H,
J ¼ 6.0 Hz, CH2), 4.88 (t, 0.28 ꢃ 2H, J ¼ 6.0 Hz, CH2), 6.83e7.03 (m,
2H, arom), 7.05 (s, 0.72 ꢃ 2H, arom), 7.07 (s, 0.28 ꢃ 2H, arom), 7.41
(d, 0.72 ꢃ 1H, J ¼ 10.5 Hz, arom), 7.50 (d, 0.28 ꢃ 1H, J ¼ 9.9 Hz,
arom), 7.69 (s, 0.72 ꢃ 1H, CH), 7.83 (s, 0.28 ꢃ 1H, CH), 10.68 (s,
0.28 ꢃ 1H, NH), 10.79 (s, 0.72 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%)
5Z) ratio (%) 88:12. 13C NMR (75 MHz, DMSO-d6)
d: 169.6, 168.3,
153.2,152.6,149.0,139.5,127.1,125.0,123.4,123.1,122.9,121.1,120.5,
116.5, 114.7, 113.0, 109.9, 102.1, 56.4, 55.8, 55.7, 45.4, 45.3. Anal.
Calcd for C24H25N3O4S (%):C, 63.84; H, 5.58; N, 9.31. Found (%): C,
63.74; H, 5.50; N, 9.35.
72:28. 13C NMR (75 MHz, DMSO-d6)
d: 169.7, 168.0, 153.5, 153.4,
139.9, 139.6, 136.0, 135.7, 133.1, 132.1, 129.4, 128.8, 121.6, 118.0, 110.6,
110.4, 108.4, 108.1, 60.5, 56.3, 56.2, 55.5, 44.9, 44.2. Anal. Calcd for
C25H26FN3O5S (%):C, 60.11; H, 5.25; N, 8.41. Found (%): C, 60.16; H,
5.32; N, 8.49.
5.4.16. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-((benzo[d]
[1,3]dioxol-5-yl)methylene)-4-oxo-2-thiazolidinylidene)indolin-2-
one (5p)
Yield: 70%. ESI-MS: m/z, 436.1 [M þ H]þ. IR (KBr) cmꢂ1: 3428.8,
3147.5, 3027.1, 2893.2, 2824.6, 1714.8, 1676.4, 1618.2, 1585.8, 1526.5,
1501.3, 1487.8, 1467.6, 1447.4, 1370.0, 1340.8, 1313.2, 1287.0, 1263.8,
5.4.20. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-((benzo[d]
[1,3]dioxol-5-yl)methylene)-4-oxo-2-thiazolidinylidene) indolin-2-
one (10a)
1209.0,1148.8,1103.5,1039.1.1H NMR (300 MHz, DMSO-d6)
d: 2.02 (s,
Yield: 65%. ESI-MS: m/z, 478.2 [M þ H]þ. IR (KBr) cmꢂ1: 3430.1,
2966.4, 1688.5, 1615.4, 1586.1, 1527.0, 1501.2, 1488.0, 1466.9, 1447.0,
1383.2, 1340.5, 1317.1, 1262.9, 1196.2, 1148.9, 1102.5, 1036.6. 1H NMR
0.60 ꢃ 6H, 2 ꢃ CH3), 2.10 (s, 0.40 ꢃ 6H, 2 ꢃ CH3), 2.41e2.49 (m, 2H,
CH2), 4.37 (t, 0.60 ꢃ 2H, J ¼ 6.0 Hz, CH2), 4.87 (t, 0.40 ꢃ 2H, J ¼ 6.0 Hz,
CH2), 6.15 (s, 2H, CH2), 6.88e7.79 (m, 8H, CH and arom), 10.66 (s,
0.40 ꢃ 1H, NH), 10.87 (s, 0.60 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%)
(300 MHz, DMSO-d6)
d
: 0.75 (t, 0.65 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3), 0.85
(t, 0.35 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3), 1.67e1.78 (m, 2H, CH2), 2.19e2.42
(m, 6H, 3 ꢃ CH2), 4.32 (t, 0.65 ꢃ 2H, J ¼ 7.2 Hz, CH2), 4.66 (t,
0.35 ꢃ 2H, J ¼ 6.9 Hz, CH2), 6.15 (s, 0.65 ꢃ 2H, CH2), 6.16 (s,
0.35 ꢃ 2H, CH2), 6.86e7.35 (m, 6H, arom), 7.47 (d, 0.65 ꢃ 1H,
J ¼ 7.2 Hz, arom), 7.68 (s, 0.65 ꢃ1H, CH), 7.78 (s, 0.35 ꢃ 1H, CH), 7.80
(d, 0.35 ꢃ 1H, J ¼ 6.6 Hz, arom),10.63 (s, 0.35 ꢃ 1H, NH), 10.84 (s,
0.65 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 65:35. 13C NMR (75 MHz,
60:40.13C NMR (75 MHz, DMSO-d6)
d: 169.6,168.3,149.1,148.3,139.4,
131.2, 128.2, 127.0, 126.5, 126.2, 123.3, 121.0, 120.5, 120.2, 109.9, 109.6,
109.3, 102.2, 101.8, 55.7, 45.3, 44.8. Anal. Calcd for C23H21N3O4S (%): C,
63.43; H, 4.86; N, 9.65. Found (%): C, 63.54; H, 4.92; N, 9.70.
5.4.17. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-((benzo[d]
[1,3]dioxol-5-yl)methylene)-4-oxo-2-thiazolidinylidene)-5-
methylindolin-2-one (5q)
DMSO-d6) d: 169.6, 168.1, 149.0, 148.6, 148.2, 139.3, 131.0, 128.2,
126.8, 126.1, 123.2, 120.8, 120.6, 120.2, 109.7, 109.5, 109.3, 102.1,
101.9, 49.2, 46.1, 45.9, 24.6, 11.2. Anal. Calcd for C26H27N3O4S (%):C,
65.39; H, 5.70; N, 8.80. Found (%): C, 65.26; H, 5.56; N, 8.72.
Yield: 74%. ESI-MS: m/z, 450.2 [M þ H]þ. IR (KBr) cmꢂ1: 3420.1,
2920.7, 2823.2,1689.9,1672.9,1620.0, 1586.8,1527.3,1502.5,1487.4,
1447.6, 1385.9, 1357.4, 1312.2, 1261.7, 1211.7, 1154.1, 1125.2, 1104.0,
1037.4. 1H NMR (300 MHz, DMSO-d6)
d: 2.05 (s, 0.52 ꢃ 6H, 2 ꢃ CH3),
5.4.21. (2(Z/E),5Z)-3-(3-(3-(diethylamino)propyl)-5-((benzo[d]
[1,3]dioxol-5-yl)methylene)-4-oxo-2-thiazolidinylidene)-5-
methylindolin-2-one (10b)
2.06 (s, 0.48 ꢃ 6H, 2 ꢃ CH3), 2.32 (s, 0.52 ꢃ 3H, CH3), 2.38 (s,
0.48 ꢃ 3H, CH3), 2.41e2.46 (m, 2H, CH2), 4.36 (t, 0.52 ꢃ 2H,
J ¼ 6.0 Hz, CH2), 4.86 (t, 0.48 ꢃ 2H, J ¼ 6.0 Hz, CH2), 6.15 (s,
0.52 ꢃ 2H, CH2), 6.16 (s, 0.48 ꢃ 2H, CH2), 6.76e7.55 (m, 6H, arom),
7.74 (s, 0.52 ꢃ 1H, CH), 7.78 (s, 0.48 ꢃ 1H, CH), 10.54 (s, 0.48 ꢃ 1H,
NH), 10.74 (s, 0.52 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 52:48. Anal.
Calcd for C24H23N3O4S (%):C, 64.13; H, 5.16; N, 9.35. Found (%): C,
64.19; H, 5.20; N, 9.29.
Yield: 63%. ESI-MS: m/z, 492.3[M þ H]þ. IR (KBr) cmꢂ1: 3422.5,
3152.5, 3029.6, 2966.9, 1697.7, 1674.1, 1620.9, 1587.0, 1521.6, 1500.3,
1485.4, 1447.3, 1430.7, 1363.8, 1333.7, 1313.6, 1248.5, 1205.9, 1153.4,
1092.4, 1037.1. 1H NMR (300 MHz, DMSO-d6)
d: 0.77 (t, 0.60 ꢃ 6H,
J ¼ 7.2 Hz, 2 ꢃ CH3), 0.85 (t, 0.40 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3),
1.68e1.77 (m, 2H, CH2), 2.22e2.42 (m, 9H, 3 ꢃ CH2 and CH3), 4.32 (t,
0.60 ꢃ 2H, J ¼ 7.2 Hz, CH2), 4.65 (t, 0.40 ꢃ 2H, J ¼ 7.2 Hz, CH2), 6.15
(s, 0.60 ꢃ 2H, CH2), 6.16 (s, 0.40 ꢃ 2H, CH2), 6.75e7.55 (m, 6H,
arom), 7.67 (s, 0.60 ꢃ 1H, CH), 7.77 (s, 0.40 ꢃ 1H, CH), 10.51 (s,
0.40 ꢃ 1H, NH), 10.73 (s, 0.60 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%)
5.4.18. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-((benzo[d]
[1,3]dioxol-5-yl)methylene)-4-oxo-2-thiazolidinylidene)-6-
fluoroindolin-2-one (5r)
Yield: 68%. ESI-MS: m/z, 454.5 [M þ H]þ. IR (KBr) cmꢂ1: 3422.2,
3131.3, 2973.3, 2826.0, 2773.5, 1694.2, 1625.5, 1600.7, 1526.4,
1502.2, 1448.7, 1384.8, 1359.8, 1319.3, 1288.5, 1262.1, 1213.6, 1165.6,
60:40. 13C NMR (75 MHz, DMSO-d6)
d: 169.7, 168.1, 148.9, 148.2,
148.1, 137.1, 130.8, 129.4, 128.2, 127.3, 126.1, 123.6, 120.7, 120.3, 109.5,
109.4, 109.2, 102.0, 49.3, 46.0, 45.4, 24.8, 21.1, 11.4.
Anal. Calcd for C27H29N3O4S (%):C, 65.97; H, 5.95; N, 8.55. Found
(%): C, 65.86; H, 5.83; N, 8.47.
1141.2, 1126.9, 1101.2, 1038.0. 1H NMR (300 MHz, DMSO-d6)
d: 2.02
(s, 6H, 2 ꢃ CH3), 2.39e2.48 (m, 2H, CH2), 4.35 (t, 0.92 ꢃ 2H,
J ¼ 6.0 Hz, CH2), 4.84 (t, 0.08 ꢃ 2H, J ¼ 6.0 Hz, CH2), 6.16 (s, 2H, CH2),
6.72e7.56 (m, 6H, arom), 7.68 (s, 0.92 ꢃ 1H, CH), 7.79 (s, 0.08 ꢃ 1H,
CH), 10.81 (s, 0.08 ꢃ 1H, NH), 11.03 (s, 0.92 ꢃ 1H, NH). (2Z, 5Z)/(2E,
5.4.22. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-((benzo[d]
[1,3]dioxol-5-yl)methylene)-4-oxo-2-thiazolidinylidene)-5-
fluoroindolin-2-one (10c)
5Z) ratio (%) 92:8. 13C NMR (75 MHz, DMSO-d6)
d: 169.9, 168.3,
149.6, 149.1, 148.3, 141.0, 131.4, 128.2, 126.3, 124.7, 120.0, 117.1, 116.6,
109.7,109.4,107.5,107.2,102.2,100.9, 55.6, 45.2, 44.9. Anal. Calcd for
C23H20FN3O4S (%): C, 60.92; H, 4.45; N, 9.27. Found (%): C, 61.02; H,
4.39; N, 9.32.
Yield: 56%. ESI-MS: m/z, 496.5 [M þ H]þ. IR (KBr) cmꢂ1: 3421.2,
3179.4, 2967.6, 1679.8, 1586.1, 1525.2, 1503.6, 1476.9, 1448.4, 1382.4,
1361.5, 1312.1, 1261.3, 1188.6, 1156.7, 1121.5, 1102.0, 1038.3. 1H NMR
(600 MHz, DMSO-d6)
d
: 0.76 (t, 0.77 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3), 0.87
(t, 0.23 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3), 1.73e1.75 (m, 2H, CH2), 2.19e2.46
(m, 6H, 3 ꢃ CH2), 4.29 (t, 0.77 ꢃ 2H, J ¼ 7.2 Hz, CH2), 4.64 (t,
0.23 ꢃ 2H, J ¼ 7.2 Hz, CH2), 6.15 (s, 0.77 ꢃ 2H, CH2), 6.16 (s,
0.23 ꢃ 2H, CH2), 6.83 (dd, 0.23 ꢃ 1H, J ¼ 8.4, 4.8 Hz, arom), 6.87 (dd,
0.77 ꢃ 1H, J ¼ 8.4, 4.8 Hz, arom), 6.97e7.03 (m, 1H, arom), 7.15e7.60
5.4.19. (2(Z/E), 5Z)-3-(3-(2-(dimethylamino)ethyl)-5-(3,4,5-trimetho
xybenzylidene)-4-oxo-2-thiazolidinylidene)-5-fluoroindolin-2-one (5s)
Yield: 55%. ESI-MS: m/z, 500.2 [M þ H]þ. IR (KBr) cmꢂ1: 2939.2,
2826.4, 2769.3, 1701.7, 1601.6, 1575.0, 1527.5, 1502.9, 1479.1, 1463.0,

3516
S. Wang et al. / European Journal of Medicinal Chemistry 46 (2011) 3509e3518
(m, 4H, arom), 7.70 (s, 0.77 ꢃ 1H, CH), 7.80 (s, 0.23 ꢃ 1H, CH), 10.62
(s, 0.23 ꢃ 1H, NH),10.85 (s, 0.77 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%)
CH and arom), 10.89 (s, 0.88 ꢃ 1H, NH), 10.98 (s, 0.12 ꢃ 1H, NH). (2Z,
5Z)/(2E, 5Z) ratio (%) 12:88. Anal. Calcd for C25H24F3N3O2S (%):C,
61.59; H, 4.96; N, 8.62. Found (%): C, 61.67; H, 5.05; N, 8.66.
77:23. 13C NMR (75 MHz, DMSO-d6)
d: 169.7, 168.0, 150.5, 149.1,
148.2, 135.4, 131.7, 128.0, 126.2, 119.9, 112.9, 112.7, 110.3, 110.1, 110.0,
109.6, 109.3, 102.1, 101.3, 49.3, 46.0, 45.9, 24.7, 11.3. Anal. Calcd for
C26H26FN3O4S (%):C, 63.01; H, 5.29; N, 8.48. Found (%): C, 63.08; H,
5.38; N, 8.52.
5.4.27. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(2,4-difluoro-
benzylidene)-4-oxo-2-thiazolidinylidene)indolin-2-one (10h)
Yield: 56%. ESI-MS: m/z, 470.1[M þ H]þ. IR (KBr) cmꢂ1
:
3429.6, 3160.9, 2967.5, 2817.5, 1706.7, 1681.5, 1607.7, 1586.4,
1533.2, 1499.0, 1468.8, 1432.4, 1382.1, 1341.7, 1276.5, 1235.6,
5.4.23. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-((benzo[d]
[1,3]dioxol-5-yl)methylene)-4-oxo-2-thiazolidinylidene)-6-
fluoroindolin-2-one (10d)
1195.4, 1138.5, 1104.1, 1086.8. 1H NMR (300 MHz, DMSO-d6)
d:
0.76 (t, 0.80 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3), 0.87 (t, 0.20 ꢃ 6H,
J ¼ 6.9 Hz, 2 ꢃ CH3), 1.74 (t, 2H, J ¼ 6.0 Hz, CH2), 2.19e2.44 (m,
6H, 3 ꢃ CH2), 4.32 (t, 0.80 ꢃ 2H, J ¼ 6.0 Hz, CH2), 4.65 (t,
0.20 ꢃ 2H, J ¼ 6.0 Hz, CH2), 6.86e7.78 (m, 8H, CH and arom),
10.67 (s, 0.80 ꢃ 1H, NH), 10.89 (s, 0.20 ꢃ 1H, NH). (2Z, 5Z)/(2E,
Yield: 60%. ESI-MS: m/z, 496.5 [M þ H]þ. IR (KBr) cmꢂ1: 3353.6,
3074.8, 1697.3, 1676.3, 1629.1, 1604.0, 1585.4, 1538.5, 1492.2, 1435.7,
1385.2,1365.9,1338.0,1316.9,1288.8,1257.0,1134.1,1106.6,1034.3.1H
NMR (300 MHz, DMSO-d6)
d: 1.08 (t, 0.24 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3),
1.19 (t, 0.76 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3), 1.93e2.18 (m, 2H, CH2),
2.88e3.23 (m, 6H, 3 ꢃ CH2), 4.31 (t, 0.24 ꢃ 2H, J ¼ 7.2 Hz, CH2), 4.47 (t,
0.76 ꢃ 2H, J ¼ 7.2 Hz, CH2), 6.17 (s, 0.24 ꢃ 2H, CH2), 6.18 (s, 0.76 ꢃ 2H,
CH2), 6.69e7.87 (m, 7H, CH and arom),10.85 (s, 0.76 ꢃ 1H, NH),11.09
(s, 0.24 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 24:76. Anal. Calcd for
C26H26FN3O4S (%):C, 63.01; H, 5.29; N, 8.48. Found (%): C, 63.06; H,
5.40; N, 8.55.
5Z) ratio (%) 80:20. 13C NMR (75 MHz, DMSO-d6)
d: 169.6, 167.7,
147.6, 140.0, 139.8, 139.5, 130.8, 127.2, 125.2, 123.4, 121.0, 120.4,
113.2, 112.9, 109.8, 105.1, 102.8, 49.2, 46.1, 45.9, 24.5, 11.1. Anal.
Calcd for C25H25F2N3O2S (%):C, 63.95; H, 5.37; N, 8.95. Found (%):
C, 64.01; H, 5.42; N, 8.98.
5.4.28. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(2,4-difluorobe-
nzylidene)-4-oxo-2-thiazolidinylidene)-6-fluoroindolin-2-one (10i)
Yield: 52%. ESI-MS: m/z, 488.2 [M þ H]þ. IR (KBr) cmꢂ1: 3442.9,
3174.9, 2969.3, 1705.3, 1683.2, 1605.7, 1536.4, 1499.0, 1461.4, 1432.3,
1381.7, 1341.1, 1275.7, 1194.5, 1136.6, 1104.9, 1086.8. 1H NMR
5.4.24. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-((benzo[d]
[1,3]dioxol-5-yl)methylene)-4-oxo-2-thiazolidinylidene)-5-
chloroindolin-2-one (10e)
Yield: 63%. ESI-MS: m/z, 512.1[M þ H]þ. IR (KBr) cmꢂ1: 3430.7,
2967.5, 1677.3, 1617.1, 1585.2, 1529.3, 1503.1, 1488.7, 1468.6, 1447.8,
1382.9, 1361.3, 1311.2, 1261.2, 1195.8, 1164.7, 1147.6, 1125.4, 1104.9,
(300 MHz, DMSO-d6)
d
: 0.76 (t, 0.80 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3), 0.88
(t, 0.20 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3), 1.73 (t, 2H, J ¼ 6.0 Hz, CH2),
2.10e2.46 (m, 6H, 3 ꢃ CH2), 4.29 (t, 0.80 ꢃ 2H, J ¼ 6.0 Hz, CH2), 4.60
(t, 0.20 ꢃ 2H, J ¼ 6.0 Hz, CH2), 6.71e7.88 (m, 7H, CH and arom),
10.83 (s, 0.80 ꢃ 1H, NH), 11.05 (s, 0.20 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z)
ratio (%) 80:20. Anal. Calcd for C25H24F3N3O2S (%):C, 61.59; H, 4.96;
N, 8.62. Found (%): C, 61.65; H, 5.03; N, 8.67.
1039.2. 1H NMR (300 MHz, DMSO-d6)
d: 0.78 (t, 0.81 ꢃ 6H,
J ¼ 6.9 Hz, 2 ꢃ CH3), 0.85 (t, 0.19 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3),
1.69e1.82 (m, 2H, CH2), 2.20e2.42 (m, 6H, 3 ꢃ CH2), 4.27 (t,
0.81 ꢃ 2H, J ¼ 7.2 Hz, CH2), 4.62 (t, 0.19 ꢃ 2H, J ¼ 7.2 Hz, CH2), 6.16 (s,
0.81 ꢃ 2H, CH2), 6.17 (s, 0.19 ꢃ 2H, CH2), 6.85 (d, 0.19 ꢃ 1H,
J ¼ 8.4 Hz, arom), 6.89 (d, 0.81 ꢃ1H, J ¼ 8.1 Hz, arom), 7.14e7.34 (m,
4H, arom), 7.42 (d, 0.81 ꢃ 1H, J ¼ 1.5 Hz, arom), 7.68 (d, 0.19 ꢃ 1H,
J ¼ 1.8 Hz, arom), 7.70 (s, 0.81 ꢃ 1H, CH), 7.82 (s, 0.19 ꢃ 1H, CH),
10.75 (s, 0.19 ꢃ 1H, NH), 10.97 (s, 0.81 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z)
5.4.29. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(2,4-difluorobe-
nzylidene)-4-oxo-2-thiazolidinylidene)-5-chloroindolin-2-one (10j)
Yield: 59%. ESI-MS: m/z, 504.1 [M þ H]þ. IR (KBr) cmꢂ1: 3420.7,
3159.3, 3045.4, 2968.7, 1699.9, 1681.9, 1606.9, 1529.1, 1499.7,
1473.3, 1433.9, 1379.7, 1330.2, 1276.8, 1241.9, 1194.9, 1173.8, 1138.2,
ratio (%) 81:19. 13C NMR (75 MHz, DMSO-d6)
d: 169.4, 168.0, 150.9,
149.2, 148.2, 137.8, 131.9, 128.0, 126.3, 126.1, 124.9, 122.5, 122.2,
119.8, 110.8, 109.6, 109.3, 102.1, 100.5, 49.2, 46.0, 45.3, 24.6, 11.2.
Anal. Calcd for C26H26ClN3O4S (%):C, 60.99; H, 5.12; N, 8.21. Found
(%): C, 61.05; H, 5.16; N, 8.26.
1086.3, 1013.8. 1H NMR (300 MHz, DMSO-d6)
d
: 0.79 (t, 0.82 ꢃ 6H,
J ¼ 6.9 Hz, 2 ꢃ CH3), 0.88 (t, 0.18 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3), 1.78 (t,
2H, J ¼ 6.3 Hz, CH2), 2.20e2.46 (m, 6H, 3 ꢃ CH2), 4.27 (t,
0.80 ꢃ 2H, J ¼ 6.3 Hz, CH2), 4.61 (t, 0.20 ꢃ 2H, J ¼ 6.3 Hz, CH2),
6.79e7.86 (m, 7H, CH and arom), 10.83 (s, 0.82 ꢃ 1H, NH), 11.02 (s,
0.18 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 82:18. Anal. Calcd for
C25H24ClF2N3O2S (%): C, 59.58; H, 4.80; N, 8.34. Found (%): C,
59.63; H, 4.85; N, 8.40.
5.4.25. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(3,4-difluorobe-
nzylidene)-4-oxo-2-thiazolidinylidene)-5-fluoroindolin-2-one (10f)
Yield: 55%. ESI-MS: m/z, 488.2 [M þ H]þ. IR (KBr) cmꢂ1: 3432.4,
2925.4, 1692.2, 1630.7, 1606.8, 1540.7, 1516.7, 1479.7, 1436.6, 1384.7,
1337.5, 1301.4, 1281.7, 1254.2, 1188.9, 1131.9. 1H NMR (300 MHz,
5.4.30. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(3,4,5-trimeth
DMSO-d6)
d
: 1.04 (t, 0.47 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3), 1.18 (t,
oxybenzylidene)-4-oxo-2-thiazolidinylidene)indolin-2-one (10k)
0.53 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3), 1.90e2.21 (m, 2H, CH2), 2.80e3.24
(m, 6H, 3 ꢃ CH2), 4.31 (t, 0.47 ꢃ 2H, J ¼ 6.9 Hz, CH2), 4.48 (t,
0.53 ꢃ 2H, J ¼ 6.9 Hz, CH2), 6.85e7.98 (m, 7H, CH and arom), 10.75
(s, 0.53 ꢃ 1H, NH),10.97 (s, 0.47 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%)
47:53. Anal. Calcd for C25H24F3N3O2S (%):C, 61.59; H, 4.96; N, 8.62.
Found (%): C, 61.64; H, 5.02; N, 8.68.
Yield: 52%. ESI-MS: m/z, 524.2 [M þ H]þ. IR (KBr) cmꢂ1
:
3169.4, 2966.6, 2831.6, 1698.5, 1676.5, 1602.6, 1575.7, 1531.2,
1502.0, 1466.7, 1420.7, 1381.9, 1333.0, 1310.9, 1238.8, 1193.9,
1133.9, 1103.8, 1032.8, 1007.7. 1H NMR (300 MHz, DMSO-d6)
d:
0.75 (t, 0.67 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3), 0.86 (t, 0.33 ꢃ 6H,
J ¼ 7.2 Hz, 2 ꢃ CH3), 1.68e1.78 (m, 2H, CH2), 2.22e2.40 (m, 6H,
3 ꢃ CH2), 3.75 (s, 3H, CH3), 3.85 (s, 0.67 ꢃ 3H, CH3), 3.86 (s,
0.67 ꢃ 3H, CH3), 3.88 (s, 0.33 ꢃ 3H, CH3), 3.89 (s, 0.33 ꢃ 3H, CH3),
4.32 (t, 0.67 ꢃ 2H, J ¼ 6.6 Hz, CH2), 4.67 (t, 0.33 ꢃ 2H, J ¼ 6.6 Hz,
CH2), 6.86e7.21 (m, 5H, arom), 7.45 (d, 0.67 ꢃ 1H, J ¼ 7.8 Hz,
arom), 7.68 (s, 0.67 ꢃ 1H, CH), 7.71 (d, 0.33 ꢃ 1H, J ¼ 7.8 Hz,
arom), 7.80 (s, 0.33 ꢃ 1H, CH), 10.63 (s, 0.33 ꢃ 1H, NH), 10.75 (s,
0.67 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 67:33. Anal. Calcd for
C28H33N3O5S (%):C, 64.22; H, 6.35; N, 8.02. Found (%): C, 64.26; H,
6.45; N, 8.09.
5.4.26. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(3,4-difluoro-
benzylidene)-4-oxo-2-thiazolidinylidene)-6-fluoroindolin-2-one (10g)
Yield: 60%. ESI-MS: m/z, 488.2 [M þ H]þ. IR (KBr) cmꢂ1: 3433.8,
1706.0, 1628.4, 1605.1, 1545.0, 1515.9, 1436.0, 1384.6, 1342.9, 1301.2,
1281.7,1180.8,1133.9,1109.4.1H NMR (300 MHz, DMSO-d6)
d: 1.09 (t,
0.12 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3),1.24 (t, 0.88 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3),
2.01e2.21 (m, 2H, CH2), 2.82e3.24(m, 6H, 3 ꢃ CH2), 4.32(t, 0.12ꢃ 2H,
J ¼ 6.9 Hz, CH2), 4.48 (t, 0.88 ꢃ 2H, J ¼ 6.9 Hz, CH2), 6.71e7.94 (m, 7H,

S. Wang et al. / European Journal of Medicinal Chemistry 46 (2011) 3509e3518
3517
5.4.31. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(3,4,5-trimeth-
oxybenzylidene)-4-oxo-2-thiazolidinylidene)-5-methylindolin-2-
one (10l)
(300 MHz, DMSO-d6)
d
: 0.78 (t, 0.70 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3), 0.88
(t, 0.30 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3), 1.71e1.78 (m, 2H, CH2), 2.23e2.45
(m, 6H, 3 ꢃ CH2), 3.76 (s, 3H, CH3), 3.86 (s, 3H, CH3), 3.90 (s, 3H,
CH3), 4.26 (t, 0.70 ꢃ 2H, J ¼ 6.9 Hz, CH2), 4.64 (t, 0.30 ꢃ 2H,
J ¼ 6.6 Hz, CH2), 6.83 (d, 0.30 ꢃ 1H, J ¼ 8.1 Hz, arom), 6.90 (d,
0.70 ꢃ 1H, J ¼ 8.4 Hz, arom), 7.04 (s, 0.70 ꢃ 2H, arom), 7.07 (s,
0.30 ꢃ 2H, arom), 7.15 (d, 0.30 ꢃ 1H, J ¼ 8.1 Hz, arom), 7.20 (d,
0.70 ꢃ 1H, J ¼ 8.4 Hz, arom), 7.42 (s, 0.70 ꢃ 1H, arom), 7.68 (s,
0.30 ꢃ 1H, arom), 7.70 (s, 0.70 ꢃ 1H, CH), 7.79 (s, 0.30 ꢃ 1H, CH),
10.75 (s, 0.30 ꢃ 1H, NH), 10.87 (s, 0.70 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z)
Yield: 46%. ESI-MS: m/z, 538.7 [M þ H]þ. IR (KBr) cmꢂ1: 3160.9,
2965.9, 1697.9, 1602.0, 1574.8, 1529.3, 1502.4, 1430.2, 1382.3, 1323.9,
1239.3, 1194.6, 1133.6, 1029.5, 1005.8. 1H NMR (300 MHz, DMSO-d6)
d: 0.78 (t, 0.37 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3), 0.88 (t, 0.63 ꢃ 6H,
J ¼ 6.9 Hz, 2 ꢃ CH3), 1.71e1.77 (m, 2H, CH2), 2.18e2.47 (m, 9H,
3 ꢃ CH2 and CH3), 3.76 (s, 3H, CH3), 3.85 (s, 0.37 ꢃ 3H, CH3), 3.86 (s,
0.37 ꢃ 3H, CH3), 3.90 (s, 0.63 ꢃ 3H, CH3), 3.91 (s, 0.63 ꢃ 3H, CH3),
4.32 (t, 0.37 ꢃ 2H, J ¼ 6.3 Hz, CH2), 4.67 (t, 0.63 ꢃ 2H, J ¼ 6.3 Hz,
CH2), 6.74 (d, 0.63 ꢃ 1H, J ¼ 7.8 Hz, arom), 6.80 (d, 0.37 ꢃ 1H,
J ¼ 7.8 Hz, arom), 6.95e7.01 (m, 1H, arom), 7.04 (s, 0.37 ꢃ 2H, arom),
7.08 (s, 0.63 ꢃ 2H, arom), 7.25 (s, 0.37 ꢃ 1H, arom), 7.56 (s,
0.63 ꢃ 1H, arom), 7.67 (s, 0.37 ꢃ 1H, CH), 7.77 (s, 0.63 ꢃ 1H, CH),
10.52 (s, 0.63 ꢃ 1H, NH), 10.64 (s, 0.37 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z)
ratio (%) 37:63. Anal. Calcd for C29H35N3O5S (%): C, 64.78; H, 6.56; N,
7.82. Found (%): C, 64.75; H, 6.46; N, 7.76.
ratio (%) 70:30. 13C NMR (75 MHz, DMSO-d6)
d: 169.4, 167.9, 153.6,
153.4, 153.3, 150.8, 139.5, 138.0, 132.0, 129.4, 126.2, 125.7, 124.9,
122.5, 122.2, 110.9, 108.3, 100.7, 60.4, 56.2, 49.3, 46.2, 46.1, 25.0, 11.5.
Anal. Calcd for C28H32ClN3O5S (%): C, 60.26; H, 5.78; N, 7.53. Found
(%): C, 60.20; H, 5.83; N, 7.61.
5.4.35. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(4-hydroxy-
benzylidene)-4-oxo-2-thiazolidinylidene)-5-methylindolin-2-one
(10p)
5.4.32. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(3,4,5-trimeth
oxybenzylidene)-4-oxo-2-thiazolidinylidene)-5-fluoroindolin-2-one
(10m)
Yield: 38%. ESI-MS: m/z, 464.6 [M þ H]þ. IR (KBr) cmꢂ1: 3427.4,
1689.9, 1587.1, 1535.6, 1512.9, 1484.7, 1434.2, 1386.6, 1337.2, 1285.5,
1254.4, 1211.8, 1173.1, 1136.3, 1084.9, 1034.4. 1H NMR (300 MHz,
Yield: 55%. ESI-MS: m/z, 542.3 [M þ H]þ. IR (KBr) cmꢂ1: 3416.8,
2966.8, 1703.2, 1676.7, 1601.6, 1575.2, 1527.8, 1502.2, 1478.6, 1429.7,
1382.5, 1322.8, 1241.4, 1190.4, 1132.9, 1023.8. 1H NMR (300 MHz,
DMSO-d6)
d
: 0.98 (t, 0.47 ꢃ6H, J ¼ 6.9 Hz, 2 ꢃ CH3),1.15 (t, 0.53 ꢃ 6H,
J ¼ 6.9 Hz, 2 ꢃ CH3), 1.91e2.09 (m, 2H, CH2), 2.33 (s, 0.47 ꢃ 3H, CH3),
2.39 (s, 0.53 ꢃ 3H, CH3), 2.70e3.20 (m, 6H, 3 ꢃ CH2), 4.34 (t,
0.47 ꢃ 2H, J ¼ 6.9 Hz, CH2), 4.49 (t, 0.53 ꢃ 2H, J ¼ 6.6 Hz, CH2),
6.80e7.77 (m, 8H, CH and arom), 8.99 (s,1H, OH),10.57 (s, 0.53 ꢃ1H,
NH), 10.77 (s, 0.47 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 47:53. 13C
DMSO-d6)
d: 0.76 (t, 0.77 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3), 0.87 (t, 0.23 ꢃ 6H,
J¼ 6.9 Hz, 2 ꢃ CH3),1.72e1.76 (m, 2H, CH2), 2.24e2.44(m, 6H, 3ꢃ CH2),
3.76 (s, 3H, CH3), 3.85 (s, 0.77 ꢃ 3H, CH3), 3.86 (s, 0.77 ꢃ 3H, CH3), 3.88
(s, 0.23 ꢃ 3H, CH3), 3.89 (s, 0.23 ꢃ3H, CH3), 4.30 (t, 0.77 ꢃ2H, J¼ 6.9 Hz,
CH2), 4.66 (t, 0.23 ꢃ 2H, J ¼ 6.9 Hz, CH2), 6.82e7.02 (m, 2H, arom), 7.06
(s, 0.77 ꢃ 2H, arom), 7.08 (s, 0.23 ꢃ 2H, arom), 7.27 (dd, 0.77 ꢃ 1H,
J¼ 10.5,1.8 Hz, arom), 7.48(dd, 0.23 ꢃ1H, J¼ 10.2, 2.1 Hz, arom), 7.71 (s,
0.77 ꢃ1H, CH), 7.83 (s, 0.23 ꢃ1H, CH),10.65 (s, 0.23 ꢃ1H, NH),10.76 (s,
0.77 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 77:23. 13C NMR (75 MHz,
NMR (75 MHz, DMSO-d6) d: 169.7, 168.4, 159.8, 148.5, 137.2, 132.8,
129.7, 127.4, 124.9, 124.3, 123.6, 120.7, 118.1, 116.7, 109.5, 102.7, 48.5,
46.4, 45.8, 21.4, 21.1, 9.0. Anal. Calcd for C26H29N3O3S (%): C, 67.36; H,
6.31; N, 9.06. Found (%): C, 67.29; H, 6.26; N, 9.03.
5.4.36. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(2-hydroxy-
benzylidene)-4-oxo-2-thiazolidinylidene)indolin-2-one (10q)
Yield: 35%. ESI-MS: m/z, 450.2 [M þ H]þ. IR (KBr) cmꢂ1: 3379.1,
1692.2, 1616.7, 1591.0, 1533.8, 1480.9, 1454.9, 1434.6, 1387.4,
1344.2, 1313.1, 1259.5, 1188.4, 1140.8, 1029.2. 1H NMR (300 MHz,
DMSO-d6) d: 169.6, 167.9, 153.5, 153.2, 150.4, 139.4, 135.6, 131.8, 129.4,
128.8, 121.5, 121.4, 110.5, 110.1, 108.2, 107.9, 101.5, 60.3, 56.1, 49.2, 46.1,
46.0, 24.7, 11.2. Anal. Calcd for C28H32FN3O5S (%): C, 62.09; H, 5.95; N,
7.76. Found (%): C, 62.02; H, 5.87; N, 7.72.
DMSO-d6)
d
: 1.07 (t, 0.40 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3), 1.18 (t,
5.4.33. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(3,4,5-trimeth
oxybenzylidene)-4-oxo-2-thiazolidinylidene)-6-fluoroindolin-2-one
(10n)
0.60 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3), 2.00e2.14 (m, 2H, CH2), 2.90e3.20
(m, 6H, 3 ꢃ CH2), 4.35 (t, 0.40 ꢃ 2H, J ¼ 6.3 Hz, CH2), 4.52 (t,
0.60 ꢃ 2H, J ¼ 6.0 Hz, CH2), 6.89e7.85 (m, 8H, arom), 8.20 (s,
0.60 ꢃ 1H, CH), 8.23 (s, 0.40 ꢃ 1H, CH), 9.00 (s, 1H, OH), 10.66 (s,
0.60 ꢃ 1H, NH), 10.89 (s, 0.40 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%)
Yield: 50%. ESI-MS: m/z, 542.3 [M þ H]þ. IR (KBr) cmꢂ1: 3427.6,
2968.3, 1700.0, 1626.8, 1601.6, 1575.4, 1531.2, 1501.8, 1462.6, 1420.2,
1383.6, 1332.8, 1240.0, 1193.5, 1133.4, 1105.3, 1008.6. 1H NMR
40:60. 13C NMR (75 MHz, DMSO-d6)
d: 169.6, 168.5, 159.1, 149.5,
(300 MHz, DMSO-d6)
d
: 0.75 (t, 0.75 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3), 0.86
139.3, 132.3, 129.2, 128.9, 128.2, 126.3, 124.1, 123.0, 121.0, 118.8,
118.5, 115.9, 109.8, 102.1, 48.3, 46.5, 43.9, 23.1, 8.6. Anal. Calcd for
C25H27N3O3S (%): C, 66.79; H, 6.05; N, 9.35. Found (%): C, 66.69; H,
6.01; N, 9.28.
(t, 0.25 ꢃ 6H, J ¼ 7.2 Hz, 2 ꢃ CH3), 1.66e1.76 (m, 2H, CH2), 2.21e2.40
(m, 6H, 3 ꢃ CH2), 3.75 (s, 3H, CH3), 3.85 (s, 0.75 ꢃ 3H, CH3), 3.86 (s,
0.75 ꢃ 3H, CH3), 3.88 (s, 0.25 ꢃ 3H, CH3), 3.89 (s, 0.25 ꢃ 3H, CH3),
4.30 (t, 0.75 ꢃ 2H, J ¼ 6.6 Hz, CH2), 4.64 (t, 0.25 ꢃ 2H, J ¼ 6.0 Hz,
CH2), 6.68e6.90 (m, 2H, arom), 7.05 (s, 2H, arom), 7.46e7.50 (m,
0.75 ꢃ 1H, arom), 7.69 (s, 0.75 ꢃ 1H, CH), 7.71e7.73 (m, 0.25 ꢃ 1H,
arom), 7.80 (s, 0.25 ꢃ 1H, CH), 10.78 (s, 0.25 ꢃ 1H, NH), 10.91 (s,
0.75 ꢃ 1H, NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 75:25. 13C NMR (75 MHz,
5.4.37. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(2-hydroxy-
benzylidene)-4-oxo-2-thiazolidinylidene)-5-methylindolin-2-one
(10r)
Yield: 40%. ESI-MS: m/z, 464.3 [M þ H]þ. IR (KBr) cmꢂ1: 3377.2,
3031.7, 1689.4, 1592.7, 1532.4, 1483.7, 1433.4, 1387.9, 1337.6, 1260.0,
DMSO-d6) d: 169.9, 167.9, 153.3, 153.2, 148.4, 141.0, 140.8, 139.3,
131.3, 129.4, 124.6, 121.6, 118.4, 117.2, 108.1, 107.0, 101.2, 60.3, 56.1,
49.2, 46.1, 45.9, 24.6, 11.2. Anal. Calcd for C28H32FN3O5S (%): C,
62.09; H, 5.95; N, 7.76. Found (%): C, 62.04; H, 5.89; N, 7.74.
1206.5, 1169.8, 1140.6, 1028.3. 1H NMR (600 MHz, DMSO-d6)
d: 1.07
(t, 0.44 ꢃ 6H, J ¼ 6.9 Hz, 2 ꢃ CH3), 1.18 (t, 0.56 ꢃ 6H, J ¼ 6.9 Hz,
2 ꢃ CH3), 2.00e2.14 (m, 2H, CH2), 2.35 (s, 0.44 ꢃ 3H, CH3), 2.36 (s,
0.56 ꢃ 3H, CH3), 2.90e3.19 (m, 6H, 3 ꢃ CH2), 4.37 (t, 0.44 ꢃ 2H,
J ¼ 7.2 Hz, CH2), 4.52 (t, 0.56 ꢃ 2H, J ¼ 7.2 Hz, CH2), 6.76 (d,
0.56 ꢃ 1H, J ¼ 7.8 Hz, arom), 6.82 (d, 0.44 ꢃ 1H, J ¼ 7.8 Hz, arom),
6.89e7.67 (m, 6H, arom), 8.12 (s, 0.56 ꢃ 1H, CH), 8.23 (s, 0.44 ꢃ 1H,
CH), 9.00 (s, 1H, OH), 10.51 (s, 0.56 ꢃ 1H, NH), 10.75 (s, 0.44 ꢃ 1H,
NH). (2Z, 5Z)/(2E, 5Z) ratio (%) 44:56. 13C NMR (75 MHz, DMSO-d6)
5.4.34. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(3,4,5-trimeth
oxybenzylidene)-4-oxo-2-thiazolidinylidene)-5-chloroindolin-2-
one (10o)
Yield: 45%. ESI-MS: m/z, 558.1 [M þ H]þ. IR (KBr) cmꢂ1: 3155.9,
2965.5, 1704.8, 1679.4, 1601.9, 1574.8, 1524.6, 1501.4, 1468.8, 1430.5,
1382.1, 1322.9, 1238.0, 1192.7, 1166.3, 1133.0, 1014.3. 1H NMR
d: 169.7, 168.1, 158.7, 149.4, 137.1, 132.2, 130.6, 129.7, 128.2, 126.7,

3518
S. Wang et al. / European Journal of Medicinal Chemistry 46 (2011) 3509e3518
124.2, 122.8, 120.7, 118.7, 118.4, 116.4, 108.9, 102.2, 48.3, 46.5, 45.6,
23.0, 21.1, 8.6. Anal. Calcd for C26H29N3O3S (%): C, 67.36; H, 6.31; N,
9.06. Found (%): C, 67.31; H, 6.28; N, 9.02.
Appendix. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ejmech.2011.05.017.
5.4.38. (2(Z/E), 5Z)-3-(3-(3-(diethylamino)propyl)-5-(2-hydroxy
benzylidene)-4-oxo-2-thiazolidinylidene)-5-bromoindolin-2-one
(10s)
References
Yield: 33%. ESI-MS: m/z, 528.1 [M þ H]þ. IR (KBr) cmꢂ1: 3384.6,
3040.9, 1701.2, 1665.6, 1594.2, 1534.7, 1469.2, 1436.3, 1388.8, 1338.7,
1302.6, 1262.1, 1236.2, 1208.1, 1191.7, 1166.1, 1143.0, 1091.7, 1052.9,
ꢀ
ꢀ
[1] T. Tomasic, L.P. Masic, Curr. Med. Chem. 16 (2009) 1596e1629.
[2] R. Lesyk, B. Zimenkovsky, D. Atamanyuk, F. Jensen, K. Kiec-Kononowicz,
A. Gzella, Bioorg. Med. Chem. 14 (2006) 5230e5240.
1007.5. 1H NMR (600 MHz, DMSO-d6)
d
: 1.08 (t, 0.45 ꢃ 6H,
[3] D. Havrylyuk, B. Zimenkovsky, O. Vasylenko, L. Zaprutko, A. Gzella, R. Lesyk,
Eur. J. Med. Chem. 44 (2009) 1396e1404.
[4] D.Kaminskyy, B. Zimenkovsky, R. Lesyk, Eur. J.Med. Chem. 44(2009)3627e3636.
[5] R. Ottana, R. Maccari, M.L. Barreca, G. Bruno, A. Rotondo, A. Rossi, G. Chiricosta,
R. Di Paola, L. Sautebin, S. Cuzzocrea, M.G. Vigorita, Bioorg. Med. Chem. 13
(2005) 4243e4252.
[6] P. Vicini, A. Geronikaki, K. Anastasia, M. Incerti, F. Zani, Bioorg. Med. Chem. 14
(2006) 3859e3864.
[7] A.A. Elbarbary, A.I. Khodair, E.B. Pedersen, C. Nielsen, Monatsh. Chem. 125
(1994) 593e598.
[8] E. Rydzik, A. Szadowska, A. Kaminska, Acta Pol. Pharm. 41 (1984) 459e464.
[9] H.L. Liu, Z.C. Li, T. Anthonsen, Molecules 5 (2000) 1055e1061.
[10] B. Samir, K. Wesam, A.F. Ahmed, Eur. J. Med. Chem. 42 (2007) 948e954.
[11] J.H. Ahn, S.J. Kim, W.S. Park, S.Y. Cho, J.D. Ha, S.S. Kim, S.K. Kang, D.G. Jeong,
S.-K. Jung, S.-H. Lee, H.M. Kim, S.K. Park, K.H. Lee, C.W. Lee, S.E. Ryu, J.-K. Choi,
Bioorg. Med. Chem. Lett. 16 (2006) 2996e2999.
J ¼ 6.6 Hz, 2 ꢃ CH3),1.18 (t, 0.55 ꢃ 6H, J ¼ 6.6 Hz, 2 ꢃ CH3),1.93e2.21
(m, 2H, CH2), 2.85e3.24 (m, 6H, 3 ꢃ CH2), 4.29 (t, 0.45 ꢃ 2H,
J ¼ 7.2 Hz, CH2), 4.48 (t, 0.55 ꢃ 2H, J ¼ 7.2 Hz, CH2), 6.82e7.86 (m,
7H, arom), 8.19 (s, 0.55 ꢃ1H, CH), 8.25 (s, 0.45 ꢃ1H, CH), 8.99 (s,1H,
OH), 10.77 (s, 0.55 ꢃ 1H, NH), 11.01 (s, 0.45 ꢃ 1H, NH). (2Z, 5Z)/(2E,
5Z) ratio (%) 45:55. 13C NMR (75 MHz, DMSO-d6)
d: 169.3, 168.0,
159.1, 149.2, 138.2, 132.0, 131.4, 129.9, 128.4, 126.2, 123.8, 122.7,
118.8, 118.2, 115.6, 112.6, 111.4, 100.7, 48.3, 46.5, 45.8, 23.0, 8.6. Anal.
Calcd for C25H26BrN3O3S (%): C, 56.82; H, 4.96; N, 7.95. Found (%): C,
56.87; H, 5.02; N, 7.98.
[12] K.J. French, R.S. Schrecengost, B.D. Lee, Y. Zhuang, S.N. Smith, J.L. Eberly,
J.K. Yun, C.D. Smith, Cancer Res. 63 (2003) 5962e5969.
[13] N.S. Cutshall, C. O’Day, M. Prezhdo, Bioorg. Med. Chem. Lett. 15 (2005)
3374e3379.
5.5. Cytotoxicity assay in vitro
[14] A. Geronikaki, P. Eleftheriou, P. Vicini, I. Alam, A. Dixit, A.K. Saxena, J. Med.
Chem. 51 (2008) 5221e5228.
[15] H.Y. Zhou, S.H. Wu, S.M. Zhai, A.F. Liu, Y. Sun, R.S. Li, Y. Zhang, S. Ekins,
P.W. Swaan, B.L. Fang, B. Zhang, B. Yan, J. Med. Chem. 51 (2008)
1242e1251.
[16] R. Ottana, S. Carotti, R. Maccari, I. Landini, G. Chiricosta, B. Caciagli,
M.G. Vigorita, E. Mini, Bioorg. Med. Chem. Lett. 15 (2005) 3930e3933.
[17] B. Eriksson, G. Kurz, C. Hedberg, J. Westman, WO2007010273, 2007.
[18] M. Krug, A. Hilgeroth, Mini-Rev. Med. Chem. 8 (2008) 1312e1327.
[19] L. Sun, C. Liang, S. Shirazian, Y. Zhou, T. Miller, J. Cui, J.Y. Fukuda, J.-Y. Chu,
A. Nematalla, X.Y. Wang, H. Chen, A. Sistla, T.C. Luu, F. Tang, J. Wei, C. Tang,
J. Med. Chem. 46 (2003) 1116e1119.
[20] G.J. Roth, A. Heckel, F. Colbatzky, S. Handschuh, J. Kley, T. Lehmann-Lintz,
R. Lotz, U. Tontsch-Grunt, R. Walter, F. Hilberg, J. Med. Chem. 52 (2009)
4466e4480.
[21] Z. Xiao, Y. Hao, B. Liu, Leuk. Lymphoma 43 (2002) 1763e1768.
[22] A. Beauchard, H. Laborie, H. Rouillard, O. Lozach, Y. Ferandin, R.L. Guével,
C. Guguen-Guillouzo, L. Meijer, T. Besson, V. Thiéry, Bioorg. Med. Chem. 17
(2009) 6257e6263.
[23] L. Mologni, R. Rostagno, S. Brussolo, P.P. Knowles, S. Kjaer, J. Murray-Rust,
E. Rosso, A. Zambon, L. Scapozza, N.Q. McDonald, V. Lucchini, C. Gambacorti-
Passerini, Bioorg. Med. Chem. 18 (2010) 1482e1496.
[24] Y. Ohishi, T. Mukai, M. Nagahara, M. Yajima, N. Kajikawa, K. Miyahara,
T. Takano, Chem. Pharm. Bull. 38 (1990) 1911e1919.
[25] Y. Momose, K. Meguro, H. Ikeda, C. Hatanaka, S. Oi, T. Sohda, Chem. Pharm.
Bull. 39 (1991) 1440e1445.
The cytotoxic activities of target compounds were evaluated
with HT-29, H460, MDA-MB-231, SMMC-7721 cancer cell lines and
WI-38 normal cell lines by the standard MTT assay in vitro, with
sunitinib as the positive control. The cancer cell lines were
cultured in minimum essential medium (MEM) supplement with
10% fetal bovine serum (FBS). Approximately 4 ꢃ 103 cells, sus-
pended in MEM medium, were plated onto each well of a 96-well
plate and incubated in 5% CO2 at 37 ꢀC for 24 h. The test
compounds at indicated final concentrations were added to the
culture medium and the cell cultures were continued for 72 h.
Fresh MTT was added to each well at a terminal concentration of
5
m
g/mL and incubated with cells at 37 ꢀC for 4 h. The formazan
crystals were dissolved in 100 L DMSO each well, and the
m
absorbency at 492 nm (for absorbance of MTT formazan) and
630 nm (for the reference wavelength) was measured with the
ELISA reader. All of the compounds were tested three times in
each of the cell lines. The results expressed as IC50 (inhibitory
concentration 50%) were the averages of three determinations and
calculated by using the Bacus Laboratories Incorporated Slide
Scanner (Bliss) software.