Design, synthesis and evaluation of novel rhodanine-containing sorafenib analogs as potential antitumor agents

Article abstract of DOI:10.1002/ardp.201000326

A series of rhodanine-containing sorafenib analogs was designed, synthesized and evaluated for their in-vitro antitumor activity against three cancer cell lines (A549, H460 and HT29). Pharmacological data indicated that some of the target compounds possessed marked antiproliferative activity superior to the reference drug sorafenib, especially the most promising compound 7r (with the IC₅₀ value of 0.8, 1.3 and 2.8 μM against A549, H460 and HT29 cell lines, respectively). The activity was found to strongly depend on the substitution pattern of the rhodanine motif at C-5″ position. Results suggested that this series of compounds could serve as the bases for the development of novel antitumor agents. Copyright

Full text of DOI:10.1002/ardp.201000326

Arch. Pharm. Chem. Life Sci. 2011, 11, 349–357
349
Full Paper
Design, Synthesis and Evaluation of Novel Rhodanine-
containing Sorafenib Analogs as Potential Antitumor Agents
Wei Li1, Xin Zhai1, Zheng Zhong2, Guangyue Li1, Yongxiao Pu1, and Ping Gong1
1 Key Laboratary of Original New Drugs Design and Discovery of Ministry of Education, School of
Pharmaceutical Engineering, Shenyang Pharmaceutical University, P.R. China
2 146 Depot, State Food and Drug Administration, Shijiazhuang, P.R. China
A series of rhodanine-containing sorafenib analogs was designed, synthesized and evaluated for their
in-vitro antitumor activity against three cancer cell lines (A549, H460 and HT29). Pharmacological data
indicated that some of the target compounds possessed marked antiproliferative activity superior to
the reference drug sorafenib, especially the most promising compound 7r (with the IC50 value of 0.8,
1.3 and 2.8 mM against A549, H460 and HT29 cell lines, respectively). The activity was found to
strongly depend on the substitution pattern of the rhodanine motif at C-500 position. Results suggested
that this series of compounds could serve as the bases for the development of novel antitumor agents.
Keywords: Antitumor activity / Design / Rhodanine-containing sorafenib analogs / Structure–activity relationship
Received: November 1, 2010; Revised: December 13, 2010; Accepted: December 15, 2010
DOI 10.1002/ardp.201000326
Introduction
optimizations of diaryl urea framework of sorafenib led to
the discovery of an interesting class of compounds with N-
methyl-4-phenoxypicolinamide motif preserved [9, 10].
Considerable studies suggest that the rhodanine scaffold is
versatile and privileged in drug discovery [11, 12]. It is known,
that the thioxo group in the rhodanine motif is a carboxylic
acid bioisoster by size with low electronegativity and pos-
sesses the ability to build hydrogen bonds [13, 14]. So far,
rhodanine-containing compounds have been developed as
promising antitumor, antimicrobial, anti-inflammatory,
antidiabetic agents, etc. [11, 12].
Chemotherapy is considered to be the mainstay of cancer
treatments, while traditional cytotoxic chemotherapeutics
are far from satisfactory due to diverse toxic side effects. It
is urgent to develop novel antitumor chemotherapeutics
with high efficiency and low toxicity. Recent advances and
applications on multiple targeted agents may afford effective
chemotherapeutics with low side effect profile.
Sorafenib, a novel oral multiple-targeted antitumor agent,
was proved to inhibit kinases involved both in tumor pro-
liferation and angiogenesis including Raf, VEGFR, PDGFR and
KIT [1–3]. In December 2005 and November 2007, sorafenib
was approved by the FDA for the treatment of primary renal
cell carcinoma and advanced primary hepatocellular carci-
noma respectively [4]. Due to the virtue of dual mechanisms,
broad-spectrum anticancer potency, and well-tolerated
results in combination trials, researchers drew attentions
to the optimization of sorafenib [5–10]. In most studies
including our previous work, it was found that sorafenib
analogs bearing a diaryl urea framework constituted various
compounds with superior antitumor activity [8]. Recently,
Inspired by the recent modifications on the diaryl urea
framework of sorafenib (compound 1 and compound 2) and
the remarkable antitumor activity of rhodanine-containing
compounds, we designed and synthesized 29 4-(4-(5-aryli-
dene-4-oxo-2-thioxothiazolidin-3-yl)phenoxy)-N-methylpicolin-
amides (Fig. 1) in an attempt to develop novel antitumor
chemotherapeutics. Herein, the N-methyl-4-phenoxypicolin-
amide motif of the sorafenib was preserved, the rhodanine
ring was hybrided into the C-40 position of the N-methyl-4-
phenoxypicolinamide scaffold. Furthermore, the arylidene
group was incorporated into the C-500 position of the rhoda-
nine motif to construct a bioisoster of the arylurea. 24 benzyl-
idenes (substituted by: Fluorine atom, chlorine atom, bromine
atom, hydroxyl group, methoxy group) and 5 heterocyclidenes
(pyridin-4-ylmethylene, thiophen-2-ylmethylene, (5-hydroxy-
thiophen-2-yl)methylene and 1H-indol-3-yl)methylene) were
Correspondence: Ping Gong, 103 Wenhua Road, Shenhe District,
110016 Shenyang, Liaoning, P. R. China.
E-mail: gongpinggp@126.com
Fax: þ86 24 2398-6429
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W. Li et al.
Arch. Pharm. Chem. Life Sci. 2011, 11, 349–357
Figure 1. The structures of sorafenib, aryl urea modified sorafenib analogs and the target compounds.
introduced to investigate the influence of the substitution
position and electrical effect of the arylidene motif.
micromolar range (Table 1). Especially the most promising
compound 7r inhibited the proliferation of A549, H460 and
HT29 cell lines with the IC50 value of 0.8, 1.3 and 2.8 mM. In
addition, compound 7w exhibited the optimal activity
against HT29 cell line with the IC50 value of 0.2 mM, and
compound 7t, the most potent compound against H460 cell
line selectively, possessed an IC50 value of 0.3 mM.
Results and discussion
Chemistry
The synthetic route was illustrated as outlined in Scheme 1.
Chloration of the commercial available picolinic acid in
thionyl chloride afforded 2, which was subsequently reacted
with 2.0 M methyl amine in tetrahydrofuran to give the
The preliminary structure–activity relationships (SARs)
suggested that substituted arylidene on the C-500 position
of the rhodanine ring is essential for the antitumoral activity.
A case in point is that compound 6 exhibited less antitumor
activity than the target compounds. Introduction of a hetero-
cyclidene (e.g. pyridin-4-yl-methylene, thiophen-2-yl-methy-
lene, and 1H-indol-3-yl-methylene) led to weakened antitumor
activity, while the introduction of benzylidene showed
enhanced antitumor activity in most compounds.
Pharmacological data indicated that the substitution po-
sition of the substituents on the benzylidene influences the
antitumor activities of the target compounds dramatically.
As shown in Table 1, it was obvious that compounds 7g, 7m,
7r and 7t with groups on the ortho-position or both ortho- and
para-position of the benzylidene showed a remarkable anti-
tumor activity against A549, H460 and HT29 cell lines.
Interestingly, a potential tendency was found that the po-
sition influenced the selectivity of HT29 cell line. Compounds
7w, 7s and 7q with a substitution on the para-position of the
benzylidene are relatively well tolerated against HT29 cell
line than the other two cell lines. However, similar tendency
corresponding compound
3
as pale-yellow crystals.
Etherification of 3 with 4-aminophenol in the presence of
potassium tert-butoxide led to the formation of the intermedi-
ate 4. Compound 5 was prepared by reacting the intermedi-
ate
4 with thiophosgen in chloroform and sodium
bicarbonate. Cyclization of 5 and thioglycolic in 1,4-dioxane
furnished the key rhodanine intermediate 6 in good yield.
Knoevenagel condensation of 6 and different substituted
aromatic aldehydes in the presence of piperidine in ethanol
gave the target compounds 7a–7x and 8a–8e.
Biological activities
In-vitro evaluation of the key intermediate 6 and the target
compounds 7a–7x and 8a–8e were performed by MTT assay
using three human cancer cell lines, A549, H460 and HT29.
The biological activity data were presented in Table 1. Some
of the compounds exhibited enhanced antitumor potency
compared to sorafenib against one or more cell lines in a low
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Arch. Pharm. Chem. Life Sci. 2011, 11, 349–357
Rhodanine-containing Sorafenib Analogs
351
Scheme 1. Synthesis of target compounds.
for different substituents of the benzylidene in the A549 and Experimental protocols
H460 are difficult to determine. It is noteworthy that the
nature of the substituents on the benzylidene affects the
antitumor activity. An electron withdrawing group exhibited
moderate to significant influence on antitumor activity.
Among the electron withdrawing groups, fluorine is more
preferable, while other electron withdrawing groups such
as chlorine, bromine, trifluoromethoxy group and the
trifluoromethyl group exhibited less antitumor potency than
fluorine (e.g. 7t and the most promising compound 7r showed
more potent antitumor activity among the tested compounds).
In contrast, an electron donating group including the hydroxyl
group and methoxy group showed no evident influence on
potency. This study may provide valuable information for
further design of rhodanine-containing antitumor agents.
Chemistry
All melting points were obtained on a Bu¨chi Melting Point B-
540 apparatus (Bu¨chi Labortechnik, Flawil, Switzerland) and
were uncorrected. Mass spectra (MS) were taken in ESI mode
on Agilent 1100 LC-MS (Agilent, Palo Alto, CA, USA). Proton
(1H) nuclear magnetic resonance spectroscopy was performed
using Bruker ARX-300, 300MHz spectrometers (Bruker
Bioscience, Billerica, MA, USA) with TMS as an internal stand-
ard. Column chromatography was run on silica gel (200–
300 mesh) from Qingdao Ocean Chemicals (Qingdao,
Shandong, China). Unless otherwise noted, all materials were
obtained from commercially available sources and were used
without further purification.
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Table 1. IC50 value for tested compounds 7a–7x and 8a–8e (mM) against A549, H460 and HT29 cancer cell lines
S
S
S
S
S
S
R
R
N
N
N
O
O
O
O
N
O
N
O
N
H
N
H
H
N
N
6
8a-8e
7a-7x
O
O
O
Compd.
R
IC50 (mM)
A549
H460
HT29
6
–
–
43.6
12.8
3.8
77.2
29.3
26.4
14.3
95.3
NA a
47.9
8.6
11.3
NA a
16.7
NA a
6.7
48.0
NA a
17.7
38.5
5.5
7a
7b
7c
7d
7e
2,4,6-trimethoxy
2,3,4-trimethoxy
3-methoxy-4-hydroxy
3-hydroxy-4-methoxy
3,4-dihydroxy
7.9
22.6
NA a
3.6
5.6
5.9
NA a
43.6
33.5
33.1
16.4
NA a
12
NA a
46
0.8
58.3
3.1
22.3
3.8
3.1
46.5
64.9
6.7
a NA
a NA
89
NA a
4.3
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
7u
7v
7w
7x
8a
8b
8c
8d
8e
Sorafenib
2,4-dichloro
2,3-dichloro
1.4
5.8
3.6
3
34.7
NA a
14.2
NA a
17.6
8.7
1.8
2.8
1.2
2.8
5.5
3.0
0.2
3,4,5-trimethoxy
3-bromo-4,5-dihydroxy
2,3,4-trihedroxy
4-benzo[d][10,30]dioxole
2,4-dimethoxy
3-hydroxy
3,5-dimethoxy-4-hydroxy
4-hydroxy
4-methoxy
4.8
NA a
59.8
NA a
9.5
2-fluoro
4-fluoro
2,4-difluoro
3,4-difluoro
1.3
6.3
0.3
NA a
1.5
2-chloro-4-fluoro
4-trifluoromethoxy
4-trifluoromethyl
2-oxoindolin-3-ylidene
1H-indol-3-yl
5-hydroxythiophen-2-yl
thiophen-2-yl
pyridin-4-yl
NA a
64.8
a NA
21.4
a NA
65.8
a NA
2.7
17.2
a NA
72.9
33.7
18.5
43
–
1.3
3.7
a
NA, not active
4-Chloropicolinoyl chloride 2
was then cooled to room temperature, diluted with toluene
(200 mL) and concentrated under reduced pressure to 70 mL.
This process was repeated twice to give 2 as brown oil which
was used in the next step without further purification.
Anhydrous N,N-dimethylformamide (0.1 mL) was added to
thionyl chloride (90 mL) at 508C under nitrogen. The solution
was stirred at 508C for 10 min prior to portionwise addition
of picolinic acid 1 (30 g, 0.244 mol) over 30 min. The initial
green color went to orange and then to purple. The solution
was heated to reflux, and vigorous SO2 evolution was
observed. A yellow solid precipitated after 17 h. The mixture
4-Chloro-N-methylpicolinamide 3
4-Chloropicolinoyl chloride 2 (20.0 g, 113.7 mmol) was added
portionwise to 2.0 M methylamine in tetrahydrofuran
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Arch. Pharm. Chem. Life Sci. 2011, 11, 349–357
Rhodanine-containing Sorafenib Analogs
353
(350 mL) and methanol (70 mL) at 08C. The mixture was
stirred at ambient temperature for 2 h, concentrated nearly
to dryness and dissolved in ethyl acetate (350 mL). The
organics were washed with brine (350 mL), dried over sodium
sulfate and concentrated to provide 3 (16.0 g, 94.3 mmol,
83%) as a yellow, crystalline solid, m.p.: 41–428C.
ethanol to give 6 (12.6 g, 35.2 mmol, 66%) as light yellow
solid. 1H-NMR (300 MHz, DMSO) d: 8.814–8.79 (m, 1H), 8.58
(d, J ¼ 5.4 Hz, 1H), 7.48 (d, J ¼ 3 Hz, 1H), 7.43–7.36 (m, 4H),
7.24–7.21 (q, J ¼ 3 Hz, J ¼ 5.4 Hz, 1H), 4.4 (s, 2H), 2.80
(d, J ¼ 4.5 Hz, 3H); ESI-MS m/z: 360.1 (M þ H)þ; Anal. calcd.
for C16H13N3O3S2 (%): C, 53.47, H, 3.56, N, 11.69, O, 13.35,
S, 17.84; found: C, 53.35, H, 3.58, N, 11.53, S, 17.95.
4-(4-Aminophenoxy)-N-methylpicolinamide 4
A solution of 4-aminophenol (9.6 g, 88.0 mmol) in dry N,N-
dimethylformamide (150 mL) was treated with potassium
tert-butoxide (10.29 g, 91.69 mmol), and the reddish-brown
mixture was stirred at room temperature for 2 h. The con-
tents were treated with 4-chloro-N-methylpicolinamide 3
(15.0 g, 87.9 mmol) and potassium carbonate (6.5 g,
47.0 mmol) and then heated to 808C under nitrogen for
6 h. The mixture was cooled to room temperature and
poured into the mixture of ethyl acetate (500 mL) and brine
(500 mL). The layers were separated and the aqueous phase
was back-extracted with ethyl acetate (300 mL). The combined
organics were washed with brine (4 ꢀ 300 mL), dried over
sodium sulfate and concentrated to afford 4 (17.1 g, 70.3 mmol,
80%) as a purple solid. 1H-NMR (300 MHz, DMSO) d: 8.74–8.72 (m,
1H), 8.45 (d, J ¼ 5.4 Hz, 1H), 7.34 (d, J ¼ 3 Hz, 1H), 7.07–7.05
(q, J ¼ 3 Hz, J ¼ 5.4 Hz, 1H), 6.87 (d, J ¼ 8.4 Hz, 2H), 6.66
(d, J ¼ 8.7 Hz, 2H), 2.78 (d, J ¼ 4.8 Hz, 3H); ESI-MS m/z: 244.0
(M þ H)þ; Anal. calcd. for C13H13N3O2 (%): C, 64.19, H, 5.38, N,
17.27, O, 13.15; found: C, 64.45, H, 5.33, N, 17.24.
General procedure for the preparation of compounds 7a–
7x and 8a–8e
A mixture of N-methyl-4-(4-(4-oxo-2-thioxothiazolidin-3-yl)-
phenoxy)picolinamide
6 (0.1 g, 0.28 mmol), substituted
benzaldehyde (0.42 mmol) and a drop of piperidine in
absolute ethanol (5 mL) was refluxed for 2–12 h to partici-
pate the crude product. The crude product was recrystallized
from proper solvent or purified by chromatography on silica
gel using MeOH/CH2Cl2 to afford the solids 7a–7x and 8a–8e.
(Z)-4-(4-(5-Benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-
phenoxy)-N-methylpicolinamide 7a
Flash chromatography (silica gel, methylene chloride/meth-
1
anol (30:1)). Yield: 66%; m.p.: 227–2288C. H-NMR (300 MHz,
DMSO) d: 8.82–8.81 (m, 1H), 8.60 (d, J ¼ 6.0 Hz, 1H), 7.87
(s, 1H), 7.73 (d, J ¼ 6.9 Hz, 2H), 7.62–7.54 (m, 5H), 7.51
(d, J ¼ 2.7 Hz, 1H), 7.44 (d, J ¼ 8.7 Hz, 2H), 7.26–7.24
(q, J ¼ 2.7 Hz, J ¼ 6 Hz, 1H), 2.81 (d, J ¼ 4.8 Hz, 3H); ESI-MS
m/z: 447.9 (M þ H)þ; Anal. calcd. for C23H17N3O3S2 (%):
C, 61.73, H, 3.83, N, 9.39, O, 10.73, S, 14.33; found:
C, 62.01, H, 3.85, N, 9.32, S, 14.28.
4-(4-Isothiocyanatophenoxy)-N-methylpicolinamide 5
To a stirred solution of 4-(4-aminophenoxy)-N-methylpicoli-
namide 4 (17.1 g, 70.3 mmol) in 1300 mL of a 6% NaHCO3
solution was added 600 mL CH2Cl2. After 20 min of vigorous
stirring at 08C, thiophosgene (4.1 mL, 70.3 mmol) was added
dropwise. The reaction mixture was left under stirring for 5 h
at room temperature and the organic solvent was removed
under reduced pressure. The crude residue was washed with
cold ethanol to afford 5 (15.4 g, 54.1 mmol, 77%) as a brown
powder. 1H-NMR (300 MHz, DMSO) d: 8.79–8.78 (m, 1H), 8.54
(d, J ¼ 6 Hz, 1H), 7.59 (d, J ¼ 9.3 Hz, 2H), 7.43(d, J ¼ 3 Hz,
1H), 7.32 (d, J ¼ 8.7 Hz, 2H), 7.20–7.17 (q, J ¼ 3 Hz, J ¼ 6 Hz,
1H), 2.80 (d, J ¼ 4.5 Hz, 3H); ESI-MS m/z: 286.2 (M þ H)þ; Anal.
calcd. for C14H11N3O2S (%): C, 58.93, H, 3.89, N, 14.73, O,
11.22, S, 11.24; found: C, 58.78, H, 3.92, N, 14.73, S, 11.31.
(Z)-N-Methyl-4-(4-(4-oxo-2-thioxo-5-(2,4,6-
trimethoxybenzylidene)thiazolidin-3-yl)-
phenoxy)picolinamide 7b
Flash chromatography (silica gel, methylene chloride/meth-
1
anol (30:1)). Yield: 62%; m.p.: 243–2448C. H-NMR (300 MHz,
DMSO) d: 8.81–8.80 (m, 1H), 8.59 (d, J ¼ 5.7 Hz, 1H), 8.01
(s, 1H), 7.54 (d, J ¼ 8.7 Hz, 2H), 7.50 (d, J ¼ 2.7 Hz, 1H),
7.40 (d, J ¼ 8.7 Hz, 2H), 7.25–7.22 (q, J ¼ 2.7 Hz, J ¼ 5.7 Hz,
1H), 6.37 (s, 2H), 3.93 (s, 6H), 3.89 (s, 3H), 2.81 (d, J ¼ 4.8 Hz,
3H); ESI-MS m/z: 538.1 (M þ H)þ; Anal. calcd. for C26H23N3O6S2
(%): C, 58.09, H, 4.31, N, 7.82, O, 17.76, S, 11.93; found:
C, 58.03, H, 4.33, N, 7.64, S, 11.97.
(Z)-N-Methyl-4-(4-(4-oxo-2-thioxo-5-(2,3,4-
trimethoxybenzylidene)thiazolidin-3-yl)-
N-Methyl-4-(4-(4-oxo-2-thioxothiazolidin-3-yl)-
phenoxy)picolinamide 6
phenoxy)picolinamide 7c
A mixture of 2-sulfanylacetic acid (3.8 mL, 54.1 mmol), 4-
(4-isothiocyanatophenoxy)-N-methylpicolinamide 5 (15.4 g,
54.1 mmol) and triethylamine (7.6 mL, 54.1 mmol) in di-
oxane (90 mL) was refluxed for 3 h. The reaction mixture
was left to cool at room temperature. The solid product, so
formed, was collected by filtration and recrystallized from
Yield: 31%; m.p.: 248–2498C. 1H-NMR (300 MHz, DMSO) d:
8.82–8.80 (m, 1H), 8.59 (d, J ¼ 6.0 Hz, 1H), 7.87 (s, 1H), 7.58
(d, J ¼ 8.7 Hz, 2H), 7.50 (d, J ¼ 2.7 Hz, 1H), 7.42 (d, J ¼ 6.9 Hz,
2H), 7.31 (d, J ¼ 9.0 Hz, 1H), 7.26–7.23 (q, J ¼ 2.7 Hz,
J ¼ 6.0 Hz, 1H), 7.08 (d, J ¼ 9.0 Hz, 1H), 3.91 (s, 6H), 3.80
(s, 3H), 2.81 (d, J ¼ 5.4 Hz, 3H); ESI-MS m/z: 537.9 (M þ H)þ;
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Anal. calcd. for C26H23N3O6S2 (%): C, 58.09, H, 4.31, N, 7.82,
O, 17.76, S, 11.93; found: C, 58.21, H, 4.29, N, 7.76, S, 11.79.
7.84–7.81 (q, J ¼ 1.8 Hz, J ¼ 7.2 Hz, 1H), 7.66–7.62 (m, 2H),
7.61–7.58 (m, 2H), 7.51 (d, J ¼ 3.0 Hz, 1H)7.43 (d, J ¼ 6.6 Hz,
2H), 7.26–7.23 (q, J ¼ 3.0 Hz, J ¼ 5.1 Hz, 1H), 2.81
(d, J ¼ 4.8 Hz, 3H); ESI-MS m/z: 514.5, 516.5 (M þ H)þ; Anal.
calcd. for C23H15Cl2N3O3S2 (%): C, 53.49, H, 2.93, Cl, 13.73,
N, 8.14, O, 9.29, S, 12.42; found C, 53.68, H, 2.90, N, 7.99,
S, 12.35.
(Z)-4-(4-(5-(4-Hydroxy-3-methoxybenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolin-amide 7d
Flash chromatography (silica gel, methylene chloride/meth-
1
anol (30:1)). Yield: 71%; m.p.: 231–2328C. H-NMR (300 MHz,
DMSO) d: 10.1 (br, 1H), 8.83–8.80 (m, 1H), 8.59 (d, J ¼ 5.7 Hz,
1H), 7.79 (s, 1H), 7.58 (d, J ¼ 8.7 Hz, 2H), 7.51 (d, J ¼ 2.1 Hz,
1H), 7.43 (d, J ¼ 8.7 Hz, 2H), 7.28–7.24 (m, 2H), 7.21–7.08
(q, J ¼ 1.8 Hz, J ¼ 6 Hz, 1H), 7.00 (d, J ¼ 6 Hz, 1H), 3.86
(s, 3H), 2.81 (d, J ¼ 4.5 Hz, 3H); ESI-MS m/z: 493.8 (M þ H)þ;
Anal. calcd. for C24H19N3O5S2 (%): C, 58.40, H, 3.88, N, 8.51,
O, 16.21, S, 12.99; found: C, 58.17, H, 3.85, N, 8047, S, 12.89.
(Z)-N-Methyl-4-(4-(4-oxo-2-thioxo-5-(3,4,5-
trimethoxybenzylidene)thiazolidin-3-yl)-
phenoxy)picolinamide 7i
Flash chromatography (silica gel, methylene chloride/
methanol (30:1)). Yield: 68%; m.p.: 252–2538C. 1H-NMR
(300 MHz, DMSO) d: 8.81–8.80 (m, 1H), 8.59 (d, J ¼ 6.0 Hz,
1H), 7.82 (s, 1H), 7.59 (d, J ¼ 8.7 Hz, 2H), 7.51 (d, J ¼ 3.0 Hz,
1H), 7.44 (d, J ¼ 8.7 Hz, 2H), 7.28–7.24 (q, J ¼ 3.0 Hz,
J ¼ 6.0 Hz, 1H), 7.02 (s, 2H), 3.88 (s, 6H), 3.76 (s, 3H),
2.81 (d, J ¼ 5.1 Hz, 3H); ESI-MS m/z: 538.0 (M þ H)þ; Anal.
calcd. for C26H23N3O6S2 (%): C, 58.09, H, 4.31, N, 7.82,
O, 17.86, S, 11.93; found: C, 58.45, H, 4.22, N, 7.96, S, 12.05.
(Z)-4-(4-(5-(3-Hydroxy-4-methoxybenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7e
Yield: 63%; m.p.: 240–2418C. 1H-NMR (300 MHz, DMSO) d:
8.81–8.80 (m, 1H), 8.59 (d, J ¼ 6.0 Hz, 1H), 7.72 (s, 1H), 7.58
(d, J ¼ 9.0 Hz, 2 H), 7.51 (d, J ¼ 2.4 Hz, 1H), 7.44 (d, J ¼ 9.0 Hz,
2 H), 7.26–7.21 (m, 2H), 7.14–7.11(m, 2H), 3.86 (s, 3H), 2.81
(d, J ¼ 4.8 Hz, 3H); ESI-MS m/z: 493.9 (M þ H)þ; Anal. calcd.
for C24H19N3O5S2 (%): C, 58.40, H, 3.88, N, 8.51, O, 16.21,
S, 12.99; found: C, 58.37, H, 3.85, N, 8.39, S, 13.11.
(Z)-4-(4-(5-(3-Bromo-4-hydroxy-5-methoxybenzylidene)-
4-oxo-2-thioxothiazolidin-3-yl)phenoxy)-N-
methylpicolinamide 7j
Flash chromatography (silica gel, methylene chloride/meth-
1
anol (30:1)). Yield: 35%; m.p.: 233–2348C. H-NMR (300 MHz,
(Z)-4-(4-(5-(3,4-Dihydroxybenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7f
Yield: 46%; m.p.: 237–2388C. 1H-NMR (300 MHz, DMSO) d:
8.82–8.80 (m, 1H), 8.59 (d, J ¼ 6.0 Hz, 1H), 7.68 (s, 1H), 7.57
(d, J ¼ 9.3 Hz, 2H), 7.52 (d, J ¼ 3 Hz, 1H), 7.42 (d, J ¼ 8.7 Hz,
2H), 7.26–7.23 (q, J ¼ 2.7 Hz, J ¼ 6.0 Hz, 1H), 7.11–7.09
(m, 2H), 6.93 (d, J ¼ 8.7 Hz, 1H), 2.81 (d, J ¼ 4.8 Hz, 3H);
ESI-MS m/z: 480.2 (M þ H)þ; Anal. calcd. for C24H17N3O5S2
(%): C, 57.61, H, 3.57, N, 8.76, O, 16.68, S, 13.37; found:
C, 57.30, H, 3.55, N, 8.65, S, 13.51.
DMSO) d: 10.61 (br, 1H), 8.81–8.78 (m, 1H), 8.59 (d, J ¼ 2.1 Hz,
1H), 7.78 (s, 1H), 7.58 (d, J ¼ 8.1 Hz, 2H), 7.51–7.49 (m, 2H),
7.43 (d, J ¼ 8.4 Hz, 2H), 7.27–7.23 (m, 2H), 3.93 (s, 3H), 2.81
(d, J ¼ 4.8 Hz, 3H); ESI-MS m/z: 572.7 (M þ H)þ; Anal.
calcd. for C24H18BrN3O5S2 (%): C, 50.35, H, 3.17, N, 13.96,
O, 13.97, S, 11.20; found: C, 50.61, H, 3.22, N, 13.88,
S, 11.31.
(Z)-N-Methyl-4-(4-(4-oxo-2-thioxo-5-(2,3,4-
trihydroxybenzylidene)thiazolidin-3-
yl)phenoxy)picolinamide 7k
(Z)-4-(4-(5-(2,4-Dichlorobenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7g
Flash chromatography (silica gel, methylene chloride/meth-
1
anol (30:1)). Yield: 70%; m.p.: 244–2458C. H-NMR (300 MHz,
Flash chromatography (silica gel, methylene chloride/meth-
1
anol (30:1)). Yield: 42%; m.p.: 229–2308C. H-NMR (300 MHz,
DMSO) d: 8.80–8.79 (m, 1H), 8.59 (d, J ¼ 5.7 Hz, 1H), 8.02
(s, 1H), 7.56–7.50 (m, 3H), 7.41 (d, J ¼ 8.4 Hz, 2H), 7.24–7.23
(m, 1H), 6.84 (d, J ¼ 8.4 Hz, 1H), 6.57 (d, J ¼ 8.4 Hz, 1H),
2.81 (d, J ¼ 4.8 Hz, 3H); ESI-MS m/z: 495.5 (M þ H)þ; Anal.
calcd. for C23H17N3O6S2 (%): C, 55.75, H, 3.46, N, 8.48,
O, 19.37, S, 12.94; found: C, 55.68, H, 3.35, N, 8.37, S, 13.09.
DMSO) d: 8.81–8.79 (m, 1H), 8.59 (d, J ¼ 6.0 Hz, 1H), 7.91 (s, 1H),
7.87 (s, 1H), 7.72 (d, J ¼ 10.0 Hz, 2H), 7.60 (d, J ¼ 9.0 Hz, 2H), 7.51
(d, J ¼ 3.0 Hz, 1H), 7.44 (d, J ¼ 9.0 Hz, 2H), 7.26–7.24
(q, J ¼ 3.0 Hz, J ¼ 6.0 Hz, 1H), 2.81 (d, J ¼ 5.1 Hz, 3H); ESI-MS
m/z: 514.2, 516.2 (M þ H)þ; Anal. calcd. for C23H15Cl2N3O3S2 (%):
C, 53.49, H, 2.93, Cl, 13.73, N, 8.14, O, 9.29, S, 12.42; found:
C, 53.61, H, 2.85, N, 8.08, S, 21.21.
(Z)-4-(4-(5-(Benzo[d][1,3]dioxol-5-ylmethylene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7l
Yield: 58%; m.p.: 235–2368C. 1H-NMR (300 MHz, DMSO) d:
8.81–8.79 (m, 1H), 8.59 (d, J ¼ 5.4 Hz, 1H), 7.80 (s, 1H), 7.58
(d, J ¼ 8.7 Hz, 2H), 7.51 (d, J ¼ 3 Hz, 1H), 7.43 (d, J ¼ 8.7 Hz,
2H), 7.30–7.23 (m, 3H), 7.16 (d, J ¼ 8.7 Hz, 1H), 6.17 (s, 2H),
(Z)-4-(4-(5-(2,3-Dichlorobenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7h
Yield: 55%; m.p.: 240–2418C. 1H-NMR (300 MHz, DMSO) d:
8.81–8.80 (m, 1H), 8.59 (d, J ¼ 5.1 Hz, 1H), 7.93 (s, 1H),
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Arch. Pharm. Chem. Life Sci. 2011, 11, 349–357
Rhodanine-containing Sorafenib Analogs
355
2.81 (d, J ¼ 4.5 Hz, 3H); ESI-MS m/z: 491.7 (M þ H)þ; Anal.
calcd. for C24H17N3O5S2 (%): C, 58.64, H, 3.49, N, 8.55,
O, 16.27, S, 13.05; found: C, 58.46, H, 3.53, N, 8.69, S, 12.89.
(Z)-4-(4-(5-(4-Methoxybenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7q
Flash chromatography (silica gel, methylene chloride/meth-
1
anol (30:1)). Yield: 58%; m.p.: 225–2268C. H-NMR (300 MHz,
(Z)-4-(4-(5-(2,4-Dimethoxybenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7m
DMSO) d: 8.81–8.79 (m, 1H), 8.59 (d, J ¼ 6.0 Hz, 1H), 7.83
(s, 1H), 7.70 (d, J ¼ 8.7 Hz, 2H), 7.58 (dd, J ¼ 8.4 Hz, 2H),
7.51 (d, J ¼ 3.0 Hz, 1H), 7.43 (dd, J ¼ 8.7 Hz, 2H), 7.26–7.24
(q, J ¼ 3.0 Hz, J ¼ 6.0 Hz, 1H), 7.17 (d, J ¼ 4.8 Hz, 2H), 2.81
(d, J ¼ 4.8 Hz, 3H); ESI-MS m/z: 478.3 (M þ H)þ; Anal. calcd.
for C24H19N3O4S2 (%): C, 60.36, H, 4.01, N, 8.80, O, 13.40,
S, 13.43; found: C, 60.62, H, 40.6, N, 9.02, S, 13.59.
Flash chromatography (silica gel, methylene chloride/meth-
1
anol (30:1)). Yield: 61%; m.p.: 226–2278C. H-NMR (300 MHz,
DMSO) d: 8.81–8.79 (m, 1H), 8.59 (d, J ¼ 6.0 Hz, 1H), 7.93
(s, 1H), 7.56 (d, J ¼ 8.7 Hz, 2H), 7.50 (d, J ¼ 3.0 Hz, 1H),
7.48 (d, J ¼ 8.4 Hz, 1H), 7.42 (d, J ¼ 9.0 Hz, 2H), 7.25–7.22
(q, J ¼ 3.0 Hz, J ¼ 6.0 Hz, 1H), 6.78–6.73 (m, 2H), 3.94 (s, 3H),
3.88 (s, 3H), 2.81 (d, J ¼ 4.5 Hz, 3H); ESI-MS m/z: 508.0
(M þ H)þ; Anal. calcd. for C25H21N3O5S2 (%): C, 59.16,
H, 4.17, N, 8.28, O, 15.76, S, 12.63; found: C, 59.27, H, 3.99,
N, 8.51, S, 12.79.
(Z)-4-(4-(5-(2-Fluorobenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7r
Yield: 63%; m.p.: 228–2298C. 1H-NMR (300 MHz, DMSO) d:
8.81–8.79 (m, 1H), 8.59 (d, J ¼ 6.0 Hz, 1H), 7.82 (s, 1H),
7.68–7.57 (m, 4H), 7.51 (d, J ¼ 2.7 Hz, 1H), 7.48–7.41
(m, 4H), 7.26–7.23 (q, J ¼ 2.7 Hz, J ¼ 6.0 Hz, 1H), 2.81
(d, J ¼ 4.5 Hz, 3H); ESI-MS m/z: 465.7 (M þ H)þ; Anal. calcd.
for C23H16FN3O3S2 (%): C, 59.34, H, 3.46, F, 4.08, N, 9.03,
O, 10.31, S, 13.78; found: C, 59.60, H, 3.53, N, 8.89, S, 13.91.
(Z)-4-(4-(5-(3-Hydroxybenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7n
Flash chromatography (silica gel, methylene chloride/meth-
1
anol (30:1)). Yield: 65%; m.p.: 236–2378C. H-NMR (300 MHz,
DMSO) d: 9.91(s, 1H), 8.81–8.80 (m, 1H), 8.59 (d, J ¼ 6.0 Hz,
1H), 7.77 (s, 1H), 7.59 (d, J ¼ 8.7 Hz, 2H), 7.51 (d, J ¼ 2.4 Hz,
1H), 7.43 (d, J ¼ 9.0 Hz, 2H), 7.38 (d, J ¼ 8.4 Hz, 1.8), 7.26–7.23
(q, J ¼ 2.4 Hz, J ¼ 6.0 Hz, 1H), 7.16 (d, J ¼ 7.5 Hz, 1H), 7.08
(s, 1H), 6.96 (d, J ¼ 7.5 Hz, 1H), 2.81 (d, J ¼ 4.8 Hz, 3H); ESI-MS
m/z: 463.9 (M þ H)þ; Anal. calcd. for C23H17N3O4S2 (%):
C, 59.60, H, 3.70, N, 9.07, O, 13.81, S, 13.84; found:
C, 59.60, H, 3.72, N, 9.01, S, 13.77.
(Z)-4-(4-(5-(4-Fluorobenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7s
Yield: 68%; m.p.: 225–2268C. 1H-NMR (300 MHz, DMSO) d:
8.81–8.79 (m, 1H), 8.59 (d, J ¼ 6.0 Hz, 1H), 7.89 (s, 1H),
7.82–7.76 (q, J ¼ 5.4 Hz, J ¼ 9.0 Hz, 2H), 7.59 (d, J ¼ 8.7 Hz,
2H), 7.51 (d, J ¼ 3.0 Hz, 1H), 7.45–7.41(m, 4H), 7.26–7.23
(q, J ¼ 3.0 Hz, J ¼ 6.0 Hz, 1H), 2.81 (d, J ¼ 4.8 Hz, 3H); ESI-
MS m/z: 465.4 (M þ H)þ; Anal. calcd. for C23H16FN3O3S2 (%):
C, 59.34, H, 3.46, F, 4.08, N, 9.03, O, 10.31, S, 13.78; found
C, 59.68, H, 3.52, N, 8.97, S, 14.00.
(Z)-4-(4-(5-(4-Hydroxy-3,5-dimethoxybenzylidene)-4-oxo-
2-thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7o
Yield: 43%; m.p.: 241–2428C. 1H-NMR (300 MHz, DMSO) d: 9.56
(s, 1H), 8.81–8.79 (m, 1H), 8.59 (d, J ¼ 6.0 Hz, 1H), 7.79 (s, 1H),
7.58 (d, J ¼ 8.7 Hz, 2H), 7.51 (d, J ¼ 3.0 Hz, 1H), 7.43
(d, J ¼ 8.7 Hz, 2H), 7.26–7.23 (q, J ¼ 3.0 Hz, J ¼ 6.0 Hz, 1H),
6.99 (s, 2H), 3.86 (s, 6H), 2.81 (d, J ¼ 4.8 Hz, 3H); ESI-MS
m/z: 523.7 (M þ H)þ; Anal. calcd. for C25H21N3O6S2 (%):
C, 57.35, H, 4.04, N, 8.03, O, 18.33, S, 12.25; found:
C, 57.78, H, 4.01, N, 8.21, S, 11.99.
(Z)-4-(4-(5-(2,4-Difluorobenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7t
Yield: 62%; m.p.: 224–2258C. 1H-NMR (300 MHz, DMSO) d:
8.81–8.79 (m, 1H), 8.59 (d, J ¼ 6.0 Hz, 1H), 7.75 (s, 1H),
7.74–7.70(m, 1H), 7.59–7.55 (m, 3H), 7.50 (d, J ¼ 3.0 Hz,
1H), 7.44 (dd, J ¼ 8.7 Hz, 2H), 7.35–7.31 (m, 1H), 7.26–7.23
(q, J ¼ 3.0 Hz, J ¼ 6.0 Hz, 1H), 2.81 (d, J ¼ 4.8 Hz, 3H); ESI-MS
m/z: 483.2 (M þ H)þ; Anal. calcd. for C23H15F2N3O3S2 (%):
C, 57.13, H, 3.13, F, 7.86, N, 8.69, O, 9.93, S, 13.26; found:
C, 56.89, H, 3.19, N, 8.81, S, 13.03.
(Z)-4-(4-(5-(4-Hydroxybenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7p
Flash chromatography (silica gel, methylene chloride/meth-
1
anol (30:1)). Yield: 39%; m.p.: 221–2228C. H-NMR (300 MHz,
(Z)-4-(4-(5-(3,4-Difluorobenzylidene)-4-oxo-2-
DMSO) d: 10.49 (s, 1H), 8.81–8.79 (m, 1H), 8.59 (d, J ¼ 6 Hz,
1H), 7.78 (s, 1H), 7.60–7.54 (m, 4H), 7.51 (d, J ¼ 3.0 Hz, 1H),
7.42 (d, J ¼ 8.7 Hz, 2H), 7.26–7.24 (q, J ¼ 3.0 Hz, J ¼ 6.0 Hz,
1H), 6.99 (d, J ¼ 6.0 Hz, 2H), 2.81 (d, J ¼ 4.5 Hz, 3H); ESI-MS
m/z: 463.9 (M þ H)þ; Anal. calcd. for C23H17N3O4S2 (%):
C, 59.60, H, 3.70, N, 9.07, O, 13.81, S, 13.84; found:
C, 59.88, H, 3.75, N, 8.86, S, 14.07.
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7u
Flash chromatography (silica gel, methylene chloride/methanol
(30:1)). Yield: 46%; m.p.: 231–2328C. 1H-NMR (300 MHz, DMSO) d:
8.81–8.79 (m, 1H), 8.60 (d, J ¼ 6.0 Hz, 1H), 7.89–7.82 (m, 2H),
7.72–7.63 (m, 1H), 7.59–7.56 (m, 3H), 7.51 (d, J ¼ 2.7 Hz, 1H), 7.44
(d, J ¼ 8.7 Hz, 2H), 7.26–7.24 (q, J ¼ 2.7 Hz, J ¼ 6.0 Hz, 1H), 2.81
(d, J ¼ 4.5 Hz, 3H); ESI-MS m/z: 483.7 (M þ H)þ; Anal. calcd.
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W. Li et al.
Arch. Pharm. Chem. Life Sci. 2011, 11, 349–357
for C23H15F2N3O3S2 (%): C, 57.13, H, 3.13, F, 7.86, N, 8.69, O, 9.93,
S, 13.26; found: C, 56.95, H, 3.12, N, 8.84, S, 13.40.
(br, 2H), 7.58–7.52 (m, 4H), 7.43 (d, J ¼ 8.4 Hz, 2H), 7.30–7.24
(m, 3H), 2.81 (d, J ¼ 4.5 Hz, 3H); ESI-MS m/z: 487.2 (M þ H)þ;
Anal. calcd. for C25H18N4O3S2 (%): C, 61.71, H, 3.73, N, 11.51,
O, 9.86, S, 13.18; found: C, 60.25, H, 3.28, N, 10.99, S, 12.67.
(Z)-4-(4-(5-(2-Chloro-4-fluorobenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 7v
Yield: 66%; m.p.: 235–2368C. 1H-NMR (300 MHz, DMSO) d: 8.81–
8.79 (m, 1H), 8.60 (d, J ¼ 6.0 Hz, 1H), 7.89 (s, 1H), 7.77–7.70 (m,
2H), 7.60 (d, J ¼ 8.7 Hz, 2H), 7.51 (d, J ¼ 2.7 Hz, 1H), 7.48
(d, J ¼ 3.0 Hz, 1H), 7.43 (d, J ¼ 8.7 Hz, 2H), 7.25–7.23
(q, J ¼ 2.7 Hz, J ¼ 5.4 Hz, 1H), 2.81 (d, J ¼ 4.8 Hz, 3H); ESI-
MS m/z: 499.1 (M þ H)þ; Anal. calcd. for C23H15ClF2N3O3S2
(%): C, 55.25, H, 3.02, Cl, 7.09, F, 3.80, N, 8.40, O, 9.60,
S, 12.83; found: C, 54.98, H, 2.93, N, 8.29, S, 12.67.
(Z)-4-(4-(5-((5-Hydroxythiophen-2-yl)methylene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicoli-namide 8c
Yield: 47%; m.p.: 233–2348C. 1H-NMR (300 MHz, DMSO) d:
8.79–8.77 (m, 1H), 8.57 (d, J ¼ 4.8 Hz, 1H), 7.50–7.41
(m, 5H), 7.33 (d, J ¼ 3 Hz, 1H), 7.24–7.22 (q, J ¼ 2.1 Hz,
J ¼ 6.0 Hz, 1H), 7.16 (d, J ¼ 3.6 Hz, 1H), 2.81 (d, J ¼ 4.8 Hz,
3H); ESI-MS m/z:470.2 (M þ H)þ; Anal. calcd. for C21H15N3O4S3
(%): C, 53.72, H, 3.22, N, 8.95, O, 13.63, S, 20.49; found:
C, 53.58, H, 3.19, N, 8.87, S, 20.21.
(Z)-N-Methyl-4-(4-(4-oxo-2-thioxo-5-(4-
(trifluoromethoxy)benzylidene)thiazolidin-3-yl)-
phenoxy)picolinamide 7w
(Z)-N-Methyl-4-(4-(4-oxo-5-(thiophen-2-ylmethylene)-2-
thioxothiazolidin-3-yl)phenoxy)picolinamide 8d
Flash chromatography (silica gel, methylene chloride/meth-
1
anol (25:1)). Yield: 61%; m.p.: 256–2578C. H-NMR (300 MHz,
Yield: 51%; m.p.: 238–2398C. 1H-NMR (300 MHz, DMSO) d:
8.81–8.80 (m, 1H), 8.59 (d, J ¼ 5.4 Hz, 1H), 8.16–8.14 (br,
2H), 7.83 (d, J ¼ 3.3 Hz, 1H), 7.51 (d, J ¼ 3.0 Hz, 1H), 7.59
(d, J ¼ 8.7 Hz, 2H), 7.51 (d, J ¼ 3.0 Hz, J ¼ 6.0 Hz, 1H), 7.43
(d, J ¼ 8.7 Hz, 2H), 7.37 (m, 1H), 7.26–7.23 (q, J ¼ 3.0 Hz,
J ¼ 6.0 Hz, 1H), 2.81 (d, J ¼ 4.5 Hz, 3H); ESI-MS m/z: 454.1
(M þ H)þ; Anal. calcd. for C21H15N3O3S3 (%): C, 55.61,
H, 3.33, N, 9.26, O, 10.58, S, 21.21; found: C, 56.00, H, 3.56,
N, 9.21, S, 21.50.
DMSO) d: 8.81–8.79 (m, 1H), 8.59 (d, J ¼ 6.0 Hz, 1H), 7.91
(s, 1H), 7.87 (d, J ¼ 9.0 Hz, 2H), 7.59–7.57 (m, 4H), 7.51
(d, J ¼ 3.0 Hz, 1H), 7.44 (d, J ¼ 8.7 Hz, 2H), 7.26–7.23
(q, J ¼ 3.0 Hz, J ¼ 6 Hz, 1H), 2.81 (d, J ¼ 5.1 Hz, 3H); ESI-MS
m/z: 531.2 (M þ H)þ; Anal. calcd. for C24H16F3N3O4S2 (%):
C, 54.23, H, 3.03, F, 10.72, N, 7.91, O, 12.04, S, 12.07; found:
C, 54.65, H, 2.99, N, 8.03, S, 12.31.
(Z)-N-Methyl-4-(4-(4-oxo-2-thioxo-5-(4-
(trifluoromethyl)benzylidene)thiazolidin-3-yl)-
phenoxy)picolinamide 7x
(Z)-N-Methyl-4-(4-(4-oxo-5-(pyridin-4-ylmethylene)-2-
thioxothiazolidin-3-yl)phenoxy)picolinamide 8e
Yield: 63%; m.p.: 229–2308C. 1H-NMR (300 MHz, DMSO) d:
8.81–8.77 (m, 3H), 8.60 (d, J ¼ 6.0 Hz, 1H), 7.83 (s, 1H), 7.65
(d, J ¼ 6 Hz, 2H), 7.60–7.57(m, 2H), 7.51 (d, J ¼ 3 Hz, 1H),
7.45–7.42 (m, 2H), 7.27–7.24 (q, J ¼ 3.0 Hz, J ¼ 6.0 Hz, 1H),
2.81 (d, J ¼ 4.8 Hz, 3H); ESI-MS m/z: 448.8 (M þ H)þ; Anal.
calcd. for C22H16N4O3S2 (%): C, 58.91, H, 3.60, N, 12.49,
O, 10.70, S, 14.30; found: C, 57.83, H, 4.11, N, 12.31, S, 14.35.
Yield: 75%; m.p.: 241–2428C. 1H-NMR (300 MHz, DMSO) d: 8.81–
8.80 (m, 1H), 8.60 (d, J ¼ 6.0 Hz, 1H), 7.96–7.91 (d, 5H), 7.61
(d, J ¼ 9.3 Hz, 2H), 7.51(d, J ¼ 3.0 Hz, 1H), 7.44 (d, J ¼ 9.3 Hz,
2H), 7.26–7.24 (q, J ¼ 3.0 Hz, J ¼ 6.0 Hz, 1H), 2.81 (d, J ¼ 4.8 Hz,
3H); ESI-MS m/z: 515.7 (M þ H)þ; Anal. calcd. for C24H16F3N3O3S2
(%): C, 55.91, H, 3.13, F, 11.06, N, 8.15, O, 9.31, S, 12.44; found:
C, 56.03, H, 3.19, N, 8.41, S, 12.65.
Pharmacology
(Z)-N-Methyl-4-(4-(4-oxo-5-(2-oxoindolin-3-ylidene)-2-
thioxothiazolidin-3-yl)phenoxy)picolinamide 8a
The cytotoxic activities of compounds 6, 7a–7x and 8a–8e
were evaluated with A549, H460 and HT29 cell lines by the
standard MTT assay. The cancer cell lines were cultured in
minimum essential medium (MEM) supplement with 10%
fetal bovine serum (FBS). The cells were maintained at
378C in a moisture-saturated atmosphere containing 5%
CO2. The compounds were used at concentrations ranging
from 0.16 to 100 mg/mL and sorafenib at the same concen-
trations was introduced as positive control. The assessment of
the antiproliferative activity was expressed as concentration
inhibiting 50% of cancer cell growth (IC50).
Yield: 31%; m.p.: 255–2568C. 1H-NMR (300 MHz, DMSO) d:
8.81–8.78 (m, 2H), 8.59 (d, J ¼ 3.0 Hz, 1H), 7.61–7.58
(m, 2H), 7.50–7.43 (m, 5H), 7.26–7.24 (m, 1H), 7.07–7.04
(m, 1H), 7.00 (d, J ¼ 6.0 Hz, 2H), 2.81 (d, J ¼ 4.8 Hz, 3H);
ESI-MS m/z: 489.6 (M þ H)þ; Anal. calcd. for C24H16N4O4S2
(%): C, 59.00, H, 3.30, N, 11.47, O, 13.10, S, 13.13; found:
C, 61.2, H, 3.52, N, 11.63, S, 13.22.
(Z)-4-(4-(5-((1H-Indol-3-yl)methylene)-4-oxo-2-
thioxothiazolidin-3-yl)phenoxy)-N-methylpicolinamide 8b
Yield: 45%; m.p.: 238–2398C. 1H-NMR (300 MHz, DMSO) d:
8.81–8.80 (m, 1H), 8.59 (d, J ¼ 5.1 Hz, 1H), 8.13 (s, 1H), 7.98
Approximately 4 ꢀ 103 cells, suspended in MEM medium,
were plated onto each well of a 96-well plate and plates were
incubated in 5% CO2 at 378C for 24 h before treatment with
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Arch. Pharm. Chem. Life Sci. 2011, 11, 349–357
Rhodanine-containing Sorafenib Analogs
357
the compounds to allow attachment to the wall of the plate.
The test compounds 6, 7a–7x and 8a–8e 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 mg/mL and incu-
bated with cells at 378C for 4 h. The formazan crystals were
dissolved in 100 mL DMSO each and the absorbencies at
492 nm (for absorbance of MTT formazan) and 630 nm (for
the reference wavelength) were measured with the ELISA
reader. All of the compounds were tested twice in each cell
line. The results expressed as IC50 (inhibitory concentration
50%) were the averages of two determinations and calculated
by using the Bacus Laboratories Incorporated Slide Scanner
(Bliss) software.
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The authors have declared no conflict of interest.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com