Synthesis of new chalcone derivatives bearing 2,4-thiazolidinedione and benzoic acid moieties as potential anti-bacterial agents

Article abstract of DOI:10.1016/j.ejmech.2011.05.012

A series of chalcone derivatives bearing the 2,4-thiazolidinedione and benzoic acid moieties (8a-s) were synthesized, characterized, and evaluated for their anti-bacterial activity. Among the tested compounds, the most effective were 8a, 8h, 8k, 8n and 8q

Full text of DOI:10.1016/j.ejmech.2011.05.012

European Journal of Medicinal Chemistry 46 (2011) 3469e3473
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of new chalcone derivatives bearing 2,4-thiazolidinedione and benzoic
acid moieties as potential anti-bacterial agents
*
Xiao-Fang Liu, Chang-Ji Zheng, Liang-Peng Sun, Xue-Kun Liu, Hu-Ri Piao
Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, Yanbian University College of Pharmacy,
Yanji 133002, 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 chalcone derivatives bearing the 2,4-thiazolidinedione and benzoic acid moieties (8aes) were
synthesized, characterized, and evaluated for their anti-bacterial activity. Among the tested compounds,
the most effective were 8a, 8h, 8k, 8n and 8q with MIC value in the range of 0.5e4 mg/mL against six
Gram-positive bacteria (including multidrug-resistant clinical isolates). None of the compounds
Received 25 March 2011
Received in revised form
3 May 2011
Accepted 4 May 2011
Available online 12 May 2011
exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 and E. coli 1682 at 64
m
g/mL.
Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords:
Chalcone
2,4-Thiazolidinedione
Benzoic acid
Anti-bacterial activity
1. Introduction
and the acetic acid moiety was changed to methylbenzoic acid. A total
of 19 chalcone derivatives bearing 2,4-thiazolidinedione and benzoic
acid moieties (8aes) were synthesized, characterized, and evaluated
for their anti-bacterial activity.
Bacterial infections can cause some of the most deadly diseases
and widespread epidemics in the world. With the increase in
resistance of bacteria to antibiotic treatment, it is significant to
develop novel approaches and new anti-bacterial agents as alter-
natives to existing antimicrobial therapies.
2. Chemistry
Chalcones and their derivatives have been reported to have
therapeutic potential including anti-inflammatory [1] and anti-
bacterial activities [2]. Thiazolidine and thiazolidinone are well
known as constitutional units in several agents possessing anti-
microbial [3], antituberculosis [4], and anti-HIV activities [5]. In
addition, benzoic acid derivatives, such as parabens, have been
used as antiseptics because of their powerful anti-bacterial
effects.
Previously, we reported the synthesis and antimicrobial evalua-
tion of (E)-4-(3-phenyl-3-oxoprop-1-enyl)benzaldehyde derivatives
[6] that showed a strong activity against Gram-positive strains
(including multidrug-resistant clinical isolates). Herein, as part of our
ongoing research, we designed and synthesized a new series of
chalcone derivatives in which the chalcone moiety was reserved,
4-thioxothiazolidine-2-one was replaced with 2,4-thiazolidinedione,
The synthesis of chalcone derivatives is presented in Scheme 1.
Thiazolidine-2,4-dione (2) was prepared by a previously described
method [7]. (Z)-4-((2,4-Dioxothiazolidin-5-ylidene)methyl)benzal-
dehyde (3) was prepared via Knoevenagel condensation between 2
and terephthalic aldehyde (1). ClaiseneSchmidt condensation
between 3 and various substituted acetophenones (4aep) afforded
the corresponding (Z)-5-(4-((E)-3-oxo-3-phenylprop-1-en-1-yl)
benzylidene)thiazolidine-2,4-dione derivatives (5aep) [8]. Methyl
4e(((Z)-2,4-dioxo-5-(4-((E)-3-oxo-3- phenylprop-1-en-1-yl)benzyl-
idene)thiazolidin-3-yl)methyl)benzoate derivatives (7aep) were
synthesized by reacting 5aep with methyl 4-(bromomethyl)
benzoate (6) using potassium carbonate as a base in refluxing
toluene. Hydroxy substituted derivatives (7qes) were prepared by
demethylation of the methoxy substituted derivatives (7nep) using
BBr3 in dichloromethane. Hydrolysis of 7aes was carried out in the
presence of acetic acid and hydrochloric acid to provide corre-
sponding carboxylic acids 8aes in good yields. The structures of the
desired compounds were determined by IR, 1H NMR, 13C NMR, mass
spectral and elemental analyses.
* Corresponding author. Tel.: þ86 433 2435003; fax: þ86 433 2435004.
E-mail address: piaohuri@yahoo.com.cn (H.-R. Piao).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.05.012

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X.-F. Liu et al. / European Journal of Medicinal Chemistry 46 (2011) 3469e3473
O
R
NH
O
O
R
S
CHO
4a-p
95% EtOH
KOH,
2
O
O
NH
NH
S
S
OHC
NaOAc, AcOH
OHC
reflux
O
O
O
3
1
5a-p
COOCH3
COOCH3
6
K2CO3, C6H5CH3 reflux
Br
O
H3CO
N
O
S
COOCH3
O
7n-p
O
N
O
R
BBr3
CH2Cl2
S
7a-p
COOCH3
O
O
HO
AcOH, HCl
reflux
N
S
O
COOH
O
7q-s
O
R
R: 8a: H
8f: 2-F
8k: 2-Br
8l: 3-Br
8m: 4-Br
8n: 2-OCH3
8o: 3-OCH3
8p: 4-OCH3
8q: 2-OH
8r: 3-OH
8s: 4-OH
N
S
8b: Phenyl(3,4-fused) 8g: 4-F
8c: 4-CH3
8d: 2,4-(CH3)2
8e: 2,4-(Cl)2
8h: 2-Cl
8i: 3-Cl
8j: 4-Cl
O
O
8a-s
Scheme 1. Synthetic scheme for the synthesis of compounds 8aes.
3. Results and discussion
corresponding carboxylic acids like 8a, 8h, 8k, 8n and 8r exhibited
significant activities. Secondly, the position of the substituent on
the phenyl ring significantly influenced the anti-bacterial activity of
the compounds. Among the chloro-, bromo- and methoxy
substituted compounds, the ortho-substituted derivatives showed
better anti-bacterial activity than the others. For the hydroxy
substituted derivatives, the ortho-substituted 8q was less active
than the meta-substituted 8r, which could be explained by the
3.1. Anti-bacterial activity
The in vitro anti-bacterial activity was evaluated using a 96-well
microtiter plate and a serial dilution method to obtain the
Minimum Inhibitory Concentration (MIC) with different strains
including multidrug-resistant clinical isolates. Oxacillin and nor-
floxacin were used as positive controls.
A preliminary in vitro assay showed that the intermediate esters
7aes did not exhibited any anti-bacterial activities at 64 mg/mL.
Table 1
Inhibitory activity (MIC,
mg/mL) of compounds 7aes and 8aes against bacteria.
Among the desired compounds, 8a, 8h, 8k, 8n and 8r showed
potent anti-bacterial activity against Gram-positive strains (Staph-
ylococcus aureus RN 4220 and S. aureus KCTC 503) and their MIC
values were in the range of 1e4 mg/mL, which was comparable to
the control drugs. The test compounds did not exhibit any activity
against Gram-negative strains (Escherichia coli 1356 and E. coli
1682) at 64 mg/mL (Table 1).
The MIC values against the clinical isolates of multidrug-
resistant Gram-positive bacterial strains are reported in Table 2.
Compounds 8a, 8h, 8k, 8n and 8r exhibited more potent activity
than the standard drugs (both oxacillin and norfloxacin) with MIC
Compound
S. aureus
E. coli
4220
503
1356
1682
7aes
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
>64
1
>64
2
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
16
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
16
>64
>64
>64
>64
>64
>64
1
>64
>64
2
>64
>64
2
>64
>64
>64
2
>64
>64
>64
>64
>64
>64
2
>64
>64
4
>64
>64
4
>64
>64
>64
4
values in the range of 0.5e2
3506. Compound 8a, with a MIC of 1
MRSA CCARM 3167 and 3506 respectively, showed eight-fold more
potency than norfloxacin (MIC ¼ 8 g/mL and 4 g/mL) and 64-fold
more activity than oxacillin (MIC > 64 g/mL). For the QRSA CCARM
3505 and 3519 strains, these compounds also presented higher
activity with MIC values of 2e4 g/mL, slightly less active than
oxacillin (MIC ¼ 1 g/mL) but much more potent than norfloxacin
(MIC > 64 g/mL).
mg/mL against MRSA CCARM 3167 and
m
g/mL and 0.5 g/mL against
m
m
m
m
8p
8q
8r
8s
m
m
>64
2
1
>64
2
1
m
Norfloxacin
Oxacillin
Several structure-activity relationships (SAR) were recognized
from the results. Firstly, it was clear that a free carboxyl group was
necessary for the anti-bacterial activity against Gram-positive
strains as all the esters (7aes) were inactive but some of their
>64
>64
S. aureus RN4220, Staphylococcus aureus RN4220; S. aureus 503, Staphylococcus
aureus 503; E. coli 1356, Escherichia coli CCARM 1356; E. coli 1682, Escherichia coli
1682.

X.-F. Liu et al. / European Journal of Medicinal Chemistry 46 (2011) 3469e3473
3471
Table 2
5.3. General procedure for the preparation of compounds 8aes
Inhibitory activity (MIC, mg/mL) of compounds 8a, 8h, 8k, 8n, and 8r against clinical
isolates of multidrug-resistant Gram-positive strains.
A mixture of 7aes (1 mmol), glacial acetic acid (8 mL), and HCl
12 N (2 mL) was refluxed for 2 h. After evaporation in vacuo, the
residue was refluxed again with glacial acetic acid (8 mL) and HCl
12 N (2 mL) for 2 h. The mixture was evaporated under reduced
pressure, and the resulting crude solid was washed with water,
recrystallized from DMSOeethanol to provide 8aes. The yield,
melting point and spectral data of each compound are given below.
Compound
MRSA
3167
QRSA
3505
3506
0.5
1
1
3519
8a
8h
8k
1
1
1
2
2
2
4
2
2
2
2
2
2
8n
2
2
8r
1
1
Norfloxacin
Oxacillin
8
>64
4
>64
>64
1
>64
1
5.3.1. 4-(((Z)-2,4-dioxo-5-(4-((E)-3-oxo-3-phenylprop-1-en-1-yl)
benzylidene)thiazolidine-3-yl)methyl)benzoic acid (8a)
MRSA 3167, methicillin-resistant S. aureus CCARM 3167; MRSA 3506, methicillin-
resistant S. aureus CCARM 3506; QRSA 3505, quinolone-resistant S. aureus CCARM
3505; QRSA 3519, quinolone-resistant S. aureus CCARM 3519.
Yield 87%; m.p. 274e275 ꢁC. IR (KBr) cmꢂ1: 3420 (OH),1686 (C]
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.93 (s, 2H, CH2), 7.72 (d,
), 8.03 (s, 1H, CH]C), 8.07 (d, J ¼ 14.1 Hz, 1H, H-
), 7.43e8.20 (m, 13H, AreH), 13.02 (s, 1H, COOH). 13C NMR
(DMSOed6, 75 MHz, ppm): 189.55, 167.63, 167.43, 165.90, 143.00,
J ¼ 14.1 Hz, 1H, H-
a
b
formation of an intramolecular hydrogen bond between the
carboxyl group and ortho-hydroxy substituent.
d
140.64, 137.84, 137.14, 135.12, 133.79, 133.08, 131.87, 131.07, 130.70,
130.14, 129.31, 129.06, 128.08, 124.27, 122.57, 44.92. MS m/z 470
(M þ 1). Anal. Calcd. for C27H19NO5S: C, 69.13; H, 4.26; N, 2.71; S,
6.79. Found: C, 69.07; H, 4.08; N, 2.98; S, 6.83.
4. Conclusion
Based on our previous work, we synthesized a new series of
chalcone derivatives bearing 2,4-thiazolidinedione and benzoic
acid moieties (8aes) and evaluated for their anti-bacterial activities
against Gram-positive and Gram-negative bacteria. Some of the
compounds showed anti-bacterial activities against Gram-positive
bacteria, particularly against multidrug-resistant strains of clinical
isolates. Compound 8a was found to have the most potent inhibi-
tory capacity. Furthermore, the results suggested that the carboxyl
group seemed to be necessary for the activity and further devel-
opment of such compounds may be of interest.
5.3.2. 4-(((Z)-5-((4-((E)-3-(naphthalen-2-yl)-3-oxoprop-1-en-1-yl)
benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8b)
Yield 85%; m.p. 280e281 ꢁC. IR (KBr) cmꢂ1: 3443 (OH), 1686
(C]O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.94 (s, 2H, CH2),
), 8.04 (s,1H, CH]C), 8.26 (d, J ¼ 15.6 Hz,
), 7.44e8.99 (m, 15H, AreH), 13.02 (s, 1H, COOH). 13C NMR
(DMSOed6, 75 MHz, ppm): 189.20, 167.62, 167.44, 165.89, 146.52,
7.85 (d, J ¼ 15.6 Hz,1H, H-
a
1H, H-
b
d
142.85, 140.63, 137.25, 135.58, 135.16, 133.09, 132.77, 131.09, 130.73,
130.15, 129.27, 128.99, 128.19, 128.08, 127.49, 124.53, 124.29, 122.55,
113.54, 44.93. MS m/z 520 (Mþ1). Anal. Calcd. for C31H21NO5S: C,
71.57; H, 4.13; N, 2.78; S, 6.05. Found: C, 71.66; H, 4.07; N, 2.70;
S, 6.17.
5. Experimental protocols
5.1. Chemistry
5.3.3. 4-(((Z)-5-(4-((E)-3-oxo-3-p-tolylprop-1-en-1-yl)benzylidene)-
2,4-dioxothiazolidin -3-yl)methyl)benzoic acid (8c)
Melting points were determined in open capillary tubes and are
uncorrected. Reaction courses were monitored by TLC on silica gel-
precoated F254 Merck plates. Developed plates were examined
with UV lamps (254 nm). IR spectra were recorded (in KBr) on
a FTIR1730. 1H NMR spectra were measured on a Bruker AV-300
spectrometer using TMS as the internal standard. Mass spectra
were measured on an HP1100LC (Agilent Technologies, USA).
Elemental analyses for C, H, N and S were within ꢀ0.4% of the
theoretical values and were carried out on a 204Q CHN Rapid
Analyzer (PerkineElmer, USA). The major chemicals were
purchased from SigmaeAldrich and Fluka.
Yield 85%; m.p. 234e235 ꢁC. IR (KBr) cmꢂ1: 3420 (OH),1682 (C]
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
2.42 (s, 3H, CH3), 4.93 (s,
), 8.02 (s, 1H, CH]C), 8.05 (d,
), 7.40e8.11 (m, 12H, AreH), 13.02 (s, 1H, COOH).
13C NMR (DMSOed6, 75 MHz, ppm):
188.91, 167.61, 167.40, 165.89,
2H, CH2), 7.76 (d, J ¼ 14.1 Hz, 1H, H-
a
J ¼ 14.1 Hz, 1H, H-
b
d
144.27, 142.60, 140.64, 137.24, 135.37, 135.03, 133.09, 131.05, 130.70,
130.13, 129.85, 129.78, 129.56, 129.12, 128.08, 124.32, 122.50, 44.93,
21.66. MS m/z 484 (M þ 1). Anal. Calcd. for C28H21NO5S: C, 69.76; H,
4.44; N, 2.63; S, 6.68. Found: C, 69.55; H, 4.38; N, 2.90; S, 6.63.
5.3.4. 4-(((Z)-5-((4-((E)-3-(2,4-dimethylphenyl)-3-oxoprop-1-en-
1-yl)benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid
(8d)
5.2. General procedure for the preparation of compounds 7aes
A mixture of 5aep (3 mmol), methyl 4-(bromomethyl)benzoate
(6 mmol) and potassium carbonate (9 mmol) in toluene (50 mL)
was refluxed for 48 h. After cooling, the precipitate was filtered off,
and the solvent was evaporated in vacuo, followed by the purifi-
cation of the resulting residue by silica gel column chromatography
(dichloromethane/methanol, 40:1). The hydroxy substituted
derivatives (7qes) were prepared by the hydrolysis of the corre-
sponding methoxy substituted derivatives (7nep). Thus, to a solu-
tion of 7nep (1 mmol) in 10 mL dichloromethane, was added
dropwise boron tribromide (3e5 mmol) in 10 mL dichloromethane
in an ice-bath. After stirring for 2 h at room temperature, the
reaction mixture was poured into ice-water and extracted with
dichloromethane. The combined solvent was dried over MgSO4 and
the solvent was evaporated in vacuo. The resulting crude solid was
directly used in the next step without purification.
Yield 82%; m.p. 218e219 ꢁC. IR (KBr) cmꢂ1: 3420 (OH), 1680 (C]
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
2.35 (s, 3H, CH3), 2.40 (s,
3H, CH3), 4.92 (s, 2H, CH2), 7.63 (d, J ¼ 14.1 Hz, 1H, H- ), 8.01 (s, 1H,
CH]C), 7.96 (d, J ¼ 14.1 Hz, 1H, H- ), 7.16e7.98 (m, 11H, AreH),
12.96 (s, 1H, COOH). 13C NMR (DMSOed6, 75 MHz, ppm):
194.14,
a
b
d
167.58, 167.40, 165.87, 142.94, 141.60, 140.62, 137.73, 137.03, 135.93,
135.03, 133.05, 132.60, 131.06, 130.70, 130.13, 129.91, 129.63, 128.16,
128.08, 126.77, 122.52, 44.92, 21.39, 20.81. MS m/z 498 (M þ 1).
Anal. Calcd. for C29H23NO5S: C, 70.18; H, 4.43; N, 2.71; S, 6.57.
Found: C, 70.00; H, 4.66; N, 2.82; S, 6.44.
5.3.5. 4-(((Z)-5-((4-((E)-3-(2,4-dichlorophenyl)-3-oxoprop-1-en-1-
yl)benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8e)
Yield 83%; m.p. 256e257 ꢁC. IR (KBr) cmꢂ1: 3420 (OH),1692 (C]
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d 4.90 (s, 2H, CH2), 7.66 (d,

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X.-F. Liu et al. / European Journal of Medicinal Chemistry 46 (2011) 3469e3473
J ¼ 15.6 Hz, 1H, H-
a
), 7.98 (s, 1H, CH]C), 7.92 (d, J ¼ 15.6 Hz, 1H,
Anal. Calcd. for C27H18ClNO5S: C, 64.22; H, 3.93; N, 2.75; S, 6.28.
Found: C, 64.35; H, 3.60; N, 2.78; S, 6.36.
H-b
), 7.34e7.95 (m, 12H, AreH), 12.96 (s, 1H, COOH). 13C NMR
(DMSOed6, 75 MHz, ppm):
d 192.58, 167.54, 167.40, 165.86, 145.50,
141.26, 140.60, 137.60, 136.46, 136.30, 135.57, 133.40, 132.90, 131.80,
131.33, 131.07, 130.69, 130.14, 128.87, 128.09, 127.97, 122.91, 44.93.
MS m/z 538 (Mþ1). Anal. Calcd. for C27H17Cl2NO5S: C, 60.00; H,
3.26; N, 2.50; S, 6.13. Found: C, 60.23; H, 3.18; N, 2.60; S, 5.96.
5.3.11. 4-(((Z)-5-((4-((E)-3-(2-bromophenyl)-3-oxoprop-1-en-1-yl)
benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8k)
Yield 81%; m.p. 265e266 ꢁC. IR (KBr) cmꢂ1: 3422 (OH), 1690
(C]O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.92 (s, 2H, CH2),
), 8.01 (s, 1H, CH]C), 7.94 (d,
), 7.41e7.96 (m, 12H, AreH), 13.02 (s, 1H,
COOH). 13C NMR (DMSOed6, 75 MHz, ppm):
194.33, 167.60,
7.54 (d, J ¼ 15.0 Hz, 1H, H-
a
5.3.6. 4-(((Z)-5-((4-((E)-3-(2-fluorophenyl)-3-oxoprop-1-en-1-yl)
benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8f)
Yield 84%; m.p. 286e287 ꢁC. IR (KBr) cmꢂ1: 3422 (OH),1686 (C]
J ¼ 15.0 Hz, 1H, H-
b
d
167.40, 165.89, 143.47, 140.63, 137.05, 136.82, 135.23, 133.04,
132.34, 132.14, 131.73, 131.06, 130.70, 130.57, 130.44, 130.13, 129.85,
128.09, 123.93, 122.65, 44.94. MS m/z 548 (M þ 1). Anal. Calcd. for
C27H18BrNO5S: C, 59.30; H, 3.07; N, 2.62; S, 5.71. Found: C, 59.13;
H, 3.31; N, 2.55; S, 5.85.
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.93 (s, 2H, CH2), 7.64 (d,
), 8.01 (s, 1H, CH]C), 7.97 (d, J ¼ 15.6 Hz, 1H, H-
), 7.37e7.99 (m, 11H, AreH), 13.02 (s, 1H, COOH). 13C NMR
(DMSOed6, 75 MHz, ppm): 189.12, 167.57, 167.41, 165.87, 143.47,
J ¼ 15.6 Hz, 1H, H-
a
b
d
140.61, 136.68, 135.34, 135.00, 134.89, 132.96, 131.12, 130.71, 130.14,
130.03, 128.08, 127.53, 127.05, 125.34, 122.74, 117.29, 117.00, 44.91.
MS m/z 488 (M þ 1). Anal. Calcd. for C27H18FNO5S: C, 66.38; H, 3.81;
N, 2.99; S, 6.29. Found: C, 66.52; H, 3.72; N, 2.87; S, 6.58.
5.3.12. 4-(((Z)-5-((4-((E)-3-(3-bromophenyl)-3-oxoprop-1-en-1-
yl)benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8l)
Yield 82%; m.p. 285e286 ꢁC. IR (KBr) cmꢂ1: 3420 (OH),1687 (C]
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.93 (s, 2H, CH2), 7.80 (d,
), 8.03 (s, 1H, CH]C), 8.09 (d, J ¼ 15.6 Hz, 1H,
), 7.43e8.37 (m, 12H, AreH), 13.02 (s, 1H, COOH). 13C NMR
(DMSOed6, 75 MHz, ppm): 188.16, 167.59, 167.40, 165.88, 143.74,
5.3.7. 4-(((Z)-5-((4-((E)-3-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)
benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8g)
Yield 81%; m.p. 233e234 ꢁC. IR (KBr) cmꢂ1: 3420 (OH),1690 (C]
J ¼ 15.6 Hz, 1H, H-
a
H-b
d
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.93 (s, 2H, CH2), 7.78 (d,
), 8.02 (s, 1H, CH]C), 8.07 (d, J ¼ 15.9 Hz, 1H, H-
), 7.39e8.31 (m, 13H, AreH), 13.02 (s, 1H, COOH). 13C NMR
(DMSOed6, 75 MHz, ppm): 187.99, 167.59, 167.40, 165.89, 143.12,
140.63, 139.84, 137.00, 136.37, 135.28, 133.04, 131.57, 131.48, 131.01,
130.70, 130.30, 130.14, 128.08, 123.79, 122.84, 122.65, 44.93. MS m/z
548 (M þ 1). Anal. Calcd. for C27H18BrNO5S: C, 59.24; H, 3.37; N,
2.29; S, 5.73. Found: C, 59.13; H, 3.31; N, 2.55; S, 5.85.
J ¼ 15.9 Hz, 1H, H-
a
b
d
140.63, 137.10, 135.14, 134.52, 133.05, 132.14, 132.01, 131.04, 130.70,
130.14, 128.08, 124.02, 122.57, 116.45, 116.16, 44.91. MS m/z 488
(M þ 1). Anal. Calcd. for C27H18FNO5S: C, 66.17; H, 3.83; N, 2.95; S,
6.77. Found: C, 66.52; H, 3.72; N, 2.87; S, 6.58.
5.3.13. 4-(((Z)-5-((4-((E)-3-(4-bromophenyl)-3-oxoprop-1-en-1-
yl)benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8m)
Yield 82%; m.p. 206e207 ꢁC. IR (KBr) cmꢂ1: 3422 (OH),1690 (C]
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.93 (s, 2H, CH2), 7.79 (d,
), 8.03 (s, 1H, CH]C), 8.09 (d, J ¼ 14.1 Hz, 1H,
), 7.43e8.14 (m, 12H, AreH), 13.01 (s, 1H, COOH). 13C NMR
(DMSOed6, 75 MHz, ppm): 188.63, 167.56, 167.41, 165.87, 145.10,
5.3.8. 4-(((Z)-5-((4-((E)-3-(2-chlorophenyl)-3-oxoprop-1-en-1-yl)
benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8h)
Yield 87%; m.p. 252e253 ꢁC. IR (KBr) cmꢂ1: 3422 (OH),1690 (C]
J ¼ 14.1 Hz, 1H, H-
a
H-b
d
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.92 (s, 2H, CH2), 7.58 (d,
), 8.01 (s, 1H, CH]C), 7.94 (d, J ¼ 15.6 Hz, 1H, H-
), 7.42e7.97 (m, 13H, AreH), 13.02 (s, 1H, COOH). 13C NMR
(DMSOed6, 75 MHz, ppm): 192.91, 167.08, 166.93, 165.40, 144.43,
140.94, 140.60, 136.50, 135.51, 133.70, 132.92, 132.48, 131.09, 130.72,
130.13, 129.76, 128.34, 128.08, 122.88, 119.12, 44.94. MS m/z 548
(M þ 1). Anal. Calcd. for C27H18BrNO5S: C, 59.35; H, 3.26; N, 2.63; S,
5.69. Found: C, 59.13; H, 3.31; N, 2.55; S, 5.85.
J ¼ 15.6 Hz, 1H, H-
a
b
d
140.14, 138.41, 138.00, 136.03, 135.02, 132.04, 131.41, 130.62, 130.16,
130.03, 129.66, 129.43, 127.72, 127.61, 127.42, 122.39, 44.93. MS m/z
504 (M þ 1). Anal. Calcd. for C27H18ClNO5S: C, 64.54; H, 3.47; N,
2.92; S, 6.18. Found: C, 64.35; H, 3.60; N, 2.78; S, 6.36.
5.3.14. 4-(((Z)-5-((4-((E)-3-(2-methoxyphenyl)-3-oxoprop-1-en-1-
yl)benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8n)
Yield 85%; m.p. 219e220 ꢁC. IR (KBr) cmꢂ1: 3420 (OH),1686 (C]
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
3.89 (s, 3H, OCH3), 4.93
), 8.01 (s, 1H, CH]C), 7.93
), 7.08e7.95 (m, 12H, AreH), 13.02 (s, 1H,
COOH). 13C NMR (DMSOed6, 75 MHz, ppm):
192.24, 167.59,
5.3.9. 4-(((Z)-5-((4-((E)-3-(3-chlorophenyl)-3-oxoprop-1-en-1-yl)
benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8i)
Yield 83%; m.p. 250e251 ꢁC. IR (KBr) cmꢂ1: 3422 (OH),1687 (C]
(s, 2H, CH2), 7.55 (d, J ¼ 15.6 Hz, 1H, H-
a
(d, J ¼ 15.6 Hz, 1H, H-
b
d
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.93 (s, 2H, CH2), 7.62 (d,
), 8.03 (s, 1H, CH]C), 7.81 (d, J ¼ 15.9 Hz, 1H, H-
), 7.41e8.24 (m, 12H, AreH), 13.00 (s, 1H, COOH). 13C NMR
(DMSOed6, 75 MHz, ppm): 188.24, 167.59, 167.40, 165.89, 143.74,
167.40, 165.89, 158.39, 141.27, 140.62, 137.14, 134.94, 133.81, 133.07,
131.16, 131.07, 130.70, 130.14, 129.74, 129.04, 128.62, 128.09, 122.46,
121.05, 112.85, 56.33, 44.92. MS m/z 500 (M þ 1). Anal. Calcd. for
C28H21NO6S: C, 67.00; H, 4.32; N, 2.15; S, 6.49. Found: C, 67.32; H,
4.24; N, 2.08; S, 6.42.
J ¼ 15.9 Hz, 1H, H-
a
b
d
140.63, 138.82, 136.32, 135.29, 134.35, 133.03, 131.23, 131.15, 131.02,
130.65, 130.29, 130.13, 128.08, 127.00, 123.82, 122.67, 120.65, 44.93.
MS m/z 504 (M þ 1). Anal. Calcd. for C27H18ClNO5S: C, 64.24; H,
3.47; N, 3.09; S, 6.13. Found: C, 64.35; H, 3.60; N, 2.78; S, 6.36.
5.3.15. 4-(((Z)-5-((4-((E)-3-(3-methoxyphenyl)-3-oxoprop-1-en-1-
yl)benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8o)
Yield 88%; m.p. 250e251 ꢁC. IR (KBr) cmꢂ1: 3420 (OH),1686 (C]
5.3.10. 4-(((Z)-5-((4-((E)-3-(4-chlorophenyl)-3-oxoprop-1-en-1-yl)
benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8j)
Yield 84%; m.p. 258e259 ꢁC. IR (KBr) cmꢂ1: 3422 (OH),1690 (C]
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
3.87 (s, 3H, OCH3), 4.93
), 8.02 (s, 1H, CH]C), 8.05
), 7.25e8.10 (m, 12H, AreH), 13.04 (s, 1H,
COOH). 13C NMR (DMSOed6, 75 MHz, ppm):
189.21,167.59,167.44,
(s, 2H, CH2), 7.76 (d, J ¼ 14.4 Hz, 1H, H-
a
(d, J ¼ 14.4 Hz, 1H, H-
b
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.95 (s, 2H, CH2), 7.81 (d,
), 8.04 (s, 1H, CH]C), 8.08 (d, J ¼ 15.6 Hz, 1H, H-
), 7.45e8.24 (m, 12H, AreH), 13.01 (s, 1H, COOH). 13C NMR
(DMSOed6, 75 MHz, ppm): 188.38, 167.58, 167.40, 165.88, 143.42,
d
J ¼ 15.6 Hz, 1H, H-
a
165.89, 160.04, 143.04, 140.60, 139.29, 137.14, 136.33, 135.11, 133.07,
131.04, 130.78, 130.42, 130.14, 128.07, 124.28, 122.54, 121.59, 119.83,
113.52, 55.85, 44.93. MS m/z 500 (M þ 1). Anal. Calcd. for
C28H21NO6S: C, 67.19; H, 4.05; N, 2.31; S, 6.36. Found: C, 67.32; H,
4.24; N, 2.08; S, 6.42.
b
d
140.62, 138.76, 137.04, 136.49, 135.20, 133.04, 131.04, 130.96, 130.70,
130.14, 129.38, 128.08, 123.91, 122.61, 44.92. MS m/z 504 (M þ 1).

X.-F. Liu et al. / European Journal of Medicinal Chemistry 46 (2011) 3469e3473
3473
5.3.16. 4-(((Z)-5-((4-((E)-3-(4-methoxyphenyl)-3-oxoprop-1-en-1-
5.4. Evaluation of anti-bacterial activity in vitro
yl)benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8p)
Yield 87%; m.p. 273e274 ꢁC. IR (KBr) cmꢂ1: 3420 (OH),1682 (C]
The micro-organisms used in the present study were S. aureus
(S. aureus RN 4220, S. aureus KCTC 503), and E. coli (E. coli 1356 and
E. coli 1682). The strains of multidrug-resistant clinical isolates
were multidrug-resistant S. aureus (MRSA CCARM 3167 and MRSA
CCARM 3506) and quinolone-resistant S. aureus (QRSA CCARM 3505
and QRSA CCARM 3519). Clinical isolates were collected from
various patients hospitalized in several clinics.
Test bacteria were grown to mid-log phase in Mueller-
Hinton broth (MHB) and diluted 1000-fold in the same
medium. The bacteria of 105 CFU/mL were inoculated into MHB
and dispensed at 0.2 mL/well in a 96-well microtiter plate. As
positive controls, oxacillin and norfloxacin were used. Test
compounds were prepared in DMSO, the final concentration of
which did not exceed 0.05%. A twofold serial dilution technique
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
3.88 (s, 3H, OCH3), 4.93
), 8.02 (s, 1H, CH]C), 8.07
), 7.09e8.21 (m, 12H, AreH), 13.02 (s, 1H,
COOH). 13C NMR (DMSOed6, 75 MHz, ppm):
187.20,167.63,167.42,
(s, 2H, CH2), 7.74 (d, J ¼ 15.6 Hz, 1H, H-
a
(d, J ¼ 15.6 Hz, 1H, H-
b
d
165.90, 163.83, 142.30, 142.13, 140.64, 137.34, 134.90, 133.13, 131.49,
131.06, 130.74, 130.15, 130.00, 128.07, 124.29, 122.41, 114.53, 56.05,
44.92. MS m/z 500 (Mþ1). Anal. Calcd. for C28H21NO6S: C, 67.10; H,
4.17; N, 2.23; S, 6.58. Found: C, 67.32; H, 4.24; N, 2.08; S, 6.42.
5.3.17. 4-(((Z)-5-((4-((E)-3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-
yl)benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8q)
Yield 73%; m.p. 254e256 ꢁC. IR (KBr) cmꢂ1: 3069 (OH),1686 (C]
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.93 (s, 2H, CH2), 7.86 (d,
), 8.02 (s, 1H, CH]C), 8.13 (d, J ¼ 15.6 Hz, 1H, H-
), 7.00e8.27 (m, 12H, AreH), 12.42 (s, 1H, OH), 12.98 (s, 1H, COOH).
13C NMR (DMSOed6, 75 MHz, ppm):
192.05,167.62,167.43,165.90,
J ¼ 15.6 Hz, 1H, H-
a
[9] was used to obtain final concentrations of 64e0.25 mg/mL.
b
The MIC was defined as the concentration of a test compound
that completely inhibited bacteria growth during 24 h incuba-
tion at 37 ꢁC. Bacteria growth was determined by measuring the
d
157.41, 140.61, 139.68, 137.23, 134.86, 133.83, 131.43, 131.07, 130.70,
130.14, 129.70, 129.66, 128.98, 128.73, 128.08, 122.60, 121.03, 114.25,
44.91. MS m/z 486 (M þ 1). Anal. Calcd. for C27H19NO6S: C, 66.66; H,
3.83; N, 2.75; S, 6.87. Found: C, 66.79; H, 3.94; N, 2.88; S, 6.60.
absorption at 650 nm using
a microtiter enzyme-linked
immunosorbent assay (ELISA) reader. All experiments were
carried out three times.
5.3.18. 4-(((Z)-5-((4-((E)-3-(3-hydroxyphenyl)-3-oxoprop-1-en-1-
yl)benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8r)
Yield 77%; m.p. 296e297 ꢁC. IR (KBr) cmꢂ1: 3341 (OH),1682 (C]
Acknowledgment
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.93 (s, 2H, CH2), 7.45 (d,
J ¼ 15.1 Hz, 1H, H-ab), 8.02 (s, 1H, CH]C), 8.05 (d, J ¼ 15.1 Hz, 1H,
H- ), 7.07e8.07 (m, 12H, AreH), 9.84 (s, 1H, OH), 12.98 (s, 1H,
COOH). 13C NMR (DMSOed6, 75 MHz, ppm):
188.04, 167.62,
This work was supported by the National Science Foundation of
China (grant number 20962021).
b
d
167.46, 165.90, 159.45, 142.33, 139.13, 137.23, 136.62, 135.55, 133.05,
131.05, 130.77, 130.20, 130.14, 129.52, 128.06, 124.42, 122.51, 121.57,
119.56, 114.90, 44.92. MS m/z 486 (Mþ1). Anal. Calcd. for
C27H19NO6S: C, 66.89; H, 3.17; N, 2.62; S, 6.54. Found: C, 66.79; H,
3.94; N, 2.88; S, 6.60.
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5.3.19. 4-(((Z)-5-((4-((E)-3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-
yl)benzylidene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (8s)
Yield 72%; m.p. 296e297 ꢁC. IR (KBr) cmꢂ1: 3341 (OH),1682 (C]
O). 1H NMR (DMSOed6, 300 MHz, ppm):
d
4.93 (s, 2H, CH2), 7.71 (d,
), 8.02 (s, 1H, CH]C), 8.09 (d, J ¼ 14.7 Hz, 1H,
), 6.90e8.12 (m, 12H, AreH), 10.50 (s, 1H, OH), 13.01 (s, 1H,
COOH). 13C NMR (DMSOed6, 75 MHz, ppm):
187.45,167.65,167.45,
J ¼ 14.7 Hz, 1H, H-
a
[7] M.C.A. DeLima, D.L.B. Costa, A.J.S. Goes, S.L. Galdino, I.R. Pitta, C. Luu-Duc,
Pharmazie 4 (1992) 182.
H-b
d
[8] S.H. Jung, S.Y. Park, Y. Kim-Pak, H.K. Lee, S.Y. Park, K.H. Shin, K. Ohuchi,
H.K. Shin, S.R. Keum, S.S. Lim, Chem. Pharm. Bull. 54 (2006) 368e371.
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crobial Susceptibility Tests for Bacteria that Grow Aerobically, Approved
Standard M7-A6. Clinical and Laboratory Standards Institute, Wayne, PA,
USA, 2003.
165.91, 162.82, 141.73, 140.63, 137.43, 134.82, 133.15, 131.76, 131.07,
130.73, 130.15, 129.92, 129.44, 128.06, 124.43, 122.38, 115.91, 44.91.
MS m/z 486 (M þ 1). Anal. Calcd. for C27H19NO6S: C, 66.55; H, 3.73;
N, 2.96; S, 6.92. Found: C, 66.79; H, 3.94; N, 2.88; S, 6.60.