Synthesis and antibacterial activity of novel 1,3-diphenyl-1H-pyrazoles functionalized with phenylalanine-derived rhodanines

Article abstract of DOI:10.1016/j.ejmech.2012.10.012

In the present study, a series of novel 1,3-diphenyl-1H-pyrazoles functionalized with phenylalanine-derived rhodanine derivatives were synthesized and evaluated for their antibacterial activity. Compounds 4, 6, 9, 10, 12 and 15 exhibited stronger activity than the standard drugs, norfloxacin and oxacillin, with MIC values of 1 μg/mL against methicillin-resistant Staphylococcus aureus and quinolone-resistant S. aureus. None of the compounds showed any activity against Gram-negative bacteria.

Full text of DOI:10.1016/j.ejmech.2012.10.012

European Journal of Medicinal Chemistry 58 (2012) 112e116
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antibacterial activity of novel 1,3-diphenyl-1H-pyrazoles
functionalized with phenylalanine-derived rhodanines
1
1
*
Chang-Ji Zheng , Li-Li Xu , Liang-Peng Sun, Jing Miao, Hu-Ri Piao
Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, Yanbian University College of Pharmacy,
Jilin Province, 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:
In the present study, a series of novel 1,3-diphenyl-1H-pyrazoles functionalized with phenylalanine-
derived rhodanine derivatives were synthesized and evaluated for their antibacterial activity.
Compounds 4, 6, 9, 10, 12 and 15 exhibited stronger activity than the standard drugs, norfloxacin and
oxacillin, with MIC values of 1 mg/mL against methicillin-resistant Staphylococcus aureus and quinolone-
resistant S. aureus. None of the compounds showed any activity against Gram-negative bacteria.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Received 1 July 2012
Received in revised form
8 October 2012
Accepted 9 October 2012
Available online 18 October 2012
Keywords:
1,3-Diphenyl-1H-pyrazoles
Phenylalanine-derived rhodanine
Antibacterial activity
1. Introduction
aureus (MRSA) [13]. Herein, we describe further modifications that
we have made to compound B. These changes were focused on
The treatment of bacterial infections remains an important and
challenging therapeutic problem for many reasons, including the
emergence of new infectious diseases and the increasing number of
multidrug-resistant microbial pathogens [1e4]. For these reasons,
the development of novel antimicrobial drugs is still necessary and
very much in demand. Pyrazoles represent a key structural motif in
preserving the rhodanine and 1,3-diarylpyrazole moieties and
substituting the fatty acid moiety with a phenylalanine while
simultaneously investigating variations to the phenyl ring substit-
uents. Thus, using the molecule hybrid approach, we designed and
synthesized 15 novel 1,3-diphenyl-1H-pyrazole derivatives bearing
phenylalanine-derived rhodanine moieties and evaluated their
antibacterial activity.
heterocyclic chemistry and occupy
a significant position in
medicinal and pesticide chemistry because of their capability to
exhibit a wide range of bioactivities, including their antimicrobial
activity [5e10]. In our previous work, we reported the identifica-
2. Chemistry
tion of
MIC ¼ 2
a
rhodanine-3-acetic acid derivatives (compound A,
The synthetic route to the phenylalanine-derived rhodanine
derivatives 3e17 is depicted in Scheme 1. A series of 1,3-diaryl-4-
formylpyrazoles 1 and the phenylalanine-derived rhodanine 2
had already been reported in a previous paper [13]. The 1,3-diaryl-
4-formylpyrazoles 1 were subjected to a Knoevenagel condensation
reaction with 2 to give the target compounds 3e17. The identities of
all of the synthesized compounds were confirmed by FTIR, 1H and
13C NMR, and mass spectral and elemental analyses.
mg/mL) bearing a 2,4-Cl2 substituent chalcone moiety that
showed high levels of inhibitory activity against Gram-positive
bacterial strains (Fig. 1) [11]. Following on from this, we reported
the identification of a 1,3-diarylpyrazole derivative (compound B,
MIC ¼ 2
mg/mL) bearing a rhodanine-3-pentanoic acid moiety that
exhibited potent antibacterial activity against multidrug-resistant
Gram-positive bacterial strains [12]. In addition, Diane Hardej
et al. reported
a
phenylalanine-derived rhodanine derivative
g/mL) that showed high levels of
(compound C, MIC ¼ 1.95
m
3. Results and discussion
inhibitory activity against methicillin-resistant Staphylococcus
3.1. Evaluation of antibacterial activity
All of the synthesized compounds were evaluated in vitro with
different antibacterial strains, including multidrug-resistant clin-
ical isolates, using the minimum inhibitory concentration (MIC),
* Corresponding author. Tel: þ86 433 2435003; fax: þ86 433 2435004.
E-mail address: piaohuri@yahoo.com.cn (H.-R. Piao).
These authors contributed equally to this work.
1
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.10.012

C.-J. Zheng et al. / European Journal of Medicinal Chemistry 58 (2012) 112e116
113
HOOC
Ph
O
S
COOH
O
S
N
N
S
Cl
Cl
S
O
compound A
compound C
PhO
COOH
HOOC
Ph
O
N
O
Cl
N
S
S
S
S
Cl
N
N
R
N
N
Ph
Ph
target compounds
compound B
Fig. 1. Previously reported compounds and structure-based design of the target compounds.
which is defined as the lowest concentration of antibacterial agent
required to visibly inhibit the growth of the bacteria. Oxacillin and
norfloxacin were used as positive controls.
The MIC values of the synthesized compounds against S. aureus
have been provided in Table 1. It is clear from the data that the
resistant S. aureus CCARM 3505) and QRSA 3519 (quinolone-
resistant S. aureus CCARM 3519), all of the synthesized compounds
exhibited higher levels of inhibitory activity than norfloxacin.
Compounds 6 and 9 showed similar levels of activity to oxacillin
against QRSA 3505 and QRSA 3519, with both compounds
majority of the compounds exhibited MIC values in the 2e8
mg/mL
providing a MIC value of 1 mg/mL.
range. Compounds 3, 4, 5, 6, and 15 were highly active against
S. aureus (S. aureus RN4220 and S. aureus KCTC 503) showing MIC
values of 2 mg/mL. Furthermore, the activities of these compounds
were comparable to norfloxacin, although they were less active
than oxacillin. This class of compounds did not show any antibac-
terial activity in vitro against the Gram-negative (Escherichia coli
From an analysis of the activities of the synthesized compounds,
some structureeactivity relationships emerged. The position of the
substituent on the phenyl ring did not have any impact on the
antibacterial activity. Most of the derivatives bearing electron-
donating substituents (except for the methyl group) showed
lower levels of activity against multidrug-resistant clinical isolates
than the corresponding derivatives bearing electron withdrawing
groups. There was no clear correlation between the effect of
different substituents and the observed activity. In comparison to
the previously reported compounds bearing a rhodanine-3-fatty
acid moiety [12], these 1,3-diphenyl-1H-pyrazole derivatives
bearing a phenylalanine moiety generally exhibited higher levels of
inhibitory activity. The current result therefore supports the
hypothesis reported by Diane Hardej et al. that the presence of
a phenylalanine moiety at the N3-position would increase the
likelihood of bacterial cell wall penetration and therefore poten-
tially improve the anti-MRSA activity of such compounds.
1924 and E. coli 1356) strains at 64 mg/mL.
The MIC values of the synthesized compound against clinical
isolates of multidrug-resistant Gram-positive bacterial strains are
shown in Table 2. It is clear from the data that all of the compounds
exhibited higher levels of inhibitory activity than oxacillin against
MRSA 3167 (methicillin-resistant S. aureus CCARM 3167) and
MRSA 3506 (methicillin-resistant S. aureus CCARM 3506).
Compounds 4, 6, 9, 10, 12 and 15 were 8-fold more active against
MRSA 3167 and 4-fold more active against MRSA 3506 than nor-
floxacin, with all of the compounds having a MIC value of 1 mg/mL
against both bacterial strains. Against QRSA 3505 (quinolone-
HOOC
O
N
CHO
HOOC
piperidine
AcOH/EtOH
R
+
S
S
O
N
N
N
R
N
S
N
S
3-17
2
1
11: Phenyl (3,4-fused)
12: 4-NO2
7: H
15: 2-Cl
16: 3-OCH3
17: 2-F
R: 3: 4-Cl
8: 3-Br
9: 4-F
4: 2,4-(Cl)2
5: 2,4-(CH3)2
6: 4-CH3
13: 2-OCH3
14: 4-OCH3
10: 4-Br
Scheme 1. Synthesis of compounds 3e17.

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C.-J. Zheng et al. / European Journal of Medicinal Chemistry 58 (2012) 112e116
Table 1
Table 2
Inhibitory activity of compounds 3e17 expressed as MIC (
m
g/mL).
MIC values (in
m
g/mL) against clinical isolates of multidrug-resistant Gram-positive
bacterial strains.
HOOC
Ph
HOOC
Ph
O
O
N
N
S
S
S
S
R
N
R
N
N
N
3-17
Ph
3-17
Ph
Compound
R
S. aureusa
E. colib
compound
R
MRSAa
3167
QRSAb
3505
4220
503
1924
1356
3506
3519
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4-Cl
2
2
2
2
2
2
4
4
2
4
2
4
2
4
4
1
2
2
2
2
1
8
>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
16
2,4-(Cl)2
2,4-(CH3)2
4-CH3
H
3-Br
4-F
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4-Cl
2
1
2
1
4
4
1
1
16
1
16
4
1
16
4
>64
8
2
1
2
1
4
4
1
1
16
1
16
4
1
16
4
>64
4
2
2
2
1
4
4
1
1
16
1
16
4
2
16
2
1
2
1
1
1
4
2,4-(Cl)2
2,4-(CH3)2
4-CH3
H
3-Br
4-F
8
16
16
16
16
16
16
2
16
16
1
4
1
4-Br
Phenyl(3,4-fused)
4-NO2
2-OCH3
4-OCH3
2-Cl
4-Br
16
16
1
16
8
1
16
4
Phenyl (3,4-fused)
4-NO2
2-OCH3
4-OCH3
2-Cl
3-OCH3
2-F
3-OCH3
2-F
Oxacillin
Norfloxacin
2
Oxacillin
Norfloxacin
1
>64
>64
a
S. aureus RN4220, Staphylococcus aureus RN4220; S. aureus 503, Staphylococcus
a
aureus 503.
MRSA 3167, methicillin-resistant S. aureus CCARM 3167; MRSA 3506,
methicillin-resistant S. aureus CCARM 3506.
b
E. coli 1924, Escherichia coli CCARM 1924; E. coli 1356, Escherichia coli CCARM
b
1356.
QRSA 3505, quinolone-resistant S. aureus CCARM 3505; QRSA 3519, quinolone-
resistant S. aureus CCARM 3519.
3.2. Evaluation of cytotoxicity
could exhibit in vitro antibacterial activity at non-cytotoxic
concentrations.
Human cervical (HeLa) cell monolayers were used as an in vitro
model of the cervicovaginal epithelium to test the cytotoxicity of
the synthesized compounds. HeLa cells were cultured in Dulbecco’s
modified Eagle’s medium (DMEM) with 10% fetal bovine serum
(FBS) and antibiotics (penicillin-streptomycin mixture [100 U/ml]).
Cells at 80e90% confluence were split by trypsin (0.25% in phos-
phate buffered saline [PBS]; pH 7.4), and the medium was changed
at 24 h intervals. The cells were cultured at 37 ꢀC in a 5% CO2
incubator. The cells were grown for three passages and approxi-
mately 1 ꢁ 104 cells were seeded into each well of a 96-well plate
and allowed to incubate overnight to allow the cells to attach to the
substrate. After 24 h, the medium was replaced with DMEM that
was supplemented with 10% FBS and contained various concen-
4. Conclusion
In conclusion, a series of novel 1,3-diphenyl-1H-pyrazoles that
have been functionalized with phenylalanine-derived rhodanine
derivatives have been synthesized and evaluated for their anti-
bacterial activity. All of the compounds displayed antibacterial
activity. Compounds 4, 6, 9, 10, 12 and 15 (MIC ¼ 1
mg/mL)
exhibited stronger activity against MRSA and QRSA than the
standard drugs, norfloxacin and oxacillin. Compounds 6 and 15
were evaluated for their cytotoxicity and exhibited no significant
influence on cell viability in the HeLa cells at their MIC (1 mg/mL).
None of the compounds showed any activity against Gram-
negative bacteria.
trations of test compounds and incubated for 48 h. A 10 ml aliquot of
MTT solution (5 mg/ml in PBS) was then added to each well.
Following 4 h of incubation, the medium was removed and the
resulting formazan crystals were dissolved in DMSO (100
mL).
Following a 10-min period of shaking, the optical density of the
solutions was measured at 570 nm using a microtiter enzyme-
linked immunosorbent assay reader. The assay was conducted
four times. The IC50 values were defined as the concentrations at
which the cell growth was inhibited by 50%.
The cytotoxicity of compounds 6 and 15 was evaluated to
determine if their observed antibacterial activity was caused by
selective toxicity towards the bacterial cells (Table 3). Compounds 6
and 15 did not affect cell viability in the HeLa cells at their MIC
Table 3
Cytotoxic activity of compounds 6 and 15 against HeLa
cell.a
b
Compound
IC50
(
mg/mL)
6
15
20.16
30.24
a
Hela cell (Human cervical) monolayers were used as
an in vitro model of cervicovaginal epithelium for testing
the cytotoxicity of the new compounds.
b
values (1
mg/mL) but showed cytotoxicity at much higher concen-
IC50 is defined as the concentration at which 50%
trations. These results suggested that both compounds 6 and 15
growth is observed.

C.-J. Zheng et al. / European Journal of Medicinal Chemistry 58 (2012) 112e116
115
5. Experimental protocols
5.3.4. (R,Z)-2-(4-oxo-5-((1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)
methylene)-2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (6)
Yield 86%; m.p. 218e220 ꢀC. IR (KBr) cmꢃ1: 3429 (OH),1697 (C]O).
1H NMR (DMSO-d6, 300 MHz, ppm):
2H), 7.72 (s,1H), 7.52 (m, 4H), 7.39 (d, J ¼ 7.4 Hz, 1H), 7.32 (d, J ¼ 7.9 Hz,
2H), 7.19 (t, J¼ 6.4 Hz, 5H), 6.01(m,1H), 3.61 (m, 2H), 2.44(s, 3H). MS m/
z 525 (M þ 1). Calcd. for C29H23N3O3S2: C, 66.26; H, 4.41; N, 7.99; S, S,
12.20. Found: C, 66.25; H, 4.40; N, 7.97; S, 12.19.
5.1. Chemistry
d
8.11 (s, 1H), 7.77 (d, J ¼ 7.8 Hz,
Melting points were determined in open glass capillaries in an
electrical melting point apparatus 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 and 13C
NMR spectra were recorded in pure DMSO-d6 on Bruker NMR
spectrometers at 300 MHz and 75 MHz respectively using tetra-
methylsilane (TMS) as internal standard. Chemical shifts were
5.3.5. (R,Z)-2-(5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-4-
oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (7)
Yield 79%; m.p. 224e226 ꢀC. IR (KBr) cmꢃ1: 3429 (OH), 1697
expressed in
d, ppm. Mass spectra were measured on an HP1100LC
(C]O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.15 (s, 1H), 7.75e7.50
(Agilent Technologies, USA). Elemental analyses for C, H, N, and S
were within ꢂ0.4% 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.
(m, 8H), 7.44e7.31 (m, 3H), 7.26e6.95 (m, 5H), 6.01 (m, 1H), 3.60
(m, 2H). MS m/z 511 (M þ 1). Calcd. for C28H21N3O3S2: C, 65.73; H,
4.14; N, 8.21; S, S, 12.53. Found: C, 65.72; H, 4.12; N, 8.20; S, 12.52.
5.3.6. (R,Z)-2-(5-((3-(3-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (8)
5.2. General synthetic procedure for the key intermediates
Yield 90%; m.p. 199e201 ꢀC. IR (KBr) cmꢃ1: 3429 (OH), 1697
Compound 1 was synthesized according to the literature [5] and
compound 2 was already reported in a previous paper [13e16].
(C]O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.12 (s, 1H), 7.87 (s,
1H), 7.77 (d, J ¼ 8.1 Hz, 2H), 7.67e7.59 (m, 2H), 7.53 (t, J ¼ 7.9 Hz,
3H), 7.44e7.38 (m, 2H), 7.23e7.16 (m, 5H), 6.01 (m, 1H), 3.62 (m,
2H). MS m/z 591 (M þ 1). Calcd. for C28H20BrN3O3S2: C, 56.95; H,
3.41; N, 7.12; S, 10.86. Found: C, 56.93; H, 3.39; N, 7.10; S, 10.84.
5.3. General synthetic procedure for the target compounds 3e17
To a solution of compound 1 (1.0 mmol) and compound 2
(1.0 mmol) in absolute ethanol (8.0 ml) was added drops of glacial
acetic acid and piperidine. The reaction mixture was stirred at
40e50 ꢀC for 2e4 h, until the completion of the reaction as evi-
denced by TLC. The resulting reaction mixture was concentrated
to dryness, purified by silica gel column chromatography
(dichloromethane/methanol, 40:1) to afford pure products 3e17.
The yield, melting point and spectral data of each compound are
given below.
5.3.7. (R,Z)-2-(5-((3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (9)
Yield87%;m.p.210e212 ꢀC.IR(KBr)cmꢃ1:3429(OH),1697(C]O).
1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.12 (s, 1H), 7.77 (d, J ¼ 7.8 Hz,
2H), 7.64 (m, 3H), 7.52 (t, J ¼ 7.6 Hz, 3H), 7.41 (d, J ¼ 7.4 Hz,1H), 7.20 (d,
J ¼ 6.9 Hz, 6H), 6.01 (m,1H), 3.62 (m, 2H). MS m/z 529 (M þ 1). Calcd.
for C28H20FN3O3S2: C, 63.50; H, 3.81; N, 7.93; S, S, 12.11. Found: C,
63.51; H, 3.83; N, 7.92; S, 12.10.
5.3.1. (R,Z)-2-(5-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (3)
5.3.8. (R,Z)-2-(5-((3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (10)
Yield 85%; m.p. 202e204ꢀC. IR (KBr) cmꢃ1: 3429 (OH),1697 (C]O).
1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.11 (s, 1H), 7.77 (d, J ¼ 7.5 Hz,
Yield 84%; m.p. 207e209 ꢀC. IR (KBr) cmꢃ1: 3429 (OH), 1697
2H), 7.65 (s, 1H), 7.60 (d, J ¼ 8.4 Hz, 2H), 7.56e7.48 (m, 5H), 7.41 (d,
J¼ 7.2 Hz, 1H), 7.20 (d, J¼ 6.8 Hz, 4H), 6.02 (m,1H), 3.62 (m, 2H). MS m/z
545 (M þ 1). Anal. calcd. for C28H20ClN3O3S2: C, 61.59; H, 3.69; N, 7.70;
S, 11.74. Found: C, 61.57; H, 3.67; N, 7.68; S, 11/72.
(C]O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.11 (s, 1H), 7.77 (d,
J ¼ 7.7 Hz, 2H), 7.66 (d, J ¼ 8.1 Hz, 3H), 7.54 (d, J ¼ 8.3 Hz, 4H), 7.41 (d,
J ¼ 7.5 Hz,1H), 7.23e7.15 (m, 5H), 6.01 (m,1H), 3.62 (m, 2H). 13C NMR
(DMSO-d6, 75 MHz, ppm):
d 190.54, 166.03, 153.50, 138.48, 135.26,
131.73, 130.49, 129.94, 129.70, 128.74, 127.55, 126.62, 119.18, 115.94,
76.10, 29.32. MS m/z 591 (M þ 1). Calcd. for C28H20BrN3O3S2: C, 56.95;
H, 3.41; N, 7.12; S, 10.86. Found: C, 56.96; H, 3.42; N, 7.11; S, 10.87.
5.3.2. (R,Z)-2-(5-((3-(2,4-dichlorophenyl)-1-phenyl-1H-pyrazol-4-
yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (4)
Yield88%;m.p. 212e214 ꢀC.IR(KBr)cmꢃ1:3429(OH),1697(C]O).
5.3.9. (R,Z)-2-(5-((3-(naphthalen-2-yl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (11)
1H NMR (DMSO-d6, 300 MHz, ppm):
2H), 7.53 (m, 3H), 7.45e7.36(m, 3H), 7.30 (s,1H), 7.19 (t, J ¼ 8.2 Hz, 6H),
5.98 (m, 1H), 3.59 (m, 2H). MS m/z 579 (M þ 1). Calcd. for
d
8.11 (s, 1H), 7.76 (d, J ¼ 7.7 Hz,
Yield 82%; m.p. 223e224 ꢀC. IR (KBr) cmꢃ1: 3429 (OH), 1697
C28H19Cl2N3O3S2: C, 57.93; H, 3.30; N, 7.24; S, 11.05. Found: C, 57.91; H,
(C]O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.15 (s, 1H), 8.12 (s,
3.28; N, 7.22; S, 11.03.
1H), 8.04e7.88 (m, 4H), 7.81 (d, J ¼ 7.3 Hz, 3H), 7.54 (m, 4H), 7.41
(d, J ¼ 7.4 Hz, 1H), 7.20 (m, 5H), 6.01 (m, 1H), 3.61 (m, 2H). MS m/z
501 (M þ 1). Calcd. for C32H23N3O3S2: C, 68.43; H, 4.13; N, 7.48; S,
11.42. Found: C, 68.42; H, 4.12; N, 7.46; S, 11.43.
5.3.3. (R,Z)-2-(5-((3-(2,4-dimethylphenyl)-1-phenyl-1H-pyrazol-4-
yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (5)
Yield 80%; m.p. 217e219 ꢀC. IR (KBr) cmꢃ1: 3429 (OH), 1697
5.3.10. (R,Z)-2-(5-((3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (12)
(C]O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.11 (s, 1H), 7.77 (d,
J ¼ 8.2 Hz, 2H), 7.50 (t, J ¼ 7.8 Hz, 3H), 7.41e7.34 (m, 2H), 7.21e7.14
(m, 7H), 5.98 (m, 1H), 3.58 (m, 2H), 2.39 (s, 3H), 2.27 (s, 3H). MS m/
z 539 (M þ 1). Calcd. for C20H25N3O3S2: C, 66.77; H, 4.67; N, 7.79; S,
11.88. Found: C, 66.76; H, 4.66; N, 7.78; S, 11.86.
Yield 81%; m.p. 205e207 ꢀC. IR (KBr) cmꢃ1: 3419 (OH),1697 (C]O).
1H NMR (DMSO-d6, 300 MHz, ppm):
1H), 7.91e7.84 (m, 2H), 7.78 (m, 2H), 7.64 (s,1H), 7.54 (t, J ¼ 7.7 Hz, 2H),
d
8.38 (d, J ¼ 8.9 Hz, 2H), 8.15 (s,

116
C.-J. Zheng et al. / European Journal of Medicinal Chemistry 58 (2012) 112e116
7.44 (d,J ¼ 7.3 Hz, 1H), 7.24e7.16 (m, 5H), 6.01 (m,1H,), 3.62(m, 2H).13
C
5.3.15. (R,Z)-2-(5-((3-(2-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (27)
NMR (DMSO-d6, 75 MHz, ppm):d 190.30,172.24,165.99,151.90,147.64,
138.32, 137.21, 135.18, 129.38, 128.72, 128.10, 126.67, 123.73, 122.31,
116.28, 76.54, 30.07. MS m/z 556 (M þ 1). Calcd. for C28H20N4O5S2: C,
60.42; H, 3.62; N, 10.07; S, 11.52. Found: C, 60.41; H, 3.63; N, 10.05; S,
11.53.
Yield 91%; m.p. 234e236 ꢀC. IR (KBr) cmꢃ1: 3419 (OH), 1707
(C]O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.11 (s, 1H), 7.79 (d,
J ¼ 7.8 Hz, 2H), 7.61 (m, 3H), 7.48 (m, 4H), 7.17 (m, 4H), 7.08 (d,
J ¼ 6.9 Hz, 2H), 6.01 (m, 1H), 3.60 (m, 2H). MS m/z 529 (M þ 1).
Calcd. for C28H20FN3O3S2: C, 63.50; H, 3.81; N, 7.93; S, 12.11.
Found: C, 63.49; H, 3.80; N, 7.94; S, 12.12.
5.3.11. (R,Z)-2-(5-((3-(2-methoxyphenyl)-1-phenyl-1H-pyrazol-4-
yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (13)
Yield89%;m.p.209e211 ꢀC.IR(KBr)cmꢃ1:3419(OH),1697(C]O).
1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.10 (s,1H), 7.77e7.59 (m, 5H),
5.4. Evaluation of antibacterial activity in vitro
7.47 (m, 3H), 7.34 (d, J ¼ 6.4 Hz, 1H), 7.18 (d, J ¼ 6.1 Hz, 4H), 7.08 (d,
J ¼ 7.8 Hz, 2H), 6.02 (m, 1H), 3.81 (s, 3H), 3.61 (m, 2H). MS m/z 541
(M þ 1). Calcd. for C29H23N3O4S2: C, 64.31; H, 4.28; N, 7.76; S, 11.84.
Found: C, 64.29; H, 4.26; N, 7.77; S, 11.83.
In vitro antibacterial activity assay method was referred in
Ref. [11].
Acknowledgement
5.3.12. (R,Z)-2-(5-((3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-
yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (14)
This work was supported by the National Science Foundation of
China (20962021).
Yield 80%; m.p. 226e228 ꢀC. IR (KBr) cmꢃ1: 3419 (OH),1697 (C]O).
1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.10 (s, 1H), 7.77 (d, J ¼ 7.9 Hz,
2H), 7.71 (s,1H), 7.59 (d, J ¼ 8.4 Hz, 2H), 7.51 (m, 3H), 7.39 (d, J ¼ 6.9 Hz,
1H), 7.20(d, J ¼ 6.4 Hz, 4H), 7.04 (d, J ¼ 8.3 Hz, 2H), 6.02(m,1H), 3.88 (s,
3H), 3.61 (m, 2H). MS m/z 541 (M þ 1). Calcd. for C29H23N3O4S2: C,
64.31; H, 4.28; N, 7.76; S,11.84. Found: C, 64.33; H, 4.29; N, 7.75; S,11.83.
References
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5.3.13. (Z)-2-(5-((3-(2-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (15)
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E. Augustynowicz-Kopec, Il Farrmaco 60 (2005) 513e517.
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5743.
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174e178.
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[15] C.G. Xing, L.Y. Wang, X.H. Tang, Y.Y. Sham, Bioorg. Med. Chem. 15 (2007)
2167e2176.
Yield 78%; m.p. 265e267 ꢀC. IR (KBr) cmꢃ1: 3419 (OH),1697 (C]O).
1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.10 (s, 1H), 7.46e7.58 (m, 5H),
7.49e7.37 (m, 5H), 7.33 (d, J ¼ 6.9 Hz, 1H), 7.16 (d, J ¼ 6.5 Hz, 4H), 6.01
(m,1H), 3.61 (m, 2H). MS m/z545 (M þ 1). Calcd. forC21H14ClN3O3S2:C,
61.59; H, 3.69; N, 7.70; S,11.74. Found: C, 61.58; H, 3.68; N, 7.71; S,11.73.
5.3.14. (R,Z)-2-(5-((3-(3-methoxyphenyl)-1-phenyl-1H-pyrazol-4-
yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (16)
Yield 82%; m.p. 227e229 ꢀC. IR (KBr) cmꢃ1: 3419 (OH),1707 (C]O).
1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.10 (s, 1H), 7.74 (d, J ¼ 7.1 Hz,
2H), 7.61(m, 3H), 7.48(m, 3H), 7.28(m, 5H), 7.08 (d,J¼ 7.7 Hz, 2H), 6.02
(m, 1H), 3.86 (s, 3H), 3.61 (m, 2H). MS m/z 541 (M þ 1). Calcd. for
C29H23N3O4S2: C, 64.31; H, 4.28; N, 7.76; S, 11.84. Found: C, 64.29; H,
4.26; N, 7.77; S, 11.83.
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