Synthesis of novel 1,3-diaryl pyrazole derivatives bearing rhodanine-3-fatty acid moieties as potential antibacterial agents

Article abstract of DOI:10.1016/j.ejmech.2011.12.011

In the present study, a series of 1,3-diaryl pyrazole derivatives bearing rhodanine-3-fatty acid moieties were synthesized and their antimicrobial activities were tested against various Gram-positive and Gram-negative bacteria. 1,3-diaryl-4-formylpyrazoles were synthesized as key intermediates following a Vilsmeier-Haack strategy. Several compounds with an MIC of 2 μg/mL, exhibited stronger antibacterial activity against the methicillin-resistant Staphylococcus aureus (MRSA) than the controls. None of the compounds showed any activity against Gram-negative bacteria.

Full text of DOI:10.1016/j.ejmech.2011.12.011

European Journal of Medicinal Chemistry 48 (2012) 174e178
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of novel 1,3-diaryl pyrazole derivatives bearing rhodanine-3-fatty acid
moieties as potential antibacterial agents
*
Li-Li Xu, Chang-Ji Zheng, 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,
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 1,3-diaryl pyrazole derivatives bearing rhodanine-3-fatty acid moieties
were synthesized and their antimicrobial activities were tested against various Gram-positive and Gram-
negative bacteria. 1,3-diaryl-4-formylpyrazoles were synthesized as key intermediates following a Vils-
Received 4 October 2011
Received in revised form
3 December 2011
Accepted 7 December 2011
Available online 13 December 2011
meiereHaack strategy. Several compounds with an MIC of 2
mg/mL, exhibited stronger antibacterial
activity against the methicillin-resistant Staphylococcus aureus (MRSA) than the controls. None of the
compounds showed any activity against Gram-negative bacteria.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords:
1,3-Diaryl pyrazole
Rhodanine-3-fatty acid
Antibacterial activity
1. Introduction
2. Chemistry
Development of novel antimicrobial drugs is still in demand
because of the increasing incidence of infection caused by the
rapid development of microbial resistance to most of the known
A group of 1,3-diaryl pyrazole derivatives containing rhodanine-
3-fatty acid moieties (6e29) were designed and synthesized
according to Scheme 1. The starting benzyl hydrazones (3)
were prepared by substituted acetophenones with phenyl-
hydrazine and sodium acetate in ethanol. Subsequent reactions of 3
under VilsmeiereHaack [15] conditions afforded 1,3-diaryl-4-
formylpyrazoles (4). The resulting 4 series were subjected to
Knoevenagel condensation with various rhodanine-3-fatty acids
(5) to form the target compounds 6e29. All the synthesized
compounds were confirmed by FTIR, 1H NMR, 13C NMR, mass
spectral and elemental analyses.
antibiotics [1]. Pyrazoles are
a novel class of heterocyclic
compounds possessing a wide variety of applications in the
agrochemical and pharmaceutical industries [2,3]. Many pyrazole
derivatives have been reported to possess diverse pharmacolog-
ical activities such as antimicrobial [4e8], anti-inflammatory
[9e12], and anti-viral among others [13]. In our previous work
[14], we found that several rhodanine-3-acetic acid derivatives
bearing a chalcone moiety showed strong activities against
Gram-positive strains (Fig. 1). Herein, we report our ongoing
study of modifications to rhodanine-3-acetic acid derivatives
with an aim to develop more efficient antimicrobial agents. We
focused on reserving the rhodanine moiety, replacing the chal-
cone moiety by 1,3-diaryl pyrazole, substituting the acetic acid
moiety with different fatty acids, and simultaneously introducing
different substituents into the phenyl ring. Thus, twenty-four
rhodanine-3-fatty acid derivatives bearing 1,3-diaryl pyrazole
were synthesized and evaluated for their antimicrobial activity
in vitro.
3. Results and discussion
In vitro antimicrobial activity was evaluated with different
strains (including multidrug-resistant clinical isolates) using the
minimum inhibitory concentration (MIC) which is defined as the
lowest concentration at which no visible growth is observed.
Oxacillin and norfloxacin were used as positive controls.
As shown in Table 1, most synthesized compounds showed good
antibacterial activity in vitro against Gram-positive strains, partic-
ularly the chlorine and bromine substituted compounds (e.g. 9, 11,
14, 20, 22, 23, 24, 25, and 27). None of the compounds showed any
activity against Gram-negative bacteria.
* 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 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.12.011

L.-L. Xu et al. / European Journal of Medicinal Chemistry 48 (2012) 174e178
175
Table 1
Inhibitory activity of compounds 6e29 (expressed as MIC (
mg/mL)) against repre-
sentative strains of Gram-positive (Staphylococcus aureus) and Gram-negative
(Escherichia coli) bacteria.
Compound
R
n
S. aureus
E. coli
4220
503
1924
1356
Fig. 1. Structure of the previously reported compound.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
4-CH3
3-Cl
4-OCH3
3-Br
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
3
3
4
4
5
5
16
16
>64
8
64
8
>64
64
8
64
32
>64
16
>64
8
>64
8
8
8
8
>64
4
>64
32
1
>64
>64
>64
32
64
8
>64
64
8
64
32
>64
16
>64
8
>64
16
4
>64
>64
>64
>64
>64
>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
>64
>64
>64
>64
>64
16
The results for the rhodanine-3-acetic acid derivatives (6e21)
showed that the antibacterial activity was significantly influenced
by the position of the substituent on the phenyl ring. Five electron
donating groups derivatives were designed and prepared, con-
taining p-CH3, 2,4-(CH3)2, m-OCH3, p-OCH3, o-OCH3. The pharma-
cology test revealed that their activities were poorer than electron
withdrawing groups derivatives, for this reason we are not clear
and need further work. The compound 17 with 4-NO2 has poorer
solubility than 4-Cl substituent, for the reason may lead to reduce
the activity. 2,4-Chlorine substituted 11 and 4-chlorine substituted
20 exhibited the best antibacterial activity against Staphylococcus
H
2,4-(Cl)2
4-F
2-F
4-Br
3-OCH3
2-Cl
4-NO2
2,4-(CH3)2
Phenyl(3,4-fused)
4-Cl
2-OCH3
4-Cl
2,4-(Cl)2
4-Cl
2,4-(Cl)2
4-Cl
aureus (S. aureus RN4220 and S. aureus KCTC 503) with MICs of 8 mg/
mL. To investigate the effects of the substituents on the nitrogen
atom of the rhodanine to the antibacterial activity, the acetic acid
moiety was changed to various fatty acids with different carbon
chain lengths, and relatively fixed the substituents on the phenyl
ring such as 2,4-chlorine or 4-chlorine simultaneously. The result
showed, as expected, some derivatives (e.g. 23, 24, 25, and 27)
exhibited better antibacterial activities against Gram-positive
4
4
>64
4
>64
8
2,4-(Cl)2
4-Cl
2,4-(Cl)2
Oxacillin
Norfloxacin
1
2
2
strains, particularly, compound 27 with a MIC of 4
mg/mL was
S. aureus RN4220, Staphylococcus aureus RN4220; S. aureus 503, Staphylococcus
aureus 503; E. coli 1924, Escherichia coli CCARM 1924; E. coli 1356, Escherichia coli
CCARM 1356.
comparable to the standard drug (norfloxacin) against S. aureus
(S. aureus RN4220 and S. aureus KCTC 503). However, no activities
against any Gram-negative strains were noted.
For those compounds exhibiting potency against S. aureus
(S. aureus RN4220 and S. aureus KCTC 503), we also evaluated their
antibacterial activity against several clinical isolates of multidrug-
resistant Gram-positive bacteria (Table 2). The results showed
that almost all of the tested compounds showed potent antibac-
terial activities against clinical isolates of multidrug-resistant
Gram-positive bacteria. Actually, the activities of the compounds
22, 23, 24, 25, and 27, which possessed the longer (n ¼ 2e4) carbon
chain fatty acids substituted at position-3 of the rhodanine, were
superior to the Norfloxacin and Oxacillin in respect to MRSA, and
were comparable to the Norfloxacin in respect to QRSA. Compound
CH3
NHNH2
R
NNH
O
b
a
R
CH3
+
Table 2
O
MIC values (in mg/mL) against clinical isolates of multidrug-resistant Gram-positive
bacterial strains.
3
1
2
COOH
O
S
Compound
R
n
MRSA
3167
QRSA
3505
N
CHO
n
N
COOH
3506
3519
S
S
R
5
6
7
9
10
11
13
14
15
16
18
20
22
23
24
25
27
4-CH3
3-Cl
3-Br
1
1
1
1
1
1
1
1
1
1
1
2
2
3
3
4
5
16
16
8
32
4
64
8
32
16
16
8
4
4
4
4
2
4
>64
8
16
32
16
32
4
64
8
64
32
16
8
16
16
16
32
8
64
8
64
32
16
8
4
4
4
4
2
32
1
64
64
64
32
8
S
N
R
N
N
c
N
H
6-29
2,4-(Cl)2
2-F
4-Br
3-OCH3
2-Cl
2,4-(CH3)2
4-Cl
4-Cl
2,4-(Cl)2
4-Cl
2,4-(Cl)2
2,4-(Cl)2
2,4-(Cl)2
64
8
18:R=2,4-(CH3)2
19:R=Phenyl(3,4-fused) n=1
20:R=4-Cl
21:R=2-OCH3
22:R=4-Cl
23:R=2,4-(Cl)2
24:R=4-Cl
25:R=2,4-(Cl)2
26:R=4-Cl
27:R=2,4-(Cl)2
28:R=4-Cl
29:R=2,4-(Cl)2
n=1
6:R=4-CH3
7:R=3-Cl
8:R=4-OCH3
9:R=3-Br
10:R=H
11:R=2,4-(Cl)2
12:R=4-F
n=1
n=1
n=1
n=1
n=1
n=1
n=1
n=1
n=1
n=1
n=1
n=1
64
32
16
16
8
4
4
4
2
n=1
n=1
n=2
n=2
n=3
n=3
n=4
n=4
n=5
n=5
4
4
4
4
13:R=2-F
14:R=4-Br
15:R=3-OCH3
16:R=2-Cl
17:R=4-NO2
2
29
32
>64
4
4
1
>64
Oxacillin
Norfloxacin
>64
Scheme 1. Synthesis of compounds 6e29. Reagents and conditions: (a) AcOH, NaOH,
EtOH, reflux, 1 h (b) (i) DMF, POCl3, 0e5 ꢀC, 0.5 h (ii) 3, DMF, 50 ꢀC, 3 h (c) Piperidine,
AcOH, EtOH, 40e50 ꢀC, 4 h.
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.

176
L.-L. Xu et al. / European Journal of Medicinal Chemistry 48 (2012) 174e178
27 (n ¼ 4) exhibited the most potent activity against both MRSA and
QRSA with a MIC of 2 g/mL. Furthermore, it was also clearly
(s, 1H), 8.07e7.88 (m, 2H), 7.59e7.37 (m, 8H), 4.71 (s, 2H), 2.40 (s,
3H). MS m/z 436 (Mþ1). Anal. Calcd. for C22H17N3O3S2: C, 60.67;
H, 3.93; N, 9.65; S, 14.72. Found: C, 60.55; H, 3.91; N, 9.66; S,
14.71.
m
observed from the results for the 2,4-dichloro substituted deriva-
tives (11, 23, 25, 27, and 29) that the activity was significantly
influenced by the length of carbon chain of the fatty acid moiety. In
this regard, more derivatives possessing different rhodanine-3-
fatty acids need to be designed and synthesized to elucidate the
structureeactivity relationship and this work is currently in prog-
ress in our laboratories.
5.3.2. (Z)-2-(5-((3-(3-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (7)
Yield 91%; m.p. 313e315 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.84 (s, 1H), 8.06 (d,
J ¼ 8.1 Hz, 2H), 7.74 (s, 1H), 7.61e7.53 (m, 6H), 7.43 (t, J ¼ 7.35 Hz,
1H), 4.49 (s, 2H). 13C NMR (DMSO-d6, 75 MHz, ppm):
245.30,
4. Conclusion
d
192.60, 167.12, 166.25, 152.27, 138.53, 133.68, 133.15, 130.98, 129.80,
122.63, 119.47, 115.74, 109.53, 40.20, 38.95. MS m/z 456 (Mþ1).
Calcd. for C21H14ClN3O3S2: C, 55.32; H, 3.09; N, 9.22; S,14.07. Found:
C, 55.31; H, 3.07; N, 9.20; S, 14.08.
In summary, in connection with our previous work, a series of
1,3-diaryl pyrazoles containing rhodanine-3-fatty acid moieties
were designed and synthesized. All the synthesized compounds
have been investigated for their in vitro antimicrobial activities.
Most of the compounds exhibited potential antibacterial activities
against Gram-positive bacteria, particularly against multidrug-
resistant strains of clinical isolates. Compound 27 bearing a rhoda-
nine-3-pentanoic acid displayed the most potent activity with
5.3.3. (Z)-2-(5-((3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (8)
Yield 87%; m.p. 308e310 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.78 (s, 1H), 8.05 (d,
a MIC of 2
m
g/mL which was more potent than the standard drugs
J ¼ 8.1 Hz, 2H), 7.63e7.51 (m, 5H), 7.41 (t, J ¼ 7.4 Hz, 1H), 7.14 (d,
J ¼ 8.7 Hz, 2H), 4.46 (s, 2H), 3.85 (s, 3H). MS m/z 452 (Mþ1). Calcd.
for C22H17N3O4S2: C, 58.52; H, 3.79; N, 9.31; S, 14.20. Found: C,
58.50; H, 3.77; N, 9.30; S, 14.21.
(norfloxacin and oxacillin) against MRSA. The results suggest that
the new skeleton possessing 1,3-diaryl pyrazole and rhodanine-3-
fatty acids may provide valuable leads for designing and develop-
ment of novel antibacterial agents.
5.3.4. (Z)-2-(5-((3-(3-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (9)
Yield 88%; m.p. 315e317 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707
5. Experimental protocols
5.1. Chemistry
(C]O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.83 (s, 1H), 8.07
(d, J ¼ 7.6 Hz, 2H), 7.87 (d, J ¼ 1.6 Hz, 1H), 7.74 (m, 1H), 7.66 (d,
J ¼ 7.9 Hz, 1H), 7.54 (m, 4H), 7.43 (t, J ¼ 7.4 Hz, 1H), 4.35 (s, 2H).
MS m/z 501 (Mþ1). Calcd. for C21H14BrN3O3S2: C, 50.41; H,
2.82; N, 8.40; S, 12.82. Found: C, 50.39; H, 2.80; N, 8.38; S,
12.81.
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. (Z)-2-(5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)acetic acid (10)
Yield 83%; m.p. 322e324 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
expressed in
d
, ppm. Mass spectra were measured on an HP1100LC
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.83 (s, 1H), 8.06 (d,
(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.
J ¼ 7.6 Hz, 2H), 7.71e7.48 (m, 8H), 7.43 (t, J ¼ 7.4 Hz,1H), 4.54 (s, 2H).
MS m/z 422 (Mþ1). Calcd. for C21H15N3O3S2: C, 59.84; H, 3.59; N,
9.97; S, 15.21. Found: C, 59.81; H, 3.57; N, 9.96; S, 15.22.
5.3.6. (Z)-2-(5-((3-(2,4-dichlorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (11)
Yield 89%; m.p. 299e301 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
5.2. General synthetic procedure for the key intermediates
Intermediates 3 and 4 were synthesized according to the liter-
ature [1]. Intermediate 5 was synthesized using the reported
procedure [16].
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.90 (s, 1H), 8.05 (d,
J ¼ 8.1 Hz, 2H), 7.90 (s,1H), 7.66e7.52 (m, 4H), 7.44 (t, J ¼ 7.3 Hz,1H),
7.19 (s, 1H), 4.49 (s, 2H). MS m/z 491 (Mþ1). Calcd. for
C21H13Cl2N3O3S2: C, 51.43; H, 2.67; N, 8.57; S, 13.08. Found: C, 51.41;
H, 2.65; N, 8.56; S, 13.09.
5.3. General synthetic procedure for the target compounds 6e29
To a solution of 1,3-diaryl-4-formylpyrazoles 4 (1.0 mmol) and
rhodanine analogs 5 (1.0 mmol) in absolute ethanol (8.0 mL) was
added drops of acetic acid and piperidine. The reaction mixture was
stirred at 40e50 ꢀC, until the completion of the reaction as evi-
denced by TLC. After the solution was cooled, the resulting reaction
mixture was filtered off and crude product was purified by 95%
ethanol to afford pure products 6e29. The yield, melting point and
spectral data of each compound are given below.
5.3.7. (Z)-2-(5-((3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (12)
Yield 90%; m.p. 310e312 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.81 (s, 1H), 8.06 (d,
J ¼ 8.4 Hz, 2H), 7.74e7.69 (m, 2H), 7.57 (t, J ¼ 7.8 Hz, 2H), 7.49e7.40
(m, 4H), 4.30 (s, 2H). MS m/z 440 (Mþ1). Calcd. for C21H14FN3O3S2:
C, 57.39; H, 3.21; N, 9.56; S, 14.59. Found: C, 57.37; H, 3.20; N, 9.55;
S, 14.57.
5.3.1. (Z)-2-(4-oxo-5-((1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)
methylene)-2-thioxothiazolidin-3-yl)acetic acid (6)
5.3.8. (Z)-2-(5-((3-(2-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (13)
Yield 90%; m.p. 306e308 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
Yield 89%; m.p. 302e304 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707
(C]O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d
13.45 (s, 1H), 8.84
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.85 (d, J ¼ 4.9 Hz, 1H),

L.-L. Xu et al. / European Journal of Medicinal Chemistry 48 (2012) 174e178
177
8.09e7.99 (m, 2H), 7.69e7.52 (m, 4H), 7.50e7.36 (m, 3H), 7.34e7.29
(m, 1H), 4.49 (s, 2H). MS m/z 440 (Mþ1). Calcd. for C21H14FN3O3S2:
C, 57.39; H, 3.21; N, 9.56; S,14.59. Found: C, 57.35; H, 3.19; N, 9.58; S,
14.56.
55.32; H, 3.09; N, 9.22; S, 14.07. Found: C, 55.31; H, 3.06; N, 9.23; S,
14.08.
5.3.16. (Z)-2-(5-((3-(2-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (21)
Yield 84%; m.p. 307e309 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
5.3.9. (Z)-2-(5-((3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (14)
Yield 89%; m.p. 303e305 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.83 (d, J ¼ 1.6 Hz, 1H),
8.05 (d, J ¼ 8.0 Hz, 2H), 7.56 (dd, J ¼ 14.0, 7.3 Hz, 3H), 7.49e7.39 (m,
2H), 7.34 (d, J ¼ 1.7 Hz, 1H), 7.25 (d, J ¼ 8.3 Hz, 1H), 7.13 (t, J ¼ 7.4 Hz,
1H), 4.68 (s, 2H), 3.77 (s, 3H). MS m/z 452 (Mþ1). Calcd. for
C22H17N3O4S2: C, 58.52; H, 3.79; N, 9.31; S, 14.20. Found: C, 58.50;
H, 3.77; N, 9.30; S, 14.21.
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.85 (s, 1H), 8.06 (d,
J ¼ 7.8 Hz, 2H), 7.79 (d, J ¼ 8.4 Hz, 2H), 7.69e7.51 (m, 5H), 7.43 (t,
J ¼ 7.2 Hz, 1H), 4.58 (s, 2H). MS m/z 501 (Mþ1). Calcd. for
C21H14BrN3O3S2: C, 50.41; H, 2.82; N, 8.40; S, 12.82. Found: C, 50.40;
H, 2.83; N, 8.39; S, 12.83.
5.3.17. (Z)-3-(5-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)propanoic acid (22)
Yield 87%; m.p. 286e288 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
5.3.10. (Z)-2-(5-((3-(3-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (15)
Yield 87%; m.p. 300e302 ꢀC. IR (KBr) cmꢂ1: 3419 (OH),1707 (C]
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.79 (s, 1H), 8.04 (d,
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.84 (s, 1H), 8.07 (d,
J ¼ 8.0 Hz, 2H), 7.60 (m, 7H), 7.42 (t, J ¼ 7.4 Hz, 1H), 4.22e4.14 (t,
J ¼ 6.0 Hz, 2H), 2.98e2.87 (t, J ¼ 6.0 Hz, 2H). MS m/z 470 (Mþ1).
Calcd. for C22H16ClN3O3S2: C, 56.22; H, 3.43; N, 8.94; S, 13.65.
Found: C, 56.20; H, 3.41; N, 8.92; S, 13.66.
J ¼ 8.1 Hz, 2H), 7.59 (t, J ¼ 3.8 Hz, 2H), 7.56e7.42 (m, 3H), 7.21 (d,
J ¼ 6.8 Hz, 2H), 7.14e7.09 (m, 1H), 4.54 (s, 2H), 3.84 (s, 3H). MS m/z
452 (Mþ1). Calcd. for C22H17N3O4S2: C, 58.52; H, 3.79; N, 9.31; S,
14.20. Found: C, 58.49; H, 3.76; N, 9.33; S, 14.19.
5.3.18. (Z)-3-(5-((3-(2,4-dichlorophenyl)-1-phenyl-1H-pyrazol-4-
yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)propanoic acid (23)
Yield 89%; m.p. 279e281 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
5.3.11. (Z)-2-(5-((3-(2-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (16)
Yield 85%; m.p. 309e311 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.85 (d, J ¼ 3.9 Hz, 1H),
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.89 (s, 1H), 8.06 (d,
8.04 (d, J ¼ 8.2 Hz, 2H), 7.89 (s, 1H), 7.68e7.52 (m, 4H), 7.43 (t,
J ¼ 7.3 Hz, 1H), 7.16 (d, J ¼ 3.1 Hz, 1H), 4.19e4.08 (t, J ¼ 7.5 Hz, 2H),
2.40e2.29 (t, J ¼ 7.5 Hz, 2H). 13C NMR (DMSO-d6, 75 MHz, ppm):
J ¼ 7.9 Hz, 2H), 7.71 (d, J ¼ 7.7 Hz, 1H), 7.68e7.49 (m, 5H), 7.44 (t,
J ¼ 7.3 Hz, 1H), 7.18 (s, 1H), 4.46 (s, 2H). MS m/z 456 (Mþ1). Calcd.
for C21H14ClN3O3S2: C, 55.32; H, 3.09; N, 9.22; S, 14.07. Found: C,
55.30; H, 3.07; N, 9.23; S, 14.06.
d
248.32, 192.50, 172.89, 166.43, 150.96, 138.53, 133.95, 129.61,
122.09, 119.44, 116.95, 101.71, 43.53, 39.54. MS m/z 503 (Mþ1).
Calcd. for C22H15Cl2N3O3S2: C, 52.39; H, 3.00; N, 8.33; S, 12.71.
Found: C, 52.37; H, 2.97; N, 8.32; S, 12.72.
5.3.12. (Z)-2-(5-((3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (17)
Yield 81%; m.p. 321e323 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
5.3.19. (Z)-4-(5-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)butanoic acid (24)
Yield 86%; m.p. 258e260 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.88 (d, J ¼ 1.1 Hz, 1H),
8.42e8.40 (m, 2H), 8.12e7.89 (m, 4H), 7.67e7.51 (m, 3H), 7.44 (t,
J ¼ 7.3 Hz, 1H), 4.52 (s, 2H). MS m/z 467 (Mþ1). Calcd. for
C21H14N4O5S2: C, 54.07; H, 3.02; N, 12.01; S, 13.75. Found: C, 54.05;
H, 3.01; N, 11.99; S, 13.76.
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.82 (s, 1H), 8.06 (d,
J ¼ 7.8 Hz, 2H), 7.75e7.63 (m, 4H), 7.56 (dd, J ¼ 16.1, 8.2 Hz, 3H), 7.43
(t, J ¼ 7.4 Hz, 1H), 4.06 (t, J ¼ 6.8 Hz, 2H), 2.29 (t, J ¼ 7.2 Hz, 2H),
1.96e1.81 (m, 2H). 13C NMR (DMSO-d6, 75 MHz, ppm):
d 228.84,
5.3.13. (Z)-2-(5-((3-(2,4-dimethylphenyl)-1-phenyl-1H-pyrazol-4-
yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (18)
Yield 88%; m.p. 297e299 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
192.96, 173.66, 166.68, 152.56, 138.53, 134.05, 129.96, 122.53, 119.41,
115.67, 43.73, 39.54. MS m/z 484 (Mþ1). Calcd. for C23H18ClN3O3S2:
C, 57.08; H, 3.75; N, 8.68; S, 13.25. Found: C, 57.06; H, 3.74; N, 8.67;
S, 13.26.
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.82 (s, 1H), 8.05 (d,
J ¼ 7.9 Hz, 2H), 7.57 (t, J ¼ 7.8 Hz, 2H), 7.41 (t, J ¼ 7.4 Hz, 1H),
7.27e7.10 (m, 4H), 4.26 (s, 2H), 2.38 (s, 3H), 2.23 (s, 3H). MS m/z 450
(Mþ1). Calcd. for C23H19N3O3S2: C, 61.45; H, 4.26; N, 9.35; S, 14.27.
Found: C, 61.43; H, 4.25; N, 9.32; S, 14.28.
5.3.20. (Z)-4-(5-((3-(2,4-dichlorophenyl)-1-phenyl-1H-pyrazol-4-
yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)butanoic acid (25)
Yield 87%; m.p. 269e271 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.87 (s, 1H), 8.04 (d,
5.3.14. (Z)-2-(5-((3-(naphthalen-2-yl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (19)
Yield 87%; m.p. 324e326 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
J ¼ 8.2 Hz, 2H), 7.90 (d, J ¼ 0.7 Hz, 1H), 7.68e7.51 (m, 4H), 7.43 (t,
J ¼ 7.3 Hz, 1H), 7.16 (s, 1H), 4.02 (t, J ¼ 7.0 Hz, 2H), 2.16 (t, J ¼ 7.3 Hz,
2H), 1.90e1.75 (m, 2H). MS m/z 503 (Mþ1). Calcd. for
C23H17Cl2N3O3S2: C, 53.28; H, 3.31; N, 8.11; S, 12.37. Found: C, 53.26;
H, 3.30; N, 8.10; S, 12.35.
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.88 (s, 1H), 8.22 (s, 1H),
8.16e7.98 (m, 5H), 7.82 (d, J ¼ 8.4 Hz, 1H), 7.70e7.57 (m, 5H), 7.44 (t,
J ¼ 7.3 Hz, 1H), 4.51 (s, 2H). MS m/z 472 (Mþ1). Calcd. for
C25H17N3O3S2: C, 63.68; H, 3.63; N, 8.91; S, 13.60. Found: C, 63.65;
H, 3.61; N, 8.90; S, 13.62.
5.3.21. (Z)-5-(5-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)pentanoic acid (26)
Yield 88%; m.p. 291e292 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707
5.3.15. (Z)-2-(5-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (20)
Yield 92%; m.p. 312e314 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
(C]O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 8.82 (s, 1H), 8.05
(d, J ¼ 8.1 Hz, 2H), 7.76e7.61 (m, 4H), 7.61e7.48 (m, 3H), 7.44 (d,
J ¼ 6.5 Hz, 1H), 4.01 (t, J ¼ 6.0 Hz, 2H), 2.19 (t, J ¼ 6.6 Hz, 2H), 1.51
(m, 4H). MS m/z 499 (Mþ1). Calcd. for C24H20ClN3O3S2: C, 57.88;
H, 4.05; N, 8.44; S, 12.88. Found: C, 57.86; H, 4.04; N, 8.42; S,
12.89.
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.84 (d, J ¼ 2.1 Hz, 1H),
8.06 (d, J ¼ 8.2 Hz, 2H), 7.75e7.50 (m, 7H), 7.43 (t, J ¼ 7.3 Hz, 1H),
4.48 (s, 2H). MS m/z 456 (Mþ1). Calcd. for C21H14ClN3O3S2: C,

178
L.-L. Xu et al. / European Journal of Medicinal Chemistry 48 (2012) 174e178
5.3.22. (Z)-5-(5-((3-(2,4-dichlorophenyl)-1-phenyl-1H-pyrazol-4-
yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)pentanoic acid (27)
Yield 89%; m.p. 283e285 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707
5.4. Evaluation of antibacterial activity in vitro
In vitro antibacterial activity assay method was referred in
Ref. [14].
(C]O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.87 (d, J ¼ 1.3 Hz,
1H), 8.04 (d, J ¼ 8.1 Hz, 2H), 7.90 (s, 1H), 7.63e7.55 (m, 4H), 7.45
(d, J ¼ 6.3 Hz, 1H), 7.17 (d, J ¼ 1.3 Hz, 1H), 3.99 (t, J ¼ 6.0 Hz, 2H),
2.16 (t, J ¼ 6.5 Hz, 2H), 1.61 (m, 2H), 1.49 (m, 2H). 13C NMR
Acknowledgment
(DMSO-d6, 75 MHz, ppm):
d 192.72, 174.57, 166.62, 150.99,
This work was supported by the National Science Foundation of
China (20962021).
138.51, 133.77, 129.60, 127.74, 122.32, 119.43, 116.93, 56.01, 40.37,
39.26. MS m/z 533 (Mþ1). Calcd. for C24H19Cl2N3O3S2: C, 54.14;
H, 3.60; N, 7.89; S, 12.04. Found: C, 54.12; H, 3.59; N, 7.87; S,
12.06.
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5.3.23. (Z)-6-(5-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)
methylene)-4-oxo-2-thioxothiazolidin-3-yl)hexanoic acid (28)
Yield 91%; m.p. 278e280 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707 (C]
O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d
8.80 (d, J ¼ 3.1 Hz, 1H),
8.04 (d, J ¼ 8.2 Hz, 2H), 7.67 (m, 4H), 7.60e7.49 (m, 3H), 7.42 (t,
J ¼ 7.4 Hz,1H), 3.97 (t, J ¼ 6.8 Hz, 2H), 2.16 (t, J ¼ 7.2 Hz, 2H), 1.62 (m,
2H), 1.51 (m, 2H), 1.30 (m, 2H). MS m/z 513 (Mþ1). Calcd. for
C25H22ClN3O3S2: C, 58.64; H, 4.33; N, 8.21; S, 12.52. Found: C, 58.61;
H, 4.32; N, 8.23; S, 12.53.
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yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)hexanoic acid (29)
Yield 90%; m.p. 270e272 ꢀC. IR (KBr) cmꢂ1: 3419 (OH), 1707
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(C]O). 1H NMR (DMSO-d6, 300 MHz, ppm):
d 11.97 (s, 1H), 8.88
(s, 1H), 8.05 (d, J ¼ 7.6 Hz, 2H), 7.91 (d, J ¼ 0.8 Hz, 1H), 7.69e7.51
(m, 4H), 7.44 (t, J ¼ 7.4 Hz, 1H), 7.17 (s, 1H), 3.97 (t, J ¼ 7.2 Hz, 2H),
2.19 (t, J ¼ 7.3 Hz, 2H), 1.60 (m, 2H), 1.49 (m, 2H), 1.29 (m, 2H). 13C
NMR (DMSO-d6, 75 MHz, ppm):
d 247.63, 192.73, 174.26, 166.60,
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151.01, 138.52, 133.77, 129.61, 127.83, 122.35, 119.44, 116.93, 44.12,
39.82, 33.37. MS m/z 547 (Mþ1). Calcd. for C25H21Cl2N3O3S2: C,
54.94; H, 3.87; N, 7.69; S, 11.73. Found: C, 54.93; H, 3.85; N, 7.66;
S, 11.75.