Synthesis of novel 4-thiazolidione derivatives as antibacterial agents against drug-resistant Staphylococcus epidermidis

Article abstract of DOI:10.1007/s00044-012-0363-9

A series of novel substituted 4-thiazolidione derivatives were designed, synthesized, and evaluated in vitro for their antibacterial activities, in comparison with methicillin and ampicillin. Compounds (7d, 7h-k) exhibit good potency in inhibiting the growth of Staphylococcus epidermidis (MIC: 1.57-3.13 μM). Further antibacterial effects of compounds (7d, 7h-k) were investigated using clinical isolates (methicillin-resistant Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus), in comparison with methicillin and levofloxacin. Compound 7k showed the most potent antibacterial activities among the synthesized compounds.

Full text of DOI:10.1007/s00044-012-0363-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3743–3750
DOI 10.1007/s00044-012-0363-9
ORIGINAL RESEARCH
Synthesis of novel 4-thiazolidione derivatives as antibacterial
agents against drug-resistant Staphylococcus epidermidis
•
Dan Zhao Huayong Liu Likang Zheng
•
•
•
Guozhen He Di Qu Shiqing Han
•
Received: 26 April 2012 / Accepted: 10 November 2012 / Published online: 7 December 2012
Ó Springer Science+Business Media New York 2012
Abstract A series of novel substituted 4-thiazolidione
derivatives were designed, synthesized, and evaluated
in vitro for their antibacterial activities, in comparison with
methicillin and ampicillin. Compounds (7d, 7h–k) exhibit
good potency in inhibiting the growth of Staphylococcus
epidermidis (MIC: 1.57–3.13 lM). Further antibacterial
effects of compounds (7d, 7h–k) were investigated using
clinical isolates (methicillin-resistant Staphylococcus epi-
dermidis and methicillin-resistant Staphylococcus aureus),
in comparison with methicillin and levofloxacin. Com-
pound 7k showed the most potent antibacterial activities
among the synthesized compounds.
(Huebner and Goldmann, 1999). In recent years, S. epide-
rmidis has gained substantial interest because it has become
an important cause of nosocomial infections related to
indwelling medical devices such as vascular catheters, pros-
¨
thetic joints, and artificial heart valves (Gotz, 2002; O’Gara
and Humphreys, 2001). A characteristic of many strains of
this microbe is the production of a capsule or slime resulting
in the formation of biofilms. In biofilms, S. epidermidis is
protectedagainstattacksfromtheimmunesystemand against
antibiotic treatment, making S. epidermidis infections diffi-
cult to cure (Hoffman et al., 2005; Davies et al., 1998; Vuong
et al., 2004). The widespread use of methicillin and other
semisynthetic antibiotics led to the emergence of drug-
resistant S. epidermidis (Sieradzki et al., 1999; Garrett et al.,
1999; Raad et al., 1998), which continuesto persist inboth the
health care and community environments. With the appear-
ance of multi-resistant strains increasing quickly, the need to
discover novel antibiotics is urgent.
Keywords 4-Thiazolidione ꢀ
Methicillin-resistant Staphylococcus epidermidis ꢀ
Methicillin-resistant Staphylococcus aureus ꢀ
Antibacterial activity
In prokaryotes, the two-component signaling systems
(TCS), each pair of which are typically composed of histidine
kinase (HK) and response regulator (RR), play important
roles in drug-resistance, pathogenesis, and bacterial growth
(West and Stock, 2001; Stephenson and Hoch, 2002). In
S. epidermidis, at least 11 TCSs were identified; among them,
YycG/YycF is essential for bacterial viability that could be a
potential target for the discovery or synthesis of novel classes
of antibacterial agents (Fabret and Hoch, 1998).
Introduction
Staphylococcus epidermidis is the most frequently isolated
member of the group of coagulase-negative staphylococci
D. Zhao, H. Liu and L. Zheng contributed equally to this study.
D. Zhao ꢀ L. Zheng ꢀ G. He ꢀ S. Han (&)
College of Biotechnology and Pharmaceutical Engineering,
Nanjing University of Technology, Nanjing 210009, China
e-mail: hanshiqing@njut.edu.cn
Not until recently, by means of a structure-based virtual
screening (SBVS) method, 7 compounds were identified as
potent inhibitors of histidine kinase YycG protein from the
compound library of SPECS (Qin et al., 2006; Schreiber
et al., 2009). A typical 1 (Fig. 1), which had a 4-thiazolidi-
none core substituted by aromatic rings, was validated
in vitro to be active in inhibiting the growth of S. epidermidis
without obivious cytoxicity to Vero cells or hemolysis.
H. Liu ꢀ D. Qu (&)
Key Laboratory of Medical Molecular Virology of Ministry
of Education and Ministry of Public Health, Institute of Medical
Microbiology and Institutes of Biomedical Sciences, Shanghai
Medical School of Fudan University, Shanghai 200032, China
e-mail: dqu@shmu.edu.cn
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Med Chem Res (2013) 22:3743–3750
Fig. 1 The structures of
compounds 1 and HSQ1001
In our previous work, choosing 1 as the leading com-
pound, a series of novel 4-thiazolidinone were designed
and found to have antibacterial activities, among which
3-[5-(4-Oxo-3-p-tolyl-2-p-tolylimino-thiazolidin-5-ylide-
nemethyl)-furan-2-yl]-benzoic acid (HSQ1001) showed
the strongest activity with MIC values of 6.25 lM. It
described the synthesis of 4-thiazolidinone derivatives
with the carboxylic acid group was indispensable and the
3-(5-formylfuran-2-yl) benzoic acid fragment resulted in
an increased antibiofilm and antibacterial activity (Pan
et al., 2011; Pan et al., 2010).
successfully prepared and characterized by 1H-NMR, FTIR,
and Mass spectral studies.
Antibacterial activity
All newly synthesized compounds (7a–m) in Table 1 were
tested for their ability to inhibit bacterial growth of Gram-
positive (S. epidermidis) and Gram-negative (Escherichia
coli and Salmonella) species. The antibacterial activities of
these compounds were also compared with two well-
known antibiotics namely methicillin and ampicillin. Most
of them exhibit good potency in inhibiting the growth of
S. epidermidis which belong to low G ? C Gram-positive
bacterial with highly conserved YycG/YycF TCS. How-
ever, none of the molecules was able to inhibit the growth
of E. coli and Salmonella (MIC [ 200 lM) which have no
homologous genes of YycG/YycF.
In this paper, in our attempt to continue to discover new,
more-effective, and less-toxic agents for the treatment of
S. epidermidis infections, 4-thiazolidinone compounds
containing carboxylic acid moieties of benzoic acid,
phenoxy-acetic acid, or 4-phenoxymethyl-benzoic acid,
which are similar to 3-(5-formylfuran-2-yl) benzoic
acid fragment, have been synthesized and tested in vitro for
their antibacterial activities against S. epidermidis, E. coli,
and Samonella which have no homologous genes of YycG/
YycF were selected as control bacteria. As halogenated
4-thiazolidinone derivatives might be expected to be more
lipophilic and thus to have better absorption and distribu-
tion properties, as well as being more stable metabolically,
the influence of the halogen substituent of the phenyl rings
on biologic activity was studied.
Among the 13 newly synthesized compounds, ten
compounds (7b, 7c, 7d, 7g, 7h, 7i, 7j, 7k, 7l, and 7m) were
found to be much better active compounds to the leading
compound 1 with MICs \50 lM. Five compounds (7d,
7h–k) showed much better activity than methicillin and
ampicillin. It is worth mentioning that the compound {4-[3-
(4-Chloro-phenyl)-2-(4-chloro-phenylimino)-4-oxo-thiazo-
lidin-5-ylidenemethyl]-phenoxy}-acetic acid (7k) was
found to be the most active agent against S. epidermidis
ATCC 35984 with MIC value of 1.57 lM.
In a first effort to optimize this series, we evaluated group
R2 utilizing benzoic acid, 4-phenoxymethyl-benzoic acid,
and phenoxy-acetic acid substituents. By introducing the
benzoic acid moiety, compounds 7a–d showed good activ-
ities with the MIC value of 3.13–50 lM, especially com-
pound 7d (MIC = 3.13 lM). However, 7e showed no
activity (MIC [ 200 lM) when the big rigid fragment
4-phenoxymethyl-benzoic acid was incorporated into the
4-thiazolidione scaffold. To our delight, the activities of
compounds 7f–m, with the phenoxy-acetic acid group, were
even better. The results suggested that the distance between
carboxylic acid and the 4-thiazolidione ring appeared to have
a direct impact on the antibacterial activity and the moieties
benzoic acid or phenoxy-acetic acid had the suitable dis-
tance. As a matter of fact, the p-phenoxy-acetic acid deriv-
ative 7k (MIC = 1.57 lM) was the most potent agent in this
Results and discussion
Chemistry
The synthetic route to the 4-thiazolidione 7a–m is shown in
Scheme 1. Treatment of amines 3 and carbon disulfide
in 10 % NaOH solution at 60 °C for 4–8 h afforded
N-substituted thioureas 4 with good yields. The construction
of thiazolidione 5 was achieved by the cyclization reaction of
N-substitutedthioureas 4 with ethyl bromoacetateinEtOH, in
the presence of sodium acetate (Ramla, 2007). The final step
of the Knoevenagel condensation of substituted aromatic
aldehydes 6 with equivalent amount of 5 was catalyzed by
b-alanine to give the target compounds 7a–m in good yields
(Luo et al., 2009). A total of 13 designed compounds were
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Med Chem Res (2013) 22:3743–3750
3745
Scheme 1 Reagents and conditions: i 10 % NaOH solution, 60 °C, ii NaOAc, absolute alcohol, reflux, iii b-alanine, acetic acid, reflux
Table 1 In vitro antibacterial
Compounds R1
R2
MIC (lM)a
activity screening of novel
4-thiazolidione derivatives
against S. epidermidis,
E. coli and Salmonella
S.epidermidis ATCC
35984
E. coli ATCC
25922
Salmonella
7a
7b
7c
7d
7e
H
4-COOH-Ph
4-COOH-Ph
4-COOH-Ph
4-COOH-Ph
4-(40-COOH-
PhCH2O)-Ph
50
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
4-F
4-Br
4-Cl
4-Cl
25
12.5
3.13
[200
7f
7g
7h
7i
H
4-OCH2COOH-Ph
4-OCH2COOH-Ph
4-OCH2COOH-Ph
4-OCH2COOH-Ph
4-OCH2COOH-Ph
4-OCH2COOH-Ph
100
25
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
4-F
4-Br
2-Cl
3-Cl
4-Cl
4-Cl
3.13
3.13
3.13
1.57
6.25
7j
7k
7l
3-OCH3-4-
OCH2COOH-Ph
7m
1
4-Cl
2-
3-OCH2COOH-Ph
25
50
[200
[200
[200
[200
a
MIC assay was performed
following the broth micro-
3-OCH3-4-
CH2CH3 OCH2COOH-Ph
dilution method (in tubes) of the
CLSI of America. In this assay,
the highest concentration of
each compound was 200 lM
Methicillin
Ampicillin
–
–
–
–
5.26
11.5
[200
[200
[200
[200
series with a fourfold increase in potency when compared to
7l (MIC = 6.25 lM), and was also 16 times more active
than the m-phenoxy-acetic acid analog 7m (MIC =
25.0 lM). The introduction of an electron-donating group
3-methoxy on the phenyl ring of phenoxy-acetic acid moiety
did not improve the antibacterial activity and m-phenoxy-
acetic acid presented a negative effect as it strongly reduced
the activity.
substituents (F, Cl, or Br) on phenyl rings of 7b–d and 7g–m
showed a positive effect as they enhanced the antibacterial
activity (Table 1). The activities of compounds 7f, 7g, 7h,
and 7k with the same phenoxy-acetic acid moiety at R2, but
different para-halogen substituents (R1) on phenyl rings
increased in the following order: H(7f) \ F(7g) \ Br(7h)
\ Cl(7k). It is noteworthy that the position of chloro group
on phenyl rings also influenced the activities of the 4-thai-
zolidinone. Compound 7k with para-chloro group on phenyl
rings was shown to be more active than compounds 7i and 7j
with ortho- and meta-chloro on phenyl ring, respectively.
This result indicated that the para halogen substituents on
In drug design, halogen atoms are used to improve pen-
etration through lipid membranes and tissues. They may also
present a significant reactivity depending on the structure of
the molecule. In this work, the introduction of halogen
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Med Chem Res (2013) 22:3743–3750
determined on an electrothermal digital apparatus model
WRS-1B (ShangHai, China) without correction. Infrared
spectra were recorded on an Avatar 360 ESP spectrometer
(Nicolet) by potassium bromide (1 % w/w) disk scanning
from 500 to 4,000 cm-1. A Bruker AM-500 MHz instru-
Table 2 Antibacterial activity of selected 4-thiazolidione derivatives
against methicillin-resistant clinical isolates
Clinical
isolates
MIC (lM)
MRSA8282
MRSA8166
MRSE
8311
MRSE
8354
1
ment (Bruker) was used to acquire H NMR spectra with
7d
3.13
3.13
3.13
3.13
3.13
65.7
22.1
12.5
6.25
12.5
12.5
6.25
65.7
22.1
3.13
3.13
3.13
3.13
1.57
65.7
22.1
3.13
3.13
3.13
3.13
1.57
65.7
22.1
TMS as internal standard. Chloroform-D and DMSO-d6
were used as solvents. Low resolution mass spectra
(LRMS) were recorded on a HP-5973 instrument (HP).
7h
7i
7j
7k
Synthesis of 1, 3-Bis-(4-chloro-phenyl)-thiourea(4a).
Representative procedure for N-substituted thioureas
(4a–f)
Methicillin
Levofloxacin
MRSA methicillin-resistant Staphylococcus aureus, MRSE methicil-
lin-resistant Staphylococcus epidermidis
p-Chloroaniline (1.27 g, 0.01 mol) was dissolved in 10 %
NaOH (30 mL) solution followed by addition of carbon
disulfide (0.015 mol) at room temperature and the mixture
was heated to 60 °C until the completion of reaction
(monitored by TLC). The mixture was cooled, acidified
with dilute hydrochloric acid, and extracted with CH2Cl2.
The combined organic layer was dried over sodium sulfate
and the solvent was removed completely. The residue was
purified by column chromatography on silica gel to obtain
1,3-Bis-(4-chloro-phenyl)-thiourea (2.39 g, 80.7 %) as
white powder.
phenyl rings were more likely to inhibit the growth of
S. epidermidis.
To examine whether the 4-thiazolidione derivatives are
effective against clinical isolates, MIC values of the selected
derivatives 7d, 7h–k were determined against methicillin-
resistant clinical isolates (MRSA8282, MRSA8166, MRSE
8311, and MRSE 8354) and were compared with methicillin
and levofloxacin. As shown in Table 2, the antibacterial
activitiesof7d, 7h–kweremuchsuperiortothatofmethicillin
andlevofloxacin. Compound7k demonstratedthemostpotent
antibacterial activities among the synthesized compounds.
3-(4-Chloro-phenyl)-2-(4-chloro-phenylimino)-
thiazolidin-4-one(5a).Representative procedure
for thiazolidione (5a–f)
Conclusion
In summary, a series of 4-thaizolidinone (7a–m) were syn-
thesized and evaluated in vitro for their antibacterial activities,
in comparison with methicillin and ampicillin. Most of the
synthesized compounds were proved to be effective agents
against to S. epidermidis, especially 7k showed the most active
with the MIC value of 1.57 lM. The carboxylic acid moieties
such as phenoxy-acetic acid fragment at R2 afforded excellent
activities. The compound bearing a chlorine atom in the para-
position (R1) of phenyl rings was favorable for achieving
antibacterial activities. Further antibacterial evaluation was
down on clinical isolates, a comparison of antibacterial activity
of the most active compounds(7d, 7h–k) with that of two well-
known antibiotics namely methicillin and levofloxacin indi-
cated that compound 7k show very good activity.
To a stirred suspension of 1,3-Bis-(4-chloro-phenyl)-thio-
urea (1.19 g, 4.0 mmol) and anhydrous sodium acetate
(0.49 g, 6 mmol) in 20 mL of absolute ethanol was added
0.48 mL of ethyl bromoacetate (4.4 mmol). The mixture
was heated at 60 °C for 3 h. After being cooled to room
temperature, the reaction mixture was extracted with
EtOAc. The organic layer was washed with brine, dried by
anhydrous Na2SO4, and concentrated under reduced pres-
sure. The crude compound was purified by silica gel col-
umn chromatography using petroleum ether/ethyl acetate
(4:1 v/v) as mobile phase to obtain pure compound as a
1
white solid: yield, 95 %; H NMR (300 MHz, CDCl3) d
7.30 (d, J = 8.2 Hz, Ph–H), 7.25 (d, J = 8.5 Hz, Ph–H),
7.10 (d, J = 8.1 Hz, Ph–H), 6.80 (d, J = 8.2 Hz, 2H,
Ph–H), 3.93 (s, 2H, CH2).
Experimental protocols
Chemistry
3-(4-Chloro-phenyl)-2-(3-chloro-phenylimino)-
thiazolidin-4-one (5b)
General remarks
3-(4-Chloro-phenyl)-2-(3-chloro-phenylimino)-thiazolidin-
4-one was prepared from 1, 3-Bis-(3-chloro-phenyl)-thio-
urea and ethyl bromoacetate according to the procedure
described above: yield 92 %, white powder; 1H NMR
All reagents and solvents were commercially available and
used without further purification. Melting points were
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Med Chem Res (2013) 22:3743–3750
3747
(300 MHz, CDCl3) d 7.93 (s, 1H, Ph–H), 7.82 (s, 1H, Ph-
H), 7.56–7.43 (m, J = 13.3 Hz, 2H, Ph–H), 7.35 (t,
J = 7.4 Hz, 1H, Ph–H, 7.27 (d, J = 7.4 Hz, 1H, Ph–H),
7.20 (d, J = 7.3 Hz, 1H, Ph–H), 7.13 (d, J = 7.0 Hz, 1H,
Ph–H), 4.16 (s, 2H, CH2).
(t, J = 7.4 Hz, 1H, Ph–H), 6.98 (dd, J = 8.3, 1.0 Hz, 2H,
Ph–H); ESI–MS: m/z 401.0(M?1)?.
4-[3-(4-Fluoro-phenyl)-2-(4-fluoro-phenylimino)-4-
oxo-thiazolidin-5-ylidenemethyl]-benzoic acid (7b)
3-(4-Fluoro-phenyl)-2-(4-fluoro-phenylimino)-
thiazolidin-4-one (5c)
4-[3-(4-Fluoro-phenyl)-2-(4-fluoro-phenylimino)-4-oxo-
thiazolidin-5-ylidenemethyl]-benzoic acid was prepared
from 3-(4-fluoro-phenyl)-2-(4-fluoro-phenylimino)-thia-
zolidin-4-one and 4-formyl-benzoic acid according to
the procedure described above: White powder, yield
87 %; mp: 224–225 °C; IR(KBr): v/cm-1 = 3412(CO–
OH), 3032(C–H), 1667(C=O), 1573(C=C), 1321(C–S);
1H NMR (300 MHz, DMSO-d6): d(ppm) = 13.10(s, 1H,
COOH), 8.04 (d, J = 8.3 Hz, 2H, Ph–H), 7.89 (s, 1H,
CH), 7.68 (d, J = 8.3 Hz, 2H, Ph–H), 7.63 (s, 4H, Ph–
H), 7.41 (d, J = 8.4 Hz, 2H, Ph–H), 7.01 (d, J = 8.4 Hz,
2H, Ph–H); ESI–MS: m/z 436.9(M?1)?.
3-(4-Fluoro-phenyl)-2-(4-fluoro-phenylimino)-thiazolidin-
4-one was prepared from 1,3-Bis-(4-Fluoro-phenyl)-thio-
urea and ethyl bromoacetate according to the procedure
described above: yield 97 %, white powder; 1H NMR
(300 MHz, CDCl3) d 7.51–7.45 (m, 2H, Ph–H), 7.30–7.23
(m, 2H, Ph–H), 7.13 (t, J = 7.7 Hz, 2H, Ph–H), 7.06 (t,
J = 7.7 Hz, 2H, Ph–H), 4.12 (s, 2H, CH2).
3-(4-Bromo-phenyl)-2-(4-bromo-phenylimino)-
thiazolidin-4-one (5d)
3-(4-Bromo-phenyl)-2-(4-bromo-phenylimino)-thiazolidin-
4-one was prepared from 1,3-Bis-(4-Fluoro-phenyl)-thio-
urea and ethyl bromoacetate according to the procedure
described above: yield 90 %, white powder; 1H NMR
(300 MHz, CDCl3) d 7.76 (d, J = 7.4 Hz, 2H, Ph–H), 7.62
(q, J = 7.6 Hz, 4H, Ph–H), 7.03 (d, J = 7.4 Hz, 2H, Ph–
H), 4.16 (s, 2H, CH2).
4-[3-(4-Bromo-phenyl)-2-(4-bromo-phenylimino)-4-
oxo-thiazolidin-5-ylidenemethyl]-benzoic acid (7c)
4-[3-(4-Bromo-phenyl)-2-(4-bromo-phenylimino)-4-oxo-
thiazolidin-5-ylidenemethyl]-benzoic acid was prepared
from 3-(4-bromo-phenyl)-2-(4-bromo-phenylimino)-thi-
azolidin-4-one and 4-formyl-benzoic acid according to
the procedure described above: White powder, yield
82 %; mp: 188–190 °C; IR(KBr): v/cm-1 = 3389(CO–
OH), 3022(C–H), 1687(C=O), 1556(C=C), 1330(C–S);
1H NMR (300 MHz, DMSO-d6): d(ppm) = 13.22 (s, 1H,
COOH), 8.04 (d, J = 8.3 Hz, 2H, Ph–H), 7.89 (s, 1H,
CH), 7.78 (d, J = 8.6 Hz, 2H, Ph–H), 7.70 (d,
J = 8.4 Hz, 2H, Ph–H), 7.57 (t, J = 8.5 Hz, 4H, Ph–H),
6.96 (d, J = 8.6 Hz, 2H, Ph–H); ESI–MS: m/z
556.9(M?1)?.
General procedure for preparation
of compounds (7a–m)
The corresponding aldehyde 6 (1 equiv), b-alanine (0.2
equiv), and thiazolidione 5 (1 equiv) were heated at 100 °C
for 1 h in glacial acetic acid. Upon completion of the
reaction, the mixture was cooled, the reaction was quen-
ched with water, and the precipitate was filtered off. The
solid products were filtered and recrystallized in methanol
to obtain pure compound.
4-[3-(4-Chloro-phenyl)-2-(4-chloro-phenylimino)-4-oxo-
thiazolidin-5-ylidenemethyl]-benzoic acid (7d)
4-(4-Oxo-3-phenyl-2-phenylimino-thiazolidin-5-
ylidenemethyl)-benzoic acid (7a)
4-[3-(4-Chloro-phenyl)-2-(4-chloro-phenylimino)-4-oxo-thi-
azolidin-5-ylidenemethyl]-benzoic acid was prepared from
3-(4-chloro-phenyl)-2-(4-chloro-phenylimino)-thiazolidin-4-
one and 4-formyl-benzoic acid according to the procedure
described above: White powder, yield 67 %; mp:
214–215 °C; IR(KBr): v/cm-1 = 3403(CO–OH), 2984(C–
H), 1707(C=O), 1571(C=C), 1236(C–S); 1H NMR (300
MHz, DMSO-d6) : d(ppm) = 13.15 (s, 1H, COOH), 8.03 (d,
J = 8.3 Hz, 2H, Ph–H), 7.88 (s, 1H, CH), 7.68 (d, J = 8.4
Hz, 2H, Ph–H), 7.63 (s, 4H, Ph–H), 7.44 (d, J = 8.6 Hz, 2H,
Ph-H), 7.01 (d, J = 8.6 Hz, 2H, Ph–H); ESI–MS: m/z 469.0
(M?1)?.
4-(4-Oxo-3-phenyl-2-phenylimino-thiazolidin-5-ylidene-
methyl)-benzoic acid was prepared from 3-phenyl-2-
phenylimino-thiazolidin-4-one and 4-formyl-benzoic
acid according to the procedure described above:
White powder, yield 69 %; mp: 168–169 °C; IR(KBr):
v/cm-1 = 3410(CO–OH), 3034(C–H), 1671(C=O), 1587
(C=C), 1322(C–S); 1H NMR (300 MHz, DMSO-d6):
d(ppm) = 13.11 (s, 1H, COOH), 8.03 (d, J = 8.4 Hz,
2H, Ph–H), 7.85 (s, 1H, CH), 7.67 (d, J = 8.4 Hz, 2H,
Ph–H), 7.57 (d, J = 4.3 Hz, 4H, Ph–H), 7.53–7.44
(m, 1H, Ph–H), 7.39 (t, J = 7.9 Hz, 2H, Ph–H), 7.18
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Med Chem Res (2013) 22:3743–3750
4-{4-[3-(4-Chloro-phenyl)-2-(4-chloro-phenylimino)-4-
oxo-thiazolidin-5-ylidenemethyl]-phenoxymethyl}-
benzoic acid (7e)
2H, Ph–H), 7.00 (dd, J = 7.5, 5.1 Hz, 2H, Ph–H), 4.73 (s,
2H, CH2); ESI–MS: m/z 467.1 (M?1)?.
{4-[3-(4-Bromo-phenyl)-2-(4-bromo-phenylimino)-4-oxo-
4-{4-[3-(4-Chloro-phenyl)-2-(4-chloro-phenylimino)-4-oxo-
thiazolidin-5-ylidenemethyl]-phenoxymethyl}-benzoic acid
was prepared from 3-(4-Chloro-phenyl)-2-(4-chloro-phe-
nylimino) -thiazolidin-4-one and 4-(4-Formyl-phenoxy-
methyl)-benzoic acid according to the procedure described
above:Whitepowder, yield48 %;mp:256–257 °C;IR(KBr):
v/cm-1 = 3387 (CO–OH), 3010 (C–H), 1698 (C=O), 1549
(C=C), 1329 (C–S), 1182 (C–O); 1H NMR (300 MHz,
DMSO-d6): d(ppm) = 12.89 (s, 1H, COOH), 7.96 (d,
J = 8.2 Hz, 2H, Ph–H), 7.79 (s, 1H, CH), 7.64–7.52 (m, 9H,
Ph–H), 7.44 (d, J = 8.5 Hz, 2H, Ph–H), 7.16 (d, J = 8.8 Hz,
2H, Ph–H), 7.01 (d, J = 8.6 Hz, 2H, Ph–H), 6.91 (d, J =
8.6 Hz, 1H, Ph–H), 5.25 (s, 2H, CH2); ESI–MS: m/z
575.0(M?1)?.
thiazolidin-5-ylidenemethyl]-phenoxy}-acetic acid (7h)
{4-[3-(4-Bromo-phenyl)-2-(4-bromo-phenylimino)-4-oxo-
thiazolidin-5-ylidenemethyl]-phenoxy}-acetic acid was
prepared from 3-(4-bromo-phenyl)-2-(4-bromo-phenyli-
mino)-thiazolidin-4-one and (4-formyl-phenoxy)-acetic
acid according to the procedure described above: White
powder, yield 77 %; mp: 192–193 °C; IR(KBr): v/cm-1
3418(CO–OH), 2904(C–H), 1700(C=O), 1548(C=C),
1
1235(C–S), 1160(C–O); H NMR (300 MHz, DMSO-d6):
=
d(ppm) = 12.94 (s, 1H, COOH), 7.79 (d, J = 5.4 Hz, 2H,
Ph–H), 7.75 (s, 1H, CH), 7.56 (dd, J = 10.5, 8.6 Hz, 6H,
Ph–H), 7.06 (d, J = 8.9 Hz, 2H, Ph–H), 6.96 (d,
J = 8.6 Hz, 2H, Ph–H), 4.74 (s, 2H, CH2); ESI–MS: m/z
586.8(M?1)?.
[4-(4-Oxo-3-phenyl-2-phenylimino-thiazolidin-5-
{4-[3-(2-Chloro-phenyl)-2-(2-chloro-phenylimino)-4-oxo-
ylidenemethyl)-phenoxy]-acetic acid (7f)
thiazolidin-5-ylidenemethyl]-phenoxy}-acetic acid (7i)
[4-(4-Oxo-3-phenyl-2-phenylimino-thiazolidin-5-ylidene-
methyl)-phenoxy]-acetic acid was prepared from 3-phenyl-
2-phenylimino-thiazolidin-4-one and 4-formyl-phenoxy-
acetic acid according to the procedure described above:
White powder, yield 45 %; mp: 176–177 °C; IR(KBr):
v/cm-1 = 3334(CO–OH), 2984(C–H), 1715(C=O), 1548
(C=C), 1244(C–S), 1175(C–O); 1H NMR (300 MHz,
DMSO-d6) : d(ppm) = 13.00 (s, 1H, COOH), 7.78 (s, 1H,
CH), 7.55 (s, 4H, Ph–H), 7.52 (d, J = 8.8 Hz, 2H, Ph–H),
7.50–7.45 (m, 1H, Ph–H), 7.39 (t, J = 7.8 Hz, 2H, Ph–H),
7.17 (t, J = 7.4 Hz, 1H, Ph–H), 7.06 (d, J = 8.8 Hz, 2H,
Ph–H), 6.98 (d, J = 7.4 Hz, 2H, Ph–H), 4.74 (s, 2H, CH2);
ESI–MS: m/z 431.0(M?1)?.
{4-[3-(2-Chloro-phenyl)-2-(2-chloro-phenylimino)-4-oxo-
thiazolidin-5-ylidenemethyl]-phenoxy}-acetic acid was
prepared from 3-(2-Chloro-phenyl)-2-(2-chloro-phenyli-
mino)-thiazolidin-4-one and (4-Formyl-phenoxy)-acetic
acid according to the procedure described above: White
powder, yield 64 %; mp: 186–187 °C; IR(KBr): v/cm-1
=
3368 (CO–OH), 3023 (C–H), 1678 (C=O), 1521 (C=C),
1316 (C–S), 1173 (C–O); 1H NMR (300 MHz, DMSO-d6):
d(ppm) = 13.21 (s, 1H, COOH), 7.45 (s, 1H, CH),
7.42–7.23 (m, 7H, Ph–H), 7.23–7.16 (m, 2H, Ph–H), 7.10
(td, J = 7.5, 1.5 Hz, 1H, Ph–H), 6.88 (d, J = 7.6 Hz, 2H,
Ph–H), 4.82 (s, 2H, CH2).
{4-[3-(3-Chloro-phenyl)-2-(3-chloro-phenylimino)-4-oxo-
thiazolidin-5-ylidenemethyl]-phenoxy}-acetic acid (7j)
{4-[3-(4-Fluoro-phenyl)-2-(4-fluoro-phenylimino)-4-oxo-
thiazolidin-5-ylidenemethyl]-phenoxy}-acetic acid (7g)
{4-[3-(3-Chloro-phenyl)-2-(3-chloro-phenylimino)-4-oxo-
thiazolidin-5-ylidenemethyl]-phenoxy}-acetic acid was
prepared from 3-(3-Chloro-phenyl)-2-(3-chloro-phenyli-
mino)-thiazolidin-4-one and (4-Formyl-phenoxy)-acetic
acid according to the procedure described above: White
{4-[3-(4-Fluoro-phenyl)-2-(4-fluoro-phenylimino)-4-oxo-thi-
azolidin-5-ylidenemethyl]-phenoxy}-acetic acid was prepared
from 3-(4-fluoro-phenyl)-2-(4-fluoro-phenylimino)-thiazoli-
din-4-one and (4-formyl-phenoxy)-acetic acid according to
the procedure described above: White powder, yield 69 %;
mp: 178–179 °C; IR(KBr): v/cm-1 =3418(CO–OH), 2984
powder, yield 58 %; mp: 176–177 °C; IR(KBr): v/cm-1
=
3321(CO–OH), 3023(C–H), 1723(C=O), 1639, 1578
(C=C), 1236 (C–S), 1160(C–O); 1H NMR (500 MHz,
DMSO-d6): d(ppm) = 13.35 (s, 1H, COOH), 7.66 (s, 1H,
CH), 7.54 (s, 1H, Ph–H), 7.39 (d, J = 7.8 Hz, 2H, Ph–H),
7.35–7.28 (m, 4H, Ph–H), 7.28–7.23 (m, 2H, Ph–H), 7.16
(d, J = 7.4 Hz, 1H, Ph–H), 6.89 (d, J = 7.5 Hz, 2H, Ph–
H), 4.82 (s, 2H, CH2).
1
(C–H), 1707(C=O), 1541(C=C), 1236(C–S), 1175(C–O); H
NMR (300 MHz, DMSO-d6): d(ppm) = 13.00 (s, 1H,
COOH), 7.77 (s, 1H, CH), 7.60 (dd, J = 7.6, 5.1 Hz, 2H, Ph–
H), 7.52 (d, J = 8.1 Hz, 2H, Ph–H), 7.37 (t, J = 8.4 Hz, 2H,
Ph–H), 7.21 (t, J = 8.4 Hz, 2H, Ph–H), 7.05 (d, J = 8.1 Hz,
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Med Chem Res (2013) 22:3743–3750
3749
{4-[3-(4-Chloro-phenyl)-2-(4-chloro-phenylimino)-4-oxo-
Ph–H), 7.05 (d, J =7.5 Hz, 1H, Ph–H), 6.96 (s, 1H, Ph–
H), 6.83 (d, J = 7.5 Hz, 1H, Ph–H), 4.82 (s, 2H, CH2).
thiazolidin-5-ylidenemethyl]-phenoxy}-acetic acid (7k)
{4-[3-(4-Chloro-phenyl)-2-(4-chloro-phenylimino)-4-oxo-
thiazolidin-5-ylidenemethyl]-phenoxy}-acetic acid was
prepared from 3-(4-Chloro-phenyl)-2-(4-chloro-phenyli-
mino)-thiazolidin-4-one and (4-Formyl-phenoxy)-acetic
acid according to the procedure described above: White
powder, yield 56 %; mp: 187–188 °C; IR(KBr): v/
cm-1 = 3367 (CO–OH), 2988 (C–H), 1679 (C=O), 1565
(C=C), 1321 (C–S), 1204 (C–O); 1H NMR (300 MHz,
DMSO-d6) : d(ppm) = 13.11 (s, 1H, COOH), 7.79 (s, 1H,
CH), 7.61 (d, J = 1.2 Hz, 4H, Ph–H), 7.54 (d, J = 8.8
Hz, 2H, Ph–H), 7.44 (d, J = 8.6 Hz, 2H, Ph–H), 7.03 (dd,
J = 14.0, 8.7 Hz, 4H, Ph–H), 4.74 (s, 2H, CH2); ESI–MS:
m/z 498.9 (M?1)?.
Minimal inhibitory concentration (MIC)
MIC assays for the antibacterial activities of the derivatives
were performed according to the broth microdilution (in
tubes) method of the Clinical and Laboratory Standards
Institute (CLSI) of America. In brief, a serial twofold
dilution of derivatives was added to eight tubes containing
4 mL Mueller–Hinton Broth (OXOID, England), making
the final concentration from 200 lM to 0.78 lM. The
turbidity of 6-h strain cultures is adjusted to match that of a
0.5 McFarland standard (*108142 CFU mL-1), and then
0.02 mL of the bacterial inoculum was added to each tube.
An inoculated broth containing no antibiotic was included
as a bacterial growth control and a tube of un-inoculated
broth was used as a sterility control. These bacteria were
incubated at 37 °C for 12 h, the lowest concentration
which completely inhibits visible growth of the organism
as detected by the unaided eye is recorded as the MIC.
{4-[3-(4-Chloro-phenyl)-2-(4-chloro-phenylimino)-4-oxo-
thiazolidin-5-ylidenemethyl]-2-methoxy-phenoxy}-acetic
acid (7l)
Acknowledgments We would like to thank Professor Guoqiang
Lin, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, for his invaluable academic advice. This work was sup-
ported by the National Natural Science Foundation of China Grant
no. 20942006 (S. Han), Grant no. 21072095 (S. Han), Grant no.
30800036 (D. Qu), Shanghai Municipal Committee of Science and
Technology (08JC1401600), National High Technology Research
and Development Program of China (863 Program 2011AA02A209)
and Program for Changjiang Scholars and Innovative Research Team
in University (Grant no. IRT1066).
{4-[3-(4-Chloro-phenyl)-2-(4-chloro-phenylimino)-4-oxo-thia-
zolidin-5-ylidenemethyl]-2-methoxy-phenoxy}-acetic acid
was prepared from 3-(4-Chloro-phenyl)-2-(4-chloro-phe-
nylimino)-thiazolidin-4-one and (4-Formyl-2-methoxy-phe-
noxy)-acetic acid according to the procedure described
above: White powder, yield 64 %; mp: 196–197 °C;
IR(KBr): v/cm-1 = 3321 (CO–OH), 3056 (C–H), 1711
1
(C=O), 1568 (C=C), 1323 (C–S), 1195 (C–O); H NMR
(300 MHz, DMSO-d6): d(ppm) = 13.36 (s, 1H, COOH),
7.45 (s, 1H, CH), 7.44–7.36 (m, 4H, Ph–H), 7.31 (d,
J = 3.4 Hz, 4H, Ph–H), 7.02 (dd, J = 7.5, 1.3 Hz, 1H, Ph–
H), 6.95 (d, J = 1.4 Hz, 1H, Ph–H), 6.84 (d, J = 7.5 Hz,
1H, Ph–H), 4.82 (s, 2H, CH2), 3.79 (s, 3H, CH3); ESI–MS:
m/z 529.4 (M?1)?.
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