Synthesis and antibacterial evaluation of furan derivatives bearing a rhodanine moiety

Article abstract of DOI:10.1007/s00044-013-0648-7

Two series of furan derivatives bearing a rhodanine moiety (4a-l and 5a-l) have been synthesized, characterized, and evaluated for their antibacterial activity. The majority of these compounds showed potent levels of inhibitory activity against a variety of different Gram-positive bacteria, including multidrug-resistant clinical isolates, with minimum inhibitory concentration (MIC) values in the range of 2-16 μg/mL. In particular, compound 4l was found to be the most potent of the synthesized compounds against the multidrug-resistant strains, with a MIC value of 2 or 4 μg/mL. None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 at 64 μg/mL. An examination of the cytotoxicities of these agents revealed that they displayed low levels of toxicity toward HeLa cells. All of the compounds synthesized in the current paper were characterized by ¹H and ¹³C NMR, infrared, and mass spectroscopy. Graphical Abstract: Two novel series of furan derivatives bearing a rhodanine moiety were synthesized, and evaluated for their antibacterial activity. Compounds 4l and 5a presented high potency against several multidrug-resistant clinical isolates.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s00044-013-0648-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0648-7
ORIGINAL RESEARCH
Synthesis and antibacterial evaluation of furan derivatives
bearing a rhodanine moiety
•
•
•
Jian Che Chang-Ji Zheng Ming-Xia Song Ya-Jing Bi Yi Liu
•
•
•
Yin-Jing Li Yan Wu Liang-Peng Sun Hu-Ri Piao
•
•
Received: 30 December 2012 / Accepted: 22 May 2013
Ó Springer Science+Business Media New York 2013
Abstract Two series of furan derivatives bearing a rho-
danine moiety (4a–l and 5a–l) have been synthesized,
characterized, and evaluated for their antibacterial activity.
The majority of these compounds showed potent levels of
inhibitory activity against a variety of different Gram-
positive bacteria, including multidrug-resistant clinical
isolates, with minimum inhibitory concentration (MIC)
values in the range of 2–16 lg/mL. In particular, com-
pound 4l was found to be the most potent of the synthe-
sized compounds against the multidrug-resistant strains,
with a MIC value of 2 or 4 lg/mL. None of the compounds
exhibited any activity against the Gram-negative bacteria
Escherichia coli 1356 at 64 lg/mL. An examination of the
cytotoxicities of these agents revealed that they displayed
low levels of toxicity toward HeLa cells. All of the com-
pounds synthesized in the current paper were characterized
documented in recent years, with particular emphasis on
Gram-positive and Gram-negative bacteria from ambula-
tory and hospitalized patients (Witte, 1999; Heinemann
et al., 2000; Levy, 1998; Komine et al., 2008; Service,
1995). Compounds beating oxo or azo heterocycles are
¨
well known to be biologically important (Gil and Brase,
2009; Butler, 2004). Furan-containing compounds show a
diverse array of favorable biological and pharmacological
properties and have consequently been used as medicines
in a variety of different disease areas (Ivie, 1987). Furan
derivatives obtained from synthetic and natural sources
have recently been the subject of considerable levels of
interest because of their wide range of pharmaceutical
applications (Kupchan et al., 1971; Shevchenko, 1999; Qu
et al., 2012; Ding et al., 2012). A large number of the
naturally occurring furans have shown interesting bio-
logical activities, such as antimicrobial (Khan et al., 2005;
Hofnung et al., 2002), cytotoxic, and antitumor properties
(Bandurraga et al., 1982), as well as several other
potentially useful activities (Jin et al., 2012; Mamta
et al., 2012).
1
by H and 13C NMR, infrared, and mass spectroscopy.
Keywords Rhodanine ꢀ Furan ꢀ Antibacterial activity
Introduction
Rhodanine compounds are known to be effective
antibacterial compounds. We previously reported the
synthesis and antimicrobial evaluation of a series of
rhodanine-3-acetic acid derivatives (Chen et al., 2010)
bearing a chalcone moiety (Fig. 1) that showed potent
The increasing levels of resistance exhibited by bacterial
pathogens toward antibiotic agents have been well
inhibitory activity toward
a
variety of different
Gram-positive bacterial strains, including multidrug-
resistant clinical isolates. Herein, as part of our
ongoing research toward the development of novel
antibacterial agents, we have designed and synthesized
two series of furan derivatives containing a rhodanine
moiety (4a–l and 5a–l). These compounds were sub-
sequently characterized and evaluated for their antibacterial
activity.
J. Che ꢀ C.-J. Zheng ꢀ M.-X. Song ꢀ Y.-J. Bi ꢀ Y. Liu ꢀ
Y.-J. Li ꢀ Y. Wu ꢀ L.-P. Sun ꢀ H.-R. Piao (&)
Key Laboratory of Natural Resources and Functional Molecules
of the Changbai Mountain, Affiliated Ministry of Education,
Yanbian University College of Pharmacy, Yanji 133002,
Jilin Province, People’s Republic of China
e-mail: piaohuri@yahoo.com.cn
123

Med Chem Res
O
O
COOH
R
Cl
Cl
O
O
N
S
N
R'
S
COOH
S
S
PHR105K
Fig. 1 Previously reported compound PHR105K and the structure-based design of the target compounds
Experimental
(dichloromethane/methanol = 100:1) to obtain a yellow
solid.
Materials
2-((5E)-5-(4-((E)-3-(2,4-Dichlorophenyl)-3-oxoprop-1-enyl)
benzylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic
Melting points were determined in open capillary tubes and
are reported uncorrected. The reactions were monitored by
thin-layer chromatography (TLC) on silica gel precoated
F254 Merck plates. The developed TLC plates were
examined with a UV lamp (254 nm). Infrared (IR) spectra
acid
(previously reported compound PHR105K) Yield: 53 %;
m.p. 235–236 °C. IR (KBr) cm-1: 3449 (OH), 1687
(C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 4.75
(s, 2H, CH2), 7.43 (d, J = 15.3 Hz, 1H, CH=CH), 7.96 (s,
1H, CH), 7.80 (d, J = 15.3 Hz, 1H, CH=CH), 7.38–7.99
(m, 7H, Ar–H), 13.50 (s, 1H, COOH). 13C NMR (DMSO-
d6, 300 MHz, ppm): d 193.37 (C=S), 192.62 (C=O),
167.71 (COOH), 166.78 (C=O), 145.44 (C=C), 137.59
(C=C), 136.88 (Ar–C), 136.33 (Ar–C), 135.40 (Ar–C),
133.24 (Ar–C), 131.82 (Ar–C), 131.67 (Ar–C), 130.28
(Ar–C), 128.16 (Ar–C), 123.57 (C=C), 45.52 (C–N). MS
m/z 479 (M?1).
1
were recorded as KBr disks on a FT-IR1730. H NMR
spectra were measured on Bruker AV-300 spectrometer,
using tetramethylsilane as internal standard. Mass spectra
were measured on an HP1100LC (Agilent Technologies,
USA).
Methods
Synthesis
(Z)-3-Methyl-2-(4-oxo-2-thioxo-5-((5-(p-tolyl)furan-2-yl)
methylene)thiazolidin-3-yl)pentanoic acid (4a) Yield:
87 %. m.p. 115–117 °C. IR (KBr) cm-1: 2966 (OH), 1713
General procedure for the preparation of compounds 3
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 0.75 (t,
A mixture of aniline (30 mmol) and sodium nitrite
(30.30 mmol) in hydrochloric acid (8 mL) and water
(6 mL) was stirred for 1 h at 0 °C. After the completion of
the reaction, the mixture was filtered and acetone (30 mL),
furfural (30 mmol), and cupric chloride (3 mmol) were
added slowly to the filtrate, and then the mixture was
stirred for 12 h at 20 °C. The excess solvent was removed
under reduced pressure and the residue was dissolved in
ethyl acetate and extracted with water, dried over MgSO4,
and the solvent was evaporated under reduced pressure.
The resulting residue was purified by silica gel column
chromatography (dichloromethane/methanol = 200:1).
J = 7.5 Hz, 3H, CH3), 0.89 (m, 1H, CH), 1.11 (d,
J = 6 Hz, 3H, CH3), 1.21 (m, 2H, CH2), 2.33 (s, 3H, CH3),
5.18 (d, J = 9 Hz, 1H, CH), 7.27 (d, J = 3 Hz, 1H, CH),
7.33 (s, 1H, CH), 7.68 (s, 1H, CH), 7.36–7.74 (m, 4H,
Ar–H), 13.15 (s, 1H, COOH). 13C NMR (DMSO-d6,
75 MHz, ppm): d 194.45 (C=S), 169.23 (COOH), 166.77
(C=O), 153.64 (C–O), 149.28 (C–O), 139.85 (C=C),
130.36 (Ar–C), 128.62 (Ar–C), 126.28 (Ar–C), 125.78
(Ar–C), 124.98 (C–S), 119.82 (Ar–C), 116.60 (Ar–C),
110.22 (C=C), 109.55 (C=C), 61.95 (C–N), 33.50 (CH),
25.30 (CH2), 21.51 (Ar–CH3), 18.08 (CH3), 11.34 (CH3).
MS m/z 417 (M?1).
General procedure for the preparation of compounds 4
(Z)-3-Methyl-2-(4-oxo-2-thioxo-5-((5-(4-(trifluoromethoxy)
phenyl)furan-2-yl)methylene)thiazolidin-3-yl)pentanoic acid
A mixture of compounds 3 (2 mmol), (2S)-3-methyl-2-(4-
oxo-2-thioxothiazolidin-3-yl)pentanoic acid (2 mmol), 10
drops piperidine, and 10 drops glacial acetic acid in ethanol
(15 mL) was refluxed for 4 h. After cooling, the solvent
was evaporated under reduced pressure. The resulting
residue was purified by silica gel column chromatography
(4b) Yield: 88 %. m.p. 112–114 °C. IR (KBr) cm-1
:
1
3028 (OH), 1713 (C=O). H NMR (DMSO-d6, 300 MHz,
ppm): d 0.80 (t, J = 7.5 Hz, 3H, CH3), 0.97 (m, 1H, CH),
1.13 (d, J = 6 Hz, 3H, CH3), 1.20 (m, 2H, CH2), 5.23 (d,
J = 9 Hz, 1H, CH), 7.40 (s, 1H, CH), 7.44 (s, 1H, CH),
7.54–8.01 (m, 4H, Ar–H), 7.76 (s, 1H, CH), 13.22 (s, 1H,
123

Med Chem Res
COOH). 13C NMR (DMSO-d6, 75 MHz, ppm): d 193.97
(C=S), 173.56 (COOH), 168.73 (C=O), 166.30 (Ar–C),
156.90 (C–O), 152.68 (C–O), 149.55 (C=C), 148.59 (Ar–
C), 127.70 (Ar–C), 126.43 (Ar–C), 123.73 (C–S), 121.94
(OCF3), 119.24 (Ar–C), 117.18 (Ar–C), 115.19 (C=C),
111.15 (C=C), 61.49 (C–N), 33.02 (CH), 24.81 (CH2),
17.56 (CH3), 10.84 (CH3). MS m/z 486 (M?1).
(Ar–C), 129.37 (Ar–C), 127.90 (Ar–C), 127.45 (Ar–C),
127.03 (Ar–C), 126.47 (Ar–C), 126.12 (Ar–C), 125.30
(Ar–C), 124.01 (Ar–C), 119.93 (C–S), 117.45 (C=C),
114.50 (C=C), 61.98 (C–N), 33.52 (CH), 25.32 (CH2),
18.05 (CH3), 11.34 (CH3). MS m/z 453 (M?1).
(Z)-2-(5-((5-(4-Bromophenyl)furan-2-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)-3-methylpentanoic acid (4f) Yield:
88 %. m.p. 111–113 °C. IR (KBr) cm-1: 3028 (OH), 1713
(Z)-2-(5-((5-(3-Chloro-4-fluorophenyl)furan-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)-3-methylpentanoic acid (4c)
Yield: 89 %. m.p. 113–115 °C. IR (KBr) cm-1: 2966
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 0.80 (t,
J = 7.5 Hz, 3H, CH3), 0.97 (m, 1H, CH), 1.16 (d,
J = 6 Hz, 3H, CH3), 1.22 (m, 2H, CH2), 5.22 (d,
J = 9 Hz, 1H, CH), 7.39 (m, 1H, CH), 7.43 (m, 1H, CH),
7.73 (s, 1H, CH), 7.77–7.84 (m, 4H, Ar–H), 13.21 (s, 1H,
COOH). 13C NMR (DMSO-d6, 75 MHz, ppm): d 194.65
(C=S), 168.95 (COOH), 167.03 (C=O), 153.62 (C–O),
148.95 (C–O), 140.10 (C=C), 131.56 (Ar–C), 129.91 (Ar–
C), 128.28 (Ar–C), 126.78 (Ar–C), 125.62 (C–S), 119.26
(Ar–C), 117.59 (Ar–C), 111.01 (C=C), 109.14 (C=C),
61.48 (C–N), 34.26 (CH), 24.98 (CH2), 17.90 (CH3), 11.32
(CH3). MS m/z 481 (M?1).
1
(OH), 1713 (C=O). H NMR (DMSO-d6, 300 MHz, ppm):
d 0.80 (t, J = 7.5 Hz, 3H, CH3), 0.97 (m, 1H, CH), 1.16
(d, J = 6 Hz, 3H, CH3), 1.22 (m, 2H, CH2), 5.22 (d,
J = 9 Hz, 1H, CH), 7.45 (d, J = 6 Hz, 1H, CH), 7.66 (t,
J = 9 Hz, 1H, CH), 7.73 (s, 1H, CH), 7.40–8.10 (m, 3H,
Ar–H), 13.22 (s, 1H, COOH). 13C NMR (DMSO-d6,
75 MHz, ppm): d 193.84 (C=S), 168.71 (COOH), 166.26
(C=O), 162.00 (Ar–C), 155.85 (C–O), 149.51 (C–O),
142.55 (C=C), 128.47 (Ar–C), 126.55 (Ar–C), 124.88
(Ar–C), 123.56 (C–S), 119.08 (Ar–C), 117.87 (Ar–C),
111.23 (C=C), 109.50 (C=C), 61.48 (C–N), 33.02 (CH),
24.82 (CH2), 17.57 (CH3), 10.87 (CH3). MS m/z 454
(M?1).
(Z)-2-(5-((5-(4-Chlorophenyl)furan-2-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)-3-methylpentanoic acid (4g) Yield:
90 %. m.p. 112–114 °C. IR (KBr) cm-1: 2966 (OH), 1713
1
(Z)-3-Methyl-2-(4-oxo-5-((5-phenylfuran-2-yl)methylene)-2-
thioxothiazolidin-3-yl)pentanoic acid (4d) Yield: 88 %.
m.p. 103–105 °C. IR (KBr) cm-1: 2966 (OH), 1713
(C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 0.80
(t, J = 7.5 Hz, 3H, CH3), 0.97 (m, 1H, CH), 1.16 (d,
J = 6 Hz, 3H, CH3), 1.23 (m, 2H, CH2), 5.23
(d, J = 9 Hz, 1H, CH), 7.39 (d, J = 3 Hz, 1H, CH), 7.47
(d, J = 6 Hz, 1H, CH), 7.75 (s, 1H, CH), 7.44–7.90 (m,
5H, Ar–H), 13.21 (s, 1H, COOH). 13C NMR (DMSO-d6,
75 MHz, ppm): d 193.88 (C=S), 172.68 (COOH), 167.38
(C=O), 156.23 (C–O), 149.68 (C–O), 143.10 (C=C),
128.32 (Ar–C), 127.98 (Ar–C), 126.78 (Ar–C), 124.96
(Ar–C), 122.88 (C–S), 118.67 (Ar–C), 117.68 (Ar–C),
111.20 (C=C), 108.99 (C=C), 61.47 (C–N), 33.11 (CH),
25.09 (CH2), 17.91 (CH3), 10.96 (CH3). MS m/z 403
(M?1).
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 0.80 (t,
J = 7.5 Hz, 3H, CH3), 0.97 (m, 1H, CH), 1.16 (d,
J = 6 Hz, 3H, CH3), 1.22 (m, 2H, CH2), 5.23 (d,
J = 9 Hz, 1H, CH), 7.40 (m, 1H, CH), 7.43 (m, 1H, CH),
7.74 (s, 1H, CH), 7.60–7.90 (m, 4H, Ar–H), 13.21 (s, 1H,
COOH). 13C NMR (DMSO-d6, 75 MHz, ppm): d 195.24
(C=S), 169.20 (COOH), 166.76 (C=O), 157.67 (C–O),
149.85 (C–O), 142.35 (C=C), 134.35 (Ar–C), 132.56 (Ar–
C), 129.89 (Ar–C), 127.76 (Ar–C), 126.57 (Ar–C), 124.24
(Ar–C), 119.67 (C–S), 117.49 (C=C), 111.45 (C=C), 61.98
(C–N), 33.52 (CH), 25.32 (CH2), 18.06 (CH3), 11.35
(CH3). MS m/z 437 (M?1).
(Z)-2-(5-((5-(3-Chlorophenyl)furan-2-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)-3-methylpentanoic acid (4h) Yield:
87 %. m.p. 110–112 °C. IR (KBr) cm-1: 2966 (OH), 1713
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 0.80 (t,
(Z)-3-Methyl-2-(5-((5-(naphthalen-2-yl)furan-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)pentanoic acid (4e) Yield:
87 %. m.p. 116–118 °C. IR (KBr) cm-1: 2966 (OH), 1713
J = 7.5 Hz, 3H, CH3), 0.96 (m, 1H, CH), 1.16 (d,
J = 6 Hz, 3H, CH3), 1.26 (m, 2H, CH2), 5.24 (d,
J = 9 Hz, 1H, CH), 7.43 (d, J = 3 Hz, 1H, CH), 7.62 (m,
1H, CH), 7.75 (s, 1H, CH), 7.49–7.94 (m, 4H, Ar–H),
13.22 (s, 1H, COOH). 13C NMR (DMSO-d6, 75 MHz,
ppm): d 194.34 (C=S), 169.18 (COOH), 166.74 (C=O),
157.04 (C–O), 150.03 (C–O), 134.56 (C=C), 131.68 (Ar–
C), 130.86 (Ar–C), 129.41 (Ar–C), 124.53 (Ar–C), 123.98
(Ar–C), 123.29 (Ar–C), 119.61 (C–S), 117.87 (C=C),
112.02 (C=C), 61.98 (C–N), 33.52 (CH), 25.32 (CH2),
18.06 (CH3), 11.36 (CH3). MS m/z 437 (M?1).
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 0.81 (d,
J = 6 Hz, 3H, CH3), 0.95 (m, 1H, CH), 1.16 (d, J = 6 Hz,
3H, CH3), 1.24 (m, 2H, CH2), 5.21 (d, J = 9 Hz, 1H, CH),
7.36 (d, J = 3 Hz, 1H, CH), 7.53 (t, J = 9 Hz, 1H, CH),
7.69 (m, 1H, CH), 7.66–8.40 (m, 7H, Ar–H), 13.21 (s, 1H,
COOH). 13C NMR (DMSO-d6, 75 MHz, ppm): d 194.44
(C=S), 169.23 (COOH), 166.82 (C=O), 158.73 (C–O),
149.94 (C–O), 134.08 (C=C), 130.76 (Ar–C), 129.49
123

Med Chem Res
(Z)-2-(5-((5-(2-Chlorophenyl)furan-2-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)-3-methylpentanoic acid (4i) Yield:
89 %. m.p. 114–116 °C. IR (KBr) cm-1: 2966 (OH), 1713
(C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 0.80
(t, J = 7.5 Hz, 3H, CH3), 0.98 (m, 1H, CH), 1.16
(d, J = 6 Hz, 3H, CH3), 1.24 (m, 2H, CH2), 5.23 (d,
J = 9 Hz, 1H, CH), 7.45 (m, 1H, CH), 7.60 (m, 1H, CH),
7.80 (s, 1H, CH), 7.46–7.98 (m, 4H, Ar–H), 13.22 (s, 1H,
COOH). 13C NMR (DMSO-d6, 75 MHz, ppm): d 194.42
(C=S), 169.13 (COOH), 166.79 (C=O), 154.99 (C–O),
149.62 (C–O), 131.60 (C=C), 131.02 (Ar–C), 130.47
(Ar–C), 128.81 (Ar–C), 127.41 (Ar–C), 123.56 (Ar–C),
123.29 (Ar–C), 119.61 (C–S), 118.33 (C=C), 115.40
(C=C), 62.03 (C–N), 33.52 (CH), 25.35 (CH2), 18.05
(CH3), 11.34 (CH3). MS m/z 437 (M?1).
d 0.80 (t, J = 7.5 Hz, 3H, CH3), 0.96 (m, 1H, CH), 1.16 (d,
J = 6 Hz, 3H, CH3), 1.26 (m, 2H, CH2), 5.22 (d,
J = 9 Hz, 1H, CH), 7.44 (d, J = 3 Hz, 1H, CH), 7.52 (m,
1H, CH), 7.79 (s, 1H, CH), 7.58–7.94 (m, 4H, Ar–H),
13.23 (s, 1H, COOH). 13C NMR (DMSO-d6, 75 MHz,
ppm): d 194.50 (C=S), 169.10 (COOH), 166.74 (C=O),
153.35 (C–O), 149.99 (C–O), 133.25 (C=C), 132.98 (Ar–
C), 130.39 (Ar–C), 129.00 (Ar–C), 128.83 (Ar–C), 127.94
(C–S), 123.20 (Ar–C), 119.36 (Ar–C), 119.06 (C=C),
116.16 (C=C), 62.06 (C–N), 33.54 (CH), 25.37 (CH2),
18.03 (CH3), 11.35 (CH3). MS m/z 471 (M?1).
General procedure for the preparation of compounds 5
A mixture of compounds 3 (2 mmol), (S)-2-(4-oxo-2-thioxo-
thiazolidin-3-yl)-3-phenylpropanoic acid (2 mmol), 10 drops
piperidine, and 10 drops glacial acetic acid in ethanol (15 mL)
was refluxed for 4 h. After cooling, the solvent was evapo-
rated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (dichloro-
methane/methanol = 100:1) to obtain a yellow solid.
(Z)-3-Methyl-2-(4-oxo-2-thioxo-5-((5-(o-tolyl)furan-2-yl)
methylene)thiazolidin-3-yl)pentanoic acid (4j) Yield:
88 %. m.p. 96–98 °C. IR (KBr) cm-1: 3028 (OH), 1713
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 0.81 (t,
J = 7.5 Hz, 3H, CH3), 0.96 (m, 1H, CH), 1.16 (d,
J = 6 Hz, 3H, CH3), 1.26 (m, 2H, CH2), 3.18 (s, 3H, CH3),
5.25 (d, J = 9 Hz, 1H, CH), 7.21 (s, 1H, CH), 7.46 (m, 1H,
CH), 7.78 (s, 1H, CH), 7.46–7.93 (m, 4H, Ar–H), 13.21
(s, 1H, COOH). 13C NMR (DMSO-d6, 75 MHz, ppm):
d 194.31 (C=S), 169.21 (COOH), 166.77 (C=O), 158.64
(C–O), 149.16 (C–O), 135.74 (C=C), 132.11 (Ar–C),
129.75 (Ar–C), 128.42 (Ar–C), 127.46 (Ar–C), 127.07
(C–S), 124.21 (Ar–C), 119.92 (Ar–C), 117.03 (C=C),
114.05 (C=C), 61.97 (C–N), 33.50 (CH), 25.31 (CH2),
22.18 (Ar–CH3), 18.07 (CH3), 11.35 (CH3). MS m/z 416
(M?1).
(Z)-2-(5-((5-(3-Chloro-4-fluorophenyl)furan-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (5a)
Yield: 88 %. m.p. 118–120 °C. IR (KBr) cm-1: 3028
1
(OH), 1713 (C=O). H NMR (DMSO-d6, 300 MHz, ppm):
d 3.52 (d, J = 9 Hz, 2H, CH2), 5.90 (m, 1H, CH), 7.15 (m,
1H, CH), 7.40 (m, 1H, CH), 7.68 (s, 1H, CH), 7.15–8.09
(m, 8H, Ar–H), 13.46 (s, 1H, COOH). 13C NMR (DMSO-
d6, 75 MHz, ppm): d 193.74 (C=S), 170.28 (COOH),
169.25 (C=O), 166.53 (C–O), 165.55 (C–O), 156.27
(Ar–C), 155.04 (C=C), 149.95 (Ar–C), 148.77 (Ar–C),
136.99 (Ar–C), 129.48 (Ar–C), 128.72 (Ar–C), 127.04
(Ar–C), 125.43 (Ar–C), 123.91 (Ar–C), 121.30 (Ar–C),
121.13 (Ar–C), 119.21 (Ar–C), 117.85 (C–S), 111.69
(C=C), 108.94 (C=C), 58.54 (C–N), 33.56 (CH2). MS
m/z 489 (M?1).
(Z)-2-(5-((5-(4-Bromophenyl)furan-2-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)-3-methylpentanoic acid (4k) Yield:
90 %. m.p. 97–99 °C. IR (KBr) cm-1: 2966 (OH), 1713
(C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 0.80
(t, J = 7.5 Hz, 3H, CH3), 0.95 (m, 1H, CH), 1.15
(d, J = 6 Hz, 3H, CH3), 1.25 (m, 2H, CH2), 5.22 (d,
J = 9 Hz, 1H, CH), 7.13 (m, 1H, CH), 7.39 (m, 1H, CH),
7.76 (s, 1H, CH), 7.39–7.82 (m, 4H, Ar–H), 13.18 (s, 1H,
COOH). 13C NMR (DMSO-d6, 75 MHz, ppm): d 194.48
(C=S), 169.18 (COOH), 166.77 (C=O), 152.95 (C–O),
149.55 (C–O), 131.53 (C=C), 126.81 (Ar–C), 125.89
(Ar–C), 123.91 (Ar–C), 119.56 (Ar–C), 118.09 (C–S),
117.18 (Ar–C), 116.91 (Ar–C), 114.60 (C=C), 114.45
(C=C), 61.98 (C–N), 33.52 (CH), 25.32 (CH2), 18.04
(CH3), 11.34 (CH3). MS m/z 421 (M?1).
(Z)-2-(4-Oxo-2-thioxo-5-((5-(4-(trifluoromethoxy)phenyl)
furan-2-yl)methylene)thiazolidin-3-yl)-3-phenylpropanoic acid
(5b) Yield: 88 %. m.p. 116–118 °C. IR (KBr) cm-1
:
1
2966 (OH), 1713 (C=O). H NMR (DMSO-d6, 300 MHz,
ppm): d 3.50 (d, J = 9 Hz, 2H, CH2), 5.90 (m, 1H, CH),
7.14 (m, 1H, CH), 7.42 (m, 1H, CH), 7.69 (s, 1H, CH),
7.13–8.08 (m, 9H, Ar–H), 13.44 (s, 1H, COOH). 13C NMR
(DMSO-d6, 75 MHz, ppm): d 193.37 (C=S), 173.90
(COOH), 167.82 (C=O), 166.08 (C–O), 158.16 (C–O),
156.81 (Ar–C), 150.87 (C=C), 149.45 (Ar–C), 148.58
(Ar–C), 139.68 (Ar–C), 136.49 (Ar–C), 135.30 (Ar–C),
128.99 (Ar–C), 128.23 (Ar–C), 127.65 (Ar–C), 126.69
(Ar–C), 126.43 (Ar–C), 123.62 (Ar–C), 121.92 (OCF3),
118.86 (C–S), 111.84 (C=C), 111.11 (C=C), 58.04 (C–N),
33.06 (CH2). MS m/z 520 (M?1).
(Z)-2-(5-((5-(2,5-Dichlorophenyl)furan-2-yl)methylene)-4-
oxo-2-thioxothiazolidin-3-yl)-3-methylpentanoic acid (4l)
Yield: 88 %. m.p. 114–116 °C. IR (KBr) cm-1: 2966
1
(OH), 1713 (C=O). H NMR (DMSO-d6, 300 MHz, ppm):
123

Med Chem Res
(Z)-2-(5-((5-(4-Bromophenyl)furan-2-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (5c) Yield:
88 %. m.p. 115–117 °C. IR (KBr) cm-1: 3028 (OH), 1713
(C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 3.52
(d, J = 9 Hz, 2H, CH2), 5.89 (m, 1H, CH), 7.14 (m, 1H,
CH), 7.41 (m, 1H, CH), 7.68 (s, 1H, CH), 7.14–7.85 (m,
9H, Ar–H), 13.45 (s, 1H, COOH). 13C NMR (DMSO-d6,
75 MHz, ppm): d 193.80 (C=S), 169.26 (COOH), 166.57
(C=O), 157.67 (C–O), 149.82 (C–O), 139.48 (C=C),
137.00 (Ar–C), 135.46 (Ar–C), 133.25 (Ar–C), 132.98
(Ar–C), 132.79 (Ar–C), 129.48 (Ar–C), 128.73 (Ar–C),
128.08 (Ar–C), 127.17 (Ar–C), 126.77 (Ar–C), 124.13
(Ar–C), 123.06 (Ar–C), 119.30 (C–S), 117.66 (C=C),
111.46 (C=C), 58.55 (C–N), 33.61 (CH2). MS m/z 515
(M?1).
7.40 (m, 1H, CH), 7.68 (s, 1H, CH), 7.14–7.86 (m, 9H, Ar–
H), 13.45 (s, 1H, COOH). 13C NMR (DMSO-d6, 75 MHz,
ppm): d 193.38 (C=S), 168.79 (COOH), 166.08 (C=O),
156.79 (C–O), 149.00 (C–O), 136.50 (C=C), 134.26 (Ar–
C), 133.02 (Ar–C), 131.05 (Ar–C), 129.00 (Ar–C), 128.24
(Ar–C), 127.20 (Ar–C), 126.70 (Ar–C), 126.34 (Ar–C),
125.44 (Ar–C), 124.23 (Ar–C), 123.40 (Ar–C), 118.76
(Ar–C), 116.68 (C–S), 113.98 (C=C), 109.52 (C=C), 58.06
(C–N), 33.09 (CH2). MS m/z 471 (M?1).
(Z)-2-(5-((5-(2-Fluorophenyl)furan-2-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (5g) Yield:
88 %. m.p. 114–116 °C. IR (KBr) cm-1: 2966 (OH), 1713
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 3.52 (d,
J = 9 Hz, 2H, CH2), 5.88 (m, 1H, CH), 7.15 (m, 1H, CH),
7.43 (m, 1H, CH), 7.72 (s, 1H, CH), 7.14–7.90 (m, 9H,
Ar–H), 13.47 (s, 1H, COOH). 13C NMR (DMSO-d6,
75 MHz, ppm): d 193.38 (C=S), 169.23 (COOH), 166.57
(C=O), 160.62 (Ar–C), 152.89 (C–O), 149.49 (C–O),
137.00 (C=C), 131.62 (Ar–C), 131.02 (Ar–C), 129.47
(Ar–C), 128.72 (Ar–C), 127.17 (Ar–C), 126.85 (Ar–C),
125.90 (Ar–C), 123.83 (Ar–C), 119.21 (Ar–C), 118.18
(Ar–C), 117.16 (C–S), 116.89 (Ar–C), 115.26 (C=C),
114.43 (C=C), 58.56 (C–N), 33.58 (CH2). MS m/z 455
(M?1).
(Z)-2-(5-((5-(2-Chlorophenyl)furan-2-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (5d) Yield:
86 %. m.p. 117–119 °C. IR (KBr) cm-1: 2966 (OH), 1713
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 3.51 (d,
J = 9 Hz, 2H, CH2), 5.88 (m, 1H, CH), 7.15 (m, 1H, CH),
7.45 (m, 1H, CH), 7.72 (s, 1H, CH), 7.14–7.92 (m, 9H,
Ar–H), 13.47 (s, 1H, COOH). 13C NMR (DMSO-d6,
75 MHz, ppm): d 193.86 (C=S), 169.24 (COOH), 166.58
(C=O), 154.88 (C–O), 149.52 (C–O), 138.47 (C=C),
136.99 (Ar–C), 131.59 (Ar–C), 130.98 (Ar–C), 130.43
(Ar–C), 129.47 (Ar–C), 128.73 (Ar–C), 128.50 (Ar–C),
127.35 (Ar–C), 127.18 (Ar–C), 123.51 (Ar–C), 121.09
(Ar–C), 119.25 (Ar–C), 118.37 (C–S), 115.39 (C=C),
114.33 (C=C), 58.57 (C–N), 33.56 (CH2). MS m/z 471
(M?1).
(Z)-2-(4-Oxo-5-((5-phenylfuran-2-yl)methylene)-2-thioxothiaz-
olidin-3-yl)-3-phenylpropanoic acid (5h) Yield: 88 %. m.p.
1
117–119 °C. IR (KBr) cm-1: 3028 (OH), 1713 (C=O). H
NMR (DMSO-d6, 300 MHz, ppm): d 3.52 (d, J = 9 Hz,
2H, CH2), 5.89 (m, 1H, CH), 7.15 (m, 1H, CH), 7.36 (d,
J = 3 Hz, 1H, CH), 7.68 (s, 1H, CH), 7.14–7.86 (m, 10H,
Ar–H), 13.45 (s, 1H, COOH). 13C NMR (DMSO-d6,
75 MHz, ppm): d 193.87 (C=S), 168.11 (COOH), 166.59
(C=O), 158.83 (C–O), 151.39 (C–O), 142.58 (C=C),
137.02 (Ar–C), 129.80 (Ar–C), 129.49 (Ar–C), 128.92
(Ar–C), 128.73 (Ar–C), 127.18 (Ar–C), 126.31 (Ar–C),
125.79 (Ar–C), 124.96 (Ar–C), 124.22 (Ar–C), 122.58
(Ar–C), 119.44 (Ar–C), 117.22 (C–S), 114.68 (C=C),
110.82 (C=C), 58.54 (C–N), 33.61 (CH2). MS m/z 437
(M?1).
(Z)-2-(5-((5-(3-Chlorophenyl)furan-2-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (5e) Yield:
88 %. m.p. 112–114 °C. IR (KBr) cm-1: 2966 (OH), 1713
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 3.52 (d,
J = 9 Hz, 2H, CH2), 5.89 (m, 1H, CH), 7.15 (m, 1H, CH),
7.40 (d, J = 3 Hz, 1H, CH), 7.69 (s, 1H, CH), 7.15–7.91
(m, 9H, Ar–H), 13.46 (s, 1H, COOH). 13C NMR (DMSO-
d6, 75 MHz, ppm): d 193.78 (C=S), 169.19 (COOH),
166.54 (C=O), 156.99 (C–O), 149.96 (C–O), 136.99
(C=C), 134.55 (Ar–C), 132.23 (Ar–C), 131.67 (Ar–C),
131.24 (Ar–C), 130.85 (Ar–C), 129.43 (Ar–C), 128.73
(Ar–C), 127.36 (Ar–C), 127.15 (Ar–C), 124.53 (Ar–C),
123.87 (Ar–C), 119.26 (Ar–C), 117.94 (C–S), 111.99
(C=C), 107.43 (C=C), 58.57 (C–N), 33.56 (CH2). MS
m/z 471 (M?1).
(Z)-2-(5-((5-(Naphthalene-2-yl)furan-2-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (5i) Yield:
88 %. m.p. 122–124 °C. IR (KBr) cm-1: 2966 (OH), 1713
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 3.52 (d,
J = 9 Hz, 2H, CH2), 5.89 (m, 1H, CH), 7.15 (m, 1H, CH),
7.36 (d, J = 3 Hz, 1H, CH), 7.76 (s, 1H, CH), 7.15–8.51
(m, 12H, Ar–H), 13.46 (s, 1H, COOH). 13C NMR (DMSO-
d6, 75 MHz, ppm): d 193.88 (C=S), 169.28 (COOH),
166.62 (C=O), 158.53 (C–O), 154.89 (C–O), 149.84
(C=C), 138.08 (Ar–C), 137.04 (Ar–C), 134.07 (Ar–C),
132.56 (Ar–C), 130.72 (Ar–C), 129.46 (Ar–C), 129.36
(Z)-2-(5-((5-(4-Chlorophenyl)furan-2-yl)methylene)-4-oxo-
2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (5f) Yield:
87 %. m.p. 115–117 °C. IR (KBr) cm-1: 3028 (OH), 1713
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 3.52 (d,
J = 9 Hz, 2H, CH2), 5.89 (m, 1H, CH), 7.15 (m, 1H, CH),
123

Med Chem Res
In vitro evaluation of the antibacterial activity
of the compounds
(Ar–C), 128.71 (Ar–C), 127.87 (Ar–C), 127.36 (Ar–C),
127.16 (Ar–C), 127.01 (Ar–C), 126.44 (Ar–C), 126.11
(Ar–C), 125.23 (Ar–C), 123.86 (Ar–C), 119.55 (C–S),
117.59 (C=C), 114.48 (C=C), 58.55 (C–N), 33.59 (CH2).
MS m/z 487 (M?1).
The antibacterial activities of the compounds were evalu-
ated in vitro in 96-well microtiter plates. A serial dilution
method was used to obtain the minimum inhibitory con-
centration (MIC) values of the synthesized compounds
against several different bacterial strains, including multi-
drug-resistant clinical isolates. Oxacillin and norfloxacin
were used as positive controls. The test bacteria were
grown to the mid-log phase in Mueller–Hinton broth
(MHB) and subsequently 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. Oxacillin and norfloxacin were used as
positive controls. The test compounds were prepared in
dimethyl sulfoxide (DMSO), with the final concentrations
of the compounds not exceeding 0.05 %. A two-fold serial
dilution technique was used to obtain final concentrations
of 64–0.5 lg/mL. The MIC value was defined as the
concentration of test compound required to completely
inhibit the growth of the bacteria during a 24-h incubation
period at 37 °C. The growth of the bacteria was determined
by measuring the absorption at 650 nm using a microtiter
enzyme-linked immunosorbent assay (ELISA) reader. All
of the experiments were conducted in triplicate.
(Z)-2-(4-Oxo-2-thioxo-5-((5-(p-tolyl)furan-2-yl)methylene)
thiazolidin-3-yl)-3-phenylpropanoic acid (5j) Yield:
87 %. m.p. 118–120 °C. IR (KBr) cm-1: 2966 (OH), 1713
(C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 3.35
(s, 3H, CH3), 3.50 (d, J = 9 Hz, 2H, CH2), 5.89 (m, 1H,
CH), 7.17 (m, 1H, CH), 7.29 (d, J = 3 Hz, 1H, CH), 7.66
(s, 1H, CH), 7.17–7.75 (m, 9H, Ar–H), 13.44 (s, 1H,
COOH). 13C NMR (DMSO-d6, 75 MHz, ppm): d 193.86
(C=S), 167.90 (COOH), 166.58 (C=O), 157.63 (C–O),
153.45 (C–O), 143.64 (C=C), 137.05 (Ar–C), 129.80
(Ar–C), 129.02 (Ar–C), 128.87 (Ar–C), 128.03 (Ar–C),
127.15 (Ar–C), 126.88 (Ar–C), 125.61 (Ar–C), 124.82
(Ar–C), 124.34 (Ar–C), 122.32 (Ar–C), 119.85 (Ar–C),
118.96 (C–S), 114.99 (C=C), 110.85 (C=C), 58.53 (C–N),
33.65 (CH2), 22.20 (Ar–CH3). MS m/z 451 (M?1).
(Z)-2-(4-Oxo-2-thioxo-5-((5-(o-tolyl)furan-2-yl)methylene)
thiazolidin-3-yl)-3-phenylpropanoic acid (5k) Yield:
87 %. m.p. 112–114 °C. IR (KBr) cm-1: 2966 (OH), 1713
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 3.17 (s,
3H, CH3), 3.52 (d, J = 9 Hz, 2H, CH2), 5.81 (m, 1H, CH),
7.11 (m, 1H, CH), 7.18 (m, 1H, CH), 7.67 (s, 1H, CH),
7.10–7.78 (m, 9H, Ar–H), 13.45 (s, 1H, COOH). 13C NMR
(DMSO-d6, 75 MHz, ppm): d 193.88 (C=S), 167.91
(COOH), 166.58 (C=O), 157.63 (C–O), 153.43 (C–O),
143.66 (C=C), 137.10 (Ar–C), 129.81 (Ar–C), 129.52
(Ar–C), 128.86 (Ar–C), 128.03 (Ar–C), 127.13 (Ar–C),
126.87 (Ar–C), 125.55 (Ar–C), 124.86 (Ar–C), 124.34
(Ar–C), 122.28 (Ar–C), 119.96 (Ar–C), 118.55 (C–S),
114.99 (C=C), 110.32 (C=C), 58.52 (C–N), 33.67 (CH2),
22.28 (Ar–CH3). MS m/z 451 (M?1).
Evaluation of cytotoxicity
Human cervical (HeLa) cell monolayers were used as an
in vitro model of the cervico-vaginal epithelium for testing
the cytotoxicities of the new compounds. HeLa cells were
grown in Dulbecco’s modified Eagle medium (DMEM)
supplemented with fetal bovine serum (10 %), and antibi-
otics (penicillin–streptomycin mixture [100 U/mL]). Cells
at 80–90 % confluence were split by trypsin (0.25 % in
phosphate-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 3
passages and *1 9 104 cells were seeded into each well of
a 96-well plate and incubated overnight to allow the cells
to become attached to the substrate. After 24 h, the med-
ium was replaced with DMEM supplemented with 10 %
FBS containing a variety of different concentrations of the
test compounds and incubated for 48 h. A 10 lL portion of
an MTT solution (5 mg/mL in PBS) was then added to
each well. Following a 4-h period of incubation, the
medium was removed and the resulting formazan crystals
were dissolved in DMSO (100 lL). Following a period of
shaking for 10 min, the optical density was measured at
570 nm using a microtiter ELISA reader. The assay was
conducted four times. The IC50 values were defined as the
concentrations inhibiting the cell growth by 50 %.
(Z)-2-(5-((5-(2,5-Dichlorophenyl)furan-2-yl)methylene)-4-
oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (5l)
Yield: 88 %. m.p. 115–117 °C. IR (KBr) cm-1: 3028
1
(OH), 1713 (C=O). H NMR (DMSO-d6, 300 MHz, ppm):
d 3.52 (d, J = 9 Hz, 2H, CH2), 5.88 (m, 1H, CH), 7.15 (m,
1H, CH), 7.42 (d, J = 3 Hz, 1H, CH), 7.79 (s, 1H, CH),
7.15–8.04 (m, 8H, Ar–H), 13.48 (s, 1H, COOH). 13C NMR
(DMSO-d6, 75 MHz, ppm): d 193.58 (C=S), 169.19
(COOH), 166.54 (C=O), 153.27 (C–O), 149.90 (C–O),
145.71 (C=C), 136.98 (Ar–C), 136.26 (Ar–C), 133.24 (Ar–
C), 132.94 (Ar–C), 130.35 (Ar–C), 129.46 (Ar–C), 128.96
(Ar–C), 128.74 (Ar–C), 127.90 (Ar–C), 127.20 (Ar–C),
123.16 (Ar–C), 119.98 (Ar–C), 118.84 (C–S), 116.14
(C=C), 115.32 (C=C), 58.59 (C–N), 33.56 (CH2). MS m/z
505 (M?1).
123

Med Chem Res
Results and discussion
Chemistry
coli 1356. The results indicated that most of the synthesized
compounds exhibited potent levels of inhibitory activity
against the three Gram-positive bacterial strains (S. aureus
RN 4220, S. aureus KCTC 209, and S. aureus KCTC 503)
with MIC values in the range of 2–16 lg/mL. Compounds
5a–l exhibited good levels of inhibitory activity against the
Gram-positive bacteria S. aureus RN4220 with MIC values
in the range of 2–4 lg/mL. Compounds 4a–l and 5a–l
exhibited moderate to good levels of inhibition against S.
aureus KCTC 209 and S. aureus KCTC 503, with MIC
values in the range of 8–16 lg/mL. None of the compounds
showed any inhibitory activity against the Gram-negative
strain E. coli 1356 (MICs [ 64 lg/mL), as shown in
Table 1.
The furan derivatives were synthesized according to the
route presented in Scheme 1. According to the previously
described method (Cui et al., 2010), anilines were used as
the starting materials and reacted with furfural to afford the
corresponding monosubstituted 5-phenylfuran-2-carbalde-
hydes (3). The N-substituted rhodanines were prepared
according to a method previously described in the literature
(Wang et al., 2008). The 24 target compounds (4a–l and
5a–l) were obtained via the Knoevenagel condensation
reactions of the 5-phenylfuran-2-carbaldehydes (3) with the
N-substituted rhodanines in good yields. The structures of
The compounds were also evaluated for their inhibitory
activities against several clinical isolates of multidrug-
resistant Gram-positive bacterial strains, including the
methicillin-resistant S. aureus strains MRSA CCARM
3167 and MRSA CCARM 3506, and the quinolone-resis-
tant S. aureus strains QRSA CCARM 3505 and QRSA
CCARM 3519. The results are shown in Table 2. All of the
compounds exhibited moderate activities against the strains
tested with MIC values in the range of 4–16 lg/mL against
the MRSA CCARM (3167 and 3506) and QRSA CCARM
(3505 and 3519) strains.
the desired compounds were determined by IR, 1H and 13
NMR, and mass spectral and elemental analyses.
C
Biological evaluation
The antimicrobial activities of the synthesized compounds
were evaluated in vitro using the broth microdilution
method to obtain their MIC values against a variety of
different bacterial strains, including multidrug-resistant
clinical isolates. Oxacillin and norfloxacin were used as
positive controls.
From the results shown in Table 2, it is clear that
compounds 4l and 5a displayed the most potent levels of
inhibitory activities against MRSA CCARM 3506 (MIC =
2 lg/mL), whereas compounds 4g, 4i, 4k, 5c, 5e, 5f, and
5i showed good levels of inhibitory activity against
the four multidrug-resistant Gram-positive bacterial strains
The synthesized compounds (4a–l and 5a–l) were
screened for their antibacterial activities against a number
of different Gram-positive organisms, including Staphylo-
coccus aureus RN4220, S. aureus KCTC 503, and S. aureus
KCTC 209; and the Gram-negative organism Escherichia
Scheme 1 Synthetic scheme
R
R
R
for the synthesis of the target
compounds 4a–l and 5a–l
O
CHO
NaNO2,HCl
O
0~5 oC
NH2
CHO
N2+Cl-
acetone,CuCl2
3
2
1
S
O
R'
COOH
R'
R
N
O
S
N
S
4a-l, 5a-l
O
CH3
S
R'=
CH3COOH, C2H5OH
CHCH2CH3
CH2C6H5
(4a-l)
(5a-l)
4a: 4-CH3
4g: 4-Cl
4h: 3-Cl
4i: 2-Cl
4j: 2-CH3
4k: 2-F
R=
5a: 3-Cl, 4-F
5b: 4-OCF3
5c: 4-Br
5d: 2-Cl
5e: 3-Cl
5g: 2-F
5h: H
5i: phenyl (3,4-fused)
5j: 4-CH3
5k: 2-CH3
5l: 2,5-(Cl)2
4b: 4-OCH3
4c: 3-Cl, 4-F
4d: H
4e: phenyl (3,4-fused)
4f: 4-Br
5f: 4-Cl
4l: 2,5-(Cl)2
123

Med Chem Res
Table 1 Inhibitory activity (MIC, lg/mL) of compounds 4a–l and 5a–l against bacteria
O
O
H
COO
H
COO
R
R
O
N
S
O
N
S
S
S
5a-5l
4a-4l
Compound
R
Gram-positive strains
S. aureus
Gram-negative strain
E. coli
4220
209
503
1356
4a
4-CH3
4-OCF3
3-Cl,4-F
H
4
4
4
8
8
2
2
4
2
4
2
2
2
4
2
4
4
2
4
4
4
2
4
2
2
1
8
16
16
8
16
16
16
16
8
[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
4b
4c
4d
4e
Phenyl(3,4-fused)
8
4f
4-Br
8
16
8
4g
4-Cl
8
4h
3-Cl
16
8
16
16
16
16
16
8
4i
2-Cl
4j
2-CH3
2-F
16
8
4k
4l
2,5-(Cl)2
3-Cl, 4-F
4-OCF3
4-Br
16
8
5a
5b
16
8
8
5c
8
5d
2-Cl
8
16
16
16
16
8
5e
3-Cl
16
16
8
5f
4-Cl
5g
2-F
5h
H
8
5i
Phenyl(3,4-fused)
4-CH3
2-CH3
2,5-(Cl)2
–
8
8
5j
8
16
16
16
2
5k
16
16
2
5l
Norfloxacin
Oxacillin
–
1
1
[64
S. aureus RN 4220, Staphylococcus aureus RN 4220; S. aureus 503, Staphylococcus aureus 503; S. aureus 209, Staphylococcus aureus 209;
E. coli 1356, Escherichia coli CCARM 1356
(MIC = 4 lg/mL). No clear structure–activity relationship
pattern was found between the antibacterial activities and
the positions and physicochemical properties of the dif-
ferent substituents on the phenyl ring.
cytotoxicities (Table 3). Compounds 4b and 5f did not
affect the cell viability of HeLa cells at their MIC values (4
or 2 lg/mL, respectively), but were cytotoxic at much
higher concentrations. The disparity between their cyto-
toxicities and antibacterial activities of compounds 4b and
5f suggested that these compounds exhibited their in vitro
antibacterial activities at non-cytotoxic concentrations.
To investigate whether the antibacterial activities of
compounds 4b and 5f related specifically to their selec-
tive toxicity toward the bacteria, we evaluated their
123

Med Chem Res
Table 2 Inhibitory activity (MIC, lg/mL) of compounds 4a–l and 5a–l against clinical isolates of multidrug-resistant Gram-positive strains
O
O
H
COO
H
COO
R
R
O
N
S
O
N
S
S
S
5a-5l
4a-4l
Compound
R
Multidrug-resistant Gram-positive strains
MRSA
QRSA
3167
3506
3505
3519
4a
4-CH3
4-OCF3
3-Cl,4-F
H
8
16
8
8
8
8
8
8
8
4b
4c
8
8
8
4d
8
8
16
8
8
4e
Phenyl(3,4-fused)
8
8
8
4f
4-Br
8
8
8
8
4g
4-Cl
8
4
4
8
4h
3-Cl
8
8
8
8
4i
2-Cl
8
4
8
8
4j
2-CH3
2-F
8
8
16
8
8
4k
8
4
8
4l
2,5-(Cl)2
3-Cl, 4-F
4-OCF3
4-Br
4
2
4
4
5a
8
2
8
8
5b
16
8
8
16
8
16
8
5c
4
5d
2-Cl
8
8
8
8
5e
3-Cl
8
4
8
8
5f
4-Cl
8
4
8
8
5g
2-F
8
8
8
8
5h
H
8
8
8
8
5i
Phenyl(3,4-fused)
4-CH3
2-CH3
2,5-(Cl)2
–
4
8
8
4
5j
8
8
8
8
5k
8
8
16
8
8
5l
8
8
8
Norfloxacin
Oxacillin
8
4
[64
1
[64
1
–
[64
[64
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
Table 3 Cytotoxic activity of
compounds 4b and 5f against
HeLa cell
activities of these compounds were evaluated and compared
with standard drugs. The results revealed that most of the
compounds exhibited good levels of antibacterial activity
against Gram-positive bacteria as well as multidrug-resistant
strains of clinical isolates. In particular, compounds 4f, 4g,
4i, 4k, 4l, 5a, 5c, 5f, 5j, and 5l showed excellent levels of
antimicrobial activity, with MIC values of 2 lg/mL against
the Gram-positive bacterial strains S. aureus RN 4220.
The mechanism of action of the compounds tested in this
study currently remains unknown. Most of the synthesized
Compound
IC50 (lg/mL)
4b
5f
16.23
8.69
Conclusion
In summary, based on our previous work, we have synthe-
sized two series of rhodanine derivatives. The antimicrobial
123

Med Chem Res
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positive bacterial strains, including multidrug-resistant
clinical isolates. Compound 4l was found to be the most
potent of the synthesized compounds against the multidrug-
resistant strains, with a MIC value of 2 or 4 lg/mL. Fur-
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norfloxacin. Compounds 4b and 5f exhibited in vitro anti-
bacterial activity at non-cytotoxic concentrations. Thus,
further studies of related compounds in the context of their
structure–activity relationship, toxicity, and other biological
effects might be helpful in designing new antimicrobials for
therapeutic use.
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Acknowledgments This work was supported by the National Sci-
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10.1016/j.jscs.2011.02.012
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sensitizer containing a furan moiety for efficient and stable
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