Synthesis and potential antibacterial activity of new rhodanine-3-acetic acid derivatives

Article abstract of DOI:10.1007/s00044-012-0417-z

A series of rhodanine-3-acetic acid derivatives were synthesized and investigated for their antibacterial activity against gram-positive bacteria including multidrug-resistant clinical isolates. Among these compounds, 6k with a MIC of 2 μg/mL was as active as the standard drug (norfloxacin) but less active than oxacillin against S. aureus. The compounds 6b, 6e, 6h, 6k, 6n, and 6u presented better activities against multidrug-resistant Staphylococcus aureus than the standard drugs (norfloxacin and oxacillin), especially 6k with a MIC of 1 μg/mL. However, none of the compounds were active against gram-negative bacteria at 64 μg/mL. Graphical Abstract: This study presents a synthesis of novel rhodanine-3-acetic acid derivatives and their antibacterial activity.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s00044-012-0417-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:4125–4132
DOI 10.1007/s00044-012-0417-z
ORIGINAL RESEARCH
Synthesis and potential antibacterial activity of new
rhodanine-3-acetic acid derivatives
•
Jing Miao Chang-Ji Zheng Liang-Peng Sun
•
•
•
Ming-Xia Song Li-Li Xu Hu-Ri Piao
•
Received: 31 July 2012 / Accepted: 11 December 2012 / Published online: 21 December 2012
Ó Springer Science+Business Media New York 2012
Abstract A series of rhodanine-3-acetic acid derivatives
were synthesized and investigated for their antibacterial
activity against gram-positive bacteria including multi-
drug-resistant clinical isolates. Among these compounds,
6k with a MIC of 2 lg/mL was as active as the standard
drug (norfloxacin) but less active than oxacillin against
S. aureus. The compounds 6b, 6e, 6h, 6k, 6n, and 6u
presented better activities against multidrug-resistant
Staphylococcus aureus than the standard drugs (norfloxacin
and oxacillin), especially 6k with a MIC of 1 lg/mL.
However, none of the compounds were active against
gram-negative bacteria at 64 lg/mL.
et al., 1984; Yoshioka et al., 1989; Momose et al., 1991;
Desai et al., 2008; Dolezel et al., 2009), pesticidal (Inamori
et al.,1992;Muroet al.,1996), antihypertensive (Frankov etal.,
1985), and antineoplastic (Chandrappa et al., 2009; Havrylyuk
et al., 2009) agent. In our previous work (Chen et al., 2010), we
reported that 2-((5E)-5-(4-((E)-3-(2,4-dichlorophenyl)-3-
oxoprop-1-enyl)benzylidene)-4-oxo-2-thioxothiazolidin-3-yl)
acetic acid (lead compound) showed strong activity against
gram-positive strains (including multidrug-resistant clinical
isolates). Modification of this compound is described in this
study (Fig. 1), where the rhodanine-3-acetic acid moiety was
reserved, the chalcone moiety was replaced with a 6-ben-
zyloxynaphthalene moiety, and different substituents were
tested on the phenyl ring of the benzyl group. Twenty-five
rhodanine-3-acetic acid derivatives were synthesized and
evaluated for their antimicrobial activity in vitro.
Keywords Rhodanine-3-acetic acid Á
Antibacterial activity Á
Minimal inhibitory concentration (MIC)
Introduction
Experimental
Increasing resistance of microorganisms to currently avail-
able antimicrobial drugs is a major cause of morbidity and
mortality throughout the world. Therefore, it is imperative to
discover new classes of antibiotics. Rhodanine-3-acetic acid
Materials
Melting points were determined in open capillary tubes and
were 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
¨
was prepared by Korner in 1908 and since that time, it has
been prepared and studied as a potential antimycobacterial
(Sortino et al., 2007; Liu et al., 2007), antifungal (Terashima
1
were recorded (in KBr) on a FTIR1730. H NMR spectra
were measured on a Bruker AV-300 spectrometer using
TMS as the internal standard. Mass spectra were measured
on an HP1100LC (Agilent Technologies, USA). Elemental
analyses for C, H, N, and S were within 0.4 % of the
theoretical values and were carried out on a 204Q CHN
Rapid Analyzer (Perkin-Elmer, USA). The major chemi-
cals were purchased from Sigma-Aldrich and Fluka.
J. Miao Á C.-J. Zheng Á L.-P. Sun Á M.-X. Song Á L.-L. Xu Á
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
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Fig. 1 Lead compound and
structure-based design of target
compounds
Methods
was stirred for 4–6 h at 40–50 °C. After the solution was
cooled, the resulting reaction mixture was filtered off and
crude product was purified by 1,4-dioxane to afford pure
products 6a–6x. The yield, melting point, and spectral data of
each compound are given below.
Synthesis
General procedure for the synthesis of compound 3
To a solution of compound 1 (1.0 mmol) and rhodanine-3-
acetic acid 2 (1.0 mmol) in absolute ethanol (8.0 mL) was
added acetic acid and piperidine. The mixture was stirred for
4–6 h at 40–50 °C. After the solution was cooled, the
resulting reaction mixture was filtered off and crude product
was purified by 1,4-dioxane to afford pure product 3.
(Z)-2-(5-((6-(Benzyloxy)naphthalen-2-yl)methylene)-4-oxo-2-
thioxothiazolidin-3-yl)acetic acid (6a) Yield 87 %; m.p.
1
291–292 °C. IR (KBr) cm-1: 3419 (OH), 1707 (C=O). H
NMR (DMSO-d6, 300 MHz, ppm): d 7.80 (s, 1H), 7.64 (d,
J = 8.6 Hz, 3H), 7.54–7.27 (m, 6H), 7.21 (d, J = 8.6 Hz,
2H), 7.80–7.20 (m, 12H, Ar–H), 5.21 (s, 2H, CH2), 4.51 (s,
2H, CH2). 13C NMR (DMSO-d6, 75 MHz, ppm): d 193.17,
169.19, 166.96, 157.77, 143.58, 136.10, 132.74, 128.75,
128.17, 118.86, 107.46, 66.71, 46.89. MS m/z 436 (M?1).
Anal. Calcd. for C23H17NO4S2: C, 63.43; H, 3.93; N, 3.22;
S, 14.73. Found: C, 63.39; H, 3.91; N, 3.19; S, 14.75.
(Z)-2-(5-((6-Hydroxynaphthalen-2-yl)methylene)-4-oxo-2-
thioxothiazolidin-3-yl)acetic acid (3) Yield 83 %; m.p.
1
263–264 °C. IR (KBr) cm-1: 3423 (OH), 1705 (C=O). H
NMR (DMSO-d6, 300 MHz, ppm): d 9.92 (s, 1H, OH),
8.09 (s, 1H), 7.99–7.75 (m, 3H), 7.57 (d, J = 8.6 Hz, 1H),
7.18 (d, J = 6.6 Hz, 2H), 8.09–7.17 (m, 7H, Ar–H), 4.41
(s, 2H, CH2). 13C NMR (DMSO-d6, 75 MHz, ppm): d
193.15, 167.44, 166.83, 158.22, 135.60, 133.20, 132.23,
130.81, 127.25, 126.49, 120.57, 120.06, 108.95, 47.72, MS
m/z 346 (M?1). Anal. Calcd. for C16H11NO4S2: C, 55.64;
H, 3.21; N, 4.06; S, 18.57. Found: C, 55.57; H, 3.19; N,
4.02; S, 18.51.
(Z)-2-(5-((6-((4-Methylbenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6b) Yield 89 %;
m.p. 287–288 °C. IR (KBr) cm-1: 3421 (OH), 1701
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 8.17 (s,
1H), 7.99 (d, J = 12.0 Hz, 1H), 7.90–7.95 (m, 2H), 7.22
(d, J = 6.0 Hz, 2H), 8.17–7.21 (m, 11H, Ar–H), 5.20 (s,
2H, CH2), 4.49 (s, 2H, CH2), 2.32 (s, 3H, CH3). 13C NMR
(DMSO-d6, 75 MHz, ppm): d 193.12, 168.43, 167.16,
158.91, 142.78, 138.19, 135.45, 132.84, 131.67, 129.18,
128.53, 127.64, 118.07, 116.05, 108.74, 66.46, 47.03,
20.56. MS m/z 450 (M?1). Anal. Calcd. for C24H19NO4S2:
C, 64.12; H, 4.26; N, 3.12; S, 14.27. Found: C, 63.87; H,
4.13; N, 3.09; S, 14.31.
General procedure for the synthesis of compounds
6a–6x
To a solution of the respective compounds 5a–5x (1.0 mmol)
in absolute ethanol (8.0 mL) was added rhodanine-3-acetic
acid 2 (1.0 mmol), acetic acid, and piperidine. The mixture
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(Z)-2-(5-((6-((3,4-Dimethylbenzyl)oxy)naphthalen-2-yl)meth-
ylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6c) Yield
84 %; m.p. 293–294 °C. IR (KBr) cm-1: 3407 (OH), 1712
(C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 8.17 (s, 1H),
8.07–7.83 (m, 3H), 7.68 (d, J = 8.6 Hz, 1H), 7.50 (s, 1H),
7.35–7.12 (m, 4H), 8.17–7.15 (m, 10H, Ar–H), 5.17 (s, 2H,
(M?1). Anal. Calcd. for C25H21NO6S2: C, 60.59; H, 4.27;
N, 2.83; S, 12.94. Found: C, 60.61; H, 4.22; N, 2.81; S,
12.95.
(Z)-2-(5-((6-((3-Fluorobenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6g) Yield 87 %;
m.p. 276–277 °C. IR (KBr) cm-1: 3418 (OH), 1703
CH2), 4.33 (s, 2H, CH2), 2.24 (d, J = 4.9 Hz, 6H, CH3). 13
C
1
NMR (DMSO-d6, 75 MHz, ppm): d 193.12, 169.27, 167.84,
157.01, 143.28, 139.09, 137.37, 133.37, 129.83, 119.09,
117.83, 107.65, 67.71, 46.56, 20.13. MS m/z 464 (M?1).
Anal. Calcd. for C25H21NO4S2: C, 64.77; H, 4.57; N, 3.02;
S, 13.83. Found: C, 64.73; H, 4.51; N, 3.06; S, 13.80.
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 8.19 (s,
1H), 8.05–7.92 (m, 3H), 7.68 (d, J = 8.7 Hz, 1H),
7.55–7.30 (m, 5H), 7.19 (t, J = 8.5 Hz, 1H), 8.19–7.16 (m,
11H, Ar–H), 5.29 (s, 2H, CH2), 4.54 (s, 2H, CH2). 13C
NMR (DMSO-d6, 75 MHz, ppm): d 193.12, 168.93,
166.67, 165.09, 157.86, 143.91, 139.42, 130.54, 128.04,
122.79, 119.13, 114.13, 107.65, 70.52, 46.83. MS m/z 454
(M?1). Anal. Calcd. for C23H16FNO4S2: C, 60.91; H, 3.56;
N, 3.09; S, 14.14. Found: C, 60.87; H, 3.52; N, 3.06; S,
14.18.
(Z)-2-(5-((6-((3-Methoxybenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6d) Yield 82 %;
m.p. 264–265 °C. IR (KBr) cm-1: 3410 (OH), 1705
(C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 8.19
(s, 1H), 8.05–7.93 (m, 3H), 7.68 (d, J = 8.7 Hz, 1H), 7.51
(d, J = 2.1 Hz, 1H), 7.38–7.27 (m, 2H), 7.09 (d, J =
6.9 Hz, 2H), 6.96–6.89 (m, 1H), 8.19–6.90 (m, 11H, Ar–
H), 5.24 (s, 2H, CH2), 4.53 (s, 2H, CH2), 3.78 (s, 3H,
OCH3). 13C NMR (DMSO-d6, 75 MHz, ppm): d 193.12,
169.31, 168.04, 160.09, 157.78, 142.15, 138.37, 133.17,
129.54, 126.93, 119.62, 116.13, 107.65, 71.71, 47.79. MS
m/z 466 (M?1). Anal. Calcd. for C24H19NO5S2: C, 61.92;
H, 4.11; N, 3.01; S, 13.78. Found: C, 61.89; H, 4.07; N,
3.02; S, 13.81.
(Z)-2-(5-((6-((4-Fluorobenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6h) Yield 84 %;
m.p. 286–287 °C. IR (KBr) cm-1: 3419 (OH), 1696 (C=O).
1H NMR (DMSO-d6, 300 MHz, ppm): d 8.18 (s, 1H),
8.07–7.86 (m, 3H), 7.70–7.52 (m, 4H), 7.36–7.17 (m, 3H),
8.18–7.22 (m, 11H, Ar–H), 5.25 (s, 2H, CH2), 4.37 (s, 2H,
CH2). 13C NMR (DMSO-d6, 75 MHz, ppm): d 193.16,
169.08, 166.41, 161.09, 157.86, 143.91, 139.58, 138.76,
130.27, 128.44, 127.59, 126.34, 119.71, 105.65, 70.84,
46.96. MS m/z 454 (M?1). Anal. Calcd. for C23H16FNO4S2:
C, 60.91; H, 3.56; N, 3.09; S, 14.14. Found: C, 60.89; H, 3.55;
N, 3.07; S, 14.16.
(Z)-2-(5-((6-((4-Methoxybenzyl)oxy)naphthalen-2-yl)meth-
ylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6e) Yield
86 %; m.p. 283–284 °C. IR (KBr) cm-1: 3417 (OH), 1701
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 8.18 (s,
(Z)-2-(5-((6-((2-Bromobenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6i) Yield 84 %;
m.p. 296–297 °C. IR (KBr) cm-1: 3417 (OH), 1708 (C=O).
1H NMR (DMSO-d6, 300 MHz, ppm): d 8.20 (s, 1H),
8.09–7.89 (m, 3H), 7.73–7.66 (m, 3H), 7.58–7.41 (m, 2H),
7.39–7.29 (m, 2H), 8.20–7.32 (m, 11H, Ar–H), 5.28 (s, 2H,
CH2), 4.52 (s, 2H, CH2). 13C NMR (DMSO-d6, 75 MHz,
ppm): d 193.12, 169.08, 166.57, 157.42, 143.18, 139.08,
131.56, 129.07, 128.34, 127.63, 125.17, 118.53, 116.03,
105.65, 69.12, 47.85. MS m/z 513 (M?1). Anal. Calcd. for
C23H16BrNO4S2: C, 53.70; H, 3.14; N, 2.72; S, 12.47. Found:
C, 53.66; H, 3.13; N, 2.65; S, 12.49.
1H), 8.04–7.87 (m, 3H), 7.68 (d, J = 8.6 Hz, 1H), 7.49 (m,
3H), 7.30 (d, J = 9.0 Hz, 1H), 6.97 (d, J = 8.6 Hz, 2H),
8.18–6.96 (m, 11H, Ar–H), 5.18 (s, 2H, CH2), 4.35 (s, 2H,
CH2), 3.77 (s, 3H, OCH3). 13C NMR (DMSO-d6, 75 MHz,
ppm): d 193.12, 167.57, 166.71, 159.75, 156.63, 142.91,
137.49, 131.67, 130.54, 129.54, 127.85, 127.14, 120.06,
117.13, 107.65, 70.87, 56.84, 47.74. MS m/z 466 (M?1).
Anal. Calcd. for C24H19NO5S2: C, 61.92; H, 4.11; N, 3.01;
S, 13.78. Found: C, 61.88; H, 4.09; N, 3.03; S, 13.79.
(Z)-2-(5-((6-((3,4-Dimethoxybenzyl)oxy)naphthalen-2-yl)meth-
ylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6f) Yield
81 %; m.p. 249–250 °C. IR (KBr) cm-1: 3421 (OH), 1697
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 8.18 (s,
(Z)-2-(5-((6-((3-Bromobenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6j) Yield 81 %;
m.p. 293–294 °C. IR (KBr) cm-1: 3419 (OH), 1696 (C=O).
1H NMR (DMSO-d6, 300 MHz, ppm): d 8.19 (s, 1H),
8.07–7.86 (m, 3H), 7.74–7.67 (m, 2H), 7.57–7.51 (m, 3H),
7.42–7.32 (m, 2H), 8.19–7.32 (m, 11H, Ar–H), 5.27 (s, 2H,
CH2), 4.44 (s, 2H, CH2). 13C NMR (DMSO-d6, 75 MHz,
ppm): d 193.16, 169.12, 166.41, 161.87, 157.52, 143.08,
1H), 8.06–7.85 (m, 3H), 7.69 (d, J = 8.4 Hz, 1H), 7.52 (s,
1H), 7.32 (d, J = 9.1 Hz, 1H), 7.15–6.94 (m, 3H),
8.18–6.96 (m, 10H, Ar–H), 5.17 (s, 2H, CH2), 4.37 (s, 2H,
CH2), 3.77 (d, J = 5.4 Hz, 6H, OCH3). 13C NMR (DMSO-
d6, 75 MHz, ppm): d 193.57, 169.84, 166.48, 157.48,
144.72, 138.93, 134.49, 131.17, 127.04, 126.84, 121.14,
121.06, 117.13, 107.65, 71.19, 56.17, 47.89. MS m/z 496
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139.46, 132.82, 129.43, 128.58, 127.44, 125.78, 119.54,
117.61, 105.82, 70.18, 47.71. MS m/z 513 (M?1). Anal.
Calcd. for C23H16BrNO4S2: C, 53.70; H, 3.14; N, 2.72; S,
12.47. Found: C, 53.69; H, 3.11; N, 2.68; S, 12.46.
MS m/z 470 (M?1). Anal. Calcd. for C23H16ClNO4S2: C,
58.78; H, 3.43; N, 2.98; S, 13.65. Found: C, 58.75; H, 3.42; N,
2.95; S, 13.70.
(Z)-2-(5-((6-((2-Cyanobenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6o) Yield 83 %;
m.p. 325–326 °C. IR (KBr) cm-1: 3422 (OH), 1697 (C=O). 1H
NMR (DMSO-d6, 300 MHz, ppm): d 8.21 (s, 1H), 8.08–7.92
(m, 4H), 7.84–7.60 (m, 5H), 7.35 (d, J = 9.0 Hz, 1H),
8.21–7.34 (m, 11H, Ar–H), 5.42 (s, 2H, CH2), 4.46 (s, 2H, CH2).
13C NMR (DMSO-d6, 75 MHz, ppm): d 193.12, 169.08,
166.47, 158.83, 144.39, 143.16, 139.08, 137.56, 134.07, 131.34,
127.64, 127.14, 119.54, 113.82, 106.73, 67.57, 46.67. MS m/
z 461 (M?1). Anal. Calcd. for C24H16N2O4S2: C, 62.59; H,
3.50; N, 6.08; S, 13.93. Found: C, 62.57; H, 3.51; N, 6.05; S,
13.91.
(Z)-2-(5-((6-((4-Bromobenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6k) Yield 85 %;
m.p.302–303 °C. IR (KBr) cm-1: 3422(OH), 1712 (C=O). 1H
NMR (DMSO-d6, 300 MHz, ppm): d 8.18 (s, 1H), 8.07–7.85
(m, 3H), 7.73–7.45 (m, 6H), 7.35–7.31 (m, 1H), 8.18–7.11 (m,
11H, Ar–H), 5.25 (s, 2H, CH2), 4.36 (s, 2H, CH2). 13C NMR
(DMSO-d6, 75 MHz, ppm): d 193.12, 169.07, 166.39, 157.91,
142.68, 138.72, 135.86, 131.83, 129.83, 128.64, 126.75,
124.43, 122.04, 119.61, 105.82, 70.87, 47.64. MS m/z 513
(M?1). Anal. Calcd. for C23H16BrNO4S2: C, 53.70; H, 3.14;
N, 2.72; S, 12.47. Found: C, 53.68; H, 3.13; N, 2.71; S, 12.49.
(Z)-2-(5-((6-((2-Chlorobenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6l) Yield 81 %;
m.p. 291–292 °C. IR (KBr) cm-1: 3415 (OH), 1703 (C=O). 1H
NMR (DMSO-d6, 300 MHz, ppm): d 8.19 (s, 1H), 8.08–7.87
(m, 3H), 7.74–7.64 (m, 2H), 7.59–7.51 (m, 2H), 7.48–7.30
(m, 3H), 8.19–7.32 (m, 11H, Ar–H), 5.32 (s, 2H, CH2), 4.44
(s, 2H, CH2). 13C NMR (DMSO-d6, 75 MHz, ppm): d 193.17,
169.08, 166.40, 157.47, 145.52, 139.08, 137.56, 132.07,
130.34, 129.63, 127.10, 126.68, 119.85, 107.65, 67.08, 47.79.
MS m/z 470 (M?1). Anal. Calcd. for C23H16ClNO4S2: C,
58.78; H, 3.43; N, 2.98; S, 13.65. Found: C, 58.79; H, 3.41; N,
2.96; S, 13.68.
(Z)-2-(5-((6-((4-Cyanobenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6p) Yield 87 %;
m.p. 327–328 °C. IR (KBr) cm-1: 3419 (OH), 1707 (C=O).
1H NMR (DMSO-d6, 300 MHz, ppm): d 8.19 (s, 1H), 8.05
(d, J = 9.1 Hz, 1H), 7.95–7.88 (m, 4H), 7.73–7.67 (m, 3H),
7.50 (s, 1H), 7.36 (dd, J = 9.0, 2.4 Hz, 1H), 8.19–7.34 (m,
11H, Ar–H), 5.38 (s, 2H, CH2), 4.54 (s, 2H, CH2). 13C NMR
(DMSO-d6, 75 MHz, ppm): d 193.12, 167.11, 166.66,
157.87, 142.39, 135.10, 133.26, 132.44, 131.90, 130.86,
128.40, 128.17, 127.99, 127.03, 119.86, 107.56, 66.51,
46.68. MS m/z 461 (M?1). Anal. Calcd. for C24H16N2O4S2:
C, 62.59; H, 3.50; N, 6.08; S, 13.93. Found: C, 62.56; H, 3.48;
N, 6.05; S, 13.95.
(Z)-2-(5-((6-((3-Chlorobenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6m) Yield 83 %;
m.p.285–286 °C. IR (KBr) cm-1: 3409(OH), 1704 (C=O). 1H
NMR (DMSO-d6, 300 MHz, ppm): d 8.18 (s, 1H), 8.07–7.87
(m, 3H), 7.72–7.55 (m, 2H), 7.53–7.29 (m, 5H), 8.18–7.32 (m,
11H, Ar–H), 5.27 (s, 2H, CH2), 4.50 (s, 2H, CH2). 13C NMR
(DMSO-d6, 75 MHz, ppm): d 193.16, 169.21, 166.33, 158.47,
144.52, 143.17, 139.28, 131.73, 129.07, 128.34, 127.63,
127.19, 125.16, 124.57, 119.43, 107.60, 69.18, 46.93. MS m/
z 470 (M?1). Anal. Calcd. for C23H16ClNO4S2: C, 58.78; H,
3.43; N, 2.98; S, 13.65. Found: C, 58.76; H, 3.41; N, 2.96; S,
13.67.
(Z)-2-(5-((6-((2,4-Dichlorobenzyl)oxy)naphthalen-2-yl)methy-
lene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6q) Yield
83 %; m.p. 308–309 °C. IR (KBr) cm-1: 3427 (OH), 1691
(C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 8.19
(s, 1H), 8.07–7.91 (m, 3H), 7.72–7.68 (m, 3H), 7.58–7.48
(m, 2H), 7.34 (dd, J = 8.9, 2.2 Hz, 1H), 8.19–7.16 (m,
10H, Ar–H), 5.30 (s, 2H, CH2), 4.54 (s, 2H, CH2). 13C
NMR (DMSO-d6, 75 MHz, ppm): d 193.15, 169.38,
167.34, 158.51, 140.57, 138.24, 135.65, 133.23, 132.72,
130.83, 129.13, 119.86, 107.56, 66.14, 46.71. MS m/z 505
(M?1). Anal. Calcd. for C23H15Cl2NO4S2: C, 54.77; H,
3.00; N, 2.78; S, 12.71. Found: C, 54.75; H, 2.97; N, 2.76;
S, 12.72.
(Z)-2-(5-((6-((4-Chlorobenzyl)oxy)naphthalen-2-yl)methylene)-
4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6n) Yield 86 %;
m.p. 313–314 °C. IR (KBr) cm-1: 3424 (OH), 1693 (C=O). 1H
NMR (DMSO-d6, 300 MHz, ppm): d 8.18 (s, 1H), 8.07–7.85
(m, 3H), 7.70–7.66 (m, 1H), 7.57–7.43 (m, 5H), 7.35–7.31
(m, 1H), 8.18–7.22 (m, 11H, Ar–H), 5.27 (s, 2H, CH2), 4.36
(s, 2H, CH2). 13C NMR (DMSO-d6, 75 MHz, ppm): d 193.12,
169.34, 166.57, 159.08, 142.82, 136.73, 133.48, 132.73,
131.73, 128.34, 127.63, 127.01, 119.72, 107.82, 69.79, 46.67.
(Z)-2-(5-((6-((3,4-Dichlorobenzyl)oxy)naphthalen-2-yl)meth-
ylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6r) Yield
84 %; m.p. 251–252 °C. IR (KBr) cm-1: 3422 (OH), 1699
(C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 8.19
(s, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 8.7 Hz,
1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.69 (d, J = 8.2 Hz, 2H),
7.52 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 8.9 Hz, 1H),
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Med Chem Res (2013) 22:4125–4132
4129
(Z)-2-(5-((6-((4-Iodobenzyl)oxy)naphthalen-2-yl)methylene)-4-
oxo-2-thioxothiazolidin-3-yl)acetic acid (6v) Yield 81 %;
m.p. 314–315 °C. IR (KBr) cm-1: 3435 (OH), 1695
(C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 8.18
(s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.97–7.85 (m, 2H), 7.78
(d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.6 Hz, 1H), 7.49 (s,
1H), 7.33 (d, J = 6.9 Hz, 3H), 8.18–7.32 (m, 11H, Ar–H),
5.23 (s, 2H, CH2), 4.39 (s, 2H, CH2). 13C NMR (DMSO-
d6, 75 MHz, ppm): d 193.12, 169.13, 166.83, 157.72,
143.18, 138.27, 136.81, 131.43, 129.67, 128.95, 128.32,
119.38, 117.29, 105.77, 69.86, 47.64. MS m/z 561 (M?1).
Anal. Calcd. for C23H16INO4S2: C, 49.21; H, 2.87; N, 2.49;
S, 11.42. Found: C, 49.19; H, 2.84; N, 2.46; S, 11.45.
8.19–7.34 (m, 10H, Ar–H), 5.29 (s, 2H, CH2), 4.36 (s, 2H,
CH2). 13C NMR (DMSO-d6, 75 MHz, ppm): d 193.21,
169.82, 167.42, 157.49, 143.42, 139.18, 138.27, 136.91,
135.72, 134.19, 132.57, 128.59, 128.07, 127.35, 118.57,
116.16, 109.73, 69.17, 46.69. MS m/z 505 (M?1). Anal.
Calcd. for C23H15Cl2NO4S2: C, 54.77; H, 3.00; N, 2.78; S,
12.71. Found: C, 54.73; H, 2.96; N, 2.77; S, 12.70.
(Z)-2-(5-((6-((2,6-Dichlorobenzyl)oxy)naphthalen-2-yl)methy-
lene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6s) Yield
82 %; m.p. 284–285 °C. IR (KBr) cm-1: 3412 (OH), 1709
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 8.21 (s,
1H), 8.05–8.01 (m, 2H), 7.91 (s, 1H), 7.75–7.46 (m, 5H),
7.30 (dd, J = 9.0, 2.2 Hz, 1H), 8.21–7.28 (m, 10H, Ar–H),
5.41 (s, 2H, CH2), 4.38 (s, 2H, CH2). 13C NMR (DMSO-
d6, 75 MHz, ppm): d 193.13, 169.82, 167.42, 157.15,
142.19, 138.16, 134.38, 133.94, 132.46, 131.75, 128.74,
119.78, 117.64, 107.73, 67.86, 46.83. MS m/z 505 (M?1).
Anal. Calcd. for C23H15Cl2NO4S2: C, 54.77; H, 3.00; N,
2.78; S, 12.71. Found: C, 54.72; H, 2.98; N, 2.79; S, 12.68.
(Z)-2-(5-((6-((4-Nitrobenzyl)oxy)naphthalen-2-yl)methy-
lene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6w) Yield
82 %; m.p. 327–328 °C. IR (KBr) cm-1: 3426 (OH), 1707
1
(C=O). H NMR (DMSO-d6, 300 MHz, ppm): d 8.29 (d,
J = 8.5 Hz, 2H), 8.19 (s, 1H), 8.05 (d, J = 9.0 Hz, 1H), 7.93
(d, J = 10.2 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.68
(d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H),
8.30–7.36 (m, 11H, Ar–H), 5.44 (s, 2H, CH2), 4.53 (s, 2H,
CH2). 13C NMR (DMSO-d6, 75 MHz, ppm): d 193.12,
167.13, 165.43, 157.46, 147.18, 145.34, 144.94, 138.61,
132.28, 129.91, 128.27, 127.29, 117.37, 105.51, 69.44,
47.64. MS m/z 481 (M?1). Anal. Calcd. for C23H16N2O6S2:
C, 57.49; H, 3.36; N, 5.83; S, 13.35. Found: C, 57.46; H, 3.35;
N, 5.81; S, 13.36.
(Z)-2-(4-Oxo-2-thioxo-5-((6-((3-(trifluoromethyl)benzyl)
oxy)naphthalen-2-yl)methylene)thiazolidin-3-yl)acetic acid
(6t) Yield 87 %; m.p. 261–262 °C. IR (KBr) cm-1: 3502
1
(OH), 1701 (C=O). H NMR (DMSO-d6, 300 MHz, ppm):
d 8.19 (s, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.99–7.80 (m,
4H), 7.75–7.65 (m, 3H), 7.54 (s, 1H), 7.37 (d, J = 9.0 Hz,
1H), 8.19–7.35 (m, 11H, Ar–H), 5.38 (s, 2H, CH2), 4.45
(s, 2H, CH2). 13C NMR (DMSO-d6, 75 MHz, ppm): d
193.21, 169.75, 167.37, 157.78, 143.38, 141.46, 139.82,
132.67, 131.81, 130.94, 129.46, 128.27, 112.49, 73.46,
47.61. MS m/z 504 (M?1). Anal. Calcd. for C24
H16F3NO4S2: C, 57.25; H, 3.20; N, 2.78; S, 12.74. Found:
C, 57.24; H, 3.18; N, 2.79; S, 12.71.
(Z)-2-(5-((6-((4-(Dimethylamino)benzyl)oxy)naphthalen-2-
yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (6x)
Yield 82 %; m.p. 319–320 °C. IR (KBr) cm-1: 3421 (OH),
1705 (C=O). 1H NMR (DMSO-d6, 300 MHz, ppm): d 8.25
(s, 1H), 8.13–8.05 (m, 2H), 7.92 (s, 1H), 7.85–7.65
(m, 4H), 7.47 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.5 Hz,
1H), 8.25–7.21 (m, 11H, Ar–H), 5.21 (s, 2H, CH2), 4.41
(s, 2H, CH2), 3.13 (s, 6H, CH3). 13C NMR (DMSO-d6,
75 MHz, ppm): d 193.12, 169.13, 167.43, 158.46, 149.18,
138.34, 132.94, 129.61, 128.28, 127.91, 119.27, 118.29,
116.37, 105.76, 70.18, 47.63. MS m/z 479 (M?1). Anal.
Calcd. for C25H22N2O4S2: C, 62.74; H, 4.63; N, 5.85; S,
13.40. Found: C, 62.73; H, 4.62; N, 5.81; S, 13.43.
(Z)-2-(4-Oxo-2-thioxo-5-((6-((4-(trifluoromethyl)benzyl)
oxy)naphthalen-2-yl)methylene)thiazolidin-3-yl)acetic acid
(6u) Yield 85 %; m.p. 293–294 °C. IR (KBr) cm-1: 3502
1
(OH), 1702 (C=O). H NMR (DMSO-d6, 300 MHz, ppm):
d 8.19 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.98–7.86 (m,
2H), 7.81–7.67 (m, 5H), 7.52 (d, J = 1.9 Hz, 1H), 7.36
(dd, J = 9.0, 2.3 Hz, 1H), 8.19–7.34 (m, 11H, Ar–H), 5.39
(s, 2H, CH2), 4.41 (s, 2H, CH2). 13C NMR (DMSO-d6,
75 MHz, ppm): d 193.12, 166.90, 166.82, 157.92, 141.51,
132.79, 131.77, 130.82, 128.40, 128.13, 127.96, 127.02,
125.38, 119.38, 107.57, 66.58, 47.53. MS m/z 504 (M?1).
Anal. Calcd. for C24H16F3NO4S2: C, 57.25; H, 3.20; N,
2.78; S, 12.74. Found: C, 57.23; H, 3.19; N, 2.80; S, 12.75.
Evaluation of antibacterial activity in vitro
In vitro antibacterial activity assay method was referred in
Ref. (Chen et al., 2010).
123

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Med Chem Res (2013) 22:4125–4132
Antimicrobial activity
Results and discussion
Chemistry
In vitro antimicrobial activity was evaluated by determining
the minimum inhibitory concentration (MIC) for differ-
ent strains (including multidrug-resistant clinical isolates).
Oxacillin and norfloxacin were used as positive controls.
Synthesized compound 3 showed no antibacterial
activity in vitro against gram-positive and gram-negative
strains at 64 lg/mL. We then introduced hydrophobic
groups at the hydroxy group of compound 3 and formed the
ether derivatives (6a–6x). The results showed that, as
expected, some derivatives exhibited potent antibacterial
activities against gram-positive strains, but still showed no
activity against gram-negative strains (Table 1).
(Z)-2-(5-((6-Hydroxynaphthalen-2-yl)methylene)-4-oxo-2-
thioxothiazolidin-3-yl)acetic acid (3) was synthesized for
the first time by a Knoevenagel condensation (Albuquerque
et al., 1997) between 6-hydroxy-2-naphthaldehyde (1) and
rhodanine-3-acetic acid (2) in good yields (Scheme 1).
Compound 2 was prepared by a previously described
method (Brown et al., 1956). Compounds 6a–6x were
synthesized in two steps as shown in Scheme 2. The
intermediates 5a–5x were obtained by reacting 4a–4x with
1 in the presence of K2CO3 in DMF at 90 °C (Patil et al.,
2010) and these intermediates were further subjected to
rhodanine-3-acetic acid (2) with catalytic amount of acetic
acid and piperidine in ethanol at 50 °C to afford com-
pounds 6a–6x. All the synthesized compounds were
Compounds 6b, 6e, 6f, 6h, 6k, 6n, and 6u were highly
active against Staphylococcus aureus (S. aureus RN4220
and S. aureus KCTC 503) with MICs of 2–8 lg/mL, in
which the 4-bromine substituted 6k with a MIC of 2 lg/mL
was as active as the standard drug (norfloxacin) but less
active than oxacillin. After analyzing the activities of
1
investigated by FTIR, H NMR, 13C NMR, mass spectral,
and elemental analyses.
Scheme 1 Synthetic scheme for the synthesis of compound 3
Scheme 2 Synthetic scheme for the synthesis of compounds 6a–6x
123

Med Chem Res (2013) 22:4125–4132
4131
Table 1 Inhibitory activity of compounds 2, 3, and 6a–6x expressed
as MIC (lg/mL)
Table 2 MIC values (in lg/mL) against clinical isolates of multi-
drug-resistant gram-positive bacterial strains
Compounds
S. aureus
E. coli
Compounds
MRSA
3167
QRSA
3505
4220
503
1924
1356
3506
3519
2
[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
[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
[64
[64
16
6a
64
64
64
4
64
8
3
6b
2
4
6a
6e
2
8
2
8
8
6b
2
4
6f
8
4
8
6c
[64
[64
4
[64
[64
8
6h
4
2
4
6d
6j
64
1
64
1
[64
4
[64
4
6e
6k
6f
4
8
6n
2
2
4
4
6g
[64
4
[64
4
6u
2
2
64
8
64
4
6h
6w
4
8
6i
[64
32
[64
64
6x
[64
[64
8
[64
[64
4
[64
1
[64
1
6j
Oxacillin
Norfloxacin
6k
2
2
[64
[64
6l
[64
[64
2
[64
[64
4
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
6m
6n
6o
[64
[64
[64
[64
[64
[64
4
[64
[64
[64
[64
[64
[64
4
6p
6q
clinical isolates of multidrug-resistant gram-positive bacte-
ria (Table 2). Compounds 6b, 6e, 6f, 6h, 6k, 6n, and 6u were
active with MICs of 1–8 lg/mL. Compound 6k exhibited
more potent activity than norfloxacin against all of the
microorganisms tested with a MIC of 1 lg/mL; hence, the
derivative substituted at the 4-position still exhibited more
potent activity than the other derivatives. Regardless, these
compounds still had low potency for quinolone-resistant
S. aureus (QRSA) compared to oxacillin. In contrast to the
previously reported rhodanine-3-acetic acid derivatives
bearing a chalcone moiety, the derivatives bearing a 6-
benzyloxynaphthalene moiety presented more potent activ-
ity in general. This suggests that the chalcone moiety can be
replaced by a naphthalene moiety and that changing the
flexible chalcone moiety to a more rigid structure may be
beneficial to increase the antibacterial activity. Further
modification of the compound 6k is in progress.
6r
6s
6t
6u
6v
[64
64
[64
32
6w
6x
64
64
Oxacillin
Norfloxacin
1
1
2
2
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
synthesized compounds 3 and 6a–6x, the following struc-
ture–activity relationships (SARs) were obtained. Intro-
ducing a class of hydrophobic groups onto the phenolic
hydroxyl group of compound 3 resulted in enhancing the
antibacterial activity of some derivatives, compound 6k
(MIC = 2 lg/mL) was 32-fold more potent than com-
pound 3 (MIC [ 64 lg/mL). Furthermore, the antibacterial
activity was significantly influenced by the position of the
substituent on the phenyl ring. Most derivatives substituted
at the 4-position (except 6v, 6w, and 6x) had good anti-
bacterial activity, and no clear correlation was determined
for the relationship between the electronic property of the
substituent and antibacterial activity.
Conclusion
Based on our previous work, we have described a simple
and efficient protocol for the synthesis of novel rhodanine-
3-acetic acid derivatives (3, 6a–6x) in good yields. All the
synthesized compounds have been investigated for their
in vitro antimicrobial activities. Most of the compounds
showed reasonably potent antibacterial activities against
gram-positive bacteria (particularly against multidrug-
resistant strains of clinical isolates). Compound 6k with a
For those compounds exhibiting potency against S. aureus,
we also evaluated their antibacterial activity against several
123

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Med Chem Res (2013) 22:4125–4132
properties of alkyl derivatives of 3-carboxyalkylrhodanine.
Khimiko-Farmakotsevticheskii Zhurnal 19:943–946
MIC of 1 lg/mL was found to be the most potent against
the multidrug-resistant strains than norfloxacin. Future
SAR studies are ongoing in the continuing search for novel
antibacterial agents.
Havrylyuk D, Zimenkovsky B, Vasylenko O, Zaprutko L, Gzella A, Lesyk
R (2009) Synthesis of novel thiazolone-based compounds containing
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(1992) Phytogrowth-inhibitory activity of sulfur-containing
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Acknowledgments This study was supported by the National
Science Foundation of China (20962021 and 81260468).
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Rhodanine derivatives as novel peroxisome proliferator-acti-
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