Synthesis and bioactivity evaluation of n-arylsulfonylindole analogs bearing a rhodanine moiety as antibacterial agents

Article abstract of DOI:10.3390/molecules22060970

Abstract: Due to the rapidly growing bacterial resistance to antibiotics and the scarcity of novel agents under development, bacterial infections are still a pressing global problem, making new types of antibacterial agents, which are effective both alone and in combination with traditional antibiotics, urgently needed. In this paper, seven series of N-arylsulfonylindole analogs 5–11 bearing rhodanine moieties were synthesized, characterized, and evaluated for antibacterial activity. According to the in vitro antimicrobial results, half of the synthesized compounds showed potent inhibition against four Gram-positive bacteria, with MIC values in the range of 0.5–8 μg/mL. For multidrug-resistant strains, compounds 6a and 6c were the most potent, with MIC values of 0.5 μg/mL, having comparable activity to gatifloxacin, moxiflocaxin and norfloxacin and being 128-fold more potent than oxacillin (MIC = 64 μg/mL) and 64-fold more active than penicillin (MIC = 32 μg/mL) against Staphylococcus aureus ATCC 43300.

Full text of DOI:10.3390/molecules22060970

molecules
Article
Synthesis and Bioactivity Evaluation of
N-Arylsulfonylindole Analogs Bearing a Rhodanine
Moiety as Antibacterial Agents
Ming-Xia Song, Song-Hui Li, Jiao-Yang Peng, Ting-Ting Guo, Wen-Hui Xu, Shao-Feng Xiong and
Xian-Qing Deng *
Basic Medical and Pharmacy College, Jinggangshan University, Ji’an 343009, Jiangxi, China;
freexiaoxiao83@aliyun.com (M.-X.S.); 18379698767@163.com (S.-H.L.); sakura367468@163.com (J.-Y.P.);
m18379680319@163.com (T.-T.G.); 13687965920@163.com (W.-H.X.); 18370669382@163.com (S.-F.X.)
* Correspondence: xqdeng@jgsu.edu.cn; Tel.: +86-157-7919-7280
Received: 28 April 2017; Accepted: 9 June 2017; Published: 14 June 2017
Abstract: Due to the rapidly growing bacterial resistance to antibiotics and the scarcity of novel
agents under development, bacterial infections are still a pressing global problem, making new types
of antibacterial agents, which are effective both alone and in combination with traditional antibiotics,
urgently needed. In this paper, seven series of N-arylsulfonylindole analogs 5–11 bearing rhodanine
moieties were synthesized, characterized, and evaluated for antibacterial activity. According to the
in vitro antimicrobial results, half of the synthesized compounds showed potent inhibition against
four Gram-positive bacteria, with MIC values in the range of 0.5–8
µg/mL. For multidrug-resistant
strains, compounds 6a and 6c were the most potent, with MIC values of 0.5
µg/mL, having
comparable activity to gatifloxacin, moxiflocaxin and norfloxacin and being 128-fold more potent
than oxacillin (MIC = 64 µg/mL) and 64-fold more active than penicillin (MIC = 32 µg/mL) against
Staphylococcus aureus ATCC 43300.
Keywords: rhodanine; N-arylsulfonylindole; propanoic acid; antibacterial activity
1. Introduction
Bacterial drug resistance has emerged and become increasingly serious on a global scale, both
in developed and developing countries [1]. Drug-resistant bacteria, such as methicillin-resistant
Staphylococcus aureus (MRSA), multi-drug resistant Escherichia coli, and multi-drug resistant
Pseudomonas aeruginosa, cause lethal diseases and cause great difficulties in the treatment of nosocomial
infections [2–5], which severely threaten global public health while resulting in very large economic
costs [ ]. Currently the development of new antimicrobial drugs cannot keep pace with the
6
development of bacterial drug resistance, and the number of new antibiotics approved for marketing
per year is declining continuously. Taking advantage of pathogens virulence is an alternative strategy
to inhibit antibiotic resistance development, and some studies have focused on anti-virulence agents
against Gram-positive pathogens and Gram-negative pathogens [7,8]. However, this strategy has some
weaknesses that limiting its development, such as the lack of a good way to assessing the efficacy
and the inapplicability in immunocompromised patients. Over the last decade, a few new antibiotics
(e.g., linezolid, ceftolozane, telavancin, ceftaroline fosamil, Xifaxan®, and daptomycin) were approved
and dozens of antibiotics are currently in Phase 2 or Phase 3 clinical trials [
9]. However, these drugs
cannot address the entire spectrum of bacteria resistance [10], therefore, there is an urgent need to
develop new antimicrobial agents, especially those with a new drug target or with the ability to
overcome drug resistance.
Molecules 2017, 22, 970; doi:10.3390/molecules22060970
www.mdpi.com/journal/molecules

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Indole, an intercellular signaling molecule, regulates various aspects of bacterial physiology,
including spore formation, plasmid stability, resistance to drugs, biofilm formation, and virulence.
The amino acid tryptophan is an indole derivative and the precursor of the neurotransmitter serotonin.
Up to now, indoles have displayed important physiological functions and potent pharmacological
activities, including anti-inflammatory and antioxidant [11], antineoplastic [12–14], antimicrobial [15,16],
antiviral [14 17 18], and anti-HIV activity [19 20]. N-Arylsulfonylindoles, as a kind of indole derivative,
,
,
,
have received a great deal of attention in the field of chemical drug research, behaving as 5-HT6 receptor
antagonists [21], anti-AIDS drugs [22], and antifungal agents [23]. However, the antibacterial activity of
N-arylsulfonylindoles has not yet been reported to our knowledge.
Previously, we reported a series of rhodanine derivatives (compounds
showed good inhibitory activity against Gram-positive bacteria (including multidrug-resistant
clinical isolates) [24 29], which suggested that the rhodanine moiety was an important fragment
I, Scheme 1) which
–
for antimicrobial activity. Fragment-based drug discovery and skeleton migration strategy is a rational
technique for molecular modification and drug design when some active fragments are obtained.
Based upon these observations, and as part of our ongoing program aiming at the discovery and
development of bioactive molecules, in this work, seven series of N-arylsulfonyl-3-substituted indoles
5–11 (Scheme 1) were designed using compound I as the lead compound. The target compounds were
prepared by combining the rhodanine groups with N-arylsulfonylindoles, and their anti-bacterial
activities were screened.
Scheme 1. The design of the target compounds 5–11.
Chen et al. [30] have reported the synthesis and antibacterial activity evaluation of chalcone
derivatives containing a rhodanine-3-acetic acid moiety, and found that the antibacterial activity of
compounds with halogen and methyl substituents on the phenyl group was obviously higher than
that of compounds with other substituents. In view of these findings, in this paper, only halogen and
methyl substituents were chosen on the indole and phenyl sulfonyl moieties.
2. Results and Discussion
2.1. Chemistry
The target compounds were synthesized as outlined in Scheme 2. A series of 3-substituted-5-
((1-(phenylsulfonyl)-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-ones were synthesized using
1H-indole-3-carbaldehydes as the starting material. Firstly, benzenesulfonyl chlorides 1a
,
1b were
2c in the presence of anhydrous potassium carbonate
, which were directly
were subjected to a Knoevenagel
condensation reaction with appropriate N-substituted rhodanines to provide seven new series of target
compounds
11. The structures of the products were well characterized by 1H-NMR, 13C-NMR, and
high-resolution mass spectrometry.
reacted with 1H-indole-3-carbaldehydes 2a
(K2CO3) at 40 C to give 1-(phenylsulfonyl)-1H-indole-3-carbaldehydes 3a
–
◦
–
f
used in the next step without purification. Next compounds 3a–f
5–

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Scheme 2. The synthesis route of compounds 5–11.
2.2. Antimicrobial Activity
All of the target compounds 5–11 were evaluated for their in vitro anti-bacterial activity
using a serial dilution method to obtain the minimum inhibitory concentration (MIC) against five
Gram-positive strains (S. aureus (CMCC(B) 26003 and CMCC 25923, Streptococcus pyogenes CMCC
32067, Enterococcus faecalis CMCC 29212, and Bacillus subtilis CMCC 63501), four Gram-negative strains
(E. coli (CMCC 25922 and CMCC 44568) and P. aeruginosa (CMCC 27853 and CMCC 10104))m as well
as two methicillin-resistant clinical isolates (S. aureus ATCC 43300 and ATCC 33591). Gatifloxacin,
moxifloxacin, norfloxacin, oxacillin, and penicillin were used as positive control drugs.
Preliminarily, compounds 5–11 were screened for their activity against five Gram-positive strains
and four Gram-negative strains. Initial screening results described as MIC values are presented in
Table 1. The results illustrate that the inhibition of the seven series of derivatives against Gram-positive
strains (effective against four bacteria) is in general superior to that of Gram-negative strains (effective
against one bacterium). For Gram-positive strains, more than half of the tested compounds showed
potent inhibition activity against S. aureus (CMCC(B) 26003 and CMCC 25923), with MIC values in the
range of 0.5–4
CMCC 29212 (MIC = 4–32
five positive control agents did not exhibit inhibition activity for the two strains (MICs > 128 µg/mL)
All compounds, however, had no effect on B. subtilis CMCC 63501 at 128 g/mL. For Gram-negative
strains, only a few of compounds showed moderate activity against P. aeruginosa CMCC 10104 with
MICs of 4–64 g/mL, while showing no inhibitory activity against three other strains at 128 g/mL.
The study found that, among the compounds synthesized, compound 8b was the most active
compound against two S. aureus with MIC values of 1 or 0.5 g/mL, along with MIC = 2 or 4 µg/mL
against S. pyogenes CMCC 32067 and E. faecalis CMCC 29212, respectively.
In the following trials, five compounds (6a, 6c 8a–c) were chosen to evaluate their inhibitory
µg/mL. Half of the target compounds exhibited moderate activity against E. faecalis
µ
g/mL) and S. pyogenes CMCC 32067 (MIC = 2–128 g/mL). Conversely,
µ
.
µ
µ
µ
µ
,
activity against two clinical isolates of multidrug-resistant Gram-positive bacterial strains (S. aureus
ATCC 43300 and S. aureus ATCC 33591), whose MICs against S. aureus (CMCC(B) 26003 or CMCC
25923 are less than 1
had excellent inhibitory activities against the two multidrug-resistant strains, with MICs of 0.5, 1,
or 2 µg/mL. Among them, compounds 6a and 6c were the most potent, with MIC values of 0.5 g/mL,
having comparable activity to gatifloxacin, moxiflocaxin and norfloxacin, while being 128-fold more
µg/mL. The results are listed in Table 2. The data illustrated that five compounds
µ
potent than oxacillin (MIC = 64 µg/mL) and 64-fold more active than penicillin (MIC = 32 µg/mL)
against S. aureus ATCC 43300.

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Table 1. Inhibitory activity (MIC, µg/mL) of compounds 5–11 against Gram-positive and Gram-negative bacteria.
Gram-Positive Strains
Gram-Negative Strains
Compd.
R1-
R2-
R3-
26003 a
32067 c
63501 e
44568 g
25923 b
29212 d
25922 f
27853 h
10104 i
5a
5b
5c
H
H
CH3
CH3
5-Br
6-Cl
5-Br
6-Cl
CH2COOH
CH2COOH
CH2COOH
CH2COOH
8
8
>128
>128
>128
>128
32
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
32
>128
8
4
>128
16
4
>128
>128
32
>128
>128
32
5d
6a
6b
6c
H
H
2
1
16
8
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
8
H
6-Cl
H
4
2
>128
>128
>128
>128
128
16
16
CH3
CH3
CH3
H
2
1
4
4
6d
6e
7a
7b
5-Br
6-Cl
H
2
2
4
4
64
2
>128
2
>128
>128
4
8
4
8
H
6-Cl
32
16
>128
7c
CH3
CH3
H
2
2
16
2
>128
>128
>128
16
>128
>128
>128
>128
>128
>128
>128
>128
>128
16
7d
5-Br

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Table 1. Cont.
Gram-Positive Strains
Gram-Negative Strains
Compd.
R1-
R2-
R3-
26003 a
32067 c
63501 e
44568 g
25923 b
29212 d
25922 f
27853 h
10104 i
8a
8b
8c
8d
8e
H
H
2
1
4
16
>128
>128
>128
>128
16
H
6-Cl
H
1
1
2
2
0.5
1
2
4
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
4
CH3
CH3
CH3
128
>128
>128
>128
64
>128
64
5-Br
6-Cl
2
2
64
64
9
H
H
4
4
>128
32
>128
>128
>128
>128
32
10
11
H
H
H
H
2
2
8
16
16
32
>128
>128
>128
>128
>128
>128
>128
>128
16
32
>128
>128
Gatifloxacin
Moxifloxacin
Norfloxacin
Oxacillin
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
0.125
0.125
0.125
0.125
0.125
0.125
0.125
0.125
0.125
0.125
d
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
e
1
1
1
128
128
2
2
2
0.125
0.125
0.125
128
0.125
0.125
0.125
>128
>128
g
2
2
2
>128
128
>128
>128
penicillin
128
a
b
c
f
S. aureus CMCC(B) 26003; S. aureus CMCC 25923; S. pyogenes CMCC 32067; E. faecalis CMCC 29212; B. subtilis CMCC 63501; E. coli CMCC 25922; E. coli CMCC 44568;
P. aeruginosa CMCC 27853; I P. aeruginosa CMCC 10104.
h

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Table 2. Inhibitory activity (MIC,
multidrug-resistant strains.
µg/mL) of compounds 6a, 6c and 8a–c against clinical isolates of
Multidrug-Resistant
Gram-Positive Strains
Compound
R1-
R2-
R3-
43300 a
33591 b
6a
6c
8a
8b
8c
H
CH3
H
H
H
0.5
1
1
2
0.5
H
1
H
6-Cl
H
2
1
2
2
CH3
Gatifloxacin
Moxifloxacin
Norfloxacin
Oxacillin
—
—
—
—
—
a
—
—
—
—
—
—
—
—
—
—
0.5
0.5
0.5
64
0.25
0.25
0.25
8
Penicillin
32
>32
S. aureus ATCC 43300; b S. aureus ATCC 33591.
2.3. Cytotoxicity
The cytotoxic properties of compounds 6a
using the CCK-8 method and the results are shown in Table 3. Compounds 6a
values of 36.90, 54.09, and 32.28 g/mL, respectively, were not cytotoxic at concentrations in the range
of 0.5–16 g/mL. The comparison between the MIC and IC50 values of the tested compounds suggests
,
8b, and 8c were also investigated on HEK 293T cells
8b, and 8c, with IC50
,
µ
µ
that compounds 6a, 8b, and 8c exhibit in vitro antibacterial activity at non-cytotoxic concentrations.
Table 3. Cytotoxic activity of compounds 6a, 8b and 8c on the HEK 293T cells.
Compound
IC50 (µg/mL) a
6a
8b
8c
36.90
54.09
32.28
a
IC50 is the concentration required to inhibit 50% of cell growth.
2.4. The Structure-Activity Relationships (SARs) Analysis
Based on the present data of the synthesized compounds, simple SARs could be proposed. For the
derivatives bearing weak electron-donating substituents (R1 = -CH3), it seems that there is no obvious
impact on the antibacterial activity in comparison with non-substituted compounds (R1 = H). In series
6
, for example, the MIC values against CMCC 26003 of compound 6c (R1 = -CH3) and compound 6a
(R1 = H) were both 2 g/mL, and the same result was discovered in the series . As evidenced from
Table 1, this could lead to the conclusion that a general inhibitory activity order of seven series of target
compounds was series > series 10 > series > series 11, but the differences are not remarkable.
Upon comparison of series and , it can be found that the activity of the R-configuration compounds
appears to be slightly better than that of S-configuration compounds.
µ
7
6,
8
7,
9
5,
7
8

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3. Materials and Methods
3.1. Instruments and Reagents
All of the reagents and solvents were purchased from Aladdin (Shanghai, China) or Sinopharm
Chemical Reagent Co. Ltd. (Shanghai, China), and were used as received. Melting points were
determined in open capillary tubes and are uncorrected. Reaction courses were monitored by thin-layer
chromatography on silica gel-precoated F254 plates (Merck, Darmstadt, Germany). Developed plates
were examined with UV lamps (254 nm). Nuclear magnetic resonance spectroscopy was performed
on an AV-300 spectrometer (Bruker, Zurich, Switzerland) operating at 300 MHz for 1H and 75 MHz
for 13C and using DMSO-d6 as solvent and tetramethylsilane as the internal standard. Electrospray
Ionization Mass Spectrometry (ESI-MS) experiments were performed on an IT-TOF mass spectrometer
(Shimadzu, Tokyo, Japan) in negative ion mode. Specific optical rotation was measured on a Digital
automatic polariscope JASCO P-1020 (JASCO, Tokyo, Japan).
3.2. Synthesis Method and Spectral Data
3.2.1. General Procedure for the Preparation of Compounds 3a–3b
To a dry dichloromethane solution (10 mL) of the appropriate 1H-indole-3-carbaldehydes
(2 mmol), anhydrous potassium carbonate (6 mmol) and benzenesulfonyl chlorides (4 mmol) in
dry dichloromethane (20 mL) were added, and the mixture was stirred for 12 h at 40 ◦C. After the
completion of the reaction, excess solvent was removed under reduced pressure to obtain a yellow
crude solid of 3a–3b which was directly used in the next step without purification.
3.2.2. General Procedure for the Preparation of Compounds 3c–3f
To a solution of the appropriate 1H-indole-3-carbaldehydes (1 mmol) in dry dichloromethane
(30 mL), sodium hydroxide (1.75 mmol), benzyltriethylammonium chloride (TEBA, 0.1 mmol), and
benzenesulfonyl chlorides (1.2 mmol) were added and stirred for 12 h at room temperature. After the
completion of the reaction, 15 mL water was added into the mixture. Then the mixture was extracted
with dichloromethane (30 mL × 3). The combined organic layers were dried over anhydrous MgSO4
before being concentrated in vacuo. The crude products 3c–3f obtained were directly used in the next
step without purification.
3.2.3. General Procedure for the Preparation of Compounds 5–11
A mixture of (1 mmol), corresponding rhodanine (1 mmol), 10 drops glacial acetic acid and
3
10 drops piperidine in ethanol (20 mL) was refluxed for 16 h. After cooling, the solvent was evaporated
in vacuo, followed by the purification of the resulting residue by silica gel column chromatography
(dichloromethane/methanol = 100/1 or 150/1) to obtain a yellow solid 5–11.
3.2.4. Spectral Data
2-(5-((5-Bromo-1-(phenylsulfonyl)-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (5a).
Yellow solid; yield 45%; m.p. 242–246 ◦C. 1H-NMR:
δ
4.64 (s, 2H, NCH2), 7.65–8.38 (m, 10H, Ar-H,
CH=C), 12.80 (br.s, 1H, COOH). 13C-NMR:
δ 192.57, 167.35, 166.27, 136.47, 135.98, 133.12, 131.05,
130.66, 129.50, 129.00, 127.79, 127.75, 125.95, 123.79, 117.92, 116.80, 115.59, 53.18. ESI-HRMS calcd. for
−
C20H12BrN2O5S3 ([M − H]−): 534.9097; found: 534.9118.
2-(5-((6-Chloro-1-(phenylsulfonyl)-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (5b).
Yellow solid; yield 47%; m.p. 206–208 ◦C. 1H-NMR:
δ
4.40 (s, 2H, NCH2), 7.44–8.24 (m, 10H, Ar-H,
CH=C), 9.24 (br.s, 1H, COOH). 13C-NMR:
δ 192.54, 167.13, 166.62, 136.53, 136.02, 134.67, 131.51,
130.75, 128.35, 127.99, 127.76, 125.39, 124.67, 122.56, 121.59, 117.33, 113.31, 43.98. ESI-HRMS calcd. for
−
C20H12ClN2O5S3 ([M − H]−): 490.9602; found: 490.9615.

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2-(5-((5-Bromo-1-tosyl-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (5c). Yellow solid;
yield 44%; m.p. 226 ◦C. 1H-NMR:
2.33 (s, 3H, CH3), 4.40 (s, 2H, NCH2), 7.37–8.40 (m, 9H, Ar-H,
CH=C), 9.31 (br.s, 1H, COOH). 13C-NMR:
194.93, 178.62, 176.66, 147.06, 146.25, 133.97, 133.13, 132.73,
δ
δ
132.63, 131.08, 130.76, 128.74, 127.75, 127.53, 117.81, 116.94, 115.62, 43.85, 22.70. ESI-HRMS calcd. for
−
C21H14BrN2O5S3 ([M − H]−): 548.9254; found: 548.9272.
2-(5-((6-Chloro-1-tosyl-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (5d). Yellow solid;
yield 57%; m.p. 205 ◦C. 1H-NMR:
δ
2.35 (s, 3H, CH3), 4.41 (s, 2H, NCH2), 7.42–8.11 (m, 9H, Ar-H,
CH=C), 9.28 (br.s, 1H, COOH). 13C-NMR:
δ
192.52, 167.45, 166.62, 147.13, 134.63, 133.57, 131.44, 131.16,
128.36, 127.96, 127.79, 125.29, 124.48, 122.46, 121.63, 117.15, 113.30, 43.89, 22.73. ESI-HRMS calcd. for
−
C21H14ClN2O5S3 ([M − H]−): 504.9759; found: 504.9774.
(R)-2-(5-((1-(Phenylsulfonyl)-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-4-methylpentanoic
acid (6a). Yellow solid; yield 51%; m.p. 271–276 ◦C. [α]D20: +35 (c = 0.20, DMF). 1H-NMR:
δ 0.89 (d, 3H,
J = 6.4 Hz, CHCH3), 0.94 (d, 3H, J = 6.4 Hz, CHCH3), 1.35–1.45 (m, 1H, CHCH3), 1.99–2.07 (m, 1H,
CH-Ha), 2.20–2.28 (m, 1H, CH-Hb), 5.61 (br.s, 1H, NCH), 7.38–8.20 (m, 11H, Ar-H, CH=C), 13.31 (br.s,
1H, COOH). 13C-NMR:
δ 193.05, 169.83, 166.48, 136.66, 135.80, 134.29, 130.56, 129.03, 128.46, 127.72,
126.88, 125.03, 123.82, 122.02, 120.82, 117.21, 113.72, 56.47, 36.88, 25.29, 23.36, 22.37. ESI-HRMS calcd.
for C24H21N2O5S3−([M − H]−): 513.0618; found: 513.0629.
(R)-2-(5-((6-Chloro-1-(phenylsulfonyl)-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-4-methyl-
pentanoic acid (6b). Yellow solid; yield 53%; m.p. 180–181 ◦C. [α]D20: +62.5 (c = 0.20, DMF). 1H-NMR:
δ
0.86 (d, 3H, J = 6.6 Hz, CHCH3), 0.91 (d, 3H, J = 6.6 Hz, CHCH3), 1.33–1.38 (m, 1H, CHCH3),
2.00–2.07 (m, 1H, CH-Ha), 2.24–2.31 (m, 1H, CH-Hb), 5.50 (br.s, 1H, NCH), 7.20–8.22 (m, 10H, Ar-H,
CH=C), 9.30 (br.s, 1H, COOH). 13C-NMR:
193.22, 170.01, 166.56, 136.51, 136.00, 134.63, 131.53, 130.70,
δ
129.78, 128.10, 127.76, 125.94, 125.38, 122.47, 120.63, 117.16, 113.29, 56.50, 37.23, 25.57, 23.49, 22.68.
−
ESI-HRMS calcd. for C24H20ClN2O5S3 ([M − H]−): 547.0228; found: 547.0244.
(R)-2-(5-((1-Tosyl-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-4-methylpentanoic acid (6c).
Yellow solid; yield 66%; m.p. 200 C. [α]2D0 +45 (c = 0.10, DMF). 1H-NMR:
δ 0.88 (d, 3H, J = 6.4 Hz,
◦
CHCH3), 0.93 (d, 3H, J = 6.5 Hz, CHCH3), 1.28–1.33 (m, 1H, CHCH3), 1.97–2.07 (m, 1H, CH-Ha),
2.20–2.27 (m, 1H, CH-Hb), 2.33 (s, 3H, Ph-CH3), 5.61 (br.s, 1H, NCH), 7.37–7.51 (m, 4H, Ar-H), 7.98–8.07
(m, 6H, Ar-H, CH=C), 13.04 (br.s, 1H, COOH). 13C-NMR:
δ 193.01, 171.68, 169.83, 157.49, 146.85, 134.27,
133.73, 130.97, 129.02, 128.48, 127.76, 126.80, 124.95, 123.87, 120.75, 117.05, 113.74, 56.46, 36.88, 25.82,
−
23.36, 22.37, 21.54. ESI-HRMS calcd. for C25H23N2O5S3 ([M − H]−): 527.0775; found: 527.0790.
(R)-2-(5-((5-Bromo-1-tosyl-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-4-methylpentanoic acid
(
6d). Yellow solid; yield 61%; m.p. 256–260 ◦C. [α]D20: +57.5 (c = 0.08, DMF). 1H-NMR:
δ
0.89 (d, 3H,
J = 6.3 Hz, CHCH3), 0.94 (d, 3H, J = 6.3 Hz, CHCH3), 1.45–1.53 (m, 1H, CHCH3), 1.99–2.08 (m, 1H,
CH-Ha), 2.20–2.26 (m, 1H, CH-Hb), 2.34 (s, 3H, Ph-CH3), 5.62 (br.s, 1H, NCH), 7.43 (d, 2H, J = 7.9 Hz
Ph-H), 7.61 (d, 1H, J = 8.7 Hz, Ph-H), 7.93–8.07 (m, 5H, Ar-H), 8.37 (s, 1H, CH=C), 13.23 (br.s, 1H,
COOH). 13C-NMR:
193.01, 171.68, 169.83, 157.49, 146.85, 134.27, 133.73, 130.97, 129.02, 128.48, 127.76,
,
δ
126.80, 124.95, 123.87, 120.75, 117.05, 113.74, 56.46, 36.88, 25.82, 23.36, 22.37, 21.54. ESI-HRMS calcd. for
−
C25H22BrN2O5S3 ([M − H]−): 604.9880; found: 604.9899.
(R)-2-(5-((6-Chloro-1-tosyl-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-4-methylpentanoic acid
(
6e). Yellow solid; yield 63%; m.p. 247–249 ◦C. [α]D20: +31.5 (c = 0.20, DMF). 1H-NMR:
δ 0.88 (d, 3H,
J = 6.6 Hz, CHCH3), 0.94 (d, 3H, J = 6.6 Hz, CHCH3), 1.46–1.54 (m, 1H, CHCH3), 1.97–2.07 (m, 1H,
CH-Ha), 2.21–2.28 (m, 1H, CH-Hb), 2.34 (s, 3H, Ph-CH3), 5.60 (br.s, 1H, NCH), 7.45 (d, 3H, J = 8.3 Hz,
Ar-H), 7.97–8.11 (m, 6H, Ar-H, CH=C), 13.04 (br.s, 1H, COOH). 13C-NMR:
δ 193.01, 169.80, 166.44,
147.16, 134.61, 133.54, 131.50, 131.13, 129.00, 127.88, 127.84, 125.34, 123.48, 122.51, 122.42, 116.93, 113.30,
−
56.46, 36.86, 25.28, 23.36, 22.36, 21.58. ESI-HRMS calcd. for C25H22ClN2O5S3 ([M
found: 561.0406.
−
H]−): 561.0385;

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(S)-2-(4-Oxo-5-((1-(phenylsulfonyl)-1H-indol-3-yl)methylene)-2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid
7a). Yellow solid; yield 58%; m.p. 156–157 ◦C. [α]D20: –150 (c = 0.12, DMF). 1H-NMR:
3.56 (d, 2H,
J = 7.6 Hz, CHCH2), 5.76 (br.s, 1H, NCH), 7.15–8.19 (m, 16H, Ar-H, CH=C), 8.85 (br.s, 1H, COOH).
13C-NMR:
192.67, 169.05, 166.55, 138.07, 136.66, 135.78, 134.23, 130.57, 129.32, 129.03, 128.73, 128.20,
(
δ
δ
127.74, 126.93, 126.85, 124.99, 122.82, 122.17, 120.77, 117.11, 113.70, 44.05, 22.70. ESI-HRMS calcd. for
−
C27H19N2O5S3 ([M − H]−): 547.0462; found: 547.0491.
(S)-2-(5-((6-Chloro-1-(phenylsulfonyl)-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenyl-
propanoic acid (7b). Yellow solid; yield 54%; m.p. 220–224 ◦C. [α]D20: –144.5 (c = 0.40, DMF). 1H-NMR:
δ
3.54 (br.s, 2H, CHCH2), 5.91 (br.s, 1H, NCH), 7.19–8.24 (m, 15H, Ar-H, CH=C), 13.26 (br.s, 1H,
COOH). 13C-NMR:
δ
192.36, 169.17, 166.37, 137.05, 136.49, 136.03, 134.56, 131.54, 130.70, 129.83, 129.45,
128.93, 128.78, 128.47, 127.85, 127.20, 125.39, 123.23, 122.52, 116.87, 113.25, 44.85, 25.77. ESI-HRMS
−
calcd. for C27H18ClN2O5S3 ([M − H]−): 581.0072; found: 581.0094.
(S)-2-(5-((1-Tosyl-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (7c).
Yellow solid; m.p. 164–166 C, yield 55%. [α]2D0: –174.25 (c = 0.40, DMF). H-NMR:
δ
2.32 (s, 3H,
Ph-CH3), 3.56 (d, 2H, J = 7.0 Hz, CHCH2), 5.71 (br.s, 1H, NCH), 7.14–7.50 (m, 9H, Ar-H), 7.90–8.05 (m,
6H, Ar-H, CH=C), 9.10 (br.s, 1H, COOH). 13C-NMR:
192.81, 169.00, 166.64, 146.83, 138.35, 134.21,
◦
1
δ
133.72, 130.98, 129.27, 129.04, 128.70, 128.13, 127.77, 126.84, 126.77,−124.90, 122.62, 122.16, 120.71,
116.99, 113.70, 43.94, 22.70, 21.55. ESI-HRMS calcd. for C28H21N2O5S3 ([M
561.06392.
−
H]−): 561.0618; found:
(S)-2-(5-((5-Bromo-1-tosyl-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid
7d). Yellow solid; yield 59%; m.p.217–221 ◦C. [α]D20: –216.25 (c = 0.08, DMF). 1H-NMR:
2.34 (s, 3H,
Ph-CH3), 3.56 (d, 2H, J = 6.8 Hz, CHCH2), 5.65 (br.s, 1H, NCH), 7.15–7.63 (m, 9H, Ar-H), 7.86–8.05
m, 4H, Ar-H), 8.35 (s, 1H, CH=C). 13C-NMR:
191.51, 173.04, 170.18, 148.15, 146.96, 142.46, 133.52,
(
δ
(
δ
133.24, 133.06, 131.08, 131.04, 129.33, 129.23, 128.68, 127.9−2, 127.80, 126.93, 126.82, 121.1, 117.9, 113.5,
44.13, 22.72, 22.17. ESI-HRMS calcd. for C28H20BrN2O5S3 ([M − H]−): 638.9723; found: 638.9745.
(R)-2-(4-Oxo-5-((1-(phenylsulfonyl)-1H-indol-3-y◦l)methylene)-2-thioxothiazolidin-3-yl)-3-phenylpropanoic
acid (8a). Yellow solid; yield 65%; m.p. 198–199 C. [α]2D0: +255 (c = 0.02, DMF). 1H-NMR:
δ 3.57 (d, 2H,
J = 6.8 Hz, CHCH2), 5.63 (br.s, 1H, NCH), 7.13–8.17 (m, 16H, Ar-H, CH=C), 9.26 (br.s, 1H, COOH).
13C-NMR:
δ
192.92, 169.15, 166.77, 139.01, 136.66, 135.76, 134.23, 130.56, 129.17, 129.07, 128.66, 127.93,
127.71, 126.82, 126.66, 124.97, 122.65, 121.98, 120.73, 117.21, 113.69, 43.89, 22.71. ESI-HRMS calcd. for
−
C27H19N2O5S3 ([M − H]−): 547.0462; found: 547.0487.
(R)-2-(5-((6-Chloro-1-(phenylsulfonyl)-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenyl-
propanoic acid (8b). Yellow solid; yield 61%; m.p. 264–265 ◦C. [α]D20: +170.36 (c = 0.28, DMF). 1H-NMR:
δ
3.54 (d, 2H, J = 6.9 CHCH2), 5.91 (br.s, 1H, NCH), 7.20–8.23 (m, 15H, Ar-H, CH=C), 12.77 (br.s, 1H,
COOH). 13C-NMR:
δ
192.35, 169.15, 166.35, 137.00, 136.48, 136.04, 134.57, 131.55, 130.71, 129.45, 128.96,
128.79, 127.85, 127.21, 125.39, 123.29, 122.54, 122.25, 116.86, 113.26, 100.00, 58.76, 29.48. ESI-HRMS
−
calcd. for C27H18ClN2O5S3 ([M − H]−): 581.0072; found: 581.0090.
(R)-2-(5-((1-Tosyl-1H-indol-3-yl)methylene◦)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid (8c).
Yellow solid; yield 57%; m.p. 176–181 C. [α]2D0: +178.25 (c = 0.40, DMF). H-NMR:
δ 2.32 (s, 3H,
1
Ph-CH3), 3.57 (d, 2H, J = 7.1 Hz, CHCH2), 5.71 (br.s, 1H, NCH), 7.14–7.50 (m, 9H, Ar-H), 7.90–8.05
(m, 6H, Ar-H, CH=C), 9.16 (br.s, 1H, COOH). 13C-NMR:
191.80, 169.17, 166.65, 146.82, 138.37, 134.21,
133.73, 130.97, 129.26, 129.04, 128.69, 128.12, 127.76, 126.83, 126.76, 124.89, 122.58, 122.17, 120.70, 116.99,
δ
−
−
H] ): 561.0618; found: 561.0643.
113.70, 43.90, 22.70, 21.54. ESI-HRMS calcd. for C28H21N2O5S3 ([M
(R)-2-(5-((5-Bromo-1-tosyl-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid
8d). Yellow solid; yield 62%; m.p. 192–193 ◦C. [α]D20: +159.13 (c = 0.80, DMF). 1H-NMR:
2.34 (s, 3H,
−
(
δ
Ph-CH3), 3.56 (d, 2H, J = 6.5 Hz, CHCH2), 5.71 (br.s, 1H, NCH), 7.13–7.20 (m, 5H, Ar-H), 7.43 (d, 2H,
J = 8.3 Hz, Ar-H), 7.61 (dd, 1H, J1 = 8.9 Hz, J2 = 1.8 Hz, Ar-H), 7.91–8.06 (m, 5H, Ar-H), 8.37 (s, 1H,

Molecules 2017, 22, 970
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CH=C). 13C-NMR:
δ
192.71, 169.11, 166.51, 147.05, 138.38, 138.27, 133.52, 133.05, 131.04, 129.39, 129.27,
129.01, 128.70, 127.80, 126.86, 123.67, 122.62, 122.51, 117.80, 116.53, 115.57, 43.94, 22.71, 21.56. ESI-HRMS
−
calcd. for C28H20BrN2O5S3 ([M − H]−): 638.9723; found: 638.9740.
(R)-2-(5-((6-Chloro-1-tosyl-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid
(
8e). Yellow solid; yield 55%; m.p. 277–280 ◦C. [α]D20: +182.5 (c = 0.80, DMF). 1H-NMR:
δ
2.34 (s, 3H,
Ph-CH3), 3.56 (d, 2H, J = 7.0 Hz, CHCH2), 5.84 (br.s, 1H, NCH), 7.18–7.45 (m, 8H, Ar-H), 7.92–8.10
(m, 6H, Ar-H). 13C-NMR:
192.32, 169.23, 166.43, 147.14, 137.43, 134.54, 133.53, 131.46, 131.12, 129.38,
δ
128.88, 128.76, 127.87, 127.09, 125.30, 122.97, 122.49, 122.34, 116.76, 113.26, 110.60, 33.77, 29.48, 21.58.
−
ESI-HRMS calcd. for C28H20ClN2O5S3 ([M − H]−): 595.0228; found: 595.0245.
2-(4-Oxo-5-((1-(phenylsulfonyl)-1H-indol-3-yl)methylene)-2-thioxothiazolidin-3-yl)3-methylbutanoic acid (
Yellow solid; yield 46%; m.p. 255–257 ◦C. 1H-NMR:
0.78 (d, 3H, J = 5.8 Hz, CHCH3), 1.22 (d, 3H,
J = 4.6 Hz, CHCH3), 2.77 (d, 1H, CH(CH3)2), 5.21 (d, 1H, J = 7.5 Hz, NCH), 7.41–8.20 (m, 11H, Ar-H,
CH=C), 13.15 (br.s, 1H, COOH). 13C-NMR:
193.02, 169.09, 166.53, 136.67, 135.81, 134.29, 130.57, 129.03,
9).
δ
δ
128.57, 127.76, 126.90, 125.04, 124.16, 121.71, 120.83, 117.17, 113.73, 62.69, 27.65, 22.15, 19.41. ESI-HRMS
−
calcd. for C23H19N2O5S3 ([M − H]−): 499.0462; found: 499.0479.
(S)-2-(4-Oxo-5-((1-(phenylsulfonyl)-1H-indol-3-yl)methylene)-2-thioxothiazolidin-3-yl)-3-methylpentanoic acid
10). Yellow solid; yield 42%; m.p. 256–260 ◦C. [α]D20: –32.5 (c = 0.4, CHCl3). H-NMR:
δ
0.82 (t, 3H,
1
(
J = 7.2 Hz, CH2CH3), 0.94–1.01 (m, 1H, CH-Ha), 1.18 (d, 3H, J = 6.5 Hz, CHCH3), 1.47–1.53 (m, 1H,
CH-Hb), 2.54–2.59 (m, 1H, CHCH3), 5.25 (d, 1H, J = 7.4 Hz, NCH), 7.39–8.20 (m, 11H, Ar-H, CH=C),
13.18 (br.s, 1H, COOH). 13C-NMR:
δ 193.00, 169.09, 166.57, 136.65, 135.81, 134.27, 130.57, 129.02, 128.58,
127.75, 126.89, 125.03, 124−.19, 121.66, 120.84, 117.17, 113.71, 62.15, 33.53, 25.37, 18.05, 11.34. ESI-HRMS
calcd. for C24H21N2O5S3 ([M − H]−): 513.0629; found: 513.0618.
(S)-3-(4-Hydroxyphenyl)-2-(4-oxo-5-((1-(phenylsulfonyl)-1H-indol-3-yl)methylene)-2-thioxothiazolidin-3-yl)
propanoic acid (11). Yellow solid; yield 47%; m.p. 167–181 C. [α]2D0: –150 (c = 0.2, DMF). 1H-NMR:
◦
δ
3.46 (br.s, 2H, CHCH2), 5.69 (br.s, 1H, NCH), 6.59 (d, 2H, J = 8.1 Hz, Ar-H), 6.94 (d, 2H, J = 8.1 Hz
,
Ar-H), 7.38–8.19 (m, 11H, Ar-H, CH=C), 9.13 (s, 1H, OH). 13C-NMR:
δ
192.67, 170.93, 166.57, 156.25,
136.66, 135.77, 134.22, 130.70, 130.56, 130.18, 129.05, 128.69, 128.16, 127.95, 127.75, 126.83, 124.98, 120.75,
−
117.10, 115.57, 113.69, 44.84, 25.78. ESI-HRMS calcd. for C27H19N2O6S3 ([M
found: 563.0430.
−
H]−): 563.0411;
3.3. Evaluation of Anti-Bacterial Activity In Vitro
The anti-bacterial activity in vitro against S. aureus (CMCC(B) 26003 and CMCC 25923, S. pyogenes
CMCC 32067, E. faecalis CMCC 29212, B. subtilis CMCC 63501; E. coli CMCC 25922 and CMCC 44568,
P. aeruginosa CMCC 27853 and CMCC 10104, as well as two methicillin-resistant clinical isolates
(S. aureus ATCC 43300 and ATCC 33591) was evaluated using a two-fold serial dilution technique [31],
and the final concentrations of compounds obtained were in the range of 0.5–128 µg/mL. Test bacteria
were grown to mid-log phase in Mueller-Hinton broth (MHB) or Tryptone Soya Broth (TSB) and
diluted 1000-fold in the same medium. The bacteria of 105 CFU/mL were inoculated into MHB or
TSB and dispensed at 0.2 mL/well in a 96-well microtiter plate. As positive controls, gatifloxacin,
moxifloxacin, norfloxacin, oxacillin, and penicillin were used. Test compounds were prepared in DMSO,
the final concentration of which did not exceed 0.05%. The MIC was defined as the concentration of
a test compound that completely inhibited bacteria growth during 24 h incubation at 37 ◦C. Bacteria
growth was determined by measuring the absorption at 630 nm using a microtiter enzyme-linked
immunosorbent assay (ELISA) reader. All experiments were carried out three times.
3.4. Evaluation of Cytotoxicity In Vitro
HEK 293T cells were used to test the cytotoxicity of the new compounds. HEK 293T cells
were grown in Dulbecco modified Eagle medium supplemented with fetal bovine serum (10%), and

Molecules 2017, 22, 970
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antibiotics (penicillin-streptomycin mixture (100 U/mL)). Cells at 80% to 90% confluence were split
by trypsin (0.25% in 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 to three passages, and approximately
1 × 104 cells were seeded into each well of a 96-well plate and allowed to incubate to allow attachment
of the cells to the substrate. After 24 h, the medium was replaced with DMEM supplemented with 10%
FBS containing various concentrations (4, 8, 16, 32, 64, 128 µg/mL) of test compounds and incubated
for 48 h. Each concentration set three wells in parallel. Then 20 µL of CCK-8 solution was added to
each well. After incubation for 3 h, the optical density was measured at 450 nm using a microtiter
ELISA reader. The IC50 values were defined as the concentrations inhibiting 50% of cell growth.
4. Conclusions
In summary, seven new series of N-arylsulfonylindoles 5–11 bearing rhodanine moieties were
designed, synthesized, and evaluated for their antibacterial activities. In accordance to the results
of antibacterial tests in vitro, some of the compounds showed good antibacterial activities against
Staphylococcus aureus, including multidrug-resistant strains. Among them compounds 6a and 6c
showed the most potent levels of activity (MIC = 0.5 µg/mL) against selected MRSA strains. These
results illustrate that N-arylsulfonylindole analogs bearing rhodanine moieties are promising leads
to develop novel antimicrobial agents against many infections caused by Gram-positive strains,
especially Staphylococcus aureus, incluing MRSA. Future studies will focus on the mechanism of action
of these compounds.
Acknowledgments: This work was supported by the National Science Foundation of China (No. 81560561) and
Natural Science Foundation of Jiangxi Province, China (No. 20161BAB215207).
Author Contributions: Xian-Qing Deng designed experiments and conducted the spectrum analysis of
target compounds; Wen-Hui Xu, Shao-Feng Xiong synthesized all the presented compounds; Ming-Xia
Song, Song-Hui Li, Jiao-Yang Peng, and Ting-Ting Guo conducted the antimicrobial activity determination;
Ming-Xia Song wrote the article, and made the discussion and conclusions.
Conflicts of Interest: The authors declare no conflict of interest.
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