Design and synthesis of biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety as novel antibacterial agents against Gram-positive bacteria

Article abstract of DOI:10.1016/j.bmcl.2018.12.012

Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed, synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a?6b. The preliminary study showed that compounds 7, 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125 μg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA, MSSA, VRE and LREF with MIC values in the range of 0.125–0.5 μg/mL, and the potency of 10e against clinical isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an IC₅₀ value of 91.04 μM against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for further investigation.

Full text of DOI:10.1016/j.bmcl.2018.12.012

Accepted Manuscript
Design and synthesis of biaryloxazolidinone derivatives containing a rhodanine
or thiohydantoin moiety as novel antibacterial agents against Gram-positive
bacteria
Yachuang Wu, Xiudong Ding, Sicong Xu, Yifeng Yang, Xue Zhang, Chu Wang,
Hong Lei, Yanfang Zhao
PII:
S0960-894X(18)30943-0
https://doi.org/10.1016/j.bmcl.2018.12.012
BMCL 26181
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 November 2018
26 November 2018
4 December 2018
Please cite this article as: Wu, Y., Ding, X., Xu, S., Yang, Y., Zhang, X., Wang, C., Lei, H., Zhao, Y., Design and
synthesis of biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety as novel antibacterial
agents against Gram-positive bacteria, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/
10.1016/j.bmcl.2018.12.012
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Design and synthesis of biaryloxazolidinone derivatives containing a rhodanine or
thiohydantoin moiety as novel antibacterial agents against Gram-positive bacteria
a
a
b
Yachuang Wu a,1, Xiudong Ding b,1, Sicong Xu , Yifeng Yang a, Xue Zhang , Chu Wang , Hong Lei b*, Yanfang
Zhao a**1
aKey Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry
of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China
bDepartment of Clinical Laboratory, The 309th Hospital of Chinese People’s Liberation Army, Beijing 100091,
China
Abstract:
Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed,
synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the
knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a-6b. The preliminary study
showed that compounds 7, 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125 ug/mL against
S.aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The
most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA,
MSSA, VRE and LREF with MIC values in the range of 0.125–0.5 µg/mL, and the potency of 10e against clinical
isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an
IC50 value of 91.04 μM against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for
further investigation.
Keywords: biaryloxazolidinone; rhodanine derivatives; antibacterial activity; Gram-positive bacteria
Antibiotic-resistant infections of pathogenic bacteria are increasingly prevalent worldwide and become a critical
global problem 1-3. Resistant Gram-positive bacteria such as vancomycin-resistant Enterococci (VRE),
methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) are pandemic and
become the main concern 4-7. There is an urgent need to find new antibacterial drugs to combat these bacterial
pathogens. However, many major pharmaceutical companies have abandoned the discovery of new antibiotics due
8-9
to commercial challenges, which led to the dwindling discovery of new antibiotics over the past 25 years
Developing new antibacterial drugs is increasingly becoming a big challenge for drug chemists.
.
The oxazolidinones are a new structural class of totally synthetic antibacterial agents which inhibit bacterial
protein biosynthesis by binding to 23S RNA of the 50S ribosomal subunit 10. Linezolid 1 (Zyvox; Fig.1), the first
antibacterial agent of the oxazolidinone family, is used for the treatment of antibiotic-resistant infections caused by
Gram-positive bacteria such as MRSA, PRSP, and VRE 11-12. Unfortunately, linezolid-resistant bacteria such as
Staphylococcus aureus and other bacteria have already been reported 13-15. Modifying the scaffold of old drugs to
develop novel antimicrobial agents with the same target is an important strategy to overcome bacterial resistance 16.
The modification of scaffolds can improve properties of parental compounds and usually increase affinity for
mutated or modified targets.
** Corresponding author.
* Corresponding author.
E-mail address: yanfangzhao@126.com (Y. Zhao), jlh309@163.com (H. Lei).
1 Yachuang Wu and Xiudong Ding contributed equally to this work.

Tedizolid phosphate 2 (Fig.1), a second-generation oxazolidinone, was approved by FDA in 2014 to treat
patients with acute bacterial skin and skin structure infections (ABSSSIs) caused by certain susceptible bacteria
17-18. Radezolid 3 (RX-1741, Fig.1), designed from the X-ray structures of linezolid, was a non-selective antibiotic
sparsomycin bound to the 50s ribosome 19-20. Linezolid and sparsomycin share an overlapping region within the
RNA bases of the peptidyl transferase center, which inspire Rib-X to develop new antibiotics enhancing the binding
to the bacterial ribosome and having a broader and more potent spectrum of antibacterial activity by molecular
hybridization and further modification. Radezolid have potential activity against resistant Gram-positive bacteria
and even some Gram-negative bacteria.
Rhodanine and its five-membered multiheterocyclic derivatives have broad spectrum of anti-infective activities,
22
23
25
such as anti-bacterial 21, anti-malarial , anti-tubercular , anti-HIV 24 and anti-fungal activities. As depicted in
Figure 2, compounds 4-8 show excellent antibacterial activity against Staphylococcus aureus, MRSA and
Mycobacterial tuberculosis 26-30
.
Since oxazolidinones and many other antibiotics share an overlapping region within the binding site of RNA
bases at the C-ring and D-ring portion16,19-20, in previous researches, our group have designed and synthesized a
series of biaryloxazolidinone analogues containing a hydrazone moiety at the D-ring portion (9, Fig. 3), which
showed excellent antibacterial activity 31. The SAR studies about those compounds suggested that biaryl scaffold
and hydrazone moiety appear to be critical for antibacterial activity. With the goal of improving the potency and
expanding the antibacterial spectrum, due to rhodanine and hydrazone moiety having similar conformations, we
inserted rhodanine moiety to the biaryloxazolidinone at D-ring portion in target compounds, as depicted in Figure
3.
Figure 1. Chemical structures of linezolid and other oxazolidinones.

Figure 2. Chemical structures of reported rhodanine derivatives
Figure 3. Design strategies for the novel oxazolidinone analogues containing a rhodanine or thiohydantoin moiety
In this paper, all the biaryloxazolidinone derivatives bearing a rhodanine or thiohydantoin moiety were evaluated
for their antibacterial activity in vitro against five Gram-positive bacteria (S.aureus ATCC29213, MRSA, MSSA,
LREF and VRE). Antibacterial activity in vitro against four clinical isolates (MRSA, MSSA, VRE and LREF) was
also carried out. Additionally, the in vitro cytotoxicity and inhibition of MAO-A test were also performed from a
safety viewpoint. Furthermore, molecular superposition model was built to better understand the potency of the
synthesized compounds.
31
The synthesis of key intermediate 5 is depicted in Scheme 1, which had been reported in our previous work .
The general synthesis of compounds 8a-8f and 10a-10h is illustrated in Scheme 2-3. Compound 7 was synthesized
by the knoevenagel condensation of intermediate 5 with rhodanine using sodium acetate as base in acetic acid.
Compounds 8a-8f were prepared through nucleophilic substitution of various halogenated hydrocarbons with 7 in
the presence of NaOH in DMF. Rhodanine analogue 1-acetyl-2-thioxoimidazolidin-4-one 6b was prepared by

cyclization of glycine with NH4SCN in the presence of acetic anhydride in 63 % yield, using a known preparation
method 32. Compounds 10a-10h were prepared from 5 in the same manner as described for the general synthesis of
compounds 8a-8h by knoevenagel condensation and nucleophilic substitution.
The synthesis of compounds 15a-15c is depicted in Scheme 4. The key intermediates 13a-13c and 14 were
synthesized via a two-step reaction from commercially available substituted amines (11a-11c) respectively. 11a-11c
were reacted with CS2 to afford isothiocyanates 12a-12c, which were subjected to ethyl mercaptoacetate or glycine
to give 13a-13c by ring closure. Compounds 15a-15c were prepared from 5 by knoevenagel condensation.
Scheme 1. Reagents and conditions: (a) methyl chloroformate, pyridine, DCM, 25 °C, 2 h; (b) KI, NCS, HI (45%), H2O, 30 °C, 3 h; (c)
(S)-1-((acetylamino)methyl)-2-chloroethyl acetate, t-BuOLi/CH3OH, 25 °C, 24 h; (d) 4-formylphenylboronic acid, Pd(PPh3)2Cl2,
K2CO3, Tol/ EtOH/ H2O, 60 °C, 12h.
Scheme 2. Reagents and conditions: (e) rhodanine (6a), sodium acetate, acetic acid, 100 °C, 2-4 h; (f) RX, NaOH, DMF, 55 °C, 2-5 h.

Scheme 3. Reagents and conditions: (g) ammonium thiocyanate, acetic anhydride, 100°C, 2-4 h; (h) 6b, CH3COOH, 100 °C, 2 h; (i)
R-Cl, NaOH, DMF, 55 °C, 2-5 h.
Scheme 4. Reagents and conditions: (j) CS2, TEA, ethyl acetate/ H2O, 25 °C, 1h. (k) ethyl mercaptoacetate, TEA, DCM, 25 °C, 2 h; (l)
sodium acetate, acetic acid, 100 °C, 2-4 h.
All of the target compounds (7, 8a-8f, 9, 10a-10h, 15a-15c) were evaluated for in vitro antibacterial activity by
the double dilution method using linezolid and radezolid as positive control. Minimum inhibitory concentration
(MIC) was calculated and summarized in Table 1.
As illustrated in Table 1, most target compounds showed moderate to significant antibacterial activities against

selected gram-positive bacteria in comparison with linezolid and radezolid, which indicated that the rhodanine
moiety maintained or even enhanced the antibacterial activity of oxazolidinones. Compound 7 showed 4-fold more
potent antibacterial activity than radezolid, having a MIC value of 0.125 μg/mL. Notably, compound 9 with a
thiohydantoin moiety showed the same antibacterial activities with compound 7. Thus, rhodanine and
thiohydantoin derivatives, including compounds 8a-8f, 10a-10h, 15a-15c with different substituents including
carboxyl, ester, acyclic and cyclic alkyl were further synthesized to probe the impact of steric hindrance,
hydrophilicity and lipophilicity on antibacterial activity. The MIC values of compounds 8a-8c and 10a-10d
indicated that substituents on the terminal rhodamine part had great effect on the antibacterial activity. The steric
hindrance of these substituents correlated with antibacterial activity, and the smaller substituent was a better
preference for enhanced antibacterial activity. Compounds 15a to 15c showed in vitro activities slightly weaker
than radezolid, which indicated that strong polar carboxyl group had negative effect on the antibacterial activity.
Compound 8f with 2-ethoxy-2-oxoethyl group and 15a with carboxymethyl group exhibited similar levels of in
vitro antibacterial activity. To our delight, compound 10e with 3-(diethylamino) propyl group showed superior
activity against all tested bacteria, with a MIC value of 0.125 μg/mL. Interestingly, compound 8d with the same
group showed 4-fold weaker in vitro antibacterial activity compared to 10e, but exhibited similar levels of in vitro
antibacterial activity with radezolid. These results implied that a small flexible aliphatic amino group is beneficial
for the antibacterial activity. Overall, Most compounds exhibited more potent antibacterial activity against S.aureus,
MRSA, MSSA, LREF and VRE pathogens as compared with linezolid and radezolid. Then, three of the most
potent compounds (7, 9, and 10e) were selected for further clinical isolates investigation.
Table 1. In vitro antibacterial activity of biaryloxazolidinone analogues.
MICs, ug/mL
Compounds
S.aureusa
0.125
0.125
0.25
0.25
2
MRSAb
0.125
0.125
0.25
0.25
2
MSSAc
0.125
0.125
0.25
0.25
2
LREFd
0.125
0.125
0.25
0.5
2
VREe
0.125
0.125
0.25
0.5
2
7
9
8a
8b
8c
0.5
1
0.5
1
0.5
1
0.5
1
0.5
1
8d
8e
1
1
1
1
1
8f
0.5
0.25
2
0.5
0.25
2
0.5
0.25
2
0.5
0.25
2
0.5
0.25
2
10a
10b
10c
10d
10e
10f
10g
1
1
1
0.5
0.125
1
0.5
0.125
1
0.125
1
0.125
1
0.125
1
2
2
2
2
2

1
1
1
1
1
10h
1
1
1
1
1
15a
1
1
1
1
1
15b
1
1
1
1
1
15c
1
1
1
＞16
0.5
2
linezolid
radezolid
0.5
0.5
0.5
0.5
a Standard Staphylococcus aureus (29213).
b Methicillin-resistant Staphylococcus aureus.
c Methicillin-sensitive Staphylococcus aureus.
d Linezolid-resistant Enterococcus faecalis.
e Vancomycin-resistant Enterococcus faecium.
Based on the in vitro antibacterial activity, three optimal compounds were selected for further evaluation against
several clinical isolates which were collected in PLA 309 hospital. These antibiotic-susceptible and
antibiotic-resistant clinical isolates included S.aureus (4 isolates of MRSA and 4 isolates of MSSA), E. faecalis (4
isolates of LREF) and E.faecium (4 isolates of VRE), and the results are listed in Table 2. Compounds 7 showed
slightly weaker in vitro antibacterial activities against tested clinical isolates, with MIC values in the range of 1–2
µg/mL. Compound 9 had MIC values of 0.25-1 μg/mL against tested clinical isolates. Significantly, compound 10e
exhibited potent antibacterial activity against tested clinical isolates with MIC values in the range of 0.125–0.5
µg/mL, and the potency of 10e against clinical isolates of LREF was much more higher than that of linezolid.
Table 2. In vitro antibacterial activity against clinical isolates
MICs, μg/mL
Compounds
MRSAa(4)b
MSSAc(4)
LREFd(4)
VREe(4)
1-2
1-2
1-2
1-2
7
0.5-1
0.125-0.5
1-4
0.5-1
0.125-0.25
1-4
0.25-0.5
0.125-0.25
＞16
0.25-0.5
0.25-0.5
1-4
9
10e
linezolid
a Clinical strains of methicillin-resistant Staphylococcus aureus.
b Number of bacterial strains tested are given in parentheses.
c Clinical strains of methicillin-sensitive Staphylococcus aureus.
d Clinical strains of vancomycin-resistant Enterococcus faecium.
e Clinical strains of linezolid-resistant Enterococcus faecalis.
In order to evaluate the toxicity issues and safety profile of novel antibacterial agent, the most potent compounds
7, 9 and 10e were tested for cytotoxicity against HepG2 cell and inhibition against MAO-A. As illustrated in Table
3, Compounds 7, 9 and 10e displayed low cytotoxicity with IC50 values (63.9, 61.7 and 91.04 μM, respectively)
against HepG2 cell, meanwhile linezolid presented low cytotoxicity with IC50 values (＞25μM). However, three
compounds both showed high MAO-A kinase inhibitory activity.
Table 3. Cytotoxicity and MAO-A inhibition of compounds 7, 9, 10e

logD (pH7.4)a
HepG2 cytotoxicity IC50 (μM)
MAO-A inhibition (%) (30 μM)
Compounds
7
2.76
1.72
0.46
0.49
63.9
99
99
98
76
9
61.7
10e
91.04
＞25
linezolid
aCalculated using instant JChem.
ADME profile and drug-likeness are significantly important in the drug discovery process, so in silico ADME
and drug-likeness prediction of compounds 7, 9, 10e were performed using the free web tool
33
(http://www.swissadme.ch/) , and the results are listed in Table 3. Compound 10e violated Lipinski's rule of five
because of the too much molecular weight (＞ 500), but the partition coefficient between n-octanol and water
33
(Log Po/w) and predicted aqueous solubility (logS) suggested that all the three compounds are hydrophilic
.
Moreover, compound 9 and 10e showed high GI valves and lower value of TPSA, which suggested they may show
good bioavailability. Low values of BBB permeant showed that it is difficult for these compounds to cross the
blood-brain barrier. The favorable ADME profile and drug-likeness suggest that 10e deserve further study.
Table 4. In silico ADME prediction of compounds 7, 9, 10e
Log Po/wb
Compounds MWa
Hbond
Hbond
GIe
TPSA (Å2)f Lipinskig logSh
BBB
donorc acceptord
permeanti
471.52 3.20
2
3
2
1
5
5
6
5
Low
High
High
High
145.13
131.86
126.31
71.11
0
0
1
0
-4.81
-4.00
-5.08
-2.22
No
No
No
No
7
454.47
2.31
9
10e
567.67 3.59
337.35 1.20
Linezolid
a Molecular weight
b Logarithm of compound partition coefficient between n-octanol and water (< 5).
c Number of hydrogen bond donor (< 5).
d Number of hydrogen bond acceptors (< 10).
e Human gastrointestinal absorption.
f Topological polar surface area (≤ 140).
g Lipinski's rule of five.
h Predicted aqueous solubility.
i Predicted brain/blood partition coefficient.

Figure 4. Superposition of compound 10e and linezolid
To further elucidate the binding mode of novel biaryloxazolidinone antibacterial agent with 50S ribosome unit, a
molecular superposition was conducted based on the crystal structure of 50S ribosome unit of E. coli with linezolid
(PDB: 3CPW 21), and the results are shown in Figure 4. It can be observed that conformations of 10e and linezolid
showed very good overlay. However, the thiohydantoin part of compound 10e extended beyond the morpholine
ring of linezolid. Jiacheng Zhou et al. reported the molecular superposition model of linezolid with the
non-selective antibiotic sparsomycin 19-20. Based on this model, due to there are number of hydrogen bond acceptor
groups in the thiohydantoin part, we speculated that this part may forms hydrogen bonds with the binding site of
other antibiotics, thus increases intrinsic affinity for the ribosome.
In summary, a series of biaryloxazolidinone derivatives bearing a rhodanine or thiohydantoin moiety were
designed and synthesized. Our preliminary antibacterial activity investigation showed that compounds 7, 9 and 10e
exhibited potent antibacterial activity with MIC values of 0.125 ug/mL against S.aureus, MRSA, MSSA, LREF and
VRE pathogens, using linezolid and radezolid as the positive controls. The exploration of preliminary
structure-activity study showed that the introduction of rhodanine and thiohydantoin moiety to the
biaryloxazolidinone at D-ring portion can improve the potency against linezolid-susceptible and linezolid-resistant
Gram-positive bacteria. Additionally, three optimal compounds 7, 9, and 10e were selected for further evaluation
against clinical isolates, and compound 10e exhibited potent antibacterial activity against tested clinical isolates
with MIC values in the range of 0.125–0.5 µg/mL, and the potency of 10e against clinical isolates of LREF was
64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an IC50 value of 91.04 μM
against HepG2 cell. However, compounds 10e exhibited better MAO-A kinase inhibitory activity compared to
linezolid. Further optimization of the structure to reduce MAO-A kinase inhibitory activity is in progress and will
be reported in the future.
Acknowledge
Supported by Basic Research Projects of Higher Education Insti tutions in Liaoning Province (2017LZD06), and
the Program for Innovative Research Team of the Ministry of Education and Program for Liaoning Innovative
Research Team in University (IRT1073).
References
1
2
3
4
Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009; 325: 1089-1093.
Service RF. Antibiotics that resist resistance. Science. 1995; 270: 724-727.
Fukuda Y. New approaches to overcoming bacterial resistance. Drugs of the Future. 2009; 34: 127-136.
Spellberg B, Guidos R, Gilbert D, et al. The Epidemic of Antibiotic-Resistant Infections: A Call to Action for the Medical
Community from the Infectious Diseases Society of America. Clinical Infectious Diseases. 2008; 46: 155-164.
Jr MR. Current treatment options for the community acquired Methicillin-resistant Staphylococcus aureus infection. Clin. Infect.
5

Dis. 2008; 46: 1032-1037.
6
7
Gold HS. Vancomycin-resistant enterococci: mechanism and clinical observations. Clin Infect Dis. 2001; 33: 210-219.
Song JH, Jung SI, Ko KS, et al. High Prevalence of Antimicrobial Resistance among Clinical Streptococcus pneumoniae Isolates
in Asia (an ANSORP Study). Antimicrobial Agents & Chemotherapy. 2004; 48: 2101-2107.
Livermore DM, Blaser M, Carrs O, et al. Discovery research: the scientific challenge of finding new antibiotics. J Antimicrob
Chemother. 2011; 66: 1941-1944.
8
9
Silver LL. Challenges of antibacterial discovery. Clinical Microbiology Reviews. 2011; 24: 71-109.
10 Ippolito JA, Kanyo ZF, Wang D, et al. Crystal structure of the oxazolidinone antibiotic linezolid bound to the 50S ribosomal
subunit. Journal of Medicinal Chemistry; 2008, 51: 3353-6.
11 Brickner SJ, Barbachyn MR, Hutchinson DK, et al. Linezolid (ZYVOX), the first member of a completely new class of
antibacterial agents for treatment of serious gram-positive infections. Journal of Medicinal Chemistry. 2008; 51: 1981-1990.
12 Perry CM, Jarvis B. Linezolid: a review of its use in the management of serious gram-positive infections. Drugs. 2001; 61:
525-551.
13 Tsiodras S, Gold HS, Sakoulas G, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet. 2001; 358:
207-208.
14 Auckland C, Teare L, Cooke F, et al. Linezolid-resistant enterococci: report of the first isolates in the United Kingdom. J
Antimicrob Chemother. 2002; 50: 743-746.
15 Morales G, Picazo JJ, Baos E, et al. Resistance to linezolid is mediated by the cfr gene in the first report of an outbreak of
linezolid-resistant Staphylococcus aureus. Clinical Infectious Diseases. 2010; 50: 821-825.
16 Wilson DN. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nature Reviews Microbiology. 2014; 12:
35-48.
17 Sivextro Approval History, June 2014. http://www.drugs.com/history/sivextro.html (accessed April 2015).
18 Das D, Tulkens PM, Mehra P, et al. Tedizolid phosphate for the management of acute bacterial skin and skin structure infections:
safety summary. Clinical Infectious Diseases. 2014; 1: 43-50.
19 Zhou J, Bhattacharjee A, Chen S, et al. Design at the atomic level: design of biaryloxazolidinones as potent orally active
antibiotics. Bioorganic & Medicinal Chemistry Letters. 2008; 18: 6175-6178.
20 Zhou J, Bhattacharjee A, Chen S, et al. Design at the atomic level: generation of novel hybrid biaryloxazolidinones as promising
new antibiotics. Bioorganic & Medicinal Chemistry Letters. 2008; 18: 6179-6183.
21 Momose Y, Meguro K, Ikeda H, et al. Studies on antidiabetic agents. X. Synthesis and biological activities of pioglitazone and
related compounds. Chemical & Pharmaceutical Bulletin. 1991; 39: 1440-1445.
22 Takasu K, Inoue H, Kim HS, et al. Rhodacyanine dyes as antimalarials. 1. Preliminary evaluation of their activity and toxicity.
Journal of Medicinal Chemistry. 2002; 45: 995-998.
23 Chandrappa S, Kavitha CV, Shahabuddin MS, et al. Synthesis of 2-(5-((5-(4-chlorophenyl)furan-2-yl)methylene)-4-
oxo-2-thioxothiazolidin-3-yl)acetic acid derivatives and evaluation of their cytotoxicity and induction of apoptosis in human
leukemia cells. Bioorganic & Medicinal Chemistry. 2009; 17: 2576-2584.
24 Rajamaki S, Innitzer A, Falciani C, et al. Exploration of novel thiobarbituric acid-, rhodanine- and thiohydantoin-based HIV-1
integrase inhibitors. Bioorganic & Medicinal Chemistry Letters. 2009; 19: 3615-3618.
25 Petrikaite V, Tarasevicius E, Pavilonis A. New ethacridine derivatives as the potential antifungal and antibacterial preparations.
Medicina. 2007; 43: 657-663.
26 Chen ZH, Zheng CJ, Sun LP, et al. Synthesis of new chalcone derivatives containing a rhodanine-3-acetic acid moiety with
potential anti-bacterial activity. European Journal of Medicinal Chemistry. 2010; 45: 5739-5743.
27 Slepikas L, Chiriano G, Perozzo R, et al. In silico driven design and synthesis of rhodanine derivatives as novel antibacterials
targeting the enoyl reductase InhA. Journal of Medicinal Chemistry. 2016; 59: 10917-10928.
28 Tomašić T, Zidar N, Šink R, et al. Structure-Based Design of a New Series of D-Glutamic Acid Based Inhibitors of Bacterial

UDP-N-acetylmuramoyl-L-alanine:D-glutamate Ligase (MurD). Journal of Medicinal Chemistry. 2011; 54: 4600-4610.
29 Sinko W, Wang Y, Zhu W, et al. Undecaprenyl Diphosphate Synthase Inhibitors: Antibacterial Drug Leads. Journal of Medicinal
Chemistry. 2014; 57:5693-5701.
30 Subhedar DD, Shaikh MH, Shingate BB, et al. Quinolidene-rhodanine conjugates: Facile synthesis and biological evaluation.
European Journal of Medicinal Chemistry. 2016; 125: 385-399.
31 Wu YC, Ding XD, Ding L, et al. Synthesis and antibacterial activity evaluation of novel biaryloxazolidinone analogues
containing a hydrazone moiety as promising antibacterial agents. European Journal of Medicinal Chemistry. 2018; 158:247-258.
32 Xiao YA, Wang ZQ, Wang XM, et al. Synthesis and in vitro biological evaluation of novel 2-aminoimidazolone derivatives as
anti-tumor agents. Chinese Chemical Letters. 2013; 44: 727-730.
33 Antoine D, Olivier M, Vincent Z. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal
chemistry friendliness of small molecules. Sci. Rep. 2017; 7: 42717.
34 Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and
permeability in drug discovery and development settings, Adv. Drug Deliv. Rev. 1997; 23: 3-25.

Highlights
1, Biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety.
2, Compound 10e exhibited a MIC value of 0.125 μg/mL against all tested bacteria.
3, The potency of compound 10e against LREF was 64-fold higher than that of linezolid.
4, Compound 10e was non-cytotoxic with an IC50 value of 91.04 μM against HepG2 cell.
35