Accepted Manuscript

4-Quinolone hybrids and their antibacterial activities

Yuan-Qiang Hu, Shu Zhang, Zhi Xu, Zao-Sheng Lv, Ming-Liang Liu, Lian-Shun Feng

PII: S0223-5234(17)30765-1
DOI: 10.1016/j.ejmech.2017.09.050
Reference: EJMECH 9765

To appear in: European Journal of Medicinal Chemistry

Received Date: 19 August 2017

Revised Date: 11 September 2017
Accepted Date: 24 September 2017

Please cite this article as: Y.-Q. Hu, S. Zhang, Z. Xu, Z.-S. Lv, M.-L. Liu, L.-S. Feng, 4-Quinolone
hybrids and their antibacterial activities, European Journal of Medicinal Chemistry (2017), doi: 10.1016/
j.ejmech.2017.09.050.

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 ACCEPTED MANUSCRIPT

Graphical Abstract

4-Quinolone hybrids and their antibacterial activities

Yuan-Qiang Hua, Shu Zhangb, Zhi Xuc, Zao-Sheng Lvc, Ming-Liang Liu∗,d, Lian-Shun Feng∗,d,e
a
School of Chemistry and Materials Science, Hubei Engineering University, Hubei, P R China;
b
Pony Testing International Group (Wuhan), Wuhan, 430000, P R China;

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c
Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials, Wuhan University of Science
and Technology, Hubei, P R China;

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d
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing 100050, China;

SC
e
WuXi AppTec (Wuhan), Hubei, P R China

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This review aims to summarize the recent advances made towards the discovery of
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4-quinolone hybrids as potential antibacterial agents as well as their structure-activity

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relationship.
 ACCEPTED MANUSCRIPT

4-Quinolone hybrids and their antibacterial activities

Yuan-Qiang Hua, Shu Zhangb, Zhi Xuc, Zao-Sheng Lvc, Ming-Liang Liu∗,d, Lian-Shun Feng∗,d,e

a
School of Chemistry and Materials Science, Hubei Engineering University, Hubei, P R China;

b
Pony Testing International Group (Wuhan), Wuhan, 430000, P R China;

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c
Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials, Wuhan University of Science
and Technology, Hubei, P R China;

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d
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing 100050, China;

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WuXi AppTec (Wuhan), Hubei, P R China

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Abstract: The emergence and wide-spread of drug-resistant bacteria including multi-drug
resistant and pan-drug resistant pathogens which are associated with considerable mortality,
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represent a significant global health threat. 4-Quinolones which are exemplified by
fluoroquinolones are the second largest chemotherapy agents used in clinical practice for the
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treatment of various bacterial infections. However, the resistance of bacteria to 4-quinolones

develops rapidly and spreads widely throughout the world due to the long-term, inappropriate use
and even abuse. To overcome the resistance and improve the potency, several strategies have been
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developed. Amongst them, molecular hybridization, which is based on the incorporation of two or
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more pharmacophores into a single molecule with a flexible linker, is one of the most practical
approaches. This review aims to summarize the recent advances made towards the discovery of
4-quinolone hybrids as potential antibacterial agents as well as their structure-activity relationship
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(SAR). The enriched SAR may pave the way for the further rational development of 4-quinolone
hybrids with excellent potency against both drug-susceptible and drug-resistant bacteria.
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Keywords: quinolone; fluoroquinolone; hybrids; antibacterial activity; structure-activity

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relationship

1. Introduction

*
Corresponding authors: Email address: lmllyx@126.com (M.L. Liu); ochemistry@163.com (L.S.
Feng).
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Bacterial infections, which represent a significant health threat throughout the world,
are responsible for the majority of hospital-acquired infections, resulting in extensive
mortality and burden on global healthcare systems [1]. The most common pathogens
in clinical settings are Gram-positive (including Staphylococcus aureus/S. aureus,
Staphylococcus epidermidis/S. epidermidis, Streptococcus pneumoniae/S. pneumoniae,

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as well as enterococci such as Enterococcus faecalis/E. faecalis and Enterococcus
faecium/E. faecium) and Gram-negative (includes Enterobacteriaceae such as

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Escherichia coli/E. coli and Klebsiella, Pseudomonas aeruginosa/P. aeruginosa,
Chlamydophila pneumonia, Mycoplasma pneumonia, Legionella pneumophila and

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Acinetobacter) bacteria, which are capable of causing serious and even fatal infections
[2,3]. Even worse, the emergence and widely spread of resistance to Gram-positive

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and Gram-negative bacteria as well as pathogens that are resistant to all current
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therapeutic options, due to the long-term, broad, inappropriate use and even abuse of
antibiotics have already been identified and are associated with considerable mortality
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[4]. Thus, it’s imperative to develop new agents with great potency against both
drug-sensitive and drug-resistant pathogens. In spite of a variety of compounds are
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currently being developed for this purpose [2,3], the number is still insufficient to
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control this global threat.

4-Quinolone antibacterials which are exemplified by fluoroquinolones (FQs) have

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been introduced in clinical practice for the treatment of urinary various infections in
humans since the discovery of nalidixic acid in 1962 [5,6]. Currently, 4-quinolones
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especially FQs, are among the most common drugs in clinical use for the treatment of
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various bacterial infections including upper and lower respiratory infections, and
some skin, bone, soft tissue infections as well as community acquired pneumonia
[7,8]. Besides their typical antibacterial activity, 4-quinolones also displayed diverse
atypical biological profiles such as anti-tumor, anti-tubercular, anti-HIV and
anti-malarial activities, and the atypical biological prosperities continue to expand
[9-22].

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In spite of great advances that have been achieved for the development of
4-quinolones in the last 5 decades, the resistance of bacteria to 4-quinolones develops
rapidly and spreads widely throughout the world, creating urgent needs to develop
new antibacterial agents.

There are two main strategies to seek for novel 4-quinolone antibacterials: the ideal

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approach is to identify new structure compounds with a novel action mechanism, but
this strategy has been met with little success [21]; the practical one is to synthesize

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new analogues or modify existing drugs with limited or without cross-resistance to
existing agents [21]. Molecular hybridization, which is based on the incorporation of

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two or more pharmacophores into a single molecule, may provide novel candidates
have complimentary activities and/or multiple pharmacological targets and/or one part

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can counterbalance the side effects caused by another part [9]. Obviously, this strategy
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represents an encouraging approach on the development of new agents with potential
therapeutic application [12-22].
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Numerous 4-quinolone hybrids have been developed in the last 30 years, and some of
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them are under clinical trial [2,3]. This review aims to outline the recent advances of
4-quinolone hybrids as potential antibacterials and summarize the structure-activity
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relationship (SAR) to provide an insight for rational designs of more active

candidates.
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2. 4-Quinolone hybrids and their antibacterial activities

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2.1 4-Quinolone-6-anilinouracil hybrids

The 6-anilinouracils (AUs) that targeting replication-specific DNA polymerase IIIC,

emerged as promising antibacterial agents. Hybridization of AUs with FQs may give
new conjugates with dual mechanisms which are useful to overcome the
drug-resistance. Based on the above consideration, several AUs-FQs (including
ciprofloxacin/CPFX, norfloxacin/NRFX, sitafloxacin/STFX and temafloxacin)
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hybrids have been assessed for their activities against both drug-sensitive and
-resistant bacteria, and the most active conjugate 251D (Fig. 1) showed great in vitro
and in vivo potency along with considerable pharmacokinetic profile, could act as a
lead for further evaluation [23,24].

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<Fig 1. Chemical structure of 4-quinolone-6-anilinouracil hybrid 251D>
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2.2 4-Quinolone-azole hybrids
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Azoles such as imidazole, oxazole, pyrrazole, thiazole and triazole, are one of the
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most important classes of nitrogen containing heterocycles with various biological

activities. Some azole derivatives such as septazole have been used in clinical practice
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as antibiotics, so hybridization of 4-quinolone with azoles may enhance the

antibacterial activity.
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2.2.1 4-Quinolone-imidazole hybrids

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The substituent at C-4 position of nitroimidazole moiety played an important role for
the antibacterial activity of hybrids 1 (Fig. 2), and the Gram-negative relative
contribution was in the order of -H > morpholinyl > pyrrolidinyl > piperidyl [25].
Further modification indicated that -NO2 at C-4 position of nitroimidazole moiety was
more favorable than at C-5 position [26]. The most active conjugate 1a (Fig. 2) with
MIC in a range of 0.25 to 2.0 µg/mL was 2-32 times more potent than CPFX, NRFX

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and clinafloxacin against both Gram-positive and Gram-negative organisms. Further

study revealed that conjugate 1a could intercalate into P. aeruginosa DNA via copper
ion bridge to form a steady 1a-Cu2+-DNA ternary complex which might further block
DNA replication to exert the powerful bioactivities.

Introduction of imidazole [27] at N-1 position (hybrids 2), N-1/C-8 (hybrids 3) or

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C-7/C-8 fused (hybrids 4) [28,29] as well as C-7/C-8 fused imidazoline (hybrids 5)
[30] into FQs is detrimental to the activity, indicating that imidazole moiety is not

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suitable for these positions.

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<Fig 2. Chemical structure of 4-quinolone-imidazole hybrids 1-7>

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For benzimidazole-NRFX/CPFX hybrids 6 (Fig. 2, MIC: 0.0312-16 µg/mL for most

strains), the linker between the benzimidazole and NRFX or CPFX and N-substituted
group was vital for the activity [31,32]. In general, the contribution order of the linker
was -CH2- > without linker > -CH2CH2- > -N=CH-, and for N-substituted group the
order was -H > substituted Bn > alkyl. The most potent hybrid 6a (Fig. 2) was 2-256

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times more potent than CPFX, NRFX and clinafloxacin against the majority tested
bacteria, and did not trigger the development of resistance in bacteria. Moreover,
conjugate 6a also showed low toxicity against mammalian cells, warrant further
investigations.

The SAR of azole-fused quinolones 7 (Fig. 2) revealed that the imidazoloquinolones

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(MIC: 0.025-6.25 µg/mL) were superior to the corresponding triazolequinilones (MIC:
0.05-12.5 µg/mL) in in vitro antibacterial activity generally; for imidazoloquinolones,

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the pyrrolodinyl series were more active than the corresponding piperazinyl series
against S. aureus, while against Gram-negative pathogens, the results were on the

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contrary; the contribution of substitutents at C-8 position to the activity against S.
aureus and E. coli was -Cl ≥ -F ≥ -H, while against P. aeruginosa, the order changed
as -F ≥ -H > -Cl [33,34].
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2.2.2 4-Quinolone-triazole hybrids

Compared with the parent CPFX (MIC: 9.43-37.72 µM for most strains),
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bis-1,2,3-triazole CPFX hybrids 8 (Fig. 3, MIC: 1.09-16.99 µM for most strains)

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showed enhanced activity against Gram-positive and Gram-negative bacteria,

especially against Gram-negative pathogens [35]. The SAR indicated that the
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conjugates bearing electron-withdrawing groups at para-position of benzene ring

were more potent than the corresponding hybrids with electron-donating groups.
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However, incorporation of 1,2,4-triazole at either N-1 or C-3 position resulted in

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significant loss of activity [36,37].

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<Fig 3. Chemical structures of 4-quinolone-triazole hybrids 8-10>
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The SAR study of CPFX-1,2,4-triazole-5(4H)-thione hybrids 9 demonstrated that
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introduction of 1,2,4-triazole-5(4H)-thione moiety has great influence on the in vitro

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antibacterial activity against both Gram-negative and Gram-positive organisms

including MSSA and methicillin-resistant S. aureus (MRSA) strains, and a significant
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part of them were more active than the parent CPFX; phenyl groups at C-3 position
of 1,2,4-triazole-5(4H)-thione moiety was indispensable for the excellent antibacterial
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activity, and electron-donating groups on the phenyl ring preferred; phenyl groups in
N-4 position of the 1,2,4-triazole motif was not vital for the high activity, and the
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shorter alkyl substituents favored the activity [38,39]; replacement of N-R2 part by
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oxygen did not reduce the activity [40]; removal of the thione was detrimental to the
activity [41]. Further investigations suggested that the enhanced activity compared
with the parent CPFX may attribute to (1) the improvement of permeation profile; (2)
novel action mechanism which is not associated with topoisomerases inhibition as
well as (3) exclusion from bacterial efflux pumps. Hybrid 9a (MIC: 0.093-1.52 µM)
with the balanced activity against Gram-positive and Gram-negative pathogens was

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2-8 times more potent than the parent CPFX, warrant further exploitations [38,39].

Several 1,3,4-oxadiazole-5-thione- and 4-amino-1,2,4-triazole-3-thione-LVFX

conjugates 10 (MIC: 0.125-1 µg/mL) were examined for their in vitro activities
against various pathogens, and most of them were as potent as or better than the
parent LVFX against the tested bacteria [42].

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2.2.3 4-Quinolone-pyrazole hybrids

According to our previous research results,

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7-(3-aminopyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)quinolone hybrids 11 showed
considerable in vitro antibacterial activities against most of the tested Gram-positive

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organisms with MIC of 0.125-1 µg/mL, but weak potency against all tested
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Gram-negative strains [43].
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<Fig 4. Chemical structures of 4-quinolone-pyrazole hybrids 11>

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The SAR suggested that hybrids bearing

3-aminopyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl at C-7 position were less than the
corresponding 2-methyl analogs; the activity was influenced significantly by the
quinolone nuclei, and the contribution order of the quinolone nuclei for hybrids with
3-aminopyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl at C-7 position was
1-(2-fluoroethyl)-8-fluoroquinolone > 1-cyclopropyl-8-methoxylquinolone >

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1-cyclopropyl-8-fluoroquinolone ≈ 1-cyclopropyl-8-difluoromethoxylquinolone >

1-cyclopropyl-1,8-naphthyridone ≈ 1-(2,4-difluorophenyl)-1,8-naphthyridine ≈
1-ethyl-8-fluoroquinolone; the order was altered to 1-cyclopropyl-8-fluoroquinolone >
1-cyclopropyl-8-difluoromethoxylquinolone > 1-cyclopropyl-1,8-naphthyridone ≈
1-(2,4-difluorophenyl)-1,8-naphthyridine ≈ 1-ethyl-8-fluoroquinolone >

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1-(2-fluoroethyl)-8-fluoroquinolone ≈ 1-cyclopropyl-8-fluoroquinolone for conjugates
bearing 3-amino-2-methyl-pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl at C-7 position.

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2.2.4 4-Quinolone-thiazole/oxadiazole hybrids

It is believed that 4-oxo-3-carboxylic acid moiety is the active DNA-gyrase binding

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site, and replacement of the carboxylic acid at C-3 position usually result in
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decreasing the antibacterial activity [5,23]. It is worth mentioning that introduction of
aminothiazole motif instead of 3-carboxylic acid moiety also demonstrated having
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potential antibacterial activity [44,45], while incorporation of thiazole motif into C-7
position of 4-quinolone moiety causes reduction of the antibacterial activity in general
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[46-49]. Analysis of SAR of hybrids 12 (Fig. 5) disclosed that 2-aminothiazole

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fragment at the 3-position of quinolone plays an important role in exerting

antibacterial activity; pyrrolidinyl at C-6 position was most favorable to the activity,
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while -F and -Me could improve the activity to some extent; at C-7 position, hybrids
with -Cl were more potent than the corresponding -F analogs, and -CF3 could boost
up the anti-Gram-negative activity, but reduced the anti-Gram-positive activity;
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halogen atoms -F and -Cl at C-8 position was disfavored to the antibacterial activity
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[44]. Amongst them, the conjugate 12a (MIC: 0.5-2.7 µg/mL) was the most active
against a panel of clinically relevant pathogens including multidrug-resistant strains,
low cytotoxicity to hepatocyte cells, strong inhibitory potency to DNA gyrase, as well
as slowly induced bacterial resistance.

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<Fig 5. Chemical structures of 4-quinolone-thiazole/oxadiazole hybrids 12-14 and MCB3837,
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MCB3681>
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The majority of 1,3,4-thiadiazole/oxadiazole 4-quinolone hybrids showed promising

activity against Gram-positive organisms, but only weak activity against
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Gram-negative bacteria [50-55], need to be further optimized.

4-Thiazolidinone motif incorporated into C-3 or C-7 position of 4-quinolones, led to

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great loss in antibacterial activity [56-59]. The SAR of isothiazolo[5,4-b]quinolone

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derivatives 13 and 14 showed that for series 13, the position of substituents at benzene
ring showed great influence on the activity, and the order was meta- > para- > ortho-;
inclusion of -OH or -NH2 into the phenyl group boost up the activity against E. coli,
while further modification of the -OH or -NH2 groups resulted in reduction of the
activity generally [60]. In particular, compound 13a was not only not toxic (CC50>100
µM) against Hep2 human laryngeal carcinoma cell line, but also most active against E.

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coli, S. aureus and MRSA with MIC in a range of 0.001 to 0.125 µg/mL which was
comparable to or more potent than the references CPFX, gatifloxacin/GTFX,
gemifloxacin/GMFX and moxifloxacin/MXFX, warrant further exploitations. For
series 14, the antibacterial activity affected significantly by substituents and their
configurations at C-7 position; -F and -OMe at C-5 and C-8 position, respectively,

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favored the activity, and the SAR was outlined in Fig. 5 [61].

The oxazolidinone-quinolone hybrids with various linkers showed promising activity

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against both Gram-negative and Gram-positive organisms including FQs- and/or
linezolid-resistant isolates, and the linker between the two pharmacophores played an

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important role in the antibacterial activity [62-65]. The most promising hybrid
MCB3637 and its active form MCB3681 exhibited excellent potency for treatment of

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infections caused by various clinically relevant bacteria including drug-resistant,
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multidrug-resistant pathogens such as FQs- and/or linezolid-resistant isolates as well
as difficult to treat bacteria. The results in clinical trials showed that both of them
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have no cross-resistance with all currently used antibiotics, suggesting the action
mechanism of this kind of hybrids differing with the common used antibiotics, and
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they may used in the near future to fight against drug-resistant, multidrug-resistant
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and pan-drug resistant bacteria caused infections [62-65].

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2.2.5 4-Quinolone-azine hybrids

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The pyrazine-NRFX/CPFX hybrids 15 showed considerable antibacterial activities,

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and the SAR revealed that the activity was positive correlation with the length of the
linkers, and for short linker (n = 1), pyrazine-NRFX hybrids were more active than
the corresponding pyrazine-CPFX hybrids, while for longer linkers (n = 2, 3), the
activity turned to be the exact opposite [66]. The most active hybrid 15a (MIC: 78 and
39 µg/mL) was 8-32 folds more potent than NRFX and CPFX (MIC: 625-1,250
µg/mL) against S. aureus and S. pyogenes, but far less potent than the two references

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against S. typhi and P. aeruginosa, needs to be further modified.

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<Fig 6. Chemical structures of 4-quinolone-azine hybrids 15 and 6>

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The 1,2,4-oxadiazine fused 4-quinolone hybrids 16 were demonstrated inactive (MIC >
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16 µg/mL) against all tested Gram-positive and Gram-negative strains except K.
pneumonia (MIC: 8 µg/mL) [67]. The triazine dendrimer showed potential
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anti-bacterial activity, but less active than the parent CPFX against most of the tested
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strains [68], the enriched SAR paved the way to the further rational development of
this kind of conjugates.
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2.3 4-Quinolone-fur(ox)an/thiophene hybrids

Fur(ox)an and thiophene derivatives are important classes of bioactive heterocyclic

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compounds in the field of pharmaceuticals. Various 4-quinolone-fur(ox)an/thiophene

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conjugates were evaluated for their antibacterial activities [69-74], and the SAR of
furan/thiophene-FQs hybrids 17 revealed that compared with carbonyl hybrids (Y =
O), (alkyl)oxime conjugates displayed lower activity generally; the majority of
furan/thiophene-FQs hybrids were less potent than the corresponding parent drugs
against both Gram-positive and Gram-negative bacteria, and similar results were also
observed for coumarin-FQs hybrids [75]. In spite of that, some conjugates showed

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promising activities, and the most emblematic example was 17a which was
comparable to or 4-32 folds more potent than the references CPFX and NRFX,
warrant further optimizations.

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<Fig 7. Chemical structures of furan/thiophene-FQs hybrids 17>

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However, thiophenes may lead to hepatotoxicity, this profile needs to be noticed once
design this kind of derivatives.
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2.4 4-Quinolone-hydrazone hybrids

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Our research results demonstrated that incorporation of hydrazone moiety into FQs
could lead to improvement of the activity against both Gram-positive and
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Gram-negative pathogens including MSSA, MRSA, MSSE and methicillin-resistant S.

epidermidis (MRSE), and GTFX conjugate 18 as the most emblematic example, has a
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broad antimicrobial spectrum with MIC in a range of 0.06-1 µg/mL [76,77]. The SAR
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showed that hybrids with hydrazone at C-3 position decreased the activity generally
[78-81]; the antibacterial activity order of the (hetero)aromatic rings was
acylhydrazones ≥ hydrazones [77].

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O
F CO2H

NH N N
N N O

18

<Fig 8. Chemical structure of 4-quinolone-hydrazone hybrid 18>

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2.5 4-Quinolone-indole hybrids

Indole including isatin is a biologically versatile structure, and the stability of its

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indole nucleus has inspired scientist to introduce many pharmacophores, so indole
nucleus is reasonable choice used to develop new antibacterial agents [82]. Moreover,

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the SAR study of isatin derivatives revealed that N-alkylation and N-Mannich base
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were effective in increasing inhibition activity against various bacteria [19-22,82-85].
Therefore, incorporation of isatin into 4-quinolones has caused great interests.
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<Fig 9. Chemical structures of 4-quinolone-indole hybrid 19>

The SAR suggested that the antibacterial activity was influenced largely by FQs
moieties, and the order was LMFX > CPFX > GTFX > NRFX against
Gram-positive pathogens, while CPFX ≥ GTFX > NRFX > LMFX against
Gram-negative bacteria [86-90]. All selected hybrids were in vivo more potent than
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the corresponding parent drugs in E. coli NCTC 10419 strain infected mice model. In
particular, the most potent CPFX-isatin hybrid 19 (MIC: 0.0002-0.0157 µM, EC50:
0.62 mg/kg) was 5.5- and 2.0-fold more active than the parent CPFX (MIC: 0.0011
µM, EC50: 1.25 mg/kg) in vitro and in vivo against E. coli NCTC 10419 strain, and
also showed the highest in vitro potency against HIV and MTB H37Rv [90]. Thus,

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this kind of hybrids has the potential for the treatment of opportunistic infection in
HIV patients, warrants further exploitations.

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2.6 4-Quinolone-β-lactam/lactone hybrids

The SAR of 4-quinolone-β-lactam hybrids showed that C-3 linked hybrids were more

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active than C-7 linked derivatives [91-93]. In particular, the C-3 ester tethered hybrid
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Ro-23-9424 exhibited promising activity against both drug-sensitive and
drug-resistant bacteria including cephalosporin- and FQs-resistant pathogens,
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suggesting novel action mechanism [92,93]. The main drawback of Ro-23-9424 is the
relative short half life which may attribute to the stability issue of the ester linker, so
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further modification should focus on prolonging the half life. Currently, Ro-23-9424
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is under phase II clinical trial, and further investigations should be performed before
using for the treatment of infections.
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<Fig 10. Chemical structures of Ro-23-9424 and 4-quinolone-lactone hybrid 20>

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The SAR studies of 4-quinolone-lactone hybrids suggested that FQs moieties

influenced the potency greatly, and the order was CPFX > SPFX > enoxacin >
NRFX; modification at the 2-position of lactone motif seems to be beneficial to
antibacterial activity, while 3-position or 4-position was detrimental to the activity;
replacement of the -F with a large volume groups -Cl, -Br, -Me and -OMe at

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4-position of benzene ring resulted in a further decrease in activity, which may be
attributed to the steric hindrance between conjugates and the protein. Further study

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indicated that the possible multi-targeting of the hybrids may be able to decline the
emergence of resistance to some extent. In particular, the most active lactone-CPFX

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hybrid 20 with MIC of 0.11 µg/mL against multi-drug resistant E. coli, was 50 times
more potent than the parent CPFX, has potential as novel antimicrobial agent.

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2.7 4-Quinolone-macrocycle hybrids
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The recent study revealed that introduction of bulky substituent at C-7 position of
4-quinolone motif was not a barrier to penetration [94], while macrocyle antibiotics
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are used widely in clinical use to treat various infections. Thus, hybridization of
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4-quinolone with macrocycles may give more potent candidates. Based on the above
considerations, various 4-quinolone macrocycle hybrids linked through C-7 or C-6
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position of 4-quinolone motif were examined for their antibacterial activities, and
some of them showed potential in vitro and in vivo activity [94-100].
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The rifamycin-quinolone conjugate CBR-2092 as one of the most emblematic

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example displayed promising in vitro and in vivo potency against Gram-positive and
Gram-negative bacteria [94-96]. It’s worth to notice that CBR-2092 is also highly
active against FQs-resistant and multi-drug resistant pathogens, suggesting the action
mechanism is different with FQs, and can overcome the cross-resistance to some
degree. Currently, CBR-2092 is under phase II clinical trial, and is expected to be
used in clinical practice in the near future [95,96].

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<Fig 11. Chemical structures of CBR-2092 and macrolide-quinolone hybrids 21 and 22>
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The SAR of various macrolide-quinolone hybrids tethered via ester-amino [97-101],

ester-alkynyl [102,103], ether-amino [104,105], ester-alkyl [106,107] as well as
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ether-alkyl [108] linkers through C-6 position of 4-quinolone moiety showed that this
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kind of hybrids was more potent against Gram-positive bacteria than against
Gram-negative bacteria generally; the antibacterial activity was influenced
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significantly by the linkers between macrolide moiety and quinolone motif, especially
against Gram-positive organisms, and ester-alkyl linked 21 [106] as well as
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ether-alkyl tethered 22 [108] showed the highest activity. The activities in the in vitro
AC

protein assay showed that these hybrids could inhibit protein synthesis, and the
potency was comparable to that of telithromycin, demonstrating they were holding
macrolide mode of action [104]. Further investigation revealed that these hybrids have
no effect on DNA gyrase and Topoisomerase IV, indicating that the action mode of
quinolone was not operative for these hybrids.

17
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2.8 4-Quinolone-oxime hybrids

Introduction of oxime, the common substructure in cephalosporins such as

ceftizoxime, led to the discovery of several fourth generation FQs such as GMFX and
its derivatives zabofloxacin as well as DW286. Numerous oxime-functionalized

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azetidines, pyrrolidines or piperidines were incorporated into the C-7 position of
4-quinolones, and some of them showed excellent in vitro and in vivo antibacterial

RI
activities against clinically relevant pathogens as well as improved pharmacokinetic

SC
and safety profiles [109-132].

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AN
M
D

<Fig 12. Chemical structure of 4-quinolone-oxime hybrid IMB-070593>

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The oxime-functionalized piperidinyl-based FQ conjugate IMB-070593, discovered

EP

in our lab possesses excellent antibacterial activity as well as extremely low

phototoxicity, hepatotoxicity and cardiac toxicity [122,133]. Currently, IMB-070593
C

is in late pre-clinical stage of research. However, the water solubility of IMB-070593

AC

(0.4 mg/mL) as well as its mesylate salt (22.5 mg/mL) is relatively low. Since the
water solubility at physiological pH is vital for pre-clinical evaluation, in vivo efficacy,
and parenteral formulation, improvement of the solubility of IMB-070593 is
necessary. Several dipeptide prodrugs of IMB-070593 have been synthesized to
improve the water solubility, and some of them showed improved solubility (>85
mg/mL) [123,134], warrant further evaluations.

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2.9 4-Quinolone-pyrimidine hybrids

Pyrimidine derivatives are important organic compounds with a wide range of

biological activities, and pyrimidines have the capacity to target the production of
tetrahydrofolic acid by inhibiting the dihydrofolate reductase enzyme that reduces

PT
dihydrofolate to tetrahydrofolate in bacterial, parasitic and epithelial cells [134,135].

RI
The SAR of CPFX pyrimidine hybrids tethered through -NH- (23a, n = 0), -NHCH2-
(23a, n = 1) and 1,2,3-triazole (23b-d) linkers demonstrated that the linkage affected

SC
the antibacterial activity significantly, and 1,2,3-triazole >> -NH- ≈ -NHCH2-; the
linked pattern of 1,2,3-triazole also influenced the activity, and the direct linked

U
pattern at C-7 position was more favorable than linked to piperazinyl subunit and
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methylene; interestingly, the ethyl esters was more potent than the corresponding
carboxylic acids [136]. It is notable that the hybrids showed dual-acting mechanisms:
M

inhibiting the targets of both trimethoprim (dihydrofolate reductase) and CPFX (DNA
gyrase and topoisomerase IV).
D
TE
C EP
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<Fig 13. Chemical structures of 4-quinolone-pyrimidine hybrids 23 and BP-4Q-002>

19
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The lead hybrid BP-4Q-002 was comparable to or more potent than trimethoprim,
CPFX alone or 1:1 a mixture of CPFX and trimethoprim against drug-sensitive and
CPFX-resistant bacteria [137].

2.10 4-Quinolone-quinoline/quinolone hybrids

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Quinoline derivatives exhibit diverse of activities such as anti-tubercular [138],

RI
anti-tumor [139], anti-malarial [140], anti-HIV [141], anti-inflammatory [142] and
anti-bacterial [143] properties, play an important role in the development of

SC
pharmaceuticals. 4-Quinolone tetrahydroquinoline conjugate 24 tethered through C-2
position via amine showed excellent in vitro and in vivo potency against

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representative Gram-positive pathogens, which was more active than erythromycin
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[144], could act as a novel lead for further optimization.
M
D
TE
EP

<Fig 14. Chemical structures of 4-quinolone-quinoline/quinolone 24 and 25>

C

Compared with the corresponding monomeric compounds, dimeric compounds often

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displayed some unique properties [145-148], so it’s worth to investigate dimeric

4-quinolone hybrids.

A variety of FQs dimers tethered through C-7 piperazinyl was screened for their
antibacterial activities against drug-sensitive and drug-resistant organisms, and the
SAR suggested that the dimers were more potent against Gram-positive bacteria than
against Gram-negative bacteria; the linkage between the two C-7 piperazinyl played a
20
 ACCEPTED MANUSCRIPT

dominate role for the activity, and 2,6-dimethylenepyridyl > m-xylenyl > p-xylenyl ≈
1,4-trans-2-butenyl > p-diphenyl >> ester [149-155]. Further investigation indicated
that those dimers would overcome the unfavorable entropy associated with the
binding of two separate quinolone monomers, and the bulky C-7 side chain may
explain dimer targeting of gyrase and activity against efflux mutants. The hybrid 25

PT
was found to be the most active against both Gram-positive and Gram-negative
bacteria including drug-resistant strains, which was >4-fold more active than CPFX

RI
against all tested strains [152].

The N-1 ethylene and C-3 amide tethered quinolone dimers showed moderate in vitro

SC
and in vivo antibacterial activities against a panel of clinically relevant Gram-positive
and Gram-negative pathogens, indicating these positions were not suitable for linking
[76,156].
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2.11 Miscellaneous 4-quinolone hybrids
M

Numerous other biological pharmacophores such as bisphosphonate [157-161],

D

catecholate [162], citrate [163], dihydrotestosterone [164], glycoside [165],

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hydroxamic acid [166], sideromycins [167], peptide [168,169], phenothiazinium [170],

pyochelin [171], pyoverdin [172], pyridyl [173-175], sulphonamide [176,177],
EP

siderophore [178-181] as well as trifluoroacetimidoyl [182] have been introduced into

the 4-quinolone moiety, in spite of a significant part of them were less potent than the
C

reference compounds, the enriched SAR paved the way to the further rational
AC

optimization of 4-quinolones.

3. Conclusion

The development and spread of pathogens resistant to 4-quinolones, make

4-quinolones more and more ineffective. Thus, it’s imperative to develop new agents.
Hybridization of other pharmacophores with 4-quinolone moiety has the potential to

21
 ACCEPTED MANUSCRIPT
provide novel candidates with a synergistic effect in terms of efficacy, lowered
resistance selection propensity, activity against resistant bacteria, and reduced
susceptibility to efflux pumps and toxicity in comparison to a cocktail of the two
drugs. Thus, various 4-quinolone hybirds were designed, synthesized and screened for
their in vitro and in vivo antibacterial activities, and several hybrids are under
pre-clinical or under clinical studies. The most emblematic examples MCB3637,

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MCB3681, Ro-23-9424 and CBR-2092 which exhibited great in vitro and in vivo
potency against both drug-sensitive and drug-resistant organisms including

RI
FQs-resistant, multidrug-resistant, and even pan-drug resistant pathogens as well as
difficult to treat bacteria, indicating have novel action mechanisms. Currently, all

SC
these hybrids are under evaluation, and may be used to treat various infections in the
near future.
In conclusion, the enriched SAR may pave the way to further rational development of

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4-quinolones with a unique mechanism of action different from that of the currently
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used drugs to overcome the resistance, well-tolerated and low toxic profiles.

Acknowledgements
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We gratefully acknowledge the financial support by NSFC (81373267).

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IMB-070593 is in late pre-clinical stage

MCB3837, MCB3681, Ro-23-9424 and CBR-2092 are in clinical trial

the SAR was enriched

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