Discovery of Benzimidazole–Quinolone Hybrids as New Cleaving Agents toward Drug-Resistant Pseudomonas aeruginosa DNA

Article abstract of DOI:10.1002/cmdc.201700739

A series of benzimidazole–quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5 b (ethyl 7-chloro-6-fluoro-1-[[1-[(2-fluorophenyl)methyl]benzimidazol-2-yl]methyl]-4-oxo-quinoline-3-carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep-2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV–DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug-resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities.

Full text of DOI:10.1002/cmdc.201700739

Accepted Article
Title: Discovery of Benzimidazole Quinolone Hybrids as New Cleaving
Agents towards Drug-resistant P. aeruginosa DNA
Authors: Cheng-He Zhou, Ya-Nan Wang, Rammohan R. Yadav
Bheemanaboina, Wei-Wei Gao, Jie Kang, and Gui-Xin Cai
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Discovery of Benzimidazole Quinolone Hybrids as New Cleaving
Agents towards Drug-resistant P. aeruginosa DNA

[a]
§[a]
§[a]
Jie Kang,[a] Gui-Xin
Ya-Nan Wang, Rammohan R. Yadav Bheemanaboina,
Wei-Wei Gao,
[
a]
[a]
Cai* and Cheng-He Zhou*

§
*
M. Sc. Y. N. Wang, M. Sc. J. Kang.
Dr. R. R. Y. Bheemanaboina(Postdoctoral fellow from CSIR-Indian Instituteof IntegrativeMedicine (IIIM), India), Dr. W. W. Gao.
A. Prof. G. X. Cai, E-mail: gxcai@swu.edu.cn, Prof. C. H. Zhou,E-mail:zhouch@swu.edu.cn(C. H. Zhou); Fax: +86-23-68254967;Tel:+86-23-68254967.
[
a] Institute ofBioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry andChemical Engineering,
Southwest University,Chongqing400715, China.
Abstract: A series of benzimidazole quinolone hybrids as new
potential antimicrobial agents w ere designed and synthesized, and
their bioactive assay indicated that some prepared compounds
exhibited potent antibacterial and antifungal activities. Notably, 2-
fluorobenzyl derivative 5b show ed remarkable antimicrobial activities
against the resistant P. aeruginosa and C. tropicalis isolated from
infected patients. The active molecule 5b could not only rapidly kill
the tested strains, but also exhibit low toxicity tow ards Hep-2 cells. It
was more difficult than norfloxacin to trigger the development of
bacterial resistance against P. aeruginosa. Molecular docking
demonstrated that it could effectively bind w ith topoisomerase IV–
DNA complexes, and quantum chemical studies theoretically
elucidated the good antimicrobial activity of compound 5b.
Preliminary experimental mechanism exploration suggested that
derivative 5b could not intercalate into DNA isolated from drug-
resistant P. aeruginosa, but it w as able to cleave DNA effectively,
which might further block DNA replication to exert the pow erful
bioactivities. In addition, compound 5b w as found to be a promising
antibacterial agent w ith membrane disruption ability.
rings were introduced into N-1 position of quinolones to
strengthen the binding affinity and overcome resistance,
because azole rings could bind with DNA, enzymes and
receptors in organism through various weak interactions like
coordination bonds, hydrogen bonds, π-π stacking and
[14-16]
hydrophobic effect.
Benzimidazole with a large conjugated rigid planar structure is
structurally similar to purine nucleoside base, and has been
arousing an increasing interest in drug design to develop
[17-19]
potential antimicrobial agents.
Benzimidazole derivatives
could interact with DNA from different microbial strains or inhibit
the biosynthesis of essential ergosterol in the membrane of fungi
[20,21]
and protozoa to exhibit the antimicrobial activities.
Previous
work reported that some benzimidazole-based hybrids, such as
sulfonamides, 5-fluorouracils and naphthalimides, exhibited
[22]
good antimicrobial activities and broad antibacterial spectrum.
Biochemical and pharmacological studies showed that the
modification of benzimidazole nucleus at N-1 and C-2 positions
could effectively improve the bioactivity and attracted
[23,24]
considerable attention.
All these findings clearly
demonstrated a large potentiality for benzimidazole compounds
in treating microbial infection.
Agreat deal of literature has reported thatsome aromatic azoles
in combination with quinolones displayed good antibacterial
efficacies, especially towards some drug-resistant bacteria like
Introduction
The successful discovery of quinolone antimicrobials greatly
decreased the morbidity and mortality caused by fatal bacterial
infections. Their good therapy effectiveness, broad antibacterial
spectrum and good safety profile rapidly promoted the
development of this class of antibacterial agents as first-line
alternative to treat respiratory, urinary tract and bone joint
methicillin-resistant Staphylococcus aureus (MRSA) with strong
[25-27]
activity and low toxicity.
However, to our best knowledge,
the combination of benzimidazole and the quinolone backbone,
especially at N-1 position has been seldom observed. In view of
the above mentioned and as an extension of our previous
[1-3]
infections. Especially, the synthesis of fluoroquinolone family
made great contribution to anti-infective agents such as
[28]
work,
herein a series of novel benzimidazole quinolone
hybrids were designed through the introduction of benzimidazole
moiety to N-1 position of quinolones using methylene as a
bridge, which allowed the flexible rotation of benzimidazole ring
[
4,5]
norfloxacin, ciprofloxacin, levofloxacin and moxifloxacin.
Antimicrobial mechanism revealed that this type of drugs could
target DNA gyrase or topoisomerase IV by binding with
enzyme–DNA binary complexes to form ternary supramolecular
complexes, thereby obstructing DNA replication and finally
resulting in bacterial death.
quinolones to manage bacterial infections has led to the
evolution and widespread distribution of resistantstrains such as
(
Figure 1). It is expected that these hybrids would have large
potentiality in the treatment of bacteria-infected diseases. The
halogen atoms on quinolone skeleton may increase protein-
[
6-8]
However, the overuse of
ligand stability, and subsequently contribute to the binding
[29]
affinity.
Various substituents including aliphatic chains and
aralkyl groups were introduced to N-1 position of benzimidazole
nucleus to investigate their effects on antimicrobial activities
since substituents in N-position of azoles could significantly
Streptococcus
Staphylococcus aureus.
pneumoniae,
Escherichia
coli
and
[9-11]
It was reported that resistance to
quinolones was mainly attributed to the mutations of some key
enzymes in quinolone-resistant pathogens. Particularly, the
alterations in the conserved ParC helix a4 residues of
topoisomerase IV–DNAcomplex, positioned in close proximity to
the groups at N-1 position of quinolones, directly weakened the
binding affinity between quinolone antimicrobials and target
influence the pharmacological properties by regulating lipid-
[30,31]
water partition coefficient and binding affinity.
All target
molecules would be screened against Gram-positive bacteria,
Gram-negative bacteria and fungal strains. To evaluate the
potentiality of the most active compound as a new antibacterial
candidate, further researches including partition coefficient
[12,13]
enzymes.
Accordingly, it is a promising strategy that azole
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1

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10.1002/cmdc.201700739
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calculation, bacterial resistance assay, time-kill kinetic and
cytotoxicity evaluation were carried out to predict its
pharmacokinetic behaviors. Moreover, ligand-receptor docking
was undertaken to rationalize the antibacterial activity and
understand the possible action mechanism. The structural
parameters such as molecular orbital energy and electrostatic
potential were also computed to demonstrate the structure
essential for antimicrobial activity. In addition, preliminary
interaction with DNA isolated from the sensitive strains and
bacterial membrane was investigated to explore the possible
[32,33]
antimicrobial action mechanism.
Figure 1. Design of novel benzimidazolequinolonehybrids.
The antimicrobial activities in vitro for all the target compounds
were evaluated for five Gram-positive bacteria (Methicillin-
Resistant Staphylococcus aureus N315 (MRSA), Enterococcus
faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC
Results and Discussion
2
5923 and Staphylococcus aureus ATCC 29213), six Gram-
negative bacteria (Klebsiella pneumonia, Escherichia coli,
Pseudomonas aeruginosa, Acinetobacter baumanii,
Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC
5922) and five fungi (Candida albicans, Candida tropicalis,
Chemistry
The target benzimidazole quinolones 4–6 were synthesized via
multi-step reactions from commercially available diethyl
malonate, 3-chloro-4-fluoroaniline and o-phenylenediamine. The
synthesis was outlined in Schemes 1–2. Diethyl 2-
2
Aspergillus fumigates, Candida albicans ATCC 90023, Candida
parapsilosis ATCC 22019) using two folds serial dilution
technique in 96–well micro-test plates recommended by Clinical
(ethoxymethylene)malonate 1 was easily prepared by the
[34]
and Laboratory Standards Institute (CLSI)
with the positive
condensation of diethyl malonate and triethyl orthoformate with
acetic anhydride, and then was reacted with 3-chloro-4-
fluoroaniline using ethanol as solvent to produce diethyl
intermediate 2 in 85% yield. The further cyclization of compound
control of clinically antimicrobial drugs norfloxacin, clinafloxacin
and fluconazole. The antibacterial and antifungal data were
summarized in Tables 1–2.
2
in phenoxybenzene under reflux formed the desired 1,4-
dihydroquinoline derivative 3 in moderate yield (58%). The
benzimidazole quinolone hybrids 4–6 were prepared by the
Antibacterial activity
coupling of quinolone
3 with a series of N-substituted
chloromethyl benzimidazoles 8, 10 and 12 in acetonitrile with
yields ranging from 25% to 52% (Scheme 1). Intermediates 8,
As depicted in Table 1, some prepared compounds exhibited
better antibacterial activities in vitro against the tested stains
than norfloxacin and clinafloxacin. The 2-fluorobenzyl derivative
5b displayed relatively efficient antibacterial activities in
comparison with other benzimidazole quinolone hybrids.
Especially towards P. aeruginosa, compound 5b gave a quite
low MIC of 1 μg/mL, which was 4- and 32-fold more potent than
reference drugs norfloxacin and clinafloxacin. Furthermore,
MRSA and S. aureus were also sensitive to compound 5b (MIC
= 8 μg/mL) comparable to norfloxacin. Moreover, this compound
displayed better inhibition activity against K. pneumonia (16
μg/mL) than the two reference drugs. These results indicated
that hybrid 5b was worthy to be further investigated as promising
antimicrobial candidate.
1
0 and 12 were prepared in 74–83% yields from the cyclization
of N-mono substituted o-phenylenediamines with chloroacetic
acid in hydrochloric acid at reflux. The mono-substituted o-
phenylenediamines 7, 9 and 11 were obtained in yields of 62–
6
9% by the nucleophilic substitution of o-phenylenediamine with
a series of alkyl halides, benzyl halides and 3-bromoprop-1-ene/
-bromoprop-1-yne at a ratio of 1.2 : 1 (Scheme 2). All the new
3
1
13
compounds were confirmed by H NMR, C NMR, IR and
HRMS spectra and their spectral data were provided in the
Experimental Section.
The structure activity relationship suggested that the length of
aliphatic chain at 1-position of benzimidazole had noticeable
Biological activity
2
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o
Scheme 1. Synthetic route of benzimidazole quinolone hybrids 4, 5 and 6. Reagents and conditions: (i) triethyl orthoformate, acetic anhydride, ZnCl
3
2
, 130 C; (ii)
o
o
-chloro-4-fluoroaniline, 80 C, ethanol, reflux; (iii) phenoxybenzene, 250 C, reflux; (iv) benzimidazoles 8a–g, potassium carbonate, acetonitrile, 70 C; (v)
benzimidazoles10a–f, potassium carbonate, acetonitrile,70 C; (vi) benzimidazoles12a–b, potassium carbonate, acetonitrile, 70 C.
Scheme 2. Synthetic route of intermediate benzimidazoles 8, 10 and 12. Reagents and conditions: (i) alkyl bromide, potassium carbonate, dimethylformamide,
o
r.t.; (ii) chloroacetic acid, 3 mol/L hydrochloric acid, reflux; (iii) halobenzyl halide, potassium carbonate, acetonitrile, 60 C; (iv) chloroacetic acid, 6 mol/L
hydrochloric acid, reflux; (v) 3-bromoprop-1-ene/ 3-bromoprop-1-yne, potassium carbonate, dimethylformamide, r.t.; (vi) chloroacetic acid, 3 mol/L hydrochloric
acid, reflux.
effect on antibacterial activity. The hexyl derivative 4c exhibited
better activity against K. pneumoniae (MIC = 8 μg/mL) than the
reference norfloxacin (MIC > 512 μg/mL). The short ethyl
compound 4a exerted more potent antibacterial activity with MIC
values of 8–64 μg/mL, especially against K. pneumoniae (MIC =
drugs clinafloxacin and norfloxacin. While the replacement of
ethyl group by hexadecyl chain generated compound 4g with
decreased inhibitory effects against all the tested strains (MIC >
64 μg/mL). From the overall trend of view, the increase of
carbon chains had no obvious enhancement of antibacterial
potency towards most of the tested strains, however, compound
8
μg/mL), which was 4-fold and even more active than reference
3
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4
b possessed the low MIC value (8 μg/mL) against MRSA strain. interesting that the antibacterial activity of compounds 5a–e
These results demonstrated that the short alkyl chain might be
more favourable for antibacterial activities. However, the allyl
and propargyl derivatives 6a–b displayed poor effects in
suppressing bacteria, which indicated that the unsaturated
aliphatic chain was notbeneficial to exert inhibitorypotency.
In comparison to the aliphatic derivatives 4a–g, most of
halobenzyl ones 5a–f exerted relatively better activities in
inhibiting the growth of the tested strains which might reveal that
the presence of benzyl group is helpful for antimicrobial activity.
The unsubstituted benzyl derivative 5a seemed to be more
sensitive towards the Gram-positive bacteria with the MIC value
of 4–64 μg/mL. Fluorobenzyl compounds 5b–c were more active
than chlorobenzyl derivatives 5d–e except for towards E. coli
and A. baumanii strains. The slightly better activities for
compounds 5b and 5d than analogs 5c and 5e against most of
the tested strains showed that the position of halogen atoms
exerted good influence in inhibiting bacterial growth. It was
towards S. aureus gradually decreased and was related to the
substituents of phenyl moiety. The order of activity was
observed: unsubstituted phenyl 5a > 2-fluorophenyl 5b > 4-
fluorophenyl 5c > 2-chlorophenyl 5d > 4-chlorophenyl one 5e. In
particular, halophenyl compound 5f with the two chloro atoms
displayed fairly good inhibition activities towards S. aureus (MIC
= 4 μg/mL) in comparison with mono-substituted ones.
In terms of the activity against P. aeruginosa, the phenyl and
unsaturated derivatives (5a–f, 6a–b) exhibited better potency
than saturated alkyl ones (4a–g) implying the low affinity of
saturated chains. It was noticeable that all target compounds
showed better activities against MRSA than reference drugs
norfloxacin and clinafloxacin which suggested the potentiality of
benzimidazole quinolone hybrids as anti-MRSA agents. As
described above, the suitable side chain was pivotal to develop
better antibacterial activities in drug design.
a,b,c
Table 1. Antibacterial dataasMIC (μg/mL) for targetcompounds4a–g, 5a–f and6a–b.
Gram-positive bacteria
Gram-negative bacteria
P. A.
P.
Compds
E.
S.
S. aureus
S. aureus
K.
E.
E. coli
ATCC25922
MRSA
aeruginosa
ATCC27853
faecalis aureus ATCC25923 ATCC29213
pneumoniae coli
aeruginosa baumanii
4
4
4
4
4
a
b
c
d
e
16
8
16
64
64
16
128
64
8
128
8
32
16
512
256
512
256
32
64
16
256
256
512
64
32
2
256
32
32
256
64
128
4
64
4
8
64
128
256
4
128
512
0.5
64
64
128
256
>512
512
256
128
64
64
512
128
512
256
512
256
64
8
8
8
64
256
128
256
4
16
4
64
256
8
64
128
32
>512
32
64
512
256
512
256
256
256
4
1
16
8
32
4
64
128
256
512
512
256
128
256
128
128
128
128
512
64
16
256
512
128
256
512
256
512
32
64
256
256
128
256
256
128
512
64
256
128
128
64
4
f
256
256
256
128
256
256
128
512
128
512
64
4
5
5
5
5
5
5
6
6
A
g
a
b
c
d
e
f
a
b
64
32
128
128
128
512
128
256
0.5
128
256
256
128
64
8
0.5
8
32
64
64
256
8
256
>512
512
64
512
32
128
512
512
64
512
0.5
1
8
32
32
32
4
128
>512
>512
64
8
32
B
32
512
512
a
Minimum inhibitory concentrationswere determinedby micro broth dilutionmethodfor microdilutionplates and MICswascompletely inhibitedconcentration.
MRSA, Methicillin-Resistant Staphylococcus aureus N315; E. faecalis, Enterococcus faecalis; S. aureus, Staphylococcus aureus; S. aureus ATCC25923,
b
Staphylococcus aureus ATCC25923; S. aureus ATCC29213, Staphylococcus aureus ATCC29213; K. pneumonia, Klebsiella pneumonia; E. coli, Escherichia coli;
P. aeruginosa, Pseudomonas aeruginosa; A. baumanii, Acinetobacter baumanii; P. aeruginosa ATCC27853, Pseudomonas aeruginosa ATCC27853; E. coli
ATCC25922, Escherichiacoli ATCC25922.
c
A = Clinafloxacin, B = Norfloxacin.
activity against C. tropicalis than fluconazole. In addition, the
Antifungal activity
unsaturated allyl or propargyl derivatives 6a–b also showed
moderate antifungal activities against most of the tested fungal
strains. It was also found that fluorobenzyl compounds 5b–c
gave equivalent or even stronger antifungal activities in
comparison to chlorobenzyl compounds 5d–e against the tested
strains, which indicated that fluorine atom on the phenyl moieties
exerted positive effect on microbial inhibition. Probably because
fluorine atom could easily and efficiently form non-covalent
forces thereby being helpful for the biological transportation and
distribution in organism. Dichlorophenyl compound 5f showed
lower MIC value of 16 μg/mL than monochlorophenyl ones 5d–e
(MIC = 256 μg/mL) against C. tropicails. On the whole, the target
molecules exerted weaker antifungal activities against the other
tested strains in comparison with C.tropicails.
The antifungal evaluation results were shown in Table 2. All
benzimidazole quinolone hybrids possessed comparative even
better antifungal efficiency (MIC = 1–256 μg/mL) against the
clinical drug-resistant C. tropicalis in contrast to fluconazole
(MIC = 256 μg/mL), especially compound 5b (MIC = 1 μg/mL),
which was 256-fold more active than fluconazole. Furthermore,
target molecule 5b also exhibited good inhibition potency
towards C. parapsilosis (ATCC 22019) (MIC = 1 μg/mL) while
fluconazole possessed the higher MIC value (2 μg/mL).
Alkyl substituted derivatives 4a–g displayed moderate antifungal
efficacy against most of the tested fungi, especially compounds
4
a and 4b with the same MIC value (16 μg/mL) exhibited better
4
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d,e
Table 2. Antifungal data asMIC (μg/mL) for compounds4a–g, 5a–f and6a–b.
Fungi
C. albicans C. tropicalis A. fumigatus
Compds
C. albicans
ATCC90023
128
C. parapsilosis
ATCC22019
4
4
4
4
4
a
b
c
d
e
256
512
512
512
256
256
32
16
16
128
64
256
256
256
4
64
64
128
128
256
128
64
128
8
1
128
256
256
128
512
256
256
256
128
256
128
256
128
128
256
128
256
256
128
256
256
256
128
64
128
16
512
32
64
1
4
f
4
5
5
5
5
5
g
a
b
c
d
e
512
256
256
256
512
512
128
512
64
1
64
256
256
16
64
128
256
64
128
512
128
128
256
2
5
f
6
a
6
b
C
d
C. albicans, Candida albicans; C. tropicalis, Candida tropicalis; A. fumigatus, Aspergillus fumigatus; C. albicans ATCC90023, Candida albicans ATCC90023; C.
parapsilosis ATCC22019, Candidaparapsilosis ATCC22019.
e
C = Fluconazole.
Effect of ClogP values on antimicrobialactivity
Bacterialresistance study
Lipophilicity/hydrophilicity
dominates
various
biological
With the increasing development and abuse of the antibiotics,
drug resistance to bacteria is inevitable. Nowadays, the study on
drug resistance has become one of the most important clinical
trials and the high-level resistance of norfloxacin to P.
aeruginosa strains has been observed. Thus, the ability of P.
aeruginosa to develop drug resistance was checked against the
most potent compound 5b and norfloxacin was used as a
positive control. We exposed a standard strain of P. aeruginosa
towards increasing concentrations of compound 5b from sub-
MIC for sustained passages. The new MIC values were tested
processes like the transportation, distribution, metabolism and
secretion of biological molecules. A good knowledge of the
lipophilicity/hydrophilicity is essential to predict the transportation
[35]
and activity of drugs. The partition coefficient (logP value) is
used to define the lipophilic character of a drug, and the suitable
values would have advantages in ideal pharmacokinetic and
pharmacodynamic properties of drugs. Therefore, we
theoretically calculated the logP values (ClogP) of all the target
molecules by the commercial ChemBioOffice 2014 (Cambridge
Soft, Massachusettes, USA) to further study their physical and
chemical properties. As shown in Table 3, the ClogP values of
the quinolone benzimidazole derivatives were related with the
length, saturation of carbon chain and the number of fluorine
and chlorine atoms in the phenyl groups. Asuitable ClogP value
exerted significant effect on antimicrobial activities. It was found
that ClogP values in the range of 4–6 exhibited more benefits to
the biological activity and higher lipophilic compounds were
unfavorable which manifested the significant role of suitable
lipophilicity in drug design. In general, compounds 4a–g, 5a–f
and 6a–b had suitable lipophilicity in comparison to clinafloxacin,
norfloxacin and fluconazole which was favorable for them to
permeate through biological membrane and to be delivered to
the binding sites.
every 24 h after propagation of P. aeruginosa cultures with fresh
o
media at 37
C on a shaker bed and serially diluted
concentrations of the tested compound 5b. The experiment was
repeated for 16 days. Results in Figure 2 revealed that bacterial
resistance to compound 5b did not emerge during 12 passages
in the presence of compound 5b (1 μg/mL), and the MIC values
just changed between 1 μg/mL and 4 μg/mL. However, P.
aeruginosa developed obvious resistance to norfloxacin and the
MIC values showed gradual increasing after 5 passages. This
assay indicated that compound 5b was more difficult to develop
resistance againstP.aeruginosa than clinicalnorfloxacin.
Bactericidalkinetic assay
In order to determine the antibacterial potency of the
synthesized compounds, the viability of exponentially growing P.
aeruginosa against highly active compound 5b was examined by
time-kill kinetics experiment. As can be seen from Figure 3, it
indicated more than 1 log (CFU/mL) reduction in the number of
viable bacteria within two hours at a concentration of 4 × MIC
while reference drug norfloxacin underwent three hours. After
three hours, the bactericidal effect of the two drugs tends to be
stable. The experimental result showed that this compound had
a rapid killing effectagainst P.aeruginosa.
a
Table 3. ClogP valuesof compounds4a–g,5a–f and 6a–b.
Compds ClogP Compds ClogP Compds
ClogP
6.68
4.51
4
4
4
4
4
a
b
c
d
e
4.26
5.32
6.38
7.44
8.49
9.55
4g
5a
5b
5c
5d
5e
11.67
5.25
5.39
5.39
5.96
5.96
5f
6a
6b
A
B
C
3.83
-0.73
-0.78
-0.44
4
f
a
A = Clinafloxacin, B = Norfloxacin, C = Fluconazole.
5
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Therefore, the active molecule 5b was selected to dock with the
topoisomerase IV–DNAcomplex.
3
2
2
1
1
0
5
0
5
0
5
0
Compound 5b
Norfloxacin
140
Hep-2
1
20
00
1
80
60
40
20
0
0
2
4
6
8
10
12
14
16
Day
Figure 2. Evaluation of resistance development against compound 5b in P.
aeruginosastrains.
Control 100
2
00
300
400
500
Concentration of compound 5b (m
μ
g/mL)
Figure 4. Cytotoxicity assay with compound 5b in the Hep-2 cell line tested by
MTT methodology. Each data bar isan averageof fivereplicates.
Control
1
0
8
6
4
Compound 5b
Norfloxacin
0
60
120
180
240
300
360
Time (min)
Figure 3. Time-kill kinetics of compound 5b (4 × MIC) against P. aeruginosa.
The data obtained are from three independent experiments performed in
triplicate.
Cytotoxicity
The active molecule 5b was further evaluated for its toxicity in
vitro against human laryngeal carcinoma epithelial cells (Hep-2)
by the colorimetric cell proliferation MTT assay. Experimental
results revealed that the cell viability of Hep-2 cell against
compound 5b was more than 84%, which suggested that this
molecule showed low toxicity to the cells at concentrations
below 500 μg/mL and the strongest cell viability was at 300
μg/mL concentration of compound 5b (Figure 4). All
demonstrated that compound 5b possessed the benign
biocompatibility which is considered to be one of the most
importantproperties for active drug candidates.
Figure 5. (i) Stereoview of conformation of compound 5b docked in
topoisomerase IV–DNA complex. (ii) Three-dimensional conformation of
compound5b dockedin topoisomerase IV–DNAcomplex.
Interaction of compound 5b with topoisomerase IV–DNA
receptor was shown in Figure 5 (i–ii). The docking result of
target compound 5b with topoisomerase IV–DNAcomplex might
rationalize the possible antibacterial mechanism. The carbonyl
group at 4-position of this molecule was in close vicinity to the
residue Asp397 of the topoisomerase IV–DNA complex and
formed hydrogen bonds. The prepared molecule 5b could also
interact with the residue Gly419 of topoisomerase IV–DNA
complex and base DT15 of DNA through hydrogen bonds with
distance of 2.4 and 2.1 Å, respectively through the oxygen atom
of ester group. These noncovalent interactions with DNA base
might block DNA replication. So, the above results showed that
this cooperative binding might be propitious to stabilize the
quinolone–enzyme–DNA ternary complexes which enabled
compound 5b to possess the strong inhibitory efficacy against P.
aeruginosa. Because clinafloxacin exposes severe side effects
such as phototoxicity and photohemolysis, these benzimidazole
Molecular docking study
To rationalize the observed antibacterial activity and understand
the possible action mechanism of the benzimidazole quinolone
hybrids, a flexible ligand–receptor docking investigation was
undertaken. The crystal structure data (topoisomerase IV–DNA
complex) were obtained from the protein data bank (PDB code:
2
XKK), which was representative target to investigate the
[36]
antibacterial mechanism. Topoisomerase IV is essential to the
bacterial cell which primarily unknots and untangles DNA and is
required for chromosome segregation. It alters DNA topology by
generating a double-stranded break in the genetic material and
passing a separate double helix through the transient DNAgate.
6
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ChemMedChem
10.1002/cmdc.201700739
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quinolones are valuable for being further developed as potential
candidates for infective chemotherapy.
did not contribute directly to HOMOs which manifested these
groups might be primarily used to modulate the physicochemical
properties. Moreover, the LUMOs of these molecules were also
mainly centered at the quinolone ring in which nucleophilic
attacks might be favorable. In order to further understand the
lower antimicrobial activities of compounds 4a and 6a together
with the higher antimicrobial activity of 5b, molecular
electrostatic potentials (MEPs) have been proceeded to check
the similarities and differences in electrostatic binding
characteristic of the surface of the molecules (Table 6).
Comparison of the electrostatic maps of compounds 4a, 5b and
6a revealed that compound 5b had a decreased positive charge
region (blue region) located on the benzimidazole ring probably
due to influence of the aromatic substituent, while 5b possessed
more negative charge region (red region) on the oxygen atom of
quinolone ring. It might indicate that compound 5b had strong
capability of interacting with positively charged polar residues of
enzymes or receptors to form hydrogen bond through the
oxygen atom of quinolone ring. This was consistent with the
binding mode obtained from above docking study(Figure 5).
Inhibitory activity against topoisomerase IV
To investigate inhibitory activity against the target enzyme of
quinolones at a molecular level, compound 5b and norfloxacin
were selected to test their inhibitory activity against
topoisomerase IV. Table 4 showed that compound 5b could
inhibit the activity of topoisomerase IV with a low IC50 value of
9
.64 μM, which gave better inhibitory potency than the standard
drug norfloxacin (IC50 = 13.48 μM).
Table 4. Inhibitory activity of compound 5b against topoisomerase IV.
Compds
Topoisomerase IV (IC50, μM)
5
b
9.64
norfloxacin
13.48
Quantum chemicalstudies
Interactions with drug-resistant P. aeruginosa DNA
It is known that intermolecular interactions were dominated by
the frontier molecular orbital (FMO), namely the highest
occupied molecular orbital (HOMO) and the lowest unoccupied
It is well known that DNA, a significant information molecule
encoding the genetic instructions, was commonly applied to
develop almost all the known living organisms. Interestingly, it
has been taken as the main cellular target to study bioactive
small molecules which was conducive to designing and
preparing new and efficient drugs. We isolated genomic DNA
from P. aeruginosa bacterial strain (Figure S4, supporting
information). The interaction of P. aeruginosa DNA with the
active compound 5b was investigated by UV–vis spectroscopy
to further explore the preliminary antimicrobial mechanism. The
purity of DNA was checked by UV–vis spectroscopic method
(Figure S1, supporting information) and the ratio of the
absorbance at 260 nm to that at 280 nm was monitored. The
solution gave a ratio of > 1.8 at A260/A280, which indicated that
the DNAwas sufficientlyfree from protein.
[37]
molecular orbital (LUMO).
A detailed knowledge of the
molecular electron density distribution and the electronic motion
are indispensable to understand the molecular recognition and
chemical reactivity of the molecule. Therefore, the concept
extends into drug–receptor binding systems and the major
contribution to binding involves the interaction between the
HOMO of the drug with the LUMO of the receptor and that
between LUMO of the drug with the HOMO of the receptor. The
extents of these stabilizing interactions are inversely related to
the energy gap between the interacting orbitals. Higher HOMO
energy and lower LUMO energy in the drug molecule result in
larger stabilizing interactions. Hence, the orbital energies of both
HOMO and LUMO and their gaps were calculated for
compounds 4a, 5b and 6a as shown in Table 5. The HOMO-
LUMO energy gap value supports the intramolecular charge-
transfer interactions within the molecule. It was noteworthy that
the most active compound 5b gave rise to the lowest energy gap
[38]
Absorption spectra of drug-resistant P. aeruginosa DNA in
the presence of compound 5b
(
∆ε) of 4.56 eV.
The investigation of DNA-binding with drug molecules was
directly related to absorption spectroscopy technique. In an
attempt to distinguish the change of DNA double-helical
structure, hypochromism and hyperchromism are very
momentous spectral features in absorption spectroscopy.
Because of the strong interaction between the electronic states
of intercalating chromophore and that of the DNA bases, the
Table 5. Energies of both HOMO and LUMO and their gaps (in eV) calculated
for compounds4a, 5b and6a.
Compds
εHOMO (eV) εLUMO (eV)
∆ε (eV)
4.61
[39]
4
5
6
a
b
a
-6.27
-6.12
-6.23
-1.66
-1.56
-1.63
4.56
4.60
observed large hypochromism strongly suggests
a close
The plots of HOMOs and LUMOs for 4a, 5b and 6a were also
obtained successfully to further analyze the main atomic
contributions for these orbitals. The results presented in Table 6
demonstrated that the electron charge cloud is located at the
quinolone ring in highest occupied molecular orbital (HOMO) of
compounds 4a, 5b and 6a which indicated that active sites might
be at this ring and biological interactions could take place
between positively charged molecules and these sites. It was
also found that benzimidazole ring and substituents on the ring
proximity of the aromatic chromophore to the DNAbases.
With a fixed concentration of DNA, UV–vis absorption spectra
were detected with the increasing concentration of compound 5b.
As shown in Figure 6, UV–vis spectra indicated that the
maximum absorption peak of DNA at 260 nm was gradually
enhanced along with a slightly red shift with the proportional
addition of compound 5b which was different from compound 5b
alone (Figure S2, supporting information). Meanwhile, spectral
data displayed that the absorption value of simply sum of free
DNA and free compound 5b was a little greater than the
7
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ChemMedChem
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FULL PAPER
0
measured value of 5b–DNA complex which revealed a weak
hypochromic effect existed between DNA and compound 5b.
This hypochromic effect on the spectra of 5b–DNAcomplex and
the slight red shift may be resulted from the charge attraction of
the prepared molecule 5b to DNA base eventually provide
convincing evidence of forming binary complexes. Moreover, the
intercalation of the aromatic fragment of compound 5b into the
helix and the strong overlap of -* states in the large -
conjugated system with the electronic states of DNAbases were
in accordance with the observed spectral changes.
A
C
C
1
(1)



0
A  A
D C  C
D C  C
K[Q]
0
A and A denote the absorbance of DNA in the absence and
presence of compound 5b at 260 nm, 
absorption coefficients of compound 5b and compound 5b–DNA
complex respectively. The plot of A /(A–A ) versus 1/[compound
b] is formed by using the absorption titration data and linear
fitting (Figure 7), producing the binding constant, K = 3.0 × 10
L/mol, R = 0.997, SD = 0.024 (R is the correlation coefficient, SD
is standard deviation).
C
and D–C represent the
0
0
5
5
In view of variations in the absorption spectra of DNA upon
binding to 5b, equation (1) can be applied to calculate the
binding constant(K).
Table 6. Plotsof the HOMO, LUMO and MEPsof compounds4a, 5b and6a.
Compds
Optimized structure
HOMO
LUMO
MEPs
4
a
5
b
6
a
1.2
1
.5
.2
.9
.6
.3
.0
1
1
1
0
0
0
0
.2
.1
.0
.9
.8
.7
.6
DNA + Compound 5b
DNA - Compound 5b Complex
1.0
0.8
0.6
0.4
1
0
0
0
0
h
4
6
8
10
12
-
6
1
0
[Q]
0.10
0.15
0.20
0.25
0.30
-6
-1
a
1
0 [Q] (L/mol)
DNA
0
0
Figure 7. The plotof A /(A-A ) versus1/[compound 5b].
240
260
280
300
320
340
Wavelength (nm)
Absorption spectra of NR interaction with drug-resistant P.
aeruginosa DNA
Figure 6. UV absorption spectra of DNA with different concentrations of
compound 5b (pH = 7.4, T = 290 K). Inset: comparison of absorption at 260
nm between the compound 5bDNA complex and the sum values of free DNA
-
5
To learn more about the interaction between compound 5b and
DNA, the absorption spectra of competitive interaction of
compound 5b was investigated. Neutral Red (NR) is a planar
and free compound 5b. c(DNA)= 7.44 × 10 mol/L, and c(compound 5b) =
-
6
-6
3
.3313.33 × 10 mol/Lfor curvesbh respectively at increment 1.67 × 10 .
8
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ChemMedChem
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FULL PAPER
phenazine dye and has been widely employed as probe due to
its lower toxicity, higher stability and more convenient application
than other common probes. Furthermore, spectrophotometric
and electrochemical techniques have already sufficiently
demonstrated that[40]NR can bind with DNA through an
intercalative mode. Therefore, NR was used as a spectral
probe to study the binding mode of 5b with DNA in our work.
The absorption spectra of the NR dye upon the addition of DNA
are shown in Figure 8. Experimental results displayed that the
absorption peak of the NR around 460 nm gradually decreased
with increasing concentration of DNAand a new band at around
0.20
0.15
0.10
0.05
1.2
0.9
0.6
0.3
i
i
a
a
0
.00
3
50
400
450
500
550
600
Wavelength (nm)
5
30 nm developed, which suggested the formation of new DNA–
DNA +NR
NR complex (Figure 8). An isosbestic point at 504 nm provided
evidence of DNA–NR complexformation.
0.0
300
400
500
600
Wavelength (nm)
0
0
0
0
.3
.2
.1
.0
Figure 9. UV absorption spectra of the competitive reaction between
-5
a
i
-
5
compound 5b and NR with DNA. c(DNA) = 7.44 × 10 mol/L, c(NR) = 2 × 10
-
6
mol/L, and c(compound 5b) = 013.3 × 10 mol/L for curves ai respectively
-
6
NR
at increment 1.67 × 10 . (Inset) Absorption spectra of the system with the
increasing concentration of 5b in the wavelength range of 350600 nm
absorption spectra of competitive reaction between compound 5b and NR with
DNA.
i
a
3.3
3.0
2.7
2.4
350
400
450
500
550
600
Wavelength (nm)
Figure 8. UV absorption spectra of NR in the presence of DNA at pH 7.4 and
-
5
-5
room temperature. c(NR) = 2 × 10 mol/L, and c(DNA) = 04.32 × 10 mol/L
2.1
-
5
for curvesai respectively at increment0.48× 10 mol/L.
1
.8
.5
1
Absorption spectra of competitive interactionof compound
0.0
0.2
0.4 2
0.6
0.8
1.0
+
5
b and NR with drug-resistant P. aeruginosa DNA
n [M (Cu )/M (5b)]
2
+
Figure 9 displayed the absorption spectra of a competitive
binding between NR and 5b with DNA. As shown in Figure 9,
with the increasing concentration of compound 5b, an apparent
intensity change was not observed in the developing band
around 460 nm. Compared with the absorption around 460 nm
of free NR in the presence of the increasing concentrations of
DNA(Figure 8), the absorbance at the same wavelength did not
exhibit the reverse process (inset of Figure 9). The results
disclosed that compound 5b failed to intercalate into the double
helix of DNAby substituting for NR in the DNA–NR complex.
Figure 10. The Job-Curve of compound 5b and Cu ion; T = 298 K, λ = 229
nm, c (Cu + 5b) = 7.5 × 10 mol/L.
2
+
-
4
Cleavge of drug-resistant P. aeruginosa DNA
To further elucidate the antibacterial mechanism of this class of
hybrids, the DNA cleavge experiment on compound 5b was
performed. Before the agarose gel electrophoresis test, the Job-
Figure 11. Agarose gel electrophoresis patterns for the cleavage of P.
aeruginosa DNA (1.26 × 10 mol/L) by 5b–Cu complexes in buffer (50 mM
-4
2+
Tris-HCl/50 mM NaCl, pH = 7.4) at 37 °C after 6 h of incubation. Lane 1, DNA
2
+
2+
+ Exonuclease III enzyme(15 U/µL); Lane 2, DNA + 5b–Cu complexes (0.75
mM); Lane 3, DNA control; Lane 4, DNA + Cu(NO (0.75 mM); Lane 5, DNA
5b (0.75 mM).
Curve of compound 5b and Cu ion was made by UV spectral
2+
3 2
)
method. When the total concentration of Cu ion and compound
+
-
4
5
b was fixed at 7.5 × 10 mol/L, the UV spectra were recorded
by changing their mole ratios. As depicted in Figure 10, the most
stable absorbance was at 0.5, meaning the concentrations of
The purity of P. aeruginosa DNA was checked by gel
2+
-4
-4
Cu ion and compound 5b were 2.5 × 10 mol/L and 5 × 102
electrophoresis (Figure S4, supporting information). The DNA
+
mol/L respectively, which suggested that compound 5b and Cu
2+
cleavage properties of 5b–Cu complex were confirmed in
ion could form complexwith the mole ratio of2:1.
Figure 11. The experimental results manifested that compound
2+
5
b–Cu complex could cleave DNA effectively (Figure 11, Lane
9
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ChemMedChem
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2
) in comparison with Exonuclease III enzyme as a positive
Gly419 and Asp397 residues of topoisomerase IV and DT15
base of DNA. Furthermore, quantum chemical studies validated
the capability of hydrogen bond formation through the oxygen
atom of quinolone ring, which was consistent with the binding
mode obtained from the docking result. The preliminary action
mechanism investigation revealed that derivative 5b could not
intercalate into DNA isolated from drug-resistant P. aeruginosa,
while the 5b–Cu complex could cleave DNA effectively, which
might block DNA replication to exert the powerful bioactivities.
More importantly, compound 5b was also able to permeabilize
and disrupt the cell membrane of P. aeruginosa. Hence,
compound 5b could open new opportunity for being developed
as therapeutic agent to tackle multidrug resistant bacterial
infections.
2+
control (Figure 11, Lane 1), but neither Cu ion nor compound
5
4
able to form complex with Cu ion, which might further destroy
DNAdirectly thus enhancing its antibacterial activity. The results
revealed that compound 5b might inhibit the growth of P.
aeruginosa by cleaving DNA, thus enhancing its antibacterial
activity.
b could cleave the P. aeruginosa DNA alone (Figure 11, Lane
and 5). Herein, it could be deduced that compound 5b was
2+
2+
Bacterialmembrane permeabilization
The ability of compound 5b to permeabilize the bacterial cell
membrane was studied using propidium iodide (PI) dye which
can pass through the membrane of compromised bacterial cells
and fluoresces upon binding to the cellular DNA. With the
addition of compound 5b, an enhancement in the fluorescence
intensity was observed in P. aeruginosa within 20 minutes and
then a stable trend was kept (Figure 12). Therefore, the
phenomenon demonstrated that compound 5b had the potential
to permeabilize the negatively charged bacterial cell membrane
of drug-resistant P. aeruginosa and disrupt the membrane
integrity.
Experimental Section
Generalmethods
Thin-layer chromatography analysis was proceeded using pre-coated
silica gel plates. Melting points were detected on M5000 melting point
apparatus made in Germany and were uncorrected. Fourier transform
infrared spectroscopy spectra were conducted on Bruker RFS100/S
spectrophotometer (Bio-Rad, Cambridge, MA, USA) using KBr pellets in
-1
1
13
the 400–4000 cm range. H NMR and C NMR spectra were recorded
on a Bruker AV 600 spectrometer using TMS as an internal standard.
The following abbreviations were used to specify groups: Ph = phenyl,
DMSO = dimethyl sulfoxide. The chemical shifts were shown in parts per
million (ppm), the coupling constants (J) are expressed in hertz (Hz) and
signals were described as singlet (s), doublet (d), triplet (t) as well as
multiplet (m). The high resolution mass spectra (HRMS) were done on an
IonSpec FTICR mass spectrometer. UV spectra were recorded at room
temperature on a TU-2450 spectrophotometer (Puxi Analytic Instrument
Ltd. of Beijing, China) equipped with 1.0 cm quartz cells. P. aeruginosa
DNA and NR were purchased from Sigma-Aldrich (St. Louis, MO, USA).
Tris, NaCl, HCl were analytical purity. Sample masses were weighed on
a microbalance with a resolution of 0.1 mg. All chemicals and solvents
were commercially available and were used without further purification.
1
1
1
1
1
400
300
200
100
000
Control
Compound 5b
9
00
00
8
0
5
10
15
20
25
30
35
Time (min)
Figure 12. Bacterial membrane permeabilization of compound 5b at
concentrationsof 12 × MIC against P. aeruginosa.
Synthesis of diethyl 2-(ethoxymethylene)malonate (1)
A mixture of diethyl malonate (1 equiv), triethyl orthoformate (1.2 equiv)
o
Conclusions
and acetic anhydride (2.5 equiv) was heated at 140 C for 5 h using
zinc(II) chloride as catalyst. After the reaction was completed (monitored
by TLC, petroleum), the generated ethanol and acetic acid were
evaporated under reduced pressure to give yellow liquid with the yield of
In conclusion, we have successfully developed a series of novel
benzimidazole quinolone hybrids 4a–g, 5a–f and 6a–b as
potential antimicrobial agents via convenient and efficient
6
5%.
1
synthetic procedures. All new compounds were confirmed by H
13
Synthesis
of
diethyl
2-(((3-chloro-4-fluorophenyl)amino)
NMR, C NMR, IR and HRMS spectra. Some of the synthesized
compounds exhibited good or even superior bioactivities to
reference drugs against the tested bacterial strains. The
structure activity relationship found that the substituents at the
N-position of benzimidazole ring exerted a noticeable effect on
the biological activity and 2-fluorobenzyl derivative 5b was the
most prominent one. Bacterial resistance study indicated that
compound 5b was more difficult to develop resistance against P.
aeruginosa than clinical norfloxacin and bactericidal kinetic
assay showed that this compound had a rapid killing effect
against P. aeruginosa. Moreover, the active molecule 5b also
displayed low toxicity against Hep-2 cells. Molecular docking
revealed that compound 5b could bind with topoisomerase IV–
DNA complexes through hydrogen bonds among compound 5b,
methylene)malonate (2)
o
Compound 1 (1 equiv) was stirred in ethanol at 80 C for 0.5 h, and then
3
-chloro-4-fluoroaniline (1 equiv) was poured into the mixture. After the
reaction was completed (monitored by TLC, eluent, petroleum/ethyl
acetate 20/3, V/V) about h, the mixture was cooled to room
8
temperature, and then the generated ethanol was evaporated under
reduced pressure. The residue was purified via silica gel column
chromatography (eluent, petroleum) to afford compound 2 as light yellow
[
41]
solid in 85% yield.
Synthesis of ethyl 7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-
carboxylate (3)
1
0
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ChemMedChem
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o
Diphenylether (50 mL) was heated to 250 C and then compound 2 (6.3
Synthesis of ethyl 7-chloro-6-fluoro-1-((1 -hexyl-1H-benzo[d]imidazol
-2-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (4c)
g, 0.02 mol) was slowly added. The mixture was refluxed for 1.5 h. When
the
reaction
was completed
(monitored
by
TLC,
eluent,
chloroform/methanol 70/1, v/v), the system was cooled to room
temperature and washed with petroleum ether to remove the excess of
diphenylether. The white solid was collected with 58% of yield (mp >
Compound 4c was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (2.000 g, 7.417
mmol), potassium carbonate (1.024 g, 7.417 mmol), sodium iodide
(1.112 g, 7.417 mmol) and compound 8c (1.860 g, 7.417 mmol). The
pure product 4c was obtained as white solid (1.867 g). Yield: 52.0%; mp:
2
50 °C).
o
-1
Synthesis of mono-substituted o-phenylenediamines (7, 9, 11) and
chloromethyl benzimidazoles (8, 10, 12)
104–105 C; IR (KBr, cm ) ν: 3046 (aromatic CH), 2956, 2931, 2858
(CH2, CH3), 1724, 1682 (C=O), 1636, 1613, 1550, 1486, (aromatic
1
frame); H NMR (600 MHz, DMSO-d6, ppm) δ 8.97 (s, quinolone-2-H,
1
H), 8.17 (d, J = 5.6 Hz, quinolone-5-H, 1H), 8.11 (d, J = 9.1 Hz,
The intermediates 7–12 were prepared according to the literature
procedure, starting from o-phenylenediamine.
[
12,42]
quinolone-8-H, 1H), 7.96 (d, J = 7.7 Hz, benzimidazolyl-4-H, 1H), 7.65 (d,
J = 8.2 Hz, benzimidazolyl-7-H, 1H), 7.54 (d, J = 7.0 Hz, benzimidazolyl-
5
-H, 1H), 7.49–7.43 (m, benzimidazolyl -6-H, 1H), 6.28 (s, quinolone-1-
Synthesis of ethyl 7-chloro-1-((1-ethyl-1H-benzo[d]imidazol-2-yl)
methyl)-6-fluoro-4-oxo-1,4-dihydro quinoline-3-carboxylate (4a)
NCH2, 2H), 4.54–4.48 (t, CH2(CH2)4CH3, 2H), 4.27 (q, J = 7.0 Hz,
COOCH2, 2H), 1.92 (d, J = 6.2 Hz, CH2CH2(CH2)3CH3, 2H), 1.48 (d, J =
6
1
3
.7 Hz, (CH2)2CH2(CH2)2CH3, 2H), 1.40–1.33 (m, (CH2)3CH2CH2CH3, 4H),
.29 (t, J = 7.0 Hz, COOCH2CH3, 3H), 0.91 (t, J = 6.8 Hz, (CH2)5CH3,
H); 13C NMR (151 MHz, DMSO-d6, ppm) δ 172.6 (C=O), 164.6
A mixture of compound 3 (500 mg, 1.854 mmol), potassium carbonate
(
256 mg, 1.854 mmol) and sodium iodide (278 mg, 1.854 mmol) in
o
acetonitrile (10 mL) was stirred at 70 C for 0.5 h. After the mixture was
(O=COCH2CH3), 155.9 (aromatic C-F), 154.3, 151.8, 149.0, 137.3, 134.2,
cooled to room temperature, compound 8a (361 mg, 1.854 mmol) was
1
29.2, 125.3, 120.5, 118.4, 116.6, 114.6, 113.0, 112.7, 112.4, 60.6, 49.0
o
added. The reaction mixture was then heated at 70 C for 3 h. After the
+
(CH2), 45.2, 31.3, 29.0, 26.4, 22.5, 14.7, 14.2; ESI-MS (m/z): 484 [M+H] ;
reaction was completed (monitored by TLC, dichloromethane/ethyl
acetate (1/1, V/V)), the reaction was cooled to room temperature and
treated with formic acid to adjust the pH value to 5.5–6.5. After the
acetonitrile was removed under reduced pressure, the resulting mixture
+
HRMS (TOF) calcd. for C26H28ClFN3O3 [M+H] : 484.1803; found,
84.1829.
4
Synthesis of ethyl 7-chloro-6-fluoro-1-((1-octyl-1H-benzo[d]imidazol-
-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (4d)
was
purified
by
silica
gel
chromatography
eluting
with
2
dichloromethane/ethyl acetate (10/1, V/V) to give the pure target
o
compound 4a as white solid (334 mg). Yield: 42.1%; mp: 103–104 C; IR
-
1
Compound 4d was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (2.000 g, 7.417
mmol), potassium carbonate (1.024 g, 7.417 mmol), sodium iodide
(
KBr, cm ) ν: 3044 (aromatic CH), 2978, 2934 (CH2, CH3), 1725, 1694
1
(
C=O), 1614, 1550, 1486, (aromatic frame); H NMR (600 MHz, CDCl3,
ppm) δ 8.62 (s, quinolone-2-H, 1H), 8.13 (d, J = 8.9 Hz, quinolone-5-H,
(
1.112 g, 7.417 mmol) and compound 8d (2.068 g, 7.417 mmol). The
1
H), 7.90 (d, J = 5.5 Hz, quinolone-8-H, 1H), 7.72 (d, J = 8.0 Hz,
benzimidazolyl-4-H, 1H), 7.38 (d, J = 8.0 Hz, benzimidazolyl-7-H, 1H),
.33 (t, 7.5 Hz, benzimidazolyl-5-H, 1H), 7.30–7.27 (m,
pure product 4d was obtained as white solid (1.822 g). Yield: 48.0%; mp:
o
-1
1
05–106 C; IR (KBr, cm ) ν: 3045 (aromatic CH), 2957, 2925, 2853
7
J
=
benzimidazolyl-6-H, 1H), 5.65 (s, quinolone-1-NCH2, 2H), 4.36–4.32 (m,
NCH2CH3, 2H), 4.30 (dd, J = 15.4, 8.1 Hz, COOCH2, 2H), 1.39–1.35 (m,
(CH2, CH3), 1726, 1690 (C=O), 1639, 1614, 1549, 1487, (aromatic
1
frame); H NMR (600 MHz, CDCl3, ppm) δ 8.64 (s, quinolone-2-H, 1H),
1
3
8.16 (d, J = 8.7 Hz, quinolone-5-H, 1H), 7.91 (d, J = 5.4 Hz, quinolone-8-
H, 1H), 7.73 (d, J = 7.1 Hz, benzimidazolyl-4-H, 1H), 7.37 (d, J = 7.8 Hz,
benzimidazolyl-7-H, 1H), 7.34–7.30 (t, benzimidazolyl-5-H, 1H), 7.28 (t, J
NCH2CH3, COOCH2CH3, 6H); C NMR (151 MHz, CDCl3, ppm) δ 172.8
C=O), 164.8 (O=COCH2CH3), 156.5 (aromatic C-F), 154.9, 149.5, 145.3,
(
1
1
42.2, 136.1, 135.1, 123.9, 123.0, 120.4, 119.30, 114.0, 113.8, 111.5,
+
2
= 8.8 Hz, benzimidazolyl-6-H, 1H), 5.65 (s, quinolone-1-NCH , 2H), 4.38–
09.7, 61.1, 51.3 (CH2), 39.2, 15.2, 14.3; ESI-MS (m/z): 428 [M+H] ;
+
4.30 (t, CH (CH ) CH , 2H), 4.20 (q, J = 7.4 Hz, COOCH , 2H), 1.70 (d, J
HRMS (TOF) calcd. for C22H19ClFN3O3 [M+H] : 428.1177; found,
28.1180.
2
2 6
3
2
=
6.6 Hz, CH2CH2(CH2)5CH3, 2H), 1.36 (d,
J
=
6.4 Hz,
4
(
CH2)2CH2CH2(CH2)3CH3, 4H), 1.31–1.18 (m, (CH2)4(CH2)3CH3,
1
3
COOCH2CH3, 9H), 0.86 (t, J = 7.0 Hz, (CH2)7CH3, 3H); C NMR (151
MHz, CDCl3, ppm) 172.9 (C=O), 164.8 (O=COCH2CH3), 156.5
Synthesis of ethyl 1-((1 -butyl-1H-benzo[d]imidazol-2-yl)methyl)-7-
chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (4b)
δ
(aromatic C-F), 154.8, 149.6, 145.7, 142.2, 136.2, 135.5, 129.2, 123.8,
1
3
22.9, 120.3, 119.3, 114.0, 111.5, 109.8, 61.0, 51.4 (CH2), 44.6, 31.6,
Compound 4b was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (1.000 g, 3.708
mmol), potassium carbonate (512 mg, 3.708 mmol), sodium iodide (556
mg, 3.708 mmol) and compound 8b (826 mg, 3.708 mmol). The pure
product 4b was obtained as white solid (760 mg). Yield: 44.9%; mp: 102–
+
0.2, 29.1, 29.1, 27.0, 22.5, 14.3, 14.0; ESI-MS (m/z): 512 [M+H] ;
+
HRMS (TOF) calcd. for C28H32ClFN3O3 [M+H] : 512.2116; found,
5
12.2123.
o
-1
Synthesis of ethyl 7-chloro-1-((1-decyl-1H-benzo[d]imidazol-2-
yl)methyl)-6-fluoro-4-oxo-1,4-dihydro quinoline -3-carboxylate (4e)
1
03 C; IR (KBr, cm ) ν: 3039 (aromatic CH), 2973, 2954, 2929, 2873,
2
852 (CH2, CH3), 1711, 1633 (C=O), 1613, 1551, 1487, (aromatic frame);
1
H NMR (600 MHz, DMSO-d6, ppm) δ 8.94 (s, quinolone-2-H, 1H), 8.09
17.9, 7.5 Hz, quinolone-5,8-H, 2H), 7.60 (d, J 8.1 Hz,
benzimidazolyl-4-H, 1H), 7.50 (d, J = 8.0 Hz, benzimidazolyl-7-H, 1H),
.25 (t, J = 7.6 Hz, benzimidazolyl-5-H, 1H), 7.14 (t, J 7.6 Hz,
Compound 4e was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (2.000 g, 7.417
mmol), potassium carbonate (1.024 g, 7.417 mmol), sodium iodide
(1.112 g, 7.417 mmol) and compound 8e (2.271 g, 7.417 mmol). The
pure product 4e was obtained as white solid (1.642 g). Yield: 41.2%; mp:
(dd,
J
=
=
7
=
benzimidazolyl-6-H, 1H), 6.06 (s, quinolone-1-NCH2, 2H), 4.36 (t, J = 7.6
Hz, CH2CH2CH2CH3, 2H), 4.25 (q, J = 7.0 Hz, COOCH2, 2H), 1.82–1.71
o
-1
1
07–108 C; IR (KBr, cm ) ν: 3053 (aromatic CH), 2926, 2854 (CH2,
(m, CH2CH2CH2CH3, 2H), 1.48–1.37 (m, CH2CH2CH2CH3, 2H), 1.29 (t, J
1
CH3), 1888, 1724 (C=O), 1614, 1551, 1485, (aromatic frame); H NMR
=
7.1 Hz, COOCH2CH3, 3H), 0.96 (t, J = 7.3 Hz, CH2CH2CH2CH3, 3H);
1
3
(600 MHz, CDCl , ppm) δ 8.53 (s, quinolone-2-H, 1H), 8.06 (d, J = 8.9 Hz,
C
NMR (151 MHz, DMSO-d6, ppm)
O=COCH2CH3), 156.0 (aromatic C-F), 154.4, 151.8, 148.9, 137.2, 129.3,
29.3, 126.1, 120.2, 118.3, 116.4, 114.5, 113.0, 112.6, 112.1, 60.5, 48.8
δ
172.7 (C=O), 164.5
3
quinolone-5-H, 1H), 7.79 (d, J = 5.4 Hz, quinolone-8-H, 1H), 7.64 (d, J =
(
7
.9 Hz, benzimidazolyl-4-H, 1H), 7.27 (d, J = 7.9 Hz, benzimidazolyl-7-H,
1
+
1H), 7.24 (t, J = 7.4 Hz, benzimidazolyl-5-H, 1H), 7.19 (t, J = 7.3 Hz,
(CH2), 45.5, 30.6, 20.0, 14.5, 13.7; ESI-MS (m/z): 456 [M+H] ; HRMS
+
benzimidazolyl-6-H, 1H), 5.54 (s, quinolone-1-NCH , 2H), 4.25 (q, J = 7.0
(TOF) calcd. for C24H24ClFN3O3 [M+H] : 456.1490; found, 456.1492.
2
Hz, COOCH2, 2H), 4.10 (t, J = 7.6 Hz, CH2(CH2)8CH3, 2H), 1.62 (dt, J =
1
5.0, 7.7 Hz, CH2CH2(CH2)7CH3, 2H), 1.27 (t, J = 7.0 Hz, COOCH2CH3,
1
1
This article is protected by copyright. All rights reserved.

ChemMedChem
10.1002/cmdc.201700739
FULL PAPER
3
H), 1.22–1.13 (m, (CH2)2(CH2)7CH3, 14H), 0.79 (t,
J
=
7.0 Hz,
CH2)9CH3, 3H); C NMR (151 MHz, CDCl3, ppm) δ 172.8 (C=O), 164.7
O=COCH2CH3), 156.5 (aromatic C-F), 154.8, 149.6, 145.7, 142.2, 136.1,
35.6, 129.1, 123.8, 122.8, 120.3, 119.3, 113.9, 111.4, 109.8, 61.0, 51.4
CH2), 50.6, 44.6, 31.8, 30.2, 29.4, 29.2, 29.2, 27.0, 22.6, 14.3 14.0; ESI-
MHz, DMSO-d6, ppm) δ 8.81 (s, quinolone-2-H, 1H), 8.02 (d, J = 9.2 Hz,
quinolone-5-H, 1H), 7.95 (d, J = 5.8 Hz, quinolone-8-H, 1H), 7.58 (d, J =
7.9 Hz, benzimidazolyl-4-H, 1H), 7.50 (d, J = 8.1 Hz, benzimidazolyl-7-H,
1H), 7.30–7.26 (m, Ph-3,4,5-H, 3H), 7.24 (t, J = 7.5 Hz, benzimidazolyl-5-
H, 1H), 7.19 (t, J = 7.3 Hz, benzimidazolyl-6-H, 1H), 7.10 (d, J = 6.6 Hz,
Ph-2,6-H, 2H), 6.03 (s, quinolone-1-NCH2, 2H), 5.70 (s, benzimidazolyl-
1-NCH2, 2H), 4.24 (q, J = 7.1 Hz, COOCH2, 2H), 1.28 (t, J = 7.0 Hz,
1
3
(
(
1
(
+
+
MS (m/z): 540 [M+H] ; HRMS (TOF) calcd. for C30H36ClFN3O3 [M+H] :
40.2429; found, 540.2313.
5
1
3
COOCH2CH3, 3H); C NMR (151 MHz, DMSO-d6, ppm) δ 172.0 (C=O),
1
1
1
4
64.5 (O=COCH2CH3), 155.6 (aromatic C-F), 154.0, 151.3, 149.1, 142.3,
37.1, 136.6, 136.3, 129.2, 128.2, 126.9, 123.5, 122.6, 120.6, 119.7,
13.0, 112.9, 111.2, 110.9, 60.5, 50.0 (CH2), 47.1, 14.7; ESI-MS (m/z):
Synthesis of ethyl 7-chloro-1-((1-dodecyl-1H-benzo[d]imidazol-2-
yl)methyl)-6-fluoro-4-oxo-1,4-dihydro quinoline-3-carboxylate (4f)
+
+
90 [M+H] ; HRMS (TOF) calcd. for C27H21ClFN3O3 [M+H] : 490.1334;
Compound 4f was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (3.800 g, 14.092
mmol), potassium carbonate (1.945 g, 14.092 mmol), sodium iodide
found, 490.1336.
Synthesis of ethyl
7-chloro-6-fluoro-1-((1-(2-fluorobenzyl)-1H-
(2.112 g, 14.092 mmol) and compound 8f (4.719 g, 14.092 mmol). The
benzo[d]imidazol-2-yl)methyl)-4-oxo-1,4-dihydro
carboxylate (5b)
quinoline-3-
pure product 4f was obtained as white solid (2.858 g). Yield: 35.7%; mp:
o
-1
1
09–110 C; IR (KBr, cm ) ν: 3054 (aromatic CH), 2925, 2853 (CH2,
1
CH3), 1920, 1725 (C=O), 1614, 1551, 1482, (aromatic frame); H NMR
600 MHz, CDCl3, ppm) δ 8.63 (s, quinolone-2-H, 1H), 8.10 (d, J = 8.9 Hz,
quinolone-5-H, 1H), 7.83 (d, J = 10.3 Hz, quinolone-8-H, 1H), 7.68 (d, J =
(
Compound 5b was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (1.850 g, 6.860
mmol), potassium carbonate (0.947 g, 6.860 mmol), sodium iodide
(1.028 g, 6.860 mmol) and compound 10b (1.885 g, 6.860 mmol). The
pure product 5b was obtained as white solid (1.592 g). Yield: 45.7%; mp:
7
1
.6 Hz, benzimidazolyl-4-H, 1H), 7.35 (d, J = 8.0 Hz, benzimidazolyl-7-H,
H), 7.30 (t, 7.5 Hz, benzimidazolyl-5-H, 1H), 7.26–7.24 (m,
J
=
benzimidazolyl-6-H, 1H), 5.66 (s, quinolone-1-NCH2, 2H), 4.30 (q, J = 6.9
Hz, COOCH2, 2H), 4.20 (t, J = 7.6 Hz, CH2(CH2)10CH3, 2H), 1.74–1.69
o
-1
213–214 C; IR (KBr, cm ) ν: 3040 (aromatic CH), 2976, 2945, 2905
1
(m, CH2CH2(CH2)9CH3, 2H), 1.33 (t, J = 6.8 Hz, (CH2)2CH2(CH2)8CH3,
(CH2, CH3), 1704, 1634 (C=O), 1614, 1551, 1488, (aromatic frame); H
COOCH2CH3, 5H), 1.23 (s, (CH2)3(CH2)8CH3, 16H), 0.87 (t, J = 7.1 Hz,
NMR (600 MHz, DMSO-d6, ppm) δ 8.84 (s, quinolone-2-H, 1H), 8.09 (d, J
= 5.7 Hz, quinolone-5-H, 1H), 7.99 (d, J = 9.2 Hz, quinolone-8-H, 1H),
7.61 (d, J = 7.8 Hz, benzimidazolyl-4-H, 1H), 7.50 (d, J = 8.0 Hz,
benzimidazolyl-7-H, 1H), 7.30 (dd, J = 13.2, 6.6 Hz, FPh-3-H, 1H), 7.22
1
3
(
CH2)11CH3, 3H); C NMR (151 MHz, CDCl3, ppm) δ 172.7 (C=O), 164.5
O=COCH2CH3), 156.4 (aromatic C-F), 154.7, 149.7, 146.0, 142.3, 136.2,
35.6, 129.0, 123.7, 122.7, 120.3, 119.4, 113.8, 111.3, 109.8, 60.9, 51.3
(
1
(
1
CH2), 44.5, 31.9, 30.2, 29.5, 29.5, 29.5, 29.4, 29.3, 29.2, 27.0, 22.6,
(dt, J = 11.1, 5.9 Hz, FPh-4,5,6-H, 3H), 6.96 (t, J = 7.4 Hz,
benzimidazolyl-5-H, 1H), 6.67 (t, J = 7.4 Hz, benzimidazolyl-6-H, 1H),
6.06 (s, quinolone-1-NCH2, 2H), 5.78 (s, benzimidazolyl-1-NCH2, 2H),
+
4.3, 14.0; ESI-MS (m/z): 568 [M+H] ; HRMS (TOF) calcd. for
+
C32H40ClFN3O3 [M+H] : 568.2742; found, 568.2756.
4
.23 (q, J = 7.0 Hz, COOCH2, 2H), 1.28 (t, J = 7.1 Hz, COOCH2CH3, 3H);
1
3
C
NMR (151 MHz, DMSO-d6, ppm)
δ
171.8 (C=O), 164.5
Synthesis of ethyl 7-chloro-6-fluoro-1-((1-hexadecyl-1H-benzo[d ]
imidazol-2-yl)methyl)-4-oxo-1,4-dihydro quinoline-3-carboxylate (4g)
(
O=COCH2CH3), 161.0, 155.6, 151.1, 149.2, 142.2, 137.2, 136.3, 130.3,
1
1
28.9, 128.4, 125.1, 123.5, 122.7, 120.7, 119.8, 116.1, 115.9, 113.0,
12.8, 111.1, 110.9, 60.4, 50.1 (CH2), 41.8, 14.7; ESI-MS (m/z): 508
Compound 4g was prepared according to the procedure for the
preparationn of compound 4a, starting from compound 3 (2.130 g, 7.899
mmol), potassium carbonate (1.090 g, 7.899 mmol) and sodium iodide
+
+
[
M+H] ; HRMS (TOF) calcd. for C27H20ClF2N3O3 [M+H] : 508.1240; found,
08.1243.
5
(
1.184 g, 7.899 mmol) and compound 8g (3.089 g, 7.899 mmol). The
Synthesis
of ethyl
7-chloro-6-fluoro-1-((1-(4-fluorobenzyl)-1H-
pure product 4g was obtained as white solid (1.795 g). Yield: 36.4%; mp:
o
-1
benzo[d]imidazol-2-yl)methyl)-4-oxo-1,4-dihydro
carboxylate (5c)
quinoline-3-
1
14–115 C; IR (KBr, cm ) ν: 3052 (aromatic CH), 2924, 2853 (CH2,
1
CH3), 1887, 1724 (C=O), 1614, 1551, 1486, (aromatic frame); H NMR
600 MHz, CDCl3, ppm) δ 8.60 (s, quinolone-2-H, 1H), 8.17 (d, J = 8.1 Hz,
quinolone-5-H, 1H), 7.90 (d, J = 3.6 Hz, quinolone-8-H, 1H), 7.73 (d, J =
(
Compound 5c was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (2.467 g, 9.148
mmol), potassium carbonate (1.262 g, 9.148 mmol), sodium iodide
(1.371 g, 9.148 mmol) and compound 10c (2.513 g, 9.148 mmol). The
pure product 5c was obtained as white solid (1.840 g). Yield: 39.6%; mp:
7
1
.8 Hz, benzimidazolyl-4-H, 1H), 7.35 (d, J = 7.8 Hz, benzimidazolyl-7-H,
H), 7.32 (t, J = 7.5 Hz, benzimidazolyl-5-H, 1H), 7.29 (t, J = 7.6 Hz,
benzimidazolyl-6-H, 1H), 5.60 (s, quinolone-1-NCH2, 2H), 4.36 (q, J = 6.6
Hz, COOCH2, 2H), 4.17 (t, J = 7.5 Hz, CH2(CH2)14CH3, 2H), 1.69 (dd, J =
o
-1
1
3
4.4, 7.3 Hz, CH2CH2(CH2)13CH3, 2H), 1.37 (t, J = 6.9 Hz, COOCH2CH3,
H), 1.24 (d, J = 12.8 Hz, (CH2)2(CH2)13CH3, 26H), 0.88 (t, J = 6.6 Hz,
203–204 C; IR (KBr, cm ) ν: 3053 (aromatic CH), 2977, 2901 (CH2,
1
CH3), 1894, 1711 (C=O), 1614, 1551, 1486, (aromatic frame); H NMR
1
3
(
CH2)15CH3, 3H); C NMR (151 MHz, CDCl3, ppm) δ 172.7 (C=O), 164.7
O=COCH2CH3), 156.5 (aromatic C-F), 154.9, 149.5, 145.5, 142.3, 136.1,
35.6, 129.2, 123.9, 122.9, 120.5, 119.2, 114.1, 111.5, 109.8, 61.2, 51.5
(600 MHz, DMSO-d6, ppm) δ 8.85 (s, quinolone-2-H, 1H), 8.03 (d, J = 9.2
Hz, quinolone-5-H, 1H), 7.99 (d, J = 5.7 Hz, quinolone-8-H, 1H), 7.58 (d,
J = 8.0 Hz, benzimidazolyl-4-H, 1H), 7.52 (d, J = 8.0 Hz, benzimidazolyl-
7-H, 1H), 7.24 (t, J = 7.5 Hz, benzimidazolyl-5-H, 1H), 7.18 (t, J = 6.4 Hz,
benzimidazolyl-6-H, FPh-3,5-H, 3H), 7.12 (t, J = 8.7 Hz, FPh-2,6-H, 2H),
6.04 (s, quinolone-1-NCH2, 2H), 5.70 (s, benzimidazolyl-1-NCH2, 2H),
(
1
(CH2), 50.7, 44.6, 31.9, 30.2, 29.7, 29.6, 29.6, 29.6, 29.6, 29.5. 29.4,
+
2
9.3, 29.2, 27.0, 22.6, 14.2, 14.0; ESI-MS (m/z): 624 [M+H] ; HRMS
+
(TOF) calcd. for C36H48ClFN3O3 [M+H] : 624.3368; found, 624.3383.
4
.24 (q, J = 7.0 Hz, COOCH2, 2H), 1.28 (t, J = 7.0 Hz, COOCH2CH3, 3H);
1
3
C
NMR (151 MHz, DMSO-d6, ppm)
δ
171.9 (C=O), 164.6
Synthesis of ethyl 1-((1-benzyl-1H-benzo[d]imidazol-2-yl)methyl)-7-
chloro-6-fluoro-4-oxo-1,4-dihydro quinoline-3-carboxylate (5a)
(
O=COCH2CH3), 161.37, 155.7, 151.3, 149.2, 142.3, 137.1, 136.3, 132.9,
1
1
29.2, 129.1, 125.7, 123.5, 122.6, 120.7, 119.8, 116.1, 116.0, 113.0,
12.8, 111.1, 110.9, 60.5, 50.0 (CH2), 46.4, 14.7; ESI-MS (m/z): 508
Compound 5a was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (2.224 g, 8.247
mmol), potassium carbonate (1.138 g, 8.247 mmol), sodium iodide
+
+
[
M+H] ; HRMS (TOF) calcd. for C27H20ClF2N3O3 [M+H] : 508.1240; found,
08.1243.
5
(
1.236 g, 8.247 mmol) and compound 10a (2.001 g, 8.247 mmol). The
Synthesis
of
ethyl
7-chloro-1-((1-(2 -chlorobenzyl)-1H-
pure product 5a was obtained as white solid (1.697 g). Yield: 42.1%; mp:
o
-1
benzo[d]imidazol-2-yl)methyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-
3-carboxylate (5d)
2
40–241 C; IR (KBr, cm ) ν: 3056 (aromatic CH), 2982, 2902 (CH2,
1
CH3), 1727 (C=O), 1613, 1552, 1483, (aromatic frame); H NMR (600
1
2
This article is protected by copyright. All rights reserved.

ChemMedChem
10.1002/cmdc.201700739
FULL PAPER
+
Compound 5d was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (2.284 g, 8.470
mmol), potassium carbonate (1.169 g, 8.470 mmol), sodium iodide
14.8; ESI-MS (m/z): 580 [M+Na] ; HRMS (TOF) calcd. for
+
C27H20Cl2FN3O3 [M+Na] : 580.0374; found, 580.0376.
(
1.270 g, 8.470 mmol) and compound 10d (2.513 g, 9.148 mmol). The
Synthesis of ethyl 1-((1-allyl-1H-benzo[d]imidazol-2-yl)methyl)-7-
chloro-6-fluoro-4-oxo-1,4-dihydro quinoline-3-carboxylate (6a)
pure product 5d was obtained as white solid (1.892 g). Yield: 42.6%; mp:
o
-1
2
20–221 C; IR (KBr, cm ) ν: 3049 (aromatic CH), 2976, 2935, 2902
1
(CH2, CH3), 1898, 1730 (C=O), 1613, 1551, 1479, (aromatic frame);
H
Compound 6a was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (2.284 g, 8.470
mmol), potassium carbonate (1.169 g, 8.470 mmol), sodium iodide
NMR (600 MHz, DMSO-d6, ppm) δ 8.82 (s, quinolone-2-H, 1H), 8.16 (d, J
=
7
5.8 Hz, quinolone-5-H, 1H), 7.94 (d, J = 9.2 Hz, quinolone-8-H, 1H),
.67 (dd, J = 5.5, 3.3 Hz, benzimidazolyl-4-H, 1H), 7.44 (d, J = 8.0 Hz,
(1.270 g, 8.470 mmol) and compound 12a (1.751 g, 8.470 mmol). The
benzimidazolyl-7-H, 1H), 7.42 (dd, J = 5.7, 3.2 Hz, ClPh-3-H, 1H), 7.22
dt, 13.6, 6.7 Hz, ClPh-4,5,6-H, 3H), 6.92 (t, 7.5 Hz,
benzimidazolyl-5-H, 1H), 6.12 (d, J = 7.6 Hz, benzimidazolyl-6-H, 1H),
pure product 6a was obtained as white solid (1.428 g). Yield: 38.3%; mp:
(
J
=
J
=
o
-1
1
(
25–126 C; IR (KBr, cm ) ν: 3050 (aromatic CH, CH=CH2), 2980, 2935
1
CH2, CH3), 1893, 1724 (C=O), 1614, 1550, 1486, (aromatic frame);
H
6
4
.05 (s, quinolone-1-NCH2, 2H), 5.75 (s, benzimidazolyl-1-NCH2, 2H),
.23 (q, J = 7.0 Hz, COOCH2, 2H), 1.29 (t, J = 7.1 Hz, COOCH2CH3, 3H);
NMR (600 MHz, CDCl3, ppm) δ 8.57 (s, quinolone-2-H, 1H), 8.12 (d, J =
8
7
7
.9 Hz, quinolone-5-H, 1H), 7.83 (d, J = 5.5 Hz, quinolone-8-H, 1H),
.74–7.68 (m, benzimidazolyl-4-H, 1H), 7.33–7.29 (m, benzimidazolyl-
,5-H, 2H), 7.28 (d, J = 9.5 Hz, benzimidazolyl-6-H, 1H), 5.97–5.88 (m,
1
3
C
NMR (151 MHz, DMSO-d6, ppm)
δ
171.7 (C=O), 164.4
(O=COCH2CH3), 155.6, 154.0, 150.9, 149.3, 142.2, 137.1, 136.3, 133.7,
1
1
31.9, 130.0, 129.7, 127.8, 126.8, 125.5, 123.8, 122.9, 120.8, 119.9,
CH2CH=CH2, 1H), 5.58 (s, quinolone-1-NCH2, 2H), 5.21 (t, J = 11.8 Hz,
CH2CH=CH2, 1H), 4.86 (t, J = 18.9 Hz, CH2CH=CH2, CH2CH=CH2, 3H),
12.9, 112.8, 111.1, 60.4, 50.2 (CH2), 45.3, 14.8; ESI-MS (m/z): 524
+
+
[
M+H] ; HRMS (TOF) calcd. for C27H20Cl2FN3O3 [M+H] : 524.0944; found,
24.0945.
4
.33 (q, J = 7.0 Hz, COOCH2, 2H), 1.36 (t, J = 7.0 Hz, COOCH2CH3, 3H);
5
13
C NMR (151 MHz, CDCl3, ppm) δ 172.8 (C=O), 164.8 (O=COCH2CH3),
56.4, 154.8, 149.8, 146.1, 142.2, 136.1, 135.7, 131.1, 124.0, 123.0,
1
Synthesis
benzo[d]imidazol-2-yl)methyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-
-carboxylate (5e)
of
ethyl
7-chloro-1-((1-(4 -chlorobenzyl)-1H-
120.4, 120.3, 119.2, 118.0, 113.9, 111.4, 109.7, 61.0, 51.3 (CH ), 46.1,
2
+
1
4.4; ESI-MS (m/z): 440 [M+H] ; HRMS (TOF) calcd. for C23H20ClFN3O3
3
+
[
M+H] : 440.1177; found, 440.1201.
Compound 5e was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (2.356 g, 8.737
mmol), potassium carbonate (1.206 g, 8.737 mmol), sodium iodide
Synthesis of ethyl 7-chloro-6-fluoro-4-oxo-1-((1-(prop-2-yn-1-yl)-1H-
benzo[d]imidazol-2-yl)methyl)-1,4-dihydroquinoline-3-carboxylate
(6b)
(1.310 g, 8.737 mmol) and compound 10e (2.544 g, 8.737 mmol). The
pure product 5e was obtained as white solid (1.764 g). Yield: 38.5%; mp:
Compound 6b was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (3.058 g, 11.340
mmol), potassium carbonate (1.565 g, 11.340 mmol), sodium iodide
o
-1
2
08–209 C; IR (KBr, cm ) ν: 3081, 3053 (aromatic CH), 2975, 2902
1
(CH2, CH3), 1884, 1722 (C=O), 1616, 1550, 1487, (aromatic frame);
H
NMR (600 MHz, DMSO-d6, ppm) δ 8.86 (s, quinolone-2-H, 1H), 8.03 (d, J
(1.670 g, 11.340 mmol) and compound 12b (2.321 g, 11.340 mmol). The
=
7
9.2 Hz, quinolone-5-H, 1H), 7.98 (d, J = 5.9 Hz, quinolone-8-H, 1H),
.58 (d, J = 8.0 Hz, benzimidazolyl-4-H, 1H), 7.51 (d, J = 8.1 Hz,
pure product 6b was obtained as white solid (1.226g). Yield: 24.7%; mp:
o
-1
1
2
81–182 C; IR (KBr, cm ) ν: 3293 (C≡CH), 3057 (aromatic CH), 2962,
benzimidazolyl-7-H, 1H), 7.36 (d, J = 8.4 Hz, ClPh-3,5-H, 2H), 7.24 (t, J =
904 (CH2, CH3), 2120 (C≡C), 1906, 1732 (C=O), 1614, 1552, 1481
7
1
5
1
.6 Hz, benzimidazolyl-5-H, 1H), 7.19 (t, J = 7.6 Hz, benzimidazolyl-6-H,
H), 7.14 (d, J = 8.5 Hz, ClPh-2,6-H, 2H), 6.03 (s, quinolone-1-NCH2, 2H),
.71 (s, benzimidazolyl-1-NCH2, 2H), 4.24 (q, J = 7.1 Hz, COOCH2, 2H),
1
(
aromatic frame);
H NMR (600 MHz, DMSO-d6, ppm) δ 8.95 (s,
quinolone-2-H, 1H), 8.06 (d, J = 4.0 Hz, quinolone-5-H, 1H), 7.69 (d, J =
3
7
.8 Hz, quinolone-8-H, benzimidazolyl-4-H, 2H), 7.53 (s, benzimidazolyl-
-H, 1H), 7.29 (d, 5.2 Hz, benzimidazolyl-6-H, 5-H), 7.19 (s,
1
3
.28 (d, J = 7.1 Hz, COOCH2CH3, 3H); C NMR (151 MHz, DMSO-d6,
J
=
ppm) δ 171.9 (C=O), 164.6 (O=COCH2CH3), 155.7, 154.0, 151.3, 149.2,
benzimidazolyl-6-H, 1H), 6.06 (s, quinolone-1-NCH2, 2H), 5.36 (s,
1
1
42.3, 137.1, 136.3, 135.7, 132.9, 129.2, 128.9, 123.5, 122.6, 120.7,
CH2C≡CH, 2H), 4.25 (q,
J
=
5.6 Hz, COOCH2CH3, 2H), 3.53 (s,
19.8, 113.0, 112.8, 111.1, 110.9, 60.5, 49.9 (CH2), 46.4, 14.7; ESI-MS
13
CH2C≡CH, 1H), 1.29 (t, J = 2.5 Hz, COOCH2CH3, 3H); C NMR (151
MHz, DMSO-d6, ppm) δ 172.9 (C=O), 164.6 (O=COCH2CH3), 156.1,
+
+
(m/z): 524 [M+H] ; HRMS (TOF) calcd. for C27H20Cl2FN3O3 [M+H] :
5
24.0944; found, 524.0975.
1
1
3
54.5, 150.1, 148.9, 142.2, 137.2, 135.6, 129.1, 123.4, 122.7, 120.7,
18.6, 113.1, 112.5, 110.9, 78.3 (C≡CH), 76.9 (C≡CH), 60.5, 50.5 (CH2),
Synthesis
benzo[d]imidazol-2-yl)methyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-
-carboxylate (5f)
of
ethyl
7-chloro-1-((1-(2,4-dichlorobenzyl)-1H-
+
1.1, 14.8; ESI-MS (m/z): 438 [M+H] ; HRMS (TOF) calcd. for
+
C23H17ClFN3O3 [M+H] : 438.1021; found, 438.1020.
3
Compound 5f was prepared according to the procedure for the
preparation of compound 4a, starting from compound 3 (1.951 g, 7.235
mmol), potassium carbonate (0.998 g, 7.235 mmol), sodium iodide
Acknowledgements
(
1.084 g, 7.235 mmol) and compound 10f (2.356 g, 7.235 mmol). The
This work was partially supported by National Natural Science
Foundation of China (Nos. 21672173) and Chongqing Special
Foundation for Postdoctoral Research Proposal (No.
Xm2017184).
pure product 5f was obtained as white solid (1.584 g). Yield: 39.2%; mp:
o
-1
2
1
24–225 C; IR (KBr, cm ) ν: 3051 (aromatic CH), 2978 (CH2, CH3),
1
724, 1692 (C=O), 1612, 1551, 1485, (aromatic frame); H NMR (600
MHz, DMSO-d6, ppm) δ 8.82 (s, quinolone-2-H, 1H), 8.15 (d, J = 5.9 Hz,
quinolone-5-H, 1H), 7.95 (d, J = 9.2 Hz, quinolone-8-H, 1H), 7.66 (dt, J =
6
1
.5, 2.5 Hz, 2,4-Cl2Ph-3-H, 1H), 7.60 (d, J = 2.1 Hz, benzimidazolyl-4-H,
H), 7.48–7.43 (m, benzimidazolyl-7-H, 1H), 7.26–7.21 (m,
Keywords: Quinolone
Antifungal • DNA
• Benzimidazole • Antibacterial •
benzimidazolyl-5,6-H, 2H), 7.03 (dd, J = 8.4, 2.1 Hz, 2,4-Cl2Ph-5-H, 1H),
6
5
1
.12 (d, J = 8.4 Hz, 2,4-Cl2Ph-6-H, 1H), 6.03 (s, quinolone-1-NCH2, 2H),
.73 (s, benzimidazolyl-1-NCH2, 2H), 4.24 (q, J = 7.1 Hz, COOCH2, 2H),
References:
1
3
.30 (t, J = 7.1 Hz, COOCH2CH3, 3H); C NMR (151 MHz, DMSO-d6,
ppm) δ 171.7 (C=O), 164.5 (O=COCH2CH3), 155.7, 154.0, 150.9, 149.3,
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4
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4
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Entry for the Table of Contents
A series of new benzimidazole quinolone hybrids as cleaving agents towards drug-resistant P. aeruginosa DNA were prepared and
evaluated on their antimicrobial activities in vitro by changing substituents at of nitrogen atom of benzimidazole ring and investigating
their influence on antimicrobial activity. Notably, 2-fluorobenzyl derivative 5b showed remarkable antimicrobial activities against the
resistantP.aeruginosa and C.tropicalis isolated from infectedpatients.
This article is protected by copyright. All rights reserved.
1
5