Design, synthesis and biological evaluation of 5-fluorouracil-derived benzimidazoles as novel type of potential antimicrobial agents

Article abstract of DOI:10.1016/j.bmcl.2016.04.036

A series of 5-fluorouracil benzimidazoles as novel type of potential antimicrobial agents were designed and synthesized for the first time. Bioactive assay manifested that some of the prepared compounds exhibited good or even stronger antibacterial and an

Full text of DOI:10.1016/j.bmcl.2016.04.036

Accepted Manuscript
Design, synthesis and biological evaluation of 5-fluorouracil-derived benzimi-
dazoles as novel type of potential antimicrobial agents
Xue-Jie Fang, Ponmani Jeyakkumar, Srinivasa Rao Avula, Qian Zhou, Cheng-
He Zhou
PII:
S0960-894X(16)30410-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.04.036
BMCL 23798
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
29 January 2016
31 March 2016
15 April 2016
Please cite this article as: Fang, X-J., Jeyakkumar, P., Avula, S.R., Zhou, Q., Zhou, C-H., Design, synthesis and
biological evaluation of 5-fluorouracil-derived benzimidazoles as novel type of potential antimicrobial agents,
Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.04.036
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Bioorganic & Medicinal Chemistry Letters
jour nal homepage: w ww.elsevier. com
Design, synthesis and biological evaluation of 5-fluorouracil-derived
benzimidazoles as novel type of potential antimicrobial agents
Xue-Jie Fang, Ponmani Jeyakkumar †, Srinivasa Rao Avula ‡, Qian Zhou, Cheng-He Zhou*
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical
Engineering, Southwest University, Chongqing 400715, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of 5-fluorouracil benzimidazoles as novel type of potential antimicrobial agents were
designed and synthesized for the first time. Bioactive assay manifested that some of the
prepared compounds exhibited good or even stronger antibacterial and antifungal activities
against the tested strains in comparison with reference drugs norfloxacin, chloromycin and
fluconazole. Noticeably, 3-fluorobenzyl benzimidazole derivative 5c gave remarkable
antimicrobial activities against S. cerevisiae, MRSA and B. proteus with MIC values of 1, 2
and 4 µg/mL, respectively. Experimental research revealed that compound 5c could effectively
intercalate into calf thymus DNA to form compound 5c–DNA complex which might block
DNA replication and thus exert antimicrobial activities. Molecular docking indicated that
compound 5c should bind with DNA topoisomerase IA through three hydrogen bonds by the
use of fluorine atom and oxygen atoms in 5-fluorouracil with the residue Lys 423.
Revised
Accepted
Available online
Keywords:
5-Fluorouracil
Benzimidazole
Antibacterial
Antifungal
DNA
2015 Elsevier Ltd. All rights reserved.
Pyrimidine ring is a six-membered aromatic heterocycle 1
bearing two nitrogen atoms, which extensively exists in
biologically active natural products. The special heterocycle can
readily interact with biological macromolecules like enzymes,
receptors, deoxyribonucleic acid (DNA) and ribonucleic acid
(RNA). Thus, pyrimidine fragment has been prevalently
employed in the design of new drugs and a lot of pyrimidines as
drugs have been successfully developed and extensively used in
clinic. Especially in antimicrobial aspects, many pyrimidine
compounds such as sulfadiazine and voriconazole have been in
widespread clinical use to treat diseases caused by bacteria and
fungi. However, the increasing incidence of multidrug-resistant
strains, intractable pathogenic microorganisms and newly
emerging pathogens gradually limited their clinical application.1
The development of new pyrimidine compounds have been an
active topic in discovering highly potential antimicrobial agents.
5-Fluorouracil (5-FU), a known anticancer drug which target the
nucleotide synthetic enzyme thymidylate synthase and disrupt
DNA synthesis and thus inhibit the growth of cell,2 is an
antimetabolite of the pyrimidine derivative in which the fluoro
and oxo groups play positive roles in exerting bioactivity.
However, so far the 5-fluorouracil-based antimicrobial research
has been seldom observed. Therefore, it is of great interest for us
to employ pyrimidine-containing 5-FU as a constructing block to
develop a series of hybrids of 5-FU and benzimidazole nucleus,
and investigate their antimicrobial potency.
OH
H3C
CH3
F3C
CF3
F
N
N
HN
N
F
F
N
CH3
HN
N
NH
GAL
O
ZHZ
NH
O
Figure 1. Structure of some antimicrobial benzimidazole derivatives.
Benzimidazoles exert various pharmacological activities such
as antiparasitic, anticancer, antihistaminic, antihypertensive,
antiulcer properties, and some of them have been successfully
developed as clinical drugs.3 This has drawn more and more
concern to investigate the other medicinal application of
benzimidazoles. Recently,
extensive biochemical and
pharmacological studies revealed that benzimidazoles possessed
large potentiality to inhibit the growth of bacterial and fungal
strains.4 Benzimidazole is structurally similar to purine, and its
derivatives could compete with purines, distinctly inhibiting the
synthesis of nucleic acids and proteins, thereby killing bacterial
strains or inhibiting their growth.5 Several benzimidazoles have
∗ Corresponding author. Tel./fax: +86-23-68254967.
E-mail: zhouch@swu.edu.cn (C.-H Zhou)
† PhD Candidate from India.
‡
Postdoctoral fellow from Medicinal and Process Chemistry Division, CSIR-
Central Drug Research Institute, Lucknow 226001, India

been found to easily interact with DNA and RNA.6
Aminobenzimidazole urea GAL as dual inhibitors could target
played a slight role in forming target compounds. Halobenzyl
halides and intermediate 3a underwent N-alkylation to produce
compounds 5a−j with a large difference in yields of 47−78%.
bacterial DNA gyrase and topoisomerase
to exert broad-
spectrum Gram-positive antibacterial activities.7 Benzimidazole
derivative ZHZ could effectively intercalate into calf thymus
DNA and block DNA replication, thus exerting powerful
antimicrobial activities (Fig. 1).8 All these findings clearly
pointed out that benzimidazole derivatives were promising
candidates for developing new antimicrobial agents.
As shown in Scheme 2, mono-substituted 5-FU derivatives 8
and 9 could be directly obtained from compound 2. The reaction
of o-phenylenediamine with alkyl halides or 1-(chloromethyl)-3-
fluorobenzene efficiently provided compounds 6 and 7 in the
presence of potassium carbonate and DMF, and the obtained
products were subsequently reacted with acid 2 in polyphosphate
(PPA) at 180 °C to produce target hybrids 8a−d and 9 in 66−71%.
1
All new compounds were characterized by H NMR, 13C NMR,
IR, and HRMS spectra.
The in vitro antimicrobial activities for all synthesized novel
benzimidazoles 3−5, 8 and 9 were evaluated against four Gram-
positive bacteria, four Gram-negative bacteria and four fungi
using two fold serial dilution technique recommended by
National Committee for Clinical Laboratory Standards
(NCCLS).10 Clinical drugs chloromycin, norfloxacin and
fluconazole were taken as positive control. The results of
antibacterial and antifungal screening are summarized in Table 1.
The antibacterial assay declared that most of the synthesized
benzimidazole derivatives exhibited moderate to excellent
activity against all the tested bacterial strains in vitro. Notably,
compound 5c displayed remarkable antibacterial activities
compared with chloromycin and norfloxacin. Towards fungi S.
cerevisiae, it displayed the highest antifungal activity (MIC = 1
µg/mL) among these prepared conjugates, which was 16-fold
more potent than fluconazole. This revealed that compound 5c
could serve as a lead compound in the development of more
effective board-spectrum antimicrobial agents.
Figure 2. Design of novel 5-fluorouracil-derived benzimidazoles.
Inspired by special features of benzimidazole and 5-FU, and
as a part of our ongoing research, it is worthwhile to introduce
benzimidazole ring into the N1-position of 5-FU core via
methylene group to form a new hybrid skeleton, which was
expected to show good antimicrobial activities through targeting
DNA (Fig. 2). Here, we explored the role of fluorine atom at 5-
position on benzimidazole ring due to its special structure and
unique properties. Various alkyl or aryl groups were introduced
into benzimidazole and 5-FU moiety to investigate the effect of
different substituents on biological activities. In order to explore
the importance of R2 fraction, we synthesized several compounds
without any substituents at 3-position of 5-FU. In view of the
above observations, a novel series of 5-FU benzimidazole
hybrids 3–5, 8 and 9 were designed and prepared. Their
antibacterial and antifungal activities were evaluated in vitro
against four Gram-positive bacteria, four Gram-negative bacteria
and four fungi strains. Moreover, the preliminary action
mechanism of highly active compound 5c was investigated by
interacting with DNA.
As shown in Table 1, the length of alkyl chain had significant
influence on biological activities. Generally, compounds bearing
short alkyl chain could effectively inhibit the growth of tested
microorganisms. Among alkyl derivatives, compound 4c with
pentyl groups showed strong anti-B. proteus activity with MIC
value of 8 µg/mL, which was comparable to or even better than
reference drugs norfloxacin (MIC = 8 µg/mL) and chloromycin
(MIC = 32 µg/mL). The replacement of pentyl fragment in hybrid
4c by ethyl or propyl group would lead to weaker activity against
B. proteus. Towards MRSA and S. aureus, benzimidazole
derivative 4c exhibited equivalent potency to chloromycin (MIC
= 16 µg/mL), which was more potentiality than compounds 4a
and 4b (MIC = 32 µg/mL). Surprisingly, shortening the length of
subsituents from pentyl to ethyl group led to the improvement of
activities against B. subtilis and E. coli. With regard to mono-
substituted 5-FU derivatives, compound 8a showed 4-fold
stronger activity than control drug chloromycin (MIC = 32
µg/mL) for E. coli DH52. When the length of alkyl chain was
extended to heptyl or even dodecyl groups, benzimidazoles 4d,
4e and 8d were not efficient to inhibit the growth of bacteria
even at high concentration. This might be explained by the
presence of long alkyl chain with good lipophilicity, which
makes them unfavorable for being delivered to binding sites.
These facts demonstrated that suitable side chain was necessary
for better antibacterial activities in drug design.
The target benzimidazole compounds and their intermediates
were prepared according to the synthetic route outlined in
Schemes 1 and 2. The reaction of commercially available 5-FU
with chloroacetic acid in presence of aqueous potassium
hydroxide afforded compound 2.9 Conjugates 3a and 3b were
efficiently prepared by cyclization of compound 2 and o-
phenylenediamine or its derivatives with yields of 80% and 78%,
respectively. The N-alkylation of intermediate 3a with a series of
alkyl bromides in acetonitrile at 70 °C with potassium carbonate
as base respectively afforded target alkyl benzimidazole
compounds 4a−e with yields ranging from 61% to 77% yields. It
was found that the length of aliphatic chain in alkyl bromides

O
O
NH
N
O
NH
N
F
O
iv
NH
NH
F
O
i
ii
R
N
F
O
O
N
H
1
2
OH
3a,
R = H
3b, R = F
iii
F
5a, R1 = H, R2 = H, R3 = H
5b, R1 = F, R2 = H, R3 = H
5c, R1 = H, R2 = F, R3 = H
R3
O
CH3
O
R2
R1
n
N
N
1
2
3
5d
, R = H, R = H, R = F
N
N
N
F
O
5e, R1 = Cl, R2 = H, R3 = H
5f, R1 = H, R2 = Cl, R3 = H
5g, R1 = H, R2 = H, R3 = Cl
N
N
O
R1
N
5h, R1 = H, R2 = H, R3 = CH3
5i, R1 = H, R2 = H, R3 = OCH3
5j, R1 = H, R2 = H, R3 = NO2
R2
H3C
n
4a-i
R3
4a 4b
, n = 1; , n = 2
4c, n = 5; 4d, n = 7; 4e, n =11
5a-l
Scheme 1. Reagents and conditions: i) chloroacetic acid, 10% potassium hydroxide, reflux, 76%; ii) o-phenylenediamine, polyphosphoric acid, 180 oC, 78−80%;
iii) substituted halobenzyl halide, potassium carbonate, acetonitrile, 70 °C, 47−78%; iv) alkyl bromide, potassium carbonate, acetonitrile, 70 °C, 61−77%.
Scheme 2. Reagents and conditions: v) alkyl bromide, potassium carbonate, DMF, r.t., 30−46%; vi) substituted halobenzyl halide, potassium carbonate, DMF,
r.t., 38%; vii) corresponding o-phenylenediamines, polyphosphoric acid, 180 oC, 66−77%; viii) corresponding o-phenylenediamine, polyphosphoric acid, 180 oC,
69%.
In comparison with alkyl benzimidazole compounds 4a−e and
8a−d, derivatives 5a−j and 9 bearing a variety of halobenzyl
groups exerted relatively better activities in inhibiting the growth
of tested strains. The activities of compound 5c with 3-
fluorobenzyl groups against S. aureus, B. subtilis, E. coli DH52
and E. coli JM109 were better than chloromycin. Moreover, its
anti-MRSA activity (MIC = 2 µg/mL) was 4-fold higher than
Antifungal screening revealed that some compounds also
showed good inhibition against various tested microbial strains
compared with standard drug fluconazole. Among the
synthesized compounds, derivatives 4c, 8a and 8b showed potent
activities against S. cerevisiae, which were superior to
fluconazole. When the length of alkyl side chain in compound 4c
was altered, the resulting derivatives 4a and 4b displyed weak
activities against S. cerevisiae. Halophenyl fragments also played
key role in antifungal potency. Fluorobenzyl derivative 5c
exhibited the highest antifungal activity (MIC = 1 µg/mL) among
these prepared conjugates of 5-FU and benzimidazole towards S.
cerevisiae, which was 16-fold higher than fluconazole.
Regrettably, all other benzimidazole compounds showed weak
antifungal activities against C. albicans and C. mycoderma.
norfloxacin (MIC
= 8 µg/mL) and 8-fold higher than
chloromycin (MIC = 16 µg/mL). For Gram-negative bacteria B.
typhi, it was the most sensitive to compound 5c among all
synthesized novel benzimidazole compounds. Removal of 3-
fluorobenzyl group at 3-position of 5-FU core in compound 5c
would produce benzimidazole 9, which afforded the best anti-B.
proteus activity with MIC value of 2 µg/mL, 4-fold higher than
norfloxacin. Considering the MIC values of 5b−d, it could be
found that biological activities largely depended on the position
of fluorine atom. Incorporation of methoxyl residue into benzene
ring of compound 3a generated benzimidazole 5i, which gave
improved potency towards the tested bacteria. The activity of
compound 5j with nitro group at 4-position of benzene ring
against B. subtilis (MIC = 32 µg/mL) and B. typhi (MIC = 32
µg/mL) was comparable to chloromycin. All the facts
demonstrated that not only the type and position of substitutions
at benzene ring but also the number of halobenzyl group exerted
important effect.
It was found that intermediate 3b displayed fairly good
activities against most of the tested bacterial and fungal strains in
comparison with compound 3a (Table 1). Particularly, compound
3b exerted 16-fold more active than intermediate 3a against S.
aureus, which was superior to reference drug chloromycin.
Towards S. cerevisiae, benzimidazole 3b exerted more inhibitory
activity than fluconazole. Consequently, the introduction of
fluorine on benzimidazole ring seemed to be favorable for their
antimicrobial efficacy.

Table 1 ClogP values and in vitro antibacterial and antifungal activities as MIC (µg/mL) for compounds 3−5, 8, 9 a,b,c,d
Gram-positive bacteria
Gram-negative bacteria
Fungi
Comp
ds
C.
mycoder
ma
S.
clogP
B.
S. aureus
M.
luteus
E. coli
(DH52)
E. coli
(JM109)
B.
proteus
C.
albicans
A.
flavus
MRSA
B. typhi
cerevisia
e
subtilis
128 68.66
16 1.75
64 6.34
64 6.34
16 1.75
128 68.66
1.16
64 6.34
128 68.66
32 3.47
64 6.34
512 49.63
512 49.63
512 49.63
64 6.34
128 68.66
16 1.75
> 512
64 6.34
16 1.75
32 3.47
32 3.47
32 3.47
512 49.63
512 49.63
128 68.66
512 49.63
64 6.34
> 512
64 6.34
32 3.47
32 3.47
128 68.66
16 1.75
16 1.75
16 1.75
32 3.47
128 68.66
32 3.47
32 3.47
32 3.47
64 6.34
128 68.66
32 3.47
32 3.47
64 6.34
128 68.66
128 68.66
64 6.34
64 6.34
> 512
0.47
0.69
2.2
3a
3b
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
8a
8b
8c
8d
9
8
2
0.21
8
1.16
32 3.47
32 3.47
16 1.75
32 3.47
64 6.34
64 6.34
64 6.34
>512
32 3.47
32 3.47
16 1.75
64 6.34
128 68.66
3.26
6.43
8.55
-
512 49.63
512 49.63
512 49.63
16 1.75
8
1.16
>512
512 49.63
512 49.63
512 49.63
128 68.66
512 49.63
8
1.16
8
1.16
512 49.63
256 137.24
64 6.34
256 137.24
128 68.66
> 512
512 49.63
32 3.47
128 68.66
512 49.63
32 3.47
> 512
512 49.63
512 49.63
64 6.34
> 512
> 512
> 512
> 512
> 512
> 512
512 49.63
> 512
> 512
> 512
> 512
> 512
> 512
> 512
4.58
4.86
4.86
4.86
6.00
6.00
6.00
5.58
4.42
4.06
1.02
1.54
4.19
6.31
2.40
-
512 49.63
16 1.75
128 68.66
128 68.66
512 49.63
128 68.66
2
0.21
4
0.59
> 512
> 512
2
0.21
> 512
> 512
8
1.16
4
0.59
8
1.16
32 3.47
>512
1
0.13
8
1.16
512 49.63
> 512
512 49.63
512 49.63
64 6.34
512
512 49.63
512 49.63
64 6.34
> 512
> 512
> 512
512 49.63
64 6.34
512 49.63
64 6.34
> 512
> 512
> 512
> 512
> 512
128 68.66
512 49.63
64 6.34
128 68.66
16 1.75
128 68.66
64 6.34
64 6.34
4
0.59
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
> 512
128 68.66
512 49.63
64 6.34
32 3.47
32 3.47
64 6.34
512 49.63
> 512
32 3.47
> 512
128 68.66
> 512
64 6.34
32 3.47
64 6.34
16 1.75
512 49.63
> 512
64 6.34
> 512
128 68.66
16 1.75
>512
32 3.47
> 512
64 6.34
512 49.63
>512
64 6.34
>512
32 3.47
> 512
> 512
>512
16 1.75
16 1.75
512 49.63
> 512
16 1.75
16 1.75
512 49.63
> 512
16 1.75
16 1.75
512 49.63
> 512
8
1.16
64 6.34
64 6.34
256 137.24
>512
32 3.47
64 6.34
512 49.63
> 512
2
2
0.21
0.21
16 1.75
16 1.75
64 6.34
512 49.63
16 1.75
-
4
8
0.59
1.16
32 3.47
32 3.47
32 3.47
> 512
64 6.34
64 6.34
> 512
32 3.47
32 3.47
64 6.34
>512
64 6.34
16 1.75
4
0.59
16 1.75
0.21
8
1.16
32 3.47
0.59
16 1.75
2
0.21
32 3.47
0.13
64 6.34
32 3.47
2
0.21
32 3.47
1.16
128 68.66
32 3.47
16 1.75
4
0.59
32 3.47
-
8
2
1.16
0.21
-
-
-
A
B
8
1.16
2
4
1
1
0.13
8
4
0.59
-
-
-
-
-
-
-
-
-
-
-
-
1
0.13
4
0.59
16 1.75
256 137.24
-
C
a Minimum inhibitory concentrations were determined by micro broth dilution method for microdilution plates.
b A = Chloromycin, B = Norfloxacin, C = Fluconazole.
c
MRSA, Methicillin-Resistant Staphylococcus aureus N315; S. aureus, Staphylococcus aureus ATCC25923; B. subtilis, Bacillus subtilis ATCC6633; M. luteus,
Micrococcus luteus ATCC4698; E. coli DH52, Escherichia coli; E. coli JM109, Escherichia coli; B. proteus, Bacillus proteus ATCC13315; B. typhi, Bacillus
typhi; C. albicans, Candida albicans ATCC10231; C. mycoderma, Candida mycoderma ATCC9888; S. cerevisia, Saccharomyces cerevisia; A. flavus,
Aspergillus flavus ATCC204304.
d ClogP values were calculated by ChemDraw Ultra 10.0.
Lipophilicity/hydrophilicity properties had significant effect
on exerting biological activity.11 Accordingly, the calculated
liposome/water partition coefficients (ClogP) by ChemDraw
Ultra 10.0 software could be applied to analyze antimicrobial
activities. The calculated values of ClogP were shown in Table 1.
The data demonstrated that most of compounds with lower
values of ClogP showed better antimicrobial activities. As seen
from Table 1, the ClogP values of compounds 4a−d and 8a−d
generally increased with the increase of alkyl length, and their
potencies were gradually reduced, which might be explained by
the possibility that higher lipophilic compounds were
unfavourable for being delivered to the binding sites in organism.
However, these were not available for compounds 5h−j. All
those facts confirmed the significant role of suitable lipophilicity
in drug design.
from the Protein Data Bank, which was a representative target to
investigate the antibacterial mechanism. Target compound 5c
was found to dock into the DNA topoisomerase IA (Topo IA)
through three hydrogen bonds by the use of fluorine atom and
oxygen atoms in 5-fluorouracil with the residue Lys 423
(Supplementary data).
In summary, a new series of 5-FU benzimidazoles were
successfully developed for the first time via an easy, convenient
and efficient synthetic procedure starting from commercial 5-
fluorouracil. All the new compounds were confirmed by 1H NMR,
13C NMR, IR and HRMS. The in vitro antimicrobial activities
manifested that some prepared compounds exhibited good or
even superior antibacterial and antifungal activities against the
tested strains to the reference drugs chloromycin, norfloxacin and
fluconazole. Hybrids 4a, 8a and 8b showed significant inhibition
against all tested strains with low inhibitory concentrations in
range of 2–64 µg/mL. Especially, benzimidazole derivative 5c
was efficacious in inhibiting the growth of MRSA (MIC = 2
µg/mL) and B. proteus (MIC = 4 µg/mL). Towards fungi S.
cerevisiae, it gave the highest antifungal activity (MIC = 1
µg/mL) among these prepared conjugates, which was 16-fold
higher than fluconazole. Experimental research revealed that
compound 5c could effectively intercalate into calf thymus DNA
to form compound 5c–DNA complex which might block DNA
replication and thus exert antimicrobial activities. Molecular
docking indicated that compound 5c should bind with DNA
topoisomerase IA through three hydrogen bonds by the use of
fluorine atom and oxygen atoms in 5-fluorouracil with the
residue Lys 423. Further researches, including the in vivo
bioactive evaluation, bacterial membrane permeabilization,
time−kill kinetic assay, toxicity, and some effect factors on
antimicrobial activities such as other heterocyclic azole rings
(benzotriazole, imidazole, triazole and their derivatives), various
functional groups (amino, halogen and nitro groups, etc.) linked
to benzimidazole fragment as well as other substituents on 5-
fluorouracil backbone are now in progress in our group.
DNA is a significant information molecule encoding genetic
instructions used in the development and function of almost all
known living organisms. It has been regarded as an important
target for studies of bioactive molecules like antimicrobial
drugs.12 Thus, the study of the interaction of small molecules
with DNA is propitious to understand action mechanism of drugs
at molecular level, and to rationally design and construct new and
efficient drugs targeting DNA. In order to explore possible
antimicrobial action mechanism, binding behavior of highly
active compound 5c with calf thymus DNA (a DNA model with
medical importance, low cost and ready availability properties)
was studied in vitro by UV−vis spectroscopic and fluorescent
methods.13-16 The results indicated that compound 5c could
effectively intercalate into calf thymus DNA by forming
compound 5c–DNA complex which might block DNA
replication and thus exert antimicrobial activities (Supplementary
data).
To rationalize the observed antibacterial activity and
understand the possible mechanism of the hybrids, a flexible
ligand receptor docking investigation was undertaken. The
crystal structure data (DNA topoisomerase IA) was obtained

6. (a) Ivanov, A. A.; Salyanov, V. I.; Streltsov, S. A.; Cherepanova,
N. A.; Gromova, E. S.; Zhuze, A. L. Bioorg. Chem. (Moscow)
2011, 37, 472; (b) Ivanov, A. A.; Koval, V. S.; Susova, O. Yu.;
Salyanov, V. I.; Oleinikov, V. A.; Stomakhin, A. A.;
Shalginskikh, Natalya. A.; Kvasha, M. A.; Kirsanova, O. V.;
Gromova, E. S.; Zhuze, A. L. Bioorg. Med. Chem. Lett. 2015, 25,
2634.
Acknowledgments
This work was partially supported by National Natural
Science Foundation of China [No. 21172181, 21372186,
81450110451 (the Research Fund for International Young
Scientists from International (Regional) Cooperation and
Exchange Program)], Chongqing Special Foundation for
Postdoctoral Research Proposal (Xm2015031).
7. Grillot, A.-L.; Tiran, A. L.; Shannon, D.; Krueger, E.; Liao, Y.;
O’Dowd, H.; Tang, Q.; Ronkin, S.; Wang, T.; Waal, N.; Li, P.;
Lauffer, D.; Sizensky, E.; Tanoury, J.; Perola, E.; Grossman, T.
H.; Doyle, T.; Hanzelka, B.; Jones, S.; Dixit, V.; Ewing, N.; Liao,
S.; Boucher, B.; Jacobs, M.; Bennani, Y.; Charifson, P. S. J. Med.
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Supplementary data
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839.

Graphical Abstract
Design, synthesis and biological evaluation of
5-fluorouracil-derived benzimidazoles as novel
type of potential antimicrobial agents
Leave this area blank for abstract info.
Xue-Jie Fang, Ponmani Jeyakkumar†, Srinivasa Rao Avula‡, Qian Zhou, Cheng-He Zhou*