Computer-aided drug discovery: Novel 3,9-disubstituted eudistomin U derivatives as potent antibacterial agents

Article abstract of DOI:10.1016/j.ejmech.2018.08.001

Thirty-two new 3,9-disubstituted eudistomin U derivatives were designed and synthesized based on computer-aided drug discovery (CADD). Sixteen 3,9-disubstituted eudistomin U derivatives (6a–6p) have exhibited potent antibacterial activity. Specially, the most active compound 6p displayed better activity than commercial drugs fosfomycin sodium, ciprofloxacin and propineb, with a peak minimum inhibitory concentration (MIC) of 1.5625 μmol/L. The antibacterial mechanism indicated that these compounds could exert bactericidal effect by damaging bacterial cell membrane and disrupting the function of DNA gyrase.

Full text of DOI:10.1016/j.ejmech.2018.08.001

Accepted Manuscript
Computer-aided drug discovery: Novel 3,9-disubstituted eudistomin U derivatives as
potent antibacterial agents
Jiangkun Dai, Wenjia Dan, Na Li, Junru Wang
PII:
S0223-5234(18)30656-1
10.1016/j.ejmech.2018.08.001
EJMECH 10612
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 2 July 2018
Revised Date: 31 July 2018
Accepted Date: 1 August 2018
Please cite this article as: J. Dai, W. Dan, N. Li, J. Wang, Computer-aided drug discovery: Novel 3,9-
disubstituted eudistomin U derivatives as potent antibacterial agents, European Journal of Medicinal
Chemistry (2018), doi: 10.1016/j.ejmech.2018.08.001.
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Computer-aided drug discovery: novel 3,9-disubstituted
eudistomin U derivatives as potent antibacterial agents
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Jiangkun Dai, Wenjia Dan, Na Li and Junru Wang*
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College of Chemistry & Pharmacy, Northwest A&F University, 22 Xinong Road,
Yangling 712100, Shaanxi, China.
*Corresponding author
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Tel./fax: +86-29-8709-2829. E-mail address: wangjunru@nwafu.edu.cn (J.-R. Wang)
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ABSTRACT
Thirty-two new 3,9-disubstituted eudistomin U derivatives were designed and
synthesized based on computer-aided drug discovery (CADD). Sixteen
3,9-disubstituted eudistomin U derivatives (6a–6p) have exhibited potent antibacterial
activity. Specially, the most active compound 6p displayed better activity than
commercial drugs fosfomycin sodium, ciprofloxacin and propineb, with a peak
minimum inhibitory concentration (MIC) of 1.5625 µmol/L. The antibacterial
mechanism indicated that these compounds could exert bactericidal effect by
damaging bacterial cell membrane and disrupting the function of DNA gyrase.
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Keywords: eudistomin U; design; synthesis; antibacterial; molecular docking;
mechanism.
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1. Introduction
Infections caused by bacterial pathogens are a major cause of morbidity and
mortality worldwide.[1] Although the successful treatment of such infections by
antibiotic drugs is widely regarded as a major medical breakthrough of the 20th
century, this achievement may not be sustainable in the future, as bacteria have
counteracted antibiotic pressure and developed or acquired resistances that render
formerly efficacious drugs inactive.[2] Moreover, the intensive antibacterial discovery
effort has seen a dramatic decline in the large pharmacy industry in the last two
decades.[3] “The cost in terms of lost global production between now and 2050 would
be an enormous 100 trillion USD if we do not take action,” as a UK Government
report states.[4] Therefore, a new antibacterial drug is urgently needed.
DNA gyrase is a type II topoisomerase which is independently essential for
bacterial DNA replication. Specifically, it is primarily responsible for introducing
negative supercoils into conformationally constrained DNA.[5] As DNA gyrase is
absent in humans it is an appealing antibacterial target with quinolones developed as a
successful class of antibiotics.[5, 6] Mechanism of DNA gyrase inhibition is known to
occur in two ways: these inhibitors may bind DNA gyrase directly or they may bind to
DNA and alter its structure, so that it cannot be recognized by DNA gyrase.[7]
Natural products are an important source of antibacterial agents.[8] Eudistomin
U L1 (Fig. 1), isolated from several species of marine ascidians, exhibited good
antibacterial activity (IC50 = 22.61 µmol/L against Staphylococcus aureus).[9]
Interestingly, it per se has two planar structure molecules, β-carboline and indole,
which is similar to the commercial quinolones to some extent. Recently, Mulcahy’s
group reported that eudistomin U could bind to DNA.[10] Moreover, many studies of
quinolones’ antibacterial mechanisms have dismissed these enzymes per se as target
and point to DNA as the direct binding species.[6, 11] So we speculate that the action
mode of eudistomin U is binding to DNA area, resulting to the altering DNA structure
could not be recognized by DNA gyrase.
Despite eudistomin U L1 exhibiting good antibacterial potency, its activity is not
sufficient to compete with commercial antibiotics, hindering its potential as a new
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bactericide. Here in an effort to enhance the antibacterial activity we designed some
eudistomin U derivatives (Fig. 1) based on computer-aided drug discovery (CADD),
molecular docking evaluation. Moreover, we studied their antibacterial mechanism
based on the most active compound.
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Fig. 1. Design of antibacterial eudistomin U analogues based on computer-aided drug discovery.
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2. Results and Discussion
2.1. Design based on CADD
CADD has emerged as a highly successful way to find quality leads for
subsequent optimization into drug candidates and approved new medicines.[12] Based
on our speculation, the DNA gyrase-DNA complex (PDB ID: 5IWM) was selected as
a template target and eudistomin U scaffold was retained as the ligand core, but was
elaborated at the C-3, N-9 and N'-1 positions with various chemical moieties. The
Surflex-Dock scoring function is a weighted sum of non-linear functions, mainly
involving hydrophobic and polar complementarity, with additional terms for entropic
and solvation effects.[13] The scores are expressed in -log10(Kd) units to represent
binding affinities. As shown in Fig. 1, the score values gradually increased with
changes in modifying groups, indicating the enhanced activity. Compounds L1 and
L2 completely bind to DNA area and compounds L3 and L4 mainly interact with
DNA, which confirms our proposed inference.
2.2. Chemistry
To realize a synthetic pathway for preparing analogues bearing the eudistomin U
core we felt that the 1H-indole-3-carbaldehyde 1 would serve as a useful raw material
(Fig. 2). Compound 2 was easily prepared by the acetylation reaction using acetic
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anhydride with 98% yield. Application of the known synthetic procedures of Waters et
al.,[14] Pictet-Spengler condensation of 2 and tryptophan methyl ester provided
tetrahydro-β-carboline 3 as diastereomers (86% yield). Dehydrogenation of 3 under
the oxygen with Pd/C as catalyst proceeded smoothly, affording 4 (L2) in 74% yield.
Further this scaffold 4 was confirmed by x-ray single crystal diffraction (CCDC
1848195). With this compound 4 in hand, attention was focused on modifying the N-9
position. Benzyl group in this position significantly increased the scores (Fig. 1). So
we synthesized a series of eudistomin U derivatives 5a–5p (81–96% yields) with
diverse substituted benzyl group on the N-9 position which varied in
electron-inducing ability and substitution position. Subsequently, eudistomin U
analogues 6a–6p (78–95% yields) with hydrophilic hydroxyl and secondary amine
groups were converted under NaBH4 and CaCl2.
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Fig. 2. Synthesis of the eudistomin U derivatives. a) Ac2O, Et3N, DMAP, DCM, 0 oC ~ r.t., 3 h; b)
o
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(i) Trp-COOMe, methylbenzene, reflux, 2 h; (ii) DCM:TFA (2:1), 0 C ~ r.t., 23 h; c) Pd/C, O2,
xylene, 150 oC, 48 h; d) K2CO3, CH3CN, benzyl bromide, 80 oC, 3 h; e) NaBH4, CaCl2, EtOH, r.t.,
0.5 h.
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All the structures of the target compounds (4, 5a–5p and 6a–6p) were confirmed
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by H NMR, C NMR and HRMS spectra. In the H NMR spectra of compound 6p
(Supporting Information), the signals of the secondary amine and the hydroxyl group
were detected around δ = 9.05 ppm and δ = 3.58 ppm, respectively. Moreover, the
signals of the methylene carbon atoms were detected around 64.87 and 47.03 ppm in
13C NMR, respectively. In addition, the signal of [M+H]+ could be found at 482.0853
Da in HRMS of compound 6p (error = 1.86 ppm), which conformed to the theoretical
value 482.0862 Da within the allowable error range (error < 5 ppm).
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2.3. Antibacterial activity and structure–activity relationship (SAR)
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S. aureus and methicillin-resistant S. aureus (MRSA) are the leading causes of
bacterial infections in humans with symptoms ranging from simple skin infections to
severe necrotizing fasciitis and pneumonia.[15] Bacillus cereus could cause food
poisoning through the production of distinct toxins.[16] Ralstonia solanacearum is a
major component of plant pathogens.[17] So three Gram-positive bacteria (S. aureus,
MRSA and B. cereus) and one Gram-negative bacteria (R. solanacearum) was
selected as the tested bacteria in this work. Thirty-three compounds (4, 5a–5p and 6a–
6p) were evaluated for their in vitro antibacterial activity through double dilution
method, with fosfomycin sodium, ciprofloxacin and propineb as the positive controls
(Table 1).
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Sixteen compounds (6a–6p) displayed better activity against S. aureus compared
with the commercial drug fosfomycin sodium (MIC = 100 µmol/L). Specifically, the
MIC of compounds 6c, 6f and 6p (MIC = 3.125 µmol/L) was equal to the commercial
drug ciprofloxacin. Six compounds (6d, 6f, 6g, 6j, 6m and 6p) displayed equal or
superior activity against MRSA compared with fosfomycin sodium (MIC = 50
µmol/L). It was worth mentioning that compounds 6j and 6p have showed about
4-fold superiority than ciprofloxacin (MIC = 12.5 µmol/L) against MRSA. Eleven
compounds (6a, 6c, 6d, 6f, 6g, 6j, 6l, 6m, 6n, 6o and 6p) displayed equal or superior
activity against B. cereus compared with fosfomycin sodium (MIC = 25 µmol/L).
Specially, four compounds (6c, 6f, 6j and 6p) have exhibited about 2-fold superiority
than ciprofloxacin. Compared with the commercial agrochemical bactericide propineb
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Table 1. Antibacterial activity and TPSA values of eudistomin U analogues (MIC, µmol/L).
Compd.
4
S. aureus
>100
>100
12.5
>100
25
MRSA
>100
>100
100
B. cereus
>100
>100
12.5
100
R. solanacearum
>100
>100
12.5
>100
12.5
>100
3.125
>100
12.5
>100
50
TPSAb
76.99
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
66.14
53.84
NCc
5a
6a
5b
6b
5c
>100
>100
>100
100
50
>100
3.125
>100
25
>100
3.125
>100
25
6c
5d
6d
5e
>100
25
>100
50
>100
100
>100
50
6e
5f
>100
3.125
>100
25
>100
12.5
>100
25
>100
3.125
>100
25
>100
3.125
>100
25
6f
5g
6g
5h
6h
5i
>100
25
>100
>100
>100
>100
>100
3.125
>100
>100
>100
>100
>100
50
>100
50
>100
25
>100
25
>100
50
>100
50
6i
5j
>100
6.25
100
>100
3.125
>100
50
>100
6.25
>100
25
6j
5k
6k
5l
25
>100
25
>100
25
>100
50
6l
5m
6m
5n
6n
5o
6o
5p
6p
F.S.a
C.a
P.a
>100
25
>100
12.5
>100
25
>100
12.5
>100
50
>100
12.5
>100
25
>100
>100
>100
>100
>100
3.125
50
>100
25
>100
25
>100
3.125
100
>100
3.125
25
>100
1.5625
50
3.125
12.5
6.25
3.125
25
NCc
50
25
50
NCc
aF.S. = Fosfomycin sodium, C. = Ciprofloxacin, P. = Propineb.
bTPSA = Topological polar surface area.
cNC = No calculation.
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(MIC = 25 µmol/L) against R. solanacearum, twelve compounds (6a, 6b, 6c, 6d, 6f,
6g, 6h, 6j, 6k, 6m, 6o and 6p) exhibited equal or better activity with a peak MIC
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lower than 1.5625 µmol/L, 16-fold superiority. Compound 6p was considered to be
the highly active eudistomin U derivative which exhibited better activity than these
three commercial drugs.
In general, the activity data of compounds 6a–6p conformed to our design. To
explore the loss in activity of compounds 4 and 5a–5p, we calculated the topological
polar surface area (TPSA) values (Table 1), which was used extensively in medicinal
chemistry to predict absorption and optimize a compound's membrane
permeability.[18, 19] The larger the value, the poorer the absorption and membrane
permeability. Obviously, the TPSA values of compounds 4 and 5a–5p were greater
than compounds 6a–6p, which indicated that the loss in activity might be due to these
compounds could not completely penetrate the cell membrane to active on the target.
SAR studies for diverse substituted benzyl group on the N-9 position could provide
some guidance for future design of eudistomin U-based antibacterial agents.
Electron-donating methyl and electron-withdrawing trifluoromethyl groups
incorporated into the meta-position of the benzyl backbone were better than that on
ortho- and para-positions. Electron-withdrawing fluorine, chlorine and bromine
substituents on para-position displayed higher activity than that on ortho- and
meta-positions.
2.4. Preliminary antibacterial mechanism
2.4.1. Fluorescence microscopy analysis
The highly active compound 6p and S. aureus were selected to explore the
antibacterial mechanism. Two dyes, Hoechst (2'-(4-ethoxyphenyl)-5-(4-methyl
-1-pipe-razinyl)-2,5'-bi-1H-benzimidazoletrihydrochl-oride) and PI (propidium
iodide), were used to differentiate between cells with either an intact or a damaged
membrane (Fig. 3).[20] Hoechst can easily permeate the membrane of intact cells and
show blue fluorescence regardless of cell viability. In contrast, PI is a DNA
intercalator but lacks cell permeability which fluoresces in red only when cell
membranes are disrupted. As shown in Fig. 3A, S. aureus exhibited blue fluorescence
in the absence of compound 6p, whereas no fluorescence was showed in the PI
channel, indicating the membranes of S. aureus were intact. However, after S. aureus
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was incubated with 6p for 1 h, they were stained by both Hoechst and PI, suggesting
that the membranes of S. aureus were damaged (Fig. 3B).
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Fig. 3. Fluorescence micrographs of S. aureus treated or not treated with 6p for 1 h. (A1) no
treatment, Hoechst stained; (A2) no treatment, PI stained; (A3) no treatment, merge graph; (B1) S.
aureus treatment with 6p, Hoechst stained; (B2) S. aureus treatment with 6p, PI stained; (B3) S.
aureus treatment with 6p, merge graph.
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2.4.2. Scanning electron microscopy analysis
SEM of S. aureus revealed morphological changes in the bacterial cell surface
(Fig. 4). The surfaces of cells in the untreated group (Fig. 4A) was relatively smooth
and regular, whereas when treated with compound 6p (Fig. 4B) there was rough and
irregular. Increased permeabilization of the membrane may explain the leakage of
cytoplasmic material.[21]
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Fig. 4. SEM of S. aureus cells: (A) blank group, left; (B) treated group (6p), right.
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2.4.3. Transmission electron microscope analysis
To further characterize the bactericidal effects of compound 6p, TEM was also
used to visualize the morphological changes of S. aureus cells (Fig. 5). In the absence
of compound 6p, the S. aureus cells showed a well-defined cell membrane. After S.
aureus cells were treated with compound 6p for 1h, the cells lose or began to lose the
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clear boundary of cell membrane.[22] Overall, the compound 6p could increase
permeabilization and disrupt integrity of the cell membrane.
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Fig. 5. TEM of S. aureus cells: (A) blank group, left; (B) treated group (6p), right.
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2.4.4. Molecular docking study
Molecular docking studies allow us to visualize the molecular interactions
between compound 6p and DNA gyrase-DNA complex. The docking evaluation gave
a good total score (7.4079) for compound 6p. As shown in Fig. 6, compound 6p
completely bound to DNA area. DNA binding agents tend to interact noncovalently
with the host molecule through two general modes: in a groove-bound fashion and
intercalative association.[23] Obviously, the mainly binding mode was groove-bound
fashion in Fig. 6. Moreover, the eudistomin U core completely bound to DNA in a
groove-bound fashion stabilized by a mixture of carbon–hydrogen bond, π–π stacked,
π–donor hydrogen bond and hydrogen bonds. Specially, the hydroxyl and secondary
amine fragments of compound 6p were adjacent to DA10 and DA11, forming two
strong hydrogen bonds (1.96 and 2.13 Å), respectively. The benzyl group bound to
DNA through an intercalative association mode. Interestingly, the bromobenzene ring
was locked into the DNA base pairs through π–alkyl bonds between bromine atom
and DA10, DA11. The score (7.4079) of 6p is lower than L4 (7.5577). However, 6p
exhibited better activity, indicating completely binding to DNA area may be favorable
for improving the activity.
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Fig. 6. Three-dimensional conformations of compound 6p docked in DNA gyrase-DNA complex.
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2.4.5. Isothermal titration calorimetry measurements
To investigate the binding studies, calf thymus DNA was selected as DNA model
because of its medical importance, low cost and ready availability properties.[6, 24]
Isothermal titration calorimetry (ITC),[25] which could give direct measurement of
the dissociation constant, the stoichiometry, the heat of reaction, and indirect access to
other thermodynamic parameters such as entropic binding contribution or Gibbs free
energy, was carried out to study the interactions of 6p with DNA. As shown in Fig. 7,
the pink purple dotted line corresponded to a binding model with a 1:1 stoichiometry
and was fitted with the change of enthalpy ∆H = −26.73 kJ/mol, entropy ∆S = 30.14
J/mol·K and free energy ∆G = −35.72 kJ/mol. The data indicated that the binding was
enthalpy-driven and entropy-driven spontaneous reaction.[26] The large negative
enthalpy change mainly contributed by hydrogen bonds, favored the molecular
docking results.[27] The dissociation constant Kd and binding constant Ka values were
5.526 × 10−7 M and 1.810 × 106 M−1, respectively. According to the calculation
formula, Score = −log10(Kd), the calculated score is 6.2576, which is close to the
molecular docking score 7.4079. The difference between these two scores may be
mainly caused by differences in DNA, which need further research.
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Fig. 7. Calorimetric titration of the DNA with compound 6p at 298 K. (A) Heat flow as a function
of time (green); (B) The pink purple dotted line corresponds to the theoretical independent model.
The thermodynamic constants are presented in the pane.
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The antibacterial mechanism was deduced that compound 6p might attack
the bacterial cell membrane and cause the membrane damage. The consequent
increased membrane permeability will then allow 6p to enter the cells. The
compound 6p in the cytoplasm will interact further with DNA, which in turn
disrupt the function of DNA gyrase and cause cell death. Overall, these
compounds could exert bactericidal effect by damaging bacterial cell membrane
and disrupting the function of DNA gyrase.
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3. Conclusions
In conclusion, 3,9-disubstituted eudistomin U derivatives have exhibited potent
antibacterial activity by damaging bacterial cell membrane and disrupting the function
of DNA gyrase. The most active compound 6p displayed better activity than
commercial drugs, 4-fold superiority against MRSA than ciprofloxacin and 16-fold
superiority against R. solanacearum than propineb. Overall, this work demonstrated
here the antibacterial potential of eudistomin U scaffold, enriched the types of
candidate antibiotics and provided more options for solving the current antibiotic
crisis.
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Acknowledgement
This work was funded by the National Natural Science Foundation of China
(Grant No. 81773603), the Open Foundation of Key Laboratory of Synthetic and
Natural Functional Molecule Chemistry of Ministry of Education and the State Key
Laboratory of Drug Research (Grant No. SIMM1705KF-09).
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Appendix A. Supplementary data
Supplementary data related to this article can be found.
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Conflict of interest
The authors state no conflict of interest.
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References
[1] B. S. Moore, G. T. Carter and M. Bronstrup, Nat. Prod. Rep. 34 (2017) 685
[2] R. Laxminarayan, A. Duse and O. Cars, Lancet. Infect. Dis. 13 (2013) 1057
[3] O. Genilloud, Nat. Prod. Rep. 34 (2017) 1203 1232.
–
686.
1098.
–
–
[4] J. O’Neill, Review on antimicrobial resistance, Government of the UK
http://apo.org.au/node/63983.
. 2016,
[5] M. D. Wallace, N. F. Waraich, A. W. Debowski, J. S. Mylne and K. A. Stubbs, Chem.
Comm. 54 (2018) 1869 1872.
[6] S. F. Cui, D. Addla and C. H. Zhou, J. Med. Chem. 59 (2016) 4488
[7] J. Kovvuri, B. Nagaraju, V. L. Nayak, R. Akunuri, M. Rao, A. Ajitha, N. Nagesh and A.
Kamal, Eur. J. Med. Chem. 143 (2018) 1563 1577.
–
–
4510.
–
[8] W. C. Chu, P. Y. Bai, Z. Q. Yang, D. Y. Cui, Y. G. Hua, Y. Yang, Q. Q. Yang, E.
Zhang and S. S. Qin, Eur. J. Med. Chem. 143 (2018) 905–921.
[9] C. M. Roggero, J. M. Giulietti and S. P. Mulcahy, Bioorg. Med. Chem. Lett. 24 (2014)
3549
[10] J. M. Giulietti, P. M. Tate, A. Cai, B. Cho and S. P. Mulcahy, Bioorg. Med. Chem.
Lett. 26 (2016) 4705 4708.
[11] L. L. Shen, L. A. Mitscher, P. N. Sharma, T. J. O’Donnell, D. W. T. Chu, C. S.
–3551.
–
Cooper, T. Rosen and A. G. Pernet, Biochemistry, 28 (1989) 3886
–3894.
13

ACCEPTED MANUSCRIPT
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
[12] J. Honegr, D. Malinak, R. Dolezal, O. Soukup, M. Benkova, L. Hroch, O. Benek, J.
Janockova, K. Kuca and R. Prymula, Eur. J. Med. Chem. 146 (2018) 38–46.
[13] T. A. Pham and A. N. Jain, J. Med. Chem. 49 (2006) 5856
[14] J. D. Panarese and S. P. Waters, Org. Lett. 12 (2010) 4086
–
–
5868.
4089.
[15] I. N. Cvijetić, T. Ž. Verbić, P. E. de Resende, P. Stapleton, S. Gibbons, I. O. Juranić,
B. J. Drakulić and M. Zloh, Eur. J. Med. Chem. 143 (2018) 1474–1488.
[16] J. K. Dai, W. J. Dan, N. Li, R. X. Wang and J. R. Wang, Food Chem. 253 (2018) 211
220.
–
[17] J. K. Dai, W. J. Dan, N. Li, H. T. Du, J. W. Zhang and J. R. Wang, Bioorg. Med.
Chem. Lett. 26 (2016) 580–583.
[18]
www.molinspiration.com.
[19] W. Hou, G. J. Zhang, Z. Luo, D. Li, H. Q. Quan, B. H. Ruan, L. Su and H. T. Xu,
Bioorg. Med. Chem. Lett. 27 (2017) 5382 5386.
Molinspiration
Cheminformatics,
Cheminformatics
on
the
Web.
–
[20] M. Su, D. L. Xia, P. Teng, C. Zhang, T. Odom, A. Cao, Y. Hu and J. F. Cai, J. Med.
Chem. 60 (2017) 8456–8465.
[21] R. Sharma, S. Patel and C. Abboud, Int. J. Antimicrob. Ag. 49 (2017) 224–232.
[22] J. Miao, J. Zhou, G. Liu, F. Chen, Y. Chen, X. Gao, W. Dixon, M. Song, H. Xiao and
Y. Cao, Food Control 59 (2016) 609–613.
[23] E. C. Long and J. K. Barton, Accounts Chem. Res. 23 (1990) 271–273.
[24] S. F. Cui, Y. Ren, S. L. Zhang, X. M. Peng, G. L. V. Damu, R. X. Geng and C. H.
Zhou, Bioorg. Med. Chem. Lett. 23 (2013) 3267–3272.
[25] O. Callies and A. Hernandez Daranas, Nat. Prod. Rep. 33 (2016) 881–904.
[26] P. S. Nagle, F. Rodriguez, B. Nguyen, W. D. Wilson and I. Rozas, J. Med. Chem. 55
(2012) 4397–4406.
[27] A. Basu and G. S. Kumar, J. Agric. Food Chem. 62 (2014) 317–326.
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ACCEPTED MANUSCRIPT
Highlights
ò Thirty-two new eudistomin U derivatives were designed and synthesized based on
CADD.
ò These compounds exerted bactericidal effect by damaging bacterial cell membrane
and disrupting the function of DNA gyrase.
ò Compound 6p displayed better activity than commercial drugs.