Synthesis and Biological Evaluation of Novel FtsZ-targeted 3-arylalkoxy-2,6-difluorobenzamides as Potential Antimicrobial Agents

Article abstract of DOI:10.1111/cbdd.12658

Novel series of 3-O-arylalkylbenzamide and 3-O-arylalkyl-2,6-difluorobenzamide derivatives were synthesized and evaluated for their on-target activity and antibacterial activity. The results indicated that the 3-O-arylalkyl-2,6-difluorobenzamide derivativ

Full text of DOI:10.1111/cbdd.12658

Chem Biol Drug Des 2016; 87: 257–264
Research Letter
Synthesis and Biological Evaluation of Novel FtsZ-
targeted 3-arylalkoxy-2,6-difluorobenzamides as
Potential Antimicrobial Agents
Shengsheng Qiang1, Changde Wang1, Henrietta
bacterial pathogens worldwide necessitates the develop-
ment of structurally novel antibacterial agents possessing
new mechanisms of action.
Venter2, Xin Li1, Yi Wang1, Liwei Guo1, Ruixin
Ma3 and Shutao Ma1,*
1Department of Medicinal Chemistry, Key Laboratory of
FtsZ (filamentous temperature-sensitive protein Z) is a
Chemical Biology (Ministry of Education), School of
Pharmaceutical Sciences, Shandong University, 44, West
Culture Road, Jinan 250012, China
widely distributed key cytoskeletal protein in archaea and
bacteria, which offers an essential skeleton for the forma-
tion of Z-ring in the presence of guanosine triphosphate
(GTP) during bacterial cell division (4). Thus, FtsZ is con-
sidered as an attractive target to develop antibacterial
agents with selective toxicity to bacterial pathogens due to
its absence in the mitochondria of higher eukaryotes and
evolutionary distance from tubulin (5).
2School of Pharmacy & Medical Sciences, Sansom
Institute for Health Research, University of South Australia,
GPO Box 2471, Adelaide, SA 5001, Australia
3Affiliated Hospital of Medical College, Qingdao University,
Qingdao 266003, China
*Corresponding author: Shutao Ma,
mashutao@sdu.edu.cn
The authors ‘Shengsheng Qiang’ and ‘Changde Wang’
contributed equally to the work.
Various studies have been conducted in recent years for
finding the FtsZ inhibitors that exert their antibacterial
activity by disturbing the polymerization behavior or the
activated GTPase of FtsZ or both of them crucial for the
formation and contraction of Z-ring (6–8). The FtsZ inhibi-
tors are mainly some natural products such as totarol and
curcumin (Figure 1) or small synthesized molecules (9–11).
Among them, 3-methoxybenzamide (3-MBA) (Figure 1) is
one of most attractive starting point for discovering more
potent FtsZ inhibitors. For example, PC190723 (Figure 1)
as a 3-MBA derivative exhibits potent antibacterial activity
against Bacillus subtilis and various resistant staphylococci
by inhibiting the GTPase activity and localization of FtsZ
(12). The preliminary structure-activity relationship (SAR)
demonstrates that the replacement of the 3-methoxy
group of 3-MBA with various groups could result in drug-
like 3-MBA derivatives with a substantial improvement in
on-target antibacterial activity (13–15). The docking model
also predicts an enough space equivalent in length to at
least 9–10 carbons for substitutions off the mother nucleus
of benzamide (16).
Novel series of 3-O-arylalkylbenzamide and 3-O-ary-
lalkyl-2,6-difluorobenzamide derivatives were synthe-
sized and evaluated for their on-target activity and
antibacterial activity. The results indicated that the
3-O-arylalkyl-2,6-difluorobenzamide derivatives pos-
sessed much better on-target activity and antibacterial
activity than the 3-O-arylalkylbenzamide derivatives.
Among them, 3-O-chlorobenzyl derivative 36 was the
most effective in antibacterial activity (0.5, 4, and 8 lg/
mL) against Bacillus subtilis ATCC9372, methicillin-re-
sistant Staphylococcus aureus ATCC29213, and
penicillin-resistant Staphylococcus aureus PR, while
3-O-methylbenzyl derivative 41 only exhibited the most
potent activity (2 lg/mL) against Staphylococcus
aureus ATCC25923.
Key words: 2,6-difluorobenzamide, antibacterial activity, FtsZ
inhibitors, on-target activity, synthesis
Received 20 March 2015, revised 9 June 2015 and accepted
for publication 18 August 2015
In our previous work, we reported the 3-arylalkoxybenza-
mide derivatives possessing the 3-elongated side chains
with two to nine atoms from 3-oxygen atom to the terminal
groups such as halogen and heteroaryl groups, exhibiting
potent antibacterial activity (17,18). In this study, to explore
the influence of the mother nucleus of 2,6-difluorobenza-
mide as well as 3-shortened side chains with one atom from
3-oxygen atom to the terminal phenyl groups on on-target
activity and antibacterial activity, we designed several
The widespread misuse of antibiotics has resulted in the
emergence and prevalence of bacterial resistance, which
makes many originally powerful antibiotics in clinic become
either weak or no activity (1). In particular, multidrug-resis-
tant Gram-positive pathogens have evolved which are
extremely difficult to eradicate (2,3). Accordingly, the criti-
cal human health outcome of antibiotic resistance among
ª 2015 John Wiley & Sons A/S. doi: 10.1111/cbdd.12658
257

Qiang et al.
ATCC25923) and grown at 37 °C. The culture was diluted
to A600 of ~0.06, and 10 lL of aliquots was added to
transparent 96-well microtiter plates containing dilutions of
the tested compounds, 3-MBA and curcumin as controls
in 100 lL volumes of medium. After incubation for approx-
imately 5 h (4–5 generations) at 37 °C, 20 lL of culture
samples was transferred to poly-L-lysine-coated slides for
microscopy. Cell morphology was assessed by phase-
contrast light microscopy. The lowest concentration at
which filamentation of B. subtilis ATCC9372 or ballooning
of S. aureus ATCC25923 was recorded as the cell division
inhibitory activity indicating on-target activity.
Antibacterial activity
The minimum inhibitory concentration (MIC) of the tested
compounds was determined applying tube dilution method
recommended by NCCLS (20). Bacterial strains were incu-
bated on MHA (Mueller–Hinton Agar) medium at 37 °C for
24 h. The bacteria solution was prepared by suspension in
10 mL of sterile water for colonies from culture on MHA
medium. MHB (Mueller–Hinton Broth) was used for bacte-
ria in this test. The cell density of each inoculum was
adjusted in sterile water of a 0.5 McFarland standard. In
this method, various concentrations of the tested com-
pounds were prepared from 128 to 0.25 lg/mL in sterile
tubes No. 1 to 10. Hundred microliters of sterile Mueller–
Hinton broth (MHB) was poured in each sterile tube
followed by addition of 200 lL test compound in tube 1.
Twofold serial dilutions were carried out from tube 1 to
tube 10, and excess broth (100 lL) was discarded from
the last tube No. 10. To each tube, 100 lL of standard
inoculum (1.5 9 108 cfu/mL) was added. 3-MBA and cur-
cumin were used as controls. Turbidity was observed after
incubating the inoculated tubes at 37 °C for 24 h. The last
tube with no growth of micro-organism was recorded to
represent the MIC value expressed in lg/mL. The tested
bacteria were four penicillin-susceptible strains of B. sub-
tilis ATCC9372, S. aureus ATCC25923, Streptococcus
pneumonia ATCC49619, and Streptococcus pyogenes
PS, two resistant strains of methicillin-resistant S. aureus
and penicillin-resistant S. aureus PR.
Figure 1: Structures of compounds inhibiting FtsZ polymerization
Z-ring formation.
structural series of novel 3-O-arylalkylbenzamide and 3-
O-arylalkyl-2,6-difluorobenzamide derivatives that had
mainly substituented benzyl side chain at the 3-position.
Methods and Materials
General
All necessary solvents were purified prior to use, unless
noted otherwise. Reactions were monitored by thin-layer
chromatography (TLC) using 0.25-mm precoated silica gel
plates (Qingdong Yumingyuan silica gel reagent factory,
Shandong, China, YUYUAN). Flash column chromatogra-
phy was performed with the indicated solvents using silica
gel 60 (particle size 0.040–0.063 mm, Qingdong Yum-
ingyuan silica gel reagent factory, Shandong, China,
YUYUAN). Infrared spectra were recorded on KBr pellets
using Nicolet Nexus 470FT-IR spectrometer (Denver, CO,
USA). 1H NMR spectra were recorded on Bruker Avance
DRX 600 spectrometer (Bruker, Billerica, MA, USA) at ambi-
ent temperature (TMS as internal standard of chemical
shifts). Mass spectra were recorded on API 4000 instrument
(Applied Biosystems, Foster City, CA, USA). The C, H, N
analyses were carried out on PE-2400 II elemental analyser
(PerkineElmer, Waltham, MA, USA). Melting points are
uncorrected and were determined on an X-6 melting point
apparatus (Beijing Tianchengwode Biotech Co. Ltd, Beijing,
China). Bacterial morphometric analysis was determined on
Olympus CKX41 microscope (Center Valley, PA, USA).
Results and Discussion
Chemistry
The 3-O-arylalkylbenzamide derivatives (4–26) were syn-
thesized from the commercially available 3-hydroxybenzoic
acid (1) as outlined in Scheme 1. The chlorination of 1 with
thionyl chloride was followed by reaction with aqueous
ammonia to give 3-hydroxybenzamide (2) in a good yield.
The alkylation of 2 with alkyl chloride or bromide (sodium
iodide was not needed for the reaction with alkyl bromide)
in the presence of sodium iodide and potassium carbon-
ate afforded 3-O-alkylbenzamide derivatives (4–8) in 57–
63% yields. Similarly, the alkylation of 2 with phenylalkyl
chloride or bromide provided 3-O-arylalkylbenzamide
Cell division inhibitory activity
Cell division inhibitory activity of the tested compounds
was performed as described previously (19). Overnight cul-
tures were grown in starvation medium supplemented with
1% hydrolyzed casein and then diluted in starvation med-
ium supplemented with 3% hydrolyzed casein (Bacillus
subtilis ATCC9372) or in (Staphylococcus aureus
258
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3-Arylalkoxy-2,6-difluorobenzamides Targeting FtsZ
Scheme 1: Reagents and conditions: (a) SOCl2, toluene, reflux, 4.5 h; (b) aqueous ammonia, rt, 18 h, 71% for two steps; (c) 1,3-
dibromopropane (or 1,4-dibromobutane), K2CO3, CH3CN, 60 °C, 18 h, 65–67%; (d) alkyl chloride and KI (or alkyl bromide), K2CO3, DMF,
60–65 °C, 16–18 h, 57–63%; (e) phenylalkyl chloride (or bromide), K2CO3, DMF, 60–65 °C, 18–20 h, 70–77%; (f) substituted phenol (or
benzylamine), K2CO3, DMF, 45–60 °C, 12–14 h, 52–65%.
derivatives (9–23) in 70-77% yields. The alkylation of 2 with
alkyl dibromide was subsequent reaction with substituted
phenol or benzylamine to produce 3-O-elongated arylalkyl-
benzamide derivatives (24–26) in yields ranging from 52 to
65%.
2,4-difluorophenol (27) as outlined in Scheme 2. The
etherification of 27 with chloromethyl ethyl ether in the
presence of DIPEA (N,N-diisopropylethylamine) was fol-
lowed by pouring onto freshly crushed carbon dioxide in
the presence of n-BuLi (n-butyl lithium) to provide
1-(ethoxymethoxy)-2,6-difluorobenzoic acid (29) in an
excellent yield. The ammoniation of 29 in the presence of
DIPEA and ethyl chloroformate was subsequently
The 3-O-arylalkyl-2,6-difluorobenzamide derivatives (32–
43) were synthesized from the commercially available
Scheme 2: Reagents and conditions: (a) chloromethyl ethyl ether, DIPEA, CH2Cl2, 0 °C, 2 h, 91%; (b) n-BuLi, CO2, À78 °C, 2 h, 93%;
(c) aqueous ammonia, DIPEA, ethyl chloroformate, rt, 6 h, 72% (d) 6M HCl: CH3OH (1:1), rt, 2 h, 70% (e) substituted benzyl chloride and
KI (or substituted benzyl bromide), K2CO3, DMF, 40–45 °C, 12–14 h, 52–72%.
Chem Biol Drug Des 2016; 87: 257–264
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Qiang et al.
subjected to deprotection of ethoxymethyl group to afford
3-hydroxy-2,6-difluorobenzamide (31) in good yield. The
alkylation of 31 with substituted benzyl chloride or bromide
(sodium iodide was not needed for the benzyl bromide) in
the presence of sodium iodide and potassium carbonate
produced the target compounds 32–43 in 61-66% yields.
the most effective cell division inhibitory activity (2 lg/mL)
and antibacterial activity (2 lg/mL) against S. aureus
ATCC25923, revealing 1024- and 512-fold higher activity
than its precursor 31, respectively. Furthermore, com-
pounds 36 and 41 exerted the most powerful activity
against the above-mentioned bacterial strains among all of
the tested compounds 4–26 and 32–43 as well. Although
3-chloro and 3-methyl groups of the two compounds
shared conflicting electrical characters to each other, they
showed electron-donating groups on the benzene ring in
the structures and belonged to hydrophobic groups. The
two hydrophobic groups might display the hydrophobic
interactions with the binding site of the thiazolopyridine
moiety of PC190723, formed by the amino acid residues
(21). Besides, compounds 34, 37, 38 and 41 against
B. subtilis ATCC9372 and compound 36 against S. au-
reus ATCC25923 were also found to possess potent
antibacterial activity (8, 8, 8 and 4 lg/mL).
Biological activity
Cell division inhibitory activity and in vitro antibacterial
activity for the 3-O-arylalkylbenzamide derivatives 4–26 are
shown in Table 1. Almost all of them showed greatly
improved cell division inhibitory activity against B. subtilis
and S. aureus, and significantly enhanced antibacterial
activity against B. subtilis and three tested strains of S. au-
reus, but failed to exhibit an improvement in antibacterial
activity against S. pyogenes and S. pneumonia compared
with 3-MBA or their precursor 2. In the subseries of the 3-
O-alkylbenzamide derivatives 4–8, compound 6 with iso-
butyl group was found to possess not only the most
greatly improved cell division inhibitory activity against
B. subtilis ATCC9372 and S. aureus ATCC25923, being
128- and 256-fold better than its precursor 2, but also the
most remarkably antibacterial activity against B. subtilis
In general, the two subseries of the 3-O-arylalkylbenza-
mide derivatives 9–22 and the 3-O-arylalkyl-2,6-difluo-
robenzamide derivatives 32–43 had the similar trend in cell
division inhibitory activity and antibacterial activity. In addi-
tion, the most active compounds 14 and 36 in their
respective subseries had the same side chain of 3-
O-chlorobenzyl group, and similarly, the most active
compounds 20 and 41 also had the same side chain of
3-O-methylbenzyl group. However, the 3-O-arylalkyl-
2,6-difluorobenzamide derivatives 32–43 showed much more
potent on-target activity and antibacterial activity than the
3-O-arylalkylbenzamide derivatives 9–22. For example,
compound 36 was 32-, 4-, and 8-fold more effective than
compound 14 in antibacterial activity against B. subtilis
ATCC9372, S. aureus ATCC25923, and S. aureus
ATCC29213, respectively, while compound 41 was 8- and
4-fold more active than compound 20 in antibacterial
activity against B. subtilis ATCC9372 and S. aureus
ATCC25923, respectively. The difference in the antibacte-
rial activity could be attributed to the mother nucleus of
2,6-difluorobenzamide that was more helpful in a remark-
able improvement in on-target activity and antibacterial
activity than that of the benzamide. For instance, com-
pounds 14 and 36 might bind to the binding pocket of
PC190723 on FtsZ due to their structural similarities. The
crystal structure of PC190723 with S. aureus FtsZ has
indicated that two fluoro groups in its scaffold display
important hydrophobic interactions with the surrounding
amino acid residues (21). Accordingly, the hydrophobic
interactions also make compound 36 share better activity
than compound 14. These results described above made
us conclude that (i) the introduction of the 3-monosub-
stituented benzyl side chain would be more benefi-
cial for increasing cell division inhibitory activity against
B. subtilis and S. aureus and antibacterial activity against
B. subtilis ATCC9372, S. aureus ATCC25923, S. aureus
ATCC29213, and S. aureus PR than other monosub-
stituented or multisubstituented benzyl side chain and
especially, 3-O-chloro or 3-O-methyl group on the benzyl
ATCC9372,
S. aureus
ATCC25923,
S. aureus
ATCC29213, and S. aureus PR, exhibiting 64-, 256-fold,
128-, and 256-fold higher activity than 3-MBA, respec-
tively. In the subseries of the 3-O-arylalkylbenzamide
derivatives 9–23, compound 14 with 3-O-chlorobenzyl
group was the most effective in cell division inhibitory
activity against B. subtilis ATCC9372 and antibacterial
activity against B. subtilis ATCC9372 and S. aureus PR,
showing 512-, 32-, and 256-fold better activity than their
precursor 2, respectively. In contrast, compound 20 with
3-O-methylbenzyl group was the most active in cell divi-
sion inhibitory activity against S. aureus ATCC25923 and
antibacterial activity against S. aureus ATCC25923, S. au-
reus ATCC29213, and S. aureus PR, being 1024-, 512-,
256-, and 256-fold better than their precursor 2, respec-
tively. As for the subseries of the 3-O-elongated arylalkyl-
benzamide derivatives 24–26, however, they did not
displayed markedly improved on-target activity and
antibacterial activity.
Cell division inhibitory activity and in vitro antibacterial
activity for the 3-O-arylalkyl-2,6-difluorobenzamide deriva-
tives 32–43 are shown in Table 2. This series presented
an apparent improvement in cell division inhibitory activity
against B. subtilis and S. aureus and antibacterial activity
against all the tested strains in comparison with their pre-
cursor 31 and curcumin. In particular, compound 36 bear-
ing 3-O-chlorobenzyl group showed the best cell division
inhibitory activity (0.5 lg/mL) against B. subtilis ATCC9372
and the strongest antibacterial activity (0.5, 4, and 8 lg/
mL) against B. subtilis ATCC9372, S. aureus ATCC29213,
and S. aureus PR, displaying 2048-, 128-, and 64-fold
better activity than its precursor 31, respectively, while
compound 41 bearing 3-O-methylbenzyl group exhibited
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3-Arylalkoxy-2,6-difluorobenzamides Targeting FtsZ
Chem Biol Drug Des 2016; 87: 257–264
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262
Chem Biol Drug Des 2016; 87: 257–264

3-Arylalkoxy-2,6-difluorobenzamides Targeting FtsZ
side chain could be the best 3-monosubstituented group
in exerting the antibacterial activity, (ii) the mother nucleus
of 2,6-difluorobenzamide could play an more important
role than that of the benzamide in enhancing cell division
inhibitory activity and antibacterial activity against the bac-
terial strains mentioned above. Notably, the findings also
clearly revealed that the 3-monosubstituented benzyl side
References
1. Rossolini G.M., Arena F., Pecile P., Pollini S. (2014)
Update on the antibiotic resistance crisis. Curr Opin
Pharmacol;18:56–60.
2. Rodvold K.A., McConeghy K.W. (2014) Methicillin-re-
sistant Staphylococcus aureus therapy: past, present,
and future. Clin Infect Dis;58(Suppl. 1):S20–20.
3. Tarai B., Das P., Kumar D. (2013) Recurrent challenges
for clinicians: emergence of methicillin-resistant Staphy-
lococcus aureus, vancomycin resistance, and current
treatment options. J Lab Physicians;5:71–78.
4. Erickson H.P., Osawa M., Anderson D.E. (2008) Re-
constitution of contractile FtsZ rings in liposomes.
Science;320:792–794.
chain might be
a suitable for interaction with the
hydrophobic cleft in FtsZ while 2,6-difluoro groups on the
benzamide might further enhanced affinity for FtsZ.
Conclusion
Several structural series of novel 3-O-arylalkylbenzamide
and 3-O-arylalkyl-2,6-difluorobenzamide derivatives were
designed, synthesized, and evaluated for their cell divi-
sion inhibitory activity and antibacterial activity. They pre-
sented greatly improved on-target activity and
antibacterial activity. In particular, the 3-O-arylalkyl-2,6-di-
fluorobenzamide derivatives showed much more potent
cell division inhibitory activity and antibacterial activity
than the 3-O-arylalkylbenzamide derivatives. Among all of
the tested compounds, compound 36 displayed the
best cell division inhibitory activity (0.5 lg/mL) against
B. subtilis ATCC9372 and the strongest antibacterial
activity (0.5, 4, and 8 lg/mL) against B. subtilis
ATCC9372, S. aureus ATCC29213, and S. aureus PR,
while compound 41 exerted the most effective cell divi-
sion inhibitory activity (2 lg/mL) and the most active
€
5. Sass P., Brotz-Oesterhelt H. (2013) Bacterial cell divi-
sion as a target for new antibiotics. Curr Opin Micro-
biol;16:522–530.
6. Nepomuceno G.M., Chan K.M., Huynh V., Martin K.S.,
Moore J.T., O’Brien T.E., Pollo L.A.E., Sarabia F.J.,
Tadeus C., Yao Z., Anderson D.E., Ames J.B., Shaw
J.T. (2015) Synthesis and evaluation of quinazolines as
inhibitors of the bacterial cell division protein FtsZ. ACS
Med Chem Lett;6:308–312.
7. Chiodini G., Pallavicini M., Zanotto C., Bissa M.,
Radaelli A., Straniero V., Bolchi C., Fumagalli L., Rug-
geri P., Morghen C.D.G., Valoti E. (2015) Benzodiox-
ane–benzamides as new bacterial cell division
inhibitors. Eur J Med Chem;89:252–265.
8. Li X., Sheng J., Huang G., Ma R., Yin F., Song D.,
Zhao C., Ma S. (2015) Design, synthesis and antibac-
terial activity of cinnamaldehyde derivatives as inhibitors
of the bacterial cell division protein FtsZ. Eur J Med
Chem;97:32–41.
9. Ma S., Ma S. (2012) The development of FtsZ inhibitors
as potential antibacterial agents. ChemMedChem;
7:1161–1172.
10. Kelley C., Zhang Y., Parhi A., Kaul M., Pilch D.S.,
Lavoie E.J. (2012) 3-Phenyl substituted 6,7-dimethoxy-
isoquinoline derivatives as FtsZ-targeting antibacterial
agents. Bioorg Med Chem;20:7012–7029.
11. Schaffner-Barbero C., Martın-Fontecha M., Chacon P.,
Andrew J.M. (2012) Targeting the assembly of bacte-
rial cell division protein FtsZ with small molecules. ACS
Chem Biol;7:269–277.
antibacterial
activity
(2 lg/mL)
against
S. aureus
ATCC25923. Moreover, compounds 36 and 41 possess-
ing 3-O-chlorobenzyl group and 3-O-methylbenzyl group
on 2,6-difluorobenzamide, respectively, belonged to the
series of 3-O-arylalkyl-2,6-difluorobenzamide derivatives.
It is worth noting that the introduction of the 3-monosub-
stituented benzyl side chain into the mother nucleus of
2,6-difluorobenzamide could greatly increase cell division
inhibitory activity against B. subtilis and S. aureus and
antibacterial activity against B. subtilis ATCC9372, S. au-
reus ATCC25923, S. aureus ATCC29213, and S. aureus
PR than that of other monosubstituented or multisub-
stituented benzyl side chain.
ꢀ
ꢀ
Acknowledgments
12. Andreu J.M., Schaffner-Barbero C., Huecas S.,
Alonso D., Lopez-Rodriguez M.L., Ruiz-Avila L.B.,
This research was supported financially by the National
Natural Science Foundation of China (21072114), the Nat-
ural Science Foundation of Shandong (ZR2015BM019),
and China–Australia Centre for Health Sciences Research
(CACHSR, 2014GJ06).
~
ꢀ
ꢀ
ꢀ
Nunez-Ramırez R., Llorca O., Martın-Galiano A.J.
(2010) The antibacterial cell division inhibitor
PC190723 is an FtsZ polymer-stabilizing agent that
induces filament assembly and condensation. J Biol
Chem;285:14239–14246.
13. Stokes N.R., Baker N., Bennett J.M., Berry J., Collins
I., Czaplewski L.K., Logan A., MacDonald R.,
MacLeod L., Peasley H., Mitchell J.P., Nayal N., Yadav
A., Srivastava A., Haydon D.J. (2013) An improved
small-molecule inhibitor of FtsZ with superior in vitro
Conflict of Interest
All authors declare no conflict of interests.
Chem Biol Drug Des 2016; 87: 257–264
263

Qiang et al.
potency, drug-like properties, and in vivo efficacy. An-
3-O-arylalkylbenzamide derivatives as FtsZ inhibitors.
Lett Drug Des Discov;10:320–326.
timicrob Agents Chemother;57:317–325.
14. Czaplewski L.G., Collins I., Boyd E.A., Brown D., East
S.P., Gardiner M., Fletcher R. et al. (2009) Antibacterial
alkoxybenzamide inhibitors of the essential bacterial
cell division protein FtsZ. Bioorg Med Chem
Lett;19:524–527.
15. Haydon D.J., Bennett J.M., Brown D., Collins I., Gal-
braith G., Lancett P., MacDonald R. et al. (2010)
Creating an antibacterial with in vivo efficacy: synthesis
and characterization of potent inhibitors of the bacterial
cell division protein FtsZ with improved pharmaceutical
properties. J Med Chem;53:3927–3936.
19. Stokes N.R., Sievers J., Barker S. (2005) Novel inhibitors
of bacterial cytokinesis identified by a cell-based antibi-
otic screening assay. J Biol Chem;280:39709–39715.
20. Jorgensen J.H. (1993) Methods for dilution antimicro-
bial susceptibility tests for bacteria that grow aerobi-
cally: approved standard: NCCLS document M7-A3.
NCCLS: 1993.
21. Matsui T., Yamane J., Mogi N., Yamaguchi H., Take-
moto H., Yao M., Tanaka I. (2012) Structural reorgani-
zation of the bacterial cell-division protein FtsZ from
Staphylococcus aureus. Acta Crystallogr D Biol Crys-
tallogr;68:1175–1188.
16. Oliva M.A., Trambaiolo D., Lӧwe J. (2007) Structural
insights into the conformational variability of FtsZ. J
Mol Biol;373:1229–1242.
17. Ma S., Cong C., Meng X., Cao S., Yang H., Guo Y.,
Lu X., Ma S. (2013) Synthesis and on-target antibacte-
rial activity of novel 3-elongated arylalkoxybenzamide
derivatives as inhibitors of the bacterial cell division
protein FtsZ. Bioorg Med Chem Lett;23:4076–4079.
18. Ma S., Wang R., Wang Y., Cao J., Ma S. (2013)
The synthesis and antibacterial activity of novel
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Appendix S1. Experimental procedures for synthesis and
spectral data of intermediates and final compounds.
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