Synthesis and antibacterial evaluation of a novel tricyclic oxaborole-fused fluoroquinolone

Article abstract of DOI:10.1016/j.bmcl.2012.12.045

We have designed and synthesized a novel class of compounds based on fluoroquinolone antibacterial prototype. The design concept involved the replacement of the 3-carboxylic acid in ciprofloxacin with an oxaborole-fused ring as an acid-mimicking group. The synthetic method employed in this work provides a good example of incorporating boron atom in complex molecules with multiple functional groups. The antibacterial activity of the newly synthesized compounds has been evaluated.

Full text of DOI:10.1016/j.bmcl.2012.12.045

Accepted Manuscript
Synthesis and antibacterial evaluation of a novel tricyclic oxaborole-fused flu‐
oroquinolone
Xianfeng Li, Yong-Kang Zhang, Jacob J. Plattner, Weimin Mao, M.R.K. Alley,
Yi Xia, Vincent Hernandez, Yasheen Zhou, Charles Z. Ding, Jinpeng Li, Zhijun
Shao, Hongwei Zhang, Musheng Xu
PII:
S0960-894X(12)01639-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2012.12.045
BMCL 19930
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Accepted Date:
9 November 2012
13 December 2012
Please cite this article as: Li, X., Zhang, Y-K., Plattner, J.J., Mao, W., Alley, M.R.K., Xia, Y., Hernandez, V., Zhou,
Y., Ding, C.Z., Li, J., Shao, Z., Zhang, H., Xu, M., Synthesis and antibacterial evaluation of a novel tricyclic
oxaborole-fused fluoroquinolone, Bioorganic & Medicinal Chemistry Letters (2012), doi: http://dx.doi.org/10.1016/
j.bmcl.2012.12.045
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Synthesis and antibacterial evaluation of a novel tricyclic
oxaborole-fused fluoroquinolone
a,*
a
a
a
Xianfeng Li , Yong-Kang Zhang , Jacob J. Plattner , Weimin Mao ,
a
a
a
a
a
M. R. K. Alley , Yi Xia , Vincent Hernandez , Yasheen Zhou , Charles Z. Ding ,
b
b
b
b
Jinpeng Li , Zhijun Shao , Hongwei Zhang , Musheng Xu
a
Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA
Wuxi AppTec Co. Ltd., No. 111 HuangHai Road, 4th Avenue, TEDA, Tianjin, 300456, PR China
b
Abstract—We have designed and synthesized a novel class of compounds based on fluoroquinolone antibacterial prototype. The design
concept involved the replacement of 3-carboxylic acid in ciprofloxacin with an oxaborole-fused ring as an acid-mimicking group. The
synthetic method employed in this work provides a good example of incorporating boron atom in complex molecules with multiple
functional groups. The antibacterial activity of the newly synthesized compounds has been evaluated.
1
Fluoroquinolones represent an important class of synthetic antibiotics for the treatment of serious bacterial infections.
TM
This class of compounds, exemplified by ciprofloxacin (Cipro ) (Figure 1), exhibit broad-spectrum activity for both
Gram-negative and Gram-positive bacteria by inhibiting bacterial DNA replication. However, the development of
2
resistance to this class of drugs, and the resulting loss of their effectiveness as antimicrobial therapies, poses a serious
global health threat. Particularly, most clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) have
3
become resistant to fluoroquinolone antibiotics within five years of their introduction. Also, the proportion of clinical
isolates of Pseudomonas aeruginosa that are resistant to fluoroquinolone antibiotics has increased by 30% over the
4
past 20 years. Furthermore, similar increases in resistance are now being observed with Escherichia coli on global
5
6
FQ resistance, which is a concern as E. coli causes more nosocomial blood stream infections than S. aureus.
Therefore, there is an urgent need to identify new fluoroquinolone derivatives with novel structural features.
Figure 1. Ciprofloxacin and the numbering scheme of fluoroquinolone.
To date all of the marketed fluoroquinolone antibiotics contain the C-3 carboxylic acid group. The SAR investigations
7
on fluoroquinolones revealed that the 3-carboxylic acid is important for their antibacterial activities. Previous studies
have produced no active quinolones with a modification of the 3-carboxylic acid group with the exception of the
8
modified groups that could be converted to the carboxylic acid in vivo. Figure 2 illustrates many examples of the
9
―
inactive or weakly active‖ replacements of the 3-carboxylic acid in fluoroquinolones, including sulfonic acid,
10
10
11
12
sulfonamide, phosphonic acid, hydroxamic acid, and tetrazole. Interestingly, bioisosteric replacement of the 3-
carboxylic acid with a fused isothiazolone ring, originally discovered by Chu and co-workers, resulted in the active
compound with enhanced acivity. Recent investigations on new variations of this isothiazoloquinolone class led to
the discovery of new antibacterial with excellent in vitro and in vivo profiles. While the possible binding interactions
of these tricyclic structures remain to be elucidated, these results prompt us to investigate other new ring-fused
analogues by replacing the 3-carboxylic acid group in fluoroquinolone.
1
3
1
4

Figure 2. The 3-carboxylic acid replacements in fluoroquinolones reported in the literature and the proposed oxaborole replacement.
1
5,16
Boronic acids derivatives have been studied extensively as potential therapeutics.
diverse set of heterocyclic benzoxaboroles with broad applications to numerous disease indications.
benzoxaborole-based compounds have entered human clinical trials for antifungal, anti-inflammatory, antibacterial
Recently, we have discovered a
1
7-20
Several
1
7
18
19
and antitrypanosomiasis indications, exemplified by AN2690, AN2728, AN3365 (GSK’052), and AN5568
SCYX-7158). Importantly, benzoxaboroles are stronger acids than phenylboronic acids with lower pK values,
20
21
(
a
and they are metabolically stable with good drug-like properties. Therefore, we became intrigued by the idea of
replacing the 3-carboxylic acid group in fluoroquinolone with a ring-fused oxaborole moiety (Figure 2). This paper
describes the synthesis and antibacterial evaluation of the oxaborole-fused tricyclic ciprofloxacin (Scheme 1).
As shown in Scheme 1, we chose to start the synthesis from commercially available ciprofloxacin (1). Ciprofloxacin 1
was first converted to its ethyl ester and was then protected with the Boc group to give 2. Compound 2 was converted
2
2
to 3 by introducing methyl group at the C-2 position according to literature procedure. Subsequently, reflux of
compound 3 with 6N hydrochloric acid in ethanol afforded decarboxylated quinolone 4 in quantitative yield in a
single step. In this step, the ester group of 3 was hydrolyzed to free carboxylic acid and decarboxylated, and the Boc-
protecting group was also removed under the reaction conditions. 2-Methyl quinine 4 was protected with the Boc
group and then was oxidized with selenium dioxide in dioxane to afford 2-formyl quinolone 5. Reduction of 5 with
sodium borohydride in methanol provided alcohol 6 in 58% yield for two steps. After selected bromination of 6 with
pyridine tribromide in dichloromethane, 3-bromo quinolone 8 was obtained in 58% yield.
With the intermediate 8 prepared as a precursor for oxaborole formation, we turned our attention to the key step to
introduce boron atom in the molecule. Since there is no literature precedent for introducing a boron atom into
quinolones, compound 8, which also contains a high density of multiple functional groups, poses a significant
2
3
challenge as a starting point with potential poor yields or boronylation failure. Initially, we investigated two standard
17-20
boronylation procedures that we have extensively used in the past.
Treatment of bromide 8 with n-BuLi followed
by reaction with triisopropyl borate gave the debrominated product 6 as a major product. Reaction of 8 with pinacol
diboron in the presence of palladium catalyst gave a complex mixture containing debrominated product 6 and
unidentified components. In either case, no trace amount of any desired boron-containing product (boronic acid,
boronate or cyclized oxaborole) in the reaction mixture was identified after multiple attempts. The free hydroxyl
group in 8 was also protected with MOM or acetyl group, and use of the resulting bromide under the same
boronylation conditions failed to give any expected boron-containing product.
These results led to the consideration of investigating other reagents for boronylation with the hope that the desired
boron product could be identified. Recently Knochel and co-workers have reported the use of turbo-Grignard reagents
2
4
for selective lithiation, deprotonation and nucleophilic additions. Towards that direction, we were gratified to find
that treatment of bromide 8 with i-PrMgCl/LiCl, followed by reaction with trimethyl borate at room temperature
afforded oxaborole 10 in 37% isolated yield. In a single step, bromide 8 was converted to lithium salt and reacted with
trimethyl borate to give the intermediate boronate, which was simultaneously hydrolyzed and cyclized to the adjacent
hydroxymethyl group to afford the five-membered oxaborole. HPLC analysis of the crude mixture suggested that 80%
of oxaborole 10 was formed, along with 20% of debrominated product 6. The low isolated yield of 10 (37%) was due
to the loss of this polar compound during the column purification, and was not optimized. Finally, treatment of 10
2
5
with HCl in dioxane provided the oxaborole-containing ciprofloxacin 11 as a light yellow solid.

Scheme 1. Reagents and conditions: (a) EtOH, conc. H
7%; (d) PhSeCl, NaH, THF, 0.5 h; (e) H , DCM, 0 °C 1 h, 62% for two steps; (f) 6N HCl, EtOH, reflux, overnight, 100%; (g) Boc
h, 64%; (h) SeO , dioxane, 80 °C, overnight; (i) NaBH , MeOH, 1 h, 58% for two steps; (j) pyridine tribromide, DCM, 2 h, 58%; (k) i-PrMgCl·LiCl, 1.3 M
solution, THF, B(OMe) , -10 °C to rt, 2 h, 37%; (l) Conc. HCl, dioxane, rt, 0.5 h, 94-95%.
2
SO
4
, reflux, 15 h, 80%; (b) Boc
2
O, TEA, DCM, rt, 24 h, 66%; (c) MeMgBr, CuI, THF, -78 °C, 2 h,
4
2
O
2
2
O, TEA, DCM, rt, 2
2
4
3
Compounds 7, 9, 10 and 11 were evaluated in vitro in the microbroth assay against some key Gram-negative and
2
6
Gram-positive bacterial organisms. The Gram-negative strains reported in Table 1 are E. coli (wild-type) and tolC
efflux pump deficient strain) and gyrA mutants. The Gram-positive strain reported in Table 1 is Staphylococcus
(
aureus. As expected, decarboxylated analog 7 and 3-bromo analog 9 exhibited no antibacterial activity, suggesting
that the 3-carboxylic acid is important for the antibacterial activity of fluoroquinolones. The lack of antibacterial
27
activity of compound 7 is consistent with the recently reported results on the decarboxylated ciprofloxacin. The
Boc-protected compound 10 was found to be devoid of antibacterial activity. The final oxaborole-fused ciprofloxacin
1
1 showed weak activities against the E. coli and S. aureus strains. The loss of activity against the E. coli gyrA
mutants demonstrated that this weak activity was on-target.
Table 1. Minimum inhibitory concentration (MIC) assay data
Compd
a
MIC (g/mL)
b
c
d
e
E. coli
E. coli tolC
E. coli gyrA S83L
E. coli gyrA D87Y
S. aureus 29213
7
9
>256
>256
>256
128
>256
128
>256
256
>256
>256
>256
32
>256
>256
>256
128
1
1
0
1
>256
16
>256
64
Ciprofloxacin
0.015
0.004
0.06
0.03
0.25
a
b
c
d
e
MIC assay was performed at least in duplicate on separate days with the highest MIC being taken, as described in Ref. 26
K12 ∆lacU169
K12 ∆lacU169 tolC::Tn10
K12 ∆lacU169 tolC::Tn10 gyrA S83L
K12 ∆lacU169 tolC::Tn10 gyrA D87Y
It has been suggested that the planarity between the 3-carboxylic acid group and the 4-keto group may be important
7
for binding to the DNA gyrase or topoisomerase. Recently x-ray co-crystal structure of moxifloxacin with
2
+
topoisomerase-DNA complexes revealed that the keto acid moiety coordinates the noncatalytic Mg ion in the active
28
site. The ―active‖ fused isothiazolone ring system possesses an aromatic character, and the nitrogen proton is very
7
acidic and can be considered to mimic the 3-carboxylic acid. For the oxaborole-fused ciprofloxacin 11, our molecular
modeling studies suggest that the oxaborole moiety maintains a flat coplanar structure with the quinolone ring system.
One possible reason for the lack of activity is that the oxaborole moiety is not very acidic compared to a carboxylic

acid and does not effectively mimic the 3-carboxylic acid in fluoroquinolones. The next step in the exploration would
be to design new boron-fused fluoroquinolone analogues with potentially improved acidity while maintaining the flat
structure of the ring system.
In summary, we have synthesized and evaluated a novel class of compounds based on fluoroquinolone antibacterial
prototype. The design concept involved the replacement of 3-carboxylic acid in ciprofloxacin with a fused oxaborole
ring as an acid-mimicking group. To the best of our knowledge, this is the first example of oxaborole-fused quinolone
(or oxaborole-fused pyridone) that has been reported. The synthetic method employed in this work provides a good
example of incorporating boron atom in complex molecules with multiple functional groups. The oxaborole-fused
ciprofloxacin displays weak antibacterial activity, presumably due to the weak acidity of the oxaborole moiety.
Continuing studies are underway to identify more effective bioisosteric replacements of the 3-carboxylic acid group in
fluoroquinolones and to uncover new compounds with improved antibacterial activity.
*
Corresponding author. Tel.: +1 650 543 7587; fax: +1 650 543 7660. E-mail address: xli@anacor.com
Acknowledgments
We would like to thank Huazhen Chen at WuXi AppTec Co. for high-resolution mass analysis, and Maureen Kully at
NAEJA Pharmaceuticals for preliminary MIC values.
References and Notes
1
.
For reviews, see: (a) Drlica, K.; Hiasa, H.; Kerns, R.; Malik, M.; Mustaev, A.; Zhao, X. Curr. Top. Med. Chem. 2009,
, 981-998; (b) Wiles, J. A.; Bradbury, B. J.; Pucci, M. J. Expert Opin. Ther. Pat. 2010, 20, 1295-1319; (c) Da Silva, A.
9
D.; De Almeida, M. V.; De Souza, M. V. N.; Couri, M. R. C. Current Med. Chem. 2003, 10, 21-39; (d) Fernandes, P.
B.; Chu, D. T. W. Annu. Rep. Med. Chem. 1988, 23, 133-140.
2
3
4
5
6
7
.
.
.
.
.
.
Higgins, P. G.; Fluit, A. C.; Schmitz, F. J. Curr. Drug Targets. 2003, 4, 181-190.
Acar, J. F.; Goldstein, F. W. Clin. Infect. Dis. 1997, 24 (Suppl. 1), S67-73.
Cooper, M. A.; Shlaes, D. Nature 2011, 472, 32.
Dalhoff, A. Interdiscip. Perspect. Infect. Dis. 2012, 2012, 976273.
de Kraker, M. E.; Davey, P. G.; Grundmann, H. PLoS Med. 2011, 8, e1001104
(a) Chu, D. T. W.; Fernandes, P. B. Antimicrob. Agents Chemother. 1989, 33, 131-135; (b) Mitscher, L. A. Chem. Rev.
2
005, 105, 559-592.
8
9
.
.
Kondo, H.; Sakamoto, F.; Kawakami, K.; Tsukamoto, G. J. Med. Chem. 1988, 31, 221-225.
(a) Albrecht, R. Chim. Ther. 1973, 8, 45-48; (b) Yanagisawa, H.; Nakao, H.; Ando, A. Chem. Pharm. Bull. 1973, 21,
1
080-1089; (c) Taguchi, M.; Kondo, H.; Inoue, Y.; Kawahata, Y.; Jinbo, Y.; Sakamoto, F.; Tsukamoto, G. J. Med.
Chem. 1992, 35, 94-99.
1
1
1
1
1
0. Yanagisawa, H.; Nakao, H.; Ando, A. Chem. Pharm. Bull. 1973, 21, 1080-1089.
1. Arayne, M. S.; Sultana, N.; Haroon, U.; Zuberi, M. H.; Rizvi, S. B. Arch. Pharm. Res. 2010, 33, 1901-1909.
2. Gilis, P. M.; Haemers, A.; Bollaert, W. Eur. J. Med. Chem. 1980, 15, 499-502.
3. Chu, D. T. W.; Fernandes, P. B.; Claiborne, A. K.; Shen, L.; Pernet, A. G. Drugs Exp. Clin. Res. 1988, 14, 379-383.
4. (a) Kim, H. Y.; Wiles, J. A.; Wang, Q.; Pais, G. C. G.; Lucien, E.; Hashimoto, A.; Nelson, D. M.; Thanassi, J. A.;
Podos, S. D.; Deshpande, M.; Pucci, M. J.; Bradbury, B. J. J. Med. Chem. 2011, 54, 3268-3282; (b) Pucci, M. J.;
Podos, S. D.; Thanassi, J. A.; Leggio, M. J.; Bradbury, B. J.; Deshpande, M. Antimicrob. Agents Chemother. 2011, 55,
2
860-2871.
1
1
5. (a) Hall, D. G. Structure, properties, and preparation of boronic acid derivatives: overview of their reactions and
applications. In Boronic Acids (2nd ed.); Hall, D. G., Ed; Wiley-VCH: Weinheim, Germany, 2011; Vol. 1, pp 1-133.
(
b) Ni, N.; Wang, B. Applications of boronic acids in chemical biology and medicinal chemistry. In Boronic Acids (2nd
ed.); Hall, D. G., Ed; Wiley-VCH: Weinheim, Germany, 2011; Vol. 2, pp 591-620.
6. (a) Smoum, R.; Rubinstein, A.; Dembitsky, V. M.; Srebnik, M. Chem. Rev. 2012, 112, 4156-4220; (b) Baker, S. J.;
Ding, C. Z.; Akama, T.; Zhang, Y.-K.; Hernandez, V.; Xia, Y. Future Med. Chem. 2009, 1, 1275-1288; (c) Touchet, S.;
Carreaux, F.; Carboni, B.; Bouillon, A.; Boucher, J.-L. Chem. Soc. Rev. 2011, 40, 3895-3914; (d) Wozniack, A. A.;
Cyranski, M. K.; Zubrowska, A.; Sporzynski, A. J. Organomet. Chem. 2009, 694, 3533-3541.

1
7. (a) Rock, F. L.; Mao, W.; Yaremchuk, A.; Tukalo, M.; Crepin, T.; Zhou, H.; Zhang, Y.-K.; Hernandez, V.; Akama, T.;
Baker, S. J.; Plattner, J. J.; Shapiro, L.; Martinis, S. A.; Benkovic, S. J.; Cusack, S.; Alley, M. R. K. Science 2007, 316,
1
759-1761; (b) Baker, S. J.; Zhang, Y.-K.; Akama, T.; Lau, A.; Zhou, H.; Hernandez, V.; Mao, W.; Alley, M. R. K.;
Sanders, V.; Plattner, J. J. J. Med. Chem. 2006, 49, 4447-4450.
1
1
8. Akama, T.; Baker, S. J.; Zhang, Y.-K.; Hernandez, V.; Zhou, H.; Sanders, V.; Freund, Y.; Kimura, R.; Maples, K. R.;
Plattner, J. J. Bioorg. Med. Chem. Lett. 2009, 19, 2129-2132.
9. Hernandez, V.; Akama, T.; Alley, M. R. K.; Baker, S.; Mao, W.; Rock, F.; Zhang, Y. K.; Zhang, Y.; Zhou, Y.; Crepin,
T.; Cusack, S.; Palencia, A.; Nieman, J.; Anugula, M.; Baek, M.; Diaper, C.; Ha, C.; Keramane, M.; Lu, X.;
Mohammad, R.; Savariraj, K.; Sharma, R.; Singh, R.; Subedi, R.; Plattner, J. 50th Interscience Conference on
Antimicrobial Agents and Chemotherapy, Boston, September 12–15, 2010; F1-1637.
2
0. Jacobs, R. T.; Nare, B.; Wring, S. A.; Orr, M. D.; Chen, D.; Sligar, J. M.; Jenks, M. X.; Noe, R. A.; Bowling, T. S.;
Mercer, L. T.; Rewerts, C.; Gaukel, E.; Owens, J.; Parham, R.; Randolph, R.; Beaudet, B.; Bacchi, C. J.; Yarlett, N.;
Plattner, J. J.; Freund, Y.; Ding, C.; Akama, T.; Zhang, Y.-K.; Brun, R.; Kaiser, M.; Scandale, I.; Don, R. PLoS Negl.
Trop. Dis. 2011, 5, e1151.
2
2
1. Tomsho, J. W.; Pal, A.; Hall, D. G.; Benkovic, S. J. ACS Med. Chem. Lett. 2012, 3, 48-52.
2. Park, C.-H.; Lee, J.; Jung, H. Y.; Kim, M. J.; Lim, S. H.; Yeo, H. T.; Choi, E. C.; Yoon, E. J.; Kim, K. W.; Cha, J. H.;
Kim, S.-H.; Chang, D.-J.; Kwon, D.-Y.; Li, F.; Suh, Y.-G. Bioorg. Med. Chem. 2007, 15, 6517-6526.
3. Wienhold, F.; Claes, D.; Graczyk, K.; Maison, W. Synthesis, 2011, 24, 4059-4067.
4. (a) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333-3336; (b) Krasovskiy, A.; Krasovskaya, V.;
Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 2958-2961; (c) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm,
M..; Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 6802-6806.
2
2
2
5. Experimental procedure for synthesis of 11 from 8: To a solution of compound 8 (500 mg, 1.0 mmol) in dry THF (2
mL) in a salt-ice bath was added i-PrMgCl·LiCl dropwise (Aldrich catalog# 656984, 1.3 M THF solution, 4.5 mL, 5.9
mmol) in 20 min. Subsequently, trimethyl borate (0.65 mL, 5.8 mmol) was added dropwise. The reaction mixture was
stirred for additional 2 h with temperature rising to room temperature. HPLC analysis of the crude mixture suggested
that 80% of 10 was formed, along with 20% of debrominated product 6. After methanol (0.65 mL) was added to
quench the reaction, and ethyl acetate and water were added for work-up. The mixture was extracted with ethyl acetate
for three times. The organic phase was combined, dried over sodium sulfate, filtered and concentrated. The residue was
purified by silica gel chromatography eluted with 0-20% methanol in dichloromethane to give 10 as a yellow solid (140
1
3
mg, yield 37%). Mp: >220 °C. H NMR (400 MHz, DMSO-d )  8.76 (s, 1H, B-OH), 7.69 (d, 1H, J = 13.6 Hz,
6
F-H
4
ArH), 7.44 (d, 1H, J = 7.2 Hz, ArH), 5.07 (s, 2H, CH -O-B), 3.50 (m, 4H, N-CH ), 3.28 (m, 1H, CH), 3.13 (m, 4H,
N-CH ), 1.40 (s, 9H, CH ), 1.23 (m, 2H, CH ), 1.06 (m, 2H, CH ). C NMR (400 MHz, DMSO-d ) 176.2 (C=O),
F-H
2
2
13
2
3
2
2
6
1
2
3
1
70.8 (C2), 154.1 (C=O), 152.2 (d, J = 244.1 Hz, C6), 143.4 (d, J = 10.4 Hz, C7), 140.2 (C9), 121.9 (d, J = 6
C-F C-F C-F
2
Hz, C10), 111.5 (d, J = 21.6 Hz, C5); 107.6 (C8), 79.5 (C), 67.1 (CH ), 50.0 (CH ), 44.0 (CH ), 43.0 (CH ), 29.5
C-F
2
2
2
2
+
(
CH), 28.5 (CH ), 9.3 (CH ), C-3 adjacent to boron was not observed. HRMS calcd for C H BFN O (M+H) ,
3 2 22 28 3 5
4
44.2106; found, 444.2109. To compound 10 (37 mg, 0.08 mmol) in 5 mL of dioxane was added 2 mL of conc. HCl.
The mixture was stirred at room temperature for 0.5 h. After LC/MS analysis indicated that 10 was completely
consumed, the solvent was removed via rotary evaporation to give 11 as a light yellow solid (30 mg, yield 95%). Mp:
1
2
3
>
220 °C. H NMR (400 MHz, DMSO-d )  9.22 (b, 2H), 7.73 (d, 1H, J =12.8 Hz, ArH), 7.46 (d, 1H, JF-H=6.8 Hz,
6
F-H
ArH), 5.10 (s, 2H, CH -O-B), 3.41 (m, 4H, N-CH ), 3.32 (m, 1H, CH), 3.27 (m, 4H, N-CH ), 1.23 (m, 2H, CH ), 1.08
m, 2H, CH ). C NMR (400 MHz, DMSO-d ) 175.7 (C=O), 171.1 (C2), 152.1 (d, J = 244.1 Hz, C6), 142.6 (d, J
10.4 Hz, C7), 140.2 (C9), 121.7 (d, JC-F = 6 Hz, C10), 111.6 (d, J = 21.6 Hz, C5); 107.5 (C8), 67.2 (CH ), 46.9
C-F 2
2
2
2
2
1
3
1
2
(
=
2 6 C-F C-F
3
2
(
(
CH ), 42.9 (CH ), 29.8 (CH), 9.4 (CH ), C-3 adjacent to boron was not observed. HRMS calcd for C H BFN O
2 2 2 17 19 3 3
+
M+H) , 344.1582; found, 344.1582.
2
6. CLSI. In M7-A7: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grows Aerobically;
Approved Standard (7th ed.); C. a. L. S. Institute, Ed.; CLSI:Wayne, 2006; Vol. 2.
2
7. (a) Marks, K. R.; Malik, M.; Mustaev, A.; Hiasa, H.; Drlica, K.; Kerns, R. J. Bioorg. Med. Chem. Lett. 2011, 21, 4585-
4
2
588; (b) Nguyen, S. T.; Ding, X.; Butler, M. M.; Tashjian, T. F.; Peet, N. P.; Bowlin, T. L. Bioorg. Med. Chem. Lett.
011, 21, 5961-5963.
2
8. Wohlkonig, A.; Chan, P. F.; Fosberry, A. P.; Homes, P.; Huang, J.; Kranz, M.; Leydon, V. R.; Miles, T. J.; Pearson, N.
D.; Perera, R. L.; Shillings, A. J.; Gwynn, M. N.; Bax, B. D. Nat. Struct. Mol. Biol. 2010, 17, 1152-1153.

Synthesis and antibacterial evaluation of a novel tricyclic oxaborole-fused fluoroquinolone
*
Xianfeng Li , Yong-Kang Zhang, Jacob J. Plattner, Weimin Mao, M. R. K. Alley, Yi Xia, Vincent Hernandez,
Yasheen Zhou, Charles Z. Ding, Jinpeng Li, Zhijun Shao, Hongwei Zhang, Musheng Xu