The synthesis and biological evaluation of a novel series of C7 non-basic substituted fluoroquinolones as antibacterial agents

Article abstract of DOI:10.1016/j.bmcl.2009.06.006

A series of non-basic building blocks was synthesized and introduced to the C7 position of the quinolone nucleus 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid to afford the corresponding fluoroquinolones in 46-85% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. The sulfur-containing quinolone, 7-(2-thia-5-azabicyclo[2.2.1]heptan-5-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid exhibited a superior antibacterial activity against quinolone-susceptible and multidrug-resistant strains in comparison with the clinically used fluoroquinolones ciprofloxacin and vancomycin, especially to the Streptococcus pneumonia and multidrug-resistant S. pneumonia clinical isolates. Crown Copyright

Full text of DOI:10.1016/j.bmcl.2009.06.006

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4130–4133
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The synthesis and biological evaluation of a novel series of C7 non-basic
substituted fluoroquinolones as antibacterial agents
*
Xiaoguang Huang, Dongliang Chen, Ning Wu, Aiqin Zhang, Zhenhua Jia, Xingshu Li
School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of non-basic building blocks was synthesized and introduced to the C7 position of the quinolone
nucleus 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid to
afford the corresponding fluoroquinolones in 46–85% yield. The antibacterial activity of these new
fluoroquinolones was evaluated using a standard broth microdilution technique. The sulfur-containing
Received 7 March 2009
Revised 20 May 2009
Accepted 1 June 2009
Available online 6 June 2009
quinolone,
7-(2-thia-5-azabicyclo[2.2.1]heptan-5-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-
naphthyridine-3-carboxylic acid exhibited a superior antibacterial activity against quinolone-susceptible
and multidrug-resistant strains in comparison with the clinically used fluoroquinolones ciprofloxacin
and vancomycin, especially to the Streptococcus pneumonia and multidrug-resistant S. pneumonia clinical
isolates.
Keywords:
Non-basic building blocks
Sulfur-containing quinolone
Streptococcus pneumonia
Multidrug-resistant Streptococcus
pneumonia
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
There is an urgent medical need for novel antibacterial agents to
treat community-acquired infections, especially community-ac-
quired pneumonia (CAP) caused by multidrug-resistant Gram-po-
sitive pathogens. It has become difficult to treat community-
acquired infections because on a worldwide basis, nosocomial
multidrug-resistant Gram-positive staphylococcal and enterococ-
cal pathogenic isolates are found to display resistance to frontline
antimicrobial agents such as methicillin and more recently vanco-
mycin.1 Streptococcus pneumoniae is one of the most significant
causes of CAP, meningitis, otitis media, sinusitis, and acute exacer-
bations of chronic bronchitis, and it is also responsible for substan-
tial morbidity and mortality worldwide.2 The fluoroquinolones are
one of the most important groups of antibiotics against CAP ther-
apy in the clinic. For example, ciprofloxacin, which was introduced
in 1986, has become one of the most potent and widely used anti-
bacterial agents today.3 However, some of these drugs currently on
the market or under development have insufficient activity which
has resulted not only in their limited use in infections caused by
Gram-positive cocci, including Staphylococci and Streptococci,
but is also believed to be one of the reasons for the rapid develop-
ment of quinolone resistance.4 Additionally, some recently
approved fluoroquinolones have had cardiovascular safety issues,
in particular the possibility of QT interval prolongation (The QT
interval is defined as the time interval between the start of the Q
wave and end of the T wave on an electrocardiogram associated
with each heartbeat), which can lead to potentially fatal torsades
de pointes.1a,5 These concerns led to sparfloxacin and grepafloxacin
being removed from the market and bolded warnings added to the
package inserts for moxifloxacin and gatifloxacin.6 From both fun-
damental and practical standpoints, it is highly desirable to devel-
op new antibacterial agents which are more safe, highly potent and
with a possible broad antibacterial spectrum for both multidrug-
resistant Gram-positive and Gram-negative pathogens.
As there are serious consequences as a result of inducing QT
interval prolongation from drug treatment, much research has
been performed to understand the effect, and several methods
have been identified for predicting it. Some results have indicated
that a basic nitrogen and two or three aromatic components at
appropriate distances from the amine confer an increased risk of
QT interval prolongation.7 A structure–activity relationship (SAR)
study has shown that substituents at the C7 position of the quino-
lone core greatly influence their potency, spectrum, and safety.
Murphy et al. found that QT interval prolongation was dramatically
decreased by reducing the C7 amine basicity and reducing the lipo-
philicity of the quinolone core, while at the same time maintaining
activity against resistant organisms.8
Although many marketed quinolones bearing side chains at the
C7 position have a secondary amine basic functionality, there are
some molecules which exhibit excellent antibacterial potency
without this characteristic structure. For example, nadifloxacin9
(Fig. 1 (1)), which contains a 4-hydroxypiperidine moiety at the
C8 position without a distal basic functionality, was introduced
only for topical use as a liniment against Propionibacterium acnes.10
It exhibited excellent antibacterial potency against both Gram-po-
sitive and Gram-negative strains, especially for the Staphylococcus
* Corresponding author.
E-mail address: lixsh@mail.sysu.edu.cn (X. Li).
0960-894X/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.006

X. Huang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4130–4133
4131
O
N
O
F
OH
O
N
O
O
N
O
F
F
N
OH
OH
Cl
F
H
O
HO
N
N
N
OMe
S
H2N
HO
CH3
F
1
2
3
Figure 1. Some quinolones containing a C7 monoamine moiety.
O
O
HO
O
N
O
HO
HO
HO
R
F
F
4
OH
a
c
OH
OH
S
b
2
monoamine
OH
+
N
Boc
9
CO2Me
N
Boc
8
N
CO2Me
N
H
R7
N
N
H
Cl
N
4
7
10
5
6.R7
TBSO
TBSO
HO
HO
R7 = 7, 10, 13, 15, 19,
22, 24, 26, 28, 30,
31, 33, 34, 36, 37
3
g
OH
5
1'
OH
N
Boc
12
S
N
S
TBSO
d, b, e
H
13
f
Scheme 1. Reagents and conditions: Et3N, CH3CN, 50–80 °C (46–85%).
8
CHO
N
Boc
11
+
aureus strains isolated from skin infections.11 The other new quin-
olones bearing a C7 non-secondary amine moiety are ABT-492
(WQ-3034) (2)12 and a sulfur-containing quinolone (3) ( Fig. 1),
which exhibited excellent activities against many Gram-positive
and Gram-negative organisms during in vitro activity assays.13
Based on these research results, we set out to develop new fluoro-
quinolones using the less lipophilic naphthyridine acid 5 as the
quinolone core and a monoamine moiety at the C7 position instead
of a diamine to avoid severe adverse effects. In addition, this quin-
olone core has less mammalian cell cytotoxicity, good activity
against resistant organisms,14 and superior pharmacokinetics
(PK), pharmacodynamics (PD), and ADME properties.15 Herein,
we report our studies based on C7 non-basic substituted quino-
lones, in particular compound 6.24, which exhibited excellent
in vitro antibacterial potencies against Gram-positive, Gram-nega-
tive, and resistant strains.
g
3
OH
5
1'
OH
N
Boc
14
R
N
H
R
15
Scheme 2. Reagents and conditions: (a) (Boc)2O, NaOH, rt (96%); (b) LiAlH4, THF,
0 °C–rt (78%); (c) HCl(g) (83%); (d) TBSCl, imidazole, DMF, 0 °C–rt (92%); (e)
SO3ꢀpyridine, Et3N, DMSO, 0 °C–rt (90%); (f) Mg, CH3I, rt (42% 12 and 30% 14); (g)
TFA/H2O (9:1), rt (quantitative).
HO
OH
HO
OH
HO
OH
HO
OH
b
c
∗
a
∗
4
S
S
2
O
O
HO2C
CO2H
N
Bn
17
N
Bn
18
N
H
16
19
Scheme 3. Reagents and conditions: (a) phenylmethanamine, toluene, reflux (76%);
(b) LiAlH4, THF, reflux (68%); (c) Pd/C, H2, MeOH (quantitative).
The synthesis of quinolone core 5 was carried out according to a
known procedure.16 We chose the cyclopropanamine for the prep-
aration of the quinolone core 5, because this group was widely
used as an N1 substituent for other quinolone antibiotics which
have exhibited good antibacterial activities.14 With the quinolone
core 5, a series of new quinolones 6 could be prepared by the reac-
tion of 5 with different monoamine intermediates (Scheme 1).
We first chose (2S,4R)-methyl 4-hydroxypyrrolidine-2-carbox-
ylate 7, which was cheap and commercially available as the start-
ing material for the preparation of C7 intermediates 10, 13, and 15
(Scheme 2).17
HO
MsO
a
O
Bn
4
ButO
b
N
c
2
OH
N
OMs
N
Boc
9
N
Boc
N
NH
Boc
20
21
22
d
h
S
S
N
NH
Boc
23
24
f
e
Another diol-containing amine, (R,R)-pyrrolidine-3,4-diol
(19),18 which has two adverse hydroxy groups in configuration at
the 3rd and 4th position of the pyrrolidine ring was synthesized
g
O
S
S
O
N
N
O
starting from the
L-tartaric acid 16 (Scheme 3).
Boc
Boc
(R)-27
(S)-25
h
S
O
Some bridged intermediates such as 22, 24, 26, 28, and 30 were
N
h
synthesized from compound 9 (Scheme 4).19–21
O
S
Boc
29
The 1,2,3-triazole intermediates 33, 34, 36, and 37, were also
prepared from 31(Scheme 5).22
h
NH
S
O
28
NH
O
The minimal inhibitory concentrations (MICs) or the lowest
drug concentration that prevents visible growth of bacteria, were
determined by a standard broth microdilution technique using
the National Committee for Clinical and Laboratory Standards
method.23 The bacterial strains used for susceptibility studies were
either clinical isolates from the hospital culture collection or refer-
ence strains from the American Type Culture Collection. The
in vitro assay results are listed in Table 1.
26
S
O
NH
30
Scheme 4. Reagents and conditions: (a) MsCl, Et3N, DCM, 0 °C–rt (93%); (b)
phenylmethanamine, toluene, reflux (82%); (c) Pd/C, H2 (76%); (d) Na2Sꢀ9H2O,
DMSO, 110 °C (70%); (e) Ti(OiPr)4-(S,S)-(ꢁ)-DET-H2O (1:2:1), tBuOOH, DCM, ꢁ25 °C
(89%); (f) Ti(OiPr)4-(R,R)-(+)-DET-H2O(1:2:1), tBuOOH, DCM, ꢁ25 °C (77%); (g) m-
CPBA, DCM, rt (81%); (h) TFA, DCM (quantitative).

4132
X. Huang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4130–4133
N
clinical isolates (0.031
the reference drug ciprofloxacin (0.008 and 0.008
tively). However, the activities of 6.24 against Staphylococcus epide-
rmidis (0.125 g/mL) and Enterococcus faecalis (0.125 g/mL) were
superior to ciprofloxacin (0.5 g/mL and 0.5 g/mL, respectively).
l
g/mL), but was somewhat less potent than
N
N
R
4
a,b,c
d,e
2
N3
lg/mL, respec-
OH
N
Boc
32
N
N
H
H
l
l
31
33: R=Ph
34: R=OH
l
l
It should be noted that quinolone 6.24 maintained good antibacte-
rial activity against both the Gram-positive and Gram-negative
R
N
N
N
4
HO
N3
R
S
b,c
strains. For example, the MIC against S. aureus (0.016
superior to ciprofloxacin (0.125 g/mL), and it had the same activ-
ity against E. coli (0.125 g/mL) as ciprofloxacin (0.125
activities of 6.24 against Pseudomonas aeruginosa (2
multidrug-resistant P. aeruginosa (32
although less than ciprofloxacin (0.5 g/mL and 16
lg/mL) was
4
d,e
S
S
2
l
2
CO2Me
N
Boc
8
CO2Me
N
Boc
35
CO2Me
N
l
l
l
g/mL). The
g/mL) and
H
36:
R=Ph
37: R=OH
l
g/mL) were also good,
g/mL, respec-
l
l
Scheme 5. Reagents and conditions: (a) (Boc)2O, NaOH, THF/H2O, rt (94%); (b)
MsCl, Et3N, DCM, 0 °C–rt (85%); (c) NaN3, DMF, 80 °C (92%); (d) 1-ethynylbenzene or
prop-2-yn-1-ol, CuI, DIPEA, MeOH, rt (91% and 85%, respectively); (e) TFA, DCM
(quantitative).
tively). On the other hand, the sulfone-containing quinolone 6.30
displayed comparable potency to quinolone 6.24 across the strains
with the exception of P. aeruginosa (8
oxide-containing quinolones 6.26 and 6.28 also exhibited excellent
activities against S. pneumoniae (0.125 g/mL and 0.5 g/mL,
respectively) and multidrug-resistant S. pneumonia (0.125 g/mL
and 0.25 g/mL, respectively). However, all four quinolones were
inactive against multidrug-resistant S. aureus (MIC >32 g/mL).
lg/mL). The two chiral sulf-
l
l
In vitro assay results revealed that the antibacterial potency of
target quinolone 6.7 was moderate for Gram-positive strains, and
mild for Gram-negative strains. These results indicated that the
new chiral center of quinolone 6.13 and 6.15 at the 10 position
did not play an important role in the antibacterial potency as the
two new compounds had similar activities against both Gram-po-
sitive and Gram-negative strains which were less than that of 6.7.
However, the antibacterial potencies of the three quinolones were
all superior to that of quinolone 6.10.
The activities of quinolones 6.19 were comparable to quinolone
6.7, and the results indicated that the chiral hydroxy group at the
4th position of the pyrrolidine ring did not play an essential role in
influencing the potency. However, quinolone 6.19 exhibited en-
hanced potency against Escherichia coli.
l
l
l
Quinolone 6.31 (Scheme 5) from 31 and quinolone nucleus 5
exhibited good activities against S. aureus, S. pneumonia, multi-
drug-resistant S. pneumonia and E. faecalis (MICs all 0.5 lg/mL),
and was more potent (8–16-fold) than quinolones 6.10 against
the other pathogens except P. aeruginosa and multidrug-resistant
P. aeruginosa. The results indicated that the chiral center at C4 of
the pyrrolidine may be obstructed during the interaction with
some bacteria.
Two quinolones 6.33 and 6.34, derived from 1,2,3-triazoles,
only displayed mild potency against all the strains. Quinolones
6.37 exhibited moderate activities against most strains with an
The quinolone 6.22 exhibited almost equivalent antibacterial
activities to most organisms as quinolone 6.19, with the exception
of S. aureus (0.25 lg/mL). Interestingly, the four sulfur-containing
quinolones, 6.24, 6.26, 6.28, and 6.30 exhibited good to excellent
activities. Especially, quinolone 6.24 provided excellent potency
against all the pathogens except the multidrug-resistant S. aureus
clinical isolates. It provided the most effective antibacterial activity
exception of E. faecalis (0.5 lg/mL). In addition, 6.37 was more
effective than 6.36 against all the strains, which was comparable
to that of quinolone 6.7. The results indicated that the 1,2,3-tria-
zole structure at the 4th position of the pyrrolidine was not an
effective moiety to influence the potency although the stereocenter
was inverted to the adverse configuration.
In conclusion, we have synthesized a series of new quinolones
based on (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate and
(S)-pyrrolidin-2-ylmethanol. From in vitro potency assay results, it
against S. aureus (MIC = 0.016
lg/mL), excellent potency against S.
pneumonia (0.031
lg/mL), and multidrug-resistant S. pneumonia
Table 1
In vitro MIC values of novel quinolones in various Gram-positive and Gram-negative bacteriaa
Compound
Gram-positive
S.p.2
Gram-negative
S.a.1
S.a.2
S.p.1
S.e.
E.f.
E.c.
P.a.1
P.a.2
6.7
6.10
6.13
6.15
6.19
6.22
6.24
6.26
6.28
6.30
6.31
6.33
6.34
6.36
6.37
Ciprofloxacin
Vancomycin
2
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
1
0.5
8
1
2
2
2
0.031
0.125
0.5
0.063
0.5
2
8
4
1
0.5
8
2
8
2
0.5
0.031
0.125
0.25
0.031
0.5
2
16
>32
32
>32
>32
4
0.125
1
4
0.5
8
>32
32
>32
8
1
4
4
2
8
32
8
16
4
4
0.125
0.5
1
0.125
2
>32
32
32
4
32
32
32
32
32
32
2
16
32
8
32
>32
32
32
32
0.5
32
32
32
32
32
32
32
32
32
32
32
>32
32
32
>32
16
16
16
32
4
0.25
0.016
1
2
0.5
0.125
0.25
1
0.063
0.5
4
4
0.016
0.5
1
32
>32
4
4
8
1
4
16
0.5
0.5
0.5
0.125
1
0.008
1
0.008
2
0.5
2
0.125
a
MICs were determined by microbroth dilution technique and values reported in the table represent the values obtained in triplicate. S.a.1, Staphylococcus aureus
ATCC25923; S.a.2, multidrug-resistant S. aureus clinical isolates; S.p.1, Streptococcus pneumoniae ATCC49619; S.p.2, multidrug-resistant S. pneumonia clinical isolates; S.e.,
Staphylococcus epidermidis ATCC12228; E.f., Enterococcus faecalis ATCC29212; E.c., Escherichia coli ATCC25922; P.a.1, Pseudomonas aeruginosa ATCC27853; P.a.2, multidrug-
resistant P. aeruginosa clinical isolate.

X. Huang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4130–4133
4133
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boxylic acid (6.24), the corresponding sulfoxides (6.26 and 6.28),
and sulfone (6.30) exhibited good to excellent activities against all
the Gram-positive and Gram-negative strains tested.24 Quinolones
6.24 and 6.30 displayed superior activities against all the strains,
whereas quinolones 6.26 and 6.28 had comparatively low potency
against all the pathogens. In general, they were all effectively potent
against strains of S. pneumoniae and multidrug-resistant S. pneumo-
nia, which are the most significant strains of CAP. Further work on
the antibacterial activity of these compounds using an expanded
panel of organisms and in vivo efficacy models are in progress.
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Acknowledgments
21. Angelis, F. D.; Attorrese, G.; Cavicchio, G.; Ciampa, S.; Tullio, A. D.; Fattori, D.;
Nicoletti, R.; Domenici, E. Eur. J. Org. Chem. 2001, 3075.
22. Fuwa, H.; Takahashi, Y.; Konno, Y.; Watanabe, N.; Miyashita, H.; Sasaki, M.;
Natsugari, H.; Kan, T.; Fukuyama, T.; Tomita, T.; Iwatsubo, T. ACS Chem. Biol.
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We thank the financial support from the Science and Technol-
ogy Foundation of Guangzhou (07A8206031) and the National Sci-
ence Foundation of China (20472116).
23. National Committee for Clinical Laboratory Standards. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 5th ed.
(Approved Standard); NCCLS Document M7-A5; NCCLS: Wayne, PA. 2000.
24. The proposed structures are supported by the 1H NMR experiments and mass
spectra. Selected NMR and LC–ESIMS data are as follows. Compound 6.24: 1H
NMR (400 MHz, CDCl3): d 15.10 (s, 1H), 8.68 (s, 1H), 8.00 (d, J = 12.4 Hz, 1H),
5.29 (s, 1H), 4.12 (s, 1H), 4.06 (s, 1H), 3.77 (s, 1H), 3.61 (m, 1H), 3.36 (s, 1H),
3.21 (s, 1H), 2.39 (d, J = 8.4 Hz, 1H), 2.10 (d, J = 10.0 Hz, 1H), 1.65 (s, 1H), 1.25
(d, J = 6.4 Hz, 2H), 1.07 (d, J = 3.2 Hz, 1H). LC–ESIMS for C17H16FN3O3S [M+H+]
calcd 361.1 found 362.0 (M+H); compound 6.26: 1H NMR (400 MHz, CDCl3): d
14.83 (s, 1H), 8.74 (s, 1H), 8.10 (d, J = 12.4 Hz, 1H), 5.35 (s, 1H), 4.08 (d,
J = 10.8 Hz, 1H), 3.97 (d, J = 4.0 Hz, 1H), 3.70 (d, J = 12.8 Hz, 1H), 3.60 (m, 1H),
3.40 (d, J = 11.6 Hz, 1H), 2.88 (d, J = 12.0 Hz, 1H), 2.62 (d, J = 12.4 Hz, 1H), 2.50
(d, J = 11.6 Hz, 1H), 1.28 (d, J = 7.6 Hz, 2H), 1.26 (s, 2H). LC–ESIMS for
C17H16FN3O4S [M+H+] calcd 377.1 found 378.0 (M+H); compound 6.28: 1H
NMR (400 MHz, CDCl3): d 14.89 (s, 1H), 8.66 (s, 1H), 8.03 (d, J = 12.4 Hz, 1H),
5.28 (s, 1H), 4.66 (d, J = 8.8 Hz, 1H), 4.02 (t, J = 12.8 Hz, 1H), 3.64 (d, J = 12.8 Hz,
1H), 3.53 (s, 1H), 3.21 (d, J = 12.4 Hz, 1H), 2.55 (d, J = 13.2 Hz, 1H), 2.45 (t,
J = 12.8 Hz, 1H), 1.91 (d, J = 11.6 Hz, 1H), 1.19 (s, 4H). LC–ESIMS for
C17H16FN3O4S [M+H+] calcd 377.1 found 378.0 (M+H); compound 6.30: 1H
NMR (400 MHz, DMSO-d6): d 15.23 (s, 1H), 8.63 (s, 1H), 8.14 (d, J = 12.0 Hz, 1H),
5.29 (s, 1H), 4.17 (s, 1H), 4.11 (d, J = 8.8 Hz, 1H), 3.71 (s, 1H), 3.47 (s, 1H), 3.09
(q, J = 6.4 Hz, 1H), 2.59 (d, J = 7.6 Hz, 1H), 2.34 (s, 1H), 1.25 (d, J = 14.4 Hz, 1H),
1.18 (t, J = 7.2 Hz, 2H), 1.11 (d, J = 7.2 Hz, 2H). LC–ESIMS for C17H16FN3O5S
[M+H+] calcd 393.1 found 394.1 (M+H).
References and notes
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