Synthesis and antibacterial activity of novel fluoroquinolones containing substituted piperidines

Article abstract of DOI:10.1016/j.bmcl.2007.05.093

The design and synthesis of new fluoroquinolone antibacterial agents having substituted piperidine rings at the C-7 position are described. Most of the new compounds demonstrated high in vitro antibacterial activity. Several of them exhibited significant activities against Gram-positive organisms, which were more potent than those of gemifloxacin, Linezolid, and vancomycin.

Full text of DOI:10.1016/j.bmcl.2007.05.093

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4523–4526
Synthesis and antibacterial activity of novel
fluoroquinolones containing substituted piperidines
Zhao Dang,a Yushe Yang,a,* Ruyun Jia and Shuhua Zhangb
aState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences,
Chinese Academy of Sciences, Shanghai 201203, China
bSichuan Industrial Institute of Antibiotics, Chengdu 610051, China
Received 15 April 2007; revised 16 May 2007; accepted 31 May 2007
Available online 6 June 2007
Abstract—The design and synthesis of new fluoroquinolone antibacterial agents having substituted piperidine rings at the C-7 posi-
tion are described. Most of the new compounds demonstrated high in vitro antibacterial activity. Several of them exhibited signif-
icant activities against Gram-positive organisms, which were more potent than those of gemifloxacin, Linezolid, and vancomycin.
Ó 2007 Elsevier Ltd. All rights reserved.
Quinolone antibacterial agents are among the most
attractive drugs in the anti-infective chemotherapy field.
These antibiotics exert their effect by inhibition of two
type II bacterial topoisomerase enzymes, DNA gyrase
and Topoisomerase IV.1
oroquinolone compounds derivatized from these amines
at the C-7 position were designed and synthesized. These
piperidine derivatives are structurally novel, having an
alkyloxime group and a substituted amino substituent.
Our primary objective was to optimize the potency of
these compounds against Gram-positive and Gram-neg-
ative organisms. A SAR study was also explored to
facilitate the further development of the new fluoroqui-
nolone compounds.
The structure–activity relationship (SAR) study of
quinolone antibacterial agents showed that substituents
at the C-7 position greatly influenced their potency,
spectrum, and safety.2 In general, the optimal substitu-
ents have proven to be 5- and 6-membered nitrogen het-
erocycles that contain peripheral nitrogens.3 The
majority of quinolone C-7 substituents can be arranged
into three main categories: the piperazinyl, pyrrolidinyl,
and piperidinyl type side chains. It is worth noting that
the piperidinyl-based quinolone antibacterial agents re-
ported in the literature were significantly fewer than that
of piperazinyl- and pyrrolidinyl-based analogues.
The novel fluoroquinolone derivatives described herein
were synthesized as shown in Schemes 1 and 2. Com-
pound 3 was prepared by quaternization of pyridine
with benzyl chloride followed by reduction with sodium
borohydride following a modified procedure developed
by Oediger and Joop.5 Catalytic hydrogenation of 1-
benzyl-1,2,3,6-tetrahydropyridine 3 did not afford the
expected 1,2,3,6-tetrahydropyridine 5.6
In our continuous efforts to develop new fluoroquino-
lones, we have focused on introducing new functional
groups to the piperidine ring. The structural modifica-
tions were made on the basis of balofloxacin 1, a well-
known 3-amino-piperidinyl-based fluoroquinolone, and
gemifloxacin 2, possessing a methoxyimino group at-
tached to the pyrrolidine ring at the C-7 position
(Fig. 1).4 New piperidine derivatives and a series of flu-
Therefore, compound 3 was converted to 1-ethoxy-
carbonyl-1,2,3,6-tetrahydropyridine 4 by refluxing it
O
N
O
O
N
O
F
F
OH
OH
H
MeO
N
N
N
N
N
O
NH2
Keywords: Fluoroquinolone; Antibacterial activity; Piperidine.
*
gemifloxacin
balofloxacin
Corresponding author. Fax: +86 2150806786; e-mail: ysyang@mail.
shcnc.ac.cn
Figure 1.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.093

4524
Z. Dang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4523–4526
O
vi)
v)
iv)
i)
iii)
ii)
N
Boc
N
N
Bn
N
N
H
N
Boc
O
O
N
3
4
5
6
7
MeO
MeO
N
OH
O
N
N
N
N
xiv)
xi)
vii)
x)
N
Boc
N
Boc
N
Boc
N
H
11
31
9
8
xii)
R2O
R2O
N
N
N
NOH
xiv)
N
xiii)
N
N
N
H
N
Boc
Boc
12 : R2 = Et
32 : R2 = Et
33 : R2 = n-Pr
34 : R2 = Bn
13 : R2 = n-Pr
10
: R2 = Bn
14
R 1
R1
R1 Boc
N
Boc
O
N
N
NH
NOR2
xii), xiii), xiv)
or xi), xiv)
x)
OH
N
H
N
Boc
Boc
19 : R1 = Me, R2=Me
20 : R1 = Me, R2=Et
21 : R1 = Me, R2=n-Pr
22 : R1 = Me, R2=Bn
: R1 = H, R2=Me
24 : R1 = c-Pr, R2=Me
15a : R1 = Me
15b : R1 = H
17a : R1 = Me
17b : R1 = H
17c : R1 = c-Pr
15c : R1 = c-Pr
O
viii)
ix)
23
N
Boc
7
R2O
R1
R1
O
OH
N
H
xii), xiii), xiv)
or xi), xiv)
N
N
x)
Boc
Boc
N
R1
N
Boc
N
Boc
N
H
25 : R1 = Me, R2=Me
26 : R1 = Me, R2=Et
27 : R1 = Me, R2=n-Pr
28 : R1 = Me, R2=Bn
16a : R1 = Me
18a
18b
1
: R = Me
: R1 = H
16b : R1 = H
1
: R = c-Pr
18c : R1 = c-Pr
16c
: R1 = H, R2=Me
30 : R1 = c-Pr, R2=Me
29
Scheme 1. Reagents and conditions: (i) BnCl, 140 °C, 1 h; (ii) NaBH4, EtOH, rt, 6 h, 46% (two-step yield); (iii) ClCO2Et, C6H6, reflux, 1 h, 93%; (iv)
NH2NH2–H20, KOH, Ethylene glycol, reflux, 1.5 h; (v) (Boc)2O, CHCl3, rt, 12 h, 82% (two-step yield); (vi) m-CPBA, CH2Cl2, rt, 18 h, 92%; (vii)
HN(CH3)2, EtOH, reflux, 6 h, 27%; (viii) R1NH2, EtOH, reflux, 6 h; (ix) (Boc)2O, CHCl3, rt, 6 h, 55–65% (two-step yield, 15a:16a = 3:4); (x)
Pyridine–SO3, Et3N, DMSO, 5 °C, 3 h, 82%; (xi) MeONH2 HCl, NaHCO3, EtOH–THF, 40 °C, 1 h, 85%; (xii) HONH2 HCl, NaHCO3, EtOH–THF,
40 °C, 1 h, 81%; (xiii) R2Br, TBAB, CH2Cl2/aq NaOH, rt, 5 h, 80–86%; (xiv) MeSO3H, THF, rt, 18 h, 85–95%.
with ethyl chloroformate. Deprotection of ethoxycar-
bonyl group was carried out by the method using
NH2NH2–H2O7 and 1,2,3,6-tetrahydropyridine 5 was
obtained. Compound 5 was treated with di-tert-butyl
dicarbonate to produce Boc-protected tetrahydropyri-
dine 6, which was reacted with m-chloroperoxybenzo-
ic acid (m-CPBA) in chloroform to furnish the
epoxide 7.8
Tert-butyl 3-(dimethylamino)-4-hydroxypiperidine-1-
carboxylate 8 was the only product when compound 7
was treated with dimethylamine in refluxing ethanol.9
However, treatment of the key intermediate 7 with
methylamine and subsequent protection of the resulting
amine by a Boc group gave a chromatographically sep-
arable mixture of tert-butyl 1-(tert-butoxycarbonyl)-3-
hydroxypiperidin-4-ylmethylcarbamate 15a (27%) and

Z. Dang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4523–4526
4525
O
N
O
The oxime functional group was introduced into the
ring by coupling 9 with hydroxylamine in EtOH–
THF–H2O to afford 10. The methyloxime 11 was
obtained by reacting the ketone 9 with methoxylamine
instead of hydroxylamine. Compounds 12, 13, and 14
were synthesized simply by alkylating 10 with bromoe-
thane, 1-bromopropane or benzyl bromide. The Boc
protective groups of the oxime 11, 12, 13, and 14 were
removed by methane sulfonic acid in THF to give the
new piperidine derivatives 31–34. Following the each
chemical modification described above, compounds
17a, 17b, 17c, 18a, 18b, and 18c were converted to the
corresponding new piperidine derivatives 19–30.
F
R1
OH
NH
35
NOR2
N
N
R2ON
HN
N
H
R1
19-24
36-41
O
N
O
R2O
F
OH
N
R3
35
R1
N
N
N
R1
N
R3
N
H
N
OR2
42-51
25-30 : R3 = H
31-34 : R3 = Me
Finally, The novel fluoroquinolones 36–51 were ob-
tained by coupling the 7-chloro-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acid
3512 with the new piperidine derivatives 19–34.13
Scheme 2. Reagents and condition: DBU, CH3CN, rt, 50–65%.
tert-butyl 1-(tert-butoxycarbonyl)-4-hydroxypiperidin-
3-ylmethylcarbamate 16a (34%).10
The new fluoroquinolones 36–51 were tested against
Gram-positive and Gram-negative organisms (Table 1)
using standard techniques.14 The minimum inhibitory
concentration (MIC) values were compared with those
of gemifloxacin, Linezolid, and vancomycin.
Reaction of 7 with cyclopropylamine or ammonia and
subsequent protection of the resulting amine yielded
15b, 16b, 15c, and 16c, respectively. Parikh–Doering
oxidant11 was a suitable reagent for the oxidation of
the alcohol 8. Thus, alcohol 8 was cleanly converted to
the ketone 9 by treatment with sulfur trioxide–pyridine
complex in DMSO. Similarly, compounds 17a, 17b,
17c, 18a, 18b, and 18c were obtained.10
The activities of the novel fluoroquinolones 36, 37, 39,
42, and 43 against methicillin-sensitive Staphylococcus
aureus (MSSA), Streptococcus pneumoniae, and Entero-
coccus faecalis (MICs < 0.001 lg/mL) were four times
more potent than those of gemifloxacin and vancomycin,
Table 1. In vitro antibacterial activities of the new fluoroquinolones 36–51
O
O
O
N
O
F
F
OH
OH
R1
N
N
N
N
N
N
R3
R2ON
HN
R2ON
R1
Q2
Q1
Compound
Structure
Substitutions on the structure
MICs (lg/mL)
MSSA
MRSA
S.p.
E.f.
E.co.
K.p.
Ps.a.
36
37
Q1
Q1
Q1
Q1
Q1
Q1
Q2
Q2
Q2
Q2
Q2
Q2
Q2
Q2
Q2
Q2
R1 = Me, R2 = Me
<0.001
<0.001
0.06
0.5
2
<0.001
<0.001
0.03
<0.001
<0.001
0.06
1
4
1
1
0.06
0.06
R1 = Me, R2 = Et
38
39
R1 = Me, R2 = n-Pr
R1 = Me, R2 = Benzyl
R1 = H, R2 = Me
2
4
4
0.06
0.5
<0.001
2
2
<0.001
2
<0.001
2
8
4
40
41
4
1
1
1
R1 = Cyclopropyl, R2 = Me
R1 = Me, R2 = Me, R3 = H
R1 = Me, R2 = Et, R3 = H
R1 = Me, R2 = n-Pr, R3 = H
R1 = Me, R2 = Benzyl, R3 = H
R1 = H, R2 = Me, R3 = H
R1 = Cyclopropyl, R2 = Me, R3 = H
R1 = Me, R2 = Me, R3 = Me
R1 = Me, R2 = Et, R3 = Me,
R1 = Me, R2 = n-Pr, R3 = Me
R1 = Me, R2 = Benzyl, R3 = Me
0.015
<0.001
<0.001
0.03
2
0.004
<0.001
<0.001
0.015
0.25
0.004
<0.001
<0.001
0.015
0.125
8
16
4
16
2
1
42
43
4
1
4
8
16
8
1
44
45
16
16
16
2
8
2
0.125
4
16
8
16
2
2
46
47
4
4
0.015
0.004
0.015
0.5
0.004
0.015
0.002
0.125
0.015
0.004
0.5
0.004
0.015
0.004
0.25
16
8
16
1
8
0.125
48
49
1
1
8
2
1
50
51
2
16
16
0.125
16
16
2
0.015
0.004
0.5
4
0.06
2
0.125
Gemifloxacin
Linezolid
Vancomycin
0.004
1
0.5
0.004
0.125
0.004
0.125
0.004
0.004
Abbreviations: MSSA, methicillin-sensitive Staphylococcus aureus 04-4; MRSA, methicillin-resistant Staphylococcus aureus 05-3; S.p., Streptococcus
pneumoniae 05-9; E.f., Enterococcus faecalis 03-4; E.co., Escherichia coli ATCC25922; K.p., Klebsiella pneumoniae 05-4; Ps.a., Pseudomonas aeru-
ginosa ATCC2785.

4526
Z. Dang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4523–4526
and 100 times superior to that of Linezolid. The most
active compound tested against methicillin-resistant
Staphylococcus aureus (MRSA) was 36, with a MIC va-
lue of 0.5 lg/mL. Compounds 37, 38, 39, 41, 47, 48, 49,
and 50 exhibited moderate activity against MRSA
(MICs 6 2 lg/mL). Compounds 36, 37, and 38 exhib-
ited excellent activity against Pseudomonas aeruginosa
(MICs = 0.06 g/mL). Compounds 36, 37, 38, 40, and
42 showed mild activity against Escherichia coli and
Klebsie pneumoniae (MICs 6 4 lg/mL).
References and notes
1. (a) Hooper, D. C. Drugs 1995, 49(Suppl. 2), 10; (b) Hoshino,
K.; Kitamura, A.; Morrissey, I.; Sato, K.; Kato, J.-I.; Ikeda,
H. Antimicrob. Agents Chemother. 1994, 38, 2623.
2. Bryskier, A.; Chantot, J. F. Drugs 1995, 49(Suppl. 2), 16.
3. Domagala, J. M. J. Antimicrob. Chemother. 1994, 33, 685.
4. (a) Sanchez, J. P.; Gogliotti, R. D.; Domagala, J. M.;
Gracheck, S. J.; Huband, M. D.; Sesnie, J. A.; Cohen, M.
A.; Shapiro, M. A. J. Med. Chem. 1995, 38, 4478; (b)
Zhanel, G. G.; Ennis, K.; Vercaigne, L.; Walkty, A.; Gin, A.
S.; Embil, J.; Smith, H.; Hoban, D. J. Drugs 2002, 62, 13.
5. Takemura, S.; Miki, Y.; Uono, M.; Yoshimura, K.;
Kuroda, M.; Suzuki, A. Chem. Pharm. Bull. 1981, 29, 3026.
6. Grishina, G. V.; Borisenko, A. A.; Nosan, Z. G.; Veselov,
I. S.; Ashkinadze, L. D.; Karamov, E. V.; Kornilaeva, G.
V.; Zefirov, N. S. Dokl. Chem. 2003, 391, 195.
The 4-methylamino-3-methyloxime piperidine derivative
36 showed the most potent antibacterial activity against
Gram-positive and Gram-negative organisms. For
Gram-positive bacteria, there was no significant differ-
ence between the activities of 4-(substituted) amino-3-al-
kyloxime piperidine series (Q1) and the 3-(substituted)
amino-4-alkyloxime piperidine series (Q2); but for
Gram-negative bacteria, the Q1 series displayed better
activity than the Q2 series.
7. Shono, T.; Matsumura, Y.; Uchida, K.; Tsubata, K.;
Makino, A. J. Org. Chem. 1984, 49, 300.
´
8. Boto, A.; Hernandez, R.; de Leon, Y.; Murguıa, J. R.;
Rodrıguez-Afonso, A. Tetrahedron Lett. 2004, 45, 6841.
´
´
´
9. Tichy, M.; Sipos, J.; Sicher, J. Collect. Czech. Chem.
Commun. 1962, 27, 2907.
The size of the alkyl group of the amine moiety might be
important in determining antibacterial activity. The
methyl group seems to be optimal; however, introduc-
tion of another methyl group to the methylamine or
replacement of the methyl by a cyclopropyl group
caused reduced antibacterial activity. Compounds 40
and 46 which have an unsubstituted amine group
showed relatively low potency against Gram-positive
pathogens.
10. The proposed structures are supported by the 1H NMR
experiment and mass spectra. Selected NMR and MS data
are given. Compound 15a: 1H NMR (400 MHz, CDCl3) d
4.36 (1H, m), 4.18 (1H, m), 3.99 (1H, m), 3.56 (1H, m),
2.79 (3H, s), 2.70 (1H, m), 1.66 (2H, m), 1.48(9H, s), 1.47
(9H, s); MS: M+ (m/e) 330. Compound 16a: 1H NMR
(400 MHz, CDCl3) d 4.09 (2H,m), 3.80 (1H, m), 3.68 (1H,
m), 2.85 (3H, s), 2.79 (1H, m), 2.68 (1H, m), 2.05 (1H, m),
1.88 (2H, m), 1.48 (9H, s), 1.47 (9H, s); MS: M+ (m/e) 330.
Compound 17a: 1H NMR (400 MHz, CDCl3) d 4.79 (1H,
m), 4.36 (1H, m), 4.28 (1H, d, J = 17.6 Hz), 4.12 (1H, m),
3.82 (1H, d, J = 17.6 Hz), 3.33 (1H, m), 2.79 (3H, s), 2.11
(2H, m), 1.48 (18H, s); MS: M+ (m/e) 328. Compound 18a:
1H NMR (400 MHz, CDCl3) d 4.73 (1H, m), 4.41 (2H, m),
3.55 (1H, m), 3.19 (1H, m), 2.88 (3H, s), 2.51 (2H, m), 1.48
(18H, s); MS: M+ (m/e) 328.
The new fluoroquinolones featuring methyloxime-incor-
porated piperidino-substitution at C-7 were more potent
than the analogues containing ethyloxime, n-propyloxime
or benzyloxime. The antibacterial activity decreased gener-
ally in the order methyloxime < ethyloxime < ben-
zyloxime, n-propyloxime.
11. Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967,
89, 5505.
12. Mich, T.F.U.S. Patent 4, 663, 457, 1987.
In conclusion, new piperidine derivatives, which bear an
oxime substituent and a substituted amino substituent in
the piperidine ring, have been synthesized and coupled
with naphthyridine acid to produce a series of novel flu-
oroquinolone derivatives. Most of the new compounds
demonstrated high in vitro antibacterial activity. Several
of them exhibited significant activities against Gram-po-
sitive organisms, which were more potent than those of
gemifloxacin, Linezolid, and vancomycin. These com-
pounds may serve as useful lead molecules for new anti-
biotic drug discoveries.
13. Hong, C. Y.; Kim, Y. K.; Lee, Y. H.; Kwak, J. H. Bioorg.
Med. Chem. Lett. 1998, 8, 221.
14. MICs were determined as described by the NCCLS (see
National Committee for Clinical Laboratory Standards.
2001. Performance standards for antimicrobial suscepti-
bility testing: 11th informational supplement. Vol. 21,
M100-S11. National Committee for Clinical Laboratory
Standards, Wayne, PA). The MIC was defined as the
lowest concentration of each compound resulting in
inhibition of visible growth of bacteria after incubation
at 37 °C for 18–24 h.