4-Substituted 4-(1H-1,2,3-triazol-1-yl)piperidine: Novel C7 moieties of fluoroquinolones as antibacterial agents

Article abstract of DOI:10.1016/j.bmcl.2010.03.044

A series of 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine building blocks was synthesized and introduced to the C7 position of the quinolone core, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, to afford the cor

Full text of DOI:10.1016/j.bmcl.2010.03.044

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2859–2863
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
4-Substituted 4-(1H-1,2,3-triazol-1-yl)piperidine: Novel C7 moieties
of fluoroquinolones as antibacterial agents
*
Xiaoguang Huang, Aiqin Zhang, Dongliang Chen, 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 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine building blocks was synthesized and intro-
duced to the C7 position of the quinolone core, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-
1,8-naphthyridine-3-carboxylic acid, to afford the corresponding fluoroquinolones in 40–83% yield. The
antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution
technique. Among them, the quinolone 1-cyclopropyl-6-fluoro-7-(4-(4-formyl-1H-1,2,3-triazol-1-
yl)piperidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (34.15) exhibited comparable
antibacterial activity against quinolone-susceptible and multidrug-resistant strains, especially to Staph-
ylococcus aureus and Staphylococcus epidermidis, in comparison with ciprofloxacin and vancomycin.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 6 November 2009
Revised 2 March 2010
Accepted 9 March 2010
Available online 12 March 2010
Keywords:
4-Substituted 4-(1H-1,2,3-triazol-1-
yl)piperidine
Antibacterial activity
Staphylococcus aureus
Staphylococcus epidermidis
Quinolones are one of the most important synthetic medicines
used in the treatment of community or hospital acquired infectious
diseases. Their excellent pharmacokinetic properties, high antibac-
terial activity, and few side effects make quinolone antibiotics
widespread use in clinical practice.1 Generally, most quinolones
have good activity against Gram-negative bacteria, but the activity
against clinical important Gram-positive pathogens is relatively
moderate. This characteristic of quinolones has resulted not only
in their limited use in some infections but is also believed to be
one of the reasons for the rapid development of quinolone resis-
tance. For example, the life-threatening infections caused by multi-
ple drug-resistant Gram-positive organisms such as methicillin-
resistant Staphylococcus aureus (MRSA), methicillin-resistant
Staphylococcus epidermidis (MRSE) and recently identified vanco-
mycin-resistant enterococci (VRE) are serious health concerns and
are widespread throughout the world.2 In addition, certain adverse
events during treatment with quinolones, such as QT interval pro-
longation (the QT interval is defined as the time interval between
the start of the Q wave and end of the T wave on an electrocardio-
gram associated with each heartbeat) can lead to potentially fatal
torsades.1,3 Thus, although there have been many advances in the
fluoroquinolone field, there is a continuous need for novel quino-
lones to overcome the limitations of existing drugs.
QT interval prolongation was dramatically decreased by reducing
the C7 amine basicity and reducing the lipophilicity of the quino-
lone core, while at the same time maintaining activity against
resistant organisms.4
1,2,3-Triazole and its derivatives have received much attention
from medicinal chemists in the past few decades due to their che-
motherapeutic value.5 Many 1,2,3-triazoles are found to be potent
antimicrobial,6 antimalarial,7 anticonvulsant,8 antitumor,9 and anti
HIV agents,10 and help to avert platelet aggregation.11 Some 1,2,3-
triazole derivatives have been used as potassium channel activa-
tors.12 Very recently, disubstituted 1,2,3-triazole analogues have
been reported as antitubercular agents13 and cannabinoid CB1
receptor antagonists.14
Piperidine and its analogues, an important pharmacophore of
many drug molecules, are reported to act as antibacterials,15 antitu-
bercular agents16 and AChE inhibitors.17 We wanted to investigate
whether there would some new beneficial properties if piperidine
and 1,2,3-triazole like cores were combined in one molecule. To
the best of our knowledge, there is no evidence in the literature of
the development of a molecular scaffold containing core 1,2,3-tria-
zole and piperidine at the C7 moiety of fluoroquinolone antibiotics.
In our previous work, we have synthesized a series of new quino-
lones based on (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate
and (S)-pyrrolidin-2-ylmethanol. The in vitro potency assay results
indicated that some of these compounds exhibited good to excellent
activities against all the Gram-positive and Gram-negative strains
tested.18 Herein, we report the synthesis of a series of 4-substituted
4-(1H-1,2,3-triazol-1-yl)piperidine as the C7 building blocks of
quinolone core 32 and their antibacterial activities.
Structure–activity relationship (SAR) studies have shown that
substituents at the C7 position of the quinolone core greatly influ-
ence their potency, spectrum and safety. Murphy et al. found that
* Corresponding author.
E-mail address: lixsh@mail.sysu.edu.cn (X. Li).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.03.044

2860
X. Huang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2859–2863
R
O
R
O
HO
N
N
N
N
H
H
N
N
N
N3
OH
N
N
N
N
N
N
a
N
c
N
N
a, b
c
e
N
N
N
H
TFA
·
Boc
N
Boc
Boc
N
Boc
14
Boc
N
H
TFA
·
5:
R=Ph
6: R=CH2OH
1
2
3:
R=Ph
4: R=CH2OH
15
4
HO
OH
N
H2N
H2N
OH
O
N3
N
N
N
N
N
N
R
N
N
R
H
N
N
N
N
e
N
N
a, b
d
N
N
N
N
N
b
N
c
N
N
N
H
N
2TFA
·
Boc
N
H
Boc
N
Boc
N
Boc
Boc
7
TFA
·
4
8
9
14
18: R=Me
19: R=Et
16: R =Me
17: R=Et
Scheme 1. Reagents and conditions: (a) MsCl, Et3N, DCM 0 °C to rt; (b) NaN3, DMF,
80 °C (93% two steps); (c) 1-ethynylbenzene or prop-2-yn-1-ol, CuI, DIPEA, MeOH
(92% and 86%, respectively); (d) Pd/C, H2 (quantitative); (e) TFA, DCM (quantitative).
Scheme 3. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, À78 °C (95%); (b) Mg,
CH3I or CH3CH2Br, THF (80% and 85%, respectively); (c) TFA, DCM (quantitative).
On the base of our previous work, we used the less lipophilic
naphthyridine acid 32 as the quinolone core as the scaffold for
the addition of novel building blocks at the C7 position instead of
a diamine to avoid QT prolongation adverse effects,18 as this quin-
olone core has less mammalian cell cytotoxicity, good activity
against resistant organisms,19 superior pharmacokinetics, pharma-
codynamics, and ADME properties.20
The synthesis of the C7 position building block series started
from N-Boc protected 4-hydroxypiperdine (1). The reaction of 1
with methanesulfonyl chloride followed by azidation provided
intermediate 2. Compound 2 reacted with ethynylbenzene or
prop-2-yn-1-ol catalyzed by CuI in the presence of DIPEA, to give
the corresponding 1,2,3-triazole intermediates 3 and 4 with 92%
and 86% yields, respectively21 (Scheme 1), which were then treated
with TFA to provide the corresponding salt, which could be directly
used in the coupling step (Scheme 5).
The other building blocks varied at 4-position of triazole are the
corresponding methyl ester and amide (11 and 13), which were
synthesized from intermediate 2. First, 2 was reacted with methyl
propiolate in the presence of CuI to give 10 with 77% yield.22 When
reacted with ammonia at 50 °C, intermediate 10 was converted to
the corresponding amide 11 with nearly quantitative yield. Then,
deprotection of compounds 10 and 12 gave 11 and 13, respectively
(Scheme 2).
Formyl substituted intermediate 15 was synthesized starting
from intermediate 4, which underwent Swern oxidation and
deprotection to afford the target compound. The reaction of Swern
oxidation product 14 with Grignard reagents generated in situ gave
two chiral moieties 16 and 17,23 followed by deprotection to pro-
vide the corresponding salts 18 and 19 in quantitative yields,
respectively (Scheme 3).
The C7 position building block series with the oxime and alky-
loxime, 21 and 27–31, were also synthesized starting from inter-
Starting from intermediate 4, intermediate 9 was also synthe-
sized by mesylation and azidation to afford the intermediate 7.
Hydrogenation of 7 catalyzed by Pd/C gave the corresponding pri-
mary amine 8 with quantitative yield, followed by deprotection in
the presence of TFA to get the corresponding diamine 9 (Scheme 1).
OH
O
N
OH
N
H
H
H
N
N
N
N
N
N
c
a
N
N
N
N
O
O
MeO
MeO
N
N
N
N
N3
N
N
H
TFA
·
Boc
N
N
Boc
20
N
c
a
14
21
N
Boc
N
H
N
OH
TFA
·
N
OR
Boc
OR
N
H
11
H
2
10
H
N
N
N
c
b
N
N
N
N
N
N
O
N
O
O
MeO
H2N
H2N
N
N
N
N
N
N
Boc
b
c
N
N
H
N
N
TFA
·
N
N
N
Boc
20
27: R=Me
22: R=Me
23: R=Et
28: R=Et
29: R=Allyl
30: R=Propargyl
31: R=Bn
24: R=Allyl
N
H
TFA
Boc
·
25: R=Propargyl
26: R=Bn
Boc
13
10
12
Scheme 4. Reagents and conditions: (a) hydroxylamine hydrochloride, CH2Cl2/aq
NaOH, (96%); (b) RBr, TBAI, CH2Cl2/aq NaOH, rt, 70–85%; (c) TFA, DCM
(quantitative).
Scheme 2. Reagents and conditions: (a) methyl propiolate, CuI, CH3CN, rt (77%); (b)
ammonia, MeOH, 50 °C (quantitative); (c) TFA, DCM (quantitative).

X. Huang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2859–2863
2861
O
N
O
mL) and Escherichia coli (0.5
l
g/mL), and compound 34.5 displayed
O
N
O
F
good activity against multidrug-resistant Staphylococcus aureus
(0.5 g/mL) clinical isolates and Enterococcus faecalis (1 g/mL).
F
OH
OH
l
l
amine
+
R7
N
Cl
N
In contrast, the quinolone 34.5 exhibited low potency against Pseu-
domonas aeruginosa and multidrug-resistant Pseudomonas aerugin-
33
osa clinical isolates (MIC >32 lg/mL).
34.R7
32
Aminomethyl substituted quinolone 34.9, compared with phe-
nyl and hydroxymethyl substituted quinolones 34.5 and 34.6, sig-
nificantly decreased the activity of most bacterial strains except P.
aeruginosa and multidrug-resistant P. aeruginosa, for which quino-
lone 34.6 was 32–64-fold more potent than quinolone 34.9.
Quinolones 34.11 and 34.13, with both a 4-substituted methyl
ester and an amide at the triazole, had similar activities against
S. aureus, P. aeruginosa and multidrug-resistant P. aeruginosa. Quin-
R7
=
5, 6, 9, 11, 13, 15, 18,
19, 21, 27, 28, 29, 30, 31
Scheme 5. Reagents and conditions: Et3N, CH3CN, 50–80 °C, 40–83%.
mediate 14 (Scheme 4), as oximes and alkyloximes are common in
antibiotic design including cephalosporins and the recently
launched fluoroquinolone gemifloxacin.24 The reaction of 14 with
hydroxylamine hydrochloride in the presence of sodium hydroxide
solution give oxime intermediate 20, which reacted with a series of
alkylation reagents to get corresponding alkyloximes 22–26. The
deprotection of 20 and 22–26 provided the corresponding salts
21 and 27–31 (Scheme 4).
olone 34.11 had superior activity against E. coli (1
quinolone 34.13 displayed superior activity against E. faecalis
(4 g/mL). However, the two quinolones were less potent than
lg/mL), whereas
l
quinolone 34.6.
Formyl at the triazole substituted quinolone 34.15 displayed
good activities against most pathogens. It exhibited excellent
With the 14 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine
building blocks in hand,25 a series of new fluoroquinolone com-
pounds were synthesized by the reaction of these building blocks
with quinolone core 32 in the presence of triethylamine with
40–83% yields (Scheme 5).
in vitro antibacterial activities against S. epidermidis (0.031
mL), which is 16-fold more potent than that of ciprofloxacin
(0.5 g/mL), and showed equal potency against S. aureus to cipro-
floxacin (0.125 g/mL). It is very interesting that quinolone 34.15
lg/
l
l
maintained good antibacterial activity against both Gram-positive
The minimal inhibitory concentrations (MICs) or the lowest drug
concentration that prevents visible growth of bacteria, were deter-
mined by a standard broth microdilution technique according to
Clinical and Laboratory Standards Institute guidelines.26 As can be
deduced from these data, all of the synthesized compounds exhib-
ited potent antibacterial activity.27 This activity seems to be modu-
lated through the 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine.
The in vitro antibacterial activity results listed in Table 1 re-
vealed that the phenyl substituted quinolone 34.5 and hydroxy-
methyl substituted quinolone 34.6 showed equal activities
against Staphylococcus epidermidis. The quinolone 34.6 exhibited
and Gram-negative strains. For example, the MIC against S. epide-
rmidis (0.031
(0.5 g/mL), while the MIC against E. coli (0.25
rable to that of ciprofloxacin (0.125 g/mL). In addition, it also
demonstrated potency against P. aeruginosa (16 g/mL) although
it was less potent than that of ciprofloxacin (0.5 g/mL). This re-
l
g/mL) was superior to that of ciprofloxacin
l
lg/mL) was compa-
l
l
l
sults was similar with that of Srivastava, B. K. reported, a series
of quinolones bearing the 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine
moiety attached at the C7 position, especially the formyl derivative
1-cyclopropyl-6-fluoro-7-(2-formyl-6,7-dihydrothieno[3,2-c]pyri-
din-5(4H)-yl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid showed excellent activity in vitro antibacterial test against all
superior activity against Staphylococcus aureus (MIC = 0.125 lg/
Table 1
In vitro MIC values of novel quinolones in various Gram-positive and Gram-negative bacteriaa
O
N
O
F
OH
N
N
N
N
R
N
Compound
R
Gram-positive
Gram-negative
P.a.1
S.a.1
S.a.2
S.e
E.f.
E.c.
P.a.2
34.5
34.6
34.9
34.11
34.13
34.15
34.18
34.19
34.21
34.27
34.28
34.29
34.30
34.31
Ciprofloxacin
Vancomycin
–Ph
–CH2OH
–CH2NH2
–COOCH3
–CONH2
–CHO
–CH(CH3)OH
–CH(C2H5)OH
–CHNOH
–CHNOCH3
–CHNOC2H5
–CHNOCH2CHCH2
–CHNOCH2CCH
–CHNOBn
0.5
0.125
16
1
0.5
>32
>32
>32
>32
>32
>32
>32
>32
>32
32
8
32
4
>32
1
0.5
0.5
32
1
1
2
>32
16
4
2
8
8
4
4
4
8
8
4
1
0.5
32
0.5
16
1
4
0.25
1
1
2
2
4
>32
32
32
32
32
16
32
32
32
32
32
32
32
32
0.5
>32
32
32
32
32
32
32
32
32
32
32
32
32
32
16
1
2
0.125
2
2
0.031
2
2
1
0.5
1
2
1
1
1
0.25
0.5
0.5
0.5
1
4
4
8
0.125
1
0.5
2
0.125
a
MIC 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 Staphylococcus aureus clinical isolates; S.e., Staphylococcus epidermidis ATCC12228; E.f., Enterococcus faecalis ATCC29212; E.c., Esche-

2862
X. Huang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2859–2863
7. Jilino, M.; Stevens, F. G. J. Chem. Soc, Perkin Trans. 1998, 1, 1677.
8. Kadaba, P. K.; Stevenson, P. J.; P-Nnane, I.; Damani, L. A. Bioorg. Med. Chem.
1996, 4, 165.
9. Passannanti, A.; Diana, P.; Barraja, P.; Mingoia, F.; Lauria, A.; Cirrincione, G.
Heterocycles 1998, 48, 1229.
10. Velarquez, S.; Alvarez, R.; Perez, C.; Gago, F.; De, C.; Balzarini, J.; Camarasa, M. J.
Antiviral Chem. Chemother. 1998, 9, 481.
11. Cunha, A. C.; Figueiredo, J. M.; Tributino, J. L. M.; Miranda, A. L. P.; Castro, H. C.;
Zingali, R. B.; Fraga, C. A. M.; de Souza, M. C. B. V.; Ferreirac, V. F.; Barreiroa, E. J.
Bioorg. Med. Chem. 2003, 11, 2051.
the bacteria strains, which exhibited 4–8-folds superior antibacte-
rial activity than ciprofloxacin.28
Two chiral quinolones 34.18 and 34.19 have equal activities
against all bacteria, and displayed moderate activities against S.
aureus (2 lg/mL), S. epidermidis (2 lg/mL) and E. coli (1 lg/mL).
The oxime and alkyloxime substituted quinolones 34.21, 34.27,
34.28, 34.29, 34.30 and 34.31 all showed good activities against
Gram-positive pathogens, such as S. aureus and S. epidermidis.
Among them, quinolone 34.27 exhibited superior potency against
12. Biagi, G.; Calderone, V.; Giorgi, I.; Livi, O.; Martinotti, E.; Martelli, A.; Nardi, A.
Farmaco 2004, 59, 397.
S. aureus (0.25
quinolones, which was comparable to that of ciprofloxacin (0.125
and 0.5 g/mL, respectively). Quinolones 34.28, 34.29, 34.30 and
34.31 exhibited good activity against multidrug-resistant S. aureus.
Benzyloxyimino substituted quinolone 34.31 exhibited good anti-
lg/mL) and S. epidermidis (0.5 lg/mL) than the other
13. Gill, C.; Jadhav, G.; Shaikh, M.; Kale, R.; Ghawalkar, A.; Nagargoje, D.; Shiradkar,
M. Bioorg. Med. Chem. Lett. 2008, 18, 6244.
14. Hou, D. R.; Alam, S.; Kuan, T. C.; Ramanathan, M.; Lin, T. P.; Hung, M. S. Bioorg.
l
Med. Chem. Lett. 2009, 19, 1022.
15. Weis, R.; Schweiger, K.; Faist, J.; Rajkovic, E.; Kungl, A. J.; Walter, M. F.;
Schunack, F. W.; Seebacher, W. Bioorg. Med. Chem. 2008, 16, 10326.
16. Aridoss, G.; Amirthaganesan, S.; Ashok Kumar, N.; Kim, J. T.; Lim, K. T.; Kabilan,
S.; Jeong, Y. T. Bioorg. Med. Chem. Lett. 2008, 18, 6542.
17. Sheng, R.; Xu, Y.; Hu, C.; Zhang, J.; Lin, X.; Li, J.; Yang, B.; He, Q.; Hu, Y. Eur. J.
Med. Chem. 2009, 44, 7.
18. Huang, X.; Chen, D.; Wu, N.; Zhang, A.; Jia, Z.; Li, X. Bioorg. Med. Chem. Lett.
2009, 19, 4130.
19. Suto, M. J.; Domagala, J. M.; Roland, G. E.; Mailloux, G. B.; Cohen, M. A. J. Med.
Chem. 1992, 35, 4745.
bacterial activities against multidrug-resistant S. aureus (4
than any other alkyloxime substituted quinolone and ciprofloxacin
(MIC >32 g/mL). In contrast, the oxime and alkyloxime substi-
lg/mL)
l
tuted quinolones 34.21, 34.27, 34.28, 34.29, 34.30, 34.31 all dis-
played moderate potency against E. coli and P. aeruginosa.
In conclusion, we have synthesized a series of new quinolones
based on 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine as the
C7 building blocks of quinolone core 32.29 The in vitro antibacterial
activity assay demonstrated that the quinolones exhibited good
antibacterial activities to most organisms. The phenyl substitute
quinolone 34.5 displayed superior antibacterial activities against
multidrug-resistant S. aureus, S. epidermidis and E. faecalis, whereas
it exhibited mild potency to Gram-negative strains. Quinolone 34.6
displayed excellent antibacterial activities against S. aureus, S. epi-
dermidis and E. coli, which is comparable to the reference drug. The
formyl substitute quinolone 34.15 displayed good and balanced
activities against both Gram-positive and Gram-negative organ-
isms, especially against S. epidermidis. The oxime and alkyloxime
substituted quinolones exhibited good antibacterial activities
against the Gram-positive strains. In particular the methoxyimino
substituted quinolone 34.27 displayed the highest inhibitory activ-
ities against S. aureus and S. epidermidis. In the light of the increas-
ing need for treatments against infections caused by Gram-positive
pathogens, this series of quinolones may be a potential scaffold for
the exploration of new quinolone antibacterials. Further work on
the antibacterial activity of these compounds using an expanded
panel of organisms and in vivo efficacy models are in progress.
20. Brighty, K. E.; Gootz, T. D. J. Antimicrob. Chemother. 1997, 39, 1.
21. 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.
2007, 2, 408.
22. Sangshetti, J. N.; Nagawade, R. R.; Shinde, D. B. Bioorg. Med. Chem. Lett. 2009,19, 3564.
23. Datta, A.; Veeresa, G. J. Org. Chem. 2000, 65, 7609.
24. Dang, Z.; Yang, Y.; Ji, R.; Zhang, S. Bioorg. Med. Chem. Lett. 2007, 17, 4523.
25. General synthetic procedure for selected compounds: Reactions were conducted
using oven-dried glassware under an atmosphere of nitrogen. NMR spectra
were recorded on Bruker 400 (400 MHz) spectrometer. Chemical shifts are
reported in ppm related to tetramethylsilane as the internal standard. The mass
spectra were recorded on Agilent 6120 quadrupole LC/MS system under electron
spray impact (ESI) ionization condition or otherwise specified. The preparation
of tert-butyl 4-(4-phenyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (com-
pound 3): A dried flask containing tert-butyl 4-azidopiperidine-1-carboxylate
(0.600 g, 2.65 mmol) and ethynylbenzene (0.271 g, 2.65 mmol) in 5 mL of
methanol, N-ethyl-N-isopropylpropan-2-amine (1.712 g, 13.30 mmol) and CuI
(1.151 g, 0.80 mmol) were added at room temperature. The mixture was stirred
at the same temperature for 32 h, and then filtered. The filtrate was concentrated
under reduced pressure and the residue were added ethyl acetate (30 mL) and
HCl solution (0.1 M, 30 mL). The organic phase was separated and the aqueous
solution was extracted with ethyl acetate. The combined organic phase was
washed with saturated NaHCO3 solution (60 mL), brine (60 mL), dried over
MgSO4. The filtrate was concentrated under reduced pressure to afford the crude
product which was purified by column chromatography (petroleum ether/ethyl
acetate = 4:1) to give compound
preparation of tert-butyl 4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperi-
dine-1-carboxylate (compound 10): dried flask containing tert-butyl 4-
3 (0.801 g, 2.44 mmol), yield 92%. The
A
azidopiperidine-1-carboxylate (1.929 g, 8.52 mmol), CuI (1.624 g, 8.52 mmol)
and methyl propiolate (1.074 g, 12.79 mmol) in 16 mL of acetonitrile. The
mixture was stirred at room temperature for 48 h and then concentrated under
reduced pressure. The residue was added ethyl acetate (80 mL) and water
(80 mL). The mixture was separated and the aqueous phase was extracted with
ethyl acetate (80 mL). The combined organic phase was washed with brine
(150 mL) and dried over MgSO4. The filtrate was concentrated under reduced
pressure and the residue was purified by column chromatography (Petroleum
ether/ethyl acetate = 6:1) to give compound 10 (2.033 g, 6.55 mmol), yield 77%.
The preparation of tert-butyl 4-(4-(1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)piperi-
dine-1-carboxylate (compound 16): A dried flask containing magnesium powder
(0.312 g, 12.84 mmol), 10 mL of THF was added under an atmosphere of nitrogen
at the room temperature. Methyl iodine was added to the suspension of
magnesium at a suitable rate. When the reaction started, the solution of methyl
iodine was added dropwise at a rate which is sufficient to maintain a gentle
reflux. After the reaction was completed, the gray solution was stirred for
another 4 h at room temperature and then cooled by an ice/water bath. A
solution of tert-butyl 4-(4-formyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbox-
ylate (0.600 g, 2.14 mmol) in 5 mL of THF was added to the Grignard reagent
above, and the mixture was warmed to room temperature. After the reaction
mixture was stirred overnight, saturated NH4Cl solution (50 mL) was added in
ice/water bath. Ethyl acetate (50 mL) was added, separated and the aqueous
phase was extracted with ethyl acetate (50 mL). The combined organic phase
was washed with brine (100 mL) and dried over MgSO4. Concentrated under
reduced pressure to give the crude produc which was purified by column
chromatography (Petroleum ether/ethyl acetate = 2:3) to get compound 16
(0.508 g, 1.71 mmol), yield 80%. The preparation of tert-butyl 4-(4-((meth-
oxyimino)methyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (compound 22):
A mixture of tert-butyl 4-(4-((hydroxyimino)methyl)-1H-1,2,3-triazol-1-yl)-
piperidine-1-carboxylate (0.591 g, 2.00 mmol), methyl iodine (1.278 g, 9.00
mmol), 4 M sodium hydroxide solution (0.75 mL) and tetrabutylammonium
iodide (0.222 g, 0.60 mmol) in THF (8 mL) was stirred at room temperature for
Acknowledgments
We thank the Science and Technology Foundation of Guangz-
hou (07A8206031) and the National Science Foundation of China
(20472116) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.03.044.
References and notes
1. Mitscher, L. A. Chem. Rev. 2005, 105, 559.
2. (a) Emami, S.; Shafiee, A.; Foroumadi, A. Mini-Rev. Med. Chem. 2006, 6, 109; (b)
Paterson, D. L. Curr. Opin. Pharmacol. 2006, 6, 486; (c) Bradbury, B. J.; Pucci, M. J.
Curr. Opin. Pharmacol. 2008, 8, 1.
3. Ball, P.; Mandell, L.; Niki, Y.; Tillotson, G. Drug Safety 1999, 21, 407.
4. Murphy, S. T.; Case, H. L.; Ellsworth, E.; Hagen, S.; Huband, M.; Joannides, T.;
Limberakis, C.; Marotti, K. R.; Ottolini, A. M.; Rauckhorst, M.; Starr, J.; Stier, M.;
Taylor, C.; Zhu, T.; Blaser, A.; Denny, W. A.; Lu, G.; Smaill, J. B.; Rivault, F. Bioorg.
Med. Chem. Lett. 2007, 17, 2150.
5. Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128.
6. Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn, M. R.; Emmert, D. E.;
Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.; Hutchinson, D. K.; Morris,
J.; Reischer, R. J.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert,
D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953.

X. Huang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2859–2863
2863
48 h. DCM (20 mL) and saturated NH4Cl solution (20 mL), were added and then
the organic phase was separated the aqueous phase was extracted with DCM
(20 mL) and the combined organic phase washed with brine (50 mL), dried over
MgSO4. The filtrate was concentrated under reduced pressure and the residue
was purified by column chromatography (Petroleum ether/ethyl acetate = 4:1)
to get compound 22 (0.433 g, 1.40 mmol), yield 70%.
27. The bacterial strains used for susceptibility studies were either clinical isolates
from the hospital culture collection or reference strains from the American
Type Culture Collection. MIC data for selected strains are expressed in lg/mL.
For comparison, ciprofloxacin and vancomycin were employed as reference
drugs.
28. Srivastava, B. K.; Solanki, M.; Mishra, B.; Soni, R.; Jayadev, S.; Valani, D.; Jain,
M.; Patel, P. R. Bioorg. Med. Chem. Lett. 2007, 17, 1924.
26. Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) guidelines.
Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow
Aerobically, 5th ed.; Approved standard: NCCLS Document M7-A5, 2000.
29. The proposed structures are supported by the 1H NMR and mass spectra.
Selected NMR and LC–ESIMS data see Supplementary data.