Synthesis and antibacterial activity of novel ketolides with 11,12-quinoylalkyl side chains

Article abstract of DOI:10.1016/j.bmcl.2018.06.039

A series of quinoylalkyl side chains was designed and synthesized, followed by introduction into ketolides by coupling with building block 6 or 32. The corresponding targets 7a–n, 33b, and 33e were tested for their in vitro activities against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed a similar antibacterial spectrum and comparable activity to telithromycin. Among them, two C2-F ketolides, compounds 33b and 33e, displayed excellent activities against macrolide-sensitive and macrolide-resistant pathogens.

Full text of DOI:10.1016/j.bmcl.2018.06.039

Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antibacterial activity of novel ketolides with
11,12-quinoylalkyl side chains
Zhe-hui Zhao⁎, Xiao-xi Zhang, Long-long Jin, Shuang Yang, Ping-sheng Lei⁎
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation,
Department of Medicinal Chemistry, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Ketolides
Antibacterial activity
Arylalkyl side chain
A series of quinoylalkyl side chains was designed and synthesized, followed by introduction into ketolides by
coupling with building block 6 or 32. The corresponding targets 7a–n, 33b, and 33e were tested for their in vitro
activities against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed a
similar antibacterial spectrum and comparable activity to telithromycin. Among them, two C2-F ketolides,
compounds 33b and 33e, displayed excellent activities against macrolide-sensitive and macrolide-resistant
pathogens.
Because these has been widespread clinic use of macrolide anti-
biotics since the 1950s, the emergence of macrolide-resistant bacteria
has become increasingly prevalent. Great efforts have been made to
develop novel macrolide structures against resistant pathogens.1 The
most successful improvement of anti-resistant macrolide antibiotics
is the development of the well-known ketolides, which are derived
from erythromycin and are represented by telithromycin,2 ce-
thromycin3 and solithromycin4 (Fig. 1). The structural features of
ketolides include a 3-keto group, an 11,12-carbamate functionality,
and a proper arylalkyl side chain. The aromatic heterocycles of the
side chain can offer an extra interaction with nucleotide A752 in
domain II of the 23S rRNA.5 In recent years, many types of aromatic
heterocycles have been introduced into ketolides by different linkers
in order to find new macrolides with improved activity and low
toxicity.6–8
During our efforts to develop novel ketolides that would be active
against bacteria, we became interested in the quinoline ring as the
aromatic heterocycle of the side chain. Many research groups have
reported that introducing a quinoline ring into the macrolides could
improve the antibacterial activity.9–14 It is well known that there is a
quinoyl group in the side chain of cethromycin at the 6-position, which
is introduced by the Heck reaction. In previous works, Nam et al.
synthesized a series of 9-O-arylpropenyloxime ketolides and evaluated
them for their antibacterial activity.9 Among the targets they synthe-
sized, compound I showed the greatest potency against clinical strains
of Streptococcus pneunoniae and Streptococcus pyogenes (Fig. 2). Liang
et al. synthesized a series of ketolides bearing a 3-aryl-E-prop-2-enyl
group at the 9-oxime and evaluated the compounds for their in vitro
antibacterial activity, in which an aryl group was introduced by the
Sonogashira reaction.11 Compound II (Fig. 2) and two isoquinoyl de-
rivatives displayed significant antibacterial activity against inducible
MLSB-resistant and efflux-mediated resistant pathogens, regardless of
the methicillin-susceptible or methicillin-resistant phenotypes they
carried. In some cases, the quinoyl group was introduced into 16-
membered macrolides, which also showed excellent antibacterial ac-
tivity against resistant pathogens. For instance, compound III (Fig. 2)
was synthesized by Miura et al., and it showed potent activity against
mef- and erm-resistant bacterial strains.14 Based on that, we deduced
that the quinoyl group may be favorable for antibacterial activity,
especially against resistant bacteria.
In this research, we focused on how the linker atom between the
quinoline ring with the alkyl of the 11,12-position of ketolides influ-
enced the antibiotic activities, and furthermore how the substituent
group of the quinoline ring influenced the antibacterial activity of new
ketolides, finally to find new ketolides as leader with improved activity
and low toxicity. Herein, we report an efficient synthetic procedure
designed for preparing a series of arylalkyl side chains with different
linker atoms, followed by coupling them with building blocks to give
novel ketolides with 11, 12-arylalkyl side chains. A new procedure for
the synthesis of C2-F ketolides is also reported.
Our approach was to find an efficient route to synthesize a series of
ketolides with 11,12-arylalkyl side chains carrying quinoline hetero-
cycles. Scheme 1 outlines the syntheses of targets 7a–g. Building block
6 was prepared via 6 steps from clarithromycin.8 Then, building block 6
was coupled with arylalkyl amines (a–g) in acetonitrile/water to give
corresponding targets 7a–7g.
⁎
Corresponding authors.
E-mail address: zhaozh@imm.ac.cn (Z.-h. Zhao).
https://doi.org/10.1016/j.bmcl.2018.06.039
Received 21 March 2018; Received in revised form 17 June 2018; Accepted 18 June 2018
0960-894X/©2018PublishedbyElsevierLtd.
Pleasecitethisarticleas:Zhao,Z.-h.,Bioorganic&MedicinalChemistryLetters(2018),https://doi.org/10.1016/j.bmcl.2018.06.039

Z.-h. Zhao et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
N
N
N
N
N
N
H2N
N
N
N
O
N
O
HO
O
HO
O
HO
O
O
O
O
O
O
H
N
O
O
N
O
N
O
O
O
O
O
O
O
O
O
O
O
F
O
O
O
Solithromycin
Telithromycin
Cethromycin
Fig. 1. Chemical structures of telithromycin, cethromycin and solithromycin.
N
OH
O
N
O
N
N
N
O
O
N
OH
O
N
HO
HO
O
O
O
N
O
O
O
N
O
O
O
OAc O
O
O
HO
HO
O
OCOEt
OCOR
O
O
O
O
O
O
II
O
I
III
Fig. 2. Chemical structures of I, II, and III.
N
N
N
N
O
AcO
HO
O
HO
O
O
O
O
AcO
O
O
O
O
O
O
O
O
HO
HO
HO
HO
d
c
O
b
a
HO
HO
O
O
O
O
O
OH
O
OH
OH
O
O
O
O
O
O
OH
O
1
O
2
O
3
N
O
N
O
N
N
AcO
O
HO
O
AcO
AcO
O
O
O
O
O
O
O
O
O
R
g
e
f
O
N
O
O
O
O
O
O
O
N
O
HO
N
O
O
O
O
O
O
O
O
O
O
4
O
O
6
O
5
7a-g
NH2
H
N
S
NH2
O
NH2
NH2
NH2
NH2
N
O
NH2
N
a
N
b
N
d
N
c
N
e
N
f
g
Scheme 1. Reagents and conditions: (a) HCl, H2O, room temperature 96%; (b) acetic anhydride, Et3N, CH2Cl2, room temperature, 84%; (c) trichloromethyl
chloroformate, pyridine, CH2Cl2, 0 °C to room temperature, 75%; (d) oxalyl chloride, DMSO, Et3N, CH2Cl2, −78 °C, 70%; (e) DBU, acetone, reflux, 75%; (f) CDI, NaH,
DMF, −15 °C, 80%; (g) a–g, MeCN/H2O, reflux, overnight.
Schemes 2–5 outline the syntheses of amines a–g. 3-Bromoquinoline
was chosen as the starting material for the synthesis of amine a. By the
Buchwald-Hartwig reaction, 3-bromoquinoline was reacted with po-
tassium thioacetate in 1,4-dioxane under microwave conditions, with
DIEA as the base, Pd2(dba)3 as the catalyst, and xantphos as the ligand,
to give compound 8. The acetyl of compound 8 was hydrolyzed by
KOH. Compound 9 was treated with one equivalent of N-(3-bromo-
propyl)phthalimide in dimethylformamide (DMF) at 90 °C to afford
compound 10 in a yield of 68% for two steps. After removing the
phthalimide group of compound 10 in a solution of 85% aqueous
2

Z.-h. Zhao et al.
Br
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
hydroxyquinoline with N-(3-hydroxypropyl)phthalimide by the
Mitsunobu reaction. After removing the phthalimide group of com-
pound 11 in a solution of 85% aqueous hydrazine in ethanol, amine b
was obtained. Amine f was obtained by a similar procedure as that used
to synthesize amine b.
SH
S
c
a
b
O
N
N
N
8
9
3-Aminoquinoline was chosen as the starting material for the
synthesis of amine c, which was reacted with (Boc)2O in the presence of
NaHMDS as the base in tetrahydrofuran (THF) to give compound 12.
Compound 13 was obtained by a procedure similar to that which was
used to obtain compound 10. After removing the Boc protective group
and phthalimide group, amine c was obtained.
O
S
NH2
S
N
d
O
N
N
a
10
3-Bromoquinoline was also chosen as the starting material for the
synthesis of amines e and d. By the Heck reaction, 3-bromoquinoline
was reacted with N-(but-3-enyl)phthalimide in acetonitrile under argon
gas, with TEA as the base, Pd(OAc)2 as the catalyst and PPh3 as the
ligand, to give compound 15. Compound 15 was reduced by Pd/C
under H2 gas in EtOH to give compound 16. Removing the phthalimide
group from compounds 15 and 16 gave corresponding amines d and e.
Amide g was obtained by a similar procedure as that used to synthesize
amine e, with 3-bromoisoquinoline as the starting material. The con-
ditions of the Heck reaction were changed to 120 °C in DMF, Na2CO3 as
the base, Pd(dba)2 as the catalyst, and PPh3 as the ligand.
With the targets 7a–g in hand, five compounds 7a–e with different
linker atoms were chosen to evaluate their antibacterial activities
against several macrolide-sensitive and macrolide-resistant strains. The
results are showed in Table 1. When compared with clarithromycin and
telithromycin, 7b, 7d, and 7e showed excellent activities against both
macrolide-sensitive and macrolide-resistant strains. Among them, 7e
displayed the best antibacterial activities, especially against methicillin-
sensitive S. pneunoniae and S. pyogenes. The results indicated that a
carbon-carbon double bond as the linker was more favorable for the
activities of ketolides than a single bond against both sensitive and
resistant pathogens. Next, target 7e was chosen as a lead, and new
ketolides were designed and synthesized to screen the influence of
substituted quinoline on their antibiotic activity (Fig. 3) (See Table 2).
Scheme 6 outlines a general approach for the syntheses of amines
h–n, which were coupled with building block 6 to give the corre-
sponding 7h–n. Some 6-substituted or 7-substituted quinolines were
chosen as starting materials, and these were bromized by bromine in
CCl4, with pyridine as the base, to give corresponding 3-bromoquino-
line derivatives 17–23. By the Heck reaction, compounds 17–23 were
reacted with N-(but-3-enyl)phthalimide in DMF under argon gas,
NaOAc as the base, Pd(OAc)2 as the catalyst, and PPh3 as the ligand, to
give compounds 24–30 respectively. Removing the phthalimide group
of compounds 24–30 gave corresponding amines h–n, which would
couple with building block 6 in acetonitrile/water to give targets
7h–7n, respectively.
Scheme 2. Reagents and conditions: (a) CH3COSK, DIEA, Pd2(dba)3, xantphos,
1,4-dioxane, microwave, 54%; (b) KOH, EtOH, reflux; (c) N-(3-bromopropyl)
phthalimide, K2CO3, DMF, 90 °C, 68% for two steps; (d) NH2NH2·H2O, EtOH,
reflux.
O
OH
c
O
NH2
O
N
a or b
O
N
N
N
11
b
Scheme 3. Reagents and conditions: (a) N-(3-bromopropyl)phthalimide,
K2CO3, DMF, 90 °C, 92%; (b) N-(3-hydroxypropyl)phthalimide, PPh3, DEAD,
88%; (c) NH2NH2·H2O, EtOH, reflux.
O
Boc
N
H
N
NH2
N
a
b
Boc
O
N
N
N
N
13
12
O
H
H
N
c
d
N
NH2
O
N
N
c
14
Scheme 4. Reagents and conditions: (a) (Boc)2O, NaHMDS, THF, 0 °C to room
temperature, 1 h, 90%; (b) N-(3-bromopropyl)phthalimide, NaH, DMF, 90 °C,
95%; (c) TFA, DCM, 0 °C, 8 h, 96%; (d) NH2NH2·H2O, EtOH, reflux, 80 °C.
hydrazine in ethanol, amine a was obtained.
3-Hydroxyquinoline was chosen as the starting material for synth-
esis of amine b. Two methods were used to obtain compound 11. One
procedure was similar to the synthesis of compound 10, where 3-hy-
droxyquinoline was treated with one equivalent of N-(3-bromopropyl)
phthalimide in DMF at 90 °C. The other was the coupling of 3-
O
Br
a
NH2
N
c
O
N
N
N
e
15
b
O
c
N
NH2
O
N
N
d
16
Scheme 5. Reagents and conditions: (a) N-(but-3-enyl)phthalimide, Pd(OAc)2, PPh3, CH3CN, TEA, reflux, 12 h, 86%; (b) H2, Pd/C, EtOH, room temperature, 18 h,
94%; (c) NH2NH2·H2O, EtOH, reflux, 80 °C.
3

Z.-h. Zhao et al.
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Table 1
In vitro antibacterial activities of the target 7a-7e.
S. aureus
S. epidermidis
S. pneunonia
S. pyogenes
H. influenzae
11B122
11B117
11X315
11C176
11G364
11 J011
11L264
11 N369
11P042
11Q373
7a
7b
7c
7d
7e
CLR
TEL
0.125
0.125
0.5
0.125
0.125
0.031
0.062
> 64
> 64
> 64
64
64
> 64
> 64
0.125
0.062
0.5
0.062
0.062
0.125
0.062
0.125
0.25
0.5
0.062
0.062
> 64
0.031
0.008
≤0.004
0.016
≤0.004
≤0.004
0.031
0.125
0.062
0.5
0.062
0.031
64
0.016
0.008
0.031
0.008
≤0.004
0.016
0.008
0.5
1
64
0.5
0.25
> 64
0.125
16
1
8
0.5
1
8
32
8
8
4
4
8
4
0.016
0.031
1
CLR: Clarithromycin; TEL: telithromycin.
There are some reports describing the synthesis of C2-fluor-
oketolides, which demonstrate favorable activities against some pa-
thogens.15–19 Herein, we report an efficient procedure to synthesize C2-
fluoroketolides (Scheme 7). Building block 6 was chosen as the starting
materials, which was treated with NISF in the presence of t-BuOK in
DMF/THF to give compound 31, following deprotection in methanol to
smoothly give building block 32 as a key intermediate. Building block
32 was coupled with amine b or e in acetonitrile/water to give targets
33b or 33e. Moreover, compound 31 could also be directly coupled
with side chains to give target molecules. The removal of the acetyl
group of compound 31 helped to reduce the amount of side chains, and
the targets separated and purified. The advantage of this new procedure
for synthesis of C2-F ketolides was efficient in that that multiple targets
could be synthesized via only one step from building block 32. All the
target compounds were confirmed by HRMS, 1H NMR, and 13C NMR
spectra.
The antibacterial activities of the target compounds 7a–n were
tested against several macrolide-sensitive and macrolide-resistant
strains. Clarithromycin and telithromycin were chosen as the reference
compounds. The in vitro antibacterial activity were reported as
minimum inhibitory concentrations (MICs), which was determined by
the broth microdilution method as recommended by the Clinical and
Laboratory Standards Institute (CLSI).20
Streptococcus pneunoniae; 11L264 is an erythromycin-sensitive
Streptococcus pyogenes; 11 N369 is an erythromycin-resistant
Streptococcus pyogenes; 11P042 is an azithromycin–sensitive
Haemophilus influenzae; and 11Q373 is an azithromycin–resistant
Haemophilus influenzae. All the resistant strains chosen in this test are
constitutively resistant strains supplied by the Ministry of Health
National Antimicrobial Resistance Investigation Net (MOHNARIN,
China).
As shown in Table 1, 5 compounds 7a–7e and two reference com-
pounds, clarithromycin and telithromycin, were tested and their MIC
values were analyzed and compared. Among them, the linker atom of
7a–7e was S, O, N, C, and C]C respectively. Compared to clari-
thromycin, the synthesized targets displayed approximately equivalent
antibacterial activity against the sensitive pathogens and obviously
more activity against the resistant ones. Compared to telithromycin,
only compound 7c showed slightly weaker activity against methicillin-
sensitive S. aureus and S. epidermidis. The activities of others were si-
milar to that of telithromycin against S. aureus and S. epidermidis. The
activities of 7a and 7c were similar to that of telithromycin against S.
pneunoniae. The activities of 7b, 7d, and 7e were slightly stronger than
that of telithromycin against erythromycin-sensitive S. pneunoniae. The
activities of 7a–7d were similar to that of telithromycin against S.
pyogenes. The activity of 7e was slightly stronger than that of teli-
thromycin against erythromycin-sensitive S. pyogenes. The activities of
7a and 7c were slightly weaker than that of telithromycin against H.
influenzae. The activities of 7b, 7d, and 7e were similar to that of tel-
ithromycin against H. influenzae.
11B122 is a methicillin-sensitive Staphylococcus aureus; 11B117 is a
methicillin-resistant Staphylococcus aureus; 11X315 is
a methi-
cillin–sensitive Staphylococcus epidermidis; 11C176 is a methicillin-re-
sistant Staphylococcus epidermidis; 11G364 is an erythromycin-sensitive
Streptococcus pneunoniae; 11 J011 is an erythromycin-resistant
ATCC29213 is a strain of methicillin-sensitive Staphylococcus aureus
N
HO
O
O
R
N
O
O
O
O
O
O
O
7h-n
NH2
O
NH2
BnO
NH2 Ph
NH2
N
h
N
i
N
j
N
k
NH2
NH2
NH2
BnO
N
O
N
N
n
m
l
Fig. 3. The structure of compounds 7h–n and h–n.
4

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Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
Table 2
The structure of compounds 17–30 and h–n.
R
6-Me
17
6-OMe
18
6-OBn
19
6-Ph
20
7-Me
21
7-OMe
22
7-OBn
23
Br
R
N
24
h
25
26
27
k
28
29
m
30
n
O
N
R
O
N
i
j
l
NH2
R
N
O
Br
NH2
N
c
b
a
R
R
R
R
O
N
N
N
N
17-23
24-30
h-n
Scheme 6. Reagents and conditions: (a) Br2, pyridine, CCl4, reflux, 2 h; (b) N-(but-3-enyl)phthalimide, Pd(OAc)2, PPh3, NaOAc, DMF, 120 °C, overnight.
N
O
N
O
N
O
N
O
HO
O
AcO
O
AcO
O
O
O
O
HO
O
O
O
O
O
O
R
N
O
a
b
c
O
N
N
O
O
N
O
N
N
N
O
O
O
O
O
O
O
O
O
O
O
F
F
F
O
O
6
O
O
32
31
33b or 33e
NH2
O
NH2
N
e
N
b
Scheme 7. Reagents and conditions: (a) NISF, t-BuOK, DMF/THF, −20 °C, 2 h, 90%; (b) MeOH, reflux, 12 h, 95%; (c) b or e, MeCN/H2O, reflux.
Table 3
In vitro antibacterial activities of the target 7f–7n, 33b and 33e.
m
S. aureus
S. epidermidis
S. pyogenes
M. catarrhalis
E. coli
KPN
PAE
ATCC 29,213
ATCC 33,591
ATCC 12,228
13–3
12–8
12–1
12–1
12–2
ATCC 25,922
ATCC 700,603
ATCC 27,853
MSSA
MRSA
MSSE
MRSE
MSSP
MRSP
CSMS
CRMS
ESBLs(-)
ESBLs(+)
–
7f
7g
7h
7i
7j
0.015
0.015
0.015
0.015
1
256
64
32
64
8
4
64
64
8
64
32
> 256
> 256
0.03
0.03
0.06
0.015
1
> 256
64
64
128
8
8
128
64
16
128
32
> 256
> 256
0.015
0.015
0.015
0.015
0.125
0.125
0.015
0.015
0.25
> 256
64
32
32
8
8
64
32
8
64
16
128
> 256
0.015
0.015
0.015
0.015
1
0.125
0.015
0.015
0.5
0.015
0.015
0.008
0.125
64
32
16
16
4
2
32
8
16
16
64
16
> 256
> 256
64
64
> 256
8
128
64
> 256
128
> 256
> 256
> 256
> 256
> 256
32
32
32
64
32
> 256
> 256
64
64
> 256
16
7k
7l
1
0.5
0.06
0.06
1
0.015
0.015
0.12
0.015
0.06
0.015
1
0.015
0.015
0.06
0.015
7m
7n
33b
33e
CLR
TEL
8
0.015
0.015
0.03
64
16
> 256
> 256
8
16
8
32
128
64
16
128
32
0.03
KPN: Klebsiella pneumoniae; PAE: Pseudomonas aeruginosa; CLR: Clarithromycin; TEL: telithromycin.
(MSSA), and ATCC 33591 is strain of methicillin-resistant
a
clarithromycin-resistant M. catarrhalis 12–2 (CRMC), Escherichia coli
ATCC 25922, Klebsiella pneumoniae ATCC 700603, and Pseudomonas
aeruginosa ATCC 27,853 were also assessed. All the resistant strains
chosen for this test are constitutively resistant strains supplied by the
Ministry of Health National Antimicrobial Resistance Investigation Net
(MOHNARIN, China).
Staphylococcus aureus (MRSA). ATCC12228 is methicillin-sensitive
Staphylococcus epidermidis (MSSE), and 13–3 is a strain of methicillin-
resistant S. epidermidis (MRSE). Additional, 12–8 is a strain of methi-
cillin-sensitive Streptococcus pyogenes (MSSP), and 12–1 is a strain of
methicillin-resistant S. pyogenes (MRSP). Some Gram-negative bacteria
such as clarithromycin-sensitive Moraxella catarrhalis 12–1 (CSMC),
As shown in Table 3, 11 compounds 7f–7n, 33b, 33e and two
5

Z.-h. Zhao et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
references compounds, clarithromycin and telithromycin, were tested
and their MIC values were analyzed and compared. Among them, the
compound 7f carried a 7-quinoline ring and compound 7g carried an
isoquinoline ring. The compounds 7h–7k had a 6-substituted quinoline
ring and 7l–7n had a 7-substituted quinoline ring. Compared to teli-
thromycin, compound 7f showed similar activities against both sensi-
tive and resistant pathogens. The activities of 7g were similar to that of
telithromycin against sensitive pathogens and slightly stronger than
that against resistant pathogens. Compared to telithromycin, com-
pounds 7h, 7i, 7l, and 7m displayed similar activities against sensitive
pathogens and were slightly stronger than those against resistant ones.
The activities of 7j, 7k, and 7n were weaker than that of telithromycin
against sensitive pathogens, while they were stronger than that of tel-
ithromycin against resistant one and exhibited no activities against
Gram-negative bacteria. Compounds 33b and 33e displayed a sig-
nificant improvement of activities against both sensitive and resistant
pathogens.
telithromycin against MRSA (4: > 256), MRSE (8: > 256), MRSP
(8: > 256), and CRMS (2: > 256). Two C2-F ketolides, compounds 33b
and 33e, not only displayed excellent activities against macrolide-sen-
sitive and macrolide-resistant pathogens, but also showed better or si-
milar activities against Gram-negative bacteria, compared with clari-
thromycin and telithromycin.
In summary, a series of novel ketolides was synthesized that carried
different quinoylallyl side chains. Some of them showed a similar an-
tibacterial spectrum and comparable activity to telithromycin. Among
them, two C2-F ketolides, compounds 33b and 33e, displayed excellent
activities against both Gram-positive bacteria and some Gram-negative
bacteria, and these were the best candidates for further investigation.
The current study presents data that can contribute to the development
of new macrolide antibiotics to effectively combat the growing pro-
blems of resistant strains.
Acknowledgments
Compared with the activities of compounds 7a–7d, whose linker
atoms were S, O, N and C, respectively, compound 7d displayed the
strongest antibiotic activity, which indicate that the carbon atom is
favorable. When comparing the activities of compound 7d with teli-
thromycin, a target in which the quinoline ring was replaced with the
imidazole-pyridine of telithromycin, compound 7d displayed similar
activities as those of telithromycin, while exhibiting 4-fold stronger
activity than that of telithromycin against methicillin-sensitive S. epi-
dermidis. The activity of 7e was slightly stronger than that of 7d, which
indicates that the carbon-carbon double bond was favored over the
carbon-carbon single bond. By the all, N as linker atom was unfavorable
the activities against methicillin-sensitive S. aureus (0.5) and methi-
cillin-resistant S. aureus (> 64). O, C, and C]C as linker atoms were
favorable against methicillin–sensitive S. epidermidis (0.062), but only
C, and C]C were favorable against methicillin-resistant S. epidermidis
(0.062). The similar trend was found against methicillin-resistant ery-
thromycin-sensitive S. pneunoniae (≤0.004), but C]C was more fa-
vorable against erythromycin-resistant S. pneunoniae (≤0.004). The
carbon-carbon double bond was more favorable against both sensitive
and resistant S. pyogenes and H. influenzae.
This work was supported by the CAMS Innovation Fund for Medical
Sciences (Item Number: CIFMS 2016-I2M-3-009 and CIFMS 2017-I2M-
3-011). And we are grateful to the Department of Instrumental Analysis
of our institute for performing the NMR and mass spectroscopy mea-
surements.
A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.bmcl.2018.06.039.
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