Synthesis and antibacterial evaluation of novel 11-O-carbamoyl clarithromycin ketolides

Article abstract of DOI:10.1016/j.bmcl.2017.07.017

A series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed improved activity compared with references against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene, S. pneumoniae B1 expressing the erm gene and S. pneumoniae AB11 expressing the mef and erm genes. In particular, compounds 9, 18, 19 and 22 showed the most potent activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.5?μg/mL. Furthermore, compounds 11, 18, 19, 24 and 29 were also found to exhibit favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.125–1?μg/mL, and moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372.

Full text of DOI:10.1016/j.bmcl.2017.07.017

Accepted Manuscript
Synthesis and antibacterial evaluation of novel 11-O-carbamoyl clarithromycin
ketolides
Li Jia, Mi Yan, Yan Shen, Yinhui Qin, Shengsheng Qiang, Shutao Ma
PII:
S0960-894X(17)30705-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.07.017
BMCL 25130
Reference:
Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
10 May 2017
30 June 2017
3 July 2017
Please cite this article as: Jia, L., Yan, M., Shen, Y., Qin, Y., Qiang, S., Ma, S., Synthesis and antibacterial evaluation
of novel 11-O-carbamoyl clarithromycin ketolides, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://
dx.doi.org/10.1016/j.bmcl.2017.07.017
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Synthesis and antibacterial evaluation of novel 11-O-carbamoyl clarithromycin ketolides
Li Jia, Mi Yan, Yan Shen, Yinhui Qin, Shengsheng Qiang, Shutao Ma*
Department of Medicinal Chemistry Key Laboratory of Chemical Biology (Ministry of Education) School of
Pharmaceutical Sciences, Shandong University a. 44 West Culture Road, Jinan 250012 (P.R. China).
Running title: 11-O-carbamoyl ketolides
* Corresponding author: Shutao Ma
Department of Medicinal Chemistry
School of Pharmaceutical Sciences, Shandong University
44, West Culture Road, Jinan 250012, P. R. China
Tel/Fax: +86 531 88382009; E-mail: mashutao@sdu.edu.cn
1

Abstract
A series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for their in vitro
antibacterial activity. The results showed that the majority of the target compounds displayed improved activity
compared with references against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene, S. pneumoniae
B1 expressing the erm gene and S. pneumoniae AB11 expressing the mef and erm genes. In particular, compounds 9, 18,
19 and 22 showed the most potent activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of
0.5 ꢀg/mL. Furthermore, compounds 11, 18, 19, 24 and 29 were also found to exhibit favorable antibacterial activity
against erythromycin-susceptible S. pyogenes with the MIC values of 0.125-1 ꢀg/mL, and moderate activity against
erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372.
Keywords: 11-O-Carbamoyl clarithromycin ketolides; Design and synthesis; Resistant bacteria; Antibacterial activity.
2

Macrolide antibiotics are weak basic and lipophilic compounds produced by Streptomycetes, the activity of which
stems from macrolide ring, a large lactone ring to which one or more deoxy sugars, usually cladinose or desosamine, are
attached.1 They have been proved to be safe and effective for use in treating upper and lower respiratory tract infections.2
Preventing the protein synthesis of bacteria by binding to the entrance of the peptide exit tunnel of the large subunit (50S)
of bacterial ribosome is the mechanism of macrolide antibiotics.3 Erythromycin A (EMA), which belongs to the
first-generation macrolides, readily degrades under acidic conditions leading to the loss of antibacterial activity and the
generation of gastrointestinal side effects.4 Clarithromycin (CAM) and azithromycin (AZM) (Fig. 1), the representatives
of the second-generation macrolides, have better acid-stability in the stomach and more excellent bioavailability, as well
as fewer gastrointestinal side effects.
However, the growth of drug-resistant bacteria appears rapidly due to the abuse of macrolide antibiotics, thus making
the effectiveness of macrolide antibiotics be severely limited.5 The macrolide-resistant pathogens are mainly divided into
two genotypes: the erm gene-mediated base-specific mono- or di-methylation of 23S ribosomal RNA, and the mef
gene-mediated membrane protein efflux pump that can export the macrolides outside of the cells.6 Therefore, it’s urgent
to develop novel macrolide antibiotics against resistant pathogens. An X-ray cocrystal structure research reveals that
3-O-cladinose is not a necessary moiety for antibacterial activity,7 and modification at the C-3 position results in
enhanced activity against efflux resistance.8 Consequently, in the late of 1990s, the third generation macrolides known as
ketolides1 and acylides9 (Fig. 1) were designed to settle the resistance.
Mounts of investigations have been carried out on the chemical modifications of 14-membered macrolides to
effectively cope with bacterial resistance over the past years. Compound EP-1553 (Fig. 1), bearing an arylalkyl group at
the C-11 position of its skeleton, exhibited good activity against macrolide-resistant bacteria.10 We also reported a
15-membered macrolide azithromycin derivative A (Fig. 1), which was modified at the C-11 and C-4ꢁ positions, and
showed remarkably improved anti-resistant activity compared to CAM and AZM.11 Besides, the ketolide telithromycin
was not only less prone to induce bacterial resistance than other macrolide antibiotics, but also displayed good
pharmacokinetic parameters in vivo, as well as high therapeutic efficacy in mice that infected with respiratory
pathogens.12
3

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Fig. 1. The structures of clarithromycin, azithromycin, EP-1553, A, ketolides and acylides
On the basis of the consideration detailed above, we designed and synthesized a series of novel 11-O-carbamoyl
clarithromycin ketolides to prevent the erm- or mef-mediated bacterial resistance and broaden their antibacterial spectra.
To our knowledge, the 11-O-carbamoyl clarithromycin ketolides were first investigated by our group. On the one hand,
3-keto group avoided the induction of bacterial resistance due to removal of the 3-O-cladinose. On the other hand, the
11-O-arylalkylcarbamoyl side chain was beneficial to bind with A752 in domain II through additional forces such as
hydrogen bonding, ꢞ-stacking or van der Waals interactions to improve the antibacterial activity.
The general synthetic method for the acrylic acids is shown in Scheme 1. The reaction of different aldehydes with
malonic acid gave corresponding acrylic acids (A1-A11) in the presence of pyridine and piperidine.
4

Scheme 1. Synthesis of acrylic acids. Reagents and conditions: a) pyridine, piperidine, reflux, 43-86%.
The synthetic method for 11-O-aralkylcarbamoyl-3-O-descladinosyl-3-oxo-clarithromycin derivatives is shown in
Scheme 2. Clarithromycin was used as the starting material for the synthesis of the target compounds, which was treated
with 36% hydrochloric acid to generate the 3-descladinosylclarithromycin 2. Then, it was coupled with acetic anhydride
catalyzed by triethylamine to give the acetyl product 3 that was subsequently reacted with bis(triehloromethyl)carbonate
(BTC) to afford the 11,12-cyclic carbonate 4 in the presence of pyridine. After that, the 3-hydroxy group of 4 was
converted into 3-ketone to obtain the ketone 5 under pyridinium chlorochromate (PCC) oxidation, which was treated
with ethylenediamine at 15 °C to give the key intermediate
2′-O-acetyl-11-O-(aminoethyl)carbamoyl-3-O-descladinosyl-3-oxo-clarithromycin 6. The structure of compound 6 was
confirmed by 1H and 13C NMR spectra which displayed in the supplementary material in detail and further HMBC
spectrum (correlation of CH-11 (ꢟ4.67)/CO (ꢟ156.12)) indicated that the ethylenediamine side chain was linked to the
C-11 position. Finally, 11-O-carbamoyl clarithromycin ketolides (7-30) were prepared by coupling 6 with the
corresponding acids in the presence of 1-hydroxybenzotrizole (HOBt) and dicyclohexylcarbodiimide (DCC), followed by
methanolysis. The corresponding acids contained substituted benzoic acids and synthesized acrylic acids (A1-A11).
5

Scheme 2. Synthesis of 11-O-aralkylcarbamoyl-3-O-descladinosyl-3-oxo-clarithromycin derivatives (7-30). Reagents
and conditions: a) HCl, H2O, rt, 84%; b) Ac2O, Et3N, DCM, 0 °C~rt, 96%; c) pyridine, BTC, DCM, 0 °C~rt, 99%; d)
PCC, DCM, rt, 24 h, 91%; e) ethylenediamine, 15 °C, 6 h, 43%; f) HOBt, DCC, THF, 0 °C~rt, 91-100%; g) CH3OH,
55 °C, 24 h, 47-90%.
All the 11-O-carbamoyl clarithromycin ketolides 7-30, as well as CAM and AZM as references, were determined for
their in vitro antibacterial activity. The minimal inhibitory concentration (MIC) values of in vitro antibacterial activity
were determined with the application of the standard broth microdilution method recommended by NCCLS. The tested
strains included eight susceptible and resistant Gram-positive strains of Staphylococcus aureus ATCC25923
(erythromycin-susceptible strain), Streptococcus pyogenes (erythromycin-susceptible strain isolated clinically), Bacillus
subtilis ATCC9372 (penicillin-susceptible strain), S. aureus ATCC29213 (methicillin-resistant strain), S. pneumoniae B1
(erythromycin-resistant strain expressing the erm gene), S. pneumoniae A22072 (erythromycin-resistant strain expressing
the mef gene), S. pneumoniae AB11 (erythromycin-resistant strain expressing the erm and mef genes), S. pyogenes R1
(erythromycin-resistant strain isolated clinically) and two Gram-negative strains of Escherichia coli ATCC 25922
(penicillin-susceptible strain) and Pseudomonas aeruginosa ATCC27853 (penicillin-susceptible strain). The MIC results
are shown in Table 1.
6

Table 1 11-O-Aralkylcarbamoyl-3-O-descladinosyl-3-oxo-clarithromycin derivatives with their in vitro antibacterial
activity
S.
E. coli S.
P.
B.
S.
S.
S.
S.
S.
ATCC
aureus
pyogenesc aeruginosa subtilis aureus pneumoniae pneumoniae pneumonae pyogenes
Compound
ATCC 25922b
25923a
ATCC
27853d
>128
128
ATCC ATCC B1g
A22072h
AB11i
R1j
9372e
29213f
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
64
64
32
16
8
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
128
4
4
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
>128
>128
4
128
64
>128
>128
>128
>128
>128
>128
>128
128
7
2
1
2
8
1
128
0.25
1
0.5
1
64
9
2
128
64
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
AZM
CAM
16
32
32
128
128
32
32
8
0.25
128
1
1
64
2
>128
>128
>128
>128
>128
128
4
1
64
4
2
2
64
16
4
4
128
64
2
16
8
16
8
>128
>128
>128
128
4
64
4
8
4
64
0.125
128
1
0.5
0.5
4
64
8
128
0.5
4
>128
>128
>128
>128
>128
128
1
64
>128
>128
>128
>128
>128
>128
>128
>128
>128
64
32
32
16
32
32
64
32
32
8
>128
>128
>128
>128
>128
>128
>128
128
8
64
2
8
4
64
2
4
0.5
2
128
128
128
64
2
4
64
1
4
128
64
1
4
>128
128
8
4
4
8
32
4
128
128
128
128
128
>128
128
2
>128
>128
>128
128
4
32
2
128
2
2
32
2
16
64
0.25
0.25
128
1
2
32
2
128
128
4
8
16
1
>128
>128
>128
16
0.03
16
0.25
8
2
64
0.03
64
0.25
64
4
a S. aureus ATCC25923: erythromycin-susceptible strain; b E. coli ATCC25922: penicillin-susceptible strain; c S.
pyogenes: erythromycin-susceptible strain isolated clinically; d P. aeruginosa ATCC27853: penicillin-susceptible strain; e
B. subtilis ATCC9372: erythromycin-susceptible strain; f S. aureus ATCC29213: methicillin-resistant strain; g S.
pneumoniae B1: erythromycin-resistant strain encoded by the ermB gene; h S. pneumoniae A22072:
erythromycin-resistant strain encoded by the mefA gene; i S. pneumoniae AB11: erythromycin-resistant strain encoded by
the ermB and mefA genes; j S. pyogenes R1: erythromycin-resistant strain isolated clinically.
Compared to the references of AZM and CAM, the 3-O-descladinosyl-3-oxo-11-O-aralkylcarbamoyl clarithromycin
derivatives universally exhibited better antibacterial activity against S. pneumoniae A22072, S. pneumoniae B1 and S.
7

pneumoniae AB11, and comparable antibacterial activity against S. aureus ATCC25923, S. pyogenes, B.
subtilis ATCC9372 and S. aureus ATCC29213, but failed to show improved antibacterial activity against E. coli
ATCC25922, P. aeruginosa ATCC27853 and S. pyogenes R1. Among them, compounds 11, 18 and 19 displayed the best
antibacterial activity with MIC values of 0.125-0.5ꢠµg/mL against S. pyogenes and compounds 8, 9, 10, 11, 18 and 19
exhibited the best antibacterial activity with MIC values of 0.25-1ꢠµg/mL against B. subtilis ATCC9372. In the inhibition
of S. aureus ATCC29213, the most active compound 30 showed an MIC value of 16 µg/mL, 4-fold better than CAM.
Furthermore, compounds 9, 18. 19 and 22 also exhibited the strongest activity against S. pneumoniae A22072 with the
same MIC value of 0.5ꢠµg/mL, showing 4-fold and 8-fold more potent activity than AZM and CAM, respectively.
Besides, many compounds demonstrated 2-fold better antibacterial activity with MIC value of 64 µg/mL against S.
pneumoniae AB11 than CAM and AZM.
On the whole, the synthesized target compounds showed comparable activity against susceptible bacteria and
improved activity against resistant bacteria in comparison with CAM and AZM. In addition, most of the compounds
exhibited favorable activity against Gram-positive bacteria but weak activity against Gram-negative bacteria. The results
indicated that the introduction of the arylalkyl group into the C-11 position of CAM was good for the potency of
compounds against some susceptible and resistant strains. What’s more, modification of the C-11 and C-3 positions of
CAM at the same time could greatly improve their activity against resistant strains. We supposed that the substituents at
the C-11 position could interacted directly with the nucleotide A752 and the removal of cladinose enhanced activity
against efflux resistance at the same time, resulting in excellent antibacterial activity.
Generally, compounds 7-19 bearing a phenyl side chain of six atoms distance from the O-11 position, exhibited better
antibacterial activity than compounds 20-30 which correspondingly had the same phenyl side chain of eight atoms
distance from the O-11 position. This result implied that the proper length of side chain could reach the chloramphenicol
binding site in bacterial ribosomes, thereby inhibiting peptide formation. In particular, among all the synthesized target
compounds, compounds 11, 18, 19 and 24, bearing the side chain of nitrophenyl groups, were the most active against all
the types of tested bacteria. In addition, the electron-withdrawing side chains (such as compounds 9, 10, 22 and 23) were
favourable to improve the antibacterial activity, while the electron-donating side chains (such as compounds 13, 14 and
25) decreased the antibacterial activity. Besides, the compounds containing same groups at the different position of
benzene ring, such as compounds 13 and 16, 22 and 27, had no significant differences in the antibacterial activity,
meaning that the substitution position of benzene ring might have no influence on the antibacterial activity.
From the data mentioned above, we could summarize their SARs as follows. Introduction of the novel
arylalkylcarbamoyl side chains into the C-11 position the ketolide skeleton could greatly improve activity against
8

erythromycin-resistant S. pneumoniae compared with CAM and AZM due to the additional binding interaction with
A752. The length of the side chains would influence antibacterial activity, suggesting that proper length the side chains
was favorable to enhance the antibacterial activity while the too long or short side chains were inclined to decrease the
antibacterial activity. In addition, the electron-withdrawing groups on the benzene ring of the side chains were good for
the improvement of the antibacterial activity, while the electron-donating groups were unfavorable. And the substitution
position the benzene ring might have no influence on the antibacterial activity. Moreover, the compounds with the
bi-substituted benzene ring exhibited higher antibacterial activity than the compounds with the mono-substituted benzene
ring, indicating that the terminal group might affect the ꢞ-stacking or the electrostatic interaction between the compounds
and the bacterial ribosomes. In particular, the compounds bearing the nitrophenyl group on the side chain were the most
active against all the types of tested bacteria.
In summary, a series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for
their in vitro antibacterial activity against various Gram-positive and Gram-negative bacteria. Among them, a majority of
the target compounds showed potent activity against erythromycin-susceptible S. pyogenes and penicillin-susceptible B.
subtilis ATCC9372, and significantly improved activity against the three phenotypes of resistant S. pneumoniae
compared to CAM and AZM. In particular, compound 18 possessed the best antibacterial activity against both sensitive
and resistant strains including S. pyogenes (0.125 µg/mL), S. aureus ATCC25923 (8 µg/mL), S. pneumoniae A22072
(0.5µg/mL) and S. pneumoniae AB11 (6 4µg/mL). Compound 9 exhibited the strongest antibacterial activity against
susceptible B. subtilis ATCC9372 (0.25 µg/mL). Besides, compound 30 showed potent activity (16 µg/mL) against S.
aureus ATCC29213, showing 4-fold higher activity than CAM. More importantly, the results demonstrated that the
modification of both C-11 and C-3 positions of clarithromycin could dramatically enhance the antibacterial activity.
Further optimization of clarithromycin derivatives with potent antibacterial activity should continue to be investigated.
Acknowledgments
This research was supported financially by the National Natural Science Foundation of China (81673284), the
Natural Science Foundation of Shandong (ZR2015BM019), Major Project of Research and development of Shandong
Province (2016GSF201202), and Major Project of Science and Technology of Shandong Province (2015ZDJS04001).
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10

Graphical Abstract:
Synthesis and antibacterial evaluation of novel 11-O-carbamoyl clarithromycin ketolides
Li Jia, Mi Yan, Yan Shen, Yinhui Qin, Shengsheng Qiang, Shutao Ma*
Department of Medicinal Chemistry Key Laboratory of Chemical Biology (Ministry of Education) School of
Pharmaceutical Sciences, Shandong University a. 44 West Culture Road, Jinan 250012 (P.R. China).
A series of novel 11-O-aralkylcarbamoyl-3-O-descladinosyl-3-oxo-clarithromycin derivatives were designed, synthesized
and evaluated for their in vitro antibacterial activity. Some compounds exerted potent and broad-spectrum antibacterial
activity.
11

Research Highlights
> 11-O-carbamoyl clarithromycin ketolides were designed and synthesized. > These derivatives were evaluated for their
in vitro antibacterial activity. > They exhibited excellent activity against susceptible and resistant strains. > Some
compounds exerted potent and broad-spectrum antibacterial activity.
12