Synthesis and Antibacterial Activity of Novel 4″-O-desosaminyl clarithromycin derivatives with 11, 12-arylalkyl side chains

Article abstract of DOI:10.1080/10286020.2018.1462341

A series of novel 4″-O-desosaminyl clarithromycin derivatives with 11, 12-arylalkyl side chains was synthesized by coupling 6-deoxy-desosamine donors (18, 19) with 4″-OH of compounds 5a–c. The activities of the target compounds were tested against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed activities against macrolide sensitive and resistant pathogens, and compounds 21d and 21e displayed significant improvement of activities against resistant pathogens.

Full text of DOI:10.1080/10286020.2018.1462341

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: http://www.tandfonline.com/loi/ganp20
Synthesis and Antibacterial Activity of Novel 4″-O-
desosaminyl clarithromycin derivatives with 11,
12-arylalkyl side chains
Zhe-Hui Zhao, Di Zhu, Xiao-Xi Zhang, Zhi-Gang Luo & Ping-Sheng Lei
To cite this article: Zhe-Hui Zhao, Di Zhu, Xiao-Xi Zhang, Zhi-Gang Luo & Ping-Sheng
Lei (2018): Synthesis and Antibacterial Activity of Novel 4″-O-desosaminyl clarithromycin
derivatives with 11, 12-arylalkyl side chains, Journal of Asian Natural Products Research, DOI:
10.1080/10286020.2018.1462341
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Journal of asian natural Products research, 2018
https://doi.org/10.1080/10286020.2018.1462341
Synthesis and Antibacterial Activity of Novel 4″-O-
desosaminyl clarithromycin derivatives with 11, 12-arylalkyl
side chains
Zhe-Hui Zhao#, Di Zhu#, Xiao-Xi Zhang, Zhi-Gang Luo and 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, china
ABSTRACT
ARTICLE HISTORY
received 24 december 2017
accepted 4 april 2018
A series of novel 4″-O-desosaminyl clarithromycin derivatives with
11, 12-arylalkyl side chains was synthesized by coupling 6-deoxy-
desosamine donors (18, 19) with 4″-OH of compounds 5a–c. The
activities of the target compounds were tested against a series of
macrolide-sensitive and macrolide-resistant pathogens. Some of them
showed activities against macrolide sensitive and resistant pathogens,
and compounds 21d and 21e displayed significant improvement of
activities against resistant pathogens.
KEYWORDS
clarithromycin; antibacterial
activity; desosamine
1. Introduction
With the macrolide antibiotics widely used in clinic since 1950s, the emergence of mac-
rolide-resistant bacteria has been increasingly prevalent. Great efforts have been made to
develop novel macrolide structures against resistant pathogens [1]. e most successful
improvement of anti-resistant macrolide antibiotics is well known as ketolides, represented
by telithromycin [2], cethromycin [3], and solithromycin [4] (Figure 1). e mechanism of
anti-resistance of ketolides is through an extra interaction between the side chain, a tethered
hetero-aromatic substituent, and A752 in domain II of the 23S rRNA [5].
CONTACT Zhe-hui Zhao
zhaozh@imm.ac.cn
#authors contributed equally to this work.
© 2018 informa uK limited, trading as taylor & francis Group

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Z.-H. ZHAO ET AL.
Figure 1. chemical structures of telithromycin, cethromycin, and solithromycin.
Ary
N
N
O
N
O
R=H;
O
HO
O
HO
O
HO
O
O
O
O
O
O
O
O
O
O
RO
RO
N
O
N
O
O
O
HO
OR
O
O
O
O
O
O
O
O
O
O
H
N
saccharide
O
O
O
O
O
O
OCH3
OCH3
OCH3
O
A60565
LPSs
Targets
Figure 2. chemical structures of a60565, lPss, and targets.
Ketolides, however, are not the only class of macrolides against resistant bacteria. Among
the many none ketolides, 4″-O-modified macrolide derivatives show a notable potent activ-
ity against macrolide-sensitive and macrolide-resistant pathogens. In 1989, Fernandes et
al. found that compound A-60565 had better activity than erythromycin against some con-
stitutively resistant Streptococcus pyogenes [6]. Since then, such 4″-O-modified macrolides
have been investigated by several research groups. 4″-OH-modified macrolide derivatives,
with ether, ester, and carbamate as linkers, have been frequently investigated in recent years
[7–12]. A series of clarithromycin derivatives with 4″-O-saccharide substituents (Figure 2)
using carbohydrate as a linker was reported by our lab [13,14]. Without 11,12-modification,
such derivatives showed poor activity against either susceptible or resistant strains [13].
To further delve into the structure–activity relationship of 4″-O-modified macrolides and
explore for novel macrolide antibiotics, Zhu et al. synthesized a series of novel clarithromy-
cin derivatives with 4″-O-desosamine substituents (Figure 2) in the next work [14]. Among
them, two compounds displayed significant improvement of activities against sensitive
pathogens and two strains of MRSE (S. epidermidis 12–4, 12–11).
It is well known that the 14-membered macrolides carrying the side chain could improve
the activities against macrolide sensitive and resistant pathogens and 4″-O-modified mac-
rolide derivatives also could improve the activities against macrolide sensitive and some of
resistant pathogens. In this research, we focused on whether the new macrolide molecular
carrying both 11, 12-arylalkyl side chains and 4″-O-desosamine substituent could promote
the activities against resistant pathogens at the same time. Herein, we reported an efficient
synthetic procedure designed for preparing a series of novel 4″-O-desosaminyl clarithro-
mycin derivatives with 11, 12-arylalkyl side chains (Figure 2) and aimed to improve their
activities, especially against resistant pathogens.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Scheme 1. reagents and conditions: (a) ac2o, pyridine, ch2cl2, room temperature, overnight, 88%; (b)
nan(tMs)2, cdi, thf, −40 °c to room temperature, 12 h, 69%; (c) 4-arylbutan-1-amine, dBu, thf, room
temperature, 24 h, 56% for 3a, 66% for 3b, 56% for 3c; (d) K2co3, Meoh, 40 °c, 24 h, 60% for 4a, 68% for
4b, 68% for 4c; (e) ac2o, tea, ch2cl2, 0 °c to room temperature, 6 h, 74% for 5a, 71% for 5b, 71% for 5c.
2. Results and discussion
2.1. Chemistry
Our approach is to find an efficient route to synthesis of new 14-membered macrolides
with 4″-O-desosaminyl and 11, 12-arylalkyl side chains. Scheme 1 outlines the synthe-
ses of compounds 5a–c, 4′-O-acetyl clarithromycin derivatives with 11, 12-arylalkyl side
chains, as acceptors. Clarithromycin was protected by treatment with acetic anhydride in
dichloromethane, pyridine as the base, to give compound 1. e compound 1 was readily
reacted with carbonyldiimidazole (CDI) in the presence of sodium bis(trimethylsilyl)amide
(NaHMDS) to give compound 2. e compound 2 was coupled with selected 4-arylbu-
tan-1-amine (12, 16, and 17) in the presence of DBU to give compounds 3a–c. Deprotection
of compounds 3a–c smoothly with K2CO3 in the methanol gave the compounds 4a–c.
Acceptors 5a–c were prepared by selectively protecting the 2′-OH of compounds 4a–c.
Scheme 2 and Scheme 3 outlines the syntheses of 4-arylbutan-1-amine (12, 16, and 17).
e compound 12 was obtained via seven steps from 3-acetylpiridine. Compounds 16 and
17 were prepared via three steps from 2,3-diamino-pyridin as the way reported in our lab
[15]. Two isomers 14 and 15 were distinguished according to the NOESY spectrum (see
Table 1).
With the acceptors 5a–c in hand, donors 18 and 19 [14] were successfully glycosylated
with acceptors 5a–c to obtain the compounds 20a–f, triethylsilyl trifluoromethanesulfonate
(TESOTf) used as a promoter (Scheme 4). Deprotection of compounds 20a–f smoothly

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Z.-H. ZHAO ET AL.
Scheme 2. reagents and conditions: (a) nh2oh•hcl, tea, Meoh, reflux, 5 h, 98%; (b) p-toluenesulphonyl
chloride, pyridine, 0 °c to room temperature, 16 h, 97%; (c) etoK, etoh, 0 °c to room temperature, 9 h,
86%; (d) Kscn, h2o, p-toluenesulfonic acid, 50 °c, 5 h, 58%; (e) hno3, 90 °c, 2 h, 85%; (f) N-(4-bromobutyl)
phthalimide, K2co3, dMf, 90 °c, 10 h, 65%; (g) nh2nh2, etoh, reflux, 5 h.
Scheme 3. reagents and conditions: (a) trimethyloxymethane, 120 °c, 12 h, 70%; (b) N-(4-bromobutyl)
phthalimide, K2co3, dMf, 90 °c, 10 h, 45% for 14, 25% for 15; (c) nh2nh2, etoh, reflux, 5 h.
Table 1. the structures of compounds 21a–f.
a
b
c
d
e
f
ary
r
Bn
h
Bn
h
Bn
h
with the methanol gave the target compounds 21a–f, which were confirmed by HR-MS,
1H NMR, and 13C NMR spectra (Tables 1 and 2).
2.2. Biological activities
e antibacterial activities of the target compounds 21a–f were assessed against some res-
piratory pathogens, including macrolide drug sensitive and resistant strains. Clarithromycin
and telithromycin were chosen as the reference compounds. e in vitro antibacterial activity
was reported as minimum inhibitory concentrations (MICs), which was determined by the
broth microdilution method as recommended by the CLSI [16] (Scheme 4).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5

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Z.-H. ZHAO ET AL.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
Scheme 4. reagents and conditions: (a) tesotf, 4a molecular sieves, ch2cl2, −20 °c to room temperature,
72 h, 85–95%, (b) Meoh, room temperature, 12 h, 40–45%.
Table 3. In vitro antibacterial activities of the target compounds.
S. pneumonia
S. pyogenes
S. aureus
S. epidermidis
H. influenzae
11G364 11J011 11L264 11N369 11B122 11B117 11X315 11C176 11P042 11Q373
21a
21b
21c
21d
21e
21f
0.5
0.25
0.5
0.062
0.031
1
0.008
0.031
8
16
16
2
4
32
0.031
64
0.062
0.125
0.25
0.031
0.016
0.062
0.016
0.016
8
16
8
2
0.5
1
0.25
0.5
2
0.031
0.031
>64
>64
>64
64
>64
>64
>64
>64
2
0.5
1
0.25
0.5
4
0.016
0.125
>64
>64
>64
32
>64
>64
0.016
>64
64
8
32
8
16
32
4
64
16
32
16
32
64
4
2
0.5
32
0.031
>64
Teli.
Clar.
8
8
11G364 is erythromycin-sensitive Streptococcus pneumonia. 11J011 is erythromy-
cin-resistant Streptococcus pneumonia. 11L264 is erythromycin-sensitive Streptococcus
pyogenes. 11N369 is erythromycin-resistant Streptococcus pyogenes. 11B122 is methicil-
lin-sensitive Staphylococcus aureus. 11B117 is methicillin-resistant Staphylococcus aureus.
11X315 is methicillin-sensitive Staphylococcus epidermidis. 11C176 is methicillin-resist-
ant Staphylococcus epidermidis. 11P042 is azithromycin-sensitive Haemophilus influenzae.
11Q373 is 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).
e antibacterial activities of compounds 21a–f were shown in Table 3. In reviewing the
data of Table 3, all the targets that we synthesized showed some activities against a panel of
sensitive and resistant pathogens, but weaker or slightly weaker than that of telithromycin.
Compounds 21a–21c, 21f showed weaker antibacterial activity than that of clarithromcin
against erythromycin-sensitive S. pneumonia, while compounds 21d and 21e preserved
antibacterial activity against erythromycin-sensitive S. pneumonia. e activity of com-
pounds 21a–21f was stronger than that of clarithromycin against erythromycin-resistant
S. pneumonia. Among them, compound 21d showed a 32-fold stronger than that of clar-
ithromycin against erythromycin-resistant S. pneumonia (2: 64). e activity of compounds
21a–21f was at same level against erythromycin-sensitive S. pyogenes compared that with
clarithromycin. e activity of compounds 21a–21f was stronger than that of clarithromy-
cin against erythromycin-resistant S. pyogenes. Among them, compound 21e showed two
orders of magnitude stronger than that of clarithromycin against erythromycin-resistant S.

8
Z.-H. ZHAO ET AL.
pyogenes (0.5:>64). e activity of compounds 21a–21f was similar or slightly weaker than
that of clarithromycin against S. aureus, S. epidermidis, and H. influenzae. Only compound
21d showed some activities against methicillin-resistant S. aureus (64) and methicillin-re-
sistant S. epidermidis (32).
From the data mentioned above, it could be seen that all targets that we synthesized
preserved activities against sensitive strains, while improved activities against some resistant
strains. It might be concluded that 11, 12-arylalkyl side chains and 4″-O-desosamine substit-
uent were favorable for activities against resistant strains. e activities of compounds 21d
and 21e were stronger than that of 21a and 21b, indicated that side chains 16 and 17 were
favorable than 12. e targets containing free 4‴-OH (compounds 21a, 21c, 21e) possessed
similar antibacterial activities compared to those with 4‴-OBn (compounds 21b, 21d, 21f),
which could indicate that 4‴-OH modified or unmodified derivatives have no influence on
the antibacterial activities.
3. Conclusion
In summary, a series of novel 4″-O-desosaminyl clarithromycin derivatives with 11,
12-arylalkyl side chains were obtained with efficient synthesis of macrolide acceptors and
desosamine donors, proper method of glycosylation, and reasonable strategy of deprotec-
tion. Some of them showed comparable activities against macrolide sensitive and resistant
pathogens and compounds 21d and 21e displayed significant improvement of activities
against some resistant pathogens. e result offered us some valuable information of mac-
rolide overcoming the resistant pathogens.
Acknowledgments
We are grateful to the Department of Instrumental Analysis of our institute for performing the NMR
and mass spectroscopy measurements.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
is work was supported by the Fundamental Research Funds for CAMS/PUMC [2016CX350034]
and the CAMS Innovation Fund for Medical Sciences [Item Number: CIFMS, 2016-I2M-3-009 and
2017-I2M-1-012].
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