Synthesis and antibacterial activity of novel 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives

Article abstract of DOI:10.1016/j.bmcl.2018.09.012

A novel series of 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives, were designed, synthesized and evaluated for their in vitro antibacterial activity. These derivatives were found to have strong activity against susceptible and resistant bacteria strains. Among them, compounds 7a and 7q showed the most potent activity (0.125 μg/mL) against erythromycin-resistant S. pneumoniae expressing the mefA gene. Moreover, compounds 7f, 7i, 7p and 7z displayed remarkably improved activity (4 μg/mL) against penicillin-resistant S. aureus ATCC31007, and compounds 7a, 7b, 7f, 7p and 7z showed improved activity (8 μg/mL) against erythromycin-resistant S. pyogenes. In particular, compound 7z exhibited potent and balanced activity against the tested drug-susceptible and -resistant bacterial strains.

Full text of DOI:10.1016/j.bmcl.2018.09.012

Accepted Manuscript
Synthesis and antibacterial activity of novel 3-O-arylalkylcarbamoyl-3-O-de-
scladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives
Yinhui Qin, Shengsheng Qiang, Shengli Ji, Zhiyang Liu, Chaoyu Hu, Shutao
Ma
PII:
S0960-894X(18)30743-1
https://doi.org/10.1016/j.bmcl.2018.09.012
BMCL 26033
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 May 2018
7 September 2018
9 September 2018
Please cite this article as: Qin, Y., Qiang, S., Ji, S., Liu, Z., Hu, C., Ma, S., Synthesis and antibacterial activity of
novel 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives,
Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.09.012
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Synthesis and antibacterial activity of novel
3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime
clarithromycin derivatives
Yinhui Qina, Shengsheng Qianga, Shengli Ji b, Zhiyang Liua, Chaoyu Hu a, Shutao Maa, *
a
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education),
School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China
b
ReaLi Tide Biological Technology (Weihai) Co. Ltd. East Longhai Road & South Yangguang Road,
Nanhai New District, Weihai 264207, China
Running title: 9-O-(2-Chlorobenzyl)oxime clarithromycin
* Corresponding author.
E-mail addresses: mashutao@sdu.edu.cn (S. Ma)
1

Abstract
A
novel series of 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime
clarithromycin derivatives, were designed, synthesized and evaluated for their in vitro antibacterial
activity. These derivatives were found to have strong activity against susceptible and resistant bacteria
strains. Among them, compounds 7a and 7q showed the most potent activity (0.125 µg/mL) against
erythromycin-resistant S. pneumoniae expressing the mefA gene. Moreover, compounds 7f, 7i, 7p and
7z displayed remarkably improved activity (4 µg/mL) against penicillin-resistant S. aureus
ATCC31007, and compounds 7a, 7b, 7f, 7p and 7z showed improved activity (8 µg/mL) against
erythromycin-resistant S. pyogenes. In particular, compound 7z exhibited potent and balanced activity
against the tested drug-susceptible and -resistant bacterial strains.
Keywords: Antibacterial activity; Bacterial resistance; Synthesis; 9-O-(2-Chlorobenzyl)oxime
clarithromycin derivatives.
2

Macrolides antibiotics are widely applied for the infections caused by Gram-positive bacteria
clinically. Erythromycin A (ERY) (Fig. 1) as the first macrolide has been used safely and effectively for
the treatment of upper and lower respiratory tract infections as well as genital infections since 1952.1,2
However, ERY readily degrade under the acidic conditions, and the resultant 6,9-hemiketal degradation
products are known to be responsible for gastrointestinal side effects and poor bioavailability.3,4 To
address the acid instability of ERY, clarithromycin (CAM) and azithromycin (AZM) (Fig. 1) as the
second-generation macrolides have been developed and widely prescribed due to their improved
antibacterial activity and pharmacokinetics as compared to ERY. 5,6
<Insert Fig. 1>
However, the increasing bacterial resistance to macrolides is emerging as a major threat to public
health.7,8 Two main resistant mechanisms to macrolides are the mono- or di-methylation of the
nucleotide A2058 of 23S rRNA via a methyltransferase encoded by the ermB gene, resulting in no
interaction between MLSB (macrolides, lincosamides and streptogramin B) antibiotics and the bacterial
ribosome,9-11 and the efflux pump encoded by the mefA gene that can pump macrolides out of the
bacterial cells.12 Therefore, it is urgent to develop newer generation macrolides to effectively overcome
the bacterial resistance.
Many studies have shown that the C-3 cladinose of macrolides is not an essential moiety for their
antibacterial activity but is responsible for the ermB-mediated inducible resistance.13 Consequently,
various structural modifications at the C-3 position of the 3-O-descladinosyl macrolides have led to
acylides, carbamate macrolides, ketolides, alkylides,14,15 and bicyclolides.16 Acylides such as
TEA077717 and TEA092918 (Fig. 2) possess significantly potent activity against efflux-resistant
Streptococcus pneumoniae in addition to MLSB-resistant Staphylococcus aureus. But the 3-O-acyl side
chains in the acylides were unstable and easily subjected to hydrolysis under physiological condition.
Then, carbamate macrolides were investigated to address this drawback. Among them, compounds A
and B (Fig. 2) display strong activity against erythromycin-resistant S. pneumoniae expressing the
mefA gene and the ermB gene, and compound C (Fig. 2) shows greatly improved activity against
erythromycin-resistant S. pneumoniae expressing the ermB and mefA genes.19 Besides, compound D
(Fig. 2) exhibits excellent activity against the above erythromycin-resistant S. pneumoniae.
3

<Insert Fig. 2>
On the other hand, introduction of 9-oxime ether side chain into macrolides has been the research
highlights to improve activity against resistant bacteria. Roxithromycin (ROX) (Fig. 3), for example,
has been successfully marketed.20 In addition, compound E21 (Fig. 3) shows remarkably improved
activity against key Gram-positive resistant pathogens as compared to CAM and AZM, while
compound F (Fig. 3) is frequently reported as an important lead compound.15,22
<Insert Fig. 3>
On
the
basis
of
the
above
considerations,
a
novel
series
of
3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives
were designed by introducing a 9-O-(2-chlorobenzyl) oxime side chain to the 9-position and
substituting various carbamate groups for the L-cladinose at the 3-position of CAM. Consequently, a
total of 26 new target compounds were synthesized from CAM in 30~36% yields as shown in Scheme
1. CAM was treated with hydroxylamine hydrochloride (HONH2⋅HCl) in the presence of sodium
acetate (NaOAc) and subsequently was subjected to diluted hydrochloric acid (HCl) to produce
3-O-descladinosyl-9-oxime product (2). Selective alkylation of 2 with 2-chlorobenzyl chloride in the
presence of potassium hydroxide (NaOH) gave 3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime
clarithromycin precursor (3) due to the hydroxyl group at the 9-position much more reactive than the
hydroxyl group at the 2ʹ-position. Protection of 2ʹ-hydroxyl group of 3 with acetic anhydride (Ac2O) in
dichloromethane (DCM) and subsequent treatment with 1,1ʹ-carbonyldiimidazole (CDI) in the presence
of sodium hydride (NaH) provided 3-O-acylimidazolide product (5) as a key intermediate. Finally, the
3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives
(7a-z) were obtained by coupling 5 with the corresponding alkylamine or arylamine in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in dimethylformamide (DMF), followed by deprotection of
the 2ʹ-O-acetyl group in methanol (MeOH). The structures of the target compounds 7a-z were
confirmed by 1H NMR, 13C NMR and MS spectra.24
4

<Insert Scheme 1>
The antibacterial screening of the 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)
oxime clarithromycin derivatives were performed by a standard dilution assay for the determination of
minimal inhibitory concentrations (MIC). The MIC values for all the target compounds were
determined in comparison with those of CAM and AZM on a panel of drug-susceptible and -resistant
bacterial strains. These bacterial strains included five susceptible strains of S. aureus ATCC25923
(erythromycin-susceptible strain), Streptococcus pyogenes 1 (erythromycin-susceptible strain isolated
clinically), Bacillus subtilis ATCC9372 (penicillin-susceptible strain), Escherichia coli ATCC25922
(penicillin-susceptible strain) and Pseudomonas aeruginosa ATCC27853 (penicillin-susceptible strain),
and six resistant strains of S. aureus ATCC29213 (methicillin-resistant strain), S. aureus ATCC31007
(penicillin-resistant strain), S. pyogenes 2 (erythromycin-resistant strain isolated clinically), S.
pneumoniae A22072 (erythromycin-resistant strain expressing the mefA gene), S. pneumoniae B1
(erythromycin-resistant strain expressing the ermB gene), S. pneumoniae AB11 (erythromycin-resistant
strain expressing the ermB and mefA genes). Their MIC values are listed in Table 1.
<Insert Table 1>
All of the 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin
derivatives showed excellent activity against erythromycin-resistant S. pneumoniae expressing the
mefA gene and penicillin-resistant S. aureus ATCC31007, compared with CAM and AZM. Among
them, compounds 7a and 7q were found to have the most potent activity against erythromycin-resistant
S. pneumoniae A22072 (0.125 µg/mL), showing 32-, 16- and 32-fold better activity than their
precursor 3 (4 µg/mL), CAM (2 µg/mL) and AZM (4 µg/mL), respectively. Compounds 7f, 7i, 7p and
7z had remarkably improved activity (4 µg/mL) against penicillin-resistant S. aureus ATCC31007,
which were 64 and 64-fold better than CAM and AZM (256 and 256 µg/mL), while compounds 7a, 7b,
7f, 7p and 7z also showed significant improved activity (8 µg/mL) against erythromycin-resistant S.
pyogenes 2, which were 32-, 32-, 32- and 32-fold more active than CAM and AZM (256 and 256
µg/mL), respectively. Similarly, all of the target compounds had much better activity than precursor 3
against S. aureus ATCC31007 and S. pyogenes 2. These results indicated that introduction of the
5

3-O-carbamoyl side chain at the 3-position of the 3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime
clarithromycin showed greatly improved activity against the above resistant bacterial strains. Although
the target compounds did not displayed better activity against erythromycin-susceptible S. aureus
ATCC25923 and S. pyogenes 1, and penicillin-susceptible B. subtilis ATCC9372, they still retained
potent antibacterial activity. For instance, compound 7z exhibited potent activity with the MIC values
of 4, 0.5 and 1 µg/mL against erythromycin-susceptible S. aureus ATCC25923, S. pyogenes 1 and B.
subtilis ATCC9372, respectively. However, the target compounds didn’t exhibit improved activity
against E. coli ATCC25922, P. aeruginosa ATCC27853, methicillin-resistant S. aureus ATCC29213
and erythromycin-resistant S. pneumonia expressing the ermB gene or the ermB and mefA genes in
comparison with their precursor 3.
It was worthy of noting that the target compounds possessed much better antibacterial activity than
their precursor 3, which suggested that simultaneously structural modification of the C-3 and the C-9
positions of CAM could significantly improve antibacterial activity. From the antibacterial activity data,
it was clear that introduction of the 3-O-carbamoyl side chain with a terminal benzene ring could
increase the antibacterial activity and in particular, the hydrogen bond receptor or donor group on the
terminal benzene ring on the 3-O-carbamoyl side chain could more significantly enhance the
antibacterial activity. The results were also consistent with the results of molecular docking (Fig 4). In
silico docking model performed by Le-dock further indicated that compound 7z bound into E. coli
ribosome (PDB code, 4v7s) in the same pocket as CAM , which suggested that the 3-O-carbamoyl side
chain in its structure could interact with the binding sites in the pocket formed by G2505, C2610 and
C2611 in domain V, resulting in a higher affinity to bacterial ribosome.
<Insert Fig 4>
In
summary,
a
novel
series
of
3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives,
were designed, synthesized and evaluated for their activity against drug-susceptible and -resistant
bacterial strains. The results indicated that compounds 7a and 7q showed the most potent activity
(0.125 µg/mL) against erythromycin-resistant S. pneumoniae expressing the mefA gene. Moreover,
compounds 7f, 7i, 7p and 7z displayed remarkably improved activity (4 µg/mL) against
6

penicillin-resistant S. aureus ATCC31007, and compounds 7a, 7b, 7f, 7p and 7z showed improved
activity (8 µg/mL) against erythromycin-resistant S. pyogenes. In particular, compound 7z exhibited
potent and balanced antibacterial activity, which would be further optimized as a leading compound in
our next work. In addition, introduction of the 3-O-carbamoyl side chain with a terminal aromatic ring
to the 3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin was found to increase activity
against erythromycin-resistant S. pneumoniae expressing the mefA gene, penicillin-resistant S. aureus
and erythromycin-resistant S. pyogenes.
Acknowledgements
This research was supported financially by the National Natural Science Foundation of China
(81673284), Major Project of Research and Development of Shandong Province (2016GSF201202),
Key Research and Development Project of Shandong Province (2017CXGC1401), and Major Project
of Science and Technology of Shandong Province (2015ZDJS04001).
A. Supplementary data
Supplementary material is available on the publishers Web site along with the published article.
References and notes
1. Washington JA, Wilson, WR. Erythromycin: A microbial and clinical perspective after 30 years of
clinical use (First of Two Parts)*. Mayo Clinic Proceedings. 1985; 60: 189-203.
2. Washington JA, Wilson, WR. Erythromycin: A microbial and clinical perspective after 30 years of
clinical use (Second of Two Parts)*. Mayo Clinic Proceedings. 1985; 60: 271-278.
3. Kurath P, Jones PH, Egan RS, et al. Acid degradation of erythromycin A and erythromycin B.
Experientia. 1971; 27: 362.
4. Omura S, Tsuzuki K, Sunazuka T, et al. Macrolides with gastrointestinal motor stimulating activity. J
Med Chem. 1987; 30: 1941-1943.
5. Keyes RF, Carter JJ, Englund EE, et al. Synthesis and antibacterial activity of 6-O-arylbutynyl
ketolides with improved activity against some key erythromycin-resistant pathogens. J Med Chem.
2003; 46: 1795-1798.
6. George G. Zhanel, Maria Dueck, Daryl J. Hoban, et al. Review of macrolides and ketolides. Drugs.
2001; 61: 443-498.
7. Bax RP, Anderson R, Crew J, et al. Antibiotic resistance-what can we do? Nat Med. 1998; 4:
545-546.
7

8. Felmingham D, Grüneberg RN. The Alexander Project 1996–1997: latest susceptibility data from
this international study of bacterial pathogens from community-acquired lower respiratory tract
infections. J Antimicrob Chemother. 2000; 45: 191-203.
9. C. J. Lai, B. Weisblum. Altered methylation of ribosomal RNA in an erythromycin-resistant strain of
Staphylococcus aureus. Proc Natl Acad Sci USA. 1971; 68: 856-860.
10. B. Weisblum. Erythromycin resistance by ribosome modification. Antimicrob Agents and
Chemother. 1995; 39; 577-585.
11. Atsushi Harimaya, Shin-ichi Yokota, Kiyoshi Sato, et al. High prevalence of erythromycin
resistance and macrolide-resistance genes, mefA and ermB, in Streptococcus pneumoniae isolates from
the upper respiratory tracts of children in the Sapporo district, Japan. J Infect Chemother. 2007; 13:
219-223.
12. Katz L, Ashley GW. Translation and protein synthesis:ꢀ macrolides. Chem Rev. 2005; 105: 499-528.
13. Ma Z, Clark RF, Brazzale A, et al. Novel erythromycin derivatives with aryl groups tethered to the
C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory
pathogens. J Med Chem. 2001; 44: 4137-4156.
14. Liang JH, Wang YH, Li XL, et al. Synthesis and antibacterial activities of a novel alkylide:
3-O-(3-aryl-2-propargyl) and 3-O-(3-aryl-2-propenyl)clarithromycin derivatives. Bioorg Med Chem
Lett. 2010; 20: 2880-2883.
15. Liang JH, Li XL, Wang YH, et al. Structure–activity relationships of novel alkylides: 3-O-Arylalkyl
clarithromycin derivatives with improved antibacterial activities. Eur J Med Chem. 2012; 49: 289-303.
16. Tang D, Gai Y, Polemeropoulos A, et al. Design, synthesis, and antibacterial activities of novel
3,6-bicyclolide oximes: Length optimization and zero carbon linker oximes. Bioorg Med Chem Lett.
2008; 18: 5078-5082.
17. Tanikawa T, Asaka T, Kashimura M, et al. Synthesis and antibacterial activity of acylides
(3-O-acyl-erythromycin derivatives):ꢀ A novel class of macrolide antibiotics. J Med Chem. 2001; 44:
4027-4030.
18. Tanikawa T, Asaka T, Kashimura M, et al. Synthesis and antibacterial activity of a novel series of
acylides:ꢀ 3-O-(3-Pyridyl)acetylerythromycin A derivatives. J Med Chem. 2003; 46: 2706-2715.
19. Zhang L, Song L, Liu Z, et al. Synthesis and antibacterial activity of novel 3-O-carbamoyl
derivatives of clarithromycin and 11,12-cyclic carbonate azithromycin. Eur J Med Chem. 2010; 45:
8

915-922.
20. Gasc JC, D'Ambrieres SG, Lutz A, et al. New ether oxime derivatives of erythromycin A. J Antibiot.
1991; 44: 313-330.
21. Liang JH, An K, Lv W, et al. Synthesis, antibacterial activity and docking of 14-membered
9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides. Eur J Med Chem. 2013; 59: 54-63.
22. Liang JH, Wang YY, Zhu DY, et al. Design, synthesis and antibacterial activity of a novel alkylide:
3-O-(3-aryl-propenyl)clarithromycin derivatives. J Antibiot. 2009; 62: 605-611.
23.
The
representative
experimental
procedure
and
analytical
data
of
3-O-(4-hydroxyphenylethyl)carbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin
(7z). To a solution of 5 (0.68 g，0.79 mmol) in anhydrous DMF (7 mL) at room temperature was added
DBU (0.24 g, 1.58 mmol, 2 equiv) and the corresponding amine (3.95 mmol, 5 equiv). The resulting
solution was heated to 55 °C and stirred for 12 h at the same temperature. After cooling to room
temperature, the solution was diluted with CH2Cl2 (21 mL) and then washed with distilled water (2×20
mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered. The filtrate was
concentrated in vacuo to afford a crude product, (dichloromethane/methanol 14:1,v/v).
A solution of the above crude product in methanol (10 mL) was heated to 55 °C and stirred for 12 h at
the same temperature. After concentrating the reaction solution in vacuo, the residue was purified by
chromatography (dichloromethane/methanol 60:1, v/v) to afford the desired product 7z as a white solid
in a 31% yield. mp 100–102 °C, TLC Rf = 0.20 (CH2Cl2:MeOH = 10:1); 1H NMR (400 MHz, CDCl3, δ
ppm): 7.41 – 7.38 (m, 1H), 7.36 – 7.34 (dd, J = 7.4, 1.7 Hz, 1H), 7.24 – 7.20 (m, 2H), 7.06 – 7.04 (d, J
= 8.3 Hz, 2H), 6.88 – 6.86 (d, J = 7.3 Hz, 2H), 5.24 – 5.21 (dd, J = 11.1, 2.2 Hz, 1H), 5.16 – 5.07 (m,
2H), 4.40 (s, 1H), 3.91 –3.89 (d, J = 7.0 Hz, 1H), 3.77 – 3.71 (m, 3H), 3.63 – 3.55 (m, 3H), 3.27 – 3.13
(m, 4H), 2.94 (s, 3H), 2.83 – 2.76 (m, 2H), 2.70 – 2.45 (m, 3H), 2.44 (s, 6H), 1.28 – 1.17 (m, 9H), 1.14
– 1.07 (m, 9H), 0.96 – 0.94 (d, J = 7.1 Hz, 3H), 0.85 – 0.81 (t, J = 7.3 Hz, 3H); MS (ESI) m/z calcd for
C46H70ClN3O12 [M + 2H]2+/2: 446.7, found: 447.2.
9

Figure captions
Fig 1. Structures of erythromycin A, clarithromycin and azithromycin.
Fig 2. Structures of TEA0777, TEA0929, and compounds A, B, C and D.
Fig 3. Structures of roxithromycin, and compounds E and F.
Scheme 1. Reagents and conditions: (a) H2NOH⋅HCl, NaOAc, MeOH, 75 °C, 12 h; dilute HCl, 5h; (b)
KOH, 2-chlorobenzyl chloride, DMF, rt, 6 h; (c) Ac2O, CH2Cl2, rt, 3 h; (d) CDI, NaH, toluene,
55 °C,10 h; (e) DBU, NH2-R, DMF, 55 °C, 12h; (f) MeOH, 55 °C, 12 h.
Fig 4. (a) The docking model of compound 7z (green) and clarithromycin (pink) in E. coli ribosome
(PDB code, 4v7s). Both are located in approximately the same spatial area in E. coli ribosome. (b)
Model of compound 7z docked into E. coli ribosome (PDB code, 4v7s). In the model, the predicted
hydrogen bonds between compound 7z and the nucleotide residues are indicated by dotted lines.
10

Fig 1.
Fig 2.
Fig 3.
11

Scheme 1.
Fig 4.
a
b
12

Table 1
In vitro antibacterial activity of 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives.
Minimum inhibitory concentration/ MIC (µg/mL)
S. aureus
E. coli
S. pyogenes
P. aeruginosa
B. Subtilis
S. aureus
S. aureus
S. pyogenes
S. pneumonia
S. pneumoniae
S. pneumonia
Compounds
ATCC25923a
ATCC25922b
1c
ATCC27853d
ATCC9372e
ATCC 29213f
ATCC 31007g
2h
A22072i
B1j
AB11k
8
4
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
1
1
2
2
4
2
8
4
2
4
2
2
2
4
2
1
1
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
2
2
4
4
4
2
8
4
2
2
2
2
2
4
2
2
4
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
16
8
8
0.125
0.5
1
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
128
128
128
128
128
128
128
128
7a
7b
7c
7d
7e
7f
8
16
16
16
8
8
16
16
16
8
8
0.5
1
8
4
0.5
2
16
16
8
8
16
16
16
16
16
8
7g
7h
7i
8
2
4
0.5
1
8
4
7j
8
4
1
7k
7l
16
16
16
4
4
1
4
8
1
7m
7n
7o
7p
7q
4
16
8
1
4
1
4
4
8
0.5
0.125
8
16
16
13

8
8
128
128
128
128
128
128
128
128
128
128
32
1
4
128
128
128
128
128
128
128
128
128
128
32
2
2
128
128
128
128
128
128
128
128
128
128
64
8
8
16
16
32
16
16
8
1
1
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
7r
7s
16
16
8
2
8
16
16
8
1
7t
1
4
0.5
1
7u
1
4
7v
8
2
4
4
1
7w
7x
4
2
2
4
8
1
8
2
2
8
16
8
1
7y
4
0.5
4
1
4
0.25
4
7z
3
64
0.25
0.25
16
0.25
0.5
32
256
256
128
256
256
0.03
0.03
2
CAM
AZM
8
16
8
4
aS. aureus ATCC25923: erythromycin-susceptible strain;
bE. coli ATCC25922: (penicillin-susceptible strain;
cS. pyogenes 1: erythromycin-susceptible strain isolated clinically;
dP.aeruginosa ATCC27853: penicillin-susceptible strain, not characterized;
eB. Subtilis ATCC9372; penicillin-susceptible strain
fS. aureus ATCC29213: methicillin-resistant strain;
gS. aureus ATCC 31007: penicillin-resistant strain;
hS. pyogenes 2: erythromycin-resistant strain isolated clinically;
iS. pneumoniae A22072: erythromycin-resistant strain expressing the mefA gene;
jS. pneumoniaeB1: erythromycin-resistant strain expressing the ermB gene;
kS. pneumoniae AB11: erythromycin-resistant strain expressing the ermB and mefA genes.
14

Research Highlights
> Novel 3-substituted derivatives of clarithromycin were synthesized and evaluated. > Some of them showed potent activity against both susceptible and resistant
strains. > Compound 7z exhibited potent and balanced antibacterial activity.
15

Graphical abstract:
Synthesis and antibacterial activity of novel 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin
derivatives
Yinhui Qin, Shengsheng Qiang, Shengli Ji, Zhiyang Liu, Chaoyu Hu, Shutao Ma
16

17