Design, synthesis and antibacterial evaluation of novel C-11, C-9 or C-2′-substituted 3-O-descladinosyl-3-ketoclarithromycin derivatives

Article abstract of DOI:10.1016/j.bmcl.2021.128110

A novel series of 3-O-descladinosyl-3-keto-clarithromycin derivatives, including 11-O-carbamoyl-3-O-descladinosyl-3-keto-clarithromycin derivatives and 2′,9(S)-diaryl-3-O-descladinosyl-3-keto-clarithromycin derivatives, were designed, synthesized and eval

Full text of DOI:10.1016/j.bmcl.2021.128110

Bioorg. Med. Chem. Lett. 43 (2021) 128110
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and antibacterial evaluation of novel C-11, C-9 or
′
C-2 -substituted 3-O-descladinosyl-3-ketoclarithromycin derivatives
1
1
*
Bingfang Bai , Fangchao Bi , Yinhui Qin, Yuetai Teng, Shutao Ma
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine,
Shandong University, 44 West Wenhua Road, Jinan 250012, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
A novel series of 3-O-descladinosyl-3-keto-clarithromycin derivatives, including 11-O-carbamoyl-3-O-descladi-
Antibacterial activity
Bacterial resistance
Synthesis
′
nosyl-3-keto-clarithromycin derivatives and 2 ,9(S)-diaryl-3-O-descladinosyl-3-keto-clarithromycin derivatives,
were designed, synthesized and evaluated for their in vitro antibacterial activity. Among them, some derivatives
were found to have activity against resistant bacteria strains. In particular, compound 9b showed not only the
most significantly improved activity (16 µg/mL) against S. aureus ATCC43300 and S. aureus ATCC31007, which
was >16-fold more active than that of CAM and AZM, but also the best activity against S. pneumoniae B1 and
S. pyogenes R1, with MIC values of 32 and 32 µg/mL. In addition, compounds 9a, 9c, 9d and 9g exhibited the
3
-O-descladinosyl-3-keto-clarithromycin
derivatives
′
most effective activity against S. pneumoniae AB11 with MIC values of 32 or 64 µg/mL as well. Unfortunately, 2 ,9
(
S)-diaryl-3-O-descladinosyl-3-keto-clarithromycin derivatives failed to exhibit better antibacterial activity than
references. It can be seen that the combined modification of the C-3 and C-11 positions of clarithromycin is
′
beneficial to improve activity against resistant bacteria, while the single modification of the C-2 ’ position is very
detrimental to antibacterial activity.
Macrolide antibiotics are lipophilic compounds with a lactone ring
hydroxyl and C-9 carbonyl groups under the catalysis of gastric acid to
generate 6,9-dehydration metabolites, and then 6,9,12-dehydrated
metabolites by intramolecular condensation with C-12 hydroxyl
group,7 which reduce the bioavailability of erythromycin and produce
gastrointestinal side effects. Consequently, this greatly limits the wide-
spread use of erythromycin clinically. Clarithromycin (CAM) and azi-
thromycin (AZM) are two representative drugs of the second generation
macrolide antibiotics and overcome the shortcoming of poor pharma-
cokinetic properties of erythromycin in vivo,7 which were approved by
FDA in 1991. They were prepared from erythromycin as the starting
material through 6 and 4 steps of chemical reactions, respectively.
Compared with erythromycin, they show significantly enhanced anti-
structure, which are produced by Streptomyces1 and show broad anti-
bacterial spectrum and excellent antibacterial activity. They has also
good pharmacokinetic properties, such as high oral bioavailability, good
plasma stability and long half-life, etc. Macrolides antibiotics are widely
used in the treatment of various respiratory infectious diseases, such as
respiratory and urinary diseases caused by Gram-positive bacteria such
as Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus
pyogenes due to their strong antibacterial activity in vivo and in vitro, low
toxicity and high safety. At present, they have become one of the most
widely used antibiotics in the world.
Macrolides promote the dissociation of peptidyl tRNA on ribosome,
inhibit the extension of peptide chain, and block the synthesis of bac-
terial protein, thereby producing antibacterial effect by binding to the
entry of peptide exit channel of peptidyl transferase center on 23S rRNA
8
bacterial activity and greatly improved pharmacokinetic properties.
Unfortunately, the prevalence of drug-resistant bacteria appears
rapidly due to the abuse of antibiotics, whcih weakens the effectiveness
2
9,10
of 50S subunit of bacterial ribosome. Erythromycin (Fig. 1) is the
of macrolides.
The bacterial resistance to macrolides are mainly
representative drug of the first generation of macrolide antibiotics,3
and was approved by FDA in 1952 to treat respiratory tract infection,
sexually transmitted diseases, skin and soft tissue infection.5,6 However,
erythromycin is subjected to the intramolecular condensation of C-6
,4
caused by the methylation of A2058 in 23S rRNA nucleotide of bacterial
1
1,12
ribosome by methyltransferase encoded by the erm gene.
This
methylation effect can block the formation of hydrogen bonds between
′
the C-2 hydroxyl group in macrolides and nucleotide residue A2058,
*
Corresponding author.
E-mail address: mashutao@sdu.edu.cn (S. Ma).
The authors contributed equally.
1
https://doi.org/10.1016/j.bmcl.2021.128110
Received 10 February 2021; Received in revised form 28 April 2021; Accepted 10 May 2021
Available online 13 May 2021
0
960-894X/© 2021 Elsevier Ltd. All rights reserved.

B. Bai et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128110
thereby greatly reducing the binding force between them. On the other
hand, the efflux pump protein encoded by the mef gene on bacterial cell
membrane can recognize macrolides and expel them out of bacterial
produce an additional binding force with U790 in domain II of 23S rRNA
of ribosome of resistant bacteria, and eventually improved anti-resistant
bacteria activity.24
1
3
cells, which reduces the accumulation of drugs in bacterial cell and
puts them below the effective concentration. This also leads to bacterial
resistance. Therefore, it is urgent to develop new macrolide antibiotics
against resistant bacteria.
The synthetic method for 11-O-carbamoyl-3-O-descladinosyl-3-keto-
clarithromycin derivatives is shown in Scheme 1. CAM as the starting
material was treated with 36% hydrochloric acid to generate 3-descladi-
nosylclarithromycin 2.25 Then, the reaction of 2 with acetic anhydride
catalyzed by triethylamine gave acetyl product 3,26 which subsequently
reacted with bis(triehloromethyl)carbonate (BTC) to afford the 11,12-
cyclic carbonate 4 in the presence of pyridine.27 After that, 4 was con-
verted into 3-ketone product 5 under pyridinium chlorochromate (PCC)
The results of X-ray eutectic structure show that 3-O-cladinose of
macrolide antibiotics is not necessary for antibacterial activity, and the
C-3 position modification can enhance the activity against resistant
bacteria.14 Consequently, the third generation macrolide antibiotics
represented by telithromycin, cethromycin and solithromycin (Fig. 2)
have been designed and synthesized to respond to bacterial resistance.
Compared with the previous two generations of macrolides, this gen-
eration of macrolides is highly active to erythromycin-resistant patho-
gens. For example, telithromycin15 was approved by FDA in 2004 to
treat chronic bronchitis, pharyngitis and community acquired pneu-
monia. It has a strong inhibitory effect on erythromycin resistant
Streptococcus pneumoniae and Haemophilus influenzae. As a promising
clinical candidate drug, cethromycin16 and solithromycin are consid-
ered to be effective drugs in the treatment of community acquired
oxidation,28 which was treated with alkanolamine at 15 C to give key
◦
′
intermediate 2 -O-acetyl-11-O-(aminoethyl)carbamoyl-3-O-descladino-
syl-3-keto-clarithromycin 6a-6b. The terminal hydroxyl group on the C-
11 side chain of 6a-6b was esterified with methanesulfonyl chloride
(MsCl) to obtain mesylate intermediate 7a-7b. Intermediate 7a-7b was
treated with sodium azide (NaN
3
) in the mixed solvent of water and N,N-
◦
dimethylformamide (DMF) at 60 C to produce key intermediate 8a-8b.
After that, the click reaction of 8a-8b with the corresponding phenyl-
17
9
acetylene catalyzed by cuprous iodide (CuI) in toluene solution and
subsequent deprotection in methanol (MeOH)29 afford target com-
pounds 9a-9g. Their structures were confirmed by 1H NMR and MS
spectra.
B
pneumonia caused by MLS resistant bacteria, and display prominent
inhibitory effect on Staphylococcus and Enterococci as well as macrolides
resistant respiratory pathogens. The common structural features of these
drugs are the C-3 keto group and arylalkyl side chains on their skeleton.
′
The synthetic method for 2 ,9(S)-diaryl-3-O-descladinosyl-3-keto-
clarithromycin derivatives (19a–19t) is shown in Scheme 2. The C-9
Our previous1
8–20
studies showed that the combined modification of
carbonyl group of CAM was reduced with sodium borohydride to obtain
′
′
the C-3 and C-11 positions of CAM could significantly improve activity
against resistant bacteria and retain activity against sensitive bacteria.
On this basis, we designed and synthesized a series of novel 11-O-car-
bamoyl-3-O-descladinosyl-3-keto-clarithromycin derivatives in order to
overcome the erm gene or the mef gene-mediated bacterial resistance
and expand antibacterial specturm. On the one hand, the removal of C-3
position cladinose can suppress the active efflux of bacteria. On the
other hand, 11-O-carbamoyl side chain is favorable to combine with
the intermediate 10. The hydroxyl groups on the C-4 ’, C-2 and C-9-
positions of the intermediate 10 reacted with TESCl to give TES pro-
tected product 11. Subsequently, the hydroxyl groups on the C-11 and C-
12 positions were subjected to oxidative cracking and ring opening by
4
treating selectively with Pb(OAc) to obtain the key intermediate 12,
which was further treated with ethanolamine to produce the secondary
3
0
amine 13 through the first reductive amination reaction. The sec-
ondary amine of 13 and 37% HCHO undergo a second reductive ami-
nation reaction to obtain tertiary amine product 14.30 We prepared
crude tertiary amine 14 through a three-step reaction from 11 using the
“one-pot method” due to the instability of 12. Under the catalysis of
LiOH, 14 was hydrolyzed to afford the carboxylic acid 15, which was
further purified by column chromatography to give its pure product. The
intramolecular esterification of 15 completed the cyclization process to
A752 through hydrogen bond,
π
- stacking or van der waals interaction,
π
2
1
so as to improve anti-resistant activity. Furthermore, we previously
opened the 14-membered lactone ring of CAM by oxidation reaction,
and reconstructed the new 15-membered lactone ring by esterification
reaction, whose stereo conformation changed to some extent to facilitate
′
binding with bacterial ribosome. Its 2 -OH can combine with the A2058
and A2059 of ribosome of sensitive bacteria through hydrogen bonding
to exhibit anti-sensitive bacteria activity.22 However, the highly meth-
ylated A2058 residue of ribosome of resistant bacteria cannot serve as an
H-bond donor to participate in coordination of the water molecule on
bacterial ribosome,23 thereby exerting activity against resistant bacteria.
Thus, it is a feasible method that introduction of new aryl side chains
obtain cyclization product 16.31 The TES protecting groups on the C-2
′
and C-9 positions, and cladinose on the C-3 position were removed from
16 to give 17 under dilute hydrochloric acid.25 The condensation of 17
with various substituted benzoyl chloride gave condensation products
32
18a-18t, whose hydroxyl groups at the C-3 position were further
oxidized by Dess-Martin periodinane to produce the target compounds
′
1
into 2 -OH to establish strong binding force with new binding site in the
19a-19t. Their structures were confirmed by H NMR and MS spectra.
ribosome of resistant bacteria. For the purpose of improving the activity
The in vitro antibacterial activity of target compounds were deter-
mined by the standard broth microdilution procedures recommended by
NCCLS. The tested strains included three susceptible strains of S. aureus
ATCC25923 (erythromycin-susceptible strain), Bacillus subtilis
ATCC9372 (penicillin-susceptible strain) and Pseudomonas aeruginosa
of compounds against resistant bacteria, we designed and synthesized
′
2
,9(S)-diaryl-3-O-descladinosyl-3-keto-clarithromycin derivatives by
′
modifying the C-2 and C-9 positions of CAM. We hoped that the aryl
′
side chains introduced at the C-2 and C-9 positions of CAM could
Fig. 1. Structures of erythromycin, clarithromycin and azithromycin.
2

B. Bai et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128110
Fig. 2. Structures of telithromycin, cethromycin and solithromycin.
Scheme 1. Synthesis of 11-O-carbamoyl-3-O-descladinosyl-3-keto-clarithromycin derivatives (9a–9 g). Reagents and conditions: (a) HCl, H
3
2
O, rt, 5 h, 83%; (b) Ac
2
O,
◦
◦
Et
N, DCM, 0 C ~ rt, 36 h, 94%; (c) pyridine, BTC, DCM, 0 C ~ rt, 20 h, 99%; (d) PCC, DCM, rt, 24 h, 88%; (e) 3-aminopropanol/4-amino-1-butanol, pyridine
◦
◦
◦
3 2
, DMF, H O, 60 C, 12 h, 72 ~ 78%; (h) i) phenylacetylene, CuI,
hydrochloride, 15 C, 2 h, 39 ~ 42%; (f) MsCl, Et
3
N, DCM, 0 ~ 25 C, 2 h, 88 ~ 89%; (g) NaN
3
OH, 55 C, 24 h, 55 ~ 60%.
◦
◦
toluene, 90 C, 24 h; ii) CH
ATCC27853 (penicillin-susceptible strain), and five resistant strains of
S. aureus ATCC43300 (methicillin-resistant strain), S. aureus
ATCC31007 (penicillin-resistant strain), S. pyogenes R1 (erythromycin-
resistant strain isolated clinically), S. pneumoniae B1 (erythromycin-
resistant strain expressing the ermB gene) and S. pneumoniae AB11
(erythromycin-resistant strain expressing the ermB and mefA genes). The
minimal inhibitory concentration (MIC) values for the above target
compounds as well as CAM and AZM as the references were tested
3

B. Bai et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128110
′
Scheme 2. Synthesis of 2 ,9(S)-diaryl-3-O-descladinosyl-3-keto-clarithromycin (19a–19 t). Regents and conditions: (a) NaBH
4
, CH
, rt, 4 h; (e) 37% HCHO, NaBH(OAc)
O, rt, 6 h, 30% in four steps from intermediate 11; (g) i) 2, 4, 6-trichlorobenzoyl chloride, Et N, THF, rt, 4 h; ii) DMAP, CH
N, 0 C to rt, 4 h; (j) Dess-Martin periodinane, DCM, rt, 2 h, 15 ~ 53% in two
3
OH-THF, rt, 24 h, 52%; (b) TESCl,
, CHCl , rt, 4 h;
CN, reflux, 0.5
◦
◦
imidazole, DMF, 0 C to rt, 18 h, 68%; (c) Pb(OAc)
4
, CHCl
3
, 0 C, 0.5 h; (d) ethanolamine, NaBH(OAc)
3
, CHCl
3
3
3
(
f) LiOH, THF-C OH-H
2
H
5
2
3
3
◦
◦
h, 51%; (h) 1 M HCl, EtOH, 60 C, 2 h, 77%; (i) Substituted benzoyl chloride, DCM, Et
steps from intermediate 17.
3
against a panel of sensitive and resistant bacteria strains, which are
presented in Table 1.
ATCC31007, but weak activity against S. aureus ATCC25923 and
B. subtilis ATCC9372. Unfortunately, none of them displayed better
antibacterial activity against P. aeruginosa ATCC27853 than AZM (MIC
Compared to the references CAM and AZM, 11-O-carbamoyl-3-O-
descladinosyl-3-keto-clarithromycin derivatives 9a-9g universally
showed greatly improved activity against S. pneumoniae B1,
S. pneumoniae AB11, S. pyogenes R1, S. aureus ATCC43300 and S. aureus
3
3
= 32 µg/mL ). Among them, 9b showed significantly improved activity
(16 µg/mL) against S. aureus ATCC43300 and S. aureus ATCC31007,
which was >16-fold more active than that of CAM and AZM (>256 and
4

B. Bai et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128110
Table 1
In vitro antibacterial activity of 3-O-descladinosyl-3-keto-clarithromycin derivatives.
Minimum inhibitory concentration/ MIC (µg/mL)
Compounds
S. aureus
S. aureus
S. pneumoniae
S. pneumoniae
S. pyogenes
P. aeruginosa
S. aureus
B. Subtilis
a
b
c
d
e
f
g
h
ATCC43300
ATCC31007
B1
AB11
R1
ATCC27853
ATCC25923
ATCC9372
9
9
9
9
9
9
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
a
256
256
64
32
64
128
16
4
b
16
16
32
32
32
128
32
16
c
＞256
64
＞256
64
256
64
256
＞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
16
32
4
d
64
32
64
64
4
e
128
256
128
64
64
64
16
f
＞256
＞256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
＞256
＞256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
256
128
256
64
32
g
256
32
256
64
16
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
9r
9s
9t
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
128
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
256
128
128
128
128
128
64
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
≤0.25
≤0.25
64
128
128
128
64
64
64
128
128
128
128
64
>256
>256
>256
>256
>256
>256
64
128
≤0.25
≤0.25
CAM
AZM
128
256
32
a
S. aureus ATCC43300: methicillin-resistant strain;
S. aureus ATCC 31007: penicillin-resistant strain;
b
c
d
e
f
S. pneumoniae B1: erythromycin-resistant strain expressing the ermB gene;
S. pneumoniae AB11: erythromycin-resistant strain expressing the ermB and mefA genes;
S. pyogenes: erythromycin-resistant strain isolated clinically;
P. aeruginosa ATCC27853: penicillin-susceptible strain, not characterized;
S. aureus ATCC25923: erythromycin-susceptible strain;
g
h
B. Subtilis ATCC9372; penicillin-susceptible strain.
>
256 µg/mL), while 9a, 9c, 9d and 9g exhibited the most effective
activity against S. pneumoniae AB11 with MIC values of 32 or 64 µg/mL,
showing 2 or 4-fold better than CAM (128 µg/mL) and 4 or 8-fold better
than AZM (256 µg/mL), respectively. In the inhibition of S. pneumoniae
AB11, the most active compound 9b exhibited an MIC value of 32 mg/
mL, >8-fold better than CAM and AZM (>256 µg/mL). In addition, 9b
displayed the best activity with MIC value of 32 µg/mL against
S. pyogenes R1, 8-fold better than CAM and AZM (256 and 256 µg/mL).
target compounds such as 9a, 9b and 9d. It is possible that the flexible
alkyl side chain is able to adapt to the binding pocket of bacterial ri-
′
bosomes and produce new forces. In contrast, 2 ,9(S)-diaryl-3-O-
descladinosyl-3-keto-clarithromycin derivatives 19a-19t did not show
effective bacteriostatic effect. This series display poor activity against
′
three susceptible bacteria because their C-2 ester side chains cannot
bind to A2058 and A2059, leading to a decrease antibacterial activity.
Similarly, this series also exhibited poor activity against five resistant
bacteria. The possible reasons were that introduction of the C-9 aryl side
chain changed the conformation of this series to a certain extent
compared with CAM, resulting in the inability to bind to the U790 of
′
Unfortunately, 2 ,9(S)-diaryl-3-O-descladinosyl-3-keto-clarithromycin
derivatives 19a-19t failed to exhibit better antibacterial activity than
references.
′
In general, the 11-O-carbamoyl-3-O-descladinosyl-3-keto-clari-
thromycin derivatives 9a-9g exhibited improved activity against resis-
tant bacteria and weak activity against susceptible bacteria in
comparison with CAM and AZM. Furthermore, some target compounds
showed favorable activity against Gram-positive bacteria but weak ac-
tivity against Gram-negative bacteria, probably because they were
difficult to pass through the cell wall of Gram-negative bacteria. The
above results indicate that simultaneous modification of the C-3 and C-
bacterial ribosome closely. Moreover, the C-2 or C-9 aryl side chain was
short and lacked flexibility, which could not reach U790 and bind to it.
′
In order to study the chemical stability of 2 ,9(S)-diaryl-3-O-descla-
dinosyl-3-keto-clarithromycin derivatives, 19a, 19i, 19j and 19p were
◦
selected and determined in a phosphate solution (pH = 7.4) at 25 C by
HPLC method. The result indicated that the peak areas of these com-
pounds were almost unchanged within 24 h, which confirmed that the
3
4,35
above tested compounds had excellent chemical stability.
1
1 positions of CAM can enhance activity against resistant bacterial
In summary, we designed and synthesized a series of novel 3-O-
descladinosyl-3-keto-clarithromycin derivatives, including 11-O-carba-
strains and partially retain activity against sensitive bacterial strains. We
believe that the C-11 side chain may directly interact with the nucleotide
A752. Especially, the alteration of the length and the different sub-
stituents on the terminal benzene ring of the C-11 side chain lead to the
change of interaction force, thereby influencing antibacterial activity for
the target compounds. Actually, the alkyl substitution on the terminal
benzene ring is more beneficial to increasing antibacterial activity of the
′
moyl-3-O-descladinosyl-3-keto-clarithromycin derivatives and 2 ,9(S)-
diaryl-3-O-descladinosyl-3-keto-clarithromycin derivatives, and evalu-
ated their in vitro antibacterial activity. The results indicated that 11-O-
carbamoyl-3-O-descladinosyl-3-keto-clarithromycin derivatives had ac-
tivity against resistant bacteria strains. Among them, 9b showed not
only the most significantly improved activity (16 µg/mL) against
5

B. Bai et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128110
S. aureus ATCC43300 and S. aureus ATCC31007, which was > 16-fold
more active than CAM and AZM (>256 and > 256 µg/mL), but also the
best activity against S. pneumoniae B1 and S. pyogenes R1, with MIC
values of 32 and 32 µg/mL, which were >8 and >8-fold stronger than
that of CAM and AZM (256 and 256 µg/mL), respectively. In addition,
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a, 9c, 9d and 9g exhibited the most effective activity against
S. pneumoniae AB11 with MIC values of 32 or 64 µg/mL, showing 2 or 4-
fold better than CAM (128 µg/mL) and 4 or 8-fold more better than AZM
′
(
256 µg/mL), respectively. Unfortunately, 2 ,9(S)-diaryl-3-O-descladi-
nosyl-3-keto-clarithromycin derivatives failed to display more potent
antibacterial activity than references. It can be seen that the combined
modification of the C-3 and C-11 positions is beneficial to improve ac-
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′
′
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Declaration of Competing Interest
1
9
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
2
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