Synthesis and antibacterial evaluation of novel clarithromycin derivatives with C-4″ elongated arylalkyl groups against macrolide-resistant strains

Article abstract of DOI:10.1016/j.ejmech.2010.11.035

Novel clarithromycin derivatives with C-4″ elongated arylalkyl groups were designed, synthesized and evaluated to probe the effect of different lengths of their C-4″ side chains on the activity against resistant bacterial strains. These derivatives had excellent activity against erythromycin-susceptible Streptococcus pneumoniae, Streptococcus aureus or Streptococcus pyogenes and some of them exhibited greatly improved activity against erythromycin-resistant strains. Compounds 18 and 16, which had the C-4″ elongated arylalkyl groups with eight atoms from the 4″-oxygen atom to the terminal benzene ring, were the most effective against S. pneumoniae expressing the erm gene and the erm and mef genes. In contrast, the most potent compounds 3, 5, 9, 17 and 18 against S. pneumoniae expressing the mef gene had C-4″ elongated arylalkyl groups with three to eight atoms between the 4″-oxygen atom and the terminal aromatic ring.

Full text of DOI:10.1016/j.ejmech.2010.11.035

European Journal of Medicinal Chemistry 46 (2011) 556e566
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antibacterial evaluation of novel clarithromycin derivatives with
C-400 elongated arylalkyl groups against macrolide-resistant strains
,
a
a
a
b
a
a
a
Shutao Ma a , Bo Jiao , Yongjing Ju , Manjie Zheng , Ruixin Ma , Lin Liu , Ling Zhang , Xuecui Shen ,
*
Chenchen Ma a, Ya Meng a, Hui Wang c, Yunkun Qi a, Xiaodong Ma a, Wenping Cui a
a Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, PR China
b Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, PR China
c Department of Clinical Laboratory, Peking Union Medical College Hospital, Beijing 100730, PR China
a r t i c l e i n f o
a b s t r a c t
Novel clarithromycin derivatives with C-400 elongated arylalkyl groups were designed, synthesized and
evaluated to probe the effect of different lengths of their C-400 side chains on the activity against resistant
bacterial strains. These derivatives had excellent activity against erythromycin-susceptible Streptococcus
pneumoniae, Streptococcus aureus or Streptococcus pyogenes and some of them exhibited greatly
improved activity against erythromycin-resistant strains. Compounds 18 and 16, which had the C-400
elongated arylalkyl groups with eight atoms from the 400-oxygen atom to the terminal benzene ring, were
the most effective against S. pneumoniae expressing the erm gene and the erm and mef genes. In contrast,
the most potent compounds 3, 5, 9, 17 and 18 against S. pneumoniae expressing the mef gene had C-400
elongated arylalkyl groups with three to eight atoms between the 400-oxygen atom and the terminal
aromatic ring.
Article history:
Received 20 August 2010
Received in revised form
18 November 2010
Accepted 18 November 2010
Available online 27 November 2010
Keywords:
Clarithromycin derivatives
Synthesis
Antibacterial activity
Macrolide-resistant strains
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
However, the therapeutic utility of the above macrolides has
been severely compromised by the emergence of resistant patho-
First generation macrolides such as erythromycin A (EMA) (Fig.1)
were introduced in the 1950s as a safe and effective agents, and have
enjoyed widespread clinical use especially in patients with allergic
reactions to penicillin [1,2]. However, the major problem associated
with erythromycin A is its acid instability [3], leading to the forma-
tion of a 6,9-hemiketal and consequential degradation products
which are directly responsible for its poor pharmacokinetic profile
and gastrointestinal (GI) side effects [4]. To address the problems,
second generation macrolides exemplified by clarithromycin (CAM)
[5] and azithromycin (AZM) [6] (Fig.1) were introduced in late 1980s
and not only prevent the formation of 6,9-hemiketal degradation
products, but also show remarkably improved pharmacokinetics
and better GI tolerability than first generation macrolides [7]. In
addition to retaining potent activity against erythromycin-suscep-
tible organisms, the second generation macrolides also exhibited
increased activity against Haemophilus influenza, Helicobactor pylori,
Legionella, Chlamydia and Pasteurella mutocida. The mechanism of
action has been elucidated that they bind reversibly to the nucleo-
tide A2058 in domain V of the 23S rRNA in the ribosomal 50S subunit
and block protein synthesis [8].
gens isolated clinically [9]. Two distinct mechanisms have
accounted for the majority of macrolide resistance [10,11]. The first
mechanism involves the methylation of A2058 by a ribosomal
methylase encoded by the erm gene, which confers a high level of
resistance to MLSB (macrolideelincosamideestreptogramin B)
antibiotics. The second mechanism involves efflux pump encoded
by the mef gene, which pumps the macrolides out of intracellular
space and prevents them from reaching the binding sites. To
overcome the bacterial resistance, third generation macrolides
known as ketolides such as telithromycin [12] and cethromycin [13]
(Fig. 2) were developed in 1990s. They show excellent activity
against several types of macrolide-resistant strains and offer
alternative therapy for Gram-positive infections attributable to
resistant pathogens. The ketolides may interact with a secondary
ribosomal binding site A752 directly in domain II of the 23S rRNA
by their C-11,12 carbamate or the C-6 side chains in addition to the
main interaction of the drugs in domain V, which imparts activity
against erm-resistant bacteria [14].
While significant efforts have gone into the discovery of increas-
ingly potent ketolides, a substantial amount of work has been done in
order to develop new generation macrolides to effectively overcome
bacterial resistance. Consequently, these investigations have led to
the discovery of C-400 modified macrolides, anhydrolides [15] and
* Corresponding author. Tel.: þ86 531 88382009; fax: þ86 531 88911612.
E-mail address: mashutao@sdu.edu.cn (S. Ma).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.11.035

S. Ma et al. / European Journal of Medicinal Chemistry 46 (2011) 556e566
557
N
N
O
HO
OH
N
N
N
HO
OR
O
N
9a
2
2
9
N
HO
HO
HO
HO
O
O
6
3
O
6
11
12
11
12
N
N
O
3
HO
O
HO
OMe
O
O
O
O
O
O
O
O
2
2
O
O
9
9
H
N
N
4
4
6
6
3
O
11
12
11
12
O
OH
OMe
O
O
O
OH
OMe
O
O
3
O
O
O
O
R = H erythromycin
R = Me clarithromycin
azithromycin
O
O
telithromycin
cethromycin
Fig. 1. Structures of erythromycin, clarithromycin and azithromycin.
N
O
N
HO
OMe
acylides [16] such as TEA0777 (Fig. 2). In particular, C-400 modified
macrolides display potent activity against Gram-positive pathogens
including MLSB-resistant and efflux-resistant Streptococcus pneu-
monia [17]. C-400 modified erythromycin A-60565 [18] (Fig. 3) repor-
ted by Abbott Laboratories in 1989 showed potent activity against
both the inducibly resistant and constitutively resistant strains. The
length of the aryl groups attached to the C-400 position is a distance of
four atoms from the 400-oxygen atom to the terminal aromatic ring. 9
(S)-Erythromycylamine C-400-carbamate CP-544372 [19] (Fig. 3)
reported in 1998 exhibited excellent in vitro and in vivo activity
against erm-resistant strains with competitive binding to chloram-
phenicol, suggesting that the anchor group reached the peptidyl
transferase center (PTC) region, the chloramphenicol-binding site
[20]. It contains a long C-400 anchor group with six atoms from 400-
oxygen atom to the terminal benzene ring. Macrolide C-400 malonic
monoesters [21] reported in 2006 were capable of binding to 50S
ribosomal subunits and inhibited protein synthesis in cell-free
system. Their C-400 malonic groups are five atoms from the 400-oxygen
atom to the terminal benzene ring. C-400 modified 10,11-anhydro-
clarithromycins [22] reported in 2008, which possesses a 400-O-het-
eroarylcarbamoyl group with six atoms between the 400-oxygen atom
and the terminal aromatic ring, showed improved activityagainst the
erythromycin-resistant strains, including S. pneumonia, Streptococcus
pyogenes and S. pyogenes expressing the erm B gene. In our previous
work [23,24], two series of 4"-carbamate and 11,12-cyclic carbonate-
4"-carbamate azithromycinderivativeswerefoundtoretainexcellent
activity against erythromycin-susceptible Streptococcus pneumoniae
and show improved activity against erythromycin-resistant S. pneu-
moniae expressing the mef gene or the erm and mef genes. The length
of their C-400 side chains is a distance of three to four atoms from the
400-oxygen atom to the terminal aromatic ring. The C-400 modified
macrolides described above display a higher affinity for the ribosome
of resistant bacteria due to the additional interaction mediated by the
C-400 arylalkyl groups. The structureeactivityrelationshipsof the C-400
modified derivatives lead us to believe that the arylalkyl groups
attached to the C-400 position of macrolides are essential for
HO
OMe
O
O
O
R
N
2
2
9
9
HO
HO
O
6
3
6
O
11
12
11
12
O
O
3
2
O
O
O
O
O
O
NO2
anhydrolides
TEA0777
Fig. 2. Structures of telithromycin, cethromycin, anhydrolides and TEA0777.
overcoming MLSB resistance, while their lengths are important for
conferring potent activity against resistant bacteria.
The studies of the high-resolution X-ray co-crystal structures
have revealed that the binding sites of CAM, clindamycin and
chloramphenicol differ from each other, but they show some
overlapping nucleotides in the domain between the PTC and the
macrolide roadblock [25]. The studies have also demonstrated that
there are a number of new nucleotide binding sites including
G2505, U2504, U2506, U2500, G2061 and C2452 in the domain.
Accordingly, a reasonably long arylalkyl group at the C-400 position
will be helpful for the interaction with these nucleotide binding
sites in the domain. To probe the effect of different lengths of the
C-400 side chains on antibacterial activity, we designed several novel
structural series of clarithromycin derivatives with C-400 elongated
arylalkyl groups which are three, four, eight, nine, ten and eleven
atoms from the 400-oxygen atom to the terminal aromatic ring. The
terminal groups of the C-400 elongated side chains chosen here are
aryl, alkyl, alkenyl and cycloalkyl groups, which may be helpful for
enhancing affinity for the ribosome of resistant bacteria through
hydrogen bonding and p-stacking, and VDW interaction.
2. Chemistry
The synthesis of 400-O-arylalkylcarbamoyl clarithromycin deriva-
tives (3e13) began with the conversion of CAM as a starting material
N
N
H2N
HO
HO
O
2
2
OH
9
9
OH
O
HO
HO
O
O
6
3
6
3
O
O
11
12
11
12
O
O
O
O
O
O
O
O
O
O
H
N
4
4
N
O
O
O
O
N
H
O
OMe
OMe
OCH3
A-60565
CP-544372
Fig. 3. Structures of A-60565 and CP-544372.

558
S. Ma et al. / European Journal of Medicinal Chemistry 46 (2011) 556e566
N
O
N
O
HO
OMe
AcO
OMe
O
O
HO
HO
HO
HO
O
O
a, b
c, d
N
O
O
O
O
O
O
O
O
O
OH
OMe
O
N
OMe
2
clarithromycin
3 R1 = benzyl
N
O
4 R1 = 4-fluorobenzyl
HO
OMe
O
R
R
R
1 = 4-methoxybenzyl
1 = phenethyl
5
6
HO
HO
O
1 = 4-hydroxyphenethyl
7
8 R1 = 2-chlorophenethyl
9 R1 = 3,4-methylenedioxyphenethyl
10
O
O
O
O
R
1 = propyl
11 R1 = propenyl
12 R1 = butyl
R1
O
N
O
OMe
H
13 R1 = pentyl
Scheme 1. Reagents and conditions: (a) Ac2O, Et3N, CH2Cl2, rt, 24 h, 86.2%; (b) CDI, Et3N, CH2Cl2, rt, 24 h, 93%; (c) arylalkylamines, DBU, DMF, 60 ꢀC, 7 h; (d) CH3OH, 45 ꢀC, 12 h,
61%e68% for 2 steps.
to 400-O-acylimidazolide intermediate (2) as a common intermediate
to introduce various functional groups at the C-400 position as shown
in Scheme 1. This was carried out by acetylation of the 20-hydroxyl
group of CAM with acetic anhydride (Ac2O) followed by trans-
formation of the 400-hydroxyl group to the acyl imidazole utilizing
1,10-carbonyldiimidazole (CDI) and triethylamine (Et3N). These
reactions proceeded very smoothly at room temperature in 80%
yield. Subsequent condensation of intermediate 2 with the corre-
sponding arylalkylamine in the presence of 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) at 60 ꢀC was followed by selective removal of the
20-O-acetyl group by heating with methanol to give the target
derivatives 3e13 in yields ranging from 61% to 68%.
Protection of the amino group of corresponding amino acid with di-
tert-butyl dicarbonate (BOC2O) provided BOC-amino acid (14).
Condensation of 14 with corresponding arylalkylamines catalyzed
by dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole
(HOBt) was followed by subsequent removal of the BOC moiety
using saturated hydrochloric acid (HCl) in ethyl acetate to give the
desired primary amines 15ae15v.
Scheme 3 describes the synthesis of 400-O-((arylalkylamino)-4-
oxo-butyl)carbamoyl and 400-O-((arylalkylamino)-6-oxo-hexyl)car-
bamoyl clarithromycin derivatives (16e26 and 27e37) starting
from the intermediate 2. Coupling of the intermediate 2 with the
corresponding primary amine hydrochloride prepared above in the
presence of DBU at room temperature and subsequent deprotection
of the acetyl group with methanol 55 ꢀC afforded the target
derivatives 16e37 in yields ranging from 69% to 79%.
In order to obtain C-400 modified clarithromycins with elongated
C-400 side chains,
a series of primary amines hydrochloride
(15ae15v) were synthesized from 4-aminobutyric acid or 6-ami-
nocaproic acid as a starting material as shown in Scheme 2.
3. Antibacterial activity
b, c
a
BOC-HN
COOH
H2N
COOH
Three series of the C-400 modified clarithromycin derivatives
3e13, 16e26 and 27e37 prepared above, as well as EMA, CAM and
AZM as references, were tested for in vitro antibacterial activity
against eight phenotypes of Gram-positive strains. Their activities
are reported as minimum inhibitory concentrations (MICs) deter-
mined using the broth microdilution method recommended by the
National Committee for Clinical Laboratory Standards. S. pneumonia
ATCC49619 is an erythromycin-susceptible strain, and S. pneumo-
niae B1, S. pneumoniae A22072 and S. pneumoniae AB11 are three
erythromycin-resistant strains whose resistance is encoded by the
erm gene, the mef gene, and the erm and mef genes, respectively.
Streptococcus aureus ATCC25923 and S. pyogenes S2 are two
erythromycin-susceptible strains. S. aureus P1 is a penicillin-
susceptible strain isolated clinically and S. pyogenes R2 is an
erythromycin-resistant strain isolated clinically.
n
n
14
4-aminobutyric acid, n=1
6-aminocaproic acid, n=3
.
HCl H2N
CONHR1
n
15a n=1, R1 = benzyl
15b
15l n=3, R1 = benzyl
n=1, R1 = 4-fluorobenzyl
15m n=3, R1 = 4-fluorobenzyl
n=3, R1 = 4-methoxybenzyl
n=3, R1 = 4-hydroxyphenethyl
15p n=3, R1 = 2-chlorophenethyl
15q n=3, R1 = cyclohexyl
n=1, R1 = 4-methoxybenzyl
15n
15c
15d n=1, R1 = 4-hydroxyphenethyl 15o
15e n=1, R1 = 2-chlorophenethyl
15f n=1, R1 = cyclohexyl
15g
n=1, R1 = isopropyl
15r n=3, R1 = isopropyl
n=3, R1 = propyl
n=1, R1 = propyl
15s
15h
15i n=1, R1 = propenyl
15j n=1, R1 = butyl
15k n=1, R1 = pentyl
15t
n=3, R1 = propenyl
15u n=3, R1 = butyl
15v n=3, R1 = pentyl
4. Results and discussion
MIC values for 400-O-arylalkylcarbamoyl clarithromycin deriva-
tives (3e13) are presented in Table 1. All of the 400-O-arylalkyl
Scheme 2. Reagents and conditions: (a) BOC2O, 1 M NaOH, THF, rt, 24 h; (b) HOBt,
DCC, THF, 0 ꢀC, 8 h, arylalkylamines, rt, 2 h; (c) HCl, AcOEt, rt, 2 h.

S. Ma et al. / European Journal of Medicinal Chemistry 46 (2011) 556e566
559
N
O
N
O
HO
OMe
AcO
OMe
O
O
HO
HO
HO
HO
O
O
a, b
N
O
O
O
O
O
O
O
O
H
N
O
R1
O
N
H
O
n
O
N
OMe
OMe
O
2
16-37
16 n=1, R1 = benzyl
27
n=3, R1 = benzyl
28 n=3, R1 = 4-fluorobenzyl
29 n=3, R1 = 4-methoxybenzyl
17 n=1, R1 = 4-fluorobenzyl
18 n=1, R1 = 4-methoxybenzyl
19
n=1, R1 = 4-hydroxyphenethyl 30 n=3, R1 = 4-hydroxyphenethyl
n=1, R1 = 2-chlorophenethyl
31
n=3, R1 = 2-chlorophenethyl
n=3, R1 = cyclohexyl
20
21 n=1, R1 = cyclohexyl
22 n=1, R1 = isopropyl
23 n=1, R1 = propyl
32
33 n=3, R1 = isopropyl
34 n=3, R1 = propyl
35 n=3, R1 = propenyl
n=1, R1 = propenyl
24
n=1, R1 = butyl
36
n=3, R1 = butyl
n=3, R1 = pentyl
25
26 n=1, R1 = pentyl
37
Scheme 3. Reagents and conditions: (a) corresponding primary amines hydrochloride, DBU, DMF, rt, 24 h; (b) CH3OH, 55 ꢀC, 24 h, 69%e79% for 2 steps.
derivatives showed excellent activity against the tested erythro-
mycin-susceptible strains. Among them, compounds 5 and 6 were
respectively. Compounds 3, 5, 9 and 13 presented the most potent
activity (0.25 g/mL) against S. pneumoniae A22072 expressing the
m
found to have the most potent activity (0.03
pneumoniae ATCC49619 comparable to EMA, CAM and AZM.
Compounds 4e6 and 8 showed the same activity (0.12 g/mL)
against S. aureus ATCC25923 as CAM, which were better than EMA
and AZM. Compounds 4e8, 11 and 13 were the most active (0.03 g/
mL) against S. pyogenes S2 similar to EMA, CAM and AZM. In
particular, compounds 5 and 6 with terminal 4-methoxybenzyl and
phenethyl groups displayed the most potent activity against all of
the three erythromycin-susceptible strains tested above. On the
other hand, most of the 400-O-arylalkyl derivatives exhibited
improved activity against erythromycin-resistant S. pneumoniae
expressing the erm gene, the mef gene or the erm and mef genes, and
erythromycin-resistant S. pyogenes R2 in comparison with the
references. Among them, compounds 3 and 4 had greatly improved
activity against S. pneumoniae B1 and S. pneumoniae AB11, showing
16-fold and 16-fold higher activity than the parent CAM,
m
g/mL) against S.
mef gene. Compounds 5 and 13 were the most effective against
erythromycin-resistant S. pyogenes R2. The results suggest that the
introduction of the C-400 arylalkyl groups with 3e4 atoms from the
400-oxygen atom to the terminal benzene ring into the C-400 position
of CAM, on the whole, retains the activity against erythromycin-
susceptible strains, and shows improved activity against erythro-
mycin-resistant strains.
m
m
The activities are reported in Table 2 for 400-O-((arylalkylamino)-
4-oxo-butyl)carbamoyl clarithromycin derivatives (16e26). Almost
all of the 400-O-arylalkylamino-4-oxo-butyl derivatives showed
potent activity against the tested erythromycin-susceptible strains
similar to the series of 400-O-arylalkyl derivatives. Among them, MIC
values of the most active compounds against S. pneumoniae
ATCC49619, S. aureus ATCC25923 and S. pyogenes S2 were 0.03, 0.12
and 0.03
mg/mL, respectively. Those indicate that the introduction
of the C-400 elongated arylalkyl groups with 8e9 atoms from the
Table 1
In vitro antibacterial activity of 400-O-arylalkylcarbamoyl clarithromycin derivatives.
Strain
MICs (
mg/mL)
3
4
5
6
7
8
9
10
0.25
64
2
11
0.25
32
0.5
128
0.25
32
0.03
12
0.25
64
1
64
0.25
8
0.25
4
13
0.06
32
0.25
128
0.25
16
0.03
0.12
EMA
0.03
128
8
256
0.25
0.25
0.03
4
CAM
0.03
64
4
128
0.12
0.03
0.03
4
AZM
0.03
128
4
256
0.25
0.12
0.03
8
S. pneumoniae ATCC49619a
S. pneumoniae B1b
S. pneumoniae A22072c
S. pneumoniae AB11d
S. aureus ATCC25923e
S. aureus P1f
0.25
4
0.25
8
0.25
1
0.06
4
0.5
8
0.12
2
0.03
0.5
0.03
16
0.25
32
0.12
0.03
0.12
0.06
16
0.5
32
0.12
0.25
0.03
0.5
0.06
32
0.25
64
0.25
0.5
0.5
0.5
16
1
64
128
4
128
32
0.12
0.25
16
0.03
0.25
0.25
16
0.5
8
0.03
0.12
0.06
0.03
0.25
S. pyogenes S2g
0.12
16
S. pyogenes R2h
1
1
a
S. pneumoniae ATCC49619: erythromycin-susceptible 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. aureus ATCC25923: erythromycin-susceptible strain.
S. aureus P1: penicillin-susceptible strain isolated clinically.
S. pyogenes S2: erythromycin-susceptible strain isolated clinically.
S. pyogenes R2: erythromycin-resistant strain isolated clinically.
b
c
d
e
f
g
h

560
S. Ma et al. / European Journal of Medicinal Chemistry 46 (2011) 556e566
Table 2
In vitro antibacterial activity of 400-O-((arylalkylamino)-4-oxo-butyl)carbamoyl clarithromycin derivatives.
Strain
MICs (
mg/mL)
16
17
18
19
20
0.03
32
1
21
0.03
32
2
64
0.5
8
0.25
8
22
23
24
25
26
0.03
8
2
EMA
0.03
128
8
256
0.25
0.25
0.03
4
CAM
0.03
64
4
128
0.12
0.03
0.03
4
AZM
0.03
128
4
256
0.25
0.12
0.03
8
S. pneumoniae ATCC49619a
S. pneumoniae B1b
S. pneumoniae A22072c
S. pneumoniae AB11d
S. aureus ATCC25923e
S. aureusf
0.03
2
0.5
0.25
0.12
4
0.03
1
0.25
2
0.12
1
0.03
0.06
0.25
1
0.12
8
0.03
0.25
0.5
1
0. 5
9
0.03
0.03
0.03
0.03
128
8
128
128
4
128
128
4
128
128
8
128
32
32
0.25
32
0.03
0.25
8
0.5
0.25
0.25
8
0.03
0.25
8
0.5
0.5
16
0.5
16
32
1
32
S. pyogenes S2g
0.25
64
0.25
16
0.03
0.5
0.5
8
S. pyogenes R2h
1
16
64
16
a
S. pneumoniae ATCC49619: erythromycin-susceptible 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. aureus ATCC25923: erythromycin-susceptible strain.
S. aureus P1: penicillin-susceptible strain isolated clinically.
b
c
d
e
f
g
h
S. pyogenes S2: erythromycin-susceptible strain isolated clinically.
S. pyogenes R2: erythromycin-resistant strain isolated clinically.
400-oxygen atom to the terminal benzene ring still retain the activity
against erythromycin-susceptible strains. As for the activity against
the erythromycin-resistant S. pneumonia, some of 400-O-arylalkyla-
mino-4-oxo-butyl derivatives showed improved activity in
comparison with corresponding 400-O-arylalkyl derivatives.
Particularly, compound 18 was found to be the most effective
compounds 28 and 29 showed the highest activity (0.5 and
0.5 g/mL) against S. pneumoniae A22072, but less activity than
corresponding compounds 17 (0.25 g/mL) and 18 (0.25 g/mL).
m
m
m
These results suggest that the introduction of the C-400 elongated
side chains with 10e11 atoms from the 400-oxygen atom to the
terminal benzene ring reduces or eliminates their activity against the
resistant S. pneumoniae strains.
(0.06 mg/mL) against S. pneumoniae B1, showing 267-fold and 1067-
fold higher activity than corresponding compound 5 and parent
CAM, respectively, and compound 16 displayed the most potent
activity (0.25 mg/mL) against S. pneumoniae AB11, exhibiting 32-fold
On the whole, although they had the different lengths of C-400
arylalkyl groups, the novel structural series described above showed
excellent activity against erythromycin-susceptible strains. The
results demonstrate that the C-400 arylalkyl groups with three to
eleven atoms from the 400-oxygen atom to the terminal benzene ring
do not obviously affect the affinity for the ribosomes of the
susceptible bacteria. The lengths and sizes of the C-400 arylalkyl
groups potentially fit the domain between the PTC and the macro-
lide roadblock in 50S ribosomal subunits. As for the erythromycin-
resistant strains, onlysome compounds in the novel structural series
exhibited improved activity against resistant strains. In particular,
compounds 18 and 19, which belong to the series of 400-O-((ary-
lalkylamino)-4-oxo-butyl)carbamoyl derivatives, displayed signifi-
cantly potent activity against S. pneumoniae expressing the erm
and 512-fold better activity than corresponding 3 and parent CAM,
respectively. The C-400 elongated side chains of compounds 16 and 18
contained 5 more atoms from the 400-oxygen atom to the terminal
benzene ring than those of corresponding compounds 3 and 5.
MIC values for the 400-O-((arylalkylamino)-6-oxo-hexyl)carba-
moyl clarithromycin derivatives (27e37) are shown in Table 3. All of
the 400-O-arylalkylamino-6-oxo-hexyl derivatives showed potent
activity against the tested erythromycin-susceptible strains similar
to 400-O-arylalkylamino-4-oxo-butyl derivatives, indicating that the
introduction of the C-400 elongated arylalkyl groups with 10e11
atoms from the 400-oxygen atom to the terminal benzene ring retains
the activity against the erythromycin-susceptible strains as well. In
contrast, only a few of the 400-O-arylalkylamino-6-oxo-hexyl deriv-
atives had improved activity against all tested erythromycin-resis-
tant strains in comparison with parent CAM. Particularly,
gene. The most active compound 18 (0.06
m
g/mL) had the C-400
elongated arylalkyl group with eight atoms from the 400-oxygen
atom to the terminal 4-methoxyphenyl group. Similarly, the most
effective compound 16 (0.25
mg/mL) against S. pneumoniae
Table 3
In vitro antibacterial activity of 400-O-((arylalkylamino)-6-oxo-hexyl)carbamoyl clarithromycin derivatives.
Strain
MICs (
m
g/mL)
27
28
29
0.03
64
0.5
64
0.12
1
0.12
32
30
0.06
64
8
64
0.25
1
0.5
64
31
0.03
64
1
32
0.25
0.5
0.06
64
32
33
34
35
36
37
EMA
0.03
128
8
256
0.25
0.25
0.03
4
CAM
0.03
64
4
128
0.12
0.03
0.03
4
AZM
0.03
128
4
256
0.25
0.12
0.03
8
S. pneumoniae ATCC49619a
S. pneumoniae B1b
S. pneumoniae A22072c
S. pneumoniae AB11d
S. aureus ATCC25923e
S. aureusf
0.03
64
2
64
0.5
8
0.03
2
0.5
4
0.25
32
0.03
0.25
0.03
0.06
0.03
0.03
0.06
0.03
128
1
128
128
8
128
128
4
128
128
2
128
0.25
16
0.5
128
1
128
128
4
128
0.25
0.25
0.5
0.25
0.5
1
1
2
8
8
S. pyogenes S2g
0.12
0.25
0.12
0.12
0.03
0.25
8
0.25
S. pyogenes R2h
32
32
16
4
16
a
S. pneumoniae ATCC49619: erythromycin-susceptible 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. aureus ATCC25923: erythromycin-susceptible strain.
S. aureus P1: penicillin-susceptible strain isolated clinically.
S. pyogenes S2: erythromycin-susceptible strain isolated clinically.
S. pyogenes R2: erythromycin-resistant strain isolated clinically.
b
c
d
e
f
g
h

S. Ma et al. / European Journal of Medicinal Chemistry 46 (2011) 556e566
561
expressing the erm and mef genes possessed the C-400 elongated
arylalkyl group with eight atoms from the 400-oxygen atom to the
terminal phenyl group as well. This led us to presume that the C-400
elongated arylalkyl group with eight atoms between the 400-oxygen
atom and the terminal aromatic ring might be a suitable length, and
the terminal 4-methoxyphenyl group might easily interact with the
new binding sites of nucleotides between PTC and the macrolide
layers were washed with brine, and dried over anhydrous Na2SO4,
filtered. The filtrate was concentrated in vacuo to afford a crude
product. A solution of the crude product in methanol (15 mL) was
heated to 45 ꢀC and stirred for 12 h at the same temperature. After
concentrating the reaction solution in vacuo, the residue was puri-
fied by flash chromatography (dichloromethane/methanol 25:1) to
give compounds 3e13 in yields ranging from 60.8% to 68.4%.
roadblock through hydrogen bonding,
a higher affinity for the ribosome of resistant bacteria. In contrast,
p
-stacking etc. resulting in
6.1.1. 400-O-(Benzyl)carbamoylclarithromycin (3)
the most active compounds 3, 5, 9, 13, 17 and 18 (0.25
m
g mLꢁ1
)
White crystals, yield 64.6%, mp 228e231 ꢀC, TLC Rf ¼ 0.35
(methanol/dichlormethane, 1:5, v/v); IR (KBr): 3450, 2974, 2938,
2883, 2832, 2786, 1732, 1639, 1498, 1456, 1378, 1339, 1279, 1266,
against S. pneumoniae expressing the mef gene had the C-400 elon-
gated arylalkyl groups with three to eight atoms between the
400-oxygen atom and the terminal aromatic ring.
1242, 1171, 1110, 1073, 1052, 1033, 1012 cmꢁ1 1H NMR (600 MHz,
;
CDCl3):
d 7.33e7.29 (m, 2H), 7.28e7.26 (m, 2H), 5.07e4.97(d,
5. Conclusions
J ¼ 1.5 Hz,1H), 4.97e4.96 (d, J ¼ 4.9 Hz,1H), 4.60e4.58 (d, J ¼ 4.1 Hz,
1H), 4.42e4.41 (m, 2H), 4.30 (m, 1H), 3.99e3.98 (m, 1H), 3.78e3.75
(m, 2H), 3.67e3.65 (d, J ¼ 7.2 Hz, 1H), 3.49 (m, 1H), 3.36 (s, 1H), 3.30
(s, 3H), 3.18e3.04 (m, 2H), 3.04 (s, 3H), 2.99e2.95 (m, 1H), 2.90 (m,
1H), 2.57 (m, 1H), 2.43e2.41 (m, 1H), 2.28 (s, 3H), 2.19e2.18 (m, 4H),
1.94e1.90 (m, 3H), 1.68e1.61 (m, 4H), 1.48e1.39 (m, 1H), 1.38 (s,
3H),1.23e1.16 (m,12H), 1.13e1.09 (m, 15H), 0.84 (t, 3H); MS (ESI) m/
z calcd. for C46H76N2O14 880.5; found [M þ H]þ 882.0; Analysis
calculated for C46H76N2O14: C 62.70, H 8.69, N 3.18. Found: C 62.79,
H 8.66, N 3.20.
The novel structural series of 400-O-arylalkylcarbamoyl, 400-O-
((arylalkylamino)-4-oxo-butyl)carbamoyl and 400-O-((arylalkylam
ino)-6-oxo-hexyl)carbamoyl clarithromycin derivatives were
designed, synthesized and evaluated for their in vitro antibacterial
activities. The novel structural series had excellent activity against
erythromycin-susceptible S. pneumoniae ATCC49619, S. aureus
ATCC25923 or S. pyogenes S2, and the most active compounds were
comparable to CAM and better than EMA and AZM. In marked contrast,
only some derivatives in the novel structural series exhibited greatly
improved activity against erythromycin-resistant S. pneumoniae B1, S.
pneumoniae A22072, S. pneumoniae AB11 or S. pyogenes R2. Among
them, compound 18 with terminal 4-methoxyphenyl group and
compound 16 with terminal phenyl group were the most effective
against S. pneumoniae expressing the erm gene and the erm and mef
genes, respectively. It is noteworthy that the length of their C-400
elongated arylalkyl side chains is a distance of eight atoms from the 400-
oxygen atom to the terminal benzene ring. Besides, the most active
compounds 3, 5, 9,17 and 18 had C-400 elongated arylalkyl groups with
three to eight atoms against S. pneumoniae expressing the mef gene.
6.1.2. 400-O-(4-Fluorobenzyl)carbamoylclarithromycin (4)
White crystals, yield 65.6%, mp 205e208 ꢀC, TLC Rf ¼ 0.40
(methanol/dichlormethane, 1:5, v/v); IR (KBr): 3658, 3447, 2976,
2938, 2876, 2834, 2788, 1732, 1687, 1607, 1547, 1511, 1458, 1378,
1349,1332,1268, 1228,1171,1128, 1110,1082,1051,1033,1011 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d 7.26e7.25 (s, 1H), 7.03e7.00 (t, 2H),
5.07e5.06 (m, 2H), 4.98e4.96 (m, 1H), 4.58e4.57 (d, J ¼ 9.7 Hz, 1H),
4.50e4.49 (d, J ¼ 7.0 Hz, 1H), 4.39e4.34 (m, 2H), 4.31e4.29 (m, 1H),
4.00e3.99 (m, 1H), 3.77e3.75 (m, 3H), 3.66e3.65 (d, J ¼ 7.2 Hz, 1H),
3.42e3.40 (m, 1H), 3.30 (m, 3H), 3.20e3.19 (m, 2H), 3.04 (s, 3H),
2.99e2.98 (m, 2H), 2.31 (s, 6H), 1.94e1.90 (m, 3H), 1.70e1.62 (m,
4H), 1.48e1.47 (m, 1H), 1.39 (s, 3H), 1.20e1.17 (m, 12H), 1.13e1.09
(m, 15H), 0.84e0.83 (t, 3H); MS (ESI) m/z calcd. for C46H75FN2O14
6. Experimental
All necessary solvents were purified prior to use, unless noted
otherwise. Reactions were monitored by thin-layer chromatog-
raphy (TLC) using 0.25-mm pre-coated silica gel plates (Qingdong
Yumingyuan silica gel reagent factory, Shandong, China, YUYUAN).
Flash chromatography was performed with the indicated solvents
using silica gel 60 (particle size 0.040e0.063 mm, Qingdong
Yumingyuan silica gel reagent factory, Shandong, China, YUYUAN).
Infrared spectra were recorded on KBr pellets using Nicolet Nexus
470FT-IR spectrometer (Wisconsin, USA). 1H NMR spectra were
recorded on Bruker Avance DRX 600 spectrometer (Bruker, Swit-
zerlands) at ambient temperature (TMS as internal standard of
chemical shifts). Mass spectra were recorded on API 4000 instru-
ment (Applied Biosystems, Connecticut, USA). The C, H, N analyses
were carried out on PE-2400 Ⅱ elemental analyser (PerkineElmer,
Massachusetts, USA). Melting points are uncorrected and were
determined on an X-6 melting point apparatus (Beijing Tian-
chengwode Biotech Co. Ltd, Beijing, China). EMA was used as
starting material from Nexchem Pharmaceutical Co., Ltd.
898.5; found [M þ H]þ 900.1; Analysis calculated for C46H75FN2O14
:
C 61.45, H 8.41, N 3.12. Found: C 61.37, H 8.44, N 3.10.
6.1.3. 400-O-(4-Methoxybenzyl)carbamoylclarithromycin (5)
White crystals, yield 66.7%, mp 145e148 ꢀC, TLC Rf ¼ 0.40
(methanol/dichlormethane, 1:5, v/v); IR (KBr): 3454, 2973, 2938,
2884, 2833, 2786, 1731, 1613, 1586, 1514, 1458, 1378, 1340, 1247,
1172, 1109, 1071, 1033, 1012 cmꢁ1 1H NMR (600 MHz, CDCl3):
;
d
7.20e7.19 (d, J ¼ 8.4 Hz, 2H), 6.87e6.85 (d, J ¼ 8.6 Hz, 2H), 5.07 (dd,
J ¼ 10.9 Hz, J ¼ 1.5 Hz, 1H), 4.97e4.96 (m, 1H), 4.58e4.56 (d,
J ¼ 9.7 Hz,1H), 4.51e4.50 (d, J ¼ 6.8 Hz,1H), 4.34e4.33 (d, J ¼ 6.1 Hz,
2H), 4.30e4.29 (m, 1H), 3.98 (s,,1H), 3.80 (s, 3H), 3.77e3.75 (m, 2H),
3.67e3.65 (m, 1H), 3.63e3.62 (m, 1H), 3.30 (s, 3H), 3.18 (m, 2H),
3.04 (s, 3H), 3.00e2.99 (m, 1H), 2.89e2.88 (m, 1H), 2.43e2.40 (m,
2H), 2.32 (s, 5H), 1.94e1.82 (m, 2H), 1.69e1.66 (m, 3H), 1.65e1.63
(m, 2H), 1.38 (s, 3H), 1.20e1.18 (m, 12H), 1.17e1.09 (m, 15H)
0.84e0.83 (t, 3H); MS (ESI) m/z calcd. for C47H78N2O15 910.5; found
[M þ H]þ 912.1; Analysis calculated for C47H78N2O15: C 61.96, H
8.63, N 3.07. Found: C 62.05, H 8.60, N 3.09.
6.1. General procedure for the preparation of 400-O-
arylalkylcarbamoyl clarithromycin derivatives (3e13)
6.1.4. 400-O-(4-Hydroxyphenethyl)carbamoylclarithromycin (6)
White crystals, yield 63.9%, mp 146e148 ꢀC, TLC Rf ¼ 0.31
(methanol/dichlormethane, 1:5, v/v); IR (KBr): 3438, 2974, 2938,
2884, 2832, 2787, 1732, 1615, 1595, 1516, 1458, 1378, 1344, 1245,
1171, 1110, 1070, 1054, 1033, 1012 cmꢁ1; 1H NMR (600 MHz, CDCl3):
To a solution of 2 (1.50 g, 1.70 mmol) in DMF (15 mL) was added
DBU (0.33 mL, 2.25 mmol) and corresponding arylalkylamine
(4.50 mmol). The resulting solution was stirred for 7 h at 60 ꢀC. The
reaction was quenched with water (15 mL) and the aqueous layer
was extracted with ethyl acetate (2 ꢂ 15 mL). The combined organic
d
7.01e6.99 (m, 2H), 6.88e6.76 (m, 2H), 5.07e5.05 (d, J ¼ 11.0 Hz,
1H), 4.96e4.95 (d, J ¼ 4.0 Hz, 1H), 4.53e4.52 (d, J ¼ 6.6 Hz, 1H),

562
S. Ma et al. / European Journal of Medicinal Chemistry 46 (2011) 556e566
4.47e4.45 (d, J ¼ 9.7 Hz, 1H), 4.43e4.41 (m, 1H), 4.13e4.11 (m, 1H),
3.96 (s, 1H), 3.80e3.76 (m, 1H), 3.75e3.73 (m, 1H), 3.64e3.63 (m,
1H), 3.50e3.48 (m, 2H), 3.39e3.37 (m, 3H), 3.30 (s, 3H), 3.18e3.02
(m, 1H), 3.02 (s, 3H), 2.99e2.97 (m, 1H), 2.87e2.84 (m, 2H),
2.77e2.73 (m, 3H), 2.71 (s, 4H), 2.59e2.56 (m, 1H), 2.42e2.37 (m,
2H), 2.08e2.06 (m, 1H), 1.94e1.88 (m, 3H), 1.63e1.61 (m, 2H),
1.65e1.57 (m, 2H), 1.33 (s, 3H), 1.29e1.27 (m, 3H), 1.21 (d, J ¼ 6.9 Hz,
3H), 1.18e1.16 (m, 2H), 1.12e1.11 (m, 11H), 1.08e1.06 (m, 3H),
0.92e0.90 (m, 3H), 0.84 (t, 3H); MS (ESI) m/z calcd. for C47H78N2O15
910.5; found [M þ H]þ 912.1; Analysis calculated for C47H78N2O15: C
61.96, H 8.63, N 3.07. Found: C 62.07, H 8.61, N 3.10.
z calcd. for C48H78N2O16 938.5; found [M þ H]þ 940.1; Analysis
calculated for C48H78N2O16: C 61.39, H 8.37, N 2.98. Found: C 61.30,
H 8.40, N 3.01.
6.1.8. 400-O-(Propyl)carbamoylclarithromycin (10)
White crystals, yield 68.4%, mp 220e223 ꢀC, TLC Rf ¼ 0.45
(methanol/dichlormethane, 1:5, v/v); IR (KBr): 3458, 2972, 2938,
2878, 2832, 2785, 1732, 1638, 1508, 1459, 1378, 1340, 1265, 1245,
1171, 1110, 1083, 1051, 1013 cmꢁ1 1H NMR (600 MHz, CDCl3):
;
d
5.07e5.04 (d, J ¼ 10.1 Hz, 1H), 4.99e4.95 (m, 1H), 4.78e4.77 (m,
1H), 4.55e4.53 (m, 2H), 4.27e4.26 (m, 1H), 3.98 (s, 1H), 3.77e3.75
(m, 2H), 3.68e3.66 (m, 2H), 3.32 (s, 3H), 3.20e3.13 (m, 4H), 3.04 (s,
3H), 3.01e2.95 (m, 1H), 2.89e2.86 (m, 1H), 2.42e2.40 (m, 3H),
1.94e1.91 (m, 2H), 1.69e1.61(m, 9H), 1.56e1.49 (m, 3H), 1.39 (s, 3H),
1.25e1.21 (m, 3H), 1.20e1.18 (m, 12H), 1.15e1.09 (m, 12H), 0.92 (t,
3H), 0.84 (t, 3H); MS (ESI) m/z calcd. for C42H76N2O14 832.5; found
[M þ H]þ 834.1; Analysis calculated for C42H76N2O14: C 60.55, H
9.20, N 3.36. Found: C 60.48, H 9.24, N 3.38.
6.1.5. 400-O-(2-Chlorophenethyl)carbamoylclarithromycin (7)
White crystals, yield 62.2%, mp 180e185 ꢀC, TLC Rf ¼ 0.37
(methanol/dichlormethane, 1:5, v/v); IR (KBr): 3450, 2973, 2937,
2884, 2832, 2785, 1732, 1057, 1458, 1378, 1342, 1267, 1245, 1171, 1110,
1071, 1051, 1034, 1012 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d 7.36e7.35
(m, 1H), 7.20 (m, 3H), 5.07 (dd, J ¼ 11.1 Hz, J ¼ 1.9 Hz, 1H), 4.96e4.95
(d, J ¼ 5.0 Hz,1H), 4.83 (m,1H), 4.55e4.53 (d, J ¼ 2.0 Hz, 2H), 4.25 (m,
1H), 3.98 (s, 1H), 3.75e3.65 (m, 2H), 3.64e3.62 (d, J ¼ 7.1 Hz, 1H),
3.62e3.60 (m, 1H), 3.57e3.55 (m, 1H), 3.55e3.50 (m, 1H), 3.29 (s,
2H), 3.18 (m, 1H), 3.04e3.00 (s, 2H), 2.99e2.96 (m, 3H), 2.89e2.87
(m, 1H), 2.59e2.57 (m, 2H), 2.41 (s, 4H), 2.05 (m, 1H), 1.94e1.90 (m,
2H), 1.83e1.81 (m, 2H), 1.68e1.62 (m, 3H), 1.48e1.47 (m, 2H), 1.38 (s,
3H), 1.27e1.24 (m, 2H), 1.20e1.19 (m, 3H), 1.19e1.09 (m, 24H)
6.1.9. 400-O-(Propenyl)carbamoylclarithromycin (11)
White crystals, yield 65.3%, mp 225e227 ꢀC, TLC Rf ¼ 0.41
(methanol/dichlormethane, 1:5, v/v); IR (KBr): 3459, 3340, 2973,
2941, 2885, 2831, 2781, 1735, 1742, 1692, 1641, 1537, 1505, 1457,
1404, 1377, 1336, 1278, 1266, 1247, 1164, 1109, 1082, 1053, 1032,
1012 cmꢁ1 1H NMR (600 MHz, CDCl3):
; d 5.85e5.82 (m, 1H),
0.84e0.83 (t, 3H); 13C NMR (600 MHz, CDCl3):
d
221.0, 175.7, 156.2,
5.20e5.13 (m, 2H), 5.08e5.06 (dd, J ¼ 9.6 Hz, J ¼ 1.9 Hz, 1H),
4.98e4.97 (d, J ¼ 4.9 Hz, 2H), 4.56e4.55 (m, 1H), 4.28 (m, 1H), 3.97
(s, 1H), 3.85e3.82 (m, 2H), 3.77e3.74 (m, 3H), 3.67e3.66 (d,
J ¼ 6.6 Hz, 1H), 3.30 (s, 4H), 3.18 (m, 1H), 3.00 (s, 3H), 2.99e2.97 (m,
1H), 2.89e2.87 (m, 2H), 2.60e2.59 (m, 3H), 2.42e2.39 (m, 2H),
1.85e2.01 (m, 3H), 1.80e1.78 (m, 2H), 1.67e1.62 (m, 6H), 1.48e1.46
(m, 2H),1.37 (s, 3H),1.22e1.18 (m,12H),1.14e1.12 (m, 9H),1.07e1.05
(m, 3H), 0.85e0.83 (t, 3H); MS (ESI) m/z calcd. for C42H74N2O14
830.5; found [M þ H]þ 832.1; Analysis calculated for C42H74N2O14: C
60.70, H 8.98, N 3.37. Found: C 60.62, H 8.95, N 3.39.
136.3, 134.2, 131.1, 129.6, 128.1, 126.9, 96.2, 80.5, 79.0, 78.3, 77.2, 77.0,
76.8, 76.6, 74.3, 73.0, 71.1, 69.0, 65.1, 63.3, 50.7, 49.5, 45.3, 44.9, 40.5,
39.3, 37.2, 35.3, 33.7, 21.6, 21.0, 20.9, 19.7, 18.3, 18.1, 16.0, 15.9, 12.4,
10.6, 9.2; MS (ESI) m/z calcd. for C47H77ClN2O14 928.5; found
[M þ H]þ 930.2; Analysis calculated for C47H77ClN2O14: C 60.73, H
8.35, N 3.01. Found: C 60.65, H 8.32, N 2.99.
6.1.6. 400-O-(Phenethyl)carbamoylclarithromycin (8)
White crystals, yield 60.8%, mp 136e139 ꢀC, TLC Rf ¼ 0.38
(methanol/dichlormethane, 1:5, v/v); IR (KBr): 3450, 2974, 2938,
2884, 2831, 2785,1731, 1634,1498, 1456,1378, 1342,1267, 1245, 1171,
6.1.10. 400-O-(Butyl)carbamoylclarithromycin (12)
1110, 1071, 1052, 1033, 1012 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
White crystals, yield 61.8%, mp 229e232 ꢀC, TLC Rf ¼ 0.45
(methanol/dichlormethane, 1:5, v/v); IR (KBr): 3459, 2973, 2938,
2877, 2832, 2785, 1733, 1638, 1507, 1459, 1378, 1342, 1266, 1245,
d
7.30e7.28 (m, 2H), 7.20 (m,1H), 7.19e7.17 (m, 2H), 5.06 (d, J ¼ 1.5 Hz,
1H), 4.96e4.95 (d, J ¼ 4.9 Hz, 1H), 4.79 (m, 1H), 4.53e4.49 (m, 2H),
4.23e4.21 (m, 1H), 3.98 (s, 1H), 3.76e3.74 (m, 2H), 3.64e3.63 (d,
J ¼ 7.3 Hz, 1H), 3.57e3.53 (m, 2H), 3.45e3.44 (m, 1H), 3.29 (s, 3H),
3.22e3.18 (m, 2H), 3.04 (s, 3H), 2.99e2.97 (m,1H), 2.86e2.82 (m, 3H),
2.58e2.56 (m, 2H), 2.39 (m, 6H),1.94e1.90 (m, 3H),1.86e1.76 (m, 2H),
1.65e1.62 (m, 3H), 1.48e1.45 (m, 1H), 1.38 (s, 3H), 1.25e1.19 (m, 4H),
1.18e1.16 (m, 6H), 1.13e1.11 (m, 9H), 1.09e1.07 (d, 3H), 1.05e1.03 (d,
3H), 0.85e0.82 (m, 3H); MS (ESI) m/z calcd. for C47H78N2O14 894.6;
found [Mþ H]þ 896.1; Analysis calculated for C47H78N2O14: C 63.09, H
8.78, N 3.13. Found: C 63.01, H 8.81, N 3.11.
1209, 1171, 1110, 1093, 1071, 1053, 1033, 1012 cmꢁ1 1H NMR
;
(600 MHz, CDCl3):
d
5.07e5.04 (d, J ¼ 8.7 Hz, 1H), 4.96 (s, 1H),
4.73e4.72 (m, 1H), 4.54e4.51 (m, 2H), 4.29e4.27 (m, 1H),
3.99e3.98 (d, J ¼ 4.4 Hz, 1H), 3.78e3.76 (m, 2H), 3.67e3.65 (m, 2H),
3.42 (m, 1H), 3.32e3.31 (m, 3H), 3.26e3.20 (m, 4H), 3.04e3.00 (m,
3H), 3.00e2.99 (m, 1H), 2.89e2.80 (m, 1H), 2.33 (s, 5H), 1.93e1.83
(m, 3H), 1.69e1.67 (m, 2H), 1.66e1.63 (m, 4H), 1.48e1.47 (m, 4H),
1.39e1.38 (m, 3H), 1.20e1.17 (m, 15H), 1.13e1.11 (m, 12H), 0.93 (t,
3H), 0.84 (t, 3H); MS (ESI) m/z calcd. for C43H78N2O14 846.6; found
[M þ H]þ 848.2; Analysis calculated for C43H78N2O14: C 60.97, H
9.28, N 3.31. Found: C 61.06, H 9.25, N 3.29.
6.1.7. 400-O-(3,4-Methylenedioxyphenethyl)
carbamoylclarithromycin (9)
White crystals, yield 67.1%, mp 235e237 ꢀC, TLC Rf ¼ 0.31
(methanol/dichlormethane, 1:5, v/v); IR (KBr): 3447, 2974, 2938,
2884, 2832, 2784,1731,1631,1054,1491,1457,1378,1339,1247,1171,
6.1.11. 400-O-(Pentyl)carbamoylclarithromycin (13)
White crystals, yield 63.8%, mp 135e137 ꢀC, TLC Rf ¼ 0.46
(methanol/dichlormethane, 1:5, v/v); IR (KBr): 3459, 2972, 2937,
2877, 2832, 2785, 1732, 1507, 1458, 1378, 1342, 1279, 1247, 1171,
1109, 1093, 1071, 1050, 1034, 1012 cmꢁ1; 1H NMR (600 MHz, CDCl3):
1109,1071,1035,1012 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d 6.74e6.73
(d, J ¼ 7.7 Hz, 1H), 6.67 (s, 1H), 6.63e6.62 (d, J ¼ 7.7 Hz, 1H),
5.94e5.92 (d, J ¼ 3.5 Hz, 2H), 5.07e5.05 (d, J ¼ 11.0 Hz, 1H),
4.98e4.96 (m, 1H), 4.58e4.51 (d, J ¼ 4.7 Hz, 2H), 4.21e4.20 (m, 1H),
3.98 (s, 1H), 3.76e3.74 (m, 2H), 3.66 (m, 2H), 3.50e3.48 (m, 1H),
3.41e3.38 (m, 1H), 3.28 (s, 4H), 3.18 (m, 1H), 3.03 (s, 3H), 3.00e2.98
(m, 1H), 2.89e2.86 (m, 1H), 2.76e2.74 (m, 2H), 2.60e2.56 (m, 2H),
2.38e2.35 (m, 2H), 2.17 (s, 1H), 1.94e1.91 (m, 2H), 1.63e1.58 (m,
10H), 1.48e1.46 (m, 1H),1.37 (s, 3H),1.25e1.21 (m, 4H), 1.20 (m, 6H),
1.17e1.09 (m, 9H), 1.08e1.04 (m, 6H), 0.86e0.82 (t, 3H); MS (ESI) m/
d
5.07e5.06 (d, J ¼ 9.9 Hz, 1H), 4.97e4.96 (d, J ¼ 4.8 Hz, 1H),
4.55e4.53(d, J ¼ 9.8 Hz, 1H), 3.98 (s, 1H), 3.78e3.74 (m, 2H),
3.69e3.66 (m, 1H), 3.31 (s, 3H), 3.25e3.16 (m, 4H), 3.04 (s, 3H),
3.00e2.97 (m, 1H), 2.89e2.87 (m, 1H), 2.17 (s, 1H), 1.93e1.91 (m,
2H), 1.67e1.63 (dd, J ¼ 15.1 Hz, J ¼ 5.1 Hz, 2H), 1.57 (s, 15H),
1.50e1.48 (m, 3H), 1.38 (s, 3H), 1.34e1.27 (m, 5H), 1.21e1.18 (m,
12H), 1.13e1.08 (m, 12H), 0.90e0.85 (t, 3H), 0.85e0.83 (t, 3H); MS
(ESI) m/z calcd. for C44H80N2O14 860.6; found [M þ H]þ 862.5;

S. Ma et al. / European Journal of Medicinal Chemistry 46 (2011) 556e566
563
Analysis calculated for C44H80N2O14: C 61.37, H 9.36, N 3.25. Found:
C 61.44, H 9.32, N 3.24.
1.66e1.64 (m, 1H), 1.61 (m, 4H), 1.52e1.34 (m, 5H), 1.26e1.20 (m,
6H), 1.20e1.15 (m, 4H), 1.14e1.12 (m, 8H), 0.85 (m, 2H); MS (ESI) m/z
calcd. for C50H83N3O15 965.6; found [M þ H]þ 967.0; Analysis
calculated for C50H83N3O15: C 62.15, H 8.66, N 4.35. Found: C 62.08,
H 8.69, N 4.32.
6.2. General procedure for the preparation of arylalkylcarbamoyl
alkylamines hydrochloride (15ae15v)
To a solution of aminoalkyl acid (15.27 mmol) in 1 mol/L sodium
hydroxide (15.30 mL) was added dropwise BOC2O (3.70 g,
16.97 mmol) in THF (5 mL). The resulting solution was allowed to
stir for 24 h at the room temperature. The reaction was concen-
trated in vacuo to remove THF. And then the reaction was
neutralized to pH 2e3 with 1 mol/L citric acid and the aqueous
layer was extracted with ethyl acetate (3 ꢂ 15 mL). The combined
organic layers were dried over anhydrous Na2SO4, filtered,
concentrated in vacuo and dried in vacuum to afford BOC-amino-
alkyl acid (14) as a white solid.
To a solution of 14 (7.35 mmol) and HOBt (1.13 g, 8.09 mmol) in
THF (10 mL) was dropwised dicyclohexylcarbodiimide (DCC)
(1.67 g, 8.09 mmol) in THF (5 mL). The resulting solution was
allowed to stir for 8 h at 0 ꢀC. After the corresponding arylalkyl-
amine (7.35 mmol) was added, the solution was stirred for another
2 h. The reaction was concentrated in vacuo to get the white solid.
And then the solid was dissolved in ethyl acetate (20 mL). After
filtration, the filtrate was washed with 1 mol/L citric acid (25 mL).
The resulting solution was allowed to stir for 0.5 h in water bath
(50 ꢀC). The aqueous layer was extracted with ethyl acetate
(3 ꢂ 15 mL). The combined organic layers were dried over anhy-
drous Na2SO4, filtered. The combined organic layers were dried
over anhydrous Na2SO4, filtered, concentrated in vacuo to afford
a crude product as a white solid. A solution of the crude product in
ethyl acetate with saturated hydrochloride acid (10 mL) was stirred
for 24 h at the room temperature. The resulting preciptitate was
collected to afford the desired products 15ae15v.
6.3.2. 400-O-(((4-Fluorobenzyl)amino)-4-oxo-butyl)
carbamoylclarithromycin (17)
White crystals, yield 74.7%, mp 127e132 ꢀC, TLC Rf ¼ 0.35
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3449, 2974, 2939,
1731, 1662, 1514, 1459, 1378, 1346, 1248, 1173, 1110, 1072, 1050,
1013 cmꢁ1 1H NMR (600 MHz, CDCl3):
; d 7.01e7.27 (m, 4H), 5.07
(dd, J ¼ 11.4 Hz, J ¼ 1.8 Hz, 2H), 4.98 (d, J ¼ 5.4 Hz, 1H), 4.54e4.51
(m, 2H), 4.42e4.41 (m, 2H), 4.30 (m, 1H), 3.99 (s, 1H), 3.79e3.77 (m,
2H), 3.68e3.66 (m, 1H), 3.32e3.18 (m, 6H), 3.05e2.97 (m, 3H),
2.91e2.89 (m, 2H), 2.64e2.52 (m, 1H), 2.44e2.41 (m, 1H),
2.32e2.26 (m, 9H), 1.94e1.90 (m, 2H), 1.90e1.86 (m, 1H), 1.71e1.63
(m, 3H), 1.49 (m, 1H), 1.39 (s, 2H), 1.23e1.17 (m, 15H), 1.14e1.11 (m,
12H), 0.87e0.84 (t, 3H); MS (ESI) m/z calcd. for C50H82FN3O15 983.6;
found [M þ H]þ 984.8; Analysis calculated for C50H82FN3O15: C
61.02, H 8.40, N 4.27. Found: C 61.11, H 8.37, N 4.30.
6.3.3. 400-O-(((4-Methoxybenzyl)amino)-4-oxo-butyl)
carbamoylclarithromycin (18)
White crystals, yield 75.7%, mp 127e132 ꢀC, TLC Rf ¼ 0.35
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3391, 2972, 2937,
1732, 1656, 1537, 1459, 1379, 1340, 1267, 1172, 1110, 1072, 1051,
1013 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
7.20 (d, J ¼ 8.4 Hz, 2H),
6.88e6.87 (d, J ¼ 9.0 Hz, 2H), 5.06 (dd, J ¼ 10.8 Hz, J ¼ 1.8 Hz, 1H),
4.97 (d, J ¼ 4.8 Hz, 1H), 4.53e4.51 (m, 2H), 4.38e4.37 (m, 2H),
4.32e4.28 (m, 1H), 3.80 (s, 3H), 3.78e3.77 (m, 2H), 3.69e3.66 (m,
2H), 3.37e3.36 (m, 2H), 3.32 (s, 3H), 3.29e3.25 (m, 2H), 3.22e3.18
(m, 2H), 3.05 (s, 2H), 3.02e3.00 (m, 1H), 2.93e2.88 (m, 1H),
2.61e2.53 (m, 2H), 2.43e2.41 (m, 1H), 2.30 (s, 6H), 2.28e2.24 (m,
1H), 1.94e1.90 (m, 2H), 1.73e1.63 (m, 3H), 1.51e1.47 (m, 1H), 1.39 (s,
3H), 1.24e1.19 (m, 18H), 1.19e1.10 (m, 9H), 0.85 (t, 3H); MS (ESI) m/z
calcd. for C51H85N3O16 995.6; found [M þ H]þ 997.1; Analysis
calculated for C51H85N3O16: C 61.49, H 8.60, N 4.22. Found: C 61.40,
H 8.57, N 4.25.
6.3. General procedure for the preparation of 400-O-
((arylalkylamino)-4-oxo-butyl)carbamoyl clarithromycin
derivatives (16e26)
To a solution of 2 (1.50 g, 1.70 mmol) in DMF (15 mL) was added
DBU (0.50 mL, 3.41 mmol),Et3N (1.50 mL, 10.90 mmol) and corre-
sponding arylalkylcarbamoyl alkylamines hydrochloride (15ae15k)
(6.67 mmol). The resulting solution was stirred for 24 h at the room
temperature. The reaction was quenched with water (30 mL) and
the aqueous layer was extracted with ethyl acetate (2 ꢂ 15 mL). The
combined organic layers were washed with brine, and dried over
anhydrous Na2SO4, filtered. The filtrate was concentrated in vacuo
to afford a crude product. A solution of the crude product in
methanol (15 mL) was heated to 55 ꢀC and stirred for 24 h at the
same temperature. After concentrating the reaction solution in
vacuo, the residue was purified by flash chromatography
(dichloromethane/methanol 40:1) to afford products 16e26 in
yields ranging from 69% to 77%.
6.3.4. 400-O-(((4-Hydroxyphenethyl)amino)-4-oxo-butyl)
carbamoylclarithromycin (19)
White crystals, yield 69.2%, mp 135e137 ꢀC, TLC Rf ¼ 0.35
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3411, 2972, 1730,
1664, 1626, 1517, 1459, 1378, 1351, 1261, 1168, 1125, 1078, 1051,
1013 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d
7.12 (d, J ¼ 9.6 Hz, 2H), 6.72
(d, J ¼ 9.6 Hz, 2H), 5.08e5.06 (d, J ¼ 8.4 Hz, 1H), 4.39e4.38 (m, 2H),
4.31e4.28 (m, 1H), 4.01 (m, 1H), 3.82e3.81 (m, 3H), 3.79e3.77 (m,
2H), 3.69e3.67 (m, 2H), 3.33e3.32 (m, 3H), 3.29e3.30 (m, 3H),
3.06e2.93 (m, 3H), 2.92e2.89 (m, 2H), 2.61e2.58 (m, 2H),
2.44e2.42 (m, 1H), 2.34e2.31 (m, 6H), 2.22e2.21 (m, 2H), 1.95e1.85
(m, 1H), 1.73e1.63 (m, 6H), 1.55e1.48 (m, 4H), 1.43e1.35 (m, 5H),
1.29e1.20 (m, 15H), 1.19e1.12 (m, 12H), 0.84 (t, 3H); MS (ESI) m/z
calcd. for C51H85N3O16 995.6; found [M þ H]þ 997.1; Analysis
calculated for C51H85N3O16: C 61.49, H 8.60, N 4.22. Found: C 61.56,
H 8.56, N 4.26.
6.3.1. 400-O-(((Benzyl)amino)-4-oxo-butyl)
carbamoylclarithromycin (16)
White crystals, yield 73.2%, mp 133e142 ꢀC, TLC Rf ¼ 0.33
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3449, 2973, 2938,
1731, 1662, 1513, 1456, 1378, 1337, 1266, 1171, 1110, 1073, 1051,
6.3.5. 400-O-(((2-Chlorophenethyl)amino)-4-oxo-butyl)
carbamoylclarithromycin (20)
1013 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d 7.27 (m, 5H), 5.79 (m, 1H),
5.63 (m, 1H), 5.14 (m, 1H), 5.08e5.06 (m, 1H), 4.98e4.97 (m, 1H),
4.53 (m, 2H), 4.35 (m, 1H), 3.99 (s, 1H), 3.79e3.74 (m, 3H),
3.68e3.67 (m, 2H), 3.39e3.36 (m, 1H), 3.34e3.30 (m, 3H),
3.28e3.25 (m, 2H), 3.25e2.90 (m, 6H), 2.62e2.52 (m, 2H),
2.44e2.41 (m, 1H), 2.31 (m, 4H), 2.25e2.23 (m, 1H), 2.21e2.19 (m,
2H), 1.99e1.89 (m, 4H), 1.88e1.78 (m, 3H), 1.73e1.67 (m, 4H),
White crystals, yield 73.1%, mp 117e122 ꢀC, TLC Rf ¼ 0.32
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3442, 2974, 2938,
1731, 1660, 1515, 1457, 1378, 1338, 1266, 1172, 1110, 1072, 1052,
1013 cmꢁ1 1H NMR (600 MHz, CDCl3):
; d 7.36e7.35 (m, 2H),
7.27e7.09 (m, 2H), 5.08 (d, J ¼ 9.6 Hz, 1H), 4.99e4.98 (m, 1H),
4.53e4.50 (m, 1H), 4.24 (m, 2H), 3.97 (m, 1H), 3.78e3.76 (m, 2H),

564
S. Ma et al. / European Journal of Medicinal Chemistry 46 (2011) 556e566
3.70e3.67 (m,1H), 3.59e3.52 (m, 3H), 3.31e3.30 (m, 3H), 3.25e3.18
(m, 3H), 3.04 (m, 3H), 3.00e2.96 (m, 2H), 2.92e2.87 (m, 2H),
2.64e2.58 (m, 3H), 2.42e2.40 (m, 3H), 2.22e2.18 (m, 3H), 1.97e1.90
(m, 3H), 1.85e1.79 (m, 3H), 1.67e1.63 (m, 4H), 1.51e1.46 (m, 1H),
1.40e1.38 (m, 3H), 1.26 (m, 3H), 1.23e1.19 (m, 9H), 1.14e1.13 (m, 6H),
1.09e1.08 (m, 6H), 0.89e0.84 (m, 3H); MS (ESI) m/z calcd. for
C51H84ClN3O15 1013.6; found [M þ H]þ 1014.6; Analysis calculated for
C51H84ClN3O15: C 60.37, H 8.34, N 4.14. Found: C 60.44, H 8.37, N 4.11.
1H), 5.22e5.19 (m, 1H), 5.16e1.15 (m, 1H), 5.08e5.06 (m, 2H),
4.98e4.97 (m, 1H), 4.54e4.52 (m, 2H), 4.31 (m, 2H), 3.99 (s, 2H),
3.90e3.89 (m, 2H), 3.79e3.77 (m, 2H), 3.68e3.67 (m, 2H), 3.3e3.28
(m, 6H), 3.20e3.18 (m, 2H), 3.05e3.00 (m, 3H), 2.91 (m, 2H),
2.44e2.41 (m, 2H), 2.28e2.24 (m, 6H), 1.94e1.85 (m, 6H), 1.73e1.63
(m, 7H), 1.40 (m, 4H), 1.27e1.19 (m, 9H), 1.17e1.13(m, 8H), 0.85 (t,
3H); MS (ESI) m/z, calcd. for C46H81N3O15 915.6; found [M þ H]þ
917.0; Analysis calculated for C46H81N3O15: C 60.31, H 8.91, N 4.59.
Found: C 60.25, H 8.94, N 4.57.
6.3.6. 400-O-(((Cyclohexyl)amino)-4-oxo-butyl)
carbamoylclarithromycin (21)
6.3.10. 400-O-(((Butyl)amino)-4-oxo-butyl)
carbamoylclarithromycin (25)
White crystals, yield 75.3%, mp 122e126 ꢀC, TLC Rf ¼ 0.30
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3415, 2973, 2935,
1732, 1650, 1540, 1454, 1379, 1348, 1257, 1171, 1110, 1072, 1051,
White crystals, yield 77.2%, mp 127e130 ꢀC, TLC Rf ¼ 0.33
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3435, 2972, 2936,
1730, 1648, 1525, 1459, 1378, 1349, 1261, 1170, 1126, 1080, 1047,
1013 cmꢁ1 1H NMR (600 MHz, CDCl3):
; d 5.18 (m, 1H), 5.06 (d,
J ¼ 9.6 Hz,1H), 4.97 (m,1H), 4.53e4.50 (m, 2H), 4.45(d, J ¼ 6.0 Hz,1H),
4.28 (m, 2H), 3.97 (s, 1H), 3.77e3.72 (m, 3H), 3.69e3.65 (m, 2H),
3.38e3.36 (m, 2H), 3.35e3.29 (m, 3H), 3.28e3.24 (m, 4H), 3.17 (m,
2H), 3.04 (m, 3H), 3.00e2.99 (m, 3H), 2.60 (m, 2H), 2.42e2.18 (m, 8H),
1.94e1.84 (m, 6H), 1.72 (m, 6H), 1.66 (m, 2H), 1.38 (m, 4H), 1.25e1.16
(m, 10H), 1.16e1.10 (m, 10H), 0.84 (t, 3H); MS (ESI) m/z calcd. for
C49H87N3O15 957.6; found [M þ H]þ 958.8; Analysis calculated for
C49H87N3O15: C 61.42, H 9.15, N 4.39. Found: C 61.35, H 9.18, N 4.42.
1012 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d 5.11 (m, 1H), 5.09 (m, 1H),
4.68 (m, 1H), 4.55e4.51 (m, 1H), 3.99e3.98 (m, 1H), 3.79e3.76 (m,
2H), 3.69e3.67 (m, 2H), 3.31 (m, 6H), 3.05 (m, 3H), 3.02e2.99 (m,
2H), 2.94e2.91 (m, 2H), 2.82e2.57 (m, 8H), 2.43e2.41 (m, 1H),
2.25e2.03 (m, 2H), 2.03 (m, 1H), 1.94e1.89 (m, 2H), 1.88e1.80 (m,
3H), 1.53e1.46 (m, 5H), 1.39e1.35 (m, 9H), 1.28e1.18 (m, 12H),
1.16e1.14 (m, 6H), 1.09e1.08 (m, 3H), 0.96e0.92 (m, 3H), 0.87e0.85
(m, 3H); MS (ESI) m/z calcd. for C47H85N3O15 931.6; found [M þ H]þ
932.9; Analysis calculated for C47H85N3O15: C 60.56, H 9.19, N 4.15.
Found: C 60.62, H 9.15, N 4.12.
6.3.7. 400-O-(((Isopropyl)amino)-4-oxo-butyl)
carbamoylclarithromycin (22)
White crystals, yield 75.1%, mp 118e121 ꢀC, TLC Rf ¼ 0.30
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3450, 2973, 2938,
1732, 1654, 1515, 1458, 1378, 1338, 1267, 1172, 1110, 1072, 1051,
6.3.11. 400-O-(((Pentyl)amino)-4-oxo-butyl)
carbamoylclarithromycin (26)
White crystals, yield 71.3%, mp 132e136 ꢀC, TLC Rf ¼ 0.35
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3450, 2973, 2938,
1732, 1654, 1515, 1458, 1378, 1338, 1267, 1172, 1110, 1072, 1051,
1013 cmꢁ1 1H NMR (600 MHz, CDCl3):
; d 5.14 (m, 1H), 5.07 (dd,
J ¼ 10.8 Hz, J ¼ 1.8 Hz, 1H), 4.98e4.97 (m, 1H), 4.54e4.52 (m, 2H),
4.32e4.30 (m, 1H), 3.99 (m, 1H), 3.82e3.78 (m, 2H), 3.70e3.67
(m, 2H), 3.34e3.32 (m, 3H), 3.28e3.25 (m, 2H), 3.21e3.18 (m, 2H),
3.05 (m, 3H), 3.03e2.99 (m, 1H), 2.92e2.89 (m, 1H), 2.60e2.56 (m,
2H), 2.43e2.41 (m, 2H), 2.36e2.27 (m, 5H), 2.21e2.17 (m, 2H),
1.95e1.89 (m, 2H), 1.88e1.82 (m, 3H), 1.72e1.63 (m, 5H), 1.50e1.47
(m, 2H), 1.42e1.40 (m, 3H), 1.32e1.24 (m, 3H), 1.23e1.22 (m, 7H),
1.20e1.15 (m, 7H), 1.14e1.10 (m, 9H), 0.89e0.84 (m, 3H); MS (ESI)
m/z calcd. for C46H83N3O15 917.6; found [M þ H]þ 919.0; Analysis
calculated for C46H83N3O15: C 60.17, H 9.11, N 4.58. Found: C 60.11, H
9.14, N 4.60.
1013 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
5.06 (d, J ¼ 9.6 Hz, 1H),
4.97e2.92 (m, 1H), 4.53e4.51 (m, 3H), 3.99 (s, 1H), 3.81e3.76 (m,
2H), 3.69e3.66 (m, 2H), 3.35e3.30 (m, 3H), 3.28e3.18 (m, 6H),
3.10e3.02 (m, 3H), 3.01e2.92 (m, 1H), 2.91e2.87 (m, 1H), 2.59e2.56
(m, 2H), 2.43e2.38 (m, 1H), 2.32e2.24 (m, 6H), 2.22e2.19 (m, 2H),
2.04e1.90 (m, 2H), 1.88e1.81 (m, 2H), 1.75e1.63 (m, 4H), 1.53e1.45
(m, 3H), 1.41e1.39 (m, 3H), 1.35e1.25 (m, 6H), 1.23e1.19 (m, 9H),
1.16 (m, 3H), 1.17e1.11 (m, 10H), 0.89 (t, 3H), 0.84 (t, 3H); MS (ESI)
m/z calcd. for C48H87N3O15 945.6; found [M þ H]þ 947.1; Analysis
calculated for C48H87N3O15: C 60.93, H 9.27, N 4.44. Found: C 60.85,
H 9.31, N 4.41.
6.3.8. 400-O-(((Propyl)amino)-4-oxo-butyl)
carbamoylclarithromycin (23)
6.4. General procedure for the preparation of 400-O-
((arylalkylamino)-6-oxo-hexyl)carbamoyl clarithromycin
derivatives (27e37)
White crystals, yield 75.7%, mp 120e126 ꢀC, TLC Rf ¼ 0.32
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3450, 2973, 2938,
1732, 1654, 1515, 1458, 1378, 1338, 1267, 1172, 1110, 1072, 1051,
1014 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
5.14 (t, 1H), 5.07 (dd,
To a solution of 2 (1.50 g, 1.70 mmol) in DMF (15 mL) was added
DBU (0.50 mL, 3.41 mmol),Et3N (1.50 mL, 10.90 mmol) and corre-
sponding arylalkylcarbamoyl alkylamines hydrochloride (15le15v)
(6.67 mmol). The resulting solution was stirred for 24 h at the room
temperature. The following procedures were carried out according
to 6.3. General procedure for the preparation of 400-O-((arylalkyla-
mino)-4-oxo-butyl)carbamoyl clarithromycin derivatives. The
crudes were purified by flash chromatography (dichloromethane/
methanol 40:1) to afford products 27e37 in yields ranging from
70% to 79%.
J ¼ 10.8 Hz, J ¼ 2.4 Hz, 1H), 4.98e4.97 (m, 1H), 4.53e4.52 (m, 2H),
4.32e4.30 (m, 1H), 3.99 (m, 1H), 3.79e3.77 (m, 2H), 3.69e3.67 (m,
2H), 3.32 (m, 2H), 3.29e3.25 (m, 2H), 3.24e3.22 (m, 2H), 3.21e3.18
(m, 2H), 3.05 (m, 3H), 3.03e2.99 (m, 1H), 2.92e2.89 (m, 1H),
2.60e2.53 (m, 2H), 2.44e2.41 (m, 2H), 2.30e2.29 (m, 5H),
2.23e2,21 (m, 2H), 1.95e1.92 (m, 2H), 1.91e1.82 (m, 3H), 1.73e1.63
(m, 5H),1.55e1.48 (m, 2H),1.40 (s, 3H),1.26e1.15 (m,12H),1.14e1.11
(m, 10H), 0.93 (t, 3H), 0.85 (t, 3H); MS (ESI) m/z calcd. for
C46H83N3O15 917.6; found [M þ H]þ 919.0; Analysis calculated for
C46H83N3O15: C 60.17, H 9.11, N 4.58. Found: C 60.24, H 9.08, N 4.55.
6.4.1. 400-O-(((Benzyl)amino)-6-oxo-hexyl)
6.3.9. 400-O-(((Propenyl)amino)-4-oxo-butyl)
carbamoylclarithromycin (24)
carbamoylclarithromycin (27)
White crystals, yield 73.3%, mp 115e118 ꢀC, TLC Rf ¼ 0.35
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3454, 2974, 2938,
White crystals, yield 74.2%, mp 135e140 ꢀC, TLC Rf ¼ 0.34
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3436, 2974, 2938,
1731, 1660, 1529, 1458, 1382, 1339, 1266, 1247, 1171, 1110, 1072, 1051,
1731, 1514, 1456, 1378, 1346, 1247, 1171, 1110, 1072, 1051, 1013 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
1H), 4.58e4.50 (m, 2H), 4.44e4.43 (m, 2H), 4.30e4.27 (m, 2H), 3.98
d
7.35e7.26 (m, 5H), 5.06 (d, J ¼ 10.8 Hz,
1013, 986, 933 cmꢁ1 1H NMR (600 MHz, CDCl3) :
; d 5.85e5.83 (m,

S. Ma et al. / European Journal of Medicinal Chemistry 46 (2011) 556e566
565
(m, 1H), 3.81e3.76 (m, 2H), 3.67e3.63 (m, 2H), 3.35e3.27 (m, 3H),
3.21e3.17 (m, 4H), 3.00e2.98 (m, 2H), 2.90e2.89 (m, 2H),
2.58e2.56 (m, 2H), 2.30e2.29 (m, 7H), 2.22 (t, 2H), 1.94e1.84 (m,
1H), 1.72e1.62 (m, 2H), 1.54e1.46 (m, 8H), 1.39e1.35 (m, 11H),
1.25e1.23 (m, 9H), 1.12e1.10 (m, 9H), 0.84 (t, 3H), MS (ESI) m/z,
calcd. for C52H87N3O15 993.6; found [M þ H]þ 995.1; Analysis
calculated for C52H87N3O155: C 62.82, H 8.82, N 4.23, Found: C 62.71,
H 8.78, N 4.25.
(d, J ¼ 11.4 Hz, 1H), 4.99e4.98 (m, 1H), 4.63e4.62 (m, 1H), 4.55e4.53
(m, 1H), 4.24e4.22 (m, 1H), 3.99 (m, 1H), 3.79e3.76 (m, 4H),
3.69e3.68 (m, 2H), 3.35e3.32 (m, 2H), 3.24e3.21 (m, 2H), 3.11e3.05
(m, 3H), 3.02e2.97 (m, 2H), 2.94e2.87 (m, 2H), 2.65e2.54 (m, 2H),
2.43e2.36 (m, 2H), 2.21e2.16 (m, 2H), 2.05e1.92 (m, 1H), 1.84e1.80
(m, 1H), 1.72e1.64 (m, 3H), 1.55e1.48 (m, 4H), 1.42e1.36 (m, 4H),
1.36e1.33 (m, 4H), 1.27e1.25 (m, 8H), 1.25e1.20 (m, 15H), 1.19e1.14
(m, 8H), 0.91e0.86 (m, 3H); MS (ESI) m/z calcd. for C53H88ClN3O15
1041.6; found [M
þ
H]þ 1043.0; Analysis calculated for
6.4.2. 400-O-(((4-Fluorobenzyl)amino)-6-oxo-hexyl)
C53H88ClN3O15: C 61.05, H 8.51, N 4.03, Found: C 61.12, H 8.48, N 4.06.
carbamoylclarithromycin (28)
White crystals, yield 73.6%, mp 110e112 ꢀC, TLC Rf ¼ 0.36
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3381, 2974, 2938,
1730, 1658, 1605, 1511, 1459, 1378, 1345, 1266, 1171, 1110, 1072, 1051,
6.4.6. 400-O-(((Cyclohexyl)amino)-6-oxo-hexyl)
carbamoylclarithromycin (32)
White crystals, yield 79.3%, mp 100e103 ꢀC, TLC Rf ¼ 0.34 (meth-
anol/dichlormethane,1:10, v/v); IR (KBr): 3435, 2972,1730,1648,1525,
1013 cmꢁ1 1H NMR (600 MHz, CDCl3):
; d 7.26e7.24 (m, 2H),
7.04e7.01 (m, 2H), 5.07 (dd, J ¼ 11.4 Hz, J ¼ 1.8 Hz, 1H), 4.98 (m, 1H),
4.41e4.40 (m, 2H), 4.30e4.26 (m, 2H), 4.10e4.09 (m,1H), 3.82e3.76
(m, 2H), 3.69e3.59 (m, 2H), 3.23e3.17 (m, 8H), 3.05e3.03 (m, 1H),
2.94e2.87 (m, 2H), 2.65e2.55 (m, 2H), 2.43e2.41 (m, 2H), 2.33 (m,
6H), 2.22e2.20 (m, 3H), 1.94e1.92 (m, 1H), 1.72e1.63 (m, 3H),
1.55e1.48 (m, 8H), 1.38e1.35 (m, 9H), 1.26e1.15 (m, 9H), 1.14e1.12
(m, 9H), 0.84 (t, 3H); MS (ESI) m/z calcd. for C52H86FN3O15 1011.6;
found [M þ H]þ 1012.8; Analysis calculated for C52H86FN3O15: C
61.70, H 8.56, N 4.15, Found (%): C 61.66, H 8.54, N 4.17.
1459, 1378, 1349, 1261, 1170, 1126, 1080, 1047, 1012 cmꢁ1 1H NMR
;
(600 MHz, CDCl3): d5.08e5.06(m,1H), 4.98e4.96(m,1H), 4.74 (m,1H),
4.54e4.51 (m, 2H), 4.31e4.28 (m, 2H), 4.10e4.09 (m, 1H), 3.99e3.97
(m, 2H), 3.79e3.74 (m, 1H), 3.69e3.64 (m, 2H), 3.33e3.31 (m, 2H),
3.26e3.17 (m, 6H), 3.05e2.97 (m, 3H), 2.92e2.88 (m, 2H), 2.60e2.57
(m, 2H), 2.44e2.41 (m, 1H), 2.31e2.92 (m, 6H), 2.17e2.14 (m, 2H),
1.73e1.63 (m, 7H), 1.54e1.47 (m, 6H), 1.40e1.26 (m,10H),1.24e1.16 (m,
9H),1.15e1.12 (m, 9H), 1.11e0.90 (t, 3H), 0.85 (t, 3H); MS (ESI) m/zcalcd.
for C51H91N3O15 985.7; found [M þ H]þ 987.1; Analysis calculated for
C51H91N3O15: C 62.11, H 9.30, N 4.26, Found: C 62.04, H 9.33, N 4.24.
6.4.3. 400-O-(((4-Methoxybenzyl)amino)-6-oxo-hexyl)
carbamoylclarithromycin (29)
6.4.7. 400-O-(((Isopropyl)amino)-6-oxo-hexyl)
carbamoylclarithromycin (33)
White crystals, yield 70.1%, mp 120e124 ꢀC, TLC Rf ¼ 0.28
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3369, 2973, 2937,
1730, 1654, 1514, 1458, 1378, 1335, 1249, 1172, 1110, 1083, 1048,
White crystals, yield 69.8%, mp 123e127 ꢀC, TLC Rf ¼ 0.29
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3377, 2973, 2933,
1730, 1643, 1544, 1460, 1382, 1349, 1266, 1170, 1127, 1082, 1046,
1012 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d
7.21 (d, J ¼ 8.4 Hz, 2H), 6.88
(d, J ¼ 8.4 Hz, 2H), 5.07 (d, J ¼ 8.4 Hz, 1H), 4.39e4.38 (m, 2H),
4.31e4.28 (m, 1H), 4.01 (m, 1H), 3.82e3.81 (m, 3H), 3.79e3.77 (m,
2H), 3.69e3.67 (m, 2H), 3.33e3.32 (m, 3H), 3.29e3.30 (m, 3H),
3.06e2.93 (m, 3H), 2.92e2.89 (m, 2H), 2.61e2.58 (m, 2H), 2.44e2.42
(m, 1H), 2.34e2.31 (m, 6H), 2.22e2.21 (m, 2H), 1.95e1.85 (m, 1H),
1.73e1.63 (m, 6H), 1.55e1.48 (m, 4H), 1.43e1.35 (m, 5H), 1.29e1.20
(m, 15H), 1.19e1.12 (m, 12H), 0.84 (t, 3H); MS (ESI) m/z calcd. for
C53H89N3O16 1023.6; found [M þ H]þ 1025.2; Analysis calculated for
C53H89N3O16: C 63.13, H 8.90, N 4.17, Found: C 63.19, H 8.86, N 4.19.
1011 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
5.10 (d, J ¼ 11.4 Hz, 1H),
5.01e5.00 (m, 1H), 4.74e4.73 (d, J ¼ 7.2 Hz, 1H), 4.59e4.53 (m, 1H),
4.12e4.06 (m, 1H), 3.84e3.82 (m, 1H), 3.79e3.73 (m, 2H),
3.69e3.68 (m,1H), 3.56e3.53 (m,1H), 3.38e3.28 (m, 6H), 3.27e3.19
(m, 3H), 3.05 (m, 2H), 3.01e2.98 (m, 2H), 2.92e2.81 (m, 2H),
2.63e2.56 (m, 3H), 2.42e2.40 (m, 1H), 2.22e2.16 (m, 3H), 1.95e1.89
(m, 1H), 1.88e1.75 (m, 3H), 1.75e1.65 (m, 5H), 1.50e1.47 (m, 2H),
1.32e1.24 (m, 3H), 1.25e1.19 (m, 15H), 1.19e1.15 (m, 9H), 1.14e1.10
(m, 6H), 0.90e0.85 (m, 6H); MS (ESI) m/z calcd. for C48H87N3O15
945.61; found [M þ H]þ 947.2; Analysis calculated for C48H87N3O15
:
6.4.4. 400-O-(((4-Hydroxyphenethyl)amino)-6-oxo-hexyl)
carbamoylclarithromycin (30)
C 60.93, H 9.27, N 4.44, Found: C 688, H 9.30, N 4.42.
White crystals, yield 70.2%, mp 129e133 ꢀC, TLC Rf ¼ 0.33
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3409, 2974, 2939,
1731, 1655, 1516, 1457, 1378, 1347, 1247, 1171, 1110, 1072, 1051,
6.4.8. 400-O-(((Propyl)amino)-6-oxo-hexyl)
carbamoylclarithromycin (34)
White crystals, yield 76.3%, mp 112e115 ꢀC, TLC Rf ¼ 0.36
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3452, 2972, 2937,
1731, 1655, 1537, 1459, 1378, 1337, 1266, 1171, 1110, 1072, 1050,
1013 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
7.05 (d, J ¼ 8.4 Hz, 2H),
6.77 (d, J ¼ 8.4 Hz, 2H), 5.07 (d, J ¼ 11.4 Hz, 1H), 4.99 (m, 1H), 4.74
(d, J ¼ 6.6 Hz, 1H), 4.50 (d, J ¼ 9.6 Hz, 1H), 4.20e4.17 (m, 1H), 3.96
(m, 1H), 3.88e3.87 (m, 1H), 3.76e3.73 (m, 2H), 3.66e3.65 (m, 2H),
3.56e3.55 (m, 2H), 3.37e3.28 (m, 6H), 3.21e3.19 (m, 3H),
3.09e3.03 (m, 3H), 3.00e2.92 (m, 2H), 2.90e2.84 (m, 6H),
2.59e2.56 (m, 4H), 2.40 (m, 2H), 1.97e1.91 (m, 1H), 1.78e1.73 (m,
3H), 1.67e1.56 (m, 3H), 1.51e1.42 (m, 2H), 1.41e1.36 (m, 3H),
1.18e1.13 (m, 18H), 1.05e1.03 (m, 4H), 0.89e0.83 (m, 6H); MS (ESI)
m/z calcd. for C53H89N3O16 1023.6; found [M þ H]þ 1025.2; Anal-
ysis calculated for C53H89N3O16: C 63.13, H 8.90, N 4.17, Found: C
63.08, H 8.93, N 4.15.
1012 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
5.07 (d, J ¼ 10.2 Hz, 1H),
4.97e4.96 (m, 1H), 4.57e4.50 (m, 2H), 3.99 (s, 1H), 3.82e3.76 (m,
2H), 3.68e3.59 (m, 2H), 3.36e3.31 (m, 2H), 3.23e3.18 (m, 6H),
3.15e3.09 (m, 1H), 3.05e3.00 (m, 2H), 2.89 (m, 2H), 2.59e2.57 (m,
2H), 2.44e2.41 (m, 1H), 2.31e2.29 (m, 6H), 2.16 (t, 2H), 1.94e1.87
(m, 1H), 1.73e1.63 (m, 3H), 1.54e1.48 (m, 3H), 1.40e1.34 (m, 4H),
1.27e1.24 (m, 2H), 1.24e1.18 (m, 14H), 1.17e1.11 (m, 16H), 0.93 (t,
3H), 0.85 (t, 3H); MS (ESI) m/z calcd. for C48H87N3O15 945.6; found
[M þ H]þ 947.1; Analysis calculated for C48H87N3O15: C 60.93, H
9.27, N 4.44, Found: C 60.89, H 9.30, N 4.41.
6.4.5. 400-O-(((2-Chlorophenethyl)amino)-6-oxo-hexyl)
carbamoylclarithromycin (31)
6.4.9. 400-O-(((Propenyl)amino)-6-oxo-hexyl)
carbamoylclarithromycin (35)
White crystals, yield 70.1%, mp 127e131 ꢀC, TLC Rf ¼ 0.31 (meth-
anol/dichlormethane, 1:10, v/v); IR (KBr): 3446, 2973, 2934, 1730,
White crystals, yield 72.3%, mp 119e122 ꢀC, TLC Rf ¼ 0.38
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3454, 2974, 2939,
1731, 1664, 1514, 1458, 1378, 1339, 1266, 1171, 1110, 1072, 1051, 1013,
1651, 1534, 1459, 1378, 1348, 1264, 1170, 1110, 1082, 1053, 1011 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
7.37 (m, 1H), 7.29e7.19 (m, 3H), 5.09
986, 934 cmꢁ1 1H NMR (600 MHz, CDCl3):
; d 5.87e5.82 (m,1H),

566
S. Ma et al. / European Journal of Medicinal Chemistry 46 (2011) 556e566
5.20e5.13 (m, 2H), 5.08e5.07 (m, 1H), 4.98e4.97 (m, 1H),
4.56e4.52 (m, 2H), 4.27 (m, 1H), 3.98 (s, 2H), 3.89 (t, 2H), 3.68e3.67
(m, 2H), 3.32 (m, 3H), 3.23e3.18 (m, 3H), 3.05 (m, 1H), 3.01 (m, 2H),
2.89 (m, 2H), 2.59 (m, 2H), 2.43e2.41 (m, 7H), 2.22e2.19 (m, 2H),
1.96e1.85 (m, 2H), 1.70e1.63 (m, 4H), 1.55e1.49 (m, 6H), 1.39e1.35
(m, 9H), 1.27e1.24 (m, 2H), 1.22e1.14 (m, 9H), 1.13e1.10 (m, 9H),
0.85 (t, 3H,); MS (ESI) m/z, calcd. for C48H85N3O15 943.6; found
[M þ H]þ 945.0; Analysis calculated for C48H85N3O15: C 61.06, H
9.07, N 4.45, Found: C 61.10, H 9.04, N 4.48.
Appendix. Supporting information
Supporting information associated with this article can be
found, in the online version, at doi:10.1016/j.ejmech.2010.11.035.
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6.4.10. 400-O-(((Butyl)amino)-6-oxo-hexyl)
carbamoylclarithromycin (36)
White crystals, yield 72.0%, mp 102e106 ꢀC, TLC Rf ¼ 0.33
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3431, 2933, 1749,
1734,1647,1547,1457,1378,1267,1172,1110,1069,1011 cmꢁ1; 1H NMR
(600 MHz, CDCl3): d 5.08e5.07 (m,1H), 5.00e4.97 (m,1H), 4.56e4.53
(m, 1H), 4.53e4.47 (m, 1H), 3.83e3.77 (m, 1H), 3.74e3.66 (m, 2H),
3.35e3.20 (m, 6H), 3.05e2.98 (m, 4H), 2.45e2.37 (m, 7H), 2.32e2.17
(m, 1H), 2.16e1.73 (m, 3H), 1.72e1.67 (m, 5H), 1.54e1.43 (m, 4H),
1.43e1.34(m, 6H),1.33e1.26(m, 8H),1.23e1.18(m,12H),1.15e1.12 (m,
12H), 0.95e0.91 (m, 3H), 0.89e0.85 (m, 6H); MS (ESI) m/z calcd. for
C49H89N3O15 959.6; found [M þ H]þ 961.0; Analysis calculated for
C49H89N3O15: C 61.29, H 9.34, N 4.38, Found: C 61.35, H 9.31, N 4.41.
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6.4.11. 400-O-(((Pentyl)amino)-6-oxo-hexyl)
carbamoylclarithromycin (37)
White crystals, yield 72.5%, mp 104e107 ꢀC, TLC Rf ¼ 0.34
(methanol/dichlormethane, 1:10, v/v); IR (KBr): 3391, 2936, 1731,
1656, 1536, 1459, 1378, 1343, 1247, 1171, 1111, 1072, 1051, 1013 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d 5.08e5.06 (m, 1H), 4.98e4.96 (m, 1H),
4.74 (m, 1H), 4.54e4.51 (m, 2H), 4.31e4.28 (m, 2H), 4.10e4.09 (m,
1H), 3.99e3.97 (m, 2H), 3.79e3.74 (m, 1H), 3.69e3.64 (m, 2H),
3.33e3.31 (m, 2H), 3.26e3.17 (m, 6H), 3.05e2.97 (m, 3H),
2.92e2.88 (m, 2H), 2.60e2.57 (m, 2H), 2.44e2.41 (m, 1H),
2.31e2.92 (m, 6H), 2.17e2.14 (m, 2H), 1.73e1.63 (m, 7H), 1.54e1.47
(m, 6H), 1.40e1.26 (m, 10H), 1.24e1.16 (m, 9H), 1.15e1.12 (m, 9H),
1.11e0.90 (t, 3H), 0.85 (t, 3H); MS (ESI) m/z calcd. for C50H91N3O15
973.7; found [M
C50H91N3O15: C 61.64, H 9.41, N 4.31, Found: C 61.60, H 9.44, N 4.29.
þ
H]þ 975.0;
A Analysis calculated for
Acknowledgements
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(2008) 5507e5511.
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Lett. 19 (2009) 1698e1701.
This research was financially supported by Major R&D Program
of New DrugseNational S&T Key Special Subject of China
(2009ZX09103-115), National Natural Science Foundation of China
(20872081and 21072114) and the Project-sponsored by SRF for
ROCS, SEM.
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F. Franceschi, Nature 413 (2001) 814e821.