Y. Wang et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
3
NH2
inhibitory concentrations (MICs). The sensitive and resistant
Gram-positive bacterial strains contain: S. aureus ATCC25923
(erythromycin-susceptible strain), S. pneumoniae ATCC49619
(erythromycin-susceptible strain), S. pyogenes S2 (erythromycin-
susceptible strain isolated clinically), S. aureus ATCC29213
(methicillin-resistant strain), S. pneumoniae B1 (erythromycin-
resistant strain encoded by the erm gene), S. pneumoniae A22072
(erythromycin-resistant strain encoded by the mef gene),
S. pneumoniae AB11 (erythromycin-resistant strain encoded by
the erm and mef genes), S. pyogenes R2 (erythromycin-resistant
strain isolated clinically). Two phenotypes of Gram-negative
strains are E. coli ATCC25922, P. aeruginosa ATCC27853.
R1
NH2
N
N
a
R1 N3
R1 Cl
N
b
A11 R1= 2,4-dichlorobenzyl
A6 R1= 4-bromobenzyl
A7 R1= 2-fluorobenzyl
A8 R1= 3-fluorobenzyl
A1 R1= 2-methylbenzyl
R1= 2-chlorobenzyl
R1= 3-methylbenzyl
A12
A2
A13 R1= 3-chlorobenzyl
A14 R1= 4-chlorobenzyl
A15 R1= cyclohexyl
A3 R1= 4-methylbenzyl
A4 R1= 4-nitrobenzyl
A5 R1= benzyl
R1= 4-fluorobenzyl
A9
A10 R1= 2,6-dichlorobenzyl
Scheme 1. Synthesis of aminomethyl triazoles. Reagents and conditions: a) NaN3,
EtOH, H20, reflux, 75–89%; b) Propargyl amine, CuSO4, Sodium ascorbate, tBuOH,
H2O, rt, 46–63%.
MIC values for 400-O-(1-aralkyl-1,2,3-triazol-4-methyl-car-
bamoyl) azithromycin analogs (4a–j) are presented in Table 1.
Most of the above analogs retained comparable activity compared
with AZM and CAM against erythromycin-susceptible S. pyogenes
S2, and all of them showed improved activity against ery-
thromycin-resistant S. pyogenes R2 and the three phenotypes of
resistant S. pneumoniae. In particular, compound 4g displayed the
most potent activity against not only erythromycin-resistant S.
Scheme 2. AZM was used as the starting material for the synthesis
of the target compounds. It was first coupled with acetic anhydride
catalyzed by triethylamine at room temperature for 24 h to gener-
ate the compound 2, which was treated with 1,1-carbonyldiimida-
zole (CDI) in toluene at 55 °C to give the important intermediate 3.
Finally, 400-carbamate azithromycin analogs (4a–j) were prepared
by coupling 3 with corresponding aminomethyl triazoles in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), followed
by methanolysis.
pyogenes S2 (0.016
thromycin-resistant S. pneumoniae B1, S. pneumoniae A22072 and
S. pneumoniae AB11 (0.5, 0.25 and 0.25 g/mL), showing 12.5,
lg/mL) but also three phenotypes of ery-
The desired target compounds, 11,12-cyclic carbonate-400-O-(1-
aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs
(8a–o) and 11,400-di-O-arylalkylcarbamoyl azithromycin analogs
(9a–k), were synthesized as shown in Scheme 3. Compound 2
was treated with 1,1-carbonyldiimidazole (CDI) in toluene at
55 °C to generate the important intermediate 1400-O-acylimida-
zolyl-11,12-cyclic carbonate 5. Then compound 6 was obtained
by coupling the intermediate 5 with propargyl amine catalyzed
by 1,8-Diazabicyclo [5,4,0]-undec-7-ene (DBU), followed by depro-
tection of the acetyl group in methanol. Subsequently, compound 7
were reacted with the corresponding aromatic azides to give the
desired target compounds 8a–o. Then corresponding 11,12-cyclic
carbonate-400-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azi-
thromycin analogs was readily converted to novel 11,400-di-O-ary-
lalkylcarbamoyl azithromycin analogs (9a–k) by coupling with the
corresponding amines in the presence of pyridine hydrochloride at
room temperature in yields ranging from 68% to 86%.
l
256, 16 and 1024-fold enhanced activity than AZM, respectively,
which suggested that introduction of the 1-aralkyl-1,2,3-triazol-
4-methyl-carbamoyl side chain into the C-400 position of AZM could
enhance antibacterial activity against erythromycin-resistant
bacteria.
Compared with their precursors 400-O-(1-aralkyl-1,2,3-triazol-4-
methyl-carbamoyl) azithromycin analogs, almost all of the 11,12-
cyclic
carbonate-400-O-(1-aralkyl-1,2,3-triazol-4-methyl-car-
bamoyl) azithromycin analogs (8a–o) showed compromised or
similar activity against all the tested strains, which suggested that
the introduction of 11,12-cyclic carbonate moiety failed to confer
lower MIC values against erythromycin-susceptible or ery-
thromycin-resistant strains. However, the compounds in this series
still showed potent activity against erythromycin-susceptible S.
pneumoniae ATCC49619 (0.5–1
lg/mL) and S. pyogenes S2 (0.008–
0.25 g/mL), and showed improved activity against all the three
l
All the target compounds, as well as CAM and AZM as refer-
ences, were tested for in vitro antibacterial activity against eight
phenotypes of Gram-positive strains and two phenotypes of
Gram-negative strains. Their activities are reported as minimum
phenotypes of resistant S. pneumoniae compared with AZM and
CAM. Among them, compounds 8a, 8e and 8g displayed the most
potent activity against S. pneumoniae ATCC49619 (0.5
l
g/mL),
and compound 8d (0.008
lg/mL) exhibited better activity against
NMe2
HO
NMe2
NMe2
O
AcO
OH
AcO
OH
O
N
O
N
O
N
OH
HO
HO
HO
HO
HO
HO
O
a
O
O
b
O
O
O
O
O
O
O
O
O
OH
OMe
N
O
N
O
OH
OMe
O
O
OMe
3
2
AZM
R1= 3-methylbenzyl
R1= 2-methylbenzyl
NMe2
4a
4b
HO
OH
N
O
4c R1= 4-methylbenzyl
4d R1= 4-nitrobenzyl
4e R1= benzyl
c,d
N
HO
HO
O
O
O
R1
N
N
NH2
4f R1= 2,6-dichlorobenzyl
4g R1= 2,4-dichlorobenzyl
4h R1= 4-chlorobenzyl
4i R1= 3-chlorobenzyl
4j R1= 2-chlorobenzyl
O
O
R1
N
N
O
OMe
O
N
H
N
4
Scheme 2. Synthesis of 400-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs (4a–j). Reagents and conditions: a) Ac2O, DCM, Et3N, rt, 24 h, 92%; b) CDI,
Et3N, toluene, 55 °C, 40 h, 95%; c) DMF, DBU, rt, 12 h, 82–93%; d) CH3OH, 55 °C, 12 h, 90–96%.