Oxazolidinone Antibacterials
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6561
Table 2. In Vitro Antibacterial Activity of Biaryl Oxazolidinones 30,
52-54: D-Ring Cyano Group
Table 4. In Vitro Antibacterial Activity of Biaryl Oxazolidinones
66-69: E-Ring N-3 Substituents
MIC (µg/mL)a
MIC (µg/mL)a
compd
R
MSSA MRSA PSSP PRSP
VRE
HI
compd
R
MSSA MRSA PSSP PRSP VRE HI
30
52
53
54
CN
0.06
0.06
0.06
4
1
0.06
8
0.5
0.5
0.125
16
4
2
2
66
67
68
69
COCH2OH
CN
Me
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06 0.125
0.06 0.06
0.06 0.25
4
2
4
CH2NH2
CONH2
NH2
4
2
1
4
2
2
128
NT
32
0.5
5-CN-2-pyridyl 0.06
0.125 0.06 0.125 >2
a Organisms selected for inclusion in the table: MSSA, methicillin-
sensitive S. aureus Smith; MRSA, methicillin-resistant S. aureus TK7; PSSP,
penicillin-susceptible S. pneumoniae IID553; PRSP, penicillin-resistant S.
pneumoniae PR44; VRE, vancomycin-resistant E. faecium A2280; HI, H.
influenzae IID983.
a Organisms selected for inclusion in the table: MSSA, methicillin-
sensitive S. aureus Smith; MRSA, methicillin-resistant S. aureus TK7; PSSP,
penicillin-susceptible S. pneumoniae IID553; PRSP, penicillin-resistant S.
pneumoniae PR44; VRE, vancomycin-resistant E. faecium A2280; HI, H.
influenzae IID983.
Table 3. In Vitro Antibacterial Activity of Biaryl Oxazolidinones
57-65: A-Ring C-5 Substituents
resulting N-substituted compounds 66-69 possessed poor
solubility for intravenous administration.
MIC (µg/mL)a
Conclusions
compd
R
MSSA MRSA PSSP PRSP VRE
HI
57
58
59
60
61
62
63
64
65
NHCOMe
NHCOEt
0.125 0.125 0.125 0.06 0.25
4
8
2
8
4
2
We have succeeded in the design, synthesis, and SAR analysis
of novel biaryl oxazolidinones bearing a bicyclo[3.1.0]hex-6-
yl ring moiety. Most of the synthesized biaryl bicyclo[3.1.0]hex-
6-yl oxazolidinones showed higher antibacterial activity against
the tested Gram-positive drug-resistant bacteria MRSA, PRSP,
and VRE and the RTI-causative Gram-negative bacteria H.
influenzae compared with 1. Among the synthesized biaryl
bicyclo[3.1.0]hex-6-yl oxazolidinones, 30 was selected for
further evaluation. Further study of 30 demonstrated its excellent
antibacterial activity against drug-resistant clinical isolates such
as MRSA and VRE and against typical pathogens such as
Mycoplasma pneumoniae and Chlamydia pneumoniae,22 its low
resistance potential,23 and its intravenous and orally active in
vivo efficacy in the linezolid-resistant MRSA mouse infection
model24 of 30. We have selected 30 (AM-7359) as a candidate
for further evaluation in clinical trials.
0.25
0.125 0.125 0.06 0.06 0.25
0.5 0.25 0.25 0.25 0.5
0.125 0.125 0.125 0.125 0.125
0.25
0.25 0.125 0.25
NHCOCHF2
NHCOcPr
NHCO2Me
NHC(dS)OMe
NHC(dS)Me
O-3-isoxazolyl
0.06
0.03
0.03
0.03
0.06 0.03 0.06
0.03 0.03 0.06
0.5
0.125 0.125 0.25 0.25 0.5
0.06 0.125 0.06 0.125
>16
NH-3-isoxazolyl 0.06
4
a Organisms selected for inclusion in the table: MSSA, methicillin-
sensitive S. aureus Smith; MRSA, methicillin-resistant S. aureus TK7; PSSP,
penicillin-susceptible S. pneumoniae IID553; PRSP, penicillin-resistant S.
pneumoniae PR44; VRE, vancomycin-resistant E. faecium A2280; HI, H.
influenzae IID983.
reduced with an increase of the number of fluorine substitutions.
In particular, 34, which carries three fluorine atoms on the B-ring
and C-ring, showed drastically reduced antibacterial activity
against H. influenzae, probably because of its increased hydro-
phobicity. Regarding the SAR trends for heteroatoms on the
E-ring, the oxothia- and dioxothia-bicyclic biaryl oxazolidinones
41-43 and 44-46 showed highly potent activity against VRE.
Our results suggested that the hydrophobicity of the heteroatoms
on the E-ring have a particularly pronounced impact on the anti-
H. influenzae activity.
As shown in Table 2, the antibacterial activity of the
aminomethyl, carbamoyl, and amino derivatives 52-54 was
dramatically reduced by replacement of a cyano group. Among
the C-6 derivatives examined, 54, which carries a basic primary
amino substituent instead of the cyano group, showed 8- to 32-
fold less activity. The antibacterial activity of 52, which
possesses a more basic and bulky aminomethyl substituent at
the C-6 position, was even less than that of 54. A carbamoyl
group in 53, which is a more hydrophilic and bulky substituent
than a cyano group, is also not preferable to the cyano group in
30 in terms of achieving a strong antibacterial activity. At the
D-ring C-6 position of 30, the cyano group plays an important
role in the highly potent antibacterial activity.
Acknowledgment. We thank Drs. Keiji Hirai and Takayoshi
Ishizaki, Kyorin Pharmaceutical Co. Ltd., for their encourage-
ment and support of this project. We are also grateful to Drs.
James V. Heck and Milton L. Hammond, Merck Research
Laboratories, for their close readings of this manuscript and
helpful comments. We also thank Hinako Gomori, Kyorin
Pharmaceutical Co., Ltd., for providing the antibacterial data.
Supporting Information Available: Experimental details, el-
emental analysis results for new compounds, and NOESY spectra
of 14a. This material is available free of charge via the Internet at
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As shown in Table 3, although the thiocarbonyl derivatives
62 and 63 showed more potent activity than 30, the other C-5
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