Potent oxazolidinone antibacterials with heteroaromatic C-ring substructure

Article abstract of DOI:10.1021/ml400280z

Novel oxazolidinone analogues bearing a condensed heteroaromatic ring as the C-ring substructure were synthesized as candidate antibacterial agents. Analogues 16 and 21 bearing imidazo[1,2-a]pyridine and 18 and 23 bearing [1,2,4]triazolo[1,5-a]pyridine as the C-ring had excellent in vitro antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP). They also showed promising therapeutic effects in a mouse model of lethal infection. Preliminary safety data (inhibitory effects on cytochrome P450 isoforms and monoamine oxidases) were satisfactory. Further evaluation of 18 and 23 is ongoing.

Full text of DOI:10.1021/ml400280z

Letter
pubs.acs.org/acsmedchemlett
Potent Oxazolidinone Antibacterials with Heteroaromatic C‑Ring
Substructure
Hideyuki Suzuki,*,† Iwao Utsunomiya,† Koichi Shudo,† Takaji Fujimura,‡ Masakatsu Tsuji,‡ Issei Kato,‡
Toshiaki Aoki,‡ Akira Ino,‡ and Tsutomu Iwaki‡
†Research Foundation Itsuu Laboratory, 2-28-10 Tamagawa, Setagaya-ku, Tokyo 158-0094, Japan
‡Medicinal Research Laboratories, Shionogi & Co., Ltd, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
S
* Supporting Information
ABSTRACT: Novel oxazolidinone analogues bearing a condensed heteroaromatic ring as the C-ring substructure were
synthesized as candidate antibacterial agents. Analogues 16 and 21 bearing imidazo[1,2-a]pyridine and 18 and 23 bearing
[1,2,4]triazolo[1,5-a]pyridine as the C-ring had excellent in vitro antibacterial activities against methicillin-resistant Staphylococcus
aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP). They
also showed promising therapeutic effects in a mouse model of lethal infection. Preliminary safety data (inhibitory effects on
cytochrome P450 isoforms and monoamine oxidases) were satisfactory. Further evaluation of 18 and 23 is ongoing.
KEYWORDS: Antibacterial, oxazolidinone, methicillin-resistant Staphylococcus aureus, condensed heteroaromatic ring
nfections caused by multidrug-resistant organisms, such as
Therapeutics and has recently completed a phase III clinical
trial.14 These candidate compounds all have a heteroaromatic
ring as the terminal chemical structure unit. However,
Okamoto et al. reported the synthesis and in vitro
antimycobacterial activity of pyrazolo[1,5-a]pyridine derivatives
and suggested that the condensed heteroaromatic ring system
was a pharmacophore exhibiting antimycobacterial activity.15
Although this scaffold has not been investigated for activity
against Gram-positive or -negative bacteria, the oxazolidinone
antibacterial sutezolid (5) is known to exhibit strong in vitro
activities against both Gram-positive bacteria (such as MRSA)
and Mycobacterium tuberculosis.16 Since the above heteroar-
omatic ring system showed antimycobacterial activity, we
suspected that it might also have antibacterial activity potential
because antimycobacterial activity is generally correlated with
antibacterial activity toward Gram-positive bacteria such as
MRSA. Therefore, we expected that introduction of the above
pyrazolo[1,5-a]pyridine or a related scaffold into oxazolidinone
antibacterials might result in potent antibacterial activity.
Herein, we report the synthesis and biological evaluations of
novel oxazolidinone derivatives bearing pyrazolo[1,5-a]pyridine
or its similar scaffold as the C-ring substructure.
I
methicillin-resistant Staphylococcus aureus (MRSA),1 vanco-
mycin-resistant Enterococcus faecalis (VRE),2 and penicillin-
resistant Streptococcus pneumoniae (PRSP),3 are a major
problem in hospitals around the world, and effective antibiotics
are urgently needed. Oxazolidinone antibacterials are a class of
synthetic antibiotics that have been developed over the last
three decades4,5 and are composed of an A-ring (oxazolidi-
none), B-ring (phenyl), and C-ring (an appropriate heterocycle,
such as morpholine or piperazine), with a C-5 side chain unit
on the A-ring substructure. Linezolid (1) was the first
oxazolidinone antibiotic to be approved by the US Food and
Drug Administration (FDA) and has been used for the
treatment of serious infections caused by Gram-positive strains
such as MRSA and VRE since 2000 (Figure 1).6 However,
linezolid-resistant Staphylococcus aureus and Enterococcus
spp.7−9 have appeared since 1 was released, and 1 is also an
inhibitor of monoamine oxidases (MAOs), which may result in
drug−drug interactions with adrenergic and serotonergic
agents.10 Thus, there is considerable interest in new
oxazolidinone-type drug candidates (Figure 1). A series of
oxazolidinones containing a pyrroloaryl substituent as C-ring
unit was developed by J&J Pharmacuetical, and one analogue
advanced to phase I clinical trial.11 Ranbezolid (2), which has a
furan ring as the terminal unit, was developed by Ranbaxy
Laboratories, and a phase I clinical trial was performed in
2003.12,13 Radezolid (3), which has a [1,2,3]triazole framework
as the terminal substructure, was developed by Rib-X
Pharmaceuticals and has completed a phase II clinical trial.5
Tedizolid phosphate (4, formerly called torezolid phosphate),
which contains a tetrazole structure, was developed by Trius
The synthesis of the desired oxazolidinone analogues was
performed by Suzuki−Miyaura coupling reaction of the known
boronic acid ester (6)17 with 6-bromopyrazolo[1,5-a]pyridine
(7),18 6-bromoimidazo[1,5-a]pyridine (8),19 6-bromoimidazo-
Received: July 17, 2013
Accepted: September 22, 2013
© XXXX American Chemical Society
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ACS Medicinal Chemistry Letters
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Figure 1. Recently developed potent antibacterials of the oxazolidinone family.
[1,2-a]pyridine (9),20 7-bromoimidazo[1,2-a]pyridine (10),21
6-bromo[1,2,4]triazolo[1,5-a]pyridine (11),22 and 7-bromo-
[1,2,4]triazolo[1,5-a]pyridine (12),23 as shown in Table 1.
The products 13−18 were recrystallized from appropriate
organic solvents. These compounds 13−18 were then
evaluated for in vitro antibacterial activity against Gram-positive
(S. aureus, E. faecalis, E. faecium, and S. pneumoniae) and Gram-
negative (Moraxella catarrhalis and Haemophilus influenzae)
bacteria using a conventional broth microdilution method.
Activity against linezolid-resistant S. aureus NRS271, a clinical
isolate, was also examined. NRS271 carries G2576T mutation
in domain V, the peptidyl transferase center, of 23S rRNA gene
(Escherichia coli 23S rRNA numbering). As shown in Table 2,
the minimum inhibitory concentrations (MICs, μg/mL) of
13−18 against S. aureus generally indicated 2- to 8-fold greater
potency in comparison with linezolid 1. Compounds 13 and 16
showed clinically relevant MIC values against linezolid-resistant
S. aureus NRS271, as well as Gram-negative M. catarrhalis.
Compound 16 with an imidazo[1,2-a]pyridine ring unit also
exhibited good antibacterial activity toward Gram-negative H.
influenzae. Next, we examined the effect of replacing the
conventional acetamide type C-5 side chain unit on the A-ring
with a [1,2,3]triazole unit, which has been reported to enhance
antibacterial activity and reduce inhibition of monoamine
oxidase (MAO).24 The compounds were synthesized via a
similar procedure to that described for compounds 13−18,
using boronic acid ester (19)25 instead of 6, with heteroaryl
bromides 9−12 (Table 3). The prepared compounds 20−23
exhibited similar in vitro antibacterial activity to the acetamide
derivatives 15−18, and compound 21 showed most potent
antibacterial activity among all the synthesized compounds
(Table 4). We then evaluated the in vivo therapeutic effect of
selected compounds via intravenous or oral administration in a
mouse lethal systemic infection model employing S. aureus
SR3637 (MRSA). The results are shown in Table 5. Though
compound 13 had potent in vitro antibacterial activity, it was
not effective in vivo. This unsuccessful result may suggest that
13 has poor pharmacokinetic (PK) properties or is
metabolically unstable. However, other tested compounds
showed moderate to excellent in vivo therapeutic effect,
regardless of administration route. Compound 18 exhibited a
4- to 6-fold greater in vivo potency than that of linezolid 1 via
both intravenous and oral administration, in line with the in
vitro results. In addition, compounds 16 and 21, bearing an
imidazo[1,2-a]pyridine C-ring unit, also showed a good
therapeutic effect, superior to that of linezolid, after both
intravenous and oral administration. Compound 23 also had a
good therapeutic effect via oral administration. The pharmaco-
kinetics (PK) of compound 18 was evaluated after oral
administration to mice (Table 6). Compound 18 showed a
sufficient AUC even at a 10-fold lower dosage than linezolid
(1), used as a reference compound. This excellent PK profile is
consistent with the in vivo efficacy of 18 regardless of the route
of administration. We made a preliminary examination of the
safety profile of the in vivo active compounds 16, 18, 21, and
23. Specifically, we examined whether these compounds inhibit
Table 1. Synthesis of Targeted Oxazolidinone Analogues
13−18 Bearing an Acetamide C-5 Side Chain on the
Oxazolidinone Ring
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ACS Medicinal Chemistry Letters
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Table 2. In Vitro Antibacterial Activity of Compounds 13−18 Bearing an Acetamide C-5 Side Chain on the Oxazolidinone Ring
minimum inhibitory concentration (μg/mL)
a
b
c
d
e
f
g
h
i
j
compd
S.a.
2
S.a.
S.a.
2
S.a.
E.f.
E.f.
2
M.c.
S.p.
S.p.
0.5
H.i.
1
2
32
2
4
8
2
4
8
2
8
4
1
16
8
13
14
15
16
17
18
0.25
0.25
0.5
0.5
1
0.25
0.5
0.5
0.5
0.5
0.25
0.5
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
4
8
1
0.5
8
0.25
0.5
4
0.25
0.5
0.25
0.5
0.25
0.5
2
0.25
0.5
2
8
0.5
4
0.25
0.5
0.25
4
0.25
0.25
4
a
b
c
d
Staphylococcus aureus SR20549. Staphylococcus aureus Smith. Staphylococcus aureus SR3637 (methicillin-resistant). Staphylococcus aureus
NRS271(linezolid-resistant). Enterococcus faecalis SR1004. Enterococcus faecium SR7940 (vancomycin-resistant). Moraxella catarrhalis SR26840.
Streptococcus pneumonoiae SR26207. Streptococcus pneumonoiae SR11031 (penicillin-resistant). Haemophilus influenzae SR27914.
e
f
g
h
i
j
Table 3. Synthesis of Targeted Oxazolidinone Analogues
20−23 Bearing a [1,2,3]Triazole C-5 Side Chain on the
Oxazolidinone Ring
Table 5. In Vivo Therapeutic Effects of Selected
Oxazolidinone Analogues in a Mouse Lethal Systemic
Infection Model Employing S. aureus SR3637
a
therapeutic effect ED50 (mg/kg)
administration route
compd
MIC (μg/mL)
iv
po
13
14
15
16
18
21
23
0.25
0.5
>10 (1: 1.98)
3.05 (1: 4.32)
3.17 (1: 2.46)
1.09 (1: 1.73)
0.34 (1: 2.13)
0.95 (1: 1.73)
N.T.
N.T.
N.T.
0.5
3.05 (1: 2.83)
1.05 (1: 2.83)
0.55 (1: 1.98)
1.02 (1: 2.83)
0.95 (1: 3.87)
0.25
0.25
0.125
0.25
a
Compound 1 was used as reference in each test, and its ED50 value
was shown in the parentheses. N.T.: not tested.
Table 6. PK Properties of in Vivo Potent Analogue 18 in
Mice
parameter
linezolid (1)
18
dose (mg/kg)
Tmax (hr)
67.7
5.56
1.00
4.78
30.93
0.50
Cmax (μg/mL)
AUC∞ (μg·h/mL)
37.00
161.85
compounds did not show marked CYP inhibition even at
concentrations greatly exceeding the antibacterial minimum
inhibitory concentrations, and their inhibition of MAO-A was
less than that of linezolid 1, though compound 18 inhibited
MAO-B slightly more strongly than 1. Compound 21 with the
[1,2,3]triazole C-5 side chain unit on the oxazolidinone ring
showed low inhibition rates of MAO-A and MAO-B.
four subtypes of cytochrome P450 (CYP) isoforms, as well as
MAO-A, and MAO-B. The results are listed in Table 7. Three
Table 4. In Vitro Antibacterial Activity of Compounds 20−23 Bearing a [1,2,3]Triazole C-5 Side Chain on the Oxazolidinone
Ring
minimum inhibitory concentration (μg/mL)
a
b
c
d
e
f
g
h
i
j
compd
S.a.
S.a.
S.a.
S.a.
E.f.
E.f.
2
M.c.
S.p.
S.p.
0.5
H.i.
1
2
2
2
32
4
4
8
4
2
8
4
1
16
4
20
21
22
23
0.25
0.5
0.25
0.125
0.25
0.25
0.5
0. 5
0.25
0.25
0.25
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
≤0.063
0.125
0.25
0.25
0.5
2
0.25
0.5
2
8
4
0.125
0.25
2
0.25
2
a
b
c
d
Staphylococcus aureus SR20549. Staphylococcus aureus Smith. Staphylococcus aureus SR3637 (methicillin-resistant). Staphylococcus aureus
e
f
g
NRS271(linezolid-resistant). Enterococcus faecalis SR1004. Enterococcus faecium SR7940 (vancomycin-resistant). Moraxella catarrhalis SR26840.
h
i
j
Streptococcus pneumonoiae SR26207. Streptococcus pneumonoiae SR11031 (penicillin-resistant). Haemophilus influenzae SR27914.
C
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ACS Medicinal Chemistry Letters
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Table 7. CYP450 Isoform and MAO-A,B Inhibition Indices
of in Vivo-Active Analogues 16, 18, 21, and 23
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The authors declare no competing financial interest.
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