α-substituted hydroxamic acids as novel bacterial deformylase inhibitor-based antibacterial agents

Article abstract of DOI:10.1016/j.bmcl.2003.07.020

We report the synthesis and biological activity of analogues of VRC3375 (N-hydroxy-3-R-butyl-3-[(2-S-(tert-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl] propionamide), an orally active peptide deformylase inhibitor. This study explores the structure-activity relationship of various chelator groups, alpha substituents, P₂′ and P₃′ substituents in order to achieve optimal antibacterial activity with minimal toxicity liability.

Full text of DOI:10.1016/j.bmcl.2003.07.020

Bioorganic & Medicinal Chemistry Letters 13 (2003) 4223–4228
ꢀ-Substituted Hydroxamic Acids as Novel Bacterial Deformylase
Inhibitor-Based Antibacterial Agents
R. Jain,a A. Sundram,a S. Lopez,a G. Neckermann,b C. Wu,a C. Hackbarth,a D. Chen,a
W. Wang,a N. S. Ryder,b B. Weidmann,b D. Patel,a J. Trias,a R. Whitea and Z. Yuana,*
aVicuron Pharmaceuticals (formerly Versicor Inc), 34790 Ardentech Court, Fremont, CA 94555, USA
bNovartis Institutes for Biomedical Research, Inc, 100 Technology Square, Cambridge, MA 02139, USA
Received 29 April 2003; accepted 29 July 2003
Abstract—We report the synthesis and biological activity of analogues of VRC3375 (N-hydroxy-3-R-butyl-3-[(2-S-(tert-butoxy-
carbonyl)-pyrrolidin-1-ylcarbonyl]propionamide), an orally active peptide deformylase inhibitor. This study explores the structure–
0
0
activity relationship of various chelator groups, alpha substituents, P2 and P3 substituents in order to achieve optimal antibacterial
activity with minimal toxicity liability.
# 2003 Elsevier Ltd. All rights reserved.
The increase in bacterial resistance has resulted in a
resurgent interest in the discovery and development of
new classes of antibacterial agents.1ꢀ4 Peptide deformyl-
ase (PDF), which catalyzes the removal of the N-term-
inal formyl group from newly synthesized polypeptides
and is essential to bacterial growth but not required by
mammalian cells, is an attractive target for the design of
new antibiotics. Since deformylase inhibitors have yet to
be used clinically as antibacterial drugs, compounds
targeting this enzyme should avoid cross-resistance with
antibacterial agents.5
Most PDF inhibitors identified to date share a common
structural feature of a ‘chelator+peptidomimetic’ scaf-
fold. Although compounds with many different chela-
tors can inhibit the enzyme, only compounds containing
hydroxamic acid or N-formyl hydroxylamine exhibit
appreciable antibacterial activity.22
VRC3375 (compound A),24 a potent PDF inhibitor with
moderate oral antibacterial activity, was identified from
combinatorial and medicinal chemistry efforts. Com-
pound A contains the hydroxamate metal chelator
pharmacophore, together with an alkyl succinate pepti-
domimetic scaffold. We report here the structure–activ-
ity relationships at different positions of this initial lead
compound.
PDF is a ferrous-containing metallohydrolase,6,7 but a
nickel-containing8 surrogate is routinely used in the
laboratory for testing inhibitors due to its increased
stability. Enzymes from several bacterial species have
been cloned9 and their three-dimensional structures10ꢀ14
and co-crystal structures15ꢀ19 with bound inhibitors
have been determined. As a metallo-enzyme, PDF lends
itself to the well precedented mechanism-based rational
drug design approach.20 Using structural and mechan-
istic information, together with high throughput
screening, several types of potent PDF inhibitors have
been identified.21ꢀ23
In this study, analogues of 2-R-butyl succinic acid-con-
taining PDF inhibitors were prepared and the corre-
sponding SAR was explored at the metal chelating site,
0
0
a-substitution to hydroxamate, and the P2 /P3 -position
(see Fig. 1). The various syntheses employed for the
preparation of inhibitors are outlined in Schemes 1–8.
*Corresponding author. Tel.: +1-510-739-3026; fax: +1-510-739-
3086; e-mail: zyuan@vicuron.com
Figure 1. General structure of succinate hydroxamate analogues.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.07.020

4224
R. Jain et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4223–4228
The synthesis of succinate hydroxamate A began with
construction of the chiral intermediate 2, namely mono-
4-methyl-2-R-butylsuccinic acid.25 Reaction of 4-S-ben-
zyloxazolidinone (1) with hexanoyl chloride (Scheme 1)
in the presence of BuLi provided the corresponding N-
hexanoyl derivative. Alkylation with methyl bromoace-
tate followed by the hydrolysis under LiOH–H2O2 con-
ditions provided the key intermediate 2. Coupling of 2
with Pro-O-t-butyl ester in the presence of HATU fol-
lowed by treatment with hydroxylamine gave the
desired compound A after HPLC purification.
Reaction of 4 with thiophosgene in the presence of
CaCO3 followed by treatment with hydroxylamine gave
N-hydroxythio-urea B. Treatment of 4 with thio-
phosgene followed by reaction with hydrazine provided
hydrazine thiourea C. Similarly, 4 was reacted with
phosgene followed by reaction with hydroxylamine to
yield N-hydroxyurea D.
Succinate hydroxamate analogues, with the common
structure as in Figure 1, were prepared to probe the
SAR at various positions.
N-Cbz protected 2-amino-S-hexanoic acid 3 was cou-
pled with Pro-O-tert.butyl followed by Cbz deprotec-
tion to provide amine intermediate 4, which was further
transformed to different metal chelating functionalities.
Compounds E, F, and G (Scheme 2) were prepared
from an a-S-hydroxy common intermediate 7. Coupling
of acetonide 6, which was prepared from dimethyl
malate 5 in six steps, with Pro-O-t-butyl under PyBOP
condition followed by acetonide opening with sodium
methoxide in methanol afforded 7. Treatment of 7 with
50% aqueous hydroxylamine in dioxane yielded the
corresponding hydroxamate E. Methylation of 7 with
sodium hydride methyl iodide in DMF under Brima-
combe26 conditions followed by hydroxylamine treat-
ment provided the a-S-methoxy derivative F.
Compound 7 was also reacted with sulfur trioxide-pyri-
dine complex27 followed by reaction with hydroxyl-
amine to give O-sulfo compound G.
Synthesis of compounds 9, 10, J, and K from S-hydroxy
intermediate 7 required inverting the stereochemistry at
the a-position. This inversion was accomplished
through the intermediacy of the triflate 8 which was
obtained from 7 via treatment with triflic anhydride in
dichloromethane (Scheme 3). Nucleophilic displacement
of triflate with sodium thiomethoxide followed by reac-
tion with hydroxylamine gave a-R-thio methyl com-
pound I. a-R-Thiol analogue H was obtained by
treatment with thioacetic acid under Mitsunobu reac-
tion conditions followed by hydroxylamine treatment.
Scheme 1. VRC3375 analogues with different metal chelators.
Reagents and conditions: (a) 4-(S)-benzyloxazolidinone, n-BuLi in
hexane, ꢀ78 to 25 ꢁC, 16 h; (b) NaHMDS, methyl bromoacetate, ꢀ78
to 25 ꢁC, 16 h; (c) LiOH, 30% H2O2, THF, H2O, 0 ꢁC, 3 h; (d) Pro-O-
tert-Bu, HATU, DIEA, DMF, 25 ꢁC, 16 h; (e) dioxane, 50% aq
NH2OH, 5 ꢁC, 16 h; (f) 10% Pd/C, H2, ethanol, 16 h; (g) thio-
phosgene, CaCO3, CH2Cl2, 0–25 ꢁC, 2 h; (h) NH2–NH2, methanol,
0 ꢁC, 1 h; (i) phosgene, CaCO3, CH2Cl2, 0–25 ꢁC, 2 h.
Scheme 2. Synthesis of a-(S)-substituted succinate hydroxamates.
Reagents and conditions: (a) LDA, crotyl bromide, THF, ꢀ78 to
25 ꢁC, 16 h; (b) 10% Pd/C, H2, ethyl acetate, 16 h; (c) NaOH, metha-
nol, water, 20 h; (d) 2,2-dimethoxypropane, p-TSA, 16 h; (e) PyBOP,
HOBT, DIEA, CH2Cl2, 16 h; (f) methanol, 0.5 M sodium methoxide, 0
ꢁC, 1 h; (g) dioxane, 50% aq NH2OH, 5 ꢁC, 16 h; (h) NaH, methyl
iodide, DMF, 3 h; (i) sulphur trioxide–pyridine complex, DMF, 0–
25 ꢁC, 16 h.
Scheme 3. Synthesis of a-(R)-substituted succinate hydroxamates
Reagents and conditions: (a) triflic anhydride, pyridine, CH2Cl2, ꢀ20
to 0 ꢁC, 2 h; (b) tetrabutyl ammonium benzoate, toluene, ꢀ30 to 0 ꢁC,
2 h; (c) methanol, sodium methoxide, 0 ꢁC, 4 h; (d) dioxane, 50% aq
NH2OH, 5 ꢁC, 16 h; (e) NaH, DMF, methyl iodide, 4 h; (f) triphenyl-
phosphine, diisopropylazo dicarboxylate, thioacetic acid, THF, 16 h;
(g) sodium thiomethoxide, DMF, 16 h.

R. Jain et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4223–4228
4225
Similarly, nucleophilic displacement of triflate 8 with
tetrabutylammonium benzoate28 in toluene followed by
de-O-benzoylation with sodium methoxide in methanol
furnished a-R-hydroxy compound 10. Hydroxylamine
treatment of 10 resulted in the formation of compound
J. Compound K was prepared via similar reaction
sequences as described for the synthesis of F from 7.
Nucleophilic displacement of the triflate 8 with Tris
(dimethylamino)sulfur(trimethylsilyl)difluoride (TASF)29
in methylene chloride followed by hydroxylamine treat-
ment afforded a-R-fluoro analogue M (Scheme 5). A
similar sequence of reaction was adopted for the
preparation of N from 10 as described earlier for the
synthesis of M from 7.
To access compounds L-1–L-6 (Scheme 4), triflate 8 was
treated with sodium azide in DMF to provide a-R-azido
compound 11, which on subsequent hydrogenolysis
afforded amine derivative 12. Hydroxylamine treatment
of 11 and 12 provided the corresponding hydroxamates
L-1 and L-2. N-Acylation of 12 with mixed anhydride of
formic acid/acetic anhydride and pyridine/acetic anhy-
dride followed by reaction with hydroxylamine afforded
N-formyl (L-3) and N-acetyl (L-4) analogues, respec-
tively. Amino compound 12 was also treated with ethyl
isocyanate and ethyl sulfonyl chloride followed by
reaction with hydroxylamine to give urea (L-5) and sul-
fonamide (L-6) hydroxamates, respectively.
The synthesis of inhibitors containing difluoro (O),
keto (P), and oxime (Q) functionalities at the a-posi-
tion was achieved from a common a-oxo intermidate
13 (Scheme 6).
The synthesis of a-keto compound (13) was achieved by
oxidation of a-S-hydroxy intermediate 7 with pyr-
idinium dichromate30 in methylene chloride. Fluorina-
tion of 13 with (diethylamino)sulfur trifluoride
(DAST)31 followed by reaction with hydroxylamine
afforded bis-fluoro derivative (O), whereas treatment of 13
with hydroxylamine furnished a mixture of P and Q that
were isolated by semi-preparative HPLC purification.
0
SAR was also examined at P2 -position by substituting
proline with other four- to six-membered cyclic amino
acids 14–17 (Scheme 7). The protection of the amino
functionality in these amino acids with a Boc group
followed by treatment with propylamine under HATU
condition and removal of Boc group with 4 M-HCl in
dioxane provided the key amine intermediates 18–21.
Scheme 6. Synthesis of a-keto, difluoro and oxime substituted succi-
nate hydroxamates. Reagents and conditions: (a) pyridinium dichro-
mate, CH2Cl2, 4 A molecular sieves, 16 h; (b) N,N-dimethylamino
sulfur trifluoride, CH2Cl2, ꢀ50 to 25 ꢁC, 16 h; (c) dioxane, 50% aq
NH2OH, 5 ꢁC, 16 h.
Scheme 4. Synthesis of a-(R)-N and S-substituted succinate hydrox-
amates. Reagents and conditions: (a) NaN3, DMF, 16 h; (b) dioxane,
50% aq NH2OH, 5 ꢁC, 16 h; (c) 10% Pd/C, H2, ethanol, 16 h; (d)
HCOOH–Ac2O, 5 ꢁC, 16 h; (e) C5H5N, Ac2O, 16 h; (f) ethyl isocya-
nate, pyridine, CH2Cl2, 0–25 ꢁC, 3 h; (g) ethyl sulfonyl chloride, pyri-
dine, CH2Cl2, 0–25 ꢁC, 3 h.
Scheme 5. Synthesis of a-fluoro substituted succinate hydroxamates
Reagents and conditions: (a) triflic anhydride, pyridine, CH2Cl2, ꢀ20
to 0 ꢁC, 2 h; (b) tris(dimethylamino)sulfur(trimethylsilyl) difluoride,
CH2Cl2, ꢀ50 to 5 ꢁC, 16 h; (c) dioxane, 50% aq NH2OH, 5 ꢁC, 16 h.
Scheme 7. Synthesis of proline mimetics. Reagents and conditions: (a)
Boc anhydride, NaHCO3, dioxane, water, 16 h; (b) HATU, DIEA,
DMF, 25 ꢁC, 16 h; (c) 4 M HCl in dioxane, 16 h; (d) dioxane, 50% aq
NH2OH, 5 ꢁC, 16 h.

4226
R. Jain et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4223–4228
Table 2 summarizes the assay results for compounds
with general structure of Figure 1 and as described in
Schemes 2–8. In addition to the summary of the enzyme
inhibition and antibacterial activities of these com-
pounds, the table also includes the inhibition of a
mammalian metalloprotease (MMP-7) and general
cytotoxicity (K562) data. Both parameters are critical in
assessing the potential of these compounds as anti-
bacterial drugs.
Analogues of a-substituted hydroxamate were prepared
to identify the most suitable groups at this position (E–
Q). It is apparent that selected small substituents, such
as hydroxy (E) and fluoro (N), can be tolerated; how-
ever, large groups such as methoxy (F), O-sulpho (G),
sp2-hybridized carbon (P and Q), thiol (H), and nitro-
gen-containing groups (L) result in loss of activity.
While no special preference was observed for the con-
figuration of a-hydroxy substitution (E and J), the S-
configuration is preferred in the a-fluoro series (M and
N). The R-isomers in a-fluoro series Yc and Ym are 10–
20-fold less active in PDF inhibition and antibacterial
activity than the corresponding S-isomers.
Scheme 8. ‘One-pot’ hydroxamate synthesis. Reagents and conditions:
(a) HATU, DIEA, DMF, 16 h; (b) 90% aq TFA, CH2Cl2, 2 h; (c)
dioxane, 50% aq NH2OH, 5 ꢁC, 8–32 h; (d) 10% Pd/C, H2, ethyl ace-
tate, 16 h.
0
Table 1. In vitro activity of VRC3375 analogues containing different
metal chelatorsa
At the P2 -postion, cyclic 4–6-member amino acid were
incorporated. Among the analogues tested, azetidine
(R) and proline analogues (S) are preferred whereas the
corresponding six-membered pipecolinic inhibitor (U) is
significantly less active. The replacement of proline with
sulfur-containing thiazolidine (T) resulted in complete
loss of antibacterial activity.
Compd
MIC (mg/mL)
IC50 (mM)
SPN
SAU
HIN
PDF
MMP-7
K562
A
B
C
D
8–16
>64
>64
16–32
0.5–4
>64
>64
2–4
>64
>64
32–64
0.002
2.9
0.59
0.72
>200
>200
>200
109
>200
>200
>200
>200
32->64
0
aryl or heteroaryl groups at the P3 position considerably
SAR of the P3 substitution was also explored. In general,
0
aMIC values are expressed in mg/mL for SPN (S. pneumoniae, 3
strains), SAU (S. aureus, three strains), and HIN (H. influenzae, 3
strains). Enzyme inhibition and cytotoxicity are expressed as IC50
(mM) for PDF (E. coli Ni-containing peptide deformylase), MMP-7
(matrix metallo protease-7), and K562 (human leukemia cell K562
(ATCC #CCL-243)].
improved antibacterial activity. When comparing close
analogues, the data suggest that increasing hydrophobicity
0
at the P3 position results in increased activity against
Streptococcus pneumoniae with concomitant decreased
activity against Heamophilus influenzae (e.g., V-a–V-e, X-j–
X-l, and W-u–W-v). A proper hydrophilic and hydro-
phobic balance is required for maximal antibacterial
activities with reduced toxicity. SAR in the V series sug-
gests that hydrophobic groups improve antibacterial
activity, with a concomitant increase of cytotoxicity.
This observation is also true for the compounds with
various aliphatic, cyclic, aryl and heteroaryl amines in
the a-hydroxy (W) and a-fluoro (X) hydroxamate series.
The tertiary amide substitutions dramatically reduced
the cytotoxicity and MMP-7 inhibition but mainain the
PDF inhibition 0 and antibacterial activity (X-q–X-t).
Pyrrolidine at P3 (X-r) shows the best combination of in
vitro potency, cytotoxicity and selectivity.
The condensation of these amines with acetonide 6
under HATU condition followed by reaction with
hydroxylamine afforded the corresponding hydrox-
amates R–U.
A cross section of hydrophilic and hydrophobic alipha-
tic, alkaryl, aryl and heteroaryl amines were incorpo-
0
rated to explore SAR at P3 in the a-hydroxy and a-
fluoro succinate hydroxamate series. This was accom-
plished by developing an efficient ‘one-pot’ method
(Scheme 8) for the synthesis of the desired inhibitors.
The coupling of acid building blocks 22, 25, 27 (pre-
pared from the corresponding t-butyl ester) and 23
(prepared from the O-benzyl ester) with the desired
amines followed by reaction with hydroxylamine
afforded the corresponding hydroxamates V–Y.
Selected compounds were scaled up and subjected to in
vivo efficacy and pharmacokinetics studies in mice
(Table 3). Although a-fluoro analogues in general exhi-
bit a better in vitro profile than the corresponding a-
hydroxy compounds, the reverse was true for the in vivo
efficacy and PK profile.
All biological evaluation was carried out as described
previously.17 In vitro data of VRC3375 analogues with
different chelators (Table 1) indicates that hydroxamate
(A) provides the best enzyme inhibition and anti-
bacterial activity amongst various chelators tested.
In conclusion, we have identified a-substituted (hydroxy
and fluoro) hydroxamates as a new class of PDF inhibitor-
based antibacterial agents.

R. Jain et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4223–4228
4227
Table 2. Summary of in vitro activities of succinic hydroxamate analogues (see Fig. 1 for general structure).
0
0
Compd
a-
P2
P3
SPN(3)
SAU(3)
HIN(3)
PDF
MMP-7
K562
V-a
V-b
V-c
V-d
V-e
V-f
V-g
V-h
E
J
F
G
N
M
H
H
H
H
H
H
H
H
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-aze.
l-pro.
l-thiaz.
l-pip.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
l-pro.
a
b
c
d
e
f
g
h
i
i
i
i
i
16
0.13–0.5
0.13–0.5
0.06–0.13
0.06–0.25
0.06–0.25
0.06–0.25
1–2
8
8–16
64
16–32
2–4
4–8
0.06–0.25
0.06–0.13
0.06
0.06–0.25
0.25–1
0.06–0.25
2–16
0.25–1
0.5–4
32–>64
1–4
0.25–1
2–8
0.25–0.5
0.5–1
0.5–2
0.5–2
1–4
0.5–2
0.5–2
4–8
4–16
2–4
32–>64
16–32
1–2
16–32
4–8
2–8
>64
16–32
0.5–1
4–8
0.5–1
1–2
2
0.12–0.5
4–8
4–8
2–4
1–2
8–32
2–4
1–4
1–2
0.25–1
1–4
2–4
4–16
16
2
2–8
4–8
0.01
>200
34
35
11
4
13
5
45
28
128
84
7
3
2
2
0.009
0.012
0.003
0.009
0.029
0.021
0.017
0.001
0.006
0.05
1
0.09
100
>28
NT
6
112
>28
NT
14
S-OH
R-OH
R-OMe
S-OSO3H
S-F
NT
0.03
>200
111
139
>200
105
>200
196
133
>32
35.3
23.9
13.1
38.1
186.7
61.3
16.2
0.9
0.002
0.016
0.0067
0.008
0.277
0.0067
0.001
0.027
0.013
0.016
0.013
0.0013
0.016
0.007
0.009
0.002
0.002
0.001
0.001
0.029
0.02
0.022
0.013
0.006
0.006
0.01
0.008
0.008
0.007
0.008
0.003
0.017
0.024
0.013
0.004
0.005
0.003
R-F
i
j
j
j
16–32
1–4
4–16
>64
16
R
S
T
U
S-OH
S-OH
S-OH
S-OH
S-F
R-F
S-F
S-F
S-F
S-F
R-F
S-F
S-F
S-F
R-F
S-F
S-F
S-F
S-F
S-F
S-F
S-F
S-F
S-OH
S-OH
S-OH
S-OH
S-OH
S-OH
S-OH
S-OH
S-OH
S-OH
S-OH
S-OH
0.5–4
1–4
16–>64
8–>64
2–4
44
83
13
j
X-a
Y-a
X-j
X-k
X-l
X-m
Y-m
X-n
X-o
X-c
Y-c
X-p
X-f
X-q
X-r
X-s
X-t
Xu
X-v
W-a
W-j
W-l
W-w
W-x
W-o
W-q
W-r
W-s
W-t
W-u
W-v
a
a
j
k
l
m
m
n
o
c
c
p
f
2–4
>200
>200
>200
102.9
21.4
>200
97.5
>200
32–64
0.25–1
0.25–0.5
0.25–0.5
0.25–2
4–8
4–16
0.5–2
0.5–1
0.12–0.5
0.5–1
2–8
2–16
4–16
0.13–0.5
0.13–0.25
1–2
0.06–0.13
0.06–0.13
1
0.5–1
0.13–0.5
0.25–1
0.13–0.5
0.13–0.5
0.5–2
0.25–1
0.25–2
1–8
64.9
24.1
33.7
6.7
5.8
0.1
0.3
4.2
>200
q
r
s
>200
>200
>200
>200
23.6
26.7
63.5
43.7
20.5
>29
>27
15.4
>200
>200
108.4
183.3
9.7
1–2
>200
>200
>200
66.5
122.2
>200
105
21.6
180.8
177.9
49.6
>200
>200
>200
0.5–2
0.25–2
0.06–0.13
0.06–0.25
16–32
1–4
1–4
4–16
4–16
1–2
4–16
8–16
4–32
8
0.25–1
1–4
t
u
v
a
j
0.25–0.5
0.25–1
2–4
4–16
l
0.5–2
4–16
1–4
1–4
1–4
2–4
1–4
8
w
x
o
q
r
s
t
u
v
4–16
8–16
8–32
2–8
1–4
16–32
4
80.9
109.7
>200
0.06–0.25
0.25–4
32–64
64
17.1
Table 3. In vivo efficacy and PK parameters of selected succinate hydroxamate PDF inhibitors
Compd
A
W-a
X-a
W-r
X-r
W-c
X-c
a
ED50 (mg/kg)
iv
po
PKb
14
25.6
1.7
NT
1.2
10.2
1.1
>10
5.0
>12.5
3.3
12
2.3
28.6
t(1/2) (h) iv
AUCb (ng h/mL ) iv
t(1/2) (h) po
AUCc (ng h/mL) po
Oral bioavailability (%)
0.3
172
0.4
16.5
9.6
1
290
1.3
29.1
10
0.6
154
1.5
16.9
10.9
0.5
546
1.5
33.1
6.1
0.7
144
2.0
10.7
7.5
0.3
86.5
NT
13.0
15.1
0.4
89.4
1.7
4.5
5
a50% Effective dose in mouse S. aureus septicemia infection model; The studies were carried out as previously described17 and the data represent
results of single experiments.
bIntravenous (iv) dosing at about 2 mg/kg and oral (po) dosing at 10 mg/kg.
cAUC values normalized to 1 mg/kg dose.

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R. Jain et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4223–4228
17. Hackbarth, C. J.; Chen, D. Z.; Lewis, J. G.; Clark, K.;
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