New classes of antibacterial oxazolidinones with C-5, methylene O-linked heterocyclic side chains

Article abstract of DOI:10.1016/j.bmcl.2003.07.033

Exploration of the structure-activity relationships of the traditional C-5 acetamidomethyl side chain of the oxazolidonone antibacterials has yielded new, potent series of compounds of which the first examples, the O-linked iosoxazoles are described in detail, leading to the selection of the pre-clinical candidate AZD2563.

Full text of DOI:10.1016/j.bmcl.2003.07.033

Bioorganic & Medicinal Chemistry Letters 13 (2003) 4179–4186
New Classes of Antibacterial Oxazolidinones with C-5, Methylene
O-Linked Heterocyclic Side Chains
Michael B. Gravestock,a,* David G. Acton,b Michael J. Betts,b Michael Dennis,b
Glenn Hatter,b Alexandra McGregor,b Michael L. Swain,b R. Geoffrey Wilson,b
Lisa Woodsb and Alan Wookeyb
aAstraZeneca R&D Boston, Infection Discovery, 35 Gatehouse Park, Waltham, MA 02451, USA
bAstraZeneca, Cancer and Infection Discovery, Alderley Park, Macclesfield, Cheshire SK104TG, UK
Received 30 May 2003; accepted 30 July 2003
Abstract—Exploration of the structure–activity relationships of the traditional C-5 acetamidomethyl side chain of the oxazolido-
none antibacterials has yielded new, potent series of compounds of which the first examples, the O-linked iosoxazoles are described
in detail, leading to the selection of the pre-clinical candidate AZD2563.
# 2003 Elsevier Ltd. All rights reserved.
The emergence of multidrug-resistant strains of Gram-
positive pathogens presents an increasingly urgent clin-
ical problem.1,2 Resistance to b-lactam antibiotics in
Streptococcus pneumoniae strains now ranges from 20 to
80% world-wide. In addition to the widely encountered
methicillin-resistant Staphylococcus aureus (MRSA) and
The attractive drug-like traits of the oxazolidinone ser-
ies encouraged further work in the area, for example the
patents by Pharmacia-Upjohn,9 Bayer10 and AstraZen-
eca11 amongst others. This work led to the clinical can-
didates eperezolid 2 and linezolid 3 having improved
potency and tolerability over the early compounds.12
The first drug in this class, linezolid was approved for
sale as ZyvoxTM in the USA in 2000.
methicillin-resistant
Staphylococcus
epidermidis
(MRSE), vancomycin-resistant enterococci (VRE) have
been a significant and increasing threat for some years
to patients in the USA and Europe.3 Yet more alarming
is the appearance in recent years of staphylococcal
strains with reduced susceptibility to vancomycin and
related glycopeptides (GISA).4 Until recently, these
antibiotics represented the agents of last resort in some
clinical situations.5 When the oxazolidinone class of
anti-Gram-positive agents were identified by Dupont
workers in the early 80’s,6 they represented the first truly
new class of synthetic antibacterial agents for nearly 30
years. Studies7 on the first candidate drug DuP 721 1
revealed many attractive features, including good oral
activity and a novel mode of action via inhibition of the
initiation of protein synthesis.8 However, this and other
early compounds were poorly tolerated in animals, and
DuP 721 did not progress through development (Fig. 1).
In keeping with their novel site of action, the oxazolidi-
nones are effective against all Gram-positive strains, and
show no cross resistance with other classes of protein
synthesis inhibitor. The target sites on the 50S ribosome
have been recently identified.13ꢀ15
The many attractive traits of the oxazolidinone series
has encouraged further work in the area, and the patent
literature reveals extensive chemical programs exist. How-
ever, some linezolid-resistant enterococcal isolates have
recently already been isolated after intensive linezolid
*Corresponding author Tel.:+1-781-839-4636;. e-mail: mike.
gravestock@astrazeneca.com
Figure 1. Oxazolidinone clinical candidates with C-5 acetamidomethyl
side chains.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.07.033

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M. B. Gravestock et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4179–4186
therapy16 and the first reports of resistant S. aureus
strains have been made.17 This unexpectedly early resis-
tance development (although only isolated examples of
such strains at present) emphasises the need for further
exploration of features of the oxazolidinone series to
overcome these deficiencies. In our work reported
here,18 we describe the first of several fundamental
changes to the oxazolidinone C-5 side chain which may
give promise for such improvements.
tion of the N-aryl function, while leaving the acetamide
side chain relatively unexplored. The only major excep-
tions were the discovery by workers at Bayer, Pharma-
cia-Upjohn and others that sulfur isosteres of the
acetamidomethyl side chain such as thioamides, thiour-
eas or thiocarbamates can also give high potency com-
pounds,21 often exceeding that of the acetamide
analogues.
As part of the AstraZeneca oxazolidinone discovery
programme, we were interested in the nature of the H-
bond and steric interactions which were apparently
optimised in the acetamidomethyl group. In particular
we were intrigued by the observation, noted in passing
in the first Dupont publication,19 that substitution of
the amide hydrogen by methyl abolishes activity. Simi-
larly, methylation of the adjacent methylene to the NH
function also abolishes activity.22 On first sight, this
suggests a critical need for an H-bond donor residue on
the side chain. An alternative explanation is that alkyl-
ation at either position may give rise to an important
change in the conformation of the amide side chain,
which might agree with the earlier findings of very lim-
ited allowable alterations to the amide substituents.19
The SAR around the oxazolidinone C-5 side chain
group was extensively explored19 by the DuPont group
in their early studies, mostly with the acetyl group of
DuP 721 as the aryl substituent. They showed that even
minor changes of the acetylaminomethyl side chain to
formylamino or cyanoacetylamino, or to the methyl
carbamate and simple urea, caused a 4- to 8-fold
increase in MICs against S. aureus strains. Bulkier
groups as in the isobutyramide, or tert-butyl carbamate
analogues, caused an even greater loss of potency. The
conclusion was drawn that there are both specific and
sterically restricted requirements in the vicinity of the
oxazolidinone side chain binding site. In contrast, these
early studies20 revealed much greater flexibility in the
variation allowed on the N-aryl ring. The outcome of
this early SAR was to direct much subsequent and more
recent work to the examination of the permitted varia-
In order to re-examine these effects we prepared various
oxazolidinone side chain amide analogues using initially
Figure 2. Dihydropyranyl oxazolidinones with alternate side chains.
Scheme 1. Preparation of dihydropyranyl oxazolidinones: (a) DIAD, Ph3P, 4-hydroxypyrimidine, 49%; (b) MeSO2Cl, Et3N, 85%; (c) NaH, DMF,
2-chloropyrazine, 45%; (d) NaH, DMF, 2-hydroxypyridine, 5—29% + 6—15%; (e) NaH, DMF, 3-chloropyridazine, 21%; (f) 30% Pd/C, ammo-
nium formate, ethanol, rt, 41%.

M. B. Gravestock et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4179–4186
4181
the aryl oxazolidinone with a known active 4-(dihy-
dropyranyl)-aryl substituent. Thus, our first target was
the cyclic amide 5. A simple alkylation of pyridine to give
5 also yielded the O-alkylation product 6 (cf. Table 1).
The target pyridone 5 had poor MICs against S. aureus
strains (mean values of 32 mg/mL) compared with the
acetamide 4 (mean 0.13 mg/mL), but the O-linked
pyridine 6 unexpectedly had MICs of 1 mg/mL, close to
that of linezolid (Fig. 2).
This result was surprising for two reasons. It conflicted
with the expected spacial limitations of the side chain-
binding region for the oxazolidinones and also demon-
strate that substituents without an H-bond donor
Table 1. In vitro MIC’s and in vivo antibacterial activity of six-ringed heterocycles
Compd
Heterocycle R
NHCOCH3
S. aureus
Oxford
S. aureus
MRQR
S. aureus
CNSMRa
S. pyogenes
PS.b
E. faecalis
MTTc 10
mg/kg
MTTc 5
mg/kg
4
5
0.13
32
0.25
32
0.13
32
0.13
32
0.13
64
1.34
0.6
6
0.5
1
4
1
4
2
2
8
0.15
0.0
14
15
16
17
18
19
20
21
22
23
24
25
4
16
8
64
32
32
64
2
2
2
2
4
1
2
2
4
4
0.34
0.35
0.23
0.22
1
1
1
1
2
16
16
16
32
64
2
2
2
4
4
8
16
16
8
32
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
MICs are recorded in mg/L. Results are expressed as log reductions compared to control.
aCoagulase ꢀve Staph. Methicillin resistant.
bPenicillin sensitive.
cMouse thigh test.

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M. B. Gravestock et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4179–4186
Table 2. In vitro MIC’s and in vivo antibacterial activity of five-ringed heterocycles
Compd
Structure
S. aur.
Oxford
S. aur.
MRQR
S. aur.
CNSMRa
S. pyog.
PS.b
E. faec.
MTTc 10
mg/kg
MTTc 5
mg/kg
26
0.5
0.5
0.5
0.5
1
0.06
ꢀ0.07
27
28
29
30
31
32
33
34
35
36
37
38
1
2
2
4
4
128
0.5
0.5
0.25
0.5
0.25
1
ꢀ0.45
8
16
32
16
0.25
0.25
0.13
0.13
0.06
0.25
4
0.25
0.25
0.25
0.25
0.13
0.5
4
0.25
0.25
0.25
0.25
0.13
0.5
8
0.5
0.25
0.25
0.25
0.13
1
0.21
0.45
1.21
1.72
1.11
1.14
0.01
0.11
0.78
1.05
0.42
0.43
8
8
1
2
2
4
2
0.2
0.03
16
16
32
16
32
1
2
1
2
2
MICs are recorded in mg/L. Results are expressed as log10 reductions compared to control.
aCoagulase –ve Staph. Methicillin resistant.
bPenicillin sensitive.
cMouse thigh test.

M. B. Gravestock et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4179–4186
4183
Scheme 2. Synthesis of 4-(tetrahydropyridinyl)-aryl oxazolidinone isoxazoles: (a) DIAD, Ph3P, 3-hydroxyisoxazole, 75%; (b) ACE chloride, then
heat/methanol; (c) acetoxyacetyl chloride, DMAP, Et3N, DCM; (d) K2CO3, methanol.
function could bind with apparently similar energies to
the acetamide group. We accordingly undertook to fur-
ther investigate the properties of a variety of O-linked
heterocycles at the C-5 terminous.
isomers of glycidic acid gave flexible access to various
intermediates 13, which were taken on to disubstituted
propionamides at different oxidation levels such as 55.
The heterocycles attached at C-50 were either available
commercially, or were obtained by literature procedures.
The preparation of the 4-(dihydropyranyl) aryl series
was straight forward. From previous work, we had
available23 the alcohol 7 and its derived mesylate 8,
hence the reaction with 2-pyridone promised a quick
entry to the original goal of the N-linked compound (5,
Scheme 1). Having established our preferred interest in
the oxygen linked series 6, other routes were examined.
Displacement of a halogen from an appropriate halo-
heterocycle after generation of an anion at C-50 was
possible, though low yielding, but represented a quick
entry to varied substituted heterocycles such as 18
because of ready intermediate availability. The best
general approach was to use the Mitsunobu reaction,
exemplified by 17. Together, these routes allowed the
ready preparation of the series of pyridines and related
diazines listed in Table 1; and using the latter procedure
the proportion of N-alkylation versus O-alkylation was
minimal. Access to the parent pyridazine 16 was
achieved by dechlorination of the product 9 obtained
from 3,6-dichloropyridazine. The phenoxy analogue 25
was prepared for comparison by displacement of the
mesylate.
Previous structure–activity analysis of the in vitro anti-
bacterial activity on oxazolidinones with acet-
amidomethyl side chains had shown that the
dihydropyranyl substituent provided a sensitive probe
of potential activity as other variations were made.23
Accordingly, this substitution was used for a compar-
ison of the effects of changing the side chain, after the
initial surprise of good activity with the 2-pyridyloxy
compound (6, Table 1). Movement of the pyridyl nitro-
gen to the 3-(14) or 4-position (15) led to decreases in
activity, and while the diazines (16–18) were comparable
in activity to the lead, there was a marked drop for the
2-pyrimidine 19. Addition of methyl substitution to the
pyridine ring of 6 led to a decline in activity as the group
became closer to the ring nitrogen (20, 21, 22), suggest-
ing an H-bond acceptor role for this atom, in line with
the documented negative effect of such substituents
adjacent to H-bonding centres. The similar negative
effect on activity of electron withdrawing groups (23)
supported this hypothesis, as did the loss of activity
when the lone pair was absent in the N-oxide 24, or the
ring nitrogen was removed in the phenyloxy compound
25. This must, however, be an over simplification, given
the retention of at least some activity in the positional
isomers of pyridine 14, 15.
It seemed likely that five-membered heterocycles might
be superior replacements for the six-membered analo-
gues because of the presumed steric limitations at the
binding site. The Mitsunobu reaction again gave ready
access to the isoxazole substituted analogues, and var-
ious analogous heterocycles in analogous conditions to
those in Scheme 1. Because of our findings in the acet-
amide series23 at C-50, we then switched our attention to
the more versatile 4-( tetrahydropyridyl)-aryl analogues
of the above compounds. Starting from the N-benzyl
alcohols 10, the key isoxazolyloxy amines 12 could be
prepared, and then acylated by a wide variety of groups
(e.g., 44, Scheme 2). Some early indications that
difluorinated compounds might be more potent led us
to prepare compounds in both series. A recurrent prob-
lem with the highly crystalline oxazolidinones is poor
aqueous solubility, but the availablity of 12 gave ample
opportunity to introduce hydrophilic groups and vary
the physical properties of the molecules. The stereo-
Given the presumed size constraints on the amide func-
tion in the acetamidomethyl series, it was hoped that the
effect of smaller five-membered heterocycles with iso-
xazole (a well known amide isostere) as an early choice
would give improved potencies. The data of Table 2
show that it is indeed an effective replacement, with the
parent dihydropyran (26) showing increased activity over
6, to become comparable to linezolid. Substitution on the
ring was again detrimental (27, 28), and given the poor
accessibility of substituted isoxazoles was not pursued.
Interestingly, given the improved antibacterial activity
of thioisosteres in the amide series,21 the same sulfur
effect is observed with these heterocycles. Thus iso-
thiazole (29) and thiadiazoles in particular (30–34) led

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M. B. Gravestock et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4179–4186
Table 3. In vitro MIC’s and in vivo antibacterial activity of isoxazole series
Compd
R/(H,F)
S. aur.
Oxford
S. aur.
MRQR
S. aur.
CNSMRa
S. pyog.
PS.b
E. faec.
MTTc
10 mg/kg
MTTc
5 mg/kg
39
40
41
42
CH3CO–/H
HCO–/F
CH3–/F
0.5
0.25
2
0.5
0.5
2
0.5
0.5
2
1
0.5
1
1
1
4
8
0.81
0.43
0.17
ꢀ0.01
HOCH2CH2–/H
4
8
4
2
0.07
43
44
/F
0.5
1
1
1
2
1
0.28
1.20
HOCH2CO–/H
0.25
0.5
0.5
0.5
0.71
0.63
45
46
47
48
49
/H
/F
0.25
0.25
0.25
0.5
0.5
0.5
0.25
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.25
0.25
1
1
1.04
0.98
0.55
1.16
1.02
0.5
0.5
1
0.70
0.31
0.64
0.49
/F
/H
0.5
1
1
50
51
HOCH2CS–/H
(HOCH2)2CHCO–/F
0.25
0.5
0.5
0.5
0.25
0.5
0.25
0.5
0.5
1
0.07
0.41
ꢀ0.01
0.37
52
53
54
55
56
57
58
3
/H
/F
0.25
1
0.5
2
0.5
2
0.5
1
1
0.48
0.27
2
/F
0.5
1
1
1
2
0.5
0.25
1.02
0.10
/F
0.25
0.25
0.25
0.25
0.5
0.25
0.5
0.5
0.5
1
0.25
0.25
0.5
0.25
0.5
0.5
0.25
0.5
0.5
1
0.5
0.5
1
1.42
0.32
/F
/F
/F (OH side chain)
Linezolid
1
1.01
1.40
0.59
0.05
1
MICs are expressed in mg/L. Results are log10 reductions from control.
aCoagulase ꢀve Staph. Methicillin resistant.
bPenicillin sensitive.
cMouse thigh test.

M. B. Gravestock et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4179–4186
4185
to exceptional potency, with 33 showing a mean MIC of
0.1 mg/mL. The parents of many of these simple five-
ring hydroxythiaheterocycles are not readily accessible,
so the results for substituted compounds such as 35 and
36, taken in conjunction with those of 27 did not
encourage us to pursue them further. The isomeric
isoxazole 38 was very promising (compare to 27), but
the parent was too reactive towards ring opening to
have further potential. The in vivo activity of these
thiaheterocycles was however limited (see below) so
further optimisation concentrated on the isosoxazoles in
the tetrahydropyridine series.
The thioamide 50, though potent in vitro, was inactive
in vivo, which was probably to be expected due to oxi-
dative metabolism at sulfur. The tetrahydropyridine-
containing thiadiazoles 31–34 showed anomalous beha-
viour. Some such as 32 seemed to be showing in vivo
effect commensurate with their in vitro potency, but
others like 33 were modest in vivo relative to their in
vitro activity. When blood levels were determined, it
became a surprise that any in vivo activity had been
seen, since the compounds were cleared at rates com-
parable to dihydropyrans. Experiments involving incu-
bation of 34 with rat hepatocytes demonstrated cleavage
of the thiadiazole heterocycle to the side chain alcohol
58, presumably via an oxidative mechanism.
Further isoxazole compounds are displayed in Table 3.
Simple acetyl (39) and formyl (40) derivatives were
roughly equivalent to the pyran in potency, but alky-
lated compounds (e.g., 41–43) were distinctly worse.
Introduction of the hydroxyacetyl motif of eperezolid
(44), and extending the theme to dihydroxypropyl ana-
logues (45–47) gave compounds with MICs significantly
better than those found for linezolid. Stereochemistry in
the side chain made no difference to activity (cf 46 and
47, or 48 and 49). In spite of some early indications that
difluoro compounds might be more potent, this was not
generally the case (cf 45, 46). Where good potency was
found for a particular substitution pattern, both series
were made in the search for what could be key differ-
ences in pharmacokinetics. The increased in vitro activ-
ity in 50-thioacetamido-methyl compounds21 mentioned
above led us to prepare the thioamide (50), which had
superior potency to its oxygen analogue 44, but like the
sulphur-containing heterocycles discussed above, was
poor in vivo.
Conclusions
Our efforts to understand the factors necessary for bio-
logical activity in the conventional C-50 acetamido sub-
stituted oxazolidinones has led to the discovery that this
feature can be replaced by a wide range of five- and six-
membered oxygen linked heterocycles. Limited sub-
stitution of the heterocycle is possible, and five-mem-
bered rings are more potent in terms of MIC than six.
The steric limitations hypothesised on the basis of work
in the acetamide series were shown to be present, but to
be more subtle than an effect of mere molecular volume,
the detailed shape of the substituent being also impor-
tant. It also becomes apparent that the loss of activity
on methylating the nitrogen in the amide series is unli-
kely to relate to the loss of an H-bond interaction, but
must relate to a steric effect, either directly from its own
bulk, or indirectly by changing the conformation of the
side chain to one in which other critical binding
interactions are lost.
One of the limiting features of these compounds for in
vivo work was their aqueous solubility. Incorporation
of potential solubilising substituents as in 51–54 gave
active compounds but of lesser potency. More promis-
ing were compounds with oxidised sulfur such as 55–57,
and these were one of several groups selected for further
study.
Good activity in vivo can be obtained with the correct
combination of substituents on oxazolidinone and pen-
dant phenyl rings, but some of the thioheterocycles
most potent in vitro give poor or misleading in vivo
results as a consequence of their rapid metabolism.
Most promising are the compounds bearing aryl tetra-
hydropyridine substitutents. With appropriate acyl
functions such as dihydroxypropanoyl and close rela-
tives, compounds can be obtained with high in vitro and
in vivo potency and excellent pharmacokinetics in mice.
One such compound 46 has been taken forward to early
clinical studies as AZD2563. A separate more detailed
desciption of the properties of this compound will be
given elsewhere.
Activity in vivo was assessed using a mouse thigh model
with a localised S. aureus infection. The lead six-mem-
bered heterocycles 6, 17 and 18 and the first isoxazole 26
showed at most marginal activity in this test. Dosing of
these compounds in mice showed that these compounds
were subject to rapid clearance. This seems to be a gen-
eric problem with the dihydropyran series, which we
had also noted in earlier work with C-50 amides. The
earliest compounds with sulphur-containing hetero-
cycles at C-50, 29, 30, were also poor in vivo, but
potentially suffered also from the presence of the pyr-
anyl function 30.
Finally, related studies on NH-linked analogues24 to the
above series have shown that comparable or more
potent compounds are possible. The potency increases
are in the order of 2–4-fold depending on Gram-positive
target strain. It seems therefore that residual hydrogen-
bond acceptor bonding potential remains in this series.
Further, other studies on direct, ring N-linked azole
heterocycles,25 show that additional potent antibacterial
series are possible. Thus, all three series in total
demonstrate a potential for oxazolidinone analogues
with improved potencies and other properties over
A simple example of a tetrahydropyridine 39, gave
activity in vivo, and showed an encouraging blood level
profile. The hydroxylated acyl compounds 44–49, 55
were even better, giving high potency in the mouse thigh
test, and detectable blood levels out to the end of the
pharmacokinetic assay period. In this screen, such
compounds showed superior performance to the
reference compound linezolid.

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M. B. Gravestock et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4179–4186
linezolid, and the scope for further diversification in this
important new class of antibacterials.
8. Eustice, D. C.; Feldman, P. A.; Zajac, I.; Slee, A. M. Anti-
microb. Agents Chemother. 1988, 32, 1218.
9. Hutchinson, D. K.; Brickner, S. J.; Barbachyn, M. R.;
Gammill, R. B.; Patel, M. V. PCT WO 93/23384, 1993.
10. Riedl, B.; Habich, D.; Stolle, A.; Wild, H.; Endermann,
¨
In vitro and in vivo assays
R.; Bremm, K.; Kroll, H.-P.; Labischinski, H.; Schaller, K.;
Werling, H.-O. EP 694543, 1996.
The bacteria used in these studies were taken from the
AstraZeneca culture collection. Minimum inhibitory
concentrations (MICs) were determined by an agar
dilution method by the NCCLS protocol using doubling
dilutions over a concentration range of 128–0.008 mg/L
and incubation at 37 ꢁC.
11. Betts, M. J.; Darbyshire, C. J. PCT WO 98/01446, 1998.
12. Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.;
Manninen, P. R.; Ulanowicz, D. A.; Garmon, S. A.; Grega,
K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.; Zurenko,
G. E. J. Med. Chem. 1996, 39, 673.
13. Xiong, L.; Kloss, P.; Douthwaite, S.; Andersen, N. M.;
Swaney, S.; Shinabarger, D. L.; Makin, A. S. J. Bacteriol.
2000, 182, 5325.
The mouse protection test (MTT) used female Alderly
park mice (Alp/ApfCD-1) weighing 25–30 g, which were
inoculated intramuscularly in the right hand thigh with
0.1 mL inoculum prepared from an overnight culture of
methicillin resistant S. aureus 601291, diluted 1:1000 and
then mixed 1:1 with cooled molten agar. At 1-h post-
innoculum, groups of four mice/treatment were dosed iv
using 20% hydroxypropyl-beta cyclodextrin and 5 h later
the thigh tissue was removed for homogenisation and
plated out to assess bacterial numbers present.
14. Kloss, P.; Xiong, L.; Shinabarger, D. L.; Mankin, A. S. J.
Mol. Biol. 1999, 294, 93.
15. Aoki, H.; Ke, L.; Poppe, S. M.; Poel, T. J.; Weaver, E. A.;
Gadwood, R. C.; Thomas, R. C.; Shinabarger, D. L.; Gonaza,
M. C. Antimicrob. Agents Chemother. 2002, 46, 1080.
16. Gonzales, R. D.; Schreckenberger, P. C.; Graham, M. B.;
Kelkar, S.; DenBesten, K.; Quinn, J. P. Lancet 2001, 357,
1179.
17. Tsiodras, S.; Gold, H. S.; Sakoulas, G.; Eliopoulas, G. M.;
Wennerstein, C.; Venkaturaman, L.; Moellering, R. C., Jr.;
Ferro, M. J. Lancet 2001, 358, 207.
18. A preliminary description of this work was presented
at 39th Interscience Conference on Antimicrobial Agents
and Chemotherapy, San Francisco, Sept. 26–29, 1999;
American Society for Microbiology: Washington; Poster F-
1825.
19. Gregory, W. A.; Brittelli, D. R.; Wang, C.-L. J.; Wuonola,
M. A.; McRipley, R. J.; Eustice, D. C. R. J.; Eberly, V. S.;
Bartholomew, P. T.; Slee, A. M.; Forbes, M. J. Med. Chem.
1989, 32, 1673.
Acknowledgements
The authors wish to thank Emma Black, Simon Brown,
Rebecca Cartwright, Eric Fisher, Paul Perkins and Chris-
topher Sheldon for supporting chemical studies to this
work and Emma Shawner for further biological support.
20. (a) Gregory, W. A.; Brittelli, D. R.; Wang, C.-L. J.;
Kezar, H. S.; Carlson, R. K.; Park, C.-H.; Corless, P. F.;
Miller, S. J.; Rajagopalan, P.; Wuonola, M. A.; McRipley,
R. J.; Eberly, V. S.; Slee, A. M.; Forbes, M. J. Med. Chem.
1990, 33, 2569. (b) Park, C.-H.; Brittelli, D. R.; Wang, C. L.-
J.; Marsh, F. D.; Gregory, W. A.; Wuonola, M. A.; McRipley,
R. J.; Eberly, V. S.; Slee, A. M.; Forbes, M. J. Med. Chem.
1992, 35, 1156.
21. Hester, J. B.; Nidy, E. G.; Perricone, S. C.; Poel, T.-J.
PCT WO 98/54161, 1998.
22. Gravestock M. B.; Mulhoney-Flynn, A.; Feron L. J.
Unpublished observations.
23. Gravestock, M. B. PCT WO 97/30995, 1997.
24. Gravestock M. B.; Roberts, D. A.; Betts, M. J.; Mills, S.
D. M.; Hatter, G. PCT WO 00/21960, 2000.
25. Gravestock M. B. Griffen, D.; Betts, M. J.; Mathews,
PCT WO 01/81350, 2001.
References and Notes
1. Norrby, R. Exp. Opin. Pharmcother. 2001, 2, 2932.
2. Tomasz, A. N. Engl J. Med. 1994, 330, 1247.
3. Spera, R. V., Jr.; Farber, B. F. Drugs 1994, 48, 678.
4. Smith, T. L.; Pearson, M. L.; Wilcox, K. R.; Cruz, C.;
Lancaster, M. V.; Robinson-Dunn, B.; Tenover, F. C.; Zervos,
M. J.; Band, J. D.; White, E.; Jarvis, W. R. Engl. J. Med. 1999,
340, 493.
5. Brumfitt, W.; Hamilton-Miller, J. M. T. Drugs Exp. Clin.
Res. 1994, XX, 215.
6. Gregory, W. A. US Patent 4,705,799, 1987.
7. Slee, A. M.; Wuonola, M. A.; McRipley, R. J.; Zajac, I.;
Zawada, M. J.; Bartholomew, P. T.; Gregory, W. A.; Forbes,
M. Antimicrob. Agents Chemother. 1987, 31, 1791.