Heterocyclic methylsulfone hydroxamic acid LpxC inhibitors as Gram-negative antibacterial agents

Article abstract of DOI:10.1016/j.bmcl.2012.09.058

The synthesis and antibacterial activity of heterocyclic methylsulfone hydroxamates is presented. Compounds in this series are potent inhibitors of the LpxC enzyme, a key enzyme involved in the production of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. SAR evaluation of compounds in this series revealed analogs with potent antibacterial activity against challenging Gram-negative species such as Pseudomonas aeruginosa and Klebsiella pneumoniae.

Full text of DOI:10.1016/j.bmcl.2012.09.058

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6832–6838
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Heterocyclic methylsulfone hydroxamic acid LpxC inhibitors as
Gram-negative antibacterial agents
⇑
Laura A. McAllister , Justin I. Montgomery, Joseph A. Abramite, Usa Reilly, Matthew F. Brown,
Jinshan M. Chen, Rose A. Barham, Ye Che, Seung Won Chung, Carol A. Menard, Mark Mitton-Fry,
Lisa M. Mullins, Mark C. Noe, John P. O’Donnell, Robert M. Oliver III, Joseph B. Penzien, Mark Plummer,
Loren M. Price, Veerabahu Shanmugasundaram, Andrew P. Tomaras, Daniel P. Uccello
Pfizer Worldwide Research and Development, 445 Eastern Point Road, Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2012
Revised 4 September 2012
Accepted 17 September 2012
Available online 24 September 2012
The synthesis and antibacterial activity of heterocyclic methylsulfone hydroxamates is presented. Com-
pounds in this series are potent inhibitors of the LpxC enzyme, a key enzyme involved in the production
of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. SAR evaluation of
compounds in this series revealed analogs with potent antibacterial activity against challenging Gram-
negative species such as Pseudomonas aeruginosa and Klebsiella pneumoniae.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
LpxC inhibitors
Pseudomonas aeruginosa
Antibacterial
Gram negative
Hydroxamic acid
Heterocycle
As resistance to existing antibiotic treatments for hospital ac-
quired Gram-negative bacterial infections becomes more preva-
lent, the need to develop medicines which target these bacteria
is increasingly urgent.1 Of particular concern are infections caused
by Pseudomonas aeruginosa (Pae), Klebsiella pneumoniae (Kpn) and
Acinetobacter baumannii (Aba), which all show resistance to stan-
dard treatments such as ciproflaxacin and aztreonam,2,3 and high-
light the need for new agents which inhibit novel antibacterial
targets and pathways.4 LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-
N-acetylglucosamine deacetylase) is an enzyme present in all
Gram-negative bacteria and plays a crucial role in the pathway
leading to the construction of Lipid A.5 Lipid A is a component of
the outer membrane of Gram-negative bacteria, without which,
bacteria have increased susceptibility to anti-bacterial agents.6 In-
deed, in Pae it has been shown that LpxC activity is essential for
growth and that inactivation of the LpxC gene suppresses bacterial
growth.7 The LpxC enzyme therefore represents an attractive tar-
get for the development of a new class of antibiotics.
recently reported sulfone hydroxamic acid compounds 1 and 2
(Fig. 1) as potent inhibitors of LpxC, with excellent whole cell activ-
ity in Pseudomonas strains.9 Compound 2 has an impressive mini-
mum inhibitory concentration (MIC) of 0.5 lg/ml in the wild-
type, efflux pump competent, Pseudomonas strain PAO1, and shows
favorable physicochemical properties for further development as
an intravenous antibiotic. X-Ray co-crystal structures of com-
pounds in this class with the Pseudomonas aeruginosa LpxC enzyme
revealed the key structural features which are crucial to their po-
tency; a hydroxamic acid head group binds to the zinc atom in
the active site; a methyl sulfone moiety where the oxygen atom
makes a hydrogen-bonding interaction with a lysine residue
(Lys238); and a hydrophobic tail group which interacts with a
hydrophobic tunnel in the enzyme. As part of our program to find
O
S
O
S
O
O
H
N
O
Numerous inhibitors of LpxC have been reported since the dis-
covery of this enzyme target, although none of these inhibitors
have yet successfully progressed through clinical trials.8 We have
H
N
OH
OH
N
O
O
1
2
⇑
Corresponding author. Tel.: + 1 860 715 0346.
E-mail address: laura.mcallister@pfizer.com (L.A. McAllister).
Figure 1. Methylsulfone hydroxamate LpxC inhibitors.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.09.058

L. A. McAllister et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6832–6838
6833
Table 1
SAR of 5-membered heterocyclic methylsulfone hydroxamic acids
O
S
O
H
N
R1
OH
O
3a-j
Compound
R1
Pae LpxC IC50 (nM)
MIC (lg/ml)
PA-7
PA-3060
1
PA-3919
0.008
PAO1
1
2
1.4
3.6
1
1
0.125
0.05
O
N
2
0.06
N
N
N
O
N
O
N
3a
0.511
0.85
1.61
3.02
3.00
13.5
>100
>100
0.5
2
1
<0.06
0.03
0.015
<0.06
0.5
0.5
1
N
3b
4
N
3c
1
2
0.5
0.5
8
N
N
3d
3ea
3fa
3ga
3ha
1
2
N
16
32
>64
32
32
64
>64
>64
N
N
N
N
0.5
8
N
NH
64
>64
16
O
N
0.5
H
N
N
3ia
3ja
>100
>100
>64
32
>64
64
4
>64
32
N
N
N
0.5
a
Racemic compound tested.

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L. A. McAllister et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6832–6838
O
S
O
O
S
O
O
O
Z
N
S
c
b
O
OEt
O
HO
OEt
7
Z = OEt
Z = NHOH
N
O
d
3a
O
O
Ph
5
6
a
I
O
S
O
S
O
O
H
O
O
OEt
O
N
8
N
e
d
d
OH
S
Ph
N
Ph
Ph
N
e
N
OEt
O
O
N
N
9
3f
4
O
S
O
S
O
O
H
N
I
N
N
OEt
N
OH
N
N
N
N
O
NH
SEM
O
N
Ph
SEM
10
Ph
3g
Ph
11
Scheme 1. (a) (i) 4-Bromo-1-butene, Cs2CO3, THF; (ii) NalO4, OsO4, pyridine; (b) NH2OHÁHCl, Na2CO3, EtOH; (c) Phenylacetylene, NaOCl, CH2Cl2; (d) LiOH, THF–H2O; (ii) THP-
hydroxylamine, CDMT, NNM, 2-MeTHF; (iii) HCl, EtOH; (e) Cs2CO3, THF.
O
O
S
H
N
N
N
N
OH
NH
O
Ph
Ph
3c
13
a, b
O
S
O
O
S
O
S
O
c, b
O
NHOH
d
N
O
H
N
N
N
OEt
N3
O
O
Br
O
Ph
3b
O
14
12
O
S
O
N
a, b
H
N
NH
N
N
N
N
OH
O
Ph
15
3j
Ph
Scheme 2. (a) (i) Cs2CO3, DMF, 60 °C; (b) (i) LiOH, THF–H2O; (ii) THP-hydroxylamine, CDMT, NNM, 2-Me THF; (iii) HCl, EtOH (c) NaN3, DMF; (d) (i) Phenylacetylene, CuSO4,
sodium ascorbate, EtOH–H2O; (ii) HCl, EtOH.
O
S
O
S
O
O
O
S
H
N
O
O
O
OEt
b
a
OH
N
N
OEt
O
O
3d
16
17
Ph
Ph
O
O
S
O
S
c
O
O
H
N
N
b
OEt
N
OH
N
N
O
N
O
N
18
3e
Ph
Ph
Scheme 3. (a) Benzaldehyde oxime, NaOCl, CH2Cl2; (b) (i) LiOH, THF–H2O; (ii) THP-hydroxylamine, CDMT, NNM, 2-MeTHF; (ii) HCl, EtOH (c) PhN3, Cul, dimethylcyclo-
hexaadimine sodium ascorbate, DMSO/H2O (5:1).
improved LpxC inhibitors in this series, we undertook a body of
work investigating the effects of replacing the central pyridone
ring in 2 with 5-membered heterocycles. We aimed to improve
parameters such as potency and antibacterial spectrum over lead
compounds in the sulfone hydroxamate series. In addition, we
hoped to improve fraction unbound in plasma, which is a crucial

L. A. McAllister et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6832–6838
6835
O
S
O
O
O
S
O
O
S
H
N
b
Z
a
Ph
OEt
HO
OEt
N
O
O
O
20
O
19
O
O
Ph
21
, Z = OEt
3i, Z = NHOH
c
d
O
S
O
O
S
O
OH
24, Z = OEt
N
e
Z
N
c
3h
, Z= NHOH
Cl
OEt
Ph
Ph
NH2
O
O
N
O
O
22
23
Scheme 4. (a) CDI, Acetophenone, THF; (b) NH2NH2ÁH2O, EtOH, 70 °C; (c) (i) LiOH, THF–H2O; (ii) THP-hydroxylamine, CDMT, NNM, 2-MeTHF; (iii) HCl, EtOH; (d) Pyridine,
reflux.
Table 2
Triazole SAR
O
O
S
H
N
OH
N
N
N
O
R1
Compound
R1
Pae LpxC IC50 (nM)
MIC (lg/ml)
PA-7
2
PA-3060
4
PA-3919
0.03
PAO1
1
3b
0.85
25a
0.657
1
2
1
2
0.008
0.06
0.5
2
Cl
Cl
F
25b
0.912
F
25c
25d
1.2
2
4
4
8
0.06
2
2
MeO
F
1.39
0.125
25e
25f
1.67
1.87
2
4
2
4
<0.06
0.06
1
4
Cl
F
Cl
F
25g
25h
25i
1.95
4.71
8.08
4
8
4
4
8
8
<0.06
0.125
0.125
2
8
4
Cl
Cl
MeO
Cl
F
F
component in achieving the necessary free AUC exposures for effi-
cacy, especially in an intraveneously administered drug that is pre-
dicted to have high clearance.10
We began by replacing the central ring of 1 and 2 with 5-mem-
bered heterocycles and assessed the potency of these analogs in a
Pseudomonas aeruginosa LpxC enzyme assay (Table 1, compounds
3a–3j). In addition, we examined MIC values in a few representa-
tive Pseudomonas strains to assess whole cell activity. PA-3919 is
a multi efflux pump knockout strain which is used to assess
whether the compound of interest is a substrate for these pumps.11

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L. A. McAllister et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6832–6838
Table 3
Isoxazole SAR
O
S
O
S
O
O
H
H
N
OH
N
OH
N
O
O
N
O
O
R1
R1
26a-d
27a-d
Compound
R1
Pae LpxC IC50 (nM)
MIC (lg/ml)
PA-7
0.5
PA-3060
1
PA-3919
<0.06
PAO1
0.5
3a
0.511
2.32
26a
0.5
1
2
0.125
0.06
0.5
MeO
Cl
F
26ba
26ca
2.66
6.75
NDb
NDb
Cl
NDb
4
<0.06
NDb
F
26da
3d
8.31
3.02
2.93
2
1
2
2
2
2
0.060
<0.06
<0.06
1
F
0.5
1
27aa
Me
27b
27c
4.4
2
4
2
8
<0.06
<0.06
1
2
MeO
F
5.32
F
OMe
27da
6.81
2
4
<0.06
2
F
F
a
Racemic compound tested.
Not determined.
b
PAO1 and PA-7 are common strains with fully functioning efflux
pumps. In addition, MICs were measured against PA-3060, which
is a quinolone resistant Pseudomonas strain. As previously observed
for this class of LpxC inhibitors, a Pae IC50 value of less than 5 nM is
generally required to observe meaningful antibacterial activity.
Isoxazole isomers 3a and 3d emerged as potent LpxC inhibitors
with sub-nanomolar IC50s in LpxC and impressive MICs (both with
ring, such as in 3h and 3j, and the presence of hydrogen bond do-
nors (analogs 3i and 3g) results in a dramatic fall off in potency.
A diverse array of chemistry was employed to access the hetero-
cyclic systems evaluated in Table 1. A general outline of synthetic
routes to compounds 3a–3j is described in Schemes 1–4. Com-
pounds 3a, 3f and 3g can be accessed from sulfone ester interme-
diate 4 (Scheme 1). Alkylation of 4 with bromobutene, followed by
oxidative cleavage, yielded aldehyde 5. Aldehyde 5 was condensed
with hydroxylamine, and then converted to oxazole 7 by an in situ
oxidation to the nitrile oxide, and subsequent cycloaddition onto
phenylacteylene. Conversion of ester 7 to the hydroxamic acid 3a
was achieved through hydrolysis to the acid, CDMT promoted cou-
pling to O-THP protected hydroxylamine, followed by acid cata-
lyzed removal of the THP group. Pyrazole 3f and triazole 3g can
be obtained by alkylation of 4 with the appropriate iodide interme-
diates 8 and 10 respectively, followed by conversion of the ester to
the hydroxamate using our standard protocol (Scheme 2). Pyrazole
3c and triazoles 3b and 3j can be obtained from bromide interme-
PAO1 = 0.5 lg/ml). MICs at PA-7 and PA-3060 show the hetero-
atom arrangement in 3a to be slightly more favorable than that
in 3d. This is also reflected in their relative Pae IC50 values. Pyra-
zole 3c showed comparable enzyme potency MICs at PAO1 to the
isoxazoles 3a and 3d. Triazole 3b was half as potent as 3c across
all Pseudomonas strains, possibly as a result of increased polarity
in the hydrophobic tunnel of the enzyme creating unfavorable
interactions. Linking the terminal phenyl ring through the N-atom
of the heterocycle, as in 3e and 3f, is disfavored; resulting in an in-
crease in MIC vs PAO1 (8
lg/ml). Similarly, it appears that the pres-
ence of heteroatoms on opposing sides of the central heterocyclic

L. A. McAllister et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6832–6838
6837
Table 4
MIC90s, LogD (measured and calculated), Mwt, and free fraction of selected analogs
Compound
MIC 90 (lg/ml)
LogD (pH 7.4)
cLogD
Mwt
hFu
Pae
Eco
Kpn
Aba
1
4
2
2
2
4
2
4
4
2
8
4
1
32
1
16
16
32
4
>64
2
32
32
2.24
0.8
2.17
0.51
0.61
À0.14
0.67
0.54
0.61
0.98
347
0.02
0.14
2a
364.4
338.4
338.4
337.4
390.8
386.4
386.4
3aa
3da
3cb
25aa
25ca
27bc
>32
>32
>256
>32
>32
32
1.31
0.99
1.04
1.34
1.36
1.23
0.016
0.013
0.048
NDd
0.085
0.072
16
4
>32
8
a
b
c
Pae, Kpa (n = 22), Eco,Aba (n = 11).
Pae (n = 51), Eco, Kpn, Aba (n = 11).
Pae (n = 22), Kpa (n = 21),Eco (n = 11) Aba (n = 10).
d
Not determined.
diate 12.12 Alkylation of phenyl pyrazole 13 with 12 and standard
conversion of the ester to the corresponding hydroxamic acid gave
3c. Triazole 3j was obtained similarly by alkylation of phenyltriaz-
ole 15 with 12. Treatment of 12 with sodium azide followed by
conversion of the ester functionality to THP-protected hydroxa-
mate, resulted in the key azide intermediate 14. Reaction of 14
with phenylacetylene under ‘click chemistry’13 conditions installed
the triazole core, then deprotection of the THP group gave the
hydroxamic acid 3b. Alkyne intermediate 16 was used to prepare
oxazole 3d via cycloaddition chemistry and 3e utilizing ‘click
chemistry’ (Scheme 3). Carboxylic acid 19 was converted to dike-
tone 20 by activation with CDI and addition of acetophenone. Con-
densation of 20 with hydrazine gave the desired intermediate
pyrazole 21 which could be converted to hydroxamic acid 3i
(Scheme 4). Similarly, oxadiazole 3j was acquired by conversion
of 19 to the acid chloride followed by subsequent reaction with
hydroxyamidine 23 to give oxadiazole intermediate 24.
In view of the promising activity of triazole 3b, and isoxazoles 3a
and 3d, we decided to prepare a more focused set of analogs with
these heterocyclic cores. Although pyrazole 3c also showed promis-
ing activity, further work based on this core is not described here.
Previous work on the sulfone hydroxamate series indicated that
we could improve potency over compounds 1 and 2, by addition
of appropriately positioned substituents (e.g. chloro, fluoro, meth-
oxy) on the terminal phenyl ring. An array of triazole analogs
(25a–25i) was prepared, varying the substituents on the terminal
phenyl ring (Table 2). We were pleased to find that the 2-fluoro-
4-chloro analog 25a had a one dilution improvement in MIC values
at PAO1 and PA7, and a fourfold improvement at PA-3060, com-
pared to the simple phenyl analog 3b. Analogs 25b and 25e, both
bearing 4-position chloro substituents had comparable activity to
the parent unsubstituted compound 3b. Two libraries of isoxazole
isomers 26a–26d and 27a–27d were prepared; applying the
chemistry detailed in Schemes 1 and 3. The most active compounds
from these libraries are shown in Table 3. In this series, activity in
the Pae LpxC enzyme assay translated into better MIC values than
expected in comparison to the triazoles. For example, 2-fluoro,
4-methoxy compound 26a had equal MIC activity to parent
compound 3a despite ꢀ4.5-fold lower enzyme potency. Notably,
isoxazole isomer 27b was much less active than 26a, again suggest-
ing that the latter arrangement of heteroatoms in the oxazole core
is preferred. Disappointingly, we did not find a compound with
superior potency to the parent in either isoxazole series.
across the species. Isoxazole 3d displayed an impressive MIC90
of 4 g/ml versus Klebsiella pneumoniae and 1 g/ml versus E. coli
Isoxazole isomer 3a had comparable MIC90 values against Pseudo-
monas aeruginosa however, Klebsiella and Ecoli activity was more
modest, with values of 32 lg/ml and 4 lg/ml respectively. A par-
l
l
ticularly impressive spectrum of activity was observed for substi-
tuted triazole compound 25a. In addition to an MIC90 value of
1
lg/ml against Pseudomonas aeruginosa, 25a had MIC 90 values
of 2 g/ml versus Klebsiella and 1 g/ml at Ecoli. These values rep-
l
l
resent a significant enhancement in antibacterial spectrum com-
pared with pyridone 2. Pyrazole 3c was also tested in MIC 90
panel against all four species but unfortunately it exhibited poorer
spectrum than pyridone 2. Surprisingly, some of the 5-membered
heterocyclic series compounds in Table 4 had significantly higher
measured logD values than compound 2, and correspondingly
much greater plasma protein binding. We saw some evidence that
this high plasma protein binding could be mitigated by addition of
substituents on the terminal phenyl ring. Indeed, in fluoro-meth-
oxy substituted triazole 25d and isoxazole 27b we observed that
fraction unbound in human plasma was increased compared with
unsubstituted compounds 3a, 3d and 3c However, these analogs
did have somewhat reduced MIC90 values and hFu did not quite
match levels observed in pyridone 2. Nonetheless, we were greatly
encouraged by the improved Gram-negative antibacterial spec-
trum observed in the isoxazole and triazole series, which opens
avenues for further exploration to enhance free fraction while
maintaining the superior spectrum.
In summary, we have explored the SAR of a diverse range of 5-
membered heterocyclic sulfone hydroxamate LpxC inhibitors. We
have identified two promising new series of LpxC inhibitors based
upon the triazole and isoxazole cores. In addition to excellent
activity against Pseudomonas, compounds from these series, such
as 3d and 25a, display impressive antibacterial spectrum against
challenging species such as Klebsiella. These compounds represent
promising leads for further exploration as antibacterial agents.
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