Design and synthesis of potent Gram-negative specific LpxC inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.12.111

Antibiotic resistant hospital acquired infections are on the rise, creating an urgent need for novel bactericidal drugs. Enzymes involved in lipopolysaccharide (LPS) biosynthesis are attractive antibacterial targets since LPS is the major structural compo

Full text of DOI:10.1016/j.bmcl.2010.12.111

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1155–1161
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of potent Gram-negative specific LpxC inhibitors
U. Faruk Mansoor a, , Dilrukshi Vitharana a, Panduranga Adulla Reddy a, Dayna L. Daubaras b,
⇑
Paul McNicholas b, Peter Orth c, Todd Black b, M. Arshad Siddiqui a
a Department of Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA
b Department of Biology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
c Department of Structural Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Antibiotic resistant hospital acquired infections are on the rise, creating an urgent need for novel bacte-
ricidal drugs. Enzymes involved in lipopolysaccharide (LPS) biosynthesis are attractive antibacterial tar-
gets since LPS is the major structural component of the outer membrane of Gram-negative bacteria. Lipid
A is an essential hydrophobic anchor of LPS and the first committed step in lipid A biosynthesis is cata-
lyzed by a unique zinc dependent metalloamidase, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosa-
mine deacetylase (LpxC). LpxC is an attractive Gram-negative only target that has been chemically
validated by potent bactericidal hydroxamate inhibitors that work by coordination of the enzyme’s cat-
alytic zinc ion. An exploratory chemistry effort focused on expanding the SAR around hydroxamic acid
zinc-binding ‘warheads’ lead to the identification of novel compounds with enzyme potency and antibac-
terial activity similar to CHIR-090.
Received 28 October 2010
Revised 21 December 2010
Accepted 21 December 2010
Available online 28 December 2010
Keywords:
LpxC
Gram-negative
Ó 2010 Elsevier Ltd. All rights reserved.
The growing emergence of multidrug resistant bacteria in hos-
pital and community clinics remains an important public health
concern throughout the world.1,2 Resistance developed by different
Gram-negative bacterial species including strains of Escherichia coli
and Pseudomonas aeruginosa to antibiotics targeting peptidoglycan,
DNA replication, or protein biosynthesis3 has driven the search for
identification and development of novel antibacterial targets.4 The
Gram-negative bacterial cell wall is surrounded by an outer mem-
brane comprised of charged lipopolysaccharide (LPS)5,6 molecules
which serve as a permeability barrier to protect the bacterium
against antibiotics.7 The hydrophobic anchor of LPS is lipid A, a
phosphorylated, D(1,6)-linked glucosamine disaccharide hexaacy-
lated with N-linked and O-linked fatty acids. Lipid A is essential
for bacterial growth and viability, and the inhibition of its biosyn-
thesis is lethal to bacteria.8,9 Bacterial strains containing a defect in
lipid A biosynthesis are hypersensitive to antibiotics10–12 and it is
this observation which has led many research groups and organi-
zations to focus on targeting lipid A biosynthesis to develop safe
and effective antibacterial agents.13–16
nism.21–23 The X-ray crystal structure of LpxC from Aquifex aeolicus
(aaLpxC) reveals a catalytic zinc ion (Zn2Aþ) coordinated by H79,
H238, D242, and a solvent molecule at the base of a ꢀ20 Å-deep
active site cleft.24 An inhibitory zinc (Zn2Bþ) is bound in the pres-
ence of excess zinc to residues E78 and H265 and a myristoyl fatty
acid which extends out into a hydrophobic tunnel. This tunnel is
required for efficient catalysis,24,25 as confirmed by NMR and
X-ray crystallography studies,26,27 accommodating the long fatty
acid side chain attached to the N-acetylglucosamine group of the
substrate analog inhibitor TU-514.28–30
Inhibitors of LpxC like TU-514 and amphipathic benzoic acid
derivatives (1)31 bind solely to the hydrophobic tunnel showing
moderate enzyme inhibitory activity (Fig. 1). However, early
work13 clearly confirmed that the LpxC inhibitor affinity was sig-
nificantly improved by the presence of a suitable ‘warhead’ that
completed a square pyramidal zinc coordination polyhedron as
well as a pendant ‘tail’ that bound to the aforementioned hydro-
phobic tunnel. Optimization resulted in (2), a hydroxamic acid at-
tached to a 2-phenyloxazoline ring system. This was a potent
inhibitor of E. coli LpxC (eeLpxC) but showed 50- to 100-fold weak-
er in vitro activity toward the P. aeruginosa LpxC enzyme (paLpxC).
More recent work by the Chiron Corporation identified compounds
containing the hydroxamic acid linked to an aromatic moiety by a
peptide linker.14 This series have Ki values of ꢀ100 nM against the
isolated paLpxC enzyme and inhibit E. coli growth at minimal
UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deace-
tylase (LpxC) catalyzes the deacetylation of UDP-3-O-
(R-3-hydroxymyristoyl)-N-acetylglucosamine, the first committed
step in the biosynthesis of lipid A.17–20 LpxC is a zinc-dependent
amidase, functioning via a general acid–base catalyst pair mecha-
inhibitory concentrations (MICs) ranging from 1.25 to 12.5 lg/mL.
Here, we report the design and synthesis of novel inhibitors of
LpxC. In a previous study targeting novel zinc-binding warheads,
⇑
Corresponding author.
E-mail address: umar.faruk.mansoor@merck.com (U. Faruk Mansoor).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.111

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U. Faruk Mansoor et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1155–1161
OH
O
O
HO
O
OH
OH
NH
O
O
OH
H
O
N
N
O
O
O
N
H
OH
O
O
O
HN
OH
O
N
1:
A. aeolicus: Kd
CHIR-090:
2:
E. coli: Ki ~ 50 nM
TU-514
E. coli: Ki ~ 650 nM
:
~ 2 nM
2
M
E. coli Ki
µ
Figure 1. Literature examples of LpxC inhibitors.
Table 1
SAR of benzolactam series
we were able to identify linear non-polar groups which made
favorable intermolecular interactions within the hydrophobic tun-
nel of LpxC. When these fragments were combined with the
hydroxamic acid zinc binding group by way of a peptide linker, a
novel series of potent inhibitors were identified.
O
OH
NH
R
OH
a
Two separate series of inhibitors were designed and synthe-
sized. Through unpublished in-house X-ray crystallography studies
with aaLpxC it was known the peptide linker made both polar and
non-polar interactions within the enzyme active site with Lys-227
and Phe-180, respectively. Modifications to incorporate the gem-
dimethyl hydroxyl moiety lead to minor improvements in both
biochemical and cellular potency. The two series of inhibitors dif-
fered by the fusion of the hydrophobic fragment to this peptide lin-
ker. Attaching the peptide linker by cyclizing through the amide
NH gave rise to the benzolactam series (Table 1). The synthetic
methods used for the preparation of these analogs are illustrated
Mol. I.D.
3
R
eeLpxC IC50 (nM)
O
N
H
2.0
CHR-12
O
N
4
5
130.0
200.0
O
N
in Scheme 1. Heating O-tert-butyl-L-threonine tert-butyl ester
N
H
hydrochloride in the presence of methyl 4-bromo-2-(bromo-
methyl)benzoate furnished the benzolactam. Sonogashira coupling
with various alkynes resulted in extension of the hydrophobic frag-
ments. Acid hydrolysis of the protecting groups and subsequent
peptide coupling with TBS-ONH2 provided the hydroxamic acids
after aqueous workup. Unfortunately, capping of the amide NH
resulted in the loss of a key hydrogen bonding interaction with
Thr-179, with a subsequent 100-fold drop in potency (comparing
compound 4 to compound 3). Attempts to regain this hydrogen
bonding interaction by incorporating an indazolinone failed (com-
pound 5). The size and length of the pendent ‘tail’ was important.
Increasing the hydrophobicity of these fragments lead to an in-
crease in the biochemical potency, because of increased favorable
interactions within the hydrophobic tunnel (compounds 9–11). If
the projection of the hydrophobic tail was away from the tunnel,
there was a significant loss in potency (compounds 8 and 12).
Although potent eeLpxC inhibitors were synthesized, there was
no observed cellular potency with this series of compounds.
The importance of the hydrogen bonding interaction between
the peptide amide NH and Thr-179 in terms of biochemical po-
tency and potentially cellular potency lead us to believe that we
needed to change our strategy. Instead of a benzolactam fusion
we decided upon a urea fusion between the peptide linker and
the hydrophobic fragment (Table 2). The synthetic methods used
for the preparation of these analogs are illustrated in Scheme 2.
The ureas were synthesized by the reaction between the previously
prepared hydrophobic fragments and the activated peptide carba-
mate. The synthesis was then completed with acid hydrolysis and
peptide coupling to incorporate the zinc binding hyroxamic acid.
Resolution (1.9 Å) X-ray crystal structures were solved for
aaLpxC with our urea inhibitors (Fig. 2). These showed the possibil-
ity of making key interactions within the active site and hydropho-
bic tunnel which could aid in the design and synthesis of potent
inhibitors. Similar to the benzolactam series of compounds, the
projection of this fragment towards the hydrophobic tunnel was
a key factor towards maintaining and increasing enzyme potency.
O
6
7
>61,000
41,000
N
Br
O
N
O
8
9
34,000
50
N
O
N
O
N
10
29
O
N
11
12
13
O
N
971
a
A high-throughput enzymatic assay using BioTrove Rapid Fire HTS Mass Spec-
trometry technology was developed for screening.32
Rigidity of the urea moiety was necessary as shown by the differ-
ence in enzyme activity when comparing cyclic ureas to aliphatic

U. Faruk Mansoor et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1155–1161
1157
to the ring (preferably 1,4-connection) also played a role in terms
of projection of the ‘tail’ towards the tunnel (compounds 15–18).
Piperidine or piperazine rings were most optimal. Biochemically
these compounds tended to be equipotent, but the piperzine ring
generally imparted increased cellular potency, likely due to en-
hanced polarity, which in turn lead to greater cell penetration
(compounds 18 and 19).
The hydrophobic moiety inserts into the hydrophobic tunnel
and depending on the length of the fragment protrudes from the
opposite end, similar to TU-514 and fatty acids. Extensive hydro-
phobic contacts are observed between the inhibitor and residues
within the tunnel, including Ile-18, Ala-181, Ile-186, Ile-189, Gly-
195, Gly-198, Ser-199, Leu-200 and Thr-203. The aromatic rings
of the biphenyl acetylene moiety are not co-planar but are off-set
by a ꢁ25° dihedral angle. This orientation provides a better fit into
the tunnel than simple biaryl fragments, leading to enhanced LpxC
enzyme potencies (compounds 18–22).
O
O
O
O
O
O
a
b
O
O
N
N
O
NH2
Br
O
O
O
O
HO
HO
d
HO
HN
c
N
N
O
HO
O
7
Scheme 1. Reagents and conditions: (a) 4-bromo-2-(bromomethyl)-benzoate,
DMF, DIEA, 80 °C, 16 h; (b) dichlorobis-(acetonitrile)palladium (II), X-Phos, cesium
carbonate, phenyl acetylene, 90 °C, 2.5 h; (c) TFA, rt, 1 h; (d) O-(tert-butyldimeth-
ylsilyl)hydroxylamine, HATU, DIEA, DMF, rt, 16 h.
ureas (compounds 13–14 and compound 15). Ring size (preferably
six-membered ring) and connection of the hydrophobic fragment
Table 2
Enzymatic activity and primary MIC profile of urea series of inhibitors
O
OH
NH
HN
R
X
O
Mol. I.D.
3
R
X
eeLpxC IC50 (nM)
eeLpxC MICa
eeLpxC MICa
paLpxC MICa
HS294b
(lg/mL)
ATCC25922c
(l
g/mL)
ATCC27853c
(lg/mL)
HO
HO
HO
2.0
0.02
0.08
0.08
NTd
CHR-12
13
14
201.4
12.5
50
>100
H
N
H
N
1268.9
>100
NT
HO
15
16
17
36
12.5
1.56
25
100
NT
N
N
HO
HO
146.4
386.7
100
>100
NT
>100
N
HO
HO
18
19
2.1
2.4
0.8
0.2
12.5
6.25
3.13
N
N
1.56–3.13
N
HO
HO
20
21
5.6
0.8
0.8
3.13
6.25
>100
3.13
N
N
N
13.8
(continued on next page)

1158
U. Faruk Mansoor et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1155–1161
Table 2 (continued)
Mol. I.D.
R
X
eeLpxC IC50 (nM)
3944.5
eeLpxC MICa
eeLpxC MICa
paLpxC MICa
HS294b
(lg/mL)
ATCC25922c
(lg/mL)
ATCC27853c
(lg/mL)
22
23
12.5
NT
25
NT
HO
HO
N
207.0
3.13
6.25
100
N
N
HO
HO
HO
24
25
26
27
10
>100
100
3.13
25
>100
>100
>100
>100
N
N
N
N
63.0
4.0
12.5
0.8
N
N
N
N
S
HO
HO
21.0
1.56
N
N
N
N
28
29
30
136
12.0
16.3
6.25
3.13
3.13
>100
100
>100
>100
>100
N
N
S
N
HO
HO
N
N
O
N
6.25
N
N
HO
HO
HO
HO
HO
HO
31
32
33
34
35
4.0
26.0
5.0
0.1
1.56
3.13
6.25
3.13
12.5
3.13
N
N
H2N
1.56
1.56
0.8
>100
>100
>100
>100
N
N
Cl
N
N
F
7.0
N
N
F3C
10.4
1.56
N
N

U. Faruk Mansoor et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1155–1161
1159
Table 2 (continued)
Mol. I.D.
R
X
eeLpxC IC50 (nM)
eeLpxC MICa
eeLpxC MICa
paLpxC MICa
HS294b
(lg/mL)
ATCC25922c
(l
g/mL)
ATCC27853c
(lg/mL)
NC
HO
36
37
38
11.0
0.8
6.25
12.5
6.25
>100
25
N
N
N
N
HO
HO
HO
HO
12.0
14.0
0.4
N
N
O
O
1.56
25
N
N
39
3.0
0.1
0.4
25
>100
N
N
HN
N
HO
HO
40
41
23.3
0.3
6.25
6.25
N
N
<0.1–0.4
0.8–4
12.5–50
N
N
HO
HO
H2N
42
43
2.5
7.0
0.2–0.4
0.8
0.8–6.25
3.13
100
N
N
>100
N
44
163.1
0.6
6.25
12.5
25
N
N
H2N
45
0.4–0.8
1.56–3.13
6.25
N
a
Minimal inhibitory concentration (MIC) analysis was performed by broth dilution methods according to CLSI standard methods.
Primary screen included cell wall compromised (‘leaky’) strains of E. coli and P. aeruginosa.
Primary screens also included wild-type strains of E. coli and P. aeruginosa.
Not tested.
b
c
d
Not surprisingly removal of a phenyl ring, shortening the hydro-
phobic fragment (compounds 22 and 23) results in a drop of po-
tency because of subsequent loss in the number of key
As mentioned earlier, the binding of these inhibitors are further
strengthened through interactions with conserved hydrophilic and
hydrophobic residues in the active site. We have already described
the importance of the hydrogen bond formed by the peptide amide
NH and Thr-179 in terms of potency, but there are key interactions
which can be targeted to further improve the biochemical potency.
The threonine methyl group forms van der Waals contacts with the
aromatic ring of Phe-180, while the threonine hydroxyl group is
well positioned to form hydrogen bonds with Lys-227, Aps-230
and the positively charged His-253 imidazole group. It is therefore
not surprising that modifications at this position have a tremen-
dous impact on enzyme potency. Replacing the threonine motif
with a gem-dimethyl hydroxyl group (compounds 41–43) leads
a
hydrophobic contacts. Introducing polarity to the hydrophobic
fragment by replacing the distal phenyl ring with heteroaryls
(compounds 24–29) has a negative impact on potency. This is be-
cause the distal ring is still situated in the back end of the hydro-
phobic tunnel. Only modifications at the 4-position are tolerated
(compound 26 and compounds 30–40). Although the projections
of groups at this position are now into the surface of the protein,
the main driving force for potency may still be a combination of
hydrophobic interactions with the surface of the protein and po-
tential hydrogen bonding interactions with the solvent.

1160
U. Faruk Mansoor et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1155–1161
O
O
O
O
O
N
H
N
O
O
NO2
a
b
O
O
O
O
NH2
N
H
O
HO
HO
HO
H
O
O
c
d
N
N
H
N
HO
N
H
N
O
O
Scheme 2. Reagents and conditions: (a) 4-nitrophenyl chloroformate, DIEA, THF, 0 °C, 1 h; (b) R2NH, DIEA, THF, 80 °C, 2 h; (c) TFA, rt, 1 h; (d) O-(tert-butyldimethylsi-
lyl)hydroxylamine, HATU, DIEA, DMF, rt, 16 h.
Figure 2. X-ray structure solved for aaLpxC with compound 18 at 1.9 Å.33 Molecular interaction map detailing key polar and non-polar interactions within the aaLpxC active
site and hydrophobic tunnel.
Table 3
Expanded Gram-negative MIC (lg/mL) profile for LpxC inhibitors
Organism
Resistance
Phenotype
Compound
21
Compound
41
Compound
45
Compound
3 (CHR-12)
Cipro-
floxacin
Tetra-
cycline
Chloram-
phenicol
Ampicillin
Azithro-
mycin
E. coli
E. coli
E. coli
E. coli
E. coli
E. coli
P. aeruginosa
P. aeruginosa
P. aeruginosa
S. maltophilia
K. pneumoniae
K. pneumoniae
P. vulgaris
S. marcescens
E. aerogenes
E. cloacae
Wild-type
MDR
MDR
ESBL
ESBL
Wild-type
Wild-type
MDR
1.56
3.13
3.13
3.13
3.13
6.25
3.13
>100
12.5
>100
>100
12.5
3.13
6.25
>100
3.13
>100
>100
>100
0.8
1.56
3.13
3.13
1.56
3.13
3.13
12.5
12.5
3.13
>50
25
12.5
6.25
12.5
25
3.13
25
0.16
0.63
0.63
0.313
0.63
1.25
10
2.5
0.63
5
1.25
0.63
1.25
1.25
2.5
0.31
1.25
1.25
>20
0.008
>32
>32
1
2
>256
2
>256
32
4
>256
8
3.13
1.56
1.56
3.13
12.5
>50
12.5
6.25
25
12.5
6.25
3.13
6.25
12.5
6.25
25
64
32
0.016
>32
0.012
>32
8
0.016
1
1
16
64
2
>256
>256
4
4
32
>256
>256
>32
>32
>32
MDR
Wild-type
Wild-type
ESBL
Wild-type
Wild-type
Wild-type
ESBL
Wild-type
Wild-type
Wild-type
>32
A. calcoaceticus
A. anitratus
A. baumannii
25
>50
25
25
to an almost 10-fold increase in potency. Likewise, removal of the
potential for van der Waals interactions leads to a significant drop
in activity (compound 44).
We have demonstrated that enzyme potency can be achieved
by exploiting several conserved and essential features of LpxC to
form a tight-binding complex (catalytic zinc binding, binding of
the peptide linker, and maintaining hydrophobic contacts within
the hydrophobic tunnel). However, achieving cellular potency re-
quires finding the right balance between polarity and hydropho-
bicity as shown by compound 45.

U. Faruk Mansoor et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1155–1161
1161
14. Kline, T.; Andersen, N. H.; Harwood, E. A.; Bowman, J.; Malanda, A.; Endsley, S.;
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bacterial properties.
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33. X-ray crystal structure (PDB ID code 3P76) deposited with the RCSB protein
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