LpxC Inhibitors: Design, Synthesis, and Biological Evaluation of Oxazolidinones as Gram-negative Antibacterial Agents

Article abstract of DOI:10.1021/acsmedchemlett.6b00057

Herein we report a scaffold-hopping approach to identify a new scaffold with a zinc binding headgroup. Structural information was used to give novel oxazolidinone-based LpxC inhibitors. In particular, the most potent compound, 23j, showed a low efflux ratio, nanomolar potencies against E. coli LpxC enzyme, and excellent antibacterial activity against E. coli and K. pneumoniae. Computational docking was used to predict the interaction between 23j and E. coli LpxC, suggesting that the interactions with C207 and C63 contribute to the strong activity. These results provide new insights into the design of next-generation LpxC inhibitors.

Full text of DOI:10.1021/acsmedchemlett.6b00057

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Letter
LpxC Inhibitors: Design, Synthesis, and Biological Evaluation
of Oxazolidinones as Gram-negative Antibacterial Agents
Haruaki Kurasaki, Kosuke Tsuda, Mariko Shinoyama, Noriko Takaya, Yuko Yamaguchi,
Ryuta Kishii, Kazuhiko Iwase, Naoki Ando, Masahiro Nomura, and Yasushi Kohno
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00057 • Publication Date (Web): 05 Apr 2016
Downloaded from http://pubs.acs.org on April 7, 2016
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LpxC Inhibitors: Design, Synthesis, and Biological Evaluation
of Oxazolidinones as Gram-negative Antibacterial Agents
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Haruaki Kurasaki*, Kosuke Tsuda, Mariko Shinoyama, Noriko Takaya, Yuko Yamaguchi, Ryuta Kishii,
Kazuhiko Iwase, Naoki Ando, Masahiro Nomura, and Yasushi Kohno
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., 1848 Nogi, Nogiꢀmachi, Shimotsugaꢀgun, Tochigi 329ꢀ0114, Japan
ABSTRACT: Herein we report a scaffoldꢀhopping approach to identify a new scaffold
with a zinc binding head group. Structural information was used to give novel oxazoliꢀ
dinoneꢀbased LpxC inhibitors. In particular, the most potent compound, 23j, showed a low
efflux ratio, nanomolar potencies against E. coli LpxC enzyme, and excellent antibacterial
activity against E. coli and K. pneumoniae. Computational docking was used to predict the
interaction between 23j and E. coli LpxC, suggesting that the interactions with C207 and
C63 contribute to the strong activity. These results provide new insights into the design of
nextꢀgeneration LpxC inhibitors.
KEYWORDS: Antibacterial, Gramꢀnegative bacteria, LpxC, scaffold hopping, oxazolidinone
In recent years, infections caused by antibioticꢀresistant bacꢀ
teria have emerged as major threats to human communities
worldwide.1 However, the lateꢀstage clinical development
pipeline for antibacterials has been unacceptably lean in recent
decades.2 In particular, no drugs have reached advanced stages
of development for the treatment of infection due to multiꢀ
drugꢀresistant Gramꢀnegative bacteria. Thus, there is a great
need to develop new mechanisms by which Gramꢀnegative
antibacterial agents can combat bacterial antibiotic reꢀ
sistance.3,4
Among the wellꢀcharacterized compounds, threonylꢀ
hydroxamate derivatives are representative LpxC inhibitors,
such as 2 (CHIR-090) and 3 (LPC-009) (Figure 1 (a)).18,19
According to a few reports on the binding modes of these
compounds, the threonylꢀhydroxamate group of 2 and that of 3
occupy the active site, and its diphenyl acetylene or phenylꢀ
diyne group penetrates the hydrophobic passage.19ꢀ21
a
OH
OH
O
O
H
HN
O
O
H
OH
One of the emerging targets in Gramꢀnegative bacteria is
LpxC, an essential enzyme in the lipid A biosynthetic pathꢀ
way. Because LpxC does not show homology to any mammaꢀ
lian protein, it is a promising antibiotic target for developing
novel therapeutics against multidrugꢀresistant Gramꢀnegative
pathogens.5 LpxC inhibitors have drawn much attention in
new entities for Gramꢀnegative antibacterial agents.6
N
N
N
OH
O
O
N
OH
N
H
H
O
O
O
N
3 (LPC-009)
1 (L-161,240)
2 (CHIR-090)
b
cycloalkyl
or
C63
C63
cycloaryl
Scaffold Hopping
O
To date, extensive investigations have been carried out on
the mechanism underlying the LpxC enzyme.7,8 Those studies
have identified a zinc ion to catalyze deacetylation and a hyꢀ
drophobic tunnel binding a myristate fatty acyl chain of the
natural substrate. Merck researchers discovered 1 (L-161,240)
containing an oxazoline scaffold in the midꢀ1990s,6 and reꢀ
cently several LpxC inhibitors have been reported as antibacꢀ
terial agents,9ꢀ17 although to our knowledge, none have reached
the market yet.
H
H
O
N
H
OH
N
N
N
OH
OH
O
H
O
Zn
K239
Binding schematic for
threonine-based inhibitors
bound to E. coli LpxC
Me
*
sp2 or sp3
*
T191
Zn
T191
Conformationally-locked
cyclic compounds
Figure 1. (a) Threonineꢀbased LpxC inhibitors. (b) Scaffold hopꢀ
ping approach to LpxC inhibitors.
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Scheme 1. Synthesis of Initially Designed Compoundsa
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3
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aReagents and conditions: (a) 5ꢀMethoxycarbonylꢀ2ꢀpyrone, pyridine, 100 oC, 37%; (b) K2CO3, MeOH, rt, 86ꢀ96%; (c) 4ꢀ(4ꢀ
Iodobenzyl)morpholine, PdCl2(PPh3)2, CuI, Et3N, THF, rt, 30ꢀ62%; (d) LiOH aq., THF/MeOH, rt; (e) THPONH2, EDCI or HATU,
iPr2NEt, DMF, rt; (f) 4 M HCl, dioxane/MeOH, rt, or TFA, CH2Cl2, rt, 46ꢀ61%; (g) Methyl (2S)ꢀglycidate or methyl (2R)ꢀglycidate, TfOꢀ
Li, CH3CN, 60 oC, 34%; (h) Bromoacetylbromide, Et3N, THF, rt; (i) NaH, THF, rt, 22% (2 steps); (j) CDI, CH3CN, 60 oC, 46% (2 steps
from 4); (k) (R)ꢀ3ꢀOxoꢀ(tritylamino)ꢀpropionic acid methyl ester, NaBH(OAc)3, CH2Cl2, rt, 24%; (l) Triphosgene, Et3N, CH2Cl2, rt, 82%;
(m) HCOOH aq., THF 65 oC, 61%; (n) NH2OH aq., iPrOH, rt, 80%.
Herein we report a scaffold hopping approach to identify a
new scaffold with a zincꢀbinding head group. Additionally, we
describe the synthesis, biological evaluation, and docking
analysis of oxazolidinoneꢀbased LpxC inhibitors. Among theꢀ
se compounds, 23j showed remarkable antibacterial activity.
lylated under basic conditions, followed by Sonogashira couꢀ
pling with 4ꢀ(4ꢀiodobenzyl)morpholine. Finally, methyl ester 6
was converted to the corresponding hydroxamic acid 7 in three
steps: employing LiOH hydrolysis, coupling with OꢀTHPꢀ
hydroxylamine, and acidic hydrolysis. A morpholinꢀ3ꢀone 9 or
In order to discover a novel scaffold to replace the threonine
moiety, we embarked on a scaffold hopping approach utilizing
structural information. The crystal structure and detailed analꢀ
ysis of the binding site for E. coli LpxC complexed with the
threonineꢀbased inhibitor LPC-009 have been reported.19,20
Inspection of the available coꢀcrystal structures20 indicated that
the threonyl hydroxy group and benzamide moiety make key
contacts with C63, T191, and K239 (left part in Figure 1 (b)).
It is striking that the C=O bond of the benzamide and the CꢀH
bond of threonyl αꢀmethine lie in the same plane. We hypothꢀ
esized that adjustment of the conformation of the amide and
the hydroxamic acid makes better interactions with C63, T191,
and zinc, thus makes it possible to improve activity even
though the interaction with K239 is not available.23 Therefore,
we decided to incorporate the conformationally restricted cyꢀ
clic moiety to retain the hydrogenꢀbonding network and overꢀ
lapping with the positions of the central phenyl moiety and
hydroxamic acid group of threonineꢀbased inhibitors, as
shown at right in Figure 1 (b).
Table 1. IC50 and MIC Values of Initial Compounds
E.c.
IC50
(nM)
MIC (ꢀg/mL)
Structure
R =
cpd
2
E.c.a
E.c.b
K.p.c
3
0.13
0.01
1
0.25
7
1000
510
130
260
700
8
2
64
16
2
(S)-13
(S)-14
(R)-14
(S)-18
0.25
0.06
0.13
0.5
0.5
1
A diphenyl acetylene hydrophobe, similar to 2 (CHIR-090),
was chosen as a starting point for the initially designed comꢀ
pounds. The syntheses of these compounds are described in
Scheme 1. All designed compounds were derived from 4ꢀ
[(trimethylsilyl)ethynyl]aniline (4). Pyridone 5 was preꢀ
pared by heating 4 with the corresponding pyrone in pyridine.
For the preparation of the diphenyl acetylene unit, 5 was desiꢀ
8
O
NH
H
8
>32
N
N
OH
*
O
aWildꢀtype E. coli TG1 strain. bEfflux mutant (acrB-) E. coli
KAM3 strain. cWildꢀtype K. pneumoniae ATCC 13883 strain.
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Scheme 2. Synthesis of Oxazolidinone-Based Diyne Compoundsa
1
2
NH2
R1
3
4
5
6
7
8
9
NH2
a,b
NH2
R1
c
d,e
R1
I
R2
R2
R2
R3
19f (R1 = OMe, R2 = H)
19g (R1 = F, R2 = H)
19h (R1 = H, R2 = NO2)
19j (R1 = H, R2 = F)
20a (R1 = H, R2 = H)
20f (R1 = OMe, R2 = H)
20g (R1 = F, R2 = H)
20h (R1 = H, R2 = NO2)
20j (R1 = H, R2 = F)
21a (R1 = H, R2 = H, R3 = hydroxyethyl)
21b (R1 = H, R2 = H, R3 = hydroxypropyl)
21c (R1 =H, R2 = H, R3 = O-THP-hydroxymethyl c-propyl)
21e (R1 = H, R2 = H, R3 = c-propyl)
21f (R1 = OMe, R2 = H, R3 = c-propyl)
21g (R1 = F, R2 = H, R3 = c-propyl)
21 (R1 = H, R2 = NO2, R3 = c-propyl)
21j (R1 = H, R2 = F, R3 = c-propyl)
10
11
12
13
14
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18
19
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O
O
O
O
HN
O
OH
COOMe
h
N
N
R1
R1
R2
R2
R3
R3
22a (R1 = H, R2 = H, R3 = hydroxyethyl)
22b (R1 = H, R2 = H, R3 = hydroxypropyl)
22c (R1 = H, R2 = H, R3 = O-THP-hydroxymethyl c-propyl)
22d (R1 = H, R2 = H, R3 = hydroxymethyl c-propyl)
22e (R1 = H, R2 = H, R3 = c-propyl)
23a (R1 = H, R2 = H, R3 = hydroxyethyl)
23b (R1 = H, R2 = H, R3 = hydroxypropyl)
23d (R1 = H, R2 = H, R3 = hydroxymethyl c-propyl)
23e (R1 = H, R2 = H, R3 = c-propyl)
23f (R1 = OMe, R2 = H, R3 = c-propyl)
23g (R1 = F, R2 = H, R3 = c-propyl)
23h (R1 = H, R2 = NO2, R3 = c-propyl)
23i (R1 = H, R2 = NH2, R3 = c-propyl)
23j (R1 = H, R2 = F, R3 = c-propyl)
f
22f (R1 = OMe, R2 = H, R3 = c-propyl)
22g (R1 = F, R2 = H, R3 = c-propyl)
22h (R1 = H, R2 = NO2, R3 = c-propyl)
g
22i (R1 = H, R2 = NH2, R3 = c-propyl)
22j (R1 = H, R2 = F, R3 = c-propyl)
aReagents and conditions: (a) TMSꢀacetylene, PdCl2(PPh3)2, CuI, Et3N, THF, rt; (b) K2CO3, MeOH, rt, 81ꢀ100% (2 steps); (c) Acetylene,
NiCl2 6H2O, TMEDA, THF, rt, 24ꢀ73%; (d) Methyl (2S)ꢀglycidate, TfOLi, CH3CN, 60 oC; (e) i. CDI, CH3CN, 60 oC, 16ꢀ56% (2 steps); ii.
NaH, THF, 0 oC, 27% (3 steps) for only 22g; (f) PPTS, MeOH, 50 C, 77%; (g) Zn, AcOH, rt, 88%; (h) NH2OH aq., iPrOH/THF, rt, 37ꢀ
o
86%.
oxazolidinone 10 was formed by Lewis acid−induced epoxide
ring opening using chiral methyl glycidate with 4, followed by
cyclization with bromoacetyl bromide or CDI. Meanwhile, for
imidazolidinone, reductive alkylation of the corresponding
aldehyde and 4, followed the by the addition of triphosgene,
affords 16. Target compounds 13, 14, and 18 were afforded
from 9, 10, and 16 in a similar manner as hydroxamic acid 7.
With oxazolidinone (S)ꢀ14 in hand, we next varied the diꢀ
phenyl acetylene moiety in order to evaluate the structureꢀ
activity relationship (SAR) of the hydrophobic group further.
According to the reported coꢀcrystal structures (3NZK24 and
3P3G20), the terminal morpholine group of 2 and the phenyl
group of 3 are surrounded by solventꢀexposed lipophilic amiꢀ
no acid residues (M195, I198, Q202, S211, and F212) at the
entrance to the hydrophobic passage. In particular, the termiꢀ
nal phenyl group of 3 forms an edgeꢀtoꢀface π−π interaction
with F212.19 These findings suggest that an sp2ꢀcharacterꢀ
bearing moiety is suitable for interacting efficiently with
F212.18ꢀ21 Thus, we explored diyne compounds having various
terminal functional groups. Moreover, we examined the SAR
of the substitution effect on the central phenyl ring because we
expected new interactions between the substituent and the
amino acids positioned at the exit to the hydrophobic pasꢀ
sage.15
Some of the newly designed compounds exhibited good celꢀ
lular activity against E. coli and K. pneumoniae, although their
activities in cellꢀfree enzymatic assay were lower than that of
2 (Table 1). Pyridone 7 showed weak enzyme inhibitory activꢀ
ity and exhibited antibacterial activities with a minimum inꢀ
hibitory concentration (MIC) of 8 ꢀg/mL against an E. coli
wildꢀtype strain. Replacement of the pyridone moiety with the
morpholineꢀ3ꢀone moiety improved IC50 value slightly and
increased antibacterial activity 4ꢀfold (compound 7 versus (S)ꢀ
13). To our delight, ring compression to the oxazolidinone (S)ꢀ
14 resulted in much higher activity. Similar shifts in IC50 value
in E. coli relative to the MIC values of E. coli and K. pneu-
moniae were observed (compound (S)ꢀ13 versus (S)ꢀ14). Inꢀ
terestingly, (S)ꢀ14 showed a good E. coli MIC value, although
its enzyme activity was significantly lower than compared to
that of 2. At the same time, the absolute configuration in the 5ꢀ
position of oxazolidinone was inverted from S to R. The acꢀ
tivity of (R)ꢀ14 was slightly lower than that of its Sꢀ
enantiomer (2ꢀfold shift in IC50 and MIC values). The substituꢀ
tion of oxazolidinone with imidazolidinone (S)ꢀ18 led to the
weakening of activity.
The synthesis of oxazolidinoneꢀbased inhibitors with modiꢀ
fied hydrophobes can be found in Scheme 2. The preparation
of target compounds was initiated by Sonogashira reactions of
4ꢀiodoaniline derivatives with TMSꢀacetylene followed by
deprotection of the TMS group. A diacetylene unit was synꢀ
thesized via Niꢀcatalyzed coupling reactions of terminal alꢀ
kynes.25 The desired hydroxamic acids were prepared in a
manner similar to that described above.
The results of the oxazolidinoneꢀbased hydrophobe screenꢀ
ing can be found in Table 2. Hydroxyethyldiyne 23a retained
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its activity, and the extension of the alkyl chain such as in 23b Figure S2, Supporting Information). On the basis of these reꢀ
1
2
3
4
5
6
7
8
showed a 3ꢀfold increase in enzyme inhibitory activity and
antibacterial activity. These results indicate that the terminal
hydroxyl group was presumably located away from the hydroꢀ
phobic passage. Potency increased slightly when the propyl
group of 23b was replaced by the methyl cyclopropyl group
having an sp2 character, such as in 23d, which likely increased
the hydrophobic interaction. Moreover, the removal of the
hydroxymethyl group from 23d increased K. pneumoniae anꢀ
tibacterial activity 4ꢀfold, although the enzyme inhibitory acꢀ
tivity was unchanged (23e).
sults, we next investigated substituent modification at the me-
taꢀposition of the Nꢀphenyl moiety, which we did not expect to
appreciably affect the dihedral restrictions. The introduction of
an electronꢀdonating amino group to give 23h significantly
weakened enzyme inhibitory activity, whereas the strongly
electronꢀwithdrawing nitro group 23i retained potency. Enꢀ
couraged by this result, we introduced another electronꢀ
withdrawing and small lipophilic substituent. Changing NO2
to F enhanced activity remarkably (E. coli MIC = 0.016
ꢀg/mL and K. pneumoniae MIC = 0.063 ꢀg/mL). As a result
of this tuning of the hydrophobic group, 23j was over 30ꢀfold
more potent than (S)ꢀ14. On the other hand, these new oxaꢀ
zolidiones had little or no effect against Pseudomonas aeru-
ginosa and Acinetobacter baumannii (see Table S1, Supportꢀ
ing Information).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. IC50 and MIC Values of Oxazolidinones
O
O
H
N
N
R
OH
S
O
E.c.
IC50
(nM)
MIC (ꢀg/mL)
Structure
R =
cpd
2
E.c.a
E.c.b
K.p.c
3
130
140
58
0.13
0.01
0.063
0.125
0.031
0.016
0.016
0.5
0.25
(S)-14
23a
23b
23dd
23e
23f
0.5
0.5
2
8
2
0.125
0.125
0.063
4
20
1
Figure 2. Comparative analysis of threonineꢀbased and oxazoliꢀ
dinone-based inhibitors. (a) Threonineꢀbased inhibitor 3 (LPC-
009) bound coꢀcrystal structure in E. coli LpxC (3P3G) showing
key hydrogen bonds (pink dotted lines) and interaction with zinc
(gray dotted lines).20 (b)(c) Docking pose of 23j bound to E. coli
LpxC showing partially resected solventꢀaccessible surface (gray).
18
0.25
32
4
2000
200
270
27
23g
23h
23i
0.5
0.25
To examine the binding mode, we performed a docking
study of 23j to E. coli LpxC (Figure 2). The model clearly
shows that the hydroxamic acid chelates the catalytic zinc ion
with its two oxygen atoms. Additionally, it forms a hydrogen
bond with T191 and E78, as in the case of 3 (LPC-009). On
the other hand, the threonyl hydroxyl group of 3 forms a hyꢀ
drogen bond with K239, but this interaction is not observed in
the case of 23j. As expected, the carbonyl oxygen atom of
oxazolidinone is capable of accepting a hydrogen bond from
the backbone NH of C63, corresponding to the oxygen atom in
the benzamide moiety of 3. Interestingly, the model indicates
that the oxygen atom in position 1 of the oxazolidinone ring
makes dual contacts with the backbone NH and the side chain
thiol of C63. Also, it suggests that the fluorine atom on the
phenyl group interacts with the thiol group of C207 (Figure 2
(b)(c)).26 The fluorine atom contributes to the strong inhibition
of enzymatic activity and antibacterial activity (compound 23e
versus 23j). It appears that such additional interactions with
C207 and C63, as in the case of 23j, plays an important role in
the remarkable activity enhancement without the key hydroꢀ
genꢀbonding interaction with K239, such as occurs in 3. In
general, oxazolidinoneꢀbased compounds can result in 2ꢀ to 8ꢀ
fold lower efflux ratios (MIC value of wildꢀtype strain/MIC
0.25
0.125
0.016
0.063
0.031
0.004
2
1
23j
6
0.063
aWildꢀtype E. coli TG1 strain. bEfflux mutant (acrB-) E. coli
KAM3 strain. cWildꢀtype K. pneumoniae ATCC 13883 strain.
dMixture of diastereomers.
Next we examined the SAR of the substitution effect on the
central phenyl ring of 23e. The introduction of a methoxy
group at the orthoꢀ position of the Nꢀphenyl moiety resulted in
a dramatic decrease in enzyme inhibitory activity, suggesting
that dihedral restriction between phenyl and oxazolidinone due
to the resonance and the steric effect of the methoxy group
may be critical for the activity (compound 23e versus 23f).
The fluorineꢀsubstituted 23g was more active than 23f, possiꢀ
bly because 23g may have fewer dihedral restrictions (see
4
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ACS Medicinal Chemistry Letters
(4) Silver, L. L. Challenges of antibacterial discovery. Clin. Microbi-
ol. Rev. 2011, 24, 71ꢀ109.
value of efflux knockout strain). The strong activity of 23j
against the E. coli wildꢀtype strain contributes to the lower
1
2
3
4
5
6
7
8
9
efflux ratio.
(5) Young, K.; Silver, L. L.; Bramhill, D.; Cameron, P.; Eveland, S.
S.; Raetz, C. R.; Hyland, S. A.; Anderson, M. S. The envA permeabilꢀ
ity/cell division gene of Escherichia coli encodes the second enzyme
In summary, we conducted a scaffold hopping approach,
which restricts the conformation of the threonine moiety, to
discover a new series of LpxC inhibitors. We found oxazoliꢀ
dinoneꢀbased inhibitors. The most potent compound, 23j, exꢀ
hibited nanomolar potencies against E. coli LpxC enzyme,
excellent antibacterial activity against E. coli and K. pneu-
moniae, and a low efflux ratio. Docking analysis of 23j with E.
coli LpxC suggested that the oxygen atom in position 1 of the
oxazolidinone ring makes dual contacts with the backbone NH
and the side chain thiol of C63 and the fluorine atom on the
phenyl group interacts with the thiol group of C207. The interꢀ
actions with C207 and C63 may contribute to the strong acꢀ
tivity of 23j. This observation provides new insights into the
rational design of new LpxC inhibitors. These oxazolidinoneꢀ
based inhibitors represent promising leads for further exploraꢀ
tion as antibacterial agents.
of lipid
A
biosynthesis. UDPꢀ3ꢀOꢀ(Rꢀ3ꢀhydroxymyristoyl)ꢀNꢀ
acetylglucosamine deacetylase. J. Biol. Chem. 1995, 270, 30384ꢀ
30391.
(6) Onishi, H. R.; Pelak, B. A.; Gerckens, L. S.; Silver, L. L.; Kahan,
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strateꢀanalog inhibitor. Nature Structural Biology 2003, 10, 645ꢀ651.
(8) Clayton, G. M.; Klein, D. J.; Rickert, K. W.; Patel, S. B.;
Kornienko, M.; ZugayꢀMurphy, J.; Reid, J. C.; Tummala, S.; Sharma,
S.; Singh, S. B.; Miesel, L.; Lumb, K. J.; Soisson, S. M. Structure of
the bacterial deacetylase LpxC bound to the nucleotide reaction prodꢀ
uct reveals mechanisms of oxyanion stabilization and proton transfer.
J. Biol. Chem. 2013, 288, 34073ꢀ34080.
ASSOCIATED CONTENT
Supporting Information
Synthetic method, characterization of compounds, protocols of
biological evaluations, and computational methods. This material
is available free of charge via the Internet at http://pubs.acs.org.
(9) Mansoor, U. F.; Vitharana, D.; Reddy, P. A.; Daubaras, D. L.;
McNicholas, P.; Orth, P.; Black, T.; Siddiqui, M. A. Design and synꢀ
thesis of potent Gramꢀnegative specific LpxC inhibitors. Bioorg. Med.
Chem. Lett. 2011, 21, 1155ꢀ1161.
AUTHOR INFORMATION
Corresponding Author
(10) Zhang, J.; Zhang, L.; Li, X.; Xu, W. UDPꢀ3ꢀOꢀ(Rꢀ3ꢀ
hydroxymyristoyl)ꢀNꢀAcetylglucosamine deacetylase (LpxC) inhibiꢀ
tors: A new class of antibacterial agents. Curr. Med. Chem. 2012, 19,
2038ꢀ2050.
*(H.K.) Tel: +81280571551; Fax: +81280572336; Eꢀmail: haꢀ
ruaki.kurasaki@mb.kyorinꢀpharm.co.jp.
Author Contributions
(11) Warmus, J. S.; Quinn, C. L.; Taylor, C.; Murphy, S. T.; Johnson,
T. A.; Limberakis, C.; Ortwine, D.; Bronstein, J.; Pagano, P.; Knafels,
J. D.; Lightle, S.; Mochalkin, I.; Brideau, R.; Podoll, T. Structure
based design of an in vivo active hydroxamic acid inhibitor of P.
aeruginosa LpxC. Bioorg. Med. Chem. Lett. 2012, 22, 2536ꢀ2543.
All authors have approved of the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are thankful to H. Furuta of Kyorin Pharmaceutical Co., Ltd.,
for his mass spectrometry and infrared spectra expertise.
(12) McAllister, L.A.; Montgomery, J.I.; Abramite, J.A.; Reilly, U.;
Brown, M.F.; Chen, J. M.; Barham, R.A.; Che, Y.; Chung, S.W.;
Menard, C.A.; MittonꢀFry, M.; Mullins, L. M.; Noe, M. C.; O'Donꢀ
nell, J. P.; Oliver, R. M. 3rd.; Penzien, J.B.; Plummer, M.; Price, L.
M.; Shanmugasundaram, V.; Tomaras, A. P.; Uccello, D. P. Heteroꢀ
cyclic methylsulfone hydroxamic acid LpxC inhibitors as Gramꢀ
negative antibacterial agents. Bioorg. Med. Chem. Lett. 2012, 22,
6832ꢀ6838.
ABBREVIATIONS
LpxC, UDPꢀ3ꢀOꢀ[(R)ꢀ3ꢀhydroxymyristoyl]ꢀNꢀacetylglucosamine
deacetylase; E.c., Escherichia coli; K.p., Klebsiella pneumoniae;
MIC, minimum inhibitory concentration; CDI, 1,1’ꢀcarbonyl
diimidazole; TMS, trimethylsilyl; THP, tetrahydropyranyl; Tr,
trityl; TMEDA, tetramethylethylenediamine; cꢀpropyl, cycloproꢀ
(13) Brown, M. F.; Reilly, U.; Abramite, J. A.; Arcari, J.T.; Oliver,
R.; Barham, R. A.; Che, Y.; Chen, J. M.; Collantes, E. M.; Chung, S.
W.; Desbonnet, C.; Doty, J.; Doroski, M.; Engtrakul, J. J.; Harris, T.
M.; Huband, M.; Knafels, J. D.; Leach, K. L.; Liu, S.; Marfat, A.;
Marra, A.; McElroy, E.; Melnick, M.; Menard, C. A.; Montgomery, J.
I.; Mullins, L.; Noe, M. C.; O'Donnell, J.; Penzien, J.; Plummer, M.
S.; Price, L. M.; Shanmugasundaram, V.; Thoma, C.; Uccello, D. P.;
Warmus, J. S.; Wishka, D. G. Potent inhibitors of LpxC for the treatꢀ
ment of Gramꢀnegative infections. J. Med. Chem. 2012, 55, 914ꢀ923
pyl;
HATU,
1ꢀ[Bis(dimethylamino)methylene]ꢀ1Hꢀ1,2,3ꢀ
triazolo[4,5ꢀb]pyridinium 3ꢀoxide hexafluorophosphate; EDCI, 1ꢀ
Ethylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide; PPTS, pyridinium
pꢀtoluenesulfonate.
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23j
E.c. IC50: 6 nM
E.c. MIC: 0.016 mg/mL
K.p. MIC: 0.063 mg/mL
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