Discovery of a potent enoyl-acyl carrier protein reductase (FabI) inhibitor suitable for antistaphylococcal agent

Article abstract of DOI:10.1016/j.bmcl.2015.08.077

We report the discovery, synthesis, and biological activities of phenoxy-4-pyrone and phenoxy-4-pyridone derivatives as novel inhibitors of enoyl-acyl carrier protein reductase (FabI). Pyridone derivatives showed better activities than pyrone derivatives

Full text of DOI:10.1016/j.bmcl.2015.08.077

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a potent enoyl-acyl carrier protein reductase (FabI)
inhibitor suitable for antistaphylococcal agent
Yun Gyeong Kim a, Jae Hong Seo a, Jin Hwan Kwak b, Kye Jung Shin a,
⇑
a Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon, Gyeonggi-do 420-743, Republic
of Korea
b School of Life and Food Sciences, Handong Global University, Pohang 791-7, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the discovery, synthesis, and biological activities of phenoxy-4-pyrone and phenoxy-4-pyri-
done derivatives as novel inhibitors of enoyl-acyl carrier protein reductase (FabI). Pyridone derivatives
showed better activities than pyrone derivatives against FabI and Staphylococcus aureus strains, including
methicillin-resistant Staphylococcus aureus (MRSA). Among the pyridone derivatives, compound 16l espe-
cially exhibited promising activities against the MRSA strain and good pharmacokinetic profiles.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 22 June 2015
Revised 24 August 2015
Accepted 28 August 2015
Available online xxxx
Keywords:
Enoyl-acyl carrier protein reductase (FabI)
Antibiotic
MRSA
Pyridone
Since the discovery of antibiotics, the emergence of antimicro-
bial resistance is one of the most important threats to human
health.1 Among the resistant strains, methicillin-resistant Staphylo-
coccus aureus (MRSA)2 is the most common and serious strain of
nosocomial infections. For the treatment of MRSA infection, gly-
copeptide antibiotics, such as vancomycin and teicoplanin, are
now clinically used. However, the re-emergence of vancomycin-re-
sistant Staphylococcus aureus (VRSA)3 has prompted the develop-
ment of novel antibiotics that are mechanistically different from
present antibiotics.
During the last decade, as the genomic sequences of bacteria
were reported, a number of novel antimicrobial targets were iden-
tified;4 in particular, the pathway of bacterial fatty acid biosynthe-
sis (FASII) has been recognized as a new antibacterial target.5 In
mammals, fatty acid biosynthesis is facilitated by a single multi-
functional polypeptide complex. In contrast, fatty acids are synthe-
sized by discrete proteins known as FabH, FabG, FabA, and FabI in
bacteria. Based upon this difference, each enzyme involved in bac-
terial fatty acid biosynthesis may be a mechanistically distinct,
antimicrobial target. Among these bacterial enzymes, the final
reduction step catalyzed by FabI has been an attractive target for
the development of novel antibiotics, because it is the rate-limiting
step of chain elongation in bacterial fatty acid biosynthesis.
Furthermore, FabI is a valid antibacterial target, because it is inhib-
ited by antibacterial agents such as isoniazid (1)6 and triclosan (2).7
As a part of our continuing effort to discover novel FabI
inhibitors that could be developed as MRSA antibiotics, we have
performed high throughput screening (HTS) of a library of com-
pounds, to obtain hit compounds with new structural skeletons.
We identified several hit compounds with new scaffolds.
Among these compounds, compound 3, consisting of a phenoxy-
4-pyrone moiety, was an attractive hit, based on its inhibition of
FabI and MRSA strains. Also, its structure was drug-like and
distinct from known FabI inhibitors. In the following Letter, we
describe the structural modification and optimization of
phenoxy-4-pyrone in the development of an MRSA antibiotic
candidate with enhanced potency, as well as the ability to be orally
administered (see Fig. 1).
According to the in silico modeling study of hit compound 3 with
FabI, the binding mode of this compound was similar to that of tri-
closan.8 The oxygen of the ketone functional group in 4-pyrone
occupies the same position as the phenolic hydroxyl group of tri-
closan that binds to the phenolic hydroxyl group of Tyr156 and
the 20-ribose hydroxyl group of the NADPH cofactor to form a
hydrogen bond. The methoxymethyl group in the pyrone 6-position
lies in a spacious hydrophobic pocket region where the meta-Cl
group of the phenol in triclosan is located. On the basis of modeling
results, we structurally modified hit compound 3 in the phenoxy
and methoxymethyl parts to obtain lead compounds with better
activities. In addition, we performed bioisosteric replacement of
⇑
Corresponding author. Tel.: +82 2 2164 4060; fax: +82 2 2164 4059.
E-mail address: kyejung@catholic.ac.kr (K.J. Shin).
http://dx.doi.org/10.1016/j.bmcl.2015.08.077
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kim, Y. G.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.077

2
Y. G. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
H
N
O
OH
Cl
O
O
NH2
O
O
O
Cl
Cl
Cl
N
1
2
3
FabI IC50 = 5.2 µM
MIC (S. aureus) = 6.25 µg/ml
Figure 1. Structure of isoniazid (1), triclosan (2) and phenoxy-4-pyrone hit compound (3), and binding mode of triclosan (2) to S. aureus FabI enzyme.
pyrone into the pyridone moiety, to characterize biological activi-
ties resulting from a change of the main skeleton.
which were subjected to the Horner–Wadsworth–Emmons reac-
tion with a variety of aldehydes and t-BuOK, to produce 15.
By using the structural modifications mentioned above, a series
of 3-phenoxy-4-pyrone analogs (13a–f, 15a–u) were synthesized.
As the first step in hit optimization, they were used to investigate
their inhibitory activities against FabI and against bacterial strains
including MRSA (Table 1). Inhibitory activity against FabI was mea-
sured spectrophotometrically at 340 nm,10 and the minimum inhi-
bitory concentration (MIC) assay was performed using the
conventional agar dilution method.11 For comparison, triclosan
and linezolid were also assayed. Phenoxymethyl compounds
(13a–f) substituted in the 6-position of pyrone showed good to
excellent inhibitory activities against FabI, compared to hit com-
pound 3 and triclosan as reference compounds. In addition, MIC
activities against Staphylococcus aureus and the MRSA strain
increased in proportion to their enzymatic activities. We next
investigated the effects of the phenoxy moiety at the 3-position
of pyrone. Generally, 2,4-substituted phenoxy compounds
(13a–c), whether the substituents were electron withdrawing or
donating groups, produced desirable enzymatic and antibacterial
activities compared with the 2,3- or 2,6-substituted phenoxy com-
pounds (13d–f). A series of olefinic analogs (15a–u) substituted in
the 6-position of pyrone possessed good to moderate inhibitory
activities against FabI. However, they showed disappointing
results for MIC activities, regardless of the phenoxy substituents
in the 3-position. Although the reasons for these results are not
definitively known, the formation of hydrogen bonding via the
phenoxymethyl substituent or differences of lipophilicity are pos-
sible explanations. Using structure–activity relationship (SAR)
analyses, there was a tendency for phenoxymethyl substituents
in the 6-position of pyrone to show superior activities, as com-
pared with alkenyl substituents, which are either aromatic or
aliphatic.
To investigate the antibacterial effect of the 3-phenoxy group
on hit compound 3, 3-phenoxy-6-hydroxymethyl-4-pyrones (6),
as key intermediates of the pyrone and pyridone derivatives, were
synthesized using two separate synthetic pathways, described in
Schemes 1 and 2. To obtain 3-phenoxy-6-hydroxymethyl-4-py-
rones (6) using a simple and expeditious synthetic method,
Ullmann-type reactions with commercially available kojic acid
(4) and various aryl halides (5) using various copper salts and
ligands were initially used (Scheme 1).9 However, the desired
products (6a–d) were produced in very low yields (6–9%) in every
Ullmann reaction. To overcome this problem, we used an
alternative long-step approach to synthesize the pyrone skeleton
(Scheme 2). Diverse phenols (7) were reacted with chloroacetone
to produce phenoxyacetones (8), which were condensed with
dimethylformamide dimethylacetal (DMF-DMA) to produce enam-
inones (9). Condensation of compounds 9 with diethyl oxalate and
sodium ethoxide, followed by ring cyclization in acidic conditions,
successfully produced pyrone fragments 11 in good yields. Pyrone
carboxylic acid ethyl esters (11) were reduced to the desired
alcohols (6a–f) using NaBH4 in EtOH. Overall yields of 3-phe-
noxy-6-hydroxymethyl-4-pyrones (6a–f) using this alternative
method ranged from 33% to 52%.
We modified the 6-position of pyrone, which is located in a
hydrophobic region described in Scheme 3. In order to transform
the 6-position of pyrone, we converted the hydroxyl group of 6
into the chloride (12) by treatment with SOCl2. Reaction of the
chloride with phenol and K2CO3 to obtain the bulkier lipophilic
substituents produced the corresponding phenoxymethyl com-
pounds 13 in good yields. Another reaction involved elongation
of the carbon chain in the 6-position of pyrone. The Arbuzov reac-
tion of 12 with triethylphosphite produced phosphonates 14,
O
O
O
Br
OH
Ullmann Rx
R
+
R
HO
HO
O
O
5
4
6a: R=2,4-dichloro
6b: R=2-methyl-4-chloro
6c: R=2,4-dimethyl
6d: R=2,3-dichloro
Scheme 1. Synthesis of 3-phenoxy-6-hydroxymethyl-4-pyrones (6a–d).
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Y. G. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
O
O
N
O
HO
O
a
b
c
R
R
R
8
7
9
O
O
N
O
O
O
O
O
O
O
EtO2C
e
d
R
R
R
HO
EtO2C
10
11
6a: R=2,4-dichloro
6b: R=2-methyl-4-chloro
6c: R=2,4-dimethyl
6d: R=2,3-dichloro
6e: R=2,6-dichloro
6f: R=2-methyl-3-nitro
Scheme 2. Reagents and condition: (a) chloroacetone, K2CO3, acetone, 60 °C, 16 h, 94–98%; (b) DMF-DMA, benzene, 80 °C, 10 h, 55–74%; (c) diethyl oxalate, NaOEt, EtOH,
80 °C, 8 h; (d) AcOH, 40 °C, 75–83% for 2 steps; (v) NaBH4, MeOH, rt, 2 h, 88–93%.
O
O
O
O
O
O
O
O
O
a
b
R
R
R
O
HO
Cl
6
12
13
c
O
O
O
O
O
d
O
P
R
R
EtO
EtO
R'
O
14
15
Scheme 3. Reagents and condition: (a) SOCl2, TEA, CH2Cl2, 40 °C, 5 h, 65–82%; (b) phenol, K2CO3, acetone, 60 °C, 3 h, 68–94%; (c) P(OEt)3, 110 °C, 2 h, 88–100%; (d) R0CHO, t-
BuOK, THF, 1–3 h, 0 °C, 43–89%.
In order to further optimize compounds, we modified the main
skeleton by replacing pyrone with the pyridone moiety. The ratio-
nale behind designing the pyridone moiety involves the observa-
tion that the physicochemical properties of the pyridone moiety,
such as LogP and the solubility, are more drug-like than the pyrone
moiety and the previous observations that some compounds with
the pyridone moiety are known to inhibit FabI.12 Using fixed
6-phenoxymethylpyrones (13a–f) that showed promising activi-
ties, we prepared a series of 1-substituted-4-pyridone compounds
by reaction of 13a–f with primary amines in refluxed MeOH, as
depicted in Scheme 4.
combination of substituents in the 3- and 1-positions involved
2,4-substituted phenoxy and methyl groups (16b, 16g, 16l).13 In par-
ticular, compound 16l which had 1-methyl and 3-(2,4-dimethylphe-
noxy) substituents showed excellent enzyme (IC50 = 0.08
lM) and
MRSA strain growth inhibition (MIC = 0.049 g/mL). Based on these
l
results, compound 16l was selected for pharmacokinetic evaluation
to assess the possibility of oral administration.
The pharmacokinetic properties of compound 16l, after dissolv-
ing in a 1:2:7 mixed solution of N-methyl pyrrolidone, Tween 80,
and water, were evaluated intravenously and orally in mice at a
dose of 10 mg/kg (Table 3). Compound 16l had an area under the
The inhibitory activities of various synthesized pyridone deriva-
tives are summarized in Table 2. First, we explored the influence of
pyridone substituents at the 1-position by introducing various
alkyl groups, according to size. With increased bulk and length,
there is a decrease in inhibitory activity for substituents at the
1-position of pyridone. The proton substituent, which was the
smallest substituent, showed good enzymatic and strain growth
inhibition; however, the optimal substituent in the 1-position
was a methyl group in the pyridone skeleton. Next, we examined
the effect on biological activities of phenoxy substituents at the
3-position of pyridone. Supporting the previous finding with pyr-
one compounds, that the 2,4-substituted phenoxy compounds
gave more favorable results compared with the 2,3- and 2,6-substi-
tuted phenoxy compounds, similar inhibitory activities against
FabI and the MRSA strain were observed for the pyridone core.
Considering SAR studies with the pyridone skeleton, the best
concentration–time curve (AUC) of 355.2 lg min/mL, moderate
clearance, a large volume distribution, and a terminal half-life of
47 min after intravenous administration. In administering com-
pound 16l orally, compound 16l was rapidly absorbed into plasma
with a Tmax time of 5 min and had an AUC of 149.4 lg min/mL.
Taken together, compound 16l possessed good pharmacokinetic
profiles. The bioavailability of compound 16l was 41.9%, so it
should be possible to administer compound 16l orally.
In summary, we have found the potent antistaphylococcal
agents that have pyrone and pyridone structural moiety from a
hit compound 3. They strongly inhibit FabI, an important enzyme
in fatty acid biosynthesis in bacteria. Importantly, pyridone com-
pound 16l showed excellent inhibitory activities against FabI and
Staphylococcus aureus strains, including MRSA bacteria.
Furthermore, compound 16l had good pharmacokinetic properties
in mice following intravenous and oral administration, and its
Please cite this article in press as: Kim, Y. G.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.077

4
Y. G. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Table 1
Antibacterial activities of 13a–f and 15a–u
O
O
R1
R2
O
Compound no.
R1
R2
IC50 (FabI,
lM)
MIC (lg/ml)
S. aureus
MRSA
13a
13b
13c
13d
13e
13f
2,4-Cl2
PhOCH2–
PhOCH2–
PhOCH2–
PhOCH2–
PhOCH2–
PhOCH2–
0.68
0.45
0.38
1.25
1.42
3.52
3.125
1.563
1.563
6.25
6.25
12.5
6.25
6.25
1.563
12.5
12.5
12.5
2-Me-4-Cl
2,4-Me2
2.3-Cl2
2,6-Cl2
2-Me-3-NO2
15a
15b
2-Me-4-Cl
2-Me-4-Cl
4.88
2.45
>20
>20
NT
NT
O
15c
15d
15e
15f
15g
2-Me-4-Cl
2-Me-4-Cl
2-Me-4-Cl
2-Me-4-Cl
2-Me-4-Cl
3.89
2.94
3.12
4.57
5.82
>20
>20
>20
>20
>20
NT
NT
NT
NT
NT
O
N
S
S
NH
15h
15i
2-Me-4-Cl
2-Me-4-Cl
6.44
5.78
>20
>20
NT
NT
15j
2,4-Cl2
2,4-Cl2
4.53
1.89
>20
>20
NT
NT
15k
O
N
15l
2,4-Cl2
2.04
5.33
2.29
>20
>20
>20
NT
NT
NT
15m
15n
2,4-Me2
2,4-Me2
O
N
15o
15p
15q
2,4-Me2
2.3-Cl2
2.3-Cl2
3.48
6.73
5.68
>20
>20
>20
NT
NT
NT
O
N
15r
15s
15t
2.3-Cl2
2,6-Cl2
2,6-Cl2
3.44
4.79
4.12
>20
>20
>20
NT
NT
NT
O
N
15u
2,6-Cl2
3.74
0.44
>20
NT
Triclosan
Linezolid
0.391
0.781
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Y. G. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
O
O
O
O
O
a
R
R
O
O
N
R'
13
16
Scheme 4. Reagents and condition: (a) R0-NH2, MeOH, 60 °C, 12 h, 48–80%.
Table 2
Acknowledgments
Antibacterial activities of 16a–x
This work was financially supported by Research Fund 2012 of
The Catholic University of Korea and the Korean Health Technology
R&D Project, Ministry of Health & Welfare, Republic of Korea.
(HI12C1087).
O
O
R1
O
N
R2
References and notes
Compound no. R1
R2
IC50 (FabI,
lM)
MIC (
lg/ml)
1. Levy, S. B.; Marshall, B. Nat. Med. 2004, 10, S122.
S. aureus MRSA
2. Voss, A.; Doebbeling, S. N. Int. J. Antimicrob. Agents 1995, 5, 101.
3. (a) Bax, R.; Mullan, N.; Verhoef, J. Int. J. Antimicrob. Agents 2000, 16, 51; (b)
Pearson, H. Nature 2002, 418, 469.
4. Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L. Nat. Rev. Drug Disc.
2007, 6, 29.
5. (a) Wang, Y.; Ma, S. ChemMedChem 2013, 8, 1589; (b) Lu, H.; Tonge, P. J. Acc.
Chem. Res. 2008, 41, 1; (c) Zhang, Y. M.; White, S. W.; Rock, C. O. J. Biol. Chem.
2006, 281, 17541; (d) Tasdemir, D. Phytochem. Rev. 2006, 5, 99.
6. Mdluli, K.; Slayden, R. A.; Zhu, Y.; Ramaswamy, S.; Pan, X.; Mead, D.; Crane, D.
D.; Musser, J. M.; Barry, C. E., III Science 1998, 280, 1607.
7. Roujeinikova, A.; Levy, C. W.; Rowsell, S.; Sedelnikova, S.; Baker, P. J.; Minshull,
C. A.; Mistry, A.; Colls, J. G.; Camble, R.; Stuitje, A. R.; Slabas, A. R.; Rafferty, J. B.;
Pauptit, R. A.; Viner, R.; Rice, D. W. J. Mol. Biol. 1999, 294, 527.
8. (a) PDB Code; 1bvr: Rozwarski, D. A.; Vilchèze, C.; Sugantino, M.;
Bittman, R.; Sacchettini, J. C. J. Biol. Chem. 1999, 274, 15582; (b) PDB Code;
1qsg: Stewart, M. J.; Parikh, S.; Xiao, G.; Tonge, P. J.; Kisker, C. J. Mol. Biol. 1999,
290, 859.
16a
16b
16c
16d
16e
16f
2,4-Cl2
2,4-Cl2
2,4-Cl2
2,4-Cl2
2,4-Cl2
2-Me-4-Cl
H
CH3
1.82
0.12
0.781
0.195
1.563
6.25
1.563
0.195
1.563
6.25
Cyclopropyl 0.48
n-Butyl
Benzyl
H
1.25
1.42
0.40
0.11
6.25
12.5
1.563
0.098
0.391
3.125
3.125
0.781
0.049
0.391
0.781
1.563
1.563
0.195
3.125
3.125
0.195
3.125
>20
1.563
0.098
0.781
3.125
6.25
1.563
0.049
1.563
1.563
3.125
1.563
0.195
6.25
16g
16h
16i
2-Me-4-Cl CH3
2-Me-4-Cl Cyclopropyl 0.47
2-Me-4-Cl n-Butyl
0.63
0.65
1.14
0.08
16j
2-Me-4-Cl Benzyl
16k
16l
2,4-Me2
2,4-Me2
2,4-Me2
2,4-Me2
2,4-Me2
2.3-Cl2
2.3-Cl2
2,3-Cl2
2.6-Cl2
2,6-Cl2
2,6-Cl2
2-Cl-3-
NO2
H
CH3
16m
16n
16o
16p
16q
16r
16s
16t
16u
16v
Cyclopropyl 3.17
n-Butyl
Benzyl
H
1.00
2.69
0.84
0.22
9. Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359.
10. Assays were carried out in half-area, 96-well microtitre plates. Compounds
CH3
Cyclopropyl 1.50
H
CH3
Cyclopropyl 6.43
H
were evaluated in 100 ll assay mixtures containing S. aureus FabI enzyme.
4.98
0.72
3.125
0.195
3.125
>20
Reduction of the trans-2-octenoyl N-acetylcysteamine substrate analog was
measured spectrophotometrically by following the utilization of NADH or
NADPH at 340 nm at 30 °C for the linear period of the assay. S. aureus FabI
11.73
0.66
assays contained 50 mM sodium acetate, pH 6.5, 400
lM trans-2-octenoyl N-
acetylcysteamine, 200 M NADPH, and 150 nM S. aureus FabI. The rate of
l
decrease in the amount of NADPH in each reaction well was measured by a
microtiter ELISA reader using SOFTmax PRO software (Molecular Devices,
California, USA). The inhibitory activity was calculated by the following
formula: % of inhibition = 100 ꢀ [1 ꢁ (rate in the presence of compound/rate in
the untreated control)]. IC50 values were calculated by fitting the data to a
sigmoid equation.
16w
16x
2-Cl-3-
NO2
2-Cl-3-
NO2
CH3
0.781
>20
3.125
>20
Cyclopropyl 17.64
0.44
Triclosan
Linezolid
0.391
0.781
11. The antibacterial activities of the test compounds were evaluated using
bacterial strains (Hoechst, Germany). The strains were inoculated into 3 ml of
Fleisch extract broth (Beef extract 1%, peptone 1%, NaCl 0.3%, Na2HPO4ꢂ12H2O
0.2%, pH 7.4–7.5) and cultured on a shaking incubator at 37 °C for 18 h. Test
compounds were serially diluted in 2-fold dilutions from 2 mM to 15 lM. The
1.5 ml volume of each diluted solution was mixed with 13.5 ml of Muller
Hinton agar (Difco, USA) and plated. The overnight-cultured strains were 100-
fold diluted with broth on a 96-well plate. The diluted bacterial culture media
were then inoculated (104 CFU/spot) on the prepared agar plates by an
automatic inoculator (Dynatech, USA). The plates were incubated at 37 °C for
18 h. The lowest concentration that prevented the growth of each bacterium
was determined to be MIC.
Table 3
Pharmacokinetic parameters after intravenous and oral administration (10 mg/kg) of
16l to male ICR mice (n = 3 per time point, time = 5 min, 15 min, 30 min, 1 h, 2 h, 4 h,
6 h)
Parameter
AUC0–1
AUClast
Terminal half-life (min)
Cmax g/ml)
Tmax (min)
CL (ml/mim/kg)
MRT (min)
Vss (ml/kg)
F (%)
Intravenous
Oral
(
l
g min/ml)
355.2
354.7
47.89
149.4
148.7
33.92
4.043
5
12. (a) Kitagawa, H.; Ozawa, T.; Takahata, S.; Iida, M. Bioorg. Med. Chem. Lett. 2007,
17, 4982; (b) Tipparaju, S. K.; Joyasawal, S.; Forrester, S.; Mulhearn, D. C.;
Pegan, S.; Johnson, M. E.; Mesecar, A. D.; Kozikowski, A. P. Bioorg. Med. Chem.
Lett. 2008, 18, 3565; (c) Kitagawa, H.; Ozawa, T.; Takahata, S.; Iida, M.; Saito, J.;
Yamada, M. J. Med. Chem. 2007, 50, 4710.
(lg min/ml)
(
l
13. 16b: 1H NMR (CDCl3, 500 MHz): d 7.40 (d, J = 2.4 Hz, 1H), 7.36–7.32 (m, 3H),
7.11 (dd, J = 8.7, 2.4 Hz, 1H), 7.07 (m, 1H), 6.97 (d, J = 8.6 Hz, 2H), 6.82 (d,
J = 8.7 Hz, 1H), 6.67 (s, 1H), 4.91 (s, 2H), 3.73 (s, 3H). 13C NMR (CDCl3,
125 MHz): d 40.9, 66.6, 114.8, 117.8, 121.1, 122.3, 123.9, 127.7, 128.0, 29.9,
130.1, 134.4, 44.4, 144.6, 151.3, 157.3, 171.8. MS: calcd for C19H15Cl2NO3 + H+,
376.04; found [M+H]+, 376.12. 16g: 1H NMR (CDCl3, 500 MHz): d 7.36 (dd,
J = 8.6, 2.2 Hz, 2H), 7.20 (d, J = 2.2 Hz, 1H), 7.08 (s, 1H), 7.08–7.06 (m, 2H), 6.89
(d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.6 Hz, 1H), 6.68 (s, 1H), 4.91 (s, 2H), 3.69 (s, 3H),
2.30 (s, 3H). 13C NMR (CDCl3, 125 MHz): 16.1, 40.9, 66.8, 114.7, 117.8, 120.6,
122.3, 129.8, 128.3, 129.9, 130.1, 191.1, 131.8, 143.6, 146.6, 153.2, 157.3, 172.2.
MS: calcd for C20H18ClNO3 + H+, 356.10; found [M+H]+, 356.18. 16l: 1H NMR
28.15
36.5
1028
41.92
bioavailability (F value) was over 40% in mice. Overall, these results
strongly suggest that compound 16l may be a potent and orally
available FabI inhibitor for the treatment of MRSA infections.
Please cite this article in press as: Kim, Y. G.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.077

6
Y. G. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
(500 MHz, CDCl3) d 7.31–7.34 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H),
151.7, 148.1, 143.1, 133.6, 132.1, 129.8, 129.7, 128.67, 127.6, 122.2, 119.7,
118.1, 114.7, 66.78, 40.8, 20.7, 16.0. MS: calcd for C21H21NO3 + H+, 336.15;
found [M+H]+, 336.28.
6.93–6.96 (m, 3H), 6.88 (s, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.65 (s, 1H), 4.88 (s, 2H),
3.63 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H); 13C NMR (125 MHz, CDCl3) d 172.2, 157.3,
Please cite this article in press as: Kim, Y. G.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.077