Antibacterial activity of quinoxalines, quinazolines, and 1,5-naphthyridines

Article abstract of DOI:10.1016/j.bmcl.2013.06.048

Several phenyl substituted naphthalenes and isoquinolines have been identified as antibacterial agents that inhibit FtsZ-Zing formation. In the present study we evaluated the antibacterial of several phenyl substituted quinoxalines, quinazolines and 1,5-naphthyridines against methicillin-sensitive and methicillin-resistant Staphylococcus aureus and vancomycin-sensitive and vancomycin-resistant Enterococcus faecalis. Some of the more active compounds against S. aureus were evaluated for their effect on FtsZ protein polymerization. Further studies were also performed to assess their relative bactericidal and bacteriostatic activities. The notable differences observed between nonquaternized and quaternized quinoxaline derivatives suggest that differing mechanisms of action are associated with their antibacterial properties.

Full text of DOI:10.1016/j.bmcl.2013.06.048

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4968–4974
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antibacterial activity of quinoxalines, quinazolines,
and 1,5-naphthyridines
Ajit K. Parhi a,b, Yongzheng Zhang b, Kurt W. Saionz b, Padmanava Pradhan c, Malvika Kaul d,
Kalkal Trivedi d, Daniel S. Pilch d, Edmond J. LaVoie a,
⇑
a Department of Medicinal Chemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA
b TAXIS Pharmaceuticals Inc., North Brunswick, NJ, USA
c Department of Chemistry, The City College and City University of New York, New York, NY 10031-9198, USA
d Department of Pharmacology, The University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Several phenyl substituted naphthalenes and isoquinolines have been identified as antibacterial agents
that inhibit FtsZ-Zing formation. In the present study we evaluated the antibacterial of several phenyl
substituted quinoxalines, quinazolines and 1,5-naphthyridines against methicillin-sensitive and methi-
cillin-resistant Staphylococcus aureus and vancomycin-sensitive and vancomycin-resistant Enterococcus
faecalis. Some of the more active compounds against S. aureus were evaluated for their effect on FtsZ pro-
tein polymerization. Further studies were also performed to assess their relative bactericidal and bacte-
riostatic activities. The notable differences observed between nonquaternized and quaternized
quinoxaline derivatives suggest that differing mechanisms of action are associated with their antibacte-
rial properties.
Received 17 April 2013
Revised 12 June 2013
Accepted 17 June 2013
Available online 26 June 2013
Keywords:
Antibiotics
Staphylococcus aureus
Enterococcus faecalis
Bacteriostatic
Bactericidal
Ó 2013 Elsevier Ltd. All rights reserved.
Quinoxalines
Quinazolines
1,5-Naphthyridines
Nosocomial infections associated with multidrug-resistant
pathogens such as methicillin-resistant Staphylococcus aureus
(MRSA) and vancomycin-resistant enterococci (VRE) represent a
major public health concern.1–4 Increased bacterial resistance to
conventional antibiotics has brought attention to the critical need
for the identification of novel therapeutic antibacterial targets.5
FtsZ is an essential and highly conserved bacterial protein in-
volved in cytokinesis.6–9 Cell division in bacteria occurs at the site
of formation of a cytokinetic Z-ring polymeric structure comprised
of FtsZ subunits. FtsZ forms the Z-ring via a process of GTP-depen-
dent self-polymerization.7–9 The Z-ring plays a key role in constric-
tion of the bacterial cell wall and serves as a scaffold for the
recruitment of other components of the cell division machinery.7,9
Several recent reviews have discussed the potential of antibacterial
agents that target FtsZ, as well as recent advances in the discovery
of small molecules that perturb processes in which FtsZ is in-
volved.10–15 FtsZ-targeting antibacterial agents can exert their dis-
ruptive effects on the Z-ring by either enhancing or inhibiting FtsZ
self-polymerization.16–25
Several phenyl substituted naphthalenes and isoquinolines
were identified as antibacterial agents that act as stimulators of
FtsZ polymerization.26–28 In the present study, we evaluated of
the bactericidal and bacteriostatic potential of phenyl substituted
quinoxalines, quinazolines and 1,5-naphthyridines and examined
their effect on FtsZ protein polymerization.
The quinoxaline derivatives evaluated in this study are listed in
Table 1. Commercially available quinoxaline 1 was converted to
1-methylquinoxalinium iodide 2 by treatment with methyl iodide
at 80 °C in a sealed vial. The 2-substituted quinoxalines 2a–10a
and the N-methylated derivatives 2b–9b were prepared as out-
lined in Scheme 1. 2-Trifluoromethylsulfonyloxyquinoxaline was
prepared as previously described.29 For the preparation of 7a, 3-
(t-butyl)-5-(carbomethoxy)phenylboronic acid pinacol ester was
used in the Suzuki coupling. This boronate ester was prepared by
treating commercially available methyl 3-bromo-5-iodobenzoate
with 4-t-butylphenylboronic acid in the presence of Pd(PPh3)4.
The resulting 3-bromo-5-carbomethoxy-40-(t-butyl)biphenyl was
converted to it’s pinacol ester by standard coupling conditions
using bis(pinacolato)diboron and PdCl2(dppf) with KOAc in
dioxane.
The assignment of the site of N-methylation in the case of
⇑
Corresponding author. Tel.: +1 848 445 2674; fax: +1 732 445 6312.
E-mail address: elavoie@pharmacy.rutgers.edu (E.J. LaVoie).
2b–9b is based upon the literature30–33 and spectral data from
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.06.048

A. K. Parhi et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4968–4974
4969
Table 1
Substituted quinoxaline derivatives evaluated for antibacterial activity
N
X
N
N
X
N
CH3
Y
b
a
Compound
X
Y
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
8a
8b
9a
9b
10a
11a
12a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Phenyl
Phenyl
3-Fluorophenyl
3-Fluorophenyl
3-Biphenyl
3-Biphenyl
3-t-Butylphenyl
3-t-Butylphenyl
4-t-Butylphenyl
4-t-Butylphenyl
3-(40-t-Butyl-5-carbomethoxybiphenyl)
3-(40-t-Butyl-5-carbomethoxybiphenyl)
3-(40-t-Butyl-5-carboxamidobiphenyl)
3-(40-t-Butyl-5-carboxamidobiphenyl)
3-(40-t-butyl-5-[carboxamido-N-(2-hydroxyethyl)]biphenyl)
3-(40-t-Butyl-5-[carboxamido-N-(2-hydroxyethyl)]biphenyl)
3-(40-t-Butyl-5-[carboxamido-N-(2-aminoethyl)]biphenyl)
3-t-Butylphenyl
CH2NC(NH2)2
CH2NC(NH2)2
4-t-Butylphenyl
R1
R1
R2
R3
R2
R3
N
N
N
N
OTf
N
N
N
OH
c
b
a
N
I
2a-7a
2b-7b
R1 = R2 = R3 = H
2a,b
3a,b R1= fluoro; R2 = R3 = H
4a,b R1 = phenyl; R2 = R3 = H
R1 = t-butyl; R2 = R3 = H
R1 = H; R2 =t-butyl; R3 = H
5a,b
6a,b
7a,b R1= 4-t-butylphenyl; R2 = H; R3 =carbomethoxy
N
N
X
N
N
N
N
X
CO2CH3
Cl
d,e
c
f
O
O
O
N
N
8a-10a
8b,9b
I
7a
8a,b X
9a,b X
= carboxamido
= N-(2-hydroxyethyl)carboxamido
X
= (2-aminoethyl)carboxamido
10a
Scheme 1. Synthesis of quinoxalines and N-methylquinoxalinium derivatives. Reagents and conditions: (a) triflic anhydride, TEA, DCM, 0 °C, 2 h; (b) dioxane, Pd((PPh3)2)Cl2,
Cs2CO3, phenylboronic acid for 2a, 4-fluorophenylboronic acid for 3a, 3-biphenylboronic acid for 4a, 3-t-butylphenylboronic acid for 5a, 3-t-butylphenylboronic acid for 6a,
3-(t-butyl)-5-(carbomethoxy)phenylboronic acid pinacol ester for 7a with (XPhos, Pd(OAc)2, K2CO3, ACN/H2O (2:1) (c) MeI, 80–90 °C, sealed vial; 12 h; (d) THF/H2O (2:1),
LiOH, 50 °C; (e) Oxalyl chloride, DCM, cat DMF, rt; (f) R-NH2, DCM, rt.
2D NOESY data that were analyzed for 2b, 5b and 6b, which are de-
tailed in the Supporting information.
The preparation of 2-phenyl-6-methylquinoxalines was per-
formed as outlined in Scheme 2. A mixture of both 5-methyl-2-
hydroxyquinoxaline and 8-methyl-2-hydroxyquinoxaline was
formed by condensing 3-methyl-1,2-phenylenediamine with
ethyl-2-oxaacetate. These hydroxyquinoxalines were converted
to their chloro derivatives using POCl3.34 The mixture of

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A. K. Parhi et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4968–4974
Table 2
chloroquinoxalines was then subester by standard coupling condi-
tions usingbisjected to Suzuki coupling conditions using either
3-t-butylphenylboronic acid or 4-t-butylphenylboronic acid.
Isolated from the mixture formed in each instance was 2-(3-t-
butylphenyl)-6-methylquinoxaline and 2-(4-t-butylphenyl)-
5-methylquinoxaline, respectively. Each of the isolated
5-methylquinoxalines were treated with NBS to form their bromo-
methyl derivatives, which subsequently was converted to their
respective guanidinomethyl derivatives, 11a and 12a.
Substituted quinazolines and 1,5-naphthyridines synthesized and evaluated for
antibacterial activity
X
X
N
N
N
N
Y
Y
13-16
17, 18
The spectral identification of the 2-phenyl-6-methylquinoxa-
line was based on a careful analysis of 2D-NOESY and gCOSY spec-
tral data. The position of the phenyl moiety was established
unequivocally on the basis of detailed gHMQC and gHMBC spectral
analyses, which are detailed in the Supporting information.
The quinazoline and 1,5-naphthyridines synthesized and evalu-
ated for antibacterial activity are listed in Table 2. The substituted
4-phenylquinazoline derivatives 13 and 14 were synthesized as
outlined in Scheme 3. 4-Chloro-8-methylquinazoline was prepared
as described in the literature.35 Suzuki coupling of this intermedi-
ate using 4-t-butylphenylboronic acid provided 4-(4-t-butyl-
phenyl)-8-methylquinazoline. Treatment of this intermediate
with NBS provided the bromomethyl derivative, which was con-
verted to its azide derivative and subsequently reduced to provide
the aminomethyl derivative 13. Alternative, this bromomethylqui-
nazoline could be treated with 1,3-bis(t-butoxycarbonyl)guanidine
and the N-Boc protecting groups removed using trifluoroacetic acid
in dichloromethane.
Compound 16 was prepared as shown in Scheme 4. Conversion
of 4-methyl-8-hydroxyquinazoline to its triflate and subsequent
Suzuki coupling using 4-t-butylphenylboronic acid gave 3-
methyl-8-(4-t-butylphenyl)quinazoline. This intermediate was
converted to its bromomethyl derivative using NBS in CCl4. Using
conditions as previously described for 4-(4-t-butylphenyl)-8-bro-
momethylquinazoline, this bromomethyl derivative could be con-
verted to its guanidinomethyl derivative 16.
Compd
X
Y
13
14
15
16
17
18
4-t-Butylphenyl
4-t-Butylphenyl
4-t-Butylphenyl
CH2NC(NH2)2
4-t-Butylphenyl
4-t-Butylphenyl
CH2NH2
CH2NC(NH2)2
CH2NC(NH2)(CH3)
4-t-Butylphenyl
CH2NH2
CH2NC(NH2)2
inomethyl derivative 18 using methodology previously described
in this study for methylquinazolines.
The relative antibacterial activities of these varied quinoxalines
and methylquinoxalinium derivatives against methicillin-sensitive
S. aureus (MSSA), methicilllin-resistant S. aureus (MRSA), vancomy-
cin-sensitive Entercoccus faecalis (VSE) and vancomycin-resistant E.
faecalis (VRE) are provided in Table3. Quinoxaline and N-methyl-
quinoxalinium iodide did not exhibit notable antibacterial activity
against S. aureus or E. faecalis. The presence of hydrophoblic moie-
ties such as a phenyl, 4-fluorophenyl, 3-biphenyl, or 4-t-butyl-
phenyl at the 3-position of 1-methylquinoxalinium iodides 2b–
6b, but not at the 2-position of quinoxaline (2a–6a), resulted in a
significant increase in antibacterial activity. A similar trend was
observed for quinoxalines structurally-related to 6a and 6b, having
a 5-carboxymethy substituent (7a and 7b), a 5-carboxyamido sub-
stituent (8a and 8b) or a 5-carboxamido-N-(2-hydroxyethyl) group
(9a and 9b). Only in the case of the related carboxamido derivative
with an N-(2-aminoethyl) substituent (10a) was significant activity
observed for a quinoxaline derivative. The placement of a guanid-
inomethyl substituent at the 5-position of either a 2-(3-t-butyl-
phenyl)quinoxaline or 2-(4-t-butylphenyl)quinoxaline (11a and
12a) did result in a notable increase in antibacterial activity.
These data tend to suggest that these highly basic substituents
that would be protonated at physiological pH could mimic the
The synthesis of the naphthyridine derivatives 17 and 18 was
accomplished as outlined in Scheme 5. Conversion of 4-hydroxy-
8-methyl[1,5]naphthyridine to its triflate, followed by Suzuki
coupling with 4-t-butylphenylboronic acid provided 4-(4-t-butyl-
phenyl)-8-methyl[1,5]naphthyridine. The methyl substituent
could be converted to its aminomethyl derivative 17 or its guanid-
N
N
N
N
Cl
+
N
N
N
OH
+
NH2
NH2
b
a
Cl
N
OH
X
CH3
CH3
CH3
CH3
CH3
c
Y
X
N
N
N
N
X
+
CH3
Y
X
CH3
Y
d
Y
e,f
N
N
N
N
H2C
H2N
NH
NH
11a
X = t-butyl; Y = H
CH2Br
12a X = H; Y = t-butyl
Scheme 2. Synthesis of the 5-guanidinomethyl quinoxaline derivatives 11a and 12a. Reagents and conditions: (a) HCOCOOCH2CH3/EtOH (1:1), reflux; 30 min; (b) POCl3,
110 °C, 1 h; (c) dioxane/H2O (3:1), Pd(PPh3)4, K2CO3, 3-(t-butyl)phenylboronic acid, 100 °C, 2 h; (d) NBS, CCl4, hm, 30 min; (e) DMF, K2CO3, 1,3-bis(t-butoxycarbonyl)guanidine,
16 h; (f) trifluoroacetic acid/DCM (1:1), 50 °C, 2 h.

A. K. Parhi et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4968–4974
4971
O
N
Cl
d,e
a
c
N
NH
b
N
N
N
N
N
N
N
N
CH2Br
CH2NH2
CH3
CH3
CH3
f,g
13
h
N
N
CH2NH
N
NH
H2N
CH2NH
14
NH
H3C
15
Scheme 3. Synthesis of the quinazoline derivatives 13–15. Reagents and conditions: (a) POCl3, CH3CN, reflux, 4 h33; (b) 4-t-butylphenylboronic acid, DME, Na2CO3, Pd(PPh3)4,
85 °C, 1 h; (c) NBS, CCl4, h , 3 h; (d) DMF, NaN3, K2CO3; 50 °C, 16 h; (e) THF/H2O (9:1), P(Ph3) on solid support, 72 h at rt; (f) DMF, K2CO3, 1,3-bis(t-butoxycarbonyl)guanidine,
m
16 h; (g) trifluoroacetic acid/DCM (1:1), 50 °C; (h) acetamidine HCl, K2CO3, DMF, 16 h, rt.
NH
H
N
CH3
H2C
N
CH3
CH2Br
NH2
N
c
a,b
d,e
N
N
N
N
N
N
OH
16
Scheme 4. Synthesis of the quinazoline derivative 16. Reagents and conditions: (a) triflic anhydride, TEA, DCM, ꢀ78 °C, 90 min; (b) 4-t-butylphenylboronic acid, DME,
Na2CO3, Pd(PPh3)4, 80 °C, 1 h; (c) NBS, CCl4, h
m
, 1 h; (d) DMF, K2CO3, 1,3-bis(t-butoxycarbonyl)guanidine, 16 h; (e) trifluoroacetic acid/DCM (1:1), 50 °C.
N
OH
N
N
d,e
N
N
a,b
c
CH2NH2
N
17
N
N
CH3
CH3
f,g
CH2Br
N
N
CH2NH
NH
18
H2N
Scheme 5. Synthesis of the 1,5-naphthyridine derivatives 17 and 18. Reagents and conditions: (a) triflic anhydride, TEA, DCM, 0 °C, 1 h; (b) 4-t-butylphenylboronic acid, DME,
Na2CO3, Pd(PPh3)4, 80 °C, 1 h; (c) NBS, CCl4, h , 1 h; (d) DMF, NaN3, K2CO3; 50 °C, 16 h; (e) THF/H2O (9:1), P(Ph3) on solid support, 72 h at rt; (f) DMF, K2CO3, 1,3-bis(t-
m
butoxycarbonyl)guanidine, 16 h; (g) trifluoroacetic acid/DCM (1:1), 50 °C.
charge associated with the analogous 1-methylquioxalinium deriv-
atives 5b and 6b.
Other diazanaphthalenes were examined including the quina-
zolines 13–16 and 1,5-naphthyridine derivatives (17 and 18). In
both instances, the less basic aminomethyl derivatives (13 and
17) did not exhibit significant antibacterial activity. While the
amidinomethyl derivative (15) did not exhibit significant activity,
in the case of the guanidinomethyl derivatives (14 and 18) more
pronounced antibacterial activity was observed. Alternating posi-
tion of the t-butylphenyl substituent and the guanidinomethyl

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A. K. Parhi et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4968–4974
Table 3
these select compounds in S. aureus 8325-4 (MSSA), S. aureus ATCC
33591 (MRSA), and E. faecalis ATCC 51575 (VRE) were determined
and subsequently compared with the corresponding MIC values
listed in Table 3. For these determinations, the bactericidal drug
vancomycin37 and the bacteriostatic drug erythromycin38 were
used as comparator controls. Per CLSI guidelines, an MBC/MIC ratio
of 1–2 is considered indicative of bactericidal behavior, with a cor-
responding MBC/MIC ratio P8 being considered indicative of bac-
teriostatic behavior.36 The comparator control agents yielded
expected results, with an MIC/MBC ratio of 1 being observed for
the bactericidal drug vancomycin and an MBC/MIC ratio of 256
being observed for the bacteriostatic drug erythromycin (see Ta-
ble 4). The nonquaternary quinoxaline (11a and 12a), quinazoline
(14), and 1,5-naphthyridine (18) compounds were all associated
with an MBC/MIC ratio of 1–2, indicative of a bactericidal mode
of action against MSSA, MRSA, and VRE. In striking contrast to
the nonquaternary compounds, the quaternary quinoxaline com-
pounds 4b, 5b, and 6b were associated with MBC/MIC ratios of
8–16 for MSSA and MRSA and 4–8 for VRE, indicative of bacterio-
static behavior on the part of these compounds. Viewed as a whole,
these observations suggest that the quaternary and nonquaternary
compounds may exert their antibacterial properties through differ-
ing mechanisms of action.
Antibacterial activities of quinoxaline, quinazoline and 1,5-naphthyridine derivatives
Compound
aMIC (
lg/mL)
S. aureus
8325-4
(MSSA)
S. aureus
E. faecalis
ATCC 19433
(VSE)
E. faecalis
ATCC 51575
(VRE)
ATCC 33591
(MRSA)
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
8a
8b
9a
9b
10a
11a
12a
>64
32
>64
>64
>64
8.0
>64
4.0
>64
0.5
>64
2.0
>64
1.0
>64
1.0
>64
2.0
>64
4.0
>64
>64
>64
32
>64
32
>64
>64
>64
>64
>64
32
>64
8.0
>64
16
>64
4.0
>64
2.0
>64
0.5
>64
2.0
>64
0.5
>64
1.0
>64
2.0
>64
4.0
4.0
4.0
4.0
>64
8.0
>64
8.0
>64
16
>64
4.0
>64
4.0
>64
8.0
8.0
8.0
8.0
>64
16
>64
4.0
>64
4.0
>64
8.0
8.0
16
4.0
4.0
4.0
16
To further explore the mechanistic differences between the
quaternary and nonquaternary compounds with regard to their
antibacterial activities, the impacts of 4b, 5b, 11a, 12a, 14, and
18 on the self-polymerization of purified S. aureus FtsZ (SaFtsZ)
were evaluated using a previously established microtiter plate-
based light-scattering assay.24–28 In this assay, FtsZ polymerization
is detected in solution by a time-dependent increase in light scat-
tering, as reflected by a corresponding increase in solution absor-
bance at 340 nm (A340). Figure 1 shows the time-dependent A340
profiles of SaFtsZ in the presence of DMSO vehicle alone or 4b,
5b, 11a, 12a, 14, or 18. Note that the nonquaternary compounds
11a, 12a, 14, and 18 stimulate SaFtsZ polymerization (Fig. 1A and
B). We next explored the stability of the SaFtsZ polymers induced
by the nonquaternary compounds. In the absence of a polymer-sta-
bilizing agent or compound, addition of GDP has been shown to
depolymerize FtsZ polymers formed in the presence of GTP.16 We
examined the impact, if any, of added GDP (10 mM) on the SaFtsZ
polymers formed in the presence of both GTP (1 mM) and the com-
13
14
15
16
32
4.0
32
16
64
8.0
64
64
64
32
64
>64
64
32
64
>64
17
18
>64
8.0
0.06
1.0
0.13
0.06
0.03
>64
8.0
>64
2.0
>64
64
>64
>64
32
>64
64
Oxacillin
Vancomycin
Erythromycin
Tetracycline
Clindamycin
8.0
1.0
1.0
0.5
2.0
>64
>64
>64
>64
>64
a
Minimum inhibitory concentration (MIC) assays were conducted in accordance
with Clinical and Laboratory Standards Institute (CLSI) guidelines for broth micro-
dilution.36 MIC is defined as the lowest compound concentration at which bacterial
growth is P90% inhibited.
substituent in the case of the quinazoline (14) from the 4 and 8
positions, to the 8 and 4 positons as in 16 resulted in a four-fold
decrease in activity.
pounds (40 lg/mL).
The addition of 10 mM GDP did not exert a significant impact on
the A340 signal, an observation indicating that SaFtsZ polymers in-
duced by the presence of the compounds are stable to the depoly-
merizing effects of GDP. These collective results are consistent with
the bactericidal activities of the non-quaternary quinoxaline,
The antibacterial activities of the more potent quinoxaline (4b,
5b, 6b, 11a, and 12a), quinazoline (14), and 1,5-naphthyridine (18)
compounds prompted further investigation as to whether these
activities are bactericidal or bacteriostatic in nature. In this con-
nection, values of minimal bactericidal concentration (MBC) for
Table 4
Comparison of the MIC and MBC values for select quinoxaline, quinazoline, and 1,5-naphthyridine derivativesa
Compound or control agentb
S. aureus
8325-4
(MSSA)
S. aureus
ATCC 33591
(MRSA)
E. faecalis
ATCC 51575
(VRE)
MIC (lg/mL)
MBC (
l
g/mL)
MBC/MIC
MIC (
lg/mL)
MBC (
l
g/mL)
MBC/MIC
MIC (
lg/mL)
MBC (lg/mL)
MBC/MIC
4b
5b
6b
11a
12a
14
18
0.5
2.0
0.5
4.0
4.0
4.0
8.0
1.0
0.13
4.0
16
8
8
16
1
1
2
1
1
256
0.5
2.0
1.0
4.0
4.0
8.0
8.0
2.0
>64
4.0
16
16
8.0
8.0
16
16
4.0
na
8
8
16
2
2
2
2
2
na
8
64
64
64
32
16
64
64
na
na
8
4
4
2
1
2
1
na
na
16
16
16
16
32
64
>64
>64
8.0
4.0
4.0
8.0
8.0
1.0
32
Vancomycin
Erythromycin
a
MIC values were determined as described in the footnote to Table 3. Minimum bactericidal concentration (MBC) values were determined as previously described.24
Na = not applicable.
b
Vancomycin and erythromycin are included as control bactericidal and bacteriostatic agents, respectively.

A. K. Parhi et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4968–4974
4973
Acknowledgments
0.6
0.5
0.4
0.3
0.2
A
This study was supported by research agreements between
TAXIS Pharmaceuticals, Inc. and both Rutgers, The State University
of New Jersey (E.J.L.) and the University of Medicine and Dentistry
of New Jersey (D.S.P). S. aureus 8325-4 was the generous gift of Dr.
Glenn W. Kaatz (John D. Dingell VA Medical Center, Detroit, MI).
The Bruker Avance III 400 MHz NMR spectrometer used in this
study was purchased with funds from NCRR Grant No.
1S10RR23698-1A1. Mass spectrometry was provided by the Wash-
ington University Mass Spectrometry Resource with support from
the NIH National Center for Research Resources Grant No.
P41RR0954.
Vehicle
4b
5b
11a
12a
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.
06.048.
0
10
20
30
Time (minutes)
References and notes
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l
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