Benzimidazoles: Novel mycobacterial gyrase inhibitors from scaffold morphing

Article abstract of DOI:10.1021/ml5001728

Type II topoisomerases are well conserved across the bacterial species, and inhibition of DNA gyrase by fluoroquinolones has provided an attractive option for treatment of tuberculosis (TB). However, the emergence of fluoroquinolone-resistant strains of Mycobacterium tuberculosis (Mtb) poses a threat for its sustainability. A scaffold hopping approach using the binding mode of novel bacterial topoisomerase inhibitors (NBTIs) led to the identification of a novel class of benzimidazoles as DNA gyrase inhibitors with potent anti-TB activity. Docking of benzimidazoles to a NBTI bound crystal structure suggested that this class of compound makes key contacts in the enzyme active site similar to the reported NBTIs. This observation was further confirmed through the measurement of DNA gyrase inhibition, and activity against Mtb strains harboring mutations that confer resistance to aminopiperidines based NBTIs and Mtb strains resistant to moxifloxacin. Structure-activity relationship modification at the C-7 position of the left-hand side ring provided further avenue to improve hERG selectivity for this chemical series that has been the major challenges for NBTIs.

Full text of DOI:10.1021/ml5001728

Letter
pubs.acs.org/acsmedchemlett
Benzimidazoles: Novel Mycobacterial Gyrase Inhibitors from Scaffold
Morphing
Shahul Hameed P,*,† Anandkumar Raichurkar,† Prashanti Madhavapeddi,† Sreenivasaiah Menasinakai,†
Sreevalli Sharma,† Parvinder Kaur,† Radha Nandishaiah,† Vijender Panduga,† Jitendar Reddy,†
Vasan K. Sambandamurthy,† and D. Sriram‡
†AstraZeneca India Pvt. Ltd., Avishkar, Bellary Road, Bangalore 560024, India
S
* Supporting Information
ABSTRACT: Type II topoisomerases are well conserved across the bacterial species, and inhibition of DNA gyrase by
fluoroquinolones has provided an attractive option for treatment of tuberculosis (TB). However, the emergence of
fluoroquinolone-resistant strains of Mycobacterium tuberculosis (Mtb) poses a threat for its sustainability. A scaffold hopping
approach using the binding mode of novel bacterial topoisomerase inhibitors (NBTIs) led to the identification of a novel class of
benzimidazoles as DNA gyrase inhibitors with potent anti-TB activity. Docking of benzimidazoles to a NBTI bound crystal
structure suggested that this class of compound makes key contacts in the enzyme active site similar to the reported NBTIs. This
observation was further confirmed through the measurement of DNA gyrase inhibition, and activity against Mtb strains harboring
mutations that confer resistance to aminopiperidines based NBTIs and Mtb strains resistant to moxifloxacin. Structure−activity
relationship modification at the C-7 position of the left-hand side ring provided further avenue to improve hERG selectivity for
this chemical series that has been the major challenges for NBTIs.
KEYWORDS: Tuberculosis, type II topoisomerases, DNA gyrase, NBTIs, aminopiperidines, benzimidazoles
aminopyrazinamides, thiazolopyridine ureas, and pyrrola-
uberculosis remains a major public health problem across
Tthe world and claims approximately 1.5 million lives each mides.3,4 The second type of inhibitors target the GyrA subunit
year.1 The current treatment regimen involves a combination of
thereby inhibiting the DNA breakage−reunion function of the
enzyme. This class is exemplified by the fluoroquinolones
(FQ), novel bacterial topoisomerase inhibitors (NBTIs) and
aminopiperidines.3,4
four drugs administered for six months. The emergence of
multidrug resistant (MDR) forms of Mycobacterium tuberculosis
(Mtb) has further aggravated the situation, and individuals with
MDR-TB require treatment with a cocktail of 6−8 drugs over
an extended period of up to 24 months.2
The approval of FQ such as ofloxacin and moxifloxacin to
treat several bacterial infections validates DNA gyrase target for
the development of newer antibacterial agents. Several studies
have shown the clinical benefit of FQs such as ofloxacin and
moxifloxacin in the treatment of TB.5 However, reports of Mtb
strains resistant to FQs pose a threat to the continued use of
this class of drugs to treat TB.5 Therefore, identification of a
novel GyrA inhibitors with unique binding mechanism that is
distinctly different from the binding mode of the FQ class is
needed. This would lead to the discovery of novel gyrase agents
that can act against FQ resistant Mtb strains.
DNA gyrase, a type II toposiomerase responsible for DNA
replication and repair, is essential in all bacteria including
mycobacteria and absent in eukaryotes. The enzyme catalyzes
the interconversion of various topological forms of DNA, an
essential process in DNA replication. It introduces negative
supercoiling into circular DNA in an ATP-dependent reaction.
This enzyme is a heterotetramer comprising of GyrA and GyrB
subunits (A2B2). The GyrA subunit contains the DNA
breakage-reunion site, while GyrB hydrolyses ATP to generate
the energy required for enzyme activity. Unlike most other
bacteria, Mtb has a functional DNA gyrase but no topoisomer-
ase IV enzyme. There are at least two types of gyrase inhibitors
reported in the literature with potent activity against Mtb. The
first type of inhibitors target the ATP recognition site of GyrB
enzyme and block ATP hydrolysis. Examples of this type are
In the recent past, numerous NBTIs have been reported in
the literature as antibacterial and antimycobacterial agents.3,4
Received: April 29, 2014
Accepted: June 2, 2014
Published: June 2, 2014
© 2014 American Chemical Society
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Letter
The crystal structure of a Staphylococcus aureus DNA gyrase
bound to one of the NBTI provides insight into the unique
binding mechanism of this class of compounds and highlights
the key interactions involved in the gyrase active site, which are
nonoverlapping to the binding site of FQs. This unique
interaction in turn confers the ability of NBTIs to retain their
activity against FQ-resistant strains of S. aureus.6
In general, the NBTIs consists of a quinoline or
naphthyridine based left-hand side (LHS) ring, a mono- or
bicyclic hydrophobic right-hand side (RHS) ring and a linker
joining the RHS and LHS in a proper orientation. Many NBTIs
with variations in the LHS, linker and RHS with antibacterial
and antimycobacterial activity have been reported. This
includes the N-linked aminoperidines with both monocyclic
and bicyclic RHS (1a-e),3,4 N-cyclobutyl piperdine-3-carboxylic
acid (1f),8 tetrahydropyran (1g),9 and oxabicyclooctane (1h)
(Figure 1).10
Figure 2. Scaffold hopping of NBTIs.
a
Scheme 1. Synthesis of Benzimidazoles
Figure 1. Novel type II topoisomerase inhibitors reported in the
literature.
The aminopiperidine-based NBTIs with both monocyclic
and bicyclic RHS (1a−1g) have shown in vitro activity against
Mtb and also been shown to retain their activity against FQ-
resistant strains of Mtb. In addition, this class of compounds
were found to be efficacious in a murine model of
tuberculosis.4,7 However, inhibition of the cardiac ion channel
(hERG) remains a serious liability for the aminopiperidine
based NBTIs with monocyclic RHS. In order to identify a
scaffold with novel RHS group, we embarked on a scaffold
hopping approach based on the literature reported amino-
piperidines and its bound crystal structure with the S. aureus
DNA gyrase (Figure 2). Herein, we report the discovery of a
novel class of benzimidazoles (5 and 6, Figure 2), which
inhibits Mtb DNA gyrase with potent antimycobacterial activity.
These compounds are bactericidal and retain their minimum
inhibitory concentration (MIC) against FQ-resistant strains of
Mtb. The identified structure−activity relationship (SAR) for
hERG mitigation provides an attractive opportunity to further
optimize the benzimidazole lead toward preclinical candidate
selection.
a
Reagents and conditions: (a) CsCO3, DMSO, 90 °C; (b) NaOMe,
MeOH, 75 °C; (c) mesyl chloride, DIPIEA, DCM, 0 °C; (d) PTSA,
ethanol, 90 °C; (e) 4 N HCl in dioxane, 50 °C; (f) Na2CO3, DMF,
130 °C.
ment of 3a with sodium methoxide in methanol under heating
conditions resulted in intermediate 3b. The mesylates (4a−d)
were obtained by treating 3a−d with mesyl chloride under
basic conditions. The mesylates (4a−d) were freshly prepared
and used immediately for the next step due to potential
instability reasons. The N-BOC protected piperidinyl benzimi-
dazoles (6a−f) were synthesized by treating corresponding
ortho-phenylenediamines (5a−f) with N-BOC piperidine-4-
carboxaldehyde (24) in the presence of para-toluene sulfonic
acid (catalytic amount) under open air conditions. The
secondary piperidines (7a−f) were obtained upon deprotection
of N-BOC group under acidic conditions. Alkylation of
secondary piperidines (7a−f) with mesylates (4a−d) in the
presence of Na2CO3 as base under thermal heating conditions
resulted in the title compounds (5 and 9−18).
The syntheses of compounds with piperidine linkers are
described in Scheme 1.
Alkylation of LHS ring (2a−c) with 2-bromoethanol in the
presence of cesium carbonate as a base provided N-alkylated
product (3a−d) as the major isomer. Nucleophilic displace-
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Treatment of mesylate 4a with N-BOC protected piperazine
(8b) under basic condition and heating provided 9a (Scheme
S2, Supporting Information). Intermediate 9b was obtained
from 9a using sodium methoxide. Alkylation of secondary
piperazines (7a−g) with 2-choro benzimidazoles (11a−c) in
the presence of a base under microwave conditions resulted in
the title compounds (6−8 and 19, Scheme S2, Supporting
Information). Compounds 2, 3, and 4 were synthesized as per
Schemes S4 and S5 (Supporting Information). Nucleophilic
displacement of fluoro naphthyridones (8 and 10) with
pyridinol (12a) or phenol (12b) or using cesium carbonate
under thermal heating conditions resulted in the title
compounds 21−23 (Scheme S3, Supporting Information).
Scaffold Hopping and Hypothesis Generation. Toward
identifying a structurally distinct novel mycobacterial gyrase
inhibitor, we attempted scaffold hopping of NBTIs. The
binding mode of NBTIs from the published crystal structures
revealed that the linker −NH group and the RHS part of
NBTIs (GSK299423, 1e, Figure 3a)6 makes a critical
interaction in the protein. So we have focused our scaffold
morphing efforts toward designing of new compounds with
novel RHS (compounds 2−6, Figure 2). We hypothesized that
constraining the NH of amino piperidine based NBTIs as part
of a bicyclic ring should provide access to the hydrogen
bonding interaction with Asp83 (Asp89 in the case of Mtb
gyrase) as observed in the NBTI bound crystal structure of S.
aureus DNA gyrase (PDB ID: 2XCS). To validate this
hypothesis, we designed compounds with benzimidzole (5
and 6, Table2), indole (2 and 3, Table 1), and oxindoles (4,
Table 1) as novel RHS (Figure 2).
The newly designed compounds 2, 3, 4, and 5 were docked
into 2XCS and a Mtb DNA gyrase subunit A (Mtb GyrA)
homology model to understand the binding interactions. Figure
3 depicts the possible binding modes of compounds 2, 3, 4, and
5 in the S. aureus DNA bound GyrA subunit and in the Mtb
GyrA model (Figure S7 in Supporting Infromation). The H-
bonding contacts with Asp83 (Asp89 in the case of Mtb GyrA
model) and hydrophobic pocket occupied by Ala68, Val71,
Gly72, and Met121 of S. aureus DNA bound GyrA (Ala74,
Val77, Ala78, and Met127 in Mtb GyrA, respectively) were key
interactions in the NBTIs binding site. The binding mode for
benzimidazole derivative 5 suggests that the hydrogen of N-1
atom of benzimidazole ring is engaged in H-bonding
interaction with the carboxylate of Asp83 (Asp89 in the case
of Mtb GyrA model) and CF3 group attached to C-5 position
point toward the hydrophobic pocket. This is similar to the
interactions observed for NBTIs. Thus, compound 5 is likely to
be active against Mtb gyrase. However, the ring NH group in
compounds 2, 3, and 4 is not suitably placed to make the
desired hydrogen bonding interaction with Asp 83 (Asp89 in
the case of Mtb GyrA model) due to the adaptation of a
different conformational orientation of indole (2 and 3) and
oxindole (4) rings in comparison to benimidazole ring (5).
Furthermore, the substituent attached to C-5 or C-6 position of
bicylic rings in compounds 2 and 4 is likely to be pointing away
from the hydrophobic pocket constituting Ala68, Val71, Gly72,
and Met121 of S. aureus GyrA (Ala74, Val77, Ala78, and
Met127 in Mtb GyrA, respectively). The CF3 group attached to
C-6 in compound 3 is likely to pick up the hydrophobic
interaction. In all cases, the naphthyridone ring assembled
between the two base pairs of DNA, similar to the reported
binding mode of NBTIs.
Figure 3. (a,b) Docking pose of compounds 5 (cyan), 4 (pink), 3
(orange), and 2 (yellow) on to the crystal bound structure of
GSK299423 (green) to S. aureus DNA gyrase.6 (c) Docking pose of
compound 5 on to the homology model of Mtb DNA gyrase subunit
A. (d) Docking pose of compound 23 on to the homology model of
Mtb DNA gyrase subunit A.
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ACS Medicinal Chemistry Letters
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On the basis of these observations, we synthesized
compounds 2−5 with different RHS and tested for Mtb gyrase
inhibition. The biological activities, in vitro safety, and logD of
these novel leads are shown in Table 1.
Compound 5 with benzimidazole RHS inhibited Mtb DNA
gyrase supercoiling in the single-digit micromolar range and
displayed potent MIC against Mtb. Compounds 2, 3, and 4
with indole and oxindole RHS, were inactive against the
enzyme (IC50 > 50 μM) and showed weak Mtb MIC (50−100
μM). As predicted by docking studies, compounds 2−4 are
Table 1. Profile of Compounds with Novel RHS
Mtb
MIC Mtb gyrase SC Msm GyrB cytotoxicity hERG logD
H37Rv
(μM)
IC50
(μM)
ATPase
IC50 (μM)
THP-1 IC50
(μM)
IC50
pH
7.4
entry
(μM)
2
3
4
5
100
50
>50
>50
>50
1.0
>100
>100
>100
>100
>50
>50
>50
>50
2
3.3
4
1.8
4.8
1.0
100
0.19
2.8
4
Table 2. SAR Modifications around the RHS and LHS Part of Benzimidazoles
a
Not determined.
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expected to be inactive against the Mtb gyrase, as these
compounds are unable to pick up the critical interaction with
Asp89. Hence, the observed lack of Mtb gyrase inhibition for
compounds 2−4 is in agreement with the results from the
docking studies. In order to rule out any contribution of Mtb
GyrB inhibition to the observed Mtb MICs, compounds were
screened against Mycobacterium smegmatis (Msm) GyrB as a
surrogate for Mtb GyrB enzyme.3 The lack of inhibitory activity
of compounds 2, 3, 4, and 5 against the Msm GyrB clearly
indicated that these compounds were inhibitors of either the
holoenzyme (GyrA2B2 complex) or GyrA subunit. In addition,
these compounds showed no signs of cellular cytotoxicity (IC50
> 50 μM) against a human monocytic cell line (THP1),
thereby demonstrating excellent selectivity. However, these
compounds showed potent hERG inhibition at single digit
micromolar range (hERG IC50 1 to 4.8 μM, Table1), likely due
to higher lipophilicity (logD = 2.8 to 4) observed with the
initial set of compounds synthesized in this study.
may be due to lowered logDs and disturbing the pi-stacking
interaction of the RHS group to the hERG channel.
To expand the SAR scope of R1 group at LHS and improve
hERG selectivity, we explored suitably substituted aryl rings at
R1 of LHS that can lower logD. Initially, introduction of 3-
pyridyloxy at R1 instead of OCH3 retained Mtb MIC but did
not show any improvement in reducing hERG liability.
Replacement of 3-pyridyloxy by 4-phenoxy sulphonamide at
R1 position of LHS showed excellent improvement in Mtb
MIC and hERG mitigation (compound 21 versus 22 and 23,
Table 2). This suggested that polar bulky substitution at R1
position may not disturb the binding orientation of NBTIs as
evident from the docking pose of 23 in Mtb GyrA homology
model (Figure 3d). Further exploration of this trend with
various combinations of RHS will be presented. In order to link
whole cell potency to Mtb gyrase inhibition, representative
compounds (5, 6, 13, 14, 19, and 23) were tested in the Mtb
DNA gyrase supercoiling assay (Table 3). Most of the
compounds with MIC against Mtb also inhibited supercoiling
activity of Mtb gyrase thus confirming their mode of inhibition.
Encouraged by the potent Mtb activity observed for
compound 5, we envisaged the SAR requirements for the
newly identified benzimidazole RHS and we used MIC as an
activity indicator to track the SAR. We assumed that the
mechanism of gyrase inhibition was similar across the newly
synthesized compounds with benzimidazole RHS. Piperidine-
based linker was found to be optimal for Mtb MIC. A
substitution of piperidine with piperazine led to the weakening
of Mtb MIC by 15-fold (compound 5 versus 6, Table 2).
Removing the R2 substitution at the C-5 position of
benzimidazole resulted in the loss of Mtb MIC by 25-fold,
thereby proving the essentiality of hydrophobic group at the C-
5 position (compound 6 versus 7, Table 2). Similarly, changing
OCH3 to F at R1 position of LHS resulted in the loss of Mtb
MIC by 4−8-fold, suggesting that a bulky substitution may be
essential for the MIC activity (7 versus 8, 5 versus 9, 10 versus
12, and 14 versus 15 as match pairs, Table 2). As suggested by
modeling studies, the RHS benzimidazole-binding region was
more hydrophobic in nature; additionally the electron with-
drawing hydrophobic groups such as CF3 strengthens the H-
bonding interaction of ring NH with Asp 89. In order to
expand the hydrophobic pocket SAR further, we varied R2
substitutions at the C-5 and introduced an R3 substitution at C-
6 position of benzimidazole RHS. Replacement of CF3 group
by Cl at the C-5 position retained the Mtb MIC (compound 5
versus 11), whereas CN substitution weakened MIC by 20-fold
(compound 5 versus 12). This data suggests that the electron
withdrawing hydrophobic group at the C-5 position is essential
for conferring potent Mtb MIC for this series. Introduction of
other hydrophobic substituents such as methyl or fluorine
enhanced the potency by 4-fold (compound 11 versus 13 and
14, Table 2). The addition of a nitrogen at the 8 position of
LHS ring as pyrido[2,3-b]pyrazin-2(1H)-one (compound 16)
or moving nitrogen to 4-position of LHS as 1,4-quinoxazoli-
none (compound 17) was broadly tolerated for potency.
Compound 17 showed moderate improvement in reducing
hERG inhibition (hERG IC50 10 μM against 1.4 μM for
compound 14). This could be due to a slight reduction in logD
or disturbance of pi-stacking of the LHS group to the hERG
channel. Furthermore, changing Cl to CN at the C-5 position
of benzimidazole RHS with both piperidine and piperazine
linker retained the Mtb MIC but showed >4-fold improvement
in mitigation of hERG (14 versus 19 and 20, Table 2). The
mitigation of hERG liability observed for compounds 19 and 20
Table 3. Activity of Benzimidazoles against Mutants
Resistant to Compounds 1a, 1d, or Moxifloxacin
MIC (μM)
Mtb
Mtb
Compd
1aR
mutant
(A74V)
gyrase SC H37Rv
Compd
MoxiR
IC50
(μM)
wild-
type
1bR mutant mutant
entry
(D89N)
(G88N)
1a
1c
5
0.11
0.25
1.0
2
0.19
0.19
0.19
0.03
0.19
0.78
0.19
0.13
0.5
4
>100
>100
25
<0.19
<0.19
0.78
0.06
0.78
1.56
0.39
4
2
50
13
19
20
23
100
>100
>100
25
25
4.3
100
100
12.5
2
a
ND
1.9
moxifloxacin
ciprofloxacin
isoniazid
12.5
0.25
0.5
a
ND
16
8
a
ND
0.06
0.015
0.06
0.008
0.03
0.015
0.06
0.008
a
rifampicin
ND
a
Not determined.
In order to differentiate benzimidazoles from FQs and
NBTIs, compounds (5, 6, 13, 14, 19, and 23) were screened
against moxifloxacin and NBTI-resistant mutant of Mtb (1a and
1b mutants).4 These compounds retained their MIC against lab
derived moxifloxacin-resistant mutant, but lost their activity
against a NBTI-resistant mutant by >25-fold. This result
indicates that this class of molecules is likely to be effective
against FQ-resistant strains of Mtb and that the mechanism of
inhibition is similar to that reported for other NBTIs.
The representative compounds (19 and 20) were evaluated
for their activity against a panel of cytochrome P450 isozymes
(CYP) and in vivo pharmacokinetics profile in rats (Table S4,
Supporting Information). Compounds 19 and 20 did not
inhibit CYP isozymes up to 20 μM, except against CYP3A4
enzyme (IC50 of 9.5 μM for 19).
Compounds 19 and 20 exhibited low to moderate in vivo
clearance, low volume of distribution, and short half-life in rats.
Oral bioavailability was found to be very low (1 to 3%) for both
compounds despite low to moderate clearance (Table S4,
Supporting Information). This could be due to poor oral
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Hmnabadkar, V.; Ghosh, A.; Narayan, C.; Ramya, V. K.; Kaur, P.;
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absorption associated with low solubility and poor intestinal
permeability of these compounds.
In conclusion, we have described the discovery of
benzimidazoles as novel gyrase inhibitors with potent Mtb
MIC and with a similar mechanism as that of NBTIs.
Introduction of polar groups at the C-7 position of LHS
provided avenues for building selectivity SARs against hERG.
Further efforts are required to optimize PK parameters and to
assess in vivo safety. We believe that this class of compounds
has potential to be developed as anti-TB drug candidate.
ASSOCIATED CONTENT
* Supporting Information
■
S
Computational methods; determining the antimycobacterial
properties; determination of IC50 for the supercoiling activity of
M. tuberculosis H37Rv gyrase holoenzyme; determination of
resistance frequency; genetic mapping of mutations conferring
resistance to N-linked aminopeperidinyl alkyl quinolones and
naphthyridones; assay procedures for log D and hERG
measurement; DMPK profile for benzimidazoles; sythetic
schemes and procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
(7) Barrows, D. Recent Advances in TB Drug Development. 40th
IUATLD Meeting, Cancun, Mexico, Dec 5, 2009. http://www.
n e w t b d r u g s . o r g / e v e n t fi l e s / p 4 /
Novel%20Mtb%20DNA%20Gyrase%20inhibitors_The%20Union_
40th.pdf.
(8) Mitton-Fry, M. J.; Brickner, S. J.; Hamel, J. C.; Brennan, L.;
Casavant, J. M.; Chen, M.; Chen, T.; Ding, X.; Driscoll, J.; Hardink, J.;
Hoang, T.; Hua, E.; Huband, M. D.; Maloney, M.; Marfat, A.;
McCurdy, S. P.; McLeod, D.; Plotkin, M.; Reilly, U.; Robinson, S.;
Schafer, J.; Shepard, R. M.; Smith, J. F.; Stone, G. G.; Subramanyam,
C.; Yoon, K.; Yuan, W.; Zaniewski, R. P.; Zook, C. Novel quinoline
derivatives as inhibitors of bacterial DNA gyrase and topoisomerase
IV. Bioorg. Med. Chem. Lett. 2013, 23, 2955−2961.
AUTHOR INFORMATION
Corresponding Author
*(S.H.P.) Tel: + 91 080 23621212. Fax: + 91 080 23611214. E-
mail: shahulmehar0615@gmail.com or shahulmehar@yahoo.
com.
■
Present Address
‡(D.S.) BITS-Pilani, Hyderabad Campus, Shameerpet, Hyder-
abad 500 078, India.
(9) Surivet, J. P.; Zumbrunn, C.; Rueedi, G.; Hubschwerlen, C.; Bur,
̀
D.; Bruyere, T.; Locher, H.; Ritz, D.; Keck, W.; Seiler, P.; Kohl, C.;
Gauvin, J. C.; Mirre, A.; Kaegi, V.; Dos Santos, M.; Gaertner, M.;
Delers, J.; Enderlin-Paput, M.; Boehme, M. Design, synthesis, and
characterization of novel tetrahydropyran-based bacterial topoisomer-
ase inhibitors with potent anti-Gram-positive activity. J. Med. Chem.
2013, 56, 7396−7415.
Author Contributions
S.H.P., V.S., A.R., P.M., and S.D. wrote the manuscript and
participated in the design and execution of this study. S.H.P.
performed the chemical syntheses. S.S., R.N., J.R., P.V., and
P.K. performed and interpreted biological data. S.M. performed
the analytical experiments to assign the structure of newly
synthesized compounds.
(10) Singh, S. B.; et al. Oxabicyclooctane-linked novel bacterial
topoisomerase inhibitors as broad spectrum antibacterial agents. ACS.
Med. Chem. Lett. 2014, 5, 609−614.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Our sincere thanks to Drs. T. Balganesh, B. Ugarkar, Pravin
Iyer Balasubramanian, and Shridhar Narayanan for their
valuable suggestions and encouragement during the course of
this work. We aslo thank CMG Bangalore, AZ Global DMPK,
Safety, Biosciences (AZ Boston, USA), and Discovery Sciences
(AZ, Alderly Park, UK) for technical support in various assays
REFERENCES
■
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