Synthesis and evaluation of pretomanid (PA-824) oxazolidinone hybrids

Article abstract of DOI:10.1016/j.bmcl.2015.12.002

Pretomanid (PA-824) is an important nitroimidazole antitubercular agent in late stage clinical trials. However, pretomanid is limited by poor solubility and high protein binding, which presents opportunities for improvement in its physiochemical properties. Conversely, the oxazolidinone linezolid has excellent physicochemical properties and has recently shown impressive activity for the treatment of drug resistant tuberculosis. In this study we explore if incorporation of the outer ring elements found in first and second generation oxazolidinones into the nitroimidazole core of pretomanid can be used to improve its physicochemical and antitubercular properties. The synthesis of pretomanid outer oxazolidinone ring hybrids was successfully performed producing hybrids that maintained antitubercular activity and had improved in vitro physicochemical properties. Three lead compounds were identified and evaluated in a chronic model of tuberculosis infection in mice. However, the compounds lacked efficacy suggesting that portions of PA-824 tail not found in the hybrid molecules are required for in vivo efficacy.

Full text of DOI:10.1016/j.bmcl.2015.12.002

Bioorganic & Medicinal Chemistry Letters 26 (2016) 388–391
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of pretomanid (PA-824) oxazolidinone
hybrids
Rakesh a, David F. Bruhn a, Michael S. Scherman b, Aman P. Singh a, Lei Yang a, Jiuyu Liu a,
Anne J. Lenaerts b, Richard E. Lee a,
⇑
a Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, USA
b Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, CO, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Pretomanid (PA-824) is an important nitroimidazole antitubercular agent in late stage clinical trials.
However, pretomanid is limited by poor solubility and high protein binding, which presents opportuni-
ties for improvement in its physiochemical properties. Conversely, the oxazolidinone linezolid has excel-
lent physicochemical properties and has recently shown impressive activity for the treatment of drug
resistant tuberculosis. In this study we explore if incorporation of the outer ring elements found in first
and second generation oxazolidinones into the nitroimidazole core of pretomanid can be used to improve
its physicochemical and antitubercular properties. The synthesis of pretomanid outer oxazolidinone ring
hybrids was successfully performed producing hybrids that maintained antitubercular activity and had
improved in vitro physicochemical properties. Three lead compounds were identified and evaluated in
a chronic model of tuberculosis infection in mice. However, the compounds lacked efficacy suggesting
that portions of PA-824 tail not found in the hybrid molecules are required for in vivo efficacy.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 29 September 2015
Revised 29 November 2015
Accepted 1 December 2015
Available online 7 December 2015
Keywords:
Tuberculosis
Antituberculosis
Oxazolidinone
Pretomanid
PA-824
Antibiotic
Mycobacterium tuberculosis is the causative agent of tuberculo-
sis (TB) and is believed to have infected one third of the global
population, resulting in nearly 2 million deaths every year.1 The
standard therapy requires 6–9 months of drug treatment, which
contributes to patient noncompliance and the subsequent develop-
ment of multidrug resistant tuberculosis (MDR-TB) and exten-
sively drug resistant tuberculosis (XDR-TB).2,3 After decades
without the introduction of new antibiotics for treatment of TB, a
few new drugs are emerging.
One promising class of candidates for the treatment of TB are the
nitroimidazoles, including pretomanid (previously known as
PA-824) and delamanid. Both compounds are currently in human
clinical trials in US.4 Pretomanid is a potent inhibitor of both actively
replicating bacteria and hypoxic M. tuberculosis. Activity against this
hypoxic nonreplicating population is particularly important for the
development of new TB drugs. The presence of this drug tolerant
subpopulation of granuloma-resident cells, contributes substan-
tially to the need for lengthy treatment regimes. In M. tuberculosis,
pretomanid is activated by the deazaflavin-dependant nitroreduc-
tase. Activation of pretomanid within the target bacteria results in
production of nitric oxide and leads to nonspecific damage of
intracellular macromolecules, including proteins and cell wall
lipids.5,6 Following the disclosure of pretomanid, several laborato-
ries attempted to optimize its antitubercular properties and synthe-
sized various analogs by modifying the nitroimidazole pyran A/B
rings,7 pyran B ring,8 ether link9 and hydrophobic side chain.10 How-
ever, these studies tended to produce leads limited by poor solubil-
ity and high protein binding, which presents opportunities for
improvement in its physiochemical properties.
Another promising class are the oxazoldinones, including line-
zolid and Sutezolid. Unlike pretomanid, they have excellent phys-
iochemical properties. Linezolid has recently shown impressive
activity for the treatment of drug resistant tuberculosis.11 Linezolid
has excellent penetration of lungs and infected tissues and is a
drug of choice for the treatment acute MRSA pneumonia. In a
previous study, we were able to improve the physiochemical prop-
erties of a series of antitubercular nitrofuran isoxazolidines by
introducing and optimizing substituted C and D rings from the
outer rings of first and second generation oxazolidinones.12 In this
study we employ a similar strategy, replacing pretomanid’s (4-tri-
fluoromethoxy)benzyl side chain with the C and D rings from our
lead nitrofuran isoxazoline (compound 1) to improve the pharma-
cokinetic profile of this promising scaffold as outlined in Figure 1.
Scheme 1 shows the general synthesis of the target compounds.
The nitroimidazopyran nucleus 7 was synthesized as reported
⇑
Corresponding author. Tel.: +1 901 595 6617; fax: +1 901 595 5715.
E-mail address: richard.lee@stjude.org (R.E. Lee).
http://dx.doi.org/10.1016/j.bmcl.2015.12.002
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

Rakesh et al. / Bioorg. Med. Chem. Lett. 26 (2016) 388–391
389
O2N
Y
N
Z
O
N
O
N
O
N
OCF3
N
+
O
N
O
X
O2N
O
O
N
O
HN
Pretomanid
O2N
1 (Lee 1643)
Oxazolidinone
N
N
Y
Z
O
N
X
O
Figure 1. Nitroimidazole oxazolidinone hybrid series design.
hybrid compounds in the series and about 10 fold more potent
than pretomanid. Compounds were tested for in vitro cytotoxicity
against mammalian cells. All hybrid compounds except 8i, 9c, 9d
and 9g were less cytotoxic than the parent compound and the spe-
cies selectivity index (calculated as the ratio of mammalian IC50
and M. tuberculosis MIC) was improved for compounds 8a, 8c, 9e,
and 9f. The selectivity index for compound 9f (>1000) was 10–25
times greater than that of pretomanid, a significant improvement.
Like pretomanid, hybrid compounds maintained a narrow spec-
trum of antibacterial activity, lacking activity against a panel of
common aerobic bacterial pathogens including Bacillus anthracis,
Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus,
Streptococcus pyogenes, Streptococcus pneumoniae, Acinetobacter
baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas
aeruginosa.
TBDMSO
X
O
TBDMSO
X
HO
X
b
a
N
Br
Br
Y
2
3
4
N
O
O2N
N
7
Br
X
O
HO
X
O
OH
c
d
N
N
e
Y
Y
5
6
O2N
O2N
N
N
O
Y
Y
O
N
f
O
N
N
X
N
X
O
O
8
9
Since several hybrid compounds maintained
a
similar
X = CH; N; C-F
Y = O; CH2; S
antibacterial profile to pretomanid, the in vitro physicochemical
properties of the series were evaluated. Incorporation of linezolid’s
outer phenyl and morpholine rings into pretomanid (compounds
8a and 8c) successfully increased solubility threefold in compar-
ison to parent pretomanid. All compounds in the series except
9d, 9f, 9g and 9h had increased solubility. 8f had the greatest sol-
Scheme 1. Synthesis of pretomanid analogues with modified side chains. Reagents
and conditions: (a) TBDMSCl, imidazole, CH2Cl2, rt, 12 h; (b) N,N0-dimethyl
ethylenediamine, K2CO3, CuI, toluene, reflux, 12 h; (c) TBAF, THF, rt, 12 h; (d)
Ph3P, CBr4, CH2Cl2, rt, 2 h; (e) 7, NaH, DMF, rt, 2 h; (f) BH3ꢀMe2S, THF, rt, 12 h.
ubility in the series (31
lg/mL), comparable to linezolid and three-
fold better than pretomanid, whose solubility was <10
l
g/mL.
previously13 while the outer side chain precursors were
synthesized from appropriate bromo-substituted benzyl alcohols
following a 4 step sequence. Alcohols 2 were protected as TBDMS
ethers 3 using TBDMSCl and imidazole in dichloromethane in
quantitative yields. The aryl bromide functionality of 3 was dis-
placed with cyclic amides using N,N0-dimethyl ethylenediamine,
K2CO3, CuI in toluene at reflux temperature in 55–70% yields.14
The TBDMS group was then deprotected by using TBAF in THF at
room temperature to afford alcohols 5, which were then converted
into bromides using triphenylphosphine and carbon tetrabromide
in dichloromethane at room temperature. These bromides were
used for alkylation of the nitroimidazopyran nucleus 7 to afford
ethers 8. The amide functionality of 8 was reduced where required
to afford amines of general structure 9 using borane-dimethyl
sulfide complex in THF at room temperature.
Microsomal stability improved from a half-life of 8.1 h for pre-
tomanid to >20 h for compounds 8e and 9b. Despite 9f’s encourag-
ing enhancement in potency against M. tuberculosis, the compound
had a very short microsomal half-life of less than 30 min due to its
high lipophilicity and metabolic susceptibility of the piperidine
ring, precluding it from further development. Caco-2 permeability
of hybrid compounds increased compared to pretomanid with
comparable efflux ratios to pretomanid, these ratios remained
below
2 for almost all compounds suggesting that hybrid
compounds, like pretomanid and linezolid, are not subject to active
cellular efflux. Pretomanid is also highly (93%) protein bound, leav-
ing only 7% free, which may limit tissue distribution.20 Binding to
plasma proteins was greatly reduced for the pretomanid oxazolidi-
none hybrids. Average protein binding for the series was 60%,
while compounds 8b and 9b were less than 30% bound, indicating
increased free fraction of compounds available.
In vivo efficacy was tested for compounds 8a, 8c, and 9c, which
had the best solubility amongst compounds that maintained
pretomanid’s in vitro potency and exhibited equal or improved
metabolic stability. Safety was first assessed in C57BL/6 mice in
maximum tolerated dose studies. No toxicity was observed for
daily oral administration of the 3 experimental compounds for
3 days even with the highest dose tested, 300 mg/kg. Although
well-tolerated, daily oral administration of 100 mg/kg for 28 days
The series of pretomanid oxazolidinone hybrids were tested for
sustained anti-tuberculosis activity using microbroth dilution
(Table 1).15 Incorporation of the C and D rings from the oxozoli-
done linezolid, which has a Minimum Inhibitory Concentration
(MIC) of 0.3 lg/mL, yielded compound 9c with an MIC of 0.8 lg/
mL comparable to that of pretomanid and linezolid. Compounds
8a, 8c,16 9d, and 9e17 also displayed comparable MIC activity to
pretomanid (0.4–0.8
was 0.02–0.05 g/mL was markedly improved compared to other
l
g/mL) and linezolid. The potency of 9f18
l

390
Rakesh et al. / Bioorg. Med. Chem. Lett. 26 (2016) 388–391
Table 1
D
Structures, inhibitory activity, and physicochemical properties
Compound
MIC M. tb
Cytotox Vero cell
Solubility (pH
t1/2
Caco-2e
Protein
H37Rva
(l
g/mL)
IC50
(l
g/mL)
7.4)c
(lg/mL)
(mouse)d
(h)
bindingf (%)
b
Papp A/B
(nm/s)
Papp B/A
(nm/s)
Efflux ratio
(B2A/A2B)
HN
F
N
O
O
0.3
—
34.6
8.5
>100
8.1
516.4
315.8
295.3
131.4
0.6
0.4
17.8
92.9
N
O
O
Linezolid
O
N
O
0.39
44.0
N
O2N
OCF3
O
Pretomanid
O
N
0.78
3.13
>100
>100
28.4
28.4
18.3
>4
400.8
434.1
305.6
238.2
0.7
0.5
50.4
27.9
O
8a
N
N
O
O2N
O2N
O
O
N
N
N
N
N
O
N
N
O
8b
8c
F
O
O
0.78
1.56
3.13
3.13
>100
>100
>100
>100
30.1
28.7
28.3
30.5
13.2
6.7
505.7
472.5
336.8
462.6
316.7
342.0
295.6
304.5
0.6
0.7
0.9
0.7
67.8
66.4
39.6
74.8
O
N
N
O
O2N
O2N
O
O
O
O
N
N
8d
8e
O
O
N
20.4
3.5
N
N
O2N
F
O
O
N
N
O
O
O
N
N
O2N
O2N
8f
O
O
25
50
>100
>100
29.0
28.0
0.51
0.60
395.6
333.9
380.5
370.5
1.0
1.1
59.8
77.6
N
N
S
8g
F
O
O
N
N
N
N
O2N
O2N
S
S
8h
O
O
N
50
15.3
42.3
>100
27.6
22.2
25.8
0.63
8.3
400.0
414.9
371.3
314.4
322.5
276.3
0.8
0.8
0.7
32.1
39.4
14.5
O
O
N
N
8i
O
N
N
3.13
3.13
N
N
O
O2N
O2N
9a
O
N
O
9b
28.1
N
N
O
F
O
N
N
N
0.78
0.39
0.78
<0.2
6.25
3.13
23.1
11.6
>100
56.2
13.7
14.2
10.1
4.9
7.7
433.3
317.6
376.4
354.6
266.8
321.1
332.8
263.3
290.4
284.7
261.3
242.6
0.8
0.8
0.8
0.8
1.0
0.8
51.3
83.0
76.7
85.6
74.5
83.2
O
N
N
O2N
O2N
O2N
O
9c
O
O
0.49
1.3
N
N
N
9d
9e
O
N
22.7
5.7
O
N
F
O
N
N
0.41
0.07
0.06
O
O
N
N
O2N
O2N
O2N
9f
O
7.7
N
N
S
S
9g
F
O
N
4.2
O
N
N
9h
D
a
b
c
Solubility, Caco-2 and protein binding were evaluated experimentally as previously described in Ref. 19.
The lowest concentration of drug that prevented visible growth.
Cytotoxicity against Vero epithelial cells using CellTiter Glo.
Maximum solubility calculated by mSol Evolution Software.
Metabolic stability performed with mouse liver microsomes.
Caco-2 permeability.
d
e
f
Plasma protein binding assays performed using human plasma.

Rakesh et al. / Bioorg. Med. Chem. Lett. 26 (2016) 388–391
391
Table 2
5. Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.;
Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D. N.;
Krelswirth, B. N.; Barry, C. E.; Baker, W. R. Nature (London) 2000, 405, 962.
6. Singh, R.; Manjunatha, U.; Boshoff, H. I. M.; Ha, Y. H.; Niyomrattanakit, P.;
Ledwidge, R.; Dowd, C. S.; Lee, I. Y.; Kim, P.; Zhang, L.; Kang, S.; Keller, T. H.;
Jiricek, J.; Barry, C. E., III Science (Washington, DC, US) 2008, 322, 1392.
7. Thompson, A. M.; Blaser, A.; Anderson, R. F.; Shinde, S. S.; Franzblau, S. G.; Ma,
Z.; Denny, W. A.; Palmer, B. D. J. Med. Chem. 2009, 52, 637.
8. (a) Kim, P.; Kang, S.; Boshoff, H. I.; Jiricek, J.; Collins, M.; Singh, R.; Manjunatha,
U. H.; Niyomrattanakit, P.; Zhang, L.; Goodwin, M.; Dick, T.; Keller, T. H.; Dowd,
C. S.; Barry, C. E. J. Med. Chem. 2009, 52, 1329; (b) Li, X.; Manjunatha, U. H.;
Goodwin, M. B.; Knox, J. E.; Lipinski, C. A.; Keller, T. H.; Barry, C. E., III; Dowd, C.
S. Bioorg. Med. Chem. Lett. 2008, 18, 2256.
Intravenous pharmacokinetic profile in mice
Compound+
AUCinf (h
lg/mL)
t1/2 (h)
CL (mL/min/kg)
Vss (L/kg)
Pretomanid*
8a
8c
9c
ND
1.6
12.1
22.5
32.3
16.5
1.6
7.41
5.18
10.1
0.48
0.28
0.98
0.79
0.63
1.16
+
All mice dosed at 10 mg/kg.
Values obtained from Ref. 22.
*
9. (a) Blaser, A.; Palmer, B. D.; Sutherland, H. S.; Kmentova, I.; Franzblau, S. G.;
Wan, B.; Wang, Y.; Ma, Z.; Thompson, A. M.; Denny, W. A. J. Med. Chem. 2012,
55, 312; (b) Cherian, J.; Choi, I.-H.; Nayyar, A.; Manjunatha, U. H.; Mukherjee, T.;
Lee, Y.-S.; Boshoff, H. I.; Singh, R.; Ha, Y.-H.; Goodwin, M.; Lakshminarayana, S.
B.; Niyomrattanakit, P.; Jiricek, J.; Ravindran, S.; Dick, T.; Keller, T. H.; Dartois,
V., ; Barry, C. E., III J. Med. Chem. 2011, 54, 5639; (c) Thompson, A. M.;
Sutherland, H. S.; Palmer, B. D.; Kmentova, I.; Blaser, A.; Franzblau, S. G.; Wan,
B.-J.; Wang, Y.-H.; Ma, Z.-K.; Denny, W. A. J. Med. Chem. 2011, 54, 6563.
10. (a) Kmentova, I.; Sutherland, H. S.; Palmer, B. D.; Blaser, A.; Franzblau, S. G.;
Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A.; Thompson, A. M. J. Med. Chem. 2010,
53, 8421; (b) Palmer, B. D.; Thompson, A. M.; Sutherland, H. S.; Blaser, A.;
Kmentova, I.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A. J. Med.
Chem. 2010, 53, 282; (c) Sutherland, H. S.; Blaser, A.; Kmentova, I.; Franzblau, S.
G.; Wan, B.; Wang, Y.; Ma, Z.; Palmer, B. D.; Denny, W. A.; Thompson, A. M. J.
Med. Chem. 2010, 53, 855.
did not yield significant reductions in bacterial loads for any of the
compounds tested using a previously described model for chronic
M. tuberculosis infection.21 To explore if this was related unex-
pected in vivo metabolism a small pharmacokinetic study was per-
formed with the results compared to prior published values of
pretomanid (Table 2).22 Results from this trial did indicate faster
clearance and lower volume of distribution for compounds 8a,
8c, and 9c. Based on this PK profile it is somewhat surprising that
9c, with the linezolid outer ring elements, was not efficacious in
the infection model. 9c’s clearance (16.5 mL/min/kg) and volume
of distribution (1.2 L/kg) are close to pretomanid (12.1 mL/min/
kg and 1.6 L/kg, respectively) with similar MIC values (0.78 vs
11. Lee, M.; Lee, J.; Carroll, M. W.; Choi, H.; Min, S.; Song, T.; Via, L. E.; Goldfeder, L.
C.; Kang, E.; Jin, B.; Park, H.; Kwak, H.; Kim, H.; Jeon, H. S.; Jeong, I.; Joh, J. S.;
Chen, R. Y.; Olivier, K. N.; Shaw, P. A.; Follmann, D.; Song, S. D.; Lee, J. K.; Lee, D.;
Kim, C. T.; Dartois, V.; Park, S. K.; Cho, S. N.; Barry, C. E., 3rd. N. Eng. J. Med. 2012,
367, 1508.
0.39 lg/mL) and much improved serum protein binding properties
(51% vs 93%).
It is notable that many of the tuberculosis specific drugs cur-
rently advancing clinically including: nitroimidazoles pretomanid
and delamanid; and imidazopyridine amide Q203 all possess ter-
minal trifluoromethoxy phenyl moiety, all also possessing physio-
chemical properties of very high serum binding that are not
typically favored for antibacterial drug development. The pre-
tomanid oxazolidinone hybrids explored in this study lack
in vivo efficacy despite superior in vitro physiochemical properties
normally associated with increased antibacterial activity. This sug-
gests that the terminal trifluoromethoxy phenyl group may be
required and afford privileged in vivo antitubercular efficacy in
mouse infection models that do not contain caseous lesions.
Important recent studies have shown that many highly bound,
tubercular drugs do not penetrate well into caseous granulomas,
limiting the sterilizing activity of these drugs in humans.23 Thus
we believe it may be worthwhile to further test compound 9c in
the new C3HeB/FeJ mouse model of tuberculosis, which better
mimics the pathology of the human disease including caseous
granuloma formation, because of its high free fraction, MIC activity
and low clearance, especially if the dosing levels can be
increased.24
12. Rakesh; Sun, D.; Lee, R. B.; Tangallapally, R. P.; Lee, R. E. Eur. J. Med. Chem. 2009,
44, 460.
13. Baker, W. R.; Cai, S.; Keeler, E. L. WO 9701562A1, 1997.
14. Iijima, T.; Yamamoto, Y.; Akatsuka, H.; Kawaguchi, T. WO 2,007,089,034, A1,
2007
15. Hurdle, J. G.; Lee, R. B.; Budha, N. R.; Carson, E. I.; Qi, J.; Scherman, M. S.; Cho, S.
H.; McNeil, M. R.; Lenaerts, A. J.; Franzblau, S. G.; Meibohm, B.; Lee, R. E. J.
Antimicrob. Chemother. 2008, 62, 1037.
16. Representative analytical data of compound 8c: 1H NMR (400 MHz, CDCl3): d
7.41 (s, 1H)), 7.25–7.35 (m, 1H), 7.12–7.17 (m, 2H), 4.57–4.77 (m, 3H), 4.31–
4.44 (m, 3H), 4.10–4.26 (m, 3H), 4.01–4.09 (m, 2H), 3.68–3.72 (m, 2H); 13C
NMR (101 MHz, CDCl3): d 166.80, 159.02, 146.93, 138.71, 129.31, 128.44,
123.61, 115.94, 115.73, 114.95, 69.83, 68.50, 67.08, 66.65, 64.04, 49.70, 47.50;
HRMS m/z [M+H]+ calcd for C17H17FN4O6: 393.113. Found: 393.120.
17. Representative analytical data of compound 9e: 1H NMR (400 MHz, C. d. d.,
J = 4.4 Hz, 1H), 7.39–7.43 (m, 1H), 7.37 (s, 1H), 6.64 (d, J = 8.8 Hz, 1H), 4.43–
4.61 (m, 3H), 4.31 (dd, J = 12.0, 1.6 Hz, 1H), 4.01–4.18 (m, 3H), 3.54 (t,
J = 4.9 Hz, 4H), 1.58–1.69 (m, 6H); 13C NMR (101 MHz, CDCl3):
d 159.62,
147.97, 147.12, 143.55, 137.97, 119.52, 115.27, 107.00, 68.73, 67.54, 65.48,
47.57, 46.19, 25.47, 24.67; HRMS m/z [M+H]+ calcd for C17H21N5O4: 360.159.
Found: 360.171.
18. Representative analytical data of compound 9f: 1H NMR (400 MHz, CDCl3): d 7.15
(s, 2H), 6.75–6.90 (m, 2H), 4.37–4.54 (m, 3H), 4.17–4.22 (m, 1H), 3.93–4.12 (m,
3H), 2.90 (t, 4H), 1.57–1.67 (m, 4H), 1.40–1.50 (m, 2H); 13C NMR (101 MHz,
CDCl3):
d 156.76, 154.30, 147.13, 143.50, 141.44, 130.15, 123.98, 119.17,
115.73, 115.46, 70.33, 67.54, 66.02, 51.95, 47.50, 29.70, 26.09, 24.17; HRMS m/
z [M+H]+ calcd for C18H21FN4O4: 377.154. Found: 377.165.
19. North, E. J.; Scherman, M. S.; Bruhn, D. F.; Scarborough, J. S.; Maddox, M. M.;
Jones, V.; Grzegorzewicz, A.; Yang, L.; Hess, T.; Morisseau, C.; Jackson, M.;
McNeil, M. R.; Lee, R. E. Bioorg. Med. Chem. 2013, 21, 2587.
Acknowledgments
20. Dartois, V.; Barry, C. E., 3rd Bioorg. Med. Chem. Lett. 2013, 23, 4741.
21. Lenaerts, A. J.; Gruppo, V.; Marietta, K. S.; Johnson, C. M.; Driscoll, D. K.;
Tompkins, N. M.; Rose, J. D.; Reynolds, R. C.; Orme, I. M. Antimicrob. Agents
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This study was supported by the National Institutes of Health –
United States Grant AI062415 and the American Lebanese Syrian
Associated Charities (ALSAC), St. Jude Children’s Research Hospital.
References and notes
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