Synthesis and anti-tubercular activity of 2-nitroimidazooxazines with modification at the C-7 position as PA-824 analogs

Article abstract of DOI:10.1016/j.bmcl.2015.06.060

Tuberculosis (TB) is a major global health problem, and new drug targets and scaffolds need to be identified to combat the emergence of drug resistant TB. The nitroimidazooxazine PA-824 represents a new class of bio-reductive drug to treat TB. In this study we report a 2-nitroimidazooxazine derivative with modification at the C-7 position that exhibited better activity than PA-824 against Mycobacterium tuberculosis (Mtb) H37Rv strain in vitro. From 7a as a key intermediate, we functionalized with benzyl ether (8), phenyl ether (9), benzyl carbonate (10) and benzyl carbamate (11). Among the 23 compounds produced, 8a-R (MIC = 0.078 μM) with trifluoromethoxy benzyl group was 5-fold more potent than PA-824 (MIC = 0.390 μM) in the in vitro assays against the wild-type Mtb, and the phenyl ether compound 9g-R (MIC = 0.050 μM) exhibited the most potent antimycobacterial activity.

Full text of DOI:10.1016/j.bmcl.2015.06.060

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and anti-tubercular activity of 2-nitroimidazooxazines
with modification at the C-7 position as PA-824 analogs
Young-Goo Kang a,b, Chan-Yong Park a,b, Hongsuk Shin a, Ramandeep Singh c, Garima Arora c,d
,
Chan-mo Yu b, Ill Young Lee a,
⇑
a Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejon 305-600, Republic of Korea
b Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Republic of Korea
c Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Haryana, India
d Symbiosis School of Biomedical Sciences, Symbiosis International University, Lavale, Pune, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Tuberculosis (TB) is a major global health problem, and new drug targets and scaffolds need to be iden-
tified to combat the emergence of drug resistant TB.
The nitroimidazooxazine PA-824 represents a new class of bio-reductive drug to treat TB. In this study
we report a 2-nitroimidazooxazine derivative with modification at the C-7 position that exhibited better
activity than PA-824 against Mycobacterium tuberculosis (Mtb) H37Rv strain in vitro. From 7a as a key
intermediate, we functionalized with benzyl ether (8), phenyl ether (9), benzyl carbonate (10) and benzyl
Received 27 March 2015
Revised 11 June 2015
Accepted 15 June 2015
Available online xxxx
Keywords:
carbamate (11). Among the 23 compounds produced, 8a-R (MIC = 0.078
benzyl group was 5-fold more potent than PA-824 (MIC = 0.390 M) in the in vitro assays against the
M) exhibited the most potent
lM) with trifluoromethoxy
2-Nitroimidazooxazine
2-Nitrodihydro-5H-imidazo[2,1-
b][1,3]oxazine
l
wild-type Mtb, and the phenyl ether compound 9g-R (MIC = 0.050
l
antimycobacterial activity.
PA-824
Ó 2015 Elsevier Ltd. All rights reserved.
Tuberculosis
Antibacterial activity
Tuberculosis (TB) is a major global health problem, and there is
an urgent need to discover new agents with improved efficacy and
safety and shorter treatment duration. According to the world
health organization (WHO), the global incidence of TB in 2013
approached 9 million cases, of which 500,000 were multidrug-re-
sistant (MDR).1 Since 2013, the situation has worsened due to
the emergence of drug resistant TB, HIV-TB coinfection and ineffec-
tiveness of the BCG vaccine against adult pulmonary TB. A number
of studies have identified various scaffolds that are currently in
clinical trials. Bedaquiline (TMC207) has recently been approved
by the FDA for the treatment of MDR-TB.2 In addition, novel
scaffolds such as nitroimidazooxazines (PA-824 and OPC-67683),
oxazolidinones (eperesol and linezolid) and ethylenediamines
(SQ109)3 are being tested in clinical trials.
PA-824 (EC50 = 0.9
l
M) in parasiticidal activity against Leishmania
donovani, the causative agent of visceral leishmaniasis (VL).5 In
Mtb, PA-824 is a prodrug that is activated by a deazaflavin-depen-
dent nitro reductase (Rv3547) in a F420-dependent manner,
resulting information of the desnitro derivative as a major metabo-
lite. The releasing of NO upon activation of PA-824 seems to be
responsible for its anaerobic activity.6 The major drawbacks of
PA-824 are its poor aqueous solubility and propensity to bind to
human plasma proteins.6 Synthesis of nitroimidazooxazine deriva-
tives have attempted to address these shortcomings, including
biphenyl analogs that replace benzyl ether with urea, carbamate
or amide linkers and the hybridization of PA-824 with oxazolidi-
none at the C-6 position, among others. When the side-chains of
(hetero)biaryl ether were introduced instead of the benzyl ether
of PA-824, these scaffolds exhibit better in vitro and in vivo
ADME properties as well as potency compared to their parent com-
pounds.7–11 In the PA-824 derivatives containing (hetero)biaryl
side-chains, TBA-354, ((S)-2-nitro-6-((6-(4-(trifluoromethoxy)
phenyl)pyridin-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]
oxazine), is currently in clinical trials.11 Furthermore, the introduc-
tion of benzyloxymethyl, biphenyl or (hetero)biaryl groups at the
C-7 position of the 2-nitrodihydro-5H-imidazo[2,1-b][1,3]oxazine
ring has been reported.12,13 As a part of the ongoing the modifica-
tion at the C-7 position of PA-824 in our laboratory,14 we
PA-824 ((6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-
dihydro-5H-imidazo[2,1-b][1,3]oxazine
has
a
4-(trifluoro-
methoxy)benzyloxy side chain with an S-configuration at the C-6
position of the 2-nitrodihydro-5H-imidazo[2,1-b][1,3]oxazine ring
and is currently in phase II clinical trials for TB.4 As another biolog-
ically property of PA-824, the enantiomer of PA-824(R-PA-824,
EC50 = 0.16 lM)) exhibited a six-fold increase in potency over
⇑
Corresponding author. Tel.: +82 42 860 7157; fax: +82 42 860 7229.
E-mail address: iylee@krict.re.kr (I.Y. Lee).
http://dx.doi.org/10.1016/j.bmcl.2015.06.060
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kang, Y.-G.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.06.060

2
Y.-G. Kang et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
linker
synthesized and investigated the antimycobacterial properties of
O
N
O
new PA-824 analogs that contain benzyloxyethyl 8, phenoxyethyl
9, ethyl benzyl carbonate 10 and ethyl phenyl carbamate 11 groups
at the C-7 position of the 2-nitrodihydro-5H-imidazo[2,1-b][1,3]
oxazine ring (Fig. 1). We expected that an ethyloxy linker would
increase the conformational mobility of the 4-trifuoromethoxy-
benzyl group, which will affect solubility through inhibition of
N
O2N
2
O2N
N
N
O
2
O
1
R
1
R = Bn (8-R)
Ph (9-R)
OCF3
PA-824
COBn (10-R)
CONHPh (11-R)
the
p–p stacking of aromatics in molecules that differ from the
tight packing of PA-824 in the crystal structure.15
Figure 1. Structure of PA-824 and synthetic targets.
These analogs 8–11 were prepared through functionalization of
chiral
2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-
yl)ethanol (7) as a key intermediate (Fig. 2). For the synthesis of
7a, the ketone group of dimethyl 3-oxoglutarate (1) was
preferentially reduced with sodium borohydride followed by
reduction of the ester with borane-dimethyl sulfide (BMS) to
yield 1,3,5-pentanetriol (2) in 69% over two steps.16 After preparing
(ꢀ)-menthone spiroketal 3 from 1,3,5-pentanetriol (2) according
to known procedures, tosylation of the alcohol in 3 yielded
4a and 4b at 60% yield with a 1.6:1 diastereomeric ratio after
purification by column chromatography.17–20 Chiral 4a was
coupled with 2-bromo-4-nitro-1H-imidazole, which was prepared
from 4-nitroimidazoles through regioselective reduction of
Figure 2. The X-ray crystal structure of 7a and 7b.22
O
O
O
O
O
1
O
O
a
TsO
TsO
4a
4b
OH
+
c
b
O
O
HO
OH
HO
2
3
O
O
4a:4b=1.6:1
Br
Br
N
N
d
e
O2N
O2N
4a
N
OH
N
O
OH
O
6a
5a
R
O
O
N
O2N
O2N
N
N
8-R
g
h
O
O
N
R
9-R
O
OH
N
f
O2N
R
N
O
O
O
i
j
N
O2N
N
O
7a
10-R
H
O
O
N
N
R
O2N
N
O
11-R
Scheme 1. Reagents and conditions: (a) (i) NaBH4 (0.85 equiv), MeOH, 0 °C–rt, 5 h, 94%; (ii) BH3Me2S (3.0 equiv), THF, 0 °C to reflux, 2 days, 73%; (b) (i) (ꢀ)-menthone
(1.1 equiv), cat. p-TsOH, CH(OMe)3 (4.0 equiv), CH2Cl2, rt, 24 h, (ii) 1 N NaOH, MeOH, 0 °C–rt, 12 h, 82%; (c) TsCl (1.1 equiv), DMAP (1.3 equiv), CH2Cl2, 0 °C–rt, 3 h, 60%;
(d) 2-bromo-4-nitro-1H-imidazole (1.0 equiv), K2CO3 (1.2 equiv), cat. TBAI, DMF, 120 °C, 3 h, 65%; (e) DowexÒ 50wx8 resin, MeOH, rt, overnight 87%; (f) Cs2CO3 (2.0 equiv),
DMF, 75 °C, overnight, 74%; (g) BnBr (10.0 equiv), NaH (2.0 equiv), DMF, ꢀ60 °C–rt, 1 h, 12–41%; (h) PhOH (1.0 equiv), PPh3 (1.3 equiv), DIAD (1.3 equiv) DMF, 0 °C–rt, >4 h,
31–41%; (i) BnBr (3.0 equiv), Ag2CO3 (3.0 equiv), cat. TBAI, DMF, 75 °C, overnight, 30–40%; (j) PhNCO (1.2 equiv), cat. CuCl, DMF, rt, overnight, 22–25%.
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Y.-G. Kang et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
Table 1
Biological activities (H37Rv) and physicochemical properties of 8 and 9
Table 2
Biological activities (H37Rv) and physicochemical properties of 10 and 11
O
OR
O
O
R'
N
N
*
*
O2N
O2N
N
N
O
R0
MIC(l
M)a
TC50(l
M)b
ClogPc
Num
R
MIC (l
M)a
TC50
(l
M)b
ClogPc
Num
O
O
8a-R
0.078
>100
3.21
OCF3
10a-R
0.078
>100
3.27
OCF3
8a-S
8b-R
8c-R
8d-R
8e-R
0.390
0.390
0.390
0.390
0.195
>100
>100
>100
>100
>100
3.21
4.00
3.04
2.89
3.06
OCF3
10a-S
10b-R
1.560
0.780
>100
>100
3.27
3.27
OCF3
OCF3
O
Br
OCF3
Cl
10c-R
0.390
>100
3.27
O
O
CF3
Ph
10d-R
10e-R
0.195
0.390
>100
>100
2.95
3.12
8f-R
9a-R
9b-R
9c-R
9d-R
9e-R
9e-S
9f-R
0.195
0.098
3.125
0.390
0.195
0.078
0.078
0.078
>100
>100
>100
>100
>100
>100
>100
>100
4.07
3.52
2.32
3.17
3.45
4.18
4.18
4.21
Cl
O
OCF3
CF3
Cl
11a-R
0.195
>100
4.88
N
H
Cl
Ph(4-OCF3)
CF3
11b-R
0.195
0.390
>100
>100
4.88
2.79
N
H
OBn
OBn
Ph
PA-824
a
b
c
MIC (
TC50
ClogP values were calculated by ChemBioDraw Ultra, version 11.0.1.
l
(
M) = minimum inhibitory concentration.
lM) = toxic concentration.
9g-R
Ph(4-F)
0.050
0.390
>100
>100
4.38
2.79
halides. The synthesis of phenyl ether 9-R was accomplished under
Mitsunobu conditions.23 To our knowledge, the carbonate linkage
between the nitroimidazooxazine ring and benzyl group in PA-
824 analogs has not been published, but linkages have been intro-
duced, such as amides, carbamates, thiourea or urea.7–11 We
attempted to obtain carbonate analog 10-R from 7a with a substi-
tuted benzyl halide and Ag2CO3 in DMF with catalytic amounts of
tetrabutylammonium iodide. The carbamate analog 11-R was pre-
pared from 7a with isocyanate by CuI-catalyzed condensation.
Synthetic procedures for 8–11 are summarized in Supplementary
data.
Table 1 presents the minimum inhibitory concentrations (MIC)
against the wild-type M. tuberculosis strain (H37Rv), toxic concen-
trations and physicochemical data for compounds 8 and 9. When
we compare 8a-R24 and PA-824 containing same 4-tri-
fuoromethoxybenzyl substituents, the activity of 8a-R
PA-824
a
b
c
MIC (
TC50
ClogP values were calculated by ChemBioDraw Ultra, version 11.0.1.
l
(
M) = minimum inhibitory concentration.
lM) = toxic concentration.
2,5-dibromo-4-nitro-1H-imidazole in 77% yield,21 to obtain the
spiroketal menthonyl nitroimidazole 5a.17,18 Hydrolysis of 5a with
Dowex 50wx8 resin in MeOH and subsequent cyclization of 6a
produced the 2-nitrodihydro-5H-imidazo[2,1-b][1,3]oxazine ring
7a. Different bases (K2CO3, Na2CO3, NaH, DBU, Ag2CO3 or Cs2CO3)
and solvents (DMF, DMSO or CH3CN) were evaluated to optimize
cyclization conditions, and the best yield (74% for 7a) was obtained
when 6a was heated with two equivalents of Cs2CO3 in DMF at
75 °C overnight. Preparation of the 7b, enantiomer of 7a, started
with 4b for the synthesis of 8-S, 9-S and 10-S with (S)-configura-
tion under the same reaction conditions as in Scheme 1.
Ò
(MIC = 0.078
(MIC = 0.390
l
l
M) was approximately 5-fold higher than PA-824
M). Compound 8a-S (MIC = 0.390 M), an enan-
1H NMR data of compounds 4a and 4b matched with data of a
literature17 among known literatures. So the structures 7a and
7b were confirmed by X-ray analysis of single crystals to assign
stereochemistry to the C-7 position on the 2-nitrodihydro-5H-im-
idazo[2,1-b][1,3]oxazine ring of 7a and 7b starting from each 4a
and 4b. Further proof for the chiral structure assignment of 7a,
the mesylation of 7a afforded (R)-2-(2-nitro-6,7-dihydro-5H-imi-
dazo[2,1-b][1,3]oxazin-7-yl)ethyl methane-sulfonate, which was
also confirmed by X-ray crystallographic data and ORTEP plots
(Fig. S3 in Supplement data).
l
tiomer of 8a-R, exhibited similar potency to PA-824. Among sub-
stituents at the para-position of the benzyl group, CF3 (8e-R;
MIC = 0.195 lM) and the phenyl group (8f-R; MIC = 0.195 lM) dis-
played a 2-fold increase in inhibition compared to PA-824, which
was different from halogens (Br or Cl) or a t-butyl group (8b-R,
8c-R and 8d-R; MIC = 0.390
ether 9, OCF3 (9a-R), Cl (9c-R), and CF3 (9d-R) also showed similar
potencies (MIC = 0.078–0.098 M) to 8-R with the same sub-
stituent. The non-substituted phenyl ether 9b-R showed weak
inhibition activity (MIC = 3.125 M). Compound 9e-R and its enan-
tiomer 9e-S had the same activity (MIC = 0.078 M), but (R)-PA-
lM). In the para-substituted phenyl
l
l
As PA-824 analogs, new nitroimidazooxazine benzyl ethers 8a–
f were synthesized from 7 by reaction with substituted benzyl
l
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4
Y.-G. Kang et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
824 is known to be 9-fold less potent in vitro than PA-824 with (S)-
configuration.25 With respect to para substituents on the phenyl
side chain, lipophilic 9g-R (ClogP = 4.38) was the most active
References and notes
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(MIC = 0.050 lM) in the biaryl compound series (9e–9g).
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News
Release,
http://www.fda.gov/NewsEvents/Newsroom/
While benzyl ether 8a-R, 8c-R and 8d-R did generally followed
the same trend of increase potency with higher ClogP that has also
been reported in literlatures,9–11 compound 8b-R and 8f-R, which
had ClogP values of 4.00 and 4.07, respectively, showed reduced
activities than 8a-R (ClogP = 3.21) despite having higher lipophili-
cites compare with 8a-R. The observed inhibition activities of 9
correlated well with ClogP compared to 8.
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12. Thompson, A. M.; Denny, W. A.; Blaser, A.; Ma, Z. Patent WO 2011/014776A1,
2011.
In the carbonyl containing linkers in Table 2, para-trifluo-
romethoxy benzyl carbonate (10a) was an unknown linker in the
PA-824 analogs. The (R)-configuration 10a-R (MIC = 0.078
had noticeably greater inhibitory activity than the (S)-configura-
tion 10a-S (MIC = 1.560 M). Changing the position of the trifluo-
lM)
l
romethoxy group from the para to the meta and ortho positions
altered the activity order as follows: para (10a-R;
MIC = 0.078
MIC = 1.560
MIC = 0.390
l
l
l
M) = meta (10b-R; MIC = 0.078
M). para-Trifluoromethyl carbonate
M) had equipotent values to PA-824. With respect
M) and 11b-R
l
M) > ortho (10c-R;
(10e-R;
to the O-carbamate linker, 11a-R (MIC = 0.195
l
(MIC = 0.195 lM) gave inferior results similar to the carbonate lin-
ker of oxazolidinone at the C-6 position.25
13. Kawano, Y.; Haraguchi, Y.; Sasaki, H.; Uematsu, Y.; Tsubouchi, H.; Shimizu, H.;
Kohashi, K.; Itotani, M.; Tai, K.; Takemura, I.; Hayashi, M.; Hashizume, H.;
Matsuba, M.; Nakamura, I.; Chen, X.; Matsumoto, M. Patent WO 2012/
141338A1, 2012.
14. Lee, I. Y.; Yoon, C. S.; Kang, M. S.; Oh, T. K.; Cho, S. R. Korea Patent Appl. KR2012-
0060077, 2012.
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Barry, C. E., III; Dowd, C. S. Bioorg. Med. Chem. Lett. 2008, 18, 2256.
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In summary, we have synthesized a novel series of 2-nitroimi-
dazooxazines with modifications including a benzyl ether (8), phe-
nyl ether (9), benzyl carbonate (10) and phenyl carbamate (11) at
the C-7 position of 2-nitroimidazooxazines as PA-824 analogs.
Among the 23 compounds screened for their in vitro activity
against Mtb, most of the compounds exhibited less than micromo-
lar potency and low toxicity (TC50 > 100
lM). 9g-R exhibited excel-
lent values with MIC = 0.050 M. In addition, chiral 7a will be used
l
as a key intermediate in the synthesis of new derivatives. Anti-my-
cobacterial activities of 2-nitrodihydro-5H-imidazo[2,1-b][1,3]ox-
azine chromophores synthesized from 7a with novel linkers and
heterocyclic side chains will be published in due course.
20. Harada, T.; Kurokawa, H.; Oku, A. Tetrahedron Lett. 1987, 41, 4843.
21. Pedada, S. R.; Satam, V. S.; Tambade, P. J.; Kandadai, S. A.; Hindupur, R. M.; Pati,
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Acknowledgments
This study was supported by a grant from Korea Research
Institute of Chemistry Technology, Republic of Korea. The chemical
library used in the study was kindly provided by Korea Chemical
Bank of Korea Research Institute of Chemical Technology. The
authors thank Department of Biotechnology, India for intramural
funding to THSTI.
22. Crystallographic details of 7a (CCDC 1054313) and 7b (CCDC 1054312) have
been deposited at the Cambridge Crystallographic Data Centre.
23. Han, Y. T.; Choi, G. I.; Son, D.; Kim, N. J.; Yun, H.; Lee, S.; Chang, D. J.; Hong, H. S.;
Kim, H.; Kim, Y. H.; Park, H. J.; Lee, J.; Suh, Y. G. J. Med. Chem. 2012, 55, 9120.
24. Spectroscopic data for compound 8a-R: 1H NMR (300 MHz, CDCl3): d 7.42 (s, 1H),
7.35 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 4.63 (m, 1H), 4.51 (dd, J = 18 Hz,
6 Hz, 2H), 4.08 (m, 2H), 3.73 (m, 2H), 2.30–2.03 (m, 4H). 13C NMR (126 MHz,
CDCl3) d 148.7, 148.2, 143.5, 136.7, 129.0, 121.4, 120.9, 119.4, 114.7, 75.2, 72.4,
65.4, 42.2, 34.8, 26.6. HRMS (EI+, [M]+): Found 387.10421, Calcd for 387.3153
C16H16F3N3O5.
Supplementary data
25. 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.;
Kreiswirth, B. N.; Barry, C. E., III; Baker, W. R. Nature 2000, 405, 962.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.06.
060. These data include MOL files and InChiKeys of the most
important compounds described in this article.
Please cite this article in press as: Kang, Y.-G.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.06.060