Synthesis and Biological Evaluation of Polar Functionalities Containing Nitrodihydroimidazooxazoles as Anti-TB Agents

Article abstract of DOI:10.1021/acsmedchemlett.5b00202

Novel polar functionalities containing 6-nitro-2,3-dihydroimidazooxazole (NHIO) analogues were synthesized to produce a compound with enhanced solubility. Polar functionalities including sulfonyl, uridyl, and thiouridyl-bearing NHIO analogues were synthes

Full text of DOI:10.1021/acsmedchemlett.5b00202

Subscriber access provided by UNIVERSITY OF MICHIGAN LIBRARY
Letter
Synthesis and biological evaluation of polar functionalities
containing nitrodihydroimidazooxazoles as anti-TB agents
Kushalava Reddy Yempalla, Gurunadham Munagala, Samsher Singh, Gurleen Kour,
Shweta Sharma, Reena Chib, Sunil Kumar, Priya Wazir, G.D. Singh, Sushil Raina,
Sonali S. Bharate, Inshad Ali Khan, Ram A. Vishwakarma, and Parvinder Pal Singh
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.5b00202 • Publication Date (Web): 11 Sep 2015
Downloaded from http://pubs.acs.org on September 12, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Medicinal Chemistry Letters is published by the American Chemical Society. 1155
Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
ACS Medicinal Chemistry Letters
1
2
3
4
5
6
7
8
9
10
Synthesis and biological evaluation of polar functionalities contain-
ing nitrodihydroimidazooxazoles as anti-TB agents
Kushalava Reddy Yempalla,1,2,⊥ Gurunadham Munagala,1,2,⊥ Samsher Singh,2,3,⊥ Gurleen Kour,2, 4
Shweta Sharma,1 Reena Chib,2,3 Sunil Kumar,2,3 Priya Wazir,4 G. D. Singh,4 Sushil Raina,1 Sonali S.
Bharate,5 Inshad Ali Khan,2,3,* Ram A. Vishwakarma1,2,* and Parvinder Pal Singh,1,2,*
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1Medicinal Chemistry Division, 2Academy of Scientific and Innovative Research, 3Clinical Microbiology, 4PKꢀPD and Toxiꢀ
cology Division, 5Preformulation Laboratory, CSIRꢀIndian Institute of Integrative Medicine, Canal Road, Jammu 180 001,
India.
KEYWORDS: Mycobacterium tuberculosis, MTB H37Rv, Multidrug resistant-TB, 6-nitro-2,3-dihydroimidazooxazole, Struc-
ture activity relationship.
ABSTRACT: Novel polar functionalities containing 6ꢀnitroꢀ2,3ꢀdihydroimidazooxazole (NHIO) analogs were synthesized to proꢀ
duce a compound with enhanced solubility. Polar functionalities including sulfonyl, uridyl and thiouridylꢀbearing NHIO analogs
were synthesized and evaluated against Mycobacterium tuberculosis (MTB) H37Rv. The aqueous solubility of compounds with
MIC values ≤0.5 µg/ml were tested, and six compounds showed enhanced aqueous solubility. The best six compounds were further
tested against resistant (RifR and MDR) and dormant strains of MTB and tested for cytotoxicity in HepG2 cell line. Based on its
overall in vitro characteristics and solubility profile, compound 6d was further shown to possess high microsomal stability, solubiliꢀ
ty under all tested biological conditions (PBS, SGF and SIF), favorable oral in vivo pharmacokinetics and in vivo efficacy.
Tuberculosis is a deadly infectious disease that has
infected approximately oneꢀthird of the world’s population.
The current lengthy treatment for TB and the development of
resistance toward existing drugs have further complicated the
treatment of this disease.1 New TB drugs that can shorten and
simplify current treatment regimes and demonstrate potency
against both drugꢀsensitive and drugꢀresistant TB are urgently
needed.2 In the past decade, the nitroimidazole skeleton has
been of great interest to TB researchers,3 which led to the
identification of one drug, delamanid or OPCꢀ676834ꢀ6 (a niꢀ
trodihydroimidazooxazole analog approved by the European
union for MDRꢀTB) and two clinical candidates, pretomanid
or PAꢀ8247 and TBAꢀ3548,9 (nitroimidazooxazine analogs in
phaseꢀII/III and phaseꢀI clinical trials, respectively). Both of
the advanced candidates, delamanid and pretomanid, are lipoꢀ
philic, which may aid their entry through the highly lipophilic
cell wall of MTB and lead to their high potency.10ꢀ12 The highꢀ
ly lipophilic nature of these compounds has presented absorpꢀ
tion issues during clinical trials, which have been managed by
altering the formulation of the compound. To address these
absorption issues, several groups have studied the nitroimidꢀ
azooxazine scaffold (PAꢀ824)13ꢀ19 and synthesized a newer
generation analog, TBAꢀ354, with improved physicochemical
properties and in vivo efficacy.8 Despite the comparatively
better antiꢀTB profile of OPCꢀ67683, no efforts were made to
improve the physicochemical properties of OPCꢀ67683, and
delamanid was approved for MDRꢀTB with a recommended
dose of 100 mg twice daily.6 The recommendation of a twiceꢀ
daily dose might limit its introduction in a firstꢀline drug regiꢀ
men, and efforts to improve its physicochemical properties are
needed.
We therefore generated novel triazolylꢀ and isoxaꢀ
zolylꢀcontaining nitrodihydroimidazooxazole (NHIO) analogs,
of which the molecule IIIM/MCDꢀ019 demonstrated good in
vitro and in vivo profiles but high lipophilicity and poor aqueꢀ
ous solubility.20 In this study, we synthesized polar functionalꢀ
ities containing nitrodihydroimidazooxazole (NHIO) analogs
to improve the aqueous solubility. The present study also proꢀ
vides further insight into existing SARs of this class, as well as
a new compound with a good activity profile, improved aqueꢀ
ous solubility, a favorable oral PK and in vivo efficacy.
Three series of analogs were synthesized with differꢀ
ent polar functional moieties (sulfonyl, uridyl and thiouridyl)
(Fig 2). In Series 1, a sulfonyl moiety was placed between ring
C and ring D. In Series 2, a sulfonyl moiety was introduced
between ring D and ring E. In Series 3, uridyl/thiouridyl moieꢀ
ties were introduced between rings C and D.
Results and discussion:
Chemistry:
First, the key phenolic intermediate 4 was syntheꢀ
sized from 4ꢀmethoxybenzene sulfonyl chloride 1 in two steps
by coupling with secondary amines 2 in the presence of triꢀ
ethylamine and DMAP followed by demethylation using boꢀ
ron tribromide.21 Then, a key epoxy intermediate 5 was synꢀ
thesized from 4ꢀnitroimidazole in seven steps, as previously
reported.20 Finally, phenolic intermediate 4, when treated with
epoxide 5 in the presence of sodium hydride, afforded NHIO
analogs 6a-g of Series 1 (Scheme 1).
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 2 of 7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Fig 1: Nitroimidazoleꢀcontaining antiꢀTB agents
ate 10 for this series was synthesized in two steps wherein: i)
NꢀBoc piperazine coupled with THP protected 4ꢀ
8
bromophenol 7 under Buchwald conditions22 gave product 9
and, ii) in the second step, THPꢀdeprotection in the presence
of pyridinium pꢀtoluenesulfonate furnished key phenolic inꢀ
termediate 10. Intermediate 10 was coupled with intermediate
5 in the presence of sodium hydride to give compound 11,
followed by Boc deprotection and subsequent coupling with
substituted benzene sulfonyl chlorides 12 in the presence of
triethyl amine and DMAP to produce NHIO analogs 13a-e.
Fig 2: Medicinal chemistry approach
Next, NHIO analogs 13a-e of Series 2 were syntheꢀ
sized as illustrated in Scheme 2. The key phenolic intermediꢀ
Scheme 1: Synthesis of sulfonyl-containing NHIO analogs of Series 1
O
S
O
S
O
S
N
X
( )n
R
N
X R
( )n
d
a
Cl
O
O
+
HN
X R
O
( )n
MeO
HO
4(a-g)
MeO
3(a-h)
1
2
3a: n=0, X=CH2
3b: n=1, X=CH2
4a:
n=0, X=CH2
4b: n=1, X=CH2
4c:
3c: n=1, X=CH, R=Ph
3d: n=1, X=O
n=1, X=CH, R=Ph
4d: n=1, X=O
3e: n=1, X=N, R=3-Cl Ph
3f: n=1,X=N, R=COOEt
3g: n=1, X=N, R=BOC
3h: n=1, X=N, R=COPh
4e:
4f:
n=1, X=N, R=3-Cl Ph
n=1, X=N, R=COOEt
4g: n=1, X=N, R=COPh
b, c
e
O
X
N
D
R
S
O
C
N
O
A
B
O
O2N
N
O
N
O2N
Cl
N
5
6(a-g)
6a: n=0, X=CH2
6b: n=1, X=CH2
6c: n=1, X=CH, R=Ph
6d: n=1, X=O
6e: n=1, X=N, R=3-Cl Ph
6f: n=1, X=N, R=COOEt
6g: n=1, X=N, R=-COPh
Reagents and conditions
a
:
) Et3N, DMAP, DCM, overnight, rt, 85-95%;
b) TFA, DCM, rt, 1 h; c) benzoyl chloride, TEA,
DMAP, DCM, rt, 3 h, 90%; d) BBr3, DCM, 12 h, rt, 60-80%; e) NaH, DMF, 0 oC to 50 oC, 6 h, 25-35%.
ACS Paragon Plus Environment

Page 3 of 7
ACS Medicinal Chemistry Letters
Scheme 2: Synthesis of sulfonyl-containing NHIO analogs of Series 2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3: Synthesis of uridyl/thiouridyl-containing NHIO analogs of Series 3
N
O
Cl
O2N
N
N
5
a
NHBoc
O
NHBoc
HO
NH2
HO
O2N
O
b
N
16
15
14
R
D
Y
NH
N
c, d
18a;
18b;
18c;
18d;
18e;
18f;
Y=O, R = 4-Me
B
O
18i;
Y=O, R = 2-Me
Y=O, R = 2-F
Y=S, R = 4-Me
Y=S, R = 4-Et
Y=S, R = 4-OMe
Y=S, R = 4-OCF3
A
N
C
NH
O
O2N
Y=O, R = 4-OMe 18j;
NCY
18k;
18l;
18m;
18n;
Y=O, R = 4-Et
18(a-n)
R
Y=O, R = 4-OEt
17
t
Y=O, R = 4- Bu
Y=O, R = 4-Cl
18g;
18h;
Y=O, R = 4-CF3
Y=O, R = 4-OCF3
Reagents and conditions:
)
a
Boc2O, NaOH, H2O, rt, 4 h, 95%; b) NaH, DMF, 0 oC to 50 oC, 12 h, 35%; c) TFA, DCM, rt, 2 h;
d) TEA, DCM, rt, 5 h, 60-80%.
The synthesis of uridylꢀ and thiouridylꢀcontaining
6d rings attached to the sulfonyl group, possessed MIC values
of 0.5 µg/ml and 0.37 µg/ml, respectively against MTB H37Rv.
The presence of a piperazine ring (6e-g) led to a decrease in
activity.
NHIO analogs 18a-n of Series 3 was performed as illustrated
in Scheme 3. The key phenolic intermediate 15 was syntheꢀ
sized from 4ꢀaminophenol 14. Treatment of intermediate 15
with intermediate 5 in the presence of sodium hydride gave the
coupled product 16. Bocꢀdeprotection of compound 16 folꢀ
lowed by coupling with substituted phenyl isocyanates or
isothiocyanates 17 produced the NHIO analogs 18a-n of Seꢀ
ries 3.
In Series 2, all five synthesized NHIO analogs with
varying substitutions on ring E (13a-e) were screened against
MTB H37Rv. The MIC values were between 0.06 and 1 µg/ml.
All the 4ꢀsubstituted ring E analogs had high MIC values and
two compounds 4ꢀF 13d and 4ꢀCF3 13e showed the best acꢀ
tivity, with MIC values of 0.06 and 0.25 µg/ml, respectively.
Biological Evaluation:
In Series 3, all fourteen synthesized NHIO analogs
with varied substitutions on ring D and a uridyl/thiouridyl
linker between the C and D rings (18a-n) were screened
against MTB H37Rv and found to have MIC values between
0.09 and 2 µg/ml. Among all of the tested analogs, uridylꢀ
containing NHIO analogs demonstrated comparatively better
activity than thiouridylꢀcontaining NHIO analogs. In uridylꢀ
based NHIO analogs, 4ꢀMe 18a, 4ꢀter-butyl 18e and 4ꢀCl 18f
substitutions on ring D are favored and demonstrated comꢀ
paratively better activity. Of the thiouridylꢀbased NHIO anaꢀ
logs, 4ꢀOCF3 substituted compound 18n demonstrated the best
activity with a MIC value of 0.25 µg/ml.
A total of 28 new NHIO analogs, 6a-g, 11, 13a-e, 16
and 18a-n, were screened for in vitro activity against MTB
H37Rv (ATCC27294 strain) using the agar dilution method.
The MIC was determined as the minimum concentration of the
compound required to inhibit 90% of bacterial growth. The
aqueous solubility was determined at pH 7. ClogP values were
calculated by Schrodinger software. The MIC, aqueous soluꢀ
bility and ClogP values of all of the synthesized compounds
are summarized in Table 1.
In Series 1, all seven synthesized NHIO analogs with
varying cyclic secondary amine rings D attached to the sulꢀ
fonyl group (6a-g) were screened against MTB H37Rv. The
MIC values of these compounds were between 0.37 and 4
µg/ml. Two NHIO analogs, with piperidyl 6b and morpholinyl
Based on the screening results of sulfonylꢀ and
uridyl/thiouridylꢀcontaining NHIO analogs, key structural
features essential for antiꢀTB activity have been identified as
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 4 of 7
Table 1: In vitro activity and aqueous solubility of 6a-g, 11, 13a-e, 16 and 18a-na
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
follows; i) the introduction of polar functionalities is acceptaꢀ
ated in the HepG2 cell line. None of the tested compounds
ble, ii) the presence of hydrophobic groups/atoms at the termiꢀ
nal rings are essential for activity, even in truncated analogs
(compounds 6b and 6d), iii) the presence of a sulfonyl group
either between rings C and D or between rings D and E is also
acceptable and iv) among the uridyl/thiouridyl analogs, uridylꢀ
containing NHIO analogs are more favorable (Fig 3).
were toxic in HepG2 cell line, and all of the compounds had
acceptable safety indices (Table 2). Among the six selected
NHIO analogs, 6d had a comparatively better profile across
the panel of assays performed.
Table 2: In vitro activity against non-replicating and re-
sistant strains of MTBa and cytotoxicity
Key features
O
# Polar functionalities are acceptable.
D
S
N
X R
O
# Hydrophobic groups/atoms at the
terminal ring (ringD/E) are essential
for activity.
O
N
B
O
N
D
N
S
E
O
C
A
N
O2N
R
O
# Sulfonyl group in between C & D
rings and D & E rings are acceptable.
Y
# Uridyl analogs are more preferable
than thiouridyl analogs.
N
N
D
H
H
R
Fig 3: Structural activity relationship of NHIO analogs and MTB
H37Rv.
Based on their preliminary in vitro profiles against
MTB H37Rv, NHIO analogs with MIC values ≤0.5 µg/ml were
selected for an aqueous solubility study. The NHIO analogs
6b, 6d, 13d, 18d, 18f and 18m demonstrated comparatively
better aqueous solubility between 6.66 and 20 µg/ml. These
analogs were further assessed for activity against resistant
strains (i.e., RifR and MDR) and nonꢀreplicating strains of
MTB, and one analog, 6d, was found to have single digit MIC
values in all of the tested panels. Cytotoxicity was also evaluꢀ
ACS Paragon Plus Environment

Page 5 of 7
ACS Medicinal Chemistry Letters
The best NHIO analog, 6d, was further assessed for
In conclusion, the present study suggests that the inꢀ
troduction of polar functionalities between rings D and C/E is
acceptable. Overall, 28 new NHIOꢀbased analogs were synꢀ
thesized and evaluated against Mycobacterium tuberculosis
(MTB) H37Rv. Potent compounds with MIC values ≤0.5 µg/ml
were further selected for the determination of aqueous soluꢀ
bility. Based on the MIC values (H37Rv) and the aqueous solꢀ
ubility data, 6 compounds were tested against both resistant
(RifR and MDR) and dormant strains of MTB, and cytotoxicity
was evaluated in the HepG2 cell line. Compound 6d was
found to have a good in vitro profile and to exhibit good aqueꢀ
ous solubility. In in vivo studies, compound 6d exhibited a
promising PK profile and showed significant log CFU reducꢀ
tions in an intranasal mouse model of acute infection. The
present study presents new opportunities for modifications to
compounds with poor physicoꢀchemical characteristics and
provides a novel compound with a simple structure, low moꢀ
lecular weight and improved aqueous solubility.
1
2
3
4
5
6
7
8
solubility, microsomal stability and in vivo oral pharmacokiꢀ
netics (data shown in Table 3). Compound 6d demonstrated a
promising solubility of 20 µg/ml under all of the tested biologꢀ
ical conditions (PBS, SGF and SIF). In microsomal stability
studies, compound 6d was found to have good stability, and
99.32% of the compound remained after 30 minutes in rat
liver microsomes. Compound 6d was evaluated by a snapshot
in vivo oral PK study and was found to have a Cmax value of
0.64 µg/ml and absorbed quickly into systemic circulation
(Tmax = 0.5 h). This compound also possesses a higher volume
of distribution (Vd = 12,970 ml/kg) than both an earlier identiꢀ
fied lead (IIIM/MCDꢀ019) and delamanid, moderate exposure
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
with an AUC0ꢀt of 0.879 µg/ml* h, a two hour halfꢀlife (t1/2
1.99 h) and moderate clearance (Cl = 75.2 ml/min/kg).
=
Table 3: Solubility, microsomal stability and in vivo phar-
macokinetic studies in mice
ASSOCIATED CONTENT
Supporting information
Full experimental details for the synthesized comꢀ
pounds, NMR and MS spectra and descriptions of biological asꢀ
says are provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
The in vivo efficacy of compound 6d was further
evaluated in an intranasal model of acute infection in Balb/C
mice (Fig 4). One week post MTB infection, compound 6d
was orally administered at 25 mg/kg once daily for 5 days.
Rifampicin (20 mg/kg) and IIIM/MCDꢀ019 (100 mg/kg) were
used as controls. Compound 6d significantly reduced the bacꢀ
terial load, demonstrating a 1.28 log CFU reduction compared
to the early control (group at the start of treatment) and a 1.61
log CFU reduction compared to the untreated control (late
control group run in parallel without drug treatment). Comꢀ
pound 6d demonstrated better in vivo efficacy than our previꢀ
ously identified lead compound, IIIM/MCDꢀ019. Moreover,
all of the mice remained healthy during the course of treatꢀ
ment.
Tel.: +91ꢀ191ꢀ2585006, Fax: +91ꢀ191ꢀ2586333; Eꢀmail:
ppsingh@iiim.res.in, ram@iiim.res.in and iakhan@iiim.res.in
Author Contributions
⊥KRY, GM and S Singh contributed equally to this
work. KRY and GM performed the chemical synthesis. S Singh
performed in vitro and in vivo antiꢀTB experiments. S Sharma
helped with chemical synthesis. SK performed cytotoxic experiꢀ
ments. GK, RC, PW and GDS performed microsomal stability
and in vivo PK studies. SSB performed the solubility study. PPS
and KRY drafted the manuscript. PPS, IAK and RAV participated
in the design and execution of this study.
Funding Sources
This work was supported by the Council of Scientific
and Industrial Research (CSIR)ꢀNew Delhi with research grants
#BSC0205 and #HCP 0001. This work is assigned the IIIM Publiꢀ
cation No: IIIM/1803/2015.
ACKNOWLEDGMENTS
KRY, GM, S Singh, S Sharma, and SK thank CSIR and UGC for
their fellowship. The authors thank Prof. Serge Mignani for
providing valuable suggestions for the selection of the best comꢀ
pounds to investigate in detail.
REFERENCES
1.
Ditiu, L., A new era for global tuberculosis control. Lancet.
2011, 378, 1293.
2.
Sasaki, H., A.; Nahid, P.; Cole, S. T., Advances in the develꢀ
opment of new tuberculosis drugs and treatment regimens. Nat.
Rev. Drug. Discov. 2013, 12, 388ꢀ404.
3.
Barry, C. E., 3rd; Boshoff, H. I.; Dowd, C. S., Prospects for
clinical introduction of nitroimidazole antibiotics for the treatꢀ
ment of tuberculosis. Curr. Pharm. Des. 2004, 10, 3239ꢀ3262.
Fig 4: In vivo activity of 6d in intranasal model of acute infection
in Balb/c mice. The mice were orally dosed once daily for 5 days
(n = 6) starting on the day after infection with 105 CFU of MTB.
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 6 of 7
4.
5.
Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.;
lar Drug (6S)ꢀ2ꢀNitroꢀ6ꢀ{[4ꢀ(trifluoromethoxy)benzyl]oxy}ꢀ
6,7ꢀdihydroꢀ5Hꢀimidazo[2,1ꢀb][1,3]oxazine (PAꢀ824). J.Med.
Chem. 2010, 53, 8421ꢀ8439.
Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M., OPCꢀ
67683, a nitroꢀdihydroꢀimidazooxazole derivative with promisꢀ
ing action against tuberculosis in vitro and in mice. PLoS. Med.
2006, 3, 2131ꢀ2144.
Sasaki, H.; Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume,
H.; Tomishige, T.; Kawasaki, M.; Matsumoto, M.; Komatsu,
M.; Tsubouchi, H., Synthesis and antituberculosis activity of a
novel series of optically active 6ꢀnitroꢀ2,3ꢀdihydroimidazo[2,1ꢀ
b]oxazoles. J. Med. Chem. 2006, 49, 7854ꢀ7860.
1
2
3
4
5
6
7
8
15. 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., Synthesis and structureꢀactivity studies of biꢀ
phenyl analogues of the tuberculosis drug (6S)ꢀ2ꢀnitroꢀ6ꢀ{[4ꢀ
(trifluoromethoxy)benzyl]oxy}ꢀ6,7ꢀdihydroꢀ5Hꢀimidazo[2,1ꢀ
b][1, 3]oxazine (PAꢀ824). J. Med. Chem. 2010, 53, 282ꢀ294.
16. 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., Synthesis and structureꢀactivity relationships
of antitubercular 2ꢀnitroimidazooxazines bearing heterocyclic
side chains. J. Med. Chem. 2010, 53, 855ꢀ866.
17. Thompson, A. M.; Sutherland, H. S.; Palmer, B. D.; Kmentova,
I.; Blaser, A.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.;
Denny, W. A., Synthesis and structureꢀactivity relationships of
varied ether linker analogues of the antitubercular drug (6S)ꢀ2ꢀ
nitroꢀ6ꢀ{[4ꢀ(trifluoromethoxy)benzyl]oxy}ꢀ6,7ꢀdihydroꢀ5Hꢀ
imidazo[2,1ꢀb][1, 3]oxazine (PAꢀ824). J. Med. Chem. 2011, 54,
6563ꢀ6585.
18. Kim, P.; Kang, S.; Boshoff, H. I.; Jiricek, J.; Collins, M.; Singh,
R.; Manjunatha, U. H.; Niyomrattanakit, P.; Zhang, L.; Goodꢀ
win, M.; Dick, T.; Keller, T. H.; Dowd, C. S.; Barry, C. E., 3rd,
Structureꢀactivity relationships of antitubercular nitroimidazꢀ
oles. 2. Determinants of aerobic activity and quantitative strucꢀ
tureꢀactivity relationships. J. Med. Chem. 2009, 52, 1329ꢀ1344.
19. Kim, P.; Zhang, L.; Manjunatha, U. H.; Singh, R.; Patel, S.;
Jiricek, J.; Keller, T. H.; Boshoff, H. I.; Barry, C. E., 3rd;
Dowd, C. S., Structureꢀactivity relationships of antitubercular
nitroimidazoles. 1. Structural features associated with aerobic
and anaerobic activities of 4ꢀ and 5ꢀnitroimidazoles. J. Med.
Chem. 2009, 52, 1317ꢀ1328.
6.
7.
Ryan, N. J.; Lo, J. H., Delamanid: first global approval. Drugs.
2014, 74, 1041ꢀ1045.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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.; Baker, W. R., A smallꢀmolecule nitroimidazopyran drug
candidate for the treatment of tuberculosis. Nature. 2000, 405,
962ꢀ966.
Upton, A. M.; Cho, S.; Yang, T. J.; Kim, Y.; Wang, Y.; Lu, Y.;
Wang, B.; Xu, J.; Mdluli, K.; Ma, Z.; Franzblau, S. G., In vitro
and in vivo activities of the nitroimidazole TBAꢀ354 against
Mycobacterium tuberculosis. Antimicrob. Agents. Chemother.
2015, 59, 136ꢀ144.
8.
9.
TB alliance drug, TBAꢀ354, enters phaseꢀI clinical trials. 2015
http://www.newtbdrugs.org/blog/tb-alliance-drugtba-354-
enters-phase-i-clinical-trials/.
10. Barry, C. E.; Crick, D. C.; McNeil, M. R., Targeting the forꢀ
mation of the cell wall core of M. tuberculosis. Infect. Disord.
Drug. Targets. 2007, 7, 182ꢀ202.
11. Rivers, E. C.; Mancera, R. L., New antiꢀtuberculosis drugs with
novel mechanisms of action. Curr. Med. Chem. 2008, 15, 1956ꢀ
1967.
12. 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., Synthesis and structureꢀactivity relationships
of azaꢀ and diazabiphenyl analogues of the antitubercular drug
(6S)ꢀ2ꢀnitroꢀ6ꢀ{[4ꢀ(trifluoromethoxy)benzyl]oxy}ꢀ6,7ꢀdihydroꢀ
5Hꢀimidazo[2,1ꢀb][1, 3]oxazine (PAꢀ824). J. Med. Chem. 2010,
53, 8421ꢀ8439.
13. Lakshminarayana, S. B.; Boshoff, H. I.; Cherian, J.; Ravindran,
S.; Goh, A.; Jiricek, J.; Nanjundappa, M.; Nayyar, A.; Guruꢀ
murthy, M.; Singh, R.; Dick, T.; Blasco, F.; Barry, C. E., 3rd;
Ho, P. C.; Manjunatha, U. H., Pharmacokineticsꢀ
pharmacodynamics analysis of bicyclic 4ꢀnitroimidazole anaꢀ
logs in a murine model of tuberculosis. PLoS. One 2014, 9,
e105222.
20. Munagala, G.; Yempalla, K. R.; Singh, S.; Sharma, S.; Kalia,
N. P.; Rajput, V. S.; Kumar, S.; Sawant, S. D.; Khan, I. A.;
Vishwakarma, R. A.; Singh, P. P., Synthesis of new generation
triazolylꢀ
and
isoxazolylꢀcontaining
6ꢀnitroꢀ2,3ꢀ
dihydroimidazooxazoles as antiꢀTB agents: in vitro, structureꢀ
activity relationship, pharmacokinetics and in vivo evaluation.
Org. Biomol. Chem. 2015, 13, 3610ꢀ3624.
21. McOmie, J. F. W.; Watts, M. L.; West, D. E., Demethylation of
aryl methyl ethers by boron tribromide. Tetrahedron. 1968, 24,
2289ꢀ2292.
22. Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S.
L., Simple, efficient catalyst system for the palladiumꢀcatalyzed
amination of aryl chlorides, bromides, and triflates. J. Org.
Chem. 2000, 65, 1158ꢀ1174.
14. 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., Synthesis and Structure−Activity Relationꢀ
ships of Azaꢀ and Diazabiphenyl Analogues of the Antitubercuꢀ
ACS Paragon Plus Environment

Page 7 of 7
ACS Medicinal Chemistry Letters
1
2
3
4
5
For Table of Contents Use Only
6
7
8
9
10
11
12
13
14
15
16
17
18
Synthesis and biological evaluation of polar functionalities contain-
ing nitrodihydroimidazooxazoles as anti-TB agents
Kushalava Reddy Yempalla,1,2,⊥ Gurunadham Munagala,1,2,⊥ Samsher Singh,2,3,⊥ Gurleen Kour,2,4 Shweꢀ
ta Sharma,1 Reena Chib,2,3 Sunil Kumar,2,3 Priya Wazir,4 G. D. Singh,4 Sushil Raina,1 Sonali S. Bharate,5
Inshad Ali Khan,2,3,* Ram A. Vishwakarma1,2,* and Parvinder Pal Singh,1,2,*
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment