One-pot synthesis of new triazole - Imidazo[2,1-b][1,3,4]thiadiazole hybrids via click chemistry and evaluation of their antitubercular activity

Article abstract of DOI:10.1016/j.bmcl.2015.08.009

A new series of triazole-imidazo[2,1-b][1,3,4]thiadiazole hybrids (6a-s, 7a) were designed by a molecular hybridisation approach and the target molecules were synthesized via one pot click chemistry protocol. All the intermediates and final molecules were

Full text of DOI:10.1016/j.bmcl.2015.08.009

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
One-pot synthesis of new triazole—Imidazo[2,1-b][1,3,4]thiadiazole
hybrids via click chemistry and evaluation of their antitubercular
activity
Jurupula Ramprasad , Nagabhushana Nayak , Udayakumar Dalimba , Perumal Yogeeswari b,
Dharmarajan Sriram
a
a
a
a,
⇑
b
Organic Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Srinivasanagar, Mangalore 575025, India
Medicinal Chemistry and Drug Discovery Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar,
b
Telangana 500078, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of triazole–imidazo[2,1-b][1,3,4]thiadiazole hybrids (6a–s, 7a) were designed by a
molecular hybridisation approach and the target molecules were synthesized via one pot click chemistry
protocol. All the intermediates and final molecules were characterised using spectral methods and one of
the target compounds (6c) was analysed by the single crystal XRD study. The derivatives were screened
for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain. Two compounds, 6f
and 6n, demonstrated significant growth inhibitory activity against the bacterial strain with a MIC of
Received 25 April 2015
Revised 18 July 2015
Accepted 5 August 2015
Available online xxxx
Keywords:
Mycobacterium tuberculosis
Imidazo[2,1-b][1,3,4]thiadiazole
3.125 lg/mL. The presence of chloro substituent on the imidazo[2,1-b][1,3,4]thiadiazole ring and ethyl,
benzyl or cyanomethylene groups on the 1,2,3-triazole ring enhance the inhibition activity of the
molecules. The active compounds are not toxic to a normal cell line which signifies the lack of general
cellular toxicity of these compounds.
1
,2,3-Triazole
Click chemistry
Drug-likeness score
Ó 2015 Elsevier Ltd. All rights reserved.
1
into a single molecular framework7,8 and (iv) the random screening
of different structural units and proceeding in an observed window
Tuberculosis (TB) is one of the dominant killer diseases and it
causes huge amount of human deaths in spite of the availability of
more than 20 antiTB drugs and the Bacille Calmette Guerin (BCG)
9
–12
of anti-TB activity,
all these approaches are being considered as
2
antiTB vaccine. The emergence of the extensively drug-resistant
promising to develop effective drugs.
tuberculosis (XDR-TB) and multidrug-resistant tuberculosis
The 1,2,3-triazole derivatives find great importance in the
(
MDR-TB), against which the traditional anti-TB drugs show
medicinal chemistry research due to their important biological
3
13,14
limited efficacy, further cause serious problem in TB control.
According to WHO global tuberculosis report 2014, globally 3.5%
of new and 20.5% of previously treated TB cases were estimated
to be multidrug-resistant. This translates into an estimated
4
an emergent need to develop more effective drugs with minimum
side effects to treat XDR-TB and MDR-TB. In view of this, a great
deal of research work is being devoted to identify newer molecular
entities which are active against the bacterial strains. The most
important molecular design strategies in this direction are (i)
structural modification of the known drug molecule;5 (ii) com-
puter-aided drug design based on the study on ligand–protein
actions in addition to their synthetic applications.
The triazole
4
ring is a core structural moiety in some of the important drugs like
tazobactam and cefatrizine (which are used for bacterial infec-
tions), carboxyamidotriazole (which is used for cancer treatment)
and rufinamide (which is used as an anticonvulsant). A few recent
Letters demonstrated the promising antitubercular activity of
80,000 people having developed MDR-TB in 2013. Thus there is
1
5,16
1,2,3-triazole derivatives.
For example, a series of (E)-N1-[(1-
aryl)-1H-1,2,3-triazole-4-yl)methylene]isonicotinoylhydrazide (I)
based molecules exhibit outstanding antitubercular activity,
several of them possess MIC value in the range 2.5–0.62 l
g/mL.17
The triazole based antitubercular agent 6-hydroxy-3-(1-(2-((4-
morpholinophenyl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)-2-
phenylbenzofuran-5-carboxylic acid (II, I-A09) which is presently
under preclinical trials, is viewed as a promising class of pharma-
6
interaction; (iii) hybridisation of two active pharmacophoric units
1
8
cophore to provide effective drug candidates. Further, Patpi
et al. designed a set of 1,2,3-triazole based hybrid molecules fol-
lowing the molecular hybridisation strategy and among these,
⇑
Corresponding author. Tel.: +91 824 2473207; fax: +91 824 2474033.
E-mail addresses: udayaravi80@gmail.com, udayakumar@nitk.ac.in
U. Dalimba).
(
http://dx.doi.org/10.1016/j.bmcl.2015.08.009
960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Ramprasad, J.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.009

2
J. Ramprasad et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
compounds 4-(4-(tert-butyl)phenyl)-1-(1-(dibenzo[b,d]thiophen-2-
yl)ethyl)-1H-1,2,3-triazole (III) and 4-(2-chloro-4-fluorophenyl)-
1,2,3-triazole containing imidazo[2,1-b][1,3,4]thiadiazoles (6a–s,
7a) and evaluated their antitubercular activity.
1
-(1-(dibenzo[b,d]thiophen-2-yl)ethyl)-1H-1,2,3-triazole (IV)
Scheme 1 depicts the synthetic route of new 1,2,3-triazole-
imidazo[2,1-b][1,3,4]thiadiazole hybrids (6a–s, 7a). The 6-aryl-2-
methylimidazo[2,1-b][1,3,4]thiadiazoles (2a–c) were synthesized
by treating compound 1a with corresponding phenacyl bromide
derivatives. These compounds were then subjected to Vilsmeier–
Haack formylation reaction to yield 6-aryl-2-methylimidazo
19
exhibited excellent antitubercular activity with MIC of 0.78 lg/mL.
Similarly, the imidazole and thiadiazole moieties also are key
scaffolds in the medicinal chemistry research and several drugs
containing these moieties are available in the market. Imidazole
containing Pretomanid (PA-824) (nitro imidazopyran) is potent
2
8
against
both
replicating
and
hypoxic,
non-replicating
[2,1-b][1,3,4]thiadiazole-5-carboxaldehydes (3a–c).
The key
2
0
Mycobacterium tuberculosis (Mtb). Megazol which acts as antipar-
asitic, contain both 1,3,4-thiadiazole and imidazole rings. However,
the amalgamation of these two molecular entities as imidazo[2,1-
b][1,3,4]thiadiazole (ITD) ring resulted an active pharmacophore
intermediates, 6-aryl-2-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)
methanol (4a–c) were synthesized by reducing the corresponding
aldehyde intermediates (3a–c) using NaBH as the reducing agent.
4
Intermediates 4a–c were then treated with propargyl bromide in
the presence of sodium hydride to yield 6-aryl-2-methyl-
5-((prop-2-ynyloxy)methyl)imidazo[2,1-b][1,3,4]thiadiazoles (5a–c).
Finally, the target compounds (6a–s) were synthesized by
following Huisgen 1,3-dipolar cycloaddition reaction (click
reaction) in which alkyne intermediates (5a–c) were treated with
different substituted alkyl bromides in the presence of sodium
2
1–24
possessing a broad spectrum of pharmacological activity.
A
few ITD derivatives carrying other active pharmacophores
particularly at C-5 (V and (Z)-2-(4-oxo-5-((6-phenyl-2-(trifluoro
methyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)-2-thioxoth-
iazolidin-3-yl)acetic acid (VI)) have been found to possess good
activity against Mtb H37Rv strain.2
5,26
For instance, Kolavi et al.
2
9
reported the synthesis and antitubercular evaluation of a series
of ITD derivatives carrying a hydroxy methyl group at position-5
azide. The ester group in compound 6m was hydrolysed using
LiOH to get the target compound 7a.
2
7
(
VII). In our previous work, we demonstrated the excellent
antitubercular activity (MIC of 3.125 g/mL) of series of
-(2-substituted-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)-1H-
The structure of newly synthesized intermediates and target
1
13
l
a
compounds was confirmed by H NMR, C NMR, mass spectral
1
2
and elemental analyses. For instance, the H NMR spectrum of
28
benzimidazole derivatives (VIII). Thus, the promising antituber-
cular activity exhibited by imidazo[2,1-b][1,3,4]thiadiazole and
1
6n showed a singlet at d 7.5 ppm due to –CH proton of the triazole
ring whereas a quartet at d 4.40 ppm and a triplet at d 1.55 ppm
correspond to methylene and methyl protons of the N-ethyl group,
,2,3-triazole systems (Fig. 1) prompted us to integrate these two
pharmacophores in a single molecular framework and to explore
the effects of this molecular hybridisation on their activity against
Mtb H37Rv strain. In view of this, we synthesized a new library of
2 2
respectively. The methylene protons of –CH -O-CH – bridge
appeared as two separate singlets at d 4.93 and 4.79 ppm in which
the singlet at a slightly higher chemical shift value corresponds to
O
N
F
N
Cl
NH
N
O
NH
O
N
N
N
N
N
N
N
N
N
N
N
N
O
HO
HO
O
S
S
I
II
III
IV
O
3
R
OH
O
N
S
3
R
S
N
NH
OH
N
S
1
N
3
N
R
R
N
N
S
N
S
2
N
2
N
F3C
1
1
R
N
R
R
R
S
N
N
N
V
VI
VII
VIII
R =4-CH C H ,4-Cl C H , CH
3
1
R =Cyclohexyl, 2-thienyl
R =CH , OCH , Cl
R =1-pyrrolidinyl, 1-piperidinyl
1
1
2
R = Cyclohexyl, R = H
3
6
4
6
4
2
2
3
3
R = CH , OCH , F, Cl
3 3
R = Cl, NO , H
3
3
2
Figure 1. Structures of some representative imidazo[2,1-b][1,3,4]thiadiazole and 1,2,3-triazole containing antitubercular agents.
Please cite this article in press as: Ramprasad, J.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.009

J. Ramprasad et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
O
OH
N
N
N
S
N
N
S
N
1
b
N
1
c
N
1
a
NH2
R
R
R
S
N
S
N
N
1a
2a-c
3a-c
4a-c
1
3
3
3
a, 4a, 5a: R = Cl
1
b, 4b, 5b: R = CH3
d
1
c, 4c, 5c: R = OCH3
2
OH
R
1
N
N
O
N
N
N
N
O
O
O
N
N
N
N
S
N
1
e
N
1
f
R
R
R
S
N
S
N
N
1
7
a (R =Cl)
6a-s
5a-c
Scheme 1. Reagents and conditions: (a) phenacyl bromide, ethanol, 80–85 °C, 24 h, yield: 80–82%; (b) DMF, POCl
3
, 60 °C, 6 h, yield: 82–85%; (c) NaBH
4
, MeOH, 0 °C–rt, 4 h,
2
yield: 92–96%; (d) propargyl bromide, NaH, THF, 0 °C–rt, 4 h, yield: 96–98%; (e) R Br, NaN
LiOHÁH O, THF, MeOH, water, rt, 5 h, yield: 82%.
3
, sodium ascorbate, copper(II) sulfate, t-BuOH and water, rt, 24 h, yield: 82–92%; (f)
2
the methylene group attached to the 1,2,3-triazole ring. In addi-
tion, the spectrum displayed a singlet at d 2.75 ppm due to methyl
group present at position-2 of the ITD ring. The 13C NMR spectrum
of 6n displayed all characteristic peaks corresponding to its molec-
methods using SHELXL-2013 package. The hydrogens were fixed
in geometrically calculated positions and refined isotropically.
The molecule crystallises in the triclinic system with P-1 space
group. The crystal structure (ORTEP diagram) and crystal data of
the compound are given in Figure 2. The asymmetric unit contains
two molecules of 6c that are held by C18—N12 short contact. The
crystal packing structure of 6c is given in Supporting information.
All the target molecules (6a–s and 7a) were screened against
Mtb H37Rv (ATCC27294) using Agar dilution method. Their antimy-
cobacterial activity was evaluated in terms of minimum inhibitory
ular structure; the two methylene carbons of –CH
appeared at d 63.88 and 60.98 ppm whereas peaks at d 45.3 and
5.5 ppm represent methylene and methyl carbons of the ethyl
2 2
-O-CH – bridge
1
group, respectively. The characterisation data of all the target com-
pounds are given in the experimental part while their physical data
are tabulated in Table 1. Some representative spectra are given in
Supplementary information.
concentration (MIC) values. The MIC values in
lg/mL of 6a–s and
The three dimensional structure of one of the target com-
pounds, 6c was evidenced by single crystal X-ray diffraction stud-
ies. The single crystals of 6c were grown from methanol and
chloroform (1:1) solvent mixture by the slow evaporation of the
solvent at room temperature. A crystal of suitable size was
mounted and single-crystal data was collected at room tempera-
ture. The crystal structure was solved and refined by direct
7a along with those of standard drugs for comparison are pre-
sented in Figure 3. The MIC values of the compounds are in the
range 3.125–50.0
pounds, 6f and 6n show potent anti-tubercular activity with MIC
of 3.125 g/mL. The MIC of these two compounds is comparable
with that of the standard drug, ethambutol. Compound 6p showed
moderate inhibition activity with MIC of 6.25 g/mL. The nature of
lg/mL. It is evident that among twenty com-
l
l
1
the substituent on imidazo[2,1-b][1,3,4]thiadiazole (R ) and 1,2,3-
2
triazole (R ) rings affect the activity of the compounds. Most of the
Table 1
chloro or methoxy substituted derivatives exhibited superior activ-
ity than their methyl substituted analogues. All the methyl substi-
Structural features, logP/ClogP values and drug-likeness score of target compounds
(6a–s and 7a)
tuted derivatives (6g–l) showed MIC P25
l
g/mL irrespective of
the nature of the substituent at R whereas a few methoxy and
chloro analogues exhibited lower MIC values (3.125–12.5 g/mL).
Product
R1
R2
LogP/ClogP
Drug-likeness score
2
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
7
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
OCH
OCH
OCH
OCH
OCH
OCH
CH
CH
CH
CH
CH
CH
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
3
3
3
3
3
3
CH
CH
CH
2
2
2
-COOEt
3.51/1.65
3.98/1.55
3.39/0.49
5.54/2.93
5.54/2.93
5.38/2.79
4.13/2.14
4.6/2.04
4.00/0.98
6.15/3.42
6.15/3.42
5.99/3.28
4.2/2.35
4.67/2.25
4.99/2.56
4.07/1.19
6.22/3.63
6.22/3.63
6.06/3.49
3.6/1.492
0.31
0.35
0.05
0.52
0.65
0.41
0.14
0.28
À0.02
0.34
0.49
0.28
0.76
0.85
1.07
0.54
0.82
0.75
1.00
1.21
l
-CH
-CN
3
This general structure–activity relationship signifies the contribu-
1
tion of chloro/methoxy substituent (R ) towards the inhibition
2-Fluorobenzyl
4-Fluorobenzyl
CH
CH
CH
CH
2-Fluorobenzyl
4-Fluorobenzyl
CH
CH
CH
CH(CH
CH -CN
2-Fluorobenzyl
4-Fluorobenzyl
CH
CH
activity of the molecules. The presence of ethyl or benzyl groups
on the 1,2,3-triazole ring enhances the inhibition activity of the
molecules, which is evident by the significant activity shown by
compounds 6n and 6f. Further, methyl analogues (6h and 6l) with
2
2
2
2
-C H
6 5
3
3
3
3
3
3
-COOEt
-CH
-CN
3
these substituents also exhibited moderate activity (MIC = 25
lg/mL).
Other substituents like CH CN, CH COOEt and 4-fluorobenzyl on
2
2
2
2
2
-C
-COOEt
-CH
6
H
5
the 1,2,3-triazole ring also contributed in enhancing the activity
of the molecules. The 4-fluorobenzyl derivatives (6e, 6k and 6r) are
either equipotent or two fold more potent than respective 2-fluo-
robenzyl analogues (6d, 6j and 6q) which reveals the dependence
of the activity on the position of the fluoro substitution. The
hydrolysis of the ester functionality on the 1,2,3-triazole ring
3
3 2
)
2
s
a
2
-C H
6 5
(6m, MIC = 12.5
lg/mL) to a carboxylic acid group substantially
2
-COOH
decreased the potency of the molecule (7a, MIC = 50
l
g/mL). The
Please cite this article in press as: Ramprasad, J.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.009

4
J. Ramprasad et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
17 7 2
Figure 2. ORTEP diagram showing the X-ray crystal structure of compound 6c. (Crystal data: CCDC no. 1059072; formula: C18H N O S; M = 395.45; unit cell parameters: a,
3
b, c (Å) = 7.664 (3), 8.644 (3), 28.420 (10);
a
, b,
c
a
= 85.80 (2)°, 89.38 (2)°, 72.46 (19)°; volume (Å ): 1790.3 (11); T: 296 K; crystal system: triclinic; space group: P-1; Z = 4;
À1
R
1
= 0.0424; wR = 0.1466; radiation type: Mo K
2
;
l
(mm ): 0.213; radiation wavelength (Å): 0.71073.
Figure 3. The antitubercular activity of 6a–s and 7a against M. tuberculosis H37RV (INH: isoniazid; EMB: ethambutol; PZA: pyrazinamide).
1
2
substitution of different groups at R and R affect the lipophilicity
of the molecules (Table 1). However, we did not observe a general
relationship between lipophilicity and the activity of the com-
pounds. Nevertheless, it is interesting to compare the logP/ClogP
values of the active molecules and to account for the activity based
on their lipophilicity. The ClogP values of the active molecules are
in the range 2.2–2.9 with logP values in the range 4–5.5. Though
The in vitro cytotoxicity of the active compounds (MIC
612.5 g/mL) were evaluated by MTT (3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyltetrazolium bromide) assay against NIH 3T3
mouse embryonic fibroblasts cell line. The graphical representation
of the cell growth inhibition by the compounds at a concentration
of 50 lg/mL is shown in Figure 4. The compounds did not show
any toxicity to the cell line signifying the lack of general cellular
toxicity.
l
2
ethyl and benzyl substituents (R ) are found to enhance the activ-
ity, ethyl derivative 6b and benzyl derivative 6s showed only a
moderate activity (MIC = 25 lg/mL) which could be rationalised
based on the lower ClogP value for 6b and a higher value for 6s.
A similar relationship between lipophilicity and activity was
observed in other active derivatives as well which contain sub-
In conclusion, a series of twenty new 1,2,3-triazole-imidazo
[2,1-b][1,3,4]thiadiazole hybrids (6a–s, 7a) were designed by
molecular hybridisation approach and were synthesized using a
click chemistry reaction. These compounds were characterised by
2
stituents like CH COOEt and 4-fluorobenzyl group. Only those
derivatives (viz. 6e and 6m), whose lipophilicity falls in the above
mentioned values have shown good activity whereas their ana-
logues with higher (6r) or lower (6s) values have shown relatively
a lower activity. Also the most promising antitubercular com-
pounds 6e, 6f, 6m, 6n and 6p exhibited positive drug-likeness
3
0
score of 0.65, 0.41, 0.76, 0.85 and 0.54, respectively, (Table 1).
So it may be concluded that in addition to the structural features,
which play a major role, the lipophilicity factor also influences
the inhibition activity of the molecules. This information on struc-
ture/lipophilicity–activity relationship explored in the present
study could be helpful in further structural modification and devel-
opment of new 1,2,3-triazole-imidazo[2,1-b][1,3,4] thiadiazole
hybrids as potent antitubercular agents.
Figure 4. Growth inhibition activity of active compounds (at a concentration of
50 lg/mL) against NIH 3T3 cell line.
Please cite this article in press as: Ramprasad, J.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.009

J. Ramprasad et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
1H NMR, 13C NMR, mass spectroscopic techniques and elemental
analysis. In the anti-tubercular screening, compounds 6f and 6n
exhibited significant activity against the growth of Mtb with MIC
5. Lima, L. M.; Barreiro, E. J. Curr. Med. Chem. 2005, 12, 23.
6.
7.
8.
Åqvist, J.; Medina, C.; Samuelsson, J.-E. Protein Eng. 1994, 7, 385.
Lazar, C.; Kluczyk, A.; Kiyota, T.; Konishi, Y. J. Med. Chem. 2004, 47, 6973.
Viegas-Júnior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E. J.; Fraga, C. A. M.
Curr. Med. Chem. 2007, 14, 1829.
of 3.125 lg/mL. A moderate activity with MIC of 6.25 lg/mL was
9.
Cappoen, D.; Claes, P.; Jacobs, J.; Anthonissen, R.; Mathys, V.; Verschaeve, L.;
Huygen, K.; Kimpe, N. D. J. Med. Chem. 2014, 57, 2895.
observed for compound 6p. The structure–activity relationship
revealed that the 4-chlorophenyl group contributes significantly
in enhancing the inhibition activity of the molecules. Further, sub-
1
0. Cappoen, D.; Jacobs, J.; Nguyen Van, T.; Claessens, S.; Diels, G.; Anthonissen, R.;
Einarsdottir, T.; Fauville, M.; Verschaeve, L.; Huygen, K.; Kimpe, N. D. Eur. J.
Med. Chem. 2012, 48, 57.
2 2
stituents like ethyl, benzyl, 4-fluorobenzyl, CH CN and CH COOEt
11. Claes, P.; Cappoen, D.; Mbala, B. M.; Jacobs, J.; Mertens, B.; Mathys, V.;
Verschaeve, L.; Huygen, K.; Kimpe, N. D. Eur. J. Med. Chem. 2013, 67, 98.
on the 1,2,3-triazole ring enhance the anti-tubercular activity.
The active molecules exhibited positive drug-likeness score and
their ClogP values are in the range 2.2–2.9. Also, none of the active
molecules is toxic to a normal cell line. Hence, these compounds
with significant anti-TB activity could serve as promising lead
molecules for further generation of potent antitubercular agents.
Further, the present study reveals that the molecular hybridisation
approach could be a promising strategy for designing potent
antitubercular agents.
12. Claes, P.; Cappoen, D.; Uythethofken, C.; Jacobs, J.; Mertens, B.; Mathys, V.;
Verschaeve, L.; Huygen, K.; Kimpe, N. D. Eur. J. Med. Chem. 2014, 77, 409.
1
1
3. Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Chem. Rev. 2013, 113, 4905.
4. Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem. Asian J. 2011, 6, 2696.
15. Addla, D.; Jallapally, A.; Gurram, D.; Yogeeswari, P.; Sriram, D.; Kantevari, S.
Bioorg. Med. Chem. Lett. 2014, 24, 1974.
16. Addla, D.; Jallapally, A.; Gurram, D.; Yogeeswari, P.; Sriram, D.; Kantevari, S.
Bioorg. Med. Chem. Lett. 2014, 24, 233.
17. Boechat, N.; Ferreira, V. F.; Ferreira, S. B.; Ferreira, M. d. L. G.; da Silva, F. d. C.;
Bastos, M. M.; Costa, M. d. S.; Lourenço, M. C. S.; Pinto, A. C.; Krettli, A. U. J. Med.
Chem. 2011, 54, 5988.
1
1
8. Shi, D.-Q.; Zhou, Y.; Rong, S.-F. Synth. Commun. 2009, 39, 3500.
9. Patpi, S. R.; Pulipati, L.; Yogeeswari, P.; Sriram, D.; Jain, N.; Sridhar, B.; Murthy,
R.; Kalivendi, S. V.; Kantevari, S. J. Med. Chem. 2012, 55, 3911.
0. 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.
Nature 2000, 405, 962.
Acknowledgments
2
Authors are thankful to NITK, Surathkal for providing the
research facilities and to Dr. Reddy’s Institute of Life Sciences,
Hyderabad Central University for providing NMR and mass spectral
analysis.
21. Kamal, A.; Reddy, V. S.; Santosh, K.; Kumar, G. B.; Shaik, A. B.; Mahesh, R.;
Chourasiya, S. S.; Sayeed, I. B.; Kotamraju, S. Med. Chem. Commun. 2014, 5,
1718.
22. Kamal, A.; Rao, M.; Das, P.; Swapna, P.; Polepalli, S.; Nimbarte, V. D.; Mullagiri,
Supplementary data
K.; Kovvuri, J.; Jain, N. Chem. Med. Chem. 2014, 9, 1463.
2
2
3. NarasimhaáRao, M.; LakshmaáNayak, V. Med. Chem. Commun. 2014, 5, 1644.
4. Kumar, S.; Gopalakrishnan, V.; Hegde, M.; Rana, V.; Dhepe, S. S.; Ramareddy, S.
A.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.; Srivastava, M.; Raghavan, S.
C.; Karki, S. S. Bioorg. Med. Chem. Lett. 2014, 24, 4682.
5. Alegaon, S. G.; Alagawadi, K. R.; Sonkusare, P. V.; Chaudhary, S. M.; Dadwe, D.
H.; Shah, A. S. Bioorg. Med. Chem. Lett. 2012, 22, 1917.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.08.
2
0
09.
26. Hegde, V. S.; Kolavi, G. D.; Lamani, R. S.; Khazi, I. A. M. J. Sulfur Chem. 2006, 27,
553.
References and notes
2
2
7. Kolavi, G.; Hegde, V.; Gadad, P. Bioorg. Med. Chem. 2006, 14, 3069.
8. Ramprasad, J.; Nayak, N.; Dalimba, U.; Yogeeswari, P.; Sriram, D.; Peethambar,
S. K.; Achur, R.; Kumar, H. S. S. Eur. J. Med. Chem. 2015, 95, 49.
9. Odlo, K.; Høydahl, E. A.; Hansen, T. V. Tetrahedron Lett. 2007, 48, 2097.
0. Bakht, M. A.; Yar, M. S.; Abdel-Hamid, S. G.; Al Qasoumi, S. I.; Samad, A. Eur. J.
Med. Chem. 2010, 45, 5862.
1.
2.
3.
Herzog, B. H. Respiration 1998, 65, 5.
Tripathi, R. P.; Tewari, N.; Dwivedi, N.; Tiwari, V. K. Med. Res. Rev. 2005, 25, 93.
Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. Nature 2011, 469,
2
3
4
83.
4
.
World Health Organization, Global Tuberculosis Report, 2014.
Please cite this article in press as: Ramprasad, J.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.009