Synthesis and evaluation of novel fluorinated pyrazolo-1,2,3-triazole hybrids as antimycobacterial agents

Article abstract of DOI:10.1016/j.bmcl.2015.05.044

A library of novel 3-trifluoromethyl pyrazolo-1,2,3-triazole hybrids (5-7) were accomplished starting from 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (1) via key intermediate 2-azido-N-(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)acetamide (3) throu

Full text of DOI:10.1016/j.bmcl.2015.05.044

Accepted Manuscript
Synthesis and evaluation of novel fluorinated pyrazolo-1,2,3-triazole hybrids as
antimycobacterial agents
Narender Reddy Emmadi, Chiranjeevi Bingi, Sudha Sravanti Kotapalli, Ramesh
Ummanni, Jagadeesh Babu Nanubolu, Krishnaiah Atmakur
PII:
S0960-894X(15)00506-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.05.044
BMCL 22734
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 April 2015
18 May 2015
20 May 2015
Please cite this article as: Emmadi, N.R., Bingi, C., Kotapalli, S.S., Ummanni, R., Nanubolu, J.B., Atmakur, K.,
Synthesis and evaluation of novel fluorinated pyrazolo-1,2,3-triazole hybrids as antimycobacterial agents,
Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.05.044
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Synthesis and evaluation of novel fluorinated pyrazolo-1,2,3-triazole hybrids as
antimycobacterial agents
Narender Reddy Emmadi,a Chiranjeevi Bingi,a Sudha Sravanti Kotapalli,b Ramesh Ummannib Jagadeesh Babu
Nanubolu c and Krishnaiah Atmakura,d*
aCrop Protection Chemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India
bChemical Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
cCentre for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India
dAcademy of Scientific and Innovative Research, CSIR- Indian Institute of Chemical Technology, Hyderabad 500007, India
ARTICLE INFO
ABSTRACT
A library of novel 3-trifluoromethyl pyrazolo-1,2,3-triazole hybrids (5-7) were accomplished
starting from 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (1) via key intermediate 2-azido-
N-(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)acetamide (3) through Click Chemistry
approach. Thus obtained compounds in 5-7 series were evaluated for in vitro antimycobacterial
activity against Mycobacterium smegmatis (MC2 155) and also verified the cytotoxicity. These
studies engendered promising lead compounds 5q, 7b and 7c with MIC ( µg/mL ) values 15.34,
16.18 and 16.60 respectively. Amongst these three compounds, 2-(4-(4-methoxybenzoyl)-1H-
1,2,3-triazol-1-yl)-N-(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl) acetamide (5q) emerged as
the most promising antitubercular agent with lowest cytotoxicity against the A549 cancer cell
line. This is the first report to demonstrate the pyrazolo triazole hybrids as potential
antimycobacterial agents.
Article history:
Received
Revised
Accepted
Available online
Keywords:
Antimycobacterial activity
Cytotoxicity
Click chemistry
3-Trifluoromethyl pyrazolo-1,2,3-triazole hybrids
Tuberculosis (TB) is a potentially serious infectious
disease caused by Mycobacterium tuberculosis which affects
mainly the lungs (pulmenory TB) apart from other vital organs.1
The World Health Organization (WHO 2013) estimated that
there are 8.6 million TB cases which includes 1.1 million co-
infected with HIV. Tuberculosis is one of the leading cause for
mortality and in the year 2012 alone, there were 4,10,000 deaths
of women affected by TB including 1,60,000 associated with
HIV positive cases.2 Additionally, multi drug resistant
tuberculosis (MDR-TB) and extremely drug resistant tuberculosis
(XDR-TB) has become a major threat to human kind.3 In these
circumstances, development of hybrid molecules through the
combination of different pharmacophores in a single frame work
with novel mechanism of action is one of the best way to achieve
effective TB control.4
Further, triazole based antitubercular agents regarded as a new
class of molecules that provide truly effective lead candidates
reported to inhibit bacteria.6 Compound II (I-A09) (Fig. 1) comes
under this category is presently in pre-clinical trials.7
F
N
O
O
O
N
N
N
N
R
N
H
NH
N
N
N
OH
R
N
N
N
R
O
O
OH
III
I
II (I-A09)
F3C
F3C
F
S
N
H
N
N
O
N
F3C
N
NH
N
O
N
N
N
H2N
N
SO2NH2
O
N
Razaxaban
VI
Penthiopyrad
V
Celocoxib
IV
Meanwhile, 1,2,3-triazoles have gained enormous
interest in recent years owing to their broad spectrum
pharmaceutical and therapeutic applications such as
antimicrobial activity against gram-positive bacteria, therapeutic
fungicides of second generation, anti-inflammatory agents,
inhibitors of tumor proliferation, invasion, metastasis and anti-
HIV activity etc (Fig. 1).5
Figure 1. Bioactive triazole and 3-trifluoromethyl containing pyrazole
moieties
Furthermore, pyrazole compounds are known to possess good
biological activities such as potent aurora A/B kinase inhibitors,
calcium (CRAC) channel inhibitors, antitumor and
Mycobacterium tuberculosis.8 Additionally, it is well
documented that incorporation of trifluoromethyl group into
*Corresponding author: Tel:91-40-27191436; Fax: 91-40-27193382; E-mail:
krishnu@iict.res.in

organic molecules can lead to profound changes in physical,
chemical, and especially biological properties of the molecule.
was reacted with sodium azide using catalytic amount of NaI to
give 2-azido-N-(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-
yl)acetamide in 98% yield (Scheme 1). The azide 3 was fully
characterized by 1H, 13C NMR and mass (ESI and HR-MS)
spectral data. On the other hand, alkynes 4a-j were procured
from commercially available sources, whereas, 4l-p were
prepared by the reaction of substituted anilines with proparzyl
bromide, K2CO3 in DMF20 and 4q-v were obtained by the
reaction of substituted aldehydes with ethynyl magnesium
bromide in Dry THF and the resulting alcohols were further
oxidised with IBX.21
Specially, insertion of trifluoromethyl group at 3rd
position of the pyrazole ring lead to good biologically active
moieties including those used as inhibitors of the measles virus
RNA polymerase complex,9 inhibitors of CRAC channel,10
modulators of AMPA receptor.11 Selective COX-2 inhibitors
such as celecoxib (IV),12 fungicide penthiopyrad (V)13 and factor
Xa inhibitor razaxaban(VI)14 (Fig. 1).
Based on the biological significance of triazole and
3-trifluoromethyl pyrazole moieties and also as a part of our
ongoing research programme on the bioactive heterocyclic
compounds,15 we envisaged the integration of 3-trifluoromethyl
pyrazole and triazole pharmacophore units with acetamide
linkage in one molecular platform to generate a new pyrazolo
triazole hybrid frame work and to determine the anti-TB activity.
In this context, the literature survey revealed that there are no
reports available on the combination of pyrazole, triazole frame
work with anti-tuberculosis properties. With the fact that 1,2,3-
triazoles were efficiently made through Cu(I) catalyzed click
chemistry,16 we herein report for the first time an efficient
synthesis of a series of novel 3-trifluoromethyl pyrazole-1,2,3-
triazole hybrids (5a–v) in excellent yields (Scheme 2). Further
the compound 5i converted into hydrazone derivatives of
3-trifluoromethyl pyrazole-1,2,3-triazole hybrids (7a-e) and all
the compounds in 5 to7 series were subjected to in vitro activity
studies against Mycobacterium smegmatis (MC2 155) and also
verified the cytotoxicity.
Scheme 1.
Synthesis of 2-Azido-N-(5-phenyl-3-(trifluoromethyl)-1H-
pyrazol-4-yl)acetamide 3
Figure 2. Design strategy for new 3-trifluoromethyl pyrazolo-1,2,3-triazole
Figure 3. ORTEP Diagram of 5-phenyl-3-(trifluoromethyl)-1H-
pyrazol-4-amine (1).
hybrids.
The designed 3-trifluoromethyl pyrazolo-1,2,3-triazole
frame work (Fig. 2) made into three parts: N-substituted 1,2,3-
triazole as a mainstay, 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-
4-amine to intensify the desired pharmacophoric behavior with
drug like properties and aliphatic or aromatic groups and aryl
amino methyl and aroyl groups adjoined to other side of 1,2,3-
triazole moiety. Distinctions in the proposed scaffold also
accomplished with the choice of aliphatic or aromatic alkynes
4a–v (Fig. 4). Synthesis of 1,2,3-triazole moiety was through the
Huisgen 1,3-dipolar cycloaddition reaction17 (click reaction)
between azide 3 and alkynes 4a–v.
Figure 4. Alkynes used for synthesis of pyrazolo triazole hybrids.
Initially, synthesis of 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-
amine (1)18 was started from 4,4,4-trifluoro-1-phenylbutane-1,3-
dione on reaction with NaNO2 in acetic acid followed by with
hydrazine hydrate in ethanol. Structure of pyrazol-4-amine (1)
was unambiguously confirmed by single crystal X-ray diffraction
analysis and the data deposited at the CCDC 1051815 (Fig. 3).
Further, compound 1 was treated with chloroacetyl chloride19
using pyridine as a base in DCM and the resulting compound 2

NH2
HN
O
H
H
N
F3
C
N
N
F3
C
N
O
N
O
N
Aldehydes, Cat. AcOH
Ethanol, Reflux, 2h
NH2NH2.H2O
N
N
N
N
O
O
Ethanol,
Reflux, 4h
Ph
N
H
Ph
N
H
5i
6
Aldehydes:
CHO
R
CHO
CHO
N
O
HN
CF3
H
N
F3
C
N
OPh
7a : R=4-CF3, 90%;
7b
N
N
CF3
CHO
CHO
O
: R=2-CF3, 89%;
7c : R=3-OPh, 92%;
7d
N
Ph
N
H
; R=4-OMe, 91%;
7e : R=3,4-OMe, 85%
OMe
OMe
OMe
Scheme 3. Synthesis of 3-trifluoromethyl pyrazolo1,2,3-triazolo hydrazones
7a-e
All the compounds in 5 to 7 series were evaluated for
antimycobacterial activity against Mycobacterium smegmatis
(MC2 155). Outcome of the screening study showed that some of
the compounds (Fig. 5) exhibited promising antimycobacterial
activity with MIC values ranging from 15 to 95 µg/mL.
Specifically, compounds 5q, 7b and 7c showed remarkable MIC
(µg/mL) values 15.34, 16.18 and 16.60 respectively. Other
compounds such as 5a, 5b, 5g, 5c, 5e and 5i showed moderate
antimycobacterial activity with MIC (µg/mL) values 35.93,
35.41, 29.94, 31.75, 35.37 and 27.73 respectively.
Having both azide 3 and alkynes 4a–v on hand, we next
subjected them to Huisgen’s (3+2) cycloaddition reaction in the
presence of CuSO4, sodium ascorbate in t-Butanol and water
(1:1, v/v) to get pyrazole-1,2,3,-triazole hybrids (5a-v) in
1
excellent yields (Scheme 2) and were characterized by H, 13C
NMR and mass spectral data.
Structure activity correlation of compounds in 5 to 7
series with respect to their antitubercular activity revealed that,
compounds in 5 series bearing 4-OCF3, Ph and pentyl (5b, c & e)
groups on phenyl ring showed moderate activity with MIC values
ranging from 31.75-35.41 µg/mL. However, 3-methyl
substitution 5g attributed to increase in activity (MIC 29.94
µg/mL). Whereas, presence of 4-t-butyl group on phenyl ring 5d
showed very poor activity in contrast to 5g. Replacement of
O
H
R
H
F3C
N
N
N
F3C
N
N
N
O
H
N
N
F3C
N
N
N
N
N
N
O
N
O
O
Ph
5a : R=H, 90%;
N
Ph
N
Ph
N
H
H
5b : R=4-OCF3, 89%;
5c : R=4-Ph, 92%;
5d ; R=4-t Butyl, 91%;
5e : R=4-n Pentyl, 90%;
5f : R=4-OMe, 2-Me, 89%;
5g : R=3-Me, 90%;
H
5i : 93%
5j : 89%
H
N
R
F3C
N
N
H
N
N
N
phenyl group in
5 series with N-methyl aniline moiety,
O
5h : R=2-CF3, 92%;
Ph
N
H
5l : R=3-CF3, 87%;
5m : R=3-OMe, 89%;
5n : R=3, 4-OMe, 92%;
5o ; R=3, 4, 5-OMe, 84%;
5p : R=2, 6-Me, 88%
irrespective of substitution on phenyl group 5l-p induced
decrease in activity. However, replacing the phenyl group with
ester functional 5i attributed to enhanced activity (MIC 27.73
µg/mL). Subsequent replacement of ester functional in 5i with 4-
methoxy benzoyl group 5q lead to tremendous increase in
activity with MIC 15.34 µg/mL (high activity compound in the
series), whereas 3,4-dimethoxy benzoyl group 5r receded the
activity. Furthermore, conversion of ester functional in 5i into
hydrazide (6) proved to be not effective. In order to get the
enhanced activity, hydrazide (6) was converted to hydrazones by
reacting with substituted aldehydes 7a-e and screened for
antimycobacterial activity. Compound 7b-c has exhibited very
good activity with MIC 16.18 and 16.60 µg/mL (Fig. 5). In order
to check the cytotoxicity of the compounds in 5 to7 series, they
were screened against lung cancer cell line A549 and outcome of
the study presented in Fig 6. Interestingly, the compounds 5q and
7b-c which have shown high antimycobacterial activity were
showed IC50 values 80.74 for 5a and >100 for 7b-c which
signifies that they are not cytotoxic.
CF3
O
N
N
O
N
O
R
F3C
N
NH
Ph
O
O
O
H
N
5k : 86%
F3C
N
N
N
N
H
N
H
N
F3C
N
N
O
N
N
N
N
Ph
N
Ph
O
Ph
H
R
5s : R=H, 90%;
N
5t : R=4-Cl, 89%;
5u : R=4-Me, 92%;
5v; R=4-OMe, 91%;
H
5q : R=4-OMe, 90%;
5r : R=3, 4-OMe, 89%;
Scheme 2. Synthesis of 3-trifluoromethyl pyrazolo1,2,3-triazole hybrids5a-v
Further compound 5i was reacted with hydrazine
hydrate to get triazolo carbonyl hydrazine (6) and further it was
condensed with aromatic aldehydes in ethanol to give triazolo
hydrazones22 (7a-e) (Scheme 3). Thus obtained hydrazones 7a-e
was well characterized by 1H, 13C NMR and mass (ESI and
HRMS) spectral data.

Figure 5. Antimycobaacterial activity of compounds in 5-7 series against M. smegmatis
Figure 6. Cytotoxicity values of 5-7 series against A549 cells.
The compounds 5a, 5b, 5g, 5c, 5e and 5i which showed
moderate antimycobacterial activity against M. megmatis were
also found to be not cytotoxic with IC50 value
60.59, 57.01, >100 and >100 respectively. How
5l, 5d and 5r are moderately cytotoxic to A549 l
with IC50 values of 25.33, 25.84 and 26.82 respecctively (Fig. 6).
Supplementary data
s
Supplementary data (experimental prrocedures, spectral data,
crystallography data and 1H, 13C, mass, IR spectras of
representative compounds) associated with this article can be
found.
s
52.19, 45.29,
eever compounds
uung cancer cells
References and Notes
In conclusion, we have synthesized a s
(4-aryl -1H-1,2,3-triazol-1-yl)-N-(5-phenyl-3-(t
1H pyrazol-4-yl) acetamide derivatives (5a-v) by Huisgen’s
(3 + 2) cycloaddition reaction of pyrazole azide ( ) with different
alkynes 4a-v in presence of copper sulphat and sodium
ascorbate. Further compound 5i was converted into triazolo
e
e
ries of novel -
r
[1]
a) Zumla, A.; Raviglione, M.; Hafneer, R.; von Reyn, C. F. N. Engl.
J. Med. 2013, 368, 745. b) Nikalje,, A. G.; Mudassar, P. Asian. J.
Biol. Sci. 2011, 4, 101. c) Russell, D. G.; Barry, III, C. E.; Flynn,
J. L. Science 2010, 328, 852.
33
e
[2]
[3]
World Health Organization, Globaal Tuberculosis Report, WHO,
hydrazones (7a-e) via triazolo carbonyl hydrazin
ee
(6) and all the
2013.
compounds were screened against Mycobacter
i
um smegmatis
a) Lawn, S. D.; Mwaba, P.; Bates, M.; Piatek, A.; Alexander, H.;
Marais, B. J.; Cuevas, L. E.; McHuggh, T. D.; Zijenah, L.; Kapata,
N.; Abubakar, I.; McNerney, R.; HHoelscher, M.; Memish, Z. A.;
Migliori, G. B.; Kim, P.; Maeurerr, M.; Schito, M.; Zumla, A.
Lancet Infect. Dis. 2013, 13, 349. b) Prabowo, S. A.; Gröschel,
M.I.; Schmidt, E.D.; Skrahina, A..; Mihaescu, T.; Hastürk, S.;
Mitrofanov, R.; Pimkina, E.; Visontai, I.; de Jong, B.; Stanford, J.
L.; Cardona, P. J.; Kaufmann, S.HH.; Vander Werf, T. S. Med.
Microbiol. Immunol. 2013, 202, 95. c) Gutierrez-Lugo, M. T.;
Bewley, C. J. Med. Chem. 2008, 51, 2606.
(MC2 155) followed by cytotoxicity against the A
5549 lung cancer
cell line. Outcome of these studies showed that the compounds
5q, 7b and 7c have a very promising antimycobacterial activity
(MIC 15.34, 16.18 and 16.60 µg/mL) with le
Further, compound 5q emerged as the potentia
candidate with lowest cytotoxicity. This is the fir
demonstrated the potential utility of 3-trifluoro
s
s
s cytotoxicity.
l
ss
t report that has
m
1,2,3-triazole hybrids as antitubercular agents which can be
exploited further.
[4]
[5]
a) Palomino, J. C.; Martin, A.; Anntimicrob. J. Chemother. 2013,
68, 275. b) Nguyen, L.; Jacobs, MM. R. Expert Rev. Anti Infect.
Ther. 2012, 10, 959. c) Nzila, A.; MMa, Z.; Chibale, K. Future Med.
Chem. 2011, 3, 1413.
Acknowledgement
a) Agalave, S. G.; Maujan, S. R.; Poore, V. S. Chem. Asian J. 2011,
6, 2696. b) Brik, A.; Alexandratos, JJ.; Lin, Y.; Elder, J. H.; Olson,
We are grateful to SERB-DST (grant no. SB/EM
E
Q-075/2013),
New Delhi for financial support. ENR is thankful
Delhi for SRF.
tto CSIR New
A. J.; Wlodawer, A.; Goodsell, D.
SS.; Wong, C. Chem. Bio. Chem.
2005, 6, 1167. c) Chen, H.; Zuo, SS.; Wang, X.; Tang, X.; Zhao,

M.; Lu, Y.; Chen, L.; Liu, J.; Liu, Y.; Liu, D.; Zhang, S.; Li. T.
Eur. J. Med. Chem. 2013, 62, 590.
[6]
a) Tripathi, R. P.; Yadav, A. K.; Ajay, A.; Bisht, S. S.; Chaturvedi,
V.; Sinha, S. K. Eur. J. Med. Chem. 2010, 45, 142. b) Gill, C.;
Jadhav, G.; Shaikh, M.; Kale, R.; Ghawalkar, A.; Nagargoje, D.;
Shiradkar, M. Bioorg. Med. Chem. Lett. 2008, 18, 6244. c)
Izumizono, Y.; Arevalo, S.; Koseki, Y.; Kuroki, M.; Aoki, S. Eur.
J. Med. Chem. 2011, 46, 1849. d) Zhou, C. H.; Wang, Y. Curr.
Med. Chem. 2012, 19, 239. e) Ahirrao, P. Mini Rev. Med. Chem.
2008, 8, 1441.
[7]
[8]
Zhou, B.; He, Y.; Zhang, X.; Xu, J.; Luo, Y.; Wang, Y.;
Franzblau, S. G.; Yang, Z.; Chan, R. J.; Liu, Y.; Zheng, J.; Zhang,
Z. Y. Proc. Natl. Acad. Sci. U.S.A 2010, 107, 4573.
a) Zheng, Y.; Zheng, M.; Ling, X.; Liu, Y.; Xue, Y.; An, L.; Gu,
N.; Jin. M. Bioorg. Med. Chem. Lett. 2013, 23, 3523. b) Yonetoku,
Y.; Kubota, H.; Okamoto, Y.; Ishikawa, J.; Takeuchi, M.; Ohta,
M.; Tsukamoto, S. Bioorg. Med. Chem. 2006, 14, 5370.
Sun, A.; Yoon, J. J.; Yin, Y.; Prussia, A.; Yang, Y.; Min, J.;
Plemper, R. K.; Snyder, J. P. J. Med. Chem. 2008, 51, 3731.
a) Yonetoku, Y.; Kubota, H.; Okamoto, Y.; Toyoshima, A.;
Funatsu, M.; Ishikawa, J.; Takeuchi, M.; Ohta, M.; Tsukamoto, S.
Bioorg. Med. Chem. Lett. 2006, 14, 4750. b) Yonetoku, Y.;
Kubota, H.; Miyazaki, Y.; Okamoto, Y.; Funatsu, M.; Yoshimura-
Ishikawa, N.; Ishikawa, J.; Yoshino, T.; Takeuchi, M.; Ohta, M.;
Bioorg. Med. Chem. 2008, 16, 9457.
[9]
[10]
[11]
[12]
Ward, S. E.; Harries, M.; Aldegheri, L.; Austin, N. E.; Ballantine,
S.; Ballini, E.; Bradley, D. M.; Bax, B. D.; Clarke, B. P.; Harris,
A. J.; Harrison, S. A.; Melarange, R. A.; Mookherjee, C.; Mosley,
J.; Dal Negro, G.; Oliosi, B.; Smith, K. J.; Thewlis, K. M.;
Woollard, P. M.; Yusaf, S. P. J. Med. Chem. 2011, 54, 78.
Chowdhury, M. A.; Abdellatif, K. R. A.; Dong, Y.; Yu, G.;
Huang, Z.; Rahman, M.; Das, D.; Velazquez, C. A.; Suresh, M. R.;
Knaus, E. E. Bioorg. Med. Chem. Lett. 2010, 20, 1324.
Culbreath, A. K.; Brenneman, T. B.; Jr. Kemerait, R. C.; Hammes,
G. G. Pest. Manag. Sci. 2009, 65, 66.
[13]
[14]
Zhang, D.; Raghavan, N.; Chen, S. Y.; Zhang, H.; Quan, M.;
Lecureux, L.; Patrone, L. M.; Lam, P. Y. S.; Bonacorsi, S. J.;
Knabb, R. M.; Skiles, G. L.; He, K. Drug. Metab. Dispos. 2008,
36, 303.
[15]
a) Reddy, E. N.; Krishnaiah, A.; Chirangeevi, B.; Reddy, G. N.;
Ganesh Kumar, Ch. Babu, N. J. Bioorg. Med. Chem. Lett. 2014,
24, 485. b) Reddy, E. N.; Krishnaiah, A.; Ganesh Kumar, Ch.;
Sujitha, P.; Babu, N. J. Bioorg. Med. Chem. Lett. 2012, 22, 7261.
c) Krishnaiah, A.; Reddy, E. N.; Sridhar, B. J. Hetercycl. Chem.
2013, 50, 513.
[16]
[17]
Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Chem. Rev. 2013,
113, 4905.
a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41, 2596. b) Himo, F.; Lovell, T.;
Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.;
Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.
[18]
[19]
Nicola, C.; Hopkins, C. R.; Majid, T.; Pedgrift, B. Tetrahedron
Lett. 2004, 45, 2137.
Hewawasam, P.; Chen, N.; Ding, M.; Natale, J. T.; Boissard, C.
G.; Yeola, S.; Gribkoff, V. K.; Starrett, J.; Dworetzky, S. I.
Bioorg. Med. Chem. Lett. 2004, 14, 1615.
[20]
[21]
Sintu, G.; Majumdar, K. C. Tetrahedron Lett. 2013, 54, 6192.
Kueny-Stotz, M.; Isorez, G.; Chassaing, S.; Brouillard, R. Synlett
2007, 1067.
[22]
Beena, D. S. Rawat, Med. Res. Rev. 2013, 33, 693.

Synthesis and evaluation of novel
fluorinated pyrazolo-1,2,3-triazole
hybrids as antimycobactirial agents
Narender Reddy Emmadi, Chiranjeevi Bingi, Sudha Sravanti Kotapalli,
Ramesh Ummanni Jagadeesh Babu Nanubolu and Krishnaiah Atmakur
Graphical abstract
OMe
F3C
F3C
N
H
N
N
HN
H
N
F3C
N
N
N
H
F3C
N
N
N
N
O
O
N
N
O
N
Ph
N
O
N
H
O
N
Ph
N
H
Ph
7c
MIC 16.60 µg/m
H
5q
7b
MIC 15.34 µg/mL
MIC 16.18 µg/mL
(against M. smegmatis (MC2 155)