2
M. H. Shaikh et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
In the last decade, 1,2,3-triazole have received much attention,
by the treatment of 2H-benzo[b][1,4]thiazin-3(4H)-one 3 (pre-
as their intriguing physical and biological properties, as well as
their excellent stability, rendering them promising drug core struc-
pared via cyclization of 2-aminothiophenol with chloroacetic acid
in CH COONa–AcOH) with propargyl bromide in presence of
3
sodium hydride as a base in N,N-dimethylformamide (DMF) at
room temperature in 90% yield (Scheme 2).
Finally, the benzyl azides 5a–h, nitro-aryl azides (5i–j) and 4-
(prop-2-yn-1-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one 4, on 1,3-
1
1
tures.
As compounds containing fused triazole derivatives
became common in pharmaceutical targets and biologically active
substances, the new strategies to synthesize this class of molecules
are highly desirable. 1,4-Disubstituted-1,2,3-triazoles with various
functionalities/pharmacophoric groups are readily accessible via
2
dipolar cycloaddition reaction in t-BuOH–H O (3:1) and catalytic
12
the copper catalyzed azide-alkyne cycloaddition (CuAAC) as pio-
amount of copper diacetate (Cu(OAc) ) at room temperature for
2
neered by Meldal and Sharpless.13
24–30 h separately, afforded the corresponding regioselective
1,4-disubstituted-1,2,3-triazole incorporated 2H-benzo[b][1,4]thi-
azin-3(4H)-one derivatives 6a–j in quantitative isolated yield
(88–95%) (Scheme 2). All the synthesized compounds (6a–j) were
Over the past few years, organic compounds bearing triazole
14
nucleus have shown antitubercular, antibacterial, antiallergic,
1
5
16
17
anti-HIV,
antifungal activity
and a-glycosidase inhibitors
1
13
activity have been explored. Moreover, 1,2,3-triazole derivatives
with regard to the antitubercular activity, have been found to show
promising activity profile.18 Triazoles have shown very promising
anti-TB and antifungal activity via inhibiting the cell wall synthe-
well characterized by advanced spectroscopic techniques ( H,
C
2
7
and Mass analysis).
The newly synthesized 1,4-disubstituted-1,2,3-triazole contain-
ing benzothiazinone derivatives 6a–j were screened for in vitro
antitubercular activity against MTB H37Ra (ATCC 25177) and M.
bovis BCG (ATCC 35743) in liquid medium. In a preliminary screen-
ing (Supporting Information, Table S1), the anti-mycobacterial
activity of these compounds were assessed at concentrations of
1
9
sis. Owing to these significant features, a number of protocols
for the synthesis of 1,2,3-triazole compounds have been devel-
2
0
oped. Among them, the most elegant and useful approach is
2
1
the Huisgen’s 1,3-dipolar cycloaddition of azides and alkynes.
The triazole containing benzothiazinone derivatives possesses
30, 10 and 3 lg/mL using an established XTT Reduction Menadione
22
23
28
class of anti-candida agents
(
(Fig. 1A), antifungal agents
Fig. 1B, C, D) and inhibitors of non-glucoside SGLT2 (Fig. 1E).
In continuation of our earlier work25 on the synthesis and bio-
assay (XRMA) anti-tubercular screening protocol using first-line
antitubercular drugs rifampicin and isoniazid as reference stan-
dards and the MIC and IC50 values are presented (Table 1). The tri-
24
logical properties of various heterocyclic moieties, herein, we
would like to report first time the synthesis of benzothiazinone
based 1,2,3-triazole derivatives and also their antitubercular,
antioxidant and cytotoxic activities. In addition to this, we have
also performed molecular docking study and in silico ADME pre-
diction for the synthesized compounds. Furthermore molecular
docking study of the title compounds was carried out for the better
understanding of the drug-receptor interaction and complements
the results obtained from the antitubercular screening.
azole derivatives 6c (MIC value = 29.24
(MIC = 27.34 g/mL) were found to be particularly active against
MTB H37Ra. Similarly, compounds 6a, 6c and 6e (MIC = 29.37,
27.5 and 28.43 g/mL, respectively) were found to be particularly
active against M. bovis BCG Remaining all the compounds
(MIC = >30 g/mL) were found to be less active against MTB and
lg/mL) and 6e
l
l
l
M. bovis BCG strains. According to the data, the activity depends
upon the substituents present on phenyl rings. For MTB H37Ra,
3
compound 6c (fluoro-group at R position) and compound 6e
2
We have described the syntheses of new substituted-((1-(ben-
zyl)-1H-1,2,3-triazol-4-yl)methyl)-2H-benzo[b][1,4]thiazin-3(4H)-
(chloro-group at R position) showed very promising antitubercu-
lar activity with MIC value 29.24 and 27.34
Replacement of chloro-group with fluoro-group at R position
(compound 6d, MIC = >30 g/mL) do not show any significant
lg/mL, respectively.
2
6
3
one 6a–j derivatives by the 1,3-dipolar cycloaddition of aryl
azides (5a–j) and 4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]thiazin-3
l
(
4H)-one (4) via click chemistry approach. The syntheses of start-
ing material benzyl azides 5a–h were prepared from correspond-
ing benzaldehydes via NaBH reduction, bromination and
change in anti-tubercular activity. The position of chloro-group is
important on the phenyl ring for antitubercular activity. In com-
4
pound 6d (MIC = >30 lg/mL) and 6f (MIC = >30 lg/mL), the
3
1
nucleophilic substitution reaction of sodium azide and azides 5i–
j from corresponding anilines via diazotization followed by azide
substitution reaction in excellent yields (Scheme 1). We have syn-
thesized 4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one 4
chloro-group at R and R position of phenyl ring, respectively,
showed less antitubercular activity compared to compound 6e
2
(MIC = >27.34
l
g/mL) in which chloro-group present at R position
of phenyl ring. Similarly, for M. bovis BCG, compound 6a
N
O
N
N
OH
N
N
N
F
N
S
OH
N
N
OH
S
N
N
S
N
N
N
O
N
O
F
A
B
C
N
N
S
N
N
F3C
O
N
S
N
O
Cl
N
S
O
N
Cl
D
E
Figure 1. 1,2,4-Triazole containing 1,4-benzothiazinone derivatives.