An efficient one-pot synthesis of pyrazolyl-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazin-6-yl)-2H-pyran-2-one derivatives via multicomponent approach and their potential antimicrobial and nematicidal activities

Article abstract of DOI:10.1016/j.tetlet.2013.07.148

A series of simple or/and aryl, heteryl hydrazono pyrazolyl-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-pyran-2-one derivatives have been efficiently synthesized in excellent yields via one-pot, multi-component approach. The importance of this methodology is that in a one-pot operation four new bonds (3C-N and 1C-S) are generated. The structure of compound 5a was confirmed by single-crystal X-ray diffraction. The newly synthesized compounds were evaluated for their in vitro antimicrobial activity against gram-positive bacteria (Staphylococcusaureus and Bacillussubtilis), gram-negative bacteria (Escherichiacoli andKlebsiellapneumoniae), antifungal activity against Candida albicans, and nematicidal activity against Meloidogyneincognita. Among all the compounds 6f showed excellent antimicrobial and nematicidal activity against tested bacteria, fungi, and nematodes.

Full text of DOI:10.1016/j.tetlet.2013.07.148

Accepted Manuscript
An efficient one-pot synthesis of pyrazolyl-[1,2,4]triazolo[3,4-b][1,3,4] thia‐
diazin-6-yl)-2H-pyran-2-one derivatives via multicomponent approach and
their potential antimicrobial and nematicidal activities
Santhosh Penta, Kranthi Kumar Gadidasu, Srinivas Basavoju, Rajeswar Rao
Vedula
PII:
S0040-4039(13)01326-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.148
TETL 43346
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 April 2013
23 July 2013
29 July 2013
Please cite this article as: Penta, S., Gadidasu, K.K., Basavoju, S., Vedula, R.R., An efficient one-pot synthesis of
pyrazolyl-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazin-6-yl)-2H-pyran-2-one derivatives via multicomponent approach
and their potential antimicrobial and nematicidal activities, Tetrahedron Letters (2013), doi: http://dx.doi.org/
10.1016/j.tetlet.2013.07.148
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Graphical Abstract
Leave this area blank for abstract info.
An efficient one-pot synthesis of pyrazolyl-[1,2,4]
triazolo[3,4-b][1,3,4] thiadiazin-6-yl)-2H-pyran-2-one
derivatives via multicomponent approach and their
potential antimicrobial and nematicidal activities
O
O
N
N
S
R1
R2
N
N
N
3
N
R1=Me, R2=Me
(b) R1=Me, R2=OEt
OH
R1
(a)
Santhosh Penta,a Kranthi Kumar Gadidasu,b
Srinivas Basavoju,a and
R2
O
i
O
5
CH3
Rajeswar Rao Vedulaa*
O
O
OH
O
O
N
N
N
H3C
OEt
SH
Br
N
N
H2N
S
N
N
+
NH
H
NH2
N
N
N
H3C
O
R3
R4
N
N
OH
H3C
2
1
O
O
aDepartment of Chemistry, National Institute of Technology, Warangal-506 004, India
b Department of Biotechnology, Kakatiya University, Warangal-506009, India
R5
NH
O
4
CH3
R3
R4
i
R5
6

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
An efficient one-pot synthesis of pyrazolyl-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazin-6-yl)-2H-pyran-2-one derivatives via multicomponent approach and
their potential antimicrobial and nematicidal activities
Santhosh Penta,a Kranthi Kumar Gadidasu,b Srinivas Basavoju,a and
Rajeswar Rao Vedulaa*
*a
Department of Chemistry, National Institute of Technology, Warangal-506 004, India , E-mail: vrajesw@yahoo.com
b Department of Biotechnology, Kakatiya University, Warangal-506009, India,
Abstract: A series of simple or/and aryl, heteryl hydrazono pyrazolyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-pyran-2-one derivatives
have been efficiently synthesized in excellent yields via one-pot, multi-component approach. The importance of this methodology is that in a one-
pot operation four new bonds (3C-N and 1C-S) are generated. The structure of compound 5a was confirmed by single-crystal X-ray diffraction. The
newly synthesized compounds were evaluated for their in vitro antimicrobial activity against gram-positive bacteria (Staphylococcus aureus and
Bacillus subtilis), gram-negative bacteria (Escherichia coli and Klebsiella pneumonia), antifungal activity against Candida albicans and nematicidal
activity against Meloidogyne incognita. Among all the compounds 6f showed excellent antimicrobial and nematicidal activity against tested
bacteria, fungi and nematodes.
Keywords:
Pyrazolyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-pyran-2-ones,
3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one,
antimicrobial activity, nematicidal activity, multi-component reaction, single-crystal X-ray diffraction.
Multi-component reactions (MCRs) are processes ‘‘in which
more than two reactants directly get converted into their
products by one-pot reaction.’’1 Remarkable features of MCRs
exhibit higher atom economy and selectivity as well as
produce fewer by-products compared to classical multistep
synthesis.2 Therefore, the discovery of novel protocols using
multicomponent strategy has become an increasingly active
area of research for generating biologically active poly-
substituted nitrogen scaffolds for drug discovery program.
The fused heterocyclic ring of triazoles and thiadiazines called
triazolo-thiadiazines, which is a core structure of various
synthetic nitrogen bridged heterocyclic systems and exhibit
various biological activities such as antibacterial, antifungal,
antiviral, anti-tubercular, anti-helmintic, diuretic, analgesic,
exhibit a wide range of antifungal, antimicrobial, cytotoxic,
neurotoxic activities10 and Alzheimer’s disease.11
The amino and mercapto groups are ready-made nucleophilic
centers for the synthesis of condensed heterocyclic rings.12 4-
Amino-5-hydrazino-4H-[1,2,4]triazole-3-thiols
can
be
considered as useful synthons in preparing to triazolo-
thiadiazines. A survey of literature revealed that, 1,3,4-
thiadiazines and triazolo-thiadiazines are prepared mainly
based on cyclocondensation of heterocyclic amino thiols with
bifunctional reagents such as α-halo/tosyloxy carbonyl
compounds, dihalides and α-halo nitriles.13 However, most of
these methods have drawbacks such as use of expensive,
hazardous reagents, tedious work-up, purification procedures,
high boiling solvents and multi-step synthesis. Recently, some
authors reported poly aza heterocyclic systems like 1,2,4-
triazolo[3,4-b][1,3,4]-thiadiazine with 5-(benzofuran-2-yl)-1-
phenylpyrazole nucleus along with their antimicrobial
anti-tumor,
anti-inflammatory,
CNS-stimulant,
PDE4
inhibitors and hypoglycemic agents.3 The 1,2,4-triazole group
is a basic structure in various marketed drugs e.g. Alprazolam,
Triazolam,5 Etizolam,6 and Furacylin.7 Pyrazoles are found
4
activity,14
1,2,4-triazolo[3,4-b][1,3,4]-thiadiazine
with
as key substructures in a large variety of compounds
exhibiting activity such as analgesic, anti-inflammatory,
antipyretic, muscle relaxant, anticonvulsant, hypertensive,
anti-diabetic and antibacterial.8 3-Acetyl-4-hydroxy-6-methyl-
2H-pyran-2-one (Dehydroacetic acid) is a pyran derivative and
exhibits high biological activity.9 4-Hydroxy-2-pyrones are
considered as one important class of anti-HIV agents and
———
thiazolo[3,2-a]benzimidazole moiety15 and 3,6-diaryl-7H-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine analogs16 as potential
phosphodiesterase-4 inhibitors in NIH-3T3 mouse fibroblastic
cells via multistep synthesis. However, to the best of our
knowledge, this one-pot multi-component reaction for tri-
heterocyclized pyrazolyl-[1,2,4]triazolo[3,4-b][1,3,4]
*
Corresponding author: Tel.: +91 9912186430; fax: +91 870 2459547;
E-mail: vrajesw@yahoo.com

2
Tetrahedron Letters
has been [1,2,4]triazole-3-thiol, attacks the carbon atom (CH2-Br) of 3-
thiadiazin-6-yl)-2H-pyran-2-one
derivatives
unprecedented to date. In view of these observations,17 it was
(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one to give
a substituted intermediate. This undergoes further intra-
molecular cyclization leading to the formation of 3-(3-
hydrazino-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-4-
hydroxy-6-methyl-pyran-2-one. This subsequently undergoes
condensation reaction with acetyl acetone / ethylacetoacetate /
thought
pharmacophores, namely triazolo-thiadiazines and pyrazole in
single molecular framework which definitely shows
worthwhile
to
synthesize
certain
active
a
significant biological activity.
Herein, a facile method has been described for the synthesis of
title products via one-pot transformation containing several
reacting centers with NaOAc/MeOH as solvent (scheme-1).
Reaction of equimolar mixture of 3-(2-bromoacetyl)-4-
hydroxy-6-methyl-2H-pyran-2-one (1) with 4-amino-5-
hydrazino-4H-[1,2,4]triazol-3-thiol (2) and acetyl acetone /
ethyl aceto acetate (3) or ethyl-2-(2-phenylhydrazono)-3-
oxobutanoates (4) in NaOAc/MeOH under reflux conditions
afforded the corresponding title products (5a) and (6a-m) in
good to excellent yield. The scope and the generality of the
present method was further demonstrated by the reaction of
different derivatives of ethyl-2-(2-aryl, heteryl hydrazono)-3-
oxobutanoates (Table-6, possessing both electron-donating
and electron-withdrawing groups) with 3-(2-bromoacetyl)-4-
hydroxy-6-methyl-2H-pyran-2-one (1) and 4-amino-5-
hydrazino-4H-[1,2,4]triazol-3-thiol. The desired product was
obtained in each case good to excellent yield. This work may
trigger an interesting chemistry involving new methodology.
The striking feature of the synthesis is that different hetero
atom bonds like C-S, N=C, N-C, N=C (compound 5) and C-
S, N=C, N-C=O and N=C (Compound 6) are formed
simultaneously in one pot leading to selective novel hetero
cyclization without formation of any other products.
different
derivatives
of
ethyl-2-(2-arylhydrazono)-3-
oxobutanoate (β-ketoester) to give end products 5 and 6
(scheme-2).
The structures of the newly synthesized compounds were
confirmed by their spectral (IR, 1H, 13C NMR, MS) and
elemental analyses. For example, in the IR spectrum of
compound 5a showed four strong absorption peaks at 1608
cm–1 for C=N, at 1707 cm–1 for lactone carbonyl and at 3367
cm–1 for OH. In the H NMR spectra, singlets were observed
1
for S-CH2 of thiadiazine at δ 4.39, C-5 proton of pyran at δ
6.21 and pyrazole proton at δ 6.28. The 13C NMR spectrum of
5a shows the peaks at δ 11.3, 13.1, 19.5, 24.0 and 171.7 for
pyran methyl, pyrazole methyls and S-CH2 of thiadiazine and
C=O of pyran respectively. Similarly, the IR spectrum of
compound 6a showed prominent peaks at 1610 cm-1 for C=N,
at 1709 cm-1 for lactone carbonyl, at 3325 cm-1 for –NH and
3437 cm-1 for –OH, whereas the H NMR of compound 6a
1
showed characteristic singlets were observed for S-CH2 of
thiadiazine at δ 4.21 and C-5 proton of pyran at δ 6.21. The –
NH proton appeared as a broad singlet at δ 12.81. The 13C
NMR spectrum of 6a shows the peaks at δ 11.6, 19.1, 24.5,
and 170.8 for pyran methyl, pyrazole methyl, S-CH2 of
thiadiazine and C=O of pyran respectively. All the other
aromatic protons of 6a-m were observed at the expected
regions. Mass spectra of the 6a showed 499 (M+H)+ peak in
agreement with molecular formulae. Like this, the remaining
spectral data confirmed the newly prepared compounds
structures (5a-b and 6a-m).
O
O
N
N
S
R1
R2
N
N
N
3
N
R1=Me, R2=Me
(b) R1=Me, R2=OEt
OH
R1
(a)
R2
O
i
O
5
CH3
O
O
OH
O
O
N
N
N
H3C
OEt
SH
Br
N
N
H2N
S
N
N
+
NH
H
NH2
N
The results average diameter of inhibition zones (IZ) of
bacterial or fungal growth values are compared with those of
standard antibiotic Kanamycin for bacteria and Clotrimazole
for fungus. From the Table-3 it should be noted that, four
compounds 6a, 6e, 6f and 6g were found to be most potent
members showing zone of inhibition against all the bacterial
and fungal strains. And also, 6f was found to be most effective
against all the tested bacteria and fungi showing maximum
zone of inhibition 28.0, 24.0, 35.0, 34.0 and 27.0 mm even
greater than the standard drug Kanamycin and Clotrimazole.
However, the compounds 5a, 5b, 6b, 6c, 6d, 6h, 6i and 6k
compounds exhibit moderatively active and 6j, 6l and 6m
compounds have not shown the activity. From the minimum
inhibitory concentration studies (MIC), Table-4 the compound
6f was identified as the most potent inhibitor with significant
MIC values of 8.0, 10.0, 10.0, 6.0 and 11.0 µg/mL which are
more or equal to the standard drugs. The antimicrobial activity
data reveal that compounds containing 3-nitro group on phenyl
(6f) ring, were showing excellent activity against the tested
bacteria and fungi. 6a, 6e and 6g are showing good activity
and the remaining compounds showing moderate activity
against all the tested bacterial and fungal strains. The
nematicidal activity experiments were performed according to
literature procedure18 and tested for against Meloidogyne
incognita.
N
N
H3C
O
R3
R4
N
N
OH
H3C
2
1
O
O
R5
NH
O
4
CH3
R3
R4
i
R5
6
Scheme 1: Reagents and conditions: (i) MeOH, fused AcONa,
reflux 4h, 85 °C
N
N
Br
S
OH
N
N
OH
O
H2N
N
N
N
SH
, -HBr
O
H
NH2
H2N
O
N
H
NH2
O
O
CH3
O
CH3
1
2
N
N
S
N
N
H2N
N
N
N
O
O
N
S
-H2O
H
HO
Et
H2N
OH
O
N
-H2O
H
N
3
O
H
HO
CH3
O
O
O
CH3
N
N
N
N
S
N
N
S
H3C
N
N
H
N
N
OH
N
N
OH
-EtOH
O
H3C
O
O
O
O
Et
O
O
CH3
5
CH3
Scheme-2: The plausible mechanism for the formation of products
During thiadiazine ring formation, the highly nucleophilic
mercapto group of the 4-amino-5-hydrazino-4H-

Tetrahedron Letters
3
Table-3: Antibacterial and antifungal activity of compounds
5a-b and 6a-m compounds
Table 5: Effect of diluted compounds on mortality of
Meloidogyne incognita at different time intervals From the
results, (Table 5) the compounds 6f and 6g were found to be
most active, as it caused 67-85% and 52-73% mortality of the
nematode larvae after an exposure 24 and 48 h. 6a, 6c, 6d and
6e compounds were found to posses good activity as these
caused only 42-55%, 35-51%, 18-28% and 40-44 % mortality
after the exposure where as compounds 5a (5-8%), 5b (5-9%),
6b (8-11%), 6h (5-8%), 6i (5-9%), 6j (5-8%), 6k (5-12%), 6l
(3-5%), 6m (2-3%) were found to be least active. All
compounds indicated time and concentration dependent
activity. The activity was higher at high concentrations and
increased with time. There was no mortality observed in
control.
Zone of inhibition in mm
Gram-negative
bacteria
Gram-negative
bacteria
Fungi
Compound
numbers
5a
5b
E.
coli
8
K.
S.
B.
C.
albicans
8
8
pneumoniae aurious subtilis
8
8
8
9
8
8
8
6a
6b
16
8
16
8
15
8
16
8
16
8
6c
6d
6e
6f
6g
6h
6i
6j
10
11
17
28
20
8
10
10
15
24
17
8
9
9
14
35
18
8
9
9
10
27
19
8
9
9
10
27
19
8
In this work an efficient methodology for the synthesis of tri-
heterocyclizedpyrazolyl-[1,2,4]triazolo[3,4-][1,3,4]thiadiazin-
6-yl)-2H-pyran-2-one derivatives has been described via one-
pot, multicomponent reaction and evaluated for their
antimicrobial activity against gram-positive, gram-negative
bacteria, fungi and nematodes. Finally, the structure of 5a was
confirmed unambiguously by single crystal X-ray diffraction
analysis. Amongst them compound 6f showed excellent
activity against bacteria, fungi and nematodes. Thus,
compound 6f was considered to be a lead analog for
subsequent optimization in the search for novel antimicrobial
agents.
3-(2-Bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one19 and
ethyl-2-(2-arylhydrazono)-3-oxobutanoates20 were prepared by
literature procedure. The antimicrobial cell susceptibility
testing was performed by agar disc-diffusion technique
according to Bauer et al., 1966.21-22 a standard Kanamycin23
(30 µg/disc) against bacteria and Clotrimazole24 (10 µg/disc)
against fungi. MIC of the synthesized compounds was
determined using method described by Villanova, 1982.
8
-
8
-
8
-
8
-
8
-
6k
6l
6m
10
-
-
13
-
-
8
-
-
8
-
-
8
-
-
Kanamycin
Clotrimazole
25
-
23
-
32
-
-
-
-
25
Table 4: Minimum Inhibitory Concentration Studies
MIC (µg/mL)
Gram negative
bacteria
Gram positive
bacteria
Fungi
Compound
numbers
E.
coli
80
80
25
80
50
45
14
08
18
75
75
-
K.
S.
B.
subtilis
80
80
25
76
50
50
19
6
C.
albicans
pneumonia
aurious
80
80
35
80
55
50
27
10
24
75
75
-
5a
5b
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
80
80
33
80
50
55
22
10
23
75
75
-
80
80
30
80
60
55
27
11
20
75
75
-
20
75
75
-
General procedure for the synthesis of compounds (5a-b
and
pyran-2-one
6a-m):
3-(2-Bromoacetyl)-4-hydroxy-6-methyl-2H-
(0.001 mol), 4-amino-5-hydrazino-4H-
6k
6l
75
-
63
-
65
-
65
-
70
-
[1,2,4]triazol-3-thiol (0.001mmol) and acetyl acetone / EAA
(0.001 mol) or different derivatives of ethyl-2-(2-
arylhydrazono)-3-oxobutanoates (0.001 mol) were taken in 5
mL of methanol, then fused sodium acetate (2 mmol) was
added to the mixture. The resultant mixture was refluxed for 4
h. After completion of reaction (monitored with TLC), the
reaction mixture was cooled to RT. The solid was formed
gradually. It was filtered, washed with water, dried and
purified by recrystallization from absolute ethanol.
6m
-
-
-
-
-
Kanamycin
Clotrimazole
8
-
11
-
10
-
4
-
-
10
Table 5: Nematicidal activity
24h
150
48h
150
Compound 250
50
250
50
numbers
µg/mL µg/mL µg/mL µg/mL µg/mL µg/mL
5a
5b
5
5
3
3
2
2
8
9
5
6
4
4
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
DMSO
42
8
28
5
15
2
55
11
51
28
44
85
73
8
9
8
12
5
33
6
26
3
Acknowledgement
We wish to thank to the Director, National Institute of
Technology, Warangal for providing facilities and research
fellowship to PS. We are also thankful to University of
Hyderabad for providing single crystal X-ray data collection.
35
18
40
67
52
5
5
5
5
3
20
10
23
43
35
3
3
3
3
0
10
6
19
32
20
1
2
2
2
0
28
16
28
63
55
5
5
6
5
2
19
10
20
45
28
3
3
3
3
0
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4
Tetrahedron Letters
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Graphical Abstract
An efficient one-pot synthesis of pyrazolyl-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazin-6-yl)-2H-pyran-2-one derivatives via multicomponent approach
and their potential antimicrobial and nematicidal activities
Santhosh Penta,a Kranthi Kumar Gadidasu,b Srinivas Basavoju,a and Rajeswar Rao
Vedula*
a Department of Chemistry, National Institute of Technology, Warangal-506 004, India
b Department of Biotechnology, Kakatiya University, Warangal-506009, India
E-mail: vrajesw@yahoo.com
A multicomponent cyclocondensation of 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-
one with 4-amino-5-hydrazino-4H-[1,2,4]triazol-3-thiol and acetyl acetone / EAA or ethyl-2-(2-
arylhydrazono)-3-oxobutanoates is described for the synthesis of pyrazolyl-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazin-6-yl)-2H-pyran-2-one derivatives and evaluated for their antimicrobial
activity.
N
N
S
N
N
N
N
N
N
N
S
OH
H3C
N
N
N
O
N
OH
R1
O
R2
NH
O
O
CH3
R3
R4
O
CH3
R5
* Corresponding author: Tel.: +91 9912186430; fax: +91 870 2459547;
E-mail: vrajesw@yahoo.com