Synthesis and biological activities of a novel series of 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles containing gem-dimethylbenzyl moiety

Article abstract of DOI:10.1002/jhet.674

A novel series of 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4- thiadiazoles (6a-r) containing gem-dimethyl benzyl moiety were prepared by the condensation of 4-amino-3-aryl/aralkyl substituted-5-mercapto-1,2,4-triazoles (5a-c) with various fluoro substituted aromatic acids in the presence of POCl₃. IR, ¹H NMR, ¹³C NMR, 2D NMR (COSY), and mass spectral data confirmed the structures of all the synthesized compounds. All the compounds were also screened for their antibacterial, antifungal and analgesic activities. Compounds 6b, 6d, 6f, 6g, 6h, 6i, 6m, 6n, 6o, 6p, and 6r exhibited promising antibacterial and compounds 6a, 6d, 6f, 6g, 6h, 6k, 6m, 6o, 6p, and 6q showed significant analgesic activities.

Full text of DOI:10.1002/jhet.674

998
Synthesis and Biological Activities of a Novel Series of
3,6-Disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles
Containing Gem-dimethylbenzyl Moiety
Vol 48
Pushpan Puthiyapurayil,a,b Boja Poojary,a* Sunil Kumar,c
and Raveendra Hunnurc
aDepartment of Chemistry, Mangalore University, Mangalagangothri-574199, Karnataka, India
bSyngene International Ltd, Jigani, Bangalore-560099, India
cDepartment of Pharmaceutical Chemistry, N. E. T. Pharmacy College,
Raichur-584103, Karnataka, India
*E-mail: bojapoojary@gmail.com
Received May 26, 1996
DOI 10.1002/jhet.674
Published online 27 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles (6a–r) containing gem-di-
methyl benzyl moiety were prepared by the condensation of 4-amino-3-aryl/aralkyl substituted-5-mer-
capto-1,2,4-triazoles (5a–c) with various fluoro substituted aromatic acids in the presence of POCl3. IR,
1H NMR, 13C NMR, 2D NMR (COSY), and mass spectral data confirmed the structures of all the synthe-
sized compounds. All the compounds were also screened for their antibacterial, antifungal and analgesic
activities. Compounds 6b, 6d, 6f, 6g, 6h, 6i, 6m, 6n, 6o, 6p, and 6r exhibited promising antibacterial and
compounds 6a, 6d, 6f, 6g, 6h, 6k, 6m, 6o, 6p, and 6q showed significant analgesic activities.
J. Heterocyclic Chem., 48, 998 (2011).
INTRODUCTION
and incorporation of a methylene chain between the
phenyl and 1,2,4-triazole cycle increased the antifungal
activity by twofold on the yeast species (C. albicans
and C. tropicalis) [13]. Compounds containing halogen
heterocycles have attracted attention due to the ability
of halogen to act as polar hydrogen or hydroxyl mimic,
substitution of hydrogen by halogen has been a strategy
in designing the molecules for biological studies [14].
Several life-saving drugs contain 1,2,4-triazole nucleus,
for example, fluconazole is used as an antimicrobial drug
[15,16] vorozole, letrozole, and anastrozole are nonsteroi-
dal drugs used for the treatment of cancer [17,18] while
loreclezole is used as an anticonvulsant [19]. Therefore, it
was assumed that chemical entity [1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole [20] containing gem-dimethyl benzyl
moiety would result in compounds with enhanced biolog-
ical activities. Prompted by these observations and in
continuation of our research work on the synthesis
of novel heterocyclic compounds exhibiting biological
activity, we report, herein, the reaction of 4-amino-5-aryl-
1,2,4-triazole-3-thiols (5a–c) with substituted aromatic
acids in the presence of phosphorous oxychloride to
The structural diversity and biological importance of
1,2,4-triazole-containing heterocycles have made them
attractive targets for synthesis over many years. Nitro-
gen-containing heterocycles are found in various natural
products and have been identifies as products of chemical
and biological importance [1]. Heterocycles bearing a
symmetrical triazole or 1,3,4-thiadiazole moieties were
reported to show a broad spectrum of pharmacological
properties such as anti-inflammatory [2], antiviral [3,4],
antibacterial [5,6], antifungal [7], and anticancer activities
[8,9]. A triazolothiadiazole system may be viewed as a
cyclic analogue of two very important components, such
as thiosemicarbazide [10,11] and biguanide [12], which of-
ten display diverse biological activities. Therefore, it was
contemplated to investigate a composite system, which
combines these two biolabile components in a ring bearing
gem-dimethyl benzyl moiety to give a compact and planar
structure and screen them for their biological activities.
A recent literature reveals that modulation of the phe-
nyl cycle enhances biological activities of 1,2,4-triazole
C
V
2011 HeteroCorporation

September 2011
Synthesis and Biological Activities of a Novel Series of Triazolothiadiazoles
999
Scheme 1. Reaction sequence for the synthesis of substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (6a–r). Reagents and conditions: (a) MeOH, H2SO4
reflux; (b) MeI, NaH, THF, ꢀ10ꢁC; (c) N2H4.H2O, MeOH, reflux; (d) CS2, KOH, MeOH, rt; (e) N2H4.H2O, water, reflux; (f) Ar-CO2H, POCl3 reflux.
afford 3,6-disubstituted [1,2,4]triazolo[3,4-b][1,3,4]thia-
diazoles (6a–r). All newly synthesized compounds were
screened for their antibacterial, antifungal, and analgesic
activities.
(AT 25923) and Bacillus subtilis (Gram positive) at 50,
100 lgm mLꢀ1 concentrations by cup-plate method
[22], in the nutrient agar media by measuring the zone
of inhibition in mm. One day before the test, two stock
cultures were aseptically inoculated on 20 mL of nutri-
ent broth and incubated overnight period at 37ꢁC in an
incubator. Nutrient broth was prepared by dissolving
peptone (6.9 gm), beef extract (1.5 gm), yeast extract
(3.0 gm), and dextrose anhydrous (1.0 g) in distilled
water (1000 mL) adjusting the pH up to 7.2 using
NaOH solution (40%) and autoclaved at 120ꢁC for 20
min at 15-lb pressure. Nutrient agar was prepared by
dissolving peptone (20.0 gm), Beef extract (5.0 gm), so-
dium chloride (5.0 gm), and agar (20.0 gm) in distilled
water (500 mL) adjusting the pH up to 7.2 using NaOH
solution, and autoclaved at 120ꢁC for 20 min. The solu-
tion of required concentrations 50, 100 lgm/mL of test
compounds were prepared by dissolving the compounds
in DMSO. The sterilized nutrient agar medium was dis-
tributed 100 mL each in two 250-mL conical flasks,
then 18–24 h grown sub cultures were added and shaken
thoroughly to ensure uniform distribution of organisms
throughout the medium. This agar medium (50 mL) was
distributed equally in all sterilized Petri dishes, and the
medium was allowed for solidification. Then, cups were
made with the help of a sterile cork borer (6 mm)
punching into the set of agar media. Two cups were
filled with 0.1 mL of two test solutions, then the Petri
dishes were kept for incubation in an inverted position
for 48 h at 37ꢁC. Streptomycin and procaine penicillin
were used as standard drugs, the inhibition zone were
measured and compared with the controls. The bacterial
zone of inhibition values were given in Table 2.
CHEMISTRY
As depicted in Scheme 1, we have synthesized three
substituted 1,2,4-triazoles (5a–c) through a multistep
reaction [21]. Commercially available substituted phenyl
acetic acids were converted into their methyl esters (1a–
c), esters on reaction with sodium hydride and methyl
iodide in THF at ꢀ10ꢁC under N2 atmosphere yielded
methyl 2-methyl-2-aryl propanoates (2a–c). The result-
ing propanoates were hydrazinolyzed to afford aryl
hydrazides (3a–c). The compounds (3a–c) on reaction
with carbon disulfide in methanolic potassium hydroxide
yielded corresponding dithiocarbazinates (4a–c) in good
yields and were directly used for the next step without
purification. 5-Substituted-4-amino-1,2,4-triazole-3-thiols
(5a-c) were synthesized by refluxing (4a–c) with hydra-
zine hydrate. Condensation of (5a–c) with various aro-
matic acids in the presence of phosphorous oxychloride
under reflux yielded 6-aryl-3-(2-aryl-propan-2-yl)[1,2,4]-
triazolo[3,4-b][1,3,4]thiadiazoles (6a–r). The reaction
sequence is outlined in Scheme 1. Characterization data
of (6a–r) are given in Table 1.
BIOLOGICAL ACTIVITY
Antibacterial activity. The newly synthesized com-
pounds were screened for their antibacterial activity against
Psuedomonas aeruginosa (ATCC-27853), Escherichia Coli
(ATCC-25922) (Gram negative), Staphylococus aureas
Antifungal activity. All the synthesized compounds
were also screened for their antifungal activity against
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1000
P. Puthiyapurayil, B. Poojary, S. Kumar, and R. Hunnur
Vol 48
Table 1
Characterization data of substituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (6a–r).
Compounds
R
Ar
4-F-C6H4
2,3,4-F3-C6H2
Thienyl
4-OCF3-C6H4
2,4,6-(CH3)3-C6H2
4-CF3-C6H4
Mol. formula (Mol. weight)
m.p. (ꢁC)
Yield (%)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
H
H
C18H15FN4S (338.40)
C18H13F3N4S (374.38)
C16H14N4S2 (325.44)
174.6–175.7
172.1–173.2
139.2–140.3
171.2–172.4
203.5–205.2
236.2–237.8
181.1–182.4
180.1–181.4
174.1–175.5
210.9–212.4
161.5–163.2
66.4–67.7
74
64
65
84
65
70
72
66
74
75
71
70
90
87
91
83
91
86
H
H
C19H15F3N4OS (404.41)
C21H22F3N4S (362.49)
C19H15F3N4S (388.41)
C18H14ClFN4S (372.84)
C18H13ClF3N4S (408.83)
C19H14ClF3N4OS (438.85)
C20H13ClF6N4S (490.85)
C19H13ClF4N4S (440.84)
C21H21ClN4OS (444.93)
C18H14BrFN4S (417.34)
C18H13BrF3N4S (453.27)
C19H14BrF3N4OS (483.41)
C20H13BrF6N4S (535.30)
C19H13BrF4N4S (485.29)
C19H13BrF3N5O2S (512.30)
H
H
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-F-C6H4
2,3,4-F3-C6H2
2-OCF3-C6H4
3,5-(CF3)2-C6H3
2-F-4-CF3-C6H3
3,4,5-(OCH3)3-C6H2
4-F-C6H4
2,3,4-F3-C6H2
2-OCF3-C6H4
3,5-(CF3)2-C6H3
2-F-4-CF3-C6H3
3-NO2-5-CF3-C6H3
186.4–187.8
184.5–185.5
166.1–168.0
203.8–205.2
161.2–162.4
168.8–170.1
the fungal organism Fusarium oxysperum at the concen-
tration levels of 50–100 lgm/mL by cup-plate method
[22], using Griseofulvin as the standard drug. Potato
dextrose agar media was prepared and sterilized by
autoclaving at 120ꢁC for 20 min at 15 lb pressure. The
sterilized potato dextrose agar media was inoculated
with 72 h subculture of fungus and shaken thoroughly
to ensure uniform distribution. Then, this was poured
into previously sterilized Petri dishses and allowed to
solidify. Four cups were made in the plate with the help
of sterilized borer. Two cups were filled with 0.1 mL of
test solutions and the other two cups with respective
concentrations of standard solutions. The plates were
left as it is for diffusion for 3 h, and, then, they were
Table 2
In vitro evaluation of antibacterial activity (zone of inhibition in mm).
Antibacterial activity (lgm mLꢀ1
)
Gram-positive bacteria
S. aureus B. subtilis
Gram-negative bacteria
P. aeruginosa
E. coli
50
(lgm mLꢀ1
100
(lgm mLꢀ1
50
(lgm mLꢀ1
100
(lgm mLꢀ1
50
(lgm mLꢀ1
100
(lgm mLꢀ1
50
(lgm mLꢀ1
100
(lgm mLꢀ1
)
Compounds
)
)
)
)
)
)
)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
14
18
13
19
14
19
18
18
14
07
15
13
16
18
19
14
12
18
–
19
19
15
24
18
23
23
21
20
14
18
17
20
23
24
19
18
23
–
11
19
09
20
10
19
20
20
15
14
16
13
15
20
18
15
14
19
–
20
25
12
25
19
25
24
22
17
19
20
16
19
23
25
20
19
24
–
09
18
14
14
12
18
18
18
16
15
15
11
16
18
18
14
10
16
20
–
14
20
15
20
14
20
21
21
19
20
21
17
19
20
21
21
15
20
23
–
15
07
06
10
11
20
19
15
17
12
14
12
13
14
08
15
12
16
22
–
18
13
10
18
08
21
20
19
21
18
19
18
18
18
15
20
17
21
24
–
6p
6q
6r
Streptomycin
Procainepencillin
21
25
22
27
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Synthesis and Biological Activities of a Novel Series of Triazolothiadiazoles
1001
Table 3
In vitro evaluation of antifungal activity (zone of inhibition in mm).
mortality during 48-h study period (short term) toxicity.
Based on the compounds short-term toxicity profile, the
doses of the next animals were determined as per OECD
guidelines NO: 425. All the animals were observed for
long-term toxicity (7 days), and, then, one-tenth of lethal
dose of the individual compound was taken as effective
dose ED50 and was used throughout the experimental
studies. The observations of this experiment were
recorded in Table 4.
Antifungal activity (lgm mLꢀ1
)
Fusarium oxysperum
Compounds
50 (lgm mLꢀ1
)
100 (lgm mLꢀ1
)
6a
6b
6c
6d
6e
6f
6g
4.0
–
5.5
5.0
2.5
1.0
2.0
–
2.0
4.0
–
2.0
1.0
1.0
–
2.5
3.5
–
RESULTS AND DISCUSSION
6h
6i
From Table 2, it is clear that all the compounds tested
showed moderate to good bacterial inhibition. Com-
pounds 6b, 6d, 6f, 6g, 6h, 6i, 6m, 6n, 6o, 6p, and 6r
showed good inhibition toward all the tested species,
while 6b, 6h, and 6n showed good inhibition against
S. aureus, B. subtilis, and E. coli species, almost equiva-
lent to that of standard drug. The investigation of analge-
sic activity revealed that compounds 6a, 6d, 6f, 6g, 6h,
6k, 6m, 6o, 6p, and 6q exhibited significant analgesic
activity, whereas compounds 6b, 6c, 6e, 6i, 6j, 6l, 6n,
and 6r do not possess analgesic activity. The antifungal
study revealed that none of the tested compounds were
active against fungal organism Fusarium oxysperum.
6j
6k
6l
6m
6n
6o
6p
6q
2.0
2.0
3.0
–
2.0
–
2.0
2.0
3.5
2.0
2.0
3.0
3.0
–
2.0
–
6r
Griseofulvin
5.0
16
–
20
kept for incubation at 37ꢁC for 7 days (168 h). After
168 h, the diameters of the zones of growth inhibition
were measured and compared with the standard drug.
Zones of inhibition were summarized in Table 3.
CONCLUSIONS
Analgesic activity. The analgesic activities of all the
synthesized compounds were determined by using
Eddy’s hot-plate method [23]. Albino mice of either sex
weighing between 18 and 22 g were selected and
divided into 12 groups, each containing six animals.
Animals were fasted for 24 h before the experiment.
Animals of group-I were considered as control, which
are administered with 2% acacia suspension, where as
group-II were treated with standard drug Pentazocin
(35 mgm/kg), which was considered as standard group
(Ref IP). In this method, heat is used as a source of pain.
Animals were individually placed on a hot plate main-
tained at constant temperature (55ꢁC). The reaction time,
that is, time taken by the animals to lick its hind paw or
to leap out after placing it on the plate is taken as the
reaction time. Animals of group III–XII were treated with
test compounds at the dose of (100 mg/kg) body weight
as suspension in 2% gum acacia orally to animals and
observed the reaction time of animals on the hot plate at
0, 30, 60, 120, and 240 min after the compound adminis-
tration. The acute toxicity of test compounds were deter-
mined under standard husbandry conditions. The animals
were fasted for 3 h before the experiment and ‘‘up and
down’’ (OECD guidelines NO: 425) method of CPSEA
was adopted for toxicity studies. Animals were adminis-
tered with single dose of compound and observed for its
We have synthesized a series of 6-arylsubstituted-3-
(1-methyl-1-substituted phenyl ethyl)-1,2,4-triazolo-[3,4-
b]-1,3,4-thiadiazoles in good yields. The antibacterial
study revealed that among the synthesized compounds
6b, 6d, 6f, 6g, 6h, 6i, 6m, 6n, 6p, and 6r showed mod-
erate to good inhibition against S. aureus, B. subtilis,
and E. coli bacteria. The compound 6o exhibited highest
degree of inhibition almost equivalent to that of standard
drugs. The structure and biological activity relationship
of title compounds showed that the presence of 1,2,4-
triazole nucleus, incorporation of gem-dimethyl benzyl
moiety and biologically active groups such as 2,3,4-
trifluoro, 2-fluoro-4-trifluoromethyl, 2-trifluoro methoxy,
4-trifluoromethyl, 4-trifluoromethoxy and 3-nitro-5-tri-
fluoromethyl groups attached to the phenyl ring of thia-
diazole nucleus are responsible for good antibacterial
activity. The antifungal study revealed that all the syn-
thesized compounds are inactive towards the fungal
strain Fusarium oxysperum. In the case of analgesic
activity, the investigation showed that the compounds
6a, 6d, 6f, 6g, 6h, 6k, 6m, 6o, 6p, and 6q were found
to possess a significant analgesic activity whereas com-
pounds 6b, 6c, 6e, 6i, 6j, 6l, 6n, and 6r do not posses an-
algesic activity. The significant analgesic activity could
be attributed to the presence of gem-dimethyl benzyl
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1002
P. Puthiyapurayil, B. Poojary, S. Kumar, and R. Hunnur
Vol 48
Table 4
In vivo evaluation of analgesic activity of compounds (6a–r).
Reaction time after compound administration
Compound
0 min (mean 6 SEa)
30 min (mean 6 SEa)
60 min (mean 6 SEa)
120 min (mean 6 SEa)
240 min (mean 6 SEa)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
Control
Standard
4.31 6 0.10
4.16 6 0.04
4.13 6 0.05
4.33 6 0.12
4.20 6 0.10
4.46 6 0.10
4.44 6 0.12
4.43 6 0.12
4.45 6 0.16
4.19 6 0.08
4.54 6 0.11
4.20 6 0.10
4.77 6 0.14
4.42 6 0.10
4.29 6 0.04
4.44 6 0.10
4.40 6 0.10
4.55 6 0.11
4.24 6 0.06
4.45 6 0.13
5.05 6 0.11
4.56 6 0.13
4.18 6 0.10
5.22 6 0.12
4.26 6 0.12
5.09 6 0.30
5.09 6 0.16
5.02 6 0.24
4.46 6 0.14
4.58 6 0.28
5.26 6 0.11
4.36 6 0.14
5.07 6 0.14
4.79 6 0.14
5.63 6 0.21
5.50 6 0.25
5.57 6 0.25
4.78 6 0.13
4.28 6 0.07
5.47 6 0.12
5.07 6 0.15
4.58 6 0.14
4.20 6 0.14
5.16 6 0.16
4.40 6 0.14
5.41 6 0.17
5.33 6 0.07
5.18 6 0.17
4.52 6 0.15
4.64 6 0.28
5.35 6 0.10
4.40 6 0.16
5.10 6 0.04
5.12 6 0.19
6.23 6 0.11
5.76 6 0.19
6.23 6 0.22
5.06 6 0.20
4.41 6 0.13
6.05 6 0.19
6.40 6 0.11
4.66 6 0.14
4.26 6 0.10
6.13 6 0.24
4.46 6 0.20
6.18 6 0.24
6.17 6 0.19
5.75 6 0.35
4.57 6 0.14
4.83 6 0.26
6.51 6 0.19
4.56 6 0.14
6.77 6 0.24
4.96 6 0.19
7.60 6 0.21
8.36 6 0.68
7.62 6 0.31
5.10 6 0.24
4.29 6 0.08
8.46 6 0.32
6.61 6 0.35
4.99 6 0.14
4.46 6 0.12
5.98 6 0.28
4.56 6 0.24
6.66 6 0.16
6.24 6 0.12
6.18 6 0.24
5.07 6 0.22
5.03 6 0.23
6.15 6 0.22
4.86 6 0.20
5.77 6 0.19
4.64 6 0.23
6.52 6 0.16
6.29 6 0.33
6.38 6 0.28
4.77 6 0.20
4.16 6 0.06
6.83 6 0.17
a Standard error.
Methyl phenylacetate (1a). Colorless oil. Yield: 16 gm
(96%). 1H NMR (400 MHz, CDCl3):
3.65 (s, 2H,
ACH2ACO2CH3), 3.71 (s, 3H, ACO2CH3), 7.27–7.37 (m, 5H,
Ar-H). Anal. Calcd. for C9H10O2: C, 71.98; H, 6.71. Found: C,
72.18; H, 6.91.
moiety and biologically active fluorine atoms in the sub-
stituted phenyl ring of triazolothiadiazole nucleus.
Hence, it is concluded that there is an ample scope for
further study in developing these compounds as antibac-
terial and analgesic agents.
d
Methyl 4-chlorophenylacetate (1b). Colorless oil. Yield: 43
gm (98%). 1H NMR (300 MHz, CDCl3): d 3.60 (s, 2H,
ACH2ACO2CH3), 3.70 (s, 3H, ACO2CH3), 7.23 (d, 2H, J ¼
8.4 Hz, Ar-H), 7.31 (d, 2H, J ¼ 8.4 Hz, Ar-H). Anal. Calcd.
for C9H9ClO2: C, 58.55; H, 4.91. Found: C, 58.87; H, 4.98.
EXPERIMENTAL PROTOCOLS
Thin layer chromatography (silica gel 60F254) was used to
reach the completion of the reaction and purity of the synthe-
sized compounds. Melting points were recorded (uncorrected)
on Buchi melting point B-545 instrument. Infrared spectra
were recorded on Thermo Scientific Nicolet 6700-FT-IR spec-
trometer. 1H NMR, 13C NMR, and 2D NMR spectra were
recorded on 400-MHz, 100-MHz, and 300-MHz Bruker spec-
trometer in DMSO-d6/CDCl3/CD3OD using TMS as an inter-
nal standard. Chemical shift values are expressed in d ppm,
and coupling constants were reported wherever it was neces-
sary in Hertz (Hz). Mass spectra were recorded in Finnigan
MAT8230 mass spectrometer. Reactions were carried out in an
oven dried three necked RB. Yields in table refer to isolated
yields of the compounds.
General method for the synthesis of methyl arylacetates
(1a–c). To a stirred solution of arylacetic acid (0.11 mol) in
anhydrous methanol (22.5 mL, 0.55 mol), concentrated sulfuric
acid (2.25 mL) was slowly added at 0–5ꢁC over a period of 10
min and refluxed for 4 h. After the complete conversion of
starting material as monitored by TLC, solvent was removed in
Rota-evaporator. Residue obtained was diluted with ether (200
mL), washed with saturated NaHCO3 solution, water, brine
solution, and dried over anhydrous Na2SO4. Solvent evaporated
in Rota-evaporator to afford pure product.
Methyl 4-bromophenylacetate (1c). Colorless oil. Yield:
17.5 gm (96%). 1H NMR (300 MHz, CDCl3): d 3.58 (s, 2H,
ACH2ACO2CH3), 3.70 (s, 3H, ACO2CH3), 7.17 (d, 2H, J ¼
8.2 Hz, Ar-H), 7.47 (d, 2H, J ¼ 8.3 Hz, Ar-H). Anal. Calcd.
for C9H9BrO2: C, 47.19; H, 3.96. Found: C, 47.49; H, 3.99.
General method for the synthesis of methyl 2-methyl-2-
arylpropanoates (2a-c). To a stirred solution of compound
(1, 0.066 mol) in anhydrous THF (120 mL), sodium hydride
(0.199 mol) was added at ꢀ10ꢁC under nitrogen atmosphere
[24]. Reaction mixture was stirred at 0ꢁC for 1 h, and methyl
iodide (0.199 mol) was slowly added at 0ꢁC for 1 h, and the
temperature was gradually raised to room temperature, and the
stirring was continued for 10 h. On completion of the reaction
(TLC), the reaction mass was quenched in crushed ice and
acidified with 1.5 N HCl. It was then extracted with ethyl ace-
tate (2 ꢂ 150 mL). Combined extracts were washed with water,
brine solution and dried over anhydrous Na2SO4. Solvent was
evaporated in Rota-evaporator. Crude sample was purified by
column chromatography (60–120 mesh size silica gels) using 4–
4.5% EtOAc in pet ether to afford the title compounds.
Methyl 2-methyl-2-phenylpropanoate (2a). Colorless oil.
1
Yield: 7.5 gm (63%). H NMR (400 MHz, CDCl3, d): 1.63 (s,
6H, CH3), 3.67 (s, 3H, OCH3), 7.30–7.36 (m, 5H, Ar-H).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Synthesis and Biological Activities of a Novel Series of Triazolothiadiazoles
1003
Anal. Calcd. for C11H14O2: C, 74.13; H, 7.92. Found: C,
73.93; H, 7.72.
4-Amino-5-(2-phenylpropan-2-yl)-4H-1,2,4-triazole-3-thiol
(5a). Off white solid. Yield: 7.2 gm (51%); m.p.: 141–142.8ꢁC.
IR (KBr) t cmꢀ1: 3304, 1323 (NH2), 3128 (Ar-H), 2980, 2950
(CAH), 2750 (SH), 1622 (C¼¼N), 1488 (C¼¼C), 1235
Methyl 2-methyl-2-(4-chlorophenyl)propanoate (2b). Color-
1
less Oil. Yield 24 gm (70%). H NMR (300 MHz, CDCl3): d
1
(NAN¼¼C). H NMR (300 MHz, CDCl3): d 1.79 (s, 6H, CH3),
1.57 (s, 6H, CH3), 3.65 (s, 3H, AOACH3), 7.28 (d, 2H, J ¼
8.0 Hz, Ar-H), 7.30 (d, 2H, J ¼ 8.0 Hz, Ar-H). Anal. Calcd.
for C11H13ClO2: C, 62.12; H, 6.16. Found: C, 62.34; H, 6.38.
Methyl 2-methyl-2-(4-bromophenyl)propanoate (2c). Color-
4.23 (s, 2H,-NH2), 7.18–7.36 (m, 5H, Ar-H), 11.4 (s, 1H,
ASH). MS: 234.9 (MþH)þ. Anal. Calcd. for C11H14N4S: C,
56.38; H, 6.02; N, 23.91. Found: C, 56.60; H, 6.17; N, 24.14.
4-Amino-5-(2-[4-chlorophenyl]propan-2-yl)-4H-1,2,4-triazole-
3-thiol (5b). Yellow solid. Yield 13 gm (74%); m.p.: 139.1–
140.6ꢁC. IR (KBr) t cmꢀ1: 3317, 1303 (ANH2), 3154 (Ar-H),
2974, 2931 (CAH), 2713 (ASH), 1634 (C¼¼N), 1488 (C¼¼C),
1226 (NAN¼¼C). 1H NMR (400 MHz, DMSO-d6): d 1.65 (s,
6H, CH3), 5.07 (s, 2H, ANH2), 7.15 (d, 2H, J ¼ 8.6 Hz, Ar-
H), 7.35 (d, 2H, J ¼ 8.5 Hz, Ar-H), 13.65 (s, 1H, SH). MS:
269 (MþH)þ. Anal. Calcd. for C11H13ClN4S: C, 49.16; H,
4.88; N, 20.85. Found: C, 49.36; H, 5.09; N, 20.74.
1
less oil. Yield: 14 gm (73%). H NMR (400 MHz, CDCl3): d
1.56 (s, 6H, CH3), 3.65 (s, 3H, AOACH3), 7.22 (d, 2H, J ¼
8.8 Hz, Ar-H), 7.46 (d, 2H, J ¼ 8.8 Hz, Ar-H). Anal. Calcd.
for C11H13BrO2: C, 51.38; H, 5.10. Found: C, 51.17; H, 4.98.
General method for the synthesis of aryl acid hydrazides
(3a–c). A mixture of methyl esters of arylacetic acids (1 mol)
in 30 mL of methanol and hydrazine hydrate (2 mol) was
heated under reflux for 6 h. After the completion of the reaction
as monitored by TLC, solvent was removed in vacuum. Residue
obtained was dissolved in ethyl acetate, washed with water,
brine solution, and dried over anhydrous Na2SO4. Solvent was
evaporated in Rota-evaporator. Solid obtained was recrystallized
from methanol to obtain the pure compounds.
4-Amino-5-(2-[4-bromophenyl]propan-2-yl)-4H-1,2,4-triazole-
3-thiol (5c). Off white solid. Yield: 7.7 gm (58%); m.p.:
186.4–188.1ꢁC. IR (KBr) t cmꢀ1: 3288, 1295 (ANH2), 3144
(Ar-H), 2976, 2940 (CAH), 2746 (SH), 1620 (C¼¼N), 1492
(C¼¼C), 1218 (NAN¼¼C). 1H NMR (400 MHz, DMSO-d6): d
1.66 (s, 6H, CH3), 5.06 (s, 2H, NH2), 7.10 (d, 2H, J ¼ 14.0
Hz, Ar-H), 7.48 (d, 2H, J ¼ 14.0 Hz, Ar-H), 13.64 (s, 1H,
ASH). MS: 314.9 (MþH)þ. Anal. Calcd. for C11H13BrN4S: C,
42.18; H, 4.18; N, 17.89. Found: C, 42.07; H, 3.96; N, 17.64.
General procedure for the preparation of 6-aryl-3-(2-
arylpropan-2-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
(6a–r). A mixture of 3-substituted 4-amino-5-mercatpo-1,2,4-tri-
azoles (5a–c, 1 mmol) and substituted aromatic acid (1.1 mmol)
in POCl3 (10 mL) was refluxed for 7 h. The reaction mixture
was poured onto crushed ice with stirring and neutralized with
solid NaHCO3. The residue obtained was extracted in EtOAc (2
ꢂ 75 mL), washed with water, brine solution, and dried over an-
hydrous Na2SO4. The residue was purified by column chroma-
tography (60–120 mesh size silica gel) using 0.5–1.0% methanol
in dichloromethane to afford the title compounds.
2-Methyl-2-phenylpropanehydrazide (3a). Off white solid.
1
Yield: 7.2 gm (73%); m.p.: 76.5–77.4ꢁC. H NMR (400 MHz,
CDCl3): d 1.60 (s, 6H, CH3), 3.80 (s, 2H, ANH2), 6.50 (s, 1H,
ANHA), 7.27–7.37 (m, 5H, Ar-H). Anal. Calcd. for
C10H14N2O: C, 67.39; H, 7.92; N, 15.72. Found: C, 67.79; H,
8.22; N, 15.97.
2-Methyl-2-(4-chlorophenyl)propanehydrazide
(3b). Off
1
white solid. Yield: 15.5 gm (77%); m.p.: 85–86.4ꢁC. H NMR
(300 MHz, CDCl3): d 1.56 (s, 6H, CH3), 3.65 (s, 2H, ANH2),
6.54 (s, 1H, ANHA), 7.30 (d, 2H, J ¼ 10.8 Hz, Ar-H), 7.36 (d,
2H, J ¼ 10.8 Hz, Ar-H). Anal. Calcd. for C10H13ClN2O: C,
56.47; H, 6.16; N, 13.17. Found: C, 56.62; H, 6.31; N, 13.34.
2-Methyl-2-(4-bromophenyl)propanehydrazide
(3c). Pale
yellow solid. Yield: 11.0 gm (78%); m.p: 79.4–80.4ꢁC. 1H
NMR (300 MHz, CDCl3): d 1.55 (s, 6H, CH3), 4.1 (s, 2H,
ANH2), 6.56 (s, 1H, ANHA), 7.24 (d, 2H, J ¼ 8.4 Hz, Ar-H),
6-(4-Fluorophenyl)-3-(2-phenylpropan-2-yl) [1,2,4]tria-
zolo[3,4-b][1,3,4]thiadiazole (6a). Off white solid. IR (KBr)
t cmꢀ1: 3039 (Ar-H), 2984, 2923 (CAH), 1605 (C¼¼N), 1465
(C¼¼C), 1099 (CAF). 1H NMR (400 MHz, DMSO-d6): d 1.89
(s, 6H, CH3), 7.20–7.33 (m, 5H, Ar-H), 7.42 (t, 2H, J ¼ 8.25 Hz,
Ar-H), 7.87 (dd, 2H, J1 ¼ 8.8 Hz and J2 ¼ 5.2 Hz, Ar-H). 13C
NMR (100 MHz, CDCl3): d 27.25, 39.89, 116.57, 116.80, 125.74,
125.77, 125.95, 126.76, 128.43, 129.21, 129.30, 144.69, 163.83,
164.26, 166.39. MS: 339 (MþH)þ. Anal. Calcd. for C18H15FN4S:
C, 63.89; H, 4.47; N, 16.56. Found: C, 64.01; H, 4.59; N, 16.73.
3-(2-Phenylpropan-2-yl)-6-(2,3,4-trifluorophenyl)[1,2,4]tria-
zolo[3,4-b][1,3,4]thiadiazole (6b). Off white solid. IR (KBr) t
cmꢀ1: 3051 (Ar-H), 2981, 2926, 2882 (CAH), 1607 (C¼¼N),
7.48 (d, 2H,
J
¼
8.4 Hz, Ar-H). Anal. Calcd. for
C10H13BrN2O: C, 46.71; H, 5.10; N, 10.89. Found: C, 46.93;
H, 5.32; N, 10.66.
General method for the synthesis of 4-amino-5-(2-arylpro-
pan-2-yl)-4H-1,2,4-triazole-3-thiols (5a–c). Arylacetic acid hy-
drazide (3, 0.1 mol) was treated with a solution of potassium
hydroxide (0.15 mol) dissolved in anhydrous methanol (50
mL) at 0–5ꢁC under N2 atmosphere with stirring. Carbon di-
sulfide (0.15 mol) was added slowly, and reaction mixture
was stirred at RT overnight. The precipitated potassium
dithiocarbazinate was collected by filtration and washed
with anhydrous ether and dried under vacuum. It was
directly used for the next step without purification. The
mixture of above potassium dithiocarbazinate (4a–c, 0.1
mol) in water (10 mL), and hydrazine hydrate (0.3 mol) was
refluxed for 7 h. The color of the reaction mixture changed to
green with evolution of hydrogen sulfide gas, and finally it
became homogeneous. The reaction mixture was then cooled
to RT and diluted with water (100 mL) and acidified with con-
centrated HCl. Then, it was extracted with ethyl acetate,
washed with water, brine solution, and dried over anhydrous
Na2SO4. Final purification was done by column chromatogra-
phy (60–120 mesh size silica gel) using 5–6% EtOAc-pet ether
as eluent to afford the title compounds as yellow solids.
1
1462 (C¼¼C), 1300 (C¼¼S), 1026 (CAF). H NMR (400 MHz,
DMSO-d6): d 1.88 (s, 6H, CH3), 7.18–7.32 (m, 5H, Ar-H),
7.52–7.54 (m, 1H, Ar-H), 7.71–7.73 (m, 1H, Ar-H). 13C NMR
(100 MHz, CDCl3): d 27.22, 39.90, 113.53, 113.56, 113.71,
113.74, 115.29, 115.33, 122.85, 125.93, 126.81, 128.45,
139.03, 141.56, 144.54, 152.03, 153.85, 154.67, 157.67. MS:
375 (MþH)þ. Anal. Calcd. for C18H13F3N4S: C, 57.75; H,
3.50; N, 14.96. Found: C, 57.96; H, 3,72; N, 15.16.
3-(2-Phenylpropan-2-yl)-6-(2-thieny)[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazole (6c). Off white solid. IR (KBr) t cmꢀ1: 3074 (Ar-
H), 2974, 2923, 2882 (CAH), 1599 (C¼¼N), 1466 (C¼¼C),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1004
P. Puthiyapurayil, B. Poojary, S. Kumar, and R. Hunnur
Vol 48
1
1310 (C¼¼S). H NMR (400 MHz, DMSO-d6): d 1.86 (s, 6H,
CH3), 7.18–7.27 (m, 5H, Ar-H), 7.30 (t, 1H, J ¼ 6.50 Hz, Ar-
H), 7.85 (dd, 1H, J1 ¼ 3.76 Hz and J2 ¼ 1.1 Hz, Ar-H), 7.93
(dd, 1H, J1 ¼ 5.0 Hz and J2 ¼ 1.1 Hz, Ar-H). 13C NMR (100
MHz, CDCl3): d 27.18, 39.82, 126.01, 126.74, 127.64, 128.14,
128.39, 128.70, 130.20, 130.97, 131.58, 144.59, 159.10. MS:
326 (MþH)þ. Anal. Calcd. for C16H14N4S2: C, 58.87; H, 4.32;
N, 17.16. Found: C, 58.75; H, 4.20; N, 16.93.
(CAO), 1015 (CAF), 825 (CACl). 1H NMR (400 MHz,
DMSO-d6): d 1.88 (s, 6H, CH3), 7.29 (d, 2H, J ¼ 11.2 Hz,
Ar-H), 7.35 (d, 2H, J ¼ 8.8 Hz, Ar-H), 7.60–7.65 (m, 2H, Ar-
H), 7.78 (dd, 1H, J1 ¼ 8.8 Hz and J2 ¼ 1.6 Hz, Ar-H), 7.98
(dd, 1H, J1 ¼ 7.6 Hz and J2 ¼ 1.6 Hz, Ar-H). 13C NMR (100
MHz, DMSO-d6): d 27.45, 39.35, 122.36, 122.46, 128.17,
128.82, 129.02, 131.09, 131.80, 134.82, 144.41, 145.77,
160.71. MS (ESþAPCI): 439 (MþH)þ. Anal. Calcd. for
C19H14ClF3N4OS: C, 52.00; H, 3.22; N, 12.77. Found: C,
52.35; H, 3.60; N, 13.09.
3-(2-Phenylpropan-2-yl)-6-(4-trifluoromethoxyphenyl)[1,2,4]-
triazolo[3,4-b][1,3,4]thiadi-azole (6d). White solid. IR (KBr) t
cmꢀ1: 3050 (Ar-H), 2980, 2928, 2850 (CAH), 1591 (C¼¼N),
6-(3,5-Bistrifluoromethylphenyl)-3-[2-(4-chlorophenyl)propan-
2-yl][1,2,4]triazolo[3,4-b] [1,3,4] thiadiazole (6j). Off white
solid. IR (KBr) t cmꢀ1: 3054 (Ar-H), 2981, 2940, 2868
(CAH), 1621 (C¼¼N), 1468 (C¼¼C), 1359 (C¼¼S), 1275
1
1462 (C¼¼C), 1365 (C¼¼S), 1275 (CAO). H NMR (400 MHz,
DMSO-d6): d 1.89 (s, 6H, CH3), 7.18–7.32 (m, 5H, Ar-H),
7.69 (d, 2H, J ¼ 7.7 Hz, Ar-H), 7.85 (d, 2H, J ¼ 7.56 Hz, Ar-
H). 13C NMR (100 MHz, CDCl3): d 27.22, 39.87, 119.28,
124.45, 125.36, 125.98, 126.83, 128.44, 130.96, 131.37, 144.51,
149.72. MS: 405 (MþH)þ. Anal. Calcd. for C19H15F3N4OS: C,
56.43; H, 3.74; N, 13.85. Found: C, 56.33; H, 3.60; N, 13.69.
3-(2-Phenylpropan-2-yl)-6-(3,4,5-trimethylphenyl)[1,2,4]-
triazolo[3,4-b][1,3,4]thiadiazole (6e). Off white solid. IR
(KBr) t cmꢀ1: 3074 (Ar-H), 2975, 2921, 2845 (CAH), 2362
1
(CAO), 533 (CACl); H NMR (400 MHz, DMSO-d6, d): 1.90
(s, 6H, CH3), 7.34 (d, 2H, J ¼ 8.8 Hz, Ar-H), 7.38 (d, 2H, J
¼ 8.8 Hz, Ar-H), 8.37 (s, 2H, Ar-H), 8.44 (s, 1H, Ar-H); MS:
491 (MþH)þ. Anal. Calcd. for C20H13ClF6N4S: C, 48.94; H,
2.67; N, 11.41: Found: C, 49.19; H, 2.93; N, 11.67.
6-(2-Fluoro-4-trifluoromethylphenyl)-3-[2-(4-chlorophenyl)-
propan-2-yl] [1,2,4]triazolo [3,4-b] [1,3,4] thiadiazole
(6k). Off white solid. IR (KBr) t cmꢀ1: 3076, 3026 (Ar-H),
2981, 2932, 2880 (CAH), 1580 (C¼¼N), 1464 (C¼¼C), 1331
(C¼¼S), 1069 (CAF), 540 (CACl). 1H NMR (400 MHz,
DMSO-d6): d 1.90 (s, 6H, CH3), 7.33 (d, 2H, J ¼ 12.0 Hz, Ar-
H), 7.37 (d, 2H, J ¼ 11.2 Hz, Ar-H), 7.82 (d, 1H, J ¼ 8.0 Hz,
Ar-H), 8.07 (d, 1H, J ¼ 11.2 Hz, Ar-H), 8.13 (t, 1H, J ¼ 7.6 Hz,
Ar-H). 13C NMR (100 MHz, DMSO-d6): d 27.08, 38.95, 114.73,
114.77, 120.86, 120.96, 121.43, 122.47, 122.51, 124.14, 127.84,
128.43, 130.25, 131.42,133.55, 133.64, 133.88, 133.97, 143.95,
152.48, 154.43, 158.06, 158.59, 160.60. MS: 441 (MþH)þ. Anal.
Calcd. for C19H13ClF4N4S: C, 51.77; H, 2.97; N, 12.71. Found:
C, 52.00; H, 3.22; N, 12.99.
1
(Ar-CH3), 1606 (C¼¼N), 1457 (C¼¼C), 1374 (C¼¼S). H NMR
(400 MHz, DMSO-d6): d 1.84 (s, 6H, CH3), 2.0 (s, 6H, Ar-
CH3), 2.27 (s, 3H, Ar-CH3), 7.0 (s, 2H, Ar-H), 7.17ꢀ7.29 (m,
5H, Ar-H). MS: 363 (MþH)þ. Anal. Calcd. for C21H22N4S: C,
69.58; H, 6.12; N, 15.46. Found: C, 69.72; H, 6.37; N, 15.69.
3-(2-Phenylpropan-2-yl)-6-(4-trifluoromethylphenyl)[1,2,4]-
triazolo[3,4-b][1,3,4]thiadi-azole (6f). Off white solid. IR
(KBr) t cmꢀ1: 3046 (Ar-H), 2983, 2925, 2856 (CAH), 1617
(C¼¼N), 1495 (C¼¼C), 1328 (C¼¼S). 1H NMR (400 MHz,
DMSO-d6): d 1.89 (s, 6H, CH3), 7.20–7.30 (m, 5H, Ar-H),
7.94 (d, 2H, J ¼ 8.12 Hz, Ar-H), 8.03 (d, 2H, J ¼ 7.96 Hz,
Ar-H); MS: 389 (MþH)þ. Anal. Calcd. for C19H15F3N4S: C,
58.75; H, 3.89; N, 14.42. Found: C, 58.92; H, 4.05; N, 14.57.
3-[2-(4-Chlorophenyl)propan-2-yl]-6-(4-fluorophenyl)[1,2,4]-
triazolo[3,4-b][1,3,4] thiadiazole (6g). Off white solid. IR
(KBr) t cmꢀ1: 3214 (Ar-H), 2986, 2933, 2865 (CAH), 1603
(C¼¼N), 1463 (C¼¼C), 1327 (C¼¼S), 1026 (CAF), 557 (CACl);
1H NMR (400 MHz, DMSO-d6): d 1.89 (s, 6H, CH3), 7.32 (d,
2H, J ¼ 8.8Hz, Ar-H), 7.38 (d, 2H, J ¼ 8.8 Hz, Ar-H), 7.43
(t, 2H, J ¼ 8.6 Hz, Ar-H), 7.90 (dd, 2H, J1 ¼ 8.8 Hz and J2
¼ 5.2 Hz, Ar-H). 13C NMR (100 MHz, CDCl3): d 27.10,
39.54, 116.58, 116.80, 125.56, 127.39, 128.50, 129.18, 129.27,
132.61, 143.15, 163.84, 164.61, 166.38. MS: 373 (MþH)þ.
Anal. Calcd. for C18H14ClFN4S: C, 57.99; H, 3.78; N, 15.03.
Found: C, 57.89; H, 3.66; N, 14.87.
3-[2-(4-Chlorophenyl)propan-2-yl]-6-(3,4,5-trimethoxyphenyl)-
[1,2,4]triazolo[3,4-b] [1,3,4] thiadiazole (6l). Pale brown solid.
IR (KBr) t cmꢀ1: 3060 (Ar-H), 2974, 2934, 2835 (CAH),
1585 (C¼¼N), 1491 (C¼¼C), 1330 (C¼¼S), 827 (C¼¼Cl). 1H
NMR (400 MHz, DMSO-d6): d 1.87 (s, 6H, CH3), 3.72 (s, 3H,
AOACH3), 3.84 (s, 6H, AOACH3), 6.97 (s, 2H, Ar-H), 7.33 (d,
2H, J ¼ 8.7 Hz, Ar-H), 7.38 (d, 2H, J ¼ 8.6 Hz, Ar-H). 13C
NMR (100 MHz, CDCl3): d 27.29, 39.61, 56.37, 61.06, 104.39,
124.42, 127.67, 128.43, 132.61, 141.91, 143.30, 153.74, 165.60;
MS: 445 (MþH)þ. Anal. Calcd. for C21H21ClN4O3S: C, 56.69;
H, 4.76; N, 12.59. Found: C, 56.49; H, 4.61; N, 12.45.
6-(4-Fluorophenyl)-3-[2-(4-bromophenyl)propan-2-yl][1,2,4]-
triazolo[3,4-b][1,3,4] thiadiazole (6m). Off white solid. IR
(KBr) t cmꢀ1: 3067 (Ar-H), 2989, 2932, 2840 (CAH), 1604
(C¼¼N), 1463 (C¼¼C), 1314 (C¼¼S), 1101 (C¼¼F), 836 (C-Br).
1H NMR (400 MHz, DMSO-d6): d 1.89 (s, 6H, CH3), 7.26 (d,
2H, J ¼ 8.4 Hz, Ar-H), 7.45 (t, 2H, J ¼ 8.8 Hz, Ar-H), 7.49
(d, 2H, J ¼ 11.2 Hz, Ar-H), 7.90 (dd, 2H, J1 ¼ 8.8 Hz & J2
¼ 5.2 Hz, Ar-H). 13C NMR (100 MHz, CDCl3): d 27.12,
39.68, 116.66, 116.89, 120.87, 125.55, 125.59, 125.92, 127.82,
128.46, 129.28, 129.37, 131.55, 143.72, 163.96, 164.82,
166.50. MS (ESþAPCI): 417.6 (M)þ. Anal. Calcd. for
C18H14BrFN4S: C, 51.81; H, 3.38; N, 13.43. Found: C, 52.03;
H, 3.63; N, 13.69.
3-[2-(4-Chlorophenyl)propan-2-yl]-6-(2,3,4-trifluorophenyl)-
[1,2,4]triazolo[3,4-b][1,3,4] thiadiazole (6h). Off white solid.
IR (KBr) t cmꢀ1: 3083 (Ar-H), 2981, 2928, 2835 (CAH),
1612 (C¼¼N), 1489 (C¼¼C), 1320 (C¼¼S), 1028 (CAF); 1H
NMR (400 MHz, CDCl3): d 1.98 (s, 6H, CH3), 7.11–7.18 (m,
2H, Ar-H), 7.28 (s, 4H, Ar-H), 7.56–7.61 (m, 2H, Ar-H). 13C
NMR (100 MHz, CDCl3): d 27.06, 39.53, 109.30, 113.55,
113.59, 113.73, 113.77, 115.20, 122.80, 127.37, 128.53,
132.68, 139.01, 141.53, 142.98, 152.07, 158.04. MS: 409
(MþH)þ. Anal. Calcd. for C18H12ClF3N4S: C, 52.88; H, 2.96;
N, 13.70. Found: C, 52.76; H, 3.09; N, 13.86.
3-[2-(4-Chlorophenyl)propan-2-yl]-6-(2-trifluoromethoxy-
phenyl[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazole (6i). Off white
solid. IR (KBr) t cmꢀ1: 3069 (Ar-H), 2976, 2932, 2840
(CAH), 1604 (C¼¼N), 1495 (C¼¼C), 1302 (C¼¼S), 1182
3-[2-(4-Bromophenyl)propan-2-yl]-6-(2,3,4-trifluorophenyl)-
[1,2,4]triazolo[3,4-b][1,3,4] thiadiazole (6n). Off white solid.
IR (KBr) t cmꢀ1: 3073 (Ar-H), 2983, 2938, 2855 (CAH),
1602 (C¼¼N), 1489, 1475 (C¼¼C), 1307 (C¼¼S), 1027 (CAF),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Synthesis and Biological Activities of a Novel Series of Triazolothiadiazoles
1005
1
622 (C-Br). H NMR (400 MHz, CD3OD): d 1.97 (s, 6H, CH3),
7.27 (d, 2H, J ¼ 8.6 Hz, Ar-H), 7.31–7.38 (m, 1H, Ar-H), 7.48
(d, 2H, J ¼ 8.6 Hz, Ar-H), 7.70–7.77 (m, 1H, Ar-H). 13C NMR
(100 MHz, CDCl3): d 27.09, 39.67, 113.60, 113.64, 113.78,
113.82, 115.24, 115.28, 120.88, 122.85, 127.82, 131.56, 143.67.
MS: 453 (Mþ). Anal. Calcd. for C18H12BrF3N4S: C, 47.70; H,
2.67; N, 12.36. Found: C, 47.92; H, 2.90; N, 12.64.
(Mþ). Anal. Calcd. for C19H13BrF3N5O2S: C, 44.55; H, 2.56;
N, 13.67. Found: C, 44.80; H, 2.82; N, 13.82.
Acknowledgments. The authors thank Drs. Ashis Baran Man-
dal, John Kallikat, Prashant Latthe, and Venktraman Sundaraman
for helpful discussions and gratefully acknowledge Dr. Goutham
Das, COO, Syngene international Ltd., for his invaluable support.
3-[2-(4-Bromophenyl)propan-2-yl]-6-(2-trifluoromethoxy-
phenyl)[1,2,4]triazolo[3.4-b] [1,3,4]thiadiazole (6o). White
solid. IR (KBr) t cmꢀ1: 3066 (Ar-H), 2976, 2924, 2854
(CAH), 1604 (C¼¼N), 1481 (C¼¼C), 1301 (C¼¼S), 1182
(CAO), 1097 (CAF), 769 (C-Br). 1H NMR (400 MHz,
DMSO-d6): d 1.88 (s, 6H, CH3), 7.21 (d, 2H, J ¼ 8.6 Hz, Ar-
H), 7.47 (d, 2H, J ¼ 8.6 Hz, Ar-H), 7.58–7.63 (m, 2H, Ar-H),
7.77 (dd, 1H, J1 ¼ 15.8 Hz and J2 ¼ 1.6 Hz, Ar-H), 7.95 (d,
1H, J ¼ 9.3 Hz, Ar-H). 13C NMR (100 MHz, CDCl3): d
27.19, 39.70, 118.94, 120.81, 120.82, 120.88, 121.54, 122.13,
125.90, 127.39, 127.82, 128.47, 129.91, 131.55, 133.57,
143.65, 146.66, 153.14, 160.50; MS: 483 (Mþ). Anal. Calcd.
for C19H14BrF3N4OS: C, 47.22; H, 2.92; N, 11.59. Found: C,
47.51; H, 3.19; N, 11.94.
REFERENCES AND NOTES
[1] Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Het-
erocycles in Life and Society, Wiley: Chichester, UK, 1997.
[2] (a) Boschelli, D. H.; Connor, D. T.; Bonemeier, D. A.;
Dyer, R. D.; Kennedy, J. A. J Med Chem 1993, 36, 1802; (b) Unangst,
P. C.; Shrum, G. P.; Connar, D. T.; Dyer, D. R.; Schrier, D. J. J Med
Chem 1992, 35, 3691; (c) Wade, P. C.; Vogt, B. R.; Kissick, T. P.;
Simpkins, L. M.; Plamer, D. M.; Miiloning, R. C. J Med Chem 1982,
25, 331; (d) Gruta, A. K.; Bhargava, K. P. Pharmazie 1978, 33, 430;
(e) Modzelewska, B.; Kalbaun, J. Pharmazie 1999, 54, 503.
[3] Srivastava, N.; Bahadur, S.; Verma, H. N.; Khan, M. M.
Curr Sci 1984, 53, 235.
[4] Witkoaski, N.; Robins, R. K.; Sidwell, R. W.; Simon, L. N.
J Med Chem 1972, 15, 1150.
6-(3,5-Bistrifluoromethylphenyl)-3-[2-(4-Bromophenyl)propan-
2-yl][1,2,4]triazolo[3.4-b] [1,3,4]thiadiazole (6p). Off white
solid. IR (KBr) t cmꢀ1: 3052 (Ar-H), 2981, 2939, 2852
(CAH), 1620 (C¼¼N), 1467 (C¼¼C), 1359 (C¼¼S), 1136
(C¼¼F), 674 (C-Br). 1H NMR (400 MHz, DMSO-d6): d 1.89
(s, 6H, CH3), 7.28 (d, 2H, J ¼ 11.4 Hz, Ar-H), 7.49 (d, 2H, J
¼ 11.3 Hz, Ar-H), 8.36 (s, 2H, Ar-H), 8.43 (s, 1H, Ar-H). 13C
NMR (100 MHz, CDCl3): d 27.14, 39.75, 121.06, 121.11,
123.82, 125.85, 126.98, 127.84, 131.47, 131.62, 132.74,
133.08, 133.42, 133.76, 143.40, 162.66. MS: 535.1 (Mþ).
Anal. Calcd. for C20H13BrF6N4S: C, 44.88; H, 2.45; N, 10.47.
Found: C, 45.14; H, 2.27; N, 10.21.
[5] Mithun, A.; Holla, B. S. Boja P. Eur J Med Chem 2007,
42, 1095.
[6] Holla, B. S.; Kalluraya, B.; Sridhar, K. R.; Drake, E.; Thomas,
L. M.; Bhandary, K. K.; Levine, M. J. Eur J Med Chem 1994, 29, 301.
[7] (a) Demirayak, S.; Benkli, K.; Guven, K. Eur J Med Chem
2000, 35, 1037; (b) Tiwari, N.; Chaturvedu, B. Nizamuddin. Agric
Biol Chem 1988, 52, 1229; (c) Tsukuda, T.; Shirator, Y.; Watanabe,
M.; Ontsuka, K.; Hattori, M.; Shirai, M.; Shimma, N. Bioorg Med
Chem Lett 1988, 8, 1824; (d) Rollas, S.; Kalyoncuoglu, N.; Sur--
Altiner, D.; Yegenoglu, Y. Pharmazie 1993, 48, 308.
[8] Holla, B. S.; Veerendra, B.; Shivananda, M. K.; Poojary, B.
Eur J Med Chem 2003, 38, 759.
6-(2-Fluoro-4-trifluoromethylphenyl)-3-[2-(4-Bromophenyl)-
propan-2-yl][1,2,4]triazolo [3.4-b] [1,3,4]thiadiazole (6q). Off
white solid. IR (KBr) t cmꢀ1: 3067 (Ar-H), 2985, 2933, 2865
(CAH), 1586 (C¼¼N), 1462 (C¼¼C), 1328 (C¼¼S), 1069
(C¼¼F), 667 (C-Br). 1H NMR (400 MHz, DMSO-d6): d 1.89
(s, 6H, CH3), 7.27 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.51 (d, 2H, J
¼ 8.4 Hz, Ar-H), 7.81 (d, 1H, J ¼ 8.4 Hz, Ar-H), 8.07 (d, 1H,
J ¼ 11.2 Hz, Ar-H), 8.13 (t, 1H, J ¼ 7.8 Hz, Ar-H). 13C
NMR (100 MHz, CDCl3): d 27.11, 39.69, 114.28, 114.32,
114.53, 114.57, 120.68, 120.79, 120.91, 121.12, 121.99,
122.03, 122.06, 123.84, 125.93, 127.82, 128.46, 129.61,
131.58, 135.46, 135.55, 135.80,135.89, 143.64, 158.25, 158.31,
161.06. MS: 485 (Mþ). Anal. Calcd. for C19H13BrF4N4S: C,
47.02; H, 2.70; N, 11.54. Found: C, 47.40; H, 3.05; N, 11.88.
3-[2-(4-Bromophenyl)propan-2-yl]-6-[3-nitro-5-trifluorome-
thylphenyl][1,2,4]triazolo [3.4-b] [1,3,4]thiadiazole (6r). Pale
yellow solid. IR (KBr) t cmꢀ1: 3076 (Ar-H), 2983, 2938,
2865 (CAH), 1629 (C¼¼N), 1544, 1316 (Ar-NO2), 1472
[9] Duran, A.; Dogan, H. N.; Rollas, S. Farmaco 2002, 57, 559.
[10] Joshi, K. C.; Giri, S. J Indian Chem Soc 1963, 40, 42.
[11] Goldsworthy, M. C. Phytopathology 1942, 32, 498.
[12] Haglind, J. Chem Abstr 1966, 64, 16507.
[13] Collin, X., Sauleau, A., Coulon, J. Bioorg Med Chem Lett
2003, 13, 2601.
[14] Sprague, J. M.; Pa, D. H. U.S. Pat. 2,407,966, September
17, 1946.
[15] Ram, V. J.; Mishra, L. N.; Pandey, H.; Kushwaha, D. S.;
Pierters, A. C.; Luc, A. T.; Vlietinck, J. Heterocycl Chem 1990,
27, 351.
[16] Milcent, R.; Vicart, P.; Bure, A. M. Eur J Med Chem 1983,
18, 215.
[17] Goss, P. E.; Strasser-Weippl, K. Best Pract Res End Met
2004, 18, 113.
[18] Clemons, M.; Colemon, R. E.; Verma, S. Cancer Treat Rew
2004, 30, 325.
[19] Johnston, G. A. R. Curr Top Med Chem 2002, 2, 903.
[20] Potts, K. T.; Huseby, R. M. J Org Chem 1966, 31, 3528.
[21] Heindel, N. D.; Reid, J. R. J Heterocycl Chem 1980, 17, 1087.
[22] Bary, A. L. The Antimicrobial Susceptibility Test Principle
and Practices; ELBS: London, 1976, pp 180.
1
(C¼¼C), 1316 (C¼¼S), 1100 (CAF), 680 (C-Br). H NMR (400
MHz, DMSO-d6): d 1.90 (s, 6H, CH3), 7.29 (d, 2H, J ¼ 8.8
Hz, Ar-H), 7.52 (d, 2H, J ¼ 8.4 Hz, Ar-H), 8.51 (s, 1H, Ar-
H), 8.72 (s, 2H, Ar-H). 13C NMR (100 MHz, CDCl3): d 27.14,
39.76, 120.71, 121.11, 123.43, 123.74, 123.78, 124.82, 126.00,
127.83, 128.54, 128.88, 131.66, 132.31, 133.37, 133.72,
134.41, 143.36, 148.94. 153.69, 153.94, 161.77. MS: 512
[23] Winter, C. A.; Risley, E. A.; Nuss, G. W. Proc Soc Exp
Biol Med 1962, 111, 544.
[24] Hama, T.; Hartwig, J. F. Org Lett 2008, 10, 1549.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet