Synthesis and antimicrobial activities of some novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines carrying thioalkyl and sulphonyl phenoxy moieties

Article abstract of DOI:10.1016/j.ejmech.2006.10.010

Thirty one new 6-aryl-3-{(4-substituted phenoxy) methyl}-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (6a-s) and 6-aryl-3-{(4-substituted phenoxy methyl}-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (7a-l) have been synthesized from 4-thioalkyl phenols (1a-b)

Full text of DOI:10.1016/j.ejmech.2006.10.010

European Journal of Medicinal Chemistry 42 (2007) 521e529
http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and antimicrobial activities of some novel 1,2,4-triazolo
[3,4-b]-1,3,4-thiadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines
carrying thioalkyl and sulphonyl phenoxy moieties
c
T. Karabasanagouda a, Airody Vasudeva Adhikari b, , N. Suchetha Shetty
*
a Strides Research and Specialty Chemicals Ltd., New Mangalore, India
b Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Srinivasnagar,
Mangalore, Karnataka 575025, India
c Department of Biochemistry, Justice K.S. Hegde Medical Academy, Deralakatte, India
Received 26 June 2006; received in revised form 15 October 2006; accepted 19 October 2006
Available online 6 December 2006
Abstract
Thirty one new 6-aryl-3-{(4-substituted phenoxy) methyl}-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (6aes) and 6-aryl-3-{(4-substituted
phenoxy methyl}-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (7ael) have been synthesized from 4-thioalkyl phenols (1aeb) through a multi-
step reaction sequence. Compounds 1aeb reacted with ethyl chloroacetate in presence of acetone and potassium carbonate to give ethyl [4-(thi-
oalkyl) phenoxy] acetates (2aeb). Further, 2a was oxidized to [4-(methyl sulphonyl) phenoxy] acetate (2c) using hydrogen peroxide in acetic
acid. Reactions of (2aec) with hydrazine hydrate in alcoholic medium furnished 2-[4-thiosubstituted phenoxy] acetohydrazides (3aeb) and 2-
[4-methyl sulphonyl phenoxy] acetohydrazide (3c) which on treatment with carbon disulphide and methanolic potassium hydroxide yielded
corresponding potassium dithiocarbazates (4aec). They were then converted to 4-amino-5-{(4-thioalkyl phenoxy) methyl}-4H-1,2,4-triazole-
3-thiols (5aeb) and 4-amino-5-{(4-methyl sulphonyl phenoxy) methyl}-4H-1,2,4-triazole-3-thiol (5c) by refluxing them with aqueous hydrazine
hydrate. The title compounds 6aes were prepared by condensing 5aec with various aromatic carboxylic acids in presence of phosphorus oxy-
chloride. The intermediates 5aec, on condensation with various substituted phenacyl bromides afforded a series of title compounds (7ael). The
structures of new compounds 2ae7l were established on the basis of their elemental analysis, IR, 1H NMR, 13C NMR and mass spectral data. All
the title compounds were subjected to in vitro antibacterial testing against four pathogenic strains and antifungal screening against three fungi.
Preliminary results indicate that some of them exhibited promising activities and they deserve more consideration as potential antimicrobials.
Ó 2006 Elsevier Masson SAS. All rights reserved.
Keywords: 6-Aryl-3-[(4-thio alkyl phenoxy) methyl]-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles; 6-Aryl-3-[(4-methyl sulphonyl phenoxy) methyl]-1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazoles; 6-Aryl-3-[(4-thioalkyl phenoxy) methyl]-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines; 6-Aryl-3-[(4-methyl sulphonyl phenoxy) methyl]-1,2,4-tri-
azolo[3,4-b]-1,3,4-thiadiazines; Antibacterial and antifungal screening
1. Introduction
antibacterial [1], antifungal [2,3], anti-inflammatory [4]
antihypertensive [5], antiviral [6], antileishmanial [7] and anti-
migraine activities [8]. A thorough literature survey reveals
that presence of 4-substituted thio phenoxy and 4-methyl sul-
phonyl phenoxy moieties is an important structural feature of
wide variety of synthetic drugs [9e11]. It has been established
that introduction of 4-methyl mercapto phenyl and 4-methyl
sulphonyl phenyl groups to different heterocycles has yielded
many biologically active compounds endowed with wide
Various 1,2,4-triazole derivatives have been reported to
possess diverse types of biological properties such as
* Corresponding author. Tel.: þ91 0824 2474000x3203; fax: þ91 0824
2474033.
E-mail addresses: avchem@nitk.ac.in, avadhikari123@yahoo.co.in (A.V.
Adhikari).
0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.10.010

522
T. Karabasanagouda et al. / European Journal of Medicinal Chemistry 42 (2007) 521e529
spectrum of pharmacological and antimicrobial activities
[12,13]. It is well known that the N-bridged heterocycles de-
rived from 1,2,4-triazoles find applications in the field of med-
The formation of 2-[4-(methyl thio) phenoxy] acetohydra-
zide (3a) from ethyl [4-(thioalkyl) phenoxy] acetate (2a)
1
was confirmed by its IR, H NMR and elemental analyses.
icine, agriculture and industry.
A
large number of
IR spectrum showed absorption band at 3310, 3224, 3045,
1680, 1544 cmꢀ1 due to eNH2, eNH, eSCH3, pC]O, and
triazolothiadiazoles and triazolothiadiazines have been re-
ported to possess CNS depressant, antibacterial, antifungal,
antitumour, anti-inflammatory, herbicidal, pesticidal and in-
secticidal properties [14e17]. Therefore, it was envisaged
that chemical entities with both 1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazoles/1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines and 4-sul-
phur substituted phenyl moieties, containing aryl ether linkage
would result in compounds of interesting biological activities.
In continuation of our research program on the synthesis of
novel heterocyclic compounds exhibiting biological activity,
it was thought to be interesting to synthesize compounds con-
taining the features, namely, 1,2,4-triazole moiety fused with
the 1,3,4-thiadiazole/1,3,4-thiadiazine rings, in addition to
have a sulphur substituted phenoxy group and to study their
antimicrobial activities. The present study describes the
synthesis of hither to unreported 6-aryl-3-{(4-thiosubstituted/
methyl sulphonyl phenoxy)methyl}-1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazoles (6aes) and 6-aryl-3-{(4-thiosubstituted/
methyl sulphonyl phenoxy) methyl}-7H-1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazines (7ael) and evaluation of their antibacterial
and antifungal activities.
1
pC]Co groups, respectively, while H NMR showed sharp
singlets at d 2.4 and 4.46, which correspond to eSCH3 and
CH2 protons. It appeared as two doublets at d 6.94 and 7.24
indicating the presence of four aromatic protons. The potas-
sium dithiocarbazate (4a) was directly used for the next step
without characterization. Further, the cyclization of 4a to 4-
amino-5-{(methyl thio) methyl}-4H-1,2,4-triazole-3-thiol
(5a) was confirmed by its IR spectrum which showed absorp-
tion bands at 3313, 2667 and 1617 cmꢀ1 due to eNH2, eSH,
1
and pC]N, respectively. Its H NMR spectrum showed two
singlets at d 2.4 and 5.1 due to eSCH3 and eCH2 protons
and two doublets at d 6.94 and 7.24 due to four aromatic pro-
tons. It appeared as a sharp singlet at d 13 for eSH group. The
disappearance of characteristic peak due to pC]O group of
4a is clearly indicated the smooth cyclization.
The structural elucidation of title compound 6a is based on
its IR, 1H NMR, 13C NMR and mass spectral studies. IR spec-
trum of 6a showed absorption bands at 3061, 2990, 1593 and
689 cmꢀ1 indicating the presence of eCH3, eCH2, phenyl and
C]S groups, respectively. In its 1H NMR spectrum, peaks due
to eSCH3 and CH2 protons appeared at d 2.4 and 5.6, respec-
tively. Peaks due to two phenyl groups appeared at d 7, 7.2, 8
as doublets and 7.6 as multiplet. Further, LC mass spectrum
showed molecular ion peak at m/z 354.9 (100%) which is in
agreement with the molecular formula C17H14N4OS2. The
peaks at m/z 215, 150 and 84 were due to the fragmentation
of molecular ion. 13C NMR spectrum of 6h showed signals
at d 29.36 and 14.52 due to eSeCH2CH3 group and peaks
at d 59.76, 115.69, 127.25, 128.31, 129.16, 129.44, 132.6,
132.8, 144.07, 156.0, and 167.39 are due to OCH2, C2H and
C6H of phenoxy moiety, C4H of 6-phenyl moiety, C4 of phe-
noxy group, C3H and C5H of 6-phenyl group, C1 of 6-phenyl
group, C2H and C6H of 6-phenyl moiety, C3H and C5H of
phenoxy moiety, C3 and C5 of triazole, C1 of phenoxy moiety,
and C7 of thiadiazole group, respectively. The peaks due to
quaternary carbon atoms of the structure disappeared on
DEPT experimentation. The absence of characteristic absorp-
tion peaks due to eNH2 and eSH groups of 5a clearly con-
firmed the formation of 6a.
2. Chemistry
The reaction sequences employed for synthesis of title
compounds are shown in Fig. 1. The key intermediate, ethyl
[4-(thioalkyl) phenoxy] acetates (2aeb) was prepared by
treating ethyl chloroacetate with 4-(thioalkyl) phenols (1ae
b) in boiling dry acetone in presence of potassium carbonate.
The compound, ethyl [4-(methyl sulphonyl phenoxy] acetate
(2c) was obtained by the oxidation of ethyl [4-(methyl thio)
phenoxy] acetate (2a) with 30% hydrogen peroxide in acetic
acid. These esters (2aec) were conveniently converted to 2-
[4-(thioalkyl/methyl sulphonyl phenoxy] acetohydrazides
(3aec) by refluxing it with hydrazine hydrate in methanol.
The compounds 3aec on reaction with carbon disulphide in
methanolic potassium hydroxide yielded corresponding
potassium dithiocarbazates (4aec) in good yield. The required
4-amino-5-{[thioalkyl/methyl sulphonyl phenoxy) methyl}-
4H-1,2,4-triazole-3-thiols (5aec) were synthesized by reflux-
ing 4aec with aqueous hydrazine hydrate. Condensation of
5aec with various aromatic carboxylic acids in presence of
boiling phosphorous oxychloride yielded 6-aryl-3-{(4-thio-
alkyl/methyl sulphonyl phenoxy) methyl}-1,2,4-triazolo
[3,4-b]-1,3,4-thiadiazoles (6aes) and with various phenacyl
bromides in refluxing ethanol gave 6-aryl-3-{(4-thioalkyl/
methyl sulphonyl phenoxy) methyl}-7H-1,2,4-triazolo[3,
4-b]-1,3,4-thiadiazines (7ael) in good yield.
The build up of N-bridged condensed heterocycle, 7a
from 5a is evidenced by its IR, 1H NMR, 13C NMR and
mass spectral data. IR spectrum of 7a indicates the presence
of eNH2, eSCH3, pC]O, pC]N, phenyl groups due to
absorption bands at 3380, 3024, 1699, 1599, and
1462 cmꢀ1, respectively. Peaks observed at d 2.4, 4.4, 5.4,
1
8, 8.2 and 13.46 as singlets in its H NMR spectrum showed
the presence of eSCH3, eCH2 (ring), eOCH2, C2H of phenyl
ring, eCONH2 and OH groups, respectively. Also, three dou-
blets at d 7, 7.3, and 7.4 are due to aromatic protons. Further,
the peak at 8.2 disappeared on D2O exchange. 13C NMR
spectrum of 7e showed signals at d 28.66 and 13.97 due to
eSCH2CH3 while peaks at d 22.31, 58.94, 113.52, 115.27,
The structural assignments to new compounds were based
1
on their elemental analysis and spectral (IR, H NMR, 13C
NMR and mass) data. The characterization data of all the
new compounds are summarized in Table 1.

T. Karabasanagouda et al. / European Journal of Medicinal Chemistry 42 (2007) 521e529
523
OH
OCH2COOC2H5
OCH2COOC2H5
H2O2
ClCH2COOC2H5
Acetone
SCH3
(1a)
SO2CH3
(2c )
SCH3
(2a)
NH2NH2.H2O
NH2NH2.H2O
OH
OCH2COOC2H5
OCH2CONHNH2
ClCH2COOC2H5
Acetone
NH2NH2.H2O
SC2H5
SC2H5
(2b)
R
(3a-c)
(1b)
CS2/ Methanolic KOH
N
N
OCH2CONHNH2CS-S-K+
O
SH
N
NH2
NH2NH2.H2O
R
ArCOCH2Br
Methanol
R
(5a-c)
POCl3/ArCOOH
(4a-c)
N
N
N
N
O
R
S
N
O
N
S
N
N
Ar
Ar
(7a-i)
R
(6a-s)
where R= SCH3, SC2H5 SO2CH3
,
Fig. 1.
118.66, 122.67, 127.51, 128.33, 131.82, 132.11, 153.28,
154.88, 156.56, 164.73 and 171.43 are due to C7H of thia-
diazine, OCH2, C8 of thiadiazine, C2H and C6H of phenoxy
group, C3H of 6-phenyl moiety, C5 of 6-phenyl moiety, C4
of phenoxy moiety, C4H of 6-phenyl moiety, C6H of 6-phe-
nyl moiety, C3H and C5H of phenoxy moiety, C3 and C5 of
triazole, C2 of 6-phenyl moiety, C1 of phenoxy moiety, C1
of 6-phenyl moiety, and carbon of amide in 6-phenyl group,
respectively. The peaks due to quaternary carbon atoms dis-
appeared on DEPT experimentation. Further, LCMS of 7a
showed the base peak at m/z 427.9 which is in agreement
with their molecular formula, C19H17N5O3S2.
3. Biological activities
3.1. Antibacterial studies
The newly synthesized compounds were screened for their
antibacterial activity against Escherichia coli (ATTC-25922),
Staphylococcus
aureus (ATTC-25923), Pseudomonas

524
T. Karabasanagouda et al. / European Journal of Medicinal Chemistry 42 (2007) 521e529
Table 1
Characterization data of compounds 6aes and 7ael
Compound
Ar
R
Mol. formula
Mol. mass
MP (ꢁC)
Yield (%)
6a
6b
6c
6d
6e
6f
C6H5
2-ClC6H4
SCH3
SCH3
C17H14N4OS2
C17H13ClN4OS2
C18H16N4OS2
354
389
368
384
369
371.5
368
368
402
382
398
383
437
384
386
420
420
400
400
427
444
437
402
441
458
451
416
459
476
469
434
140
110
142
110
120
106
112
129
102
105
98
65
63
60
64
66
63
68
66
67
63
64
66
63
67
65
65
65
65
65
68
69
69
69
68
69
69
69
68
69
69
69
4-CH3C6H4
4-OCH3C6H4
4-NH2C6H4
2,3-(Cl)2C6H4
C6H5CH2
SCH3
SCH3
C18H16N4O2S2
C17H15N5OS2
SCH3
SCH3
SCH3
C17H12Cl2N4OS2
C18H16N4O2S2
C18H16N4OS2
6g
6h
6i
C6H5
2-ClC6H4
SC2H5
SC2H5
SC2H5
SC2H5
SC2H5
SC2H5
SC2H5
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SCH3
C18H15ClN4OS2
C19H18N4OS2
6j
4-CH3C6H4
4-CH3OeC6H4
2-NH2C6H4
2,3-(Cl)2C6H4
2-OHC6H4
6k
6l
C19H18N4O2S2
C18H17N5OS2
120
118
185
220
200
196
170
110
180
100
110
190
175
136
104
116
218
120
110
180
6m
6n
6o
6p
6q
6r
6s
7a
7b
7c
7d
7e
7f
C18H14Cl2N4OS2
C18H16N4O2S2
C17H14N4O3S2
C17H13ClN4O3S2
C17H13ClN4O3S2
C18H16N4O3S2
C17H12Cl2N4O3S2
C19H17N5O3S2
C24H20N4OS2
C6H5
2-ClC6H4
3-ClC6H4
CH2C6H5
2,3-Dichloro-C6H4
2-OH-benzamide
Biphenyl
SCH3
SCH3
SCH3
2,4-Dichloro-C6H3
4-ClC6H4
C18H14Cl2N4OS2
C18H15Cl2N4OS2
C20H19N5O3S2
C25H22N4OS2
2-OH-benzamide
Biphenyl
SC2H5
SC2H5
SC2H5
SC2H5
SO2CH3
SO2CH3
SO2CH3
SO2CH3
7g
7h
7i
2,4-Dichloro-C6H3
4-ClC6H4
C19H16Cl2N4OS2
C19H17ClN4OS2
C19H17N5O5S2
C24H20N4O3S2
C18H14Cl2N4O3S2
C18H15ClN4O3S2
2-OH-benzamide
Biphenyl
7j
7k
7l
2,4-Dichloro-C6H3
4-ClC6H4
Note: Microanalysis data is summarized in Table 4 and included in supplementary material.
aeruginosa (ATCC-27853) and Klebsiella pneumoniae
(recultured) bacterial stains by serial plate dilution method
[18,19]. Serial dilutions of the drug in MullereHinton broth
were taken in tubes and their pH was adjusted to 5.0 using
phosphate buffer. A standardized suspension of the test bacte-
rium was inoculated and incubated for 16e18 h at 37 ꢁC. The
minimum inhibitory concentration (MIC) was noted by seeing
the lowest concentration of the drug at which there was no vis-
ible growth.
A number of antimicrobial discs are placed on the agar for
the sole purpose of producing zones of inhibition in the bacte-
rial lawn. Twenty milliliters of agar media was poured into
each Petri dish. Excess of suspension was decanted and plates
were dried by placing in an incubator at 37 ꢁC for an hour.
Using a punch, wells were made on these seeded agar plates
and minimum inhibitory concentrations of the test
compounds in dimethylsulfoxide (DMSO) were added into
each labeled well. A control was also prepared for the plates
in the same way using solvent DMSO. The Petri dishes were
prepared in triplicate and maintained at 37 ꢁC for 3e4 days.
Antibacterial activity was determined by measuring the
diameter of inhibition zone. Activity of each compound was
compared with ciprofloxacin as standard [22,23]. Zone of
inhibition was determined for 6ae7l and the results are
summarized in Table 2.
3.2. Antifungal studies
Newly prepared compounds were screened for their antifun-
gal activity against Aspergilus flavus (NCIM No.524), Aspergi-
lus fumigatus (NCIM No. 902), Penicillium marneffei
(recultured) and Trichophyton mentagrophytes (recultured) in
DMSO by serial plate dilution method [20,21]. Sabourands
agar media was prepared by dissolving peptone (1 g), D-glucose
(4 g) and agar (2 g) in distilled water (100 ml) and adjusting the
pH to 5.7. Normal saline was used to make a suspension of spore
of fungal strains for lawning. A loopful of particular fungal
strain was transferred to 3 ml saline to get a suspension of
corresponding species. Twenty milliliters of agar media was
poured into each Petri dish. Excess of suspension was decanted
and plates were dried by placing in incubator at 37 ꢁC for 1 h.
Using a punch, wells were made on these seeded agar plates
minimum inhibitory concentrations of the test compounds in
DMSO were added into each labeled well. A control was also
prepared for the plates in the same way using solvent DMSO.
The Petri dishes were prepared in triplicate and maintained at
37 ꢁC for 3e4 days. Antifungal activity was determined by
measuring the diameter of inhibition zone. Activity of each
compound was compared with cyclopiroxolamine as standard.
Zones of inhibition were determined for 6ae7l and the results
are summarized in Table 3.

T. Karabasanagouda et al. / European Journal of Medicinal Chemistry 42 (2007) 521e529
525
Table 2
Antibacterial activity of title compounds
Compound
MIC in mg/ml and zone of inhibition in mm
E. coli
K. pneumoniae
P. aeruginosa
S. aureus
6a
6b
6.25 (16e20)
25 (<10)
6.25 (16e20)
25 (<10)
6.25 (16e20)
25 (<10)
6.25 (16e20)
25 (<10)
6c
6d
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6e
6f
6g
6h
6i
6j
6k
6.25 (16e20)
25 (<10)
25 (<10)
6.25 (16e20)
25 (<10)
25 (<10)
6.25 (16e20)
25 (<10)
25 (<10)
6.25 (16e20)
25 (<10)
25 (<10)
6l
6m
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
6n
6o
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
6.25 (16e20)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
6.25 (16e20)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
6.25 (16e20)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
6.25 (16e20)
25 (<10)
6p
6q
6r
6s
7a
7b
7c
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
7d
7e
7f
7g
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
7h
7i
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
25 (<10)
7j
7k
7l
Standard (ciprofloxacin)
6.25 (30e40)
6.25 (23e27)
6.25 (25e33)
1.56 (22e30)
Note: The MIC values were evaluated at concentration range, 1.56e25 mg/ml. The figures in the table show the MIC values in mg/ml and the corresponding zone of
inhibition in mm.
4. Results and discussion
strains. The structure of these compounds contains biologi-
cally active eCH3, OCH3, NH2, 2,3-dichloro groups attached
to phenyl group in position 6 of the thiadiazole ring and aryl
moiety carrying phenyl, 2,4-dichloro, 4-chloro, and 2-hy-
doxy-4-amide groups, in position 6 of thiadiazine. The com-
pounds 6o, 6p, 6q, 6r, and 7iek exhibited moderate activity
compared to that of standard against T. mentagrophytes, A. fla-
vus, and A. fumigatus. Results of antifungal screening showed
that the presence of SeCH3 and SeC2H5 groups at position 4
of phenoxy group caused increased activity. It has been
observed that the thiadiazole derivatives are found to be
more active than thiadiazines.
The investigation of antibacterial and antifungal screening
data revealed that all the tested compounds 6aes and 7ael
showed moderate to good inhibition at 1.56e25 mg/ml in
DMSO. The compounds 6a, 6c, 6d, 6e, 6f, 6g, 6h, 6j, 6s,
and 7bee showed comparatively good activity against all
the bacterial strains. The good activity is attributed to the pres-
ence of pharmacologically active eCH3, OCH3, NH2, and 2,3-
dichloro groups attached to phenyl group at position 6 of the
thiadiazole ring. Introduction of aryl moiety carrying phenyl,
2,3-dichloro, 4-chloro, and 2-hydoxy-4-amide groups at posi-
tion 6 of thiadiazine caused enhanced activity. The presence of
SeCH3 and SeC2H5 groups at position 4 of phenoxy group
caused good antibacterial activity while methyl sulphonyl
group caused decrease in activity against most of the strains.
The compounds 6o, 6p, 6q, 6r, and 7iek, exhibited moderate
activity compared to that of standard against all the bacterial
strains. This may be due to presence of methyl sulphonyl
group in position 4 of phenoxy moiety.
5. Conclusion
The research study reports the successful synthesis and an-
timicrobial activity of new 1,2,4-triazolothiadiazoles and
1,2,4-trazolothiadiazines carrying 4-methyl/ethyl thio and
methyl sulphonyl phenoxy moieties at position 3. The antimi-
crobial activity study revealed that all the compounds tested
showed moderate to good antibacterial and antifungal activi-
ties against pathogenic strains. Structureebiological activity
The compounds 6a, 6c, 6d, 6e, 6f, 6g, 6h, 6j, 6s, and 7bee
showed comparatively good activity against all the fungal

526
T. Karabasanagouda et al. / European Journal of Medicinal Chemistry 42 (2007) 521e529
Table 3
Antifungal activity of title compounds
Compound
MIC in mg/ml and zone of inhibition in mm
P. marneffei
T. mentagrophytes
A. flavus
A. fumigatus
6a
6b
6.25 (16e20)
25 (<10)
6.25 (16e20)
25 (<10)
6.25 (16e20)
25 (<10)
6.25 (16e20)
25 (<10)
6c
6d
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6e
6f
6g
6h
6i
6j
6k
6.25 (16e20)
25 (<10)
25 (<10)
25 (<5)
25 (<10)
25 (<5)
25 (<10)
25 (<5)
25 (<10)
6l
6m
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
6n
6o
25 (<10)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
6.25 (16e20)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
6.25 (16e20)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
6.25 (16e20)
25 (<10)
6p
6q
25 (<10)
25 (<10)
6r
6s
7a
6.25 (16e20)
25 (<10)
7b
7c
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
7d
7e
7f
7g
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
25 (<10)
7h
7i
25 (<10)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
25 (<10)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
25 (<10)
7j
7k
25 (<10)
25 (<10)
6.25 (20e27)
7l
Standard (cyclo-piroxolamine)
3.125 (27e33)
3.125 (25e30)
6.25 (25e30)
Note: The MIC values were evaluated at concentration range, 1.56e25 mg/ml. The figures in the table show the MIC values in mg/ml and the corresponding zone of
inhibition in mm.
relationship of title compounds showed that the presence 4-thi-
oalkyl phenoxy groups at position 3 and biologically active
groups like eCH3, OCH3, NH2, and 2,3-dichloro groups at
aryl moiety attached to position 6 of title compounds are
responsible for increased antimicrobial activity in newly
synthesized title compounds.
spectrophotometer/Data system using Argon/Xenon (6 KV,
10 mA) FAB gas, at 70 eV. Elemental analysis was carried
out using Flash EA 1112 Series, CHNSO Analyzer (Thermo).
Solvents and reagents were purchased from the commercial
venders in the appropriate grade and were used without
purification.
6. Experimental protocols
6.1. General procedure for the preparation of ethyl
Melting points were determined in open capillaries and un-
corrected [melting point apparatus: SERWELL Instruments
Inc., India]. Purity of the compounds was checked by thin
layer chromatography (TLC) on a silica coated aluminum
sheet (silica gel 60 F254) using chloroform and methanol
(9:1, v/v). IR spectra were recorded on NICOLET AVATAR
[4-(thioalkyl) phenoxy] acetates (2aeb)
4-Thioalkyl phenols, 1aeb (1 mmol) were dissolved in
5 ml of super dry acetone and mixed with 1.2 mmol of an-
hydrous potassium carbonate. This was treated with
1.2 mmol of ethyl chloroacetate slowly with shaking for
10 min and the mixture was heated under reflux for 3 h.
When the reaction was complete (monitored by TLC), the
reaction mixture was filtered and the filtrate was distilled un-
der reduced pressure. The fraction collected at 140e144 ꢁC,
2aec was directly used for the next step without further
purification.
1
330-FTIR spectrometer. H and 13C NMR spectra recorded
on a Varian 300 MHz NMR spectrometer using TMS as an in-
ternal standard. Chemical shifts are reported in ppm (d) and
signals are described as singlet (s), doublet (d), triplet (t),
quartet (q), broad (br), and multiplet (m). The FAB mass spec-
tra were recorded on
a
JEOL SX 102/DA-6000

T. Karabasanagouda et al. / European Journal of Medicinal Chemistry 42 (2007) 521e529
527
6.2. Procedure for the preparation of ethyl [4-methyl
sulphonyl phenoxy] acetate (2c)
under stirring. Then 1.5 mmol of carbon disulfide was added
slowly and the reaction mixture was stirred overnight at
room temperature. The solid product of potassium dithiocarba-
zates (4aec), separated were filtered, washed with chilled
methanol and finally dried. It was directly used for next step
without purification.
The above potassium dithiocarbazates (4aec) were mixed
with a mixture of water (8 ml) and hydrazine hydrate
(2 mmol) and was refluxed for 4e5 h. During progress of
the reaction, the reaction mixture turned to green with evolu-
tion of hydrogen sulphide and finally it became homogeneous.
It was then diluted with little cold water and treated with
concentrated hydrochloric acid. The white precipitate was fil-
tered, washed with cold water and recrystallized from aqueous
methanol.
The compound 2a (1 mmol), dissolved in 10 ml of glacial
acetic acid was added slowly with 2 mmol of 30% hydrogen
peroxide over a period of 1 h, below 70 ꢁC. It was further
kept at 70e75 ꢁC with stirring for 3 h, cooled to ambient tem-
perature and finally quenched in 20 ml ice cold water. The
compound 2c was extracted with ethyl acetate and after giving
water wash, the solvent was removed by distillation; the liquid
left over was further purified by distillation under reduced
pressure. The fraction collected at 160e164 ꢁC at 10 mm pres-
sure was used directly for the next step.
6.3. General procedure for the preparation of 2-
[4-(thioalkyl) phenoxy] acetohydrazides (3aeb) and 2-
[4-methyl sulphonyl phenoxy] acetohydrazide (3c)
6.4.1. 4-Amino-5-{(methyl thio) methyl}-4H-1,2,4-
triazole-3-thiol (5a)
A mixture of [4-(thioalkyl)/methyl sulphonyl phenoxy]
acetate (1 mmol), and hydrazine hydrate (2 mmol) in 10 ml
of methanol was heated under reflux for 5e6 h. The reaction
mixture was left overnight at room temperature and the solid
separated was collected by filtration. It was washed with meth-
anol, dried and recrystallized from methanol.
Compound 5a was obtained as whiteꢀso1lid in 85% yield, mp
200e201 ꢁC (methanol), IR: 3313 cm (NH2), 2667 cmꢀ1
(SH), 1617 cmꢀ1 (C]N), 964 cmꢀ1 (NeC]S); 1H NMR
(DMSO-d6): d 2.4 (s, 3H, SCH3), d 5.1 (s, 2H, CH2), d 5.63
(s 2H, NH2), d 6.94 (d, 2H, C3, C5-H of phenoxy moiety),
d 7.24 (d, 2H, C2, C6-H of phenoxy moiety), d 13 (s, 1H,
SH); Anal. Calculated for C10H12N4OS2: C, 44.76; H, 4.51;
N, 20.88; found: C, 44.8; H, 4.55; N, 20.9.
6.3.1. 2-[4-(Methyl thio) phenoxy] acetohydrazide (3a)
Compound 3a was obtained as white solid in 90% yield, mp
128e129 ꢁC, IR: 3310 cmꢀ1 (NH2), 3224 cmꢀ1 (NH),
3045 cmꢀ1 (SCH3), 1680 cmꢀ1 (pC]O), 1544 cmꢀ1 (C]C),
814 cmꢀ1 (SCH3); 1H NMR (DMSO-d6): d 2.4 (s, 3H, SCH3),
d 4.46 (s, 2H, CH2), d 6.94 (d, 2H, C3, C5-H of 4-methyl thio
phenoxy moiety J ¼ 8.5 Hz), d 7.24 (d, 2H, C2, C6-H of 4-eth-
ylthio phenoxy moiety J ¼ 8.5 Hz); Anal. Calculated for
C9H12N2O2S: C, 50.92; H, 5.7; N, 13.2; found: C, 50.8; H,
5.9; N, 13.1.
6.4.2. 4-Amino-5-{(ethyl thio) methyl}-4H-1,2,4-
triazole-3-thiol (5b)
Compound 5b was obtained as white solid in 80% yield,
mp 198e200 ꢁC (methanol), IR: 3312 cmꢀ1 (NH2),
2667 cmꢀ1 (SH), 1617 cmꢀ1 (C]N), 962 cmꢀ1 (NeC]S);
Anal. Calculated for C11H14N4OS2: C, 46.79; H, 5.0; N,
19.84; found: C, 46.82; H, 5.1; N, 19.9.
6.4.3. 4-Amino-5-{(methyl sulphonyl) methyl}-
4H-1,2,4-triazole-3-thiol (5c)
6.3.2. 2-[4-(Ethyl thio) phenoxy] acetohydrazide (3b)
Compound 3b was obtained asꢀw1hite solid in 92% yield, mp
126 ꢁC (methanol), IR: 3310 cm (NH2), 3224 cmꢀ1 (NH),
3041 cmꢀ1 (SCH3), 1680 cmꢀ1 (C]O), 1547 cmꢀ1 (C ¼ C),
813 cmꢀ1 (SCH3); Anal. Calculated for C10H14N2O2S: C,
53.08; H, 6.24; N, 12.38; found: C, 53.12; H, 6.3; N, 12.45.
Compound 5c was obtained as white ꢀso1lid in 72% yield, mp
218e219 ꢁC (methanol), IR: 3310 cm (NH2), 2667 cmꢀ1
(SH), 1617 cmꢀ1 (C]N), 962 cmꢀ1 (NeC]S); Anal. Calcu-
lated for C10H12N4O3S2: C, 39.99; H, 4.03; N, 18.65; found:
C, 39.96; H, 4.05; N, 18.71.
6.3.3. 2-[4-Methyl sulphonyl phenoxy] acetohydrazide (3c)
Compound 3c wasꢀo1btained as white solid in 85% yield, mp
190 ꢁC, IR: 3315 cm (NH2), 3276 cmꢀ1 (NH), 3101 cmꢀ1
(SCH3), 1689 cmꢀ1 (C]O), 1615 cmꢀ1 (C]C), 1496 cmꢀ1
(C]C); Anal. Calculated for C9H12N2O4S: C, 44.25; H, 4.95;
N, 11.47; found: C, 44.28; H, 4.99; N, 11.45.
6.5. General procedure for the preparation of 3-
{[4-thioalkyl/methyl sulphonyl phenoxy] methyl}-6-aryl-
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (6aes)
A mixture 4-amino-5-{thio alkyl/methyl sulphonyl phe-
noxy) methyl}-4H-1,2,4-triazole-3-thiols (5aec) (1 mmol)
and (un)substituted benzoic acid (1.1 mmol) in POCl3 (5 ml)
was refluxed for 6e7 h. The reaction mixture was slowly
quenched into crushed ice with stirring and neutralized it
with solid sodium bicarbonate. The solid which separated after
standing overnight was filtered, washed with cold water, dried,
and recrystallized from appropriate solvent to afford the title
compounds. Characterization data of compounds 6aes are
summarized in Table 1.
6.4. General procedure for the preparation of 4-amino-
5-{(methyl thio) methyl}-4H-1,2,4-triazole-3-thiols
(5aec)
[4-(Thioalkyl/methyl sulphonyl) phenoxy] acetohydrazides
(3aec) (1 mmol) was treated with a solution of potassium hy-
droxide (1.5 mmol) dissolved in methanol (10 ml) at 0e5 ꢁC

528
T. Karabasanagouda et al. / European Journal of Medicinal Chemistry 42 (2007) 521e529
6.5.1. 3-{[4-Methyl thio phenoxy] methyl}-6-phenyl-1,2,
4-triazolo[3,4-b]-1,3,4-thiadiazole (6a)
6.5.5. 3-{[4-(Methyl sulphonyl) phenoxy] methyl}-6-phenyl-
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (6o)
IR: 3024, 2927 cmꢀ1 (SeCH3), 1699 cmꢀ1 (C]N), 1595,
1550, 1471 cmꢀ1 (aromatic skeleton), 1249 cmꢀ1 (Ne
N]C), 692 cmꢀ1 (CeSeC); LCMS: m/z 386.9 (Mþ, 100%).
Characterization data of 6aes are summarized in Table 1.
IR: 3061 cmꢀ1, 2990 cmꢀ1 (CH3), 1593 cmꢀ1, 1492 cmꢀ1
,
1466 cmꢀ1 (aromatic skeleton), 1276 cmꢀ1 (NeN]C),
689 cmꢀ1 (CeSeC); 1H NMR (DMSO-d6): d 2.4 (s, 3H,
SCH3), d 5.6 (s, 2H, CH2), d 7 (d, 2H, C3, C5-H of 4-methyl
thio phenoxy moiety J ¼ 8.72 Hz), d 7.2 (d, 2H, C2, C6-H of
4-methyl thio phenoxy moiety J ¼ 8.82 Hz), d 7.6 (m, 3H,
C3, C4, C5-H of 6-phenyl moiety), d 8 (d, 2H, C2, C6-H of
6-phenyl moiety J ¼ 6.93 Hz); LCMS: m/z 354.9 (Mþ,
100%), 215 (30%), 150 (10%), 84 (10%).
6.6. General procedure for the preparation of 6-aryl-3-
{(4-thioalkyl/methyl sulphonyl phenoxy) methyl}-7H-
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (7ael)
A mixture 4-amino-5-{[thioalkyl/methyl sulphonyl phe-
noxy) methyl}-4H-1,2,4-triazole-3-thiols 5aec (1 mmol) and
substituted phenacyl bromides (1.2 mmol) in 10 ml of absolute
ethanol was refluxed for 6e7 h. The reaction mixture was
slowly quenched onto crushed ice with stirring and it was
neutralized with solid sodium bicarbonate. The solid which
separated after standing overnight was filtered, washed with
cold water, dried and recrystallized from absolute ethanol to
afford the title compounds 7ael.
6.5.2. 3-{[4-Methyl thio phenoxy] methyl}-6-(4-methyl
phenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (6c)
IR: 3061, 2990 cmꢀ1 (SeCH3), 1593 cmꢀ1, 1492 cmꢀ1
,
1466 cmꢀ1 (aromatic skeleton), 1276 cmꢀ1 (NeN]C),
689 cmꢀ1 (CeSeC); 1H NMR (CDCl3): d 2.4 (s, CH3),
d 2.55 (s, 3H, SCH3), d 5.59 (s, 2H, CH2), d 7 (d, 2H, C3,
C5-H of phenoxy moiety J ¼ 8.72 Hz), d 7.29 (d, 2H, C2,
C6-H of phenoxy moiety J ¼ 8.8 Hz), d 7.35 (d, 2H, C3, C5-
H of 6-phenyl moiety J ¼ 8.6 Hz), d 7.67 (d, 2H, C2, C6-H
of 6-phenyl moiety J ¼ 8.5 Hz); MS FABþ (m/z, %):
(Mþ þ 1) 369 (86%), Mþ 368 (45%), 229 (70%), 165
(10%), 107 (25%), 89 (15%).
6.6.1. 2-Hydorxy-5-(3-{[4-(methyl thio) phenoxy] methyl}-
7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine-6-yl)
benzamide (7a)
IR: 3380 cmꢀ1 (NH2), 3024, 2927 cmꢀ1 (SeCH3),
1699 cmꢀ1 (C]O), 1599 cmꢀ1 (C]N), 1462 cmꢀ1 (aromatic
skeleton), 1237 cmꢀ1 (NeN]C), 694 cmꢀ1 (CeSeC); 1H
NMR (DMSO-d6): d 2.4 (s, 3H, SCH3), d 4.4 (s, 2H, CH2),
d 5.5 (s, 2H, CH2), d 7 (d, 2H, C3, C5-H of phenoxy moiety
J ¼ 8.8), d 7.3 (d, 2H, C2, C6-H of phenoxy moiety J ¼ 8.6),
d 7.4 (d, 2H, C5, C6-H of 6-phenyl moiety), d 8.0 (s, C2-H
of 6-phenyl moiety), d 8.2 (s, 2H, CONH2 of 6-phenyl moi-
ety), 13.46 (s, 1 H, OH of 6-phenyl moiety), D2O exchange
study showed absence of peak at d 8.2 and 8.4; LCMS: m/z
427.9 (Mþ, 100%).
6.5.3. 3-{[4-(Ethylthio) phenoxy] methyl}-6-phenyl-1,2,4-
triazolo [3,4-b]-1,3,4-thiadiazole (6h)
IR: 3060, 2968 cmꢀ1 (SeCH2CH3), 1699 cmꢀ1 (C]N),
1591, 1520, 1491 cmꢀ1 (aromatic skeleton), 1278 cmꢀ1 (Ne
1
N]C), 689 cmꢀ1 (CeSeC); H NMR (DMSO-d6) d 1.27 (t,
3H, CH3), d 2.8 (q, 2H, SCH2), d 5.5 (s, 2H, CH2), d 7 (d,
2H, C3, C5-H of 4-ethylthio phenoxy moiety J ¼ 8.1), d 7.3
(d, 2H, C2, C6-H of 4-ethylthio phenoxy moiety J ¼ 8.6),
d 7.6 (m, 3H, C3, C4, C5-H of 6-phenyl moiety J ¼ 8.0), d 8
(d, 2H, C2, C6-H of 6-phenyl moiety J ¼ 7.8); 13C NMR d:
14.52 (SCH3), 29.36 (SCH2), 59.76 (OCH2), 115.69 (C2H
and C6H), 127.25 (C4), 128.31 (C4), 129.16 (C3H and C5H),
129.44 (C1), 132.6 (C2H and C6H), 132.8 (C3H and C5H),
144.07 (C3 and C5 of triazole), 156.0 (C1), 167.39 (C7 of thia-
diazole); DEPT: CH and CH3 d: 14.54, 115.71, 127.27,
129.46, 132.62, 132.88, CH2 d: 29.39, 59.78; MS FABþ
(m/z, %): (Mþ þ 1) 369 (100%), Mþ 368 (45%),165 (10%),
215 (60%), 107 (10%), 105 (8%).
6.6.2. 2-Hydroxy-5-(3-{[4-(ethylthio) phenoxy] methyl}-7H-
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazin-6-yl) benzamide (7e)
IR: 3375 cmꢀ1 (NH2), 3024, 2927 cmꢀ1 (SeCH2CH3),
1689 cmꢀ1 (C]O), 1592 cmꢀ1 (C]N), 1500, 1462 cmꢀ1
(aromatic skeleton), 1230 cmꢀ1 (NeN]C), 688 cmꢀ1 (Ce
1
SeC); H NMR (DMSO-d6): d 1.2 (t, 3H, CH3), d 2.8 (q,
2H, SCH2), d 4.176 (s, 2H, CH2), d 5.37 (s, 2H, CH2),
d 6.9 (d, 2H, C3, C5-H of phenoxy moiety J ¼ 8.6), d 6.9
(d, 1H, C5-H of phenyl moiety J ¼ 6.1), d 7.29 (d, 2H,
C2, C6-H of phenoxy moiety J ¼ 9,0), d 8.03 (d, 2H, C5-
H, C6-H of phenyl moiety J ¼ 8.2), d 8.4 (s, C2-H of phenyl
moiety), 13.41 (s, 1 H, OH of phenyl moiety); 13C NMR d:
28.66 (SCH3), 13.97 (SCH2), 22.31 (C7H2), 58.94 (OCH2),
113.52 (C8), 115.27 (C2H and C6H), 118.66 (C3H), 122.67
(C5), 127.51 (C4), 128.33 (C6H), 131.82 (C3H and C5H),
132.11 (C3 and C5), 153.28 (C3 and C5), 154.88 (C2),
156.56 (C1), 164.73 (C1), 171.43 (amide carbon); DEPT:
CH and CH3 d: 14.09, 115.38, 118.77, 128.44, 131.93,
132.23, CH2 d: 22.43, 28.77, 59.06; MS FABþ (m/z, %):
(Mþ þ 1) 442 (100%), Mþ 441 (50%), 288 (40%), 271
(10%), 107 (8%), 105 (5%).
6.5.4. 3-{[4-(Ethylthio) phenoxy] methyl}-6-
(4-methylphenyl)-1,2,4-triazolo[3,4-b]-1,3,
4-thiadiazole (6j)
IR: 3060, 2968 cmꢀ1 (SeCH2CH3), 1699 cmꢀ1 (C]N),
1591, 1520, 1491 cmꢀ1 (aromatic skeleton), 1278 cmꢀ1 (Ne
1
N]C), 689 cmꢀ1 (CeSeC); H NMR (DMSO-d6): d 1.25
(t, 3H, CH3), d 2.4 (s 3H, CH3), d 2.8 (q, 2H, SCH2), d 5.52
(s, 2H, CH2), d 7.01 (d, 2H, C3, C5-H of 4-ethylthio phenoxy
moiety J ¼ 8.1), d 7.26 (m, 4H, C2, C6-H of 4-ethylthio phe-
noxy moiety and C3, C5-H of 6-phenyl moiety), d 7.75 (d,
2H, C2, C6-H of 6-phenyl moiety J ¼ 7.8); MS FABþ (m/z,
%): (Mþ þ 1) 383 (100%), Mþ 382 (40%), 229 (70%), 154
(8%), 153 (8%), 135 (10%), 119 (5%).

T. Karabasanagouda et al. / European Journal of Medicinal Chemistry 42 (2007) 521e529
529
[2] R.H. Khan, R.A.K. Srivastava, R.C. Rastogi, Indian J. Chem. 24B
(1985) 883.
6.6.3. 2-Hydroxy-5-(3-{[4-(Methyl sulphonyl) phenoxy]
methyl}-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazin-6-yl)
benzamide (7i)
IR: 3350 cmꢀ1 (NH2), 3024, 2927 cmꢀ1 (SeCH3),
1672 cmꢀ1 (C]O), 1599 cmꢀ1 (C]N), 1462 cmꢀ1 (aromatic
skeleton), 1237 cmꢀ1 (NeN]C), 694 cmꢀ1 (CeSeC). MS
FABþ (m/z, %): (Mþ þ 1) 460 (80%), Mþ 459 (30%), 289
(10%), 105 (30%).
[3] J. Heeres, L.J. Backx, J. Med. Chem. 27 (1984) 894.
[4] M.D. Mullican, M.W. Wilson, D.T. Connor, C.R. Kostlan, d.J. Schrier,
R.D. Dyer, J. Med. Chem. 36 (1993) 1090.
[5] A. Czarnocka, Janowicz, H. Foks, A. Nasal, J. Petrusewicz,
B. Damasiewicz, A. Radwanska, R. Kaliszan, Pharmazie 46 (1991) 109.
[6] R.W. Sidwell, L.B. Allen, J.H. Hoffman, J.T. Witkowshi, L.N. Simon,
Proc. Soc. Exp. Biol. Med. 148 (1975) 854; Chem. Abstr. 118 (1993)
11961z.
Characterization data of 7ael are given in Table 1.
[7] K. Singh, A. Hasan, R. Pratap, P.Y. Guru, D.S. Bhakuni, J. Indian Chem.
Soc. 66 (1989) 686.
[8] C. Hart, Drugs for migraine, in: Modern Drug Discovery, American
Chemical Society, 1999.
Acknowledgments
[9] M.E. Deason, K.R. Whitten, US 5,962,725, Oct. 5, 1999.
[10] A.S. Bell, D. Brown, N.K. Terrett, US 5,250,534, Oct. 5, 1993.
[11] A.L. Rawlins, G.P. Woods, US 2,589,211, March 18, 1952.
[12] J.M. Sprague, D.H. Pa, US 2,407,966, Sept. 17, 1946.
[13] B. Camerino, G.P. Milan, US 3,098,069, July 16, 1963.
[14] D.H. Boschelli, D.T. Connor, C.R. Kostlan, J.B. Kramer, M.D. Mullican,
J.C. Sircar, US 5,102,897, April 7, 1992.
We are grateful to the Managing Director, Strides Research
& Specialty Chemicals Ltd., New Mangalore, and the Head of
Chemistry Department, National Institute of Technology
Karnataka, Surathkal, for providing laboratory facilities. The
authors are also thankful to Prof. A. Srikrishna, Department
1
of Organic chemistry, IISc, Bangalore for providing H NMR
[15] A.R. Farghaly, E.D. Clercq, H. El-Kashef, ARKIVOC 10 (2006) 137.
[16] Z.Y. Zhang, M. Li, L. Zhao, Z.M. Li, R.A. Liao, Chin. J. Org. Chem. 13
(1993) 397.
and 13C NMR spectral facilities and Dr. S. Badiger, Gulbarga
University, Gulbarga for providing LC Mass spectra. Thanks
are also due to SAIF, CDRI, Lucknow for providing 1H
NMR and Mass FAB spectral analysis.
[17] R. Gupta, S. Sudan, V. Mengi, P.L. Kachroo, Indian J. Chem., Sect. B 35
(1996) 621.
[18] A.L. Barry, Procedure for testing antimicrobial agents in agar media, in:
V.L. Corian (Ed.), Antibiotics in Laboratory Medicine, Williams and
Wilkins, Baltimore, MD, 1991, p. 1.
Appendix. Supplementary material
[19] D. James, Mac. Lowry, Marry J. Jaqua, Sally T. Selepak, Appl. Micro-
biol. 20 (1970) 46.
[20] B.A. Arthington-Skaggs, M. Motley, D.W. Warnock, C.J. Morrison,
J. Clin. Microbiol. 38 (2000) 2254.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.ejmech.2006.
10.010.
[21] R.S. Verma, Z.K. Khan, A.P. Singh (Eds.), Antifungal Agents: Past, Pres-
ent and Future Prospects, National Academy of Chemistry and Biology,
Lucknow, India, 1998, p. 55.
[22] Christine H. Fenlon, Michael H. Cynamon, Antimicrob. Agents Chemo-
ther. 29 (1986) 386.
References
[23] R. Davis, A. Markham, J.A. Balfour, Ciprofloxacin, An updated review
of its pharmacology, therapeutic efficacy and tolerability, Drugs 51 (6)
(1996) 1019.
[1] B.N. Goswami, J.C.S. Kataky, J.N. Baruah, J. Heterocycl. Chem. 21
(1984) 1225.