Studies on synthesis and pharmacological activities of 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and their dihydro analogues

Article abstract of DOI:10.1016/j.ejmech.2006.12.010

Several 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole and their dihydro analogues were synthesized from hetero aromatic acids and hetero aromatic aldehydes, respectively, by microwave-assisted dry media and conventional methods. Elemental analysis, IR, ¹H NMR, ¹³C NMR and mass spectral data elucidated the structures of all newly synthesized compounds. Synthesized compounds are studied for their antibacterial, antifungal, anti-inflammatory and analgesic activities. Some of the tested compounds showed significant pharmacological activities.

Full text of DOI:10.1016/j.ejmech.2006.12.010

European Journal of Medicinal Chemistry 42 (2007) 823e840
http://www.elsevier.com/locate/ejmech
Original article
Studies on synthesis and pharmacological activities of 3,6-disubstituted-
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and their dihydro analogues
b
b
a
Vinod Mathew a, , J. Keshavayya , V.P. Vaidya , D. Giles
*
a Acharya & B.M. Reddy College of Pharmacy, Pharmaceutical Chemistry, #90 Soladevanahally, Hesaraghatta Road, Chikbanavara Post,
Bangalore-560090, Karnataka, India
b Department of Studies in Chemistry, Kuvempu University, Jnana Sahayadri, Shankaraghatta-577451, Shimoga, Karnataka, India
Received 15 October 2006; received in revised form 10 December 2006; accepted 12 December 2006
Available online 9 January 2007
Abstract
Several 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole and their dihydro analogues were synthesized from hetero aromatic acids and
1
hetero aromatic aldehydes, respectively, by microwave-assisted dry media and conventional methods. Elemental analysis, IR, H NMR, 13C
NMR and mass spectral data elucidated the structures of all newly synthesized compounds. Synthesized compounds are studied for their
antibacterial, antifungal, anti-inflammatory and analgesic activities. Some of the tested compounds showed significant pharmacological
activities.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Amino triazoles; Triazolo thiadiazoles; Dihydro triazolo thiadiazoles; Microwave synthesis; Phosphorous oxychloride
1. Introduction
ethanol, DMF, 1,2-dichloroethane, and o-dichlorobenzene as
energy transfer media which absorb microwave energy effi-
ciently through dipole rotation. Microwave-assisted reactions
using dry media have attracted much interest because of the
simplicity in operation, greater selectivity and rapid synthesis
of variety of heterocyclic compounds.
1,2,4-Triazole and 1,3,4-thiadiazoles represent one of the
most biologically active classes of compounds, possessing
a wide spectrum of activities [1e5]. Various substituted
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and their dihydro ana-
logues are associated with diverse pharmacological activities
such as antimicrobial [6], antibacterial [7], antitubercular
[8], anti-inflammatory [9,10], and antifungal [11]. A triazolo
thiadiazole system may be viewed as a cyclic analogue of
two very important components thiosemicarbazide [12] and
biguanide [13], which often display diverse biological
activities.
Quinolines, a fused benzopyridine, pyridine and indole,
fused benzopyrrole are some important nitrogen containing
heterocyclic compounds having biological activities. It is
reported [19] that the pyridine nucleus is associated with anti-
tubercular, antimicrobial, antineoplastic activities and also the
presence of halogen atom augments the antimicrobial proper-
ties [20] of the system. Quinoline and its derivatives are
known for their antimalarial and therapeutic effects [21].
A number of quinoline derivatives are known to possess
antibacterial, antifungal, hypotensive, analgesic and anti-
inflammatory activities [22e25]. Applications of quinoline
derivatives are fast spreading from antimalarial to almost every
branch of medicinal chemistry [26,27]. Prompted by these ob-
servations, as part of our research program aimed at developing
new biologically active nitrogen and sulphur containing
Recently most of the reported reactions [14e17] have been
carried out either in sealed vessels or in the solid phase. Micro-
wave irradiation has been also applied to carry out organic
synthesis in open vessels [18] using organic solvents such as
* Corresponding author. Tel.: þ91 080 57650815; fax: þ91 08282 256255.
E-mail address: vinmathew_mb@yahoo.co.uk (V. Mathew).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.12.010

824
V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
heterocycles, we report the synthesis of some new 3,6-disubsti-
tuted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and their 5,6-
dihydro analogues by incorporating these biologically active
heterocyclic rings. The synthesis entailed the union of two
biologically active nuclei, viz, triazole and thiadiazole and
screening the biological activity of these fused heterocycles.
4-Amino-3-aryl/aralkyl/heteroaryl substituted-5-mercapto-
1,2,4-triazole 3aec were prepared using the method given in
Ref. [28] (Scheme 1). The structures of the intermediate tria-
zole derivatives were based on their elemental analysis and
other spectral data.
CS2
N2H4.H2O
Ar
CONHNH2
Ar
COOR
Condensation of the triazoles 3aec with hetero aromatic
acids in the presence of phosphorous oxychloride
(Schemes 2 and 3) produced a series of triazolo thiadiazoles
(4e12); while its condensation with hetero aromatic alde-
hydes (Schemes 4 and 5) afforded a series of 5,6-dihydro
triazolo thiadiazoles (13e16). The structure assigned to
compounds was substantiated by their analytical and other
spectral data.
KOH/C2H5OH
(1)
N
N
N2H4.H2O
N
N
Ar
N
SH
O
Ar
SH
NH2
3(a-c)
(2)
Scheme 1.
COOH
COOH
N
N
N
N
N
R'
N
R
R
N
N
S
N
N
Ar
N
N
S
N
Ar
POCl3
R = Phenyl, methyl, H
Ar
N
R
POCl3
SH
NH2
N
R=OH,Cl,F
R'=OH,H
3(a-c)
R
R'
7-9(a-c)
4-6(a-c)
H
N
R'
POCl3
R
CH2 COOH
R=OCH3,H
R'=CH3,H
N
N
S
N
N
Ar
H2
C
R'
NH
R
10-12(a-c)
Scheme 2.
Where Ar =
Cl
MeO
'
C
'
H2
CH3
O
MeO
MeO
3c
3a
3b

V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
825
N
Ar'-COOH
N
S
N
S
N
N
Ar'-CHO
N
N
SH
SH
Ar'
Ar'
N
N
N
N
N
N
POCl3
DMF
N
H
Ar
Ar
p-toluene sulphonic acid
Microwave irradiation
Microwave irradiation
NH2
NH2
Ar
Ar
3 (a-c)
4-12 (a-c)
3 (a-c)
13-16 (a-c)
Scheme 3.
Scheme 5.
SH proton and the down fielding of NH2 protons (integration
for one proton) in the 1H NMR spectra established that eCHO
group of the aromatic aldehydes reacted with eSH and eNH2
groups of triazoles and thus converted to dihydro triazolo thia-
2. Results and discussion
Synthesis of 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazoles and their 5,6-dihydro analogues under refluxing
condition required 6e7 h and 10e12 h, respectively, while
on solid support under microwave irradiation required shorter
reaction times and higher product yields making it superior
method. The IR spectra of the cyclized products showed
absorption band at 3270e3290 cmꢀ1 due to the NH functional
group and the weak absorption band around 2580 cmꢀ1 due to
the SH group. This confirmed the involvement of NH2 and SH
groups of the parent amino mercapto triazole in the ring for-
mation. An absorption band observed for all the synthesized
compounds in the range of 3060e3090 cmꢀ1 may be
attributed to aromatic stretching vibration, while that seen at
1610e1614 cmꢀ1 corresponds to C]N linkage. Thus, the for-
mation of iminomethine functional group in the compound
was indicated.
1
diazoles (13e16). The H NMR, 13C NMR, mass spectra, IR
and elemental analysis supported the structure of various
synthesized triazolo thiadiazoles and their dihydro analogues
(Tables 1e6).
The antimicrobial results showed that some of the com-
pounds are active against the both Gram-positive and
Gram-negative bacteria. Compounds showed good inhibition
of growth of the yeast-like Candida albicans and the fungi
Aspergillus niger. Compounds 4e6, 8 and 9aec showed
the highest inhibitory effect against all the tested organisms.
It can be concluded that none of the prepared compounds
were superior to positive controls against various tested
microbial strains, but the antibacterial and antifungal activi-
ties of some of the compounds are comparable to those of
positive controls.
In the 1H NMR spectra of synthesized compound, the
peaks due to NH2 and SH, which were present in the amino
mercapto triazole, were absent and that further confirmed
the involvement of these functional groups in the cyclization
of triazole to triazolo thiadiazoles. Similarly the absence of
It was observed that the maximum antimicrobial activity
was shown in the tested compounds 9aec having 2-flouro
pyridine group at sixth position of triazolo thiadiazole system.
When 2-flouro pyridine group was replaced by 2-chloro group
O
OHC
R
N
N
N
N
N
S
Ar
Ar
SH
N
R = H,
DMF
p-toluene sulfonic acid
NO2
N
H
C
H
NH2
O
R
3(a-c)
13-14 (a-c)
R
R = H,
DMF
p-toluene sulfonic acid
CH3
N
CHO
N
N
N
S
Ar
R
N
N
H
C
H
15-16 (a-c)
Scheme 4.

826
V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
Table 1
Physical characterization of 5-substituted aryl-4-amino-3-mercapto-1,2,4-triazole
N
N
SH
Ar
N
NH2
Compound
Ar
Melting point
(m.p.) (ꢁC)
Yield (%)
Molecular
formula
Elemental analysis
Calculated (found) (%)
C
H
N
S
3a
3b
3c
2-Chloro-5-methoxy phenyl
3,4-Dimethoxy benzyl
2-Methyl-3-furanyl
230
142
158
58
54
52
C9H9N4OSCl
C11H14N4O2S
C7H8N4OS
42.11 (42.24)
49.61 (49.55)
42.84 (42.92)
3.53 (3.46)
5.30 (5.35)
4.11 (4.15)
21.82 (21.91)
21.04 (21.12)
28.55 (28.61)
12.49 (12.44)
12.04 (11.98)
16.34 (16.29)
8aec there was a decrease in the activity while its replacement
with 2-hydroxy group 7aec observed a sharp decrease in the
antimicrobial activity. Replacement of pyridine ring by quino-
line ring produced compounds with moderate activity while
indole ring produced compounds with less activity.
In the quinoline substituted triazolo thiadiazole derivatives
it was observed that substitution at the second position pro-
duced a decrease in the antimicrobial activity. Replacement
of hydrogen at the second position by methyl produced com-
pounds with moderate activity while its replacement by phenyl
group has little role to play as far as antimicrobial activity is
concerned.
None of the dihydro triazolo thiadiazoles showed good
antimicrobial activity. Antimicrobial effects of the newly
synthesized compounds are reported in Tables 7 and 8 as
zone of inhibition against various bacterial and fungal strains,
respectively.
and 12b showed good anti-inflammatory and analgesic activi-
ties. Compounds 10 and 11b showed moderate anti-inflamma-
tory and analgesic activities. Results revealed that maximum
protection was shown in the tested compounds having indole
ring at the sixth position of the triazolo thiadiazole system
10e12 (aec). In the series, substitution of a methoxy group
at the fifth position of indole ring produced a decrease in the
anti-inflammatory and analgesic activities. Further decrease
in the activities is observed with introduction of another elec-
tron releasing methyl group at the second position of 5-me-
thoxy indole ring. Thus it was concluded that among the
10e12 (aec) series, anti-inflammatory and analgesic activities
decrease with the introduction of electron releasing groups.
Replacement of indole ring by other heterocyclic ring and
the cyclization of triazoles to dihydro triazolo thiadiazoles pro-
duced compounds with moderate to weak anti-inflammatory
and analgesic activities. Anti-inflammatory and analgesic
effects of the newly synthesized compounds are reported in
Tables 9 and 10, respectively.
Anti-inflammatory and analgesic activity screening indi-
cated that some of the tested compounds 10e12 (a and c)
Table 2
Spectral characterization of 5-substituted aryl-4-amino-3-mercapto-1,2,4-triazole
Compound
IR (KBr) n (cmꢀ1
)
1H NMR d (ppm)
MS m/z
3a
3291 (NH stretching), 1613 (C]N stretching),
3130 (aromatic CH stretching), 2586 (SH),
2934, 2840 (methyl CH stretch), 1269
(asymmetric CeOeC stretching), 1021
(symmetric CeOeC stretching), 1284
(NeN]C), 1582, 1552, 1479, 1455
(C]C ring stretching)
13.92 (s, 1H, SH), 7.2, 7.5, 7.6 (3d, 3H, Ar),
5.46 (s, 2H, NH2), 3.83 (s, 3H, OCH3)
256 (Mþ), 258 (M þ 2)
3b
3c
3286 (NH stretching), 1610 (C]N stretching);
3090 (aromatic CH stretching), 2580 (SH), 2934,
2847 (methyl CH stretch), 1264
13.5 (s, 1H, SH), 6.92 (s, 1H of C-2 of Ar),
6.86, 6.74 (2d, 2H of C-5 and C-6 of Ar), 5.54
(s, 2H, NH2), 3.78 (s, 6H, OCH3), 3.98 (s, 2H, CH2)
266 Mþ
(asymmetric CeOeC stretching), 1018
(symmetric CeOeC stretching), 1280 (NeN]C),
1588, 1548, 1486, 1455 (C]C ring stretching)
3271 (NH stretching), 1607 (C]N stretching),
3163 (aromatic CH stretching), 1571, 1558,
1480, 1451 (C]C ring stretching), 2585
(SH), 2935, 2838 (methyl CH stretch), 1261
(asymmetric CeOeC stretching), 1037
13.80 (s, 1H, SH), 7.7, 7.17 (2d, 2H of furan ring),
5.6 (s, 2H, NH2), 2.45 (s, 3H, CH3)
196 Mþ
(symmetric CeOeC stretching), 1287 (NeN]C)

V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
827
Table 3
Physical characterization of 3,6-disubstituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
N
N
N
N
S
Ar
Ar '
Molecular
(microwave) formula
Compound Ar0
Melting point Yield (%)
Elemental analysis
(m.p.) (ꢁC)
Calculated (found) (%)
C
H
N
S
4a
4b
2-Phenyl-4-quinolinyl
198
186
212
212
208
186
224
210
200
282
262
270
240
224
238
182
174
156
194
172
184
47 (60)
40 (55)
36 (51)
49 (61)
41 (57)
40 (54)
48 (63)
42 (56)
37 (48)
49 (61)
43 (59)
34 (47)
47 (61)
41 (56)
38 (50)
51 (64)
42 (57)
34 (50)
43 (56)
40 (52)
35 (49)
46 (59)
41 (54)
38 (51)
44 (60)
38 (57)
35 (59)
C
25H16N5OSCl 63.89 (63.81) 3.43 (3.46) 14.90 (14.97) 6.82 (6.85)
2-Phenyl-4-quinolinyl
2-Phenyl-4-quinolinyl
2-Methyl-4-quinolinyl
2-Methyl-4-quinolinyl
2-Methyl-4-quinolinyl
4-Quinolinyl
C27H21N5O2S 67.62 (67.73) 4.41 (4.47) 14.60 (14.68) 6.69 (6.62)
C23H15N5OS 67.47 (67.38) 3.69 (3.72) 17.10 (17.16) 7.83 (7.80)
C20H14N5OSCl 58.89 (58.82) 3.46 (3.49) 17.17 (17.24) 7.86 (7.82)
4c
5a
5b
5c
C22H19N5O2S 63.29 (63.36) 4.59 (4.54) 16.77 (16.79) 7.68 (7.64)
C18H13N5OS 62.23 (62.15) 3.77 (3.73) 20.16 (20.27) 9.23 (9.26)
C19H12N5OSCl 57.94 (57.81) 3.07 (3.10) 17.78 (17.86) 8.14 (8.11)
6a
6b
4-Quinolinyl
4-Quinolinyl
C21H17N5O2S 62.52 (62.43) 4.25 (4.30) 17.36 (17.42) 7.95 (7.91)
C17H11N5OS 61.25 (61.36) 3.33 (3.30) 21.01 (20.96) 9.62 (9.58)
C15H10N5O3SCl 47.94 (48.01) 2.68 (2.71) 18.64 (18.61) 8.53 (8.48)
6c
7a
2,6-Dihydroxy-4-pyridinyl
2,6-Dihydroxy-4-pyridinyl
2,6-Dihydroxy-4-pyridinyl
2-Chloro-4-pyridinyl
2-Chloro-4-pyridinyl
2-Chloro-4-pyridinyl
2-Flouro-4-pyridinyl
2-Flouro-4-pyridinyl
2-Flouro-4-pyridinyl
5-Methoxy-3-indolyl methyl
5-Methoxy-3-indolyl methyl
5-Methoxy-3-indolyl methyl
7b
7c
C17H15N5O4S
C13H9N5O3S
52.98 (52.85) 3.92 (3.90) 18.17 (18.25) 8.32 (8.30)
49.52 (49.46) 2.88 (2.91) 22.21 (22.16) 10.17 (10.21)
8a
8b
C15H9N5OSCl2 47.63 (47.54) 2.40 (2.43) 18.52 (18.58) 8.58 (8.53)
C17H14N5O2SCl 52.65 (52.60) 3.64 (3.61) 18.06 (17.97) 8.27 (8.28)
8c
9a
C13H8N5OSCl
15H9N5OSCF 49.80 (49.86) 2.51 (2.50) 19.36 (19.39) 8.86 (8.82)
C17H14N5O2SF 54.98 (54.87) 3.80 (3.76) 18.86 (18.90) 8.63 (8.60)
C13H8N5OSF 51.82 (51.75) 2.68 (2.71) 23.24 (23.29) 10.64 (10.58)
C20H16N5O2SCl 56.40 (56.28) 3.79 (3.83) 16.44 (16.37) 7.53 (7.49)
49.14 (49.05) 2.54 (2.59) 22.04 (22.10) 10.09 (10.05)
C
9b
9c
10a
10b
10c
11a
11b
11c
12a
12b
12c
C
22H21N5O3S
60.67 (60.78) 4.86 (4.91) 16.08 (16.17) 7.36 (7.31)
59.16 (59.24) 4.14 (4.19) 19.17 (19.25) 8.78 (8.73)
21H18N5O2SCl 57.33 (57.47) 4.12 (4.08) 15.92 (15.95) 7.29 (7.30)
C18H15N5O2S
5-Methoxy-2-methyl-3-indolyl methyl 206
5-Methoxy-2-methyl-3-indolyl methyl 186
5-Methoxy-2-methyl-3-indolyl methyl 180
C
C23H23N5O3S 61.45 (61.52) 5.16 (5.11) 15.58 (15.67) 7.13 (7.08)
C19H17N5O2S 60.14 (60.21) 4.52 (4.55) 18.46 (18.49) 8.45 (8.42)
C19H14N5OSCl 57.65 (57.73) 3.56 (3.51) 17.69 (17.74) 8.10 (8.06)
3-Indolyl methyl
3-Indolyl methyl
3-Indolyl methyl
210
194
178
C21H19N5O2S
C17H13N5OS
62.20 (62.30) 4.72 (4.67) 17.27 (17.31) 7.91 (7.88)
60.88 (60.95) 3.91 (3.93) 20.88 (20.91) 9.56 (9.53)
3. Pharmacological activity
Percentage inhibition ¼ 100ð1 ꢀ Vtest=VcontrolÞ;
where Vtest ¼ mean increase in paw volume of drug-treated
group; Vcontrol ¼ mean increase in paw volume of control
group.
The results were expressed as percentage inhibition of
oedema over the untreated control group.
3.1. Anti-inflammatory activity
All the synthesized compounds were evaluated for their
anti-inflammatory activity against carrageenan-induced acute
paw oedema in albino rats (Wistar strain) weighing 150e
200 g [29,30]. The animals were weighed and divided into con-
trol, standard, and test groups and each group contained six
rats. The first group of rats was treated with 0.1 ml of 1%
gum acacia suspension orally (control), second group was ad-
ministered with a dose of 20 mg/kg of the suspension of phen-
ylbutazone (standard) and the third group was treated with
20 mg/kg of the suspension of test compounds. After 30 min
the animals were injected with 0.1 ml of 1% carrageenan in
normal saline subcutaneously to the sub-plantar region of right
hind paw. The paw volume was measured immediately (‘0’ h)
and after 1 h, 2 h, 3 h and 4 h, respectively, by using plethys-
mograph. The amount of oedema in the drug-treated groups
was compared in relation to the control group with the corre-
sponding time intervals. The percentage of inhibition by the
drugs was calculated by using the formula
3.2. Analgesic activity
All the compounds were tested for their analgesic activity
using Eddy’s hot plate technique [31]. Mice (Swiss strain) of
either sex weighing between 25 and 35 g were used for the
experiment. In this method heat is used as a source of pain.
Animals were individually placed on a hot plate maintained
at constant temperature (55 ꢁC) and the reaction of animals,
such as paw licking or jump response (whichever appears first)
was taken as the end point. A cut-off time of 15 s was taken as
maximum analgesic response to avoid injury to the paws. The
tested compounds and diclofenac sodium (standard) at a dose
of 20 mg/kg body weight in 1% gum acacia were given as
suspension orally to animals and observed the reaction time

828
V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
Table 4
Spectral characterization of 3,6-disubstituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
Compound
IR (KBr) n (cmꢀ1
)
1H NMR d (ppm)
13C NMR d (ppm)
MS m/z
4a
3080 (aromatic CH stretching), 1604
(C]N stretching), 1591, 1572, 1490,
1451 (C]C ring stretch), 2940, 2840
(methyl CH stretch), 1264 (asymmetric
CeOeC stretching), 1014 (symmetric
CeOeC stretch), 1280 (NeN]C)
7.18e8.6 (m, 13H, Ar-H), 3.83
(s, 3H, OCH3)
151.29 (C3 of triazolo
470 Mþ, 472 M þ 2
thiadiazole), 56.26 (C of
OCH3), 161.92, 120.71,
147.84, 129.03, 128.24,
131.87, 151.19 and 124.70
(C1, C2, C3, C4, C5, C6, C8
and C9 of quinoline ring,
respectively), 140.76, 125.62,
133.76, 120.69, 160.94 and
117.48 (C1, C2, C3 C4, C5
and C6 of Ar)
4b
4c
5a
5b
1611 (C]N stretching), 3085, 3048
(aromatic CH stretching), 1585, 1570,
1480, 1446 (C]C ring stretching), 2945,
2840 (methyl CH stretch), 1261
(asymmetric CeOeC stretching), 1021
(symmetric CeOeC stretching), 1280
(NeN]C)
6.7e8.5 (m, 13H, Ar-H), 3.78
(s, 6H, OCH3), 4.18 (s, 2H, CH2)
29.96 (C of CH2), 55.48 (C of
OCH3), 160.4 (C3 of triazolo
thiadiazole ring), 148.71
(C8 of triazolo thiadiazole),
136.47, 125.38, 117.27,
479 Mþ
148.11, 149.31and 115.00
(C1, C2, C3, C4, C5 and C6
of Ar), 160.90, 120.04,
147.75, 129.23, 128.35,
131.05, 151.62 and 125.21
(C1, C2, C3, C4, C5, C6, C8
and C9 of quinoline ring)
3095 (aromatic CH stretching), 1614
(C]N stretching), 1585, 1551, 1479,
1453 (C]C ring stretch), 2955, 2840
(methyl CH stretch), 1274 (NeN]C)
7.14e8.4 (m, 12H, Ar-H), 2.48
(s, 3H, CH3)
13.50 (C of CH3 in furan),
160.87 (C3 of triazolo
409 Mþ
thiadiazole ring), 147.43
(C8 of triazolo thiadiazole),
164.35, 137.41, 121.02 and
153.20 (C2, C3, C4 and C5 of
Ar, respectively), 161.41,
120.12, 146.91, 128.70,
130.49, 131.29, 150.08 and
125.87 (C1, C2, C3, C4, C5,
C6, C8 and C9 of quinoline
ring, respectively)
3085 (aromatic CH stretching), 1610
(C]N stretching), 1572, 1480, 1450
(C]C ring stretch), 2960, 2840 (methyl
CH stretch), 1260 (asymmetric CeOeC
stretching), 1020 (symmetric CeOeC
stretching), 1286 (NeN]C)
7.2e8.0 (m, 8H, Ar-H), 3.85
(s, 3H, OCH3), 2.42 (s, 2H, CH3)
55.81 (C of OCH3), 152.14
(C8 of triazolo thiadiazole),
140.21, 126.67, 132.10,
408 Mþ, 410 M þ 2
120.90, 160.27 and 116.81
(C1, C2, C3 C4, C5 and C6 of
Ar, respectively), 24.30 (C of
CH3 in quinoline), 162.06,
121.47, 144.75, 128.06,
127.72, 131.87, 130.19,
151.80 and 124.08 (C1, C2,
C3, C4, C5, C6, C7, C8 and
C9 of quinoline ring)
1608 (C]N stretching), 3080, 3040
(aromatic CH stretching), 1580, 1570,
1480, 1445 (C]C ring stretching), 2942,
2846 (methyl CH stretch), 1266
(asymmetric CeOeC stretching), 1024
(symmetric CeOeC stretching), 1286
(NeN]C)
6.8e7.9 (m, 8H, Ar-H), 3.79
(s, 6H, OCH3), 4.14 (s, 2H, CH2),
2.46 (s, 2H, CH3)
29.73 (C of CH2), 24.30 (C of
CH3 in quinoline), 162.67,
121.12, 144.91, 128.71,
127.50, 131.29, 130.08,
151.87 and 124.31 (C1, C2,
C3, C4, C5, C6, C7, C8 and
C9 of quinoline ring,
418 Mþ
respectively), 55.00 (C of
OCH3), 160.42 (C3 of
triazolo thiadiazole ring),
147.11 (C8 of triazolo
thiadiazole), 136.84, 125.42,
117.47, 148.36, 149.53 and
115.72 (C1, C2, C3, C4, C5
and C6 of Ar)

V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
829
Table 4 (continued)
Compound
IR (KBr) n (cmꢀ1
)
1H NMR d (ppm)
13C NMR d (ppm)
MS m/z
5c
3090 (aromatic CH stretching), 1610
(C]N stretching), 1580, 1561, 1484,
1445 (C]C ring stretch), 2965, 2848
(methyl CH stretch), 1276 (NeN]C)
7.1e7.9 (m, 7H, Ar-H), 2.10
(s, 3H, CH3 of furan), 2.48
(s, 3H, CH3 of quinoline)
13.38 (C of CH3 in furan),
25.99 (C of CH3 in
347 Mþ
quinoline), 161.934 (C3 of
triazolo thiadiazole ring),
147.59 (C8 of triazolo
thiadiazole), 166.50, 137.29,
123.086 and 153.88,
(C2, C3, C4 and C5 of Ar,
respectively), 161.59, 121.90,
145.60, 128.25, 127.72,
131.72, 130.12, 151.91 and
125.71 (C1, C2, C3, C4, C5,
C6, C7, C8 and C9 of
quinoline ring, respectively)
6a
3073 (aromatic CH stretching), 1607
(C]N stretching), 1592, 1570 (C]C
ring stretch), 2945, 2854 (methyl CH
stretch), 1267 (asymmetric CeOeC
stretching), 1023 (symmetric CeOeC
stretching), 1275 (NeN]C)
7.2e8.0 (m, 9H, Ar-H), 3.84
(s, 3H, OCH3)
28.43 (C of CH2), 55.00 (C of
OCH3), 162.42 (C3 of triazolo
thiadiazolering),147.11(C8of
triazolo thiadiazole), 152.84,
120.42, 144.47, 128.36,
394 Mþ, 396 M þ 2
127.53, 130.72, 150.99 and
127.38 (C1, C2, C3, C4, C5,
C6, C8 and C9 of quinoline
ring, respectively), 141.93,
123.59, 131.90, 118.60, 154.25
and 115.72 (C1, C2, C3 C4, C5
and C6 of Ar)
6b
3065, 3042 (aromatic CH stretching),
1586, 1573 (C]C ring stretching),
2960, 2854 (methyl CH stretch), 1616
(C]N stretching), 1258 (asymmetric
CeOeC stretching), 1020 (symmetric
CeOeC stretching), 1281 (NeN]C)
6.8e8.1 (m, 9H, Ar-H), 3.78
(s, 6H, OCH3), 4.24 (s, 2H, CH2)
29.25 (C of CH2), 54.72 (C of
OCH3), 114.12 (C3 of
403 Mþ
triazolo thiadiazole ring),
147.91 (C8 of triazolo
thiadiazole), 135.71, 122.50,
112.29, 145.08, 147.88 and
110.06 (C1, C2, C3, C4, C5
and C6 of Ar, respectively),
152.21, 120.02, 144.34,
128.19, 127.80, 129.50,
150.99 and 126.18 (C1, C2,
C3, C4, C5, C6, C8 and C9 of
quinoline ring, respectively)
6c
3078 (aromatic CH stretching), 1614
(C]N stretching), 1590, 1575 (C]C
ring stretch), 2970, 2848 (methyl CH
stretch), 1284 (NeN]C)
7.1e8.0 (m, 8H, Ar-H), 2.10
(s, 3H of furan)
13.54 (C of CH3 in furan),
161.22 (C3 of triazolo
333 Mþ
thiadiazole ring), 147.00
(C8 of triazolo thiadiazole),
163.77, 137.20, 120.13 and
153.54, (C2, C3, C4 and C5
of Ar, respectively), 151.31,
119.99, 143.68, 127.20,
126.88, 129.77, 148.51 and
126.24 (C1, C2, C3, C4, C5,
C6, C8 and C9 of quinoline
ring, respectively)
7a
3430 (OH stretch), 3074 (aromatic CH
stretch), 1612 (C]N stretch), 1590,
1541, 1480, 1455 (C]C ring stretch),
2965, 2931 (methyl CH stretch), 1230
(asymmetric CeOeC stretch), 1026
(symmetric CeOeC stretch), 1290
(NeN]C)
7.20, 7.52, 7.6 (3d, 3H of C-4, C-5,
C-6 of Ar), 7.36 (s, 2H, C-3, C-5 of
pyridine), 6.26 (s, 2H, OH), 3.85
(s, 3H, OCH3)
55.37 (C of OCH3), 155.49
(C3 of triazolo thiadiazole
ring), 156.35 (C8 of triazolo
thiadiazole), 140.57, 126.40,
132.81, 118.61, 160.56 and
116.83 (C1, C2, C3 C4, C5
and C6 of Ar, respectively),
159.20, 108.71, 146.63,
375 Mþ 377 M þ 2
124.85 and 156.90 (C2, C3,
C4 and C5 of pyridine ring,
respectively)
(continued on next page)

830
V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
Table 4 (continued)
Compound
IR (KBr) n (cmꢀ1
)
1H NMR d (ppm)
13C NMR d (ppm)
MS m/z
7b
3443 (OH stretching), 3076, 3034
(aromatic CH stretching), 1607 (C]N
stretching), 1590, 1538, 1478, 1448
(C]C ring stretch), 2970, 2934 (methyl
CH stretch), 1262 (asymmetric CeOeC
stretching), 1045 (symmetric CeOeC
stretch), 1283 (NeN]C)
6.76, 6.84 (2d, 2H of C-5, C-6 in Ar),
7.0 (s, 1H of C-2 in Ar), 7.34 (s, 2H,
C-3, C-5 of pyridine), 6.28 (s, 2H,
OH), 3.78 (s, 6H, OCH3), 4.22
(s, 2H, CH2)
29.84 (C of CH2), 55.84
(C of OCH3), 162.11
386 Mþ
(C3 of triazolo thiadiazole
ring), 154.39 (C8 of triazolo
thiadiazole), 136.47, 126.38,
119.27, 149.11 and 152.31
(C1, C2, C3 and C6, C4 and
C5 of Ar, respectively),
158.25, 109.72, 148.49,
121.21 and 157.26
(C2, C3, C4, C5 and C6 of
pyridine ring, respectively)
7c
3450 (OH stretching), 3080, 3031
(aromatic CH stretching), 1610 (C]N
stretching), 1590, 1541, 1482, 1448
(C]C ring stretch), 2958, 2930 (methyl
CH stretch), 1286 (NeN]C)
7.1, 7.72 (2d, 2H of furan), 7.36
(s, 2H, C-3, C-5 of pyridine), 6.3
(s, 2H, OH), 2.84 (s, 3H, CH3)
13.73 (C of CH3 in furan),
164.53 (C3 of triazolo
315 Mþ
thiadiazole ring), 154.47
(C8 of triazolo thiadiazole),
163.182, 136.09, 121.40 and
152.28, (C2, C3, C4 and C5
of Ar, respectively), 160.25,
106.72, 146.49, 119.21 and
154.26 (C2, C3, C4, C5 and
C6 of pyridine ring,
respectively)
8a
3065 (aromatic CH stretching), 1610
(C]N stretching), 1585, 1567, 1484,
1455 (C]C ring stretch), 2970, 2840
(methyl CH stretch), 1254 (asymmetric
CeOeC stretching), 1034 (symmetric
CeOeC stretch), 1275 (NeN]C)
7.22, 7.5, 7.6 (3d, 3H of C-4, C-5,
C-6 in Ar), 7.76 (s, 1H, C-3 of
pyridine), 7.38,7.56 (2d, 2H, C-5,
C-6 of pyridine), 3.83 (s, 3H, OCH3)
56.33 (C of OCH3), 154.26
(C3 of triazolo thiadiazole
ring), 156.48 (C8 of
377 Mþ, 379 M þ 2,
381 M þ 4
triazolo thiadiazole),
139.66, 125.96, 131.80,
118.32, 162.00 and
115.68 (C1, C2, C3,
C4, C5 and C6 of Ar,
respectively), 161.28,
126.12, 152.14, 124.99
and 156.00 (C2, C3,
C4, C5 and C6 of
pyridine ring, respectively)
8b
3084, 3048 (aromatic CH stretching),
1607 (C]N stretching), 1585, 1554,
1464, 1448 (C]C ring stretch), 2984,
2854 (methyl CH stretch), 1260
(asymmetric CeOeC stretching), 1028
(symmetric CeOeC stretching), 1284
(NeN]C)
6.76, 6.84 (2d, 2H of C-5, C-6 in Ar),
6.94 (s, 1H of C-2 in Ar), 7.8 (s, 1H,
C-30 of pyridine), 7.42, 7.56 (2d, 2H,
C-50, C-60 of pyridine), 3.77 (s, 6H,
OCH3), 4.18 (s, 2H, CH2)
29.50 (C of CH2),
387 Mþ, 389 M þ 2
55.173 (C of OCH3),
160.89 (C3 of triazolo
thiadiazole ring), 147.10
(C8 of triazolo thiadiazole),
133.46, 124.79, 117.32,
145.94, 149.34 and
116.87 (C1, C2, C3,
C4, C5 and C6 of Ar,
respectively), 153.27,
123.83, 148.27, 121.94
and 150.55 (C2, C3,
C4, C5 and C6 of
pyridine ring, respectively)
8c
3080, 3038 (aromatic CH stretching),
1614 (C]N stretching), 1587, 1550,
1482, 1448 (C]C ring stretch), 2958,
2854 (methyl CH stretch), 1276
(NeN]C)
7.86 (s, 1H of C-3 of pyridine), 7.38,
7.6 (2d, 2H, C-50, C-60 of pyridine),
7.14, 7.70 (2d, 2H of furan), 2.0
(s, 3H, CH3 of furan)
13.57 (C of CH3 in furan),
164.19 (C3 of triazolo
317 Mþ, 319 M þ 2
thiadiazole ring), 155.10
(C8 of triazolo thiadiazole),
164.10, 136.10, 120.39 and
154.01 (C2, C3, C4 and C5 of
furan, respectively), 159.41,
134.14, 151.97, 128.04 and
157.36 (C2, C3, C4, C5 and
C6 of pyridine ring,
respectively)

V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
831
Table 4 (continued)
Compound
IR (KBr) n (cmꢀ1
)
1H NMR d (ppm)
13C NMR d (ppm)
MS m/z
9a
3082 (aromatic CH stretching), 1618
(C]N stretching), 1580, 1574 (C]C
ring stretch), 2964, 2846 (methyl CH
stretch), 1258 (asymmetric CeOeC
stretching), 1028 (symmetric CeOeC
stretching), 1280 (NeN]C)
7.16, 7.44, 7.6 (3d, 3H, C-4, C-5, C-6
of Ar), 7.86 (s, 1H of C-3 of
56.38 (C of OCH3), 151.72
(C3 of triazolo thiadiazole
ring), 151.22 (C8 of
362 Mþ, 364 M þ 2
pyridine), 7.32, 7.52 (2d, 2H of C-5,
C-6 of pyridine), 3.85 (s, 3H, OCH3)
triazolo thiadiazole),
139.65, 125.70, 131.12,
118.91, 163.71 and
115.50 (C1, C2, C3,
C4, C5 and C6 of Ar,
respectively), 167.29,
110.08, 152.87, 120.50 and
150.73 (C2, C3, C4, C5 and
C6 of pyridine ring,
respectively)
9b
3090 (aromatic CH stretching), 1617
(C]N stretching), 1575, 1560 (C]C
ring stretch), 2954, 2837 (methyl CH
stretch), 1260 (asymmetric CeOeC
stretching), 1024 (symmetric CeOeC
stretching), 1284 (NeN]C)
6.74, 6.88 (2d, 2H of C-5, C-6 in Ar),
6.98 (s, 1H of C-2 in Ar), 7.80 (s, 1H
of C-3 of pyridine), 7.44, 7.62
29.18 (C of CH2), 56.72
(C of OCH3), 160.30
372 Mþ
(C3 of triazolo thiadiazole
ring), 147.51 (C8 of triazolo
thiadiazole), 131.27, 123.83,
116.27, 144.83, 147.27 and
115.94 (C1, C2, C3, C4, C5
and C6 of Ar, respectively),
166.55, 110.38, 150.61,
121.13 and 149.93 (C2, C3,
C4, C5 and C6 of pyridine
ring, respectively)
(2d, 2H of C-5, C-6 of pyridine), 3.79
(s, 6H, OCH3), 4.22 (s, 2H, CH2)
9c
3080, 3038 (aromatic CH stretch), 1614
(C]N stretching), 1587, 1550, 1482,
1448 (C]C ring stretch), 2958, 2854
(methyl CH stretch), 1276 (NeN]C)
7.80 (s, 1H of C-3 of pyridine), 7.48,
7.60 (2d, 2H, C-5, C-6 of pyridine),
7.10, 7.70 (2d, 2H of furan), 2.1
(s, 3H, CH3 of furan)
13.51 (C of CH3 in furan),
161.45 (C3 of triazolo
thiadiazole ring), 156.61
(C8 of triazolo thiadiazole),
163.92, 135.47, 119.76,
154.36, (C2, C3, C4, C5 of
furan), 171.18, 116.26,
153.16, 125.93, 155.41
(C2, C3, C4, C5 and C6 of
pyridine ring)
301 Mþ
10a
3084 (aromatic CH stretching), 1614
(C]N stretching), 1587, 1565 (C]C
ring stretch), 2980, 2849 (methyl CH
stretch), 1265 (asymmetric CeOeC
stretching), 1018 (symmetric CeOeC
stretching), 1282 (NeN]C)
7.22, 7.5, 7.6 (3d, 3H of C-4, C-5,
C-6 of Ar), 7.4 (s, 1H of C-40 of
indole), 7.66, 7.7 (2d, 2H of C-60,
C-70 of indole), 7.1 (s, 1H of C-20
of indole), 3.82e3.84 (2s, 6H, of
OCH3), 4.68 (s, 2H, CH2), 9.8 (s, 1H,
NH of pyrrole)
28.315 (C of CH2), 154.385
(C3 of triazolo thiadiazole
ring), 156.708 (C8 of triazolo
thiadiazole), 55.945 (C of
OCH3), 126.327, 115.190,
139.75, 109.49, 163.59,
107.851, 116.271 and
426 Mþ, 428 M þ 2
134.485 (C2, C3, C4, C5, C6,
C7, C8 and C9 of indole ring,
respectively), 147.82,
127.105, 133.49, 121.406,
167.31 and 113.217 (C1, C2,
C3, C4, C5 and C6 of Ar,
respectively)
10b
3070 (aromatic CH stretching), 1624
(C]N stretching), 1588, 1546 (C]C
ring stretch), 2956, 2864 (methyl CH
stretch), 1260 (asymmetric CeOeC
stretching), 1021 (symmetric CeOeC
stretching), 1285 (NeN]C)
9.74 (s, 1H, NH), 6.76, 6.84 (2d, 2H
of C-5, C-6 of Ar), 6.94 (s, 1H of
C-20 of Ar), 7.4 (s, 1H of C-40 of
indole), 7.6, 7.72 (2d, 2H of C-60,
C-70 of indole), 7.12 (s, 1H of C-2 of
indole), 4.24 (s, 2H, CH2 of Ar), 3.78
(s, 6H, OCH3 in Ar), 3.84 (s, 3H,
OCH3 in indole), 4.60 (s, 2H, CH2 of
indole)
29.34 and 28.80 (C of
two CH2), 54.69 (C of
OCH3), 124.58,
435 Mþ
115.10, 134.73,
126.85, 128.04, 123.61,
115.94 and 141.60 (C2,
C3, C4, C5, C6, C7, C8 and
C9 of indole ring,
respectively), 139.56,
127.47, 120.39, 144.14,
149.25, 116.31 (C1, C2, C3,
C4, C5 and C6 of Ar,
respectively)
(continued on next page)

832
V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
Table 4 (continued)
Compound
IR (KBr) n (cmꢀ1
)
1H NMR d (ppm)
13C NMR d (ppm)
MS m/z
10c
3063 (aromatic CH stretching), 1616
(C]N stretching), 1587, 1549, 1479,
1452 (C]C ring stretch), 2964, 2838
(methyl CH stretch), 1267 (asymmetric
CeOeC stretching), 1029 (symmetric
CeOeC stretching), 1280 (NeN]C)
7.2, 7.8 (2d, 2H of C-4, C-5 of Ar),
7.44 (s, 1H of C-40 of indole), 7.62,
7.7 (2d, 2H of C-60, C-70 of indole),
7.06 (s, 1H of C-20 of indole), 3.83
(s, 3H, of OCH3 in indole), 4.62
(s, 2H, CH2 of indole), 9.8
13.73 (C of CH3) 28.65
(C of CH2), 54.63
365 Mþ
(C of OCH3), 126.56,
117.16, 136.24, 109.10,
159.031, 108.47,
116.25 and 131.49
(s, 1H, NH), 1.98 (s, 3H, CH3)
(C2, C3, C4, C5, C6, C7,
C8 and C9 of indole ring,
respectively), 157.48,
127.25, 114.37 and 150.71
(C2, C3, C4 and C5 of furan,
respectively)
11a
3075 (aromatic CH stretching), 1610
(C]N stretching), 1587, 1565 (C]C
ring stretch), 2980, 2849 (methyl CH
stretch), 1265 (asymmetric CeOeC
stretching), 1018 (symmetric CeOeC
stretching), 1282 (NeN]C)
7.2, 7.5, 7.64 (3d, 3H of C-4, C-5,
C-6 of Ar), 7.4 (s, 1H of C-40 of
indole), 7.62, 7.74 (2d, 2H of C-60,
C-70 of indole), 3.82e3.84 (2s, 6H,
of OCH3), 4.62 (s, 2H, CH2 of
indole), 9.68 (s, 1H, NH of pyrrole),
2.72 (s, 3H, CH3)
28.42 (C of CH2), 13.93
(C of CH3), 54.38
440 Mþ, 442 M þ 2
(C of OCH3), 139.91,
127.60, 136.51, 121.57,
163.27 and 115.90
(C1, C2, C3, C4,
C5 and C6 of Ar,
respectively), 126.32,
115.19, 139.75, 109.49,
163.59, 107.85,
116.27 and 134.48
(C2, C3, C4, C5, C6, C7, C8
and C9 of indole ring,
respectively)
11b
3082 (aromatic CH stretching), 1610
(C]N stretching), 1588, 1561 (C]C
ring stretch), 2956, 2856 (methyl CH
stretch), 1268 (asymmetric CeOeC
stretching), 1024 (symmetric CeOeC
stretching), 1286 (NeN]C)
9.74 (s, 1H, NH of pyrrole), 6.72,
6.84 (2d, 2H of C-5, C-6 in Ar), 6.96
(s, 1H of C-2 in Ar), 7.44 (s, 1H of
C-40 of indole), 7.56, 7.68 (2d, 2H of
C-60, C-70 of indole), 4.32 (s, 2H,
CH2 of Ar), 3.77 (s, 6H, OCH3 in
Ar), 3.83 (s, 3H, OCH3 in indole),
4.60 (s, 2H, CH2 of indole), 2.8
(s, 3H, CH3)
29.21 and 28.77 (C of two
CH2), 54.50 and 54.16
(C of two OCH3), 13.30
(C of CH3), 139.91,
450 Mþ
127.60, 136.51, 148.70,
149.05 and 117.38
(C1, C2, C3, C4,
C5 and C6 of Ar,
respectively), 144.53,
117.35, 137.19, 109.30,
160.94, 106.73, 114.20 and
132.15 (C2, C3, C4, C5, C6,
C7, C8 and C9 of indole ring,
respectively)
11c
3068 (aromatic CH stretching), 1616
(C]N stretching), 1587, 1554 (C]C
ring stretch), 2943, 2860 (methyl CH
stretch), 1254 (asymmetric CeOeC
stretching), 1023 (symmetric CeOeC
stretching), 1288 (NeN]C)
7.16, 7.8 (2d, 2H of furan), 7.36
(s, 1H of C-40 in indole), 7.56, 7.66
(2d, 2H of C-60, C-70 in indole), 3.85
(s, 3H, OCH3), 4.64 (s, 2H, CH2 of
indole), 9.74 (s, 1H, NH), 1.98
(s, 3H, CH3), 2.8 (s, 3H, CH3)
13.49 and 14.01 (C of two
CH3), 28.06 (C of CH2),
54.58 (C of OCH3),
379 Mþ
143.17, 117.44,
136.53, 109.13, 161.27,
108.25, 114.14 and 132.06
(C2, C3, C4, C5, C6, C7, C8
and C9 of indole ring,
respectively), 154.35, 127.11,
114.50 and 149.31 (C2, C3,
C4 and C5 of furan,
respectively)
12a
3092 (aromatic CH stretching), 1623
(C]N stretching), 1583, 1545 (C]C
ring stretch), 2980, 2855 (methyl CH
stretch), 1267 (asymmetric CeOeC
stretching), 1018 (symmetric CeOeC
stretching), 1282 (NeN]C)
7.18, 7.48, 7.6 (3d, 3H of C-4, C-5,
C-6 of Ar), 7.36 (s, 1H of C-40 in
indole), 7.7 (d, 1H of C-70 in indole),
7.5e7.66 (m, 2H, C-50, C-60 of
indole), 7.06 (s, 1H of C-20 of
indole), 3.81 (s, 3H, of OCH3), 4.68
(s, 2H, CH2 of indole), 9.84
(s, 1H, NH)
28.506 (C of CH2), 56.47
(C of OCH3), 145.19, 127.53,
136.71, 119.10, 167.49 and
114.23 (C1, C2, C3, C4, C5
and C6 of Ar, respectively),
126.29, 115.37, 134.10,
396 Mþ
121.35, 123.07, 120.21,
112.29 and 140.53 (C2, C3,
C4, C5, C6, C7, C8 and C9 of
indole ring, respectively)

V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
833
Table 4 (continued)
Compound
IR (KBr) n (cmꢀ1
)
1H NMR d (ppm)
13C NMR d (ppm)
MS m/z
12b
3071 (aromatic CH stretching), 1608
(C]N stretching), 1574, 1540 (C]C
ring stretch), 2956, 2834 (methyl CH
stretch), 1261 (asymmetric CeOeC
stretching), 1019 (symmetric CeOeC
stretching), 1280 (NeN]C)
6.78, 6.86 (2d, 2H of C-5, C-6 in Ar),
6.94 (s, 1H of C-2 in Ar), 7.44 (s, 1H
of C-40 in indole), 7.5e7.64 (m, C-50,
C-60 of indole), 7.7 (d, 1H of C-70
in indole), 7.12 (s, 1H of C-2 of
pyrrole), 4.24 (s, 2H, CH2 of Ar),
3.77 (s, 6H, OCH3 in Ar), 4.60
(s, 2H, CH2 of indole), 9.74
29.47 and 28.65 (C of two
CH2), 54.38 (C of OCH3),
126.57, 117.14, 136.82,
121.07, 123.39, 120.01,
116.64 and 142.09 (C2, C3,
C4, C5, C6, C7, C8 and C9 of
indole ring, respectively),
138.21, 128.30, 121.07,
149.49, 151.52 and 117.13
(C1, C2, C3, C4, C5 and C6
of Ar, respectively)
406 Mþ
(s, 1H, NH)
12c
3060 (aromatic CH stretching), 1616
(C]N stretching), 1571, 1549 (C]C
ring stretch), 2952, 2839 (methyl CH
stretch), 1271 (NeN]C)
7.16, 7.8 (2d, 2H of C-4, C-5 of Ar),
7.38 (s, 1H of C-40 in indole), 7.7
(d, H of C-70 in indole), 7.5e7.64
(m, C-50, C-60 of indole), 7.08 (s, 1H
of C-20 of indole), 4.64 (s, 2H, CH2
of indole), 9.82 (s, 1H, NH), 1.96
(s, 3H, CH3)
13.73 (C of CH3) 28.72
(C of CH2), 126.56, 117.16,
136.24, 109.10, 159.03,
108.47, 116.25 and 131.49
(C2, C3, C4, C5, C6, C7, C8
and C9 of indole ring,
respectively), 157.48, 127.25,
114.37 and 150.71 (C2, C3,
C4 and C5 of furan,
335 Mþ
respectively)
of animals on the hot plate at 15, 30, 60, 90 and 120 min after
the compound administration. Percentage analgesic activity
shown by the tested compounds is recorded in Table 10.
Bacillus subtilis (Gram-positive) at 10 mg/ml, 20 mg/ml,
30 mg/ml concentrations, respectively. Under identical condi-
tions, the positive control antibiotics amikacin at 30 mg/ml
showed zone of inhibition 23e24 mm for Gram-negative
organism and vancomycin at 30 mg/ml showed zone of inhibi-
tion 23 mm for Gram-positive organism. Similarly, the anti-
fungal screening of the compounds was carried out in vitro
by paper disc method against two fungi A. niger and C. albi-
cans by using griseofulvin (30 mg/ml) as the positive control,
which showed 23 mm and 25 mm, respectively, as the zone
of inhibition.
3.3. Antibacterial and antifungal activities
Applying the agar plate diffusion technique [32] all of the
newly synthesized compounds were screened in vitro for anti-
bacterial activity against Escherichia coli (E. coli), Pseudo-
monas aeruginosa (Gram-negative), Staphylococcus aureus,
Table 5
Physical characterization of 3,6-disubstituted-5,6-dihydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
N
N
N
S
Ar
N
H
CH
Ar'
Compound
Ar0
Melting point
(m.p.) (ꢁC)
Yield (%)
(microwave)
Molecular
formula
Elemental analysis
Calculated (found) (%)
C
H
N
S
13a
13b
13c
14a
14b
14c
15a
15b
15c
16a
16b
16c
2-Furanyl
2-Furanyl
2-Furanyl
172
160
180
224
218
214
176
162
180
184
174
162
45 (59)
42 (53)
38 (53)
50 (65)
41 (56)
35 (52)
47 (62)
43 (58)
40 (57)
47 (60)
40 (57)
36 (54)
C
C
13H11N4O2SCl
16H16N4O3S
50.23 (50.30)
55.80 (55.87)
52.54 (52.46)
44.28 (44.34)
49.35 (49.43)
45.14 (45.08)
50.38 (50.47)
55.96 (56.06)
52.73 (52.67)
58.60 (58.67)
62.99 (63.06)
61.87 (61.79)
3.31 (3.34)
4.68 (4.68)
3.67 (3.69)
2.65 (2.67)
3.88 (3.90)
2.84 (2.86)
3.62 (3.60)
4.99 (5.02)
4.06 (4.04)
3.93 (3.96)
5.05 (5.01)
4.33 (4.34)
16.74 (16.80)
16.27 (16.32)
20.43 (20.41)
18.44 (18.51)
17.99 (18.04)
21.93 (21.89)
20.98 (21.07)
20.39 (20.45)
25.62 (25.68)
17.09 (17.13)
16.69 (16.73)
20.04 (19.92)
9.58 (9.59)
9.31 (9.29)
11.69 (11.65)
8.44 (8.42)
8.23 (8.26)
10.04 (10.01)
9.61 (9.57)
9.34 (9.30)
11.73 (11.69)
7.82 (7.85)
7.64 (7.66)
9.18 (9.20)
C12H10N4O2S
C14H10N5O4SCl
5-Nitro-2-furanyl
5-Nitro-2-furanyl
5-Nitro-2-furanyl
Pyrol-2-yl
C
C
16H15N5O5S
12H9N5O4S
C14H12N5OSCl
C16H17N5O2S
Pyrol-2-yl
Pyrol-2-yl
C12H11N5OS
C20H16N5OSCl
C22H21N5O2S
N-Methyl-pyrol-2-yl
N-Methyl-pyrol-2-yl
N-Methyl-pyrol-2-yl
C
18H15N5OS

834
V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
Table 6
Spectral characterization of 3,6-disubstituted-5,6-dihydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
Compound
IR (KBr) n (cmꢀ1
)
1H NMR d (ppm)
13C NMR d (ppm)
MS m/z
13a
3370 (NH stretching), 3056 (aromatic
CH stretching), 1618 (C]N stretching),
1580, 1535 (C]C ring stretch), 1264
(asymmetric CeOeC stretching), 1017
(symmetric CeOeC stretching)
7.14, 7.5, 7.60 (3d, 3H of C-4, C-5,
C-6 of Ar), 6.84 (d, 1H, C-30 of Ar),
7.24 (m, 1H of C-40 of furan), 7.78
(d, 1H C-50 of furan), 5.56
56.23 (C of OCH3), 90.74
(C6 of triazolo thiadiazole),
161.39, 113.24, 125.37 and
153.14 (C2, C3, C4 and C5 of
furan ring, respectively),
144.80, 127.18, 137.21,
118.57, 165.64 and 116.38
(C1, C2, C3, C4, C5 and C6
of Ar, respectively)
335 Mþ, 337 M þ 2
(s, 1H, CH, in eCHeNH), 6.20
(s, 1H of NH in eNHeCH), 3.83
(s, 3H, OCH3)
13b
3350 (NH stretching), 3076 (aromatic
CH stretching), 1617 (C]N stretching),
1576, 1552, 1480 (C]C ring stretch),
1262 (asymmetric CeOeC stretching),
1020 (symmetric CeOeC stretching)
6.80, 6.92 (2d, 2H, C-5, C-6 of Ar),
7.0 (s, 1H, C-2 of Ar), 6.96 (d, 1H,
C-30 of furan), 7.24 (m, 1H, C-40 of
furan), 7.76 (d, 1H, C-50 of furan),
5.60 (s, 1H, CH, in CHeNH), 6.22
(s, 1H of NH in NHeCH), 3.83
(s, 6H, OCH3), 4.28 (s, 2H, CH2)
93.15 (C6 of triazolo
344 Mþ
thiadiazole), 159.96, 112.18,
125.32 and 153.63 (C2, C3,
C4 and C5 of furan ring,
respectively), 37.26 (C of
CH2), 54.31 (C of OCH3),
140.62, 127.53, 118.68,
148.81, 152.07 and 116.39
(C1, C2, C3, C4, C5 and C6
of Ar, respectively)
13c
3328 (NH stretching), 3080 (aromatic
CH stretching), 1620 (C]N stretching),
1580, 1552, 1484 (C]C ring stretch),
1258 (asymmetric CeOeC stretching),
1023 (symmetric CeOeC stretching)
7.1, 7.64 (2d, 2H, C-4 and C-5 of
Ar), 6.90 (d, 1H, C-30 of furan at
C-6), 7.20 (m, 1H, C-40 of furan at
C-6), 7.76 (d, 1H C-50 of furan at
C-6), 5.58 (s, 1H, CH, eCHeNH),
6.16 (s, 1H, NH in eNHeCH), 1.92
(s, 3H, CH3 of Ar)
14.28 (C of CH3), 155.29,
131.48, 117.51 and 153.35
(C2, C3, C4 and C5 of Ar,
respectively), 90.74 (C6 of
triazolo thiadiazole), 161.29,
113.75, 126.61 and 153.48
(C2, C3, C4 and C5 of furan
ring, respectively)
274 Mþ
14a
3338 (NH stretch), 3086 (aromatic CH
stretch), 1619 (C]N stretch), 1590,
1558 (C]C ring stretch), 1265
(asymmetric CeOeC stretch), 1017
(symmetric CeOeC stretch), 1527
(asymmetric NO2 stretch), 1347
(symmetric NO2 stretch)
7.16, 7.56, 7.62 (3d, 3H of C-4, C-5,
C-6 of Ar), 7.36 (d, 1H, C-30 of
furan), 7.90 (d, 1H of C-40 of furan),
5.58 (s, 1H, CH of eCHeNH), 6.24
(s, 1H of NH in eNHeCH), 3.83
(s, 3H, OCH3)
55.47 (C of OCH3), 92.38
(C6 of triazolo thiadiazole),
163.38, 115.62, 131.07 and
159.15 (C2, C3, C4 and C5 of
furan ring, respectively),
146.26, 127.10, 139.47,
120.50, 166.02 and 118.13
(C1, C2, C3, C4, C5 and C6
of Ar, respectively)
380 Mþ, 382 M þ 2
14b
3350 (NH stretch), 3079 (aromatic CH
stretch), 1615 (C]N stretch), 1584,
1547, 1492 (C]C ring stretch), 1258
(asymmetric CeOeC stretch), 1021
(symmetric CeOeC stretch), 1519
(asymmetric NO2 stretch), 1348
(symmetric NO2 stretch)
6.82, 6.90 (2d, 2H of C-5, C-6 in Ar),
7.0 (s, 1H of C-2 in Ar), 7.40 (d, 1H,
C-30 of furan), 7.94 (d, 1H of C-40 of
furan), 5.58 (s, 1H, CH in eCHe
NH), 6.16 (s, 1H of NH in eNHe
CH), 3.79 (s, 6H, OCH3), 4.32
(s, 2H, CH2)
94.27 (C6 of triazolo
389 Mþ
thiadiazole), 166.31, 117.49,
130.04 and 159.24 (C2, C3,
C4 and C5 of furan ring,
respectively), 35.19 (C of
CH2), 54.72 (C of OCH3),
143.58, 126.96, 120.47,
151.17, 152.90 and 116.39
(C1, C2, C3, C4, C5 and C6
of Ar, respectively)
14c
3345 (NH stretching), 3084 (aromatic
CH stretching), 1620 (C]N stretching),
1580, 1542, 1490 (C]C ring stretch),
1530 (asymmetric NO2 stretch), 1340
(symmetric NO2 stretch)
7.1, 7.72 (2d, 2H, C-4 and C-5 of
Ar), 7.42 (d, 1H, C-30 of furan),
7.92 (d, 1H of C-40 of furan), 5.60
(s, 1H, CH in eCHeNH), 6.26
(s, 1H of NH in eNHeCH), 1.96
(s, 3H, CH3 of Ar)
14.28 (C of CH3), 155.29,
131.48, 117.51 and 153.35
(C2, C3, C4 and C5 of Ar,
respectively), 93.38 (C6 of
triazolo thiadiazole), 165.74,
115.23, 128.59 and 159.71
(C2, C3, C4 and C5 of furan
ring, respectively)
319 Mþ
15a
3352 (NH stretching), 3070 (aromatic
CH stretching), 1619 (C]N stretching),
1586, 1554 (C]C ring stretch), 1263
(asymmetric CeOeC stretching), 1019
(symmetric CeOeC stretching)
7.14, 7.52, 7.64 (3d, 3H of C-4, C-5,
C-6 of Ar), 6.42 (d, 1H, C-30 of
pyrrole), 6.60 (m, 1H, C-40 of
pyrrole), 7.04 (d, 1H, C-50 of
pyrrole), 5.60 (s, 1H, CH in CHe
NH), 6.26 (s, 1H of NH in eNHe
CH), 9.8 (s, 1H, NH of pyrrole), 3.82
(s, 3H, OCH3)
56.31 (C of OCH3), 94.27
(C6 of triazolo thiadiazole),
144.35, 121.14, 120.74 and
130.06 (C2, C3, C4 and C5 of
pyrrole ring, respectively),
147.10, 126.83, 139.05,
120.17, 165.68 and 118.24
(C1, C2, C3, C4, C5 and C6
of Ar, respectively)
334 Mþ, 336 M þ 2

V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
835
Table 6 (continued)
Compound
IR (KBr) n (cmꢀ1
)
1H NMR d (ppm)
13C NMR d (ppm)
MS m/z
15b
3365 (NH stretching), 3083 (aromatic
CH stretching), 1617 (C]N stretching),
1586, 1550, 1470 (C]C ring stretch),
1257 (asymmetric CeOeC stretching),
1021 (symmetric CeOeC stretching)
6.82, 6.90 (2d, 2H of C-5, C-6 in Ar),
7.0 (s, 1H of C-2 in Ar), 6.46 (d, 1H,
C-30 of pyrrole), 6.60 (m, 1H of C-40
of pyrrole), 7.06 (d, 1H of C-50 of
pyrrole), 5.68 (s, 1H, CH in eCHe
NH), 6.26 (s, 1H of NH in eNHe
CH), 9.6 (s, 1H, NH of pyrrole), 3.78
(s, 6H, OCH3), 4.32 (s, 2H, CH2)
94.17 (C6 of triazolo
343 Mþ
thiadiazole), 145.30, 128.14,
122.69, 154.58, 157.17 and
118.30 (C1, C2, C3, C4, C5
and C6 of Ar, respectively),
144.51, 120.42, 119.80 and
131.37 (C2, C3, C4 and C5 of
pyrrole ring, respectively),
37.60 (C of CH2), 55.43
(C of OCH3)
15c
3348 (NH stretching), 3076 (aromatic
CH stretching), 1615 (C]N stretching),
1580, 1568, 1490 (C]C ring stretch),
1259 (asymmetric CeOeC stretching),
1024 (symmetric CeOeC stretching)
7.1, 7.68 (2d, 2H, C-4 and C-5 of
Ar), 6.59 (m, 1H of C-40 of pyrrole),
7.06 (d, 1H of C-50 of pyrrole), 5.64
(s, 1H, CH in eCHeNH), 6.18
(s, 1H of NH in eNHeCH), 9.8
(s, 1H, NH of pyrrole), 1.94
13.47 (C of CH3), 157.10,
131.71, 118.15 and 153.29
(C2, C3, C4 and C5 of Ar),
94.79 (C6 of triazolo
273 Mþ
thiadiazole), 144.47, 121.03,
120.95 and 130.24 (C2, C3,
C4 and C5 of pyrrole ring,
respectively)
(s, 3H, CH3 of Ar)
16a
3364 (NH stretching), 3062 (aromatic
CH stretching), 1610 (C]N stretching),
1580, 1553 (C]C ring stretch), 1266
(asymmetric CeOeC stretching), 1021
(symmetric CeOeC stretching), 2963,
2847 (methyl CH stretch)
7.12, 7.48, 7.60 (3d, 3H of C-4, C-5,
C-6 of Ar), 6.88 (d, 1H, C-50 of
pyrrole), 6.56 (m, 1H, C-40 of
pyrrole), 6.40 (d, 1H, C-30 of
pyrrole), 5.62 (s, 1H, of eCHeNH),
6.20 (s, 1H of NH in eNHeCH),
3.56 (s, 3H, NeCH3), 3.84
47.61 (C of CH3 in pyrrole),
87.10 (C6 of triazolo
409 Mþ, 411 M þ 2
thiadiazole), 148.36, 126.72,
138.68, 119.55, 165.40 and
118.21 (C1, C2, C3, C4, C5
and C6 of Ar, respectively),
56.31 (C of OCH3), 149.38,
121.82, 120.90 and 137.53
(C2, C3, C4 and C5 of
(s, 3H, OCH3)
pyrrole ring, respectively)
48.63 (C of CH3 in pyrrole),
86.57 (C6 of triazolo
16b
3364 (NH stretching), 3058 (aromatic
CH stretching), 1615 (C]N stretching),
1589, 1565, 1480 (C]C ring stretch),
1258 (asymmetric CeOeC stretching),
1025 (symmetric CeOeC stretching),
2958, 2849 (methyl CH stretch)
6.80 (d, 1H of C-5 of Ar), 7.0 (s, 1H
of C-2 in Ar), 6.9 (m, 2H, C-6 of Ar
and C-50 of pyrrole), 6.52 (m, 1H,
C-40 of pyrrole), 6.38 (d, 1H, C-30 of
pyrrole), 5.52 (s, 1H, of eCHeNH),
6.26 (s, 1H of NH in eNHeCH),
3.64 (s, 3H of NeCH3), 3.79 (s, 6H,
OCH3), 4.34 (s, 2H, CH2)
419 Mþ
thiadiazole), 57.15 (C of
OCH3), 148.36, 121.75,
120.33 and 137.07 (C2, C3,
C4 and C5 of pyrrole ring,
respectively), 34.13 (C of
CH2), 145.05, 128.27,
123.14, 154.71, 158.38 and
118.16 (C1, C2, C3, C4, C5
and C6 of Ar, respectively)
14.18 (C of CH3), 48.39 (C of
CH3 in pyrrole), 85.38 (C6 of
triazolo thiadiazole), 156.29,
131.52, 117.36 and 153.20
(C2, C3, C4 and C5 of Ar,
respectively), 149.11, 121.75,
121.19 and 137.40 (C2, C3,
C4 and C5 of pyrrole,
16c
3345 (NH stretching), 3072 (aromatic
CH stretching), 1616 (C]N stretching),
1587, 1549, 1480 (C]C ring stretch),
1264 (asymmetric CeOeC stretching),
1022 (symmetric CeOeC stretching),
2965, 2850 (methyl CH stretch)
7.14, 7.7 (2d, 2H, C-4 and C-5 of
Ar), 7.00 (d, 1H, C-50 of pyrrole),
6.82 (m, 1H, C-40 of pyrrole), 6.64
(d, 1H, C-30 of pyrrole), 5.50 (s, 1H,
of CHeNH), 6.16 (s, 1H of NH of
NHeCH), 3.60 (s, 3H of NeCH3),
1.92 (s, 3H, CH3 of Ar)
349 Mþ
respectively)
4. Experimental section
performed using Thermo Finnigan FLASH EA 1112 CHNS
analyser. The purity of the compounds was checked on silica
gel-G coated plates by using ethyl acetate and petroleum ether
(1:1) as the eluent and observed under UV light. All the synthe-
sized compounds gave satisfactory elemental analyses.
Thin layer chromatography was used to reach the comple-
tion of the reaction and purity of the compounds synthesized.
Melting points were determined in open glass capillary tubes
using thiels tube containing liquid paraffin and were uncor-
rected. IR spectra were obtained in KBr discs on a Shimadzu-
8400 FTIR spectrophotometer, 1H NMR spectra were recorded
on Brucker spectrophotometer (400 MHz) in DMSO-d6/CDCl3
using TMS as an internal standard, mass spectra were recorded
on Finnigan MAT 8230 mass spectrophotometer, 13C NMR
spectra were recorded on Brucker spectrophotometer
(100 MHz) in DMSO-d6/CDCl3 and elemental analyses were
5. Materials and methods
5.1. General procedure for the preparation of aryl
hydrazide (1)
To the methyl/ethyl esters of substituted aromatic acids
(0.1 M), hydrazine hydrate (0.1 M) was added and refluxed
the solution for 30 min. Ethanol (20 ml) was added to the

836
V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
Table 7
Antifungal activities of compoundsa (3e16)
Compound
Candida albicans
Aspergillus niger
10 (mg/ml) ꢂ SDb
20 (mg/ml) ꢂ SDb
30 (mg/ml) ꢂ SDb
10 (mg/ml) ꢂ SDb
20 (mg/ml) ꢂ SDb
30 (mg/ml) ꢂ SDb
3a
3b
2.33 ꢂ 0.58
2.76 ꢂ 0.58
3.00 ꢂ 0.00
5.64 ꢂ 1.16
5.82 ꢂ 0.58
6.27 ꢂ 0.58
6.18 ꢂ 1.16
5.48 ꢂ 0.58
5.84 ꢂ 0.53
6.48 ꢂ 0.58
6.14 ꢂ 0.58
5.78 ꢂ 0.58
4.14 ꢂ 0.58
3.82 ꢂ 0.58
5.34 ꢂ 0.58
7.14 ꢂ 0.47
6.82 ꢂ 0.58
7.26 ꢂ 0.58
7.68 ꢂ 0.58
8.14 ꢂ 0.47
8.82 ꢂ 0.58
5.44 ꢂ 0.58
4.12 ꢂ 0.58
5.62 ꢂ 0.58
4.35 ꢂ 0.58
4.62 ꢂ 0.58
5.04 ꢂ 0.58
5.86 ꢂ 0.58
4.10 ꢂ 0.58
5.38 ꢂ 0.58
5.19 ꢂ 0.61
5.48 ꢂ 0.58
5.41 ꢂ 0.58
5.58 ꢂ 1.73
5.43 ꢂ 0.58
5.89 ꢂ 0.47
4.61 ꢂ 0.47
4.70 ꢂ 1.16
5.24 ꢂ 0.47
4.30 ꢂ 1.16
4.18 ꢂ 0.61
4.50 ꢂ 0.58
e
5.18 ꢂ 1.53
5.14 ꢂ 1.16
6.82 ꢂ 1.73
12.84 ꢂ 1.73
11.37 ꢂ 0.58
14.84 ꢂ 1.16
13.82 ꢂ 0.58
12.00 ꢂ 1.00
12.62 ꢂ 0.58
13.92 ꢂ 1.73
13.66 ꢂ 0.47
11.00 ꢂ 1.00
7.15 ꢂ 0.58
6.82 ꢂ 0.61
10.00 ꢂ 2.00
13.72 ꢂ 0.58
12.88 ꢂ 0.61
14.00 ꢂ 2.00
14.46 ꢂ 1.16
14.75 ꢂ 0.58
16.58 ꢂ 0.58
9.20 ꢂ 0.58
8.30 ꢂ 0.47
10.83 ꢂ 0.61
8.72 ꢂ 1.16
8.02 ꢂ 2.08
9.86 ꢂ 1.16
9.48 ꢂ 1.63
7.46 ꢂ 0.47
9.30 ꢂ 0.27
10.26 ꢂ 1.73
10.41 ꢂ 1.16
10.96 ꢂ 0.61
11.26 ꢂ 0.61
10.92 ꢂ 1.16
11.14 ꢂ 0.27
8.82 ꢂ 0.29
8.12 ꢂ 0.53
9.16 ꢂ 1.73
7.40 ꢂ 1.73
7.10 ꢂ 1.16
8.06 ꢂ 0.61
e
9.79 ꢂ 0.47
11.00 ꢂ 1.00
12.44 ꢂ 1.53
18.78 ꢂ 1.53
17.95 ꢂ 1.73
19.36 ꢂ 1.53
18.75 ꢂ 0.61
17.48 ꢂ 1.53
19.00 ꢂ 1.00
18.00 ꢂ 1.00
17.82 ꢂ 0.27
19.24 ꢂ 1.53
15.00 ꢂ 1.00
13.88 ꢂ 1.53
17.28 ꢂ 1.53
19.28 ꢂ 0.47
19.36 ꢂ 0.61
21.86 ꢂ 1.53
21.68 ꢂ 1.16
21.72 ꢂ 1.53
23.76 ꢂ 1.53
11.16 ꢂ 1.16
10.00 ꢂ 2.00
13.46 ꢂ 1.53
11.72 ꢂ 1.16
12.10 ꢂ 1.16
13.14 ꢂ 1.53
12.46 ꢂ 1.53
10.20 ꢂ 1.53
12.70 ꢂ 0.63
14.81 ꢂ 1.53
14.65 ꢂ 0.61
14.82 ꢂ 0.58
15.21 ꢂ 1.16
14.79 ꢂ 1.53
15.75 ꢂ 1.16
13.44 ꢂ 1.16
13.12 ꢂ 0.47
14.81 ꢂ 0.27
12.61 ꢂ 0.27
12.05 ꢂ 0.58
13.25 ꢂ 0.47
24.67 ꢂ 1.16
2.59 ꢂ 0.58
2.67 ꢂ 0.53
3.27 ꢂ 0.58
6.04 ꢂ 0.58
6.14 ꢂ 0.58
5.92 ꢂ 0.58
5.62 ꢂ 0.47
6.25 ꢂ 0.58
6.00 ꢂ 0.00
6.40 ꢂ 0.61
6.32 ꢂ 0.61
6.14 ꢂ 0.58
4.82 ꢂ 0.58
4.16 ꢂ 1.16
5.14 ꢂ 0.58
6.64 ꢂ 0.58
7.23 ꢂ 0.58
7.38 ꢂ 0.27
6.68 ꢂ 0.58
7.14 ꢂ 0.58
7.36 ꢂ 0.58
5.38 ꢂ 1.73
4.24 ꢂ 0.47
5.06 ꢂ 0.58
4.56 ꢂ 2.08
4.90 ꢂ 0.58
5.14 ꢂ 0.58
5.10 ꢂ 0.58
5.24 ꢂ 0.58
5.60 ꢂ 0.58
5.16 ꢂ 0.47
4.80 ꢂ 0.58
5.21 ꢂ 0.58
5.32 ꢂ 0.53
5.21 ꢂ 0.47
5.48 ꢂ 0.58
4.89 ꢂ 0.61
4.68 ꢂ 0.61
5.10 ꢂ 0.58
4.71 ꢂ 0.61
4.35 ꢂ 0.47
4.93 ꢂ 0.53
e
5.02 ꢂ 0.53
4.92 ꢂ 0.58
6.94 ꢂ 0.61
11.63 ꢂ 0.58
11.54 ꢂ 1.16
11.00 ꢂ 2.00
12.62 ꢂ 0.58
13.00 ꢂ 1.00
13.46 ꢂ 0.58
12.85 ꢂ 0.58
13.00 ꢂ 2.00
12.00 ꢂ 1.00
8.06 ꢂ 0.47
7.84 ꢂ 1.16
8.48 ꢂ 0.58
11.84 ꢂ 1.73
13.00 ꢂ 0.00
14.26 ꢂ 0.58
12.57 ꢂ 0.58
12.44 ꢂ 0.58
13.00 ꢂ 0.00
10.12 ꢂ 0.61
8.10 ꢂ 0.58
9.80 ꢂ 0.61
8.24 ꢂ 1.16
7.58 ꢂ 1.16
9.06 ꢂ 0.63
10.12 ꢂ 0.27
9.62 ꢂ 0.27
8.74 ꢂ 0.61
7.13 ꢂ 0.58
6.96 ꢂ 0.47
8.12 ꢂ 1.16
9.72 ꢂ 0.61
9.64 ꢂ 0.61
10.42 ꢂ 0.47
9.17 ꢂ 0.47
9.12 ꢂ 0.27
9.42 ꢂ 0.61
7.65 ꢂ 0.58
7.90 ꢂ 0.61
8.08 ꢂ 0.61
e
11.04 ꢂ 0.61
10.67 ꢂ 1.53
13.48 ꢂ 0.58
17.58 ꢂ 1.16
16.72 ꢂ 1.53
17.67 ꢂ 0.58
18.54 ꢂ 0.27
16.72 ꢂ 0.27
17.42 ꢂ 1.16
19.10 ꢂ 1.53
18.00 ꢂ 0.00
19.62 ꢂ 0.58
13.62 ꢂ 1.16
11.88 ꢂ 1.16
14.84 ꢂ 0.58
18.42 ꢂ 1.16
18.38 ꢂ 0.27
20.66 ꢂ 0.58
20.48 ꢂ 1.73
20.96 ꢂ 0.58
22.66 ꢂ 0.58
12.16 ꢂ 0.61
10.36 ꢂ 1.53
13.10 ꢂ 0.58
12.26 ꢂ 2.08
10.78 ꢂ 1.53
12.40 ꢂ 0.58
12.94 ꢂ 0.47
11.12 ꢂ 0.58
13.16 ꢂ 1.16
13.14 ꢂ 0.61
12.28 ꢂ 0.58
14.19 ꢂ 0.58
14.46 ꢂ 1.53
14.32 ꢂ 0.58
15.32 ꢂ 0.58
12.31 ꢂ 0.27
12.15 ꢂ 0.53
13.15 ꢂ 0.47
12.88 ꢂ 0.47
12.62 ꢂ 0.58
13.71 ꢂ 0.53
23.14 ꢂ 0.17
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
14b
14c
15a
15b
15c
16a
16b
16c
Griseofulvin
a
Zone of inhibition in millimeter.
b
SD ¼ standard deviation.
refluxing mixture as a solvent in order to homogenise solution.
The resulting mixture was further allowed to reflux for 6 h. Ex-
cess ethanol was distilled out and the contents were allowed to
cool. The crystals formed were filtered, washed thoroughly
with water and dried. The completion of the reaction was mon-
itored on TLC by using silica gel-G coated plates by using
ethyl acetate and petroleum ether (1:1) as the eluent and
observed under UV light.
refluxed for about 5 h till evolution of hydrogen sulfide was
ceased. The reaction mixture was cooled at room temperature
and diluted with water. On acidification with dilute hydro-
chloric acid, the required oxadiazole was precipitated. It was
filtered, thoroughly washed with cold water and recrystallised
from ethanol.
5.3. General procedure for the preparation of
3-substituted-4-amino-5-mercapto-1,2,4-triazole 3aec
5.2. General procedure for the preparation of 2-aryl
substituted-5-mercapto-1,3,4-oxadiazole (2)
A mixture of 2 (0.1 M) and hydrazine hydrate (0.1 M) in
dry pyridine (15 ml) was refluxed for about 4 h. The reaction
mixture was cooled at room temperature and was neutralized
with dilute hydrochloric acid. The solid obtained was filtered,
To a solution of 1 (0.1 M) in ethanol (30 ml), KOH (0.1 M)
in absolute ethanol (50 ml) and CS2 (0.2 M) were added and

Table 8
Antibacterial activity of compoundsa (3e16)
Compound
Escherichia coli
Pseudomonas aeruginosa
Bacillus subtilis
Staphylococcus aureus
10 (mg/ml)
ꢂ SDb
20 (mg/ml)
ꢂ SDb
30 (mg/ml)
ꢂ SDb
10 (mg/ml)
ꢂ SDb
20 (mg/ml)
ꢂ SDb
30 (mg/ml)
ꢂ SDb
10 (mg/ml)
ꢂ SDb
20 (mg/ml)
ꢂ SDb
30 (mg/ml)
ꢂ SDb
10 (mg/ml)
ꢂ SDb
20 (mg/ml)
ꢂ SDb
30 (mg/ml)
ꢂ SDb
3a
3b
5.08 ꢂ 0.26
4.86 ꢂ 1.16
6.74 ꢂ 1.16
7.16 ꢂ 0.58
9.17 ꢂ 0.45 5.23 ꢂ 0.26
7.26 ꢂ 1.16
9.10 ꢂ 2.09 4.25 ꢂ 0.61
7.05 ꢂ 0.58 10.11 ꢂ 1.53 5.16 ꢂ 0.58
7.26 ꢂ 0.61 9.83 ꢂ 1.16 4.72 ꢂ 0.47
8.94 ꢂ 1.53 11.21 ꢂ 1.53 5.46 ꢂ 1.16
7.28 ꢂ 0.17
9.06 ꢂ 0.58
7.58 ꢂ 0.58 10.06 ꢂ 0.58 5.06 ꢂ 1.16
9.16 ꢂ 1.53 12.85 ꢂ 2.09 6.12 ꢂ 0.58
6.76 ꢂ 0.26
8.24 ꢂ 0.58 5.06 ꢂ 0.45
7.14 ꢂ 0.58
9.52 ꢂ 0.61
3c
4a
9.16 ꢂ 0.47 12.78 ꢂ 0.61 5.80 ꢂ 0.26
8.16 ꢂ 2.09 11.26 ꢂ 1.53
6.86 ꢂ 1.73 11.72 ꢂ 2.52 16.52 ꢂ 2.65 6.72 ꢂ 1.16 11.38 ꢂ 0.61 15.49 ꢂ 0.58 6.82 ꢂ 0.47
6.08 ꢂ 1.73 11.28 ꢂ 2.52 16.86 ꢂ 2.89 5.92 ꢂ 1.16 10.85 ꢂ 1.53 16.04 ꢂ 0.58 5.76 ꢂ 1.71
7.64 ꢂ 1.16 13.18 ꢂ 0.58 17.36 ꢂ 1.53 7.12 ꢂ 0.26 12.04 ꢂ 0.58 17.26 ꢂ 1.16 6.16 ꢂ 2.09
11.15 ꢂ 1.16 16.16 ꢂ 1.53 5.82 ꢂ 0.45 10.12 ꢂ 0.61 16.36 ꢂ 0.37
10.24 ꢂ 0.61 15.92 ꢂ 0.45 5.12 ꢂ 0.58 10.26 ꢂ 0.17 16.74 ꢂ 1.16
11.84 ꢂ 0.58 16.86 ꢂ 2.89 6.18 ꢂ 0.26 12.69 ꢂ 0.58 17.48 ꢂ 2.09
11.10 ꢂ 0.58 16.38 ꢂ 1.73 6.89 ꢂ 0.58 12.06 ꢂ 0.61 16.10 ꢂ 0.26
10.18 ꢂ 1.73 16.12 ꢂ 0.45 6.72 ꢂ 0.17 11.68 ꢂ 1.16 16.60 ꢂ 0.26
12.48 ꢂ 0.45 17.10 ꢂ 1.53 7.10 ꢂ 0.61 13.73 ꢂ 0.58 17.92 ꢂ 0.61
13.06 ꢂ 0.45 18.80 ꢂ 1.71 7.21 ꢂ 0.58 13.19 ꢂ 1.16 18.12 ꢂ 0.58
13.26 ꢂ 1.16 18.66 ꢂ 1.53 6.96 ꢂ 0.58 12.61 ꢂ 1.16 18.27 ꢂ 0.26
14.10 ꢂ 0.58 19.79 ꢂ 1.16 8.16 ꢂ 0.26 14.10 ꢂ 0.58 19.12 ꢂ 1.16
4b
4c
5a
5b
5.16 ꢂ 0.58
5.25 ꢂ 1.16
9.12 ꢂ 0.58 16.67 ꢂ 1.53 5.31 ꢂ 0.45 10.26 ꢂ 0.58 16.11 ꢂ 1.16 7.06 ꢂ 1.16
8.80 ꢂ 0.47 16.00 ꢂ 0.00 5.26 ꢂ 0.58 10.12 ꢂ 1.16 16.05 ꢂ 2.09 6.29 ꢂ 1.16
5c
6a
6.28 ꢂ 0.58 10.48 ꢂ 1.16 17.00 ꢂ 2.00 6.00 ꢂ 1.00 11.84 ꢂ 1.53 16.82 ꢂ 0.45 7.38 ꢂ 2.09
8.28 ꢂ 0.58 14.48 ꢂ 1.16 18.78 ꢂ 0.58 7.82 ꢂ 2.09 13.27 ꢂ 0.17 18.71 ꢂ 0.58 7.68 ꢂ 1.53
7.85 ꢂ 0.26 14.36 ꢂ 0.58 18.64 ꢂ 1.16 7.70 ꢂ 1.16 14.10 ꢂ 0.58 18.16 ꢂ 1.73 7.40 ꢂ 1.53
8.74 ꢂ 0.17 15.27 ꢂ 0.58 19.41 ꢂ 1.16 8.17 ꢂ 1.16 14.15 ꢂ 2.09 19.10 ꢂ 0.58 8.14 ꢂ 1.16
6b
6c
7a
7b
4.18 ꢂ 2.09
4.26 ꢂ 0.45
5.38 ꢂ 0.47
8.00 ꢂ 2.00 13.15 ꢂ 0.58 4.84 ꢂ 0.26
8.10 ꢂ 0.58 13.27 ꢂ 1.16 4.63 ꢂ 1.16
8.79 ꢂ 0.58 14.10 ꢂ 1.16 5.95 ꢂ 1.16
9.06 ꢂ 1.16 13.28 ꢂ 0.58 4.70 ꢂ 1.53
8.90 ꢂ 0.17 13.10 ꢂ 1.73 4.58 ꢂ 1.16
9.81 ꢂ 1.53 14.23 ꢂ 0.58 6.02 ꢂ 1.16
8.38 ꢂ 0.58 13.78 ꢂ 1.16 4.57 ꢂ 0.58
8.12 ꢂ 0.17 13.89 ꢂ 1.53 4.61 ꢂ 0.58
8.82 ꢂ 1.16 13.70 ꢂ 0.26
8.93 ꢂ 0.63 13.87 ꢂ 0.26
7c
8a
10.41 ꢂ 0.58 14.85 ꢂ 2.62 6.07 ꢂ 0.58 10.80 ꢂ 1.76 14.51 ꢂ 0.45
13.84 ꢂ 0.17 18.63 ꢂ 0.63 6.98 ꢂ 0.26 13.70 ꢂ 1.16 18.58 ꢂ 1.53
13.92 ꢂ 1.53 18.91 ꢂ 1.53 7.05 ꢂ 0.37 13.61 ꢂ 0.26 18.14 ꢂ 1.16
14.55 ꢂ 0.17 20.38 ꢂ 0.47 7.82 ꢂ 2.09 14.66 ꢂ 0.45 19.23 ꢂ 1.53
14.12 ꢂ 0.58 19.16 ꢂ 0.63 7.29 ꢂ 0.45 14.11 ꢂ 1.16 19.25 ꢂ 0.61
14.38 ꢂ 2.09 19.26 ꢂ 1.53 7.10 ꢂ 0.17 13.85 ꢂ 1.71 19.19 ꢂ 0.58
14.76 ꢂ 0.58 19.86 ꢂ 1.16 7.90 ꢂ 0.58 14.18 ꢂ 0.58 20.17 ꢂ 0.47
6.39 ꢂ 0.61 12.23 ꢂ 1.16 19.21 ꢂ 2.09 7.02 ꢂ 0.45 12.48 ꢂ 0.58 19.11 ꢂ 0.61 7.12 ꢂ 1.53
6.72 ꢂ 0.26 12.82 ꢂ 0.58 19.67 ꢂ 1.16 6.93 ꢂ 2.09 12.19 ꢂ 0.58 19.39 ꢂ 1.73 7.19 ꢂ 1.16
7.48 ꢂ 0.47 14.78 ꢂ 0.58 20.19 ꢂ 1.16 7.79 ꢂ 0.26 13.78 ꢂ 0.45 20.59 ꢂ 0.61 7.82 ꢂ 1.16
8.10 ꢂ 2.09 14.65 ꢂ 1.16 19.67 ꢂ 0.47 8.68 ꢂ 1.16 14.92 ꢂ 2.09 19.52 ꢂ 0.26 7.78 ꢂ 1.53
7.96 ꢂ 0.17 14.39 ꢂ 0.45 19.29 ꢂ 1.16 8.21 ꢂ 1.53 14.88 ꢂ 0.58 19.26 ꢂ 1.73 7.64 ꢂ 1.16
8.54 ꢂ 1.71 14.27 ꢂ 0.58 20.79 ꢂ 1.16 8.39 ꢂ 1.16 15.21 ꢂ 0.26 21.29 ꢂ 0.58 8.12 ꢂ 1.16
8b
8c
9a
9b
9c
10a
5.10 ꢂ 0.58
4.72 ꢂ 0.45
5.16 ꢂ 0.61
4.26 ꢂ 0.26
4.48 ꢂ 0.58
5.12 ꢂ 0.47
4.78 ꢂ 0.26
4.90 ꢂ 0.17
5.78 ꢂ 0.61
4.12 ꢂ 0.58
4.29 ꢂ 0.47
4.82 ꢂ 0.58
8.39 ꢂ 0.47 13.15 ꢂ 0.17 4.83 ꢂ 0.61
8.49 ꢂ 1.71 12.90 ꢂ 1.16 4.90 ꢂ 1.16
9.35 ꢂ 0.58 14.16 ꢂ 1.16 5.36 ꢂ 1.16
7.28 ꢂ 0.47 12.28 ꢂ 0.61 4.15 ꢂ 0.17
7.42 ꢂ 0.58 12.36 ꢂ 1.16 4.04 ꢂ 1.16
9.10 ꢂ 0.58 13.84 ꢂ 1.16 4.92 ꢂ 1.53
8.12 ꢂ 1.16 12.39 ꢂ 0.58 4.12 ꢂ 0.58
8.22 ꢂ 2.09 12.52 ꢂ 1.16 4.25 ꢂ 1.73
9.18 ꢂ 0.58 13.62 ꢂ 1.16 4.85 ꢂ 1.73
7.39 ꢂ 0.45 14.37 ꢂ 0.61 4.82 ꢂ 0.58
7.49 ꢂ 1.16 14.25 ꢂ 0.26 3.73 ꢂ 1.53
9.18 ꢂ 2.09 12.80 ꢂ 0.26 4.76 ꢂ 1.53
8.42 ꢂ 0.58 12.27 ꢂ 1.73 4.92 ꢂ 1.16
9.62 ꢂ 0.58 14.49 ꢂ 0.58 5.82 ꢂ 1.16
7.92 ꢂ 2.09 12.37 ꢂ 0.58 4.12 ꢂ 1.53
7.42 ꢂ 0.58 12.62 ꢂ 1.73 4.07 ꢂ 2.09
8.14 ꢂ 0.45 14.62 ꢂ 0.61 4.60 ꢂ 1.16
8.16 ꢂ 0.61 12.19 ꢂ 2.09 4.33 ꢂ 1.53
8.23 ꢂ 0.58 12.37 ꢂ 1.73 4.33 ꢂ 1.16
8.90 ꢂ 0.58 13.48 ꢂ 0.45 5.67 ꢂ 1.16
8.95 ꢂ 0.45 14.15 ꢂ 1.16 4.39 ꢂ 0.178
7.11 ꢂ 0.26 12.68 ꢂ 0.17 3.80 ꢂ 1.16
8.79 ꢂ 0.58 13.17 ꢂ 1.16 4.58 ꢂ 0.63
8.18 ꢂ 1.16 13.65 ꢂ 1.53 4.82 ꢂ 2.09
9.61 ꢂ 0.58 14.15 ꢂ 0.61 4.85 ꢂ 0.58
7.18 ꢂ 0.47 11.91 ꢂ 0.47 4.17 ꢂ 0.61
7.21 ꢂ 1.16 12.28 ꢂ 1.53 4.06 ꢂ 0.71
8.38 ꢂ 0.58 13.25 ꢂ 2.00 4.89 ꢂ 0.58
7.60 ꢂ 0.45 12.29 ꢂ 1.16 4.80 ꢂ 0.47
7.32 ꢂ 1.16 12.67 ꢂ 1.53 4.59 ꢂ 0.45
8.75 ꢂ 2.09 13.79 ꢂ 0.61 5.12 ꢂ 0.58
7.68 ꢂ 0.47 13.57 ꢂ 1.53 4.82 ꢂ 0.61
6.65 ꢂ 1.16 12.16 ꢂ 1.73 3.70 ꢂ 0.58
8.52 ꢂ 1.16 13.72 ꢂ 0.58
8.39 ꢂ 0.61 13.60 ꢂ 0.17
9.10 ꢂ 0.58 13.27 ꢂ 0.47
8.12 ꢂ 1.16 12.12 ꢂ 0.17
8.08 ꢂ 0.45 12.02 ꢂ 0.17
9.12 ꢂ 2.09 13.29 ꢂ 1.53
7.59 ꢂ 1.16 12.58 ꢂ 0.58
7.38 ꢂ 0.61 12.18 ꢂ 0.26
8.19 ꢂ 0.17 13.49 ꢂ 0.47
8.61 ꢂ 0.47 14.12 ꢂ 0.17
7.31 ꢂ 0.63 11.81 ꢂ 0.58
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
8.04 ꢂ 0.63 15.16 ꢂ 1.16 6.67 ꢂ 1.53 12.33 ꢂ 0.58 17.67 ꢂ 1.16 5.33 ꢂ 0.47
10.67 ꢂ 1.53 11.33 ꢂ 2.09 6.67 ꢂ 1.73 12.33 ꢂ 0.61 13.33 ꢂ 0.58
5.21 ꢂ 0.58 10.11 ꢂ 0.58 15.12 ꢂ 1.53 4.88 ꢂ 0.58
5.16 ꢂ 1.71 10.03 ꢂ 1.16 14.96 ꢂ 1.16 4.42 ꢂ 1.53
7.36 ꢂ 0.58 13.21 ꢂ 1.73 5.12 ꢂ 0.58
7.88 ꢂ 0.58 13.13 ꢂ 0.45 4.92 ꢂ 1.16
8.71 ꢂ 1.73 13.61 ꢂ 1.53 5.20 ꢂ 1.73
8.49 ꢂ 1.53 13.50 ꢂ 1.73 5.10 ꢂ 0.47
8.82 ꢂ 0.58 14.21 ꢂ 0.58
8.37 ꢂ 0.61 14.02 ꢂ 0.58
14b
14c
5.78 ꢂ 0.58 11.02 ꢂ 0.47 16.85 ꢂ 1.16 6.12 ꢂ 1.73 11.82 ꢂ 0.58 17.14 ꢂ 1.16 6.25 ꢂ 2.09
11.52 ꢂ 1.73 17.23 ꢂ 0.47 6.11 ꢂ 0.75 11.51 ꢂ 0.61 17.48 ꢂ 1.16
15a
15b
4.71 ꢂ 0.47
4.48 ꢂ 1.53
5.11 ꢂ 0.58
3.82 ꢂ 0.26
3.95 ꢂ 1.79
4.11 ꢂ 0.58
e
7.90 ꢂ 0.58 14.27 ꢂ 1.73 1.33 ꢂ 0.58
4.33 ꢂ 0.58
8.00 ꢂ 0.00 1.67 ꢂ 0.58
4.00 ꢂ 0.00
8.33 ꢂ 1.53 1.33 ꢂ 0.61
4.33 ꢂ 0.47
8.33 ꢂ 0.45
7.18 ꢂ 2.09 14.18 ꢂ 1.16 7.33 ꢂ 1.53 11.66 ꢂ 0.58 13.30 ꢂ 0.58 4.32 ꢂ 1.16
8.42 ꢂ 0.26 15.65 ꢂ 1.16 6.67 ꢂ 0.63 12.33 ꢂ 0.26 14.67 ꢂ 1.16 5.33 ꢂ 0.58
8.32 ꢂ 1.16 12.00 ꢂ 1.73 4.02 ꢂ 0.61
10.67 ꢂ 0.37 16.33 ꢂ 0.45 4.60 ꢂ 2.09
7.64 ꢂ 0.47 10.60 ꢂ 0.58
8.12 ꢂ 0.61 12.26 ꢂ 0.17
6.10 ꢂ 2.09 11.04 ꢂ 0.26
5.92 ꢂ 0.61 10.61 ꢂ 0.47
6.23 ꢂ 0.61 11.19 ꢂ 0.58
15c
16a
6.90 ꢂ 0.58 10.12 ꢂ 0.47 3.90 ꢂ 0.45
6.71 ꢂ 1.16 10.17 ꢂ 1.16 4.12 ꢂ 1.53
7.19 ꢂ 0.47 12.10 ꢂ 1.16 4.36 ꢂ 0.61
7.10 ꢂ 0.17 11.90 ꢂ 1.73 3.60 ꢂ 0.58
7.48 ꢂ 0.26 11.39 ꢂ 0.58 3.30 ꢂ 1.16
7.90 ꢂ 0.58 13.18 ꢂ 1.16 4.52 ꢂ 0.58
6.82 ꢂ 0.47
6.30 ꢂ 2.09
9.33 ꢂ 1.53 3.82 ꢂ 0.47
9.12 ꢂ 1.73 3.74 ꢂ 0.61
16b
16c
7.48 ꢂ 1.53 11.38 ꢂ 0.47 4.42 ꢂ 0.26
Chloramphenicol
Chloramphenicol
e
e
e
e
e
e
e
e
e
e
e
e
24.61 ꢂ 0.27
e
e
e
26.12 ꢂ 0.17
e
23.67 ꢂ 0.47
25.39 ꢂ 1.73
e
e
e
a
Zone of inhibition in millimeter.
SD ¼ standard deviation.
b

838
V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
Table 9
Anti-inflammatory activity of compounds (4e16)
Compound
Change in paw volume (in ml) after (ꢂSE)a
Percentage inhibition of oedema volume after
1 h
2 h
3 h
4 h
1 h
2 h
3 h
4 h
4a
4b
0.64 ꢂ 0.02
0.61 ꢂ 0.03
0.70 ꢂ 0.02
0.61 ꢂ 0.03
0.53 ꢂ 0.03
0.54 ꢂ 0.02
0.80 ꢂ 0.02
0.68 ꢂ 0.02
0.70 ꢂ 0.02
0.73 ꢂ 0.03
0.72 ꢂ 0.02
0.75 ꢂ 0.03
0.46 ꢂ 0.02
0.56 ꢂ 0.02
0.53 ꢂ 0.03
0.73 ꢂ 0.03
0.80 ꢂ 0.02
0.75 ꢂ 0.05
0.74 ꢂ 0.02
0.73 ꢂ 0.03
0.62 ꢂ 0.02
0.60 ꢂ 0.04
0.70 ꢂ 0.02
0.68 ꢂ 0.02
0.70 ꢂ 0.04
0.68 ꢂ 0.02
0.62 ꢂ 0.02
0.77 ꢂ 0.03
0.79 ꢂ 0.03
0.71 ꢂ 0.03
0.76 ꢂ 0.02
0.77 ꢂ 0.03
0.76 ꢂ 0.04
0.78 ꢂ 0.04
0.78 ꢂ 0.02
0.78 ꢂ 0.02
0.77 ꢂ 0.05
0.78 ꢂ 0.02
0.77 ꢂ 0.03
0.72 ꢂ 0.02
0.95 ꢂ 0.03
0.97 ꢂ 0.03
1.00 ꢂ 0.00
0.83 ꢂ 0.03
0.77 ꢂ 0.01
0.80 ꢂ 0.02
1.10 ꢂ 0.04
0.97 ꢂ 0.03
0.97 ꢂ 0.03
1.00 ꢂ 0.00
1.02 ꢂ 0.04
1.03 ꢂ 0.03
0.72 ꢂ 0.04
1.00 ꢂ 0.00
0.77 ꢂ 0.03
0.97 ꢂ 0.03
1.10 ꢂ 0.04
1.05 ꢂ 0.03
1.05 ꢂ 0.07
1.12 ꢂ 0.02
0.84 ꢂ 0.02
0.90 ꢂ 0.02
0.98 ꢂ 0.04
0.94 ꢂ 0.02
0.98 ꢂ 0.02
0.90 ꢂ 0.05
0.78 ꢂ 0.06
0.91 ꢂ 0.03
0.92 ꢂ 0.02
0.88 ꢂ 0.02
0.91 ꢂ 0.03
0.92 ꢂ 0.02
0.92 ꢂ 0.02
0.95 ꢂ 0.03
0.94 ꢂ 0.02
0.92 ꢂ 0.02
0.93 ꢂ 0.07
0.94 ꢂ 0.02
0.91 ꢂ 0.03
0.92 ꢂ 0.02
1.06 ꢂ 0.04
1.33 ꢂ 0.01
1.41 ꢂ 0.03
1.10 ꢂ 0.02
1.15 ꢂ 0.03
1.14 ꢂ 0.02
1.47 ꢂ 0.03
1.42 ꢂ 0.02
1.40 ꢂ 0.04
1.38 ꢂ 0.04
1.45 ꢂ 0.03
1.53 ꢂ 0.03
1.05 ꢂ 0.03
1.28 ꢂ 0.04
1.05 ꢂ 0.03
1.33 ꢂ 0.03
1.50 ꢂ 0.04
1.43 ꢂ 0.03
1.36 ꢂ 0.02
1.24 ꢂ 0.02
1.04 ꢂ 0.06
1.10 ꢂ 0.02
1.16 ꢂ 0.02
1.08 ꢂ 0.02
1.14 ꢂ 0.04
1.10 ꢂ 0.02
1.14 ꢂ 0.02
1.25 ꢂ 0.05
1.26 ꢂ 0.04
1.23 ꢂ 0.07
1.27 ꢂ 0.03
1.27 ꢂ 0.05
1.25 ꢂ 0.03
1.32 ꢂ 0.04
1.33 ꢂ 0.03
1.29 ꢂ 0.03
1.32 ꢂ 0.02
1.30 ꢂ 0.05
1.27 ꢂ 0.05
0.97 ꢂ 0.03
1.65 ꢂ 0.01
1.60 ꢂ 0.02
1.66 ꢂ 0.02
1.48 ꢂ 0.04
1.48 ꢂ 0.02
1.42 ꢂ 0.02
1.78 ꢂ 0.04
1.55 ꢂ 0.05
1.58 ꢂ 0.04
1.58 ꢂ 0.02
1.53 ꢂ 0.05
1.78 ꢂ 0.02
1.56 ꢂ 0.04
1.64 ꢂ 0.02
1.43 ꢂ 0.03
1.62 ꢂ 0.02
1.77 ꢂ 0.03
1.70 ꢂ 0.04
1.46 ꢂ 0.02
1.42 ꢂ 0.04
1.26 ꢂ 0.02
1.18 ꢂ 0.02
1.38 ꢂ 0.02
1.16 ꢂ 0.04
1.26 ꢂ 0.04
1.32 ꢂ 0.04
1.36 ꢂ 0.02
1.67 ꢂ 0.03
1.70 ꢂ 0.04
1.67 ꢂ 0.05
1.71 ꢂ 0.03
1.72 ꢂ 0.02
1.69 ꢂ 0.03
1.79 ꢂ 0.05
1.79 ꢂ 0.07
1.74 ꢂ 0.04
1.79 ꢂ 0.03
1.80 ꢂ 0.04
1.75 ꢂ 0.03
1.00 ꢂ 0.00
11.64
12.35
11.76
08.68
10.16
07.23
11.11
14.62
12.50
08.35
10.54
06.25
14.42
11.16
10.06
18.52
11.11
16.66
6.10
17.24
18.68
14.46
20.18
13.25
13.44
14.26
17.15
17.09
14.23
12.86
11.40
20.15
13.25
15.34
24.65
14.26
18.16
14.38
11.60
20.10
20.03
16.16
24.82
16.48
26.78
21.54
18.7
20.12
20.17
16.45
24.07
21.22
18.61
18.55
19.08
20.28
20.97
17.14
16.47
23.48
22.50
24.12
25.94
16.66
20.38
21.35
19.14
26.14
26.05
21.42
29.40
21.35
28.32
26.52
23.1
24.46
22.21
24.45
27.45
24.86
26.34
20.88
24.79
23.37
23.37
20.79
21.69
27.24
24.18
27.10
28.13
21.46
24.44
33.87**
29.62*
30.82*
32.66**
28.42*
31.16**
34.68**
28.48*
30.02*
25.64
24.60
25.93
24.20
23.71
24.94
20.62
21.47
22.70
20.68
19.92
22.35
45.40***
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
14b
14c
15a
15b
15c
16a
16b
16c
Phenylbutazone
04.11
15.96
11.32
10.46
19.69
08.80
16.10
15.96
13.9
12.0
17.5
21.1
24.1
16.4**
15.6**
14.5*
15.6**
12.8*
13.2*
13.7*
14.1*
13.4*
14.6*
21.24***
21.6*
18.5
17.6
21.7
21.4
18.1
15.2
22.8
18.4
15.9
18.2
17.7
20.3
16.8
15.8
18.5
18.4
18.9
33.59***
21.5
40.81***
For all other comparisons P > 0.05.
* P < 0.05; ** P < 0.01; *** P < 0.001.
a
ꢂ Standard error.
thoroughly washed with cold water and recrystallised from
ethanol.
was raised to 8, to remove the excess of phosphorous
oxychloride. The mixture was allowed to stand overnight
and the solid was separated. It was filtered, washed thoroughly
with cold water, dried and recrystallised from a mixture of
DMF and ethanol. Similarly other compounds were synthe-
sized and characterized by various spectral studies.
5.4. Conventional procedure for the synthesis of 3-aryl/
aralkyl/heteroaryl-6-(2-substituted-4-quinolinyl)-1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazoles (4a)
An equimolar mixture of respective triazole (0.02 M) and
2-phenyl-quinoline-4-carboxylic acid (0.02 M) was dissolved
in 10 ml of dry phosphorous oxychloride. The resulted
solution was further heated under reflux for 7 h. The reaction
mixture was cooled to room temperature and the mixture was
gradually poured onto crushed ice with stirring. Finely pow-
dered potassium carbonate and the required amount of solid
potassium hydroxide were added till the pH of the mixture
5.5. Microwave method for the synthesis of
3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles
(Scheme 3)
A solution of 3aec (0.01 M) and respective aromatic acids in
phosphorous oxychloride was prepared. Acidic alumina was
added to the above solution at room temperature. The reaction
mixture was mixed, adsorbed, dried and kept inside the alumina

V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
839
Table 10
Analgesic activity of compounds (4e16)
Compound
Reaction time (s) after drug administration
Percent increase in reaction time
30 min ꢂ SEa
60 min ꢂ SEa
90 min ꢂ SEa
30 min
60 min
90 min
4a
4b
6.17 ꢂ 0.47
5.20 ꢂ 0.21
5.43 ꢂ 0.26
6.43 ꢂ 0.15
6.24 ꢂ 0.48
6.33 ꢂ 0.33
4.46 ꢂ 0.34
4.50 ꢂ 0.34
4.50 ꢂ 0.60
6.24 ꢂ 0.34
5.83 ꢂ 0.31
5.00 ꢂ 0.40
5.54 ꢂ 0.17
6.17 ꢂ 0.52
7.65 ꢂ 0.33
8.17 ꢂ 0.31
6.00 ꢂ 0.73
5.87 ꢂ 0.33
6.50 ꢂ 0.43
4.33 ꢂ 0.42
7.50 ꢂ 0.43
4.56 ꢂ 0.26
4.33 ꢂ 0.42
7.33 ꢂ 0.56
5.17 ꢂ 0.70
6.33 ꢂ 0.50
6.33 ꢂ 0.43
6.17 ꢂ 0.55
5.43 ꢂ 0.21
6.24 ꢂ 0.34
5.83 ꢂ 0.17
6.00 ꢂ 0.73
6.17 ꢂ 0.34
5.20 ꢂ 0.33
6.43 ꢂ 0.33
5.54 ꢂ 0.31
5.54 ꢂ 0.33
4.50 ꢂ 0.24
4.50 ꢂ 0.34
5.67 ꢂ 0.50
6.85 ꢂ 0.56
5.84 ꢂ 0.42
6.37 ꢂ 0.55
7.67 ꢂ 0.42
7.14 ꢂ 0.51
7.40 ꢂ 0.48
4.92 ꢂ 0.55
5.00 ꢂ 0.37
5.20 ꢂ 0.42
6.92 ꢂ 0.42
6.67 ꢂ 0.38
5.17 ꢂ 0.34
7.67 ꢂ 0.21
7.67 ꢂ 0.45
8.46 ꢂ 0.31
8.83 ꢂ 0.48
6.50 ꢂ 0.43
8.24 ꢂ 0.60
7.67 ꢂ 0.33
5.00 ꢂ 0.26
9.00 ꢂ 0.58
6.17 ꢂ 0.48
5.00 ꢂ 0.10
8.67 ꢂ 0.50
6.17 ꢂ 0.48
7.33 ꢂ 0.42
9.00 ꢂ 0.00
7.67 ꢂ 0.45
6.37 ꢂ 0.55
6.92 ꢂ 0.42
6.67 ꢂ 0.70
6.50 ꢂ 0.43
6.85 ꢂ 0.56
5.84 ꢂ 0.55
7.67 ꢂ 0.67
7.67 ꢂ 0.34
8.17 ꢂ 0.60
5.20 ꢂ 0.45
5.00 ꢂ 0.37
6.50 ꢂ 0.43
8.70 ꢂ 0.37
6.71 ꢂ 0.50
7.03 ꢂ 0.27
8.00 ꢂ 0.45
8.16 ꢂ 0.42
8.22 ꢂ 0.17
5.26 ꢂ 0.48
5.33 ꢂ 0.21
8.37 ꢂ 0.34
7.84 ꢂ 0.34
7.33 ꢂ 0.34
5.83 ꢂ 0.32
8.00 ꢂ 0.40
7.67 ꢂ 0.60
8.46 ꢂ 0.21
9.83 ꢂ 0.17
7.50 ꢂ 0.35
9.17 ꢂ 0.31
9.67 ꢂ 0.22
5.83 ꢂ 0.31
10.67 ꢂ 0.42
7.67 ꢂ 0.21
5.83 ꢂ 0.31
10.17 ꢂ 0.61
7.67 ꢂ 0.21
9.00 ꢂ 0.12
10.67 ꢂ 0.42
7.67 ꢂ 0.61
7.03 ꢂ 0.18
7.84 ꢂ 0.34
7.33 ꢂ 0.64
7.50 ꢂ 0.35
8.70 ꢂ 0.37
6.71 ꢂ 0.45
8.00 ꢂ 0.06
8.00 ꢂ 0.45
9.17 ꢂ 0.31
8.37 ꢂ 0.34
5.33 ꢂ 0.21
7.33 ꢂ 0.21
5.34
5.36
4.86
7.60
5.96
6.04
7.69
7.55
5.62
5.68
5.71
4.35
7.14
6.24
6.04
4.12
2.83
4.13
13.69
11.92
13.84
19.48
19.23
9.18
19.48
13.16
6.66
6.24
5.36
5.68
5.71
2.83
5.34
4.86
7.60
7.14
4.38
5.62
7.55
32.23***
15.68
17.26
14.48
12.65
11.05
11.35
17.24
16.80
10.24
15.18
14.10
11.45
17.45
12.55
11.35
11.35
10.30
6.20
26.85
25.11
21.10
21.06
20.14
20.34
23.84
21.96
19.24
26.14
23.45
19.35
23.00
23.89
20.34
20.34
22.66
16.43
31.48*
28.32*
31.86*
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
10a
10b
23.76
19.06
24.76
28.54*
27.82*
23.17
28.32*
25.00*
22.22
12.55
17.26
15.18
14.10
10.30
15.68
14.48
12.65
17.45
6.20
10c
11a
35.24**
29.04*
33.49**
34.24**
31.88*
35.33**
23.89
11b
11c
12a
12b
12c
13a
13b
13c
25.11
26.14
14a
14b
23.45
22.66
14c
15a
26.85
21.10
15b
15c
21.06
23.00
16a
16b
19.67
19.24
10.24
16.80
38.15***
16c
Diclofenac sodium
21.96
43.25***
For all other comparisons P > 0.05.
* P < 0.05; ** P < 0.01; *** P < 0.001.
a
Standard error.
bath and subjected to microwave irradiation intermittently at
30 s for 7e8 min. The mixture was cooled and then poured
onto crushed ice cubes. Finely powdered potassium carbonate
and the required amount of solid potassium hydroxide were
added till the pH of the mixture was raised to 8, to remove the
excess of phosphorous oxychloride. The solid thus separated
was filtered, washed thoroughly with cold water, dried and re-
crystallised from a mixture of DMF and ethanol (2:1).
acatalytic amount of p-toluenesulphonic acid (10 mg)was taken
in a round bottom flask. The mixture was refluxed for about
10e12 h, concentrated to half its volume and cooled to room
temperature. The cooled mixture was poured gradually onto
crushed ice cubes with stirring. The mixture was allowed to
stand and solid was separated. It was filtered, washed thoroughly
with cold water, dried and recrystallised from hot ethanol.
5.7. Microwave method for the synthesis of 5,6-dihydro-
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (Scheme 5)
5.6. Conventional procedure for the preparation of 5,6-
dihydro-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles 13e16
(aec) (Scheme 4)
A solution of 3aec (0.01 M), respective hetero aromatic
aldehyde (0.01 M) and p-toluenesulphonic acid (10 mg) in
dry DMF (30 ml) was prepared. The resulting solution was
adsorbed over 20 g of acidic alumina at room temperature.
An equimolecular mixture of substituted triazole (0.02 M)
and 2-furfuraldehyde (0.02 M) (13a), dry DMF (30 ml) and

840
V. Mathew et al. / European Journal of Medicinal Chemistry 42 (2007) 823e840
[9] R. Gupta, S. Sudan, P.L. Kachroo, Indian J. Chem. 23B (1984) 793.
[10] R. Gupta, Satya Paul, A.K. Gupta, P.L. Kachroo, S. Bani, Indian J. Chem.
37B (1998) 498.
The reaction mixture was mixed, dried and kept inside the alu-
mina bath and subjected to microwave irradiation at an inter-
val of 30 s for 6e7 min. The mixture was cooled and then the
product was extracted with dry toluene and cooled. The solid
thus separated was filtered, washed thoroughly with water and
recrystallised from ethanol.
[11] H.M. Hirpara, V.A. Sodha, A.M. Trivedi, B.L. Khatri, A.R. Parikh,
Indian J. Chem. 42B (2003) 1756.
[12] K.C. Joshi, S. Giri, J. Indian Chem. Soc. 40 (1963) 42.
[13] J. Haglind, Chem. Abstr. 64 (1966) 16509.
[14] M. Shiradkar, R. Kale, Indian J. Chem. 45B (2006) 1009.
[15] S.S. Joshi, A.V. Karnik, Indian J. Chem. 45B (2006) 1057.
[16] B.P. Nandeshwarappa, D.B. Aruna Kumar, H.S. Bhojya Naik,
V.P. Vaidya, K.M. Mahadevan, Indian J. Chem. 44B (2005) 2155.
[17] R. Gupta, A.K. Gupta, Satya Paul, Indian J. Chem. 39B (2000) 847.
[18] M. Kidwai, Y. Goel, K. Seema, J. Indian Chem. Soc. 76 (1999) 51.
[19] K. Mohammaed, H. Hilmy, Arch. Pharm. 15 (2004) 337.
[20] V.S. Dubey, V.N. Ingel, J. Indian Chem. Soc. 66 (1989) 174.
[21] A.R. Katritzky, C.W. ReesComprehensive Heterocyclic Chemistry, vol. 4
(1984) p. 992.
Acknowledgements
We gratefully acknowledge IISc (Bangalore), IIT (Chennai)
and STIC (Cochin) for the Spectral analysis. Also we are
thankful to the Chairman, Department of Chemistry, and Ku-
vempu University and to the Principal, Acharya & B.M.
Reddy College of Pharmacy for providing laboratory facilities.
[22] B. Vaitilingam, A. Nayyar, P.B. Palde, V. Monga, R. Jain, S. Kaur,
P.P. Singh, Bioorg. Med. Chem. 12 (2004) 4178.
References
[23] C. Benard, F. Zouhiri, M.N. Danet, D. Desmaele, H. Leh, J.F. Mouscadet,
G. Mbemba, C.M. Thomas, S. Bonnenfant, M.L. Bret, J. D’Angelo,
Bioorg. Med. Chem. Lett. 14 (2004) 2473.
[1] K. Colanceska-Ragenovic, V. Dimova1, V. Kakurinov, D. Labor,
A.B. Molnar, Molecules 6 (2001) 815.
[24] M.A. Quraishi, V.R. Thakur, S.N.Dhawan, IndianJ. Chem. 28B(1989)891.
[25] M. Bala, A. Naparzewska, W. Chojnacka, Pol. J. Pharmacol. Pharm. 38
(1986) 22; Chem. Abstr. 105 (1986) 164770.
[2] L. Labanauskas, E. Udrenaite, P. Gaidelis, A. Bruktus, IL Farmaco 59
(2004) 255.
[26] Norwich Pharmaceutical Co, Chem. Abstr. 65 (1966) 18567.
[27] Pfizer and Co, Chem. Abstr. 66 (1967) 115616.
[3] Y.A. Al-Soud, M.N. Al-Dweri, N.A. Al-Masoudi, IL Farmaco 59 (2004)
775.
[28] J.R. Reid, N.D. Heindel, J. Heterocycl. Chem. 13 (1976) 925.
[29] C.A. Winter, E.A. Risley, G.W. Nuss, Proc. Soc. Exp. Biol. Med. 111
(1962) 544.
[4] A. Foroumadi, M. Mirzaei, A. Shafiee, IL Farmaco 56 (2001) 621.
[5] S.K. Jain, P. Mishra, Indian J. Chem. 43B (2004) 184.
[6] S.N. Swamy, B.S. Basappa, P.B. Prabhuswamy, B.H. Doreswamy,
J.S. Prasad, K.S. Rangappa, Eur. J. Med. Chem. 41 (2006) 531.
[7] Z. Wang, T. You, Yu Xu, S. Haijian, S. Haoxin, Molecules 1 (1996) 68.
[8] R.H. Udupi, A. Kushnoor, A.R. Bhat, J. Indian Chem. Soc. 76 (1999)
461.
[30] S.K. Kulkarni, Handbook of Experimental Pharmacology, third ed.
Vallabh Publications, 1999 p. 128.
[31] N.B. Eddy, D.J. Leimbach, J. Pharmacol. Exp. Ther. (1953) 385.
[32] R.S. Verma, S.A. Imam, Indian J. Microbiol. 13 (1973) 45.