Synthesis and biological evaluation of novel Bis[1,2,4]triazolo[3,4-b] [1,3,4]oxadiazoles

Article abstract of DOI:10.1002/jhet.1528

A series of novel 6-2-methoxy-5-[4-methoxy-3-(3-aryl[1,2,4]triazolo[3,4-b] [1,3,4]oxadiazol-6-yl)benzyl]phenyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4] oxadiazoles 7a-j has been synthesized and characterized via IR, ¹H NMR, ¹³C NMR, MS, and elemental analyses. Compounds 7a-j were also screened for their antibacterial activity against Gram-positive bacteria viz. Bacillus subtilis (MTCC 441), Bacillus sphaericus (MTCC 11), and Staphylococcus aureus (MTCC 96), and Gram-negative bacteria viz. Pseudomonas aeruginosa (MTCC 741), Klobsinella aerogenes (MTCC 39), and Chromobacterium violaceum (MTCC 2656). The antibacterial screening reveal that the presence of 2,4-difluorophenyl (7e) or 4-nitrophenyl (7f) of 2-pyrazyl (7i), or 2-furyl (7j) on the triazole moiety exhibited potent inhibitory activity comparable with the standard drug streptomycin, at the tested concentrations, and emerged as potential molecules for further development.

Full text of DOI:10.1002/jhet.1528

Month 2013
Synthesis and Biological Evaluation of Novel Bis[1,2,4]triazolo[3,4-b]
[1,3,4]oxadiazoles
Ch. Sanjeeva Reddy,a,* M. Vani Devi,a G. Rajesh Kumar,a M. Sunitha,a and A. Nagarajb
aDepartment of Chemistry, Kakatiya University, Warangal 506 009, India
bDepartment of Pharmaceutical Chemistry, Telangana University, Nizamabad 503 175, India
*
E-mail: chsrkuc@yahoo.co.in
Received January 13, 2011
DOI 10.1002/jhet.1528
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
N
N
Ar
OMe
COOH
Ar
N
O
N
O
OH
HO
N
6 steps
N
N
N
COOH
MeO
7a-j
A series of novel 6-2-methoxy-5-[4-methoxy-3-(3-aryl[1,2,4]triazolo[3,4-b][1,3,4]oxadiazol-6-yl)benzyl]
phenyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4]oxadiazoles 7a–j has been synthesized and characterized via IR, 1H
NMR, 13C NMR, MS, and elemental analyses. Compounds 7a–j were also screened for their antibacterial
activity against Gram-positive bacteria viz. Bacillus subtilis (MTCC 441), Bacillus sphaericus (MTCC
11), and Staphylococcus aureus (MTCC 96), and Gram-negative bacteria viz. Pseudomonas aeruginosa
(MTCC 741), Klobsinella aerogenes (MTCC 39), and Chromobacterium violaceum (MTCC 2656). The
antibacterial screening reveal that the presence of 2,4-difluorophenyl (7e) or 4-nitrophenyl (7f) of 2-pyrazyl
(7i), or 2-furyl (7j) on the triazole moiety exhibited potent inhibitory activity comparable with the standard
drug streptomycin, at the tested concentrations, and emerged as potential molecules for further development.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
other hand, 1,3,4-oxadiazole derivatives were reported to
possess significant antibacterial [23], anti-inflammatory
[24], tyrosinase inhibitory [25], antiviral [26], antihyper-
tensive [27], cortical muscarinic receptor agonists [28],
herbicidal [29], Ca+2 channel blocker [30], antitumour
[31], anticonvulsant [32], anti-elmintic [33], and antioxi-
dant activities [34].
In recent years, attention has been increasingly paid to
the synthesis of bis-heterocyclic compounds, which exhibit
various biological activities [35–38], including antibacte-
rial, fungicidal, tuberculostatic, and plant growth regulative
properties. Further, recent reports [39] indicate that bis-
heterocyclic compounds displayed much better antibacte-
rial activity than the mono heterocyclic compounds.
Owing to the immense importance and varied bioactiv-
ities exhibited by triazolo-oxadiazole and in continua-
tion of our ongoing research on biologically active
bis-heterocyclics [40–45], it was thought of interest to
accommodate triazole and oxadiazole moieties in a single
molecular framework and to obtain new bis-heterocyclic
compounds with potential biological activity. In the pres-
ent study, we performed the synthesis and biological
evaluation of some new bis-triazolo-oxadiazoles.
Heterocyclics represent one of the most active classes of
compounds possessing a wide spectrum of biological
activities, including antibacterial, antifungal, and other bio-
logical activities [1–6]. The 1,2,4-triazole derivatives and
their N-bridged heterocyclic analogs have been widely in-
vestigated as antitumor [7], antiviral [8], anti-inflammatory
[9], analgesic [10], and antidepressant [11]. 1,2,4-triazole
system is also an important starting material in the synthe-
sis of biologically active heterocycles, which constitute an
important class of organic compounds with diverse biolog-
ical activities, including antiparasitic, analgesic, antibacte-
rial, and anti-inflammatory activities [12–15]. The triazole
system fused to another heterocyclic ring has attracted
with a wide spectrum of biological activities such as
antibacterial, antidepressant, antiviral, antitumoral, and
anti-inflammatory agents, pesticides, herbicides, dyes,
lubricant, and also analytical reagents [16]. The commonly
known triazole fused to other heterocyclic systems is
triazole-pyridines [17], triazolo-pyridazines [18], triazolo-
pyrimidines [19], triazolo-pyrazines [20], triazolo-triazines
[21], and triazolo-thiadiazines [22]. Although there are not
many triazole fused to oxadiazole, even the number of
them are incorporated into a wide variety of therapeutically
important compounds possessing a broad spectrum of
biological activities. Further, there is no report on the tria-
zolefused oxadiazole of bis-heterocyclic systems. On the
RESULTS AND DISCUSSION
Compound 1, required for the synthesis of the title com-
pounds, was prepared according to the procedure described
© 2013 HeteroCorporation

C. S. Reddy, M. V. Devi, G. R. Kumar, M. Sunitha, and A. Nagaraj
Vol 000
in literature [46]. Compound 1 on reaction with methyl
iodide, in the presence of K2CO3 in DMF at room temper-
ature for 12 h, furnished the 5-(3-carboxy-4-methoxybenzyl)-
2-methoxybenzoic acid 2 in 74% yield. Compound 2 on
reaction with absolute ethyl alcohol in the presence of a
catalytic amount of conc. H2SO4 at reflux for 3 h, gave the
ethyl-5-[3-(ethoxycarbonyl)-4-methoxybenzyl]-2-methoxy-
benzoate 3 in 69% yield (Scheme 1).
values. In addition, elemental analysis is also consistent
with the structure proposed for compound 3.
The intermediate, 5-[3-(hydrazinocarbonyl)-4-methoxy-
benzyl]-2-methoxy-1-benzenecarbohydrazide 4, was pre-
pared on hydrazinolysis of 3 with hydrazine hydrate, in
ethyl alcohol at reflux for 4 h, with 70% of yield. The com-
pound 4 on reaction with carbon disulfide in the presence
of potassium hydroxide, in ethanol at reflux for 12 h,
followed by acidification afforded the 5-2-methoxy-5-[4-
methoxy-3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)benzyl] phenyl-
1,3,4-oxadiazole-2-thiol 5 in 72% yield. Compound 5 on
reaction with the hydrazine hydrate, in the presence of
potassium hydroxide, in ethanol at reflux for 8 h, produced
1-(5-5-[3-(5-hydrazino-1,3,4-oxadiazol-2-yl)-4-methoxy-
benzyl]-2-methoxyphenyl-1,3,4-oxadiazol-2-yl)hydrazine
6 in 79% yield. The one-pot cyclo-condensation of com-
pound 6 with different aroyl/heteroyl chlorides in the pres-
ence of pyridine at reflux temperature resulted the new
series of 6-2-methoxy-5-[4-methoxy-3-(3-aryl[1,2,4]triazolo
[3,4-b][1,3,4]oxadiazol-6-yl)benzyl]phenyl-3-aryl[1,2,4]
triazolo[3,4-b][1,3,4]oxadi-azoles 7a–j (Scheme 2). The
The structure of compound 3 was confirmed by its IR,
1H, 13C NMR MS, and elemental analyses. The IR spec-
trum of compound 3 showed two absorption bands in the
region of 1696 and 1229 cm-1, assigned to C = O and
O-Et groups, provides a strong evidence for the formation
1
of ester. Its H NMR spectrum showed two signals at d
1.27 and 4.32 parts per million (ppm) corresponding to
CH3 and CH2 of ethyl protons, respectively. The aromatic
protons appeared in the region d 6.69, 7.36, and 7.56 ppm
are in accord with its structure. 13C NMR spectrum showed
signals at d 16.7 and 62.0 ppm corresponding to the CH3,
CH2 of ethyl group, respectively. The other signals
observed were at the expected chemical shifts and integral
Scheme 1
COOH
EtO
O
COOH
OMe
OMe
OEt
OH
MeI, K2CO3
DMF
COOH
HO
MeO
MeO
EtOH
H2SO4
COOH
1
O
2
3
Scheme 2
HS
N
N
NHNH2
O
O
OMe
MeO
NH2NH2.H2O
OMe
CS2/KOH
EtOH
MeO
3
EtOH
NHNH2
N
N
O
4
NHNH2
O
5
N
SH
O
N
N
N
NH2NH2.H2O
KOH/EtOH
Ar
OMe
OMe
O
ArCOCl
Py
MeO
Ar
N
N
O
N
N
N
N
N
O
N
Mv
6
NHNH2
7a-j
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Bis[1,2,4]triazolo[3,4-b][1,3,4]oxadiazoles
structures of the newly synthesized compounds were
selected compounds 7 and standard drug streptomycin
against B. subtilis is presented in Figure 1.
1
confirmed by their IR, H, 13C NMR MS, and elemental
analyses.
In conclusion, a series of novel 6-2-methoxy-5-[4-methoxy-
3-(3-aryl[1,2,4]triazolo[3,4-b][1,3,4]oxadiazol-6-yl)benzyl]
phenyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4]oxadi- azoles 7a–j
has been synthesized and evaluated for their antibacterial
activity against various Gram-positive and Gram-negative
bacteria. Most of the bis compounds showed good antibac-
terial activity. Among them, compounds 7e, 7f, 7i, and 7j
were found to be most active against all the microorganisms
employed. Further, the presence of 2,4-difluorophenyl moi-
ety in the molecule enhanced the inhibitory activity.
Antibacterial assay.
All the newly synthesized
compounds 7a–j were screened for their antibacterial
activity against Gram-positive bacteria viz. Bacillus subtilis
(MTCC 441), Bacillus sphaericus (MTCC 11), and
Staphylococcus aureus (MTCC 96), and Gram-negative
bacteria viz. Pseudomonas aeruginosa (MTCC 741),
Klobsinella aerogenes (MTCC 39), and Chromobacterium
violaceum (MTCC 2656) by disc diffusion method [47].
For the antibacterial assay, standard inoculums
(1–2 Â 107 c.f.u/mL 0.5 Mc Farland standards) were
introduced on to the surface of sterile agar plates, and a
sterile glass spreader was used for even distribution of the
inoculums. The disks measuring 6.26 mm in diameter were
prepared from Whatman no.1 filter paper and sterilized by
dry heat at 140ꢀC for 1 h. The sterile disks previously
soaked in a known concentration of the test compounds
were placed in nutrient agar medium. The plates were
inverted and incubated for 24 h at 37ꢀC. The inhibition
zones were measured and compared with the standard drug
streptomycin, and zone of inhibition are presented in Table 1.
The antibacterial screening data reveal that all the tested
compounds 7a–j showed moderate to good inhibition
towards all the tested strains. Compounds 7e, 7f, 7i, and
7j exhibited potent inhibitory activity compared with stan-
dard drug at the tested concentrations. The results also
reveal that the presence of 2,4-difluorophenyl (7e) or
4-nitrophenyl (7f) or 2-pyrazyl (7i), or 2-furyl (7j) on tria-
zole ring might be the reason for the significant inhibitory
activity. The presence of 2,4-difluorophenyl moiety in the
molecules would enhance the inhibitory activity as shown
by 7e. However, the presence of 4-bromophenyl (7c) and
2-chloro-3-pyridyl (7h) did not show significant inhibition.
Further, comparison of inhibition zones (in mm) of the
EXPERIMENTAL
Melting points were determined on a Fisher-Johns melting
point apparatus and are uncorrected. The purities of the com-
pounds were checked using precoated TLC plates. IR spectra
were recorded on a Perkin-Elmer FTIR 5000 spectrometer using
1
KBr pellets. H, 13C NMR spectra in DMSO-d6 were recorded
on a Varian Gemini 300 MHz spectrometer (Fall River, MA) and
the chemical shifts were reported as parts per million (d ppm) down
field using TMS as an internal standard. Mass spectra were obtained
27
26
25
24
23
22
21
20
7e
7f
7i
7j
Streptomycin
B. subtilis
Figure 1. Comparison of inhibition zone (mm) of the selected compounds
7 and standard drug against Bacillus subtilis.
Table 1
Antibacterial activity of compounds 7a–j.
Zone of inhibition at 50 mg/mL (mm)
Bacillus
subtilis
Bacillus
sphaericus
Staphylococcus
aureus
Pseudomonas
aeruginosa
Klobsinella
aerogenes
Chromobacterium
violaceum
Compound
7a
7b
7c
7d
7e
7f
7g
7h
12
10
14
15
26
25
10
10
22
25
25
14
12
10
14
28
24
10
12
26
28
30
12
10
14
16
28
24
13
12
28
28
30
15
12
10
10
29
26
10
12
30
28
30
10
11
14
12
25
24
10
10
24
25
25
12
18
16
14
30
28
18
14
29
26
30
7i
7j
Streptomycin
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

C. S. Reddy, M. V. Devi, G. R. Kumar, M. Sunitha, and A. Nagaraj
Vol 000
on a VG micromass 7070H spectrometer. Elemental analyses were
performed on a Perkin-Elmer CHN elemental analyzer. All the sol-
vents and chemicals were purchased from Sigma-Aldrich chemical
company and used without further purification.
(M+ +1). Anal. Calcd. for C19H16N4O4S2: C, 53.26; H, 3.76; N,
13.08. Found: C, 53.22; H, 3.78; N, 13.00.
1-(5-5-[3-(5-Hydrazino-1,3,4-oxadiazol-2-yl)-4-methoxybenzyl]-
2-methoxyphenyl-1,3,4-oxadiazol-2-yl)hydrazine (6).
To a
5-(3-Carboxy-4-methoxybenzyl)-2-methoxybenzoic acid
mixture of compound 5 (0.01 mol) and potassium hydroxide
(0.02 mol) in ethanol (50mL), 80% hydrazine hydrate (0.03mol)
was added drop wise, and the reaction mixture was heated under
reflux for 8 h. The solvent was distilled off in vacuo, cooled and
the crystals separated were filtered, washed with cold ethanol, and
recrystallized from alcohol to give the pure compound 6 as yellow
solid; Yield 79%, mp 156–58ꢀC; IR (KBr) n: 3300–3200, 3047,
1600, 1062, 1030cm-1; 1H NMR (DMSO-d6): d 3.84 (s, 6H,
OCH3), 4.01 (s, 2H, CH2), 5.32 (s, 4H, NH2), 6.76 (d, J = 8.6 Hz,
2H, ArH), 7.38 (d, J = 8.6 Hz, 2H, ArH), 8.10 (s, 2H, NH), 8.22
(s, 2H, ArH); 13C NMR (DMSO-d6): d 41.2, 55.1, 113.9, 116.4,
127.4, 131.6, 133.2, 154.7, 157.8, 165.5; MS: m/z 424 (M+).
Anal. Calcd. for C19H20N8O4: C, 53.77; H, 4.75; N, 26.40. Found:
C, 53.72; H, 4.71; N, 26.44.
(2).
To a solution of 1 (0.01 mol) and K2CO3 (0.04 mol) in
DMF (16 mL), MeI (0.03 mol) was added. The reaction mixture
was stirred for 12 h at room temperature (TLC, EtOAc: Pet-ether,
2:1). The mixture was poured in water (30 mL) and extracted with
Et2O (3 Â 20 mL). Washing the organic phase with 2N NaOH
solution, dried over Na2SO4 and evaporation of solvent gave
compound 2 as white solid; Yield 74%, mp 194–96ꢀC; IR (KBr)
1
n: 3300–3200, 3037, 1698, 1070cm-1; H NMR (DMSO-d6): d
3.82 (s, 6H, OCH3), 3.91 (s, 2H, CH2), 6.60 (d, J = 8.7 Hz, 2H,
ArH), 7.72 (d, J = 8.7 Hz, 2H, ArH), 7.87 (s, 2H, ArH), 10.7
(s, 2H, COOH); 13C NMR (DMSO-d6): d 41.2, 54.2, 122.0,
122.8, 131.9, 133.0, 134.3, 156.1, 170.1; MS m/z: 316 (M+).
Anal. Calcd. for C17H16O6: C, 64.55; H, 5.10. Found: C, 64.50;
H, 5.03.
6-2-Methoxy-5-[4-methoxy-3-(3-aryl[1,2,4]triazolo[3,4-b]
[1,3,4]oxadiazol-6-yl)benzyl]phenyl-3-aryl[1,2,4]triazolo[3,4-
ethyl-5-[3-(Ethoxycarbonyl)-4-methoxybenzyl]-2-methoxy
benzoate (3). To the solution of 2 (0.01 mol) in absolute ethyl
alcohol (25 mL), conc. H2SO4 (2 mL) was added. The mixture
was refluxed for 3 h. After completion of the reaction (TLC),
the mixture was poured into ice-cold water. Crude product was
collected by filtration, washed with 10% NaHCO3 solution,
dried and recrystallized from ethyl alcohol to afford the
compound 3 as pink solid; Yield 69%, mp 249–51ꢀC; IR (KBr)
b] [1,3,4]oxadiazoles (7a–j).
To a solution of compound 6
(0.01 mol) in dry pyridine (25 mL), the corresponding acid
chlorides (0.02 mol), was added in drops. The reaction mixture
was stirred at room temperature for 2 h and then heated for 2 h
in a steam bath. It was then poured onto crushed ice. The solid
products obtained by filtration were crystallized from the
appropriate solvents to furnish the pure compounds 7a–j, which
were characterized by 1H, 13C NMR, IR, MS, and elemental
analyses.
1
n: 3041, 1696, 1229, 1067 cm-1; H NMR (DMSO-d6): d 1.27
(t, 6H, CH3), 3.83 (s, 6H, OCH3), 3.90 (S, 2H, CH2), 4.32 (q,
4H, CH2), 6.69 (d, J = 8.9 Hz, ArH), 7.36 (d, J = 8.9 Hz, 2H,
ArH), 7.56 (s, 2H, ArH); 13C NMR (DMSO-d6): d 16.7, 41.2,
53.7, 62.0, 116.8, 121.6, 128.0, 128.7, 132.5, 156.7, 170.2; MS:
m/z 372 (M+). Anal. Calcd. for C21H24O6: C, 67.73; H, 6.50.
Found: C, 67.69; H, 6.52.
6-2-Methoxy-5-[4-methoxy-3-(3-phenyl[1,2,4]triazolo[3,4-
b][1,3,4]oxadiazol-6-yl)benzyl]phenyl-3-phenyl[1,2,4]triazolo
[3,4-b][1,3,4]oxadiazole (7a).
This compound was obtained
as brown solid; Yield 74%; mp 166–68ꢀC; IR (KBr) n: 3037,
1590, 1070, 1024 cm-1; 1H NMR (DMSO-d6): d 3.47 (s, 2H,
CH2), 3.66 (s, 6H, OCH3), 6.70–6.90 (m, 4H, ArH), 7.30–7.40
(m, 12H, ArH); 13C NMR (DMSO-d6): d 42.7, 54.7, 117.2,
119.2, 126.5, 128.3, 130.2, 131.6, 132.3, 133.0, 134.5, 151.6,
156.5, 159.1, 160.4; MS: m/z 596 (M+). Anal. Calcd. for
C33H24N8O4: C, 66.44; H, 4.05; N, 18.78. Found: C, 66.40; H,
4.01; N, 18.71.
5-[3-(Hydrazinocarbonyl)-4-methoxybenzyl]-2-methoxy-1-
benzenecarbohydrazide (4).
A mixture of compound 3
(0.01 mol) and hydrazine hydrate (0.025 mol) in ethanol (50 mL)
was refluxed for 4 h, cooled at room temperature and filtered.
The crude product was recrystallized from ethanol to give new
intermediate 4 as white crystal; Yield 70%, mp 141–43ꢀC; IR
1
(KBr) n: 3300–3200, 3065, 1680, 1072 cm-1; H NMR (DMSO-
3-(4-Chlorophenyl)-6-(5-3-[3-(4-chlorophenyl)[1,2,4]triazolo
[3,4-b][1,3,4]oxadiazol-6-yl]-4-methoxybenzyl-2-methoxyphe- nyl)
d6): d 3.82 (s, 6H, OCH3), 4.21 (s, 2H, CH2), 5.49 (s, 4H,
NH2), 6.87 (d, J = 8.4 Hz, 2H, ArH), 7.20 (s, 2H, ArH), 7.47
(d, J= 8.4 Hz, 2H, ArH), 8.20 (s, 2H, NH); 13C NMR (DMSO-d6):
d 41.6, 54.6, 119.4, 124.2, 126.3, 130.9, 133.2, 157.6, 168.6; MS:
m/z 345 (M+ +1). Anal. Calcd. for C17H20N4O4: C, 59.29; H, 5.85.
Found: C, 59.23; H, 5.80.
[1,2,4]triazolo[3,4-b][1,3,4]oxadiazole (7b).
This compound
was obtained as yellow solid; Yield 71%; mp 170–72ꢀC; IR
(KBr) n: 3041, 1592, 1580, 1064, 1032, 685cm-1; 1H NMR
(DMSO-d6): d 3.46 (s, 2H, CH2), 3.66 (s, 6H, OCH3), 6.70–6.90
(m, 4H, ArH), 7.30–7.40 (m, 6H, ArH), 8.31 (d, J = 8.6 Hz, 4H,
ArH); 13C NMR (DMSO-d6): d 42.6, 54.5, 117.2, 119.2, 127.4,
131.3, 132.5, 133.0, 133.6, 134.9, 136.2, 151.4, 156.3, 159.1,
160.1; MS: m/z 666 (M+). Anal. Calcd. for C33H22Cl2N8O4: C,
59.56; H, 3.33; N, 16.84. Found: C, 59.51; H, 3.30; N, 16.79.
3-(4-Bromophenyl)-6-(5-3-[3-(4-bromophenyl)[1,2,4]triazo lo
[3,4-b] [1,3,4]oxadiazol-6-yl]-4-methoxybenzyl-2-methoxy phenyl)
5-2-Methoxy-5-[4-methoxy-3-(5-sulfanyl-1,3,4-oxadiazol-2-
yl)benzyl]phenyl-1,3,4-oxadiazole-2-thiol (5).
A mixture of
compound 4 (0.01 mol), potassium hydroxide (0.02 mol), and
carbon disulfide (0.03 mol) in ethanol (150 mL) was heated
under reflux, stirring for 12 h and the solvent was distilled
in vacuo, the residual mass was poured over crushed ice and
neutralized the alkaline solution with 10% hydrochloric acid.
The precipitated crude product was filtered, washed with water,
dried, and recrystallized from ethanol to give pure compound 5
as yellow solid; Yield 72%, mp 187–89ꢀC; IR (KBr) n: 3030,
2902, 1601, 1570, 1067, 1030 cm-1; 1H NMR (DMSO-d6): d
3.84 (s, 6H, OCH3), 3.98 (s, 2H, CH2), 6.76 (d, J = 8.9 Hz, 2H,
ArH), 7.38 (d, J = 8.9 Hz, 2H, ArH), 8.21 (s, 2H, ArH), 11.20
(s, 2H, NH/SH); 13C NMR (DMSO-d6): d 40.9, 54.1, 114.8,
115.4, 128.7, 131.0, 133.3, 154.7, 163.5, 172.2; MS: m/z 429
[1,2,4]triazolo[3,4-b][1,3,4]oxadiazole (7c).
This compound
was obtained as white solid; Yield 76%; mp 159–61ꢀC; IR (KBr):
n 3033, 1594, 1570, 1067, 1027, 586 cm-1; 1H NMR (DMSO-d6):
d 3.47 (s, 2H, CH2), 3.67 (s, 6H, OCH3), 6.70–6.90 (m, 4H,
ArH), 7.40–7.50 (m, 6H, ArH), 7.71 (d, J = 8.3 Hz, 4H, ArH); 13C
NMR (DMSO-d6): d 42.1, 54.7, 117.2, 119.6, 126.6, 128.1,
130.8, 131.6, 132.5, 133.8, 134.5, 151.3, 156.5, 159.4, 160.7;
MS: m/z 754 (M+). Anal. Calcd. for C33H22Br2N8O4: C, 52.54; H,
2.94; N, 14.85. Found: C, 52.49; H, 2.95; N, 14.80.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Bis[1,2,4]triazolo[3,4-b][1,3,4]oxadiazoles
3-(2-Fluorophenyl)-6-(5-3-[3-(2-fluorophenyl)[1,2,4]triazolo
[3,4-b][1,3,4]oxadiazol-6-yl]-4-methoxybenzyl-2-methoxyphenyl)
6-(2-Methoxy-5-4-methoxy-3-[3-(2-pyrazinyl)[1,2,4]triazolo
[3,4-b][1,3,4]oxadiazol-6-yl]benzylphenyl)-3-(2-pyrazinyl)[1,2,4]
[1,2,4]triazolo[3,4-b][1,3,4]oxadiazole (7d).
This compound
triazolo[3,4-b][1,3,4]oxadiazole (7i).
This compound was
was obtained as yellow solid; Yield 70%; mp 171–73ꢀC; IR
(KBr): n 3065, 1590, 1575, 1062, 1030 cm-1; 1H NMR
(DMSO-d6): d 3.48 (s, 2H, CH2), 3.64 (s, 6H, OCH3), 6.70–
6.90 (m, 4H, ArH), 7.30–7.40 (m, 8H, ArH), 8.22 (d, J = 7.9
Hz, 4H, ArH); 13C NMR (DMSO-d6): d 42.7, 54.7, 116.8,
117.2, 119.2, 121.4, 125.2, 129.7, 131.6, 132.8, 133.0, 134.5,
151.6, 156.5, 159.1, 160.4, 162.7; MS: m/z 632 (M+). Anal.
Calcd. for C33H22F2N8O4: C, 62.66; H, 3.51; N, 17.71. Found:
C, 62.60; H, 3.47; N, 17.75.
obtained as brown solid; Yield 68%; mp 152–154ꢀC; IR (KBr): n
3032, 2972, 1590, 1070, 1025 cm-1; 1H NMR (DMSO-d6): d 3.45
(s, 2H, CH2), 3.65 (s, 6H, OCH3), 6.70–6.90 (m, 4H, ArH), 7.41
(s, 2H, ArH), 8.21 (d, J = 8.7 Hz, 2H, ArH), 8.20–8.30 (m, 4H,
ArH); 13C NMR (DMSO-d6): d 42.7, 54.7, 117.2, 119.2, 131.6,
133.0, 134.5, 141.2, 145.7, 146.9, 148.5, 151.6, 156.5, 159.1,
160.4; MS: m/z 600 (M+). Anal. Calcd. for C29H20N12O4: C,
58.00; H, 3.36; N, 27.99. Found: C, 57.94; H, 3.31; N, 27.92.
3-(2-Furyl)-6-(5-3-[3-(2-furyl)[1,2,4]triazolo[3,4-b][1,3,4]oxa-
diazol-6-yl]-4-methoxybenzyl-2-methoxyphenyl)[1,2,4]lo[3,4-b]
[1,3,4]oxadiazole (7j). This compound was obtained as brown
solid; Yield 69%; mp 167–69ꢀC; IR (KBr): n 3072, 2961, 1590,
3-(2,4-Difluorophenyl)-6-(5-3-[3-(2,4-difluorophenyl)[1,2,4]
triazolo[3,4-b][1,3,4]oxadiazol-6-yl]-4-methoxybenzyl-2-meth-
oxyphenyl)[1,2,4]triazolo[3,4-b][1,3,4]oxadiazole (7e).
This
1
compound was obtained as brown solid; Yield 68%; mp 187–
89ꢀC; IR (KBr): n 3064, 1597, 1581, 1063, 1030 cm-1; 1H
NMR (DMSO-d6): d 3.46 (s, 2H, CH2), 3.65 (s, 6H, OCH3),
6.70–6.90 (m, 4H, ArH), 7.20–7.30 (m, 6H, ArH), 7.91 (d,
J = 8.2 Hz, 2H, ArH); 13C NMR (DMSO-d6): d 42.3, 54.4,
108.1, 114.9, 115.1, 117.1, 119.5, 129.9, 131.6, 133.2, 134.6,
151.6, 156.0, 156.7, 159.1, 160.6, 172.2; MS: m/z 668 (M+).
Anal. Calcd. for C33H22F4N8O4: C, 59.29; H, 3.02; N, 16.76.
Found: C, 59.22; H, 3.37; N, 16.70.
1030 cm-1; H NMR (DMSO-d6): d 3.46 (s, 2H, CH2), 3.68 (s,
6H, OCH3), 6.70–6.90 (m, 4H, ArH), 6.50–6.60 (m, 4H, ArH),
7.40–7.50 (m, 4H, ArH); 13C NMR (DMSO-d6): d 42.7, 54.7,
113.1, 117.2, 119.2, 121.5, 131.6, 133.0, 134.5, 134.9, 145.3,
151.6, 156.5, 159.1, 160.4; MS: m/z 576 (M+). Anal. Calcd. for
C29H20N8O6: C, 60.42; H, 3.50; N, 19.44. Found: C, 60.36; H,
3.45; N, 19.39.
6-(2-Methoxy-5-4-methoxy-3-[3-(4-nitrophenyl)[1,2,4]triazolo
[3,4-b][1,3,4]oxadiazol-6-yl]benzylphenyl)-3-(4-nitrophenyl)
[1,2,4]triazolo[3,4-b][1,3,4]oxadiazole (7f). This compound
was obtained as brown solid; Yield 75%; mp 184–186ꢀC; IR
Acknowledgments. The authors are grateful to the Director, Indian
Institute of Chemical Technology, Hyderabad, India, for providing
NMR and mass spectral data. Financial assistance from the
UGC SAP (Phase-I)DRS Programme, New Delhi, India, is
greatly acknowledged.
1
(KBr): n 3032, 1590, 1580, 1565, 1370, 1061 cm-1; H NMR
(DMSO-d6): d 3.47 (s, 2H, CH2), 3.66 (s, 6H, OCH3), 6.70–
6.90 (m, 4H, ArH), 7.34 (s, 2H, ArH), 8.14 (d, J = 8.7 Hz,
4H, ArH), 8.82 (d, J = 8.7 Hz, 4H, ArH); 13C NMR (DMSO-
d6): d 42.7, 54.7, 117.2, 119.2, 127.6, 131.6, 132.4, 133.0,
134.0, 134.8, 149.3, 151.6, 156.5, 159.1, 160.4; MS: m/z 686
(M+). Anal. Calcd. for C33H22N10O8: C, 57.73; H, 3.23; N,
20.40. Found: C, 57.70; H, 3.17; N, 20.41.
REFERENCES AND NOTES
[1] Colak, A. T.; Colak, F.; Atar, N. Acta Chim Slov 2010, 57, 212.
[2] Gaber, H. M.; Hafiz, I. S. A.; EISawy, K. M. Acta Chim Slov
2010, 57, 230.
6-(2-Methoxy-5-4-methoxy-3-[3-(3-pyridyl)[1,2,4]triazolo
[3,4-b][1,3,4]oxadiazol-6-yl]benzylphenyl)-3-(3-pyridyl)[1,2,4]
[3] Rohini, R.; Reddy, P. M.; Shanker, K. Acta Chim Slov 2009, 56, 900.
[4] Kotb, E. R.; EI-Hashash, M. A.; Salama, M. A. Acta Chim
Slov 2009, 56, 908.
[5] Anderluh, P. S.; Vilfan, G.; Prezelj, A. Acta Chim Slov 2009,
56, 669.
[6] EI-Gazzar, A. R. B. A.; Hafez, H. N. Acta Chim Slov 2008,
55, 359.
[7] Kohn, E. C.; Liotta, L. A. U.S. Patent 637145; Chem Abstr
1991, 115, 248099.
[8] Srivatava, A. J.; Swarup, S.; Saxena, V. K. J Indian Chem Soc
1991, 68, 103.
[9] Udupi, R. H. G.; Suresh, V.; Setty, S. R.; Bhat, A. R. J Indian
Chem Soc 2000, 77, 303.
[10] Turan, Z. G.; Kaplancikli, Z. A.; Erol, K. F. S. Il Farmaco
1999, 54, 218.
[11] Kane, M. J.; Wdudley, M.; Sorensen, S. M.; Miller, F. P. J
Med Chem 1988, 31, 1253.
triazolo[3,4-b][1,3,4]oxadiazole (7g).
This compound was
obtained as yellow solid; Yield 73%; mp 139–41ꢀC; IR (KBr):
n 3049, 1595, 1580, 1550, 1030 cm-1; H NMR (DMSO-d6): d
1
3.47 (s, 2H, CH2), 3.65 (s, 6H, OCH3), 6.70–6.90 (m, 4H,
ArH), 7.60–7.70 (m, 6H, ArH), 8.34 (d, J = 7.9 Hz, 2H, ArH),
8.80 (s, 2H, ArH); 13C NMR (DMSO-d6): d 42.2, 54.1, 117.6,
119.2, 123.9, 125.3, 131.1, 132.8, 133.5, 134.4, 150.7, 151.8,
152.7, 156.9, 159.1, 160.4; MS: m/z 598 (M+). Anal. Calcd. for
C31H22N10O4: C, 62.20; H, 3.70; N, 23.40. Found: C, 62.16; H,
3.62; N, 23.33.
3-(2-Chloro-3-pyridyl)-6-(5-3-[3-(2-chloro-3-pyridyl)[1,2,4]
triazolo[3,4-b][1,3,4]oxadiazol-6-yl]-4-methoxybenzyl-2-meth-
oxyphenyl)[1,2,4]triazolo[3,4-b][1,3,4]oxadiazole (7h).
This
compound was obtained as yellow solid; Yield 70%; mp
144–46ꢀC; IR (KBr): n 3031, 1595, 1070, 1026, 689 cm-1;
1H NMR (DMSO-d6): d 3.46 (s, 2H, CH2), 3.66 (s, 6H,
OCH3), 6.70–6.90 (m, 4H, ArH), 7.42 (s, 2H, ArH), 7.80–
7.90 (m, 4H, ArH), 8.34 (d, J = 8.0 Hz, 2H, ArH); 13C
NMR (DMSO-d6): d 42.7, 54.7, 117.2, 119.2, 125.1, 126.7,
131.6, 133.0, 134.5, 135.3, 146.1, 151.6, 156.5, 157.0,
159.1, 160.4; MS: m/z 668 (M+). Anal. Calcd. for
C31H20Cl2N10O4: C, 55.78; H, 3.02; N, 20.98. Found: C,
55.71; H, 3.00; N, 20.94.
[12] Hovsepian, T. R.; Dilanian, E. R.; Egoyan, A. P.; Melik-Ohanjaian,
R. G. J Chem Heterocycl Compds 2004, 40, 1194.
[13] Cansiz, A.; Koparir, M.; Demirdag, A. Molecules 2004, 9, 204.
[14] Li-Xue, A.; An-Jian, Z.; Xian-Xin, C.; Xin-Xiang, L.; Xiang
Yun, N.; Dong-Yung, C.; Zhang, Z. Molecules 2002, 7, 681.
[15] Wasfy, A. A. F. J Chem Res 2003, 8, 457.
[16] Holla, B. S.; Akberali, P. M.; Shivananda, M. K. Il Farmaco
2001, 56, 919.
[17] Yao, G.; Haque, S.; Sha, L.; Kumaravel, G.; Wang, J.; Enger,
T. M.; Whalley, T. M.; Conlon, P. R.; Chang, H.; Kiesman, F. W.; Petter,
R. C. Bioorg Med Chem Lett 2005, 15, 511.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

C. S. Reddy, M. V. Devi, G. R. Kumar, M. Sunitha, and A. Nagaraj
Vol 000
[18] Vu, C. B.; Shields, P.; Peng, B.; Kumaravel, G.; Jin, X.;
Phadke, D.; Wang, J.; Engber, T.; Ayyub, E.; Petter, R. C. Bioorg Med
Chem Lett 2004, 14, 4835.
[33] Srinivas, K.; Kumar, K. P. Int J Biopharm 2010, 1, 14.
[34] Rajasekaran, S.; Rao, G. K.; Vedavathy, J. J. Chem Pharm Res
2010, 2, 101.
[19] Sadana, K. A.; Mirza, Y.; Aneja, K. R.; Prakash, O. Eur J Med
Chem 2003, 38, 533.
[20] Bussolari, J. C.; Panzica, R. P. Bioorg Med Chem 1999, 7, 2373.
[21] Zafer, A. K.; Gulhan, T. Z.; Ahmet, O.; Gilbert, R. Eur J Med
Chem 2005, 43, 155.
[35] Kritsanida, M.; Mouroutsou, A.; Marakos, P.; Pouli, N.;
Papakonstantinou-Garoufalias, S.; Pannecouque, C.; Witvouw, M.; De
Clercq, E. Il Farmaco 2002, 57, 253.
[36] Holla, B. S.; Sarojini, B.; Rao, S. B.; Akberali, P. M.; Kumari,
N. S.; Shetty, V. Il Farmaco 2001, 56, 565.
[22] Vennerstrom, J. L.; Maklet, M. T.; Angerhofer, C. K.;
Williams, J. A. Antimicrob Agents Chemother 1995, 39, 2671.
[23] Kucukguzel, S. G.; Oruc, E. E.; Rollas, S. Eur J Med Chem
2002, 37, 197.
[24] Amir, M.; Shikla, K. Eur J Med Chem 2004, 39, 535.
[25] Lam, K. W.; Syahida, A.; Ul-Haq, Z.; Abdul Rahman, M. B.;
Lajis, N. H. Bioorg Med Chem Lett 2010, 20, 3755.
[26] Srivastava, P. C.; Robins, R. K. J Med Chem 1981, 24, 1172.
[27] Tyrkov, A. G.; Tyurenkov, I. N.; Tmchenko, M. V.; Perfilova,
V. N. Pharm Chem J 2006, 40, 240.
[28] Street, L. J.; Baker, R.; Book, T.; Kneen, C. O.; MacLeod, A.
M.; Merchant, K. J.; Showell, G. A.; Saunders, J.; Herbert, R. H.;
Freedman, S. B. J Med Chem 1990, 33, 2690.
[29] Zhao, O.; Liu, S.; Li, Y.; Wang, O. J Agric Food Chem 2009,
57, 2849.
[37] Turan-Zitouni, G.; Kaplancikli, Z. A.; Erol, K.; Kilic, F. S. Il
Farmaco 1999, 54, 218.
[38] Holla, B. S.; Gonsalves, R.; Shenoy, S. Il Farmaco 1998, 53, 574.
[39] Onca, S.; Punar, M.; Erakosy, H. Chemotherapy, 2004, 50, 98.
[40] Srinivas, A.; Nagaraj, A.; Sanjeeva Reddy, C. Eur J Med
Chem 2010, 45, 2353.
[41] Sanjeeva Reddy, C.; Srinivas, A.; Nagaraj, A. Chem Pharm
Bull 2010, 58, 805.
[42] Sanjeeva Reddy, C.; Sanjeeva Rao, L.; Vani Devi, M.; Kumar,
G. R.; Nagaraj, A. Chin Chem Lett 2010, 21, 1045.
[43] Sanjeeva Reddy, C. Sanjeeva Rao, L.; Kumar, G. R.; Nagaraj,
A. Chem Pharm Bull 2010, 58, 1328.
[44] Sanjeeva Reddy, C.; Sanjeeva Rao, L.; Nagaraj, A. Acta Chim
Slov 2010, 57, 726.
[45] Sanjeeva Reddy, C.; Vani Devi, M.; Sunitha, M.; Nagaraj, A.
Chem Pharm Bull 2010, 58, 1622.
[46] Clemmensen, E.; Heitman, A. H. C. J Am Chem Soc 1911, 33, 733.
[47] National Committee for Clinical Laboratory Standards
(NCCLS). Standard methods for dilution antimicrobial susceptibility
tests for bacteria, which grows aerobically. Nat Comm Lab Stands
Villanova, 1982, pp. 242.
[30] Schlecker, R.; Thieme, P. C. Tetrahedron, 1988, 44, 3289.
[31] Savariz, F. C.; Formagio, A. S. N.; Barbosa, V. A.; Foglio, M.
A.; Duarte, M. C. T.; Filhoc, B. P. D.; Sarragiotto, M. H. J Braz Chem Soc
2010, 21, 288.
[32] Bhat, M. A.; Siddiqui, N.; Khan, S. A. Acta Poloniae Pharm
Drug Res 2008, 65, 235.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet