Synthesis and antimicrobial activity of some novel substituted 1,2,4-triazoles bearing 1,3,4-oxadiazoles or pyrazoles

Article abstract of DOI:10.1002/jhet.718

Several derivatives of substituted 1,2,4-triazole bearing the pyrazole (or oxadiazole) ring were synthesized via the reaction of 2,4-dihydro-4-benzyl-5- (isomeric pyridyl)-3H-1,2,4-triazole-3-thione 1a-c with ethyl chloroacetate, hydrazine hydrate, and ac

Full text of DOI:10.1002/jhet.718

1366
Synthesis and Antimicrobial Activity of Some Novel Substituted
1,2,4-Triazoles Bearing 1,3,4-Oxadiazoles or Pyrazoles
Vol 48
Mehdi Kalhor,a Akbar Mobinikhaledi,b* Akbar Dadras,c
and Maryam Tohidpourd
aDepartment of Chemistry, Payame Noor University, Qom, Iran
bDepartment of Chemistry, Arak University, Arak 38156-879, Iran
cDepartment of Chemistry, Guilan University, Rasht 41335-1914, Iran
dDepartment of Microbiology, Islamic Azad University, Shahre Ghods Branch, Tehran, Iran
*E-mail: akbar_mobini@yahoo.com
Received October 15, 2009
DOI 10.1002/jhet.718
Published online 30 June 2011 in Wiley Online Library (wileyonlinelibrary.com).
Several derivatives of substituted 1,2,4-triazole bearing the pyrazole (or oxadiazole) ring were synthe-
sized via the reaction of 2,4-dihydro-4-benzyl-5-(isomeric pyridyl)-3H-1,2,4-triazole-3-thione 1a–c with
ethyl chloroacetate, hydrazine hydrate, and acetyl acetone (or CS2/KOH) in absolute ethanol. The inter-
mediate then undergoes an intramolecular cyclization in acidic medium. The newly synthesized com-
pounds 4a–c to 7a–c were characterized using IR, NMR, and MS Spectroscopy. Some of the
synthesized compounds 4,5,7a–c were evaluated for their antibacterial and antifungal activities. Most of
these compounds indicated activity comparable to Gentamycine. Also some of them are more active
than Tolnaftate, a known antifungal drug.
J. Heterocyclic Chem., 48, 1366 (2011)
INTRODUCTION
cyclic analogue of two very important components. In
view of this report and also as a continuation of our
work on the synthesis of heterocyclic compounds with
biological interest [23,24], the synthesis of new 1,2,4-tri-
azole ring bearing 1,3,4-oxadiazoles or pyrazoles in a
single molecular framework is reported.
A variety of 1,2,4-triazole derivatives have been
described for their biological activities including antide-
pressive, anti-inflammatory, antibacterial, antifungal, and
insecticidal properties [1–4]. Oxadiazoles have been
reported to show a broad spectrum of biological activ-
ities [5–7] such as anti-inflammatory, fungicidal, and
herbicidal activities [8–12]. Pyrazole derivatives are also
used as important reagents in organic synthesis and have
found applications as pharmaceutical, multidrug resist-
ance (MDR) modulators, herbicide, herbicide fungicide,
insecticide, and dyestuffs [13–17]. Some of the reported
compounds bearing a pyrazole ring are used as analge-
sic, anti-inflammatory [18], and anticancer agents [19],
which are selective as in vitro inhibitors of human T
and B leukemias [20]. Likewise, the 1,2,4-triazole ring
is associated with a broad spectrum of biological activ-
ities e.g., fungicidal [21] and hypoglycemic activity
[22]. It is also known that if an active nucleus is linked
to another nucleus, the resulting molecule may possess
greater potential for biological activity. A triazole-pyraz-
ole or triazole-oxadiazole system may be viewed as a
RESULTS AND DISCUSSION
The synthetic routes for the preparation of the target
compounds are outlined in Scheme 1. 2,4-Dihydro-4-
benzyl-5-(isomeric pyridyl)-3H-1,2,4-triazole-3-thiones
1a–c were synthesized according to the previously
reported procedure [25]. The esters 2a–c and acid hydra-
zides 3a–c were also prepared from triazole thiones
1a–c as previously reported [26]. The hydrazones 4a–c
were synthesized by reaction of mercaptoacetic acid
hydrazides 3a–c with acetylacetone in absolute ethanol.
One of the substituted hydrazones 4b, which was syn-
thesized as an intermediate for preparation of substituted
1
pyrazoles, was characterized using FTIR, H NMR and
1
Mass spectral data. In the H NMR spectrum of 4b, the
C
V
2011 HeteroCorporation

November 2011 Synthesis and Antimicrobial Activity of Some Novel Substituted 1,2,4-Triazoles
Bearing 1,3,4-Oxadiazoles or Pyrazoles
1367
Scheme 1. Conditions: (a) Et-I, 96% EtOH, KOH, 12–15 h, reflux. (b) ClCH2CO2Et, NaOH, EtOH, 4–10 h, reflux. (c) 100% N2H5OH, EtOH, 4.5–7 h,
reflux. (d) acetyl acetone, EtOH, 1.5–5 h, reflux. (e) EtOH, 0.l mL 37% HCl, 22.5–30 h, reflux. (f) 1. CS2, KOH, EtOH, 6–14 h, reflux, 2. HCl.
two singlets were observed due to the resonance of the
two methyl groups which were observed at 2.51 and
2.54 ppm. 13C NMR spectra of compounds 4a and 4c,
showed 19 and 17 peaks, respectively, for aliphatic and
aromatic carbons in the expected region, which are con-
sistent with their structures. The resonance of all other
protons appeared in the expected region of spectrum.
The mass spectra of this compound exhibited a low mo-
lecular radical cation peak at m/z 422 (18%). Elimina-
tion of the O¼¼CNHN¼¼C(CH3)CH2(CH3)C¼¼O radical
gave a cation as a base peak at m/z 281 (100%).
8%). Although, the molecular radical cation of com-
pounds was observed in low intensities, the mass
spectral fragmentation patterns are in support of the
novel synthesized compounds. Further evidence for
the formation of the pyrazole ring was obtained from
the 13C NMR spectra of compound 5c. 13C NMR of
compound 5c exhibited 15 peaks for aliphatic and ar-
omatic carbons in the expected region of the spectrum
and the carbonyl carbon of this compound was
observed at 169 ppm.
Ethyl sulfide derivatives of triazoles 6a–c were
obtained by reaction of respective triazole with ethyl
iodides in alkaline ethanol. The IR spectra of the syn-
thesized compounds showed the elimination of bands
in the region 2500–2658 cmꢀ1 due to the thiol group.
1,3,4-oxadiazole derivatives of the triazoles 7a–c were
obtained by reaction of an alkaline solution of 3a–c
in ethanol with carbon disulfide. In the IR spectra of
the synthesized compounds, the absence of a carbonyl
group is in support of the expected reaction. The
reflux time, melting point, yield and solvent for
recrystallization of all synthesized compounds are
tabulated in Table 1.
The intramolecular dehydrative cyclization of hydra-
zone derivatives of 1,2,4-triazoles 4a–c in absolute etha-
nol and acidic medium as catalyst afforded 5a–c. In the
IR spectra of these compounds, a prominent peak was
observed for the carbonyl absorption at 1734–1743 cmꢀ1
.
1H NMR spectra of 5a–c exhibited two singlets at 2.3–3.6
ppm related to the resonance of two methyl groups substi-
tuted on the pyrazole ring. All other required peaks
appeared in the exhibited region of the spectrum.
However, the proton on position 4 of the pyrazole
ring was not observed in the spectrum of all synthesized
pyrazoles, probably due to the effect of exchange of this
acidic proton of the pyrazole ring with deuterium of
small amounts of D2O, which is present in DMSO-d6,
which was used as a solvent [27].
Antimicrobial activities. Applying the agar plate
diffusion technique [6], some of newly synthesized com-
pounds were screened in vitro for antimicrobial activ-
ities against Staphylococcus aureus PTCC-1337 (Gram-
positive), Escherichia coli PTCC-1338 (Gram-negative)
In the mass spectra of 5a–c, the molecular radical
cation was observed at m/z 404 in low intensities (5–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1368
M. Kalhor, A. Mobinikhaledi, A. Dadras, and M. Tohidpour
Vol 48
Table 1
Physicochemical data of the novel compounds (4-7 a–c).
EXPERIMENTAL
Melting points were measured in open capillaries tubes and
1
are uncorrected. H and 13C NMR spectral data were obtained
No.
R
Compound
M.p./ꢂC
Time/h Yield/%
using a Bruker 500-MHz FTNMR spectrometer in DMSO-d6 as
a solvent. The IR spectral data were obtained using a Glaxy
FTIR 5000 spectrometer with KBr sample disk. The Mass spec-
tra were recorded on a Varian model Mat MS-311 spectrometer
at 70 eV. Elemental analyses were performed on a Vario EL III
elemental analyzer. The purity of all compounds was confirmed
on silica gel coated aluminum plates (Merck). Benzyl isothiocy-
anate, 4-Benzyl-1-(isomeric pyridoyl) thiosemicarbazides were
synthesized as previously reported method [25].
1
2
2-pyridyl
3-pyridyl
4-pyridyl
2-pyridyl
3-pyridyl
4-pyridyl
2-pyridyl
3-pyridyl
4-pyridyl
2-pyridyl
3-pyridyl
4-pyridyl
4a
4b
4ca
5a
5b
5c
6a
6b
6c
7a
7b
7c
192–193
201.5–203
221
1.5
5
67
66.5
63
68
89
76
75
65
70
66
58
67
3
4
–
97
22.5
30
23
12
15
14
6
5
121–122
171.5–172
103–104
81–82
6
7
8
9
70–71
General procedure for the synthesis of 2-{[-4-benzyl-5-
(isomeric pyridyl)-4H-1,2,4-triazole-3-ylthio]-N (2) [1-methyl-
3-oxobutilidin]} acetohydrazide (4a–c). Compounds 3a–c (0.4
g, 1 mmol) was dissolved in absolute ethanol (15 mL) and
mixed with acetylacetone (0.18 mL, 1.7 mmol). The mixture
was refluxed for 1.5–5 h. After cooling, the precipitate was fil-
tered and recrystallized from ethanol to give pure (4a–c).
2-{[-4-Benzyl-5-(2-pyridyl)-4H-1,2,4-triazole-3-ylthio]-N(2)
[1-methyl-3-oxobutilidin]} acetohydrazine, (4a) IR (KBr):
3331 (NAH), 2953 (CAHaliphatic), 1734 (C¼¼O), 1475, 1423,
10
11
12
193–194
191–191.5
221–222
8
14
a In this case, after 40 s stirring the product was formed.
bacteria. The compounds were also tested against Can-
dida albicans PTCC-5027 fungi (Table 2). The com-
pounds were diluted in DMSO for bioassay. The solvent
control was included, although no antibacterial and anti-
fungal activity has been noted. Gentamycine and Tolnaf-
tate as drug references were included for comparison
with compounds (4, 5, 7a–c). All samples were tested in
triplicate, and the average results were recorded. In this
method, a standard 8-mm diameter sterile filter paper
disk impregnated with the test compound (500 lg) was
placed on an agar plate seeded with the microorganism
(1.5 ꢁ 108 CFU mLꢀ1). The plates were incubated at
5ꢂC for 11 h to permit good diffusion and then incu-
bated at 37ꢂC for 24 h. Fungi were incubated at 25–
28ꢂC for 48 h. The zone of inhibition of bacteria and
fungi growth around the disk was observed and recorded
in mm. The screening results are given in Table 2.
The screening results indicate that all compounds
(except for 5a) are active against E. Coli and S. aureus.
Compound 7c shows the highest inhibitory effect against
all organism tests. Oxadiazole 7c also shows the highest
inhibition zone diameter against C. albicans (16 mm)
compared with Tolnaftate (10 mm), which was used as a
standard in the same procedure (500 lg diskꢀ1). Com-
pounds 4a, 4b, 5b, 7a, and 7c were found to be more
active against C. albicans than Tolnaftate, which is a
known antifungal drug. We can also compare the inhibi-
tory effects of compounds 4a–c with their products, pyra-
zoles 5a–c, after cyclization. For instance, after cycliza-
tion of 4b and 4c, the inhibitory effect of the resulting
pyrazoles 5b and 5c is essentially the same as before.
Interestingly, the inhibitory effect of 4a completely disap-
pears upon ring formation to 5a.
1389, 1290 (C¼¼N, C¼¼C), 719 (CASAC) cmꢀ1
;
1H NMR
(CDCl3, 500 MHz): dH 1.92 (s, 3H, CH3C¼¼O), 2.03 (s, 3H,
CH3-C¼¼N), 2.83 (s, 2H, N¼¼CACH2), 4.20 (s, 2H, SCH2),
5.35 (s, 2H, CH2N), 6.98 (d, J ¼ 7.6 Hz, 2H, phenyl), 7.22–
7.33 (m, 3H, phenyl), 7.38 (t, 1H, J ¼ 6.0 Hz, pyridyl), 7.83–
8.01 (m, 2H, pyridyl), 8.33 (d, 1H, J ¼ 5.2 Hz, pyridyl), 12.97
(br., 1H, NH); 13C NMR (CDCl3, 125 MHz): dC 16.3, 27.8,
38.1, 49.0, 51.6, 91.9, 121.2, 124.2, 127.0, 128.5, 128.3, 134.9,
136.9, 148.5, 149.0, 153.1, 155.3, 158.2, 169.3; Anal. Calcd
for C21H22N6O2S: C, 59.70; H, 5.25; N, 19.89; S, 7.59. Found:
C, 59.58; H, 5.27; N, 19.86; S, 7.61.
2-{[-4-Benzyl-5-(3-pyridyl)-4H-1,2,4-triazole-3-ylthio]-N(2)
[1-methyl-3-oxobutilidin]} acetohydrazine (4b) IR (KBr):
3360 (NAH), 3037 (CAHaromatic), 2991 (CAHaliphatic), 1709
(C¼¼O), 1611, 1488, 1415, 1294 (C¼¼N, C¼¼C), 723 (CASAC)
cmꢀ1 1H NMR (DMSO-d6, 500 MHz): dH 2.51 (s, 3H,
;
CH3C¼¼O), 2.54 (s, 3H, CH3-C¼¼N), 4.04 (s, 2H, N¼¼CACH2),
Table 2
Results of antimicrobial activity using the agar plate diffusion
techniquea (inhibition zone diameter in mm).
Escherichia
coli
Staphylococcus
aureus
Candida
albicans
Compound
4a
4b
4c
5a
5b
5c
7a
11
11
12
10
11
12
15
11
b
–
b
–
b
–
b
–
14
10
10
10
11
18
28
10
10
10
11
11
33
b
–
14
13
16
7b
7c
b
Gentamycinec
Tolnaftatec
–
10
b
–
b
–
In conclusion, we have synthesized some new 1,2,4-
triazole rings bearing 1,3,4-oxadiazole or pyrazole in a
single molecular framework and also were evaluated the
antimicrobial activities of these synthesized bicycles.
a The concentration of the tested compounds was 500 lg diskꢀ1
b Activity was not observed.
c Reference compound.
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011 Synthesis and Antimicrobial Activity of Some Novel Substituted 1,2,4-Triazoles
Bearing 1,3,4-Oxadiazoles or Pyrazoles
1369
4.10 (s, 2H, SCH2), 5.30 (s, 2H, CH2N), 6.91–7.30 (m, 5H,
phenyl), 7.50–8.70 (m, 4H, pyridyl), 12.95 (br., 1H, NH); Ms
(m/z, %): 422 (Mþ, 18), 368 (63), 299 (20), 281 (100), 267
(50), 234 (63), 91 (42). Anal. Calcd. for C21H22N6O2S: C,
59.70; H, 5.25; N, 19.89; S, 7.59. Found: C, 59.77; H, 5.26;
N, 19.85; S, 7.56.
Hz, phenyl), 7.34 (m, 3H, phenyl), 7.91 (d, 2H, J ¼ 5.0 Hz,
pyridyl), 8.83 (d, 2H, J ¼ 6.1 Hz, pyridyl); 13C NMR
(DMSO-d6, 125 MHz): dC 34.9, 48.4, 53.4 (Caliphatic), 103.8,
120.2, 124.9, 127.2, 129.0, 129.8, 135.4, 136.1, 140.5, 145.7,
152.9, 154.5 (Caromatic), 169.0 (AC¼¼O); Ms (m/z, %): 404
(Mþ, 8), 353 (21), 340 (100), 325 (8), 281 (56), 267 (50), 235
(15). Anal. Calcd. for C21H20N6OS: C, 62.36; H, 4.98; N,
20.78; S, 7.93. Found: C, 62.41; H, 5.01; N, 20.72; S, 7.90.
General procedure for synthesis of 4-Benzyl-5-(isomeric
pyridyl)-4H-1,2,4-triazol-3- ylethyl sulfides (6a–c). A solu-
tion of 1a–c (0.2 g, 70 mmol) in alkaline ethanol (0.04 g, 70
mmol KOH in 25 mL ethanol 95%) was mixed with ethyl iodide
(0.057 mL, 70 mmol) refluxed for 12–15 h. After cooling the
reaction mixture was poured in crushed ice. The precipitate was
separated by filtration, which then recrystallized from ethanol
and water to give the pure product. The reaction progress was
monitored by TLC (ethyl acetate/n-hexane, 8:5, Rf: 0.5).
2-{[-4-Benzyl-5-(4-pyridyl)-4H-1,2,4-triazole-3-ylthio]-N(2)
[1-methyl-3-oxobutilidin]} acetohydrazin, (4c). IR (KBr):
3317 (NH), 3009 (CAHaromatic), 2995 (CAHaliphatic), 1718
(C¼¼O), 1618, 1464, 1402, (C¼¼C, C¼¼N), 725 (CASAC)
cmꢀ1
;
1H NMR (CDCl3, 500 MHz): dH 1.85 (s, 3H,
CH3C¼¼O), 2.03 (s, 3H, CH3-C¼¼N), 3.02 (s, 2H, N¼¼CACH2),
4.46 (s, 2H, SCH2), 5.35 (s, 2H, CH2N), 7.05 (d, J ¼ 7.0 Hz,
2H, pyridyl), 7.32–7.39 (m, 3H, phenyl), 7.49 (d, J ¼ 5.7 Hz,
2H, pyridyl), 8.68 (d, J ¼ 4.9 Hz, 2H, pyridyl), 12.94 (br., 1H,
NH); 13C NMR (CDCl3, 125 MHz): dC 16.5, 27.2, 37.8, 48.8,
51.9, 92.2, 122.7, 126.4, 128.9, 129.7, 134.9, 135.3, 150.6,
153.5, 154.1, 156.2, 166.4; Anal. Calcd. for C21H22N6O2S: C,
59.70; H, 5.25; N, 19.89; S, 7.59. Found: C, 59.83; H, 5.24;
N, 19.91; S, 7.58.
General procedure for synthesis of 1-[(4-benzyl)-5-(iso-
meric pyridyl)-4H-1,2,4-triazol-3-ylthiomethyl carboxyl]-3,5-
dimethyl-1H-pyrazole, (5a–c). Compounds 4a–c (0.2 g, 0.47
mmol) was dissolved in absolute ethanol or methanol (25 mL),
then treated with HCl (37%, 0.2 mL) and refluxed for 22.5–30
h. The reaction mixture was then cooled and poured in to cold
water. The solid product was filtered, washed with water, and
recrystallized from ethyl acetate to give pure 5a–c. The reac-
tion progress was monitored by TLC (ethyl acetate/methanol,
5:6, Rf: 0.8).
4-Benzyl-5-(2-pyridyl)-4H-1,2,4-triazol-3-ylethyl sulfides (6a). IR
(KBr): 3080 (CAHaromatic), 2972 (CAHaliphatic), 1585, 1457,
1400 (C¼¼N, C¼¼C), 725 (CASAC) cmꢀ1
;
1H NMR (DMSO-
d6, 500 MHz): dH 1.30 (t, 3H, J ¼ 7.3, CH3), 3.10 (q, 2H, J ¼
7.3, CH2), 5.80 (s, 2H, NCH2), 7.12–7.31(m, 5H, phenyl),
7.49–8.66 (m, 4H, pyridyl); Ms (m/z, %): 296 (Mþ, 8), 297
(65), 235 (43), 213 (100), 184 (43), 91 (15). Anal. Calcd. for
C16H16N4S: C, 64.84; H, 5.44; N, 18.90; S, 10.82. Found: C,
64.61; H, 5.51; N, 18.83; S, 10.79.
4-Benzyl-5-(3-pyridyl)-4H-1,2,4-triazol-3-ylethyl sulfides (6b). IR
(KBr): 3020 (CAHaromatic), 2982 (CAHaliphatic), 1588, 1389,
1346 (C¼¼N, C¼¼C), 705 (CASAC) cmꢀ1
;
1H NMR (DMSO-
d6, 500 MHz): dH 1.30 (t, 3H, J ¼ 7.3, CH3), 3.20 (q, 2H, J ¼
7.3, CH2), 5.30 (s, 2H, CH2), 6.94–7.31 (m, 5H, phenyl),
7.52–8.75 (m, 4H, pyridyl); Ms (m/z, %): 296 (Mþ, 12), 297
(52), 235 (37), 213 (100), 184 (48), 91 (32). Anal. Calcd. for
C16H16N4S: C, 64.84; H, 5.44; N, 18.90; S, 10.82. Found: C,
65.05; H, 5.47; N, 18.82; S, 10.75.
1-[(4-Benzyl)-5-(2-pyridyl)-4H-1,2,4-triazol-3-ylthiomethyl-
carboxyl]-3,5-dimethyl-1H-pyrazole (5a). IR (KBr): 3047
(CAHaromatic), 2999 (CAHaliphatic), 1740 (C¼¼O), 1589, 1469,
1387, 1303 (C¼¼N, C¼¼C), 711 (CASAC) cmꢀ1
;
1H NMR
(DMSO-d6, 500 MHz): dH 2.38 (s, 6H, 2CH3 of pyrazole),
4.10 (s, 2H, SCH2), 5.85 (s, 2H, CH2N), 7.12 (d, 2H, J ¼ 7.7
Hz, phenyl), 7.26 (m, 3H, phenyl), 7.49 (t, 1H, J ¼ 6.1 Hz,
pyridyl), 7.96 (t, 1H, J ¼ 7.8 Hz, pyridyl), 8.13 (d, 1H, J ¼
8.0 Hz, pyridyl), 8.65 (d, 1H, J ¼ 4.3 Hz, pyridyl); Ms (m/z,
%): 404 (Mþ, 6), 353 (20), 340 (22), 325 (100), 282 (21), 267
(27), 235 (42). Anal. Calcd. for C21H20N6OS: C, 62.36; H,
4.98; N, 20.78; S, 7.93. Found: C, 62.19; H, 4.96; N, 20.82; S,
7.91.
4-Benzyl-5-(4-pyridyl)-4H-1,2,4-triazol-3-ylethyl sulfides (6c). IR
(KBr): 3040 (CAHaromatic), 2990 (CAHaliphatic), 1606, 1429,
1369, 1209 (C¼¼N, C¼¼C), 736 (CASAC) cmꢀ1
;
1H NMR
(DMSO-d6, 500 MHz): dH 1.30 (t, 3H, J ¼ 7.2 CH3), 3.10 (q,
2H, J ¼ 7.2, CH2), 5.30 (s, 2H, CH2), 6.96–7.34 (m, 5H, phe-
nyl), 7.60–8.69 (m, 4H, pyridyl); Ms (m/z, %): 296 (Mþ, 17),
297 (62), 235 (48), 213 (100), 184 (31), 9 (24). Anal. Calcd.
for C16H16N4S: C, 64.84; H, 5.44; N, 18.90; S, 10.82. Found:
C, 64.81; H, 5.45; N, 18.93; S, 10.79.
1-[(4-Benzyl)-5-(3-pyridyl)-4H-1,2,4-triazol-3-ylthiomethyl-
carboxyl]-3,5-dimethyl-1H-pyrazole (5b). IR (KBr): 3025
(CAHaromatic), 2892 (CAHaliphatic), 1734 (C¼¼O), 1604,
General procedure for synthesis of 5-[4-benzyl-5-(isomeric
pyridyl)-1,2,4-triazole-3-ylthiomethyl] oxadiazole-2(3H)-thione
(7a–c). Compounds, 3a–c (0.2 g, 0.58 mmol) were dissolved
in a solution of KOH in ethanol (1.6 mmol in 5 mL absolute
ethanol). The solution of carbon disulfide (1.16 mL, 19 mmol)
in absolute ethanol (15 mL) was added, and the reaction mix-
ture refluxed for 6–14 h. The reaction progress was monitored
by TLC (ethyl acetate/methanol, 1:1, Rf: 0.5). The mixture
was cooled to room temperature and diluted with water
(5 mL). Acidification with dilute hydrochloric acid gave a
white solid, which then filtered washed with water and recrys-
tallized from AcOH / H2O to give pure 7a, 7b and methanol
to give 7c.
1450,1303, 1164 (C¼¼N, C¼¼C), 709 (CASAC) cmꢀ1
;
1H
NMR (DMSO-d6, 500 MHz): dH 2.30 (s, 6H, 2CH3 of pyraz-
ole), 4.20 (s, 2H, SCH2), 5.30 (s, 2H, CH2N), 6.30 (s, 1H, CH
of pyrazole), 7.00 (d, 2H, J ¼ 5.1 Hz, phenyl), 7.30 (m, 3H,
phenyl), 7.67 (t, 1H, J ¼ 5.2 Hz, pyridyl), 8.18 (d, 1H, J ¼
7.9 Hz, pyridyl), 8.77 (d, 1H, J ¼ 5.0 Hz, pyridyl) and 8.85 (s,
1H, pyridyl); Ms (m/z, %): 404 (Mþ, 5), 340 (64), 309 (14),
281 (22), 267 (13), 94 (100), 95 (85), 91 (84). Anal. Cald. for
C21H20N6OS: C, 62.36; H, 4.98; N, 20.78; S, 7.93. Found: C,
62.23; H, 4.94; N, 20.69; S, 7.96.
1-[(4-Benzyl)-5-(4-pyridyl)-4H-1,2,4-triazol-3-ylthiomethyl-
carboxyl]-3,5-dimethyl-1H-pyrazole (5c). IR (KBr): 3084
(CAHaromatic), 2964 (CAHaliphatic), 1743 (C¼¼O), 1635, 1496,
5-[4-Benzyl-5-(2-pyridyl)-1,2,4-triazole-3-ylthiomethyl]oxa-
diazole-2(3H)-thione (7a). IR (KBr): 3311 (NH), 2935
(CAHaliphatic), 2520–2610 (SH), 1734 (C¼¼N) of oxadiazole,
1379, 1165 (C¼¼N, C¼¼C), 740 (CASAC) cmꢀ1
;
1H NMR
1479, 1432, 1377, 1352 (C¼¼N, C¼¼C), 727 (CASAC) cmꢀ1
;
(DMSO-d6, 500 MHz): dH 2.33 (s, 6H, 2CH3 of pyrazole),
4.20 (s, 2H, SCH2), 5.41 (s, 2H, CH2N), 7.05 (d, 2H, J ¼ 7.5
1H NMR (DMSO-d6, 500 MHz): dH 4.00 (s, 2H, SCH2), 5.80
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1370
M. Kalhor, A. Mobinikhaledi, A. Dadras, and M. Tohidpour
Vol 48
[5] Gogoi, P. C.; Kataky, J. Indian
1159.
[6] El-masry, A. H.; Fahmy, H. H.; Abdelwahed, S. H. A. Mol-
ecules 2000, 5, 1429.
[7] Maslat, A. O.; Abussaud, M.; Tashtoush, H.; Al-Talib, M.
J
Chem 1990, 29B,
(s, 2H, CH2N), 7.12–7.31 (m, 5H, phenyl), 7.48–8.66 (m, 4H,
pyridyl), 13.00 (br., 1H, NH); Ms (m/z, %): 382 (Mþ, 13), 325
(60), 281 (22), 267 (9), 235 (43), 91 (100). Anal. Calcd. for
C17H14N6OS2: C, 53.39; H, 3.69; N, 21.97; S, 16.77. Found:
C, 53.25; H, 3.70; N, 22.04; S, 16.74.
Pol J Phrmacol 2002, 54, 55.
5-[4-Benzyl-5-(3-pyridyl)-1,2,4-triazole-3-ylthiomethyl][oxa-
diazole-2(3H)-thione (7b). IR (KBr): 3020 (CAHaromatic), 2982
(CAHaliphatic), 1707 (C¼¼N) of oxadiazole ring, 1604, 1473, 1415
[8] Omar, F. A.; Mahfouz, N. M.; Rahman, M. A. Eur J Med
Chem 1996, 31, 819.
[9] Li, Y.; Liu, J.; Zhang, H.; Yanga, X.; Liub, Z. Bioorg Med
Chem Lett 2006, 16, 2278.
(C¼¼N, C¼¼C), 1294 (C¼¼S), 721 (CASAC) cmꢀ1
;
1H NMR
(DMSO-d6, 500 MHz): dH 4.10 (s, 2H, SCH2), 5.30 (s, 2H,
CH2N), 6.99–7.31 (m, 5H, phenyl), 7.52–8.77 (m, 4H, pyridyl),
13.00 (br., H, NH); 13C NMR (DMSO-d6, 125 MHz): dC 35.6,
48.3 (Caliphatic), 124.1, 124.6, 127.1, 128.8, 129.7, 135.0 136.0,
149.3, 151.2, 151.8, 152.4, 153.9, (Caromatic), 170.2 (C¼¼S); Ms (m/
z, %): 382 (Mþ, 25), 325 (15), 281 (88), 280 (100), 267 (44), 235
(21), 91 (50). Anal. Calcd. for C17H14N6OS2: C, 53.39; H, 3.69; N,
21.97; S, 16.77. Found: C, 53.51; H, 3.70; N, 21.89; S, 16.75.
5-[4-Benzyl-5-(4-pyridyl)-1,2,4-triazole-3-ylthiomethyl]oxa-
diazole-2(3H)-thione (7c). IR (KBr): 3294 (NH), 3037
(CAHaromatic), 2982 (CAHaliphatic), 1722 (C¼¼N) of oxadiazole,
1618, 1464, 1394 (C¼¼N, C¼¼C), 1215 (C¼¼S), 725 (CASAC)
[10] Chen, Q.; Zhu, X. L.; Jiang, L. L.; Liu, Z. M.; Yang, G. F.
Eur J Med Chem 2008, 43, 595.
[11] Chen, Q.; Liu, Z. M.; Chen, C. N.; Jiang, L. L.; Yang, G.
F. Chem Biodivers 2009, 6, 1254.
[12] Liu, Z.; Yang, G.; Qin, X. J Chem Technol Biotechnol
2001, 76, 1154.
[13] Singh, P.; Paula, K.; Holzer, W. Bioorg Med Chem 2006,
14, 5061.
[14] Suzuki, H.; Hanaue, M.; Nishikubo, M. Jpn. Kokai Tokkyo
Koho JP03,236,368,1993; Suzuki, H.; Hanaue, M.; Nishikubo, M.
Chem Abstr 116, 106285.
[15] Ahmad, R.; Zia-Ul-Haq, M.; Jabeen, R.; Duddeck, H. Turk
J Chem 1996, 20, 186.
cmꢀ1 1H NMR (DMSO-d6, 500 MHz): dH 4.10 (s, 2H,
;
[16] Zhao, P. L.; Wang, L; Xiao-Lei Zhu, X. L.; Huang, X.;
Zhan, C. G.; Wu, J. W.; Yang, G. F. J Am Chem Soc 2010, 132,
185.
SCH2), 5.30 (s, 2H, CH2N), 7.01–7.34 (m, 5H, phenyl), 7.54–
7.69 (m, 4H, pyridyl), 13.10 (br., 1H, NH); Ms (m/z, %): 382
(Mþ, 4), 325 (7), 281 (100), 267 (18), 91 (32). Anal. Calcd.
for C17H14N6OS2: C, 53.39; H, 3.69; N, 21.97; S, 16.77.
Found: C, 53.55; H, 3.68; N, 21.96; S, 16.81.
[17] Zhao, P. L.; Wang, F.; Zhang, M. Z.; Liu, Z. M.; Huang,
W.; Yang, G. F. J Agric Food Chem 2008, 56, 10767.
[18] Zaki, M. E. A. Molecules 1998, 3, 71.
[19] Wheate, N. J., Broomhead, J. A.; Collins, J. G.; Day, A. I.
Aust J Chem 2001, 54, 141.
Acknowledgments. We thank the Chemistry Department of
Arak University for providing financial support and the Mi-
crobiology Department of Islamic Azad University, Shahre
Ghods Branch of Tehran for the evaluation of the biological
activities.
[20] Almerico, A. M.; Lauria, A.; Diana, P.; Barraja, P.; Cirrin-
cione, G.; Dattolo, G. Arkivoc 2000, 1, 486.
[21] Yoo, B. R.; Suk, M. Y.; Yu, Y.; Hong, S.; Jung, N. Bull
Korean Chem Soc 1998, 19, 358.
[22] Colanceska-Ragenovic, K.; Dimova, V.; Kakurinov, V.;
Molnar, D. G.; Buzarovskal, A. Molecules 2001, 6, 815.
[23] Mobinikhaledi, A.; Foroughifar, N.; Alipour Safari, J.;
Amini, E. J Heterocycl Chem 2007, 44, 697.
[24] Mobinikhaledi, A.; Foroughifar, N.; Kalhor, M.; Mirabolfa-
thy M. J Heterocycl Chem 2010, 47, 77.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet