Hypervalent iodine(III) mediated synthesis of novel unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles as antibacterial and antifungal agents

Article abstract of DOI:10.1016/j.ejmech.2010.06.023

A series of novel 2,5-disubstituted 1,3,4-oxadiazoles 4 have been conveniently synthesized by oxidative cyclization of pyrazolylaldehyde N-acylhydrazones 3 promoted by iodobenzene diacetate under mild conditions (11 examples, up to 92% isolated yields). All the eleven compounds were tested in vitro for their antibacterial activity against Gram-positive bacteria namely, Staphylococcus aureus, Bacillus subtilis and two Gram-negative bacteria namely, Escherichia coli and Pseudomonas aeruginosa. All the synthesized compounds were also tested for their inhibitory action against two strains of fungus. A series of novel 2,5-disubstituted 1,3,4-oxadiazoles 4 have been conveniently synthesized by oxidative cyclization of pyrazolylaldehyde N-acylhydrazones 3 promoted by iodobenzene diacetate under mild conditions (11 examples, up to 92% isolated yields).

Full text of DOI:10.1016/j.ejmech.2010.06.023

European Journal of Medicinal Chemistry 45 (2010) 4252e4257
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Hypervalent iodine(III) mediated synthesis of novel unsymmetrical
2,5-disubstituted 1,3,4-oxadiazoles as antibacterial and antifungal agents
,
a
b
c
c
Om Prakash a , Manoj Kumar , Rajesh Kumar , Chetan Sharma , K.R. Aneja
*
a Department of Chemistry, Kurukshetra University, Kurukshetra 136 119, Haryana, India
b Post Graduate Department of Chemistry, M. L. N. College, Yamuna Nagar 135001, Haryana, India
c Department of Microbiology, Kurukshetra University, Kurukshetra 136 119, Haryana, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 2,5-disubstituted 1,3,4-oxadiazoles 4 have been conveniently synthesized by oxidative
cyclization of pyrazolylaldehyde N-acylhydrazones 3 promoted by iodobenzene diacetate under mild
conditions (11 examples, up to 92% isolated yields). All the eleven compounds were tested in vitro for
their antibacterial activity against Gram-positive bacteria namely, Staphylococcus aureus, Bacillus subtilis
and two Gram-negative bacteria namely, Escherichia coli and Pseudomonas aeruginosa. All the synthe-
sized compounds were also tested for their inhibitory action against two strains of fungus.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Received 11 November 2009
Received in revised form
3 June 2010
Accepted 15 June 2010
Available online 22 June 2010
Keywords:
2,5-Disubstituted 1,3,4-oxadiazoles
Oxidative cyclization
Iodobenzene diacetate
Antibacterial activity
Antifungal activity
1. Introduction
reagents have been successfully proven their usefulness as agents
foroxidative cyclization of aldehyde N-acylhydrazones tosynthesize
Among five-membered aromatic heterocycles, 1,3,4-oxadiazoles
[1,2] are of particular interest, since some of the members belonging
to this class display various biological activities including 5-HT-
receptor antagonists [3], muscarinic receptor agonists [4,5], benzo-
diazepine receptor agonists [6], or tyrosinase inhibitors [7].
Oxadiazoles exhibit important biological activities such as anti-
inflammatory [8], anticonvulsant [9,10], analgesic [11], antibacterial
[12] and muscle relaxant properties [13]. Pyrazole nucleus has
pronounced pharmacological applications as anti-anxiety [14],
antidiabetic [15], antimicrobial [16e18], herbicidal [19,20], anti-
inflammatory drugs [21] and antibacterial [22e24]. Besides the
dehydration of diacylhydrazines, oxidative cyclization of aldehyde
N-acylhydrazones is the most known method to prepare unsym-
metrically 2,5-disubstituted 1,3,4-oxadiazoles, and several reagents
have been reported to in the literature which include oxidation with
ceric ammonium nitrate [25], chloramine T [26], lead tetraacetate
[27,28], potassium permanganate under microwaves conditions
[29], ferric chloride [30], bromine/sodium acetate [31], or yellow
mercuric oxide/iodine [32]. In recent years, hypervalent iodine
2,5-disubstituted 1,3,4-oxadiazoles [33e38]. In continuation of our
ongoing interestin the developmentof hypervalent iodine mediated
methodologies in heterocyclic synthesis coupled with the signifi-
cant biological importance of oxadiazoles and pyrazole derivatives,
prompted us to undertake the synthesis of hitherto unknown 2,5-
disubstituted 1,3,4-oxadiazoles. We report herein synthesis of
unsymmetrically 2,5-disubstituted 1,3,4-oxadiazoles by the oxida-
tion of pyrazolylaldehyde N-acylhydrazones using iodobenzene
diacetate (IBD) in dichloromethane with an expectation to find new
and more potent antibacterial and antifungal agents.
2. Chemistry
We have synthesized a series of pyrazolylaldehyde N-acylhy-
drazones in order to test the scope of their oxidative cyclization.
These substrates are easily accessible in high yields and purity from
N-benzoylhydrazine and formylpyrazoles. Accordingly, an etha-
nolic solution of N-benzoylhyrazine was refluxed with for-
mylpyrazoles in the presence of two drops of acetic acid for about
1e2 h. Usual work-up of the reaction afforded the pure pyr-
azolylaldehyde N-benzoylhydrazones (3ae3k) in 88e96% yields
(Scheme 1, Table 1) [39]. The structures of all the new compounds 3
were confirmed by their elemental analysis and also spectral
* Corresponding author. Tel.: þ91 1744 234366; fax: þ91 1744 238277.
E-mail addresses: dromprakash50@rediffmail.com (O. Prakash), rajesh_chem12a@
rediffmail.com (R. Kumar).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.06.023

O. Prakash et al. / European Journal of Medicinal Chemistry 45 (2010) 4252e4257
4253
Ar
N
Ar
N
N
N
O
O
EtOH
reflux
+
N
Ar'
Ph
NHNH2
Ph
N
H
CHO
Ar'
3
1
2
stirring at room temp.
PhI(OAc)2, CH2Cl2
Ar'
N
N
Ph
N
N
O
Ar
4
Scheme 1. Synthesis of 1,3,4-oxadiazoles 4 from N-benzoylhydrazones 3 using iodobenzene diacetate.
techniques (IR, 1H NMR). The IR spectra of the compound 3a
exhibited characteristic absorption band at 1643 cmꢀ1 and
3217 cmꢀ1 due to for carbonyl and NH functional groups, respec-
tively. The 1H NMR spectra of the products 3a showed two singlet
characterization of products 4 was based upon a careful compar-
ison of their IR and 1H NMR spectra with those of 3. IR spectra of 4
were found to be transparent in the region of NH stretch and NH
bends and also CO stretch, thus confirming the oxidation of 3 into 4.
An important characteristic feature in the 1H NMR spectra of 4 was
due to C(5)-H of pyrazole ring and N]CH at
d
8.41 and
d 8.54,
respectively and also a broad singlet due to NH at
disappears on addition of D2O. Other protons appeared as multiplet
in the aromatic regions.
d
9.69 which is
the disappearance of the singlet due to N]CH around
which present in the spectra of 3.
The mechanism of this transformation is plausible which is
analogous to earlier reports [37,38].
d 8.51e8.68,
Initially, the reaction of pyrazolylaldehyde N-acylhydrazone (3a)
was carried out with 1.1 equivalents of IBD in dichloromethane by
stirring at room temperature for 15e20 min. The usual work-up of
the reaction afforded single product 2,5-disubstituted 1,3,4-oxa-
diazoles (4a) in 90% yield. To study the scope of reaction, we
studied oxidation of a wide range of substituted pyrazolylaldehyde
N-acylhydrazones (3be3k) under similar conditions. It was
observed that IBD mediated oxidative approach worked nicely to
give the desired products 4be4g in all cases in 80e92% yields
(Scheme 1, Table 1).
3. Antibacterial activity
All the eleven compounds 4 were tested in vitro for their anti-
bacterial activity against two Gram-positive bacteria namely,
Staphylococcus aureus (MTCC 96), Bacillus subtilis (MTCC 121), and
two Gram-negative bacteria namely, Escherichia coli (MTCC 1652)
The structures of all new compounds 4 were confirmed by
Table 2
their spectral (IR, 1H NMR) and elemental analytical data. The
Antibacterial activity of compounds 4 by using agar well diffusion assay method.
Compounds
Diameter of growth of inhibition zone (mm)a
Staphylococcus
aureus
Bacillus
subtilis
Escherichia
coli
Pseudomonas
aeruginosa
Table 1
Synthesis of bezoylhydrazones 3 and 1,3,4-oxadiazoles 4.
4a
4b
4c
4d
4e
4f
4g
4h
20.3
21.6
18.6
20
18.3
22.6
23.3
20.6
24.3
21.3
22.6
26.0
18.6
19.6
20.6
18.3
21.6
20.3
21.6
24.3
23.6
24.3
23.6
24.0
14.3
15.6
14.3
16.6
15.6
16.3
15.6
18.6
20.6
20
13.6
13.6
14.3
14.6
13.6
14
14.3
15.3
18.6
16.6
14.6
22.0
Entry
Product 3
Product 4
Ar
Ar0
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-CleC6H4
4-FeC6H4
4-BreC6H4
4-MeeC6H4
4-OMeeC6H4
4-NO2eC6H4
Ph
4-OMeeC6H4
4-FeC6H4
4-NO2eC6H4
4i
4j
4k
4-NO2eC6H4
4-NO2eC6H4
4-NO2eC6H4
4-NO2eC6H4
9
10
11
18.3
25.0
3j
3k
4j
4k
Ciprofloxacin
a
Values, including diameter of the well (8 mm), are means of three replicates.

4254
O. Prakash et al. / European Journal of Medicinal Chemistry 45 (2010) 4252e4257
Table 3
used for comparison with antifungal activity shown by compounds
4ae4k. A careful analysis of percentage mycelial growth inhibition
revealed that almost all of the newly synthesized compounds 4
showed comparable antifungal activity with commercial antibiotic
Fluconazole as shown in Table 4. Compounds 4e and 4h showed
maximum inhibition against both of the fungi, A. niger (66.6) and A.
flavus (66.6). Compound 4c was found more effective against A.
niger (66.6). It also inhibited the growth of A. flavus (50).
Compounds 4a, 4f and 4g also showed maximum inhibition against
A. flavus (66.6), but both inhibited the growth of A. niger (44.4).
Compounds 4b, 4d, 4i, 4j and 4k displayed almost same inhibition
against both of the fungi.
Minimum inhibitory concentration (MIC) (in
macrodilution method.
mg/ml) of compounds 4 by using
Compounds
MIC (m
g/ml)a
Staphylococcus
aureus
Bacillus
Subtilis
Escherichia
coli
Pseudomonas
aeruginosa
4a
4b
4c
4d
4e
4f
4g
4h
64
32
128
64
128
16
8
64
8
32
16
5
128
64
32
128
16
32
16
8
8
8
8
5
>128
>128
>128
128
>128
128
>128
128
64
>128
>128
>128
>128
>128
>128
>128
>128
64
4i
4j
4k
5. Conclusion
64
128
128
5
>128
5
We have described herein an efficient and convenient synthesis
of unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles via the
oxidative cyclization of N-benzoyl-N0-pyrazolidene hydrazines,
thereby emphasizing the increasing utility of hypervalent iodine
(III) mediated methods and this method stands as a feasible alter-
native for convenient access to this class of heterocycles. The
antibacterial and antifungal activities of compounds have proved
them potent antibacterial and antifungal agents.
Ciprofloxacin
a
Mean of three replicates.
and Pseudomonas aeruginosa (MTCC 741) (Tables
2 and 3).
Minimum Inhibitory concentration (MIC) of those compounds was
determined which are showing activity in primary screening.
Standard antibiotics namely Ciprofloxacin was used for comparison
with antibacterial activity shown by compounds 4ae4g. All the
compounds of the tested series possessed good antimicrobial
activity. Two of these compounds 4i and 4j exhibited good anti-
bacterial activity against both Gram-positive and Gram-negative
bacteria. In case of Gram-positive bacteria compounds 4g and 4i
were found to be most effective against S. aureus with zone of
inhibition ranging between 23.3 and 24.3 and compounds 4h, 4i, 4j,
and 4k were most effective against B. subtilis, with zone of inhibi-
tion ranging between 23.6 and 24.3. However, in case of Gram-
negative bacteria, compound 4i and 4j were found to be most
effective against E. coli and P. aeruginosa with zone of inhibition
ranging between 16.6 and 20.6 (Table 2).
6. Experimental
Melting points were determined in open capillaries with elec-
trical melting point apparatus and are uncorrected. The IR spectra
were obtained with a Buck Scientific IR M-500 spectrophotometer.
The 1H NMR spectra were recorded on a Bruker (300 MHz) spec-
trometer using tetramethylsilane as an internal standard. All the
new compounds gave satisfactory analytical results (within 0.4 of
the theoretical values). The starting material formylpyrazoles were
prepared by literature method [40].
6.1. N-Benzoyl-N0-pyrazolylidene hydrazines 3
In the whole series, compounds 4g and 4i showed maximum
antibacterial activity against S. aureus (MIC
compounds 4h, 4i, 4j and 4k against B. subtilis (MIC 8
whereas in case of Gram-negative bacteria lowest MIC was found to
be 64 g/ml in case of E. coli by compounds 4i and 4j and 64 g/ml
8
m
g/ml) and
General procedure: To an ethanolic solution of phenyl hydrazide
(1, 0.01 mol) was added formylpyrazoles (2, 0.011 mol) and the
solution was refluxed in the presence of two drops of acetic acid for
1e2 h. The solvent was evaporated in vacuo to half its volume and
cool to room temperature. The solid obtained was filtered and
washed with ethanol.
mg/ml)
m
m
in case of P aeruginosa by compound 4i (Table 3).
4. Antifungal activity
6.1.1. N-Benzoyl-N0-(1,3-diphenyl-4-pyrazolylidene) hydrazine (3a)
Yield 96%, Mp 180e182 ꢁC, IR (nmax, in KBr): 3217 cmꢀ1 (eNH
All the eleven compounds were tested in vitro for their anti-
fungal activity against two fungi, namely Aspergillus niger and
Aspergillus flavus. Standard antibiotics namely Fluconazole was
str.), 1641 cmꢀ1 (C]O str.); 1H NMR (CDCl3, 300 MHz):
d 7.32e7.35
(m, 3H), 7.45e7.49 (m, 4H), 7.51e7.55 (m, 3H), 7.70e7.79 (m, 5H),
8.41 (s, 1H), 8.51 (s, 1H), 10.06 (s, 1H, exchangeable with D2O); Anal.
Calculated for C23H18N4O: C 75.41, H 4.92, N 15.30; Found: C 75.11, H
4.76, N 15.38.
Table 4
In vitro antifungal activity of compounds 4 using poisoned food method.
Compounds
Mycelial growth inhibition (%)a
6.1.2. N-Benzoyl-N0-[1-phenyl-3-(4-chlorophenyl)-4-
pyrazolylidene] hydrazine (3b)
Aspergillus niger
Aspergillus flavus
Yield 92%, Mp 212e214 ꢁC, IR (nmax, in KBr): 3220 cmꢀ1 (eNH
4a
4b
4c
4d
4e
4f
4g
4h
44.4
55.5
66.6
61.1
66.6
44.4
50
66.6
55.5
44.4
55.5
81.1
61.1
44.4
50
55.5
61.1
66.6
61.1
66.6
50
str.), 1643 cmꢀ1 (C]O str.); 1H NMR (CDCl3, 300 MHz):
d 7.30e7.36
(m, 3H), 7.41e7.48 (m, 4H), 7.53e7.57 (m, 3H), 7.68e7.71 (m, 2H),
7.92e7.95 (m, 2H), 8.41 (s, 1H), 8.51 (s, 1H), 10.06 (s, 1H,
exchangeable with D2O); Anal. Calculated for C23H17N4OCl: C 68.91,
H 4.24, N 13.98; Found: C 68.71, H 4.22, N 14.07.
4i
4j
4k
6.1.3. N-Benzoyl-N0-[1-phenyl-3-(4-fluorophenyl)-4-
pyrazolylidene] hydrazine (3c)
55.5
44.4
77.7
Yield 88%, Mp 210e212 ꢁC, IR (nmax, in KBr): 3220 cmꢀ1 (eNH
Fluconazole
str.), 1645 cmꢀ1 (C]O str.); 1H NMR (CDCl3, 300 MHz):
d 7.17
a
Mean of three replicates.

O. Prakash et al. / European Journal of Medicinal Chemistry 45 (2010) 4252e4257
4255
(m, 2H), 7.33e7.38 (m, 1H), 7.45e7.57 (m, 5H), 7.65e7.69 (m, 2H),
7.80 (m, 2H), 7.89e7.91 (m, 2H), 8.42 (s, 1H), 8.68 (s, 1H), 9.64 (s, 1H,
exchangeable with D2O); Anal. Calculated for C23H17N4OF: C 71.87,
H 4.43, N 14.58; Found: C 71.92, H 4.34, N 14.69.
J ¼ 8.1 Hz), 7.37e7.49 (m, 3H), 7.45 (d, 2H, J ¼ 8.1 Hz), 7.88e7.90 (m,
2H), 7.97 (d, 2H, J ¼ 8.7 Hz), 8.27 (d, 2H, J ¼ 8.7 Hz), 8.52 (s, 1H), 8.75
(s, 1H), 11.6 (s, 1H, exchangeable with D2O); Anal. Calculated for
C23H16N5O3: C 64.33, H 3.73, N 16.32; Found: C 64.26, H 3.61,
N 16.45.
6.1.4. N-Benzoyl-N0-[1-phenyl-3-(4-bromophenyl)-4-
pyrazolylidene] hydrazine (3d)
6.1.11. N-Benzoyl-N0-[1,3-di(4-nitrophenyl)-4-pyrazolylidene]
hydrazine (3k)
Yield 90%, Mp 220e222 ꢁC, IR (nmax, in KBr): 3226 cmꢀ1 (eNH
str.), 1639 cmꢀ1 (C]O str.); 1H NMR (CDCl3, 300 MHz):
d
7.30e7.36
Yield 92%, Mp 230e232 ꢁC, IR (nmax, in KBr): 3224 cmꢀ1 (eNH
(m, 3H), 7.41e7.48 (m, 4H), 7.53e7.57 (m, 3H), 7.68e7.71 (m, 2H),
7.92e7.95 (m, 2H), 8.41 (s, 1H), 8.51 (s, 1H), 10.06 (s, 1H,
exchangeable with D2O); Anal. Calculated for C23H17N4OBr: C 62.03,
H 3.82, N 12.59; Found: C 61.93, H 3.88, N 12.54.
str.), 1641 cmꢀ1 (C]O str.); 1H NMR (CDCl3, 300 MHz):
d 7.37e7.49
(m, 3H), 7.87 (d, 2H, J ¼ 8.1 Hz), 7.88e7.90 (m, 2H), 7.97 (d, 2H,
J ¼ 8.7 Hz), 8.27 (d, 2H, J ¼ 8.7 Hz), 8.39 (d, 2H, J ¼ 8.1 Hz), 8.52 (s,
1H), 8.75 (s, 1H), 11.6 (s, 1H, exchangeable with D2O); Anal. Calcu-
lated for C23H16N6O5: C 60.53, H 3.51, N 18.42; Found: C 60.45, H
3.36, N 18.73.
6.1.5. N-Benzoyl-N0-[1-phenyl-3-(4-methylphenyl)-4-
pyrazolylidene] hydrazine (3e)
Yield 96%, Mp 220e222 ꢁC, IR (nmax, in KBr): 3234 cmꢀ1 (eNH
6.2. 2,5-Disubstituted 1,3,4-oxadiazoles 4
str.), 1644 cmꢀ1(C]O str.); 1H NMR (CDCl3, 300 MHz):
d 2.36 (s, 3H,
CH3), 7.22e7.28 (m, 3H), 7.45e7.52 (m, 7H), 7.73e7.75 (m, 2H),
7.90e7.92 (m, 2H), 8.35 (s, 1H), 8.58 (s, 1H), 9.84 (s, 1H, exchange-
able with D2O); Anal. Calculated for C24H20N4O: C 75.79, H 5.26,
N 14.74; Found: C 75.78, H 5.32, N 14.71.
General procedure: To a stirred solution of 3 (0.001 mol) in
dichloromethane (25 mL) at room temperature was added IBD
(0.011 mol) in four to five portions during 5 min and the mixture
was stirred for 20e30 min. The solvent was evaporated on a steam
bath and the residual mass containing product and iodobenzene
triturated with petroleum ether to give solid product, which was
recrystallised from methanol to yield pure 2,5-disubstituted 1,3,4-
oxadiazoles 4 in 80e92% yields.
6.1.6. N-Benzoyl-N0-[1-phenyl-3-(4-methoxyphenyl)-4-
pyrazolylidene] hydrazine (3f)
Yield 95%, Mp 208e210 ꢁC, IR (nmax, in KBr): 3217 cmꢀ1 (eNH
str.), 1643 cmꢀ1(C]O str.); 1H NMR (CDCl3, 300 MHz):
d 3.86 (s, 3H,
OCH3), 7.00 (d, 2H, J ¼ 8.7), 7.32e7.36 (m, 1H), 7.46e7.52 (m, 5H),
7.59 (d, 2H, J ¼ 8.7 Hz), 7.78e7.81 (m, 2H), 7.87e7.89 (m, 2H), 8.29
(s, 1H), 8.67 (s, 1H), 9.35 (s, 1H, exchangeable with D2O); Anal.
Calculated for C24H20N4O2: C 72.73, H 5.05, N 14.14; Found: C 72.61,
H 4.98, N 14.19.
6.2.1. 2-Phenyl-5-(1,3-diphenyl-4-pyrazolyl) 1,3,4-oxadiazole (4a)
Yield 90%, mp 136e138 ꢁC, IR (nmax, in KBr): transparent in the
region of eNH str. and C]O str.; 1H NMR (CDCl3, 300 MHz):
d
7.37e7.43 (m, 1H), 7.49e7.54 (m, 8H), 7.84e7.86 (m, 2H),
7.93e7.99 (m, 4H), 8.76 (s, 1H); 13C NMR (CDCl3, 300 MHz):
d
106.3,
119.2,119.7,123.8,126.7,126.9, 127.4,127.8, 129.0, 129.4, 129.6, 130.1,
131.6, 139.1, 159.9, 163.8; Anal. Calculated for C23H16N4O: C 75.82, H
4.39, N 15.38; Found: C 75.81, H 4.34, N 15.41.
6.1.7. N-Benzoyl-N0-[1-phenyl-3-(4-nitrophenyl)-4-pyrazolylidene]
hydrazine (3g)
Yield 95%, Mp 228e230 ꢁC, IR (nmax, in KBr): 3221 cmꢀ1 (eNH
str.), 1641 cmꢀ1(C]O str.); 1H NMR (CDCl3, 300 MHz):
d
7.37e7.42
6.2.2. 2-Phenyl-5-[1-phenyl-3-(4-chlorophenyl)-4-pyrazolyl] 1,3,4-
oxadiazole (4b)
(m, 1H), 7.49e7.57 (m, 5H), 7.78e7.81 (m, 2H), 7.89e7.92 (m, 4H),
8.31 (d, 2H, J ¼ 7.8), 8.48 (s, 1H), 8.67 (s, 1H), 9.60 (s, 1H,
exchangeable with D2O); Anal. Calculated for C23H17N5O3: C 67.15,
H 4.14, N 17.03; Found: C 67.16, H 4.12, N 17.05.
Yield 86%, mp 168e170 ꢁC, IR (nmax, in KBr): transparent in the
region of eNH str. and C]O str.; 1H NMR (CDCl3, 300 MHz):
d
7.26e7.28 (m, 2H), 7.42e7.45 (m, 1H), 7.49 (d, 2H, J ¼ 9.0 Hz),
7.53e7.61 (m, 3H), 7.84e7.87 (m, 2H), 7.97 (d, 2H, J ¼ 9.0 Hz),
8.00e8.03 (m, 2H), 8.73 (s, 1H); 13C NMR (CDCl3, 300 MHz):
106.4,
6.1.8. N-Benzoyl-N0-[1-(4-nitrophenyl)-3-phenyl-4-pyrazolylidene]
hydrazine (3h)
d
119.4,123.6, 126.8,127.5,128.5, 129.1,129.5, 129.7, 130.2, 130.7,131.7,
139.2, 150.6, 159.6, 163.9; Anal. Calculated for C23H15N4OCl: C 69.26,
H 3.76, N 14.05; Found: C 69.21, H 3.77, N 14.05.
Yield 94%, Mp 226e228 ꢁC, IR (nmax, in KBr): 3220 cmꢀ1 (eNH
str.), 1643 cmꢀ1 (C]O str.); 1H NMR (CDCl3, 300 MHz):
d 7.51e7.62
(m, 6H), 7.67e7.70 (m, 2H), 7.83e7.87 (m, 2H), 8.01e8.06 (m, 2H),
8.39e8.45 (m, 3H), 8.82 (s, 1H), 10.12 (s, 1H, exchangeable with
D2O); Anal. Calculated for C23H17N5O3: C 67.15, H 4.14, N 17.03;
Found: C 67.09, H 4.06, N 17.02.
6.2.3. 2-Phenyl-5-[1-phenyl-3-(4-fluorophenyl)-4-pyrazolyl] 1,3,4-
oxadiazole (4c)
Yield 82%, mp 134e136 ꢁC, IR (nmax, in KBr): transparent in the
region of eNH str. and C]O str.; 1H NMR (CDCl3, 300 MHz):
6.1.9. N-Benzoyl-N0-[1-(4-nitrophenyl)-3-(4-methoxyphenyl)-4-
pyrazolylidene] hydrazine (3i)
d
7.24e7.25 (t, 2H, J ¼ 8.7 Hz), 7.41e7.43 (m, 1H), 7.55e7.58 (m, 5H),
7.84e7.87 (d, 2H, J ¼ 9.0 Hz), 7.97e8.02 (m, 4H), 8.69 (s, 1H); 13C
Yield 95%, Mp 234e236 ꢁC, IR (nmax, in KBr): 3228 cmꢀ1 (eNH
NMR (CDCl3, 300 MHz): d 106.4, 119.5, 123.7, 126.8, 127.7, 127.9,
str.),1643 cmꢀ1 (C]O str.); 1H NMR (CDCl3, 300 MHz):
d
3.78 (s, 3H,
129.1, 129.4, 129.7, 130.9, 131.1, 131.7, 139.1, 150.9, 159.8, 163.9; Anal.
Calculated for C23H15N4OF: C 72.25, H 3.93, N 14.66; Found: C 72.03,
H 3.83, N 14.78.
OCH3), 6.93 (d, 2H, J ¼ 8.1 Hz), 7.37e7.49 (m, 3H), 7.58 (d, 2H,
J ¼ 8.1 Hz), 7.88e7.90 (m, 2H), 7.97 (d, 2H, J ¼ 8.7 Hz), 8.27 (d, 2H,
J ¼ 8.7 Hz), 8.52 (s, 1H), 8.75 (s, 1H), 11.6 (s, 1H, exchangeable with
D2O); Anal. Calculated for C24H19N5O4: C 65.31, H 4.31, N 15.87;
Found: C 65.34, H 4.32, N 15.85.
6.2.4. 2-Phenyl-5-[1-phenyl-3-(4-bromophenyl)-4-pyrazolyl] 1,3,4-
oxadiazole (4d)
Yield 92%, mp 178e180 ꢁC, IR (nmax, in KBr): transparent in the
6.1.10. N-Benzoyl-N0-[1-(4-nitrophenyl)-3-(4-fluorophenyl)-4-
pyrazolylidene] hydrazine (3j)
region of eNH str. and C]O str.; 1H NMR (CDCl3, 300 MHz):
d
7.40e7.44 (m, 1H), 7.53e7.58 (m, 5H), 7.65 (d, 2H, J ¼ 8.7 Hz),
7.83e7.87 (m, 2H), 7.90 (d, 2H, J ¼ 8.7 Hz), 8.00e8.03 (m, 2H), 8.69
(s, 1H); 13C NMR (CDCl3, 300 MHz):
106.4, 119.4, 123.4, 123.7,
Yield 96%, Mp 218e220 ꢁC, IR (nmax, in KBr): 3238 cmꢀ1 (eNH
str.),1646 cmꢀ1 (C]O str.); 1H NMR (CDCl3, 300 MHz):
d
7.68 (d, 2H,
d

4256
O. Prakash et al. / European Journal of Medicinal Chemistry 45 (2010) 4252e4257
126.8, 127.8, 128.5, 129.1, 129.5, 129.7, 130.6, 131.7139.0, 150.7, 159.6,
163.9; Anal. Calculated for C23H15N4OBr: C 62.32, H 3.39, N 12.64;
Found: C 62.33, H 3.39, N 12.68.
300 MHz): d 106.2, 116.1, 119.4, 122.1, 123.5, 126.6, 127.5, 129.2, 129.4,
129.7, 131.1, 131.6, 144.9, 149.2, 162.1, 163.7; Anal. Calculated for
C23H14N5O3: C 64.64, H 3.28, N 16.39; Found: C 64.62, H 3.31, N 16.45.
6.2.5. 2-Phenyl-5-[1-phenyl-3-(4-methylphenyl)-4-pyrazolyl]
1,3,4-oxadiazole (4e)
6.2.11. 2-Phenyl-5-[1-(4-nitrophenyl)-3-(4-nitrophenyl)-4-
pyrazolyl] 1,3,4-oxadiazole (4k)
Yield 86%, mp 106e108 ꢁC, IR (nmax, in KBr): transparent in the
Yield 90%, mp 224e226 ꢁC, IR (nmax, in KBr): transparent in the
region of eNH str. and C]O str.; 1H NMR (CDCl3, 300 MHz):
d 2.47
region of eNH str. and C]O str.; 1H NMR (CDCl3, 300 MHz):
(s, 3H, CH3), 7.33 (d, 2H, J ¼ 7.8 Hz), 7.38e7.43 (m,1H), 7.49e7.57 (m,
d
7.37e7.49 (m, 3H), 7.88e7.90 (m, 2H), 7.91 (d, 2H, J ¼ 8.1 Hz), 8.01
(d, 2H, J ¼ 8.7 Hz), 8.31 (d, 2H, J ¼ 8.1 Hz), 8.39 (d, 2H, J ¼ 8.7 Hz),
8.52 (s, 1H); 13C NMR (CDCl3, 300 MHz):
106.2, 119.1, 119.7, 122.1,
5H), 7.85e7.87 (m, 4H), 8.0 (d, 2H, J ¼ 7.8 Hz), 8.71 (s, 1H); 13C NMR
(CDCl3, 300 MHz):
d
21.4, 106.3, 119.1, 119.6, 123.8, 126.8, 127.5,
d
127.8, 129.1, 129.5, 129.6, 130.1, 131.6, 139.2, 141.8, 159.9, 163.8; Anal.
Calculated for C24H18N4O: C 76.19, H 4.76, N 14.81; Found: C 76.04,
H 4.68, N 14.86.
123.5, 126.6, 127.5, 129.2, 129.4, 129.7, 131.1, 131.6, 145.2, 145.6,
149.2, 163.7; Anal. Calculated for C23H14N6O5: C 60.79, H 3.08,
N 18.50; Found: C 60.87, H 2.99, N 18.54.
6.2.6. 2-Phenyl-5-[1-phenyl-3-(4-methoxyphenyl)-4-pyrazolyl]
1,3,4-oxadiazole (4f)
7. Biological activity
Yield 84%, mp 110e112 ꢁC, IR (nmax, in KBr): transparent in the
Antibacterial [41e44] and antifungal activity [45e47] is carried
out by the literature method.
region of eNH str. and C]O str.; 1H NMR (CDCl3, 300 MHz):
d 3.9 (s,
3H, OCH3), 7.05 (d, 2H, J ¼ 8.7 Hz), 7.38e7.42 (m, 1H), 7.51e7.57 (m,
5H), 7.83e7.87 (m, 2H), 7.93 (d, 2H, J ¼ 8.7 Hz), 8.00e8.03 (m, 2H),
Acknowledgements
8.69 (s, 1H); 13C NMR (CDCl3, 300 MHz):
d 55.4, 106.2, 113.7, 119.4,
123.8, 124.2, 126.8, 127.5, 129.1, 129.4, 129.7, 130.4, 131.6, 139.2,
160.0, 160.3, 163.8; Anal. Calculated for C24H18N4O2: C 73.09, H 4.57,
N 14.21; Found: C 73.13, H 4.52, N 14.28.
We are thankful to UGC, New Delhi for the award of Junior
Research Fellowship to Manoj Kumar and Department of Science &
Technology, New Delhi for financial support of this work. Thanks are
also due to RSIC, Lucknow, India, for providing elemental analysis.
6.2.7. 2-Phenyl-5-[1-phenyl-3-(4-nitrophenyl)-4-pyrazolyl] 1,3,4-
oxadiazole (4g)
Yield 82%, mp 220e222 ꢁC, IR (nmax, in KBr): transparent in the
References
region of eNH str. and C]O str.; 1H NMR (CDCl3, 300 MHz):
[1] G.W. Weaver, in: R.C. Storr, T.L. Gilchrist (Eds.), Science of Synthesis, vol. 13,
Thieme, Stuttgart, 2004, pp. 219e251.
[2] J. Hill, in: R.C. Storr (Ed.), Comprehensive Heterocyclic Chemistry II, vol. 4,
Pergamon, Oxford, 1996, pp. 267e287 and 905e1006.
[3] C.J. Swain, R. Baker, C. Kneen, J. Moseley, J. Saunders, E.M. Seward,
G. Stevenson, M. Beer, J. Stanton, K. Watling, J. Med. Chem. 34 (1991)
140e151.
[4] B.S. Orlek, F.E. Blaney, F. Brown, M.S.G. Clark, M.S. Hadley, J. Hatcher, G.J. Riley,
H.E. Rosenberg, H.J. Wadsworth, P. Wyman, J. Med. Chem. 34 (1991)
2726e2735.
[5] J. Saunders, M. Cassidy, S.B. Freedman, E.A. Harley, L.L. Iversen, C. Kneen, A.
M. MacLeod, K.J. Merchant, R.J. Snow, R. Baker, J. Med. Chem. 33 (1990)
1128e1138.
[6] W.R. Tully, C.R. Gardner, R.J. Gillespie, R. Westwood, J. Med. Chem. 34 (1991)
2060e2067.
[7] M.T.H. Khan, M.I. Choudhary, K.M. Khan, M. Rani, A.U. Ahman, Bioorg. Med.
Chem. 13 (2005) 3385e3395.
[8] E. Palaska, G. Sahin, P. Kelicen, N. Tugbadurlu, G. Altinok, IL Farmaco 57 (2002)
101e107.
d
7.43e7.47 (m, 1H), 7.54e7.61 (m, 5H), 7.84e7.89 (m, 2H),
8.03e8.06 (m, 2H), 8.32 (d, 2H, J ¼ 8.7 Hz), 8.38 (d, 2H, J ¼ 8.7 Hz),
8.72 (s, 1H); 13C NMR (CDCl3, 300 MHz):
106.2, 119.1, 119.7, 122.5,
d
124.2, 126.8, 127.5, 129.1, 129.4, 129.7, 130.4, 131.6, 139.2, 148.1,
160.3, 163.8; Anal. Calculated for C23H15N5O3: C 67.48, H 3.67,
N 17.11; Found: C 67.46, H 3.63, N 17.19.
6.2.8. 2-Phenyl-5-[1-(4-nitrophenyl)-3-phenyl-4-pyrazolyl] 1,3,4-
oxadiazole (4h)
Yield 84%, mp 214e216 ꢁC, IR (nmax, in KBr): transparent in the
region of eNH str. and C]O str.; 1H NMR (CDCl3, 300 MHz):
d 7.48
(d, 2H, J ¼ 8.7 Hz), 7.67e7.70 (m, 4H), 7.83e7.87 (m, 2H), 7.95 (d, 2H,
J ¼ 8.7 Hz), 8.01e8.06 (d, 2H), 8.39e8.45 (d, 2H, J ¼ 8.7 Hz), 8.85 (s,
1H, J ¼ 8.7 Hz); 13C NMR (CDCl3, 300 MHz):
d 106.2, 119.4, 123.3,
124.5, 126.8, 127.5, 129.1, 129.4, 129.7, 130.4, 130.8, 131.6, 144.5,
149.2, 159.3, 163.7; Anal. Calculated for C23H15N5O3: C 67.48, H 3.67,
N 17.11; Found: C 67.53, H 3.59, N 17.16.
[9] H. Dogan, A. Daran, S. Rollas, G. Sener, M.K. Uysal, D. Gulen, Bioorg. Med.
Chem. 10 (2002) 2893e2898.
[10] G.W. Adelstein, C.H. Yen, E.Z. Dajani, R.G. Bianchi, J. Med. Chem. 19 (1976)
1221e1225.
[11] I. Angelini, L. Angelini, F. Sparaco, Brit. Pat. 1.161.801 (1969),. Chem. Abstr. 71
(1969) 112937.
6.2.9. 2-Phenyl-5-[1-(4-nitrophenyl)-3-(4-methoxyphenyl)-4-
pyrazolyl] 1,3,4-oxadiazole (4i)
[12] P. Brown, D.J. Best, N.J.P. Broom, R. Cassels, P.J. Bhanlon, T.J. Mitchell,
N.F. Osborne, J.M. Wilson, J. Med. Chem. 40 (1997) 2563e2570.
[13] H.L. Yale, K. Losee, J. Med. Chem. 9 (1966) 478e483.
[14] D.J. Wustrow, T. Capiris, R. Rubin, J.A. Knobelsdorf, H. Akunne, M.D. Davis,
R. MacKenzie, T.A. Pugsley, K.T. Zoski, T.G. Heffner, L.D. Wise, Bioorg. Med.
Chem. Lett. 8 (1998) 2067e2070.
[15] K.L. Kees, J.J. Fitzgerald Jr., K.E. Steiner, J.F. Mattes, B. Mihan, T. Tosi,
D. Mondero, M.L. McCaled, J. Med. Chem. 39 (1996) 3920e3928.
[16] C. Romagnoli, D. Mares, A. Bruni, E. Andreotti, M. Manfrini, C.B. Vicentini,
Mycopathologia 153 (2002) 129e132.
[17] H.S. Chen, Z.M. Li, Y.F. Han, J. Agric. Food Chem. 48 (2000) 5312e5315.
[18] A. Tanitame, Y. Oyamada, K. Ofuji, H. Terauchi, M. Kawasaki, M. Wachi,
J. Yamagichi, Bioorg. Med. Chem. Lett. 15 (2005) 4299e4303.
[19] G. Meazz, F. Bettarini, P. La Porta, P. Piccardi, Pest Manag. Sci. 60 (2004)
1178e1188.
[20] J.C. Jung, E.B. Walkins, M.A. Avery, Tetrahedron 58 (2002) 3639e3646.
[21] T.D. Penning, J.J. Talley, S.R. Bertenshaw, J.S. Carter, P.W. Collins,
S. Docter, M.J. Graneto, L.F. Lee, J.W. Malecha, J.M. Miyashiro, R.S. Rogers,
D.J. Rogier, S.S. Yu, G.D. Anderson, E.G. Burton, J.N. Cogburn, S.A. Gregory,
C.M. Koboldt, W.E. Perkins, K. Seibert, A.W. Veenhuizen, Y.Y. Zhang, P.
C. Isakson, J. Med. Chem. 40 (1997) 1347e1365.
Yield 88%, mp 222e224 ꢁC, IR (nmax, in KBr): transparent in the
region of eNH str. and C]O str.; 1H NMR (CDCl3, 300 MHz):
d 3.92
(s, 3H, OCH3), 7.07 (d, 2H, J ¼ 8.1 Hz), 7.50e7.59 (m, 3H), 7.93(d, 2H,
J ¼ 8.1 Hz), 8.01e8.07 (m, 4H), 8.43 (d, 2H, J ¼ 9.0 Hz), 8.82 (s, 1H);
13C NMR (CDCl3, 300 MHz):
d 56.2, 106.2, 113.7, 119.4, 121.3, 123.2,
126.8, 127.5, 129.1, 129.4, 129.7, 130.4, 131.6, 145.1, 149.2, 159.3,
163.7; Anal. Calculated for C24H17N5O4: C 65.60, H 3.87, N 15.95;
Found: C 65.58, H 3.87, N 16.02.
6.2.10. 2-Phenyl-5-[1-(4-nitrophenyl)-3-(4-fluorophenyl)-
4pyrazolyl] 1,3,4-oxadiazole (4j)
Yield 87%, mp 216e218 ꢁC, IR (nmax, in KBr): transparent in the
region of eNH str. and C]O str.; 1H NMR (CDCl3, 300 MHz):
d
7.50e7.59 (m, 5H), 7.66 (d, 2H, J ¼ 8.1 Hz), 7.89 (d, 2H, J ¼ 8.1 Hz), 7.99
(d, 2H, J ¼ 9.0 Hz), 8.43 (d, 2H, J ¼ 9.0 Hz), 8.82(s,1H); 13C NMR (CDCl3,

O. Prakash et al. / European Journal of Medicinal Chemistry 45 (2010) 4252e4257
4257
[22] R. Aggarwal, V. Kumar, P. Tyagi, S.P. Singh, Bioorg. Med. Chem. 14 (2006)
[36] D.B. Dess, J.C. Martin, J. Org. Chem. 48 (1983) 4155e4156.
[37] R.Y. Yang, L.X. Dai, J. Org. Chem. 58 (1993) 3381e3383.
[38] V.S. Rao, K. Sekhar, Synth. Commun. 34 (2004) 2153e2157.
[39] M. Okimoto, T. Chiba, J. Org. Chem. 55 (1990) 1070e1076.
[40] M.A. Kira, M.O. Abdel-Rahman, K.Z. Gadalla, Tetrahedron Lett. 10 (1969)
109e110.
[41] I.A.J. Ahmad, J. Ethnopharmacol. 74 (2001) 113e123.
[42] J. McFarland, J. Am. Med. Assoc. 14 (1907) 1176e1178.
[43] D. Greenwood, R. Slack, J. Peutherer, Medical Microbiology,
Microbial Infections: Pathogenesis, Immunity, Laboratory Diagnosis and
Control, fifteenth ed.. ELST Publishers, 1997.
[44] Nccls, Method for Dilution Antimicrobial Susceptibility Test for Bacteria that
Grow Aerobically, Approved Standards, M7eA5, fifth ed. National Committee
for Clinical Laboratory Standards, Villanova, PA, 2000.
[45] Y.L. Nene, P.N. Thapliyal, Fungicides in Plant Disease Control, third ed. Oxford
and IBH Publishing, New Delhi, 1993, 531pp.
[46] V. Parkash, A. Aggarwal, S. Sharma, S. Gupta, A. Gupta, Ecol. Environ. Manage.
15 (2005) 215e218.
1785e1791.
[23] V. Kumar, R. Aggarwal, P. Tyagi, S.P. Singh, Eur. J. Med. Chem. (2005) 922e927.
[24] J.L. Kane, B.H. Hirth, O. Laing, B.B. Gourlie, S. Nahill, G. Barsomiam, Bioorg.
Med. Chem. Lett. 13 (2003) 4463e4466.
[25] M. Dabiri, P. Salehi, M. Baghbanzadeh, M. Bahramnejad, Tetrahedron Lett. 47
(2006) 6983e6986.
[26] E. Jedlovska, J. Lesko, Synth. Commun. 24 (1994) 1879e1885.
[27] R. Milcent, G.J. Barbier, Heterocycl. Chem. 20 (1983) 77e80.
[28] H. Saikahi, N. Shimojo, Y. Uehara, Chem. Pharm. Bull. 20 (1972) 1663e1668.
[29] S. Rostamizadeh, S.A. Ghasem Housaini, Tetrahedron Lett. 34 (2004) 8753e8756.
[30] B.H.M. Mruthyunjayaswamy, B.K. Shanthaveerappa, Indian J. Heterocycl.
Chem. 8 (1998) 31e38.
a Guide to
[31] G. Werber, F. Bucherri, R. Noto, M. Gentile, J. Heterocycl. Chem. 14 (1977)
1385e1388.
[32] H.M. Faidallah, E.M. Sharshira, S.A. Basaif, A.E.K.A. Ba-Oum, Phosphorus, Sulfur
Silicon Relat. Elem. 177 (2002) 67e79.
[33] Z. Shang, Synth. Commun. 36 (2006) 2927e2937.
[34] Z. Shang, J. Reiner, J. Chang, K. Zhao, Tetrahedron Lett. 46 (2005) 2701e2704.
[35] D.B. Dess, J.C. Martin, J. Am. Chem. Soc. 113 (1991) 7277e7287.
[47] S.K.S. Al-Burtamani, M.O. Fatope, R.G. Marwah, A.K. Onifade, S.H. Al-Saidi, J.
Ethnopharmacol. 96 (2005) 107e112.