Synthesis, characterization and antibacterial activity of 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles

Article abstract of DOI:10.1016/j.ejmech.2009.06.020

In the present investigation a series of novel 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles (4a-j) were synthesized by cyclization of substituted-benzoic acid N′-[1-(5-chloro-2-methoxy-phenyl)-5-meth

Full text of DOI:10.1016/j.ejmech.2009.06.020

European Journal of Medicinal Chemistry 44 (2009) 4522–4527
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, characterization and antibacterial activity of 2-[1-(5-chloro-2-
methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-
[1,3,4]oxadiazoles
,
,
*
Neithnadka Premsai Rai a c, Venugopala Katharigatta Narayanaswamy b, Sheena Shashikanth a
,
Pirama Nayagam Arunachalam c
a Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
b Department of Pharmaceutical Chemistry, Al-Ameen College of Pharmacy, Hosur Road, Opp. Lalbagh Main Gate, Bangalore 560 027, Karnataka, India
c Syngene International Ltd., Biocon Park, Plot #2 and 3, Bommasandra – Jigani Road, Bangalore 560 099, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present investigation a series of novel 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-
yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles (4a–j) were synthesized by cyclization of substituted-
benzoic acid N0-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-hydrazide by using
phosphorousoxychloride at 120 ꢀC. The chemical structure of the newly synthesized compounds was
characterized by analytical and spectral (IR, 1H NMR, 13C NMR and LC–MS) methods. The title compounds
were screened for qualitative (zone of inhibition) and quantitative antibacterial activity (MIC) by agar cup
plate and microtitration methods, respectively. Among the synthesized compounds in this series
compound 2-[1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-yl]-5-(4-fluorophenyl)-1,3,4-oxa-
diazole (4b) was found to exhibit significant antibacterial activity with MICs of 22.4, 29.8, 29.6 and
Received 5 January 2009
Received in revised form
17 June 2009
Accepted 19 June 2009
Available online 26 June 2009
Keywords:
2-[1-(5-Chloro-2-methoxy-phenyl)-5-
methyl-1H-pyrazol-4-yl]-5-(substituted-
phenyl)-[1,3,4]oxadiazoles
Antibacterial activity
30.0 mg/mL against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae,
respectively. The other compounds exhibited moderate activity when compared to standard substance
Minimum inhibitory concentration
Ampicillin.
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
oxadiazole exhibits diuretic [22], antipyretic [23], bactericidal
[24,25] and antimitotic activity [26]. The synthesis of heterocyclic
Pyrazole and its derivatives represent one of the most active
classes of compounds possessing a wide spectrum of biological
activities. During the past years, considerable evidence has been
accumulated to demonstrate the efficacy of pyrazole derivatives
including antibacterial [1], antifungal [2,3], herbicidal [4], insecti-
cidal [5] and other biological activities [6,7]. Up till now, a great
variety of these kind of compounds have been synthesized, among
which some commercial pesticides have been developed including
fripronil (MB46030) [8], ET-751 [9] and pyrazolate (A-544) [10].
1,3,4-Oxadiazole is associated with potent pharmacological
activity due to the presence of toxophoric –N]C–O– linkage [11].
Considerable evidence has been accumulated to demonstrate the
efficacy of 1,3,4-oxadiazole, including its use as analgesic [12],
antimalarial [13], antiacetylcholine esterase [14], anti-inflamma-
tory [15–17], hyperglycemic [18], antifeedent [19], nervous system
depressant [20] and anticonvulsant [21] agent. Furthermore, 1,3,4-
compounds containing multi-structure in a molecule has received
much attention in recent years [27]. Encouraged by these obser-
vations and in continuation of our research work on the synthesis
of nitrogen and sulfur containing heterocycles for biological activity
[28–34] and development of polymorph in bioactive molecules
[35], it was considered valuable to integrate two five membered
heterocyclic rings together in a molecular frame work to see the
additive effect of these rings towards the antibacterial activity.
2. Chemistry
The synthetic route of title compounds (4a–j) is shown in
Scheme 1. Intermediate 1-(5-chloro-2-methoxyphenyl)-5-methyl-
1H-pyrazole-4-carboxhydrazide (2) was synthesized by refluxing
a
reaction mixture of ethyl 1-(5-chloro-2-methoxyphenyl)-5-
methyl-1H-pyrazole-4-carboxylate (1) and hydrazine hydrate in
ethanolic medium. This on reaction with proper substituted benzoyl
chlorides in the presence of pyridine yielded the compounds (3a–j)
which, when heated with phosphorousoxychloride at 120 ꢀC, gave
* Corresponding author. Tel.: þ91 0821 2547279.
E-mail address: shashisheena@yahoo.com (S. Shashikanth).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.06.020

N.P. Rai et al. / European Journal of Medicinal Chemistry 44 (2009) 4522–4527
4523
O
O
NH2
R1
O
NH
R
R2
N
N
Hydrazine hydrate
Ethanol reflux
N
N
+
H3CO
H3CO
O
Cl
Cl
Cl
( 1 )
( 2 )
R1
R
Pyridine
Dichlormethane
R
R2
R1
N
O
HN
N
NH
R2
O
O
POCl3 / 1200 C
N
N
N
N
H3CO
H3CO
Cl
Cl
( 4 a-j )
( 3 a-j )
4f: R =C H3, R1 = Br, R2 = H
4g: R = F, R1 = H, R2 = H
4h: R =Cl, R1 = H, R2 =Cl
4i: R = Cl, R1 = Cl, R2 = H
4j: R = NO2, R1 = CH3, R2 = H
4a: R = H, R1 = Cl, R2 = H
4b: R = H, R1 = F, R2 = H
4c: R = Br, R1 = CH3, R2 = H
4d: R = H, R1 = H, R2 = H
4e: R = H, R1 = Br, R2 = H
Scheme 1.
the respective title compounds (4a–j). The intermediate (1) was
synthesized as its phenyl unsubstituted analog [36].
the cavity were carried out. From analysis of Table 2 we can
conclude that compound 2-[1-(5-chloro-2-methoxy-phenyl)-5-
methyl-1H-pyrazol-4-yl]-5-phenyl-[1,3,4]oxadiazole (4d) which
is unsubstituted showed significant MIC at 29.8
subtilis and moderate activity at 39.8, 40.6, and 40.6
m
g/mL against B.
g/mL
3. Results and discussion
m
against S. aureus, E. coli and K. pneumonia, respectively. Fluorine
incorporated phenyl ring of 1,3,4-oxadiazole displayed varied
pharmacological properties such as fluorine atom at para posi-
tion of phenyl ring showed improved activity at 22.4, 30.6, 29.6
In the 1H NMR spectrum of 1-(5-chloro-2-methoxyphenyl)-5-
methyl-1H-pyrazole-4-carbohydrazide (2) two singlet peaks at 2.25
and 3.76 were due to –CH3 and OCH3 protons respectively. In LC–MS
spectra, 280 ionpeakwas incompliancewith molecular weightof the
proposed intermediate (2). In analogs (4a–j) –CH3 protons are
and 30.0 mg/mL against both Gram positive and Gram negative,
respectively. Dichloro analogs 4h and 4i also exhibited similar
pattern of activity where as monochloro analog 2-[1-(5-chloro-2-
methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(4-chlorophenyl)-
[1,3,4]oxadiazole (4a) exhibited moderate activity when
compared to 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-
pyrazol-4-yl]-5-phenyl-[1,3,4]oxadiazole (4d). Monofluoro analog
2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-
(3-fluorophenyl)-[1,3,4]oxadiazole (4g) exhibited better activity
against S. aureus when compared to other analogs in the series.
observed in the range of d 3.83–3.84. In LC–MS, molecular ion peaks
were in good agreement with proposed molecular weight and
elemental analysis resultswerewithin ꢁ0.4%of the calculated values.
All the title compounds (4a–j) were subjected for determi-
nation of partition coefficient by shake flask method using n-
octanol/water system and the values are found between 4.26 and
6.42. A screening of antibacterial activities using two Gram
negative (Escherichia coli and Klebsiella pneumonia) and two Gram
positive bacteria (Bacillus subtilis and Staphylococcus aureus) was
performed for a series of 2-[1-(5-chloro-2-methoxy-phenyl)-5-
methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazole
analogs (4a–j). The diameters of the inhibition zones corre-
sponding to the MICs are presented in Table 2. Positive control
using only inoculation and negative control using only DMSO in
4. Conclusion
We have synthesized several substituted 2-[1-(5-chloro-2-
methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)

4524
N.P. Rai et al. / European Journal of Medicinal Chemistry 44 (2009) 4522–4527
Table 1
Physicochemical characteristics of 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazole analogs (4a–j).
R
R1
N
N
R2
O
N
N
H3CO
Cl
( 4 a-j)
Compd no.
R
R1
R2
MF
M. wt.
Yielda (%)
m.p. (ꢀC)
Cryst. solvent
Anal.b
log P
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
Br
H
H
CH3
F
Cl
Cl
NO2
Cl
F
H
H
H
H
H
H
H
Cl
H
H
C
19H14Cl2N4O2
400
384
460
366
446
460
384
434
434
425
75
77
76
80
79
69
70
79
81
66
171.8–172.6
162.6–163.7
186.2–187.7
155.2–156.9
177.2–177.7
179.1–180.5
144.5–145.6
148.2–149.4
157.0–158.0
199.5–201.0
EtOH
MeOH–H2O
EtOH
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
4.51
4.26
5.19
4.32
4.88
5.20
4.28
5.61
5.57
6.42
C19H14ClFN4O2
C20H16BrClN4O2
C19H15ClN4O2
C19H14BrClN4O2
C20H16BrClN4O2
C19H14ClFN4O2
C19H13Cl3N4O2
CH3
H
Br
Br
H
H
Cl
CH3
EtOH
MeOH
MeOH
MeOH–H2O
EtOH
EtOH
CCl4
C19H13Cl3N4O2
4j
C20H16ClN5O4
a
All the yields are on isolated basis. All the compounds gave satisfactory results for elemental analysis. Purified by silica gel flash column chromatography with ethyl
acetate–n-hexane (1:9).
b
Detailed results of elemental analyses are given in Section 5.4.
-[1,3,4]oxadiazole analogs (4a–j) and the yields are found to be
satisfactory Table 1. Phenyl group bearing few functional groups
such as chloro, fluoro, bromo, methyl and nitro on 1,3,4-oxadiazole
which is in turn on pyrazole moiety has been synthesized for
antibacterial activity against two Gram positive and Gram negative
strains. It was noticed that dichloro analogs 4h and 4i revealed
similar spectrum of activity than monofluoro analogs 4b and 4g.
Unsubstituted analog 4d exhibited moderate activity against S.
aureus, E. coli, and K. pneumonia when compared to all other
analogs in the series.
5.1. Ethyl 1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-pyrazole-4-
carboxylate (1)
To a solution of ethyl-2-acetyl-3-(dimethylamino)acrylate [36]
(5 g, 0.027 mol) in ethanol (50 mL) was added (5-chloro-2-
methoxyphenyl) hydrazine hydrochloride (5.64 g, 0.027 mol) and
sodium bicarbonate (4.54 g, 0.054 mol) and it was stirred at room
temperature for 4 h. The reaction mixture was concentrated to
remove ethanol, diluted with ethylacetate, washed with water, brine
solution and dried over sodium sulfate and concentrated to get oily
liquid which was purified bycolumn chromatography (60–120 silica
gel) using ethyl acetate:petroleum ether as an eluent to get pure
white solid (70%); m.p. 120.3–121.2 ꢀC, 1H NMR (CDCl3):
d 1.34–1.37
(t, 3H, CH3), 2.36 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 4.28–4.33 (q, 2H,
OCH2–), 6.96–6.98 (d, 1H, J ¼ 8.9 Hz, Ar–H), 7.33–7.34 (d, 1H,
J ¼ 2.64 Hz, Ar–H), 7.39–7.41 (dd, 1H, J ¼ 2.64 Hz, Ar-H), 8.02 (s, 1H,
Hetero Ar-H); MS: m/z ¼ 294.7 (Mþ). Anal. Calcd for C14H15N2O3Cl: C,
57.05; H, 5.13; N, 9.50. Found: C, 56.83; H, 5.27; N, 9.35.
5. Experimental
Chemicals were procured from Aldrich Chemical Co. Reactions
were monitored and purity of the products was checked by thin
layer chromatography (TLC). TLC was performed on Merck
60 F-254 silica gel plates with visualization by UV-light using ethyl
acetate and n-hexane as solvent system. Melting points were
determined on a Bu¨chi Melting Point B-545 apparatus. The IR
spectra (in KBr pellets) were recorded on a Nicolet 6700 FT-IR
spectrometry. 1H NMR spectra were recorded on Bruker (300 and
400 MHz) spectrometer instruments, in CDCl3. Chemical shifts
were recorded in parts per million downfield from tetramethylsi-
lane. Mass spectra were recorded on LC–MS-Aglilent 1100 series
with MSD (Ion trap) using 0.1% aqueous TFA in acetonitrile system
on C18-BDS column for 10 min duration and elemental analysis was
performed on Thermo Finningan FLASH EA 1112 CHN analyzer.
Analysis results were within 0.4% of the calculated value. Column
5.2. 1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazole-4-
carbohydrazide (2)
A mixture of ethyl 1-(5-chloro-2-methoxyphenyl)-5-methyl-
1H-pyrazole-4-carboxylate (10 g, 0.034 mol), ethanol (100 mL), and
hydrazine hydrate (1.3 mL, 0.34 mol) was heated to reflux and
left overnight. The solid formed was filtered and washed with
cold water and ether, to obtain compound 2. Yield (90%), m.p.
203.2–204.2 ꢀC, 1H NMR (CDCl3):
d 2.25 (s, 3H, CH3), 3.76 (s, 3H,
OCH3), 4.32 (s, 2H, NH2), 7.25–7.28 (d, 1H, J ¼ 9.0 Hz, Ar-H),
7.42–7.43(d, 1H, J ¼ 2.67 Hz, Ar-H), 7.55–7.59 (dd, 1H, J ¼ 2.7 Hz,
Ar-H), 8.0 (s, 1H, Hetero Ar-H), 9.32 (s, 1H, NH); MS: m/z ¼ 280.0
(Mþ). Anal. Calcd for C12H13N4O2Cl: C, 51.34; H, 4.67; N, 19.96.
Found: C, 51.12; H, 4.78; N, 19.72.
chromatography
was
performed
on
silica
gel
(230–400 mesh) supplied by Acme Chemical Co. (India) for
compound purification.

N.P. Rai et al. / European Journal of Medicinal Chemistry 44 (2009) 4522–4527
4525
Table 2
5.4.3. 2-[1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-
In-vitro antibacterial activity data of 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-
1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazole analogs (4a–j).
yl]-5-(3-bromo-4-methylphenyl)-1,3,4-oxadiazole (4c)
IR (cmꢂ1) 3425, 3089, 1621, 1501, 1280. 1H NMR (CDCl3):
d 2.49
Compd no.
Control
Zone of inhibition in mm (MIC in mg/mL)
(s, 3H, CH3), 2.55 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 7.01–7.03 (d, 1H,
J ¼ 8.84 Ar-H), 7.39–7.48 (m, 3H, Ar-H), 7.96–7.98 (m, 1H, Ar-H),
8.20 (s, 1H, Ar-H), 8.28 (d, 1H J ¼ 1.5 Hz, Ar-H); 13C NMR (CDCl3):
B. subtilis
S. aureus
E. coli
K. pneumonia
4a
4b
4c
4d
4e
4f
4g
4h
–
–
–
–
–
–
–
–
–
–
–
15(39.6)
25(22.4)
15(39.6)
20(29.8)
14(40.6)
15(39.8)
19(30.0)
15(31.8)
19(30.0)
15(39.6)
32(3.28)
18(30.6)
20(29.8)
20(29.8)
15(39.8)
19(30.0)
15(39.8)
27(21.5)
13(41.0)
20(29.8)
14(40.6)
31(3.36)
14(40.0)
21(29.6)
14(40.6)
14(40.6)
15(39.8)
17(30.8)
18(30.6)
25(22.4)
27(21.5)
17(30.8)
30(3.88)
13(41.0)
19(30.0)
15(39.0)
14(40.6)
13(41.6)
14(40.0)
20(29.8)
21(29.6)
15(39.6)
12(42.0)
30(4.00)
d
11.49, 23.10, 56.15, 105.45, 113.15, 123.16, 125.39, 125.76, 128.12,
128.80, 128.95, 130.33, 130.80, 133.89, 139.45, 141.75, 142.75,
153.14, 160.42, 162.04. MS: m/z ¼ 459.0 (Mþ). Anal. Calcd for
C20H16N4O2BrCl: C, 52.25; H, 3.51; N, 12.19. Found: C, 52.11; H,
3.65; N, 12.09.
4i
4j
5.4.4. 2-[1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-
yl]-5-phenyl-1,3,4-oxadiazole (4d)
Ampicillin
IR (cmꢂ1) 3406, 3003 1699,1617,1537,1505,1282. 1H NMR (CDCl3):
d
2.56 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 7.01–7.03 (d, 1H, J ¼ 8.67 Hz, Ar-
H), 7.43–7.55(m, 5H, Ar-H), 8.11–8.14 (m, 2H, Ar-H), 8.2 (s,1H, Ar-H); 13C
NMR (CDCl3): 11.54, 56.24, 105.62, 113.19, 123.94, 125.76, 126.80,
5.3. General procedure for the preparation of N0-(4-substituted
benzoyl)-1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-pyrazole-4-
carbohydrazide (3a–j)
d
128.16,129.03,130.81,131.49,139.49,142.68,153.16,160.33,163.27. MS:
m/z ¼ 366.0 (Mþ). Anal. Calcd for C19H15N4O2Cl: C, 62.21; H, 4.12; N,
15.27. Found: C, 62.10; H, 4.24; N, 15.18.
A mixture of 1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-pyr-
azole-4-carboxhydrazide (2) (5 g, 0.018 mol), dichloromethane
(50 mL), pyridine (1.4 g, 0.018 mol) and substituted benzoyl chlo-
rides (0.018 mol) was stirred overnight at room temperature.
Reaction completion was monitored through thin layer chroma-
tography and reaction mixture was concentrated to get solid and as
such taken for the next step.
5.4.5. 2-[1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-
yl]-5-(4-bromophenyl)-1,3,4-oxadiazole (4e)
IR (cmꢂ1) 3445, 3086, 1615, 1502, 1279: 1H NMR (CDCl3):
d 2.55
(s, 3H, CH3), 3.83 (s, 3H, OCH3), 7.01–7.04 (d, 1H, J ¼ 8.79, Ar-H),
7.42–7.48(m, 2H, Ar-H), 7.67–7.70 (d, 2H, J ¼ 8.46 Hz, Ar-H), 7.98–
8.01 (d, 2H, J ¼ 8.46 Hz Ar-H), 8.18 (s, 1H, Ar-H); 13C NMR (CDCl3):
5.4. General procedure for the preparation of 2-[1-(5-chloro-2-
methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-
phenyl)-[1,3,4]oxadiazoles (4a–j)
d
11.48, 56.16, 105.41, 113.17, 122.84, 125.75, 126.10, 128.14, 129.94,
130.82, 131.529, 132.35, 139.42, 142.78, 153.12, 160.5, 162.53. MS:
m/z ¼ 445.0 (Mþ). Anal. Calcd for C19H14N4O2BrCl: C, 51.20; H, 3.17;
N, 12.57. Found: C, 51.11; H, 3.19; N, 12.45.
Substituted-benzoic acid N0-[1-(5-chloro-2-methoxy-phenyl)-
1H-pyrazole-4-carbonyl]-hydrazide (3a–j) (6 g, 0.0143 mol) was
treated with POCl3, (60 mL) and heated at 120 ꢀC overnight. Reac-
tion completion was monitored through thin layer chromatography
and reaction medium was concentrated, then quenched with ice
cubes and left aside for 2 h. Reaction mixture was extracted with
dichloromethane and combined extract was washed with water,
10% sodium bicarbonate solution and finally with brine solution
and concentrated to get solid. The solid obtained was purified by
column chromatography using silica gel 60–120 mesh and
petroleum ether:ethyl acetate as eluent, to afford 2-[1-(5-chloro-
2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-
phenyl)-[1,3,4]oxadiazoles (4a–j) in 66–81% yield (Table 1).
5.4.6. 2-[1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-
yl]-5-(4-bromo-3-methylphenyl)-1,3,4-oxadiazole (4f)
IR (cmꢂ1) 3117, 3053, 1715, 1627, 1282. 1H NMR (CDCl3):
d 2.46 (s,
3H, CH3), 2.55 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 7.00–7.03 (d, 1H,
J ¼ 8.76, Ar-H), 7.42–7.48 (m, 2H, Ar-H), 7.68–7.71 (d, 1H, J ¼ 8.46 Hz
Ar-H), 7.76–7.80 (m, 1H, Ar-H), 7.99 (s, 1H, Ar-H), 8.19 (s, 1H, Ar-H);
13C NMR (CDCl3):
d 11.46, 22.90, 56.12, 105.43, 113.11, 122.93, 125.37,
125.72, 128.05, 128.58, 128.64, 130.79, 133.11, 139.05, 139.40, 142.73,
153.09, 160.40, 162.65. MS: m/z ¼ 459.0 (Mþ). Anal. Calcd for
C20H16N4O2BrCl: C, 52.25; H, 3.51; N,12.19. C, 52.26; H, 3.53; N,12.20.
5.4.7. 2-[1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-
yl]-5-(3-fluorophenyl)-1,3,4-oxadiazole (4g)
5.4.1. 2-[1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-
yl]-5-(4-chlorophenyl)-1,3,4-oxadiazole (4a)
IR (cmꢂ1) 3074, 2920, 2848, 1698, 1616, 1267. 1H NMR (CDCl3):
IR (cmꢂ1) 3090, 2995, 1614, 1503, 1279. 1H NMR (CDCl3): 2.55
(s, 3H, CH3), 3.83 (s, 3H, OCH3), 7.01–7.03 (d, 1H, J ¼ 8.76, Ar–H), 7.42–
7.53 (m, 4H, Ar-H), 8.05–8.08 (d, 2H J ¼ 8.49 Ar-H), 8.18 (s, 1H, Hetero
d
2.56 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 7.01–7.03 (d, 1H, J ¼ 8.76 Hz,
Ar-H), 7.23–7.27 (m, 1H, Ar-H), 7.43–7.55 (m, 3H, Ar-H), 7.81–7.83
(d, 1H, J ¼ 9.1 Hz, Ar-H), 7.91–7.93 (d, 1H, J ¼ 7.7 Hz, Ar-H), 8.20 (s,
1H, Ar-H); 13C NMR (CDCl3):
d 11.55, 56.19, 105.41, 113.17, 113.19,
Ar-H); 13C NMR (CDCl3):
d 11.55, 56.19, 105.47, 113.16, 122.44, 125.77,
113.93, 118.70, 122.58, 125.84, 128.04, 128.97, 130.97, 139.49, 142.90,
153.14, 160.65, 161.62, 162.32, 164.08. MS: m/z ¼ 385.0 (Mþ). Anal.
Calcd for C19H14N4O2ClF: C, 59.31; H, 3.67; N,14.56. Found: C, 59.02;
H, 3.71; N, 14.43.
128.05, 128.09, 128.98, 129.45, 130.88, 137.74, 139.47, 142.82, 153.14,
160.54,162.49. MS: m/z ¼ 401.0 (Mþ). Anal. Calcd for C19H14N4O2Cl2: C,
56.87; H, 3.52; N, 13.96. Found: C, 56.76; H, 3.71; N, 13.87.
5.4.2. 2-[1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-
yl]-5-(4-fluorophenyl)-1,3,4-oxadiazole (4b)
5.4.8. 2-[1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-
yl]-5-(3,5-dichlorophenyl)-1,3,4-oxadiazole (4h)
IR (cmꢂ1) 3425, 1621, 1501, 1280. 1H NMR (CDCl3):
d 2.55 (s, 3H,
IR (cmꢂ1) 3090, 2995, 1614, 1503, 1279. 1H NMR (CDCl3): 2.56 (s,
3H, CH3), 3.84 (s, 3H, OCH3), 7.01–7.04 (d, 1H, J ¼ 8.79 Hz, Ar-H),
7.42–7.48 (m, 2H, Ar-H), 7.61–7.64 (d, 1H, Ar-H),7.95-7.98(dd, 1H,
CH3), 3.83 (s, 3H, OCH3), 7.01–7.03 (d,1H, J ¼ 8.76 Ar-H), 7.20–7.26 (m,
2H, Ar-H), 7.43–7.47 (m, 2H, Ar-H), 8.11–8.18 (m, 3H, Ar-H); 13C NMR
(CDCl3):
d 11.53, 56.19, 105.52, 113.17, 116.30, 116.52, 120.29, 120.32,
Ar-H), 8.20–8.21 (m, 2H, Ar-H); 13C NMR (CDCl3):
d 11.51, 56.13,
125.79, 128.12, 129.00, 129.02, 129.11, 130.87, 139.44, 142.75, 153.16,
160.40,165.93. MS: m/z ¼ 385.0 (Mþ). Anal. Calcd for C19H14N4O2ClF:
C, 59.31; H, 3.67; N, 14.56. Found: C, 59.02; H, 3.71; N, 14.43.
105.07, 113.13, 124.95, 125.76, 128.42, 127.80, 128.42, 128.97, 130.94,
135.96, 139.47, 142.82, 153.06, 161.09, 168.33. MS: m/z ¼ 435.0 (Mþ).

4526
N.P. Rai et al. / European Journal of Medicinal Chemistry 44 (2009) 4522–4527
Anal. Calcd for C19H13N4O2Cl3: C, 59.31; H, 3.67; N, 14.56. Found:
C, 59.32; H, 3.70; N, 14.55.
synthesized promising compounds and a standard antibiotic
(Ampicillin) in 20% water in dimethyl sulfoxide were added and
incubated at 37 ꢀC for 24 h. At the end of incubation the effect of the
drugs on the growth of organisms was monitored by measuring the
optical density at 540 nm using ELISA reader (Multiscan MS, Lab-
systems, Helsinki, Finland). The MIC was defined as the lowest
concentration of the antibiotic or test sample allowing no visible
growth. The results of 2-[1-(5-chloro-2-methoxy-phenyl)-5-
methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazole
analogs (4a–j) are recorded in Table 2.
5.4.9. 2-[1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-
yl]-5-(3,4-dichlorophenyl)-1,3,4-oxadiazole (4i)
IR (cmꢂ1) 3090, 2995, 1614, 1503, 1279. 1H NMR (CDCl3): 2.55 (s,
3H, CH3), 3.83 (s, 3H, OCH3), 7.01–7.04 (d, 1H, J ¼ 8.79 Hz, Ar-H),
7.42–7.48 (m, 2H, Ar-H), 7.61–7.64 (d, 1H, J ¼ 8.37 Hz, Ar-H),
7.95–8.20 (m, 2H, Ar-H), 8.21 (s,1H, Ar-H); 13C NMR (CDCl3):
d 11.49,
56.12, 105.16, 113.13, 123.62, 125.72, 128.35, 128.87, 128.42, 128.99,
130.87, 133.60, 135.89, 139.42, 142.95, 153.05, 161.41,. MS: m/
z ¼ 435.0 (Mþ). Anal. Calcd for C19H13N4O2Cl3: C, 52.38; H, 3.01; N,
12.86. Found: C, 52.40; H, 3.02; N, 12.83.
Acknowledgements
Authors NPR are grateful to Dr. Goutham Das, President, Syn-
gene International Ltd., Biocon group of company, Bangalore for
giving permission to carryout research work and KNV is thankful to
Prof. B.G. Shivananda, Principal, Al-Ameen College of Pharmacy,
Bangalore for encouragement.
5.4.10. 2-[1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-
yl]-5-(3-nitro-4-methylphenyl)-1,3,4-oxadiazole (4j)
IR (cmꢂ1) 3086, 2925, 1618, 1528, 1279. 1H NMR (CDCl3): 2.56
(s, 3H, CH3), 2.70 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 7.01–7.04 (d, 1H,
J ¼ 8.79 Hz, Ar-H), 7.27–7.47 (m, 2H, Ar-H), 7.53–7.55 (d, 1H,
J ¼ 8.08 Hz, Ar-H), 8.21 (s, 1H, Ar-H) 8.25–8.27 (m, 1H, Ar-H), 8.66–
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