Synthesis and antibacterial activity of novel series of 2-(p-tolyloxy)-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)quinoline

Article abstract of DOI:10.1002/jhet.653

Figure represented. A new series of 2-(p-tolyloxy)-3-(5-(pyridin-4-yl)-1,3, 4-oxadiazol-2-yl)quinoline were synthesized from oxidative cyclization of N′-((2-(p-tolyloxy)quinoline-3-yl)methylene)isonicotinohydrazide in DMSO/I₂ at reflux condition for 3-4 h. The structures of the new compounds were confirmed by elemental analyses as well as IR, ¹H-NMR, and mass spectral data. All the synthesized compounds were screened for their antibacterial activities against various bacterial strains. Several of these compounds showed potential antibacterial activity.

Full text of DOI:10.1002/jhet.653

872
Synthesis and Antibacterial Activity of Novel Series of
2-(p-Tolyloxy)-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)quinoline
Vol 48
Ratnadeep S. Joshi,a Priyanka G. Mandhane,a Wajid Khan,b
and Charansingh H. Gilla*
aDepartment of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad 431004, India
bDepartment of Microbiology, Maulana Azad College, Aurangabad 431 210, India
*E-mail: chgill50@yahoo.com
Received February 15, 2010
DOI 10.1002/jhet.653
Published online 15 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
A new series of 2-(p-tolyloxy)-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)quinoline were synthesized
from oxidative cyclization of N0-((2-(p-tolyloxy)quinoline-3-yl)methylene)isonicotinohydrazide in
DMSO/I2 at reflux condition for 3–4 h. The structures of the new compounds were confirmed by ele-
1
mental analyses as well as IR, H-NMR, and mass spectral data. All the synthesized compounds were
screened for their antibacterial activities against various bacterial strains. Several of these compounds
showed potential antibacterial activity.
J. Heterocyclic Chem., 48, 872 (2011).
INTRODUCTION
There are several methods for the synthesis of substituted
1,3,4-oxadiazole. The classical synthetic routes to substituted
1,3,4-oxadiazoles involve ring-forming reactions. Widely
used methods are cyclodehydration of 1,2-diacylhydrazines
with various reagents such as thionyl chloride, phosphorus
oxychloride, poly phosphoric acid (PPA), or sulfuric acid
[20], oxidation of N-acylhydrazones with different oxidizing
agents [21] and direct reaction of acyl chlorides or carboxylic
acids with hydrazine or acid hydrazides [22]. Another con-
venient method of 1,3,4-oxadiazole synthesis is the thermal
recyclization of N-acyltetrazoles, which are commonly gener-
ated in situ from appropriate N-unsubstituted tetrazoles and
acyl chlorides [23]. Preparative methods via ring-metalated
1,3,4-oxadiazoles are much less common because of the
opening of the heterocycles. Thus, the synthesis of the
substituted 1,3,4-oxadiazoles via lithium derivative was
described for the first time only several years ago [24].
Quinoline ring systems represent a major class of het-
erocycles as they occur in various natural products espe-
cially in alkaloids [1]. It possesses diverse biological
and physiological activities such as antimalarial [2],
anti-inflammatory [3], antitumor [4], DNA binding
capacity [5], and antibacterial properties [6]. Recently,
quinoline has been used in the study of bio-organic and
bio-organometallic processes [7]. There are many quino-
line-based compounds which are known to exhibit anti-
TB properties. Compound TMC207 [8] bearing a bulky
biaryl side chain at position C3, is a highly potent anti-
TB agent and is currently in phase II clinical trials. In
particular, 2-chloroquinoline-3-carbaldehyde has been
used as a key intermediate for the synthesis of variety
of medicinally valuable compounds [9].
The substituted oxadiazoles are heterocyclic com-
pounds, which serve both as biomimetic and reactive phar-
macophores. It also act as key elements with potential bio-
logical activities [10] such as pesticidal [11], antiperipheral
vasomotility [12], CNS stimulant, antiinflammatory, hypo-
tensive [13], insecticidal [14], bactericidal [15], hypoglyce-
mic [16], analgesic, anticonvulsive, antiemetic, diuretic
[17], muscle relaxant [18], and fungicidal activities [19].
In our continuous program in the search of new potent
and safe synthesis of biologically active heterocycles
[25,26], we have planned to synthesize some new series
of various substituted 2-(p-tolyloxy)-3-(5-(pyridin-4-yl)-
1,3,4-oxadiazol-2-yl)quinoline by oxidative cyclisation of
N-((2-(p-tolyloxy)quinoline-3-yl)methylene)isonicotinohy-
drazide using DMSO/I2 and evaluating their antibacterial
C
V
2011 HeteroCorporation

July 2011
Synthesis and Antibacterial Activity of Novel Series of
2-(p-Tolyloxy)-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)quinoline
873
Scheme 1
activity against the standard drug Streptomycin and
Ampicillin.
The structure of (4a) is interpreted from spectroscopic
data, IR spectra of compound (4a) reveals absorption
band in the region 1560 cmꢁ1 corresponding to AC¼¼N
stretching at 1640 cmꢁ1
.
1
The H-NMR spectra of (4a) exhibits a sharp singlet
at d 2.01 for ACH3 and one broad singlet at d 10.50 of
ANH. The pyridine ring protons appeared doublet at d
8.92 and 8.75, respectively. C4- proton of quinoline
nuclei appears as a singlet at d 8.33. All other aromatic
protons arise at respective position. The IR spectrum of
compound (5a) showed absorption peak at 1576 cmꢁ1
due to C¼¼N stretching vibrations. The absence of CO
peak at 1640 cmꢁ1 confirms the formation of oxadiazole
ring, its 1H-NMR spectrum revealed a multiplet at d
7.02–8.98 due to quinoline and pyridine ring protons.
The physical data are summarized in Table 1.
RESULTS AND DISCUSSION
Chemistry. The synthetic work was carried out begin-
ning from 2-chloro-3-formylquinoline (1a–j) according to
Scheme 1. The reaction of 2-chloro-3-formylquinoline (1a–
j) with p-cresol in presence of K2CO3/N,N-dimethylmetha-
namide (DMF) at 80–90ꢀC for 4–5 h gave substituted 2-(p-
tolyoxy)quinoline-3-carbaldehyde (2a–j). Further reaction
of isonicotinohydrazide (3) with substituted 2-(p-tolyoxy)-
quinoline-3-carbaldehyde (2a–j) gave corresponding
N0-((2-(p-tolyloxy)quinoline-3-yl)methylene)isonicotinohy-
drazide (4a–j) in acetic acid in ethanol at room tempera-
ture, followed by the oxidative cyclisation of N0-((2-(p-
tolyloxy)quinoline-3-yl)methylene)isonicotinohydrazide
using DMSO and iodine at reflux condition gave our
targeted product i.e., substituted 2-(p-tolyloxy)-3-(5-
(pyridin-4-yl)-1,3,4-oxadiazol-2-yl) (5a–j). All the syn-
thesized compounds were characterized by their physi-
cal and spectral data (IR, 1H-NMR, and Mass).
Antibacterial activity. The antibacterial activities of
the synthesized compounds were determined by the
well-diffusion method [27]. In this work, two Gram-pos-
itive bacteria, Bacillus subtilis (ATCC 6633), Staphylo-
coccus aureus (ATCC 25923) and two Gram-negative
bacteria, Salmonella typhimurium (ATCC 23564), Pseu-
domonas aeruginosa (ATCC 27853) were used to inves-
tigate the antibacterial activities. The bacterial liquid
cultures were prepared in fusion broth for their activity
tests. The compounds were dissolved in DMSO at con-
centration of 1 mg mLꢁ1. Antibacterial activity of
DMSO against the test organisms was investigated, and
was found to be nil. Molten nutrient agar (15 cm3) kept
at 45ꢀC, was then poured into the Petri dishes and
allowed to solidify. Ten millimeter diameter holes were
Spectral analysis. The structures of the synthesized
compounds were confirmed by spectral analysis (IR,
1H-NMR, and Mass). The IR spectrum of compound
(2a) showed a peak at 1690 cmꢁ1 due to C¼¼O stretch.
1
In H-NMR spectrum, it exhibited two singlets, one at d
2.41 due to ACH3 protons and second at d 10.65 due to
ACHO proton. Mass spectrum was consistent with
assigned structure showing (Mþ1) peak at m/z ¼ 264.1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

874
R. S. Joshi, P. G. Mandhane, W. Khan, and C. H. Gill
Vol 48
Table 1
rial activity. Most of these compounds showed moderate
antibacterial activity compared with commercially avail-
able drugs. Therefore, it becomes lead molecules for
further synthetic and biological evaluation. It can be
concluded that this class of compounds certainly holds a
great promise toward pursuit to discover novel class of
antibacterial agents. Further studies are being conducted
to acquire more information about quantitative struc-
ture–activity relationships.
Physical data of the compounds (5a–j).
Comp. No.
R1
R2
R3
Yield (%) M.P. (ꢀC)
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
CH3
H
H
H
H
68
72
67
74
76
64
70
73
69
72
121–124
135–136
127–129
140–142
124–125
130–131
143–145
147–149
141–142
132–134
H
CH3
H
H
H
CH3
H
OCH3
H
H
H
OCH3
H
H
OCH3
H
OC2H5
H
H
OC2H5H
H
H
OC2H5
EXPERIMENTAL
5j
H
Melting points were recorded in an open capillary in liquid
paraffin bath and are uncorrected. The progress of reaction was
monitored by thin layer chromatography using silica gel
(Merck). IR spectra were recorded on a SHIMADZU–FT-IR
then punched carefully using a sterile cork borer and
completely filled with the test solutions. The plates were
incubated for 24 h at 37ꢀC. After 24 h, the inhibition
zone that appeared around the holes in each plate was
measured. Antibacterial activity was determined by
measuring the diameter of inhibition zone and examin-
ing the minimal inhibitory concentration. Activity of
each compound was compared with streptomycin and
ampicillin as standards. The observed data of antibacte-
rial activity of compounds and the standard drugs are
given in Table 2. The compounds (5c), (5d), (5i), and
(5j) show excellent antibacterial activity against Gram-
positive bacterial strains. Likewise, compounds (5a),
(5b), (5f), and (5g) showed excellent activity against
Gram-negative bacterial strains.
1
spectrophotometer in KBr disc. H-NMR spectra were recorded
on BRUKER ADVANCE–II 400 NMR spectrophotometer in
DMSO-d6 as a solvent and tetramethyl silane (TMS) as an inter-
nal standard. Peak values are shown in d ppm. Mass spectra
were recorded on a PEP-SCIUX-APIQ pulsar (electron preioni-
zation) mass spectrometer. Elemental analyses were performed
on Perkin-Elmer EAL-240 elemental analyzers.
General procedure for the synthesis of 2-(p-tolyloxy)-
quinoline-3-carbaldehydes (2a-j). To the mixture of p-cresol
(3.7 g, 0.034 mol) and K2CO3 (12.8 g, 0.093 mol) in DMF,
compound 1a (6 g, 0.031 mol) was added, and the reaction
mixture was stirred at 80–90ꢀC for 4–5 h. The completion of
the reaction was monitored on TLC. After completion of the
reaction, ice cold water (50 mL) was poured on the reaction
mixture, and the solid thus obtained was filtered off and
washed with water, further the compound was recrystallized
in ethyl acetate.
2-(p-tolyloxy)quinoline-3-carbaldehyde (2a). IR (KBr,
cmꢁ1): 1690 (C¼¼O), 1610 (C¼¼N), 1525 (C¼¼C); 1H-NMR-
(400 Hz, DMSO-d6): d 10.65 (s, 1H, ACHO), 8.72 (s, 1H, Ar-
H), 7.89 (d, J ¼ 8 Hz, 1H, Ar-H), 7.73 (d, J ¼ 8 Hz, 1H, Ar-
H), 7.70 (t, 1H, Ar-H), 7.45 (t, 1H, Ar-H), 7.27 (d, J ¼ 8 Hz,
2H, Ar-H), 7.18 (d, J ¼ 8 Hz, 2H, Ar-H), 2.41 (s, 3H, ACH3);
ES-MS (m/z): 264.4 (Mþ1).
CONCLUSION
In this report, we have synthesized novel series of
2-(p-tolyloxy)-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)-
quinoline from N0-((2-(p-tolyloxy) quinoline-3-yl)methy-
lene)isonicotinohydrazide which shows potent antibacte-
Table 2
The minimum inhibitor concentrations of tested compounds (5a–j) in lg/mL.
Tested compounds
B. subtili ZIa(MIC)b
S. aureus ZIa(MIC)b
S. typhi ZIa(MIC)b
P. aeroginosa ZIa(MIC)b
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
13.2 (15)
13.8 (15)
14.3 (10)
15.1 (10)
14.8 (10)
13.1 (15)
13.4 (15)
13.1 (15)
14.1 (10)
15.6 (10)
15.1 (10)
14.3 (10)
13.5 (15)
13.3 (15)
14.1 (10)
14.7 (10)
14.6 (10)
13.6 (15)
13.7 (15)
13.2 (15)
14.6 (10)
15.3 (10)
14.9 (10)
14.7 (10)
14.8 (10)
15.1 (10)
12.8 (15)
13.5 (15)
12.9 (15)
14.2 (10)
15.1 (10)
11.1 (20)
12.2 (15)
11.7 (15)
16.4 (5)
14.5 (10)
14.9 (10)
12.7 (15)
13.4 (15)
12.8 (15)
14.0 (10)
14.8 (10)
10.4 (20)
12.6 (15)
11.2 (15)
16.1 (5)
Streptomycin
Ampicillin
16.3 (5)
15.9 (5)
a Zone of inhibition.
b Minimum inhibitory concentration in lg/mL.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Synthesis and Antibacterial Activity of Novel Series of
2-(p-Tolyloxy)-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)quinoline
875
General procedure for the synthesis of (E)-N0-((2-tolyloxy)
quinoline-3-yl)methylene)isonicotinohydrazide (4a-j). An equi-
molar mixture of 2-chloro-3-formyl quinoline (1a) (0.004 mol)
and isonicotinohydrazide (3) (0.004 mol) in 10 mL ethanol
containing few drops of glacial acetic acid was stirred at room
temperature. After completion of reaction (checked by TLC),
the excess of solvent was removed on rotary evaporator to
yield solid which was washed with petroleum ether followed
by crystallization from ethanol.
8.62 (d, J ¼ 10.12 Hz, 2H, Ar-H), 7.69–7.84 (m, 3H, Ar-H),
7.32 (t, J ¼ 1.45 Hz, 2H, Ar-H), 7.10 (dd, J ¼ 9.21 and 3.14
Hz, 4H, Ar-H), 2.65 (s, 3H, Ar-CH3), 2.34 (s, 3H, Ar-CH3);
ES-MS (m/z): 395 (Mþ1); Anal. Calcd. C24H18N4O2 C,
73.08; H, 4.60; N, 14.20, found C, 73.10; H, 4.62; N, 14.23%.
2-(p-tolyloxy)-7-methoxy-3-(5-(pyridin-4-yl)-1,3,4- oxadiazol-
2yl)quinoline (5f). IR (KBr, cmꢁ1): 2925 (C–H), 1570 (C¼¼N);
1H-NMR (400 Hz, DMSO-d6): d ppm 8.85 (s, 1H), 8.76 (d,
J ¼ 9.2 Hz, 2H, Ar-H), 7.63–7.82 (m, 3H, Ar-H), 7.25 (t, J ¼
12 Hz, 2H, Ar-H), 7.08 (dd, J ¼ 8 and 4.2 Hz, 4H, Ar-H),
3.82 (s, 3H, Ar-OCH3), 2.93 (s, 3H, Ar-CH3); ES-MS (m/z):
411 (Mþ1); Anal. Calcd. C24H18N4O3 C, 70.23; H, 4.42; N,
13.65, found C, 70.27; H, 4.47; N, 13.70%.
(E)-N0-((2-tolyloxy) quinoline-3-yl) methylene)isonicotino-
hydrazide (4a). IR (KBr, cmꢁ1): 2980 (NH), 1560 (C¼¼N),
1
1513 (C¼¼C); H-NMR- (400 Hz, DMSO-d6): d 10.72 (s, 1H,
ANH), 8.90 (s, 1H), 8.77 (d, J ¼ 7.92 Hz, 3H, Ar-H), 7.75–
7.80 (m, 4H, Ar-H), 7.26 (t, J ¼ 10.94 Hz, 2H, Ar-H), 7.19
(dd, J ¼ 8.21 and 4.24 Hz, 4H, Ar-H) 2.30 (s, 3H, Ar-CH3),
ES-MS (m/z): 383 (Mþ1); Anal. Calcd. C23H18N4O2 C,
72.24; H, 4.74; N, 14.65, found C, 72.22; H, 4.80; N, 14.56%.
(E)-N0-((2-tolyloxy)-6-ethoxyquinoline-3-yl)methylene)isonico-
tinohydrazide (4h). IR (KBr, cmꢁ1): 3009 (ANH), 1577
2-(p-tolyloxy)-6-methoxy-3-(5-(pyridin-4-yl)-1,3,4 oxadiazol-2yl)-
1
quinoline (5g). IR (KBr, cmꢁ1): 2932 (C–H), 1562 (C¼¼N); H-
NMR (400 Hz, DMSO-d6): d ppm 8.80 (s, 1H), 8.66 (d, J ¼ 8.6
Hz, 2H, Ar-H), 7.82–7.92 (m, 3H, Ar-H), 7.39 (t, J ¼ 11.78 Hz,
2H, Ar-H), 7.21 (dd, J ¼ 7.9 and 3.9 Hz, 4H, Ar-H) 3.64 (s, 3H,
Ar-OCH3), 2.02 (s, 3H, Ar-CH3); ES-MS (m/z): 411 (Mþ1);
Anal. Calcd. C24H18N4O3 C, 70.23; H, 4.42; N, 13.65, found C,
70.21; H, 4.46; N, 13.68%.
1
(C¼¼N), 1510 (C¼¼C); H-NMR- (400 Hz, DMSO-d6): d 10.79
(s, 1H, ANH), 8.92 (s, 1H), 8.73 (d, J ¼ 8.21 Hz, 2H, Ar-H)
7.84–7.89 (dd, 4H, Ar-H), 7.21 (t, J ¼ 11.30 Hz, 2H, Ar-H),
7.16 (dd, J ¼ 8.44 and 4.66 Hz, 4H, Ar-H), 2.67 (s, 3H, Ar-
CH3), 1.41 (s, 3H, ACH3); ES-MS (m/z): 427 (Mþ1); Anal.
Calcd. C25H22N4O3 C, 70.41; H, 5.20; N, 13.14, found C,
70.43; H, 5.30; N, 13.21%.
2-(p-tolyloxy)-6-ethoxy-3-(5-(pyridin-4-yl)-1,3,4 oxadiazol-2yl)-
quinoline (5h). IR (KBr, cmꢁ1): 2950 (C–H), 1547 (C¼¼N);
1H-NMR (400 Hz, DMSO-d6): d ppm 8.89 (s, 1H), 8.70 (d, J
¼ 8.21 Hz, 2H, Ar-H), 7.71–7.75 (m, 3H, Ar-H), 7.34 (t, J ¼
12.17 Hz, 2H, Ar-H), 7.09 (dd, J ¼ 9 and 4.34 Hz, 4H, Ar-H),
2.87 (s, 3H, Ar-CH3), 1.43 (s, 3H, ACH3); ES-MS (m/z): 425
(Mþ1); Anal. Calcd. C25H20N4O3 C, 70.74; H, 4.75; N,
13.20, found C, 70.80; H, 4.79; N, 13.18%.
General procedure for the synthesis of substituted 2-(p-
tolyloxy)-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)quinoline
(5a-j). (0.1 g, 0.00028 mol) of N0-((2-(p-tolyloxy)quinoline-
3-yl)methylene)isonicotinohydrazide (4a) was dissolved in
10 mL of DMSO. To this reaction mixture, catalytic amount
of iodine was added. The reaction mixture was heated in an
oil bath for 3–4 h at 120ꢀC and left for overnight. 10-mL ice
cold water was slowly added to the flask and the separated
product was filtered and washed with water. Further reaction
mass washed with dil sodium thiosulphate solution for several
times. It was again washed with water dried under vacuum. The
residue was subjected to column chromatography (60–120 mesh
size silica gel) eluted with hexane-ethyl acetate (80:20) to obtain
the pure product. The compounds (5a–j) were prepared by fol-
lowing the above procedure and their percentage yield and
physical constants were recorded in Table 1. Their structures
2-(p-tolyloxy)-8-ethoxy-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2yl)-
1
quinoline (5j). IR (KBr, cmꢁ1): 2954 (C–H), 1544 (C¼¼N); H-
NMR (400 Hz, DMSO-d6): d ppm 8.91 (s, 1H), 8.72 (d, J ¼
8.28 Hz, 2H, Ar-H), 7.74–7.78 (m, 3H, Ar-H), 7.38 (t, J ¼ 11.92
Hz, 2H, Ar-H), 7.07 (dd, J ¼ 8.98 and 4.31 Hz, 4H, Ar-H), 3.90
(q, 2H, AOCH3), 2.67 (s, 3H, Ar-CH3), 1.21 (s, 3H, ACH3);
ES-MS (m/z): 425 (Mþ1); Anal. Calcd. C25H20N4O3, C, 70.74;
H, 4.75; N, 13.20, found C, 70.78; H, 4.80; N, 13.23%.
Acknowledgments. The authors are thankful to The Head,
Department of Chemistry, Dr. Babasaheb Ambedkar Marath-
wada University, Aurangabad, for his valuable support and labo-
ratory facilities and RSJ is thankful to University Grants
Commission, New Delhi, for awarding the fellowship.
1
have been confirmed by IR H-NMR and mass spectra.
2-(p-tolyloxy)-3-(5-(pyridin-4-yl)-1,3,4 oxadiazol-2yl)quino-
line (5a). IR (KBr, cmꢁ1): 2930 (CAH), 1577 (C¼¼N); 1H-NMR
(400 Hz, DMSO-d6): d ppm 8.73 (s, 1H), 8.69 (d, J ¼ 8.9 Hz, 2H,
Ar-H) 7.72–7.65 (m, 4H, Ar-H), 7.30 (t, J ¼ 11.76 Hz, 2H, Ar-H),
7.12 (dd, J ¼ 8.3, 3.92 Hz, 4H, Ar-H), 2.87 (s, 3H, Ar-CH3); ES-
MS (m/z): 381 (Mþ1); Anal. Calcd. C23H16N4O2 C, 72.62; H,
4.24; N, 14.73, found C, 72.59; H, 4.29; N, 14.71%.
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8.65 (d, J ¼ 9.29 Hz, 2H, Ar-H), 7.67–7.62 (m, 3H, Ar-H),
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R. S. Joshi, P. G. Mandhane, W. Khan, and C. H. Gill
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet