Synthesis and biological evaluation of 1,3,4-oxadiazole fused pyridine derivatives as antibacterial and antifungal agents

Article abstract of DOI:10.1134/S1070363217030276

A series of novel 1,3,4-oxadiazole fused pyridine derivatives were synthesized 11a–11f and their structures confirmed by IR, ¹H NMR and Mass spectral data. The compounds were evaluated for their antibacterial and antifungal activities against Gram negative and positive bacterial strains including Escherichia coli (MTCC 443), K. Pneumoniae (MTCC 109), S. Aureus (MTCC 96), B. Subtilis (MTCC 441) and Sclerotium rolfsii, Macrophomina phaseolina. Compounds 11d, 11e, and 11f demonstrated high antibacterial activity.

Full text of DOI:10.1134/S1070363217030276

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 3, pp. 550–553. © Pleiades Publishing, Ltd., 2017.
Synthesis and Biological Evaluation
of 1,3,4-Oxadiazole Fused Pyridine Derivatives
as Antibacterial and Antifungal Agents1
N. J. P. Subhashinia*, B. Bhadraiaha,b, and P. Janakia
a Department of Chemistry, University College of Technology, Osmania University, Hyderabad, 500007 India
*e-mail: njsubhashini@yahoo.co.in
b Chemistry Services, GVK Biosciences Pvt.Ltd, IDA Nacharam, Hyderabad, 500076 India
Received December 31, 2016
Abstract—A series of novel 1,3,4-oxadiazole fused pyridine derivatives were synthesized 11a–11f and their
1
structures confirmed by IR, H NMR and Mass spectral data. The compounds were evaluated for their
antibacterial and antifungal activities against Gram negative and positive bacterial strains including Escherichia
coli (MTCC 443), K. Pneumoniae (MTCC 109), S.Aureus (MTCC 96), B. Subtilis (MTCC 441) and Sclerotium
rolfsii, Macrophomina phaseolina. Compounds 11d, 11e, and 11f demonstrated high antibacterial activity.
Keywords: nicotinic acid, isoniazid, furamizole, antibacterial activity
DOI: 10.1134/S1070363217030276
INTRODUCTION
antihepatitis B virus [5], antibacterial [6], and many
others [7-9]. Some pyridine containing drugs such as
Nicotinic acid (1) are used for treatment of
cardiovascular disease [10]. Isoniazid (2) is used for
tuberculosis [11] (Scheme 1).
Compounds with the pyridine backbone possess a
variety of biological activities including antimicrobial
[1], herbicidal [2], insecticidal [3], antiprion [4],
Scheme 1.
N
O
N
H
NH2
O
N
NH2
O
CO2H
O2N
O
N
N
3
1
2
1,3,4-Oxadiazole is another important five-member
heterocyclic compound associated with potent
pharmacological activity due to the presence of the
–N=C–O– linkage [12].
Synthesis of the compounds 11a–11f is outlined in
Scheme 2.
EXPERIMENTAL
In view of the above, we have synthesized a novel
series of 1,3,4-oxadiazole incorporated pyridine deriva-
tives 11a–11f. The structures of products were
confirmed by IR, H NMR and mass spectra and their
antibacterial and antifungal activities were evaluated.
All chemicals and reagents were obtained from
Aldrich (Sigma–Aldrich, St. Louis, MO, USA),
Lancaster (Alfa, Johnson Matthey Company, Ward
Hill, MA, USA) and used without further purification.
Reactions were monitored by TLC, performed on silica
gel glass plates containing 60 F-254, and visualized by
UV light or iodine vapor. Melting points were
1
1 The text was submitted by the authors in English.
550

SYNTHESIS AND BIOLOGICAL EVALUATION
551
Scheme 2. Synthetic pathway to 11a–11f.
Br
Br
N
NO2
Br
Br
CHO
2
NO2
1
3
+
H
N
N
CO2Et
N
N
CONHNH2
N
CO2H
O
6
7
8
5
4
4
HO
OH
O2N
B
O2N
R
N
N
N
N
5
Br
+
R
O
O
N
N
11a−11f
10a−10f
9
R = H (11a), 3-OH (11b), 4-OMe (11c), 2-CF3 (11d), 4-CN (11e), 3,4-difluoro (11f). Reagents and conditions: (1) Ethanol,
conc H2SO4, reflux, 12 h. (2) Ethanol, N2H4.H2O, reflux, 12 h. (3) Ethanol, reflux, 12 h. (4) (Diacetoxyiodo)benzene, CH2Cl2,
40°C, 12 h. (5) DME, H2O, Na2CO3, Pd(PPh3)4, 100oC, 10 min.
determined with an electro thermal melting point
apparatus. IR spectra were recorded on a Schimadzu-
FT-IR Spectrophotometer in KBr discs. H NMR
was heated at 70°C for 12 h. Upon completion of the
reaction (TLC), the solid precipitate was filtered off
and dried under vacuum to give compound 6 (85%).
1
spectra were measured at 400 MHz using TMS as the
theinternal standard. ESI spectra were measured on
Micro mass, Quattro LC using ESI+ software with
capillary voltage 3.98 kV and ESI mode positive ion
trap detector.
(E)-4-Bromo-N'-(2-nitrobenzylidene)picolino-
hydrazide (8). To a stirred solution of 4-bromo-
picolinohydrazide 6 (12 g, 55.82 mmol) in ethanol
(120 mL) was added 2-nitrobenzaldehyde 7 (10.11 g,
66.99 mmol). The reaction mixture was heated at 70°C
for 12 h. Upon completion of the reaction (monitored
by TLC), the solid precipitate was filtered off and
washed with n-hexane (50 mL), and dried under
vacuum to give compound 8 (82%).
Ethyl 4-bromopicolinate (5). To a stirred solution
of 4-bromopicolinic acid 4 (20 g, 87.33 mmol) in
ethanol (250 mL) cooled to 5°C, sulfuric acid (3 mL)
was added and the reaction mixture was slowly cooled
down to room temperature and then heated at 70°C for
12 h. Upon completion of the reaction (TLC), the
solvent was evaporated under vacuum. The residue
was dissolved in ethyl acetate (500 mL), washed with
ice cold water (100 mL), saturated by sodium bi-
carbonate solution (100 mL) and brine solution (100 mL).
The organic layer was separated and dried over
anhydrous sodium sulfate. The solvent was evaporated
under vacuum and purified by column chromatography
(hexane–ethyl acetate = 20 : 80) to give compound 5
(86%).
2-(4-Bromopyridin-2-yl)-5-(2-nitrophenyl)-1,3,4-
oxadiazole (9). To a stirred solution of (E)-4-bromo-
N'-(2-nitrobenzylidene) picolinohydrazide 8 (10 g,
28.73 mmol) in CH2Cl2 (100 mL) was added diacetoxy
iodobenzene (13.87 g, 42.69 mmol). The reaction
mixture was heated at 40°C for 12 h. Upon completion
of the reaction (TLC), the mixture was diluted with
DCM (200 mL) and washed with water (50 mL). The
organic layer was separated and dried over anhydrous
sodium sulfate, filtered and evaporated under vacuum
to give compound 9 (80.5%).
4-Bromopicolinohydrazide (6). To a stirred solu-
tion of ethyl 4-bromopicolinate 5 (15 g, 65.51 mmol)
in ethanol (150 mL) was added hydrazine hydrate
(6.55 g, 6.42 mL, 131.01 mmol). The reaction mixture
Synthesis of 1,3,4-oxadiazole fused pyridine deri-
vatives 11a–11f. To a stirred solution of 2-(4-bromo-
pyridin-2-yl)-5-(2-nitrophenyl)-1,3,4-oxadiazole 9 (100 mg,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017

552
SUBHASHINI et al.
Table 2. Antibacterial activity of compounds 11a–11f
Gram negative Gram positive
Table 1. Comparable studies of the Suzuki coupling reaction
Conventional method
Microwave method
Comp.
no.
time, h
10.00
12.10
14.30
8.20
yield, % time, min yield, %
11a
11b
11c
11d
11e
11f
51
48
55
49
56
60
20
15
10
12
30
25
75
77
83
71
80
82
Compound
Zone of inhibition, mm
11a
11b
6
7
–
8
12
14
13
16
18
16
20
9.30
10
12
14
13
14
22
12
10
12
13
13
15
16.10
11c
8
11d
9
0.28 mmol) were added a substituted arylboronic acid
10a–10f (1.2 equiv.) in 1,2-dimethoxy ethane (5 mL),
water (2 mL), Na2CO3 (3 eq). The mixture was de-
gassed with Ar within 10 min and Pd(PPh3)4
(0.05 equiv.) was added. The reaction mixture was
heated at 100°C for an appropriate period of time.
Upon completion of the reaction (TLC), the mixture
was diluted with ethyl acetate (20 mL) and washed
with water (2×5 mL). The organic layer was separated
and dried over anhydrous sodium sulfate and the
solvent evaporated under vacuum to give products
11a–11f. The similar processes carried out under
microwave irradiation using CEM microwave at 490 W
led to higher overall yields (75–82%) of the products
(Table 1).
11e
12
10
15
11f
Gentamycin
(1H), 8.80 d (J = 5.2 Hz, 1H). ESI-MS: m/z = 375.20
[M + H]+.
4-[2-(Trifluoromethyl)phenyl]-2-[5-(2-nitrophenyl)-
1,3,4-oxadiazol-2-yl]pyridine (11d). Yield 71%, mp
195–200°C. IR spectrum, ν, cm–1: 3434, 3085, 1551,
1529, 1353, 1316, 1170, 1118, 854, 775. 1H NMR spec-
trum, δ, ppm: 7.58 d (J = 7.6 Hz, 1H), 7.70 d (J =
4.8 Hz, 1H), 7.76 t (J = 7.6 Hz, 1H), 7.84 t (J = 7.6 Hz,
1H), 7.94–8.02 m (3H), 8.16–8.20 m (2H), 8.25 d.d
(J = 1.6,7.2 Hz, 1H), 8.91 d (J = 5.2 Hz, 1H). ESI-MS:
m/z = 412.9 [M + H]+.
2-(2-Nitrophenyl)-5-(4-phenylpyridine-2-yl)-1,3,4-
oxadiazole (11a). Yield 75%, mp 150–152°C. IR spec-
1
trum, ν, cm–1: 3432, 2925, 1531, 1348, 857, 727. H
4-{2-[5-(2-Nitrophenyl)-1,3,4-oxadiazol-2-yl]pyri-
din-4-yl}benzonitrile (11e). Yield 80%, mp 165–170°C.
NMR spectrum, δ, ppm: 7.64–7.54 m (3H), 7.93–8.03
m (5H), 8.20 d (J = 8.4 Hz, 1H), 8.26 d (J = 7.2 Hz,
1H), 8.51 s (1H), 8.87 d (J = 4.8 Hz, 1H). ESI-MS:
m/z = 345 [M + H]+.
Table 3. Anti-fungal activity of target compounds 11a–11f
3-(2-(5-(2-Nitrophenyl)-1,3,4-oxadiazol-2-yl)pyri-
din-4-yl) phenol (11b). Yield 77%, mp 145–150°C.
IR spectrum, ν, cm–1: 3209, 2923, 1601, 1535, 1365,
1220, 834, 719. 1H NMR spectrum, δ, ppm: 6.95 d (J =
8.8 Hz, 1H), 7.26 s (1H), 7.41–7.33 m (1H), 7.53–7.65
m (2H), 8.26 d (J = 8.8 Hz, 2H), 8.19 d.d (J = 2.76 Hz,
2H), 8.42 s (1H), 8.85 d (J = 5.6 Hz, 1H), 9.81 s (1H).
ESI-MS: m/z = 361.15 [M + H]+.
Zone of inhibition, cm
Compound
Sclerotium
rolfsii
Macrophomina
phaseolina
11a
11b
0.1
0.2
0.2
0.3
0.1
0.3
0.4
0.2
0.1
0.2
0.2
0.3
0.2
0.4
11c
2-(4-(3-Methoxyphenyl)-pyridine-2-yl)-5-(2-nitro-
phenyl)-1,3,4-oxadiazole (11c). Yield 83%, mp 201–
205°C. IR spectrum, ν, cm–1: 3445, 2935, 1597, 1540,
1365, 1256, 828, 573. 1H NMR spectrum, δ, ppm: 3.85
s (3H), 7.13 d (J = 8.8 Hz, 2H), 7.91–8.03 m (5H),
8.19 d (J = 8.4 Hz, 1H), 8.26 d (J = 8.4 Hz, 1H), 8.46 s
11d
11e
11f
Mancozeb
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017

SYNTHESIS AND BIOLOGICAL EVALUATION
ACKNOWLEDGMENTS
553
IR spectrum, ν, cm–1: 3409, 2919, 2228, 1599, 1363,
1
830. H NMR spectrum, δ, ppm: 7.96–8.27 m (9H),
The autohrs are thankful to GVK Bio sciences for
constant encouragement in providing laboratory
facilities and analytical data.
8.56 s (1H), 8.93 d (J = 5.2 Hz, 1H). ESI-MS: m/z =
369.9 [M + H]+.
4-(3,4-Difluorophenyl)-2-[5-(2-nitrophenyl)-1,3,4-
oxadiazol-2-yl]pyridine (11f). Yield 82%, mp 135–
140°C. IR spectrum, ν, cm–1: 3855, 3422, 2920, 2228,
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A novel series of 1,3,4-oxadiazole fused pyridine
derivatives 11a–11f was synthesized and the structures
were confirmed by IR, 1H NMR and Mass spectra. All
derivatives were evaluated for their antibacterial and
antifungal activities against Gram nagative and
positives bacterial strains, including Escherichia coli
(MTCC 443), K. Pneumoniae (MTCC 109), S.Aureus
(MTCC 96), B. Subtilis (MTCC 441) and Sclerotium
rolfsii, Macrophomina phaseolina. Compounds 11d,
11e, and 11f demonstrated high antibacterial activity.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017