Comparison between antioxidant activity of 2,5-disubstituted 1,3,4-oxadiazoles containing heteroaromatic ring and aromatic ring at 2nd position

Article abstract of DOI:10.1007/s00044-010-9480-5

A series of 4-[5-(substitutedphenyl)-1,3,4-oxadiazol- 2-yl]-pyridine) and 2-[5-substitutedphenyl)-1,3,4- oxadiazol-2-yl]-benzenamine derivatives were synthesized from substituted esters and hydrazine hydrate in the presence of ethanol to give isonicotinic acid hydrazide and 2-aminobenzohydrazide followed by reaction with phosphorus oxychloride and various aromatic acids. All the compounds were tested for their in vitro antioxidant activity by 1,1-diphenyl-2-picryl hydrazyl (DPPH) method. Compounds containing aromatic group at 2nd position showed significant activity as compared to standard (ascorbic acid) which concludes that the presence of aromatic group increases the free radical scavenging activity. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9480-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1650–1655
DOI 10.1007/s00044-010-9480-5
ORIGINAL RESEARCH
Comparison between antioxidant activity of 2,5-disubstituted
1,3,4-oxadiazoles containing heteroaromatic ring and aromatic
ring at 2nd position
•
Radhika Maheshwari Pooja Chawla
•
Shubhini A. Saraf
Received: 27 February 2010 / Accepted: 15 October 2010 / Published online: 4 November 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series of 4-[5-(substitutedphenyl)-1,3,4-oxa-
diazol-2-yl]-pyridine) and 2-[5-substitutedphenyl)-1,3,4-
oxadiazol-2-yl]-benzenamine derivatives were synthesized
from substituted esters and hydrazine hydrate in the pres-
ence of ethanol to give isonicotinic acid hydrazide and
2-aminobenzohydrazide followed by reaction with phos-
phorus oxychloride and various aromatic acids. All the
compounds were tested for their in vitro antioxidant
activity by 1,1-diphenyl-2-picryl hydrazyl (DPPH) method.
Compounds containing aromatic group at 2nd position
showed significant activity as compared to standard
(ascorbic acid) which concludes that the presence of aro-
matic group increases the free radical scavenging activity.
et al., 2008), antitubercular (Somani and Shirodkar, 2008),
anticonvulsant (Zarghi et al., 2005), and antitumour activity
(Holla et al., 2005). Not only this, 1,3,4-oxadiazole nucleus
is also emerging as antioxidant moiety (Padmavathi et al.,
2009, 2010; Rajasekaran et al., 2010). It is a well estab-
lished that free radicals are responsible for inflammation
process. Prostaglandins are important mediators of inflam-
mation and free radicals are involved in the biosynthesis of
prostaglandins. Compounds with antioxidant activity are
supposed to have good anti-inflammatory activity. In view
of above mentioned findings, the purpose of present study
was to synthesize some novel analogues of 2,5-disubstituted
1,3,4-oxadiazole expecting their enhanced antioxidant
activity.
Keywords 1,3,4-Oxadiazoles ꢀ Heteroaromatic ring ꢀ
Antioxidant activity
Experimental
Introduction
Synthetic method
A diversity of useful biological effects is possessed by
heterocyclic compounds containing oxadiazole nucleus
(Franski, 2005). In particular, compounds bearing 1,3,
4-oxadiazole nucleus are known to exhibit unique antie-
dema and anti-inflammatory activity (Omar et al., 1996;
Narayana et al., 2005; Kamble and Sudha, 2006; Hussain
and Ahuja, 2009). Differently substituted oxadiazole moi-
ety has been found to have other interesting activities such
as analgesic, antimicrobial (Ingole et al., 2007; Karthikeyan
Synthesis of isonicotinic acid hydrazide
Isonicotinic acid ester (0.01 mol) and hydrazine hydrate
(0.02 mol) were mixed gently and refluxed for 5 h with
30 ml of ethanol. Excess of solvent was distilled off. The
reaction mixture was cooled to 4–5°C and separated solid
crystals were filtered, washed with cold water, dried and
recrystallized from ethanol (Furniss et al., 1989). Yield
76.6%, melting range 175–178°C.
Synthesis of 2-aminobenzhydrazide
R. Maheshwari ꢀ P. Chawla (&) ꢀ S. A. Saraf
Faculty of Pharmacy, Babu Banarasi Das National Institute of
Technology and Management, Dr. Akhilesh Das Nagar, Sector 1,
Faizabad Road, Lucknow 227105, UP, India
A mixture of 2-aminomethyl benzoate (0.01 mol), excess
of hydrazine hydrate (20 ml, 0.04 mol) and absolute
alcohol (50 ml) was refluxed for 5 h. Excess of solvent was
e-mail: pj_abrol@yahoo.com
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Med Chem Res (2011) 20:1650–1655
1651
distilled off. The reaction mixture was cooled to 4–5°C and
separated solid crystals were filtered, washed with cold
water, dried and recrystallized from ethanol. Yield 80.45%,
Melting range 122–124°C.
Melting points of the synthesized compounds were
taken in open-end capillary tubes and are uncorrected.
Purity of compounds was checked by TLC on silica gel
plates and spots were visualized by exposure to iodine
vapours. IR spectra were recorded on Perkin Elmer Spec-
trum RX1 FTIR spectrophotometers. NMR spectra were
recorded on Bruker DRX 300 spectrophotometer. Mass
spectra were recorded on JEOL-Accu TOF JMS-T100LC
spectrometer at Central Drug Research Institute, Lucknow.
The spectral data of the synthesized compounds are sum-
marized below.
Syntheses of 4-[5-(4-aryl)-[1,3,4-oxadiazol-2-yl]-pyridine
(1–4)
1,3,4-Oxadiazoles can be synthesized by reacting hydra-
zides with various carboxylic acids (Reddy and Reddy,
1988; Pachhamia and Parikh, 1989). A mixture of 4-isoni-
cotinic acid hydrazide (0.01 mol) and appropriate aromatic
acid (0.01 mol) were dissolved in phosphorus oxychloride
(15 ml) and refluxed over a water bath for 5 h. The progress
of reaction was monitored by TLC using ethylacetate:
acetone (9:1) as eluent. The reaction mixture was cooled
and poured on to a crushed ice dropwise with continuous
stirring. The separated solid mass was neutralized with
ammonia solution. The mixture was left overnight in
refrigerator. The resulting solid thus obtained was collected
by filtration, washed well with cold water, dried and
recrystallized from absolute ethanol (Nagalakshmi, 2008).
4-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-pyridine (1)
C13H8N3OCl, yield: 85.6%, Mp: 110–117°C. TLC ethyl-
acetate: acetone (9:1) Rf: 0.71. IR cm-1 (KBr): t 3095
(aromatic C–H), 1598, 1481(aromatic C=C), 1722.7 (C=N),
1227 (asymmetric C–O–C), 1087 (symmetric C–O–C),
1050 (Ar-Cl), 738.4 (C–H Para subst); 1HNMR (DMSO-d6,
d ppm): 7.38–8.59 (m, 4H, C–H Pyr), 7.30–7.32 (m, 4H);
MS (FAB) m/z: 257 (M?), 258 (M? ? 1, 100%).
4-[5-(4-Aminophenyl)-1,3,4-oxadiazol-2-yl]-pyridine (2)
Syntheses of 2-aryl-5-(2-aminophenyl)-1,3,4-oxadiazole
(5–9)
C13H10N4O, yield: 82.5%, Mp: 100–105°C. TLC ethyl-
acetate: acetone (9:1) Rf: 0.72. IR cm-1 (KBr): t 3443
(stretch NH2), 1600 (bend NH2), 3100 (aromatic C–H),
1654, 1405 (aromatic C=C), 1654 (C=N), 1256 (asym-
metric C–O–C), 1182 (symmetric C–O–C), 846 (C–H Para
subst); 1HNMR (DMSO-d6, d ppm): 7.41–8.59 (m, 4H,
C–H Pyr), 7.30–7.35 (m, 4H Arom.), 4.13 (s, NH2); MS
(FAB) m/z: 238 (M?), 239 (M? ? 1, 100%).
A mixture of 2-aminobenzhydrazide (0.01 mol) and
appropriate aromatic acid was dissolved in phosphorus
oxychloride (15 ml) refluxed over a water bath for 3–5 h.
The progress of reaction was monitored by TLC using
ethylacetate: acetone (9:1) as eluent. The reaction mixture
was cooled and poured on to a crushed ice drop wise with
continuous stirring. The separated solid mass was neutral-
ized with ammonia solution. The mixture was left over-
night in refrigerator. The resulting solid thus obtained was
collected by filtration, washed well with cold water, dried
and recrystallized from absolute ethanol. The physico-
chemical parameters of the synthesized compounds are
given in Table 1 (Scheme 1).
4-[5-(4-Nitrophenyl)-1,3,4-oxadiazole-2-yl]-pyridine (3)
C13H8N4O3, yield: 60.2%, Mp: 160–166°C. TLC ethyl-
acetate: acetone (9:1) Rf: 0.48. IR cm-1 (KBr): t 3091
(aromatic C–H), 1606, 1485 (aromatic C=C), 1664 (C=N),
1220 (asymmetric C–O–C), 1066 (symmetric C–O–C), 858
Table 1 Physical characterization of synthesized compounds (1–9)
S. no.
Compound
code
R0
Molecular formula
Molecular
weight
Reaction
time (h)
% Yield
Melting
range (°C)
Rf value
1
2
3
4
5
6
7
8
9.
1
2
3
4
5
6
7
8
9
4-Cl
C13H8N3OCl
C13H10N4O
C13H8N4O3
C13H8N4O3
257
238
268
268
271
282
268
258
267
4
4
5
4
3
4
5
2
4
85.6
82
60
79
80
80
75
88
84
110–115
100–105
160–165
126–130
152–157
170–175
166–169
155–160
141–145
0.71
0.72
0.48
0.63
0.60
0.48
0.71
0.66
0.56
4-NH2
4-NO2
3-NO2
4-Cl
C14H10N3OCl
3-NO2
C14H10N4O3
C14H12N4O2
C12H12N4O
C15H13N3O2
2-OH-4-NH2
2-NH2
2-OH-3-CH3
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Med Chem Res (2011) 20:1650–1655
Scheme 1 Synthesis of 2,5-
disubstituted 1,3,4-oxadiazole
derivatives
C2H5OH
RCONHNH2
R-COOC2H5
NH2 NH2 .H2O
reflux for 4 hrs
substituted
hydrazide
substituted
esters
Hydrazine
hydrate
COOH
1.
R'
reflux 4-5 hrs
2.
POCl3
N
N
R
O
R'
2,5 disubstituted-1,3,4-oxadiazoles
R=C6H5, C6H4N; R’= 4-ClC6H4, 4-NH2C6H4, 4-NO2C6H4, 3-NO2C6H4, 2-OH-3-CH3C6H3, 4-NH2-2-OHC6H3
(C–H Para subst); 1549 (asymm. Ar-NO2), 1341(symm.
1
(stretch NH2), 1551 (bend NH2), 3167 (aromatic C–H),
1619, 1402 (aromatic C=C), 1681 (C=N), 1258 (asym-
metric C–O–C), 1086 (symmetric C–O–C), 746, 815 (C–H
ortho and meta subst); 1531 (asymm. Ar-NO2), 1350
Ar-NO2); HNMR (DMSO-d6, d ppm): 7.40–8.62 (m, 4H,
C–H Pyr), 7.28–7.35 (m, 4H Arom.); MS (FAB) m/z: 268
(M?), 269 (M? ? 1, 100%).
1
(symm. Ar-NO2); HNMR (DMSO-d6, d ppm): 6.52–7.01
(m, 4H, C–H Arom.), 7.52–8.19 (m, 4H Arom.), 4.20
(s, NH2); MS (FAB) m/z: 282 (M?), 283 (M? ? 1, 100%).
4-[5-(3-Nitrophenyl)-1,3,4-oxadiazol-2-yl]-pyridine (4)
C13H8N4O3, yield: 79.8%, Mp: 125–130°C. TLC ethyl-
acetate: acetone (9:1) Rf: 0.63. IR cm-1 (KBr): t 3074
(aromatic C–H), 1596, 1475 (aromatic C=C), 1716 (C=N),
1225 (asymmetric C–O–C), 1062 (symmetric C–O–C), 725,
827 (C–H meta subst); 1528 (asymm. Ar-NO2), 1344
2-[5-(4-Amino-2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]-
benzenamine (7)
C14H12N4O2, yield: 75.1%, Mp: 163–169°C. TLC ethyl-
acetate: acetone (9:1) Rf: 0.71. IR cm-1 (KBr): t 3695
(Aromatic OH), 3190 (stretch NH2), 1565 (bend NH2),
3167 (aromatic C–H), 1596, 1477 (aromatic C=C), 1670
(C=N), 1256 (asymmetric C–O–C), 1093 (symmetric
1
(symm. Ar-NO2); HNMR (DMSO-d6, d ppm): 7.40–8.62
(m, 4H, C–H Pyr), 7.35–8.19 (m, 4H Arom.); MS (FAB)
m/z: 268 (M?), 269 (M? ? 1, 100%).
1
2-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-benzenamine
(5)
C–O–C), 768, 831 (C–H ortho and para subst); HNMR
(DMSO-d6, d ppm): 4.22 (s, NH2), 6.51–7.01 (m, 4H, C–H
Arom.), 6.75–7.10 (m, 4H Arom.), 5.92 (d, OH), 4.03
(d, NH2); MS (FAB) m/z: 268 (M?), 269 (M? ? 1, 100%).
C14H10N3OCl, yield: 80.3%, Mp: 152–157°C. TLC ethyl-
acetate: acetone (9:1) Rf: 0.60. IR cm-1 (KBr): t 3413 (stretch
NH2), 1560 (bend NH2), 3074 (aromatic C–H), 1596, 1475
(aromatic C=C), 1614 (C=N), 1217 (asymmetric C–O–C),
1087(symmetric C–O–C), 1050(Ar-Cl), 769, 827 (C–Hortho
and para subst); 1HNMR (DMSO-d6, d ppm): 6.52–7.01 (m,
4H, C–H Arom.), 7.22–7.34 (m, 4H Arom.), 4.21 (s, NH2);
MS (FAB) m/z: 281 (M?), 282 (M? ? 1, 100%).
2-[5-(2-Aminophenyl-(1,3,4-oxadiazol-2-yl]-benzenamine
(8)
C12H12N4O, yield: 88.3%, Mp: 155–160°C. TLC ethyl-
acetate: acetone (9:1) Rf: 0.66. IR cm-1 (KBr): t 3213
(stretch NH2), 1562 (bend NH2), 3020 (aromatic C–H),
1597, 1490 (aromatic C=C), 1674 (C=N), 1216 (asym-
metric C–O–C), 1094 (symmetric C–O–C), 1050 (Ar-Cl),
827 (C–H ortho subst); 1HNMR (DMSO-d6, d ppm):
6.49–7.01 (m, 4H, C–H Arom.), 6.51–7.01 (m, 4H Arom.),
4.28 (d, NH2); MS (FAB) m/z: 258 (M?), 260 (M? ? 2,
100%).
2-[5-(3-Nitrophenyl)-1,3,4-oxadiazol-2-yl]-benzenamine
(6)
C14H10N4O3, yield: 80.6%, Mp: 170–175°C. TLC ethyl-
acetate: acetone (9:1) Rf: 0.48. IR cm-1 (KBr): t3440
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Med Chem Res (2011) 20:1650–1655
1653
2-(5-(2-Hydroxy-3-methylphenyl)-1,3,4-oxadiazol-2-yl]-
benzenamine (9)
C15H13N3O2, yield: 84.4%, Mp: 141–145°C. TLC ethyl-
acetate: acetone (9:1) Rf: 0.56. IR cm-1 (KBr): t 3506
(Aromatic OH), 3418 (stretch NH2), 1601 (bend NH2),
3157 (aromatic C–H), 1597, 1490 (aromatic C=C), 1674
(C=N), 1254 (asymmetric C–O–C), 1087 (symmetric
C–O–C), 690, 770, 837 (C–H ortho and meta subst);
1HNMR (DMSO-d6, d ppm): 6.49–7.01 (m, 4H, C–H
Arom.), 6.79–7.01 (m, 4H Arom.), 4.01 (s, NH2), 1.30
(d, CH3), 5.82 (s, OH Phenolic); MS (FAB) m/z: 267 (M?),
268 (M? ? 1, 100%).
Antioxidant activity
Fig. 1 Antioxidant activity compounds 1–4
Synthesized compounds were subjected to free radical
scavenging activity by DPPH assay method. This assay has
often been used to estimate the antiradical activity of
antioxidants. The free radical scavenging capabilities of the
compounds were measured in terms of hydrogen donating
or free radical scavenging ability after adding methanolic
solution of DPPH (2,2-Diphenyl-1-Picrylhydrazyl) to the
sample solution of different concentrations. The test com-
pounds react with DPPH and convert it to 1,1-diphenyl-2-
picrylhydrazine. The degree of decolorizing indicates the
potentialities of the antioxidant drug. Ascorbic acid was
used as standard.
Procedure
Free radical scavenging activity of the test compounds was
studied by the diphenyl picryl hydrazyl (DPPH) assay
method. Drug stock solution (1 mg/ml) was diluted to final
concentrations of 2, 4, 6, 8 and 10 lg/ml in methanol.
Minimum amount of dimethyl sulphoxide was used to
solubilize the samples (George et al., 2008). Methanolic
DPPH solution (1 ml, 0.3 mmol) was added to 3.0 ml of
drug solutions of different concentrations and allowed to
react at room temperature. After 30 min the absorbance
values were measured at 517 nm in Schimadzu 1700
UV–Visible Spectrophotometer and converted into the
percentage antioxidant activity. Each experiment was per-
formed in triplicate. Scavenging activity was calculated by
following formula (Chandrashekar and Karvekar, 2008).
Fig. 2 Antioxidant activity of compounds 5–9
(Figs. 1, 2). The IC50 values were calculated by linear
regression of plots where the abscissa represented the
concentration of the compounds (lg/ml) and the ordinate,
the average percentage of antioxidant activity. Results in
the form of percent inhibition are summarized in Table 2.
Results and discussion
The free radical scavenging activity was carried out for the
synthesized compounds 4-[5-(substitutedphenyl)-1,3,4-ox-
adiazol-2-yl]-pyridine) (1–4) and 2-[5-substitutedphenyl)-
1,3,4-oxadiazol-2-yl]-benzenamine (5–9).
Control absorbance ꢁ Test absorbance
% Reduction =
Control absorbance
ꢂ 100
DPPH is a stable free radical that can accept electron or
hydrogen radical to become a diamagnetic molecule. Due
to its odd electron, the methanolic solution of DPPH shows
a strong absorption at 517 nm. DPPH radical reacts with
suitable reducing agent, then electrons become paired off,
Ascorbic acid was used as standard. Methanolic DPPH
solution (1 ml, 0.3 mM) was used as control. The inhibi-
tory concentration (IC50) value, representing the concen-
tration required to exhibit 50% antioxidant activity
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Med Chem Res (2011) 20:1650–1655
Table 2 Quantitative screening of antioxidant activity by DPPH assay method (n = 3)
S.no
Compound
Absorbance
Absorbance at 517 nm
IC50 lg/ml
2 lg/ml
4 lg/ml
6 lg/ml
8 lg/ml
10 lg/ml
1
2
Control
(Abscontrol
Abssample
(AA%)
)
0.9426 0.08
0.8223 0.71
12.76
0.9426 0.08
0.7127
0.9426 0.09
0.6127
0.9426 0.09
0.5316
0.9426 0.08
0.4353
1
9.01
12.08
12.47
6.99
24.38
38.99
43.60
53.81
3
2
Abssample
(AA%)
0.8646 0.07
8.27
0.7866 0.07
16.54
0.7086 0.07
24.82
0.6306 0.06
33.09
0.5526 0.06
41.37
4
3
Abssample
(AA %)
Abssample
(AA%)
0.8798 0.09
6.66
0.8018 0.08
14.93
0.7238 0.08
23.21
0.6458 0.07
31.48
0.5678 0.07
39.76
5
4
0.8012 0.08
15.00
0.6719 0.07
28.71
0.5423 0.06
42.46
0.3991 0.04
57.659
0.2718 0.03
71.16
6
5
Abssample
(AA %)
0.8226 0.09
12.30
0.7213 0.08
23.47
0.6016 0.07
36.17
0.4914 0.04
49.98
0.3817 0.04
59.50
8.26
7
6
Abs
0.8906 0.09
5.51
0.8086 0.09
14.21
0.7566 0.08
19.73
0.7046 0.07
25.24
0.6526 0.07
30.76
16.04
20.05
7.76
sample
(AA%)
8
7
Abssample
(AA%)
0.8956 0.09
4.98
0.8486 0.09
9.97
0.8016 0.09
14.95
0.7546 0.08
19.94
0.7076 0.07
24.93
9
8
Abssample
(AA%)
0.8228 0.09
12.07
0.6991 0.07
25.83
0.5791 0.06
38.56
0.4593 0.05
52.12
0.3397 0.04
63.96
10
11
9
Abssample
(AA%)
0.7924 0.08
15.93
0.6420 0.07
31.89
0.4825 0.05
48.81
0.3310 0.04
64.88
0.1706 0.02
81.90
6.00
Std.
Abssample
(AA%)
0.7723 0.08
18.24
0.6113 0.06
35.32
0.4424 0.05
53.24
0.2912 0.03
69.28
0.1217 0.01
87.26
5.68
Acknowledgments One of the authors is thankful to All India
Council for Technical Education (AICTE), New Delhi for scholar-
ship. The authors are also thankful to Director, CDRI, Lucknow for
spectral analysis.
and the solution loses colour stoichiometrically with the
number of electrons taken up. Such reactivity has been
widely used to test the ability of compound to act as free
radical scavengers. Reduction of the DPPH radicals can be
observed by the decrease in absorbance at 517 nm. The
IC50 are the 50% inhibition concentration and were cal-
culated from regression lines.
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In the series of synthesized compounds, Compound 9
was found to possess maximum antioxidant activity (IC50
6.00) against the standard drug ascorbic acid (IC50 5.68).
However, 4-(5-methyl-[1,3,4] oxadiazole-2-yl)-pyridine
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(8) showed good free radical scavenging activity (IC50
6.99, 8.26, 7.76). Moderate activity was shown by (3-
nitrophenyl)-5-(2-aminophenyl)1,3,4-oxadiazole (1), 4-[5-
(4-nitrophenyl)-[1,3,4-oxadiazol-2-yl]-pyridine) (2) (IC50
9.01 and 12.08, respectively), whereas phenyl substituted
compound 2-(4-amino-2-hdroxyphenyl)-5-(2-aminophe-
nyl)-1,3,4-oxadiazole (7) showed minimum antioxidant
activity (IC50 20.05). To conclude, aromatic ring at posi-
tion 2 of oxadiazole possesses better activity as compared
to heteroaromatic group. However, heteroaromatic ring
gives considerable activity with meta nitro group.
123

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