Synthesis, Characterization, and Screening for Analgesic and Anti-Inflammatory Activities of Schiff Bases of 1,3,4-Oxadiazoles Linked With Quinazolin-4-One

Article abstract of DOI:10.1002/jhet.2934

Sixteen Schiff bases of quinazolin-4-one-linked 1,3,4-oxadiazoles were synthesized by reaction with different aromatic aldehydes. Purity of newly synthesized derivatives was confirmed through thin-layer chromatography, combustion analysis, and melting poi

Full text of DOI:10.1002/jhet.2934

Month 2017
Synthesis, Characterization, and Screening for Analgesic and Anti-
Inflammatory Activities of Schiff Bases of 1,3,4-Oxadiazoles Linked With
Quinazolin-4-One
*
Dhansay Dewangan,
Kartik T. Nakhate, Vinay Sagar Verma, Kushagra Nagori, and Dulal Krishna Tripathi
Rungta College of Pharmaceutical Sciences and Research, Bhilai 490024, Chhattisgarh, India
*
E-mail: danu_drugs@yahoo.com
Received February 28, 2017
DOI 10.1002/jhet.2934
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Sixteen Schiff bases of quinazolin-4-one-linked 1,3,4-oxadiazoles were synthesized by reaction with
different aromatic aldehydes. Purity of newly synthesized derivatives was confirmed through thin-layer
chromatography, combustion analysis, and melting point. The structure of the derivatives was confirmed
by determining infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy. All the
synthesized derivatives were evaluated for their analgesic and anti-inflammatory activities in mice and rats,
respectively. In animal studies, the derivative (E)-3-(5-(4-(4-methoxybenzylideneamino)phenyl)-1,3,4-
oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one showed more potent analgesic activity and the derivative
(Z)-3-(5-(2-(2-hydroxybenzylideneamino)phenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one showed
more potent anti-inflammatory activity as compared with other derivatives. The results of the present study
indicate that reactions of 3-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one and 3-(5-
(2-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one with different aromatic aldehydes produce
Schiff bases of quinazolin-4-one-linked 1,3,4-oxadiazoles with potent analgesic and anti-inflammatory activities.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
In this background, the aspiration of the present research
effort was to synthesize new series of Schiff bases of
quinazolin-4-one-linked 1,3,4-oxadiazoles with a potential
biological activity. We synthesized new Schiff bases of
quinazolin-4-one-linked 1,3,4-oxadiazoles by reacting them
with different aromatic aldehydes. Purity of the synthesized
derivatives was confirmed by thin-layer chromatography
(TLC), combustion analysis, and melting point. Structure of
the derivatives was set up by infrared spectroscopy (IR),
proton nuclear magnetic resonance (1H-NMR), and mass
spectroscopy (MS). Further, all the synthesized derivatives
were screened for analgesic and anti-inflammatory activities
in rodents employing acetic acid-induced writhing reflex
and carrageenan-induced paw edema methods, respectively.
Heterocyclic compound synthesis has accredited a lot
concern in recent years, mostly those containing more
than one heterocyclic ring in a molecule. Oxadiazole and
quinazolin-4-one moieties have revealed a range of
biological activities such as analgesic, anti-inflammatory
[1–4], antibacterial [5,6], antifungal [7], antitubercular [8],
anticancer [9], anticandidal [10], antioxidant [11], and
antidepressant [12]. In our recent study [13], we linked
quinazolin-4-one with 1,3,4-oxadiazole, which revealed
attractive analgesic and anti-inflammatory activities. It is
worth noting here that, like oxadiazole and quinazolin-4-one
moieties, Schiff bases also produce a broad range of
biological activities such as antimalarial [14], anticancer
[15], antibacterial, antifungal [16], antitubercular [17], and
anti-inflammatory [18]. Therefore, we hypothesized that
inclusion of Schiff bases may further improve the
biological activities of quinazolin-4-one-linked 1,3,4-
oxadiazole moiety.
RESULTS AND DISCUSSION
In the present study, for the first time, we have reported the
synthesis of Schiff bases of 3-(5-(4-aminophenyl)-1,3,4-
© 2017 Wiley Periodicals, Inc.

D. Dewangan, K. T. Nakhate, V. S. Verma, K. Nagori, and D. K. Tripathi
Vol 000
oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one and 3-(5-(2-
aminophenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-
4(3H)-one by directly reacting them with aromatic aldehydes.
The newly synthesized Schiff bases of quinazolin-4-one-
linked 1,3,4-oxadiazoles were subjected to confirmation of
physical and analytical parameters using techniques like
TLC, combustion analysis, IR, NMR, and MS. Finally,
biological activity of the compounds was evaluated in mice
and rats.
The synthetic approach used to make different Schiff
bases of quinazolin-4-one-linked 1,3,4-oxadiazoles is outlined
in scheme given in Figure 1. Total 16 Schiff bases of 3-(5-(2-
aminophenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-
4(3H)-one (III) and 3-(5-(4-aminophenyl)-1,3,4-oxadiazol-
2-yl)-2-phenylquinazolin-4(3H)-one (IV) were produced
by reacting them with different aromatic aldehydes.
Chemical structure, melting point, and other physical data
are mentioned in Table 1. Combustion analysis is mentioned
in Table 2. Formations of different Schiff bases of 3-(5-(2-
aminophenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-
4(3H)-one (III) and 3-(5-(4-aminophenyl)-1,3,4-oxadiazol-
2-yl)-2-phenylquinazolin-4(3H)-one (IV) were established
1
by recording the IR, H-NMR, and MS. IR spectrum of
one Schiff base of quinazolin-4-one-linked 1,3,4-oxadiazoles,
that is, (Z)-3-(5-(2-(4-methoxybenzylideneamino)phenyl)-
1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one, shows
strong C═N stretching (str) band at 1607.76 cmꢀ1 and C─O
absorption band at 1287.34 cmꢀ1, which indicate ring
closure of 1,3,4-oxadiazole ring. An absorption band at
3046.58 cmꢀ1 is due to aromatic Ar─C─H str, band at
1565.98 cmꢀ1 is due to C═C str, band at 1728.85 cmꢀ1 is
due to C═O str, and band at 1012.65 cmꢀ1 is due to OCH3
Figure 1. Representation of the series of reactions for the synthesis of Schiff bases of quinazolin-4-one-linked 1,3,4-oxadiazoles.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Schiff Bases of Oxadiazole-Linked Quinazoline-4-One
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Dewangan, K. T. Nakhate, V. S. Verma, K. Nagori, and D. K. Tripathi
Vol 000
Table 2
Combustion analysis of synthesized derivatives.
Combustion analysis
Derivatives
Theoretical value
Observed values
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
VIi
VIj
VIk
VIl
VIm
VIn
VIo
VIp
C (68.08%) H (4.05%) N (16.54%) O (11.34%)
C (64.57%) H (3.30%) N (16.37%) O (7.48%)
C (63.01%) H (3.22%) N (19.17%) O (14.60%)
C (70.75%) H (4.21%) N (17.19%) O (7.85%)
C (70.22%) H (3.84%) N (17.80%) O (8.13%)
C (67.48%) H (3.69%) N (17.11%) O (11.72%)
C (67.64%) H (3.95%) N (20.58%) O (7.83%)
C (65.75%) H (4.14%) N (19.17%) O (10.95%)
C (68.08%) H (4.05%) N (16.54%) O (11.34%)
C (64.57%) H (3.30%) N (16.37%) O (7.48%)
C (63.01%) H (3.22%) N (19.17%) O (14.60%)
C (70.75%) H (4.21%) N (17.19%) O (7.85%)
C (70.22%) H (3.84%) N (17.80%) O (8.13%)
C (67.48%) H (3.69%) N (17.11%) O (11.72%)
C (67.64%) H (3.95%) N (20.58%) O (7.83%)
C (65.75%) H (4.14%) N (19.17%) O (10.95%)
C (67.83%) H (4.06%) N (16.61%) O (10.98%)
C (64.49%) H (3.32%) N (16.30%) O (7.53%)
C (63.20%) H (3.17%) N (19.23%) O (14.49%)
C (70.59%) H (4.27%) N (17.28%) O (7.63%)
C (69.94%) H (3.80%) N (17.86%) O (8.07%)
C (67.81%) H (3.64%) N (17.16%) O (11.61%)
C (67.23%) H (4.01%) N (20.63%) O (7.89%)
C (66.01%) H (4.10%) N (19.11%) O (11/01%)
C (67.89%) H (4.01%) N (16.44%) O (11.43%)
C (64.37%) H (3.34%) N (16.34%) O (7.53%)
C (62.81%) H (3.20%) N (19.13%) O (14.66%)
C (71.02%) H (4.25%) N (17.24%) O (7.90%)
C (70.51%) H (3.80%) N (17.84%) O (8.17%)
C (67.63%) H (3.73%) N (17.15%) O (11.76%)
C (67.31%) H (4.01%) N (20.67%) O (7.77%)
C (66.02%) H (4.13%) N (19.13%) O (11.00%)
str. Strong absorption at 3046.68 cmꢀ1 and around
1575.98 cmꢀ1 was present in all final derivatives, which
was evidence for aromatic C─H and C═C bonds,
respectively. The presence of specific functional groups in
final synthesized derivatives was confirmed by 1H-NMR
standard drug acetylsalicylic acid showed 64.17%
inhibition (Table 4). Similarly, derivatives also elicited
31.93% to 47.84% inhibition of carrageenan-induced paw
edema, whereas standard drug indomethacin produced
53.32% inhibition (Table 5). In animal studies, the derivative
(E)-3-(5-(4-(4-methoxybenzylideneamino)phenyl)-1,3,4-
oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one showed
more potent analgesic activity and the derivative (Z)-3-
(5-(2-(2-hydroxybenzylideneamino)phenyl)-1,3,4-oxadiazol-
2-yl)-2-phenylquinazolin-4(3H)-one showed more potent
anti-inflammatory activity as compared with other
derivatives. The results of the present study indicate that
condensation reaction of 3-(5-(2-aminophenyl)-1,3,4-
oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one and 3-(5-
(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4
(3H)-one with different aromatic aldehyde produces Schiff
bases of quinazolin-4-one-linked 1,3,4-oxadiazoles that
resulted in significant analgesic and anti-inflammatory
activities.
1
data. The H-NMR spectrum of derivative (Z)-3-(5-(2-(4-
methoxybenzylideneamino)phenyl)-1,3,4-oxadiazol-2-yl)-
2-phenylquinazolin-4(3H)-one shown in the region 6.84–7.89
is due to 13 aromatic protons, 8.25 is due to one imine group
proton, 7.40–7.90 is due to four quinazolin-4-one proton, and
3.75 is due to three ─OCH3 proton. The presence of other
groups like ─OH and ─NH2 groups in synthesized
derivatives was confirmed by shift values 5.33 and 4.03,
respectively. The mass spectra of derivative (Z)-3-(5-(2-(4-
methoxybenzylideneamino)phenyl)-1,3,4-oxadiazol-2-yl)-
2-phenylquinazolin-4(3H)-one showed molecular ion peak
at m/z 499, which is in conformity with the molecular
formula C24 H18 N4 O4. In the same way, spectral data of
remaining derivatives are represented in Table 3.
In our recent study, we observed analgesic and anti-
inflammatory activities of 1,3,4-oxadiazole derivatives [4].
Further, we linked 1,3,4-oxadiazole with quinazolin-4-one
moieties and noticed significant analgesic and anti-
inflammatory activities as compared with 1,3,4-oxadiazole
derivatives [13]. In the present study, we have synthesized
Schiff bases of quinazolin-4-one-linked 1,3,4-oxadiazoles,
which showed improved analgesic and anti-inflammatory
activities as compared with quinazolin-4-one-linked 1,3,4-
oxadiazole derivatives. The extremely important sites for
molecular modification are the 2-position and 5-postion,
Oxadiazole nucleus-containing compounds have
revealed nice-looking analgesic and anti-inflammatory
activities [1]. It may note that the 2-position and 5-postion
of oxadiazole nucleus are extremely important sites for
molecular modification, which can play a dominant role in
determining the pharmacological activities of oxadiazole
derivatives. Therefore, we have attempted to develop the
derivatives of oxadiazole nucleus at 2-position and 5-
postion with a view to evaluate further the potency of the
molecules. In our previous study [4], we have synthesized
1,3,4-oxadiazole derivatives. These agents produced up to
47% inhibition of acetic acid-induced writhing reflex and
up to 41% inhibition of carrageenan-induced paw edema.
In our subsequent work [13], linking of quinazolin-4-one
with 1,3,4-oxadiazoles was carried out. This modification
which play
a
leading role in determining the
pharmacological activities of 1,3,4-oxadiazole derivatives.
The tested derivatives exhibited 37.63% to 59.21%
inhibition of acetic acid-induced writhing reflex, whereas
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Schiff Bases of Oxadiazole-Linked Quinazoline-4-One
Table 3
Spectral data of synthesized derivatives.
Derivatives
Va
IR (KBr cmꢀ1
)
1H NMR δ (ppm) (DMSO-d6)
MS
3046.58 (Ar─C─H str), 1565.98 (C═C str), 1607.76 (C═N
str), 1728.85 (C═O str), 1287.34 (C─O str), 1144.87
(Ar─C─C str), 1087.86 (C─O─C str, ring), 1012.65 (C─O─C
str OCH3)
6.84–7.89 (m 13H, Ar─H), 8.25 (s 1H, ─imine), 7.40– 499+
7.90 (m 4H, quinazolinone ring), 3.75 (s 3H, ─OCH3)
Vb
Vc
Vd
3078.58 (Ar─C─H str), 1555.28 (C═C str), 1629.71 (C═N
str), 1718.80 (C═O str), 1226.44 (C─O str), 1187.44
(Ar─C─C str), 1087.65 (C─O─C str), 732.78 (C─Cl str)
3123.51 (Ar─C─H str), 1512.43 (C═C str), 1612.43 (C═N
str), 1728.82 (C═O str), 1206.44 (C─O str), 1107.44
(Ar─C─C str), 1017.65 (C─O─C str), 1297.12 (NO2 str)
3013.51 (Ar─C─H str), 1561.13 (C═C str), 1622.40 (C═N
str), 1720.20 (C═O str), 1210.10 (C─O str), 1102.44
(Ar─C─C str), 1010.65 (C─O─C str), 2912.10 (C─H str,
─CH3)
2990.23 (Ar─C─H str), 1500.32 (C═C str), 1596.13 (C═N
str), 1722.12 (C═O str), 1190.44 (C─O str), 1112.40
(Ar─C─C str), 1010.65 (C─O─C str)
3087.56 (Ar─C─H str), 1474.23 (C═C str), 1574.89 (C═N
str), 1684.89 (C═O str), 1311.89 (C─O str), 1231.78
(Ar─C─C str), 1143.90 (C─O─C str), 3453.89 (O─H str)
2967.68 (Ar─C─H str), 1575.90 (C═C str), 1627.70 (C═N
str), 1728.00 (C═O str), 1187.34 (C─O str), 1094.87
(Ar─C─C str), 3487.67 (NH str)
3143.78 (Ar─C─H str), 1512.89 (C═C str), 1598.37 (C═N
str), 1720.23 (C═O str), 1207.23 (C─O str), 1300.12
(Ar─C─C str), 1132.54 (C─O─C str), 3412.32 (O─H str)
3016.50 (Ar─C─H str), 1555.90 (C═C str), 1605.70 (C═N
str), 1720.80 (C═O str), 1280.30 (C─O str), 1141.82
(Ar─C─C str), 1081.85 (C─O─C str), 1018.62 (C─O─C str)
3023.15 (Ar─C─H str), 1545.28 (C═C str), 1625.71 (C═N
str), 1728.80 (C═O str), 1216.44 (C─O str), 1157.44
(Ar─C─C str), 1057.65 (C─O─C str), 722.78 (C─Cl str)
3113.51 (Ar─C─H str), 1572.43 (C═C str), 1652.13 (C═N
str), 1726.82 (C═O str), 1256.32 (C─O str), 1117.44
(Ar─C─C str), 1047.65 (C─O─C str), 1287.12 (NO2 str)
3113.51 (Ar─C─H str), 1571.10 (C═C str), 1573.40 (C═N
str), 1709.26 (C═O str), 1190.10 (C─O str), 1112.44
(Ar─C─C str), 1060.65 (C─O─C str), 2892.10 (C─H str,
─CH3)
6.46–7.76 (m 13H, Ar─H), 8.37 (s 1H, ─imine), 7.44– 502+
7.89 (m 4H, quinazolinone ring)
7.29–7.90 (m 13H, Ar─H), 8.35 (s 1H, ─imine), 7.40– 513+
7.89 (m 4H, quinazolinone ring)
7.09–7.90 (m 13H, Ar─H), 8.20 (s 1H, ─imine), 7.40– 482+
7.90 (m 4H, quinazolinone ring), 2.31 (s 1H,
─Ar─CH3)
Ve
7.29–7.90 (m 14H, Ar─H), 8.31 (s 1H, ─imine), 7.44– 468+
7.89 (m 4H, quinazolinone ring)
Vf
6.76–7.80 (m 13H, Ar─H), 8.37 (s 1H, ─imine), 7.44– 484+
7.89 (m 4H, quinazolinone ring), 5.33 (s 1H, ─Ar─OH)
Vg
Vh
VIi
VIj
VIk
VIl
6.49–7.76(m 13H, Ar─H), 8.20 (s 1H, ─imine), 7.40–
7.90 (m 4H, quinazolinone ring), 4.03(s 1H,
─Ar─NH2)
483+
6.27–7.62 (m 12H, Ar─H), 8.30 (s 1H, ─imine), 7.20– 514+
7.76 (m 4H, quinazolinone ring), 5.14 (s 1H,
─Ar─OH), 3.73 (s 3H, ─OCH3)
6.80–7.62 (m 13H, Ar─H), 8.39 (s 1H, ─imine), 7.27– 490+
7.72 (m 4H, quinazolinone ring), 3.71 (s 3H, ─OCH3)
7.29–7.72 (m 13H, Ar─H), 8.31 (s 1H, ─imine), 7.40– 502+
7.90 (m 4H, quinazolinone ring)
7.29–8.30(m 13H, Ar─H), 8.39 (s 1H, ─imine), 7.40–
7.90 (m 4H, quinazolinone ring)
513+
7.10–7.82 (m 13H, Ar─H), 8.31 (s 1H, ─imine), 7.26– 482+
7.78 (m 4H, quinazolinone ring), 2.31 (s 1H,
─Ar─CH3)
VIm
VIn
VIo
VIp
2930.21 (Ar─C─H str), 1550.31 (C═C str), 1586.19 (C═N
str), 1710.12 (C═O str), 1187.44 (C─O str), 1121.40
(Ar─C─C str), 1043.65 (C─O─C str)
3187.56 (Ar─C─H str), 1574.23 (C═C str), 1514.89 (C═N
str), 1714.89 (C═O str), 1361.89(C─O str), 1231.78 (Ar─C─C
str), 1113.90 (C─O─C str), 3403.89 (O─H str)
2307.68 (Ar─C─H str), 1505.90 (C═C str), 1627.10 (C═N
str), 1718.00 (C═O str), 1117.34 (C─O str), 1090.87
(Ar─C─C str), 3487.07 (NH str)
3140.78 (Ar─C─H str), 1512.19 (C═C str), 1590.37 (C═N
str), 1710.23 (C═O str), 1217.23 (C─O str), 1320.12
(Ar─C─C str), 1132.14 (C─O─C str), 3432.32 (O─H str)
7.29–7.68 (m 14H, Ar─H), 8.36 (s 1H, ─imine), 7.24– 468+
7.89 (m 4H, quinazolinone ring)
6.76–7.86 (m 13H, Ar─H), 8.39 (s 1H, ─imine), 7.14– 484+
7.78 (m 4H, quinazolinone ring), 5.33 (s 1H, ─Ar─OH)
6.40–7.78 (m 13H, Ar─H), 8.25 (s 1H, ─imine), 7.40– 483+
7.80 (m 4H, quinazolinone ring), 4.06 (s 1H,
─Ar─NH2)
6.29–7.60 (m 12H, Ar─H), 8.32 (s 1H, ─imine), 7.22– 514+
7.66 (m 4H, quinazolinone ring), 5.20 (s 1H,
─Ar─OH), 3.71 (s 3H, ─OCH3)
produced up to 54% inhibition of acetic acid-induced
writhing reflex and up to 43% inhibition of carrageenan-
induced paw edema. This indicates improvement of the
activity of 1,3,4-oxadiazole derivatives linked with
quinazolin-4-one as compared with 1,3,4-oxadiazole
derivatives. In the present study, as discussed in the
preceding texts, we have further modified the 1,3,4-
oxadiazole derivatives linked with quinazolin-4-one by
inclusion of Schiff bases. The resulting compounds
produced up to 59% inhibition of acetic acid-induced
writhing reflex and up to 48% inhibition of carrageenan-
induced paw edema. This suggests that Schiff bases of
quinazolin-4-one-linked 1,3,4-oxadiazoles resulted in
significantly higher analgesic and anti-inflammatory
activities as compared with 1,3,4-oxadiazole derivatives
and 1, 3,4-oxadiazole derivatives linked with quinazolin-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Dewangan, K. T. Nakhate, V. S. Verma, K. Nagori, and D. K. Tripathi
Vol 000
Table 4
CONCLUSION
Effects of 1,3,4-oxadiazoles (100 mg/kg) and acetylsalicylic acid (25 mg/
kg) on acetic acid induced writhing reflex.
A new series of different Schiff bases of 3-(5-(4-
aminophenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4
(3H)-one and 3-(5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl)-
2-phenylquinazolin-4(3H)-one were synthesized by
Treatment
group
Total number of writhes
(mean SEM)
%
inhibition
Control
72.02 1.802
—
64.17
treating
3-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-
Acetylsalicylic
25.29 1.385*
acid
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
VIi
VIj
VIk
VIl
VIm
VIn
VIo
VIp
phenylquinazolin-4(3H)-one and 3-(5-(2-aminophenyl)-
1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one with
different aromatic aldehydes by a simple, well-situated
and efficient procedure. Physical and analytical
parameters of the newly synthesized Schiff bases of
quinazolin-4-one linked 1, 3, 4-oxadiazoles were
confirmed by TLC, IR, NMR, and MS. Subsequently, in
biological evaluation, the derivatives exhibit analgesic
and anti-inflammatory activities. The derivative (E)-3-(5-
(4-(4-methoxybenzylideneamino)phenyl)-1,3,4-oxadiazol-
2-yl)-2-phenylquinazolin-4(3H)-one showed more potent
analgesic activity, and the derivative (Z)-3-(5-(2-(2-
hydroxybenzylideneamino)phenyl)-1,3,4-oxadiazol-2-yl)-2
-phenylquinazolin-4(3H)-one showed more potent anti-
inflammatory activity compared with other derivatives.
We conclude that the results of the present study may lay
concrete on a way for the innovation of novel analgesic
and anti-inflammatory molecules with superior efficacy
and minimum side effects.
42.83 0.9458*#
46.67 0.4216*#
46.50 0.9574*#
44.33 1.145*#
44.67 0.7601*#
40.33 0.9189*#
40.33 0.4216*#
45.50 0.6191*#
32.00 1.065*#
41.33 0.4944*#
42.83 0.9458*#
45.67 0.6146*#
43.83 1.249*#
40.50 0.8851*#
42.83 0.9458*#
40.33 0.4216*#
42.76
37.63
37.85
40.75
40.30
46.11
46.10
39.21
59.21
44.78
42.77
38.98
41.44
45.89
42.76
46.10
The results are given as % inhibition of writhing. The data were analyzed
by one way analysis of variance (ANOVA) followed by Bonferroni’s
multiple comparison test.
*p < 0.001 versus control.
#p < 0.05 versus acetylsalicylic acid.
Table 5
Effects of 1,3,4-oxadiazoles (100 mg/kg) and indomethacin (10 mg/kg) on
carrageenan-induced paw edema.
EXPERIMENTAL
Treatment
group
Paw volume (mL) after 3 h
(mean SEM)
%
All chemicals and reagents used were purchased from
Sigma Aldrich and Loba Chemie. The open capillary
method was employed to determine the melting point of
the synthesized molecules and was reported uncorrected.
By TLC (Mobile phase: CHCl3: MeOH: Glacial acetic
acid 90:10:0.1) and combustion analysis, purity of the
derivatives was checked. IR spectra (KBr, cmꢀ1) were
inhibition
Control
Indomethacin
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
VIi
VIj
VIk
VIl
VIm
VIn
VIo
VIp
3.451 0.052
—
1.624 0.03976*
2.425 0.04787*#
2.550 0.1190*#
2.625 0.0750*#
2.625 0.0750*#
2.600 0.04080*#
2.000 0.08165*#
2.550 0.1190*#
2.375 0.02500*#
2.225 0.04787*#
2.325 0.04787*#
2.325 0.0250*#
2.425 0.02500*#
2.550 0.06455*#
2.325 0.8539*#
2.425 0.04787*#
2.400 0.04082*#
53.32
37.14
33.76
31.93
31.94
32.46
47.84
33.76
38.44
42.33
39.74
39.74
37.14
33.76
39.74
37.14
37.66
1
recorded on Perkin Elmer Infrared-283 FTIR. H-NMR
(CDCl3) spectra were obtained from the Brooker 300-
MHz spectrometer by using tetra methyl silane as an
internal reference. On an API 3000 LC–MS, the mass
spectra were recorded.
Synthesis of 2-phenyl-4H-3,1-benzoxazin-4-one (1). Benzoyl
chloride (0.2 mol) was added to a solution of anthranilic
acid (0.1 mol) and pyridine (60 mL). The reaction mixture
was stirred for 30 min at room temperature, followed by
addition of 15 mL of 5% NaHCO3. After filtration,
crystalline compound was obtained, which was washed
with water, dried, and recrystallized by using ethanol.
Synthesis of 2-phenyl 4-oxoquinazoline-3-(4H)-carbohydrazide
The results are given as % inhibition of writhing. The data were analyzed
by one way analysis of variance (ANOVA) followed by Bonferroni’s
multiple comparison test.
*p < 0.001 versus control.
#p < 0.05 versus indomethacin.
(2).
The mixture of intermediate 1 (0.5 mol) and
4-one. Thus, inclusion of Schiff bases produced additive
effect in the biological activities of quinazolin-4-one-
linked 1,3,4-oxadiazoles.
semicarbazide (0.5 mol) was refluxed by using ethanol
(50 mL) on water bath for a period of 3 h at 70°C. The
reaction mixture was cooled at room temperature, and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Schiff Bases of Oxadiazole-Linked Quinazoline-4-One
then the content was poured on crushed ice. The product
obtained was filtered, washed with water, dried, and
recrystallized by using ethanol to give crystalline product.
Synthesis of 3-(5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-
Animal experiments. In the present study, adult male
Swiss albino mice (25–30 g) were used for the evaluation
of analgesic activity, whereas adult male Sprague Dawley
rats (240–260 g) were used for the assessment of anti-
inflammatory activity. The animals were housed in the
acrylic cages. In each cage, the mice were kept in a
group of six, whereas the rats were kept in a group of
three. All animals were maintained under a constant room
temperature (25 1°C), relative humidity (50–70%), and
on a 12:12-h light/dark cycle (lights on 07:00–19:00 h).
The experiments were carried out between 9:00 and
13:00 h. Standard laboratory animals' chow diet and
drinking water were available ad libitum except during
the period of experimentation. All protocols of animal
experiments were approved by the Institutional Animal
Ethics Committee.
phenylquinazolin-4(3H)-one (3).
The intermediate 2
(0.01 mol) that was obtained in the previous step was
dissolved in ethanol (30 mL) containing few drops of
phosphoryl chloride. o-Amino benzoic acid (0.01 mol)
was added to the solution, and the reaction mixture was
refluxed for 4–6 h at 120°C. This hot reaction mixture
was cooled to room temperature and poured over crushed
ice with continuous stirring. After filtration, crystalline
compound as a product was obtained, which was washed
with water, dried, and recrystallized by using ethanol.
Synthesis of 3-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-
phenylquinazolin-4(3H)-one
(4).
Few drops of
phosphoryl chloride were added in ethanol (30 mL), and
intermediate 2 (0.01 mol) was dissolved in it. p-Amino
benzoic acid (0.01 mol) was added to this solution, and
the reaction mixture was refluxed for 4–6 h at 120°C.
This hot reaction mixture was cooled at room temperature
and poured over crushed ice with continuous stirring.
After filtration, crystalline compound as a product was
obtained, which was washed with water, dried, and
recrystallized by using ethanol.
In the overnight fasted animals, all newly synthesized
Schiff bases of quinazolin-4-one-linked 1,3,4-oxadiazoles
were administered via oral route. The maximum tolerated
dose of the derivatives was found to be 1500 mg/kg.
According to Organization for Economic Cooperation
and Development guidelines [19], twofold to fourfold
descending dose level of maximum tolerated dose should
be selected to examine the activity of the compound.
Therefore, we have carried out dose response studies of
the 1,3,4-oxadiazole derivatives by using significantly
lower dose. Based on the results, we choose 100 mg/kg
dose of Schiff bases of quinazolin-4-one-linked 1,3,4-
oxadiazoles to test their analgesic and anti-inflammatory
activities.
Analgesic activity. The test was performed according to
the method given by Husain and Ajmal [1] and Dewangan
et al. [13]. The mice were subjected to the acetic acid-
induced writhing reflex method to screen the analgesic
activity of 1,3,4-oxadiazole derivatives. The animals were
randomly divided into three groups: (a) control [acetic
Synthesis of Schiff bases of 3-(5-(2-aminophenyl)-1,3,4-
oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one
(5).
A
solution of 3-(5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-
phenylquinazolin-4(3H)-one (3) (0.01 mol) and ethanol
(20 mL) was prepared in a round-bottomed flask. The
required aromatic aldehyde (0.01 mol) was dissolved in
ethanol (15 mL), which was then added to the solution of
intermediate (3) and ethanol contained in the round bottom
flask. The mixture was refluxed for 5–6 h at 80°C. The
volume of ethanol was reduced to half by distillation
under reduced pressure. The resulting solution was poured
over crushed ice. The precipitate obtained was separated,
dried, and then recrystallized by using ethanol. Total eight
derivatives were synthesized by this step (Va–Vh).
acid treated (n
=
6)], (b) 1,3,4-oxadiazole
derivatives + acetic acid treated (n = 6), and (c) acetyl
salicylic acid + acetic acid treated (n = 6). As a positive
control, a standard analgesic drug acetylsalicylic acid
(25 mg/kg) was taken for the comparison. The derivatives
were given at the dose of 100 mg/kg. All derivatives
were administered to overnight fasted animals via oral
route 1 h prior to intraperitoneal 0.7% glacial acetic acid
(10 mL/kg). The numbers of writhes were recorded in
each mouse for a period of 30 min. The inhibition of
writhing by newly synthesized derivatives was compared
against the inhibition of writhing by acetyl salicylic acid
by using a formula:
Synthesis of Schiff bases of 3-(5-(4-aminophenyl)-1,3,4-
oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one
(6).
A
solution of 3-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-
phenylquinazolin-4(3H)-one (4) (0.01 mol) and ethanol
(20 mL) was prepared in a round-bottomed flask. The
required aromatic aldehyde (0.01 mol) was dissolved in
ethanol (15 mL), which was then added to the solution of
intermediate (4) and ethanol contained in the round
bottom flask. The mixture was refluxed for 5–6 h. The
volume of ethanol was reduced to half by distillation
under reduced pressure. The resulting solution was
poured over crushed ice. The precipitate obtained was
separated, dried, and then recrystallized by using ethanol.
Total eight derivatives were synthesized by this step
(VIi–VIp).
100 ꢀ test
% Inhibition ¼
controlꢁ100
Postexperimentation adverse effects were not observed
with any of the aforementioned treatments.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Dewangan, K. T. Nakhate, V. S. Verma, K. Nagori, and D. K. Tripathi
Vol 000
REFERENCES AND NOTES
Anti-inflammatory activity. The activity was performed
according to the method given by Amir et al. [20] and
Dewangan et al. [13]. The rats were subjected to
carrageenan-induced paw edema test to evaluate anti-
inflammatory activity of 1,3,4-oxadiazole derivatives. The
animals were randomly divided into three groups: (a)
control [carrageenan treated (n = 6)], (b) 1,3,4-oxadiazole
derivatives + carrageenan treated (n = 6), and (c)
indomethacin + carrageenan treated (n = 6). As a positive
control, a standard anti-inflammatory drug indomethacin
(10 mg/kg) was used for the comparison. The derivatives
were given at the dose of 100 mg/kg. All compounds were
administered to overnight fasted animals via oral route 1 h
prior to carrageenan challenge. Carrageenan suspension
(1%) was prepared in saline. Foot paw edema was induced
by injecting 0.05 mL of carrageenan suspension into the
planter tissue of left hind paw. In control animals, the equal
volume of saline was injected. Mercury displacement
method using plethysmograph was used to measure the paw
volume of rats. We did not observe any adverse effects in
the animals following treatment of chemicals in the
administered dose range.
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Acknowledgments. The authors thank the Management of Rungta
College of Pharmaceutical Sciences and Research, Bhilai, for
providing necessary infrastructural facilities and IISER, Bhopal,
for providing immense help in the spectral analysis. The authors
gratefully acknowledge the financial support received under
Start-up grant for Young Scientists (file no. SB/YS/LS-106/2014)
of the Science and Engineering Research Board (SERB),
Department of Science and Technology, New Delhi, India.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet