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Research Article
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Synthesis of Quinazolinone Based Schiff Bases as Potential
Anti-inflammatory and Analgesic Agents
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Rashmi Arora,
N.S. Gill
and
Ashish Kapoor
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ABSTRACT
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Quinazolinone is a an important heterocyclic compound possessing a wide range of biological activities such as anti-tumour, sedative, antidiabetic, analgesic, anti-inflammatory, antimicrobial and anticancer. It is a versatile lead molecule for the design of potential bioactive agents. They show anti-inflammatory and analgesic action by inhibiting the microsomal prostaglandin E2-synthase 1 (mPGES-1) which is a key enzyme of the arachidonic acid. The aim of the present study includes the synthesis of some novel Schiff bases of amino derivatives of quinazolinone as anti-inflammatory and analgesic agent. A new series of the title compounds incorporated into diverse N heterocyclic moieties. First step involves the synthesis of 6,8-diiodo-2-phenyl-4H-3,1- benzoxazin-4-one. In second step this compound reacts with hydrazine hydrate to form a new intermediate 6,8-diiodo-2-phenylquinazolin-4(3H)-one. Schiff bases (5a-5f) were synthesized by the reaction of 6,8-diiodo-2-phenylquinazolin-4(3H)-one with different aromatic aldehydes. Maximum yield of 79% was obtained from p-hydroxy derivative. Schiff bases formed were evaluated for anti-inflammatory and analgesic activities. O-hydroxy derivative showed maximum anti-inflammatory activity with percentage inhibition of 50.45%. It was proved to be good analgesic agent as well. It was concluded that Schiff bases containing hydroxyl group showed promising activity as compared to chloro derivatives.
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Received: July 26, 2012;
Accepted: September 28, 2012;
Published: February 27, 2014
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INTRODUCTION
Quinazolinone is an important heterocyclic compound with nitrogen as a part of
the ring ( Arora et al., 2011). 2-Quinazolinone
and 4-Quinazolinone are the two structural isomers. Out of the two isomers, 4-isomer
is present in most of the compounds ( Kumar et al.,
2012). The Quinazolin-4-(3H)-one and its analogues have shown a wide range
of biological activities such as anti-tumour, sedative, antidiabetic, analgesic,
anti-inflammatory, antimicrobial and anticancer ( Wu et
al., 2010; Kashaw et al., 2010; Levien
and Baker, 2009; Yesilada et al., 2004; Fawzy
et al., 2008; Khalil et al., 2003).
They are frequently used in medicine for example Methaqualone, Afloqualone, Diproqualone,
Fluproquazone, Tiacrilast, Halofuginone and Raltitrexed possessing different biological
activities ( Smyth et al., 1973; Ochiai
and Ishida, 1982; Audeval et al., 1988; Wheatley,
1982; Welton et al., 1986; Sundrud
et al., 2009; Widemann et al., 1999).
It is a versatile lead molecule for the design of potential bioactive agents.
They show their anti-inflammatory and analgesic action by inhibiting the microsomal
prostaglandin E2-synthase 1 (mPGES-1) which is a key enzyme of the arachidonic
acid cascade. Its product PGE2 plays an important role in various inflammatory
processes, pain, fever and cancer. Selective inhibition of mPGES-1 might be a
promising step to avoid cyclooxygenase-related effects and reduction of PGE2 will
make them a good anti-inflammatory and analgesic agents ( Rorsch
et al., 2012).
Schiff base is also called as azomethine and secondary aldimines having general
formula:
R1R2C = NR3
where, R is an organic side chain. Reflux of mixture of aldehyde (or ketone)
and amine in organic medium leads to synthesis of Schiff bases (Bendale
et al., 2011). Schiff bases that contain aryl substituents having
effective conjugation are substantially more stable and more readily synthesized
while those which contain alkyl substituent are relatively unstable. They have
been found to possess various pharmacological activities such as antimalarial,
anticancer, anti-microbial, antitubercular, anti-inflammatory and antiviral
(Harpstrite et al., 2008; Ghorab
et al., 2012; Saravanan et al., 2010a;
Ferreira et al., 2009; Jayakumarswamy
et al., 2011; Chinnasamy et al., 2010).
They are important not only in medical chemistry but also in organic synthetic
chemistry. They are the important compound owing to their wide range of biological
activities and industrial application (Wang et al.,
2008).
The past studies revealed that the Schiff bases of 2-phenylquinazolin-4-(3H)-one
possess various biological activities. In this study some novel Schiff bases
of 3-amino-6,8-diiodo-2-phenylquinazolin-4(3H)-one with anti-inflammatory and
analgesic activities were synthesized. This work was based on the fact that
several quinazolinone derivatives have potent anti-inflammatory and analgesic
effect (Mariappan et al., 2011; Mosaad
et al., 2010).
MATERIALS AND METHODS
The study was started on 1st of September, 2011 and was carried out till 30th
June, 2012.
Chemicals: Carrageenan and 3,5-diiodoanthranillic acid were obtained
from HiMedia Labs, Mumbai. All other chemical reagents were used of analytical
grade which were procured from different companies (Loba Chem, Merck Limited
and S D Fine). The progress of the reaction was monitored on readymade silica
gel plates (Merck) using chloroform-methanol (6:4) as a solvent system. Iodine
was used as a developing agent. Melting points were determined with a Buchi
530 melting point apparatus in open capillaries. IR spectra details as mentioned
in experimental part below were recorded on KBr discs, using a Perkin-Elmer
Model 1600 FT-IR spectrometer. The proton magnetic resonance spectra (1H-NMR)
were recorded on Perkin Elmer Spectrophotometer-300 MHz in DMSO-d6 using TMS
as an internal standard. Elemental analysis was performed by CHNS (O) Analyzer.
Animals: The Wistar albino rats (150-200 g) of either sex were obtained
from Zoin Co. Biologicals, Ambala. They were kept at standard laboratory diet,
environmental temperature and humidity. A 12 h light and dark cycle was maintained
throughout the experimental protocol. The experimental protocol was duly approved
by Committee for the Purpose of Control and Supervision of Experiments on Animals.
Synthesis: Synthesis of 6, 8-diiodo-2-phenyl-4H-3, 1-benzoxazin-4-one
(3): 3,5-diiodoanthranilic acid (1) (3.88 g, 0.01 mol) was reacted with
benzoyl chloride (1.17 mL, 0.01 mol)(2) in presence of pyridine and stirred
for 3 h and the resulting mixture was treated with 5% sodium bicarbonate solution
to get 2-phenylbenzoxazin-4-one (3). The precipitate was filtered, dried and
recrystallized from ethanol. The percentage yield obtained was 73%, m.p. 231°C,
FTIR: 525 cm-1 (-I), 1689 cm-1 (-C = O), 1610 cm-1
(-C = N-), 1201 (C-O), 1H-NMR (DMSO-d6, δ ppm): 8.5612 (2H,
s, fused Ar-H), 7.9201-7.9413 (2H, d, Ar-H), 7.3801-7.5403 (3H, t, Ar-H).
Synthesis of 3-Amino-6,8-diiodo-2-phenylquinazolin-4(3H)-one (4): Compound
(3) (4.75 g, 0.01 mol) was treated with hydrazine hydrate (0.64 g, 0.02 mol)
in presence of ethanol and refluxed for 2-3 h to form 6,8-diiodo-2-phenylquinazolin-4(3H)-one
(4). The content was then cooled, filtered off and recrystallized from ethanol.
The percentage yield obtained was 69%, m.p. 239°C, FTIR: 513 cm-1
(-I), 1700 cm-1 (-C = O), 1617 cm-1 (-C = N), 3431 and
3337 cm-1 (-NH2), 1102 cm-1 (C-N), 1H-NMR
(DMSO-d6, δ ppm): 2.5537 (2H, s, NH2), 8.0284 (2H, s, fused
Ar-H), 7.1360-7.9563 (5H, m, Ar-H).
General Synthesis of Schiff bases of 6, 8-Diiodo-2-phenylquinazolin-4(3H)-one
(5a-5f): Different aromatic aldehydes (0.01 mol) were treated with compound
(4) (4.89 g, 0.01 mol) in presence of ethanol and refluxed for 3-4 h. After
that the reaction mixture was cooled and the product was filtered off. All the
compounds were recrystallized from ethanol. The physicochemical data of synthesized
Schiff bases are represented in Table 1.
3-{[(E)-(2-chlorophenyl)methylidene]amino}-6,8-diiodo-2-phenylquinazolin-4(3H)-one
(5a): FTIR: 546 (-I), 1679 (-C = O), 1629 (-C = N), 713 (-Cl); 1H-NMR
(DMSO-d6, δ ppm): 8.1710 (2H, s, fused Ar-H), 7.1803-7.9460 (5H, m, Ar-H),
8.1272 (1H, s, H-C = N), 7.3489-7.7757 (4H, m, subst. Ar-H). Anal Calcd. for
C21H12ClI2N3O (%): C, 41.21; H,
1.98; N, 6.87; O, 2.62. Found: C, 41.03; H, 1.93; N, 6.89; O, 2.41.
3-{[(E)-(3-chlorophenyl)methylidene]amino}-6,8-diiodo-2-phenylquinazolin-4(3H)-one
(5b): FTIR: 545 (-I),1700 cm-1 (-C = O), 1624 cm-1
(-C = N), 710 cm-1 (-Cl); 1H-NMR (DMSO-d6, δ ppm):
8.6361(2H, s, fused Ar-H), 7.4164-7.7850 (5H, m, Ar-H), 8.1491(1H, s, H-C=N),
7.5311-7.6848 (4H, m, subst. Ar-H). Anal. Calcd. for C21H12ClI2N3O
(%): C, 41.21; H, 1.98; N, 6.87; O. Found: C, 40.95; H, 2.1; N, 6.76; O, 2.64.
3-{[(E)-(4-chlorophenyl)methylidene]amino}-6,8-diiodo-2-phenylquinazolin-4(3H)-one
(5c): FTIR: 553 (-I), 1703 cm-1 (-C = O), 1624 cm-1
(-C = N), 705 cm-1 (-Cl); 1H-NMR (DMSO-d6, δ ppm):
8.6041(2H, s, fused Ar-H), 7.3911-7.9181(5H, m, Ar-H), 8.0317 (1H, s, H-C =
N), 7.2305-7.8056 (4H, m, subst. Ar-H). Anal. Calcd. for C21H12ClI2N3O
(%): C, 41.21; H, 1.98; N, 6.87; O, 2.62. Found: C, 41.89; H, 1.95; N, 6.65;
O, 2.84.
| Table 1: |
Physicochemical parameters of some Novel 6,8-Diiodo-2-phenylquinazolin-4(3H)-one
Schiff bases (5a-5f) |
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3-{[(E)-(2-hydroxyphenyl)methylidene]amino}-6,8-diiodo-2-phenylquinazolin-4(3H)-one
(5d): FTIR: 564 (-I), 1702 (-C = O), 1623 (-C = N), 730 (-Cl), 3432 (-OH);
1H-NMR (DMSO-d6, δ ppm): 8.9158 (2H, s, fused Ar-H), 8.0901
(1H, s, -C=N), 7.3215-7.5807 (5H, m, Ar-H), 6.9040-7.5617 (4H, m, subst. Ar-H),
5.1494 (1H, s, O-H). Anal. Calcd. for C21H12ClI2N3O
(%): C, 42.52; H, 2.21; N, 7.08; O, 5.39. Found: C, 41.39; H, 2.20; N, 6.9;
O, 5.27.
3-{[(E)-(4-hydroxyphenyl)methylidene]amino}-6,8-diiodo-2-phenylquinazolin-4(3H)-one
(5e): FTIR (cm-1): 551 (-I), 1701 (-C = O), 1625 (-C = N), 742
(-Cl), 3466 (-OH); 1H-NMR (DMSO-d6, δ ppm): 8.2123 (2H, s, fused
Ar-H), 7.2926-7.9983 (5H, m, Ar-H), 7.1951-7.8537 (4H, d, subst. Ar-H), 5.4381
(1H, s, O-H). Anal. Calcd. for C21H12ClI2N3O
(%): C, 42.52; H, 2.21; N, 7.08; O, 5.39; I, 42.79. Found: C, 42.63; H, 2.01;
N, 7.26; O, 5.47.
3-{[(E)-(4-hydroxy-3-methoxyphenyl)methylidene]amino}-6,8-diiodo-2-phenylquinazolin-4(3H)-one.
(5f): FTIR: 588 (-I), 1669 (-C = O), 1621 (-C = N), 732 (-Cl); 3479 (-OH);
1H-NMR (DMSO-d6, δ ppm ): 3.8563(3H, s, CH3), 8.5408
(2H, s, fused Ar-H), 8.0995 (1H, s, H-C=N), 7.338-7.9238 (5H, m, Ar-H), 6.8484-7.1965
(3H, m, subst. Ar-H), 4.9315(1H, s, O-H). Anal Calcd. for C21H12ClI2N3O
(%): C, 42.40; H, 2.43; N, 6.74; O, 7.70; I, 40.73. Found: C, 42.31; H, 2.22;
N, 6.43; O, 7.90.
Anti-inflammatory activity: Carrageenan-induced rat paw edema:
The carrageenan-induced rat paw edema assay was carried out according to Winter
et al. (1962). Wistar rats were divided into 8 groups each consisting
of 6 animals (Gill et al., 2010):
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Group I: Disease control: Carrageenan (1%) was
administered in the plantar surface of rat (p.o.) |
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Group II: Standard: Suspension of Diclofenac sodium (10
mg kg-1) in 1% gum acacia (p.o.)+ Carrageenan |
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Group III to VIII: Test: Suspension of test compounds 5a-5f,
respectively (200 mg kg-1) in 1% Gum acacia (p.o.)+carrageenan |
Edema was induced on the left hind paw of the rats by subplantar injection
of 0.1 mL of a solution of 1% (w/v) carrageenin in a 0.9% NaCl (w/v). The paw
volume was measured at intervals of 60, 120, 180 min by the mercury displacement
method using a plethysmograph after administration of the suspension of test
compounds in 1% Gum acacia orally. The average paw edema volume of all the groups
were calculated and compared with that of control. The percentage inhibition
of paw edema in drug treated group was compared with the carrageenan control
group and calculated according to the following equation:
where, Vc is the inflammatory increase in paw volume of control
group of animals and Vt is the inflammatory increase in paw volume
of drug-treated animals.
Analgesic activity: Swiss albino mice of either sex were divided into
8 groups each consisting of 6 animals:
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Group I: Control: One percent gum acacia (p.o.) |
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Group II: Standard: Suspension of Diclofenac sodium (10
mg kg-1) in 1% gum acacia (p.o.) |
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Group III-VIII: Test: Suspension of test compounds 5a-5f,
respectively (200 mg kg-1) in 1% gum acacia (p.o.) |
Eddy’s Hot plate method: The analgesic activity of the test compounds
(5a-5f) were measured by hot-plate method. The rats were placed on a hot plate
maintained at 55±0.5°C. The reaction time was taken as the interval
from the instant animal reached the hot plate until the moment animal licked
its feet or jumped out (Zakaria et al., 2006;
Franzotti et al., 2001; Sahu
et al., 2012). The reaction time was recorded before and after 0,
30, 60 and 90 min following oral administration of tests compounds (5a-5f) and
standard drug in the form 1% Gum acacia suspension. Following groups were made
and latency period in which rat responded to hot plate was calculated.
Statistical analysis: All the results were expressed as Standard Error
of Means (SEM). The data was statistically analyzed by one way Analysis of Variance
(ANOVA) followed by Tukey using GraphPad Prism 5 Software. The p-value <0.05
was considered to be statistically significant.
RESULTS
Anti-inflammatory activity: The positive control, Diclofenac and test
compounds (5a-5f) significantly inhibited the paw edema response in comparison
to control group. Diclofenac showed an inhibition of 66.7% after 3 h. Compound
5d showed maximum activity with an inhibition of 50.45% and compound 5a showed
minimum activity with an inhibition of 38.9% after 3 h as shown in Table
2.
Analgesic activity: Diclofenac showed marked analgesic response. All
the test compounds (5a-5f) also showed good analgesic activity with compound
5d having maximum activity and compound 5f with minimum analgesic activity.
All values were significant with p-value <0.05 as compared to standard and
control as shown in Table 3.
| Table 2: |
Anti-inflammatory effect of some novel 6,8-Diiodo-2-phenylquinazolin-4(3H)-one
Schiff bases (5a-5f) on carrageenan induced paw edema |
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| Values are Mean±SEM, All values are significant at
ap<0.05 when compared to control and at bp<0.05
when compared to diclofenac (Tukey’s test) |
| Table 3: |
Analgesic activity of some novel 6,8-diiodo-2-phenylquinazolin-4(3H)-one
Schiff bases (5a-5f) on Eddy’s hot plate |
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| Values are Mean±SEM, All values are significant at
ap<0.05 when compared to control and at bp<0.05
when compared to diclofenac (Tukey’s test) |
DISCUSSION
Past literature revealed that quinazolinone nucleus and Schiff bases of 3-aminoquinazolinone
derivatives possessed anti-inflammatory and analgesic agent (Venkataraman
et al., 2010; Mosaad et al., 2010;
Babu and Nadendla, 2011; Tyagi et
al., 1998; Mohamed et al., 2011; Saravanan
et al., 2010a, 2012; Mariappan
et al., 2011). In accordance with the results of past studies, the
present study revealed that the Schiff bases of 6,8-diiodo derivatives were
also active as anti-inflammatory and analgesic agent.
Anti-inflammatory activity: Action of carrageenan takes place as a biphasic
event. Presence of edema takes place in two phases. First phase involves the
release of histamine, serotonin and kinin like substances. Second phase is the
accelerating phase of swelling with a release of prostaglandins. Inhibition
of edema may be occurred due to the suppression of any of these chemical mediators
(Emma et al., 2010). Hydroxyl derivatives showed
good anti-inflammatory activity with o-hydroxy derivative showing maximum activity
of 50.45%. Chloro derivatives were seem to be less potent as compared to hydroxyl
derivatives with p-chloro derivative showing maximum activity of 48.15%.
Analgesic activity: The mechanism of pain transmission is very complex
and many different neuromodulators and receptors could be involved. The central
analgesic activity of the synthetic compounds were studied using Eddy’s
Hot plate method and significantly increased reaction time was observed. Again
o-hydroxy derivative showed maximum central analgesic activity.
It may be considered that Schiff bases of quinazolinone showed their anti-inflammatory
and analgesic activity by inhibiting the microsomal prostaglandin E2-synthase
1 (mPGES-1) like other quinazol-4-(3H)-ones derivatives.
The maximum activity was shown by o-hydroxy phenyl derivative of quinazololinone
with 6.30±0.22 retention time. Chloro substituents too showed moderate
analgesic activity.
It may be concluded that Schiff bases containing hydroxyl group showed promising
ant-inflammatory and analgesic activity as compared to chloro derivatives. Inhibition
of microsomal prostaglandin E2-synthase 1 (mPGES-1) may be involved in their
mechanism of action.
ACKNOWLEDGMENTS
Thanks to Professor A.C. Rana and all faculty members of Rayat Institute of
Pharmacy for their encouragement and support.
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