Synthesis and evaluation of novel 2-substituted-quinazolin-4(3H)-ones as potent analgesic and anti-inflammatory agents

Article abstract of DOI:10.1002/ardp.200900231

A novel series of 2-substituted-quinazolin-4(3H)-ones were synthesized by reacting 3,5-disubstituted-anthranilic acid with acetic anhydride/benzoyl chloride, which were further reacted with different primary amines to obtain 2,6,8-substituted-quinazolin-4(3H)-ones 6a-f, 7, 8. All the synthesized compounds were characterized and screened for analgesic and anti-inflammatory activities. Compounds 6,8-dibromo-2-phenyl-3-(4′-carboxyl phenyl)quinazolin-4(3H)-one 7 and 6,8-dibromo-2-phenyl-3-(2′- phenylethanoic acid)quinazolin-4(3H)-one 8 displayed good analgesic and anti-inflammatory activity in comparison to the reference standards acetyl salicylic acid and indomethacin, respectively.

Full text of DOI:10.1002/ardp.200900231

108
Arch. Pharm. Chem. Life Sci. 2010, 343, 108–113
Full Paper
Synthesis and Evaluation of Novel 2-Substituted-quinazolin-
4(3H)-ones as Potent Analgesic and Anti-inflammatory Agents
Bilal Ahmad Rather1, Tilak Raj1, Aravind Reddy2, Mohan Paul S. Ishar1, Samitha Sivakumar2, and
Perumal Paneerselvam2
1 Bio-Organic and Photochemistry Laboratory, Department of Pharmaceutical Sciences, Guru Nanak Dev
University, Amritsar, Punjab, India
2 Department of Pharmaceutical Chemistry, C. L. Baid Metha College of Pharmacy, Chennai, Tamil Nadu,
India
A novel series of 2-substituted-quinazolin-4(3H)-ones were synthesized by reacting 3,5-disubsti-
tuted-anthranilic acid with acetic anhydride/benzoyl chloride, which were further reacted with
different primary amines to obtain 2,6,8-substituted-quinazolin-4(3H)-ones 6a–f, 7, 8. All the syn-
thesized compounds were characterized and screened for analgesic and anti-inflammatory activ-
ities. Compounds 6,8-dibromo-2-phenyl-3-(49-carboxyl phenyl)quinazolin-4(3H)-one 7 and 6,8-
dibromo-2-phenyl-3-(29-phenylethanoic acid)quinazolin-4(3H)-one 8 displayed good analgesic and
anti-inflammatory activity in comparison to the reference standards acetyl salicylic acid and
indomethacin, respectively.
Keywords: Analgesic / Anti-inflammatory activity / Quinazolines / Quinazolinones /
Received: June 24, 2009; Accepted: September 28, 2009
DOI 10.1002/ardp.200900231
Quinazolin-4(3H)-ones with 2,3-disubstitutions are
Introduction
reported to possess significant anticonvulsant [3, 4], anti-
microbial [5–7], antihelminthic [8, 9], antiallergic [10],
antitumor [11], anticancer [12], monoamine oxidase
(MAO) inhibitor [13], and CNS activities [14], and, in partic-
ular, analgesic as well as anti-inflammatory activities [15–
36]. Some important analgesic and anti-inflammatory
active quinazolinones include 2-phenyl-3-[substituted-
benzothiazol-2-yl]-4(3H)-quinazolinones 1a–c, which are
COX-1 and COX-2 enzyme inhibitors [22], 3-(4-methoxy-
phenyl)-2-substituted-amino-quinazolin-4(3H)-ones 2a–b
with lower gastrointestinal and ulcerogenic side effects
in comparison to acetyl salicylic acid [23], and 4-(4-fluoro-
phenyl)-1-isopropyl-7-methyl-1H-quinazolin-2-one 3 (Fig.
1). Substitution of the aromatic ring [24, 25] and substi-
tuted aryl moiety [26, 27] at the 3-position [28, 29] of the
quinazolin-4(3H)-one nucleus are reported to generate
potential analgesic and anti-inflammatory agents.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are com-
monly prescribed for the treatment of acute and chronic
inflammation, pain, and fever. Most of the NSAIDs that
are available in the market are known to inhibit isoforms
of the enzyme cyclooxygenase (COX), a constitutive form,
COX-1, and an inducible form, COX-2, to elicit therapeu-
tic effect. However, long-term clinical use of NSAIDs is
associated with significant side effects such as gastroin-
testinal lesions, bleeding, and nephrotoxicity. Develop-
ment of analgesic and anti-inflammatory active drugs
with less ulcerogenic side effects is still a distinct dream,
therefore, discovery of new and safer anti-inflammatory
drugs represents a challenging goal [1–2].
Correspondence: Perumal Paneerselvam, Department of Pharmaceuti-
cal Chemistry, C. L. Baid Metha College of Pharmacy, Jyothi Nagar, Rajiv
Gandhi Salai, Thorapakkam, Chennai-600 097, Tamil Nadu, India.
E-mail: rather_bilu@rediffmail.com
Recently, we had reported the synthesis and antimicro-
bial evaluation of 2-methyl-quinazolin-4(3H)-ones [26, 27].
Keeping in view the reported high analgesic and anti-
inflammatory activity of the substituted quinazolin-
4(3H)-ones, it was decided to synthesize a series of novel
Fax: +91 94 427-12951
Abbreviations: monoamine oxidase (MAO); percent analgesic activity
(PAA)
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Arch. Pharm. Chem. Life Sci. 2010, 343, 108–113
Novel 2-Substituted-quinazolin-4(3H)-ones
109
Table 1. Reaction yields of products 6a–f, 7, 8 (in %).
Entry
Reactants
Products
Yield (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
ii
ii
ii
ii
ii
ii
iii
iv
6a
6b
6c
6d
6e
6f
7
80
82
82
81
80
81
83
81
5e
5e
8
Figure 1. Some potential analgesic and anti-inflammatory
agents.
Table 2. Percent analgesic activity of the test compounds (ace-
tic-acid-induced writhing technique).
2-substituted-quinazoline-4(3H)-ones and evaluate their
analgesic and anti-inflammatory activities.
Compound
Dose
(mg/kg)
Mean € SD
Protection
(%)
6a
200
400
200
400
200
400
200
400
200
400
200
400
200
400
200
400
–
28.83 € 1.666§
23.00 € 0.894#
28.50 € 1.892§
23.16 € 0.909#
30.66 € 2.043§
24.83 € 0.666#
29.66 € 0.954§
23.66 € 1.201#
30.66 € 1.358
24.83 € 0.945#
30.66 € 1.763
24.66 € 0.802#
23.50 € 0.885#
22.00 € 0.577#
24.66 € 1.429#
20.33 € 0.557#
35.33 € 1.801
6.50 € 0.662#
18.38
34.72
19.95
34.25
19.48
32.83
16.02
32.83
13.19
29.61
13.82
30.09
33.47
37.55
30.17
42.27
–
Results and discussion
6b
Chemistry
6c
The key intermediates, substituted-2-methyl-benzoxazin-
4(3H)-ones 5a–c were obtained in high yield when a mix-
ture of 3,5-disubstituted-anthranilic acid 4 and acetic
anhydride was refluxed under anhydrous conditions for
4 h. The excess of acetic anhydride was distilled off under
reduced pressure and the reaction mixture was cooled to
room temperature. Similarly, substituted-2-phenyl-ben-
zoxazin-4(3H)-ones 5d–f were obtained by reacting 3,5-
disubstituted-anthranilic acid 4 dissolved in 120 mL of
pyridine with benzoyl chloride, added dropwise with
constant stirring at 0–58C over a period of 1 h. After com-
pletion of the addition, the reaction mixture was stirred
for half an hour at room temperature; at the end of the
reaction, a solid mass of substituted-2-phenylbenzoxazin-
4(3H)-ones 5d–f was obtained. The solid mass was filtered,
washed successively with sodium bicarbonate solution
(10%) to remove the unreacted acid followed by water,
dried, and recrystallized from alcohol. The intermediates
5a–f obtained as solid masses were used immediately for
the next step. Thus, 2,6,8-substituted-benzoxazin-4-ones
5a–f were refluxed with different substituted aromatic
amines i.e., 4-(2-aminophenyl)morpholine, p-amino-ben-
zoic acid, and a-amino-phenyl acetic acid in glacial acetic
acid over a period of 6 h. The progress of the reaction was
monitored by TLC. After completion of the reaction, the
reaction mixture was allowed to cool and was then
poured in ice cold water with constant stirring; it was
kept overnight, in the refrigerator. The resulting solid
compounds 6a–f, 7, and 8 were further washed with dis-
tilled water, dried, and recrystallized from ethanol. The
purified compounds obtained after recrystallization
(Table 1, Scheme 1) were characterized by detailed spec-
6d
6e
6f
7
8
Control
Acetyl salicylic 100
acid
81.60
Each value is the mean € SEM using six animals in each group.
Significant differences with respect to the control group were
evaluated by student9s test.
P a 0.05; § P a 0.01; # P a 0.001
troscopic (1H- and 13C-NMR, IR, Mass) and elemental anal-
ysis.
Pharmacology
All the synthesized products 6a–f, 7, 8 were evaluated for
their analgesic [30] and anti-inflammatory activity [31].
Analgesic activity was evaluated using the acetic-acid-
induced writhing reflex model in Wistar albino mice
with acetyl salicylic acid as positive control. The evalua-
tion of analgesic activity of all the test compounds was
carried out at two dose levels of 200 and 400 mg/kg body
weight (Table 2). After oral administration of the test
compounds, control and positive control (acetyl salicylic
acid), the writhings were counted for 20 min in an iso-
lated individual cage. The %-protection was calculated
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110
B. A. Rather et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 108–113
Reactions and reaction conditions: (i) Ac2O / C6H5COCl; (ii) 2-(morpholino-4-yl)-aniline; (iii) p-aminobenzoic acid; (iv) a-amino-phenyl-acetic acid.
Scheme 1. Synthesis of some novel 2-substituted quinazolin-4(3H)-ones.
inhibition was recorded at 5 h. Maximum inhibitory
activity was observed for compound 7 (41.01%) and 8
(38.45%) at 2 h, which is followed by moderately active
35.03% (6e), 29.90% (6c), and 29.05% (6a, d). However, low-
est %-inhibitory activity of 24.78% was observed for 6b.
Structure-activity relationships
The preliminary structure-activity relationships for all
the compounds was developed at the dose level of 100
Figure 2. Structure–activity relationship.
using percent analgesic activity (PAA). Compounds 7 and mg/kg for both analgesic and anti-inflammatory activity
8 with 2-morpholino-phenyl and 2-phenylethanoic acid (Fig. 2).
substitution showed maximum (PAA) protection of
33.47% and 30.17%, respectively. It is followed by 19.95% Analgesic activity
(6b), 19.48% (6c), 18.38% (6a), and 16.02% (6d) protection; Maximum analgesic activity was observed for 6,8-
these compounds were moderately analgesic at 200 mg/ dibromo-substituted compounds 7 and 8 bearing -p-Ph-
kg body weight, whereas, compound (6e) shows a very COOH and -CH(COOH)-Ph moieties. Moderate activity was
low analgesic activity of 13.19%.
observed for compounds 6a, b, d bearing methyl at C2.
Very low activity was observed for 6, 8-dibromo-substi-
tuted compound 6e bearing a -C6H5 moiety at C2.
Anti-inflammatory activity
The anti-inflammatory activity of the test compounds
was evaluated by carrageenan-induced paw oedema test Anti-inflammatory activity
in rats using indomethacin as positive control. The anti- Maximum anti-inflammatory activity was observed for
inflammatory inhibition (in %; Table 3) of all the test 6,8-dibromo-substituted and C2 phenyl-substituted com-
compounds and the positive control was observed at pounds 7, 8, and 6e, bearing -p-Ph-COOH-, -CH(COOH)-Ph,
different time intervals of 1, 2, 4, and 5 h. The maximum and -o-morpholino-Ph moiety. Subsquently, replacement
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www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2010, 343, 108–113
Novel 2-Substituted-quinazolin-4(3H)-ones
111
Table 3. Percent anti-inflammatory activity of the test compounds (carrageenan-induced paw oedema method).
Compounds/ Dose
30 min
%
1 h
%
2 h
%
3 h
%
Standard
(mg/kg)
inhibition
inhibition
inhibition
inhibition
6a
200
400
200
400
200
400
200
400
200
400
200
400
200
400
200
400
0.22 € 0.009
0.22 € 0.007
0.21 € 0.20
0.20 € 0.020
0.22 € 0.016
0.19 € 0.013
0.22 € 0.013
0.20 € 0.15
0.20 € 0.011
0.19 € 0.018
0.21 € 0.013
0.20 € 0.013
0.22 € 0.013
0.22 € 0.012
0.23 € 0.016
0.22 € 0.012
0.20 € 0.013
0.19 € 0.008
7.77
7.77
8.88
5.55
14.44
13.32
4.44
6.66
8.88
11.10
7.77
8.88
7.77
12.21
9.99
7.77
0.29 € 0.013
0.27 € 0.009
0.30 € 0.014
0.29 € 0.001
0.20 € 0.020
0.28 € 0.019
0.29 € 0.006
0.30 € 0.008
0.27 € 0.009
0.27 € 0.013
0.27 € 0.006
0.28 € 0.012
0.29 € 0.001
0.27 € 0.012
0.30 € 0.014
0.29 € 0.015
0.30 € 0.005
0.28 € 0.015
11.6
10
21.66
16.66
20
11.66
15
15
0.27 € 0.013#
0.25 € 0.013#
0.29 € 0.015#
0.26 € 0.014#
0.27 € 0.016#
0.25 € 0.009#
0.27 € 0.009#
0.24 € 0.012#
0.25 € 0.009#
0.22 € 0.011#
0.24 € 0.010#
0.23 € 0.008#
0.23 € 0.014#
0.23 € 0.014#
0.24 € 0.012#
0.22 € 0.014#
0.39 € 0.012#
0.10 € 0.008#
29.05
35.03
24.78
32.47
29.90
35.03
29.05
36.74
35.03
41.87
38.45
41.02
41.01
39.31
38.45
43.58
0.29 € 0.019#
0.26 € 0.014#
0.30 € 0.017#
0.28 € 0.015#
0.27 € 0.014#
0.26 € 0.012#
0.28 € 0.009#
0.26 € 0.015#
0.26 € 0.008#
0.24 € 0.013#
0.24 € 0.011#
0.24 € 0.007#
0.24 € 0.016#
0.22 € 0.011#
0.25 € 0.015#
0.22 € 0.016#
0.36 € 0.014#
0.16 € 0.005#
19.43
25.92
16.66
21.29
23.14
27.77
21.29
26.84
27.77
33.32
31.47
33.32
32.40
38.88
29.62
37.03
6b
6c
6d
6e
10
15
6f
11.66
11.66
11.66
11.66
18.33
16.66
7
8
Control
Indomethacin 20
8.33
11.10
74.35
55.55
Each value is the mean € SEM using six animals in each group. Significant differences with respect to the control group were eval-
uated by student’s test.
P a 0.05; § P a 0.01; # P a 0.001
trometer (Perkin-Elmer, Norwalk, CT, USA). The 1H-NMR and 13C-
NMR spectra were recorded on 300 MHz-Bruker DPX 200 NMR
of the -C6H5 with CH3 in case of 6a, d, c resulted in a
decrease in activity. Moderate activity was observed for
spectrometer (Bruker Bioscience,USA). The chemical shifts were
compounds 6a, b, d bearing methyl at C2. Very low activ-
reported as parts per million (d ppm) using tetramethyl silane
ity was observed for 6, 8-dibromo-substituted compound
(TMS) as internal standard. Mass spectra were obtained on Finni-
6e bearing -C6H5 at C2.
gan MAT 8230 MS instrument (Thermo Finnigan MAT GmbH,
Bremen, Germany) using fast atom bombardment (FAB positive).
Elemental analysis was performed on Perkin-Elmer 2400 C, H, N
analyzer and values were within the acceptable limits (€0.4%) of
the calculated values. The purity of the synthesized compounds
were checked by TLC using E-Merck TLC aluminum sheets silica
gel 60 F254 (0.2 mm; Merck, Germany) using chloroform/metha-
nol (9:1) as eluent and visualized in an iodine chamber. All the
chemicals used were of analytical grade.
Conclusion
A number of quinazolines were synthesized and eval-
uated for their analgesic and anti-inflammatory activ-
ities. 6,8-Dibromo-3-phenylquinazoline compounds 7, 8,
bearing -p-COOH-Ph, -CH(COOH)-Ph at N3 displayed mod-
erate analgesic and anti-inflammatory activity. Further
structural modification i. e., replacement of bromo at C6
and C8 position, C2 Phenyl/CH3 and replacement of o-
morpholino-Ph with -p-COOH-Ph, -CH(COOH)-Ph moieties
at N3 position resulted in a decrease in both analgesic
and anti-inflammatory activity. The high activity
observed in case of compounds 7, 8 may be due to the
hydrogen bonding ability of -p-COOH-Ph, -CH(COOH)-Ph
groups. These lead quinazolines may be subjected to fur-
ther structural modifications.
Synthesis of substituted benzoxazin-4(3H)-ones 5a, b
Unsubstituted/substituted anthranilic acid (0.05 mol) in 0.1 mol
of acetic anhydride was refluxed under anhydrous conditions
for 4–6 h. The excess of acetic anhydride was then distilled off
under reduced pressure and cooled to room temperature. 2-
Methyl-benzoxazin-4(3H)-one 5a obtained was filtered and dried
under vacuum. Likewise, 2-phenyl-benzoxazin-4(3H)-one 5b was
prepared by reacting unsubstituted/substituted anthranilic acid
(1 M) dissolved in 120 mL of pyridine by adding benzoyl chloride
(1 M) dropwise with constant stirring at 0–58C over the period of
1 h. After completion of the addition, the reaction mixture was
stirred for half an hour at room temperature. At the end of the
reaction, a solid mass of 2-phenyl-benzoxazin-4(3H)-ones 5b was
obtained. It was filtered, washed successively with sodium bicar-
bonate solution (10%) to remove the unreacted acid and the
water, then it was dried and recrystallized from spirit.
Experimental
Chemistry
Melting points were taken in open capillaries on Thomas Hoover
melting point apparatus (Thomas Hoover Capillary Apparatus,
Philadelphia, PA, USA) and are uncorrected. The IR spectra were
recorded in potassium bromide discs on a Perkin-Elmer 398 spec-
Synthesis of quinazolin-4(3H)-ones 6a-f, 7, 8
Equimolar quantities of unsubstituted/substituted 2-methyl-
benzoxazin-4(3H)-one/2-phenyl-benzoxazin-4(3H)-one 5a, b and
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112
B. A. Rather et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 108–113
the corresponding amine in glacial acetic acid was refluxed for 6
h. After cooling, the contents were poured into crushed ice. The
resulting solid was washed with distilled water, filtered, dried in
vacuum, and recrystallized from warm ethanol.
126.4 (C3999 & C5999), 126.2 (C10), 125.6 (C2999 & C6999), 125.4 (C49), 124.8
(C19), 124.2 (C59), 122.5 (C4), 114.6 (C39), 113.6 (C8), 67.1 (C399 & C599),
46.4 (C299 & C699); MS (m/z): 540 [M+]. Anal. calcd. for C24H19N3Br2O2:
C, 53.26; H, 5.54; N, 7.76. Found: C, 53.12; H, 3.34; N, 7.01.
6-Bromo-2-phenyl-3-(29-morpholinophenyl)quinazolin-
4(3H)-one 6f
2-Methyl-3-(29-morpholinophenyl)quinazolin-4(3H)-one
6a
Yield: 73%; m.p.: 132–1358C; IR (KBr) (in cm–1): 1685 (C=O), 1602
(C=C), 1674 (C=N), 1065 (C-O-C), 795 (C-H), 554 (C-Br); 1H-NMR
(CDCl3) d: 8.14 (s, 1H, ArH), 6.52–8.01 (m, 11H, ArH), 3.61 (brs,
4H), 2.90 (brs, 4H); 13C-NMR (CDCl3) d: 163.7 (C4), 160.8 (C2), 150.6
(C9), 142.7 (C29), 136.6 (C6), 133.1 (C7), 130.2 (C1999), 128.7 (C4999),
126.5 (C5), 126.3 (C3999 & C5999), 125.4 (C10), 124.9 (C2999 & C6999), 123.6
(C49), 122.5 (C19), 121.7 (C59), 118.3 (C4), 114.4 (C39), 113.6 (C8), 66.7
(C399 & C599, 46.8 (C299 & C699); MS (m/z): 461 [M+]. Anal. calcd. for
C24H20N3BrO2: C, 62.35; H, 4.36; N, 9.09. Found: C, 62.22; H, 4.28;
N, 8.93.
Yield: 64%; m.p.: 185–1878C; IR (KBr) (in cm–1): 1652 (C=O), 1607
(C=C), 1694 (C=N), 1088 (C-O-C); 1H-NMR (CDCl3) d: 6.51–7.95 (m,
8H, Ar-H), 3.63 (brs, 4H), 2.94 (brs, 4H), 0.91 (s, 3H, -CH3); 13C-NMR
(CDCl3) d: 160.2 (C4), 151.2 (C2), 147.2 (C99), 143.0 (C29), 133.5 (C7),
128.6 (C5), 127.6 (C6), 125.0 (C49), 124.3 (C19), 122.6 (C69), 122.3 (C8),
120.9 (C10), 118.4 (C59), 114.7 (C39), 66.7 (C39 & C59), 46.3 (C299 & C699),
22.4 (-CH3); MS (m/z): 321 [M+]. Anal. calcd. for C19H19N3O2: C,
71.01; H, 5.96; N, 13.08. Found: C, 70.99 ; H, 5.73; N, 12.92.
6,8-Dibromo-2-methyl-3-(29-
morpholinophenyl)quinazolin-4(3H)-one 6b
6,8-Dibromo-2-phenyl-3-(49-carboxylphenyl)quinazolin-
4(3H)-one 7
Yield: 68%; m.p.: 205–2078C; IR (KBr) (in cm–1): 1772 (C=O), 1603
1
(C=C), 1670 (C=N), 1010 (C-O-C); H-NMR (CDCl3) d: 8.17 (s, 1H,
Yield: 71%; m.p.: 236–2388C; IR (KBr) (in cm–1): 1681 (C=O), 1600
(C=C), 1660 (C=N), 1064 (C-O-C), 852 (C-H), 544 (C-Br); 1H-NMR
(CDCl3) d: 10.96 (s, 1H, -COOH), 7.23–7.81 (m, 9H, ArH), 7.87 (s,
1H, ArH), 8.11 (s, 1H, ArH); 13C-NMR (CDCl3) d: 169.3 (-COOH),
164.3 (C4), 161.2 (C2), 153.9 (C10), 139.6 (C19), 138.1 (C7), 131.2 (C199),
130.6 (C9), 130.2 (C5), 129.5 (C39 & C59), 129.1 (C499), 128.9 (C399 & C599),
128.2 (C6), 126.1 (C299 & C699), 125.9 (C8), 121.6 (C69 & C29); MS (m/z):
496 [M+]. Anal. calcd. for C21H12N2Br2O3: C, 50.43; H, 2.42; N, 5.60.
Found: C, 50.24; H, 2.18; N, 5.43.
ArH), 7.63–6.25 (m, 5H, ArH), 3.67 (brs, 4H), 2.93 (brs, 4H), 0.93 (s,
3H, -CH3); 13C-NMR (CDCl3) d: 160.4 (C4), 151.3 (C2), 150.6 (C99),
142.2 (C29), 139.3 (C7), 131.2 (C5), 125.6 (C10), 125.3 (C49), 124.4 (C19),
123.7 (C6), 122.5 (C69), 118.6 (C59), 114.4 (C39), 113.4 (C8), 66.3 (C399 &
C599), 46.9 (C299 & C699), 22.3 (-CH3); MS (m/z): 478 [M+]. Anal. calcd. for
C19H17N3Br2O2: C, 47.63; H, 3.58; N, 8.77. Found: C, 47.56; H, 3.41;
N, 8.61.
6-Bromo-2-methyl-3-(29-morpholinophenyl)quinazolin-
4(3H)-one 6c
6,8-Dibromo-2-phenyl-3-(29-phenylethanoic acid)
Yield: 75%; m.p.: 198–2008C; IR(KBr) (in cm–1): 1684 (C=O), 1601
quinazolin-4(3H)-one 8
1
(C=C), 1645 (C=N), 1010 (C-O-C); H-NMR (CDCl3) d: 8.15 (s, 1H,
Yield: 86%; m.p.: 152–1548C; IR (KBr) (in cm–1): 1681 (C=O), 1602
ArH), 7.73–6.58 (m, 6H, ArH), 3.66 (brs, 4H), 2.90 (brs, 4H), 0.92 (s,
3H, -CH3); 13C-NMR (CDCl3) d: 160.8 (C4), 152.2 (C2), 146.1 (C99),
143.1 (C29), 136.5 (C7), 132.4 (C5), 125.7 (C10), 125.3 (C49), 124.6 (C19),
123.2 (C6), 122.6 (C69), 118.7 (C59), 114.9 (C39), 113.1 (C8), 66.7 (C399 &
C599), 46.4 (C299 & C699), 22.1 (-CH3); MS (m/z): 399 [M+]. Anal. calcd.
for C19H18N3BrO2: C, 57.01; H, 4.53; N, 10.50. Found: C, 56.88; H,
4.34; N, 10.30.
1
(C=C), 1651 (C=N), 876 (C-H), 562 (C-Br); H-NMR (CDCl3) d: 10.92
(s, 1H, -COOH), 8.11 (s, 1H, ArH), 7.88 (s, 1H, Ar-H), 7.03–7.67 (m,
10H, ArH), 5.73 (s, 1H, -CH-COOH); 13C-NMR (CDCl3) d: 176.2 (-
COOH), 163.9 (C4), 161.9 (C2), 154.6 (C10), 139.6 (C19), 136.2 (C7),
131.5 (C199), 130.8 (C9), 130.3 (C5), 129.7 (C39 & C59), 129.2 (C499),
128.8 (C399 & C599), 127.5 (C6), 126.1 (C299 & C699), 128.7 (C8), 125.3 (C299
& C699), 123.9 (C8), 120.9 (C69 & C29), 57.2 (-CH-COOH); MS (m/z): 513
[M+]. Anal. calcd. for C22H14N2 Br2O3: C, 51.39; H, 2.74; N, 5.45.
Found: C, 51.23; H, 2.41; N, 5.31.
2-Phenyl-3-(29-morpholinophenyl)quinazolin-4(3H)-one
6d
Yield: 62%; m.p.: 110–1138C; IR(KBr) (in cm–1): 1685 (C=O), 1602
(C=C), 1673 (C=N), 1068 (C-O-C), 795(C-H); 1H-NMR (CDCl3) d: 7.91–
6.43 (m, 13H, ArH), 3.60 (brs, 4H), 2.98 (brs, 4H); 13C-NMR (CDCl3)
d: 164.2 (C4), 160.3 (C2), 151.4 (C9), 142.3 (C29), 133.7 (C6), 130.5 (C7),
128.9 (C1999), 128.8 (C4999), 128.7 (C5), 127.5 (C3999 & C5999), 126.1 (C10),
125.6 (C2999 & C6999), 125.4 (C49), 122.6 (C19), 120.9 (C59),118.6 (C4),
114.8 (C39), 113.1 (C8), 66.7 (C399 & C599), 46.2 (C299 & C699); MS (m/z):
382 [M+]. Anal. calcd. for C24H21N3O2: C, 75.18; H, 5.52; N, 10.96.
Found: C, 75.08; H, 5.32; N, 10.01.
Pharmacology
The synthesized compounds were evaluated for analgesic and
anti-inflammatory activities. The test compounds and the stand-
ard drugs were administered in form of a suspension (polyethy-
lene glycol as vehicle) by i. p. route of administration for analge-
sic and anti-inflammatory activity. Each group consisted of six
animals. The animals were maintained in colony cages at
25 € 28C, relative humidity of 45–55% under 12 h light and dark
cycles. All the animals were acclimatized for a week before use.
The animals were fed with standard animal feed and water ad
libitum. The Institutional Animal Ethics Committee approved
the protocol adopted for experimentation with animals.
6,8-Dibromo-2-phenyl-3-(29-morpholinophenyl)-
quinazolin-4(3H)-one 6e
Yield: 78%; m.p.: 165–1688C; IR (KBr) (in cm–1): 1653 (C=O), 1451
1
Analgesic activity
(C=C), 1653 (C=N), 1057 (C-O-C); H-NMR (CDCl3) d: 8.12 (s, 1H,
ArH), 7.86 (s, 1H, ArH), 7.67–6.53 (m, 9H, ArH), 3.64 (brs, 4H), 2.95
(brs, 4H); 13C-NMR (CDCl3) d: 164.5 (C4), 160.3 (C2), 154.7 (C9), 142.8
(C29), 139.7 (C6), 130.3 (C7), 131.3 (C1999), 128.8 (C4999), 128.7 (C5),
Analgesic activity was performed by acetic-acid induced writh-
ing reflux model in mice using Wistar albino mice (25–35 g;
Tamil Nadu Veterinary College and Research Institute, Chennai)
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Arch. Pharm. Chem. Life Sci. 2010, 343, 108–113
Novel 2-Substituted-quinazolin-4(3H)-ones
113
of either sex selected by random sampling technique. At a dose
level of 100 mg/kg, acetyl salicylic acid was administered i. p. as
reference drug for comparison. Each group of animal received
0.1 mL/10 g body weight of 0.6% v/v of acetic acid after half an
hour of administration of the title compounds in the two dose
level of 200, 400 mg/kg body weight p. o. immediately after the
administration of acetic acid, the animal was isolated in an indi-
vidual cage and the writhing were counted for 20 min.
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PAA = [T2 – T1/10 – T1]6100
(1)
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in which T1 is the reaction time (s) before treatment and T2 is the
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Anti-inflammatory activity
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induced paw oedema test in rats [31]. Indomethacin 10–20 mg/
kg was administered as a standard drug for comparison. The test
compounds were administered at two dose levels: 200, 400 mg/
kg body weight p. o. The paw volumes were measured using the
mercury displacement technique with the help of a plethysmo-
graph, immediately before and at 30 min, 1, 2, and 3 h after car-
ageenan injection. The percent inhibition I of paw oedema was
calculated.
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I = 100 [1 – (a – x)/(b – y)]
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Where x is the mean paw volume of rats before the administra-
tion of carrageenan and test compounds or reference com-
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tion of carrageenan in the test group (drug treated), b is the
mean paw volume of rats before the administration of carra-
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Statical analysis
Stastical analysis of the biological activity of the synthesized
compounds on animals was evaluated using a one-way analysis
of variance (ANOVA). In all cases, post hoc comparisons of the
mean of the individual groups were performed using Tukey’s
test. A significance level of p a 0.05 denoted significance in all
cases. All values are expressed as means € SD (standard devia-
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The authors have declared no conflict of interest.
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i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com