Synthesis and anti-inflammatory activity of 2,3-diaryl-4(3H)-quinazolinones

Article abstract of DOI:10.1007/s10593-006-0201-4

2,3-Diaryl-4(3H)-quinazolinones containing various substituents on diaryl rings have been synthesized and evaluated for their cyclooxygenase-2 inhibitory activity by the colorimetric COX (ovine) inhibitor screening assay and anti-inflammatory activity by the carrageenan-induced rat paw edema assay. 2-(4-Nitrophenyl)-3-(4-tolyl)-4(3H)-quinazolinone showed a maximum COX-2 inhibition of 27.72% at 22 μM concentration in the present series and exhibited a mild anti-inflammatory activity at a dose of 50 mg/kg in carrageenan-induced rat paw edema assay.

Full text of DOI:10.1007/s10593-006-0201-4

Chemistry of Heterocyclic Compounds, Vol. 42, No. 8, 2006
SYNTHESIS AND ANTI-INFLAMMATORY
ACTIVITY OF 2,3-DIARYL-
4(3H)-QUINAZOLINONES
M. R. Yadav, S. T. Shirude, A. Parmar, R. Balaraman, and R. Giridhar
2,3-Diaryl-4(3H)-quinazolinones containing various substituents on diaryl rings have been synthesized
and evaluated for their cyclooxygenase-2 inhibitory activity by the colorimetric COX (ovine) inhibitor
screening assay and anti-inflammatory activity by the carrageenan-induced rat paw edema assay.
2-(4-Nitrophenyl)-3-(4-tolyl)-4(3H)-quinazolinone showed a maximum COX-2 inhibition of 27.72% at
22 µM concentration in the present series and exhibited a mild anti-inflammatory activity at a dose of 50
mg/kg in carrageenan-induced rat paw edema assay.
Keywords: 4(3H)-quinazolinones, COX-2 inhibitors.
One of the aims of medicinal chemists is to develop drugs that would hit single targets. Selective drug
action is intended to minimize undesired side effects. By optimizing binding to a selected target protein, safe and
efficacious drug molecules could be developed for the treatment of a disease. The discovery of isoforms of
cyclooxygenase enzyme as COX-1 and COX-2 showed that the side effects of NSAIDs were due to their
unwanted inhibition of COX-1 along with the desired blockade of COX-2 enzyme. This discovery led to the
development of selective COX-2 inhibitors, which are almost free of gastric side effects and possess potent anti-
inflammatory activity [1]. The COX-2 inhibitors have been successful in treating such inflammatory diseases as
acute pain, rheumatoid arthritis, and osteoarthritis; a few of them are also being studied for treating different
types of cancers and Alzheimer's disease [2]. Despite a few latest cautionary reports, COXIB treatment has a
high degree of benefit over risk, and the strategies for the use of NSAIDs have been described [3].
Unlike classic NSAIDs, which have a diverse class of chemical structures, the selective COX-2
inhibitors can be classified into two classes as (i) acidic methane sulfonamides containing diphenyl ethers, e.g.,
nimesulide 1 [4] and NS-398 2 [5], and (ii) vicinal diaryl heterocycles with sulfamoyl or methylsulfonyl
substitution, e.g., etoricoxib [6], celecoxib [7], refocoxib [8], and valdecoxib [9]. A central carbo/heterocyclic
ring system bearing two vicinal aryl moieties is a prerequisite for selective COX-2 inhibitors. A wide variety of
heterocycles can serve as a template for COX-2 inhibitors, i.e., pyrazole (celecoxib), isoxazole (valdecoxib,
paracoxib sodium), furan (rofecoxib), oxazole (JTE-522), thiophene (DuP-697), pyridine 3 (etoricoxib), pyrazine
4 [10], and quinoxaline 5 [10].
__________________________________________________________________________________________
Pharmacy Department, Faculty of Technology and Engineering, Kalabhavan, The M. S. University of
Baroda, Vadodara-390 001, India; e-mail: mryadav11@yahoo.co.in. Published in Khimiya Geterotsiklicheskikh
Soedinenii, No. 8, pp. 1198-1205, August, 2006. Original article submitted May 17, 2006.
1038
0009-3122/06/4208-1038©2006 Springer Science+Business Media, Inc.

SO2Me
NHSO2Me
O
NHSO2Me
O
Cl
N
NO2
NO2
N
Me
NS-398 2
Nimesulide 1
Etoricoxib 3
SO2NH2
SO2Me
N
N
N
N
OMe
F
Quinoxaline derivative 5
Pyrazine derivative 4
In vicinal diaryl heterocyclic COX-2 inhibitors, along with five-membered central heterocyclic rings,
six-membered heterocyclic rings have been used as a template. But there is only one report [10] on the use of
fused-ring system like quinoxaline as a central template for COX-2 inhibitors. It was planned in this work to use
4(3H)-quinazolinone as a central fused heterocyclic ring in place of quinoxaline for the synthesis of potential
COX-2 inhibitors.
Aryl acid chlorides 7, the required starting materials for the synthesis of benzoxazin-4(3H)-ones, were
obtained by treating the corresponding aryl acids with thionyl chloride, while benzoyl chloride was
commercially available. Anthranilic acid 6 reacted with these acid chlorides under basic conditions to afford the
substituted 2-aryl-3,1-benzoxazin-4(3H)-ones 8 following the reported [11] procedure (Scheme). Formation of
3,1-benzoxazin-4(3H)-ones was confirmed by matching the melting points with the reported values. The IR
spectra of compounds 8 showed the presence of characteristic stretching vibrations at about 1770 cm-1 for the
carbonyl of lactone.
Substituted diamides 10, important intermediates in the preparation of 4-quinazolinones, were prepared
by heating substituted 2-aryl-3,1-benzoxazin-4(3H)-ones 8 with aryl amines 9 following the reported procedure
[11]. When the reaction mixture of compounds 8 and amines 9 did not melt at 100°C, the temperature was raised
to 200°C. Interestingly, it was observed that heating the mixture of 2-phenyl-3,1-benzoxazin-4(3H)-one 8 and 2-
aminopyridine 9 yielded diamide 10 under milder conditions (at lower temperatures, 100°C), while at higher
temperatures (200°C) the cyclized product 4(3H)-quinazolinone 24 was isolated (Route B). This observation is
restricted to compounds having the pyridyl ring either in the 3,1-benzoxazin-4(3H)-one 8 component or in amine
9 component. With the rest of the substituents (H, Me, Cl, F, OMe and NO2) only amides 10 were obtained even
at higher temperatures. For their cyclization into the final quinazolinones, a catalytic amount of anhydrous zinc
chloride (Route A) was used. Compounds 23 and 24 were synthesized by both routes, i.e., with the isolation of
diamides 10 and directly in the fused form, while compound 25 was synthesized without the isolation of diamide
10. The IR spectra of compounds 10 demonstrated the presence of characteristic NH stretching vibrations and
amide peaks at about 3300 and 1655 cm-1, respectively. The IR spectra of compounds 11-25 showed the
presence of characteristic carbonyl stretching vibrations at about 1680 cm-1.
1039

O
COCl
COOH
NH2
dry pyridine
ice-bath
O
+
X
N
R1
6
R1
R2
8
X
7
H2N
∆
Y
9
route A
route B
R2
R2
O
O
N
H
Y
X
∆
Y
X
N
O
N
H
N
R1
R1
10
11–28
R1, R2 = H, Cl, F, Me, OMe, NO2, NHSO2Me, NHCOMe
a, b
a, c
Reagents and conditions: a) iron powder and NaCl in aq. MeOH, reflux 7 h on water bath;
b) mesyl chloride, pyridine 4 h; c) acetic anhydride, pyridine 12 h.
11 R1 = R2 = H, 12 R1 = Cl, R2 = H, 13 R1 = NO2, R2 = H, 14 R1 = H, R2 = NO2, 15 R1 = Cl,
R2 = NO2, 16 R1 = H, R2 = Me, 17 R1 = Cl, R2 = Me, 18 R1 = NO2, R2 = Me, 19 R1 = H,
R2 = OMe, 20 R1 = Cl, R2 = OMe, 21 R1 = F, R2 = OMe, 22 R1 = H, R2 = F, 23, 24 R1 = R2 = H,
25 R1 = Cl, R2 = H, 26 R1 = NHSO2Me, R2 = H, 27 R1 = H, R2 = NHSO2Me, 28 R1 = NHCOMe,
R2 = H; 11-22, 24-28 X = C, 23 X = N; 11-23, 26-28 Y = C, 24, 25 Y = N
Nitroquinazolinones 13 and 14 were reduced to the corresponding amine derivatives by iron powder and
sodium chloride in boiling aqueous methanol. These amino derivatives were treated with mesyl chloride under
basic conditions to afford methanesulfonamide compounds 26 and 27. Similarly, the amino derivative obtained
from compound 13 was also treated with acetic anhydride to yield amide derivative 28. The physical data for
substituted 2,3-diaryl-4(3H)-quinazolinones 11-28 are given in Table 1 and the spectral data of compounds 11-
28 are listed in Table 2.
All the synthesized compounds were evaluated for their cyclooxygenase-2 inhibitory activity by the
colorimetric COX (ovine) inhibitor screening assay [12] and anti-inflammatory activity by the carrageenan-
induced rat paw edema assay [13] (Table 3). Compounds 26 and 27 with a well-known COX-2 pharmacophore
were found to be inactive at 22 µM concentration. Compound 18 with an electron-withdrawing group (NO2) was
found to be the most potent compound in the series with an inhibition of 27.72% at 22 µM concentration; in
comparison, valdecoxib, a well-known clinically used COX-2 inhibitor, showed 87.2% inhibition at this
concentration. Compound 18 exhibited a mild anti-inflammatory activity at a dose of 50 mg/kg in the
carrageenan-induced rat paw edema assay. This study showed that 4(3H)-quinazolinone may not be a good
bioisostere of the five/six-membered central ring present in the clinically used COX-2 inhibitors.
1040

TABLE 1. The Spectral and Analytical Data for Substituted 2,3-Diaryl-
4(3H)-quinazolinones 36-53
Found, %
Calculated, %
Com-
pound
Molecular
formula
mp, °C
(Lit. [11] mp)
Yield %
(Route)
Rf*
C
H
N
C20H14N2O
C20H13ClN2O
C20H13N3O3
—
—
—
—
—
—
—
—
—
158-159
(156-157)
0.70
0.83
0.64
22 (A)
63 (A)
38 (A)
11
12
13
177-178
(177)
224-225
(224-225)
C20H13N3O3
C20H12ClN3O3
C21H16N2O
69.66
69.97
63.24
63.59
81.02
80.75
72.58
72.73
71.02
70.58
77.09
76.81
69.72
69.52
72.64
72.82
3.69
3.82
2.96
3.20
4.89
5.16
4.02
4.36
3.94
4.23
4.65
4.91
4.42
4.17
3.98
4.37
12.42
12.24
11.34
11.12
8.67
8.97
7.79
8.08
11.87
11.76
8.36
8.53
7.49
7.72
8.25
8.09
204-205
224-225
182-183
190-192
218-219
—
0.74
0.81
0.68
0.62
0.60
0.80
0.84
0.60
0.65
0.62
32 (A)
29 (A)
46 (A)
57 (A)
31 (A)
10 (A)
31 (A)
42 (A)
30 (A)
14
15
16
17
18
19
20
21
22
23
C21H15ClN2O
C21H15N3O3
C21H16N2O2
C21H15ClN2O2
C21H15FN2O2
C20H13FN2O
C19H13N3O
168-170
167-169
148-150
76.51
76.82
—
4.12
3.99
—
8.22
8.53
—
175-177
(175-177)
47 (A)
27 (B)
C19H13N3O
75.86
76.24
4.12
4.38
13.89
14.04
188-189
0.67
64 (A)
56 (B)
24
C19H12ClN3O
C21H17N3O3S
C21H17N3O3S
C22H17N3O2
68.63
68.37
64.76
64.44
64.71
64.44
74.25
74.35
3.92
3.62
4.59
4.38
4.62
4.38
3.95
4.82
12.26
12.59
10.53
10.73
10.96
10.73
11.92
11.82
182-183
144-145
>280
0.69
0.23
0.29
0.60
32 (B)
25
26
27
28
48
31
246-247
48
_______
* 5% methanol in chloroform.
TABLE 2. Spectral Data for Substituted 2,3-Diaryl-4(3H)-quinazolinones 11-28
UV spectrum
Com-
IR spectrum, ν, cm-1
1H NMR spectrum, δ, ppm
(MeOH),
pound
λ
max, nm (log ε)
1
2
3
4
11
12
13
1680 (C=O)
1680 (C=O)
229 (4.55)
279.5 (4.04)
225 (4.53)
—
—
—
1682 (C=O),
1519 (NO2 asym.),
1350 (NO2 sym.)
14
1694 (C=O),
1519 (NO2 asym.),
1350 (NO2 sym.)
278.5 (4.55)
7.22-8.36 (13H, m, ArH)
1041

TABLE 2 (continued)
1
2
3
4
15
1679 (C=O),
1521 (NO2 asym.),
1334 (NO2 sym.)
278.5 (4.58)
7.23-8.35 (13H, m, ArH)
16
17
18
1678 (C=O)
225 (4.44)
225 (4.49)
293 (4.39)
2.30 (3H, s, CH3);
7.00- 8.36 (13H, m, ArH)
1678 (C=O)
2.33 (3H, s, CH3);
7.00- 8.35 (12H, m, ArH)
1683 (C=O),
1521 (NO2 asym.),
1347 (NO2 sym.)
2.34 (3H, s, CH3);
6.99- 8.35 (12H, m, ArH)
19
20
21
1682 (C=O), 1250 (Ar–O),
1025 (O–Me)
—
3.81 (3H, s, OCH3);
6.85-8.35 (13H, m, ArH)
1685 (C=O), 1248 (Ar–O),
1024 (O–Me)
230.5 (4.53)
230.5 (4.65)
3.79 (3H, s, OCH3);
6.87-8.33 (12H, m, ArH)
1679 (C=O),
1250 (Ar–O),
1022 (O–Me)
3.78 (3H, s, OCH3);
6.82-8.35 (12H, m, ArH)
22
23
24
25
26
1675 (C=O)
1676 (C=O)
1682 (C=O)
1683 (C=O)
228.5 (4.58)
280 (4.31)
6.96-8.33 (13H, m, ArH)
—
229 (4.44)
7.16-8.46 (13H, m, ArH)
7.12-8.45 (12H, m, ArH)
228.5 (4.75)
282.5 (4.47)
3267 (NH, b), 1686 (C=O),
1331 (SO2 asym.),
2.91 (3H, s, CH3); 6.85 (1H, br.s, NH);
6.98-8.34 (13H, m, ArH)
1146 (SO2 sym.)
27
28
3269 (NH, b), 1684 (C=O),
1332 (SO2 asym.),
—
2.96 (3H, s, CH3); 6.48 (1H, br.s, NH);
7.14-8.36 (13H, m, ArH)
1150 (SO2 sym.)
3385 (NH), 1685 (C=O)
279.5 (4.34)
2.10 (3H, s, CH3);
7.13-8.34 (14H, m, ArH, NH)
TABLE 3. In vitro COX-2 Inhibition and in vivo Anti-inflammatory Data for
Substituted 2,3-Diaryl-4(3H)-quinazolinones 11-28
Anti-inflammatory activity
Compound
1
COX-2 % inhibition*
2
Dose, mg/kg
3
% Edema inhibition*2
4
11
12
13
14
15
16
17
18
19
20
IA
IA
50
50
50
50
50
50
50
50
50
50
5.2
4.1
8.6
5.3
IA
10.1
8.7
3.37
4.2
IA
IA
6.2
27.72
IA
35.7
0.0
IA
5.9
1042

TABLE 3 (continued)
1
2
3
4
21
IA
8.82
IA
50
50
50
50
50
50
50
50
25
8.9
18.5
7.6
22
23
24
IA
6.9
25
26
27
12
IA
22.8
8.2
8.05
IA
87.2
16.2
9.36
70
28
Valdecoxib
_______
* Compounds were screened for inhibitory activity on COX-2 at a
concentration of 22 µM. IA: inactive at a concentration of 22 µM.
*2 Carrageenan-induced rat paw edema assay.
EXPERIMENTAL
The yields reported here are unoptimized. Melting points were determined using a heating block-type
melting point apparatus and are uncorrected. Purity of the compounds and reactions were monitored by thin-
layer chromatography (TLC) on silica gel plates (60 F254, Merck), visualizing with ultraviolet light or iodine
vapors. The UV spectra were recorded on a Shimadzu UV-1601 spectrophotometer, and the values in
parentheses indicate the log of molar extinction coefficients. The IR spectra were recorded using the KBr disc
1
method on a Shimadzu FT-IR model 8300. The H NMR spectra were recorded on a Brucker 300 MHz
spectrometer in CDCl3. The final compounds were purified by passing through a silica gel H (100-200 mesh)
purifying column, using a mixture of ethyl acetate and petroleum ether or chloroform alone as eluents before
submitting for elemental analysis.
Syntheses of Substituted 2-Aryl-3,1-benzoxazin-4(3H)-ones 8. Representative preparation of
2-(4-fluorophenyl)-3,1-benzoxazin-4(3H)-one. A mixture of 4-fluorobenzoic acid (5 g, 35.69 mmol) and thionyl
chloride (5 ml) was refluxed in a round bottom flask (50 ml) for 3 h under anhydrous conditions. Excess of
thionyl chloride was removed under vacuum. A solution of anthranilic acid 6 (5.0 g, 36.50 mmol) in dry pyridine
(15 ml) was added dropwise to a stirred solution of the above acid chloride in dry pyridine (15 ml) at a
temperature below 10°C over a period of 15 min under anhydrous conditions. After complete addition the
reaction mixture was stirred for 4 h at room temperature. The reaction mixture was poured into crushed ice
(500 g). The precipitated solid was filtered, washed with aqueous sodium bicarbonate (5%) followed by water,
and dried. The crude product was crystallized from acetone to yield the title compound (6.00 g, 68%);
mp 174-176°C. Rf 0.65 (chloroform). IR spectrum, ν, cm-1: 1762 (carbonyl of lactone), 1625, 1591, 1507, 1472,
and 772. UV spectrum (MeOH), λmax, nm (log ε): 271 (4.12).
Syntheses of Substituted Diamides 10. 2-(4-Fluorobenzamido)-N-(4-methoxyphenyl)benzamide. A
mixture of 2-(4-fluorophenyl)-3,1-benzoxazin-4(3H)-one (1.0 g, 4.15 mmol) and 4-anisidine (2.0 g, 16.26 mmol)
was heated on a water bath for 4 h. The reaction mixture was suspended in methanol, and the solid was filtered,
washed repeatedly with methanol, and dried to yield the title compound: 1.10 g, 73%. IR spectrum, ν, cm-1: 3294
(NH stretching), 1656 (amide peak), 1236, 1180, 1033, 825, and 750.
Syntheses of Substituted 2,3-Diaryl-4(3H)-quinazolinones 11-24. A. Representative preparation of
2-(4-fluorophenyl)-3-(4-methoxyphenyl)-4(3H)-quinazolinone 21. 2-(4-Fluorobenzamido)-N-(4-methoxyphenyl)-
benzamide (0.5 g, 1.37 mmol) was fused in the presence of anhydrous zinc chloride (0.1 g) on a diethylene
1043

glycol (digol) bath at its boiling point for 10 min. The reaction mixture was suspended in water, and the resulting
solid was filtered and dried. The product so obtained was passed through a purifying column of silica gel (100-
200 mesh) using chloroform as a mobile phase. The product was crystallized from methanol to give compound
21. The physical and analytical data are given in Tables 1 and 2.
2-(4-Chlorophenyl)-3-(2-pyridyl)-4(3H)-quinazolinone 25. B. A mixture of 2-(4-chlorophenyl)-3,1-
benzoxazin-4(3H)-one (0.6 g, 2.33 mmol) and 2-aminopyridine (0.25 g, 2.66 mmol) was fused on digol bath for
half an hour. The crude product obtained from the reaction mixture was crystallized from methanol to afford
compound 25.
2-(4-Methanesulfonamidophenyl)-3-phenyl-4(3H)-quinazolinone 26. Sodium chloride (1.0 g) and
iron powder (1.0 g) were added in parts to a refluxing solution of 2-(4-nitrophenyl)-3-phenyl-4(3H)-
quinazolinone 13 (0.5 g, 1.46 mmol) in aqueous methanol (200 ml, 95%). Refluxing was continued further for 7
h. The reaction mixture was filtered through a filtering aid (high flow supercel), and the filtrate was concentrated
in vacuo to remove methanol. The resulting aqueous solution was neutralized by adding sodium bicarbonate and
extracted with chloroform (3 × 25 ml). The combined organic extract was dried and the solvent removed to
obtain a sticky residue. This residue was dissolved in dry pyridine (2 ml) and cooled on an ice bath, and mesyl
chloride (0.4 ml) was added dropwise with stirring. The stirring was continued for 4 h at room temperature. The
reaction mixture was poured into crushed ice (50 g) containing concentrated hydrochloric acid (5 ml). The solid
so obtained was filtered, dried, and crystallized from methanol to yield compound 26.
Compound 27 was prepared similarly starting with compound 14, and compound 28 was prepared by
replacing mesyl chloride with acetic anhydride.
Assay of in vitro COX-2 Inhibition [12]. The final compounds were evaluated for their ability to inhibit
ovine COX-2 enzyme (percent inhibition at 22 µM). Inhibition of the enzyme was determined using a
colorimetric COX (ovine) inhibitor screening assay kit (Catalog No. 760111, Cayman Chemicals, Ann Arbor,
MI, USA) following the procedure described in the catalog.
Assay of in vivo Carrageenan-induced Rat Paw Edema. Anti-inflammatory activity was determined
using the carrageenan-induced rat paw edema method [13] applying a plethysmometer (UGO-Basil, Italy).
The authors are grateful to the All India Council for Technical Education (AICTE) for the award of a
National Doctoral Fellowship (NDF) to S.T.S.
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