Synthesis, analgesic and anti-inflammatory evaluation of some new 3H-quinazolin-4-one derivatives

Article abstract of DOI:10.1002/ardp.200700271

In this study, we have synthesized a series of 3H-quinazolin-4-ones in order to obtain new compounds with potential analgesic and anti-inflammatory activity. The structures of the newly synthesized compounds were confirmed by means of infrared, nuclear magnetic resonance and mass spectroscopy. Some compounds were evaluated for their analgesic and anti-inflammatory activities by writhing and carrageenan-induced rat paw edema tests, respectively. In comparison to the standard drug indomethacine, compounds 4, 6c, 12-14, 16, 18, 19, and 22 induced significant reduction in the writhing response while compounds 6c, 12, 14, 16, 18, and 22 produced a good dose-dependent anti-inflammatory activity. The best dual analgesic/anti-inflammatory relative activity was observed with compounds 6c, 14, 16, 18, and 22.

Full text of DOI:10.1002/ardp.200700271

Arch. Pharm. Chem. Life Sci. 2008, 341, 377–385
A. M. Alafeefy et al.
377
Full Paper
Synthesis, Analgesic and Anti-Inflammatory Evaluation of
Some New 3H-Quinazolin-4-one Derivatives
Ahmed M. Alafeefy1, Adnan A. Kadi1, Adel S. El-Azab1, Sami G. Abdel-Hamide1,
and Mohamad-Hesham Y. Daba2
1 Department of Pharmaceutical Chemistry, King Saud University, Riyadh, Saudi Arabia
2 Department of Clinical Pharmacy College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
In this study, we have synthesized a series of 3H-quinazolin-4-ones in order to obtain new com-
pounds with potential analgesic and anti-inflammatory activity. The structures of the newly syn-
thesized compounds were confirmed by means of infrared, nuclear magnetic resonance and
mass spectroscopy. Some compounds were evaluated for their analgesic and anti-inflammatory
activities by writhing and carrageenan-induced rat paw edema tests, respectively. In comparison
to the standard drug indomethacine, compounds 4, 6c, 12–14, 16, 18, 19, and 22 induced signifi-
cant reduction in the writhing response while compounds 6c, 12, 14, 16, 18, and 22 produced a
good dose-dependent anti-inflammatory activity. The best dual analgesic / anti-inflammatory rel-
ative activity was observed with compounds 6c, 14, 16, 18, and 22.
Keywords: Analgesic / Anti-inflammatory / COX-inhibitors / Oxadiazole / 3H-Quinazolin-4-one /
Received: December 22, 2007; accepted: February 11, 2008
DOI 10.1002/ardp.200700271
So far, one has paid attention to various substituted
1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-triazol-5-thio-
nes, and their condensed derivatives as anti-inflamma-
tory agents [5, 6]. Moreover, several 3H-quinazolin-4-one
derivatives have shown analgesic and anti-inflammatory
activities [7–10]. Recently, reduction of prostaglandin-E2
production [11] and inhibition of pro-inflammatory cyto-
kines transcription were reported for a variety of substi-
tuted quinazoline derivatives [12].
From the literature review, we noticed that most of the
previously reported quinazolines with anti-inflamma-
tory activity had 6-F, 6-Cl, 6-Br, 6-CH3, 6-OCH3 substituent
and the 2-position was substituted with phenyl, thienyl,
aliphatic, or alicyclic moieties [5–12].
Based on the present facts, it was decided to prepare
some new 2,3,6-trisubstituted quinazoline derivatives for
evaluation as potential anti-inflammatory agents where
we kept a 4-chlorophenyl moiety at the 2-position and
the 6-position was substituted with an iodine atom, as
the 6-iodo-quinazolines are not fully explored for this
activity, while the 3-position was substituted with some
heterocycles which are known to add to the analgesic
and anti-inflammatory activities.
Introduction
Non steroidal anti-inflammatory drugs (NSAIDs) have a
long history. They exert excellent analgesic action with
relatively high safety; therefore, they are used to reduce
pain and swelling associated with many diseases [1]. They
exert their therapeutic effect through down-regulation
of prostaglandin synthesis by inhibiting the two isoforms
of the cyclooxygenase enzymes (COX-1 and COX-2) in the
arachidonic acid metabolism [2].
Although these drugs are generally well tolerated in
patients with arthritic conditions, a high incidence of
gastrointestinal side effects, such as mucosal lesions,
hemorrhage, and ulceration has been a serious problem
in their medication [3, 4]. These current therapeutic defi-
ciencies intensify the need to develop safer drugs.
Correspondence: Ahmed M. Alafeefy, Department of Pharmaceutical
Chemistry, King Saud University, Riyadh 11451, P. O. Box 2457, Saudi
Arabia.
E-mail: aalafeefy@yahoo.com
Fax: +9661 4676220
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378
A. M. Alafeefy et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 377–385
Scheme 1. Synthesis route of compounds 1–9.
3 with carbon disulphide and potassium hydroxide in
boiling ethanol. Boiling 4 with hydrazine hydrate in
ethanol afforded the corresponding 3-[1-(4-amino-5-mer-
capto-4H-1,2,4-triazol-3-yl)-ethyl]-2-(4-chlorophenyl)-6-
iodo-3H-quinazolin-4-one 5 [15]. Alkylation of 4 using
methyl iodide, chloroacetonitrile, or benzyl bromide
yielded the corresponding 2-(4-chlorophenyl)-6-iodo-3-[1-
(5-substituted thio-1,3,4-oxadiazol-2-yl)-ethyl]-3H-quinazo-
lin-4-one 6a–c. Condensation of 3 with 4-chlorobenzalde-
hyde in acetic acid produced the corresponding N9-(4-
chlorobenzylidine)-2-[2-(4-chlorophenyl)-6-iodo-4-oxo-4H-
quinazolin-3-yl]-propionic acid hydrazide 7. Treating 7
with excess acetic anhydride afforded the corresponding
3-{1-[4-acetyl-5-(4-chlorophenyl)-4,5-dihydro-1,3,4-oxadia-
Results and discussion
Chemistry
2-(4-Chlorophenyl)-6-iodo-3H-quinazolin-4-one 1 was pre-
pared by adopting the procedure of Jiang et. al. [13]. Com-
pound 2 was prepared in our laboratory [14] by alkylation
of 1 at room temperature and ethyl 2-[2-(4-chlorophenyl)-
6-iodo-4-oxo-4H-quinazolin-3-yl]-propionate 2 was obtain-
ed in a considerable yield. Hydrazinolysis of 2 afforded
the key intermediate 2-[2-(4-chlorophenyl)-6-iodo-4-oxo-
4H-quinazolin-3-yl]-propionic acid hydrazide 3.
2-(4-Chlorophenyl)-6-iodo-3-[1-(5-mercapto-1,3,4-oxadia-
zol-2-yl)-ethyl]-3H-quinazolin-4-one 4 was obtained in
nearly quantitative yield by the interaction of compound
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Arch. Pharm. Chem. Life Sci. 2008, 341, 377–385
New Quinazoline-4(3H)-One Derivatives
379
Table 1. Melting points, yield percentages, molecular formulas,
and microanalytical data of compounds 3–22.a)
phenyl-4-{2-[2-(4-chlorophenyl)-6-iodo-4-oxo-4H-quinazo-
lin-3-yl)-ethyl]-propionyl}-2-thiosemicarbazide 15.
Compound 16, 2-(4-chlorophenyl)-6-iodo-3-[1-(5-phenyl-
amino-1,3,4-oxadiazol-2-yl)-ethyl]-3H-quinazolin-4-one,
was prepared adopting the procedures cited in the litera-
ture [16]. However, cyclization of 15 under alkaline condi-
tions gave 3-[1-(phenyl-5-mercapto-4H-1,2,4-triazol-3-yl-
ethyl]-2-(4-chlorophenyl)-6-iodo-3H-quinazolin-4-one 17.
On the other hand, cyclo-condensation reaction under
acidic conditions afforded 2-(4-chlorophenyl)-6-iodo-3-[1-
(5-phenylamino-1,3,4-thiadiazole-2-yl)-ethyl]-3H-quinazo-
lin-4-one 18 when following the literature procedures
[17] (Scheme 2, Table 1).
Compound
Mol. Formula
Mp. (8C)
Yield (%)
3
4
5
6a
6b
6c
7
C17H14ClIN4O2
C18H12ClIN4O2S
C18H14ClIN6OS
C19H14ClIN4O2S
C20H13ClIN5O2S
C25H18ClIN4O2S
C24H17Cl2IN4O2
C26H19Cl2IN4O3
C26H19Cl2IN4O3S
C18H14ClIN4O3
C20H18ClIN4O3
C18H12ClIN4O2
C18H12ClIN4OS
C24H16ClIN4O2
C24H19ClIN5O2S
C24H17ClIN5O2
C24H17ClIN5OS
C24H17ClIN5OS
C19H12ClIN6OS
C20H14ClIN6OS
C26H18ClIN6OS
C33H24ClIN6OS
157-9
270-2
255-7
215-7
219-21
226-28
280-2
232-4
211-3
283-5
202-4
216-8
216-8
243-5
259-61
250-2
206-8
251-3
274-6
277-9
233-5
247-9
85
74
65
68
65
80
83
88
35
67
48
40
36
30
80
54
50
51
45
50
72
36
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
The compounds 19, 5-{1-[2-(4-chlorophenyl)-6-iodo-4-
oxo-3H-quinazolin-3-yl)]-ethyl}-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazole, and 20, 5-{1-[2-(4-chlorophenyl)-6-
iodo-4-oxo-3H-quinazolin-3-yl)]-ethyl}-2-methyl-1,2,4-tria-
zolo[1,3,4-b][1,3,4]thiadiazole, were prepared by heating
compound 5 with formic acid and acetic anhydride,
respectively. Compound 5 was reacted with phenacyl bro-
mide adopting the reported procedure [18] to furnish the
corresponding 6-{1-[2-(4-chlorophenyl)-6-iodo-4-oxo-3H-
quinazolin-3-yl)]-ethyl}-3-phenyl-7H-1,2,4-triazolo[3,4-b]
[1,3,4]thiadiazole 21. 7-{1-[2-(4-Chlorophenyl)-6-iodo-4-
oxo-3H-quinazolin-3-yl)]-ethyl}-2,4-diphenyl-7,8-dihydro-
1,2,4-triazolo[3,4-b][1,3,4]thiadiazoine 22 was obtained
through reaction of compound 5 with 1,3-diphenyl-2-pro-
penone in acetic acid (Scheme 3, Table 1).
a)
Analytical data (C, H, N) were within l 0.4% of theoretical val-
ues.
zol-2-yl]-ethyl}-2-(4-chlorophenyl)-6-iodo-3H-quinazolin-4-
one 8, while condensation of 7 with thioglycolic acid
yielded the corresponding 2-[2-(4-chlorophenyl)-6-iodo-4-
oxo-4H-quinazolin-3-yl]-N-[2-(4-chlorophenyl)-4-oxo-thia-
zolidin-3-yl]-propionamide 9 (Scheme 1, Table 1).
Pharmacological results
Nineteen compounds (4–9, 12–22) were initially eval-
uated for their analgesic activity using the acetic acid-
induced writhing response in albino mice. The results
are shown in Table 2.
Compound 12, 2-(4-chlorophenyl)-6-iodo-3-(1-[1,3,4]oxa-
diazol-2-yl-ethyl)-3H-quinazolin-4-one, was obtained from
the hydrazide 3 via two routes: Following the first route,
2-[2-(4-chlorophenyl)-6-iodo-4-oxo-4H-quinazolin-3-yl]-pro-
pionic acid hydrazide 3 was boiled with formic acid to
afford N9-formyl 2-[2-(4-chlorophenyl)-6-iodo-4-oxo-4H-qui-
nazolin-3-yl]propionic acid hydrazide 10, dehydrative
cyclization of 10 was accomplished using phosphorus
pentoxide to afford 12. Using the second route, the hydra-
zide 3 was boiled with excess triethylorthoformate to
afford the corresponding N9-ethoxymethylene-2-[2-(4-
chlorophenyl)-6-iodo-4-oxo-4H-quinazolin-3-yl]propionic
acid hydrazide 11. Heating the latter compound above its
melting point yielded 12. Treating 10 with phosphorus
pentasulphide afforded 2-(4-chlorophenyl)-6-iodo-3-(1-
[1,3,4]thiadiazole-2-yl-ethyl)-3H-quinazolin-4-one 13. The
hydrazide 3 was also reacted with benzoic acid in the
presence of phosphorus oxychloride to afford 2-(4-chloro-
phenyl)-6-iodo-3-[1-(5-phenyl-1,3,4-oxadiazol-2-yl)-ethyl]-
3H-quinazolin-4-one 14.
Nine compounds 4, 6c, 12–14, 16, 18, 19, and 22
induced significant reduction in the writhing response
in comparison to control and to the reference drug Indo-
methacine as follows (4, 67.77%), (6c, 81.67%), (12,
66.18%), (13, 57.26%), (14, 50.18%), (16, 86.06%), (18,
83.71%), (19, 50.00%), (22, 79.60%), and Indomethacine
(91.28%). Since these nine compounds showed significant
analgesic activity, we decided to evaluate their anti-
inflammatory profile by means of the carrageenan-
induced rat paw edema test and the results are summar-
ized in Table 3. Compounds 6c, 12, 14, 16, 18, and 22
showed significant anti-inflammatory activity in compar-
ison to control and the reference drug Indomethacine.
The other compounds were inactive. However, none of
the screened compounds were found to be as potent as
the reference drug.
The pharmacological results of the present study
showed good analgesic profile and moderate anti-inflam-
Condensation of the hydrazide 3 with phenylisothio-
cyanate resulted in the formation of the corresponding 1-
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380
A. M. Alafeefy et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 377–385
Scheme 2. Synthesis route of compounds 10–18.
matory activity in comparison to the well known analge- matory activity in the carrageenan-induced rat paw
sic and anti-inflammatory drug Indomethacinem. edema test. The best dual analgesic and anti-inflamma-
The oxadiazole derivatives 6c, 12, 14, 16, the thiadia- tory activity was observed with compounds 6c, 14, 16, 18,
zole derivatives 13, 18, the fused 1,2,4-triazolo[3,4- and 22. The triazole derivatives 5, 17, 19–21, and the thio-
b][1,3,4]thiadiazole derivative 19, and the diazepine semicarbazide derivative 15 were practically inactive.
derivative 22 showed significant analgesic activity pro-
The structure-activity correlation of the synthesized
ducing more than 50% inhibition in the writhing test. compounds revealed that the activity is dependant on
Meanwhile, the oxadiazole derivatives 6c, 12, 14, 16, the the basic skeleton; some of the oxadiazoles and the thia-
thiadiazole derivative 18, and the thiadiazepine deriv- diazoles are active whereas the triazoles and the acyclic
ative 22 showed significant dose-dependant anti-inflam- thiosemicarbazides are inactive. In the oxadiazole as well
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Arch. Pharm. Chem. Life Sci. 2008, 341, 377–385
New Quinazoline-4(3H)-One Derivatives
381
Scheme 3. Synthesis route of compounds 19–22.
as in the thiadiazole derivatives it seemed that 5-phenyl- inflammatory reactions to activate immune cells by
amino – and to less extent 5-phenyl – moieties promote mechanisms either related or unrelated to their enzy-
the activity.
matic activity. Thus, inhibition of these molecules will
Since in-vivo activity depends on highly complex phys- lead to alleviation of various metabolic disorders.
iological interactions in addition to the high number of
enzyme/receptors involved in the inflammatory process,
it is quite difficult, therefore, to hypothesize a mecha-
nism of action without specific tests. These compounds
Experimental
may exert their action via inhibition of cyclooxygenase
enzyme isoforms like other NSAIDs. In addition, the
Chemistry
General
recently reported activity of some quinazoline deriv-
atives as potent inhibitors for the production of pro-
inflammatory cytokines, tumor necrosis factor-a (TNF-a),
and chemokines, interleukin, IL8 (CXCL8), should be
taken into consideration [13, 14, 19]. Pro-inflammatory
cytokines and chemokines are enzymes released during
All melting points (in 8C and uncorrected) were determined
using a Gallenkamp melting point apparatus (Weiss-Gallen-
kamp, London, UK). NMR spectra were run on a Bruker AC 500
ultra Shield NMR spectrometer at 500 MHz for 1H- and 125 MHz
for 13C-NMR (Bruker Bioscience, Billerica, MA USA), the chemical
shifts are expressed in d (ppm) downfield from tetramethylsilane
(TMS), in dimethylsulfoxide (DMSO)-d6 as solvent. Silica gel
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382
A. M. Alafeefy et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 377–385
Table 2. Effects of compounds that showed activity in the
abdominal constrictions induced by acetic acid in mice.
133, 139, 147, 152, 154, 163, 166, 170 (Ar-C). MS, m/z (Rel. Int.):
468 [M+ + 2] (32), 466 [M+] (100).
Compound
Control
Indomethacine 10
4
Dose
(mg/kg)
Analgesic
activitya)
Inhibitionb) Relative
2-(4-Chlorophenyl)-6-iodo-3-[1-(5-mercapto-1,3,4-
oxadiazol-2-yl)-ethyl]-3H-quinazolin-4-one 4
(%)
activity
–
71.47c) l 3.0
–
–
A mixture of the hydrazide 3 (4.68 g, 0.01 mol), carbon disul-
phide (1.14 g, 0.015 mol) and potassium hydroxide (0.84 g,
0.015 mol) was heated under reflux in ethanol for 6 h. After
removal of the solvent, the residual solid was dissolved in water,
acidified with dilute hydrochloric acid, and the precipitated
solid was filtered, washed with water, and crystallized from
ethanol. 1H-NMR: 1.15 (d, 3H, CH3), 3.45 (s, 1H, SH, D2O exchang.)
3.71 (q, 1H, CH), 7.25–8.11 (m, 7H, Ar-H). 13C-NMR: 23 (CH3), 45
(CH), 100, 118, 120, 170, 131, 137, 139, 143, 168, 170, 173 (Ar-C &
oxadiazole-C). MS, m/z (Rel. Int.): 512 [M+ + 2] (0.85), 510 [M+]
(2.34), 102 (100), 383 (32.9), 381 (97.4).
6.23c) l 2.58 91.28
23.03c) l 4.42 67.77
13.10c) l 3.25 81.67
24.17c) l 4.11 66.18
30.54c) l 3.37 57.26
35.60c) l 3.08 50.18
9.96c) l 2.02 86.06
11.64c) l 2.96 83.71
35.70c) l 3.75 50.00
14.58c) l 3.75 79.60
1
40
40
40
40
40
40
40
40
40
0.74
0.89
0.75
0.63
0.55
0.94
0.91
0.54
0.87
6c
12
13
14
16
18
19
22
a)
b)
Number of writhing reflexes induced by acetic acid (ip.).
Results are expressed as mean l S. E. M. (n = 6) and compared
with ANOVA test.
3-[1-(4-Amino-5-mercapto-4H-1,2,4-triazol-3-yl)-ethyl]-2-
(4-chlorophenyl)-6-iodo-3H-quinazolin-4-one 5
c)
Significantly different from control at P a 5%.
Carbon disulphide (1.14 g, 0.015 mol) was added to a solution of
the hydrazide 3 (4.68 g, 0.01 mol) and potassium hydroxide
(0.84 g, 0.015 mol) in ethanol (50 mL) with continuous stirring
at room temperature. Stirring was continued for 5 h, the precipi-
tated solid was filtered, washed with ether, dried, suspended in
98% hydrazine hydrate (10 mL), and heated under reflux for 2 h.
On cooling, the mixture was diluted with water (200 mL) and
neutralized with 10% hydrochloric acid. The precipitated solid
was filtered, washed with water, dried, and crystallized from
ethanol. 1H-NMR: 1.13 (d, 3H, CH3), 1.92 (s, 1H, SH, D2O-exchang.),
2.21 (q, 1H, CH), 5.78 (s, 2H, NH2, D2O-exchang.), 7.15–7.32 (m,
7H, Ar-H). MS, m/z (Rel. Int.): 526 [M+ + 2] (35.15), 524 [M+] (100),
409 (5.61), 383 (21.76), 381 (64.32).
Table 3. Anti-inflammatory effects of various doses of com-
pounds (4, 6c, 12–14, 16, 18, 19, 22) and Indomethacine
against carrageenan-induced rat paw edema
Compounds
% Reduction of paw edema from controla)
20 mg/kg
–
40 mg/kg
–
60 mg/kg
Control
–
Indomethacineb) 66.95c) l 3.24 66.95c) l 3.24
66.95c) l 3.24
13.05 l 3.98
64.21c) l 3.95
50.15c) l 3.88
20.66 l 4.70
57.08c) l 4.88
70.85c) l 3.13
71.81c) l 3.25
21.15 l 3.90
50.83c) l 4.88
4
6c
12
13
14
16
18
19
22
11.67 l 3.27
13.71 l 3.38
37.33c) l 4.09 50.29c) l 3.78
30.62c) l 3.70 42.91c) l 3.06
12.51 l 5.12 20.38c) l 4.27
34.12c) l 4.19 45.64c) l 4.30
46.49c) l 3.95 67.36c) l 4.36
37.58c) l 3.87 56.65c) l 3.41
2-(4-Chlorophenyl)-6-iodo-3-[1-(5-substituted thio-1,3,4-
oxadiazol-2-yl)-ethyl]-3H-quinazolin-4-one 6a–c
A mixture of 5 (2.85 g, 0.005 mol), anhydrous potassium carbo-
nate (0.3 g) and the appropriate alkyl halide (0.01 mol) in ace-
tone (25 mL) was refluxed for 6 h. The reaction mixture was fil-
tered while hot, the filtrate was cooled, and the precipitated
solid was filtered and crystallized from methanol. 6a: 1H-NMR:
1.37 (d, 3H, CH3), 2.55 (s, 3H, CH3), 4.82 (q, 1H, CH), 7.34–8.09 (m,
7H, Ar-H). MS, m/z (Rel. Int.): 526 [M+ + 2] (8.12), 524 [M+] (26), 409
9.11 l 2.95
18.10 l 3.87
33.65c) l 3.92 46.05c) l 4.05
a)
Results are expressed as mean l S. E. M. (n = 6) and compared
with ANOVA test.
Indomethacine dose 10 mg/kg.
b)
c)
1
(18.61), 383 (23.50), 381 (69.33), 115 (100). 6b: H-NMR: 1.36 (d,
Significantly different from control at P a 5%.
3H, CH3), 4.29 (s, 2H, CH2), 4.79 (q, 1H, CH), 7.27–7.85 (m, 7H, Ar-
H). MS, m/z (Rel. Int.): 551 [M+ + 2] (6.92), 549 [M+] (24.39), 523
(13.61), 102 (100). 6c: 1H-NMR: 1.36 (d, 3H, CH3), 4.05 (s, 2H, CH2),
4.85 (q, 1H, CH), 7.27–8.05 (m, 12H, Ar-H). MS, m/z (Rel. Int.): 602
[M+ + 2] (9.82), 600 [M+] (31.36), 92 (100).
plates 60 F254 (Merck, Darmstadt, Germany) were used for moni-
toring the reaction. Mass spectra were obtained on Kratos MS 50-
spectrometer (Kratos Analytical, Manchester, UK) at 70 eV. Ana-
lytical data (C, H, N) were within l 0.4% of the theoretical values.
N9-(4-Chlorobenzylidene)-2-[2-(4-chlorophenyl)-6-iodo-4-
oxo-4H-quinazolin-3-yl]-propionic acid hydrazide 7
2-[2-(4-Chlorophenyl)-6-iodo-4-oxo-4H-quinazolin-3-yl]-
propionic acid hydrazide 3
To a hot ethanolic solution of the hydrazide 3 (0.94 g, 0.02 mol),
4-chlorobenzaldehyde (0.40 g, 0.003 mol) was added; the reac-
tion mixture was then heated under reflux for 3 h. The solid sep-
arated upon cooling was filtered, dried, and crystallized from
A mixture of compound 2 (4.81g, 0.01 mol) and 98% hydrazine
hydrate (0.5 g, 0.015 mol) in ethanol (10 mL) was refluxed for
2 h. The solvent was evaporated under reduced pressure, the
obtained solid was washed with water and crystallized from
ethanol. 1H-NMR: 1.37 (d, 3H, CH3), 3.43 (d, 2H, NH2, D2O
exchang.) 4.55 (q, 1H, CH), 7.25–8.20 (m, 7H, Ar-H), 8.31 (t, 1H, N,
D2O exchang.). 13C-NMR: 18 (CH3), 50 (CH), 99, 126, 127, 129, 130,
1
ethanol. H-NMR: 1.52 (d, 3H, CH3), 5.05 (q, 1H, CH), 7.15–8.11
(m, 12H, Ar-H & =C-H), 8.66 (bs, 1H, NH, D2O-exchange). MS, m/z
(Rel. Int.): 594 [M+ + 4] (2.87), 592 [M+ + 2] (17.61), 590 [M+] (26.11),
383(32.61), 381 (100).
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Arch. Pharm. Chem. Life Sci. 2008, 341, 377–385
New Quinazoline-4(3H)-One Derivatives
383
solid was purified by preparative TLC using hexane / ethyl ace-
tate 3 : 1 as eluent to afford 12 with the same physical constants
and in a comparable yield with that obtained by route A.
3-{1-[4-Acetyl-5-(4-chlorophenyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl]-ethyl}-2-(4-chlorophenyl)-6-iodo-3H-
quinazolin-4-one 8
The hydrazone 7 (0.59 g, 0.001 mol) was heated under reflux in
acetic anhydride (5 mL) for 30 min. On cooling, the mixture was
poured onto crushed ice (100 g). The separated solid was filtered,
washed with water, dried, and crystallized from acetic acid. 1H-
NMR: 1.13 (d, 3H, CH3), 2.19 (s, 3H, CH3), 4.21 (q, 1H, CH), 6.28 (s,
1H, oxadiazolidine-H), 7.13–8.29 (m, 11H, Ar-H). MS, m/z (Rel.
Int.): 636 [M+ + 4] (5.05), 634 [M+ + 2] (15.91), 632 [M+] (25.08), 383
(32.81), 381 (100).
2-(4-Chlorophenyl)-6-iodo-3-(1-[1,3,4]thiadiazole-2-yl-
ethyl)-3H-quinazolin-4-one 13
A mixture of 10 (0.49 g, 0.001 mol) and phosphorus pentasulfide
(2.20 g, 0.01 mol) in xylene was refluxed for 1 h. The solvent was
removed under reduced pressure and the residue was triturated
with ethanol and filtered. The collected solid was crystallized
from dioxane. MS, m/z (Rel. Int.): 496 [M+ + 2] (8.36), 494 [M+]
25.35), 383 (25.58), 381 (70.28), 114 (100).
2-[2-(4-Chlorophenyl)-6-iodo-4-oxo-4H-quinazolin-3-yl]-
N-[2-(4-chlorophenyl)-thiazolidin-3-yl]-propionamide 9
A mixture of the hydrazone 8 (0.59 g, 0.001 mol) and thiogly-
colic acid (0.18 g, 0.002 mol) and anhydrous sodium acetate
(1.0 g) in dry toluene (10 mL), was refluxed for 10 h and the mix-
ture was then filtered while hot. The filtrate was evaporated
under reduced pressure and the obtained solid was crystallized
from dioxane.1H-NMR: 1.35 (d, 3H, CH3), 3.08 (s, 2H, thiazolidine-
CH2), 4.66 (q, 1H, CH), 5.78 (s, 1H, thiazolidine-CH), 7.13–8.12 (m,
11H, Ar-H), 8.65 (bs, 1H, NH, D2O-exchange). MS, m/z (Rel. Int.):
668 [M+ + 4] (311), 666 [M+ + 2] (17.75), 664 [M+] (25.15), 383 (8.31),
381 (21.31), 213 (100).
2-(4-Chlorophenyl)-6-iodo-3-[1-(5-phenyl-1,3,4-
oxadiazol-2-yl)-ethyl]-3H-quinazolin-4-one 14
A mixture of the hydrazide 3 (0.46 g, 0.001 mol) and benzoic
acid (0.12 g, 0.001 mol) in phosphorus oxychloride (5 mL) was
refluxed for 2 h. The reaction mixture was quenched with ether.
The precipitated solid was filtered off, washed with water, and
crystallized from ethanol. 1H-NMR: 1.50 (d, 3H, CH3), 4.66 (q, 1H,
CH), 7.32–8.21 (m, 12H, Ar-H). MS, m/z (Rel. Int.): 556 [M+ + 2]
(7.61), 554 [M+] (20.43), 383 (8.27), 381 (26.31), 145 (100).
N9-Formyl-2-[2-(4-chlorophenyl)-6-iodo-4-oxo-4H-
quinazolin-3-yl]propionic acid hydrazide 10
1-Phenyl-4-{2-[2-(4-chlorophenyl)-6-iodo-4-oxo-4H-
quinazolin-3-yl)ethyl]propionyl}-2-thiosemicarbazide 15
A mixture of the hydrazide 3 (0.46 g, 0.001 mol) phenylisothio-
cyanate (014 g, 0.001 mol) in butanol was refluxed for 3 h. The
solvent was removed under reduced pressure. The obtained solid
was filtered, dried, and crystallized from ethanol. MS, m/z (Rel.
Int.): 605 [M+ + 2] (12.28), 603 [M+] (32.70), 383 (6.42), 381 (16.34),
92 (100).
A solution of the hydrazide 3 (0.94 g, 0.002 mol) in formic acid
(20 mL) was refluxed for 30 min. After cooling, the precipitated
solid was filtered, washed with water, and crystallized from
dioxane. 1H-NMR: 1.39 (d, 3H, CH3), 4.26 (bs, 1H, NH, D2O-
exchang.), 4.66 (q, 1H, CH), 7.13–8.12 (m, 7H, Ar-H), 8.45 (bs, 1H,
NH, D2O-exchange), 12.10 (s, 1H, HC=O). MS, m/z (Rel. Int.): 498
[M+ + 2] (6.81), 496 [M+] (21.21), 437 (100).
2-(4-Chlorophenyl)-6-iodo-3-[1-(5-phenylamino-1,3,4-
oxadiazol-2-yl)ethyl]-3H-quinazolin-4-one 16
N9-Ethoxymethylene-2-[2-(4-chlorophenyl)-6-iodo-4-oxo-
4H-quinazolin-3-yl] propionic acid hydrazide 11
Aqueous solution of iodine, potassium iodide mixture (5%,
10 mL) was added dropwise to a solution of 15 (0.30 g,
0.0005 mol) in dimethylformamide (10 mL), and sodium hydrox-
ide (2 N, 10 mL). The mixture was warmed for 3 h with frequent
addition of iodine solution. The solvents were removed, and the
residue was acidified with 10% acetic acid. The obtained solid
was filtered, washed with sodium thiosulfate solution, then
A mixture of the hydrazide 3 (0.94 g, 0.002 mol) and triethylor-
thoformate (5 mL) was refluxed for 30 min. After cooling, the
precipitated solid was filtered, washed with water, and crystal-
lized from ethanol.1H-NMR: 1.12 (t, 3H, CH3), 1.38 (d, 3H, CH3),
3.33 (q, 2H, CH2O), 4.61 (q, 1H, CH), 7.32–8.19 (m, 8H, Ar-H &
N=CH) 8.55 (bs, 1H, NH, D2O-exchang.). MS, m/z (Rel. Int.): 526
[M+ + 2] (10.31), 524 [M+] (27.0), 437 (100).
1
with water, dried, and crystallized from ethanol. H-NMR: 1.52
(d, 3H, CH3), 4.66 (q, 1H, CH), 5.58 (bs, 1H, NH, D2O-exchang.),
7.32–8.21 (m, 12H, Ar-H). MS, m/z (Rel. Int.): 571 [M+ + 2] (33.0),
569 [M+] (100), 383 (25.72), 381 (72.14).
2-(4-Chlorophenyl)-6-iodo-3-(1-[1,3,4]oxadiazol-2-yl-
ethyl)-3H-quinazolin-4-one 12
Route A:
To a solution of 10 (0.52 g, 0.001 mol) in xylene (10 mL), phos-
phorus pentoxide (0.2 g) was added. The reaction mixture was
refluxed for 2 h and filtered while hot. The solvent was evapo-
rated under reduced pressure and the residue was crystallized
from dioxane. 1H-NMR: 1.51 (d, 3H, CH3), 4.64 (q, 1H, CH), 7.32–
8.33 (m, 8H, Ar-H). MS, m/z (Rel. Int.): 480 [M+ + 2] (8.67), 478 [M+]
(23.59), 383 (28.0), 381 (77.32), 98 (100).
3-[1-(Phenyl-5-mercapto-4H-1,2,4-triazol-3-yl-ethyl]-2-(4-
chlorophenyl)-6-iodo-3H-quinazolin-4-one 17
Thiosemicarbazide 15 (0.30 g, 0.0005 mol) was heated under
reflux in sodium hydroxide solution (2 N, 25 mL) for 3 h. The
reaction mixture was cooled and acidified to pH 6 using dilute
hydrochloric acid. The precipitated solid was filtered, washed
with water, dried, and crystallized from dioxane. 1H-NMR: 1.52
(d, 3H, CH3), 3.19 (bs, 1H, SH, D2O-exchang.), 4.66 (q, 1H, CH),
7.20–8.14 (m, 12H, Ar-H). MS, m/z (Rel. Int.): 587 [M+ + 2] (6.82),
585 [M+] (20.0), 383 (21.33), 381 (58.42), 77 (100).
Route B:
Compound 11 (0,526 g, 0.001 mol) was heated at 1808C for
30 min. The reaction mixture was left to cool and the obtained
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www.archpharm.com

384
A. M. Alafeefy et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 377–385
Saud University, Riyadh, Saudi Arabia. Mice were used for writh-
ing (abdominal constriction), while rats were used for the carra-
geenan-induced rat paw edema test. The protocol for this study
was approved by the Research Ethics Committee of the College
of Pharmacy, KSU. All animals were left for two days in the labo-
ratory conditions for acclimatization and had free access to pulv-
erized standard pellet diet and water ad libitum. Animals were
then fasted for 24 h before the experiment. Test and reference
compounds were suspended in 0.5% carboxymethylcellulose,
and all experiments were performed in triplicate.
2-(4-Chlorophenyl)-6-iodo-3-[1-(5-phenylamino-1,3,4-
thiadiazol-2-yl)-ethyl]-3H-quinazolin-4-one 18
The thiosemicarbazide derivative 15 (0.30 g, 0.0005 mol) was
slowly added with stirring to phosphoric acid (85%, 25 mL). The
mixture was refluxed for 30 min and then stirred at room tem-
perature for further 30 min. The precipitated solid was filtered,
washed with water, and crystallized from ethanol. MS, m/z (Rel.
Int.): 587 [M+ + 2] (10.74), 585 [M+] (34.19), 176 (100).
5-{1-[2-(4-Chlorophenyl)-6-iodo-4-oxo-3H-quinazolin-
3-yl)]-ethyl}-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole 19
A mixture of compound 5 (0.52 g, 0.001 mol), formic acid
(10 mL), and phosphorus oxychloride (10 mL) was heated under
reflux for 3 h. Crushed ice (20 g) was then added and the precipi-
tated solid was filtered, washed with water, dried, and crystal-
lized from dioxane. 1H-NMR: 1.57 (d, 3H, CH3), 4.80 (q, 1H,
CHCH3), 7.19-8.22 (m, 8H, Ar-H & =CH)). MS, m/z (Rel. Int.): 536
[M+ + 2] (32.28), 534 [M+] (100), 383 (17.35), 381 (53.26).
Evaluation of analgesic activity
The analgesic activity was determined in mice using acetic acid-
induced writhing response according to Siegmund et. al. [20]
and the results are recorded in Table 2. The test compounds
were administered orally, 40 mg/kg, to six groups of mice. The
first four groups received the test compounds while the fifth
and sixth groups, which served as positive and negative control,
respectively, received 10 mg/kg Indomethacinem and 5.0 mL/kg
vehicle. One hour after treatment, each mouse was injected,
intraperitoneally (ip.), with 0.1 mL of acetic acid (3%) to induce
the characteristic writhing response. The number of writhes
occurring within 30 min was recorded and the mean was com-
pared with that of the control and converted into%-inhibition.
5-{1-[2-(4-Chlorophenyl)-6-iodo-4-oxo-3H-quinazolin-
3-yl)]-ethyl}-2-methyl-1,2,4-triazolo[3,4-b][1,3,4]-
thiadiazole 20
A mixture of compound 5 (0.52 g, 0.001 mol), acetic anhydride
(10 mL) and phosphorus oxychloride (10 mL) was heated under
reflux for 3 h. Ether (20 mL) was then added and the precipitated
solid was filtered, washed with water, dried, and crystallized
from dioxane.1H-NMR: 1.57 (d, 3H, CH3), 2.29 (s, 3H, CH3), 4.81 (q,
1H, CHCH3), 7.19-8.22 (m, 7H, Ar-H). MS, m/z (Rel. Int.): 550
[M+ + 2] (33.50), 548 [M+] (100).
Evaluation of anti-inflammatory activity
The anti-inflammatory activity of eight of the newly synthesized
compounds was determined in rats using the carrageenan-
induced rat paw edema test as described by Winter et. al. [21].
Rats were divided in groups of six animals each. A mark was
made on both the hind paws just below the tibio-tarsal junction
so that each time the paw could be dipped in the mercury col-
umn of plethysmograph up to the mark to ensure constant paw
volume. To each group, except the control group, test com-
pounds were administered orally in three dose levels (20, 40,
60 mg/kg). The control group received an equivalent amount of
vehicle. One group received indomethacine (10 mg/kg). After
one hour, carrageenan (0.1 mL, 1% w/v solution in saline) was
injected into the subplantar tissue of the left hind paw of control
and indomethacine-treated group as well. The same volume of
saline solution was injected into that of the right hind paw to
serve as reference non-inflamed paw for comparison. The initial
paw volume was measured immediately after injection. The dif-
ference in paw volume, 3 h after carrageenan injection, was
measured in control, standard, and treated groups. The percent
reduction in paw volume was calculated from the equation%
anti-inflammatory = [(n– n9)/n]6100, where n was the average
difference in thickness between the left and the right hind paw
of control group and n9 was that of the test group of rats.
6-{1-[2-(4-Chlorophenyl)-6-iodo-4-oxo-3H-quinazolin-
3-yl)]ethyl}-3-phenyl-7H-1,2,4-triazolo[3,4-b][1,3,4]-
thiadiazine 21
A mixture of compound 5 (0.52 g, 0.001 mol), phenacyl bromide
(0.2 g, 0.001 mol) and sodium ethoxide (0.68 g) in ethanol
(30 mL) was heated under reflux for 5 h. The solvent was then
removed by distillation and the remaining residue was washed
with water, filtered dried and crystallized from dioxane. 1H-
NMR: 1.54 (d, 3H, CH3), 3.01 (s, 2H, CH2), 4.67 (q, 1H, CH), 7.20–
8.25 (m, 12H, Ar-H). MS, m/z (Rel. Int.): 626 [M+ + 2] (32.56), 624
[M+] (100).
7-{1-[2-(4-Chlorophenyl)-6-iodo-4-oxo-3H-quinazolin-3-
yl)]ethyl}-2,4-diphenyl-7,8-dihydro-1,2,4-triazolo[3,4-b]
[1,3,4]thiadiazine 22
A mixture of 5 (0.52 g, 0.001 mol) and 1,3-diphenyl-2-propen-1-
one (0.20 g, 0.001 mol) in acetic acid (20 mL) was heated under
reflux for 5 h. After cooling, the separated solid was filtered,
dried, and crystallized from dioxane. 1H-NMR: 1.53 (d, 3H, CH3),
1.91 (d, 2H, thiadiazepin-CH2), 3.38 (t, 1H, thiadiazepin-CH), 4.77
(q, 1H, CHCH3), 7.20-8.16 (m, 17H, Ar-H). MS, m/z (Rel. Int.): 716
[M+ + 2] (3.44), 714 [M+] (10.07), 383 (26.47), 381 (77.21), 92 (100).
The authors have declared no conflict of interest.
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