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Synthesis Analgesic and Anti-Inflammatory Evaluation of Some New 3H-Quinazolin-4-one Derivatives.

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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
2
Department of Pharmaceutical Chemistry, King Saud University, Riyadh, Saudi Arabia
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 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.
Keywords: Analgesic / Anti-inflammatory / COX-inhibitors / Oxadiazole / 3H-Quinazolin-4-one /
Received: December 22, 2007; accepted: February 11, 2008
DOI 10.1002/ardp.200700271
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 deficiencies 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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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
So far, one has paid attention to various substituted
1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-triazol-5-thiones, and their condensed derivatives as anti-inflammatory 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 cytokines transcription were reported for a variety of substituted quinazoline derivatives [12].
From the literature review, we noticed that most of the
previously reported quinazolines with anti-inflammatory 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.
378
A. M. Alafeefy et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 377 – 385
Scheme 1. Synthesis route of compounds 1 – 9.
Results and discussion
Chemistry
2-(4-Chlorophenyl)-6-iodo-3H-quinazolin-4-one 1 was prepared by adopting the procedure of Jiang et. al. [13]. Compound 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 obtained in a considerable yield. Hydrazinolysis of 2 afforded
the key intermediate 2-[2-(4-chlorophenyl)-6-iodo-4-oxo4H-quinazolin-3-yl]-propionic acid hydrazide 3.
2-(4-Chlorophenyl)-6-iodo-3-[1-(5-mercapto-1,3,4-oxadiazol-2-yl)-ethyl]-3H-quinazolin-4-one 4 was obtained in
nearly quantitative yield by the interaction of compound
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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-mercapto-4H-1,2,4-triazol-3-yl)-ethyl]-2-(4-chlorophenyl)-6iodo-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-quinazolin-4-one 6a – c. Condensation of 3 with 4-chlorobenzaldehyde in acetic acid produced the corresponding N9-(4chlorobenzylidine)-2-[2-(4-chlorophenyl)-6-iodo-4-oxo-4Hquinazolin-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-oxadiawww.archpharm.com
Arch. Pharm. Chem. Life Sci. 2008, 341, 377 – 385
New Quinazoline-4(3H)-One Derivatives
Table 1. Melting points, yield percentages, molecular formulas,
and microanalytical data of compounds 3 – 22.a)
Compound
Mol. Formula
Mp. (8C)
Yield (%)
3
4
5
6a
6b
6c
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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
a)
Analytical data (C, H, N) were within l 0.4% of theoretical values.
zol-2-yl]-ethyl}-2-(4-chlorophenyl)-6-iodo-3H-quinazolin-4one 8, while condensation of 7 with thioglycolic acid
yielded the corresponding 2-[2-(4-chlorophenyl)-6-iodo-4oxo-4H-quinazolin-3-yl]-N-[2-(4-chlorophenyl)-4-oxo-thiazolidin-3-yl]-propionamide 9 (Scheme 1, Table 1).
Compound 12, 2-(4-chlorophenyl)-6-iodo-3-(1-[1,3,4]oxadiazol-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]-propionic acid hydrazide 3 was boiled with formic acid to
afford N9-formyl 2-[2-(4-chlorophenyl)-6-iodo-4-oxo-4H-quinazolin-3-yl]propionic acid hydrazide 10, dehydrative
cyclization of 10 was accomplished using phosphorus
pentoxide to afford 12. Using the second route, the hydrazide 3 was boiled with excess triethylorthoformate to
afford the corresponding N9-ethoxymethylene-2-[2-(4chlorophenyl)-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-chlorophenyl)-6-iodo-3-[1-(5-phenyl-1,3,4-oxadiazol-2-yl)-ethyl]3H-quinazolin-4-one 14.
Condensation of the hydrazide 3 with phenylisothiocyanate resulted in the formation of the corresponding 1-
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
379
phenyl-4-{2-[2-(4-chlorophenyl)-6-iodo-4-oxo-4H-quinazolin-3-yl)-ethyl]-propionyl}-2-thiosemicarbazide 15.
Compound 16, 2-(4-chlorophenyl)-6-iodo-3-[1-(5-phenylamino-1,3,4-oxadiazol-2-yl)-ethyl]-3H-quinazolin-4-one,
was prepared adopting the procedures cited in the literature [16]. However, cyclization of 15 under alkaline conditions gave 3-[1-(phenyl-5-mercapto-4H-1,2,4-triazol-3-ylethyl]-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-quinazolin-4-one 18 when following the literature procedures
[17] (Scheme 2, Table 1).
The compounds 19, 5-{1-[2-(4-chlorophenyl)-6-iodo-4oxo-3H-quinazolin-3-yl)]-ethyl}-1,2,4-triazolo[3,4b][1,3,4]thiadiazole, and 20, 5-{1-[2-(4-chlorophenyl)-6iodo-4-oxo-3H-quinazolin-3-yl)]-ethyl}-2-methyl-1,2,4-triazolo[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 bromide adopting the reported procedure [18] to furnish the
corresponding 6-{1-[2-(4-chlorophenyl)-6-iodo-4-oxo-3Hquinazolin-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-4oxo-3H-quinazolin-3-yl)]-ethyl}-2,4-diphenyl-7,8-dihydro1,2,4-triazolo[3,4-b][1,3,4]thiadiazoine 22 was obtained
through reaction of compound 5 with 1,3-diphenyl-2-propenone in acetic acid (Scheme 3, Table 1).
Pharmacological results
Nineteen compounds (4 – 9, 12 – 22) were initially evaluated for their analgesic activity using the acetic acidinduced writhing response in albino mice. The results
are shown in Table 2.
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 Indomethacine 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 antiinflammatory profile by means of the carrageenaninduced rat paw edema test and the results are summarized in Table 3. Compounds 6c, 12, 14, 16, 18, and 22
showed significant anti-inflammatory activity in comparison 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-inflamwww.archpharm.com
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 analgesic and anti-inflammatory drug Indomethacinem.
The oxadiazole derivatives 6c, 12, 14, 16, the thiadiazole derivatives 13, 18, the fused 1,2,4-triazolo[3,4b][1,3,4]thiadiazole derivative 19, and the diazepine
derivative 22 showed significant analgesic activity producing more than 50% inhibition in the writhing test.
Meanwhile, the oxadiazole derivatives 6c, 12, 14, 16, the
thiadiazole derivative 18, and the thiadiazepine derivative 22 showed significant dose-dependant anti-inflam-
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
matory activity in the carrageenan-induced rat paw
edema test. The best dual analgesic and anti-inflammatory activity was observed with compounds 6c, 14, 16, 18,
and 22. The triazole derivatives 5, 17, 19 – 21, and the thiosemicarbazide derivative 15 were practically inactive.
The structure-activity correlation of the synthesized
compounds revealed that the activity is dependant on
the basic skeleton; some of the oxadiazoles and the thiadiazoles are active whereas the triazoles and the acyclic
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-phenylamino – and to less extent 5-phenyl – moieties promote
the activity.
Since in-vivo activity depends on highly complex physiological interactions in addition to the high number of
enzyme/receptors involved in the inflammatory process,
it is quite difficult, therefore, to hypothesize a mechanism of action without specific tests. These compounds
may exert their action via inhibition of cyclooxygenase
enzyme isoforms like other NSAIDs. In addition, the
recently reported activity of some quinazoline derivatives as potent inhibitors for the production of proinflammatory 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
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
inflammatory reactions to activate immune cells by
mechanisms either related or unrelated to their enzymatic activity. Thus, inhibition of these molecules will
lead to alleviation of various metabolic disorders.
Experimental
Chemistry
General
All melting points (in 8C and uncorrected) were determined
using a Gallenkamp melting point apparatus (Weiss-Gallenkamp, 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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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.
Compound
Dose
(mg/kg)
Analgesic
activitya)
Inhibitionb) Relative
(%)
activity
Control
Indomethacine
4
6c
12
13
14
16
18
19
22
–
10
40
40
40
40
40
40
40
40
40
71.47c) l 3.0
6.23c) l 2.58
23.03c) l 4.42
13.10c) l 3.25
24.17c) l 4.11
30.54c) l 3.37
35.60c) l 3.08
9.96c) l 2.02
11.64c) l 2.96
35.70c) l 3.75
14.58c) l 3.75
–
91.28
67.77
81.67
66.18
57.26
50.18
86.06
83.71
50.00
79.60
a)
b)
c)
–
1
0.74
0.89
0.75
0.63
0.55
0.94
0.91
0.54
0.87
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.
Significantly different from control at P a 5%.
Table 3. Anti-inflammatory effects of various doses of compounds (4, 6c, 12 – 14, 16, 18, 19, 22) and Indomethacine
against carrageenan-induced rat paw edema
Compounds
Control
Indomethacineb)
4
6c
12
13
14
16
18
19
22
a)
b)
c)
% Reduction of paw edema from controla)
20 mg/kg
40 mg/kg
60 mg/kg
–
66.95c) l 3.24
11.67 l 3.27
37.33c) l 4.09
30.62c) l 3.70
12.51 l 5.12
34.12c) l 4.19
46.49c) l 3.95
37.58c) l 3.87
9.11 l 2.95
33.65c) l 3.92
–
66.95c) l 3.24
13.71 l 3.38
50.29c) l 3.78
42.91c) l 3.06
20.38c) l 4.27
45.64c) l 4.30
67.36c) l 4.36
56.65c) l 3.41
18.10 l 3.87
46.05c) l 4.05
–
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
Results are expressed as mean l S. E. M. (n = 6) and compared
with ANOVA test.
Indomethacine dose 10 mg/kg.
Significantly different from control at P a 5%.
plates 60 F254 (Merck, Darmstadt, Germany) were used for monitoring the reaction. Mass spectra were obtained on Kratos MS 50spectrometer (Kratos Analytical, Manchester, UK) at 70 eV. Analytical data (C, H, N) were within l 0.4% of the theoretical values.
2-[2-(4-Chlorophenyl)-6-iodo-4-oxo-4H-quinazolin-3-yl]propionic acid hydrazide 3
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,
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
133, 139, 147, 152, 154, 163, 166, 170 (Ar-C). MS, m/z (Rel. Int.):
468 [M+ + 2] (32), 466 [M+] (100).
2-(4-Chlorophenyl)-6-iodo-3-[1-(5-mercapto-1,3,4oxadiazol-2-yl)-ethyl]-3H-quinazolin-4-one 4
A mixture of the hydrazide 3 (4.68 g, 0.01 mol), carbon disulphide (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).
3-[1-(4-Amino-5-mercapto-4H-1,2,4-triazol-3-yl)-ethyl]-2(4-chlorophenyl)-6-iodo-3H-quinazolin-4-one 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 precipitated 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).
2-(4-Chlorophenyl)-6-iodo-3-[1-(5-substituted thio-1,3,4oxadiazol-2-yl)-ethyl]-3H-quinazolin-4-one 6a – c
A mixture of 5 (2.85 g, 0.005 mol), anhydrous potassium carbonate (0.3 g) and the appropriate alkyl halide (0.01 mol) in acetone (25 mL) was refluxed for 6 h. The reaction mixture was filtered 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
(18.61), 383 (23.50), 381 (69.33), 115 (100). 6b: 1H-NMR: 1.36 (d,
3H, CH3), 4.29 (s, 2H, CH2), 4.79 (q, 1H, CH), 7.27 – 7.85 (m, 7H, ArH). 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).
N 9-(4-Chlorobenzylidene)-2-[2-(4-chlorophenyl)-6-iodo-4oxo-4H-quinazolin-3-yl]-propionic acid hydrazide 7
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 reaction mixture was then heated under reflux for 3 h. The solid separated upon cooling was filtered, dried, and crystallized from
ethanol. 1H-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
3-{1-[4-Acetyl-5-(4-chlorophenyl)-4,5-dihydro-1,3,4oxadiazol-2-yl]-ethyl}-2-(4-chlorophenyl)-6-iodo-3Hquinazolin-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. 1HNMR: 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-[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 thioglycolic 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 mixture 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, thiazolidineCH2), 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).
N 9-Formyl-2-[2-(4-chlorophenyl)-6-iodo-4-oxo-4Hquinazolin-3-yl]propionic acid hydrazide 10
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, D2Oexchang.), 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).
New Quinazoline-4(3H)-One Derivatives
383
solid was purified by preparative TLC using hexane / ethyl acetate 3 : 1 as eluent to afford 12 with the same physical constants
and in a comparable yield with that obtained by route A.
2-(4-Chlorophenyl)-6-iodo-3-(1-[1,3,4]thiadiazole-2-ylethyl)-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-(4-Chlorophenyl)-6-iodo-3-[1-(5-phenyl-1,3,4oxadiazol-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).
1-Phenyl-4-{2-[2-(4-chlorophenyl)-6-iodo-4-oxo-4Hquinazolin-3-yl)ethyl]propionyl}-2-thiosemicarbazide 15
A mixture of the hydrazide 3 (0.46 g, 0.001 mol) phenylisothiocyanate (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).
N 9-Ethoxymethylene-2-[2-(4-chlorophenyl)-6-iodo-4-oxo4H-quinazolin-3-yl] propionic acid hydrazide 11
2-(4-Chlorophenyl)-6-iodo-3-[1-(5-phenylamino-1,3,4oxadiazol-2-yl)ethyl]-3H-quinazolin-4-one 16
A mixture of the hydrazide 3 (0.94 g, 0.002 mol) and triethylorthoformate (5 mL) was refluxed for 30 min. After cooling, the
precipitated solid was filtered, washed with water, and crystallized 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).
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 hydroxide (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
with water, dried, and crystallized from ethanol. 1H-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-ylethyl)-3H-quinazolin-4-one 12
Route A:
To a solution of 10 (0.52 g, 0.001 mol) in xylene (10 mL), phosphorus pentoxide (0.2 g) was added. The reaction mixture was
refluxed for 2 h and filtered while hot. The solvent was evaporated 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).
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
i
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
3-[1-(Phenyl-5-mercapto-4H-1,2,4-triazol-3-yl-ethyl]-2-(4chlorophenyl)-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).
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384
A. M. Alafeefy et al.
2-(4-Chlorophenyl)-6-iodo-3-[1-(5-phenylamino-1,3,4thiadiazol-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 temperature 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-quinazolin3-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 precipitated solid was filtered, washed with water, dried, and crystallized 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).
5-{1-[2-(4-Chlorophenyl)-6-iodo-4-oxo-3H-quinazolin3-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).
6-{1-[2-(4-Chlorophenyl)-6-iodo-4-oxo-3H-quinazolin3-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. 1HNMR: 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-3yl)]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-1one (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).
Biological testing
General
Swiss albino mice of both sexes weighing 20 – 25 g, and adult
Wistar albino rats of both sexes, weighing 100 – 150 g, were
obtained from animal care center, College of Pharmacy, King
i
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2008, 341, 377 – 385
Saud University, Riyadh, Saudi Arabia. Mice were used for writhing (abdominal constriction), while rats were used for the carrageenan-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 laboratory conditions for acclimatization and had free access to pulverized 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.
Evaluation of analgesic activity
The analgesic activity was determined in mice using acetic acidinduced 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 compared with that of the control and converted into%-inhibition.
Evaluation of anti-inflammatory activity
The anti-inflammatory activity of eight of the newly synthesized
compounds was determined in rats using the carrageenaninduced 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 column of plethysmograph up to the mark to ensure constant paw
volume. To each group, except the control group, test compounds 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 difference 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.
The authors have declared no conflict of interest.
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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