Synthesis, characterization, and evaluation of some novel 4(3H)-quinazolinone derivatives as anti-inflammatory and analgesic agents

Article abstract of DOI:10.1007/s00044-012-0046-6

Some of new 3-(4-chlorophenyl or 4-fluorophenyl)-6-iodo-4-oxo-3,4- dihydroquinazoline derivatives having a Schiff bases, oxazolone, imidazolidine, pyrazolidine, pyridine, pyrimidine, and various substituted C-2 have been synthesized. Screening for some selected compounds was carried out for their potential anti-inflammatory and analgesic activity.

Full text of DOI:10.1007/s00044-012-0046-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0046-6
ORIGINAL RESEARCH
Synthesis, characterization, and evaluation of some novel
4(3H)-quinazolinone derivatives as anti-inflammatory
and analgesic agents
•
Awatef A. Farag Ebtsam M. Khalifa Naima A. Sadik
•
•
•
Samir Y. Abbas Abdullah G. Al-Sehemi
•
Yousry A. Ammar
Received: 27 December 2011 / Accepted: 27 March 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Some of new 3-(4-chlorophenyl or 4-fluoro-
phenyl)-6-iodo-4-oxo-3,4-dihydroquinazoline derivatives
having a Schiff bases, oxazolone, imidazolidine, pyrazoli-
dine, pyridine, pyrimidine, and various substituted C-2
have been synthesized. Screening for some selected com-
pounds was carried out for their potential anti-inflamma-
tory and analgesic activity.
inflammation (Sng and Schug, 2009), pain (Chou et al.,
2009) and fever (Eccles, 2006). However, long-term
clinical usage of NSAIDs is associated with significant
side effects of gastrointestinal lesions, bleeding, and
nephrotoxicity (Rathee et al., 2009). Therefore, the dis-
covery of new and safer anti-inflammatory drugs repre-
sents a challenging goal for such a research area. In
general quinazoline derivatives are known to possess
remarkable anti-inflammatory activity as NOS-II (Harris
et al., 2000), TNF-a (Tobe et al., 2001), IMPDH-II
(Buckley et al., 2005), MAPK (Schlapbach et al., 2004),
PDE-3 (Piaz and Giovannoni, 2000), and PDE-4 (Chandrika
et al., 2008) inhibitors. Furthermore, imidazo[1,2-c]quin-
azolines (Balakumar et al., 2010), pyrroloquinazolines
(Rioja et al., 2002), 4-phenethylaminoquinazolines (Tobe
et al., 2003), 2,3,6-trisubstituted quinazolines (Kumar et al.,
2003), 2-substituted aminoquinazolinones (Alagarsamy
and Murugesan, 2007) and benzothiazolylquinazolinones
(Laddha et al., 2006) were reported to have significant
anti-inflammatory, analgesic and antipyretic properties
(Chao et al., 1999; Balakumar et al., 2010). A recent lit-
erature survey revealed that many of the halogen con-
taining heterocyclic moiety have attracted attention due to
the ability of halogen to act as polar hydrogen or hydroxyl
mimic. Substitution of hydrogen by halogen has been a
strategy in designing molecules for biological studies
(Karegoudar et al., 2008; Alafeefy et al., 2010). Based on
the above observations and in continuation of our drug
research program, it was of interest to synthesize a novel
series of quinazolinone derivatives with structure modifi-
cations involving incorporation of the iodine atom at
position 6, aryl halogen at position 3, and a heterocyclic
moiety at position 2 of 4(3H)-quinazolinone moiety as a
trial to obtain safer and potent anti-inflammatory and
analgesic agents.
Keywords 4(3H)-quinazolinone Á Imidazolidine Á
Pyrazolidine Á Pyridine Á Pyrimidine Á Anti-inflammatory Á
Analgesic agent
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are
useful tools in the treatment of acute and chronic
A. A. Farag
Chemistry Department, Faculty of Science, Al-Azhar University
(Girls), Cairo, Egypt
E. M. Khalifa Á N. A. Sadik
Chemistry Department, Faculty of Education, Taif University,
Taif, Saudi Arabia
S. Y. Abbas (&)
Organometallic and Organometalloid Chemistry Department,
National Research Centre, Cairo 12311, Egypt
e-mail: samiryoussef98@yahoo.com
A. G. Al-Sehemi Á Y. A. Ammar
Department of Chemistry, Faculty of Science, King Khaled
University, Abha, Saudi Arabia
Y. A. Ammar
Department of Chemistry, Faculty of Science, Al-Azhar
University, Cairo, Egypt
123

Med Chem Res
Discussion
The scope of the reaction of aldehydes 2a,b with various
nitrogen nucleophile was studied with the objective of
obtaining biologically active compounds. Thus, the reac-
tion of aldehydes 2a,b with the selected amines, o-phe-
netidine, o-aminothiophenol and isonicotinic hydrazide, in
dioxane led to the formation of Schiff’s bases 3, 4 and the
hydrazone derivative 5 in high yield (Scheme 2). The
formation of 3–5 may be interpreted through correct ele-
Chemistry
In this investigation, 2-methyl-4(3H) quinazolinones
1a,b were synthesized according to a previously reported
method (Rajendra and Bhaduri, 1979). One of the reasons
for the interest in 2-methyl-4(3H) quinazolinones
1a,b relates to the possibility of oxidation of the methyl
group in their structure with the possibility that further
useful functionalization might be generated at this position.
Therefore, oxidation of the methyl group in products
1a,b to a formyl group using SeO2 was carried out, and the
novel 4(3H)-quinazolinone-2-carboxaldehyde derivatives
2a,b were furnished. Presumably, the oxidizing agent
(SeO2) acts as an electrophile and initially attacks the
methyl group. So, the reaction probably proceeds by a
mechanism similar to that proposed by Sokai et al., (1972)
involving direct oxidation of methyl group via intermedi-
ates A and B to give the proposed structure 2a,b
(Scheme 1). The structural elucidation of the 4(3H)-qui-
nazolinone-2-carboxaldehydes 2a,b was inferred from
correct elemental analysis and carful inspection of their
spectral data.
1
mental analysis and spectral data. H NMR spectrum of
compound 3a displayed one triplet signal at 1.35 and one
quartet signal at 4.04 equivalents to five protons of OC2H5
group, also, its 13C NMR revealed signals at 15.43 (CH3)
and 67.45 (CH2) due to OC2H5 group.
Five-membered heterocycles are ideal representatives of a
recurring core structure that is found in numerous biologically
active compounds. Thus, condensation of the aldehydes
2a,b with 2-thioxothiazolidin-4-one afforded the corre-
sponding thioxothiazolidinone derivatives 6a,b. In addition,
the oxazolone derivatives 7a,b were produced upon cyclo-
condensation of the aldehydes 2a,b with hippuric acid. When,
the oxazolone derivatives 7a,b were subjected to react with
o-phenetidine in acetic acid containing sodium acetate
afforded the corresponding imidazole derivatives 8a,b. Anti-
inflammatory of pyrazole motivated us to synthesize a novel
X
X
X
X
O
O
O
O
I
I
I
I
N
N
N
N
SeO2
Se H2O
N
C
H
N
CH3
N
CHO
N
CH2
O
H
1a, X = Cl
1b, X = F
H
[ A ]
2a, X = Cl
2b, X = F
O
Se OH
[ B ]
Se O
Scheme 1 Synthesis of aldehydes
NH2
X
X
O
OC2H5
O
N
N
I
I
N
N
N
C
H
CHO
2a, X = Cl
2b, X = F
3a, X = Cl
3b, X = F
C2H5O
NH2
CONHNH2
SH
X
N
I
X
O
N
N
O
N
I
N
O
H
N
C
C
N N
N
H
H
HS
4a, X = Cl
4b, X = F
5a, X = Cl
5b, X = F
Scheme 2 Synthesis of Schiff’s bases derivatives
123

Med Chem Res
series of 4(3H)-quinazoline derivatives containing pyrazole
moiety. The Schiff’s base derivatives 9a,b were obtained via
the reaction of the aldehydes 2a,b with 4-aminoantipyrene.
pyrimidine 2,4,6-trione 16a,b. In addition, multicomponent
Biginelli reaction was occurred via the reaction of the
aldehyde derivatives 2a,b with ethyl acetoacetate and thio-
urea in the presence of hydrochloric acid to get pyrimidine
derivatives 17a,b. The arylidene derivatives 10a,b were
used as intermediates in the synthesis of pyrimidine deriv-
atives 17a,b upon reaction with thiourea (Scheme 4). The
identity of the products was determined by spectral studies.
The IR spectrum of compound 17a revealed a sharp strong
absorption band above 1,720 cm-1 due to the presence of
the ester function in the structure. The characteristic signals
of an ester moiety confirm the presence of ester group in the
structure by resonating as triplet and quartet for CH2 and
CH3 at d = 1.54, 4.23 ppm, respectively, and a doublet at:
4.77 attributed for H-4 of pyrimidine ring. The aromatic
protons resonate as multiplets at d 7.32–8.43 ppm.
1
The H NMR spectrum of 9a revealed the appearance of
characteristic singlet at d = 2.03 and 3.20 ppm assigned to
CH3 and N-CH3 protons, while its 13C NMR exhibited the
carbon of these groups at 18.98 and 34.42. Also, the pyraz-
oline derivatives 11a,b were obtained through the conden-
sation of the compounds 2a,b with ethyl acetoacetate to give
10a,b followed by reaction with hydrazine hydrate in ethanol.
Structures of compounds 10a,b and 11a,b were elucidated on
the basis of elemental analysis and spectral data. The 1H NMR
spectrum compound 10a as example revealed triplet and
quartet signals at: d = 1.18, 4.15 due to ethyl protons in
addition to singlet signal at d = 2.44 due to acetyl group. On
1
the other hand, H NMR spectrum of compound 11a dis-
played signal at: d = 2.27 due to methyl group, aromatic
multiplet in the region d = 7.23–8.56, in addition to two
singlets at: 9.45, 9.87 due to two NH groups and revealed the
lack of signals characteristic for ethyl group. The lack of
carbonyl ester in the IR spectra supported the formation of
structure 11. In this paper, the synthesis of the chalcone
derivatives 12a,b were accomplished according to the
Claisen-Schmidt condensation of the corresponding quinaz-
oline-2-aldehydes 2a,b with acetophenone. Cyclocondensa-
tion of the chalcone derivatives 12a,b with hydrazine hydrate
affording the corresponding pyrazoline derivatives
13a,b. Structures of compounds 12, 13 were inferred from
their correct elemental analyses and spectral data. Thus,
IR spectrum of 12a showed bands at: 1708, 1682 cm-1
Biological activity
Some new selected synthesized 4(3H)-quinazolinone
derivatives 3b, 5b, 6b, 7a, 9a, 9b, 11a, 12b, 13a, and 15b
(10 compounds) were screened for anti-inflammatory and
analgesic activities. Adult albino rats of both sexes
weighting 120–150 gm were divided into 12 groups, one
group as control, 10 groups for the test compounds and one
group receiving the reference standard. Each group consists
of 6 animals. They were housed in colony rooms with
12/12 light/dark cycle at 21 2 °C room temperature and
had free access to cubed dry food and water. The test
compounds and the reference standards were prepared as
suspensions in 2 % tween 80 while the negative control
groups received 1 ml of water suspended in tween 80
(vehicle). Doses of the tested compounds (100 mg/kg body
weight) and the reference standards were calculated
according to the reported method (Sastry et al., 1989).
1
attributed to the C=O groups. H NMR spectra of the com-
pounds 12, 13 were compatible with the assigned structure
(Scheme 3).
The synthesis of pyridine derivatives was carried out
aiming to develop new drugs. Condensation of the quinaz-
oline-2-aldehyde derivatives 2a,b with malononitrile affor-
ded the corresponding arylidene derivatives 14a,b. These
arylidene derivatives were used as intermediates in the
synthesis of 4(3H)-quinazolinone containing pyridine moi-
ety 15a,b upon reaction with N-(o-ethoxyphenyl) cyanoac-
tanilide in the presence of ethanolic piperidine. An important
evidence for the latter products was arrived from their
synthesis via another synthetic route. Thus, multicomponent
reaction of the aldehyde derivatives 2a,b with malononitrile
and N-(o-ethoxyphenyl) cyanoactanilide in the presence of
few drops of piperidine gave 15a,b. (m.p. and mixed m.p.).
The IR spectrum of the compound 15a revealed two sharp
strong absorption bands at: 3247, 3234 cm-1 for NH2 group.
Anti-inflammatory studies
The anti-inflammatory activity was investigated through
acute and chronic model.
Acute model (carrageenan hind paw edema assay)
The procedure of Winter et al. (1962) was adopted, all the
tested compounds and the reference drug (indomathacin;
5 mg/kg body weight) were administered orally for each
rat. 1 h later, the hind paw edema was induced by injecting
0.05 ml of 1 % carrageenan sodium into the subplantar
region of the right hind paw of each rat. The initial hind
paw volume was measured immediately following carra-
geenan injection. The edema in each test group of animals
after 3 h of carrageenan administration was measured,
using mercury plethysmography, to calculate the percent
1
Further, H NMR spectrum of 15a exhibited a triplet and
quartet at 1.55 and 4.21 for ethoxy group. It is of great
interest that specifically functionalized pyrimidinones may
possess specific biological properties. Thus, condensation of
the aldehyde derivatives 2a,b with barbituric acid furnished
123

Med Chem Res
X
H
X
O
N
O
N
N
S
O
I
I
N
N
S
S
S
C
H
CHO
NH
2a, X = Cl
2b, X = F
6a, X = Cl
6b, X = F
O
X
X
N
NH2
O
N
O
N
OC2H5
CH2COOH
I
I
N
N
Ph
Ph
NHCOPh
N
N
OC2H5
C
H
C
O
H
8a, X = Cl
8b, X = F
7a, X = Cl
7b, X = F
O
O
H2N
CH3
CH3
X
O
N
N
I
O
N
N
Ph
CH3
N
C
H
N
9a, X = Cl
9b, X = F
O
N
CH3
Ph
X
X
O
O
OC2H5
O
N
O
N
I
I
N2H4.H2O
COCH3
O
N
N
O
CH
HN
O
N
H
OC2H5
10a, X = Cl
10b, X = F
11a, X = Cl
11b, X = F
COCH3
X
X
O
N
N
O
I
I
N2H4.H2O
N
N
C
H
N
HN
13a, X = Cl
13b, X = F
12a, X = Cl
12b, X = F
O
Scheme 3 Synthesis of the arylidene, oxazolone, imidazolidine, and pyrazole derivatives
edema achieved by the reference drug and the tested
compounds (Table 1).
tissues were removed. The pellets were dried overnight to
have a constant weight. The gain in pellets weight were
calculated for both the tested compounds and the Indo-
methacin and compared to the control group (Table 1). The
screening of the anti-inflammatory activity (chronic model)
of the tested 4(3H)-quinazlinone compounds revealed that,
the 3-(4-fluorophenyl)-2-[(1,5-dimethyl-3-oxo-2-phenyl-
2,3-dihydro-1H-pyrazol-4-ylimino)-methyl]-6-iodo-3H-
quinazolin-4-one (9b), which has azomethine side chain at
C-2 position ending with a pyrazole moiety and chloro-
phenyl at position 3, showed strong anti-inflammatory
activity. When the chlorophenyl at position 3 of this
compound was replaced by fluorophenyl moiety in case of
Chronic model
The procedure of Meier et al. (1950) was followed; rats
were divided into 12 groups, each of 6 animals, where 4
cotton pellets weighting 30–35 mg were channeled sub-
cutaneously to the pectoral area of each rat. Daily oral
doses of the tested compounds (100 mg/kg) and the ref-
erence drug (Indomethacin; 5 mg/kg) were given for seven
successive days. The rats were killed in following day and
the cotton pellets with the surrounding granulomatous
123

Med Chem Res
X
X
X
O
N
O
O
N
I
I
I
CH2(CN)2
N
N
N
barbituric acid
CHO
N
O
CH
CH
CN
2a,
O
X=Cl
2b, X=F
C
N
H
NC
3
C
C
O
S
HN
NH
14a, X=Cl
14b,
C
H
2
)
H
2
N
X=F
C
2 C
(
O
O
H
2
N
O
C
H
2
C
2
16a, X=Cl
16b,
ArNH
NC
O
H
5
X=F
X
X
X
O
N
O
N
O
I
I
I
N
N
N
NH2CSNH2
CN
COOC2H5
O
N
O
CH
CH3
NH
N
O
HN
NC
Ar
NH2
OC2H5
10a, X = Cl
S
17a,
X=Cl
15a,
15b,
X=Cl Ar = C6H4(OC2H5)-2
X=F Ar = C6H4(OC2H5)-2
17b, X=F
10b,
X = F
Scheme 4 Synthesis of pyridinone and pyrimidine derivatives
Table 1 Anti-inflammatory
activity of the tested compounds
and indomethacin
Compd. no.
Anti-inflammatory activity
Acute model
Chronic model
S.E.
X
S.E.
Change %
Potency
X
Change %
Potency
Control
57.6 1.1
35.2 0.8
31.5 1.2
31.8 1.8
29.4 2.1
30.3 1.7
26.8 1.8
29.8 3.1
41.3 2.8
28.6 3.6
45.7 1.8
12.4 1.1
–
–
0.5
0.6
0.6
0,6
0.6
0.7
0.6
0.4
0.7
0.3
1.0
112.4 5.5
55.9 2.2
37.4 2.2
36.8 1.8
30.8 3.1
44.2 1.7
29.8 1.8
31.2 2.3
65.4 3.8
31.5 2.6
53.7 1.8
27.9 2.6
–
–
3b
38.9
45.3
44.8
49.6
47.4
53.5
48.3
28.3
50.4
20.7
78.3
50.2
66.7
67.3
72.6
60.7
73.5
72.2
41.8
71.9
52.2
75.2
0.6
0.8
0.8
0.9
0.8
1.0
0.9
0.5
0.9
0.7
1.0
5b
6b
7a
9a
9b
11a
12b
13a
15b
Indomethacin
compound 9a, the potency was dropped to 0.8 potency.
Compound 11a incorporating pyrazole moiety at C-2
showed strong anti-inflammatory activity (0.9 potency);
Also, compound 13a showed strong anti-inflammatory
activities (0.9 potency), the activity showed by compound
13a may be due to the presence of pyrazoline moiety at
C-2. On the other hand, compounds 5b, 6b, and 7a (which
have hydrazone, thiazole, and oxazole at C-2 position,
respectively) exhibited strong anti-inflammatory activities,
ranged from 0.8 to 0.9 potencies comparable to the refer-
ence drug. Compound 15b with pyridine moiety at position
2 showed moderate activities (0.7 potency). While mild
effects were exerted by compounds 3b and 12b which have
at C-2 position 2-ethoxyphenyl azomethine and chalcone
moieties, respectively (Table 1).
Analgesic activity
The analgesic activity was evaluated according to the reported
method of Charlier et al. (1961) Electric current as noxious
stimulus was used as described by Charlier et al. and the min-
imum voltage that caused the rat to emit a cry was determined.
Electrical stimulation of the tail was applied by means of 515
master Schoker (Lafayette Inst. Indiana, USA). The minimum
123

Med Chem Res
Table 2 The analgesic
activities of the tested
compounds and novalgin
Compd. no.
Voltage needed after treatment
1 h
2 h
X
X
S.E.
Change %
Potency
S.E.
Change %
Potency
Control
3b
79.9 3.7
111.3 2.8
125.5 2.9
126.2 3.2
128.6 2.1
122.8 3.2
131.7 2.2
118.2 2.2
117.4 2.6
124.2 3.8
115.9 3.6
146.2 1.6
–
–
80.6 3.2
125.8 3.5
132.4 2.6
130.0 2.7
131.6 2.2
124.3 2.3
133.5 1.8
130.5 3.7
124.2 3.4
128.3 1.5
123.4 2.8
149.7 1.5
–
–
39.3
57.1
57.9
60.9
53.7
64.8
47.9
46.9
55.4
45.1
82.9
0.5
0.7
0.7
0.7
0.6
0.8
0.6
0.6
0.7
0.5
1.0
56.1
64.3
61.3
63.3
54.2
65.6
61.9
54.1
59.2
53.1
85.7
0.7
0.8
0.7
0.7
0.6
0.8
0.7
0.6
0.7
0.6
1.0
5b
6b
7a
9a
9b
11a
12b
13a
15b
Novalgin
voltage required for the animal to emit a cry was recorded for
the control and treated groups with the tested compounds (dose;
100 mg/kg body weight) and Novalgin as a reference standard
(dose; 5 mg/kg body weight). The mean voltage for each group
was obtained. Analgesic activity was measured for the tested
compounds and the reference (Table 2). The screening of the
analgesic activity of the tested 4(3H)-quinazlinone compounds
revealed that, the activity was nearly increased by time and all
compounds showed moderate analgesic activity compared
to that of novalgin except the 3-(4-fluorophenyl)-2-[(1,5-
dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylimino)-
methyl]-6-iodo-3H-quinazolin-4-one (9b) exhibited strong
analgesic activities.
(200 MHz) spectrometer, using TMS as an internal stan-
dard; chemical shifts are reported as dppm units. Mass
spectra (m/z, %) were obtained on GC MS-QP 100 Ex
mass spectrometer at 70 eV. Elemental analyses were
carried out at Microanalytical Unit, Cairo University,
Cairo, Egypt.
Synthesis of 3-(4-chlorophenyl)-6-iodo-4-oxo-3,4-
dihydroquinazoline-2-carbaldehyde (2a)
2-Methyl-3(4H)-quinazolinone 1a (0.01 mol) was dissolved
in hot dioxane (50 ml), powdered selenium dioxide
(0.02 mol) was added portion-wise while stirring. After
complete addition, the reaction mixture was boiled with
stirring for 6 h.The reaction mixture was then filtered off. The
filtrate was poured onto crushed ice, the solid product
obtained was filtered and crystallized from benzene to give 2a
Conclusions
as beige crystals, mp 217–218 °C. Yield 65 %. IR: t/cm-1
:
In summary, a series of new 4(3H)-quinazolinone deriva-
tives carrying many heterocyclic rings could be synthe-
sized and evaluated for their anti-inflammatory and
analgesic activities. Some of 4(3H)-quinazolinones which
contain pyrazole moiety showed highly significant anti-
inflammatory effect, as compounds 9b, 11a, 13a compa-
rable to the standard (Indomethacin).
1
1719, 1687 (C=O). H NMR: d/ppm: 7.32–7.51 (m, 4H,
ArH), 7.73 (d, 1H, Ar–H at C8–H quinazoline), 8.29 (d, 1H,
ArH at C7–H quinazoline), 8.49 (s, 1H, ArH at C5–H qui-
nazoline), 9.43 (s, 1H, CHO); MS, m/z (%): 410 (M?;
100 %), 411 (M ? 1; 25.2 %), 412 (M ? 2; 32.9 %), 409
(M-1; 18.1 %), 382 (M-CO; 35.6 %), 381 (M-CHO; 69.2 %),
270 (M-[C6H4Cl ? CHO]; 14.8 %), 255 (M-[I ? CO];
33.9 %), 227 (M-[I ? 2CO]; 32.3 %), 76 (phenylene moiety;
66.3 %). Anal. Calcd for C15H8ClIN2O2 (410.59): C, 43.88;
H, 1.96; N, 6.82; Found: C, 43.90; H, 2.00; N, 6.70.
Experimental
General
Synthesis of 3-(4-fluorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazoline-2-carbaldehyde (2b)
All melting points are recorded on digital Gallen Kamp
MFB-595 instrument and are uncorrected. The IR spectra
(KBr) (cm-1) were measured on a Shimadzu 440 spec-
trophotometer. NMR spectra (d, ppm) were obtained in
deutrated dimethyl sulfoxide on a Varian Gemini 200
It was synthesized according to our reported method (Aly
et al., 2010).
123

Med Chem Res
Synthesis of Schiff’s bases derivatives 3a,b
99.65, 115.54, 115.96, 118.23, 122.97, 123.76, 123.98,
125.12, 126.43, 128.56, 129.63, 129.98, 132.65, 139.48,
146.54, 147.43, 153.54, 156.23 (18C–Ar), 163.29, 164.54
(2C=N) and 168.35 (C=O); Anal. Calcd for C21H13ClI-
N3OS (517.77): C, 48.71; H, 2.53; N, 8.12; Found: C,
49.00; H, 2.60; N, 8.10.
A
mixture of 4(3H)-quinazolinone-2-carboxaldehydes
2a,b (0.01 mol) and o-phenetidine (0.01 mol) in dioxane
(30 ml) was heated under reflux for 1 h. The reaction
mixture was concentrated under vacuum, left to cool and
then cold ethanol was added. The solid product obtained
was filtered off and crystallized from ethanol to give the
final products.
3-(4-Fluorophenyl)-6-iodo-2-((2-mercaptophenylimino)
methyl)quinazolin-4(3H)-one (4b)
mp 230–232 °C. Yield 73 %. IR: t/cm-1: 3253 (SH), 1682
(C=O), 1604(CH=N); 1H NMR: d/ppm: 4.34 (bs, 1H, SH),
6.74–8.23 (m, 11H, ArH), 8.24 (s, 1H, CH=N); 13C NMR:
99.23, 115.56, 115.82, 118.45, 122.56, 123.56, 123.87,
125.24, 126.54, 128.34, 129.56, 129.79, 132.67, 139.40,
146.23, 147.54, 149.12, 156.45 (18C–Ar), 163.12, 164.87
(2C=N) and 167.34 (C=O); Anal. Calcd for C21H13FIN3OS
(501.32): C, 50.31; H, 2.61; N, 8.38; Found: C, 50.50; H,
2.70; N, 8.50.
3-(4-Chlorophenyl)-2-((2-ethoxyphenylimino)methyl)-
6-iodoquinazolin-4(3H)-one (3a)
mp 215–216 °C. Yield 85 %. IR: t/cm-1: 1686 (C=O),
1610 (CH=N); 1H NMR: d/ppm: 1.35 (t, 3H, CH3), 4.04 (q,
2H, CH2), 6.65–8.25 (m, 11H, ArH), 8.76 (s, 1H, CH=N);
13C NMR: 15.43(CH3), 67.45(CH2), 100.20, 116.43,
120.78, 121.32, 121.54, 122.43, 123.85, 123.95, 126.43,
128.54, 129.43, 129.68, 131.32, 132.43, 139.54, 146.65,
147.43, 148.54 (18C–Ar), 164.49, 166.64 (2C=N) and
173.06 (C=O); Anal. Calcd for C23H17ClIN3O2 (529.76):
C, 52.15; H, 3.23; N, 7.93; Found: C, 52.30; H, 3.10; N,
7.70.
Synthesis of hydrazide derivatives 5a,b
A
mixture of 4(3H)-quinazolinone-2-carboxaldehydes
2a,b (0.01 mol) and isonicotinic hydrazide (0.01 mol) in
dioxane (30 ml) was heated under reflux for 1 h. The
reaction mixture was concentrated under vacuum, left to
cool. The solid product obtained was filtered off and
crystallized from ethanol to give the final products.
3-(4-Fluorophenyl)-2-((2-ethoxyphenylimino)methyl)-
6-iodoquinazolin-4(3H)-one (3b)
mp 212–214 °C. Yield 78 %. IR: t/cm-1: 1672 (C=O),
1607(CH=N); 1H NMR: d/ppm: 1.36 (t, 3H, CH3), 4.08 (q,
2H, CH2), 6.87–8.34 (m, 11H, ArH), 8.66 (s, 1H, CH=N),
13C NMR: 14.83(CH3), 66.76 (CH2), 104.10, 116.14,
116.63, 120.58, 121.43, 121.63, 123.76, 123.98, 126.43,
128.56, 129.63, 129.98, 132.65, 139.48, 146.54, 147.43,
153.54, 156.23 (18C–Ar), 164.29, 166.54 (2C=N) and
167.34 (C=O); Anal. Calcd for C23H17FIN3O2 (513.30): C,
53.82; H, 3.34; N, 8.19; Found: C, 53.70; H, 3.20; N, 8.30.
N’-((3-(4-chlorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)methylene)isonicotinohydrazide
(5a)
mp [ 300 °C. Yield 74 %. IR: t/cm-1: 3241(NH), 1698,
1
1675 (C=O). H NMR: d/ppm: 7.59–8.32 (m, 11H, ArH),
8.50 (s, 1H, CH=N), 8.90 (s, 1H, NH); 13C NMR, 94.50,
116.54, 122.59, 123.76, 126.32, 128.12, 129.54, 129.78,
131.13, 131.34, 132.23, 134.65, 135.34, 136.75, 139.45,
146.34, 146.12 (17C–Ar), 159.22, 163.12 (2C=N) and
170.34, 173.56 (2C=O); MS, m/z (%): 529 (M?, 3.87), 426
(9.61), 423 (M-nicotinoyl moiety; 38.05), 360 (M-
C6H5ClN3O; 52.58), 233 (C15H9N2O; 13.77), 127 (I, 9.12),
106 (nicotinoyl moiety; 100), 103 (C7H3O; 30.73), 78
(pyridine moiety; 88.14); Anal. Calcd for C21H13ClIN5O2
(529.72): C, 47.61; H, 2.47; N, 13.22; Found: C, 47.48; H,
2.65; N, 13.34.
Synthesis of Schiff’s bases derivatives 4a,b
A
mixture of 4(3H)-quinazolinone-2-carboxaldehydes
2a,b (0.01 mol) and o-aminothiophenol (0.01 mol) in
dioxane (30 ml) was heated under reflux for 1 h. The
reaction mixture was concentrated under vacuum, left to
cool and then cold ethanol was added. The solid product
obtained was filtered off and crystallized from ethanol to
give the final products.
3-(4-Chlorophenyl)-6-iodo-2-((2-mercaptophenylimino)
methyl)quinazolin-4(3H)-one (4a)
N’-((3-(4-Fluorophenyl)-6-iodo-4-oxo-3,4-
dihydroquinazolin-2-yl)methylene)isonicotinohydrazide
(5b)
mp 253–255 °C. Yield 73 %. IR: t/cm-1: 3251 (SH), 1685
(C=O), 1612 (CH=N); 1H NMR: d/ppm: 4.20 (bs, 1H, SH),
6.79–8.36 (m, 11H, ArH), 8.68 (s, 1H, CH=N); 13C NMR:
mp 280–282 °C. Yield 73 %. IR: t/cm-1: 3232(NH), 1687,
1675 (2C=O). 1H NMR: d/ppm: 7.60–8.33 (m, 11H, ArH),
123

Med Chem Res
8.49 (s, 1H, CH=N), 8.90 (s, 1H, NH), 13C NMR, 94.35,
116.93, 122.98, 123.89, 126.45, 128.32, 129.08, 129.54,
131.04, 131.34, 132.23, 134.79, 135.65, 136.87, 139.75,
146.45, 151.43, 150.88 (17C–Ar), 159.33, 163.38 (2C=N)
and 170.32, 173.00 (2C=O); Anal. Calcd for
C21H13FIN5O2 (513.72): C, 49.14; H, 2.55; N, 13.64.
Found: C, 49.20; H, 2.60; N, 13.30.
solid product obtained was filtered off and recrystallized
from toluene to give 7a,b.
4-((3-(4-Chlorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)methylene)-2-phenyloxazol-
5(4H)-one (7a)
mp 176–177 °C, Yield 75 %. IR: t/cm-1: 1723, 1686
1
Synthesis of the arylidene derivatives 6a,b
(C=O); H NMR: d/ppm: 5.52 (s, 1H, CH = oxazolone),
7.43–8.56 (m, 12H, Ar–H); 13C NMR: 96.95, 122.43,
122.56, 123.67, 124.23, 126.45, 128.89, 129.23, 129.71,
130.32, 130.56, 131.23, 131,45, 132.45, 134.77, 137.65,
139.37, 142.32, 146.54, 148.38, (18C–Ar ? C=C), 164.89,
165.32 (2C=N), 166.84, 170.32 (2C=O); MS, m/z (%): 553
(M?, 0.11), 427 (M-C7H5NO; 0.41), 398 (0.57), 382
(M-C10H6NO2; 32.51), 245 (C7H4INO; 6.42), 169 (33.19),
171(C10H5NO2; 33.19), 127 (I; 100), 110 (21.48), 98
(16.84), 76 (phenylene moiety; 30.18), 61 (42.78); Anal.
Calcd for C24H13ClIN3O2 (553.74): C, 52.06; H, 2.37; N,
7.59, Found: C, 52.20; H, 2.50; N, 7.30.
To equimolar amount of the aldehyde derivatives 2a,b and
2-thioxothiazolidin-4-one (0.01 mol) in dioxane (30 ml),
few drops of piperidine was added. The reaction mixture
was heated under reflux for 2 h., then allowed to cool. The
obtained product was collected by filtration and crystal-
lized from dioxane.
5-((3-(4-Chlorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)methylene)-2-thioxothiazolidin-
4-one (6a)
mp [ 300 °C. Yield 72 %. IR: t/cm-1: 3342 (NH), 1682,
1667 (2C=O). H NMR: d/ppm: 5.6 (s, 1H, CH = thia-
4-((3-(4-Fluorophenyl)-6-iodo-4-oxo-3,4-
dihydroquinazolin-2-yl)methylene)-2-phenyloxazol-5(4H)-
one (7b)
1
zolidine), 7.28–7.54 (m, 4H, ArH), 7.64 (d, 1H, C8–H
quinazoline), 8.00 (d, 1H, C7-quinazoline), 8.43 (s, 1H, C5-
quinazoline), 13.40 (s, 1H, NH); 13C NMR: 97.32, 122.21,
123.66, 125.32, 126.43, 128.54, 129.76, 130.43, 136.32,
137.87, 139.54, 140.45, 142.32, 148.54, (12C–Ar ? C=C),
164.49, (C=N), 165.60, 170.45 (2C=O), 197.06 (C=S);
Anal. Calcd for C18H9ClIN3O2S2 (525.77): C, 41.12; H,
1.73; N, 7.99; Found: C, 41.30; H, 1.60; N, 7.80.
mp 156–157 °C, Yield 71 %. IR: t/cm-1: 1714, 1687
1
(C=O). H NMR: d/ppm: 5.45 (s, 1H, CH = oxazolone),
7.45–8.53 (m, 12H, Ar–H); 13C NMR: 96.95, 116.32,
116.56, 122.43, 123.67, 124.23, 128.89, 129.23, 129.71,
130.32, 130.56, 131.23, 131,45, 132.45, 134.77, 137.65,
142.32, 146.54, 148.38, 156.32 (18C–Ar ? C=C), 164.65,
165.76 (2C=N), 166.76, 170.87 (2C=O); Anal. Calcd for
C24H13FIN3O2 (537.28): C, 53.65; H, 2.44; N, 7.82; Found:
C, 53.50; H, 2.50; N, 7.70.
5-((3-(4-Fluorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)methylene)-2-thioxothiazolidin-
4-one (6b)
Synthesis of imidazolidine derivatives 8a,b
mp [ 300 °C. Yield 70 %. IR: t/cm-1: 3233 (NH), 1676,
1664 (C=O). H NMR: d/ppm: 5.52 (s, 1H, CH = thia-
1
To a solution of the oxazolone derivatives 7a or 7b in
acetic acid (20 ml) containing sodium acetate (0.5 gm),
o-phenetidine (0.01 mol) was added. The reaction mixture
was heated under reflux for 3 h, left to cool, then poured
into crushed ice. The resulting precipitate was filtrated off,
dried, and crystallized from ethanol to give 8a,b.
zolidine), 7.25–7.65 (m, 4H, ArH), 7.74 (d, 1H, C8-H
quinazoline), 8.06 (d, 1H, C7-quinazoline), 8.32 (s, 1H,
C5-quinazoline), 13.45 (s, 1H, NH); 13C NMR: 99.34,
121.22, 122.67, 124.35, 126.54, 127.34, 129.56, 130.46,
136.43, 137.77, 139.64, 140.23, 142.43, 156.89, (12C–
Ar ? C=C), 164.56, (C=N), 165.89, 172.43 (2C=O),
197.45 (C=S); Anal. Calcd for C18H9FIN3O2S2 (509.32): C,
42.45; H, 1.78; N, 8.25; Found: C, 42.30; H, 1.60; N, 8.10.
3-(4-Chlorophenyl)-2-((1-(2-ethoxyphenyl)-5-oxo-
2-phenyl-1H-imidazol-4(5H)-ylidene)methyl)-6-
iodoquinazolin-4(3H)-one (8a)
Synthesis of the oxazolone derivatives 7a,b
mp 282–283 °C, Yield 75 %. IR: t/cm-1: 1695, 1682
(C=O); H NMR: d/ppm: 1.26 (t, 3H, CH3), 4.14 (q, 2H,
1
A
mixture of 4(3H)-quinazolinone-2-carboxaldehydes
2a,b (0.01 mol), hippuric acid (0.01 mol) and fused
sodium acetate (0.5 gm) in acetic anhydride (30 ml) was
heated under reflux for 1 h.The reaction, left to cool. The
CH2), 5.64 (s, 1H, CH = imidazolidine), 6.83–8.54 (m,
16H, Ar–H); 13C NMR: 14.67(CH3), 66.54(CH2), 96.94,
115.34, 120.32, 120.89, 121.47, 121.87, 122.43, 123.67,
123

Med Chem Res
124.23, 125.98, 126.45, 128.89, 129.23, 129.71, 130.32,
130.56, 131,45, 132.45, 134.77, 137.65, 139.37, 142.32,
143.56, 146.54, 148.38, 150.43 (24C–Ar ? C=C), 164.45,
165.67 (2C=N), 166.84, 167.23 (2C=O); Anal. Calcd for
C32H22ClIN4O3 (672.90): C, 57.12; H, 3.30; N, 8.33;
Found: C, 57.20; H, 3.40; N, 8.40.
(s, 3H, CH3), 3.24 (s, 3H, N–CH3), 7.47-8.53 (m, 12H, ArH),
9.05 (s, 1H, CH=N); 13C NMR: 19.04 (CH3), 34.98
(N–CH3), 92.98, 114.15, 114.15, 122.65, 124.59, 125.98,
125.98, 127.83, 128.87, 129.45, 129.89, 130.97, 132.87,
133.45, 134.76, 136.54, 143.34, 146.65, 146.87, 146.97
(18C–Ar ? C=C), 150.56, 151.98 (2C=N) and 157.78,
160.76 (2C=O); Anal. Calcd for C26H19FIN5O2 (579.36): C,
53.90; H, 3.31; N, 12.09; Found: C, 53.70; H, 3.40; N, 12.20.
3-(4-Fluorophenyl)-2-((1-(2-ethoxyphenyl)-5-oxo-
2-phenyl-1H-imidazol-4(5H)-ylidene)methyl)-6-
iodoquinazolin-4(3H)-one (8b)
Synthesis of the arylidene derivatives (10a,b)
mp 282–283 °C, Yield 75 %. IR: t/cm-1: 1696, 1684
(C=O). H NMR: d/ppm: 1.33 (t, 3H, CH3), 4.05 (q, 2H,
To equimolar amount of the aldehyde derivatives 2a,b and
ethyl acetoacetate (0.01 mol) in dioxane (30 ml), few
drops of piperidine was added. The reaction mixture was
heated under reflux for 2 h., then allowed to cool. The
obtained product was collected by filtration and crystal-
lized from dioxane.
1
CH2), 5.74 (s, 1H, CH = imidazolidine), 6.80–8.45 (m,
16H, Ar–H); 13C NMR: 14.68(CH3), 66.34(CH2), 96.93,
115.12, 115.78, 120.81, 121.34, 122.67, 123.45, 124.32,
125.67, 126.42, 128.80, 129.56, 130.34, 130.76, 131.32,
131.52, 132.45, 134.67, 137.57, 139.43, 142.12, 143.74,
146.82, 148.32, 150.43, 156.32(24C–Ar ? C=C), 164.23,
165.45 (2C=N), 166.34, 167.46 (2C=O); Anal. Calcd. for
C32H22FIN4O3 (656.44): C, 58.55; H, 3.38; N, 8.53; Found:
C, 58.40; H, 3.40; N, 8.60.
Ethyl 2-((3-(4-chlorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)methylene)-3-oxobutanoate (10a)
mp 240–241 °C, Yield 78 %. IR: t/cm-1: 2876 (CH-
1
aliph.), 1732, 1703, 1679 (3C=O); H NMR: d/ppm: 1.18
Synthesis of Schiff’s bases derivatives 9a,b
(t, J = 7.3 Hz 3H, CH3-ester), 2.44 (s, 3H, CH3), 4.15 (q,
J = 7.2 Hz 2H, CH2), 6.38 (s, 1H, CH=), 7.28–7.54 (m,
4H, ArH), 7.64 (d, 1H, C8-H quinazoline), 8.00 (d, 1H, C7-
quinazoline); 8.43 (s, 1H, C5-quinazoline); 13C NMR: 13.8
(CH3-ester), 28.21(CH3), 60.34 (CH2), 99.05, 122.21,
122.54, 123.66, 126.23, 128.34, 129.76, 130.45, 136.32,
137.87, 139.54, 140.45, 142.32, 148.54, (12C–Ar ? C=C),
164.49, (C=N), 165.60, 166.45 (2C=O), 197.12 (COCH3);
Anal. Calcd for C21H16ClIN2O4 (522.72): C, 48.25; H,
3.09; N, 5.36. Found: C, 48.30; H, 3.20; N, 5.50.
A
mixture of 4(3H)-quinazolinone-2-carboxaldehydes
2a,b (0.01 mol) and 4-aminoantipyrene (0.01 mol) in dioxane
(30 ml) was heated under reflux for 1 h. The reaction mixture
was concentrated under vacuum, left to cool and then cold
ethanol was added. The solid product obtained was filtered off
and crystallized from dioxane to give the final products.
3-(4-Chlorophenyl)-2-((1,5-dimethyl-3-oxo-2-phenyl-2,
3-dihydro-1H-pyrazol-4-ylimino)methyl)-6-
iodoquinazolin-4(3H)-one (9a)
Ethyl 2-((3-(4- fluorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)methylene)-3-oxobutanoate (10b)
mp 269–271 °C. Yield 72 %. IR: t/cm-1: 2898 (CH-aliph),
1685, 1678 (2C=O), 1614 (CH=N); 1H NMR: d/ppm: 2.03 (s,
3H, CH3), 3.20 (s, 3H, N–CH3), 7.43-8.41 (m, 12H, ArH),
9.15 (s, 1H, CH=N); 13C NMR: 18.98 (CH3), 34.42 (N–CH3),
92.72, 114.14, 114.14, 122.54, 124.54, 125.90, 125.90,
127.78, 128.97, 129.23, 129.75, 130.60, 132.97, 133.70,
134.68, 136.71, 143.20, 146.50, 146.58, 146.89 (18C–Ar ?
C=C), 150.78, 151.75 (2C=N) and 157.99, 160.22 (2C=O);
Anal. Calcd for C26H19ClIN5O2 (595.82): C, 52.41; H, 3.21;
N, 11.75. Found: C, 52.10; H, 3.30; N, 11.60.
mp 200–201 °C, Yield 75 %. IR: t/cm-1
:
2876
1
(CH-aliph.), 1728, 1700, 1684 (3C=O); H NMR: d/ppm:
1.15 (t, J = 7.2 Hz 3H, CH3-ester), 2.51 (s, 3H, CH3), 4.15
(q, J = 7.3 Hz, 2H, CH2), 6.56 (s, 1H, CH=), 7.41–7.59
(m, 4H, ArH), 7.67 (d, 1H, C8–H quinazoline), 8.12 (d, 1H,
C7-quinazoline); 8.47 (s, 1H, C5-quinazoline); 13C NMR:
13.68 (CH3-ester), 26.72 (CH3), 61.15 (CH2-ester), 93.75,
115.97, 116.63, 122.65, 123.79, 126.23, 129.71, 130.99,
133.60, 134.70, 134.77, 139.37, 145.38, 158.81 (12C–Ar ?
C=C), 160.89, (C=N), 161.30, 162.84 (2C=O), 199.58
(COCH3); MS, m/z (%): 506 (M?; 0.26), 491 (M-CH3;
2.42;), 435 (M-COCH3; 0.33), 366 (M-C7H8O3; 100), 245
(9.79), 234 (M-C7H8IO3; 10.07), 183 (18.01), 122 (10.72),
95 (C6H4F; 86.38), 88 (22.84), 74 (89.35), 62 (43.27);
Anal. Calcd for C21H16FIN2O4 (506.27): C, 49.82; H, 3.19;
N, 5.53. Found: C, 49.80; H, 3.20; N, 5.60.
3-(4-Fluorophenyl)-2-((1,5-dimethyl-3-oxo-2-phenyl-2,
3-dihydro-1H-pyrazol-4-ylimino)methyl)-6-iodoquinazolin-
4(3H)-one (9b)
mp 275–277 °C. Yield 70 %. IR: t/cm-1: 2930 (CH-aliph),
1
1671, 1654 (2C=O), 1598 (CH=N); H NMR: d/ppm: 2.06
123

Med Chem Res
Synthesis of the pyrazole derivatives 11a,b
(512.73): C, 53.88; H, 2.75; N, 5.46, Found: C, 53.60; H,
2.40; N, 5.30.
A solution of the arylidene derivatives 10a or 10b
(0.01 mol) in ethanol (20 ml) was treated with hydrazine
hydrate (0.012 mol). The reaction mixture was heated
under reflux for 4 h, left to cool. The solid product obtained
was filtered off and crystallized from ethanol to give 11a,b.
3-(4-Fluorophenyl)-6-iodo-2-(3-oxo-3-phenylprop-
1-enyl)quinazolin-4(3H)-one (12b)
mp 242–244 °C, Yield 75 %. IR: t/cm-1: 1707, 1695
1
(2C=O); H NMR: d/ppm: 6.85–6.94 (2d, 2H, CH=CH),
7.22–8.48 (m, 12H, Ar–H); 13C NMR: 96.97, 116.32,
116.67, 121.65, 123.32, 124.76, 128.87, 129.23, 129.57,
130.12, 130.87, 131.12, 131.32, 132.43, 137.75, 139.56,
142.23, 143.86, 148.34, 156.54 (18C–Ar ? C=C), 165.12
(C=N), 166.34, 168.56 (2C=O); Calcd for C23H14FIN2O2
(496.27): C, 55.66; H, 2.84; N, 5.64; Found: C, 55.40; H,
2.50; N, 5.70.
2-(4-Acetyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-
3-(4-chlorophenyl)-6-iodoquinazolin-4(3H)-one (11a)
mp 282–283 °C, Yield 75 %. IR: t/cm-1: 3453, 3376,
(NH), 1708, 1695, 1667 (3C=O); 1H NMR: d/ppm: 2.27 (s,
3H, CH3), 7.23–8.56 (m, 7H, Ar–H), 9.45, 9.87 (2s, 2H,
2NH); 13C NMR: 24.34 (CH3), 96.34, 118.34, 121.89,
121.97, 123.67, 125.98, 128.89, 129.23, 129.71, 131,45,
134.77, 137.45, 146.54, 148.38 (12C–Ar ? C=C), 164.46
(C=N), 166.84, 167.23, 198.23 (3C=O); Anal. Calcd for
C19H12ClIN4O3 (506.68): C, 45.04; H, 2.39; N, 11.06;
Found: C, 45.20; H, 2.40; N, 11.20.
Synthesis of the pyrazoline derivatives 13a,b
A solution of the chalcone derivatives (12a,b) (0.01 mol)
and hydrazine hydrate (0.012 mol) in ethanol (20 ml) was
heated under reflux for 4 h, left to cool. The solid product
obtained was filtered off and crystallized from ethanol to
give 13a,b.
2-(4-Acetyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-
3-(4-fluorophenyl)-6-iodoquinazolin-4(3H)-one (11b)
mp 276–278 °C, Yield 71 %. IR: t/cm-1: 3565, 3399,
(NH), 1698, 1687, 1664 (3C=O); 1H NMR: d/ppm: 2.34 (s,
3H, CH3), 7.20–8.45 (m, 7H, Ar–H), 9.43, 9.80 (2s, 2H,
2NH); 13C NMR: 24.62 (CH3), 96.30, 116.45, 116.89,
121.89, 123.56, 125.64, 128.82, 129.78, 129.97, 131,23,
134.56, 137.43, 146.34, 156.43 (12C–Ar ? C=C), 164.23
(C=N), 166.56, 167.45, 198.12 (3C=O); Anal. Calcd for
C19H12FIN4O3 (490.23): C, 46.55; H, 2.47; N, 11.43;
Found: C, 46.30; H, 2.30; N, 11.20.
3-(4-Chlorophenyl)-6-iodo-2-(3-phenyl-4,5-dihydro-
1H-pyrazol-5-yl)quinazolin-4(3H)-one (13a)
mp 254–255 °C, Yield 67 %. IR: t/cm-1: 3241 (NH), 1676
(C=O); 1H NMR: d/ppm: 3.10 (dd, 1H, H-pyrazoline), 3.77
(dd, 1H, H-pyrazoline), 5.53 (dd, 1H, H-pyrazoline),
7.32–8.43 (m, 12H, Ar–H), 12.32(s, 1H, NH); Calcd for
C23H16ClIN4O (526.76): C, 52.44; H, 3.06; N, 10.64;
Found: C, 52.50; H, 3.00; N, 10.50.
Synthesis of the chalcone derivatives 12a,b
3-(4-Fluorophenyl)-6-iodo-2-(3-phenyl-4,5-dihydro-
1H-pyrazol-5-yl)quinazolin-4(3H)-one (13b)
A mixture of the aldehyde derivatives 2a,b (0.01 mol),
acetophenone (0.01 mol) and piperidine (1 ml) in dioxane
(20 ml) was heated under reflux for 4 h, left to cool. The
solid product obtained was filtered off and crystallized
from ethanol to give 12a,b.
mp 277–278 °C, yield 69 %. IR: t/cm-1: 3254 (NH), 1674
(C=O); 1H NMR: d/ppm: 3.13 (dd, 1H, H-pyrazoline), 3.76
(dd, 1H, H-pyrazoline), 5.66 (dd,1H, H-pyrazoline),
7.24–8.46 (m, 12H, Ar–H), 12.56 (s, 1H, NH); Calcd for
C23H16FIN4O (510.30): C, 54.13; H, 3.16; N, 10.98,
Found: C, 54.30; H, 2.90; N, 11.10.
3-(4-Chlorophenyl)-6-iodo-2-(3-oxo-3-phenylprop-
1-enyl)quinazolin-4(3H)-one (12a)
Synthesis of arylidene derivatives 14a,b
mp 232–234 °C, Yield 73 %. IR: t/cm-1: 1708, 1682
(2C=O); H NMR: d/ppm: 7.46–7.59 (2d, 2H, CH=CH),
1
To equimolar amount of the aldehyde derivatives 2a,b and
malononitrile (0.01 mol) in dioxane (30 ml), few drops of
piperidine was added. The reaction mixture was heated
under reflux for 2 h. then allowed to cool, the obtained
product was collected by filtration and crystallized from
dioxane.
7.60-8.46 (m, 12H, Ar–H); 13C NMR: 95.79, 123.60,
128.03, 128.44, 128.57, 128.82, 129.12, 129.30, 129.51,
130.18, 131.18, 132.14, 133.37, 133.42, 134.52, 134.64,
136.10, 142.97, 143.67, 145.24, (18C–Ar ? C=C), 147.48
(C=N), 158.59, 185.87 (2C=O); Calcd for C23H14ClIN2O2
123

Med Chem Res
2-((3-(4-Chlorophenyl)-6-iodo-4-oxo-
3,4-dihydroquinazolin-2-yl)methylene)malononitrile (14a)
(660.85): C, 52.71; H, 2.75; N, 12.72, Found: C, 52.60; H,
2.50; N, 12.50.
mp 256–258 °C, yield 76 %. IR: t/cm-1: 2223 (CN), 1689
(C=O); 1H NMR: d/ppm: 7.76–8.65 (m, 8H, ArH ? CH=);
13C NMR: 91.34, 95.98, 111.87, 113.23, 116.56, 116.75,
123.54, 129.98, 131.23, 131.56, 131.78, 134.98, 143.87,
144.87, 146.99, 150.98 (12C–Ar ? C=C ? 2CN), 161.87
(C=N), 163.98, (C=O); Anal. Calcd. for C18H8ClIN4O
(458.64): C, 47.14; H, 1.76; N, 12.22; Found: C, 47.20; H,
1.80; N, 12.30.
6-Amino-4-(3-(4-fluorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)-1-(2-ethoxyphenyl)-2-oxo-
1,2-dihydropyridine-3,5-dicarbonitrile (15b)
mp 245–246 °C, yield 68 %. IR: t/cm-1: 3257, 3241
(NH2), 2222, 2216(2CN), 1696, 1674 (2C=O); H NMR:
1
d/ppm: 1.33 (t, 3H, CH3-ethoxy), 4.34(q, 2H, CH2-ethoxy),
6.78-8.54(m, 11H, Ar–H), 913 (s, 2H, NH2); 13C NMR:
15.01 (CH3-ethoxy), 58.41 (CH2-ethoxy), 117.12, 117.76
(2CN), 76.38, 96.67, 110.45, 115.46, 119.77, 120.34,
120.87, 121.39, 121.98, 124.12, 124.76, 126.67, 129.23,
129.56, 130.67, 131.34, 137.56, 142.12, 143.56, 148.45,
154.34, 158.56 (18C–Ar ? 4C-pyridyl), 163.34 (C=N),
166.56, 167.78 (2C=O); Calcd for C29H18FIN6O3 (644.39):
C, 54.03; H, 2.82; N, 13.04, Found: C, 54.20; H, 2.50; N,
13.10.
2-((3-(4-Fluorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)methylene)malononitrile (14b)
mp 246–247 °C Yield 77 %. IR: t/cm-1: 2218(CN),
1687(C=O). 1H NMR: d/ppm: 7.46–8.48 (m, 8H,
ArH ? CH=); 13C NMR: 91.15, 95.45, 111.82, 113.08,
116.67, 116.86, 123.46, 129.66, 131.16, 131.24, 134.97,
143.81, 144.93, 146.99, 150.42, 159.18 (12C–Ar ?
C=C ? 2CN), 161.55 (C=N), 163.52(C=O); Anal. Calcd.
for C18H8FIN4O (442.19): C, 48.89; H, 1.82; N, 12.67;
Found: C, 48.70; H, 1.90; N, 12.40.
Synthesis of arylidene derivatives 16a,b
To equimolar amount of the aldehyde derivatives 2a,b and
barbituric acid (0.01 mol) in dioxane (30 ml), few drops of
piperidine was added. The reaction mixture was heated
under reflux for 2 h. then allowed to cool. The obtained
product was collected by filtration and crystallized from
dioxane.
Synthesis of pyridinone derivatives 15a,b
Method A: to a mixture of the arylidene derivatives
14a,b (0.01 mol) and N-ethoxyphenylcyanoacetanilide
(0.01 mol) in ethanol (20 ml), piperidine (0.5 ml) was
added. The reaction mixture was heated under reflux for
3 h, left to cool and the obtained product was filtered off,
crystallized from ethanol to give (15a,b).
5-((3-(4-Chlorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)methylene)pyrimidine-
2,4,6(1H,3H,5H)-trione (16a)
Method B: A mixture of the aldehyde derivatives 2a,b,
malononitrile (0.01 mol), N-ethoxyphenyl cyanoacetani-
lide (0.01 mol) and piperidine (0.5 ml) in dioxane (20 ml),
was heated under reflux for 3 h, left to cool. The solid
product obtained was filtered off and crystallized to give
15a,b.
mp 225–227 °C, Yield 78 %. IR: t/cm-1: 3343, 3227
(2NH), 1683, 1676, 1664 (C=O). 1H NMR: d/ppm: 6.78 (s,
1H, CH=), 7.56-8.45 (m, 7H, ArH), 10.23, 10.56 (2s, 2H,
2NH); 13C NMR: 95.98, 122.45, 122.76, 123.79, 126.23,
129.71, 130.99, 133.60, 134.70, 134.77, 137.65, 138,34,
139.37, 145.38, (12C–Ar ? C=C), 152.58 (C=O); 164.89,
(C=N); 165.84, 167.43, 167.87 (3C=O); MS, m/z (%):
520 (M?, 5.13), 522 (M ? 2, 3.47), 410 (2.92), 382
(M-C5H2N2O3; 23.32), 354 (3.15), 245 (6.75), 190 (3.14),
128 (barbituric acid; 100), 110 (25.79), 100 (31.03), 85
(84.38), 74 (22.94); Anal. Calcd for C19H10ClIN4O4
(520.66): C, 43.83; H, 1.94; N, 10.76; Found: C, 43.70; H,
1.70; N, 10.60.
6-Amino-4-(3-(4-chlorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)-1-(2-ethoxyphenyl)-2-oxo-
1,2-dihydropyridine-3,5-dicarbonitrile (15a)
mp 265–266 °C, Yield 66 %. IR: t/cm-1: 3247, 3234
(NH2), 2223, 2218(2CN), 1698, 1676 (2C=O); H NMR:
1
d/ppm: 1.55 (t, 3H, CH3-ethoxy), 4.21(q, 2H, CH2-ethoxy),
7.12–8.48(m, 11H, Ar–H), 8.90(s, 2H, NH2); 13C NMR:
15.01 (CH3-ethoxy), 58.41 (CH2-ethoxy), 116.87, 116.98
(2CN), 76.34, 96.25, 110.32, 115.43, 119.56, 120.12,
120.87, 121.37, 121.78, 124.34, 124.87, 126.23, 129.43,
129.23, 130.34, 131.34, 137.59, 142.23, 143.89, 148.45,
150,56, 158.43 (18C-Ar ? 4C-pyridyl), 163.13 (C=N),
166.34, 167.43 (2C=O); Calcd for C29H18ClIN6O3
5-((3-(4-Fluorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)methylene)pyrimidine-
2,4,6(1H,3H,5H)-trione (16b)
mp 213–215 °C, Yield 78 %. IR: t/cm-1: 3319, 3228
(2NH), 1687, 1672, 1660 (C=O). 1H NMR: d/ppm: 6.45 (s,
123

Med Chem Res
1H, CH=), 7.45-8.34 (m, 7H, Ar–H), 10.45, 10.98 (2s, 2H,
2NH); 13C NMR: 96.56, 116.12, 116.45, 123.79, 126.23,
129.71, 130.99, 133.60, 134.70, 134.77, 137.65, 138,34,
139.37, 156.43, 157.32 (12C–Ar ? C=C ? C=O), 164.76,
(C=N), 165.76, 167.44, 167.89 (3C=O); Anal. Calcd for
C19H10FIN4O4 (504.21): C, 45.26; H, 2.00; N, 11.11;
Found: C, 45.40; H, 1.90; N, 11.00.
(564.37): C, 46.82; H, 3.21; N, 9.93, Found: C, 46.60; H,
3.30; N, 9.70.
References
Alafeefy AM, Kadi AA, Al-Deeb OA, El-Tahir KEH, Al-Jaber NA
(2010) Synthesis, analgesic and anti-inflammatory evaluation
of some novel quinazoline derivatives. Eur J Med Chem
45:4947–4952
Synthesis of pyrimidine derivatives 17a,b
Alagarsamy V, Murugesan S (2007) Synthesis and pharmacological
evaluation of some 3-(4-methoxyphenyl)-2-substitutedamino-
quinazolin-4(3H)-ones as analgesic and anti-inflammatory agent.
Chem Pharm Bull 55:76–80
Method A:
a mixture of the aldehyde derivatives
2a,b (0.01 mol), thiourea (0.01 mol), ethyl acetoacetate
(0.01 mol) and few drops of conc. HCl in dioxane (20 ml)
was heated under reflux for 3 h, left to cool. The solid
product obtained was filtered off and crystallized from
dioxane to give 17a,b.
Aly MM, Mohamed YA, El-Bayouki KAM, Basyouni WM, Abbas
SY (2010) Synthesis of some new 4(3H)-quinazolinone-2-
carboxaldehyde thiosemicarbazones and their metal complexes
and a study on their anticonvulsant, analgesic, cytotoxic and
antimicrobial activities—Part-1. Eur J Med Chem 45:3365–3373
Balakumar C, Lamba P, Pran KD, Lakshmi NB, Venkat RK,
Rajwinder K, Raghuram RA, Shireesha B, Narsaiah B (2010)
Synthesis, anti-inflammatory evaluation and docking studies of
some new fluorinated fused quinazolines. Eur J Med Chem
45:4904–4913
Buckley GM, Davies N, Dyke HJ, Gilbert PJ, Hannah DR, Yaughan
AF, Hunt CA, Pitt WR, Profit RH, Ray NC, Richard MD, Sharpe
A, Taylor AJ, Whitworth JM, Williams SC (2005) Quinazolin-
ethiones and quinazolinediones, novel inhibitors of inosine
monophosphate dehydrogenase: synthesis and initial structure-
activity relationships. Bioorg Med Chem Lett 15:751–754
Chandrika PM, Yakaiah T, Rao ARR, Narsaiah B, Reddy NC, Sridhar
V, Rao JV (2008) Synthesis of novel 4,6-disubstituted quinaz-
oline derivatives, their anti-inflammatory and anti-cancer activity
(cytotoxic) against U937 leukemia cell lines. Eur J Med Chem
43:846–852
Chao Q, Deng L, Shih H, Leoni LM, Genini D, Carson DA, Cottam
HB (1999) Substituted isoquinolines and quinazolines as
potential antiinflammatory agents. synthesis and biological
evaluation of inhibitors of tumor necrosis factor a. J Med Chem
42:3860–3873
Charlier RPM, Binon F, Deltour G (1961) Arch Intern Pharmacodyn
134:306
Chou R, Fanciullo GJ, Fine PG, Adler JA, Ballantyne JC, Davies P
(2009) Clinical guidelines for the use of chronic opioid therapy
in chronic noncancer pain. J Pain 10:113–130
Method B: a mixture of the arylidene derivatives
10a,b (0.01 mol), thiourea (0.01 mol) and few drops of
conc. HCl in ethanol (20 ml) was heated under reflux for
3 h, left to cool. The solid product obtained was filtered off
and crystallized from dioxane to give 17a,b.
Ethyl 4-(3-(4-chlorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)-6-methyl-2-thioxo-1,2,3,
4-tetrahydropyrimidine-5-carboxylate (17a)
mp 243–244 °C, Yield 62 %. IR: t/cm-1: 3241, 3214
(2NH), 1723, 1675 (2C=O); 1H NMR: d/ppm: 1.54 (t,
J = 7.2 Hz, 3H, CH3-ester), 1.89 (s, 3H, CH3), 4.23(q,
J = 7.3 Hz, 2H, CH2-ester), 4.77(d, 1H, CH), 7.32-8.43(m,
7H, Ar–H), 10.13, 10.54(2 s, 2H, 2NH); 13C NMR: 18.34
(CH3-ester), 18.43 (CH3), 58.43 (CH2-ester), 54.43 (C4-
pyrimidine), 104.54, 154.45(C-5, C6-pyrimidine), 96.43,
121.35, 121.68, 124.34, 129.43, 129.23, 130.34, 131.34,
137.59, 142.23, 143.89, 148.45 (12C–Ar), 163.13 (C=N),
166.34 (C=O), 167.12 (C=O), 178.32 (C=S); Calcd for
C22H18ClIN4O3S (580.83): C, 45.49; H, 3.12; N, 9.65;
Found: C, 45.60; H, 3.22; N, 9.48.
Eccles R (2006) Efficacy and safety of over-the-counter analgesics in
the treatment of common cold and flu. J Clin Pharm Ther
31:309–319
Ethyl 4-(3-(4-fluorophenyl)-6-iodo-4-oxo-3,
4-dihydroquinazolin-2-yl)-6-methyl-2-thioxo-1,2,3,
4-tetrahydropyrimidine-5-carboxylate (17b)
Harris RE, Alshafie GA, Abou-Issa H, Seibert K (2000) Chemopre-
vention of breast cancer in rats by Celecoxib, a cyclooxygenase 2
inhibitor. Cancer Res 60:2101–2103
Karegoudar P, Prasad DJ, Ashok M, Mahalinga M, Poojary B, Holla
BSh (2008) Synthesis, antimicrobial and anti-inflammatory
activities of some 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles and
1,2,4-triazolo[3,4-b][1,3,4]thiadiazines bearing trichlorophenyl
moiety. Eur J Med Chem 43:808–815
Kumar A, Sharma S, Bajaj K, Panwara H, Singla T, Srivastava VK
(2003) Some new 2,3,6-trisubstituted quinazolinones as potent
anti-inflammatory, analgesic and COX-II inhibitors. Bioorg Med
Chem 11:5293–5299
Laddha SS, Wadodkar SG, Meghal SK (2006) Studies on some
biologically active substituted 4(3H)-quinazolinones. Part 1.
Synthesis, characterization and anti-inflammatory-antimicrobial
activity of 6,8-disubstituted 2-phenyl-3-[substituted-benzothia-
zol-2-yl]-4(3H)-quinazolinones. Arkivoc XI:1–20
mp 263–264 °C, Yield 62 %. IR: t/cm-1: 3245, 3234
(2NH), 1714, 16765 (2C=O); 1H NMR: d/ppm: 1.54 (t, 3H,
CH3-ester), 1.90 (s, 3H, CH3), 4.54(q, 2H, CH2-ester),
4.75(d, 1H, CH), 7.13–8.23 (m, 7H, Ar–H), 10.34,
10.65(2s, 2H, 2NH); 13C NMR: 18.30 (CH3-ester), 18.41
(CH3), 58.48 (CH2-ester), 54.12 (C4-pyrimidine), 104.52,
154.40(C5-, C6-pyrimidine), 96.43, 115.34, 115.98, 121.35,
124.34, 129.23, 130.34, 131.34, 137.59, 142.23, 143.89,
154.32 (12C-Ar), 163.24 (C=N), 166.56 (C=O), 167.08
(C=O), 178.76 (C=S); Calcd for C22H18ClFN4O3S
123

Med Chem Res
Meier R, Schuler W, Desaullus P (1950) Experientia 6:469
Piaz VD, Giovannoni MP (2000) Phosphodiesterase 4 inhibitors,
structurally unrelated to Rolipram, as promising agents for the
treatment of asthma and other pathologies. Eur J Med Chem
35:463–480
Rajendra P, Bhaduri AP (1979) Ind J Chem 18B(5):443
Rathee P, Chaudhary H, Rathee S, Rathee D, Kumar V, Kohli K
(2009) Mechanism of action of flavonoids as anti-inflammatory
agents: a review. Inflamm Allergy Drug Targets 3:229–235
Rioja I, Terencio MC, Ubeda A, Molina P, Tarraga A, Tejero AG,
Alkaraz MJ (2002) A pyrroloquinazoline derivative with anti-
inflammatory and analgesic activity by dual inhibition of cyclo-
oxygenase-2 and 5-lipoxygenase. Eur J Pharmacol 434:177–185
Sastry CVR, Marwah P, Marwah AK, Rao GS (1989) Ind J Chem
28B:885
Sng BL, Schug SA (2009) The role of opioids in managing chronic
non-cancer pain Ann. Acad Med Singap 38:960–966
Sokai S, Kubo A, Katsuura K, Mochinaya K, Ezak M (1972) Chem
Pharm Bull 20:76–81
Tobe M, Isobe Y, Tomizawa H, Matsumoto M, Obara F, Nagasaki T,
Hayashi H (2001) Structure-activity relationships of quinazoline
derivatives: dual-acting compounds with inhibitory activities
toward both TNF-a production and T Cell proliferation. Bioorg
Med Chem Lett 11:545–548
Tobe M, Isobe Y, Tomizawa H, Nagasaki T, Takahashi H, Fukazawa
T, Hayashi H (2003) Discovery of quinazolines as a novel
structural class of potent inhibitors of NF-jB activation. Bioorg
Med Chem 11:383–389
Winter CA, Risly EA, Nuss GW (1962) Proc Soc Exp Biol Med
111:544
Schlapbach A, Heng R, Padov FD (2004) A novel Pd-catalyzed
cyclization reaction of ureas for the synthesis of dihydroquinaz-
olinone kinase inhibitors. Bioorg Med Chem Lett 14:357–360
123