Synthesis and antitumor activity of some 2, 3-disubstituted quinazolin-4(3H)-ones and 4, 6- disubstituted- 1, 2, 3, 4-tetrahydroquinazolin- 2H-ones

Article abstract of DOI:10.1016/j.ejmech.2010.10.008

The synthesis of some new 3-substituted quinazolin-4(3H)-ones and 3,4-dihydro-quinazolin-2(1H)-one derivatives and their biological evaluation as antitumor agents using the National Cancer Institute (NCI), disease oriented antitumor screening protocol are

Full text of DOI:10.1016/j.ejmech.2010.10.008

European Journal of Medicinal Chemistry 45 (2010) 6058e6067
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antitumor activity of some 2, 3-disubstituted quinazolin-4(3H)-
ones and 4, 6- disubstituted- 1, 2, 3, 4-tetrahydroquinazolin-2H-ones
*
Nagwa M. Abdel Gawad, Hanan H. Georgey , Riham M. Youssef, Nehad A. El-Sayed
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, El-Kasr El-Eini Street, 11562, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of some new 3-substituted quinazolin-4(3H)-ones and 3,4-dihydro-quinazolin-2(1H)-one
derivatives and their biological evaluation as antitumor agents using the National Cancer Institute (NCI),
disease oriented antitumor screening protocol are investigated. Compounds 2-[2-(4-chlorophenyl)-
2-oxo-ethylthio]-3-(4-methoxyphenyl)quinazolin-4(3H)-one (3b), and 3-(4-chlorophenyl)-2-[2-(4-
methoxyphenyl)-2-oxo-ethylthio]quinazolin-4(3H)-one (3d), are broad-spectrum antitumors showing
effectiveness toward numerous cell lines that belong to different tumor subpanels, Compounds 3b, 3d
are the most active members in this study. Those two quinazoline analogues could be considered as
useful templates for future development to obtain more potent antitumor agent(s).
Received 8 June 2010
Received in revised form
30 September 2010
Accepted 10 October 2010
Available online 15 October 2010
Keywords:
Synthesis
Quinazolinone
Thiadiazole
Ó 2010 Elsevier Masson SAS. All rights reserved.
Antitumor screening
1. Introduction
2. Results and discussion
Quinazolines are considered to be an important chemical syn-
thon of various physiological significance and pharmaceutical
utility. They possess variety of biological effects including antihy-
pertensive [1,2], antimicrobial [3,4], antihyperlipidemic [5,6] anti-
inflammatory [7,8] and anticonvulsant [9e13] activities. Moreover,
many quinazolines contributed to the quest for an ultimate anti-
tumor chemotherapeutic agent [14e18]. It was reported that 2-
thioxo-3-substituted quinazolinones (I) [19] and their S-methyl
thioether counterparts (II), in addition to the 6-substituted
quinazolinone derivatives (III) [20] showed promising antitumor
potency, (Chart 1).
The aforementioned compounds have inspired the idea of
synthesizing hybrid derivatives where heterocyclic moieties
reported to possess antitumor activity, such as thiadiazole [21],
imidazole [22], uracil [23] and sulfonamides [24] could be incor-
porated into the quinazoline nucleus. In the present study, a new
series of substituted quinazolinone derivatives were designed to be
combined with imidazole, thiadiazole, and pyrimidine heterocy-
cles, in addition to substituted phenyl moieties, in one molecule, as
hybrid compounds anticipated acquiring antitumor efficacy.
2.1. Chemistry
The strategy to synthesize the target quinazoline derivatives is
depicted in Schemes 1e3. 3-Substituted-2-thioxo-2,3-dihydro-
quinazolin-4(1H)-ones (1aed) were synthesized according to
reported methods [25e28]. Compounds 1aed were then reacted
with the appropriate freshly prepared substituted phenacyl
bromides 2a,b [29] to yield 2-(2-(4-substituted phenyl)-2-oxo-eth-
ylthio)-3-substituted-quinazolin-4(3H)-ones (3aee). On the other
hand, the reaction of 1aed with dimethyl sulphate in ethanolic
sodium hydroxide afforded the 2-methylthio derivatives 4aed
[25e28]. Nucleophilic displacement of the eSCH3 function of 4aed
by 2-amino-5-aryl-10,30,40-thiadiazoles (5aec), produced the target
compounds 2-(5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl-
amino)-3-substituted-quinazolin-4(3H)-ones (6aef); Scheme 1.
Further nucleophilic displacements of the 2-SCH3 function in 4aed
using imidazole, 6-aminouracil, substituted sulfonamides and 6-
amino-2-mercaptopyrimidin-4-ol afforded the corresponding
derivatives 7aed, 8aed, 9aeg and 10aed respectively; Scheme 2.
Fusion of 1,10-(4-substituted-phenyl-methylene)diurea derivatives
(11a,b) with different aromatic amines such as 4-aminobenzoic acid,
4-methylaniline and sulfapyridine afforded the corresponding
target compounds 4-(4-substituted phenyl)-2-oxo-1,2,3,4-tetrahy-
dro-quinazoline-6-carboxylic acids (12a,b); 4-(4-substituted-
phenyl)-6-methyl-3,4-dihydro-quinazolin-2(1H)-ones (15a,b) and
* Corresponding author. Tel.: þ20 1 75600699; fax: þ20 2 23628426.
E-mail address: hanan-hanna@hotmail.com (H.H. Georgey).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.10.008

N.M. Abdel Gawad et al. / European Journal of Medicinal Chemistry 45 (2010) 6058e6067
6059
Regarding the activity toward individual cell lines; compounds
6f and 8c showed selective potency against leukemia K-562 and
MOLT-4 cell lines with GI values of 52.0 and 34.6%, respectively;
while ovarian cancer IGORV1 proved to be selectively sensitive to 8b
with GI value of 72.3%. Compounds 8d and 10a showed activity
against CNS cancer SF-295 with GI values of 80.8 and 59.9%,
respectively. Compounds 17a and 18b showed GI values of 43.9%
and 40.5% against breast T-47D and renal UO-31 cancer cells,
respectively. Meanwhile, 3b showed a remarkable activity against
non small cell lung cancer NCI-H226, melanoma UACC-62, and
breast cancer HS 578T with GI values of 75.6, 68.6, and 80.6%,
respectively; 3d showed GI effectiveness against CNS cancers SNB-
75, U251; and ovarian cancer OVCAR-8 with values of 71.1, 65.1, and
76.2%, respectively; 6a and 7b showed remarkable potency against
ovarian cancer IGORV1 and non small cell lung cancer HOP-92 with
GI values of 65.9 and 76.6%, respectively. In addition, compounds 3c
and 6c proved lethal to the ovarian cancer cell line OVCAR-8; the
same was observed in case of 4d and 7d toward non small cell lung
cancer HOP-92. With regard to broad-spectrum antitumor activity;
close examination of the data presented in Tables 1 and 2, revealed
that compounds 3b and 3d are the most active members of this
study, showing effectiveness toward numerous cell lines that belong
to different tumor subpanels. The same analogy indicated that 14a
possess a moderate antitumor activity, while compounds 3e, 4c, 9c
and 10c possess selective potency toward leukemia cell lines; and
17b possess selective activity toward breast cancer cell lines.
Chart 1.
4-(4-substituted-phenyl)-2-oxo-N-(pyridin-2-yl)-1,2,3,4-tetrahyd-
ro-quinazoline-6-sulfonamides (18a,b), respectively. Compounds
12a,b were converted to their corresponding acid chlorides 13a,b
and allowed to react with 2-aminopyridine to yield 4-(4-
substituted-phenyl)-2-oxo-N-(pyridin-2-yl)-1,2,3,4-tetrahydro-qu-
inazoline-6-carboxamide (14a,b). The 6-methyl groups of 15a,b
were brominated using NBS to give the 6-bromomethyl derivatives
16a,b which were subsequently reacted with 2-aminopyridine to
afford the targets 4-(4-substituted-phenyl)-6-(pyridin-2-yl-ami-
nomethyl)-3,4-dihydro-quinazolin-2(1H)-one (17a,b); Scheme 3.
2.2. Preliminary in-vitro antitumor screening
The synthesized compounds (3e18; Schemes 1e3), were sub-
jected to the NCI’s disease-oriented human cell lines screening
assay to be evaluated for their in-vitro antitumor activity. A single
high dose (10 mM) of the test compounds were used in the full NCI
60 cell lines panel assay which includes nine tumor subpanels
namely; leukemia, non small cell lung cancer, colon, CNS, mela-
noma, ovarian, renal, prostate, and breast cancer cells [30e33]. The
data were reported as mean graph of the percent growth of treated
cells, and presented as percentage growth inhibition (GI %), Tables 1
and 2. The obtained results of the tested quinazoline derivatives
3aee, 4a, 4c, 4d, 6a, 6c, 7aed, 9c, 9d, 10c, 14a, b and 17d showed GI
values >30%, distinctive potential pattern of selectivity, as well as
broad-spectrum antitumor activity.
2.3. Structureeactivity correlation
Structureeactivity correlation, based on the number of cell lines
proved sensitive toward each of the synthesized individual
compounds, revealed that, 3-substituted quinazolin-4(3H)-ones
heterocycles (3e10) are more active antitumors than 3,4-dihydro-
quinazolin-2(1H)-one counterparts (12e18). The presence of
aromatic substitution at position 3- of the quinazolin-4(3H)-one
nucleus proved essential for activity rather than the aliphatic
O
O
Br
R1
N
R1
K2CO3
N
R2
+
R2
N
H
S
N
S
O
2a,b
1a-d
3a-e
O
R1 = Et, Ph, 4-ClPh, 4-CH3OPh
R2 = Cl, CH3O
(CH3)2SO4
R2
H2N
N
N
O
O
S
R1
N
R1
K2CO3
N
S
N
+
N
SCH3
N
N
N
H
R2
5a-c
4a-d
6 a-f
R1 = Et, Ph, 4-ClPh, 4-CH3OPh
R2 = Cl, CH3O, N(CH3)2
Scheme 1. Syntheses of the target compounds 3aee, 4aed and 6aef.

6060
N.M. Abdel Gawad et al. / European Journal of Medicinal Chemistry 45 (2010) 6058e6067
O
R1
N
N
N
N
7a-d
N
H
N
NH2
N
NH2
O
N
O
N
O
O
SH
N
N
R1
R1
R1
N
H
N
N
HO
O
N
N
N
NH
OH
N
HO
SH
N
H
N
H
OH
N
SCH3
8a-d
4a-d
10a-d
NH2
SO2NHR2
O
N
R1
SO2NHR2
N
N
H
R1 = Et, Ph, 4-ClPh, 4-CH3OPh
R2 = H, guanidino.
9a-g
Scheme 2. Syntheses of the target compounds 7aed, 8aed, 9aeg, and 10aed.
R1
R1
R1
N
O
HOOC
ClOC
NH
SOCl2/benzene
NH
N
H
NH
H2N
N
N
H
O
N
H
O
N
H
O
13a,b
12a,b
14a,b
COOH
R1
R1
NH
2
NH
2
H3C
H2NOCHN
H2NOCHN
BrH2C
H C
3
NH
NBS/DMF
NH
R1
N
H
O
N
H
O
11a.b
15a,b
16a,b
N
SO2NH
H2N
N
NH2
R1
R1
R1 = Cl, CH3O
N
S
O
N
HN
N
H
NH
NH
O
N
H
O
N
H
O
18a,b
17a,b
Scheme 3. Syntheses of the target compounds 14a,b, 15a,b, 17a,b, and 18a,b.

N.M. Abdel Gawad et al. / European Journal of Medicinal Chemistry 45 (2010) 6058e6067
6061
Table 1
Percentage growth inhibition (GI %) of in-vitro subpanel tumor cell lines at 10
m
M concentration of compounds 3ae6c.
Subpanel tumor cell lines
% Growth Inhibition (GI %)a
Compd
3a
3b
3c
3d
3e
4a
4c
4d
6a
6c
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
SR
RPMI-8226
Non small cell lung cancer
A549/ATCC
HOP-92
NCI-H226
NCI-H23
NCI-H522
Colon cancer
COLO 205
HCT-116
e
e
e
e
e
e
e
e
e
nt
e
e
nt
nt
e
70.3
43.0
nt
49.4
34.9
nt
49.5
34.8
e
nt
e
e
e
e
e
e
e
e
e
e
e
e
e
33.3
nt
e
32.0
44.1
31.4
nt
e
nt
e
30.1
e
e
e
e
e
e
nt
nt
e
35.8
e
e
nt
nt
75.6
41.1
23.0
e
e
e
e
e
nt
nt
e
30.8
e
e
e
e
e
e
e
e
L
e
e
e
e
e
e
e
e
e
e
60.8
e
e
e
e
e
e
e
e
e
e
52.6
e
e
e
31.9
e
e
e
53.1
54.6
41.8
e
e
e
48.9
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
58.9
e
KM12
e
e
CNS cancer
SF-268
SF-539
SNB-75
U251
e
e
e
e
49.0
68.6
47.4
31.6
e
e
e
e
48.8
48.6
71.1
65.1
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
Melanoma
M14
e
e
e
e
e
e
e
e
e
38.4
34.2
37.3
42.2
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
SK-MEL-2
SK-MEL-28
UACC-62
Ovarian cancer
IGORV1
OVCAR-4
OVCAR-8
SK-OV-3
e
e
76.7
43.7
e
45.7
32.1
nt
e
e
L
48.9
53.5
76.2
44.7
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
65.9
e
e
e
L
nt
e
e
31.9
e
e
e
Renal cancer
786e0
CAKI-1
SN12C
UO-31
e
e
e
e
31.1
nt
32.5
e
e
41.3
nt
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
nt
e
42.9
e
e
e
31.6
37.2
30.3
e
Prostate cancer
PC-3
nt
55.3
e
e
e
e
50.3
e
e
e
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578T
T-47D
MDA-MB-468
e
e
e
e
e
34.3
33.3
80.6
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
40.9
e
e
e
e
e
e
e
47.0
e
41.4
35.4
30.8
a
e, GI ‘ 30%; nt, not tested; L, compound proved lethal to the cancer cell line.
substituent, as in case of 3c, 6b, 9a, 9e, 10a. Among the compounds
of 2-(4-substituted phenyl)-2-oxo-ethylthio- series (3aee); elec-
tronegativity of substituent at the aromatic rings manipulated the
magnitude of activity. The two chlorine atoms of 3a (4-chlor-
ophenyl-ethylthio and 3-chlorophenyl-quinazoline) rendered the
compound merely active, while their replacement by two methoxy
groups enhanced the activity with selectivity toward leukemia
cell lines as in 3e. Mixed electronegative substituents at the said
positions produced compounds 3b and 3d; the most active
members of this study, with broad-spectrum antitumor activity
(Fig. 1). Introduction of 2-[5-(4-substituted phenyl)-1,3,4-thiadia-
zol-2-yl-amino]- to the quinazoline nucleus afforded the hybrid
series 6aef, with diminished activity. The pattern of the effect of
electronegative functions on activity has been repeated in this
series as well. Unsubstituted phenyl moiety at position 3- of the
quinazoline nucleus favor the potency rather than substituted
phenyls and chloro group at 4-chlorophenyl-1,3,4-thiadiazole
contributed to activity rather than methoxy moiety (6a versus
6def). The same analogy was observed upon the introduction of
2-(1H-imidazole), 7aed. Introducing other heterocycles to position
2- of the quinazoline moiety, such as 6-hydroxy-2-oxo-1,2-dihydro-
pyrimidin-4-yl-amino- (8aed), benzene sulfonamides or sulfo-
nylguanidines (9aeg), and 6-hydroxy-2-mercaptopyrimidin-4-yl-
amino- (10aed) did not contribute to the enhancement of the
antitumor activity.
3. Conclusion
Compounds 2-[2-(4-chlorophenyl)-2-oxo-ethylthio]-3-(4-meth-
oxyphenyl)quinazolin-4(3H)-one (3b), and 3-(4-chlorophenyl)-2-
[2-(4-methoxyphenyl)-2-oxo-ethylthio]quinazolin-4(3H)-one (3d),
(Fig. 1); are broad-spectrum antitumors showing effectiveness
toward numerous cell lines that belong to different tumor subpanels,
Compounds 3b, 3d are the most active members in this study. Those
two quinazoline derivatives could be considered as useful templates
for future development to obtain more potent antitumor agent(s).
4. Experimental
Unless specified all chemicals were of commercial grade, used
without further purification and were obtained from Aldrich
Chemical Co. (Milwaukee, WI). Solvents used for work ups were

6062
N.M. Abdel Gawad et al. / European Journal of Medicinal Chemistry 45 (2010) 6058e6067
Table 2
Percentage growth inhibition (GI %) of in-vitro subpanel tumor cell lines at 10
m
M concentration of compounds 7ae17b.
Subpanel tumor cell lines
% Growth Inhibition (GI %)a
Compd
7a
7b
7c
7d
9c
9d
10c
14a
14b
17b
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
SR
RPMI-8226
Non small cell lung cancer
A549/ATCC
HOP-92
NCI-H226
NCI-H23
NCI-H522
Colon cancer
COLO 205
HCT-116
HT29
e
e
e
e
e
nt
e
nt
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
37. 9
nt
nt
37.1
47.7
nt
30.8
nt
nt
e
34.3
38.1
30.2
e
47.1
e
36.5
30.8
36.4
e
e
33.9
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
L
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
76.6
e
e
e
e
30.4
e
e
e
e
e
e
nt
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
33.6
e
36.7
e
39.8
37.4
e
36.8
e
KM12
e
e
e
CNS cancer
SF-268
SF-539
SNB-75
U251
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
Melanoma
M14
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
SK-MEL-2
SK-MEL-28
UACC-62
Ovarian cancer
IGORV1
OVCAR-4
OVCAR-8
SK-OV-3
nt
e
e
e
nt
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
Renal cancer
786e0
CAKI-1
SN12C
UO-31
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
46.3
e
e
e
e
e
e
41.8
34.3
Prostate cancer
PC-3
e
e
40.3
e
e
e
e
32.9
e
e
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578T
BT-549
T-47D
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
39.2
e
e
e
e
e
e
30.2
e
e
e
e
e
e
e
31.8
44.9
e
e
e
39.0
e
e
37.6
e
33.1
e
MDA-MB-468
37.5
a
e, GI ‘ 30%; nt, not tested; L, compound proved lethal to the cancer cell line.
dried over MgSO4, filtered and removed on a rotary evaporator.
Melting points were carried out by the open capillary tube method
using a Gallenkamp digital melting point Griffin apparatus 1901 and
they are uncorrected. Elemental Microanalyses were recorded using
Heraew and Vario El III (elemntar), CHNS analyzer (Germany) at the
Micro Analytical Center, Faculty of Science, Cairo University. Infrared
Spectra were recorded on Bruker FT-IR spectrophotometer Vector
22, Schimadzu 435, PerkineElmer 457 and Jasco FT-IR plus 460
Japan, and expressed in wave number (cmꢀ1), using potassium
bromide discs. 1H NMR Spectra were carried out using a Varian
Gemini 200 MHz spectrophotometer. The chemical shifts were
expressed in
d ppm units using trimethylsilane as the internal
standard. The exchangeable protons were exchanged by D2O. Mass
Spectra were recorded on Shimadzu QP-2010 plus. All reactions
were monitored by thin layer chromatography. Silica gel/TLC-cards
DC-Alufolien-Kieselgel with fluorescent indicator 254 nm; layer
thickness 0.2 mm; 20 ꢁ 20 cm aluminum cards were used. Petro-
leum ether:ethyl acetate (1:1) or (1:2) was the adopted solvent
system. Compounds 1aed, 4aed [25e28] and 2a,b [29] were
prepared according to reported procedures.
OCH3
Cl
O
N
O
N
N
N
4.1. Chemistry
Cl
OCH3
S
S
4.1.1. General procedure for the preparation of 2-[2-(4-substituted
phenyl)-2-oxo-ethylthio]-3-substituted quinazolin-4(3H)-ones
3aee
O
O
A mixture of 2-thioxo-dihydro-quinazolinones 1aed (10 mmol)
and the appropriate freshly prepared substituted phenacyl bromide
2a,b (10 mmol) was refluxed in dry acetone (30 mL) in the presence
3b
3d
Fig. 1. Structures of the active antitumor agents.

N.M. Abdel Gawad et al. / European Journal of Medicinal Chemistry 45 (2010) 6058e6067
6063
of anhydrous potassium carbonate (1.37 g, 10 mmol) for 24 h. The
reaction mixture was then filtered while hot and the filtrate was
evaporated to dryness. The obtained solid was recrystallized from
acetone.
4.1.2.2. 3-Ethyl-2-[5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-ylamino]
quinazolin-4(3H)-one 6b. Yield: 59; mp 204e205 ꢂC; IR (KBr, cmꢀ1):
3251 (NH), 3108 (CH aromatic), 2959, 2922 (CH aliphatic),1670 (C]
O),1609 (NH bending),1550,1464 (C]C); 1H NMR (DMSO-d6):
d 1.21
(t, 3H, CH2CH3, J ¼ 6.7 Hz), 3.79 (s, 3H, OCH3), 4.45 (q, 2H, CH2CH3,
4.1.1.1. 3-(4-Chlorophenyl)-2-[2-(4-chlorophenyl)-2-oxo-ethylthio]
quinazolin-4(3H)-one 3a. Yield: 67; mp 218e219 ꢂC; IR (KBr, cmꢀ1):
3065 (CH aromatic), 2920, 2852 (CH aliphatic), 1691 (br., C]Os),
J ¼ 5.1 Hz), 6.98e7.91 (m, 8H, AreH), 8.60 (s, 1H, NH); 13C NMR
(DMSO-d6): d 12.08 (CH2CH3), 37.63 (CH2CH3), 55.29 (OCH3),114.46,
120.68, 123.48, 126.86, 127.74, 134.71 (arom. C), 152.0 (HNeC]N),
160.6 (CeOCH3), 166.6 (NeC]N), 168.81 (C]O), 185.59 (SeC]N);
EIMS, m/z: 379 (Mþ); Anal. Calcd. For C19H17N5O2S: C, 60.14; H, 4.52;
N, 18.46. Found: C, 59.44; H, 4.04; N, 18.19.
1591, 1548 (C]C), 769 (CeCl); 1H NMR (DMSO-d6):
d 4.67 (s, 2H,
SCH2), 7.06e8.11 (m, 12H, AreH); Anal. Calcd. For C22H14Cl2N2O2S:
C, 59.87; H, 3.20; N, 6.35. Found: C, 60.00; H, 3.10; N, 5.97.
4.1.1.2. 2-[2-(4-Chlorophenyl)-2-oxo-ethylthio]-3-(4-methoxyphenyl)-
quinazolin-4(3H)-one 3b. Yield: 65; mp 212e213 ꢂC; IR (KBr, cmꢀ1):
3061 (CH aromatic), 2966, 2952 (CH aliphatic), 1693 (br., C]Os),
4.1.2.3. 2-[5-(4-Methoxyphenyl)-1,3,4-thiadiazol-2-yl-amino]-3-phe-
nyl-quinazolin-4(3H)-one 6c. Yield: 68; mp 172e173 ꢂC; IR (KBr,
cmꢀ1): 3265 (NH), 3060 (CH aromatic), 2928 (CH aliphatic), 1686
(C]O), 1605 (NH bending), 1544, 1515 (C]C); 1H NMR (DMSO-d6):
1586, 1548 (C]C), 769 (CeCl); 1H NMR (DMSO-d6):
d 3.85 (s, 3H,
OCH3), 4.69 (s, 2H, SCH2), 7.06e8.12 (m, 12H, AreH); EIMS, m/z: 436
(Mþ); Anal. Calcd. For C23H17ClN2O3S: C, 63.23; H, 3.92; N, 6.41.
Found: C, 63.10; H, 3.92; N, 6.10.
d 3.87 (s, 3H, OCH3), 7.08e8.13 (m, 13H, AreH), 12.62 (s, 1H, NH);
Anal. Calcd. For C23H17N5O2S: C, 64.62; H, 4.01; N, 16.38. Found: C,
64.60; H, 4.00; N, 16.30.
4.1.1.3. 3-Ethyl-2-[2-(4-methoxyphenyl)-2-oxo-ethylthio]quinazolin-
4(3H)-one 3c. Yield: 68; mp 130e131 ꢂC; IR (KBr, cmꢀ1): 2965,
2922 (CH aliphatic), 1675 (br., C]Os), 1567, 1545 (C]C); 1H NMR
4.1.2.4. 3-(4-Chlorophenyl)-2-[5-(4-methoxyphenyl)-1,3,4-thiadiazol-
2-ylamino]-quinazolin-4(3H)-one 6d. Yield: 65; mp 157e158 ꢂC; IR
(KBr, cmꢀ1): 3292 (NH), 3063 (CH aromatic), 2976, 2924 (CH
aliphatic), 1688 (C]O), 1607 (NH bending), 1544, 1487 (C]C), 766
(DMSO-d6):
4.16 (q, 2H, CH3CH2, J ¼ 7.8 Hz), 4.85 (s, 2H, SCH2), 7.10e8.08 (m, 8H,
AreH); 13C NMR (DMSO-d6):
14.97 (CH2CH3), 38.67 (CH2CH3),
d
1.34 (t, 3H, CH3CH2, J ¼ 8.4 Hz), 3.89 (s, 3H, OCH3),
(CeCl);1H NMR(DMSO-d6):
d 3.90 (s, 3H, OCH3), 6.95e8.15 (m, 13H,
d
12AreH þ NH); Anal. Calcd. For C23H16ClN5O2S: C, 59.80; H, 3.49; N,
38.95 (SCH2), 55.58 (OCH3), 120.67, 125.84, 125.99, 126.49, 129.47,
131.39, 134.86 (arom. C), 147.0 (C]CeN), 153.4 (NeC]N), 160.6
(CeOCH3), 161.0 (NeC]O), 194.10 (H2CSeC]O); EIMS, m/z: 355
(M þ 1); Anal. Calcd. For C19H18N2O3S: C, 64.39; H, 5.12; N, 7.90.
Found: C, 64.20; H, 5.00; N, 7.96.
15.16. Found: C, 60.09; H, 3.54; N, 15.05.
4.1.2.5. 3-(4-Methoxyphenyl)-2-[5-(4-methoxyphenyl)-1,3,4-thiadia-
zol-2-ylamino]- quinazolin-4 (3H)-one 6e. Yield: 62; mp 129e
130 ꢂC; IR (KBr, cmꢀ1): 3285 (NH), 3060 (CH aromatic), 3001, 2926
(CH aliphatic), 1685 (C]O), 1607 (NH bending), 1546, 1509 (C]C);
4.1.1.4. 3-(4-Chlorophenyl)-2-[2-(4-methoxyphenyl)-2-oxo-ethylthio]-
quinazolin-4(3H)-one 3d. Yield: 68; mp 217e218 ꢂC; IR (KBr, cmꢀ1):
3064 (CH aromatic), 2956, 2919 (CH aliphatic), 1682 (br., C]Os),
1H NMR (DMSO-d6):
d 3.83, 3.86 (2s, 6H, 2OCH3), 7.05e8.08 (m,13H,
12AreH þ NH); Anal. Calcd. For C24H19N5O3: C, 63.01; H, 4.19; N,
15.31. Found: C, 63.21; H, 4.32; N, 15.38.
1548, 1489 (C]C), 758 (CeCl); 1H NMR (DMSO-d6):
d 3.87 (s, 3H,
OCH3), 4.72 (s, 2H, SCH2), 7.11e8.07 (m, 12H, AreH); Anal. Calcd.
For C23H17ClN2O3S: C, 63.23; H, 3.92; N, 6.41. Found: C, 63.35; H,
4.21; N, 6.16.
4.1.2.6. 2-[5-(4-(Dimethylamino)phenyl)-1,3,4-thiadiazol-2-ylamino]-
3-phenyl-quinazolin-4(3H)-one 6f. Yield: 62; mp 117e118 ꢂC; IR (KBr,
cmꢀ1): 3347 (NH), 3057 (CH aromatic), 2925 (CH aliphatic), 1686
(C]O), 1603 (NH bending), 1544, 1466 (C]C); 1H NMR (CDCl3):
4.1.1.5. 3-(4-Methoxyphenyl)-2-[2-(4-methoxyphenyl)-2-oxo-ethyl-
thio]quinazolin-4(3H)-one 3e. Yield: 65; mp 204e205 ꢂC; IR (KBr,
cmꢀ1): 3051 (CH aromatic), 1682 (br., C]Os) 1545, 1503 (C]C); 1H
d
2.46 (s, 6H, 2CH3), 7.18e8.19 (m, 14H, 13AreH þ NH); EIMS, m/z:
440 (Mþ); Anal. Calcd. For C24H20N6OS: C, 65.44; H, 4.58; N, 19.08.
Found: C, 65.24; H, 4.71; N, 19.50.
NMR (CDCl3):
d 3.78, 3.87 (2 s, 6H, 2OCH3), 4.56 (s, 2H, SCH2),
6.85e8.22 (m, 12H, AreH); Anal. Calcd. For C24H20N2O4S: C, 66.65;
H, 4.66; N, 6.48. Found: C, 66.75; H, 4.56; N, 6.10.
4.1.3. General procedure for the preparation of 3-substituted-2-(1H-
imidazol-1-yl)-quinazolin-4(3H)-ones 7aed
A mixture of 2-methylthio-quinazolinone derivatives 4aed
(10 mmol) and imidazole (0.68 g, 10 mmol) was refluxed for 22 h in
dry dimethyl formamide (20 mL). The reaction mixture was poured
onto crushed ice; the precipitated solid was filtered, washed with
water, dried and recrystallized from acetone.
4.1.2. General procedure for the preparation of 2-[5-(4-substituted
phenyl)-1,3,4-thiadiazol-2-yl-amino]-3-substituted quinazolin-4
(3H)-ones 6aef
A mixture of 2-methylthio-quinazolinone derivatives 4aed
(10 mmol) and 2-amino-5-(4-substituted phenyl)-1,3,4-thiadiazol
(5aec, 10 mmol) in absolute ethanol (20 mL) was refluxed for 24 h
in the presence of anhydrous potassium carbonate (1.37 g,
10 mmol). The reaction mixture was filtered while hot; the filtrate
was evaporated to dryness and the obtained solid was recrystal-
lized from methanol.
4.1.3.1. 3-Ethyl-2-(1H-imidazol-1-yl)quinazolin-4(3H)-one 7a. Yield:
62; mp 68e69 ꢂC; IR (KBr, cmꢀ1): 3050 (CH aromatic), 2970, 2849
(CH aliphatic), 1680 (C]O), 1594, 1466 (C]C); 1H NMR(DMSO-d6):
d
1.17 (t, 3H, CH3CH2, J ¼ 7.0 Hz), 4.43 (q, 2H, CH3CH2, J ¼ 7.2 Hz),
7.36e8.11 (m, 7H, AreH); Anal. Calcd. For C13H12N4O$1/2H2O: C,
62.63; H, 5.26; N, 22.46. Found: C, 62.11; H, 5.70; N, 22.13.
4.1.2.1. 2-[5-(4-Chlorophenyl)-1,3,4-thiadiazol-2-ylamino]-3-phenyl-
quinazolin-4(3H)-one 6a. Yield: 78; mp 207e209 ꢂC; IR (KBr,
cmꢀ1): 3270 (NH), 3087 (CH aromatic), 2959, 2919 (CH aliphatic),
1686 (C]O), 1597 (NH bending), 1569, 1514 (C]C), 828 (CeCl); 1H
4.1.3.2. 2-(1H-Imidazol-1-yl)-3-phenylquinazolin-4(3H)-one
7b.
Yield: 56; mp 124e125 ꢂC; IR (KBr, cmꢀ1): 3059, 3005 (CH
aromatic), 2956, 2850 (CH aliphatic), 1687 (C]O), 1573, 1464 (C]
NMR (DMSO-d6):
d
7.54e8.13 (m, 13H, AreH), 8.80 (s, 1H, NH);
C); 1H NMR (DMSO-d6):
d 7.39e8.10 (m, 12H, AreH); Anal. Calcd.
For C17H12N4O: C, 70.82; H, 4.20; N, 19.43. Found: C, 70.75; H, 4.42;
N, 19.68.
EIMS, m/z: 433 (M þ 2), 431 (Mþ); Anal. Calcd. For C22H14ClN5OS: C,
61.18; H, 3.27; N, 16.22. Found: C, 61.00; H, 3.10; N 16.44.

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4.1.3.3. 3-(4-Chlorophenyl)-2-(1H-imidazol-1-yl)quinazolin-4(3H)-
one 7c. Yield: 58; mp 104e106 ꢂC; IR (KBr, cmꢀ1): 3087, 3065 (CH
aromatic), 2938, 2850 (CH aliphatic), 1687 (C]O), 1570, 1545 (C]
OCH3), 6.99e7.97 (m, 11H, 8AreH
þ
C5H of pyrimidine
ring þ 2NHs), 12.91 (s, 1H, OH); Anal. Calcd. For C19H15N5O4: C,
60.47; H, 4.01; N, 18.56. Found: C, 60.99; H, 4.09; N, 18.79.
C), 766 (CeCl); 1H NMR (DMSO-d6):
d 7.47e8.10 (m, 11H, AreH);
EIMS, m/z: 321 (M ꢀ 1), 319 (M ꢀ 3); Anal. Calcd. For C17H11ClN4O:
4.1.5. General procedure for the preparation of 4-[(3-substituted-4-
oxo-3,4-dihydro-quinazolin-2-yl) amino]benzene sulfonamides or
sulfonylguanidines 9aeg
C, 63.23; H, 3.44; N, 17.36. Found: C, 63.35; H, 3.65; N, 17.48.
4.1.3.4. 2-(1H-Imidazol-1-yl)-3-(4-methoxyphenyl)quinazolin-4(3H)-
one 7d. Yield: 50; mp 166e167 ꢂC; IR (KBr, cmꢀ1): 3059, 3002 (CH
aromatic), 2957, 2849 (CH aliphatic), 1688 (C]O),1571, 1545 (C]C);
A mixture of 2-methylthio-quinazolinone derivatives 4aed
(10 mmol) and the appropriate sulfonamide (10 mmol) was refluxed
for 24 h in dry dimethyl formamide (10 mL). The reaction mixture
was poured onto crushed ice; the precipitated solid was filtered,
washed with water, dried and recrystallized from aqueous ethanol.
1H NMR (CDCl3):
d C
3.88 (s, 3H, OCH3), 7.03e8.22 (m, 11H, AreH); 13
NMR (DMSO-d6):
d
55.44 (OCH3), 114.55, 118.81, 119.43, 120.87,
124.34, 125.39, 125.95, 126.51. 126.69, 127.74, 128.37, 129.43, 130.51
(arom. C), 134.67 (NeC]N), 147.27 (C]CeN), 158.63 (CeOCH3),
4.1.5.1. 4-(3-Ethyl-4-oxo-3,4-dihydroquinazolin-2-yl-amino)benze-
nesulfonamide 9a. Yield: 70; mp 57e59 ꢂC; IR (KBr, cmꢀ1): 3345,
3190 (NH2, NH), 3074, 3017 (CH aromatic), 2979, 2923 (CH
aliphatic), 1678 (C]O), 1604 (NH bending), 1564, 1467 (C]C), 1353,
N
160.81 (C]O), 162.04 (
N=C-N
); EIMS, m/z: 319 (M þ 1); Anal.
(N)
1163 (SO2); 1H NMR (DMSO-d6):
4.41 (q, 2H, CH2CH3,
d
1.19 (t, 3H, CH2CH3, J ¼ 7.2 Hz),
Calcd. For C18H14N4O2: C, 67.91; H, 4.43; N, 17.60. Found: C, 68.55; H,
4.76; N, 17.89.
J
¼
7.2 Hz), 7.37e8.11 (m, 11H,
8AreH þ NH2 þ NH); Anal. Calcd. For C16H16N4O3S: C, 55.80; H,
4.68; N, 16.27. Found: C, 56.00; H, 4.46; N, 16.25.
4.1.4. General procedure for the preparation of 3-substituted-2-(6-
hydroxy-2-oxo-1,2-dihydro-pyrimidin-4-yl-amino)quinazolin-4
(3H)-ones 8aed
A mixture of 2-methylthio-quinazolinone derivatives 4aed
(10 mmol) and 6-aminouracil (1.27 g, 10 mmol) was refluxed for
36 h in absolute ethanol (20 mL) in the presence of anhydrous
potassium carbonate (1.37 g, 10 mmol). The reaction mixture was
filtered while hot, the filtrate evaporated to dryness and the
obtained solid was recrystallized from acetone.
4.1.5.2. 4-(4-Oxo-3-phenyl-3,4-dihydroquinazolin-2-yl-amino)ben-
zenesulfonamide 9b. Yield: 75; mp 97e98 ꢂC; IR (KBr, cmꢀ1): 3362
(br., NH2, NH), 3058(CH aromatic), 2989, 2922 (CH aliphatic), 1688
(C]O), 1609 (NH bending), 1544, 1490 (C]C), 1318, 1206 (SO2); 1H
NMR (DMSO-d6):
d
7.37e8.10 (m, 16H, 13AreH þ NH2 þ NH); EIMS,
m/z: 393 (M þ 1); Anal. Calcd. For C20H16N4O3S: C, 61.21; H, 4.11; N,
14.28. Found: C, 61.30; H, 3.80; N, 14.29.
4.1.5.3. 4-(3-(4-Chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
amino)benzene-sulfonamide 9c. Yield: 68; mp 147e149 ꢂC; IR (KBr,
cmꢀ1): 3300, 3198 (NH2, NH), 3087 (CH aromatic), 2921, 2850 (CH
aliphatic), 1685 (C]O), 1606 (NH bending), 1545, 1487 (C]C), 1321,
4.1.4.1. 3-Ethyl-2-(6-hydroxy-2-oxo-1,2-dihydro-pyrimidin-4-yl-am-
ino)quinazolin-4(3H)-one 8a. Yield: 48; mp 197e198 ꢂC; IR (KBr,
cmꢀ1): 3474 (OH), 3196, 3136 (NHs), 3077 (CH aromatic), 2982,
2926 (CH aliphatic), 1716, 1645 (C]Os), 1622 (NH bending), 1502,
1205 (SO2); 1H NMR (DMSO-d6):
d
7.47e7.80 (m, 15H,
1467 (C]C); 1H NMR (DMSO-d6):
d
1.27 (t, 3H, CH3, J ¼ 7.0 MHz),
12AreH þ NH2 þ NH); Anal. Calcd. For C20H15ClN4O3S: C, 56.27; H,
4.11 (q, 2H, CH2, J ¼ 7.2 MHz), 7.39e8.08 (m, 5H, 4AreH þ C5H of
pyrimidine ring), 10.2 (s, 2H, 2NHs), 10.5 (s, 1H, OH); 13C NMR
3.54; N, 13.12. Found: C, 55.79; H, 4.10; N, 12.86.
(DMSO-d6): d 14.40 (CH3), 38.95 (CH2), 62.23 (C]NeCeOH),118.66,
4.1.5.4. 4-(3-(4-Methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
amino)benzene-sulfonamide 9d. Yield: 65; mp 305e306 ꢂC; IR (KBr,
cmꢀ1): 3362, 3195 (NH2, NH), 3066 (CH aromatic), 2927, 2854 (CH
aliphatic), 1722 (C]O), 1603 (NH bending), 1512, 1488 (C]C), 1341,
125.60, 125.76, 126.22, 134.38 (arom. C), 146.77 (CeOH), 156.73,
160.16 (2 C]Os), 168.37 (HNeC]N); Anal. Calcd. For C14H13N5O3:
C, 56.18; H, 4.38; N, 23.40. Found: C, 56.44; H, 4.64; N, 23.50.
1154 (SO2); 1H NMR (DMSO-d6):
d 3.86 (s, 3H, OCH3), 7.04e7.98 (m,
4.1.4.2. 2-(6-Hydroxy-2-oxo-1,2-dihydro-pyrimidin-4-yl-amino)-3-
phenyl-quinazolin-4(3H)-one 8b. Yield: 52; mp 144e145 ꢂC; IR
(KBr, cmꢀ1): 3406 (OH), 3194, 3140 (NHs), 3058 (CH aromatic),
2922, 2851 (CH aliphatic), 1727, 1686 (C]Os), 1604 (NH bending),
15H, 11AreH þ NH2 þ NH); 13C NMR (DMSO-d6):
d 55.27 (OCH3),
113.85, 114.43, 116.33, 121.43, 127.31, 128.80, 129.92, 134.62, 141.95,
151.23 (arom. C), 158.54 (CeOCH3), 162.71 (C]O), 168.37 (N]
CeN); Anal. Calcd. For C21H18N4O4S: C, 59.70; H, 4.29; N, 13.26.
Found: C, 60.01; H, 4.45; N, 12.87.
1544, 1490 (C]C); 1H NMR (DMSO-d6):
d 7.44e8.10 (m, 13H,
9AreH þ 2NH þ OH þ C5H of pyrimidine ring); EIMS, m/z: 347
(Mþ); Anal. Calcd. For C18H13N5O3: C, 62.24; H, 3.77; N, 20.16.
Found: C, 62.44; H, 3.97; N, 20.42.
4.1.5.5. 4-(3-Ethyl-4-oxo-3,4-dihydroquinazolin-2-yl-amino)benze-
nesulfonylguanidine 9e. Yield: 67; mp 186e187 ꢂC; IR (KBr, cmꢀ1):
3325, 3291, 3245 (NH2, NHs), 3050 (CH aromatic), 2922 2851 (CH
aliphatic), 1674 (C]O), 1611 (NH bending), 1533, 1490 (C]C), 1375,
4.1.4.3. 3-(4-Chlorophenyl)-2-(6-hydroxy-2-oxo-1,2-dihydro-pyrimi-
din-4-yl-amino)-quinazolin-4(3H)-one 8c. Yield: 49; mp 125e
127 ꢂC; IR (KBr, cmꢀ1): 3294 (OH), 3196 (br., NHs), 3087, 3065 (CH
aromatic), 2979, 2925 (CH aliphatic), 1731, 1687 (C]Os), 1607 (NH
bending), 1544, 1489 (C]C), 768 (CeCl); 1H NMR (DMSO-d6):
1175 (SO2); 1H NMR (DMSO-d6):
d
1.29 (t, 3H, CH3, J ¼ 6.59 Hz), 4.11
(q, 2H, CH2, J ¼ 5.79 Hz), 5.75 (s, 2H, 2NHs), 6.60 (s, 3H, NH and
NH2), 7.44e8.14 (m, 8H, AreH); EIMS, m/z: 386 (Mþ); Anal. Calcd.
For C17H18N6O3S: C, 52.84; H, 4.70; N, 21.75. Found: C, 52.42; H,
5.13; N, 21.85.
d
7.21e8.15 (m, 12H, 8AreH þ 2NH þ OH þ C5H of pyrimidine ring);
Anal. Calcd. For C18H12ClN5O3: C, 56.63; H, 3.17; N, 18.34. Found: C,
56.82; H, 3.37; N, 18.32.
4.1.5.6. 4-(3-(4-Chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
amino)benzene-sulfonylguanidine 9f. Yield: 65; mp 193e194 ꢂC; IR
(KBr, cmꢀ1): 3487, 3401, 3341, 3221 (NH2, NHs), 3098, 3062 (CH
aromatic), 2927, 2850 (CH aliphatic), 1682 (C]O), 1617 (NH
bending), 1549, 1488 (C]C), 1301, 1131 (SO2), 812 (CeCl); 1H NMR
4.1.4.4. 2-(6-Hydroxy-2-oxo-1,2-dihydro-pyrimidin-4-yl-amino)-3-
(4-methoxy-phenyl)-quinazolin-4(3H)-one 8d. Yield: 46; mp
139e140 ꢂC; IR (KBr, cmꢀ1): 3344 (OH), 3297 (br., NHs), 3059, 3036
(CH aromatic), 2971, 2927 (CH aliphatic), 1687 (br., C]Os), 1607
(NH bending), 1545, 1507 (C]C); 1H NMR (DMSO-d6):
d
3.81 (s, 3H,
(DMSO-d6): d 5.75 (s, 2H, 2NHs), 6.61 (s, 3H, NH and NH2),

N.M. Abdel Gawad et al. / European Journal of Medicinal Chemistry 45 (2010) 6058e6067
6065
7.42e8.15 (m, 12H, AreH); Anal. Calcd. For C21H17ClN6O3S: C, 53.79;
H, 3.65; N, 17.92. Found: C, 53.51; H, 3.79; N, 18.19.
reaction mixture was heated under reflux for 4 h. Ethanol was
distilled off and the residue was left to solidify, the obtained solid
was recrystallized from methanol/chloroform (3:1).
4.1.5.7. 4-(3-(4-Methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
amino)benzene-sulfonylguanidine 9g. Yield: 63; mp 303e304 ꢂC; IR
(KBr, cmꢀ1): 3433, 3400, 3343, 3221 (NH2, NHs), 3065 (CH
aromatic), 2922, 2852 (CH aliphatic), 1620 (C]O), 1573 (NH
bending), 1535, 1507 (C]C), 1302, 1132 (SO2); 1H NMR (DMSO-d6):
4.1.7.1. 1,10-(4-Chloro-phenylmethylene)diurea 11a. Yield: 85; mp
195e197 ꢂC; IR (KBr, cmꢀ1): 3444, 3336 (NH2s, NHs), 3000 (CH
aromatic), 2974, 2923 (CH aliphatic), 1666 (br., C]Os), 1601 (NH
bending), 1541, 1489 (C]C), 816 (CeCl); 1H NMR (DMSO-d6):
d 5.16
d
3.86 (s, 3H, OCH3), 5.75 (s, 2H, 2NHs), 6.57 (s, 3H, NH and NH2),
(s, 4H, 2NH2), 5.82 (s, 1H, CH aliphatic), 7.38e7.95 (m, 4H, 4AreH),
10.00 (s, 2H, 2NH); Anal. Calcd. For C9H11ClN4O2: C, 44.55; H, 4.57;
N, 23.09. Found: C, 44.64; H, 4.67; N, 23.28.
6.61e7.46 (m, 12H, CH aromatic); Anal. Calcd. For C22H20N6O4S: C,
56.89; H, 4.34; N, 18.09. Found: C, 56.91; H, 4.42; N, 18.49.
4.1.6. General procedure for the preparation of 3-substituted-2-(6-
hydroxy-2-mercaptopyrimidin-4-yl-amino) quinazolin-4(3H)-ones
10aed
A mixture of 2-methylthio-quinazolinone derivatives 4aed
(10 mmol) and the freshly prepared 6-amino-2-mercaptopyr-
imidin-4-ol (1.43 g, 10 mmol) was refluxed in absolute ethanol
(20 mL) in the presence of anhydrous potassium carbonate (1.37 g,
10 mmol) for 36 h. The reaction mixture was then filtered while hot,
the filtrate evaporated to dryness and the obtained solid was
recrystallized from aqueous ethanol.
4.1.7.2. 1,10-(4-Methoxy-phenylmethylene)diurea 11b. Yield: 82; mp
193e194 ꢂC; IR (KBr, cmꢀ1): 3449, 3342 (NH2s, NHs), 3006 (CH
aromatic), 2962, 2935 (CH aliphatic), 1674 (C]Os), 1599 (NH
bending),1599,1543 (C]C); 1H NMR (DMSO-d6):
d 3.83 (s, 3H, OCH3),
5.60 (s, 4H, 2NH2), 6.14 (s, 1H, CH), 7.36e7.93 (m, 4H, 4AreH), 9.97 (s,
2H, 2NH); EIMS, m/z: 241 (M þ 3); Anal. Calcd. For C10H14N4O3: C,
50.41; H, 5.92; N, 23.52. Found: C, 50.03; H, 6.00; N, 23.68.
4.1.8. General procedure for the preparation of 4-(4-substituted-
phenyl)-2-oxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid
12a,b
4.1.6.1. 3-Ethyl-2-(6-hydroxy-2-mercaptopyrimidin-4-yl-amino)qui-
nazolin-4(3H)-one 10a. Yield: 62; mp 93e94 ꢂC; IR (KBr, cmꢀ1):
3304, 3258, 3198 (OH, NH, SH), 3055, (CH aromatic), 2916 (CH
aliphatic), 1678 (C]O), 1596 (NH bending), 1570, 1462 (C]C); 1H
1,10-(4-Substituted-phenylmethylene)diurea 11a,b (60 mmol)
and 4-aminobenzoic acid (11.0 g, 80 mmol) were fused together at
145e150 ꢂC for 4 h on a sand bath. A clear liquid was obtained on
heating which solidified on cooling at room temperature. On trit-
urating the solid using 1 M hydrochloric acid (50 mL), a solid was
separated, filtered off, washed with water, dried and recrystallized
from aqueous ethanol.
NMR (DMSO-d6):
d
1.23 (t, 3H, CH2CH3, J ¼ 6.80 Hz), 4.45 (q, 2H,
CH2CH3, J ¼ 7.40 Hz), 7.40e8.12 (m, 7H, 4CH aromatic þ C5H of
pyrimidine ring þ OH þ NH), 9.20 (s, 1H, SH); 13C NMR (DMSO-d6):
d
13.81 (CH3), 35.98 (CH2), 63.94 (C]NeCeOH), 118.09, 123.95,
125.06, 126.25, 134.05 (arom. C), 146.57 (CeOH), 152.08 (C]O),
161.22 (CeSH); Anal. Calcd. For C14H13N5O2S: C, 53.32; H, 4.16; N,
22.21. Found: C, 53.60; H, 4.70; N, 22.43.
4.1.8.1. 4-(4-Chlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-6-
carboxylic acid 12a. Yield: 83; mp 298e299 ꢂC; IR (KBr, cmꢀ1):
3317, 3215 (NHs), 3063 (CH aromatic), 2555 (OH carboxylic), 1697,
1654 (C]Os), 1594 (NH bending), 1525, 1458 (C]C), 764 (CeCl); 1H
4.1.6.2. 2-(6-Hydroxy-2-mercaptopyrimidin-4-yl-amino)-3-phenyl-
quinazolin-4(3H)-one10b. Yield: 64; mp 127e129 ꢂC; IR (KBr, cmꢀ1):
3324, 3281, 3190 (OH, NH, SH), 3057, (CH aromatic), 2922 (CH
aliphatic), 1687 (C]O), 1602 (NH bending), 1572, 1544 (C]C); 1H
NMR (DMSO-d6): d 5.54 (s, 1H, C4H), 7.15e8.19 (m, 7H, AreH), 9.27
(s, 2H, 2NH), 11.20 (s, 1H, OH); Anal. Calcd. For C15H11ClN2O3: C,
59.52; H, 3.66; N, 9.25. Found: C, 59.81; H, 3.90; N, 8.76.
NMR (DMSO-d6):
d
6.99e8.13 (m, 12H, 9AreH þ C5H of pyrimidine
4.1.8.2. 4-(4-Methoxyphenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-
6-carboxylic acid 12b. Yield: 80; mp 220e221 ꢂC; IR (KBr, cmꢀ1):
3309, 3260 (NHs), 3100 (CH aromatic), 2947, 2917 (CH aliphatic),
2628, 2529 (OH carboxylic), 1686 (br., C]Os), 1599 (NH bending),
ring þ OH þ NH), 8.95 (s, 1H, SH); Anal. Calcd. For C18H13N5O2S: C,
59.49; H, 3.61; N, 19.27. Found: C, 59.68; H, 3.38; N, 19.00.
4.1.6.3. 3-(4-Chlorophenyl)-2-(6-hydroxy-2-mercaptopyrimidin-4-
yl-amino)quinazolin-4(3H)-one 10c. Yield: 62; mp 117e119 ꢂC; IR
(KBr, cmꢀ1): 3295 (br., OH, NH, SH), 3086, 3065, (CH aromatic),
2922, 2851 (CH aliphatic), 1686 (C]O), 1607 (NH bending), 1545,
1511, 1480 (C]C);1HNMR(DMSO-d6):
d3.91(s, 3H, OCH3), 5.78(s,1H,
C4H), 7.29e8.35 (m, 7H, CH aromatic), 9.39 (s, 1H, NH), 11.63 (s, 1H,
NH), 13.10 (s, 1H, OH); EIMS, m/z: 296 (M ꢀ 2); Anal. Calcd. For
C16H14N2O4:C,64.42;H, 4.73;N,9.39. Found:C,64.80;H,3.90;N,9.00.
1487 (C]C), 767 (CeCl); 1H NMR (DMSO-d6):
d 6.81e8.21 (m, 11H,
8AreH þ C5H of pyrimidine ring þ OH þ NH), 9.12 (s, 1H, SH); Anal.
Calcd. For C18H12ClN5O2S: C, 54.34; H, 3.04; N, 17.60. Found: C,
54.60; H, 3.50; N, 17.82.
4.1.9. General procedure for the preparation of 4-(4-substituted-
phenyl)-2-oxo-1,2,3,4-tetrahydro-quinazoline-6-carbonyl chloride
13a,b
To a mixture of 4-(4-substituted-phenyl)-2-oxo-1,2,3,4-tetra-
hydro-quinazoline-6-carboxylic acid (12a,b; 10 mmol) in dry
benzene (10 mL), thionyl chloride (1.18 mL, 10 mmol) was added
and the reaction mixture was refluxed for 3 h. The solvent was
distilled off under reduced pressure and the residue was azoe-
troped twice with dry benzene, then used in the next reaction
without further purification.
4.1.6.4. 2-(6-Hydroxy-2-mercaptopyrimidin-4-yl-amino)-3-(4-
methoxyphenyl)quinazolin-4(3H)-one10d. Yield: 59; mp 135e136 ꢂC;
IR (KBr, cmꢀ1): 3295 (br., OH, NH, SH), 3060, (CH aromatic), 2922,
2851 (CH aliphatic), 1687 (C]O),1606 (NH bending),1545,1509 (C]
C); 1H NMR (DMSO-d6):
d 3.81 (s, 3H, OCH3), 7.01e8.15 (m, 11H,
8AreH þ C5H of pyrimidine ring þ OH þ NH), 9.05 (s, 1H, SH); EIMS,
m/z: 393 (Mþ); Anal. Calcd. For C19H15N5O3S: C, 58.01; H, 3.84; N,
17.80. Found: C, 57.88; H, 3.46; N, 17.96.
4.1.10. General procedure for the preparation of 4-(4-substitued-
phenyl)-2-oxo-N-(pyridin-2-yl)-1,2,3,4-tetrahydro-quinazoline-6-
carboxamide 14a,b
A solution of freshly prepared acid chlorides 13a,b (10 mmol) in
dry dimethyl formamide (10 mL) was refluxed with 2-amino-
pyridine (0.94 g, 10 mmol) in the presence of triethylamine (1 mL)
4.1.7. General procedure for the preparation of 1,10-(4-substituted-
phenylmethylene)-diurea 11a,b
A mixture of the appropriate aldehyde (10 mmol) and urea
(1.5 g, 25 mmol) was dissolved in absolute ethanol (50 mL) and the

6066
N.M. Abdel Gawad et al. / European Journal of Medicinal Chemistry 45 (2010) 6058e6067
for 12 h. The reaction mixture was poured onto crushed ice and the
separated solid was filtered, washed with water, dried and recrys-
tallized from aqueous ethanol.
4.1.12.1. 6-(Bromomethyl)-4-(4-chlorophenyl)-3,4-dihydro-quinazo-
lin-2(1H)-one 16a. Yield: 68; mp 168e169 ꢂC; IR (KBr, cmꢀ1): 3427,
3308 (NHs), 3035 (CH aromatic), 2916, 2856 (CH aliphatic),1644 (C]
O), 1595 (NH bending), 1513, 1459 (C]C), 778 (CeCl), 639 (CeBr); 1H
4.1.10.1. 4-(4-Chlorophenyl)-2-oxo-N-(pyridin-2-yl)-1,2,3,4-tetrahy-
dro-quinazoline-6-carboxamide 14a. Yield: 65; mp 108e109 ꢂC; IR
(KBr, cmꢀ1): 3399, 3205 (NHs), 3048 (CH aromatic), 2824, 2771 (CH
aliphatic), 1701, 1669 (C]Os), 1598 (NH bending), 1509, 1489 (C]
NMR (CDCl3): d 2.21 (s, 2H, CH2), 4.50 (s, 1H, C4H), 6.70 (s, 2H, 2NH),
7.20e7.51 (m, 7H, AreH); Anal. Calcd. For C15H12BrClN2O: C, 51.24; H,
3.44; N, 7.97. Found: C, 51.64; H, 3.94; N, 7.96.
C), 836 (CeCl); 1H NMR (DMSO-d6):
d
4.10 (s, 1H, C4H), 7.60e8.04
4.1.12.2. 6-(Bromomethyl)-4-(4-methoxyphenyl)-3,4-dihydro-quina-
zolin-2(1H)-one 16b. Yield: 62; mp 211e212 ꢂC; IR (KBr, cmꢀ1):
3419, 3300 (NHs), 3031 (CH aromatic), 2919, 2854 (CH aliphatic),
1638 (C]O), 1588 (NH bending), 1513, 1477 (C]C), 644 (CeBr); 1H
(m, 13H, 11AreH þ 2NHs), 9.94 (s, 1H, NH); Anal. Calcd. For
C20H15ClN4O2: C, 63.41; H, 3.99; N, 14.79. Found: C, 63.43; H, 3.75;
N, 14.30.
NMR (DMSO-d6): d 2.36 (s, 2H, CH2), 3.94 (s, 3H, OCH3), 5.51 (s, 1H,
4.1.10.2. 4-(4-Methoxyphenyl)-2-oxo-N-(pyridin-2-yl)-1,2,3,4-tetra-
hydro-quinazoline-6-carboxamide 14b. Yield: 60; mp 230e231 ꢂC;
IR (KBr, cmꢀ1): 3421 (brs, NHs), 3050 (CH aromatic), 2923, 2853 (CH
aliphatic), 1733, 1700 (C]Os), 1626 (NH bending), 1561, 1542 (C]C);
C4H), 6.07 (s, 1H, NH), 7.28e8.71 (m, 7H, AreH), 9.88 (s, 1H, NH);
EIMS, m/z: 349 (Mþ þ 2); Anal. Calcd. For C16H15BrN2O2: C, 55.35; H,
4.35; N, 8.07. Found: C, 54.93; H, 3.92; N, 8.16.
1H NMR (DMSO-d6):
d
3.79 (s, 3H, OCH3), 4.86 (s, 1H, C4H), 7.23e8.41
(m, 11H, AreH), 9.06 (s, 2H, 2NHs), 11.80 (s, 1H, NH); 13C NMR
(DMSO-d6): 55.35 (OCH3), 56.43 (HC4),112.17,112.49,113.84,114.06,
128.21, 128.37, 130.63, 131.24, 131.34, 131.55, 132.06, 132.15, 133.42,
4.1.13. General procedure for the preparation of 4-(4-substituted-
phenyl)-6-(pyridin-2-yl-aminomethyl)-3,4-dihydro-quinazolin-2
(1H)-ones 17a,b
A solution of bromomethyl analogues 16a,b (10 mmol) in dry
dimethyl formamide (10 mL) was refluxed with 2-aminopyridine
(0.94 g, 10 mmol) in the presence of triethylamine (1 mL) for 12 h.
The reaction mixture was poured onto crushed ice and the sepa-
rated solid was filtered, washed with water, dried and recrystallized
from aqueous ethanol.
d
ph
NH
133.98 (arom. C), 120.61 (
N=C-N
), 157.70 (HN C
), 158.10
ONH
(N)
(CeOCH3), 158.50 (HNeC]N); Anal. Calcd. For C21H18N4O3: C, 67.37;
H, 4.85; N, 14.96. Found: C, 66.75; H, 4.65; N, 14.98.
4.1.11. General procedure for the preparation of 4-(4-substituted-
phenyl)-6-methyl-3,4-dihydro-quinazolin-2(1H)-ones 15a,b
1,10-(4-substituted-phenylmethylene)diurea (11a,b; 60 mmol)
and 4-methylaniline (8.6 g, 80 mmol) were fused together at
145e150 ꢂC for 4 h on a sand bath. A clear liquid was obtained on
heating which solidified on cooling at room temperature. On trit-
urating the solid using 1 M hydrochloric acid (50 mL), a solid was
separated, filtered off, washed with water, dried and recrystallized
from aqueous ethanol.
4.1.13.1. 4-(4-Chlorophenyl)-6-(pyridin-2-yl-aminomethyl)-3,4-dihy-
dro-quinazolin-2(1H)-ones 17a. Yield: 58; mp 232e233 ꢂC; IR (KBr,
cmꢀ1): 3451 (br., NH s), 2933 (CH aromatic), 2882 (CH aliphatic),
1718 (C]O), 1591 (NH bending), 1501, 1436 (C]C), 664 (CeCl); 1H
NMR (DMSO-d6):
d 5.51 (s, 2H, CH2), 5.60 (s, 1H, C4H), 6.20 (s, 1H,
NH), 7.02e8.60 (m, 11H, AreH), 11.96 (s, 2H, 2NHs); Anal. Calcd. For
C20H17ClN4O: C, 65.84; H, 4.70; N, 15.36. Found: C, 65.20; H, 4.71; N,
15.75.
4.1.13.2. 4-(4-Methoxyphenyl)-6-(pyridin-2-yl-aminomethyl)-3,4-
dihydro-quinazolin-2(1H)-ones 17b. Yield: 55; mp 146e148 ꢂC; IR
(KBr, cmꢀ1): 3295 (br., NHs), 3062 (CH aromatic), 2921, 2850 (CH
aliphatic), 1658 (C]O), 1596 (NH bending), 1542, 1500 (C]C); 1H
4.1.11.1. 4-(4-Chlorophenyl)-6-methyl-3,4-dihydro-quinazolin-2
(1H)-one 15a. Yield: 68; mp 165e167 ꢂC; IR (KBr, cmꢀ1): 3294,
3212 (NHs), 3082 (CH aromatic), 2917, 2825 (CH aliphatic), 1702
(C]O), 1565 (NH bending), 1563, 1457 (C]C), 781 (CeCl); 1H NMR
NMR (DMSO-d6):
d 3.78 (s, 3H, OCH3), 5.10 (s, 1H, NH), 5.50 (s, 2H,
(DMSO-d6):
d 2.23 (s, 3H, CH3), 5.5 (s, 1H, C4H), 7.05e8.59 (m, 7H,
CH2), 5.62 (s, 1H, C4H), 7.17e8.56 (m, 13H, 11AreH þ 2NHs); Anal.
Calcd. For C21H20N4O2: C, 69.98; H, 5.59; N, 15.55. Found: C, 69.54;
H, 6.04; N, 16.00.
AreH), 10.40 (s, 1H, NH), 11.13 (s, IH, NH); EIMS, m/z: 272 (Mþ), 270
(M ꢀ 2); Anal. Calcd. For C15H13ClN2O: C, 66.06; H, 4.80; N, 10.27.
Found: C, 66.26; H, 5.00; N, 10.30.
4.1.14. General procedure for the preparation of 4-(4-substituted-
phenyl)-2-oxo-N-(pyridin-2-yl)-1,2,3,4-tetrahydro-quinazoline-6-
sulfonamides 18a,b
4.1.11.2. 4-(4-Methoxyphenyl)-6-methyl-3,4-dihydro-quinazolin-2
(1H)-one 15b. Yield: 63; mp 136e138 ꢂC; IR (KBr, cmꢀ1): 3220 br.
(NHs), 3061 (CH aromatic), 2985, 2947 (CH aliphatic), 1668 (C]O),
1,10-(4-substituted-phenylmethylene)diurea (11a,b; 60 mmol)
and 4-amino-N-(pyridin-2-yl)benzenesulfonamide (19.9 g,
80 mmol) were fused together at 145e150 ꢂC for 4 h on a sand bath.
A clear liquid was obtained on heating which solidified on cooling
at room temperature. On triturating the solid using 1 M hydro-
chloric acid (50 mL), a solid was separated, filtered off, washed with
water, dried and recrystallized from aqueous ethanol.
1599 (NH bending), 1516, 1486 (C]C); 1H NMR (DMSO-d6):
d 2.32
(s, 3H, CH3), 3.86 (s, 3H, OCH3), 5.5 (s, 1H, C4H), 7.02e8.12 (m, 7H,
AreH), 8.79 (s, 1H, NH), 9.86 (s, IH, NH); Anal. Calcd. For
C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.81; H, 5.92; N,
10.90.
4.1.12. General procedure for the preparation of 6-(bromomethyl)-
4-(4-substituted-phenyl)-3,4-dihydro-quinazolin-2(1H)-ones 16a,b
A solution of 4-(4-substituted phenyl)-6-methyl-3,4-dihydro-
quinazolin-2(1H)-one 15a,b (10 mmol) and N-bromosuccinimide
(1.76 g, 10 mmol) in dry dimethyl formamide (10 mL) was stirred at
room temperature for 24 h. The reaction mixture was poured onto
crushed ice; the obtained solid was filtered, washed with water,
dried and recrystallized from ethanol:chloroform mixture (3:1) to
give the desired compounds.
4.1.14.1. 4-(4-Chlorophenyl)-2-oxo-N-(pyridin-2-yl)-1,2,3,4-tetrahy-
dro-quinazoline-6-sulfonamide 18a. Yield: 52; mp 239e241 ꢂC; IR
(KBr, cmꢀ1): 3415, 3328, 3240 (NHs), 3050 (CH aromatic), 2924 (CH
aliphatic), 1666 (C]O), 1585 (NH bending), 1523, 1499 (C]C), 1259,
1128 (SO2), 769 (CeCl); 1H NMR (DMSO-d6):
d 5.52 (s, 1H, C4H), 6.03
(s,1H, NH), 6.16 (s,1H, NH), 6.59e8.16 (m,11H, AreH), 9.17 (s,1H, NH);
EIMS, m/z: 416 (M þ 2), 414 (Mþ); Anal. Calcd. For C19H15ClN4O3S: C,
55.01; H, 3.64; N, 13.50. Found: C, 55.20; H, 3.20; N, 13.62.

N.M. Abdel Gawad et al. / European Journal of Medicinal Chemistry 45 (2010) 6058e6067
6067
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Acknowledgements
Thanks are due to the NCI, Bethesda, MD, for performing the
antitumor testing of the synthesized compounds. Also, authors are
profoundly grateful to Prof. Dr. Hussein I. El-Subbagh, Department
of Pharmaceutical Chemistry, College of Pharmacy, King Saudi
University, for his keen interest and sincere help that deserves all
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