Design and synthesis of novel 7-aminoquinazoline derivatives: Antitumor and anticonvulsant activities

Article abstract of DOI:10.1016/j.bmcl.2012.01.071

A novel series of 7-substituted-4(3H)-quinazolinone were designed, synthesized and evaluated for their antitumor and anticonvulsant activity. Compound 7 revealed broad-spectrum antitumor effectiveness toward numerous cell lines that belong to different tumor subpanels, whereas compounds 9 and 18 possess selective activity toward leukemia cell lines. Additionally, compounds 3, 15, 16, 18, 19 and 20 showed advanced anticonvulsant activity as well as lower neurotoxicity than reference drugs. The achieved results proved that the distinctive compounds could be valuable as a model for future devise, acclimatization and investigation to construct more active analogues.

Full text of DOI:10.1016/j.bmcl.2012.01.071

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1879–1885
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of novel 7-aminoquinazoline derivatives: Antitumor
and anticonvulsant activities
Adel S. El-Azab a,b, , Kamal E.H. ElTahir c
⇑
a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia
b Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo 11884, Egypt
c Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of 7-substituted-4(3H)-quinazolinone were designed, synthesized and evaluated for their
antitumor and anticonvulsant activity. Compound 7 revealed broad-spectrum antitumor effectiveness
toward numerous cell lines that belong to different tumor subpanels, whereas compounds 9 and 18 pos-
sess selective activity toward leukemia cell lines. Additionally, compounds 3, 15, 16, 18, 19 and 20
showed advanced anticonvulsant activity as well as lower neurotoxicity than reference drugs. The
achieved results proved that the distinctive compounds could be valuable as a model for future devise,
acclimatization and investigation to construct more active analogues.
Received 3 December 2011
Revised 10 January 2012
Accepted 20 January 2012
Available online 28 January 2012
Keywords:
Synthesis
Ó 2012 Elsevier Ltd. All rights reserved.
Quinazolinone
Antitumor
Anticonvulsant
Chimney test
Neurotoxicity
NCI
Cancer is continuing to be a major health problem in developing
as well as developed countries.1,2 Surpassing heart diseases, it is
taking the position number one killer due to various worldwide
factors. Although major advances have been made in the chemo-
therapeutic management of some patients, the continued commit-
ment to the laborious task of discovering new anticancer agents
remains critically important.
Quinazolines are considered to be an important chemical
synthon of various physiological significance and pharmaceutical
utility. They possess a variety of biological effects including antihy-
pertensive,3 antimicrobial,4–6 antihyperlipidemic,7,8 antioxidant,9
anti-inflammatory,10–12 anticonvulsant,13–16 and anticancer activi-
ties.17–19
Interests in quinazolines as anticancer agents have further
increased since the discovery of raltitrexed I and thymitaq II
(Fig. 1), both compounds proved to be thymidylate synthase inhib-
itors.20–22 Moreover, many quinazolines contributed to the quest
for an ultimate antitumor chemotherapeutic agent.17,18 Interest-
ingly, it was reported that the sulfonamide, Schiff’s base and amide
functions were enhanced the antitumor activity of quinazoline
core III–VII (Fig. 1).18,19,23
Much efforts devoted in the recent years for the development of
novel therapeutics resulted in the availability of several newer
drugs as promising anticonvulsants.24,25 However, the currently
available anticonvulsants are effective in reducing the severity
and number of seizures in less than 70% of patients. Moreover,
their usage is associated with undesirable numerous side ef-
fects.26–29 Therefore, continued search for safer and more effective
anticonvulsants is urgently necessary. Literature survey revealed
that the presence of a methyl group at position 2 and a substituted
aromatic ring at position 3 in a quinazoline nucleus are preferential
requirement for the CNS depression and anticonvulsant activities30
VIII–XI (Fig. 1).
The present study aimed to synthesize and evaluate the biolog-
ical activity of some new quinazoline derivatives as potential
anticonvulsant and anticancer agents, a new series of quinazoline
compounds were designed, in such a way to accommodate an
amino function group at position 7 that used to introduce amides,
sulfonamides, biquinazoline and Schiff’s base, the later compound
was converted into phenylthiazolidin-4-one moiety (Fig. 1).
The designed target compounds were obtained as outlined in
Schemes 1–3 starting with 4-nitroanthranilic acid.
On the other hand, Epilepsy is one of the most common neuro-
logical disorders, affecting about 1% of the world’s population.
Synthesis of 2-methyl-3-(2-methylphenyl)-7-amino-4(3H)-qui-
nazolinone (2) as a key intermediate was achieved by the reaction
of 4-nitroanthranilic acid with acetic anhydride followed by treat-
ment with o-toludine in anhydrous pyridine. The latter compound
⇑
Corresponding author. Fax: +966 1 467 6383.
E-mail address: adelazaba@yahoo.com (A.S. El-Azab).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.01.071

1880
A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 1879–1885
O
R
N
NH
N
NH
N
Cl
NH2
N
S
N
S
NH
N
O
NH
COOH
COOH
I-raltitrexed
O
II-thymitaq
III- R= H
IV-R= Bz
R
O
O
O
N
N
Bn
S
R
N
N
N
RHN
N
VIII-R=CH3
IX-R=C2H5
X-R=Cl
V-R=NHSO2Ph
VI-R=NHCOPh
3-27
VII-R=benzylidineamino
XI-R=Br
Figure 1. Reported and designed quinazolinones (3–27) as anticancer and CNS active agents.
O
O
O
1-Ac2O
2-o-toludine,
pyridine
N
N
OH
Fe/HCl
EtOH
ClCOOEt
N
2
N
1
H2N
NH2
O2N
O2N
P2S5
P2S5
O
N
S
N
N
S
N
N
4
N
Fe/HCl
EtOH
HN
H2N
O2N
O
O
5
3
Scheme 1. Synthesis of 7-ethoxycarbonylamino-4(3H)-quinazolinone 3 and 7-substituted-4(3H)-quinazolinthione 4–5.
O
N
O
N
RXCl
X=CO, SO2
N
N
X
N
H
H2N
no.
R
X
R
2
Ph
6
CO
4-Cl-Ph
4-tolyl
7
CO
8
CO
2-thiophen
Ph
9
CO
RCHO
AcOH
10
11
12
13
SO2
SO2
SO2
SO2
4-tolyl
4-NO2-Ph
4-Br-Ph
O
N
N
O
N
SHCH2COOH
xylene, reflux
R
S
N
R
N
N
O
14, R =Ph
18, R=Ph
19, R=4-F-Ph
20, R=4-Cl-Ph
15, R =4-F-Ph
16, R=4-Cl
17, R=2-furfuryl
Scheme 2. Reactions of 7-amino-4(3H)-quinazolinone 2.

A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 1879–1885
1881
O
O
N
N
O
N
24
O
O
O
O
O
O
N
O
O
X
O
N
O
O
O
O
N
O
N
N
N
NH2
O
N
N
O
N
21 X=H
25
2
X
O
X
22 X=tetrabromo
23 X=tetrachloro
O
O
N
O
N
X
N
N
26 X= H
27 X= Cl
Scheme 3. Synthesis of cyclic imides 21–25 and 4,4-biquinazolindione 26–27.
was subjected to metal reduction by reaction with Fe/HCl in boil-
ing ethanol.
kidney, skin, prostate and brain). The compounds were tested at
a single dose concentration of 10 M, and the percentages of
l
Amino function of compound 2 was reacted with ethyl chloro-
formate in boiling pyridine to produce 2-methyl-3-(2-methyl-
phenyl)-7-ethoxycarbonylamino-4(3H)-quinazolinone (3) in 84%
yield. Thiation of compound 1 and 2 was accomplished by reaction
with P2S5 in anhydrous xylene to give the corresponding 2-methyl-
3-(2-methylphenyl)-7-nitro-4(3H)-quinazolinthione (4) and 2-
methyl-3-(2-methylphenyl)-7-amino-4(3H)-quinazolinthione (5),
in 81%, 53% yield, respectively. Compound 4 was subjected to me-
tal reduction16 using Fe/HCl in boiling ethanol to afford 5 in 50%
yield (Scheme 1).
7-Amino-4(3H)-quinazolinone 2 was reacted with various acid
chlorides and sulfonyl chlorides in dichloromethane in the pres-
ence of triethylamine at room temperature to furnish 7-(substi-
tuted carbonylamino)-4(3H)-quinazolinones 6–9 in 87–92% yield
and 2-methyl-3-(2-methylphenyl)-7-(substituted sulfonylamino)-
4(3H)-quinazolinones 10–13 in excellent yield. Schiff’s base
14–17 was obtained in 60–66% yields, by reaction of 2 with various
aldehyde in boiling methanol, compound 14–16 was subjected to
cyclization via reaction with thioglycolic acid in anhydrous
benzene to afford 2-phenylthiazolidin-4-ones 18–20 in 47–55%
yields (Scheme 2).
growth inhibitions (GI %) over the 60 tested cell lines were
determined.
The obtained results of the tested quinazoline derivatives
showed potential pattern of selectivity, as well as broad-spectrum
antitumor activity of compound 7.
Regarding the activity toward individual cell lines; compounds
7, 9, 18, 19 and 20 showed selective activity against leukemia
MOLT-4 cell lines with GI values of 28.3%, 25.6%, 46.3%, 28.9%
and 39.1%, respectively; while Non-Small Cell Lung EKVX and ovar-
ian Cancer OVAR-4 proved to be selectively sensitive to 7 with GI
value of 48.5% and 69.9%, respectively. Compounds 3 and 7 showed
GI values of 41.6% and 56.4% against melanoma MDA-MB-435,
while compounds 6 and 7 showed GI values of 26.6% and 24.4%,
against colon KM12, 24.0%, 51.9% renal ACHN cancer cells and
27.9%, 71.0% against breast cancer T-47D, respectively. Compounds
7 and 18 showed GI values of 39.8% and 26.9% against prostate PC-
3 and 71.0%, 25.8%, 24.7% GI values of breast-T-47D cancer cells,
respectively. Compounds 3, 6, 7 and 18 showed activity against
CNS cancer SNB 75 with GI values of 21.3%, 21.2%, 21.2% and
19.5%, respectively. The percentages of growth inhibitions over
the most sensitive 9-cell lines are shown in Figure 2.
On the other hand, compound 2 was reacted with various anhy-
drides and 1,3-benzoxazine-4-one in boiling glacial acetic acid in
the presence of anhydrous sodium acetate to give the correspond-
ing imides 21–25 in 84–89% and 4,4-biquinazolindione 26–27 in
72–76% yield.
In vitro antitumor evaluation of the nine compounds indicated
in (Tables 1) were selected by National Cancer Institute, Bethesda,
Maryland, USA on the basis of degree of the structure variation and
computer modeling techniques for evaluation of their anticancer
activity. The selected compounds were subjected to in vitro anti-
cancer assay against tumor cells in a full panel of 60-cell lines ta-
ken from nine different organs (lung, colon, breast, ovary, blood,
Compound 20 demonstrated certain activity toward numerous
cell lines that belong to different tumor subpanels such as UACC-
62, SK-OV-3 and MDA-MB-231/ATCC with GI values 18%, 29.2%
and 23.7%, respectively. Meanwhile, compound 9 and 18 showed
a moderate activity against leukemia CCRF-CEM, HL-60TB, K-562,
MOLTT-4, RPMI-8226, RPMI-8226 with GI values in percentages
of (12.2, 31.1), (19.2, 32.7), (12.8, 37.6), (25.6, 46.3), (8.0, 21.4)
and (21.0, 35.3), respectively.
In addition, compound 7 revealed effectiveness toward numer-
ous cell lines that belong to different tumor subpanels such as
CCRF-CEM, MALME-3M, SK-MEL-5 and UACC-62 cancer with GI
values of 47.3%, 56.5%, 99.1% and 57.8%, respectively. Concurrently,

1882
A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 1879–1885
Table 1
Percentage growth inhibition (GI%) of in vitro subpanel tumor cell lines at 10
l
M concentration
% Growth inhibition (GI%)a
Subpanel tumor cell lines
Compound
3
5
6
7
9
10
18
19
20
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
2.2
—
6.2
—
6.5
24.1
9.5
—
—
—
4.0
—
—
47.3
35.5
44.2
29.3
55.4
26.3
12.2
19.2
12.8
25.6
8.0
13.0
4.0
10.0
12.2
12.0
—
31.1
32.7
37.6
46.3
21.4
35.3
13.2
7.0
10.0
28.9
10.0
4.0
11.3
6.0
8.4
39.1
9.2
—
6.0
9.0
8.2
2.0
3.5
21.0
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
3.0
11.6
—
—
—
—
—
—
—
11.0
11.1
5.0
—
—
—
27.8
48.5
3.0
12.0
35.7
6.0
—
11.0
—
—
—
—
—
—
5.0
14.3
—
2.5
5.2
—
8.1
12.8
—
14.3
4.4
—
2.0
—
—
—
—
—
—
18.0
12.0
4.0
—
—
—
—
—
—
15.2
5.5
—
—
11.1
—
—
—
27.5
nt
—
2.2
—
18.0
NCI-H522
4.0
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
—
—
—
6.4
7.8
12.0
2.0
—
16.6
—
2.5
—
8.3
—
—
—
—
—
—
—
—
11.0
—
—
—
—
—
—
—
—
5.0
3.0
4.0
—
—
—
—
—
—
—
—
19.1
25.2
36.3
38.1
24.4
14.0
4.0
4.0
—
3.0
—
3.2
3.7
—
26.6
—
16.0
13.3
—
15.5
—
—
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
—
—
17.2
5.7
21.3
4.5
10.6
16.6
2.0
2.0
15.5
6.0
—
32.3
40.3
31.8
24.2
21.2
32.4
—
6.0
—
—
—
—
14.2
—
—
9.7
19.5
13.0
—
7.0
—
—
8.5
11.0
—
—
5.0
—
7.6
—
29.0
10.0
14.0
21.2
9.0
9.0
4.0
4.0
14.8
4.0
12.0
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
—
5.4
—
41.6
1.72
2.4
7.0
15.8
—
—
6.0
12
16.3
—
17.0
—
31.6
56.5
32.3
56.4
20.4
99.1
40.3
57.8
4.2
—
—
6.0
—
—
—
—
—
—
2.4
—
—
—
—
—
9.7
5.0
—
—
—
5.0
—
—
9.7
11.0
—
9.0
14.0
—
—
—
7.7
—
17.0
4.0
9.8
—
—
—
4.0
—
8.0
9.0
23.0
9.0
18.0
Ovarian cancer
IGROV1
—
3.8
—
3.2
—
—
—
—
—
10.0
—
—
—
17.3
12.0
À5.0
—
21.4
41.1
69.9
24.1
16.0
17.6
16.8
—
—
—
—
—
—
—
—
—
—
—
5.4
—
—
—
3.0
—
5.0
—
—
—
—
—
—
—
3.0
—
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
5.2
5.0
—
—
—
—
5.0
—
—
—
—
29.2
Renal cancer
786-0
A498
—
—
20.0
—
5.0
—
—
—
32.4
39.4
52.0
41.2
23.2
32.4
nt
—
9.0
—
—
—
—
—
—
—
8.0
—
4.0
—
—
3.0
—
—
15.6
—
3.0
—
—
—
3.0
—
—
—
—
11.7
—
—
4.0
4.0
5.3
—
—
—
23.0
24.0
4.0
ACHN
3.5
3.0
3.0
5.0
—
CAKI-1
RXF 393
SN12C
TK-10
—
15.0
24.0
2.5
10.0
22.0
—
13.6
UO-31
24.1
22.2
22.0
15.0
Prostate cancer
PC-3
DU-145
11.2
—
9.5
—
8.0
—
39.8
12.4
—
—
8.0
—
26.9
—
12.2
—
8.0
—
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578T
BT-549
T-47D
5.0
—
—
3.5
—
—
—
—
—
8.0
11.0
—
7.0
—
—
18.0
28.0
2.0
42.2
42.7
17.9
nt
71.0
nt
—
—
—
8.0
7.8
—
—
—
3.2
—
—
21.8
17.3
6.0
—
25.8
25.8
9.0
8.0
—
—
—
5.2
23.7
—
—
4.0
—
MDA-MB-468
—
2.5
nt = not tested; a = the showed growth inhibition percentages are measured at a single concentration of 10
from 100.
lM % inhibition is calculated by simple abstraction of the % activity

A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 1879–1885
1883
Figure 2. The percentages of growth inhibition of the nine selected compounds over the most sensitive tumor cell lines.
Table 2
Preliminary anticonvulsant activity of the new synthesized compounds (1.0 mmol/kg), valproate (1.5 mmol/kg) and methaqualone (1.4 mmol/kg)
Compound no.
PTZ (% of protection)
Strychnine (% of protection)
Picrotoxin (% of protection)
MES (% of protection)
Valproate
Methaqualone
3
6
7
11
14
15
16
17
18
19
20
25
26
27
100
100
100
33
0.0
66
0.0
100
100
0.0
100
100
100
0.0
0.0
33
100
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
100
50
100
100
100
33
50
0.0
50
100
100
50
100
100
100
33
100
0.0
0.0
0.0
0.0
75
50
0.0
50
75
75
0.0
0.0
0.0
100
50
PTZ = pentylenetetrazol, MES = maximal electroshock test.
Table 3
Comparison of the anticonvulsant activity (ED50), acute neurotoxic effects (TD50), median lethal dose (LD50), therapeutic and protective indexes of the most promising
anticonvulsant new synthesized compounds, valproate and methaqualone in mice
Compound no.
ED50 (mmol/kg)
TD50 (mmol/kg)
LD50 (mmol/kg)
Therapeutic index
Protective index
Valproate
Methaqualone
3
15
16
18
19
20
1.50
1.40
0.74
0.31
0.35
0.70
0.40
0.41
2.70
1.60
1.78
0.93
0.89
0.75
0.56
0.60
3.00
2.00
1.93
1.71
1.81
1.50
1.02
1.04
2.00
1.40
2.60
5.50
4.6
2.13
2.55
2.53
1.80
1.14
2.40
3.00
2.54
1.06
1.40
1.50
ED50 = median effective dose providing anticonvulsant protection in 50% of mice against pentylenetetrazole (PTZ) induced seizures.
TD50 = median toxic dose producing minimal neurological toxicity in 50% of mice subjected to the Chimney test.
LD50 = median lethal dose that causes 50% mortality in mice.
Therapeutic index = LD50/ED50
Protective index = TD50/ED50
.
.
compound 7 proved to inactive against different tumor subpanels
such as HOP-92, NCI-H322M, SNB-75 and COLO 205.
standard techniques.31,32 The preliminary screening was per-
formed at 1.0 mmol/kg of all synthesized compounds (3–27) by
using of pentylenetetrazole (PTZ), picrotoxin, and strychnine in-
duced seizure and maximal electroshock seizure (MES) model of
seizures. The MES test is associated with the electrical induction
of the seizure, whereas PTZ, picrotoxin and strychnine methods in-
volve a chemical induction to generate the convulsion.32 The initial
anticonvulsant evaluation showed that some of these compounds
are inactive; however, compounds 3, 6, 11, 15, 16, 18, 19, 20,
With regard to antitumor activity; close examination of the data
presented in Table 1 revealed that compound 7 is the most active
member of this study, showing effectiveness toward numerous cell
lines that belong to different tumor subpanels, while compounds 9
and 18 possess selective activity toward leukemia cell lines.
The anticonvulsant activity and the acute neurotoxicity of the
new synthesized compounds were evaluated by the use of

1884
A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 1879–1885
and 27 were active against PTZ at 1.0 mmol/kg, among which com-
pounds 3, 15, 16, 18, 19 and 20 were presented 100% protection,
compounds 11 was offered 66% protection, while compounds 6
and 27 proved 33% protection.
Compounds 3, 6, 7, 14, 15, 16, 17, 18, 19, 20, 25, 26 and 27
exhibited anticonvulsant activity against MES-induced seizure at
the dose of 1.0 mmol/kg. The most active of these compounds were
3, 15, 16, 18, 19, 20 and 26 which showed 100% protection. The
compounds 7, 14, 17, and 27 accessible anti-MES effect by 50%,
while compound 6 and 25 revealed 33% protection.
The anticonvulsant activity against picrotoxin-induced seizure
at the dose of 1.0 mmol/kg, the most active of these compounds
was 3 which presented 100% protection, compounds 15, 19 and
20 gave protection by 75%, while compound 16, 18 exhibited 50%
protection. Nevertheless, none of all synthesized compounds
exhibited any potency towards anti-strychnine activity at the same
dose levels (Table 2).
chloride influx via brain chloride channel (such as picrotoxin) or
directly antagonizes the inhibitory spinal reflexes of glycine (such
as strychnine).35–37 Generally, in the MES test, one can determine
the anti-seizure effects of agents or drugs that suppress tonic–clo-
nic seizures by suggesting that those compounds possess the abil-
ity to prevent the spread of seizure discharge throughout neuronal
tissues and to raise seizure threshold.33
On account of their partial effectiveness, it is difficult to report
that our synthesized compounds as having anticonvulsant effects
via influencing glycine neurotransmission. However, most of our
new compounds can control the seizures induced by PTZ, MES
and picrotoxin, this might suggest that these compounds exhibit
a broad spectrum of anticonvulsant activity in animal models of
partial and generalized epilepsy via GABA activation. In addition,
more detailed study on the GABA pathways and the neurotrans-
mitter levels might be interesting and might provide more insights
for the anticonvulsant effects of these new 4(3H)-quinazolines
against convalsants induced seizures, which will be considered
extensively in our future study. However, at present some of the
new synthesized compounds have relatively potent anticonvulsant
effects combined with relatively low neurotoxicity.
As a result of preliminary screening, the most active compounds
3, 15, 16, 18, 19 and 20 were subjected to further investigations at
different doses for quantification of their anticonvulsant activity
(indicated by ED50) and neurotoxicity (indicated by TD50) in mice
(Table 3). The selected compounds 3, 15, 16, 18, 19 and 20 were
displayed anticonvulsant activity against PTZ-induced seizure with
ED50 values of 0.74, 0.31, 0.35, 0.70, 0.40 and 0.41 mmol/kg,
respectively. Methaqualone and valproate were used as reference
drugs and these compounds produced ED50 values of 1.40 and
1.5 mmol/kg, respectively. Interestingly, the ED50 values of the se-
lected compounds were found to be smaller compared to the refer-
ence anticonvulsant drugs at the same molar doses (Table 3).
The protective index (TD50/ED50) is considered to be an index
representing the margin of safety and tolerability between anti-
convulsant doses and doses of anticonvulsant drugs exerting acute
adverse effects (e.g., sedation, motor coordination impairment,
ataxia or other neurotoxic manifestations).33 Evaluation of the
acute adverse effect profile (TD50) of compounds 3, 15, 16, 18, 19
and 20 revealed that these agents exerted low neurological deficit
(Table 3). Almost the protective index values of the selected com-
pounds (2.40, 3.00, 2.54, 1.06, 1.40 and 1.50) were higher than or
equal to the reference drugs as compared to 1.14 for methaqualone
and 1.80 for valproate. It is obvious that the protective index values
for these selected compounds revealed a difference between the
doses producing neurotoxic action (TD50) and those exerting
anti-PTZ (ED50) actions in mice. The present results are in agree-
ment with the results of the anticonvulsant study of 2-substituted
3-aryl-4(3H)-quinazolinones in mice34 by Wolfe et al., Wolfe et al.
reported that the series of 4(3H)-quinazolinones which possessing
3-o-tolyl and 3-o-chlorophenyl groups showed good protection
against MES and PTZ induced seizures, combined with relatively
low neurotoxicity after ip administration 4(3H)-quinazolinones in
mice.
Compounds 3, 15, 16, 18, 19 and 20 revealed LD50 values of
1.93, 1.71, 1.81, 1.50, 1.02 and 1.04 with therapeutic index
(LD50/ED50) values 2.60, 5.50, 4.60, 2.13, 2.55 and 2.53. It is worth-
while to note that the therapeutic index of the selected compounds
was found to be higher as compared to the reference anticonvul-
sant drugs at the same molar doses (Table 3).
The results of the seizure induction screening methods in the
current study showed that some new quinazolines were effective
in controlling the seizures induced by PTZ, picrotoxin and MES
but failed to control those induced by strychnine, this effect is sim-
ilar to that of 4(3H)-quinazolinones, which have anticonvulsant
effects on seizures induced by PTZ, picrotoxin and MES but are
ineffective against strychnine-induced seizures in mice.34
It has been reported that the convulsants induce seizures by
Structure activity correlation, based on the number of cell lines
proved sensitive toward each of the synthesized individual com-
pounds, revealed that, the presence of electron withdrawing group
at aromatic ring of 7-phenylcarbonylamino-4(3H)-quinazolinone
enhance the antitumor activity as compared with unsubstituted
phenyl or heterocyclic ring, for examples 7-[4-chlorophenylcar-
bonylamino]-4(3H)-quinazolinone
7
is extra forceful than
7-[phenylcarbonylamino]-4(3H)-quinazolinone 6 or 7-[thiophen-
2-carbonylamino]-4(3H)-quinazolinone 9. The presence of electron
withdrawing group at aromatic ring of 2-(2-flourophenyl)]-thiaz-
olidin-4-one reduce the antitumor activity match up to unsubsti-
tuted phenyl ring, such as compound 18 more active than 19.
The anticonvulsant activity correlation of the newly synthesized
compounds revealed that compounds having hydrazones or 2-phe-
nylthiazolidin-4-ones fragments at position 7 possess significant
anticonvulsant activity such as compounds 14–20. Compounds
containing hydrazones moieties such as 14–17 were potent as
compared to the parent amine 2. It is clear that the presence of
electron withdrawing group at aromatic ring of Schiff’s base
enhance the activity compared with unsubstituted phenyl ring,
or heterocyclic ring, for examples compound 15 and 16 are more
active than compounds 14 and 17.
Attractively, cyclization of Schiff’s base 14–16 into phenylthiaz-
olidin-4-one 18–20 improves the anticonvulsant activity. On the
other hand, replacement of hydrazones or phenylthiazolidin-4-
one moieties into carbonylamino or sulfonylamino fragment in
position 7 dramatically reduces the anticonvulsant activity. Mean-
while, the presence of electron withdrawing group at aromatic ring
slightly enhance the activity compared with unsubstituted or elec-
tron donating group in phenyl ring, for examples compound 8
more active than 6 as well as compound 11 more active than 10,
12 and 13. Furthermore, the presence of cyclic amide at position
7 eliminates the activity, for instance compounds 21–25.
More interestingly, the presence of ethoxycarbonylamino frag-
ment absolutely increases the anticonvulsant activity like
compound 3. The obtained new findings point to the hydrazones,
2-phenylthiazolidin-4-ones or ethoxycarbonylamino moieties at
position 7 are important for the anticonvulsant activity, so further
investigations of structural features are required for anticonvulsant
activity and probably the pharmacokinetic profile of these
compounds.3.
In conclusion, new derivative of 7-substituted-4(3H)-quinazoli-
nones were synthesized and evaluated for their antitumor and
anticonvulsant activity. The results of this study demonstrated that
compound 7, is broad-spectrum antitumor showing effectiveness
inhibiting
c-aminobutyric acid (GABA) neurotransmission (such
as PTZ), GABAA-antagonist GABAA receptor agonist by increasing

A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 1879–1885
1885
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toward numerous cell lines that belong to different tumor subpan-
els, whereas compounds 9 and 18 possess selective activity toward
leukemia cell lines.
Additionally, compounds 3, 15, 16, 18, 19 and 20 showed
advanced anticonvulsant activity as well as lower toxicity than
methaqualone and valproate reference drugs. The obtained results
showed that certain compounds could be useful as a template for
future design, modification and investigation to produce more
active analogues.
Acknowledgments
The authors extend their appreciation to the Deanship of Scien-
tific Research at King Saud University for funding the work through
the research group Project No. RGP-VPP-163. Thanks are due to the
NCI, Bethesda, MD, USA for performing the antitumor testing of the
synthesized compounds.
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Supplementary data
Supplementary data associated with this article can be found, in
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