Synthesis and anticonvulsant evaluation of some novel 4(3H)-quinazolinones

Article abstract of DOI:10.1007/s00706-011-0525-3

A series of novel quinazoline derivatives, methaqualone analogs, were synthesized, evaluated for their anticonvulsant activity against electrically and chemically (pentylenetetrazole, picrotoxin, and strychnine) induced seizures and compared with the stan

Full text of DOI:10.1007/s00706-011-0525-3

Monatsh Chem (2011) 142:837–848
DOI 10.1007/s00706-011-0525-3
ORIGINAL PAPER
Synthesis and anticonvulsant evaluation of some novel
4(3H)-quinazolinones
•
Adel S. El-Azab Kamal E. H. ElTahir
•
Sabry M. Attia
Received: 14 October 2010 / Accepted: 3 May 2011 / Published online: 31 May 2011
Ó Springer-Verlag 2011
Abstract A series of novel quinazoline derivatives,
methaqualone analogs, were synthesized, evaluated for
their anticonvulsant activity against electrically and
chemically (pentylenetetrazole, picrotoxin, and strychnine)
induced seizures and compared with the standard drugs
methaqualone and sodium valproate. 3,4-Dihydro-2-
methyl-3-(2-methylphenyl)-4-oxoquinazolin-8-yl propano-
ate, benzenesulfonate, and 4-nitrobenzenesulfonate as well
as 2-methyl-3-(2-methylphenyl)-8-methoxy-4(3H)-quinaz-
olinone and 2-[3,4-dihydro-2-methyl-3-(2-methylphenyl)-
4-oxoquinazolin-8-yloxy]acetic acid hydrazide were found
to be the most potent compounds of this series accompa-
nied with relatively low neurotoxicity and low toxicity in
the median lethal dose test as compared with the reference
drugs.
Introduction
Epilepsy is one of the most common neurological disor-
ders, affecting about 1% of the world’s population. Many
efforts devoted in recent years to the development of novel
therapeutics have resulted in the availability of several
newer drugs as promising anticonvulsants [1, 2]. 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
numerous undesirable side effects [3–6]. Therefore, the
continued search for safer and more effective anticonvul-
sants is urgently necessary.
One of the most frequently encountered heterocycles in
medicinal chemistry is 4(3H)-quinazolinone, which has
diverse pharmacological activities, such as anti-tumor
[7, 8], anti-inflammatory [9], anticonvulsant [10, 11] and
anti-microbial activities [12, 13]. A literature survey
revealed that the presence of a methyl group at position 2
and a substituted aromatic ring at position 3 are necessary
requirements for the CNS depression and anticonvulsant
activities of compounds such as methaqualone, etaqualone,
mecloqualone, mebroqualone, and afloqualone. Figure 1
represents the similarities between the reported CNS active
quinazolinone agents and our designed compounds.
Keywords Methaqualone Á Thiadiazol Á Triazole Á
Neurotoxicity
A. S. El-Azab (&)
Department of Pharmaceutical Chemistry,
College of Pharmacy, King Saud University,
P.O. Box 2457, Riyadh 11451, Saudi Arabia
e-mail: adelazaba@yahoo.com
Etaqualone and mecloqualone are analogues of meth-
aqualone, which were developed and marketed mainly in
France, and some other European countries as sedative
hypnotic for the treatment of insomnia [14–16]. Meth-
ylmethaqualone and mebroqualone presumably have
similar sedative and hypnotic properties to its parent
compound, whereas afloqualone has sedative and muscle
relaxant effects [17, 18]. Despite the therapeutic benefits
of these drugs, there is strong circumstantial evidence
that these drugs can cause photosensitization as a side
A. S. El-Azab
Department of Organic Chemistry,
Faculty of Pharmacy Al-Azhar University,
Nasr City, Cairo, Egypt
K. E. H. ElTahir Á S. M. Attia
Department of Pharmacology,
College of Pharmacy, King Saud University,
P.O. Box 2457, Riyadh 11451, Saudi Arabia
123

838
A. S. El-Azab et al.
Fig. 1 Reported and designed
quinazolinones as CNS active
agents
R
N
O
N
O
N
O
N
O
N
H2N
N
N
F
N
OR
Methaqualone, R=CH3
Etaloqualone, R=C2H5
Mecloqualone, R=Cl
Mebroqualone, R=Br
Afloqualone
Methylmethaqualone
2-34
effect that can cause skin problems such as dermatitis
[19, 20].
quinazolinones 13–18 in 90–96% yield. Moreover, reaction
of 3 with various halides (methyl iodide, ethyl iodide,
benzyl chloride, p-nitrobenzyl chloride, and chloroaceto-
nitrile) in acetone in the presence of potassium carbonate at
room temperature gave the corresponding 8-(substituted
methoxy)-4(3H)-quinazolinones 19–23 in 80–92% yield
(Scheme 2).
In our laboratory, much research effort focuses on syn-
thesizing quinazoline derivatives with substituted moieties
possessing high lipid solubility in the hope of developing
potent and safe new effective compounds [21, 22]. Herein, a
new series of methaqualone analogues possessing carbo-
nyloxy, sulfonyloxy, acetamidoxy, alkoxy, acetonitriloxy,
benzyloxy, ethylacetoxy, acetohydrazino, hydrazincarbox-
amido, hydrazincarbothioamido, 1,2,4-triazol-3-yl, and
1,3,4-thiadiazol-2-yl moieties at position 8 were designed,
synthesized, and investigated for anticonvulsant activity.
The chosen substituted moieties were known to increase the
lipid solubility [21]. Therefore, the objective of the current
study was to synthesize and investigate if the substituents at
position 8 could enhance the anticonvulsant activity of
methaqualone with lower neurotoxicity in mice, a mam-
malian model.
On the other hand, 8-hydroxymethaqualone 3 was
reacted with ethyl bromoacetate in dry acetone in the
presence of potassium carbonate at room temperature to
afford a quantitative yield of ethyl 2-[3,4-dihydro-2-
methyl-3-(2-methylphenyl)-4-oxoquinazolin-8-yloxy]ace-
tate (24), which was treated with hydrazine hydrate in
ethanol at room temperature to furnish 2-[3,4-dihydro-2-
methyl-3-(2-methylphenyl)-4-oxoquinazolin-8-yloxy]ace-
tic acid hydrazide (25) as a second key intermediate in 90%
yield.
Acid hydrazide 25 was reacted with p-chlorophenyl
isocyanate in ethanol at room temperature to produce 2-[3,4-
dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquinazolin-8-
yloxy]acetic acid 2-[(4-chlorophenyl)aminocarbonyl]-
hydrazide (26) in 88% yield. Reaction of 25 with various
isothiocyanates in ethanol at room temperature produced
2-[3,4-dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquina-
zolin-8-yloxy]acetic acid 2-[(substituted amino)thioxom-
ethyl]hydrazides 27–29 in 88, 84, and 90% yield,
respectively.
Results and discussions
Chemistry
Synthesis of 8-hydroxy-2-methyl-3-(2-methylphenyl)-
4(3H)-quinazolinone (3) as a first key intermediate was
done by the reaction of 3-hydroxyanthranilic acid with
acetic anhydride followed by treatment with o-toludine in
anhydrous pyridine to afford 8-acetyloxy-2-methyl-3-(2-
methylphenyl)-4(3H)-quinazolinone (2). The latter com-
pound was subjected to catalytic hydrolysis by the reaction
with potassium carbonate in methanol to give compound 3
in 70% overall yield.
Compounds 27–29 were cyclized according to the
reported procedure [23] to the corresponding 8-[(4-
substituted 5-mercapto-4H-1,2,4-triazol-3-yl)methoxy]-2-
methyl-3-(2-methylphenyl)-4(3H)-quinazolinones 30–32
by boiling in ethanol containing triethylamine. An attempt
to cyclize compound 26 under the same reaction conditions
failed. Compounds 30–32 were also obtained in another
pathway on treatment of 25 with various isothiocyanates in
boiling ethanol containing triethylamine in 86, 85, and 88%
yield, respectively.
Compound 3 was reacted with various acid chlorides
(benzoyl chloride, p-chlorobenzoyl chloride, p-tolyl chlo-
ride, thiophen-2-carbonyl chloride, and propionyl chloride)
in anhydrous pyridine at room temperature to obtain
8-(substituted carbonyloxy)-4(3H)-quinazolinones 4–8. Also,
3 was reacted with various substituted phenylsulfonyl
chlorides in anhydrous pyridine to afford 8-(substituted
phenylsulfonyloxy)-4(3H)-quinazolinones 9–12 in 88–94%
yield (Scheme 1).
The acid dehydrative cyclization of compounds 27 and
28 by using concentrated H2SO4 at room temperature
yielded
8-[(5-amino-1,3,4-thiadiazol-2-yl)methoxy]-2-
methyl-3-(2-methylphenyl)-4(3H)-quinazolinone (33) and
2-methyl-3-(2-methylphenyl)-8-[(5-phenylamino-1,3,4-
thiadiazol-2-yl)methoxy]-4(3H)-quinazolinone (34) in 62
and 68% yield, respectively (Scheme 3).
Compound 3 was heated with various chloroacetani-
lides in anhydrous acetone in the presence of potassium
carbonate to give 8-(substituted acetamido)-4(3H)-
123

Synthesis and anticonvulsant evaluation of 4(3H)-quinazolinones
839
Scheme 1
O
N
O
N
O
N
COOH
O
N
N
K2CO3
MeOH
o-Toludine
Ac2O
NH2
OH
OAc
OAc
OH
3
2
1
RXCl
R
Ph
X
4
5
6
7
8
9
CO
CO
CO
O
N
N
4-Cl-Ph
4-Tolyl
2-Thienyl CO
Ethyl
Ph
4-Tolyl
CO
SO2
SO2
OXR
10
11 4-NO2-Ph SO2
12
4-Br-Ph
SO2
Scheme 2
O
N
O
N
N
R-NHCOCH2 Cl
N
OCH2CONHR
OH
3
13 R = H
14 R = Ph
RCH2X
X = Cl or I
15 R = 4-F-Ph
16 R = 4-EtO-Ph
17 R = 4-Tolyl
18 R = 3,4,5-tri-MeO-Ph
O
19 R = H
CH
CN3
Ph
20 R =
R =
22 R =
N
21
N
23 R = 4-NO2-Ph
OCH2 R
Pharmacology
while compound 8 presented 50% protection. Compounds
8, 9, 19, and 25 exhibited anticonvulsant activity against
MES-induced seizure at the dose of 0.5 mmol/kg. The
most active of these compounds were 8 and 19, which
presented 100% protection. The remaining two compounds
9 and 25 exhibited an anti-MES effect by only 50%.
Nevertheless, none of all synthesized compounds exhibited
any potency towards anti-strychnine activity at the same
dose levels.
The anticonvulsant activity and the acute neurotoxicity of
the newly synthesized compounds were evaluated by the
use of standard techniques [24, 25]. The preliminary
screening was performed at 0.5 mmol/kg of all synthesized
compounds 2–34 by use of pentylenetetrazole (PTZ), pic-
rotoxin, strychnine induced and maximal electroshock
seizure (MES) model of seizures. The MES test is associ-
ated with the electrical induction of the seizure, whereas
PTZ, picrotoxin, and strychnine methods involve a chem-
ical induction to generate the convulsion [26].
As a result of preliminary screening, the most active
compounds 8, 9, 11, 19, and 25 were subjected to further
investigations at different doses for quantification of their
anticonvulsant activity (indicated by ED50) and neurotox-
icity (indicated by TD50) in mice (Table 2). The selected
compounds 8, 9, 11, 19, and 25 exhibited anticonvulsant
activity against PTZ-induced seizure with ED50 values of
0.3, 0.24, 0.22, 0.36, and 0.29 mmol/kg, respectively.
Methaqualone and valproate were used as reference drugs,
and these compounds produced ED50 values of 1.4 and
4.8 mmol/kg, respectively. Interestingly, the ED50 values
of the selected compounds were found to be smaller
The initial anticonvulsant evaluation showed that many
of these compounds are inactive; however, compounds 8,
9, 11, 13, 15, 18, 19, 25, and 29 were active against PTZ at
0.5 mmol/kg, among which compounds 8, 9, 11, 19, and 25
presented 100% protection, while compounds 13, 15, 18,
and 29 presented 50% protection (Table 1). Compounds 8
and 19 appear unique among these anticonvulsants in their
ability to antagonize picrotoxin-induced seizures at a dose
of 0.5 mmol/kg. Compound 19 possessed 100% protection,
123

840
A. S. El-Azab et al.
Scheme 3
O
N
O
N
O
N
N
BrCH 2 COOEt
NH2NH2
N
N
OCH2COOEt
OCH2CONHNH2
OH
24
3
25
RNCX
r.t., EtOH
RNCS, EtOH,
TEA,reflux
O
N
O
N
O
N
N
EtOH, TEA
Reflux
N
N
conc.
H2SO4
N
OCH2CONHNHCXNHR
O
O
N
N
N
R
X
O
S
S
S
S
26 4-Cl-Ph
N
R
27
Bn
NHR
SH
28 Et
29
33
Ph
R = H
34 R = Ph
30
R = Bn
31 R = Et
32
R = Ph
Table 1 Preliminary
Compound
PTZ/%
of protection
Strychnine/%
of protection
Picrotoxin/%
of protection
MES/%
of protection
anticonvulsant activity of the
synthesized compounds
(0.5 mmol/kg), valproate
(1.5 mmol/kg), and
Valproate
100
100
100
100
100
50
100
0
100
50
50
0
100
100
100
50
50
0
Methaqualone
methaqualone (1.4 mmol/kg)
8
0
9
0
11
13
15
18
19
25
29
0
0
0
0
50
0
0
0
50
0
0
0
100
100
50
0
100
0
100
50
0
0
PTZ pentylenetetrazol, MES
maximal electroshock test
0
0
compared to the reference anticonvulsant drugs at molar
doses.
exceptional difference between the doses producing neu-
rotoxic action (TD50) and those exerting anti-PTZ (ED50)
actions in mice. The present results are in agreement with
the results of the anticonvulsant study of 2-substituted
3-aryl-4(3H)-quinazolinones in mice by Wolfe et al. [28].
Wolfe and colleagues reported that a series of 4(3H)-qui-
nazolinones possessing 3-(o-tolyl) and 3-(o-chlorophenyl)
groups showed good protection against MES- and PTZ-
induced seizures combined with relatively low neurotox-
icity after i.p. administration of 4(3H)-quinazolinones in
mice.
The protective index (ED50/TD50) is considered to be an
index representing the margin of safety and tolerability
between anticonvulsant doses and doses of anticonvulsant
drugs exerting acute adverse effects (e.g., sedation, motor
coordination impairment, ataxia, or other neurotoxic
manifestations) [27]. Evaluation of the acute adverse effect
profile (TD50) of compounds 8, 9, 11, 19, and 25 revealed
that these agents exerted a low neurological deficit
(Table 2). The protective index values of the selected
compounds were higher than the reference drugs and ran-
ged from 1.2 to 3.9 as compared to 1.14 for methaqualone
and 2.0 for valproate. It is obvious that the protective index
values for these selected compounds revealed an
Compounds 8, 9, 11, 19, and 25 revealed LD50 values of
2.79, 1.97, 2.66, 2.89, and 2.96 with therapeutic index
(LD50/ED50) values ranging from 8 to 12.1. It is worth-
while to note that the therapeutic index of the selected
123

Synthesis and anticonvulsant evaluation of 4(3H)-quinazolinones
841
Table 2 Comparison of the anticonvulsant activity (ED50), acute neurotoxic effects (TD50), median lethal dose (LD50), therapeutic and
protective indexes of the most promising anticonvulsant synthesized compounds, valproate, and methaqualone in mice
Compound
ED50 (mmol kg-1
)
TD50 (mmol kg-1
)
LD50 (mmol kg-1
)
Therapeutic index
Protective index
Valproate
4.8
9.6
11.9
2.00
2.79
1.97
2.66
2.89
2.96
2.48
1.40
9.3
2.00
1.14
3.2
Methaqualone
1.40
0.3
1.60
0.97
0.94
0.27
0.89
0.79
8
9
0.24
0.22
0.36
0.29
8.2
3.9
11
19
25
12.1
8.0
1.2
2.4
10.2
2.7
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
compounds was found to be much higher as compared to
the reference anticonvulsant drugs at molar doses
(Table 2). However, compounds 9, 11, and 25 showed
slight sedative activity 5 min after injection with a duration
range from 5 to 15 min at doses close to those required for
anticonvulsant activity.
methaqualone analogues have relatively potent anticon-
vulsant effects combined with relatively low neurotoxicity.
In conclusion, new derivatives of 4(3H)-quinazolinones
were synthesized and evaluated for their anticonvulsant
activity in mice. The results of this study demonstrated that
8-substituted-4(3H)-quinazolinone derivatives possess a
good anticonvulsant activity; especially compounds 8, 9,
11, 19, and 25 showed better anticonvulsant activity and
much lower toxicity than the benchmark marketed drugs
valproate and methaqualone. In addition, compounds 8 and
19 demonstrated potent antagonistic activity against sei-
zures induced by PTZ, picrotoxin, and MES, but failed to
control those induced by strychnine. These experiments
suggested that compounds 8 and 19 possess a broad spec-
trum of anticonvulsant activity in animal models of partial
and generalized epilepsy via GABA activation.
The results of the seizure induction screening methods
in the current study showed that several new methaqualone
analogues were effective in controlling the seizures
induced by PTZ, picrotoxin, and MES, but failed to control
those induced by strychnine. This effect is similar to that of
4(3H)-quinazolinones, which have anticonvulsant effects
on seizures induced by MES and PTZ and are ineffective
against strychnine-induced seizures in mice [28]. It has
been reported that the convulsants induce seizures by
inhibiting c-aminobutyric acid (GABA) neurotransmission
(such as PTZ) and GABAA-antagonist (such as picrotoxin),
or directly antagonizes the inhibitory spinal reflexes of
glycine (such as strychnine) [29–31]. Generally, in the
MES test, one can determine the anti-seizure effects of
agents or drugs that suppress tonic-clonic seizures and, to a
certain extent, partial convulsions in humans [27]. Because
of their partial effectiveness, it is difficult to report that our
synthesized compounds had anticonvulsant effects via
influencing glycine neurotransmission. However, most of
our new compounds can control the seizures induced by
PTZ, picrotoxin, and MES. This might suggest that these
compounds exhibit a broad spectrum of anticonvulsant
activity in animal models of partial and generalized epi-
lepsy via GABA activation. In addition, a more detailed
study on the GABA pathways, GABAA receptors, and the
neurotransmitter levels might be interesting and provide
more insights for the anticonvulsant effects of these new
methaqualone analogues against convulsant-induced sei-
zures, which will be considered extensively in our future
study. However, at present several of the newly synthesized
Structure activity relationship
Considering the pharmacological results of all newly syn-
thesized compounds, it can be shown that compounds
having phenylsulfonyl, aliphatic alkanoyl, or methyl frag-
ments at position 8 possess a significant anticonvulsant
activity, such as compounds 8, 9, 11, and 19. Presence of a
nitro group at the aromatic ring of benzenesulfonyl
enhances the activity compared with a methyl group, for
example, compounds 9, 10, and 11, which indicated the
requirement of a small electron deficient group on the
benzenesulfonyl moiety. Moreover, a propionyl moiety at
position 8 greatly increases the anticonvulsant activity
when compared with the aryl moieties such as compounds
4–8. Compound 25 was more potent as compared to its
ester form 24 and cyclized fragments 32 or 34, which
indicated the requirement of a small hydrogen bond-rich
group at position 8 of the aromatic ring. The obtained new
findings indicate that further investigations of structural
123

842
A. S. El-Azab et al.
General procedure for the synthesis of compounds 4–8
features are required for anticonvulsant activity and prob-
ably the pharmacokinetic profile of these compounds.
A mixture of 532 mg 8-hydroxymethaqualone (3, 2 mmol)
and the appropriate benzoyl chloride (2.1 mmol) in 10 cm3
pyridine was stirred at room temperature for 10–12 h. The
solvent was removed under reduced pressure, and the res-
idue was triturated with water and filtered. The solid
obtained was dried and recrystallized.
Experimental
Melting points (corrected) were recorded on a Barnstead
1
9100 Electrothermal melting apparatus. H NMR and 13C
NMR spectra were recorded in DMSO-d6 or CDCl3 on a
Bruker 500 MHz instrument using TMS as internal stan-
dard (chemical shifts: d in ppm). Mass spectra were
recorded on a Shimadzu PQ-5000 GC-MS apparatus. Sol-
vent evaporation was performed under reduced pressure
using a Buchan Rotatory Evaporator unless otherwise sta-
ted. TLC was performed on precoated silica gel plates (60-
F254, 0.2 mm) manufactured by E.M. Sciences, Inc.
(CH2Cl2-EtOH 10:1), and shortwave UV (254 nm) was
used to detect the UV absorbing compounds.
3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquina-
zolin-8-yl benzoate (4, C23H18N2O3)
Yield 94%; m.p.: 165–167 °C; 1H NMR (CDCl3):
d = 8.21 (d, 2H, J = 7.5 Hz), 8.09 (d, 1H, J = 8.0 Hz),
7.82 (d, 1H, J = 8.0 Hz), 7.78 (t, 1H, J = 7.5 Hz),
7.65–7.58 (m, 3H), 7.46–7.38 (m, 4H), 2.04 (s, 3H), 1.99
(s, 3H) ppm; 13C NMR (CDCl3): d = 17.3, 24.5, 122.3,
124.7, 127.0, 127.9, 128.2, 128.8, 129.3, 129.5, 129.9,
130.4, 131.6, 134.5, 135.5, 137.1, 140.9, 146.2, 155.5,
160.7, 165.0 ppm; MS (70 eV): m/z = 370.
8-Acetyloxy-2-methyl-3-(2-methylphenyl)-4(3H)-
quinazolinone (2, C18H16N2O3)
3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquina-
zolin-8-yl 4-chlorobenzoate (5, C23H17ClN2O3)
3-Hydroxyanthranilic acid (20 mmol, 3.08 g) was refluxed
with 50 cm3 acetic anhydride for 3 h. The reaction mixture
was cooled, filtered, washed with petroleum ether, and
dried to yield 8-acetyloxy-2-methyl-4H-3,1-benzoxazin-4-
one (1) as an a gummy compound, which was used in the
next step without further purification.
1
Yield 95%; m.p.: 220–222 °C (EtOH); H NMR (CDCl3):
d = 8.27–8.08 (m, 3H), 7.61 (d, 1H, J = 7.5 Hz),
7.55–7.37 (m, 6H), 7.15 (d, 1H, J = 7.5 Hz), 2.14 (s,
3H), 2.11 (s, 3H) ppm; 13C NMR (CDCl3): d = 17.4, 24.3,
122.5, 125.1, 126.4, 127.1, 127.7, 129.0, 129.4, 131.6,
131.8, 135.4, 136.7, 140.2, 141.4, 146.0, 154.9, 161.1,
164.4 ppm; MS (70 eV): m/z = 404, 406 (M ? 2).
A mixture of 2.19 g benzoxazinone 1 (10 mmol) and
1.18 g o-toludine (11 mmol) in 30 cm3 pyridine was
heated under reflux for 8 h. The reaction mixture was
cooled, the solvent was removed under reduced pressure,
and the residue was triturated with water and filtered. The
solid obtained was dried and chromatographed (CHCl3).
Yield 93%; m.p.: 130–132 °C; 1H NMR (CDCl3):
d = 8.10 (d, 1H, J = 7.5 Hz), 7.68 (d, 1H, J = 7.5 Hz),
7.42 (d, 1H, J = 7.5 Hz), 7.36–7.25 (m, 3H), 7.07 (d, 1H,
J = 7.0 Hz), 2.35 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H) ppm;
13C NMR (CDCl3): d = 17.3, 20.8, 24.3, 122.4, 124.7,
124.9, 125.8, 126.3, 127.2, 129.7, 131.5, 135.4, 136.7,
140.6, 145.9, 154.8, 161.1, 169.4 ppm; MS (70 eV):
m/z = 308.
3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquina-
zolin-8-yl 4-methylbenzoate (6, C24H20N2O3)
1
Yield 95%; m.p.: 192–194 °C (EtOH); H NMR (CDCl3):
d = 8.25–8.22 (m, 3H), 7.64 (d, 1H, J = 7.5 Hz), 7.52 (t,
1H, J = 7.5 Hz), 7.43–7.28 (m, 5H), 7.15 (d, 1H,
J = 7.5 Hz), 2.49 (s, 3H), 2.15 (s, 3H), 2.11 (s, 3H)
ppm; 13C NMR (CDCl3): d = 17.4, 21.8, 24.3, 120.7,
124.9, 126.4, 126.7, 127.4, 127.6, 127.9, 129.3, 129.6,
130.5, 131.5, 135.4, 136.8, 141.0, 144.5, 146.3, 154.7,
161.2, 165.3 ppm; MS (70 eV): m/z = 384.
3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquina-
zolin-8-yl thiophene-2-carboxylate
(7, C21H16N2O3S)
1
8-Hydroxy-2-methyl-3-(2-methylphenyl)-4(3H)-
quinazolinone (3)
Yield 94%; m.p.: 184–186 °C (EtOH); H NMR (CDCl3):
d = 8.24 (d, 1H, J = 7.5 Hz), 8.10 (d, 1H, J = 3.5 Hz),
7.71 (d, 1H, J = 5.0 Hz), 7.65 (d, 1H, J = 8.0 Hz), 7.50 (t,
1H, J = 8.0 Hz), 7.40–7.36 (m, 3H), 7.22 (t, 1H,
J = 8.5 Hz), 7.15 (d, 1H, J = 7.0 Hz), 2.14 (s, 3H), 2.13
(s, 3H) ppm; 13C NMR (CDCl3): d = 17.4, 24.3, 122.4,
125.1, 126.4, 127.4, 127.7, 127.9, 128.1, 129.6, 131.9,
132.6, 133.7, 135.0, 135.4, 136.8, 141.0, 145.8, 154.9,
160.5, 161.1 ppm; MS (70 eV): m/z = 376.
A mixture of 3.08 g 4(3H)-quinazolinone 2 (10 mmol) and
1.52 g anhydrous potassium carbonate (11 mmol) in
50 cm3 methanol was stirred at room temperature for 6 h.
The reaction mixture was filtered, the solvent was removed
under reduced pressure, and the solid obtained was dried
and chromatographed (CHCl3). Yield 70%; m.p.:
162–164 °C, Ref. [32] m.p.: 149.5 °C.
123

Synthesis and anticonvulsant evaluation of 4(3H)-quinazolinones
843
3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-
oxoquinazolin-8-yl propanoate (8, C19H18N2O3)
130.6, 131.6, 135.0, 136.2, 140.8, 141.9, 143.5, 151.0,
155.4, 160.4 ppm; MS (70 eV): m/z = 451.
1
Yield 88%; m.p.: 98–100 °C (EtOH); H NMR (CDCl3):
3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-
oxoquinazolin-8-yl 4-bromobenzenesulfonate
(12, C22H17BrN2O4S)
d = 8.17 (d, 1H, J = 7.5 Hz), 7.50–7.35 (m, 5H), 7.14 (d,
1H, J = 7.0 Hz), 2.76 (q, 2H, J = 7.5 Hz), 2.16 (s, 3H),
2.12 (s, 3H), 1.36 (t, 3H, J = 7.5 Hz) ppm; 13C NMR
(CDCl3): d = 9.3, 17.4, 24.3, 27.5, 122.3, 124.7, 126.3,
127.2, 127.7, 127.9, 129.6, 131.5, 135.3, 136.7, 140.7,
146.1, 154.7, 161.1, 173.0 ppm; MS (70 eV): m/z = 325
(M ? 3).
1
Yield 93%; m.p.: 178–180 °C (EtOH); H NMR (CDCl3):
d = 8.21 (d, 1H, J = 8.0 Hz), 7.80–7.75 (m, 3H), 7.62 (d,
2H, J = 9.0 Hz), 7.48–7.36 (m, 4H), 7.10 (d, 1H,
J = 6.5 Hz), 2.05 (s, 3H), 1.95 (s, 3H) ppm; 13C NMR
(CDCl3): d = 17.2, 23.7, 122.5, 126.4, 127.7, 129.1, 129.3,
129.8, 130.6, 131.6, 132.0, 135.0, 135.1, 136.3, 140.9,
143.6, 155.0, 160.5 ppm; MS (70 eV): m/z = 484, 486
(M ? 2).
General procedure for the synthesis of compounds 9–12
A mixture of 532 mg 8-hydroxymethaqualone (3, 2 mmol)
and the appropriate benzenesulfonyl chloride (2.1 mmol)
in 15 cm3 pyridine was stirred at room temperature for
10–12 h. The solvent was removed under reduced pressure,
and the residue was triturated with water and filtered. The
solid obtained was dried and recrystallized.
General procedure for the synthesis of compounds
13–17
A mixture of 532 mg 8-hydroxymethaqualone (3, 2 mmol)
and the appropriate chloroacetanilide (2.1 mmol) in
15 cm3 acetone containing 415 mg anhydrous potassium
carbonate (3 mmol) was heated under reflux for 10–12 h.
The reaction mixture was filtered while hot, the solvent
was removed under reduced pressure, and the solid
obtained was dried and recrystallized.
3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquina-
zolin-8-yl benzenesulfonate (9, C22H18N2O4S)
1
Yield 91%; m.p.: 165–167 °C (EtOH); H NMR (CDCl3):
d = 8.19 (d, 1H, J = 7.0 Hz), 7.97 (d, 2H, J = 7.0 Hz),
7.72–7.62 (m, 2H), 7.51–7.27 (m, 6H), 7.07 (d, 1H,
J = 7.0 Hz), 2.00 (s, 3H), 1.96 (s, 3H) ppm; 13C NMR
(CDCl3): d = 17.20, 23.8, 122.5, 126.2, 126.3, 127.7,
127.8, 128.7, 128.8, 129.0, 129.7, 131.6, 134.0, 135.1,
136.3, 136.4, 141.1, 143.9, 155.0, 160.6 ppm; MS (70 eV):
m/z = 405 (M - 1).
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquina-
zolin-8-yloxy]acetamide (13, C18H17N3O3)
1
Yield 94%; m.p.: 119–121 °C (EtOH); H NMR (CDCl3):
d = 8.02 (s, 1H), 7.90 (d, 1H, J = 8.0 Hz), 7.44–7.38 (m,
4H), 7.30 (t, 1H, J = 7.5 Hz), 7.16 (d, 1H, J = 7.5 Hz),
6.39 (s, 1H), 4.72 (s, 2H), 2.21 (s, 3H), 2.12 (s, 3H) ppm;
13C NMR (CDCl3): d = 17.3, 24.0, 70.1, 119.2, 120.9,
122.2, 127.0, 127.7, 127.8, 129.8, 131.6, 135.5, 136.5,
138.9, 152.7, 154.5, 161.1, 171.6 ppm; MS (70 eV):
m/z = 323.
3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-
oxoquinazolin-8-yl 4-methylbenzenesulfonate
(10, C23H20N2O4S)
1
Yield 93%; m.p.: 182–184 °C (EtOH); H NMR (CDCl3):
d = 8.19 (d, 1H, J = 8.0 Hz), 7.85 (d, 2H, J = 8.0 Hz),
7.69 (d, 1H, J = 8.0 Hz), 7.46–7.37 (m, 4H), 7.29 (d, 2H,
J = 8.0 Hz), 7.08 (d, 1H, J = 7.5 Hz), 2.43 (s, 3H), 2.04
(s, 3H), 1.99 (s, 3H) ppm; 13C NMR (CDCl3): d = 17.1,
21.7, 23.8, 100.0, 122.5, 126.1, 126.3, 127.7, 128.7, 129.0,
129.3, 129.7, 131.6, 133.2, 135.1, 136.4, 141.2, 144.0,
145.1, 154.8, 160.7 ppm; MS (70 eV): m/z = 419
(M - 1).
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-
oxoquinazolin-8-yloxy]-N-phenylacetamide
(14, C24H21N3O3)
Yield 93%; yellow oil; 1H NMR (CDCl3): d = 9.74 (s, 1H,
exchangeable), 7.95 (d, 1H, J = 7.0 Hz), 7.61–7.38 (m,
7H), 7.03–6.89 (m, 3H), 4.81 (s, 2H), 2.23 (s, 3H), 2.15 (s,
3H) ppm; 13C NMR (CDCl3): d = 17.3, 24.3, 70.1, 115.5,
115.7, 120.1, 121.5, 122.3, 126.6, 127.8, 129.8, 131.8,
133.7, 135.1, 136.5, 139.1, 152.5, 154.8, 158.6, 160.3,
161.0, 165.8 ppm; MS (70 eV): m/z = 398 (M - 1).
3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-
oxoquinazolin-8-yl 4-nitrobenzenesulfonate
(11, C22H17N3O6S)
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-
oxoquinazolin-8-yloxy]-N-(4-fluorophenyl)acetamide
(15, C24H20FN3O3)
1
Yield 93%; m.p.: 142–144 °C (EtOH); H NMR (CDCl3):
d = 8.33 (d, 2H, J = 8.5 Hz), 8.21 (d, 3H, J = 8.5 Hz),
7.74 (d, 1H, J = 7.5 Hz), 7.48 (t, 1H, J = 8.0 Hz),
7.41–7.34 (m, 3H), 7.06 (d, 1H, J = 7.5 Hz), 1.99 (s,
3H), 1.91 (s, 3H) ppm; 13C NMR (CDCl3): d = 17.1, 23.7,
122.7, 123.7, 126.5, 126.7, 127.7, 127.8, 128.8, 129.8,
1
Yield 92%; m.p.: 157–159 °C (EtOH); H NMR (CDCl3):
d = 9.91 (s, 1H, exchangeable), 8.01 (d, 1H, J = 7.0 Hz),
7.61–7.38 (m, 7H), 7.17 (d, 1H, J = 7.5 Hz), 7.04–7.00
(m, 2H), 4.85 (s, 2H), 2.25 (s, 3H), 2.13 (s, 3H) ppm; 13C
123

844
A. S. El-Azab et al.
NMR (CDCl3): d = 17.3, 24.2, 71.1, 115.4, 115.7, 120.3,
121.5, 122.3, 126.9, 127.8, 129.8, 131.7, 133.4, 135.2,
136.5, 139.1, 152.8, 154.8, 158.6, 160.6, 161.0, 166.8 ppm;
MS (70 eV): m/z = 416 (M - 1).
reduced pressure, and the solid obtained was dried and
recrystallized.
2-Methyl-3-(2-methylphenyl)-8-methoxy-4(3H)-
quinazolinone (19)
Yield 90%; m.p.: 166–168 °C (AcOH), Ref. [33] m.p.:
166–167 °C.
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-
oxoquinazolin-8-yloxy]-N-(4-ethoxyphenyl)acetamide
(16, C26H25N3O4)
8-Ethoxy-2-methyl-3-(2-methylphenyl)-4(3H)-quina-
zolinone (20, C18H18N2O2)
1
Yield 96%; m.p.: 126–128 °C (EtOH); H NMR (CDCl3):
1
d = 9.84 (s, 1H, exchangeable), 8.00 (d, 1H, J = 7.5 Hz),
7.52 (d, 2H, J = 8.5 Hz), 7.46-7.37 (m, 5H), 7.16 (d, 1H,
J = 7.5 Hz), 6.86 (d, 2H, J = 8.5 Hz), 4.83 (s, 2H), 4.01
(q, 2H, J = 7.0 Hz), 2.23 (s, 3H), 2.12 (s, 3H), 1.39 (t, 3H,
J = 7.0 Hz) ppm; 13C NMR (CDCl3): d = 14.8, 17.6,
24.1, 63.7, 71.1, 114.8, 120.1, 121.2, 122.2, 122.3, 127.1,
127.7, 127.8, 129.8, 130.4, 131.6, 135.2, 136.6, 139.1,
152.9, 154.7, 156.1, 161.0, 166.5 ppm; MS (70 eV):
m/z = 443.
Yield 92%; m.p.: 148–150 °C (AcOH); H NMR (DMSO-
d6): d = 7.64 (d, 1H, J = 7.5 Hz), 7.44-7.33 (m, 6H), 4.18
(q, 2H, J = 7.0 Hz), 2.07 (s, 3H), 2.00 (s, 3H), 1.41 (t, 3H,
J = 7.0 Hz) ppm; 13C NMR (DMSO-d6): d = 15.1, 17.3,
24.0, 64.7, 116.7, 117.7, 121.9, 127.3, 128.8, 129.7, 131.5,
135.4, 137.4, 138.5, 153.1, 153.8, 161.1 ppm; MS (70 eV):
m/z = 294.
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquina-
zolin-8-yloxy]acetonitrile (21, C18H15N3O2)
1
Yield 88%; m.p.: 216–218 °C (AcOH); H NMR (DMSO-
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-
oxoquinazolin-8-yloxy]-N-(4-methylphenyl)acetamide
(17, C25H23N3O3)
d6): d = 7.81–7.37 (m, 7H), 5.38 (s, 2H), 2.08 (s, 3H), 2.01
(s, 3H) ppm; 13C NMR (DMSO-d6): d = 17.3, 24.1, 55.4,
117.0, 119.0, 120.6, 122.4, 127.0, 127.9, 128.8, 129.8,
131.5, 135.5, 137.2, 139.0, 151.5, 154.4, 160.8 ppm; MS
(70 eV): m/z = 305.
1
Yield 95%; m.p.: 174–176 °C (EtOH); H NMR (CDCl3):
d = 9.71 (s, 1H, exchangeable), 8.01 (d, 1H, J = 7.0 Hz),
7.51–7.40 (m, 7H), 7.19–7.14 (m, 3H), 4.86 (s, 2H), 2.33
(s, 3H), 2.26 (s, 3H), 2.14 (s, 3H) ppm; 13C NMR (CDCl3):
d = 17.4, 20.9, 24.3, 71.3, 120.2, 120.5, 121.4, 122.3,
127.0, 127.8, 127.9, 129.5, 129.8, 130.4, 131.6, 134.4,
134.8, 135.2, 136.6, 139.3, 153.0, 154.7, 161.0, 166.7 ppm;
MS (70 eV): m/z = 413 (M - 1).
8-Benzyloxy-2-methyl-3-(2-methylphenyl)-4(3H)-quina-
zolinone (22, C23H20N2O2)
Yield 86%; m.p.: 176–178 °C (AcOH); 1H NMR (CDCl3):
d = 7.89 (d, 1H, J = 8.0 Hz), 7.53 (d, 2H, J = 7.0 Hz),
7.41–7.31 (m, 7H), 7.22 (d, 1H, J = 8.0 Hz), 7.17 (d, 1H,
J = 7.5 Hz), 5.40 (s, 2H), 2.27 (s, 3H), 2.15 (s, 3H) ppm;
13C NMR (CDCl3): d = 17.4, 24.3, 71.3, 117.1, 119.0,
122.1, 126.6, 127.0, 127.6, 127.9, 128.0, 128.6, 129.5,
131.5, 135.3, 136.8, 137.0, 138.8, 153.3, 153.6, 161.5 ppm;
MS (70 eV): m/z = 356.
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-4-
oxoquinazolin-8-yloxy]-N-(3,4,5-trimethoxyphenyl)-
acetamide (18, C27H27N3O6)
1
Yield 92%; m.p.: 112–114 °C (EtOH); H NMR (CDCl3):
d = 9.69 (s, 1H, exchangeable), 7.92 (d, 1H, J = 7.5 Hz),
7.39–7.28 (m, 5H), 7.10 (d, 1H, J = 7.5 Hz), 6.91 (s, 2H),
4.76 (s, 2H), 3.77 (s, 9H), 2.18 (s, 3H), 2.06 (s, 3H) ppm;
13C NMR (CDCl3): d = 17.3, 24.2, 54.0, 56.2, 60.9, 70.9,
120.0, 121.1, 122.2, 126.5, 127.0, 129.8, 130.4, 131.6,
133.2, 133.4, 135.1, 135.2, 136.5, 139.0, 152.7, 153.3,
154.5, 161.0, 164.0, 166.6 ppm; MS (70 eV): m/z = 491
(M ? 2).
2-Methyl-3-(2-methylphenyl)-8-(4-nitrobenzyloxy)-4(3H)-
quinazolinone (23, C23H19N3O4)
Yield 80%; m.p.: 140–142 °C (AcOH); 1H NMR (CDCl3):
d = 8.25 (d, 2H, J = 8.5 Hz), 7.91 (d, 1H, J = 8.0 Hz),
7.71 (d, 2H, J = 8.0 Hz), 7.41–7.32 (m, 4H), 7.17 (d, 2H,
J = 7.5 Hz), 5.47 (s, 2H), 2.26 (s, 3H), 2.14 (s, 3H) ppm;
13C NMR (CDCl3): d = 17.4, 24.3, 70.2, 117.2, 119.8,
122.3, 123.9, 126.6, 127.5, 127.7, 127.8, 129.6, 131.6,
135.3, 136.8, 138.9, 144.3, 147.6, 152.6, 154.0, 161.3 ppm;
MS (70 eV): m/z = 401.
General procedure for the synthesis of compounds
19–23
Ethyl 2-[3,4-dihydro-2-methyl-3-(2-methylphenyl)-4-oxo-
quinazolin-8-yloxy]acetate (24, C20H20N2O4)
A mixture of 532 mg 8-hydroxymethaqualone (3, 2 mmol)
and the appropriate alkyl halides, aryl halides, or chloro-
acetonitrile (2.1 mmol) in 15 cm3 acetone containing
415 mg anhydrous potassium carbonate (3 mmol) was
heated under reflux for 10–12 h. The reaction mixture
was filtered while hot, the solvent was removed under
A mixture of 2.66 g 8-hydroxymethaqualone (3, 10 mmol),
1.84 g ethyl bromoacetate (11 mmol), and 1.66 g anhy-
drous potassium carbonate (12 mmol) in 100 cm3 dry
acetone was stirred at room temperature for 6 h. The
reaction mixture was filtered, the solvent was removed
123

Synthesis and anticonvulsant evaluation of 4(3H)-quinazolinones
845
under reduced pressure, and the solid obtained was dried
and recrystallized from ethanol. Yield 80%; m.p.:
100–102 °C; 1H NMR (CDCl3): d = 7.84 (d, 1H,
J = 7.0 Hz), 7.32–7.26 (m, 4H), 7.09 (d, 3H,
J = 7.0 Hz), 4.85 (s, 2H), 4.20 (q, 2H, J = 7.5 Hz), 2.16
(s, 3H), 2.04 (s, 3H), 1.21 (t, 3H, J = 7.5 Hz) ppm; 13C
NMR (CDCl3): d = 14.0, 17.2, 24.7, 61.0, 66.7, 119.9,
120.1, 122.0, 126.4, 127.4, 127.9, 129.5, 131.4, 135.2,
136.8, 138.3, 150.8, 153.7, 161.2, 169.0 ppm; MS (70 eV):
m/z = 352.
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-
4-oxoquinazolin-8-yloxy]acetic acid
2-[(benzylamino)thioxomethyl]hydrazide
(27, C26H25N5O3S)
1
Yield 88%; m.p.: 127–129 °C (AcOH); H NMR (DMSO-
d6): d = 10.38 (s, 1H, exchangeable), 9.46 (s, 1H,
exchangeable), 8.64 (s, 1H, exchangeable), 7.74 (d, 1H,
J = 7.0 Hz), 7.46-7.22 (m, 11H), 4.86 (s, 2H), 4.76 (s,
2H), 2.09 (s, 3H), 2.02 (s, 3H) ppm; 13C NMR (DMSO-d6):
d = 17.3, 24.0, 47.2, 68.6, 119.4, 122.0, 126.9, 127.1,
127.2, 127.4, 128.5, 128.8, 129.3, 129.8, 131.6, 135.5,
137.2, 138.9, 139.6, 153.5, 153.9, 161.0, 168.2, 182.8 ppm;
MS (70 eV): m/z = 487.
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-
4-oxoquinazolin-8-yloxy]acetic acid hydrazide
(25, C18H18N4O3)
A mixture of 3.52 g ester 3 (10 mmol) and 750 mg
hydrazine hydrate (15 mmol) in 50 cm3 absolute ethanol
was stirred at room temperature for 8 h. The reaction
mixture was filtered and dried. Yield 90%; m.p.:
116–118 °C; 1H NMR (CDCl3): d = 9.88 (s, 1H,
exchangeable), 7.98 (d, 1H, J = 7.5 Hz), 7.44–7.32 (m,
4H), 7.33 (d, 1H, J = 7.5 Hz), 7.16 (d, 1H, J = 7.5 Hz),
4.79 (s, 2H), 3.97 (s, 1H, exchangeable), 2.62 (s, 1H,
exchangeable), 2.26 (s, 3H), 2.13 (s, 3H) ppm; 13C NMR
(CDCl3): d = 17.3, 24.0, 71.0, 120.5, 121.4, 122.2, 127.0,
127.7, 127.8, 129.8, 131.6, 135.2, 136.5, 139.2, 153.0,
154.9, 161.0, 168.8 ppm; MS (70 eV): m/z = 338.
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-
4-oxoquinazolin-8-yloxy]acetic acid
2-[(ethylamino)thioxomethyl]hydrazide
(28, C21H23N5O3S)
1
Yield 84%; m.p.: 122–124 °C (AcOH); H NMR (DMSO-
d6): d = 10.25 (s, 1H, exchangeable), 9.24 (s, 1H,
exchangeable), 8.06 (s, 1H, exchangeable), 7.75–7.35 (m,
7H), 4.84 (s, 2H), 3.47 (q, 2H, J = 7.0 Hz), 2.09 (s, 3H),
2.03 (s, 3H), 1.05 (t, 3H, J = 7.0 Hz) ppm; 13C NMR
(DMSO-d6): d = 14.9, 17.3, 24.0, 39.0, 68.6, 119.3, 122.0,
127.2, 137.3, 127.9, 128.8, 129.8, 131.6, 135.5, 137.2,
138.9, 135.5, 153.8, 161.0, 167.3, 181.9 ppm; MS (70 eV):
m/z = 426 (M ? 1).
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-
4-oxoquinazolin-8-yloxy]acetic acid
2-[3,4-Dihydro-2-methyl-3-(2-methylphenyl)-
4-oxoquinazolin-8-yloxy]acetic acid
2-[(phenylamino)thioxomethyl]hydrazide
(29, C25H23N5O3S)
2-[(4-chlorophenyl)aminocarbonyl]hydrazide
(26, C25H22ClN5O4)
A mixture of 676 mg acid hydrazide 25 (2.0 mmol) and
323 mg p-chlorophenylisocyanate (2.0 mmol) in 20 cm3
absolute ethanol containing 405 mg TEA (4 mmol) was
refluxed for 10 h. The reaction mixture was allowed to
cool, the solvent was removed under reduced pressure, and
the solid obtained was dried and recrystallized from acetic
acid. Yield 88%; m.p.: 134–136 °C; 1H NMR (DMSO-d6):
d = 10.38 (s, 1H, exchangeable), 8.98 (s, 1H, exchange-
able), 8.27 (s, 1H, exchangeable), 7.86 (m, 1H), 7.50–7.29
1
Yield 90%; m.p.: 150–152 °C (AcOH); H NMR (DMSO-
d6): d = 10.53 (s, 1H, exchangeable), 9.72 (s, 1H,
exchangeable), 7.76 (d, 1H, J = 7.5 Hz), 7.52–7.35 (m,
10H), 7.18 (d, 1H, J = 6.5 Hz), 4.90 (s, 2H), 3.46 (s, 1H,
exchangeable), 2.10 (s, 3H), 2.02 (s, 3H) ppm; 13C NMR
(DMSO-d6): d = 17.3, 24.0, 68.8, 119.5, 122.1, 125.6,
126.9, 127.2, 127.9, 128.6, 129.8, 131.6, 135.5, 137.2,
138.9, 139.5, 153.6, 153.9, 161.0, 168.0, 181.6 ppm; MS
(70 eV): m/z = 472 (M - 1).
(m, 10H), 4.87 (s, 2H), 2.10 (s, 3H), 2.02 (s, 3H) ppm; 13
C
NMR (DMSO-d6): d = 17.2, 24.0, 68.9, 119.4, 119.5,
119.6, 120.6, 122.0, 126.1, 127.3, 127.9, 128.7, 128.9,
129.8, 131.6, 135.4, 137.2, 138.9, 139.0, 153.4, 154.1,
155.6, 161.0, 167.3, 168.3 ppm; MS (70 eV): m/z = 491.
General procedures for the synthesis of compounds
30–32
Method A: A mixture of 676 mg acid hydrazide 25
(2.0 mmol) and appropriate isothiocyanate (2.0 mmol) in
20 cm3 absolute ethanol containing 405 mg TEA (4 mmol)
was refluxed for 10–12 h. The reaction mixture was
allowed to cool, the solvent was removed under reduced
pressure, and the solid obtained was dried and
recrystallized.
General procedure for the synthesis of compounds
27–29
A mixture of 676 mg acid hydrazide 25 (2.0 mmol) and
appropriate isothiocyanate (2.0 mmol) in 20 cm3 absolute
ethanol was stirred at room temperature for 9–12 h. The
solvent was removed under reduced pressure, and the solid
obtained was dried and recrystallized.
Method B: N-Substituted hydrazinecarbothioamide
27–29 (1.0 mmol) was refluxed in 20 cm3 absolute ethanol
123

846
A. S. El-Azab et al.
2.09 (s, 3H), 2.03 (s, 3H) ppm; 13C NMR (DMSO-d6):
d = 17.3, 24.1, 66.1, 118.8, 119.3, 122.2, 127.1, 127.9,
128.8, 129.8, 131.5, 135.5, 137.3, 139.0, 152.8, 153.8,
154.4, 161.0, 170.5 ppm; MS (70 eV): m/z = 381 (M ? 2).
in the presence of 203 mg TEA (1.5 mmol) for 6–8 h. The
reaction mixture was allowed to cool, the solvent was
removed under reduced pressure, and the solid obtained
was dried and recrystallized.
2-Methyl-3-(2-methylphenyl)-8-[(5-phenylamino-1,3,4-
thiadiazol-2-yl)methoxy]-4(3H)-quinazolinone
(34, C25H21N5O2S)
8-[(4-Benzyl-5-mercapto-4H-1,2,4-triazol-3-yl)methoxy]-
2-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone
(30, C26H23N5O2S)
1
1
Yield 68%; m.p.: 292–294 °C (AcOH); H NMR (DMSO-
Yield 86%; m.p.: 258-260 °C (AcOH); H NMR (DMSO-
d6): d = 10.51 (s, 1H, exchangeable), 7.77–7.12 (m, 12H),
5.61 (s, 2H), 2.11 (s, 3H), 2.03 (s, 3H) ppm; 13C NMR
(DMSO-d6): d = 17.3, 24.1, 66.3, 116.9, 119.3, 119.6,
122.2, 127.1, 127.8, 128.8, 129.8, 131.5, 135.5, 137.3,
139.1, 141.0, 142.6, 152.8, 153.8, 153.9, 156.3, 161.0,
165.9 ppm; MS (70 eV): m/z = 455.
d6): d = 14.04 (s, 1H, exchangeable), 7.75 (d, 1H,
J = 5.5 Hz), 7.54–7.27 (m, 11H), 5.46 (s, 2H), 5.24 (s,
2H), 2.06 (s, 3H), 2.03 (s, 3H) ppm; 13C NMR (DMSO-d6):
d = 17.3, 24.2, 46.8, 63.2, 119.3, 122.2, 123.5, 127.1,
127.8, 127.9, 128.1, 128.8, 129.0, 129.8, 131.5, 136.8,
138.1, 140.2, 148.4, 154.0, 160.9, 169.4, 201.2 ppm; MS
(70 eV): m/z = 471 (M ? 2).
Pharmacology
8-[(4-Ethyl-5-mercapto-4H-1,2,4-triazol-3-yl)methoxy]-
2-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone
(31, C21H21N5O2S)
Animals and treatment
Adult male white Swiss albino mice weighing 20–25 g
(10–12 weeks old) were obtained from the Experimental
Animal Care Center, College of Pharmacy, King Saud
University. The animals were maintained under standard
conditions of humidity, temperature (25 2 °C), and light
(12 h light/12 h dark). They were fed with a standard mice
pellet diet and had free access to water. All animal experi-
mentation described in the article was conducted in accord
with accepted standards of humane animal care in accor-
dance with the King Saud University guidelines and the
legal requirements in the Kingdom of Saudi Arabia. Each
treatment group and vehicle control group consisted of ten
animals.
1
Yield 85%; m.p.: 269–271 °C (AcOH); H NMR (DMSO-
d6): d = 13.86 (s, 1H, exchangeable), 7.76 (d, 1H,
J = 6.5 Hz), 7.61 (d, 1H, J = 6.5 Hz), 7.48–7.36 (m,
5H), 5.40 (s, 2H), 4.16 (q, 2H, J = 6.5 Hz), 2.05 (s, 3H),
2.01 (s, 3H), 1.40 (t, 3H, J = 6.5 Hz) ppm; 13C NMR
(DMSO-d6): d = 13.7, 17.3, 24.0, 39.0, 62.1, 119.1, 119.8,
122.1, 127.1, 127.9, 128.8, 129.8, 131.5, 135.4, 137.2,
139.1, 148.3, 152.5, 153.9, 161.0, 167.8 ppm; MS (70 eV):
m/z = 407.
2-Methyl-3-(2-methylphenyl)-8-[(4-phenyl-5-mercapto-
4H-1,2,4-triazol-3-yl)methoxy]-4(3H)-quinazolinone
(32, C25H21N5O2S)
Yield 88%; m.p.: 147–149 °C (AcOH); 1H NMR (CDCl3):
d = 11.33 (s, 1H, exchangeable), 8.00 (d, 1H, J = 8.0 Hz),
7.41–7.11 (m, 11H), 4.82 (s, 2H), 2.26 (s, 3H), 2.09 (s, 3H)
ppm; 13C NMR (CDCl3): d = 17.4, 23.9, 71.4, 121.4,
121.9, 122.2, 124.4, 126.2, 127.1, 127.7, 127.8, 129.0,
129.8, 131.6, 135.3, 136.4, 137.6, 139.3, 152.9, 155.3,
161.0, 168.2, 180.8 ppm; MS (70 eV): m/z = 456
(M ? 1).
Anticonvulsant activity
The anticonvulsant activity of all synthesized compounds
was evaluated by four models, namely pentylentetrazole
(PTZ), picrotoxin, strychnine, and maximal electroshock
(MES) models [26]. The test compounds were dissolved in
10% DMSO and injected intraperitoneally (i.p.) at a dose
of 0.5 mmol/kg 30 min before seizure induction. Sodium
valproate (1.5 mmol/kg) and methaqualone (1.4 mmol/kg)
were used as reference drugs [34, 35]. In the MES test,
seizures were elicited with a 75-Hz alternating current of
99 mA intensity in mice. The current was applied via ear
electrodes for 2 s. Protection against the spread of MES-
induced seizures was defined as the abolition of the hind
leg and tonic maximal extension component of the seizure
[36]. The PTZ test was carried out by the i.p. injection of a
convulsant dose of PTZ (100 mg/kg). Seizures and tonic-
clonic convulsions, hypnosis, and death were recorded. As
with PTZ, the chemo-convulsants picrotoxin and strych-
nine were administered i.p. to mice in a dose eliciting
convulsions in 100% of control mice. The doses needed
General procedure for the synthesis of compounds
33 and 34
A mixture of carbothioamide 27 or 29 (2 mmol) and 5 cm3
conc. H2SO4 was stirred at room temperature for 12 h. The
reaction mixture was neutralized with KHCO3, filtered,
washed with water, dried, and recrystallized.
8-[(5-Amino-1,3,4-thiadiazol-2-yl)methoxy]-2-methyl-3-(2-
methylphenyl)-4(3H)-quinazolinone (33, C19H17N5O2S)
1
Yield 62%; m.p.: 244–246 °C (AcOH); H NMR (DMSO-
d6): d = 7.73 (d, 1H, J = 7.5 Hz), 7.56 (d, 1H, J = 7.5 Hz),
7.44–7.32 (m, 5H), 5.49 (s, 2H), 3.38 (s, 2H, exchangeable),
123

Synthesis and anticonvulsant evaluation of 4(3H)-quinazolinones
847
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