Synthesis of some new quinazolin-4(3H)-one derivatives and evaluation of their anticonvulsant activity

Article abstract of DOI:10.1007/s00706-016-1710-1

We reported the synthesis of a novel series of quinazolin-4(3H)-one derivatives bearing oxadiazole, thiadiazole, and other moieties in the 3-position of the quinazolinone nucleus using appropriate synthetic route. The compounds were evaluated for their anticonvulsant activity using picrotoxin model, GABA-A receptor antagonist. Five compounds showed significantly prolonged times for convulsions compared with the standard drug phenobarbital. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-016-1710-1

Monatsh Chem
DOI 10.1007/s00706-016-1710-1
ORIGINAL PAPER
Synthesis of some new quinazolin-4(3H)-one derivatives
and evaluation of their anticonvulsant activity
Nader M. Boshta2 Farag A. El-Essawy1,2 Ramy M. Ammar3
•
•
•
Abd El-Hamid Ismail2 Nancy E. Wahba2
•
Received: 19 November 2015 / Accepted: 15 February 2016
Ó Springer-Verlag Wien 2016
Abstract We reported the synthesis of a novel series of
quinazolin-4(3H)-one derivatives bearing oxadiazole,
thiadiazole, and other moieties in the 3-position of the
quinazolinone nucleus using appropriate synthetic route.
The compounds were evaluated for their anticonvulsant
activity using picrotoxin model, GABA-A receptor antag-
onist. Five compounds showed significantly prolonged
times for convulsions compared with the standard drug
phenobarbital.
Keywords Quinazolinone Á
Structure–activity relationships Á Anticonvulsant Á
Heterocycles Á Drug research
Introduction
Epilepsy is a chronic neurological disorder disease char-
acterized by periodic and unpredictable occurrence of
seizures that affects the people of all ages. It has been
estimated that 65 million people worldwide are currently
suffering from epilepsy, and approximately 80 % of cases
occur in developing countries. The mainstay treatment of
epilepsy is based upon pharmacological anticonvulsant
medications [1–3]. The serendipitous discovery of the
anticonvulsant properties of phenobarbital in 1912 marked
the foundation of the modern pharmacotherapy of epilepsy.
The subsequent 70 years saw the introduction of pheny-
toin, ethosuximide, carbamazepine, sodium valproate, and
a range of benzodiazepines. Collectively, these compounds
have come to be regarded as the established antiepileptic
drugs (AEDs). A concerted period of development of drugs
for epilepsy throughout the 1980s and 1990s has resulted
(to date) in 16 new agents being licensed as add-on treat-
ment for difficult-to-control adult and/or pediatric epilepsy,
with some becoming available as monotherapy for newly
diagnosed patients. Together, these have become known as
the modern AEDs [4, 5].
Graphical abstract
O
Het/
Pharmacophore
Ar
N
N
(X)n
Quinazolinone
basic moiety
X= C and/or N
N
O
N
O
S
N
N
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-016-1710-1) contains supplementary
material, which is available to authorized users.
& Nader M. Boshta
Nader_boshta@yahoo.com
AEDs are neither preventive nor curative and are
employed solely as a means of controlling symptoms. They
can directly affect ion channels or indirectly influence
synthesis, metabolism, or function of neurotransmitters or
receptors that control channel opening and closing. For the
simplest understanding of AEDs mechanisms, they fall into
a number of general categories: the main groups include
1
Preparatory Year Deanship, Basic Science Department,
Prince Sattam Bin Abdulaziz University, 151 Alkharj 11942,
Kingdom of Saudi Arabia
2
Chemistry Department, Faculty of Science, Menoufia
University, Shibin Al Kawm, Egypt
3
Faculty of Pharmacy, Sinai University, Al-Arish, Egypt
123

N. M. Boshta et al.
sodium channel blockers, calcium current inhibitors, c-
aminobutyric acid (GABA) enhancers, and glutamate
blockers [6, 7].
might be thought to attain more potent anticonvulsant
compound. In this context, we have synthesized derivatives
by molecular hybridization of quinazolin-4(3H)-one
nucleus B and have been investigated for their anticon-
vulsant activity. Since the anticonvulsant activity of
quinazolinones is GABA dependent, we decided to use the
picrotoxin (PIC) model, GABA-A receptor antagonist, to
evaluate the activity of the new compounds.
These drugs have proven to be effective in reducing
seizures, whilst their therapeutic efficacy is overcome by
some undesirable side effects such as drowsiness, ataxia,
gastrointestinal disturbance, gingival hyperplasia, hir-
sutism, and megaloblastic anemia. In addition about 30 %
of patients are refractory to these treatments. In view of the
above observations, there is an urgent need to find new
anticonvulsant compounds with more selectivity and lower
side effect profile.
Results and discussion
Chemistry
Nitrogen heterocycles are among the most privileged
molecular scaffolds of pharmaceuticals, in which quina-
zoline is an important landmark that is present in a total of
9 U.S. FDA approved pharmaceuticals [8]. One of the most
important quinazoline families are quinazolinones which
are the key scaffold components of approximately 150
naturally occurring alkaloids and drugs [9]. Several reports
have documented the biological activity of quinazolinone
derivatives including anti-tubercular [10], anti-cancer [11–
13], anti-diabetic [10], and anti-inflammatory [14–16].
They are also used in the central nervous system (CNS)
related disorders such as convulsion [17–21] and anxiety
[22, 23].
Construction of the starting material (Scheme 1) began by
N-alkylation of quinazolin-4(3H)-one (1) with ethyl bro-
moacetate in the presence of potassium carbonate in
stirring dimethylformamide at room temperature yielding
the desired ethyl 2-(4-oxoquinazolin-4(3H)-yl)acetate (2)
as similarly reported by Mali et al. [34]. Hydrazinolysis of
2 at room temperature afforded the key intermediate 2-(4-
oxoquinazolin-4(3H)-yl)acetohydrazide (3). When the
acetohydrazide derivative was treated with carbon disulfide
in ethanol in the presence of potassium hydroxide, 3-[(5-
mercapto-1,3,4-oxadiazol-2-yl)methyl]quinazolin-4(3H)-
one (4) was obtained. The treatment of 4 with iodoethane,
benzyl chloride, or ethyl bromoacetate under alkaline
conditions provided 3-[(5-substituted sulfanyl-1,3,4-oxa-
diazol-2-yl)methyl]quinazolin-4(3H)-one 5, 6, and 7,
respectively (Scheme 1). On the other hand, the reaction of
acetohydrazide 3 with phenyl isothiocyanate in ethanol
gave the corresponding 2-[2-(4-oxoquinazolin-4(3H)-yl)-
acetyl]-N-phenylhydrazinecarbothioamide (8). Depending
on the reaction medium, thiadiazole or oxadiazole deriva-
tives can be formed during the cyclization reaction of the
thiosemicarbazide derivative 8 [35]. Thus, stirring at 0 °C
of 8 in the presence of sulfuric acid provided 3-[[5-
(phenylamino)-1,3,4-thiadiazol-2-yl]methyl]quinazolin-
4(3H)-one (9) in 50 % yield. However, cyclization of 8 in
the presence of HgO under reflux condition gave 3-[[5-
(phenylamino)-1,3,4-oxadiazol-2-yl]methyl]quinazolin-
4(3H)-one (10) in 24 % yield. The thiosemicarbazide
derivative 8 was then reacted with ethyl bromoacetate in
the presence of anhydrous sodium acetate in absolute
ethanol to afforded N0-(4-oxo-3-phenylthiazolidin-2-yli-
dene)-2-(4-oxoquinazolin-4(3H)-yl)acetohydrazide (11) in
91 % yield (Scheme 1).
Methaqualone (A, 2-methyl-3-o-tolyl-4(3H)-quinazoli-
none) is a well-known lead compound in the field of
synthetic anticonvulsant [24]. The structural activity rela-
tionships (SAR) for the methaqualone derivatives
suggested that, the methyl group at the second position of
quinazolin-4(3H)-one is not always necessary for the CNS
activity [25, 26]; moreover, the presence of a substituted
ring at position 3 appears to be beneficial for the CNS
depression and anticonvulsant activity [27]. On the other
hand, oxadiazole and thiadiazole derivatives are associated
with broad spectrum of biological activities [28–32]. Spe-
cially
the
1,3,4-thiadiazoles
nucleus
exhibits
anticonvulsant, sedative-hypnotic, and CNS neurotoxicity
activities [33]. Incorporating these moieties and others in
the 3-position of the quinazolinone nucleus B (Fig. 1)
O
O
N
N
3NH
N
>
<
Methaqualone
Quinazolin-4(3H)-one
B
A
The structures of the synthesized compounds were
1
O
N
determined using IR spectroscopy, mass spectrometry, H
Het/
Ar
NMR and 13C NMR spectroscopy. IR spectra of compound
4 showed absorption band at 2567 cm-1 due to stretching
vibration of the SH group with the disappearance of the
Pharmacophore
N
( )
X
n
Quinazolinone
basic moiety
X= C and/or N
1
Fig. 1 Structural modifications
NH2 and CO groups were observed. In addition, H NMR
123

Synthesis of some new quinazolin-4(3H)-one derivatives and evaluation of their…
Scheme 1
O
N
O
N
O
O
K
2CO3
DMF,
N
NH
+
Br
O
O
1
2
NH2NH2.H
2O
O
N
O
N
O
N
S
H
H
N
N
O
CS2 KOH
,
N
N
NH2
PhNCS
SH
N
N
H
N
H
N
O
N
O
3
4
8
NaOAc/EtOH
O
I: H2SO4
Or
II: HgO
O
RX
DMF, K2CO3
Br
O
N
O
N
O
S
H
O
O
X
N
N
S
N
N
NH
N
N
N
R
N
N
N
O
N
:
=
=
=
5
RX
I
CH3CH2
11
:
6 RX
H
C6 5CH2Cl
: X = S (I)
: X = O (II)
9
10
:
7
RX
Br
EtOOCCH2
of compound 4 indicated the disappearance of singlet sig-
nals at 9.40 and 4.27 ppm for NH and NH2 groups [34].
The structures of 5, 6, and 7 were confirmed on the basis of
spectral and analytical data, in which the IR spectra
showed disappearance of band at 2567 cm-1 to SH group.
In 1H NMR, the appearance of additional aliphatic protons
at 3.21 ppm (CH2) and 1.35 ppm (CH3) for compound 5, as
well as the appearance of new aliphatic protons at
4.46 ppm (CH2) and aromatic protons at 7.20–7.40 ppm
(C6H5) for compound 6. While compound 7 showed the
presence of new aliphatic protons at 4.19 ppm (CH2), at
4.09 and 1.15 ppm for (CH2CH3). The structure of com-
pound 8 was confirmed by 1H NMR, the signal which
correspond to the NH2 protons in compound 3 at 4.27 ppm
[34] were replaced by signals attributable to the new
CSNHPh proton at 10.54 ppm and aromatic protons at
7.15, 7.35, and 7.49 ppm. In addition, the 13C NMR
showed new peak at 180.8 ppm corresponding to CS
group. Cyclisation of compound 8 resulted into compounds
9 and 10 which were confirmed by the absence of broad
peaks at 9.45 and 9.77 ppm (NHNH) and by the presence
Quinazolin-4(3H)-one Schiff base derivatives have been
reported to have several biological activities [36–39].
Therefore, we attempted to prepare a series of quinazolin-
4(3H)-one Schiff base derivatives. The condensation of the
acetohydrazide 3 with appropriate aldehyde provided the
corresponding benzylidene derivatives 12, 13, and 14
(Scheme 2) as previously reported by Mali et al. [34]. On
the other hand, the reaction of acetohydrazide 3 with
alkene derivative diethyl ethoxymethylenemalonate in
ethanol afforded 15. When acetohydrazide 3 was reacted
with ethyl chloroformate leads to the corresponding ethyl-
2-[1-(4-oxoquinazolin-3(4H)-yl)acetyl]hydrazine carboxy-
late (16), on further condensation with hydrazine hydrate in
ethanol to afford 17. The latter product was reacted with
aromatic aldehyde or cyclic ketones gave the correspond-
ing arylidene 18, and cycloalkylidene derivatives 19 and
20, respectively. Compound 17 upon treatment with carbon
disulfide and potassium hydroxide in boiling ethanol, pro-
vided the oxadiazole derivative 21 which undergo facile
alkylation by benzyl chloride under alkaline conditions to
afford the corresponding derivative 22 (Scheme 2).
1
of a singlet at 10.48 ppm (NH) for 10 in the H NMR
The structure of compound 15 was confirmed by the
disappearance of NH2 signal at 4.27 ppm in compound 3
and the presence of new signal corresponding to the new
methine proton (HNCHCR2) at 7.80 ppm. On the other
hand, the structure of compounds 17 was established by 1H
NMR, in which the signals corresponding to COOCH2CH3
in compound 16 were replaced by signals attributable to the
spectrum. In addition the disappearance of CS peak at
180.8 ppm and CO peak at 166.6 ppm in 13C NMR spec-
trum. Compound 11 was confirmed by the loss of CS peak
at 180.8 ppm in 13C NMR spectrum with the presence of
new peak at 168.1 ppm for CO group and also new singlet
1
signal at 4.15 ppm for CH2 in H NMR spectrum.
123

N. M. Boshta et al.
Scheme 2
O
N
H
N
12
13
14
R2CHO
N
N
R2
O
O
R2
HO
O
SH
O
O
H
O
O
N
O
H
N
H
N
N
N
N
ClCOOEt
NH2
N
N
O
NH2NH2.H2O
CS2 KOH
,
N
N
H
N
H
N
N
H
H
3
O
O
N
O
N
21
16
17
COOEt
COOEt
EtOH
O
C6H5CH2Cl
EtO
Piperidine
O
DMF, K2CO3
S
O
N
H
O
N
O
H
N
N
O
N
N
N
R
H
N
N
H
N
H
N
N
N
COOEt
COOEt
N
N
N
H
O
H
O
22
O
18
19
20
15
F
O
O
O
O
H
Cl
new NHNH2 groups at 9.42 and 4.29 ppm, respectively.
The 1H NMR signals corresponding to NH2 group in
compound 17 at 4.29 ppm are disappeared in compounds
19 and 20, while replaced by signal attributable to the new
Schiff base proton (NCHR) in compound 18 at 8.35 ppm.
Cyclization of compound 17 resulted into compound 21
which was confirmed by the absence of signals at 9.42 and
4.29 ppm for NH and NH2 groups with appearance of new
typical singlet proton of SH at 14.49 ppm for compound
21. Compound 22 showed the disappearance of singlet
signal at 14.49 ppm (SH group), with appearance of a
singlet signal at 4.35 ppm corresponding to CH2Ph in the
1H NMR spectrum.
treatment of hydrazide derivative 28 with carbon disulfide
and potassium hydroxide at reflux condition for 4 h gave
32 in 47 % yield. The benzyl chloride was reacted with 32
in the presence of potassium carbonate to give 33 in 85 %
yield (Scheme 3).
The IR spectrum of compound 23 [40] showed absorp-
tion band at 2200 cm-1 due to stretching vibration of the
CN group. This absorption band disappeared in the IR
spectrum of compound 24. Compound 26 was confirmed
by the absence of a singlet signal at 12.40 ppm (COOH
1
group) [41]. The H NMR spectrum of 29 and 30 showed
signals attributable to the new Schiff base proton (NCHR)
at 8.86 and 8.36 ppm, respectively. While compound 31
showed signal attributable to the new two methyl groups at
1.75 ppm. The 1H NMR spectrum of 32, showed signal for
one proton (SH group) appeared at 13.76 ppm. Compound
33 showed fading proton at 13.76 ppm of SH group with
appearance of a singlet signal at 4.42 ppm corresponding to
The preparation of nitrile derivative 23 by treatment of
quinazolin-4(3H)-one with acrylonitrile in the presence of
trimethylamine [40], appeared to be a practical starting
point for the elaboration into compounds 24, 25, 26, and 27
(Scheme 3). The cyclisation of compound 23 using sodium
azide and ammonium chloride under reflux condition pro-
viding tetrazole derivative 24 in 75 % yield. The versatile
nitrile derivative 23 was converted into acid 25 by
hydrolysis using sodium hydroxide. The treatment of 25
with N-aminothiourea and phosphoryl chloride afforded 26
in low yield. The methyl ester derivative 27, treated
directly with hydrazine hydrate to give 28. The hydrazide
derivative 28 is a key intermediate, which give rise to a
variety of compounds by condensation with p-nitroben-
zaldehyde, 3-chloro-4-fluorobenzaldehyde, or acetone
afforded 29, 30, and 31, respectively. Alternatively,
1
CH2Ph in the H NMR spectrum.
Pharmacology
Adult male albino mice, 8–10 weeks old, weighing about
25–30 g were used in experiments. Animals were obtained
from the modern veterinary office for laboratory animals,
Cairo, Egypt. All animals were allowed to acclimatize
under standard animal house conditions (Faculty of Phar-
macy, Sinai University) for at least 1 week before
assignment to the experimental protocol. Animals were fed
123

Synthesis of some new quinazolin-4(3H)-one derivatives and evaluation of their…
Scheme 3
N
O
N
N
S
O
N
O
N
NH
CN
CN
NaN
3/NH4Cl
N
N
N
NH
N
24
23
1
NaOH
NH2
N
O
N
O
N
N
O
O
N
O
H2SO4/MeOH
POCl3
N
S
OH
N
O
NH
Cl
2NHCSNH2
26
25
27
NH2NH2.H2O
SH
N
O
N
O
O
O
O
O
N
CS2 KOH
,
NH2
N
N
N
N
N
N
H
DMF, K2CO3
N
32
33
N
28
O
29
30
31
O
N
N
O
Cl
N
R
O
H
O
H
EtOH
O
N
H
O
NO2
F
Piperidine
on a standard pellet diet, and allowed free access to tap
water. They were kept at an ambient temperature of 22 °C
( 3 °C) and constant relative humidity throughout the
experimental protocol. The study was carried out according
to The European Communities Council Directive of 1986
(86/609/EEC) on the Protection of Animals Used for
Experimental and Other Scientific Purposes [42].
prevent such episodes or delayed this time pattern in
varying magnitude will be considered to possess an anti-
convulsant activity. Compounds 4, 6, 11, 12, 14, 15, 18, 19,
22, 26, 29, 31, and 32 proved to be inactive in this test
indicating that they may not have anti-convulsant activity
or they may act through a mechanism other than GABAA
receptor agonism. Compounds 5, 7, 10, 21, 24, and 33
significantly prolonged the onset time for convulsions
(Table 1). The order in prolonging the onset time for
convulsions was 24 [ 7 [ 33 [ 5 [ 21 [ 10. Phenobar-
bital (reference drug) showed 83.33 % protection against
PIC induced convulsion and delayed the onset of convul-
sion in the remaining animal.
Picrotoxin induced convulsion
The mice were divided randomly into three groups (con-
trol, standard, and test) and each group consisted of six
animals. The test compounds were administered intraperi-
toneally (ip) at a dose 100 mg/kg; 30 min prior to the ip
injection of PIC (10 mg/kg). After the injection of PIC
each animal was placed into an individual plastic cage and
observed for 30 min. During this period, the following
parameters were evaluated, latency, number of protected
animals, status of animal after 30 min, and the mortality
rate [43]. The results of onset of seizures in PIC-induced
seizures and latency of death were analyzed using the
paired Student’s t test. P value of\0.05 was considered as
statistically significant.
Effect on death latency and mortality rate
PIC showed 100 % death rate. Compounds 4, 7, 21, and 24
successfully protected 16.67 % of animals from death and
significantly delayed the death latency in the remaining ani-
mals. Compound 5 was able not only to protect 33.33 % of
animals from convulsion induced death but also significantly
delay the death time in the remainings (Table 1). Unfortu-
nately compounds 10 and 33, with anticonvulsant activity, did
not affect the mortality rate (Table 1). Phenobarbital (refer-
ence drug) protected 100 % of animals from death.
Effect of synthesized compounds on PIC induced
convulsion
The present study examined the anticonvulsant effect of
newly synthesized compounds using the PIC model. PIC, a
potent, selective GABA-A receptor antagonist [45], pro-
duces seizures by blocking the effect of GABA at central
PIC induced clonic convulsions within 6.42 min and ani-
mals died in 11.45 min. Any compound was able to
123

N. M. Boshta et al.
Table 1 Effect of newly
synthesized compounds on PIC-
induced convulsion in mice
Treatment
Dose/kg
% Prolongation of
convulsion onset time
% Delay of death time
Mortality/%
Control (DMSO)
2.5 cm3
100 mg
0
0
100
4
0
25
83.33
66.67
83.33
100
5
100 mg
44.24
57.54
26.8
34
20.24
57
7
100 mg
10
21
24
33
PHNB
100 mg
0
100 mg
56.24
60.6
0
83.33
83.33
100
100 mg
85.36
46.73
114.8
100 mg
40 mg [43, 44]
–
0
PHNB phenobarbital
GABA-A receptors, which have been associated with epi-
lepsy [46, 47]. Postsynaptic GABA-A receptors are
functionally linked to benzodiazepine receptors, barbiturate
receptors, and chloride ion channels to form GABA–
chloride ionophore complex, which is intimately involved
in the modulation of GABAergic neurotransmission epi-
lepsy [48]. PIC, a GABA-A receptor antagonist, produces
seizures by blocking the chloride-ion channels linked to
GABA-A receptors, thus preventing the entry of chloride
ions into the brain [9]. This process will, in turn, inhibit
GABA neurotransmission and activity in the brain.
Phenobarbital is believed to enhance GABAergic neuro-
transmission by increasing chloride ion flux through the
chloride-ion channels at GABA-A receptor sites [49]. This
hypothesis may explain the observed protective effects
and/or antagonistic actions, of phenobarbital against PIC-
induced seizures in the mice used. So, the obtained results
suggest that the six compounds which showed protection
against PIC induced convulsion may act by facilitating
GABAergic transmission.
prolongation the onset time for convulsions. In this context
the SAR of the former compounds 5, 7, 10, 21, and 33
indicated that incorporation of the oxadiazole moiety
through a different linker in the 3-position of the quina-
zolinone nucleus was essential for anticonvulsant activity.
On the other hand, 3-[2-(2H-tetrazol-5-yl)ethyl]quina-
zolin-4(3H)-one (24) significantly prolonged the onset time
for convulsions (85.36 %) and the substitution of the
tetrazole ring for further modification is needed to prepare
more active analogues.
Conclusion
In conclusion, a series of novel quinazolin-4(3H)-one
derivarives were synthesized by incorporating different
moieties in the 3-position of the quinazolinone nucleus and
their structures were established based on spectroscopic
data. The obtained compounds were evaluated for their
anticonvulsant activities using Picrotoxin model. The
results of this study demonstrated that, compounds 4, 6, 11,
12, 14, 15, 18, 19, 22, 26, 29, 31, and 32 proved to be
inactive, while compounds 5, 7, 10, 21, 24, and 33 sig-
nificantly prolonged the onset time for convulsions. The
order in prolonging the onset time for convulsions was
24 [ 7 [ 33 [ 5 [ 21 [ 10. Additionally compounds 4,
7, 21, and 24 successfully protected 16.67 % of animals
from death and 5 protect 33.33 % and all significantly
delayed the death latency in the remaining animals.
The pharmacological results obtained in the current
studies proved that incorporation of the oxadiazole moiety
through a different linker in the 3-position of the quina-
zolinone nucleus for example 5, 7, 10, 21, and 33 was
essential for anticonvulsant activity in this series of com-
pounds. The present active compounds, especially 5 could
be useful as a template for further modifications to produce
more active analogues.
Concerning the structure–activity relationship (SAR),
compound 4, in which the 1,3,4-oxadiazole-2-thiol moiety
is unsubstituted, proved to be inactive. While the substi-
tution of the SH group by CH2CH3 or CH2COOEt group
(compound 5 or 7) rendered the compound having good
activity. However, the substitution by benzyl moiety
(compound 6) did not improve the activity. Contrarily to
compound 6, compound 33 which has SH group substituted
by benzyl derivative in the 2-position of the oxadiazole
moiety caused 46.73 % prolongation the onset time for
convulsions. Cyclization of compound 8 produced com-
pounds 9 (thiadiazole derivative) and 10 (oxadiazole
derivative) with different anticonvulsant activity. In which
compound 10 caused 26.8 % prolongation the onset time
for convulsions, while compound 9 proved to be inactive.
Moreover the cyclization of compound 17 produced com-
pound 21 (oxadiazole derivative) accompanied with 34 %
123

Synthesis of some new quinazolin-4(3H)-one derivatives and evaluation of their…
The reaction mixture was stirred for 12 h at rt, poured onto
Experimental
ice water and the solid product was collected by filtration to
give 5 (0.145 g, 63 %) as a white powder. M.p.: 149–
;
1H NMR
All reagents were used in analytical grades. Solvents were
desiccated if necessary by standard methods. Reactions
were monitored by TLC (silica gel 60F254, Merck,
Darmstadt, Germany). Melting points were determined on
a Melting Point Apparatus (Stuart Scientific, Stone,
Staffordshire, UK). NMR spectra were carried out with a
300 MHz spectrometer at Cairo University and with a
400 MHz spectrometer at Ulm University, Germany.
Chemical shifts (d) are reported in parts per million (ppm)
relative to the respective solvent or tetramethylsilane
(TMS) as internal standard and standard abbreviations
were used (a = apparent; b = broad; s = singlet;
d = doublet; t = triplet; q = quartet; m = multiplet).
Mass spectra were obtained on a GC MS-QP 1000 EX
Mass Spectrometer (Shimadzu, Tokyo, Japan), Microan-
alytical Laboratory, Faculty of Science, Cairo University.
Elemental analyses were determined on a Yanaca CHN
Corder MT-3 elemental analyser in the microanalysis
laboratory at Cairo University. The IR spectra were
recorded on a Perkin-Elmer 1720 FT-IR spectrometer,
using KBr disks. The required starting materials, 2 and 3,
were prepared by adopting the earlier reported procedures
[30]. Quinazolin-4(3H)-one derivatives 12 [34], 14 [34],
16 [50], and 23 [51] were synthesized according to the
literature.
151 °C; IR (KBr): mꢀ = 1682 (CO) cm-1
(400 MHz, DMSO-d6): d = 1.35 (t, J = 7.33 Hz, 3H,
–CH2–CH3), 3.21 (q, J = 7.07 Hz, 2H, –CH2–CH3), 5.49
(s, 2H, –CH2–), 7.58 (m, 1H, Ar–H), 7.72 (d, J = 8.08 Hz,
1H, Ar–H), 7.83–7.90 (m, 1H, Ar–H), 8.15 (d,
J = 8.08 Hz, 1H, Ar–H), 8.52 (s, 1H, Ar–H) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 14.7, 26.6, 40.6, 121.3,
126.1, 127.4, 127.5, 134.8, 147.5, 147.8, 159.9, 163.3,
164.1 ppm; MS (EI, 70 eV): m/z (%) = 288.11(40.6,
[M?Á]), 259.10 (1.5), 227.13 (100), 187.11 (16), 171.11
(7.6), 159.08 (51.3).
3-[[5-(Benzylthio)-1,3,4-oxadiazol-2-yl]methyl]quinazolin-
4(3H)-one (6, C18H14N4O2S)
The procedure for the preparation of 6 was performed
similar to the protocol for 5. 4 (0.104 g, 0.4 mmol),
0.055 g K2CO3 (0.4 mmol), 1.4 cm3 DMF, and 0.05 g
benzyl chloride (0.4 mmol). Stirred for 3 h at rt, poured
onto ice water and the solid product was collected by
filtration to give 6 (0.131 g, 98 %) as a white powder.
ꢀ
1
M.p.: 139–141 °C; IR (KBr): m = 1691 (CO) cm-1; H
NMR (400 MHz, DMSO-d6): d = 4.46 (s, 2H, –S–CH2-),
5.48 (s, 2 H, –CH2-), 7.20–7.28 (m, 3H, Ar–H), 7.35–7.40
(m, 2H, Ar–H), 7.57–7.63 (m, 1H, Ar–H), 7.75 (d,
J = 7.58 Hz, 1H, Ar–H), 7.89 (m, 1H, Ar–H), 8.16 (dd,
J = 7.83, 1.26 Hz, 1H, Ar–H), 8.51 (s, 1H, Ar–H) ppm;
13C NMR (100 MHz, DMSO-d6): d = 35.8, 40.6, 121.3,
126.2, 127.4, 127.6, 127.7, 128.5, 129.0, 134.9, 136.5,
147.6, 147.8, 159.9, 163.6, 163.7 ppm; MS (EI, 70 eV):
m/z (%) = 350.12 (23.5, [M?Á]), 227.09 (8), 187.11 (55.4),
159.07 (25.2), 91.08 (100), 76.06 (6.3).
3-[(5-Mercapto-1,3,4-oxadiazol-2-yl)methyl]quinazolin-
4(3H)-one (4, C11H8N4O2S)
To a solution of 0.05 g KOH (0.92 mmol) in 4.6 cm3
ethanol/water (1:1), 0.2 g hydrazide 3 (0.92 mmol) and
0.07 g CS2 (0.92 mmol) were added. The reaction mixture
was refluxed for 4 h and after that, the solvent was
concentrated under reduced pressure. The residue was
diluted with water, acidified with 1 M hydrochloric acid
and the formed solid was filtered off, washed with water to
give 4 (0.176 g, 74 %) as a white solid. M.p.: 219–221 °C;
Ethyl 2-[[5-[(4-oxoquinazolin-4(3H)-yl)methyl]-1,3,4-
oxadiazol-2-yl]thio]acetate (7, C15H14N4O4S)
The procedure for the preparation of 7 was performed
similar to the protocol for 5. 4 (0.208 g, 0.4 mmol), 0.11 g
K2CO3 (0.8 mmol), 2.8 cm3 DMF, and 0.132 g ethyl
bromoacetate (0.8 mmol). Stirred for 24 h at rt, poured
onto ice water and the solid product was collected by
filtration to give 7 (0.155 g, 56 %) as a white powder.
-1
ꢀ
IR (KBr): m = 2567 (SH), 1696 (CO) cm
;
1H NMR
(300 MHz, DMSO-d6): d = 5.32 (br, 2H, –CH2-),
7.46–7.61 (m, 1H, Ar–H), 7.69 (dd, J = 7.50, 4.57 Hz,
1H, Ar–H), 7.76–7.89 (m, 1H, Ar–H), 8.04–8.18 (m, 1H,
Ar–H), 8.44 (m, 1H, Ar–H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 40.7, 121.2, 126.2, 127.4, 127.6, 135.0,
147.5, 147.8, 159.4, 159.9, 177.9 ppm; MS (EI, 70 eV):
m/z (%) = 260.06 (100, [M?Á]), 227.08 (3.1), 201.10 (2.1),
187.07 (31.6), 159.07 (39.4), 145.06 (5.3).
ꢀ
M.p.: 141–143 °C; IR (KBr): m = 1739 (CO), 1676 (CO)
cm-1 1H NMR (400 MHz, DMSO-d6): d = 1.15 (t,
;
J = 7.07 Hz, 3H, –CH2-CH3), 4.09 (q, J = 7.07 Hz,
2H, –CH2–CH3), 4.19 (s, 2H, –CH2-), 5.48 (s, 2H,
–CH2-), 7.59 (t, J = 7.58 Hz, 1H, Ar–H), 7.74 (d,
J = 8.08 Hz, 1H, Ar–H), 7.85–7.92 (m, 1H, Ar–H),
8.13–8.18 (m, 1H, Ar–H), 8.51 (S, 1H, Ar–H) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 13.8, 33.7, 40.5, 61.5,
121.2, 126.1, 127.3, 127.4, 134.8, 147.4, 147.7, 159.8,
163.3, 163.5, 167.4 ppm; MS (EI, 70 eV): m/z
3-[[5-(Ethylthio)-1,3,4-oxadiazol-2-yl]methyl]quinazolin-
4(3H)-one (5, C13H12N4O2S)
A mixture of 0.208 g 4 (0.8 mmol) and 0.11 g K2CO3
(0.8 mmol) in 2.8 cm3 DMF was stirred for about 30 min
at rt. Then, 0.124 g ethyl iodide (0.8 mmol) was added.
123

N. M. Boshta et al.
(%) = 346.07 (55.7, [M?Á]), 301.06 (9.1), 259.06 (47.2),
d = 40.5, 117.0, 121.4, 122.0, 126.2, 127.4, 127.6, 129.1,
134.9, 138.6, 147.7, 147.9, 155.6, 160.0, 160.1 ppm.
227.09 (90.6), 199.08 (72), 159.09 (100).
N0-(4-Oxo-3-phenylthiazolidin-2-ylidene)-2-(4-oxoquina-
zolin-4(3H)-yl)acetohydrazide (11, C19H15N5O3S)
2-[2-(4-Oxoquinazolin-4(3H)-yl)acetyl]-N-phenylhy-
drazinecarbothioamide (8, C17H15N5O2S)
In a 25 cm3 one-necked flask, 0.109 g 3 (0.5 mmol) and
0.067 g phenylisothiocyanate (0.5 mmol) were dissolved
in 1.5 cm3 absolute ethanol. The mixture was heated to
reflux for 30 min and the formed solid was filtered off,
washed with ethanol to give 8 (0.156 g, 88 %) as a white
A mixture of 0.211 g 8 (0.6 mmol) and 0.1 g ethyl
bromoacetate (0.6 mmol) in 18 cm3 absolute ethanol
containing 0.196 g anhydrous sodium acetate (0.6 mmol)
was heated under reflux for 6 h. The reaction mixture was
cooled, diluted with water, and allowed to stand overnight.
The precipitated solid was filtered off, washed with water
ꢀ
solid. M.p.: 201–202 °C; IR (KBr): m = 1701 (CO), 1275
1
(CS) cm-1; H NMR (400 MHz, DMSO-d6): d = 4.78 (s,
to give 11 (0.2211 g, 91 %) as a white solid. M.p.: 280–
ꢀ
1
281 °C; IR (KBr): m = 1734 (CO), 1685 (CO) cm-1; H
2H, –CH2-), 7.15–7.20 (m, 1H, Ar–H), 7.35 (m, 2H, Ar–
H), 7.49–7.53 (m, 2H, Ar–H), 7.56–7.60 (m, 1H, Ar–H),
7.72 (d, J = 7.88 Hz, 1H, Ar–H), 7.84–7.88 (m, 1H, Ar–
H), 8.14 (dd, J = 8.04, 1.10 Hz, 1H, Ar–H), 8.32 (s, 1H,
Ar–H), 9.45 (br, 1H, NH), 9.77 (br, 1H, NH), 10.54 (s, 1H,
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 47.3,
121.3, 125.1, 125.9, 127.2, 128.1, 134.6, 138.9, 148.0,
148.2, 160.5, 166.6, 180.8 ppm.
NMR (300 MHz, DMSO-d6): d = 4.15 (s, 2H, –CH2-),
4.95 (s, 2H, –CH2-), 6.91 (d, J = 7.69 Hz, 2H, Ar–H),
7.10–7.20 (m, 1H, Ar–H), 7.37 (t, J = 7.78 Hz, 2H, Ar–
H), 7.51–7.62 (m, 1H, Ar–H), 7.70 (d, J = 7.42 Hz, 1H,
Ar–H), 7.86 (t, J = 8.01 Hz, 1H, Ar–H), 8.16 (d,
J = 8.51 Hz, 1H, Ar–H), 8.36 (s, 1H, Ar–H), 11.29 (br,
1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 29.9,
46.2, 120.7, 121.3, 124.5, 126.0, 127.2, 129.3, 134.5,
147.3, 148.2, 159.9, 165.8, 168.1 ppm; MS (EI, 70 eV):
m/z (%) = 393.13 (5.1, [M?Á]), 234.05 (100), 202.10 (1.2),
187.09 (39.1), 159.09 (63.1), 131.08 (7.7).
3-[[5-(Phenylamino)-1,3,4-thiadiazol-2-yl]methyl]quina-
zolin-4(3H)-one (9, C17H13N5OS)
The 8 (0.21 g, 0.6 mmol) was added gradually with stirring
to 6 cm3 ice-cooled conc. sulfuric acid over 10 min. The
reaction mixture was stirred for 3 h at 0 °C and then
carefully poured onto ice water. The solid separated out
was filtered off, washed with water to give 9 (0.10 g, 50 %)
N0-(2-Hydroxybenzylidene)-2-(4-oxoquinazolin-4(3H)-
yl)acetohydrazide (13, C17H14N4O3)
Synthesis procedure as reported in Ref. [30], (0.29 g,
90 %) as a white solid. M.p.: 250–251 °C; IR (KBr):
ꢀ
as a white solid. M.p.: 248–249 °C; IR (KBr): m = 3269
1
m = 3207 (NH), 1673 (CO) cm-1; H NMR (400 MHz,
1
ꢀ
(NH), 1668 (CO) cm-1; H NMR (400 MHz, DMSO-d6):
DMSO-d6): d = 4.80 (s, 1H, OH), 5.21 (s, 2H, –CH2-),
6.85–6.95 (m, 2H, Ar–H), 7.25–7.33 (m, 1H, Ar–H),
7.55–7.61 (m, 2H, Ar–H), 7.72–7.78 (m, 1H, Ar–H),
7.85–7.90 (m, 1H, Ar–H), 8.15–8.18 (m, 1H, Ar–H),
8.36–8.46 (m, 2H, Ar–H and –N=CH–), 11.76 (br, 1H, NH)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 46.9, 121.4,
126.0, 126.9, 127.0, 127.1, 127.2, 128.7, 128.8, 130.0,
133.8, 134.4, 144.2, 148.1, 148.5, 160.2, 163.3, 168.2 ppm.
d = 5.49 (s, 2H, –CH2-), 7.45–7.63 (m, 6H, Ar–H), 7.72
(d, J = 7.88 Hz, 1H, Ar–H), 7.85–7.89 (m, 1H, Ar–H),
8.19 (dd, J = 7.88, 0.95 Hz, 1H, Ar–H), 8.68 (s, 1H, Ar–
H) ppm; 13C NMR (100 MHz, DMSO-d6): d = 44.6,
116.4, 121.2, 126.2, 126.6, 127.6, 134.9, 140.6, 141.6,
146.7, 148.0, 154.1, 159.8, 165.4 ppm; MS (EI, 70 eV):
m/z (%) = 335.09 (15.1, [M?Á]), 217.05 (7.5), 191.10 (5.2),
146.08 (100), 118.09 (36.7), 104.08 (37).
Diethyl 2-[[2-(2-(4-oxoquinazolin-4(3H)-yl)acetyl)hy-
drazinyl]methylene]malonate (15, C18H20N4O6)
3-[[5-(Phenylamino)-1,3,4-oxadiazol-2-yl]methyl]quina-
zolin-4(3H)-one (10, C17H13N5O2)
To a solution of 0.22 g 3 (1 mmol) in 20 cm3 absolute
ethanol, 0.216 g diethyl ethoxymethylenemalonate
(1 mmol) was added and the reaction mixture was refluxed
for 10 h. The product which separated on cooling was
collected by filtration to give 15 (0.28 g, 72 %) as a white
Mercuric oxide (0.13 g, 0.6 mmol) was added to a solution
of 0.21 g 8 (0.6 mmol) in 6 cm3 methanol and the resulting
mixture was refluxed for 3 h. The precipitated mercuric
sulfide was filtered off and washed several times with hot
methanol. The filtrate on cooling gave a solid product
which was filtered to give 10 (0.046 g, 24 %) as a white
ꢀ
solid. M.p.: 180–181 °C; IR (KBr): m = 3220 (NH), 1735
1
(CO), 1675 (CO) cm-1; H NMR (400 MHz, DMSO-d6):
ꢀ
solid. M.p.: 210–211 °C; IR (KBr): m = 3353 (NH), 1687
(CO) cm-1 1H NMR (300 MHz, DMSO-d6):
;
d = 1.15–1.28 (m, 6H, 2(–CH2–CH3)), 4.01–4.20 (m, 4H,
2(–CH2–CH3)), 4.75 (s, 2H, –CH2-), 7.54–7.62 (m, 1H,
Ar–H), 7.72 (d, J = 7.58 Hz, 1H, Ar–H), 7.80 (d,
J = 12.13 Hz, 1H, NH-CH=), 7.83–7.90 (m, 1H, Ar–H),
8.16 (dd, J = 7.83, 1.26 Hz, 1H, Ar–H), 8.35 (s, 1H, Ar–
H), 10.11 (d, J = 12.13 Hz, 1H, NH), 11.19 (br, 1H, NH)
d = 5.35–5.41 (m, 2H, –CH2-), 6.90–6.99 (m, 1H, Ar–
H), 7.28 (t, J = 7.50 Hz, 2H, Ar–H), 7.46–7.60 (m, 3H,
Ar–H), 7.66–7.74 (m, 1H, Ar–H), 7.79–7.90 (m, 1H, Ar–
H), 8.14 (d, J = 7.68 Hz, 1H, Ar–H), 8.49 (s, 1H, Ar–H),
10.48 (br, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
123

Synthesis of some new quinazolin-4(3H)-one derivatives and evaluation of their…
ppm; 13C NMR (100 MHz, DMSO-d6): d = 14.2, 46.8,
59.2, 59.3, 89.9, 121.4, 126.0, 127.1, 127.2, 134.5, 148.0,
148.2, 158.4, 160.2, 164.5, 166.4 ppm; MS (EI, 70 eV):
m/z (%) = 388.18 (2, [M?Á]), 242.17 (1), 230.13 (3),
187.10 (100), 159.12 (73), 131.09 (7.4).
Ar–H), 8.14 (d, J = 7.78 Hz, 1H, Ar–H), 8.31 (s, 1H, Ar–H),
10.48 (br, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 26.1, 31.9, 38.3, 49.3, 123.1, 127.7, 128.8, 129.1, 136.3,
149.8, 150.6, 161.9, 162.2, 165.1, 170.4 ppm; MS (EI,
70 eV): m/z (%) = 342.64 (1, [M?Á]), 196.22 (1.1), 171.15
(5), 112.14 (4.1), 96.12 (2.5), 81.09 (100).
N0-(Hydrazinylcarbonyl)-2-(4-oxoquinazolin-4(3H)-yl)ace-
tohydrazide (17, C11H12N6O3)
2-(4-Oxoquinazolin-3(4H)-yl)acetic acid, 2-[[2-
(cycloheptylidene)hydrazinyl]carbonyl]hydrazide
(20, C18H22N6O3)
In a 100 cm3 one-necked flask, 7.0 g 16 (24.2 mmol) and
3.63 g hydrazine hydrate (72.6 mmol) were dissolved in
97 cm3 absolute ethanol. The mixture was heated to reflux
for 5 h and after that, the solvent was concentrated under
reduced pressure and the resulting precipitate was filtered
off, washed with ethanol to give 17 (3.625 g, 54 %) as a
Yield 0.228 g (85 %) as a white solid. M.p.: 200–201 °C;
-1
ꢀ
IR (KBr): m = 3213 (NH), 1688 (CO) cm
;
1H NMR
(300 MHz, DMSO-d6): d = 1.49 (br, 8H, 4 –CH2-),
2.31–2.43 (m, 4H, 2 –CH2-), 5.03–5.04 (m, 2H, –CH2-),
7.48–7.56 (m, 1H, Ar–H), 7.62–7.70 (m, 1H, Ar–H),
7.76–7.86 (m, 1H, Ar–H), 8.05–8.16 (m, 1H, Ar–H),
8.28–8.30 (m, 1H, Ar–H), 10.48–10.51 (m, 1H, NH) ppm;
13C NMR (75 MHz, DMSO-d6): d = 25.8, 28.9, 31.5,
32.1, 38.5, 49.1, 123.3, 127.9, 128.9, 129.0, 136.3, 149.9,
150.5, 161.7, 162.1, 165.2, 170.3 ppm; MS (EI, 70 eV):
m/z (%) = 370.73 (1.2, [M?Á]), 286.11 (8), 202.08 (8),
187.06 (71.2), 146.05 (27.8), 40.15 (100).
ꢀ
white solid. M.p.: 224–225 °C; IR (KBr): m = 3302 (NH2),
3160 (NH), 1685 (CO) cm-1; 1H NMR (300 MHz, DMSO-
d6): d = 4.29 (br, 2H, NH2), 4.61 (s, 2H, –CH2-),
7.51–7.61 (m, 1H, Ar–H), 7.70 (d, J = 8.15 Hz, 1H, Ar–
H), 7.84 (m, 1H, Ar–H), 8.13 (d, J = 7.60 Hz, 1H, Ar–H),
8.29 (s, 1H, Ar–H), 9.42 (br, 1H, NH) ppm; MS (EI,
70 eV): m/z (%) = 276.14 (3, [M?Á]), 217.19 (2), 202.19
(2.8), 145.09 (11.9), 118.09 (1.3), 67.06 (16.8).
General procedure for the synthesis of 18, 19, and 20
A mixture of 0.20 g 17 (0.73 mmol) and aldehyde or
ketone (0.73 mmol) in 22 cm3 absolute ethanol in the
presence of few drops of piperidine was refluxed for 8 h.
The formed solid was filtered off and dried. The obtained
compounds were further purified by crystallized from
ethanol.
N0-(5-Mercapto-1,3,4-oxadiazol-2-yl)-2-(4-oxoquinazolin-
4(3H)-yl)acetohydrazide (21, C12H10N6O3S)
To a solution of 0.21 g KOH (3.70 mmol) in 18.6 cm3
ethanol/water (1:1), 1.02 g hydrazide 17 (3.70 mmol) and
0.28 g CS2 (3.70 mmol) were added. The reaction mixture
was refluxed for 4 h and after that, the solvent was
concentrated under reduced pressure. The residue was
diluted with water, acidified with 1 M hydrochloric acid
and the formed solid was filtered off, washed with water to
give 21 (0.884 g, 76 %) as a white solid. M.p.: 195–
2-(4-Oxoquinazolin-3(4H)-yl)acetic acid, 2-[[2-(2-chloro-
6-fluorophenylmethylene)hydrazinyl]carbonyl]hydrazide
(18, C18H14ClFN6O3)
ꢀ
196 °C; IR (KBr): m = 2360 (NH), 2560 (SH), 1694 (CO)
Yield 0.213 g (71 %) as a white solid. M.p.: 238–239 °C;
1
cm-1; H NMR (400 MHz, DMSO-d6): d = 5.34 (s, 2H,
ꢀ
IR (KBr): m = 3238 (NH), 1716 (CO), 1699 (CO), 1668
–CH2-), 7.56–7.61 (m, 1H, Ar–H), 7.72 (d, J = 7.89 Hz,
1H, Ar–H), 7.87 (ddd, J = 8.25, 7.15, 1.47 Hz, 1H, Ar–H),
8.15 (dd, J = 7.89, 1.28 Hz, 1H, Ar–H), 8.45 (s, 1H, Ar–
H), 14.49 (br, 1H, SH) ppm; 13C NMR (100 MHz, DMSO-
d6): d = 44.7, 121.2, 126.1, 128.5, 129.1, 135.0, 136.4,
147.7, 147.9, 160.2, 163.9, 164.4 ppm; MS (EI, 70 eV):
m/z (%) = 318.98 (1.8, [M?Á]), 187.07 (92), 159.07 (78.9),
145.05 (24), 131.07 (18.4), 118.07 (18.9).
1
(CO) cm-1; H NMR (400 MHz, DMSO-d6): d = 5.14 (s,
2H, –CH2-), 7.30–7.37 (m, 1H, Ar–H), 7.40–7.45 (m, 1H,
Ar–H), 7.45–7.51 (m, 1H, Ar–H), 7.56 (t, J = 7.52 Hz,
1H, Ar–H), 7.70 (d, J = 7.89 Hz, 1H, Ar–H), 7.82–7.87
(m, 1H, Ar–H), 8.14 (dd, J = 7.89, 1.28 Hz, 1H, Ar–H),
8.30 (s, 1H, Ar–H), 8.35 (s, 1H, N = CH-), 11.99 (s, 1H,
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 46.8,
115.5, 115.6, 120.1, 121.4, 126.0, 126.3, 127.1, 127.2,
131.6, 134.4, 137.2, 148.1, 148.5, 160.2, 161.3, 168.5 ppm.
N0-[5-(Benzylthio)-1,3,4-oxadiazol-2-yl]-2-(4-oxoquina-
zolin-4(3H)-yl)acetohydrazide (22, C19H16N6O3S)
2-(4-Oxoquinazolin-3(4H)-yl)acetic acid,
2-[[2-(cyclopentylidene)hydrazinyl]carbonyl]hydrazide
(19, C16H18N6O3)
A mixture of 0.30 g 21 (0.95 mmol) and 0.13 g K2CO3
(0.95 mmol) in 3.3 cm3 dry DMF was stirred for about
30 min at rt. Then, 0.12 g benzyl chloride (0.95 mmol) was
added. The reaction mixture was stirred for 24 h at rt,
poured onto ice water and the solid product was collected
by filtration to give 22 (0.38 g, 98 %) as a yellow powder.
Yield 0.239 g (96 %) as a white solid. M.p.: 220–221 °C; IR
-1
ꢀ
(KBr): m = 3179 (NH), 1688 (CO) cm
;
1H NMR
(300 MHz, DMSO-d6): d = 1.65–1.84 (m, 4H, 2 –CH2-),
2.27–2.41 (m, 4H, 2 –CH2-), 5.05 (s, 2H, –CH2-), 7.51–7.60
(m, 1H, Ar–H), 7.67–7.73 (m, 1H, Ar–H), 7.81–7.90 (m, 1H,
ꢀ
M.p.: 127–128 °C; IR (KBr): m = 3215 (NH), 1691 (CO)
cm-1; 1H NMR (300 MHz, DMSO-d6): d = 4.35–4.47 (m,
123

N. M. Boshta et al.
2H, –S–CH2-), 5.36–5.48 (m, 2H, –CH2-), 7.12–7.24 (m,
3H, Ar–H), 7.34 (m, 2H, Ar–H), 7.48–7.62 (m, 1H, Ar–H),
7.62–7.75 (m, 1H, Ar–H), 7.77–7.92 (m, 1H, Ar–H),
8.05–8.17 (m, 1H, Ar–H), 8.41–8.50 (m, 1H, Ar–H) ppm;
13C NMR (75 MHz, DMSO-d6): d = 35.8, 40.6, 121.3,
126.2, 127.4, 127.6, 127.7, 128.5, 129.0, 134.9, 136.5,
147.6, 147.8, 159.9, 163.6, 163.7 ppm; MS (EI, 70 eV):
m/z (%) = 408.17 (5.8, [M?Á]), 331.11 (28.4), 192.12
(12.5), 165.12 (93.1), 151.14 (0.6), 119.09 (100).
18 cm3 absolute ethanol. The mixture was heated to reflux
for 4 h and after that, the solvent was concentrated under
reduced pressure and the resulting precipitate was filtered
off, washed with ethanol to give 28 (0.5 g, 50 %) as a
ꢀ
white solid. M.p.: 240–241 °C; IR (KBr): m = 3466 (NH2),
3290 (NH), 1667 (CO) cm-1; 1H NMR (300 MHz, DMSO-
d6): d = 2.56 (t, J = 6.45 Hz, 2H, –CH2-), 4.19 (t,
J = 6.64 Hz, 2H, –CH2-), 7.49–7.58 (m, 1H, Ar–H),
7.66 (d, J = 8.33 Hz, 1H, Ar–H), 7.82 (t, J = 7.60 Hz,
1H, Ar–H), 8.16 (d, J = 8.33 Hz, 1H, Ar–H), 8.26 (s, 1H,
Ar–H), 8.99 (br, 1H, NH) ppm.
3-[2-(2H-Tetrazol-5-yl)ethyl]quinazolin-4(3H)-one
(24, C11H10N6O)
A mixture of 0.52 g 23 (2.60 mmol), 0.17 g sodium azide
(2.60 mmol), and 0.14 g ammonium chloride (2.60 mmol) in
1.4 cm3 DMF was refluxed for 7 h. And after that, the solvent
was concentrated under reduced pressure. The residue was
diluted with water, acidified with 1 M hydrochloric acid at
0 °C and the formed solid was filtered off, washed with water
togive24 (0.475 g, 75 %)asa white solid.M.p.: 160–161 °C;
General procedure for the synthesis of 29 and 30
A mixture of 0.21 g 28 (0.90 mmol) and aldehyde
(0.90 mmol) in 27 cm3 absolute ethanol in the presence
of few drops of piperidine was refluxed for 8 h. The formed
solid was filtered off and dried. The obtained compounds
were further purified by crystallized from ethanol.
N0-(4-Nitrobenzylidene)-3-(4-oxoquinazolin-3(4H)-
-1
;
1H NMR
ꢀ
IR (KBr): m = 3218 (NH), 1710 (CO) cm
yl)propanehydrazide (29, C18H15N5O4)
Yield 0.266 g (81 %) as a yellow solid. M.p.: 215–216 °C;
(400 MHz, DMSO-d6): d = 2.48–2.51 (m, 2H, –CH2-),
3.34–3.37 (m, 2H, –CH2-), 7.50 (ddd, J = 8.04, 7.09,
1.26 Hz, 1H, Ar–H), 7.63–7.67 (m, 1H, Ar–H), 7.79 (ddd,
J = 8.28, 7.01, 1.73 Hz, 1H, Ar–H), 8.07 (s, 1H, Ar–H),
8.09–8.12 (m, 1H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-
d6): d = 33.9, 40.1, 122.6, 125.8, 126.7, 127.2, 134.2, 145.4,
148.7, 149.9, 160.6 ppm.
-1
ꢀ
IR (KBr): m = 3217 (NH), 1702 (CO), 1663 (CO) cm
;
1H NMR (300 MHz, DMSO-d6): d = 3.15–3.21 (m, 2H,
–CH2-), 4.24–4.32 (m, 2H, –CH2-), 7.45–7.71 (m, 1H,
Ar–H), 7.84–7.95 (m, 2H, Ar–H), 8.18 (m, 4H, Ar–H),
8.34–8.39 (m, 2H, Ar–H), 8.86 (s, 1H, –N=CH–),
11.69–11.70 (m, 1H, NH) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 31.2, 42.5, 121.4, 123.8, 125.9, 127.0,
127.6, 127.9, 134.1, 140.2, 140.9, 147.5, 147.9, 148.3,
160.2, 172.5 ppm; MS (EI, 70 eV): m/z (%) = 365.12 (1.8,
[M?Á]), 257.26 (3.3), 216.09 (19.9), 201.09 (48.7), 173.10
(9.5), 147.06 (100).
3-[2-(5-Amino-1,3,4-thiadiazol-2-yl)ethyl]quinazolin-
4(3H)-one (26, C12H11N5OS)
A mixture of acid 2.0 g 25 (9.2 mmol) and 8.37 g
thiosemicarbazide (92 mmol) in 15 cm3 phosphorus oxy-
chloride was refluxed for 3 h. The reaction mixture was
cooled and quenched (highly exothermic) with 27 cm3 cold
water and the resulting solution was refluxed for additional
4 h. The solution was allowed to cool and basified with
aqueous potassium hydroxide solution. The solid product
was collected by filtration, washed with water to give 26
N0-(3-Chloro-4-fluorobenzylidene)-3-(4-oxoquinazolin-
3(4H)-yl)propanehydrazide (30, C18H14ClFN4O2)
Yield 0.295 g (88 %) as a white solid. M.p.: 195–196 °C;
-1
ꢀ
IR (KBr): m = 3228 (NH), 1696 (CO), 1665 (CO) cm
;
1H NMR (400 MHz, DMSO-d6): d = 3.09–3.18 (m, 2H,
–CH2-), 4.21–4.30 (m, 2H, –CH2-), 7.38–7.40 (m, 1H,
Ar–H), 7.42–7.48 (m, 1H, Ar–H), 7.51–7.61 (m, 2H,
Ar–H), 7.64–7.86 (m, 3H, Ar–H), 8.07–8.17 (m, 1H,
Ar–H), 8.36 (s, 1H, –N=CH–), 11.46–11.60 (m, 1H, NH)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 31.2, 42.7,
117.2, 120.2, 121.5, 125.9, 126.7, 127.0, 128.2, 132.0,
134.1, 140.7, 147.8, 148.2, 160.2, 166.4, 172.3 ppm.
(0.17 g, 7 %) as a brown powder. M.p.: 250–251 °C; IR
1
(KBr): m = 3359 (NH2), 3320 (NH2), 1621(CO) cm-1; H
ꢀ
NMR (400 MHz, DMSO-d6): d = 3.11 (t, J = 6.61 Hz,
2H, –CH2-), 4.35 (t, J = 6.67 Hz, 2H, -CH2-), 6.56 (s,
2H, NH2), 7.51–7.57 (m, 1H, Ar–H), 7.62 (d, J = 8.07 Hz,
1H, Ar–H), 7.75–7.81 (m, 1H, Ar–H), 8.10–8.18 (m, 1H,
Ar–H), 8.40 (s, 1H, Ar–H) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 25.1, 42.5, 121.4, 126.1, 126.9, 127.6,
135.0, 147.8, 147.9, 160.5, 162.1, 178.3 ppm; MS (EI,
70 eV): m/z (%) = 273.14 (4.6, [M?Á]), 227.12 (61.1),
187.09 (100), 185.10 (16.3), 159.96 (6.2), 145.13 (12.2).
3-(4-Oxoquinazolin-4(3H)-yl)-N0-(propan-2-yli-
dene)propanehydrazide (31, C14H16N4O2)
In a 25 cm3 one-necked flask, 0.12 g 28 (0.50 mmol) was
dissolved in 5 cm3 acetone. The solution was heated to
reflux for 2 h and after cooling the resulting precipitate was
filtered off to give 31 (0.119 g, 85 %) as a white solid.
3-(4-Oxoquinazolin-4(3H)-yl)propanehydrazide
(28, C11H12N4O2)
In a 50 cm3 one-necked flask, 1.0 g 27 (4.40 mmol) and
0.66 g hydrazine hydrate (13.20 mmol) were dissolved in
ꢀ
M.p.: 180–181 °C; IR (KBr): m = 3209 (NH), 1688 (CO)
123

Synthesis of some new quinazolin-4(3H)-one derivatives and evaluation of their…
cm-1; 1H NMR (300 MHz, DMSO-d6): d = 1.75 (s, 6H, 2
–CH3), 2.99 (t, J = 6.73 Hz, 2H, –CH2-), 4.21 (t,
J = 6.45 Hz, 2H, –CH2-), 7.48–7.59 (m, 1H, Ar–H),
7.66 (d, J = 8.15 Hz, 1H, Ar–H), 7.76–7.89 (m, 1H,
Ar–H), 8.16 (d, J = 7.87 Hz, 1H, Ar–H), 8.25–8.40 (m,
1H, Ar–H), 10.11 (s, 1H, NH) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 21.2, 24.7, 26.2, 42.5, 121.5, 126.4, 127.1,
127.2, 134.6, 147.8, 147.9, 155.0, 161.3, 168.6 ppm; MS
(EI, 70 eV): m/z (%) = 272.19 (18.1, [M?Á]), 257.13
(11.4), 201.12 (33.1), 173.15 (2.7), 159.12 (4.1), 147.10
(100).
Acknowledgments We are grateful to Professor Gerhard Maas
from Institute of Organic Chemistry I, University of Ulm, Germany
for assistance with NMR measurements.
References
1. Stefan H, Feuerstein T (2007) Pharmacol Ther 113:165
2. Pollard JR, French J (2006) Lancet Neurol 5:1064
3. Donner EJ, Snead OC III (2006) NeuroRX 3:170
4. McAuley JW, Biederman TS, Smith JC, Moore JL (2002) Ann
Pharmacother 36:119
5. Rho JM, Sankar R (1999) Epilepsia 40:1471
6. Shorvon S (2000) Handbook of epilepsy treatment. Blackwell
Science, MA
7. Guimara˜es J, Ribeiro JAM (2010) Neurol 16:353
8. Vitaku E, Smith DT, Njardarson JT (2014) J Med Chem
57:10257
9. Al-Salem HSA, Hegazy GH, El-Taher KEH, El-Messery SM, Al-
Obaid AM, El-Subbagh HI (2015) Bioorg Med Chem 25:1490
10. Witt A, Bergman J (2003) Curr Org Chem 7:659 (references
cited therein)
3-[2-(5-Mercapto-1,3,4-oxadiazol-2-yl)ethyl]quinazolin-
4(3H)-one (32, C12H10N4O2S)
To a solution of 0.25 g KOH (4.40 mmol) in 22 cm3
ethanol/water (1:1), 1.02 g hydrazide 28 (4.40 mmol) and
0.34 g CS2 (4.40 mmol) were added. The reaction mixture
was refluxed for 4 h and after that, the solvent was
concentrated under reduced pressure. The residue was
diluted with water, acidified with 1 M hydrochloric acid
and the formed solid was filtered off, washed with water to
give 32 (0.56 g, 47 %) as a white solid. M.p.: 215–216 °C;
11. Al-Omary FA, Abou-Zeid LA, Nagi MN, El-Habib SE, Abdel-
Aziz AA, El-Azab AS, Abdel-Hamide SG, Al-Omar MA, Al-
Obaid AM, El-Subbagh HI (2010) Bioorg Med Chem 18:2849
12. Al-Obaid AM, Abdel-Hamide SG, El-Kashef HA, Abdel-Aziz
AA, El-Azab AS, Al-Khamees HA, El-Subbagh HI (2009) Eur J
Med Chem 4:2379
-1
ꢀ
IR (KBr): m = 2620 (SH), 1680 (CO) cm
;
1H NMR
(400 MHz, DMSO-d6): d = 3.22 (t, J = 6.69 Hz, 2H,
–CH2-), 4.31 (t, J = 6.60 Hz, 2H, –CH2-), 7.54 (t,
J = 7.43 Hz, 1H, Ar–H), 7.66 (d, J = 8.07 Hz, 1H, Ar–
H), 7.79–7.84 (m, 1H, Ar–H), 8.11–8.16 (m, 1H, Ar–H),
8.38 (s, 1H, Ar–H), 13.76 (br, 1H, SH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 24.7, 42.5, 121.4, 126.0,
127.1, 127.2, 134.4, 147.8, 147.9, 160.3, 161.6, 177.8 ppm.
13. El-Azab AS, Al-Omar MA, Abdel-Aziz AA, Abdel-Aziz NI, El-
Sayed MA, Aleisa AM, Sayed-Ahmed MM, Abdel-Hamid SG
(2010) Eur J Med Chem 45:4188
14. Alafeefy AM, Kadi AA, El-Azab AS, Abdel-Hamide SG, Daba
MH (2008) Arch Pharm (Weinheim) 341:377
15. Kumar A, Sharma S, Archana A, Bajaj K, Panwar H, Singh T,
Srivastava VK (2003) Bioorg Med Chem 11:5293
16. Alagarsamy V, Solomon VR, Dhanabal K (2007) Bioorg Med
Chem 15:235
3-[2-[5-(Benzylthio)-1,3,4-oxadiazol-2-yl]ethyl]quina-
zolin-4(3H)-one (33, C19H16N4O2S)
17. Srivastava AVK, Kumar A (2002) Eur J Med Chem 37:873
18. Chapleo CB, Mayer M, Myer PL, Saville JF, Smith ACB, Stilling
MR, Tulloch IF, Walter DS, Welbourn AP (1986) J Med Chem
29:2273
19. Srivastava AVK, Kumar A (2004) Bioorg Med Chem 12:1257
20. Aziza MA, Ibrahim MK, El-Helpy AG (1994) J Pharm Sci
14:193
21. Bekhit AA, Khalil MA (1998) Pharmazie 53:539
22. Ergenc N, Buyuktimkin S, Capan G, Baktir G, Rollas S (1991)
Pharmazie 46:290
23. Kashaw SK, Kashaw V, Mishra P, Jain NK (2008) Arkivoc
xiv:17
A mixture of 0.41 g 32 (1.50 mmol) and 0.21 g K2CO3
(1.50 mmol) in 5 cm3 dry DMF was stirred for about
30 min at rt. Then, 0.19 g benzyl chloride (1.50 mmol) was
added. The reaction mixture was stirred for 24 h at rt,
poured onto ice water and the solid product was collected
by filtration to give 33 (0.46 g, 85 %) as a white powder.
ꢀ
M.p.: 107–108 °C; IR (KBr): m = 1688 (CO) cm-1; H
1
NMR (400 MHz, DMSO-d6): d = 3.34 (t, J = 6.62 Hz,
2H, –CH2-), 4.35 (t, J = 6.62 Hz, 2H, –CH2-), 4.42 (s,
2H, –S–CH2-), 7.24–7.32 (m, 3H, Ar–H), 7.37–7.40 (m,
2H, Ar–H), 7.54 (ddd, J = 7.96, 7.01, 1.10 Hz, 1H, Ar–H),
7.67 (dd, J = 8.20, 0.63 Hz, 1H, Ar–H), 7.82 (ddd,
J = 8.35, 7.09, 1.58 Hz, 1H, Ar–H), 8.13 (dd, J = 7.88,
1.26 Hz, 1H, Ar–H), 8.36 (s, 1H, Ar–H) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 24.3, 35.8, 42.9, 121.4, 126.0,
127.0, 127.1, 127.7, 128.5, 128.9, 134.4, 136.3, 147.8,
147.9, 160.2, 163.0, 165.4 ppm; MS (EI, 70 eV): m/z
(%) = 364.15 (20, [M?Á]), 241.14 (1.1), 201.13 (5.8),
185.11 (1.7), 104.09 (3.9), 91.10 (100).
24. Gujral M, Saeen K, Kohli R (1957) Ind J Med Res 45:207
25. Boltze KH, Dell HD, Lehwald H, Loranz D, Ruberg-Schweer M
(1963) Arzneim-Forsch Drug Res 13:688
26. Wolfe JF, Rathman TL, Sleevi MC, Campbell JA, Greenwood
TD (1990) J Med Chem 33:161
27. Kashaw SK, Kashaw V, Mishra P, Jain NK, Stables JP (2009) Eur
J Med Chem 44:4335
28. Kumar KA, Jayaroopa P, Kumar G (2012) Int J ChemTech Res
4:1782
29. Chapleo L, Saville JF, Smith ACB, Stilling MR, Tullock IF,
Walter DS, Welbourn AP (1986) J Med Chem 29:2273
30. Srivastava K, Pandeya SN (1993) Bioorg Med Chem 3:547
31. Prakash A, Murthi KN, Singh RP, Pandeya SN (1994) Indian J
Heterocycl Chem 4:65
123

N. M. Boshta et al.
32. Khazi IAM, Mahajanshetti CS, Gadad AK, Tarnalli AD,
Sultanpur CM (1996) Arzneim Forsch 46:949
33. Jain SK, Mishra P (2000) Asian J Chem 12:1341
34. Mali JR, Pratap UR, Netankar PD, Mane RA (2009) Tetrahedron
Lett 50:5025
35. El-Essawy FA, El-Sayed WA (2013) J Heterocycl Chem 50:E1
36. Sing I, Saxena AK, Sinha JN, Bhargava KP, Shanker K (1984)
Indian J Chem 23:592
43. Farag AA, Abd-Alrahman SN, Ahmed GF, Ammar RM, Ammar
YA, Abbas SY (2012) Arch Pharm 345:703
44. Heidari MR, Mandegary A, Hosseini A, Vahedian M (2006) Pak
J Biol Sci 9:772
45. Heidari MR, Khalili F, Ghazi-khansari M, Hashemi B, Zarrindast
MR (1996) Pharmacol Toxicol 78:313
46. Gale K (1992) Epilepsia 33(Suppl 5):S3
´
47. Salami P, Levesque M, Gotman J, Avoli M (2015) J Neuro-
physiol 113:2840
48. Kalueff AV (2007) Neurochem Int 50:61
37. Pathak US, Rathod IS, Patel MB, Shirsath VS, Jain KS (1995)
Indian J Chem 34:617
´ ´
49. Navarro RA, Bastidas RBE, Garcıa EJ, Garcıa LP, Garzon P
´
38. Abdel-Hamid SG (1997) J Indian Chem Soc 74:619
39. Singh S, Shukla M, Srivastava VK, Shanker K (1986) Indian J
Chem 26:712
40. Darshan R, Firdous F, Sanjiv M, Krishnan K (1986) Heterocycles
24:2493
(1995) J Ethnopharmacol 45:199
50. Shemchuk LA, Al-Asri JM, Levashov DV, Shenhof YO, Arzu-
manov PS (2011) Visnik Farmatsii 3:30
51. Ranganathan D, Farooqui F, Mehrotra S, Kesavan K (1986)
Heterocycles 24:2493
41. Suesse M, Johne S (1985) Helv Chim Acta 68:892
42. Louhimies S (2002) Altern Lab Anim 30(Suppl 2):217
123