Synthesis, Anticonvulsant Activity, and SAR Study of Novel 4-Quinazolinone Derivatives

Article abstract of DOI:10.1002/ardp.201600332

Series of N-(4-substitutedphenyl)-4-(1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-alkanamides (5a–j) and 4-chloro-N′-((1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-alkaloyl)benzohydrazides (6a–f) were designed based on the previously reported essential structural features for anticonvulsant activity. Several amino acids were incorporated within the synthesized quinazolin-4(3H)-ones to improve their bioavailability and the anticonvulsant activity. Synthesis of the target compounds was accomplished in four steps starting from the reaction between N-methyl isatoic anhydride and the appropriate amino acid. Then, the carboxylic acid group was utilized to synthesize the required final structures. The new quinazolinone derivatives were evaluated for their anticonvulsant activity according to the Anticonvulsant Drug Development (ADD) Program protocol. All the 16 new quinazolinones exhibited good anticonvulsant activity; especially 5f, 5b, and 5c showed superior anticonvulsant activities in comparison to the reference drug, with ED₅₀ values of 28.90, 47.38, and 56.40 mg/kg, respectively.

Full text of DOI:10.1002/ardp.201600332

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Full Paper
Synthesis, Anticonvulsant Activity, and SAR Study of Novel
4-Quinazolinone Derivatives
Nada A. Noureldin1, Hend Kothayer1, El-Sayed M. Lashine1, Mohamed M. Baraka1, Wafaa El-Eraky2,
and Sally A. El Awdan2
1
Faculty of Pharmacy, Department of Medicinal Chemistry, Zagazig University, Zagazig, Egypt
Department of Pharmacology, National Research Center, Dokki, Cairo, Egypt
2
Series of N-(4-substitutedphenyl)-4-(1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-
alkanamides (5a–j) and 4-chloro-N0-((1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-
alkaloyl)benzohydrazides (6a–f) were designed based on the previously reported essential structural
features for anticonvulsant activity. Several amino acids were incorporated within the synthesized
quinazolin-4(3H)-ones to improve their bioavailability and the anticonvulsant activity. Synthesis of the
target compounds was accomplished in four steps starting from the reaction between N-methyl
isatoic anhydride and the appropriate amino acid. Then, the carboxylic acid group was utilized to
synthesize the required final structures. The new quinazolinone derivatives were evaluated for their
anticonvulsant activity according to the Anticonvulsant Drug Development (ADD) Program protocol.
All the 16 new quinazolinones exhibited good anticonvulsant activity; especially 5f, 5b, and 5c
showed superior anticonvulsant activities in comparison to the reference drug, with ED50 values of
28.90, 47.38, and 56.40 mg/kg, respectively.
Keywords: Amino acids / Anticonvulsant / Quinazolin-4(3H)-ones
Received: November 11, 2016; Revised: December 21, 2016; Accepted: January 4, 2017
DOI 10.1002/ardp.201600332
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
difficulty arises from the unknown mechanism of AEDs
resistance [3, 4]. Moreover, the effectiveness of the available
Introduction
Epilepsy is a state of chronic, unprovoked seizures, suggesting
that the brain has become permanently altered to support
abnormal neuronal firing [1].
Till the moment, although several antiepileptic drugs
(AEDs) have been discovered, approximately one third of
patients are still suffering from poor seizure control [1, 2]. The
biggest challenge in epilepsy treatment is AEDs therapy
resistance. In which, if developed, treatment may not be able
to end seizures for a period of 12 months [3]. The major
marketed drugs is largely compromised by notable adverse
effects in patients [2]. Neurotoxicity, impaired memory
function, symptoms of depression with life threatening
hepatotoxicity, and megaloblastic anemia are examples of
such adverse effects [5–7].
Thus, getting safer, more selective and more effective AEDs will
remainthegoal ofthe futureresearch inmedicinalchemistry[8, 9].
The diverse chemical structures of AEDs make it difficult to
find a common pharmacophore for anticonvulsant activity.
However, the conformational analysis of already biologically
active AEDs as barbituric acids, hydantoin, succinamids can
accelerate the common features for anticonvulsant activity.
These features can be summarized in the presence of two
aromatic rings with another region containing a number of
hydrogen bonding groups, which seem to be of less
significance than the correct conformational arrangement
of the hydrophobic components [10].
Correspondence: Dr. Hend Kothayer, Faculty of Pharmacy,
Department of Medicinal Chemistry, Zagazig University, 44511
Zagazig, Egypt.
E-mail: hendo1311@hotmail.com,
HKElhamalawy@pharmacy.zu.edu.eg
Fax: þ20-55-2303266
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The quinazolin-4(3H)-one nucleus constitutes
a hopeful
chemical moiety affecting the central nervous system with
its anticonvulsant effect [11]. 2-Methyl-3-o-tolyl-4(3H)-quina-
zolinone (methaqualone, I) (Fig. 1) represents a significant
turning point in the field of synthetic anticonvulsant and
prototype sedative-hypnotic containing quinazolinone ring
system [12].
A
literature survey concerning quinazolin-4(3H)-one
nucleus-based anticonvulsants implied that alteration in its
substituents has led to the generation of many CNS active
agents [11–21]. Several natural and synthetic quinazolin-
4(3H)-one compounds with a substituent at 1-position that is
not likely present in the prototype methaqualone retain
neuroprotective propriety and hence anticonvulsant activity
(II and III) [13, 22]. In addition, it has been reported that if the
2-position is substituted with a substituent other than methyl
group or even if not substituted, compounds will still have
CNS depressant activity (II–IV) [11, 17, 22]. Compounds with
hydrogen bonding region at 3-position are proven as a good
lead for anticonvulsant activity (IV) [13, 17] (Fig. 1).
Figure 2. Structures and design strategy of target compounds
based on the previously reported anticonvulsant structural
features of quinazolinones. (A) Hydrophobic unit, (B) electron
donor group, (C) hydrogen donor/acceptor unit.
Herein, we designed a series of quinazolin-4-ones that
keep the essential structural anticonvulsant features
reported in various references [11, 13, 14, 17, 23], as
hydrophobic binding unit, electron donor group and hydro-
gen bonding domain as shown in Fig. 2. At the same time, we
attempted to understand the effect of substitution at 2-
position as well as the effect of the length of the 3-position
hydrogen bonding area on the anticonvulsant activity of
quinazolin-4(3H)-one-derived compounds (Fig. 2).
We also incorporated different amino acids, which are
D-alanine, b-alanine, and g-aminobutyric acid (GABA) with
quinazolin-4(3H)-one as a trial to improve its bioavailability
and hence enhancing its anticonvulsant activity [24] and this
enables us to separate the quinazolinone ring from the
hydrogen bonding area by one, two, or three atoms distance,
respectively, to identify the optimum distance for the
anticonvulsant activity (Fig. 2).
Results and discussion
Chemistry
Compounds 5a–j and 6a–f were synthesized according to
Scheme 1. Appropriate amino acid was allowed to react with
N-methyl isatoic anhydride at 40–50°C in water containing
triethylamine to yield the benzamidocarboxylic acids 2a–c.
Then cyclization of these intermediates (2a–c) with the
appropriate aldehyde formed the (4-oxo-1,2-dihydroquina-
zolin-3(4H)-yl)carboxylic acids 3a–f. These acids (3a–f) were
then converted into the acyl benzotriazole analogs 4a–f using
1H-benzotriazole and SOCl2 at room temperature in dry DCM.
The final compounds (5a–j and 6a–f) were obtained by
coupling the acyl benzotriazole derivatives (5a–j and 6a–f)
with either 4-substituted anilines or p-chlorobenzoic acid
hydrazide using triethylamine in dry THF at room tempera-
ture for 4 h.
Pharmacology
Anticonvulsant screening
Based on the Anticonvulsant Drug Development (ADD)
Program protocol [25], the final synthesized compounds
(5a–j and 6a–f) were subjected to anticonvulsant screening.
This involves using the gold standard animal seizure models
that could be used in early screening stages, the maximal
electroshock seizure (MES) and the subcutaneous pentylene-
tetrazol seizure (scPTZ) animal models. The MES test
pharmacological profile is proposed to be useful in indicating
the drug’s utility in generalized tonic–clonic seizures in
humans. This test is thought to be sensitive to sodium
channel inhibitors such as phenytoin. When tested com-
pounds show activity in the MES test this suggests possessing
voltage-gated ion channels inhibitory activity, while the scPTZ
test pharmacological profile is thought to be effective in
identifying drug’s utility in generalized absence seizures in
humans. Pentylenetetrazole is thought to inhibit GABA
Figure 1. Methaqualone (I) and structures of some reported
quinazolinone derivatives (II–IV) with anticonvulsant activity.
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Scheme 1. Synthetic route of the target compounds. Reagents and conditions: (a) Appropriate amino acid, NEt3, H2O, 40–50°C, 5 h,
then acidified using 1 N HCl; (b) appropriate aldehyde, ethanol/water (2:3), reflux, 2 h; (c) 1H-benzotriazole, CH2Cl2, SOCl2, rt, 4.5 h;
(d) 4-substituted aniline, NEt3, THF, rt, 24 h; (e) p-chlorobenzoic acid hydrazide, NEt3, THF, rt, 24 h.
neurotransmission, thus producing seizures. When tested
compounds show activity in this test this suggests possessing
GABAerging activity enhancement activity [26–29].
The compounds 5a–j and 6a–f were administered intraperi-
toneally (i.p.) into the mice using doses of 30, 100, and
300 mg/kg and the observations were taken at two different
time intervals (0.5 and 4 h). Neurotoxicity was measured by
the rotarod test. The calculated Log p-values were calculated
using the ACD lab version 8.0 software. The results are shown
in Table 1.
whereas compounds 5a, 5b, 5d, 6a, and 6b were active at a
dose of 100 mg/kg and compounds 5h, 5i, 6c, 6d, and 6f
showed activity at 300 mg/kg dose level. Compounds 5h, 6c,
6d, and 6f became active after 0.5 h and did not show
protection after 4 h, while compounds 5a–d, 5f, 5i, 6a, and 6b
were active at both time points. Moreover, in MES test
compound 5b showed protection at 30 mg/kg, compounds 5a,
5e, and 6d protection was at 100 mg/kg, and compounds 5g,
5i, 5j, 6a, 6b, 6e, and 6f needed 300 mg/kg dose level to
protect against MES-induced seizures. Compounds 5b, 5e, 5i,
6e, and 6f were active after 0.5 h while compounds 5a, 5g, 5j,
6a, 6b, and 6d were active at both time points. There is no
obvious connection between the relative lipophilicity and the
anticonvulsant activity of the target compounds, suggesting
The preliminary pharmacological screening indicated that
all synthesized compounds 5a–j and 6a–f showed anticonvul-
sant activity in i.p. MES and/or scPTZ screenings. In the scPTZ
test, compounds 5c and 5f were active at a dose of 30 mg/kg,
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Table 1. Preliminary screening results.
MES screeningb)
Intraperitoneal injection in micea)
scPTZ screeningc)
NT screeningd)
Compound
0.5 h
4 h
0.5 h
4 h
0.5 h
4 h
Log pe)
5a
5b
5c
5d
5e
5f
5g
5h
5i
300
30
100
–
300
100
30
100
–
100
300
30
100
–
–
300
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
3.09
3.29
3.37
2.69
2.89
2.97
3.34
2.94
3.14
3.22
2.56
2.76
2.84
2.8
–
–
–
–
–
100
–
–
–
–
30
–
100
–
300
–
300
–
300
–
300
300
–
–
–
300
300
300
300
–
–
300
–
100
–
5j
300
300
300
–
6a
6b
6c
6d
6e
6f
100
100
300
300
–
300
300
–
–
100
–
100
300
300
100
–
–
–
–
300
–
3
3.08
–
300
–
a) Doses of 30, 100, and 300 mg/kg were administered. Each group consists of four animals. The animals were examined at 0.5 and
4.0 h after injection was made. The dash (–) indicates the absence of activity at maximum dose administered (300 mg/kg).
b) Maximal electroshock test.
c) Subcutaneous pentylenetetrazole test.
d) Neurotoxicity screening (rotarod test).
e) Log p was calculated using ACD lab version 8.0.
that other factors are involved. Results from neurotoxicity test
revealed that compounds 5i and 6b caused neurotoxicity
at 100 mg/kg and compounds 5b, 5f, and 6e became
neurotoxic at 300 mg/kg dose level. Other compounds did
not show neurotoxicity at the maximum administered dose
(300 mg/kg).
Standing on the primary pharmacological screening (Phase
I) results, compounds 5a–f, 6a, and 6d were subjected to
quantitative studies (Phase II) to determine the pharmacolog-
ical parameters, median effective dose (ED50), median toxic
dose (TD50), and therapeutic index (PI). Time of peak effect
(TPE) for each of these compounds was estimated and used for
quantitative studies tests. Compounds 5f, 5b, and 5c showed
the lowest ED50 among other compounds with values of
28.90, 47.38, 56.40 mg/kg, respectively. All compounds tested
in this phase showed high TD50 of more than 500 mg/kg.
Compound 5f showed therapeutic index of more than 17.30
that indicates highly safe anticonvulsant therapy. The results
are shown in Table 2.
series. Surprisingly, compounds with no substituent in 2-
position, i.e. 5a–f and 6a, have higher activity compared to 2-
methyl-substituted analogs, indicating the non-essential role
of
2-position
substituent
in
quinazolin-4(3H)-one
derivatives to be active as anticonvulsant agents. Branching
in the substituent at 3-position is undesired as compounds
with D-alanine in their structure showed more neurotoxicity
than these with b-alanine or g-aminobutyric acid (GABA) in
their structures. Within 5a–j series, compounds with GABA
linker showed better activity than those with other amino
acid linker. This may be due to the increase in their
lipophilicity. While, within 6a–f series, compounds with
b-alanine amino acid linker were more active, suggesting
that the length of the hydrogen-bonding domain has an
important impact on the activity. Compound 5f with GABA
linker at position 3 and with no substituent at position 2
showed the lowest ED50 of 28.90 mg/kg and the highest
therapeutic index PI of more than 17.30.
Structure–activity relationship (SAR)
Conclusion
All synthesized compounds (5a–j and 6a–f) were designed to
follow the aforementioned structural requirements.
The preliminary pharmacological screening inferred several
SAR conclusions. It is obvious that 5a–j series possesses higher
activity than 6a–f series. This may be due to longer hydrogen
bonding linker in 6a–f series comparing with that of 5a–j
In summary, a series of N-(4-substitutedphenyl)-4-(1-methyl (or
1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)alkana-
mides(5a–j)and4-chloro-N0-((1-methyl(or1,2-dimethyl)-4-oxo-
1,2-dihydroquinazolin-3(4H)yl)alkaloyl)benzohydrazides
(6a–f) were designed, synthesized, and evaluated for their
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Table 2. Quantitative study results.
ED50 MESb)
(mg/kg)
ED50 scPTZb)
(mg/kg)
Compound
TPEa) (h)
TD50 (mg/kg)
PIc) (TD50/ED50
)
5a
5b
5c
5d
5e
5f
6a
6d
1.0
1.0
1.0
1.0
0.5
1.0
1.0
1.0
1.0
0.25
NDd)
123.6 (98.0–155.9)
ND
56.40 (28.45–111.80)
128.1 (81.29–201.8)
ND
28.90 (15.87–52.62)
135.2 (106.6–171.5)
ND
>500
>500
>500
>500
>500
>500
>500
>500
>4.05 (scPTZ)
>10.55 (MES)
>8.87 (scPTZ)
>3.90 (scPTZ)
>3.89 (MES)
>17.30 (scPTZ)
>3.70 (scPTZ)
>2.77 (MES)
5.56 (MES)
47.38 (25.67–87.45)
ND
ND
128.5 (85.88–192.3)
ND
ND
180.2 (105.0–307.6)
6.34 (3.55–11.34)
>500
Phenytoine)
Ethosuximidee)
>500
121.8 (69.54–213.4)
44.42 (31.95–61.75)
291.5 (242–350.5)
2.26 (scPTZ)
a) Time of peak effect.
b) Number of animals used: six; results are represented as mean ꢀ SEM at 95% confidence limit (MES, maximum electroshock test;
scPTZ, subcutaneous pentylenetetrazol test).
c) Protective index (TD50/ED50).
d) ND, not done.
e) Reference AEDs tested in the same conditions.
anticonvulsant activity using both MES and scPTZ screens. In
addition, they were evaluated for their neurotoxicity using
rotarod test. All compounds showed good anticonvulsant
activity with minimum levels of neurotoxicity. In this study, we
prove the non-essentiality of 2-position substituent in quina-
zolin-4(3H)-one derivatives to be active as anticonvulsant
agents. Hydrogen bonding region length plays an important
role in determination of quinazolin-4(3H)-one derivatives
anticonvulsant activity. The most active compounds are 5b,
5c, and 5f with ED50 47.38, 56.40, and28.90 mg/kg, respectively.
Compound 5f has therapeutic index >17.30 that indicates high
safety margin.
Tokyo, Japan). Elemental analyses were determined using
the Vario EL-III (Elementar) CHNS analyzer (Hanau, Germany).
All reactions were monitored by thin layer chromatography
(TLC) using silica gel 60 GF245 (E-Merck, Germany) and were
visualized by UV-lamp at wavelength (l) 254 nm.
1H and 13C NMR spectra as well as the InChI codes of the
investigated compounds together with some biological
activity data are provided as Supporting Information.
Synthesis of compounds 2a–c
Compounds 2a–c (2-(methylamino)benzamido)carboxylic
acids) were synthesized according to previously reported
procedures [30].
General method for the synthesis of (1-methyl (or 1,2-
dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-
carboxylic acids (3a–f)
Experimental
Chemistry
General
A mixture of benzamidocarboxylic acid (2a–c, 0.018 mol)
and appropriate aldehyde (0.18 mol) in ethanol/water (2:3)
was heated under reflux for 2 h, then ethanol was
evaporated and the reaction mixture was allowed to cool.
The product crystals that formed were collected under
vacuum and washed with water and petroleum ether to
provide the (4-oxo-1,2-dihydroquinazolin-3(4H)-yl)carbox-
ylic acid (3a–f) in 59.7–91.89% yield and sufficient purity for
the next step.
Melting points (°C) were measured on a Gallenkamp melting
point apparatus (London, UK), and are uncorrected. NMR
spectra were performed in the Microanalytical Center, Faculty
of Pharmacy, Cairo University, Egypt or Microanalytical
Center, Faculty of Science, Zagazig University, Egypt. Elemen-
tal analyses were performed in the Microanalytical Center,
Faculty of Science, Cairo University, Egypt, or in the Regional
Center for Mycology and Biotechnology, Al-Azhar University,
Egypt. Mass spectra were performed in the the Microanalyti-
cal Center, Faculty of Science, Cairo University, Egypt. NMR
spectra were recorded on a Bruker high performance Digital
FT-NMR spectrometer Avance III 400 MHz using dimethyl
sulfoxide (DMSO)-d6 and chloroform (CDCl3)-d as solvent and
tetramethylsilane (TMS) as an internal standard (chemical
shift in d, ppm). Mass spectra were determined using a
GC/MS Shimadzu Qp-2010 plus (Shimadzu Corporation,
3-(1-Methyl-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-
propanoic acid (3a)
(63.29% yield). M.p.: 144–147°C. 1H NMR (DMSO-d6) d 2.55
(2H, t, J 7.2, CH2CO), 2.82 (3H, s, NCH3), 3.62 (2H, t, J 7.2,
NCH2CH2CO), 4.49 (2H, s, NCH2N), 6.77–6.85 (2H, m, H-6, H-8),
7.39 (1H, t, J 8, H-7), 7.72 (1H, dd, J 8, H-5), 12.29 (1H, s, COOH
exch.).
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2-(1-Methyl-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-
propanoic acid (3b)
35.40–79.96% yield and sufficient purity for use in the next
step.
(63.29% yield). M.p.: 191–193°C. 1H NMR (DMSO-d6) d 1.43
(3H, d, J 7.2, COCHCH3), 2.86 (3H, s, NCH3), 4.47–4.52 (2H, m,
NCH2N), 4.91–4.96 (1H, m, COCHCH3), 6.81–6.86 (2H, m, H-6,
H-8), 7.41 (1H, t, J 7.2, H-7), 7.73 (1H, d, J 6.4, H-5), 12.83 (1H, s,
COOH exch.).
3-(3-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-oxopropyl)-1-
methyl-2,3-dihydroquinazolin-4(1H)-one (4a)
(70.18% yield). M.p.: 139–141°C. 1H NMR (CDCl3) d 2.93 (3H, s,
NCH3), 3.90 (2H, t, J 8, CH2CO), 4.09 (2H, t, J 8, NCH2CH2CO), 4.67
(2H, s, NCH2N), 6.75 (1H, d, J 8.2, H-8), 6.92 (1H, t, J 7.6, H-6), 7.40
(1H, t, J 8.6, ArH), 7.53 (1H, t, J 8, ArH), 7.68 (1H, t, J 8, H-7), 7.96
(1H, dd, J 7.6, H-5), 8.15 (1H, d, J 8.4, ArH), 8.31 (1H, d, J 8, ArH).
4-(1-Methyl-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-
butanoic acid (3c)
(67.62%yield). M.p.:128–131°C. 1H NMR(DMSO-d6) d1.76–1.81
(2H, m, COCH2CH2CH2), 2.24 (2H, t, J 7.2, COCH2CH2CH2), 2.83
(3H, s, NCH3), 3.44 (2H, t, J 6.8, COCH2CH2CH2), 4.45 (2H, s,
NCH2N), 6.78–6.85 (2H, m, H-6, H-8), 7.39 (1H, t, J 7.2, H-7), 7.72
(1H, d, J 7.2, H-5), 12.08 (1H, s, COOH).
3-(1-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-oxopropan-2-yl)-1-
methyl-2,3-dihydroquinazolin-4(1H)-one (4b)
(35.09% yield). M.p.: 133–136°C. 1H NMR (CDCl3) d 1.88 (3H, d,
J 7.2, COCHCH3), 2.95 (1H, bs, COCHCH3), 3.03 (3H, s, NCH3),
4.76 (1H, d, J 9.2, NCH2N), 4.91 (1H, d, J 9.2, NCH2N), 6.80 (1H,
d, J 8, H-8), 6.91 (1H, t, J 7.6, H-6), 7.44 (1H, t, J 8.5, ArH), 7.54
(1H, t, J 8, ArH), 7.68 (1H, t, J 7.6, H-7), 7.91 (1H, dd, J 8, H-5),
8.13 (1H, d, J 8.4, ArH), 8.27 (1H, d, J 8.4, ArH).
3-(1,2-Dimethyl-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-
propanoic acid (3d)
(59.7% yield). M.p.: 156–159°C. 1H NMR (DMSO-d6) d 1.13 (3H,
d, J 6, NCHCH3), 2.50–2.57 (1H, m, CH2CO), 2.60–2.67 (1H, m,
CH2CO), 2.82 (3H, s, NCH3), 3.16–3.23 (1H, m, NCH2CH2CO),
3.88–3.95 (1H, m, NCH2CH2CO), 4.88–4.93 (1H, m, NCHCH3),
6.69 (1H, d, J 8, H-8), 6.77 (1H, t, J 7.6, H-6), 7.37 (1H, t, J 8, H-7),
7.68 (1H, dd, J 7.6, H-5), 12.32 (1H, s, COOH exch.).
3-(4-(1H-Benzo[d][1,2,3]triazol-1-yl)-4-oxobutyl)-1-
methyl-2,3-dihydroquinazolin-4(1H)-one (4c)
1
(83.93% yield). M.p.: 115–117°C. H NMR (CDCl3) d 2.22–2.29
(2H, m, COCH2CH2CH2), 2.84 (3H, s, NCH3), 3.15 (2H, t, J 6.8,
COCH2CH2CH2), 3.71 (2H, t, J 6.8, COCH2CH2CH2), 4.45 (2H, s,
NCH2N), 6.62 (1H, d, J 8.4, H-8), 6.84 (1H, t, J 7.2, H-6), 7.33 (1H,
t, J 7.6, ArH), 7.47 (1H, t, J 7.6, ArH), 7.61 (1H, t, J 7.7, H-7), 7.90
(1H, d, J 7.6, H-5), 8.08 (1H, d, J 8.4, ArH), 8.23 (1H, d, J 8.4,
ArH).
2-(1,2-Dimethyl-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-
propanoic acid (3e)
(59.7% yield). M.p.: 172–174°C. 1H NMR (CDCl3) d 1.31 (3H, d, J
6, NCHCH3), 1.63 (3H, d, J 7.2, COCHCH3), 2.96 (3H, s, NCH3),
4.82–4.91 (1H, m, NCHCH3þ COCHCH3), 6.70 (1H, d, J 8.2, H-8),
6.91 (1H, t, J 7.4, H-6), 7.46 (1H, t, J 8.6, H-7), 7.96 (1H, dd, J 7.6,
H-5).
3-(3-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-oxopropyl)-1,2-
dimethyl-2,3-dihydroquinazolin-4(1H)-one (4d)
(80.36% yield). Semisolid product. 1H NMR (CDCl3) d 1.36 (3H,
d, J 6, NCHCH3), 2.93 (3H, s, NCH3), 3.53–3.60 (1H, m, CH2CO),
3.77–3.84 (1H, m, CH2CO), 4.03–4.11 (1H, m, NCH2CH2CO),
4.44–4.49 (1H, m, NCH2CH2CO), 4.96–5.01 (1H, m, NCHCH3),
6.69 (1H, d, J 8.4, H-8), 6.89 (1H, t, J 7.6, H-6), 7.40 (1H, t, J 8.4,
ArH), 7.53 (1H, t, J 7.6, ArH), 7.68 (1H, t, J 8, H-7), 7.95 (1H, dd, J
7.6, H-5), 8.14 (1H, d, J 8.4, ArH), 8.31 (1H, d, J 8.4, ArH).
4-(1,2-Dimethyl-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-
butanoic acid (3f)
(91.89% yield). M.p.: 124–126°C. 1H NMR (CDCl3) d 1.27 (3H, d,
J 6, NCHCH3), 1.98–2.06 (2H, m, COCH2CH2CH2), 2.44–2.49
(2H, m, COCH2CH2CH2), 2.92 (3H, s, NCH3), 3.01–3.08 (1H, m,
COCH2CH2CH2), 4.05–4.12 (1H, m, COCH2CH2CH2), 4.63–4.67
(1H, m, CHCH3), 6.66 (1H, d, J 8, H-8), 6.88 (1H, t, J 7.2, H-6),
7.41 (1H, t, J 8.4, H-7), 7.94 (1H, dd, J 7.6, H-5).
3-(4-(1H-Benzo[d][1,2,3]triazol-1-yl)-4-oxobutyl)-1,2-
dimethyl-2,3-dihydroquinazolin-4(1H)-one (4f)
General method for the synthesis of 3-(1H-benzo[d][1,2,3]-
triazol-1-yl)-3-oxoalkyl)-1-methyl (or 1,2-dimethyl)-2,3-
dihydroquinazolin-4(1H)-one (4a–f)
(96.36% yield). M.p.: 110–111°C. 1H NMR (CDCl3) d 1.31 (3H, d,
J 6, NCHCH3), 2.27–2.41 (2H, m, COCH2CH2CH2), 2.89 (3H, s,
NCH3), 3.07–3.14 (1H, m, COCH2CH2CH2), 3.55 (2H, t, J 7.2,
COCH2CH2CH2), 4.26–4.33 (1H, m, COCH2CH2CH2), 4.68–4.72
(1H, m, NCHCH3), 6.61 (1H, d, J 8.4, H-8), 6.87 (1H, t, J 7.2, H-6),
7.37 (1H, t, J 8.4, ArH), 7.51 (1H, t, J 7.6, ArH), 7.65 (1H, t, J 7.2,
H-7), 7.94 (1H, dd, J 7.6, H-5), 8.13 (1H, d, J 8.4, ArH), 8.28 (1H,
d, J 8, ArH).
To
a
solution of 1H-benzotriazole (3.57 g, 0.03 mol) in
anhydrous
dichloromethane, thionylchloride (1.43 g,
0.012 mol) was added and the reaction mixture was stirred
at room temperature for 30 min, then the (4-oxo-1,2-
dihydroquinazolin-3(4H)-yl)carboxylic acids (3a–f, 0.01 mol)
were added and the reaction mixture was stirred at room
temperature for a further 4 h. The precipitate formed was
filtered off and the organic layer was extracted twice with 5%
Na2CO3 solution, washed with water, and dried over
anhydrous sodium sulfate, then the solvent was removed
in vacuo to obtain the desired N-acylbenzotriazole (4a–f) in
General method for the synthesis of N-(4-
substitutedphenyl)-4-(1-methyl (or 1,2-dimethyl)-4-oxo-
1,2-dihydroquinazolin-3(4H)-yl)alkanamides (5a–j)
A solution of N-acylbenzotriazole derivative (4a–f, 0.005 mol)
and the 4-substituted aniline (0.005 mol) in anhydrous THF
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containing triethyl amine (0.76 g, 0.0075 mol) was stirred at
room temperature for 24 h, then THF was evaporated under
reduced pressure and the residue was then treated with
appropriate method suitable for each.
The residue was washed with diethyl ether and the
produced solid is filtered off and washed with ether twice
as in 5a, 5d, and 5h.
Or the residue was then dissolved in dichloromethane and
extracted twice with 5% Na2CO3 solution then 1 N HCl
solution, then the organic layer was washed with water and
dried with anhydrous sodium sulfate and the solvent was
evaporated under reduced pressure as in 5b, 5e, 5g, and 5i.
Or the residue was then dissolved in methanol and boiled
for 5 min, the methanol was evaporated and then the residue
was dissolved in dichloromethane and extracted twice with
5% Na2CO3 solution then 1 N HCl solution, then the organic
layer was washed with water and dried with anhydrous
sodium sulfate and the solvent was evaporated under
reduced pressure as in 5c, 5f, and 5j. This step afforded the
desired products in a 35–53% yield.
d, J 8.8, H-30, H-50), 7.44 (1H, t, J 7.8, H-7), 7.66 (2H, d, J 8.8,
H-20, H-60), 7.99–8.01 (1H, d, J 7.7, H-5), 9.59 (1H, s, CONH,
exch.). 13C NMR (CDCl3)
d 24.41 (COCH2CH2CH2), 34.57
(COCH2CH2CH2), 35.93 (NCH3), 44.39 (COCH2CH2CH2), 66.44
(NCH2N), 112.21 (ArCH), 117.22 (ArCH), 119.22 (ArCH), 120.98
(ArCH), 128.51 (ArCH), 128.73 (ArCH), 128.98 (ArC), 133.94
(ArC), 137.33 (ArC), 149.22 (ArC), 164.84 (ArC), 171.26
(ArC). MS, m/z: 357 (Mþ), 359 (Mþþ2). Anal. calcd. for
C
19H20ClN3O2: C, 63.77; H, 5.63; N, 11.74. Found: C, 63.48; H,
5.50; N, 11.71.
N-(4-Fluorophenyl)-3-(1-methyl-4-oxo-1,2-
dihydroquinazolin-3(4H)-yl)propanamide (5d)
(35.62% yield). M.p.: 189–191°C. 1H NMR (CDCl3) d 2.77 (2H, t,
J
5.6, CH2CO), 2.83 (3H, s, NCH3), 3.86 (2H, t, J 5.6,
NCH2CH2CO), 4.54 (2H, s, NCH2N), 6.65 (1H, d, J 8.4, H-8),
6.82 (1H, t, J 7.6, H-6), 6.96 (2H, t, J 8.4, H-30, H-50), 7.37 (1H, t,
J 7.6, H-70), 7.57 (dd, J ¼ 7.9, 5.2 H-20, H-60), 7.84 (1H, d, J 7.6,
H-5), 9.25 (1H, s, CONH, exch.). 13C NMR (CDCl3) d 35.96
(CH2CO), 36.54 (NCH3), 42.86 (NCH2CH2CO), 67.85 (NCH2N),
112.38 (ArCH), 115.67 (ArCH), 117.47 (ArCH), 119.16 (ArCH),
121.82 (ArCH), 128.72 (ArCH), 133.98 (ArC), 134.63 (ArC),
149.63 (ArC), 160.54 (ArC), 164.53 (ArC), 169.55 (ArC). MS, m/z:
327 (Mþ). Anal. calcd. for C18H18FN3O2: C, 66.04; H, 5.54; N,
12.84. Found: C, 65.79; H, 5.26; N, 13.01.
N-(4-Chlorophenyl)-3-(1-methyl-4-oxo-1,2-
dihydroquinazolin-3(4H)-yl)propanamide (5a)
(46.75% yield). M.p.: 220–223°C. 1H NMR (DMSO-d6) d 2.67
(2H, t, J 6.8, CH2CO), 2.79 (3H, s, NCH3), 3.70 (2H, t, J 6.8,
NCH2CH2CO), 4.49 (2H, s, NCH2N), 6.77–6.85 (2H, m, H-6, H-8),
7.33–7.41 (3H, m, H-30, H-50, H-7), 7.60 (2H, d, J 8.8, H-20, H-60),
7.71 (1H, d, J 7.6, H-5), 10.15 (1H, s, CONH exch.). 13C NMR
(CDCl3) d 36.03 (CH2CO), 36.59 (NCH3), 42.67 (NCH2), 67.62
(NCH2N), 112.50 (ArCH), 117.34 (ArCH), 119.42 (ArCH), 121.16
(ArCH), 128.71 (ArCH), 128.86 (ArCH), 129.04 (ArC), 134.00
(ArC), 136.91 (ArC), 149.19 (ArC), 164.46 (ArC), 169.37 (ArC).
MS, m/z: 343 (Mþ), 345 (Mþþ2). Anal. calcd. for C18H18ClN3O2:
C, 62.88; H, 5.28; N, 12.22. Found: C, 62.61; H, 5.00; N, 12.13.
N-(4-Fluorophenyl)-2-(1-methyl-4-oxo-1,2-
dihydroquinazolin-3(4H)-yl)propanamide (5e)
(35.41% yield). M.p.: 151–152°C. 1H NMR (CDCl3) d 1.52 (3H,
d, J 7.2, COCHCH3), 2.91 (3H, s, NCH3), 4.39–4.51 (2H, m,
NCH2N), 5.42–5.47 (1H, m, COCHCH3), 6.73 (1H, d, J 8, H-8),
6.90–6.99 (3H, m, H-30, H-50, H-6), 7.40–7.49 (3H, m, H-20,
H-60, H-7), 7.97 (1H, d, J 8, H-5), 8.73 (1H, s, CONH). 13C NMR
(CDCl3) d 13.60 (COCHCH3), 36.40 (NCH3), 51.67 (COCHCH3),
62.76 (NCH2N), 112.69 (ArCH), 115.59 (ArCH), 117.45 (ArCH),
119.54 (ArCH), 121.71 (ArCH), 129.42 (ArCH), 133.96 (ArC),
134.31 (ArC), 149.69 (ArC), 160.69 (ArC), 164.80 (ArC),
169.11 (ArC). MS, m/z: 327 (Mþ). Anal. calcd. for
N-(4-Chlorophenyl)-2-(1-methyl-4-oxo-1,2-
dihydroquinazolin-3(4H)-yl)propanamide (5b)
(36% yield). M.p.: 161–163°C. 1H NMR (DMSO-d6) d 1.47 (3H, d,
J 7.2, COCHCH3), 2.88 (3H, s, NCH3), 4.58 (1H, d, J 9.6, NCH2N),
4.64 (1H, d, J 9.6, NCH2N), 5.19–5.24 (1H, m, COCHCH3),
6.82–6.87 (2H, m, H-6, H-8), 7.35–7.44 (3H, m, H-30, H-50, H-7),
7.63 (2H, d, J 8.8, H-20, H-60), 7.74 (1H, d, J 7.7, H-5), 10.27 (1H, s,
CONH, exch.). 13C NMR (CDCl3) d 13.69 (COCHCH3), 36.33
(NCH3), 51.66 (COCHCH3), 62.64 (NCH2N), 112.65 (ArCH),
117.31 (ArCH), 119.47 (ArCH), 121.12 (ArCH), 128.91 (ArCH),
129.21 (ArCH), 129.25 (ArC), 134.21 (ArC), 136.50 (ArC), 149.47
(ArC), 164.64 (ArC), 169.22 (ArC). MS, m/z: 343 (Mþ), 345
(Mþþ2). Anal. calcd. for C18H18ClN3O2: C, 62.88; H, 5.28; N,
12.22. Found: C, 62.91; H, 5.52; N, 12.47.
C
18H18FN3O2: C, 66.04; H, 5.54; N, 12.84. Found: C, 65.80;
H, 5.85; N, 13.00.
N-(4-Fluorophenyl)-4-(1-methyl-4-oxo-1,2-
dihydroquinazolin-3(4H)-yl)butanamide (5f)
(25.5% yield). M.p.: 104–107°C. 1H NMR (DMSO-d6)
d
1.85–1.88 (2H, m, COCH2CH2CH2), 2.33 (2H, t,
COCH2CH2CH2), 2.83 (3H, s, NCH3), 3.49 (2H, t,
J
J
7.2,
6.8,
COCH2CH2CH2), 4.47 (2H, s, NCH2N), 6.78–6.85 (2H, m, H-6,
H-8), 7.11 (2H, t, J 8.4, H-30, H-50), 7.39 (1H, t, J 8, H-7), 7.59 (2H,
dd, J 8.0, 5.3, H-20, H-60), 7.72 (1H, d, J 7.6, H-5), 9.96 (1H, s,
CONH, exch.). 13C NMR (DMSO-d6) d 23.15 (COCH2CH2CH2),
33.59 (COCH2CH2CH2), 35.24 (NCH3), 43.90 (COCH2CH2CH2),
65.46 (NCH2N), 112.30 (ArCH), 115.24 (ArCH), 117.28 (ArCH),
118.11 (ArCH), 120.77 (ArCH), 128.01 (ArCH), 133.21 (ArC),
135.68 (ArC), 149.62 (ArC), 158.97 (ArC), 162.42 (ArC), 170.49
(ArC). MS, m/z: 341 (Mþ). Anal. calcd. for C19H20FN3O2: C,
66.85; H, 5.91; N, 12.31. Found: C, 67.08; H, 5.95; N, 12.49.
N-(4-Chlorophenyl)-4-(1-methyl-4-oxo-1,2-
dihydroquinazolin-3(4H)-yl)butanamide (5c)
(26.46% yield). M.p.: 88–91°C. 1H NMR (CDCl3) d 2.02–2.07
(2H, m, COCH2CH2CH2), 2.41 (2H, t, J 6, COCH2CH2CH2), 2.91
(3H, s, NCH3), 3.68 (2H, t, J 6, COCH2CH2CH2), 4.46 (2H, s,
NCH2N), 6.70 (1H, d, J 8.4, H-8), 6.94 (1H, t, J 7.6, H-6), 7.28 (2H,
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N-(4-Chlorophenyl)-3-(1,2-dimethyl-4-oxo-1,2-
dihydroquinazolin-3(4H)-yl)-propanamide (5g)
(1H, m, NCHCH3), 6.56 (1H, d, J 8.4, H-8), 6.85 (1H, t, J 7.6, H-6),
6.96 (2H, t, J 8.4, H-30, H-50), 7.37 (1H, t, J 7.6, H-7), 7.61 (2H, dd,
J 7.7, 5.2, H-20, H-60), 7.93 (1H, d, J 7.6, H-5), 9.48 (1H, s, CONH).
13C NMR (CDCl3) d 14.32(NCHCH3), 25.07 (COCH2CH2CH2), 34.61
(COCH2CH2CH2), 35.56 (NCH3), 43.46 (COCH2CH2CH2), 72.40
(NCHCH3), 112.61 (ArCH), 115.50 (ArCH), 116.61 (ArCH), 118.46
(ArCH), 121.49 (ArCH), 128.72 (ArCH), 134.14 (ArC), 134.95
(ArC), 146.61(ArC), 160.31(ArC), 163.82(ArC), 171.26(ArC). MS,
m/z: 355 (Mþ). Anal. calcd. for C20H22FN3O2: C, 67.59; H, 6.24; N,
11.82. Found: C, 67.56; H, 6.55; N, 11.51.
(44.16% yield). M.p.: 155–157°C. 1H NMR (DMSO-d6) d 1.14
(3H, d, J 6, NCHCH3), 2.60–2.66 (1H, m, CH2CO), 2.70–2.76
(1H, m, CH2CO), 2.78 (3H, s, NCH3), 3.28–3.32 (1H, m,
NCH2CH2CO), 3.94–4.01 (1H, m, NCH2CH2CO), 4.86–4.91
(1H, m, NCHCH3), 6.67 (1H, d, J 8, H-8), 6.77 (1H, t, J 7.6,
H-6), 7.33–7.39 (3H, m, H-30, H-50, H7), 7.60 (2H, d, J 8.8, H-20,
H-60), 7.69 (1H, d, J 7.6, H-5), 10.14 (1H, s, CONH exch.).
13C NMR (CDCl3) d 14.61 (NCHCH3), 35.49 (CH2CO), 36.83
(NCH3), 41.82 (NCH2CH2CO), 73.63 (NCHCH3), 112.75 (ArCH),
116.43 (ArCH), 118.33 (ArCH), 121.17 (ArCH), 128.15 (ArCH),
128.81 (ArCH), 134.06 (ArC), 137.23 (ArC), 146.55 (ArC), 163.25
(ArC), 169.72 (ArC). MS, m/z: 357 (Mþ), 359 (Mþþ2). Anal.
calcd. for C19H20ClN3O2: C, 63.77; H, 5.63; N, 11.74. Found: C,
63.90; H, 5.91; N, 11.88.
General method for the synthesis of 4-chloro-N0-((1-methyl
(or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-
alkaloyl)benzohydrazides (6a–f)
A
solution of N-acylbenzotriazole derivative (4a–f,
0.005 mol) and p-chlorobenzoic acid hydrazide (0.85 g,
0.005 mol) in anhydrous THF containing triethyl amine
(0.76 g, 0.0075 mol) was stirred at room temperature for
24 h, then THF was evaporated under reduced pressure. The
residue was washed with diethyl ether, the formed solid is
then boiled with 1 N HCl, then the solid is filtered off and
washed with water twice to afford the desired product 6a–f
in a 10–48.5% yield.
3-(1,2-Dimethyl-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-
(4-fluorophenyl)propanamide (5h)
(53.42% yield). M.p.: 138–140°C. 1H NMR (CDCl3) d 1.25 (3H, d,
J 6, NCHCH3), 2.69–2.74 (1H, m, CH2CO), 2.81 (3H, s, NCH3),
2.83–2.87 (1H, m, CH2CO), 3.41–3.48 (1H, m, NCH2CH2CO),
4.13–4.19 (1H, m, NCH2CH2CO), 4.77–4.82 (1H, m, NCHCH3),
6.59 (1H, d, J 8, H-8), 6.82 (1H, t, J 7.6, H-6), 6.98 (2H, t, J ¼ 12.0,
5.4 H-30, H-50), 7.38 (1H, t, J ¼ 7.8, H-7), 7.54 (2H, dd, J ¼ 9.0, 4.9
H-20, H-60), 7.87 (1H, d, J ¼ 7.7, H-5), 8.92 (1H, s, CONH exch.).
13C NMR (CDCl3) d 14.58 (NCHCH3), 35.40 (CH2CO), 36.74
(NCH3), 41.90 (NCH2CH2CO), 73.60 (NCHCH3), 112.65 (ArCH),
115.85 (ArCH), 116.47 (ArCH), 118.22 (ArCH), 121.73 (ArCH),
128.17 (ArCH), 133.99 (ArC), 134.62 (ArC), 146.62 (ArC), 160.39
(ArC), 163.23 (ArC), 169.60 (ArC). MS, m/z: 341 (Mþ). Anal.
calcd. for C19H20FN3O2: C, 66.85; H, 5.91; N, 12.31. Found: C,
66.95; H, 6.05; N, 12.46.
4-Chloro-N0-(3-(1-methyl-4-oxo-1,2-dihydroquinazolin-
3(4H)-yl)propanoyl)benzohydrazide (6a)
(48% yield). M.p.: 216–219°C. 1H NMR (DMSO-d6) d 2.55
(2H, t, J 6.8, CH2CO), 2.83 (3H, s, NCH3), 3.68 (2H, t, J 6.8,
NCH2CH2CO), 4.52 (2H, s, NCH2N), 6.79–6.85 (2H, m, H-6,
H-8), 7.40 (1H, t, J 8, H-7), 7.57 (2H, d, J 8.4, H-30, H-50), 7.72
(1H, d, J 7.6, H-5), 7.88 (2H, d, J 8.4, H-20, H-60), 10.06 (1H, s,
CONHNHCOAr exch.), 10.44 (1H, s, CONHNHCOAr, exch.).
13C NMR (CDCl3) d 32.10 (CH2CO), 35.21 (NCH3), 41.62
(NCH2CH2CO), 66.22 (NCH2N), 112.31 (ArCH), 117.14
(ArCH), 118.06 (ArCH), 127.92 (ArCH), 128.57 (ArCH),
129.34 (ArCH), 131.19 (ArC), 133.32 (ArC), 136.62 (ArC),
149.64 (ArC), 162.41 (ArC), 164.45 (ArC), 169.81 (ArC). MS,
m/z: 385 (Mþ), 387 (Mþþ2). Anal. calcd. for C19H19ClN4O3:
C, 58.99; H, 4.95; N, 14.48. Found: C, 59.26; H, 4.98; N,
14.72.
2-(1,2-Dimethyl-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-
(4-fluorophenyl)propanamide (5i)
(35.89% yield). M.p.: 150–153°C. 1H NMR (CDCl3) d 1.17 (3H, d,
J 6, NCHCH3), 1.55 (3H, d, J 6.8, COCHCH3), 2.92 (3H, s, NCH3),
4.83–4.87 (1H, m, NCHCH3), 5.27–5.33 (1H, m, COCHCH3), 6.63
(1H, d, J 8.4, H-8), 6.87 (1H, t, J 7.6, H-6), 6.96–7.00 (2H, t, J 8.4,
H-30, H-50), 7.42 (1H, t, J 7.6, H-7), 7.50 (2H, dd, J 8.1, 5.3, H-20,
H-60), 7.97 (1H, d, J 8, H-5), 9.31 (1H, s, CONH). 13C NMR (CDCl3)
d 13.41 (COCHCH3), 15.19 (NCHCH3), 35.83 (NCH3), 51.56
(COCHCH3), 68.69 (NCHCH3), 112.81 (ArCH), 115.58 (ArCH),
115.87 (ArCH), 118.48 (ArCH), 121.71 (ArCH), 129.13 (ArCH),
134.19 (ArC), 134.72 (ArC), 146.41 (ArC), 160.59 (ArC), 164.45
(ArC), 169.72 (ArC). MS, m/z: 341 (Mþ). Anal. calcd. for
4-Chloro-N0-(2-(1-methyl-4-oxo-1,2-dihydroquinazolin-
3(4H)-yl)propanoyl)benzohydrazide (6b)
(29.3% yield). M.p.: 96–99°C. 1H NMR (CDCl3) d 1.51 (3H, d, J 7,
COCHCH3), 2.95 (3H, s, NCH3), 4.47 (1H, d, J 9.2, NCH2N), 4.62
(1H, d, J 9.2, NCH2N), 5.44–5.46 (1H, m, COCHCH3), 6.73 (1H, d,
J 8, H-8), 6.90 (1H, t, J 7.2, H-6), 7.36–7.43 (3H, m, H-30, H-50,
H-7), 7.73 (2H, d, J 8, H-20, H-60), 7.95 (1H, d, J 7.2, H-5), 8.72
(1H, s, CONHNHCO, exch.), 9.14 (1H, s, CONHNHCO, exch.).
13C NMR (CDCl3) d 13.98 (COCHCH3), 36.01 (NCH3), 49.77
(COCHCH3), 62.84 (NCH2N), 112.47 (ArCH), 117.16 (ArCH),
119.22 (ArCH), 128.82 (ArCH), 128.90 (ArCH), 129.11 (ArCH),
129.94 (ArC), 134.14 (ArC), 138.51 (ArC), 149.76 (ArC), 164.54
(ArC), 165.04 (ArC), 170.46 (ArC). MS, m/z: 386 (Mþ), 388
(Mþþ2). Anal. calcd. for C19H19ClN4O3: C, 58.99; H, 4.95; N,
14.48. Found: C, 59.21; H, 4.99; N, 14.59.
C
19H20FN3O2: C, 66.85; H, 5.91; N, 12.31. Found: C, 67.02; H,
5.97; N, 12.47.
4-(1,2-Dimethyl-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-
(4-fluorophenyl)butanamide (5j)
(28.57% yield). 1H NMR (CDCl3) d 1.26 (3H, d, J 8, NCHCH3),
2.02–2.05 (2H, m, COCH2CH2CH2), 2.38 (2H, t,
COCH2CH2CH2), 2.86 (3H, s, NCH3), 3.04–3.10 (1H, m,
COCH2CH2CH2), 4.08–4.15 (1H, m, COCH2CH2CH2), 4.58–4.63
J 5.6,
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Anticonvulsant Quinazolinones
Archiv der Pharmazie
4-Chloro-N0-(4-(1-methyl-4-oxo-1,2-dihydroquinazolin-
3(4H)-yl)butanoyl)benzohydrazide (6c)
Research Centre, Dokki, Cairo, Egypt and the whole study was
approved by the institutional Medical Research Ethics
Committee with a registration number (16064). Adult Swiss
albino mice (20–25 g) of both sexes were used as experimental
animals and each mouse was used only once. All animals were
purchased from National Research Center animal house. The
animals were housed at room temperature 22 ꢀ 2°C, under
light/dark cycle (12/12) and were allowed free access to food
and water. MES and scPTZ are the two animal models used for
anticonvulsant activity screening while rotarod test is used for
neurotoxicity screening, and the response evaluation was
estimated by procedures described elsewhere [31]. The tested
compounds were suspended in 1% Tween 80/water mixture
and injected intraperitoneally at doses of 30, 100, 300 mg/kg
into one to four animals followed by anticonvulsant activity
and neurotoxicity assessment at two different time intervals
(0.5 and 4 h) after administration.
(12.28% yield). M.p.: 151–154°C. 1H NMR (CDCl3) d 1.09 (2H,
bs, COCH2CH2CH2), 2.38 (2H, bs, COCH2CH2CH2), 2.88 (3H, s,
NCH3), 3.71 (2H, bs, COCH2CH2CH2), 4.42 (2H, bs, NCH2N), 6.69
(1H, d, J 7.6, H-8), 6.89–6.90 (1H, m, H-6), 7.33–7.39 (3H, m,
H-30, H-50, H-7), 7.75 (2H, d, J 6.8, ArH), 7.93 (1H, d, J 6.8, H-5),
9.13 (1H, s, CONHNHCO, exchangeable), 9.91 (1H, s, CON-
HNHCO, exch.). 13C NMR (CDCl3) d 24.04 (COCH2CH2CH2),
31.21 (COCH2CH2CH2), 35.90 (NCH3), 44.49 (COCH2CH2CH2),
66.56 (NCH2N), 112.13 (ArCH), 117.39 (ArCH), 119.19 (ArCH),
128.76 (ArCH), 128.91 (ArCH), 129.00 (ArCH), 130.04 (ArC),
133.78 (ArC), 138.33 (ArC), 149.28 (ArC), 164.46 (ArC), 164.66
(ArC), 172.06 (ArC). MS, m/z: 400 (Mþ), 402 (Mþþ2). Anal.
calcd. for C20H21ClN4O3: C, 59.92; H, 5.28; N, 13.98. Found: C,
59.66; H, 5.25; N, 13.66.
4-Chloro-N0-(3-(1,2-dimethyl-4-oxo-1,2-
dihydroquinazolin-3(4H)-yl)propanoyl)benzohydrazide
(6d)
The MES test
In the MES test, animals were subjected to electrical shock
through a current of 60 Hz and 50 mA intensity delivered via
ear-lip electrodes for 0.2 s duration. The test compound is
considered able to inhibit MES-induced seizure spread upon
absence of hind limb tonic extension [28, 32].
(30.59% yield). M.p.: 107–110°C. 1H NMR (CDCl3) d 1.16 (3H, d,
J 5.6, NCHCH3), 2.60–2.74 (2H, m, CH2CO), 2.79 (3H, s, NCH3),
3.20–3.25 (1H, m, NCH2CH2CO), 4.06 (1H, t, J 6.8, NCH2CH2CO),
4.75 (1H, bs, NCHCH3), 6.52 (1H, d, J 8.4, H-8), 6.75–6.78 (1H, t,
J 7.2, H-6), 7.27–7.34 (3H, m, H-30, H-50, H-7), 7.74–7.81 (3H, m,
H-20, H-60, H-5), 9.62 (1H, s, CONHNHCOAr), 9.72 (1H, s,
CONHNHCOAr). 13C NMR (CDCl3) d 14.52 (NCHCH3), 33.42
(CH2CO), 35.33 (NCH3), 41.90 (NCH2CH2CO), 73.45 (NCHCH3),
112.57 (ArCH), 116.50 (ArCH), 118.28 (ArCH), 128.43 (ArCH),
128.89 (ArCH), 129.10 (ArCH), 130.16 (ArC), 134.07 (ArC),
138.52 (ArC), 146.75 (ArC), 163.13 (ArC), 164.85 (ArC), 170.21
(ArC). MS, m/z: 400 (Mþ), 402 (Mþþ2). Anal. calcd. for
The scPTZ test
In the scPTZ test, animals were injected subcutaneously with
pentylenetetrazol in a dose of 85 mg/kg at the predetermined
time of testing and animals were observed over 30 min. The
test compound considered able to abolish pentylenetetrazol
induced seizures upon absence of even the threshold seizure
(a single episode of clonic spasm of at least a duration of
5 s) [28, 32].
C
20H21ClN4O3: C, 59.92; H, 5.28; N, 13.98. Found: C, 59.97; H,
5.45; N, 13.85.
Neurotoxicity-minimal motor impairment (MMI)
4-Chloro-N0-(4-(1,2-dimethyl-4-oxo-1,2-
Standardized rotarod was the test used to determine the
neurotoxicity effect of the tested compounds. Untreated
control mouse can maintain its equilibrium when placed on a
6 rpm rotation rod for a prolonged period of time. Acute
motor impairment is deduced when the test animal fails to
maintain equilibrium on the 6 rpm revolving roller for 1 min in
each of three successive trials [28, 32].
dihydroquinazolin-3(4H)-yl)butanoyl)benzohydrazide (6f)
(10.6% yield). M.p.: 80–83°C. 1H NMR (CDCl3) d 1.25 (3H, d,
J 5.9, NCHCH3), 2.01 (2H, bs, COCH2CH2CH2), 2.37 (2H, t, J 6,
COCH2CH2CH2), 2.88 (3H, s, NCH3), 3.04–3.10 (1H, m,
COCH2CH2CH2), 4.28–4.35 (1H, m, COCH2CH2CH2), 4.58–4.63
(1H, m, NCHCH3), 6.60 (1H, d, J 8.4, H-8), 6.85 (1H, t, J 7.6, H-6),
7.34–7.40 (3H, m, H-30, H-50, H-7), 7.75 (2H, d, J 8, H-20, H-60),
7.92 (1H, d, J 7.6, H-5), 8.97 (1H, s, CONHNHCO), 10.00 (1H, s,
CONHNHCO). 13C NMR (CDCl3) d 13.12 (NCHCH3), 23.66
(COCH2CH2CH2), 30.19 (COCH2CH2CH2), 34.46 (NCH3), 42.45
(COCH2CH2CH2), 71.42 (NCHCH3), 111.45 (ArCH), 115.75
(ArCH), 117.44 (ArCH), 127.65 (ArCH), 127.90 (ArCH), 129.08
(ArCH), 132.79 (ArC), 132.91 (ArC), 137.27 (ArC), 145.43 (ArC),
162.36 (ArC), 163.61 (ArC), 171.13 (ArC). Anal. calcd. for
The authors have declared no conflicts of interest.
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