Design, synthesis, and potential CNS activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-methyl- 4H-quinazolin-3-yl)-urea

Article abstract of DOI:10.1007/s00044-010-9362-x

Twelve new 1-(4-substituted-phenyl)-3-(4-oxo- 2-methyl-4H-quinazolin-3-yl)- urea were synthesized and screened for anticonvulsant, CNS depressant, and sedativehypnotic activity. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight 2,3-Disubstitutedquinazolin- 4(3H)-one were examined in the maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. Spectroscopic data and elemental analysis were consistent with the newly synthesized compounds. The neurotoxicity was assessed using the rotorod method. M3, M4 and M10 were found to be active in both MES screen and scPTZ screen at 0.5 h. All except M11 showed more than 44% decrease in locomotor activity after 1 h of compound administration via actophotometer screen. CNS-depressant activity screened with the help of the forced swim method resulted into some potent compounds. Except for M6 and M11 other tested compounds were found to exhibit potent CNS depressants activity as indicated by increased immobility time. It can be concluded that newly synthesized compounds possessed sedative-hypnotic and CNS depressant activities. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9362-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:738–745
DOI 10.1007/s00044-010-9362-x
ORIGINAL RESEARCH
Design, synthesis, and potential CNS activity of some
new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-methyl-
4H-quinazolin-3-yl)-urea
•
Sushil K. Kashaw Varsha Kashaw
•
•
Pradeep Mishra N. K. Jain J. P. Stables
•
Received: 10 August 2009 / Accepted: 3 May 2010 / Published online: 1 July 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Twelve new 1-(4-substituted-phenyl)-3-(4-oxo-
2-methyl-4H-quinazolin-3-yl)-urea were synthesized and
screened for anticonvulsant, CNS depressant, and sedative-
hypnotic activity. After i.p. injection to mice at doses of
30, 100, and 300 mg/kg body weight 2,3-Disubstituted-
quinazolin-4(3H)-one were examined in the maximal
electroshock-induced seizures (MES) and subcutaneous
pentylenetetrazole (scPTZ) induced seizure models in mice.
Spectroscopic data and elemental analysis were consistent
with the newly synthesized compounds. The neurotoxicity
was assessed using the rotorod method. M3, M4, and M10
were found to be active in both MES screen and scPTZ
screen at 0.5 h. All except M11 showed more than 44%
decrease in locomotor activity after 1 h of compound
administration via actophotometer screen. CNS-depressant
activity screened with the help of the forced swim method
resulted into some potent compounds. Except for M6 and
M11 other tested compounds were found to exhibit potent
CNS depressants activity as indicated by increased immo-
bility time. It can be concluded that newly synthesized
compounds possessed sedative-hypnotic and CNS depres-
sant activities.
Introduction
Epilepsy is one of the most common diseases of the brain
affecting at least 50 million persons worldwide. There is
currently a need for improved agents for the treatment of
seizures. Polytherapy with antiepileptic drugs is necessary
in clinical practice because of the limited efficacy of
monotherapy. In recent years many new chemical entities
(NCE) have been designed that were structurally dissimilar
from many common anticonvulsant containing dicarboxi-
mide function (CONRCO), which contributes to toxic side
effects. 4(3H)-Quinazolinones and related quinazolines are
classes of fused heterocyclic that are of considerable
interest. Quinazoline and quinazolinone derivatives have
continued to attract a widespread interest for a long
time due to their diverse pharmacological activities like
anti-tumor, anti-inflammatory, central nervous system
depressant, stimulant, anthelmintic, muscle relaxant,
hypoglycemic, and anti-microbial activities (Armarego,
1963; Chaurasia and Sharma, 1982; Gupta et al., 2008;
Kumar et al., 1983; Misra et al., 1982, 2006; Mukerji et al.,
1980; Saxena et al., 1992). Literature survey revealed that
presence of substituted aromatic ring at position 3 and
methyl group at position 2 are necessary requirement for the
central nervous system (CNS) depression and anticonvul-
sant activities. Modification of methyl group by some other
chemical moiety yielded structural analogues with anti-
convulsant activity. Various hypotheses were analyzed
before we undertook chemical syntheses of the compounds
synthesis (Boltze et al., 1963; Wolfe et al., 1990; Jatav
et al., 2008a, b; Dimmock et al., 1995a, b; Kashaw et al.,
2008, 2009). The present work was carried out on three
objectives: (i) The first objective was the synthesis of the
hybrid compounds possessing mentioned molecular fea-
tures; (ii) the second objective was anticonvulsant screening
Keywords 4(3H)-quinazolinone ꢀ Anticonvulsant ꢀ
Sedative-hypnotic
S. K. Kashaw (&) ꢀ V. Kashaw ꢀ P. Mishra ꢀ N. K. Jain
Pharmaceutical Chemistry Division, Department of
Pharmaceutical Sciences, Dr. H.S. Gour University, Sagar, India
e-mail: sushilkashaw@gmail.com
J. P. Stables
Preclinical Pharmacology Section, Epilepsy Branch, National
Institutes of Health, Bethesda, MD 20892-9020, USA
123

Med Chem Res (2011) 20:738–745
739
of the synthesized compounds by MES and subcutaneous
pentylenetetrazole (scPTZ) methods; (iii) the third objective
was the sedative-hypnotic, CNS depressant, and pheno-
barbitone induced hypnosis potentiation screening of the
synthesized compounds. In hope of getting synergistic
response of 4(3H)-quinazolinone nucleus itself, placement
of substitution semicarbazides at third position and chemi-
cally modifying second position of 4(3H)-quinazolinone
(substituting –CH3), this article reports on the synthesis,
anticonvulsant, neurotoxicity, CNS depressant, and behav-
ioral study of twelve 1-(4-substituted-phenyl)-3-(4-oxo-2-
methyl-4H-quinazolin-3-yl)-urea.
depicted spectrum at (C-2) 163, (C-4) 166, (C-11) 112, and
(Cz) 146. Thin layer chromatography (TLC) was run
throughout the reaction to optimize the reaction for purity
and completion.
Results and discussion
Initial anticonvulsant activity and neurotoxicity data for the
quinazolinone analogs are reported in Table 1, along with
the literature data on Phenytoin, Carbamazapine, Sodium
valproate, Phenobarbital, and Ethosuximide. All the qui-
nazolinone analogs showed potent sedative-hypnotic and
CNS-depressant activity than anticonvulsant activity. In the
prepared series M3, M4, and M10 were found to be active in
the MES screen at 0.5 h, whereas M10 showed anticon-
vulsant activity at 4 h. All the compounds exhibited activity
at 300 mg/kg body weight. Except M3, M4, and M10, all
the remaining compounds were inactive in the scPTZ screen
at 0.5 h. Only M10 observed activity at both 0.5 and 4 h
interval time which indicate their rapid action and long
duration of activity. Synthesized compounds exhibited NT
at only 300 mg/kg. M3 and M12 showed extend NT lasting
up to 4 h. The NT of the compounds as indicated by their
unableness to grasp the rotating rot for sufficient time may
be due to the increase BBB penetration and accumulation at
neuroprotein sites and then binding to unwanted receptor
sites. All the compounds were also screened for behavior
study and CNS-depressant activity. In the behavioral study
using actophotometer scoring technique, the entire synthe-
sized compounds showed decrease in locomotor activity
where 42% was the lowest and 53% was the maximal
decrease in locomotor activity when compared to phenytoin
as reported in Table 2. All the compounds except M11
showed more than 44% decrease in locomotor activity
(P \ 0.05) after 1 h of compound administration. In a
Chemistry
The synthesis of the target compounds was accomplished
as shown in Fig. 1. Synthesis of 2-methyl benzoxazin-4-
one is based on the earlier reported methods (Mishra et al.,
2006; Smith et al., 1996). Anthranilic acid (4) was refluxed
under standard conditions with acetic anhydride to yield
2-methyl benzoxazin-4-one. Various substituted aryl
semicarbazides were synthesized according to the proce-
dure mentioned in the literature. Substituted aniline (1) was
treated with sodium cyanate in the presence of glacial
acetic acid according to the known urea method to yield
substituted phenyl urea (2). These substituted phenyl urea
derivatives on condensation with hydrazine hydrate in
ethanol under alkaline conditions provided substituted aryl
semicarbazides (3). Synthesis of the target compounds was
carried out according to the scheme presented in Fig. 1.
Different substituted semicarbazides were refluxed in the
presence of glacial acetic acid with 2-methyl benzoxazin-4-
one to yield M1–M12, respectively. The infrared (IR)
spectra showed the C=O str. at 1670 cm-1, C=N stretching
of quinazolinone ring at 1590 cm-1. The 13C NMR
Fig. 1 Scheme for the synthesis
NH2NH2.H2O
NaCNO
NHCONHNH2
R1
of substituted phenyl
semicarbazides (3a–3L),
2-methyl benzoxazin-4-one (6),
and 1-(4-substituted-phenyl)-
3-(2-methyl-4-oxo-4H-
quinazolin-3-yl)-urea
(M1–M12)
NH2
R1
NHCONH2
NaOH
R1
,Reflux
Glacial acetic acid
(1a-1L)
(3a-3L)
(2a-2L)
O
COOH
COOH
O
Ac2O
(CH3CO)2O
Reflux
N
CH3
NHCOCH3
NH2
(4)
O
(5)
2-Methylbenzoxazone
(6)
O
O
N
N
H
N
R1
CH3COOH
Reflux
O
H
NHCONHNH2
R1
+
N
CH3
(M1 - M12)
N
CH3
(3a-3L)
(6)
123

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Med Chem Res (2011) 20:738–745
similar study with forced swim pool test, the immobility
time after administration of the test compounds was com-
pared with carbamazepine (Table 3). Readings of control
groups were taken individually for each compound 24 h
prior to compound administration. Experimental results
indicate that our compound exhibited better sedative hyp-
notic and CNS-depressant activity as compare to anticon-
vulsant activity. Biological activity was also ascertained for
PEG because it was used as a vehicle for the synthesized
compounds. Except for M6 and M11 other tested com-
pounds were found to exhibit potent CNS-depressants
activity as indicated by increased immobility time. Bulkier
compounds are more lipophilic and can cross blood brain
barrier to exert their effect at CNS. 2-Methyl substituted
compounds (M1–M12) possessed better CNS activity as
compared to unsubstituted compounds (H1–H12). Among
M7–M9 para phenyl substituted compounds showed better
activity may be due to proper spatial orientation of –CH3
toward receptor site. This study explored that substitution of
aryl semicarbazides at third position and –CH3 moiety at
second position of 4(3H)-quinazolinone leads to the
development of NCE with potent CNS activity.
Table 1 Anticonvulsant activity and minimal motor impairment of
1-(4-substituted-phenyl)-3-(4-oxo-2-methyl-4H-quinazolin-3-yl)-urea
(M1–M12)
Code no.
Intraperitoneal injection in micea
MES screen scPTZ screen Neurotoxicity screen
0.5 h 4 h 0.5 h 4 h 0.5 h
4 h
M1
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
300
–
–
M2
–
300
–
M3
300
300
–
300
300
–
300
300
–
M4
M5
–
M6
–
–
–
–
M7
–
–
–
–
M8
–
–
–
–
M9
–
–
–
–
M10
300
–
300 300
–
–
M11
–
–
–
–
–
–
–
M12
–
300
100
300
100
300
–
Phenytoin
Carbamazepine
Sodium valproate
Phenobarbitals
Ethosuximide
a
30
30
–
30
100 100
300 100
–
30
–
300
30
–
–
100
–
300 100
300
–
300
–
–
Conclusion
Doses of 30, 100, and 300 mg/kg were administered. The figure in
the table indicates the minimum dose whereby bioactivity was dem-
onstrated in half or more of the mice. The animals were examined 0.5
and 4 h after injections. – indicates an absence of activity at maxi-
mum dose administered (300 mg/kg)
Based upon the experimental results it may be concluded
that the synthesized NCE showed potent sedative-hypnotic
Table 2 Behavioral study of 1-(4-substituted-phenyl)-3-(4-oxo-2-methyl-4H-quinazolin-3-yl)-urea (M1–M12)
Compounda
Activity scoreb
% Inhibition
Control (24 h prior)
Post-treatment
0.5 h after
1 h after
M1
484.32 0.72
485.56 0.32
324.76 0.84
515.54 0.82
476.62 1.26
416.50 0.65
530.54 0.82
400.62 0.98
520.71 1.21
480.62 1.26
490.67 0.78
495.56 0.32
646.40 31.12
289.19 0.77
322.56 1.29
312.32 0.82
298.73 0.48
273.55 0.99
391.76 1.29
298.73 0.48
282.13 0.76
326.28 2.20
273.55 0.99
342.82 1.14
322.56 1.29
251.02 12.32
242.24 0.18
262.36 0.82
120.45 0.86
251.10 0.19
220.30 1.20
209.48 1.36
266.10 0.19
187.78 0.99
249.41 0.28
223.30 1.20
285.42 1.24
272.36 0.82
194.10 30.11
50
45
48
51
53
40
51
51
52
53
42
45
70
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
Phenytoinc
a
The compounds were tested at a dose of 100 mg/kg (i.p.)
b
Each score represents the mean SEM of six mice, significantly different from the control score at\0.02 and NS indicate not significant at
P [ 0.02 (student’s t-test)
c
Tested at 25 mg/kg i.p
123

Med Chem Res (2011) 20:738–745
741
100 ml with water. To this sodium cyanate (6.5 g,
0.1 mol), 50 ml of warm water was added with constant
stirring. Solution was allowed to stand for 60 min than
cooled in ice and filtered with suction and dried. Physico-
chemical data and m.p. of the synthesized products was in
agreement with the data reported in the literature.
Table 3 CNS study on 1-(4-substituted-phenyl)-3-(4-oxo-2-methyl-
4H-quinazolin-3-yl)-urea (M1–M12)
Compounda
Immobility timeb(s)
Control (24 h prior) Post-treatment (60 min after)
PEG
M1
174.67 10.72
73.32 18.50
120.47 17.12
130.58 18.36
45.60 19.45
130.73 15.15
176.87 17.78
180.97 14.15
172.47 17.95
174.57 13.15
162.67 17.58
177.77 18.49
152.87 8.37
178 .53 14.23 NS
130.56 11.25
188.16 12.67
204.70 12.59
70.63 14.63
Synthesis of substituted phenyl semicarbazides (3a–3L)
M2
M3
Equimolar quantity of substituted phenyl urea (0.1 mol)
and hydrazine hydrate (0.1 mol; 5 ml) in ethanol under
alkaline condition (NaOH, 4 g) were refluxed for 4–10 h
with stirring. Excess ethanol was distilled off under vac-
cum and then poured into ice. The product was filtered and
recrystallized from 90% aqueous ethanol. In general,
compounds exhibited IR (KBr) mmax 3450, 1650, 3269,
840 cm-1. 1H NMR d 7.2–7.5 (m, 4H, Ar–H), 8.26 (s, 1H,
Ar–NH).
M4
M5
194.05 13.16
190.29 12.84 NS
226.29 16.76
218.29 20.27
210.29 19.28
208.29 20.99
202.29 12.95 NS
198.29 15.97
240.30 14.18
M6
M7
M8
M9
M10
M11
M12
Carbamazepinec 138.12 15.03
Synthesis of 2-methyl benzoxazin-4-one (7)
a
The compounds were tested at a dose of 100 mg/kg (i.p.)
b
Each value represent the mean – SEM of six rats significantly
Anthranilic acid (4) (0.1 mol) was refluxed with acetic
anhydride for 2 h to get N-acetyl anthranilic acid (6),
which was cyclized under reflux with acetic anhydride.
Excess of acetic anhydride was distilled off under vaccum
and recrystallized with petroleum ether to get 2-methyl-
benzoxazone (7). Physico-chemical data and m.p. of the 6
and 7 was in agreement with the data reported in the
literature.
different from the control at P \ 0.05 and NS denotes not significant
at P \ 0.05 (student’s t-test)
c
Tested at 30 mg/kg (i.p.)
and CNS-depressant activity as compared to anticonvulsant
activity.
Experimental
Synthesis of title compounds (M1–M12)
Chemistry
The title compounds were synthesized following procedure
reported earlier. To a solution of 6 (0.01 M), substituted
phenyl semicarbazides (3a–3L; 0.01 M) in glacial acetic
acid was added and refluxed for 4 h. Obtained reaction
mixture was poured into crushed ice and left overnight.
The solid which separated out was filtered, washed thor-
oughly with cold distilled water, dried, and recrystallized
from hot ethanol. The yield, melting point, and other
physical properties of synthesized compound are recorded
in Table 4.
Melting point was determined in one end open capillary
tubes on a Buchi 530 melting point apparatus and is
uncorrected. IR spectra were recorded for the compounds
on Perkin Elmer Spectrum RXI Spectrophotometer in KBr.
13C nuclear magnetic resonance (13C NMR) and 1H nuclear
magnetic resonance (1H NMR) spectra were recorded for
the compounds on Advance bruker (300 MHz) instrument.
Chemical shifts are reported in parts per million using
tetramethylsilane as an internal standard. Elemental anal-
ysis (C & N) was undertaken with Elemental vario EL III
Carlo Erba 1108 analyzer. The purity of the compounds
was confirmed by TLC using silica gel glass plates and a
solvent system of benzene: ethanol (9:1). The spots were
developed in iodine chamber and visualized under ultra
violet lamp.
M1
IR (cm-1) 1680 (C=O str. of (3H)-quinazolinone
ring), 1696 (C=O str. of phenyl urea), 1573 (C=N),
3048 (Ar–CH str.), 3420 (secondary amide NH str.):
13C NMR (300 MHz, d) 13C NMR (300 MHz, d) 166
(C-4), 164 (C-2), 122.1 (C8 of 4(3H)-quinazolinone
ring), 126.9 (C10 of 4(3H)-quinazolinone ring),
127.1 (C6 of 4(3H)-quinazolinone ring), 147.8 (C9
of 4(3H)-quinazolinone ring), 14.0 (Ca), 124.3 (C04 of
Synthesis of substituted phenyl urea (2a–2L)
1
p-Substituted aniline (1a–1L; 0.1 mol) was dissolved in
10–50 ml of glacial acetic acid and volume was made up to
phenyl urea), 154 (CZ of phenyl urea): H NMR
(300 MHz, d) 7.3–7.8 (m, 4H, Ar–H of (3H)-
123

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Med Chem Res (2011) 20:738–745
Table 4 Physical data of 1-(4-substituted-phenyl)-3-(4-oxo-2-methyl-4H-quinazolin-3-yl)-urea (M1–M12)
O
O
R1
3'
2'
6'
Z
5
8
4
3
N
1'
4'
6
7
N
H
N
H
9
10
5'
2
CH3
N
a
1
Code no.
M1
R1
–H
Yield (%)
66
m.p. (°C)
Mol. formula
C16H14N4O2
Rf
Elementb (found % calculated %)
210
7.1
N (19.04/19.01)
C (65.30/65.28)
N (17.94/17.92)
C (61.53/61.50)
N (17.04/17.02)
C (58.45/58.43)
N (15.01/15.0)
C (51.49/51.46)
N (13.33/13.30)
C (45.73/45.71)
N (20.64/20.63)
C (56.64/56.62)
N (18.17/18.15)
C (66.22/66.20)
N (18.17/18.15)
C (66.22/66.20)
N (18.17/18.15)
C (66.22/66.20)
N (17.38/17.37)
C (67.07/67.03)
N (17.27/17.25)
C (62.95/62.93)
N (16.56/16.54)
C (63.89/63.88)
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
a
–F
63
69
57
50
49
59
62
71
64
68
58
275
242
C
16H13FN4O2
16H13ClN4O2
7.3
5.2
5.5
5.0
5.3
6.5
6.0
5.7
6.1
5.6
6.3
–Cl
C
–Br
[300a
250
C16H13BrN4O2
–I
C16H13IN4O2
–NO2
234
C16H13N5O4
C17H16N4O2
C17H16N4O2
C17H16N4O2
C18H18N4O2
C17H16N4O3
C18H18N4O3
o-CH3(b)
m-CH3(b)
p-CH3(b)
–CH2(b)–CH3(c)
–OCH3(b)
–OCH2(b)–CH3(c)
262
270
278
229
248
[300a
Melting point of the compound at their decomposition
b
Elemental analyses for C and N were within 0.4% of the theoretical value
quinazolinone ring), 7.1–7.64 (m, 5H, Ar–H of
phenyl urea), 2.34 (s, 3H, –CH3), 6.1 (s, 2H of –NH–
CO–NH–).
M3
IR (cm-1) 1690 (C=O str. of (3H)-quinazolinone
ring), 1696 (C=O str. of phenyl urea), 1570 (C=N),
3045 (Ar–CH str.), 3420 (secondary amide NH
str.): 13C NMR (300 MHz, d) 166 (C-4), 163 (C-2),
123 (C8 of 4(3H)-quinazolinone ring), 127 (C10 of
4(3H)-quinazolinone ring), 128.2 (C6 of 4(3H)-
quinazolinone ring), 14.0 (Ca), 148.3 (C9 of 4(3H)-
quinazolinone ring), 156 (CZ of phenyl urea), 129.4
ðC04Þ: 1H NMR (300 MHz, d) 7.4–7.9 (m, 4H, Ar–H
of (3H)-quinazolinone ring), 7.15–7.52 (m, 4H, Ar–
H of phenyl urea), 6.2 (s, 2H of –NH–CO–NH–).
IR (cm-1) 1685 (C=O str. of (3H)-quinazolinone
ring), 1692 (C=O str. of phenyl urea), 1588 (C=N),
3040 (Ar–CH str.), 3426 (secondary amide NH
M2
IR (cm-1) 1682 (C=O str. of (3H)-quinazolinone
ring), 1695 (C=O str. of phenyl urea), 1585 (C=N),
3045 (Ar–CH str.), 3423 (secondary amide NH
str.): 13C NMR (300 MHz, d) 165 (C-4), 162 (C-2),
122 (C8 of 4(3H)-quinazolinone ring), 126 (C10 of
4(3H)-quinazolinone ring), 127.2 (C6 of 4(3H)-
quinazolinone ring), 14.0 (Ca), 147.3 (C9 of 4(3H)-
quinazolinone ring), 155 (CZ of phenyl urea), 157.7
ðC04Þ: 1H NMR (300 MHz, d) 7.3–7.8 (m, 4H, Ar–H
of (3H)-quinazolinone ring), 6.94–7.61 (m, 4H, Ar–
H of phenyl urea), 6.0 (s, 2H of –NH–CO–NH–).
M4
123

Med Chem Res (2011) 20:738–745
743
str.): 13C NMR (300 MHz, d) 165 (C-4), 164 (C-2),
121.1 (C8 of 4(3H)-quinazolinone ring), 125.9 (C10
of 4(3H)-quinazolinone ring), 126.1 (C6 of 4(3H)-
quinazolinone ring), 14.0 (Ca), 146.8 (C9 of 4(3H)-
quinazolinone ring), 154 (CZ of phenyl urea): 118.4
ðC04Þ: 1H NMR (300 MHz, d) 7.4–7.9 (m, 4H, Ar–H
of (3H)-quinazolinone ring), 7.41–7.52 (m, 4H, Ar–
H of phenyl urea), 6.0 (s, 2H of –NH–CO–NH–).
(300 MHz, d) 7.1–7.6 (m, 4H, Ar–H of (3H)-
quinazolinone ring), 6.84–7.50 (m, 4H, Ar–H of
phenyl urea), 2.34 (s, 3H, –CH3), 6.1 (s, 2H of
–NH–CO–NH–).
M9
IR (cm-1) 1678 (C=O str. of (3H)-quinazolinone
ring), 1694 (C=O str. of phenyl urea), 1563 (C=N),
3041 (Ar–CH str.), 3420 (secondary amide NH
str.), 2970 (C–H str): 13C NMR (300 MHz, d) 165
(C-4), 164 (C-2), 121.1 (C8 of 4(3H)-quinazolinone
ring), 14.0 (Ca), 125.9 (C10 of 4(3H)-quinazolinone
ring), 126.1 (C6 of 4(3H)-quinazolinone ring),
146.8 (C9 of 4(3H)-quinazolinone ring), 154 (CZ
of phenyl urea): 133 ðC04Þ; 11.8 (Cb): 1H NMR
(300 MHz, d) 7.0–7.6 (m, 4H, Ar–H of (3H)-
quinazolinone ring), 6.88–7.52 (m, 4H, Ar–H
of phenyl urea), 2.35 (s, 3H, –CH3), 6.0 (s, 2H of
–NH–CO–NH–).
M5
M6
M7
IR (cm-1) 1679 (C=O str. of (3H)-quinazolinone
ring), 1690 (C=O str. of phenyl urea), 1571 (C=N),
3044 (Ar–CH str.), 3431 (secondary amide NH
str.): 13C NMR (300 MHz, d) 165 (C-4), 164 (C-2),
121.1 (C8 of 4(3H)-quinazolinone ring), 125.9 (C10
of 4(3H)-quinazolinone ring), 126.1 (C6 of 4(3H)-
quinazolinone ring), 14.0 (Ca), 146.8 (C9 of 4(3H)-
quinazolinone ring), 154 (CZ of phenyl urea): 92.9
ðC04Þ: 1H NMR (300 MHz, d) 7.4–7.7 (m, 4H, Ar–H
of (3H)-quinazolinone ring), 7.12–7.40 (m, 4H, Ar–
H of phenyl urea), 6.3 (s, 2H of –NH–CO–NH–).
IR (cm-1) 1680 (C=O str. of (3H)-quinazolinone
ring), 1690 (C=O str. of phenyl urea), 1590 (C=N),
3048 (Ar–CH str.), 3421 (secondary amide NH
str.): 13C NMR (300 MHz, d) 165 (C-4), 164 (C-2),
121.1 (C8 of 4(3H)-quinazolinone ring), 14.0 (Ca),
125.9 (C10 of 4(3H)-quinazolinone ring), 126.1 (C6
of 4(3H)-quinazolinone ring), 146.8 (C9 of 4(3H)-
quinazolinone ring), 154 (CZ of phenyl urea): 114
ðC04Þ: 1H NMR (300 MHz, d) 7.2–7.8 (m, 4H, Ar–H
of (3H)-quinazolinone ring), 7.92–8.14 (m, 4H, Ar–
H of phenyl urea), 6.0 (s, 2H of –NH–CO–NH–).
IR (cm-1) 1670 (C=O str. of (3H)-quinazolinone
ring), 1690 (C=O str. of phenyl urea), 1576 (C=N),
3041 (Ar–CH str.), 3430 (secondary amide NH
str.), 2971 (C–H str): 13C NMR (300 MHz, d) 165
(C-4), 164 (C-2), 121.1 (C8 of 4(3H)-quinazolinone
ring), 14.0 (Ca), 125.9 (C10 of 4(3H)-quinazolinone
ring), 126.1 (C6 of 4(3H)-quinazolinone ring),
146.8 (C9 of 4(3H)-quinazolinone ring), 154 (CZ
M10 IR (cm-1) 1692 (C=O str. of (3H)-quinazolinone
ring), 1698 (C=O str. of phenyl urea), 1595 (C=N),
3041 (Ar–CH str.), 3422 (secondary amide NH
str.), 2970 (C–H str): 13C NMR (300 MHz, d) 165
(C-4), 164 (C-2), 121.1 (C8 of 4(3H)-quinazolinone
ring), 14.0 (Ca), 125.9 (C10 of 4(3H)-quinazolinone
ring), 126.1 (C6 of 4(3H)-quinazolinone ring),
146.8 (C9 of 4(3H)-quinazolinone ring), 154 (CZ
1
of phenyl urea): 133 ðC04Þ; 28.8 (Cb), 16.1 (Cc): H
NMR (300 MHz, d) 7.4–7.9 (m, 4H, Ar–H of (3H)-
quinazolinone ring), 6.88–7.52 (m, 4H, Ar–H of
phenyl urea), 1.24–2.59 (m, 5H, –CH2CH3), 6.0 (s,
2H of –NH–CO–NH–).
M11 IR (cm-1) 1680 (C=O str. of (3H)-quinazolinone
ring), 1692 (C=O str. of phenyl urea), 1580 (C=N),
3042 (Ar–CH str.), 3423 (secondary amide NH str.),
2970 (C–H str): 13C NMR (300 MHz, d) 165 (C-4),
164 (C-2), 121.15 (C8 of 4(3H)-quinazolinone ring),
14.0 (Ca), 125.9 (C10 of 4(3H)-quinazolinone ring),
126.1 (C6 of 4(3H)-quinazolinone ring), 146.8 (C9 of
4(3H)-quinazolinone ring), 154 (CZ of phenyl urea):
157 ðC04Þ; 28.6 (Cb): 1H NMR (300 MHz, d) 7.4–7.9
(m, 4H, Ar–H of (3H)-quinazolinone ring), 6.74–
7.53 (m, 4H, Ar–H of phenyl urea), 3.73 (s, 3H,
–CH3), 6.0 (s, 2H of –NH–CO–NH–).
1
of phenyl urea): 129.6 ðC02Þ; 11.8 (Cb): H NMR
(300 MHz, d) 7.4–7.9 (m, 4H, Ar–H of (3H)-
quinazolinone ring), 6.88–7.52 (m, 4H, Ar–H of
phenyl urea), 2.35 (s, 3H, –CH3), 6.0 (s, 2H of
–NH–CO–NH–).
M12 IR (cm-1) 1689 (C=O str. of (3H)-quinazolinone
ring), 1695 (C=O str. of phenyl urea), 1580 (C=N),
3045 (Ar–CH str.), 3420 (secondary amide NH
str.), 2970 (C–H str): 13C NMR (300 MHz, d) 165
(C-4), 164 (C-2), 121.1 (C8 of 4(3H)-quinazolinone
ring), 14.0 (Ca), 125.9 (C10 of 4(3H)-quinazolinone
ring), 126.1 (C6 of 4(3H)-quinazolinone ring),
146.8 (C9 of 4(3H)-quinazolinone ring), 154 (CZ
M8
IR (cm-1) 1670 (C=O str. of (3H)-quinazolinone
ring), 1698 (C=O str. of phenyl urea), 1570 (C=N),
3041 (Ar–CH str.), 3430 (secondary amide NH
str.), 2970 (C–H str): 13C NMR (300 MHz, d) 165
(C-4), 164 (C-2), 121.1 (C8 of 4(3H)-quinazolinone
ring), 14.0 (Ca), 125.9 (C10 of 4(3H)-quinazolinone
ring), 126.1 (C6 of 4(3H)-quinazolinone ring),
146.8 (C9 of 4(3H)-quinazolinone ring), 154 (CZ
1
of phenyl urea): 157 ðC02Þ; 65.1 (Cb), 14.1 (Cc): H
1
of phenyl urea): 124.6 ðC03Þ; 11.8 (Cb): H NMR
NMR (300 MHz, d) 7.4–7.9 (m, 4H, Ar–H of (3H)-
123

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Med Chem Res (2011) 20:738–745
chamber (diameter 45 cm, height 20 cm) containing water
up to a height of 15 cm at 25 2°C. Two swim sessions
were conducted an initial 15 min pre test, followed by a
5-min test session 24 h later. The animals were drug
administrated (100 mg/kg) the test compound i.p. 30 min
before the test session. The period of immobility (passive
floating without struggling, making only those movements
which are necessary to keep its head above the surface of
water) during the 5 min test period was measured. The
results are presented in Table 3.
quinazolinone ring), 6.75–7.53 (m, 4H, Ar–H of
phenyl urea), 1.33–3.98 (m, 5H, –CH2CH3), 6.0 (s,
2H of –NH–CO–NH–).
Pharmacology
The new derivatives obtained from the reaction sequence
were injected intraperitoneally into mice and evaluated in
the MES, scPTZ, and neurotoxicity screens, using doses
of 30, 100, and 300 mg/kg at two different time inter-
vals. These data are presented in Table 1. These com-
pounds were also screened for their CNS behavioral
activity in mice using actophotometer, CNS-depressant
activity with the help of the forced swim method. The
data of the pharmacological studies are reported in
Tables 1–3.
Acknowledgment The authors acknowledge the assistance of
the Antiepileptic Drug Development Program, Epilepsy Branch,
Preclinical Pharmacology Section, NIH, USA.
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