Synthesis and anticonvulsant activity evaluation of 2-Phenyl-2H-benzo[e][1, 3]oxazin-4(3H)-ones

Article abstract of DOI:10.14233/ajchem.2014.15725

A series of new 2-phenyl-2H-benzo[e][1,3]oxazin-4(3H)-one derivatives (1a-1t) were designed based on the known anticonvulsant activity of quinolinone derivatives. All target compounds 1a-1t, characterized by IR, ¹H NMR and MS, have been evaluated for their anticonvulsant activity against MES-induced seizures. The pharmacological results showed that all the compounds displayed some degree of anticonvulsant activity. Among them, 2-phenyl-2,3-dihydrobenzo[e][1,3]oxazin-4-one (1a) and 2-(2-fluorophenyl)-2,3- dihydrobenzo-[e][1,3]oxazin-4- one (1b) were considerd more promising because of their lower ED₅₀ (34.1 and 28.4 mg/kg) and higher protective index (11.1 and 8.0).

Full text of DOI:10.14233/ajchem.2014.15725

Asian Journal of Chemistry; Vol. 26, No. 9 (2014), 2553-2556
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.15725
Synthesis and Anticonvulsant Activity Evaluation of 2-Phenyl-2H-benzo[e][1,3]oxazin-4(3H)-ones
1
2
2,*
LI-JING CUI , JUN GUO , GUO-HUA GONG3,* and ZHE-SHAN QUAN
1Department of Pharmacy, Guangdong Food and Drug Vocational College, Guangzhou 510520, P.R. China
2College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, P.R. China
3Institute of Medicinal Chemistry, Inner Mongolia University for Nationalities, Tongliao 028002, Inner Mongolia Autonomous Region, P.R. China
*Corresponding authors: Fax: +86 433 2436020; E-mail: gongguohua0211@163.com; zsquan@ybu.edu.cn
Received: 3 May 2013;
Accepted: 28 August 2013;
Published online: 28 April 2014;
AJC-15067
A series of new 2-phenyl-2H-benzo[e][1,3]oxazin-4(3H)-one derivatives (1a-1t) were designed based on the known anticonvulsant activity
of quinolinone derivatives.All target compounds 1a-1t, characterized by IR, 1H NMR and MS, have been evaluated for their anticonvulsant
activity against MES-induced seizures. The pharmacological results showed that all the compounds displayed some degree of anticonvulsant
activity. Among them, 2-phenyl-2,3-dihydrobenzo[e][1,3]oxazin-4-one (1a) and 2-(2-fluorophenyl)-2,3-dihydrobenzo-[e][1,3]oxazin-4-
one (1b) were considerd more promising because of their lower ED50 (34.1 and 28.4 mg/kg) and higher protective index (11.1 and 8.0).
Keywords: Anticonvulsant, 1-Isoquinolinone, Benzo[e][1,3]oxazin-4(3H)-one, Maximal electroshock test, Neurotoxicity.
The structures of all the target compounds were charac-
terized using IR, 1H NMR, MS and elemental analysis tech-
niques. Their anticonvulsant activities was all evaluated by
MES test in mice and their neurotoxicity was evaluated with
the rotarod test.
INTRODUCTION
Epilepsy, one of the most frequent neurological afflictions
in men characterized by excessive temporary neuronal discharges
resulting in uncontrolled convulsion, inflicts more than 60
million people worldwide1, 2. Despite the development of
several new anticonvulsants, the treatment of epilepsy remains
still inadequate. It is roughly estimated that up to 28-30 % of
patients are poorly treated with the available antiepileptic drugs
EXPERIMENTAL
Melting points were determined in open capillary tubes
and were uncorrected. IR spectra were recorded (in KBr) on
IRPrestige-21. 1H NMR spectra were measured on an AV-300
(Bruker, Switzerland) and all chemical shifts were given in
ppm relative to tetramethysilane. Mass spectra were measured
on an HP1100LC (Agilent Technologies, USA). The ionization
technique used for recording mass spectra was Atmospheric
Pressure Chemical Ionization (APCI). Elemental analyses were
performed on a 204Q CHN (Perkin-Elmer, USA). The
chemicals were purchased fromAldrich Chemical Corporation.
General procedure for the synthesis of 2-phenyl-2,3-
dihydrobenzo[e][1,3]oxazin-4-ones: To a round bottomed
flask containing 50 mL of toluene, 2-hydroxybenzamide 1.37 g
(0.01 mol) and substituted benzaldehyde (0.015 mol) were
added followed by the catalytic amount of piperidine. The
mixture was stirred for 22 h at 110 °C. After removing the
solvent under reduced pressure, the residue was added 30 mL
methanol and stirred to precipitation. The resulting precipitate
was filtrated, washed with petroleum ether, then recrystallized
by ethanol to afford compounds 1a-1t (Scheme-I).
(AEDs)3,4. Moreover, many AEDs have serious side effects5-10
,
and lifelong medication may be required. Therefore, there is a
continuing demand for new anticonvulsant agents with more
selectivity and lower toxicity.
In the previous works, quinolinone derivatives were found
to be active in anti-epileptic animal models and some of them
showed better effect and lower toxicity than marketed drugs11-15
.
It is known that switch direction of the amide in quinolinone
lead to 1-isoquinolinone, which possess the same moieties to
the quinolinone. Based on the anticonvulsant profile of quino-
linone derivatives, we speculated the 1-isoquinolinone nucleus
incorporating some important elements required for anti-
convulsant profile such as hydrophobic site and electron donor
group would give some new anti-epileptic compounds. So in
this study, we conducted the design and synthesis of a series
of 1-isoquinolinone derivatives, 2-phenyl-2H-benzo[e]-[1,3]-
oxazin-4(3H)-ones, which possessing the electron donor
group-oxygen atom in first position and the hydrophobic site-
phenyl group in second position.

2554 Cui et al.
Asian J. Chem.
1691 ν(C=O). MS m/z 294.0 (M+H). Anal. calcd. (%) for
C14H9NO2Cl2: C, 57.17; H, 3.08; N, 4.76. Found: C, 57.09; H,
3.18; N, 4.66.
O
O
O
O
N
H
NH
NH2
OH
H
R
toluene
2-(3,4-Dichlorophenyl)-2,3-dihydrobenzo[e][1,3]-
oxazin-4-one (1i): Yield: 34.2 %, m.p. 199-201 °C. 1H NMR
(CDCl3, 300 MHz): δ 6.24 (s, 1H, -CH-), 6.82 (s, 1H, -NH),
7.00-7.97 (m, 7H, Ar-H). IR (KBr, νmax, cm-1): 3175 ν(N-H),
1690 ν(C=O). MS m/z 294.1 (M+H). Anal. calcd. (%) for
C14H9NO2Cl2: C, 57.17; H, 3.08; N, 4.76. Found: C, 57.05; H,
3.26; N, 4.56.
R
1a-1t
Scheme-I: Synthesis of title compounds 1a-1t
2-Phenyl-2,3-dihydrobenzo[e][1,3]oxazin-4-one (1a):
Yield: 84.5 %, m.p. 144-146 °C. 1H NMR (CDCl3, 300 MHz):
δ 6.23 (s, 1H, -NH), 6.26 (s, 1H, -CH-), 7.02-8.02 (m, 9H,
Ar-H). IR (KBr, νmax, cm-1): 3188 ν(N-H), 1669 ν(C=O). MS
m/z 226.3 (M+H). Anal. calcd. (%) for C14H11NO2 : C, 74.65;
H, 4.92; N, 6.22. Found: C, 74.61; H, 4.82; N, 6.24.
2-(2-Fluorophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-
one (1b): Yield: 20.1 %, m.p. 154-156 °C. 1H NMR (CDCl3,
300 MHz): δ 6.24 (s, 1H, -NH), 6.62 (s, 1H, -CH-), 7.02-8.02
(m, 8H, Ar-H). IR (KBr, νmax, cm-1): 3180 ν(N-H), 1690
ν(C=O). MS m/z 244.1 (M+H). Anal. calcd. (%) for
C14H10NO2F: C, 69.13; H, 4.14; N, 5.76. Found: C, 69.15; H,
4.24; N, 5.61.
2-(2,6-Dichlorophenyl)-2,3-dihydrobenzo[e][1,3]-
oxazin-4-one (1j): Yield: 35.4 %, m.p. 130-134 °C. 1H NMR
(CDCl3, 300 MHz): δ 6.05 (s, 1H, -NH), 7.02 (s, 1H, -CH-),
7.04-8.03(m, 7H, Ar-H). IR (KBr, νmax, cm-1): 3172 ν(N-H),
1693 ν(C=O). MS m/z 294.4 (M+H). Anal. calcd. (%) for
C14H9NO2Cl2: C, 57.17; H, 3.08; N, 4.76. Found: C, 57.05; H,
3.20; N, 4.69.
2-(2-Bromophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-
one (1k): Yield: 18.3 %, m.p. 170-172 °C. 1H NMR (CDCl3,
300 MHz): δ 6.22 (s, 1H, -NH), 6.64 (s, 1H, -CH-), 7.04-8.02
(m, 8H, Ar-H). IR (KBr, νmax, cm-1): 3182 ν(N-H), 1679
ν(C=O). MS m/z 304.0 (M+H). Anal. calcd. (%) for
C14H10NO2Br: C, 55.29; H, 3.31; N, 4.61. Found: C, 55.27; H,
3.13; N, 4.64.
2-(3-Fluorophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-
one (1c): Yield: 30.3 %, m.p. 136-138 °C. 1H NMR (CDCl3,
300 MHz): δ 6.25 (s, 1H, -CH-), 6.57 (s, 1H, -NH), 7.01-7.98
(m, 8H, Ar-H). IR (KBr, νmax, cm-1): 3182 ν(N-H), 1687
ν(C=O). MS m/z 244.2 (M+H). Anal. calcd. (%) for
C14H10NO2F: C, 69.13; H, 4.14; N, 5.76. Found: C, 69.15; H,
4.24; N, 5.60.
2-(3-Bromophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-
one (1l): Yield: 18.7 %, m.p. 184-186 °C. 1H NMR (CDCl3,
300 MHz): δ 6.23 (s, 1H, -CH-), 6.41 (s, 1H, -NH), 7.01-8.01
(m, 8H, Ar-H). IR (KBr, νmax, cm-1): 3181 ν(N-H), 1680
ν(C=O). MS m/z 304.1 (M+H). Anal. calcd. (%) for
C14H10NO2Br: C, 55.29; H, 3.31; N, 4.61. Found: C, 55.26; H,
3.44; N, 4.62.
2-(4-Fluorophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-
one (1d): Yield: 42.9 %, m.p. 169-172 °C. 1HNMR (CDCl3,
300 MHz): δ 6.24 (s, 1H, -CH-), 6.55 (s, 1H, -NH), 6.99-8.00
(m, 8H, Ar-H). IR (KBr, νmax, cm-1): 3179 ν(N-H), 1686
ν(C=O). MS m/z 244 (M+H).Anal. calcd. (%) for C14H10NO2F:
C, 69.13; H, 4.14; N, 7.76. Found: C, 69.15; H, 4.04; N, 7.81.
2-(2-Chlorophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-
one (1e): Yield: 17.1 %, m.p. 142-144 °C. 1H NMR (CDCl3,
300 MHz): δ 6.16 (s, 1H, -NH), 6.68 (s, 1H, -CH-), 7.04-8.03
(m, 8H, Ar-H). IR (KBr, νmax, cm-1): 3172 ν(N-H), 1691
ν(C=O). MS m/z 260.4 (M+H). Anal. calcd. (%) for
C14H10NO2Cl: C, 64.75; H, 3.88; N, 5.39. Found: C, 63.76; H,
3.77; N, 5.49.
2-(4-Bromophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-
one (1m): Yield: 24.2 %, m.p. 202-204 °C. 1H NMR (CDCl3,
300 MHz): δ 6.23 (s, 1H, -CH-), 6.56 (s, 1H, -NH), 6.99-7.98
(m, 8H, Ar-H). IR (KBr, νmax, cm-1): 3187 ν(N-H), 1674
ν(C=O). MS m/z 304.1 (M+H). Anal. calcd. (%) for
C14H10NO2Br: C, 55.29; H, 3.31; N, 4.61. Found: C, 55.27; H,
3.13; N, 4.63.
2-(2-(Trifluoromethyl)phenyl)-2,3-dihydrobenzo-
[e][1,3]oxazin-4-one (1n): Yield: 33.1 %, m.p. 158-161 °C.
1H NMR (CDCl3, 300 MHz): δ 6.23 (s, 1H, -NH), 6.67 (s, 1H,
-CH-), 7.01-8.14 (m, 8H, Ar-H). IR (KBr, νmax, cm-1): 3190
ν(N-H), 1667 ν(C=O). MS m/z 294.3 (M+H). Anal. calcd.
(%) for C15H10NO2F3: C, 61.44; H, 3.44; N, 4.78. Found: C,
61.46; H, 3.66; N, 4.74.
2-(3-Chlorophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-
one (1f): Yield: 31.3 %, m.p. 156-158 °C. 1H NMR (CDCl3,
300 MHz): δ 6.24 (s, 1H, -CH-), 6.67 (s, 1H, -NH), 7.01-7.99
(m, 8H, Ar-H). IR (KBr, νmax, cm-1): 3175 ν(N-H), 1690
ν(C=O). MS m/z 260.1 (M+H). Anal. calcd. (%) for
C14H10NO2Cl: C, 64.75; H, 3.88; N, 5.39. Found: C, 64.74; H,
3.68; N, 5.39.
2-(4-(Trifluoromethyl)phenyl)-2,3-dihydrobenzo-
[e][1,3]oxazin-4-one (1o): Yield: 30.6 %, m.p. 212-215 °C.
1H NMR (CDCl3, 300 MHz): δ 6.35 (s, 1H, -CH-), 6.67 (s,
1H, -NH), 7.01-7.99 (m, 8H,Ar-H). IR (KBr, νmax, cm-1): 3191
ν(N-H), 1662 ν(C=O). MS m/z 294.6 (M+H). Anal. calcd.
(%) for C15H10NO2F3: C, 61.44; H, 3.44; N, 4.78. Found: C,
61.40; H, 3.58; N, 4.76.
2-(4-Chlorophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-
one (1g): Yield: 35.3 %, m.p. 198-200 °C. 1H NMR (CDCl3,
300 MHz): δ 6.23 (s, 1H, -CH-), 6.47 (s, 1H, -NH), 6.99-7.99
(m, 8H, Ar-H). IR (KBr, νmax, cm-1): 3176 ν(N-H), 1687
ν(C=O). MS m/z 260.0 (M+H). Anal. calcd. (%) for
C14H10NO2Cl: C, 64.75; H, 3.88; N, 5.39. Found: C, 64.78; H,
3.98; N, 5.26.
2-(3-Nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-
one (1p) Yield: 37.7 %, m.p. 204-206 °C. 1H NMR (CDCl3,
300 MHz): δ 6.41 (s, 1H, -CH-), 7.02-8.35 (m, 8H, Ar-H),
8.53 (s, 1H, -NH). IR (KBr, νmax, cm-1): 3197 (N-H), 1685 (C=O).
MS m/z 270.4 (M+H).Anal. calcd. (%) for C14H10N2O4: C, 62.22;
H, 3.73; N, 10.37. Found: C, 62.24; H, 3.61; N, 10.58.
2-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[e][1,3]-
oxazin-4-one (1h):Yield: 35.8 %, m.p. 180-184 °C. 1H NMR
(CDCl3, 300 MHz): δ 6.34 (s, 1H, -NH), 6.63 (s, 1H, -CH-),
7.03-8.00 (m, 7H, Ar-H). IR (KBr, νmax, cm-1): 3174 ν(N-H),

Vol. 26, No. 9 (2014)
Synthesis and Anticonvulsant Activity Evaluation of 2-Phenyl-2H-benzo[e][1,3]oxazin-4(3H)-ones 2555
2-p-Tolyl-2,3-dihydrobenzo[e][1,3]oxazin-4-one (1q):
Yield: 39.1 %, m.p. 158-162 °C. 1H NMR (CDCl3, 300 MHz):
δ 2.42 (s, 3H, -CH3), 6.16 (s, 1H, -NH), 6.21 (s, 1H, -CH-),
6.99-8.01 (m, 8H, Ar-H). IR (KBr, νmax, cm-1): 3185 ν(N-H),
1688 ν(C=O). MS m/z 240.5 (M+H). Anal. calcd. (%) for
C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.33; H,
5.55; N, 5.94.
constants. The spectra showed the amide (NH) proton as a
blunt singlet at 6.05-6.82 ppm and the methenyl group (CH)
at 6.17-7.02 ppm.
Anticonvulsant activity: The pharmacological testing of
all the target compounds were performed according to the
standard protocol given by epilepsy branch of the National
Institute of Neurological Disorders and Stroke (NINDS) and
adopted by the Antiepileptic Drug Development (ADD)
program19. Their anticonvulsant activity was assessed by the
most adopted animal model electroshock (MES) test. All the
synthesized compounds were administered intraperitoneally
into mice using doses of 30, 100 and 300 mg/kg and the
observations were taken at two different time intervals (0.5 h
and 4.0 h). Neurological impairment was evaluated by rotarod
method and the data are presented in Table-1.
2-(4-Methoxyphenyl)-2,3-dihydrobenzo[e][1,3]oxazin-
4-one (1r): Yield: 22.3 %, m.p. 179-182 °C. 1H NMR (CDCl3,
300 MHz): δ 3.87 (s, 3H, -OCH3), 6.19 (s, 1H, -CH-), 6.23 (s,
1H, -NH), 6.96-7.99 (m, 8H,Ar-H). IR (KBr, νmax, cm-1): 3187
ν(N-H), 1689 ν(C=O). MS m/z 256.3 (M+H). Anal. calcd.
(%) for C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.47;
H, 5.03; N, 5.29.
2-(3,4-Dimethoxyphenyl)-2,3-dihydrobenzo[e][1,3]-
oxazin-4-one (1s): Yield: 16.8 %, m.p. 146-150 °C. 1H NMR
(CDCl3, 300 MHz): δ 3.92-3.94 (m, 6H, -OCH3), 6.20 (s, 1H,
-CH-), 6.39 (s, 1H, -NH), 6.91-8.00 (m, 7H, Ar-H). IR (KBr,
νmax, cm-1): 3191 ν(N-H), 1689 ν(C=O). MS m/z 286.1 (M+H).
Anal. calcd. (%) for C16H15NO4: C, 67.36; H, 5.30; N, 4.91.
Found: C, 67.34; H, 5.42; N, 4.83.
TABLE-1
PHASE-I EVALUATION OF ANTICONVULSANT
ACTIVITY IN MICE (i.p.)
O
NH
2-(3,4,5-Trimethoxyphenyl)-2,3-dihydrobenzo[e][1,3]-
oxazin-4-one (1t): Yield: 32.1 %, m.p. 166-169 °C. 1H NMR
(CDCl3, 300 MHz): δ 3.88-3.90 (m, 9H, -OCH3), 6.17 (s, 1H,
-CH-), 6.54 (s, 1H, -NH), 6.83-8.00 (m, 6H, Ar-H). IR (KBr,
νmax, cm-1): 3194 ν(N-H), 1694 ν(C=O). MS m/z 316.5 (M+H).
Anal. calcd. (%) for C17H17NO5: C, 64.75; H, 5.43; N, 4.44.
Found: C, 64.70; H, 5.28; N, 4.56.
O
R
MESa (mg/kg)
0.5 h
MES(mg/kg)
4 h
Compd.
R
300 100
3/3 3/3b 2/3
30
300 100
c
30
-H
o-F
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2/3
2/3
3/3
3/3
2/3
1/3
2/3
1/3
1/3
0/3
2/3
0/3
0/3
1/3
0/3
0/3
2/3
0/3
0/3
1/3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1a
1b
1c
1d
1e
1f
Maximal electroshock test (MES): The maximal electro-
shock seizure test was carried out according to the standard
protocol16,17. KunMing mice were stimulated through corneal
electrodes to 50 mA current at a pulse of 60 Hz applied for 0.2 s.
Animals were previously administered with the test drug i.p.
Abolition of hind limb tonic extension spasm was recorded as
the anticonvulsant activity. The test compounds were dissolved
in DMSO. In the preliminary screening, each compound was
administered as an i.p. injection at three dose levels (30, 100
and 300 mg/kg) and the anticonvulsant activity assessed after
0.5 h and 4.0 h intervals of administration.
Neurotoxicity (NT) screening16,17: The neurotoxicity of
the compounds were measured in mice by the rotarod test.
The mice were trained to stay on an accelerating rotarod of
diameter 3.2 cm that rotates at 10 rpm. Trained animals were
given i.p. injection of the test compounds. Neurotoxicity was
indicated by the inability of the animal to maintain equilibrium
on the rod for at least 1 min in each of the trials.
3/3
3/3
3/3
3/3
3/3
1/3
1/3
1/3
1/3
2/3
2/3
1/3
2/3
1/3
1/3
3/3
1/3
1/3
3/3
3/3
3/3
2/3
2/3
0/3
0/3
0/3
0/3
1/3
0/3
0/3
1/3
0/3
0/3
2/3
0/3
0/3
2/3
1/3
1/3
2/3
1/3
1/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
1/3
0/3
0/3
0/3
m-F
p-F
o-Cl
m-Cl
p-Cl
1g
1h
1i
2,4-Cl
3,4-Cl
2,6-Cl
o-Br
1j
1k
1l
m-Br
p-Br
1m
1n
1o
1p
1q
1r
1s
1t
o-CF3
p-CF3
m-NO2
p-CH3
p-OCH3
3,4-(OCH3)2
3,4,5-(OCH3)3 3/3
aMaximal electroshock: doses of 30, 100 and 300 mg/kg were
administrated intraperitoneally in mice; The animals were examined
0.5 h after administration.
RESULTS AND DISCUSSION
bThe figures n1/n2: the animals protected/the animals tested.
cThe dash (-) : not tested.
In this paper, the target compounds 2-phenyl-2H-
benzo[e][1,3]oxazin-4(3H)-ones (1a-1t), were prepared
according to a reported procedure18. Briefly, they were obtained
by cyclization of 2-hydrozybenzamide and substituted
benzaldehyde in the presence of piperidine at 110 °C in toluene.
All compounds were identified by the spectral data. In general,
IR spectra showed the C=O peak at 1694-1662 cm-1, the
NH stretching vibrations at 3197-3172 cm-1. In the nuclear
magnetic resonance spectra (1H NMR), the signals of the
respective protons of the synthesized compounds were verified
on the basis of their chemical shifts, mutiplicitiesand coupling
In the phase I preliminary anticonvulsant screening, all
the compounds showed some degree of protection in MES
screen which was the indicative of the good ability of these
compounds to prevent the seizure spread. Half of the comp-
ounds were active at a dose of 100 mg/kg after 0.5 h. These
include compounds 1a-1f, 1k, 1n, 1q and 1t. Compounds 1a-
1f and 1q showed protection from seizure at the dose 30 mg/kg
after 0.5 h. At 4 h interval, compounds 1a-1i, 1k, 1n, 1q and

2556 Cui et al.
Asian J. Chem.
1t showed activity at dose of 100 mg/kg. Compounds 1a-1f,
1k, 1n, 1q and 1t have shown activity at dose of 100 mg/kg at
0.5 h and 4 h indicating that these compounds having quick
onset and long duration of action. From these data, we can see
that compounds with non-substituted or F-substituted phenyl
group showed better activity. The effect of electron withdrawing
groups or electron releasing groups were found to be uncertain
on the anticonvulsant activity such as 1n (o-CF3), 1o (p-CF3),
1p (m-NO2), 1q (p-CH3), 1r (p-OCH3), 1s (3,4-(OCH3)2), 1t
(3,4,5-(OCH3)3).
vulsant activity in mice. Among them, 2-phenyl-2,3-dihydro-
benzo[e][1,3]oxazin-4-one (1a) and 2-(2-fluorophenyl)-2,3-
dihydrobenzo[e][1,3]oxazin-4-one (1b) were considered more
promising because of their lower ED50 (34.1 and 28.4 mg/kg)
and higher protective index (11.1 and 8.0). The obtained results
showed that certain compounds could be useful as a template
for future design, modification and investigation to produce
more active and lower toxic analogues.
ACKNOWLEDGEMENTS
On the basis of the considerable anticonvulsant promise
suggested in phase I testing, compounds 1a-1c and 1e were
subjected to phase II trials for quantification of their anticon-
vulsant activity (indicated by ED50) and neurotoxicity (indicated
by TD50) in mice. Results of the quantitative test for selected
compounds, along with the data on the standard drug carbamaze-
pine and valproate, are reported in Table-2. All the compounds
showed weaker anticonvulsant activity compared to currently
used antiepileptic drugs carbamazepine but better than
valproate. Addtion, all the tested compounds showed the safer
profile than carbamazepine and valproate with the higher
protective index. 2-Phenyl-2,3-dihydrobenzo[e][1,3]oxazin-
4-one (1a) and 2-(2-fluorophenyl)-2,3-dihydrobenzo[e][1,3]
oxazin-4-one (1b) were considerd more promising in these
compounds because of their lower ED50 (34.1 and 28.4 mg/kg)
and higher protective index (11.1 and 8.0).
This work was supported by the National Natural Science
Foundation of China (No. 81160382); Guangdong Medical
Scientific Research Subject (No. B2010056) and Guangdong
Food and DrugVocational College Courtyard Level Scientific
Research Projects (No. 2010YZ004).
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(369-450)
In conclusion, a series of new 2-phenyl-2H-benzo[e][1,3]-
oxazin-4(3H)-one derivatives were designed based on the
known anticonvulsant activity of quinolinone derivatives. All
target compounds 1a-1t displayed some degree of anticon-