Synthesis and biological evaluation of some new quinazolin-4(3H)-ones derivatives as anticonvulsants

Article abstract of DOI:10.1007/s00044-012-0293-6

Epilepsy is the most common neurological disorder known, affecting around 1 % of the world's population, characterized by recurrent seizure attack. A new series of 2-phenyl-3-(3-(substituted-benzylideneamino)-quinazolin-4(3H)-one derivatives (6a-h) was sy

Full text of DOI:10.1007/s00044-012-0293-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3282–3288
DOI 10.1007/s00044-012-0293-6
ORIGINAL RESEARCH
Synthesis and biological evaluation of some new quinazolin-4(3H)-
ones derivatives as anticonvulsants
•
Deepak Gupta Rajiv Kumar Ram Kumar Roy
•
•
•
Adish Sharma Israr Ali Md. Shamsuzzaman
•
Received: 5 December 2011 / Accepted: 20 October 2012 / Published online: 22 November 2012
Ó Springer Science+Business Media New York 2012
Abstract Epilepsy is the most common neurological
disorder known, affecting around 1 % of the world’s
population, characterized by recurrent seizure attack. A
new series of 2-phenyl-3-(3-(substituted-benzylidenea-
mino)-quinazolin-4(3H)-one derivatives (6a–h) was syn-
thesized through condensation of anthranilic acid (1) and
benzoyl chloride to give 2-phenyl-benzo[d][1,3]oxazin-
4-one (2). Compound 2 was refluxed with hydrazine hydrate
and yielded intermediate 3. Further, the intermediate 3 was
dehydrated with catalytic amount of GAA and yielded
3-amino-2-phenyl-1H-quinazolin-4-one (4). Compound 4
was further treated with 3-hydroxy benzaldehyde and small
amount of GAA to afford schiff base derivative 5. Finally,
the Schiff base was treated with various alkyl halide to
provide desired compounds 6a–h and structures of the final
compounds were confirmed on the basis of their FTIR,
NMR, and Mass spectral data. Anticonvulsant activity was
evaluated by the maximal electroshock test, further their
minimum motor impairment and CNS depressant effect
were evaluated by the rotorod motor impairment and Por-
solt’s force swim tests, respectively. The results showed that
2-phenyl-3-(3-(propoxybenzylideneamino)-3H-quinaz-
olin-4-one (6c) is the most promising compound with the
lowest side effects.
Keywords Quinazolin-4(3H)-one ꢀ Schiff base ꢀ
MES ꢀ Motor impairment ꢀ CNS depressant
Introduction
Epilepsy is a chronic and often progressive disorder char-
acterized by the periodic and unpredictable occurrence of
epileptic seizures that are caused by abnormal discharge of
cerebral neurons. Epilepsy is not a disease, but a syndrome
of different cerebral disorders of the CNS. This syndrome is
characterized by paroxysmal, excessive, and hyper syn-
chronous discharges of large numbers of neurons (Loscher,
1998) and epilepsy treatment, nearly 95 % of clinically
available drugs were approved before 1985 and they could
provide satisfactory seizure control for 60–70 % of patients.
These drugs, however, also cause notable adverse side
effects such as drowsiness, ataxia, gastrointestinal distur-
bance, hepatotoxicity, and megaloblastic anemia (Leppik,
1994; Perucca, 1996; Lin and Kadaba, 1997) and even life
threatening conditions (Al-Soud et al., 2003). Research to
find more effective and safer antiepileptic drugs are, there-
fore, imperative and challenging in medicinal chemistry.
In medicinal chemistry, quinazolin-4(3H)-one is one of
the most versatile nucleus with a wide range of biological
properties including antihypertensive (Alagarsamy and
Pathak, 2007), anti-inflammatory (Kumar et al., 2007;
Alagarsamy et al., 2008), anticonvulsant (Archana and
D. Gupta ꢀ R. Kumar ꢀ R. K. Roy ꢀ A. Sharma ꢀ I. Ali (&)
Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Dr. K. N. Modi Institute of Pharmaceutical Education
and Research, Modi Nagar, Uttar Pradesh 201204, India
e-mail: israrali004@yahoo.com
`
Kumar, 2002; Zappala et al., 2003; Jatav et al., 2008;
Kashaw et al., 2009), antimicrobial (Grover and Kini,
2006; Pandey et al., 2009), antitumor (Bavetsias et al.,
2002; Al-Rashood et al., 2006), and anti-diabetic (Malamas
and Millen, 1991) activities. Quinazolin-4(3H)-one and
their derivatives are also building block for approximately
150 naturally occurring alkaloids isolated from a number of
Md. Shamsuzzaman
Department of Pharmacology, V. P. Chest Institute,
Delhi University, New Delhi 110007, India
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Med Chem Res (2013) 22:3282–3288
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families of the plant kingdom, from microorganisms and
animals.
system. After completion of reaction it was poured into ice-
cold water to yield white solid which was filtered and
dried. The dried compound was purified by crystallization
with ethyl acetate. It gives yellow color with ninhydrin
reagent. Yield 70 %; Rf value: 0.3; m.p. 144–146 °C; IR
(KBr, cm-1): 3365 (NH), 3400 (br, OH), 1690 (C=O);
1HNMR (300 MHz, DMSO-d6) d (ppm): 4.63 (br s, 2H,
NH2, D2O exchangeable), 7.09–8.44 (m, 9H, ArH), 10.27
(br s, 1H, NH, D2O exchangeable), 12.43 (s, 1H, OH, D2O
exchangeable); MS: m/z 255.9 (M?1)?.
Schiff base derivatives are an emerging new class of
potent anticonvulsants (Sridhar et al., 2002; Verma et al.,
2004), antibacterial, antifungal, and anti-HIV (Karthikeyan
et al., 2006; Pandeya et al., 1999a, b, c) agents.
Materials and methods
Chemistry
Synthesis of 3-amino-2-phenyl-1H-quinazolin-4-one (4)
Raw materials for the synthesis were supplied by Spect-
rochem chemicals (India) and S.D. Fine Chemicals (India).
Melting points of newly synthesized compounds were
determined in open glass capillary and are uncorrected. IR
(KBr) spectra were recorded on a Nicolet 5PC FTIR
Compound 4 (0.010 mol) was dissolved in 20 mL ethanol
in dry and clean rbf with condenser and guard tube. GAA
(2 mL) was added to it at room temperature and the reac-
tion mixture was refluxed for 4 h. The progress of reaction
was monitored by aluminum coated Merck TLC plate
using 50 % ethyl-hexane solvent system. After completion
of reaction it was poured into ice-cold water to yield white
solid which was filtered and dried, it was purified by
crystallization with ethyl acetate. It gives orange color with
ninhydrine reagent. Yield: 65 %; Rf value: 0.6; m.p. 140–
145 °C; IR (KBr, cm-1): 3343 (NH), 1699 (C=O); 1HNMR
(300 MHz, CDCl3) d (ppm): 5.00 (br s, 2H, NH2, D2O
exchangeable), 7.49–8.32 (m, 9H, ArH); MS: m/z 238.2
(M?1)?.
1
spectrophotometer (k-max in cm-1) and H NMR and 13C
NMR spectra were recorded on a Brucker Model-300 NMR
Spectrometer in DMSO-d6 using tetramethylsilane (TMS)
as the internal reference (chemical shifts in d ppm).
Chemical shifts are reported in ppm downfield from TMS.
Mass spectra were recorded on Jeol SX- 102/DA-6000
spectrometer. The reaction monitoring was performed on
Silica gel-GF coated aluminum plate using iodine vapors
and UV light as visualizing agents. Evaporation of solvents
was performed at reduced pressure, using a Buchi rotary
evaporator. Solid products were purified by recrystalliza-
tion and column chromatography.
Synthesis of 3[(3-hydroxy-benzylidene)-amino]-2-
phenyl-3H-quinazolin-4-one (5)
Synthesis of 2-phenyl-benzo[d][1,3]oxazin-4-one (2)
In a clean rbf, compound (4) (0.0021 mol) and conc. HCl
(1 mL) was taken. It was stirred at room temperature for
5 min. Water (15 mL), sodium acetate (0.0021 mol), and
ethanol (15 mL) were added to the reaction mixture and
it was further stirred 10 min. 3-Hydroxy-benzaldehyde
(0.0021) was dissolved in ethanol (10 mL) and added into
the reaction mixture. The clear solution changed into tur-
bid suspension which was further stirred for 1 h. The
progress of reaction was monitored by aluminum coated
Merck TLC plate using 50 % ethyl-hexane solvent system.
The reaction mixture was poured into ice-cold water to
yield white solid which was filtered and dried. The com-
pound was recrystallized with ethanol. Yield: 70 %; Rf
value: 0.3; m.p. 160–165 °C; IR (KBr, cm-1): 3423 (OH),
Anthranilic acid (1) (0.0365 mol) was dissolved in pyridine
(15 mL) in dry and clean rbf with guard tube. Benzoyl
chloride (0.547 mol) was added slowly while maintaining
the temperature at 0–5 °C with proper stirring. The reac-
tion was further stirred at room temperature for 15 min and
it was slowly converted into semi solid paste; further it was
diluted with saturated NaHCO3 solution. The white solid
thus obtained was filtered and dried. The compound was
used in the next step without further purification, Yield:
75 %; m.p. 143–148 °C.
Synthesis of 3-amino-2-hydroxy-2-phenyl-2,3-
dihydroquinazolin-4(1H)-one (3)
1
1680 (C=O), 1630 (C=N); H NMR (300 MHz, DMSO-
Compound 2 (0.01255 mol) was dissolved in 20 mL eth-
anol in dry and clean rbf with condenser and guard tube.
Hydrazine hydrate (0.99 %) (0.015 mol) was added to it at
room temperature and the reaction mixture was refluxed for
2 h. The progress of reaction was monitored by aluminum
coated TLC plate using 100 % ethyl acetate solvent
d6): d 10.26 (s, 1H, OH, D2O exchangeable), 9.20 (s, 1H,
CH=N), 8.26–6.85 (m, 13H, ArH); 13C NMR (75 MHz,
DMSO-d6): d 168.2 (C=O), 161.2 (C–O), 158.1, 158.0
(N=C), 154.2, 146.2, 133.2, 130.9, 130.2, 128.5, 128.0,
126.9, 126.7, 126.1, 124.0, 123.0, 119.0, 120.2 115.8; MS:
m/z 342.2 (M?1)?.
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Med Chem Res (2013) 22:3282–3288
Synthesis of 3-[(3-substituted-benylidene)-amino]-2-
phenyl-quinazolin-4(3H)-one (6a–h)
C24H21N3O2: C, 75.18, H, 5.52, N, 10.96; Found: C, 75.02;
H, 5.53; N, 10.96 %.
3-(3-Hydroxybenzylideneamino)-2-phenyl-quinazolin-4(3H)-
one (5) (0.00145 mol) was dissolved in 20 mL DMF in dry
and clean rbf with condenser and guard tube. Anhydrous
K2CO3 (0.00217 mol) was added and the reaction mixture
was stirred at 0–5 °C for 15 min. Alkyl halide (0.00217 mol)
was added at same temperature and stirred at room temper-
ature for 1–3 h. The progress of reaction was monitored by
aluminum coated Merck TLC plate using 60 % ethyl-hexane
solvent system. After completion of reaction, it was poured
into ice-cold water to yield solid, which was purified and
dried. The compound was purified by recrystallization in
ethyl acetate and hexane.
3-[(3-Iso-propoxy-benzylidene)-amino]-2-phenyl-3H-qui-
nazolin-4-one (6d) Yield: 69 %; Rf value: 0.4; m.p.: 155–
157 °C. IR (KBr, cm-1): 1625 (N=C), 1680 (C=O), 1230
(C–O); 1HNMR (300 MHz, DMSO-d6) d (ppm): d 9.23 (s,
1H, CH=N), 8.27–6.94 (m, 13H, ArH), 4.70 (m, 1H, OCH),
1.30 (d, 6H, J = 6.0 Hz, 2CH3); 13C NMR (75 MHz,
DMSO-d6): d 169.5 (C=O), 163.0, 162.5 (C–O), 158.1
(N=C), 153.6, 146.2, 139.2 130.0, 129.9, 128.9, 128.6,
127.1, 126.6, 126.3, 124.1, 122.0, 121.8, 116.8, 114.0, 71.0
(OCH), 22.8 (CH3)2; MS: m/z 384 (M?1)?; Anal. Calcd
for C24H21N3O2: C, 75.18, H, 5.52, N, 10.96; Found: C,
75.00; H, 5.54; N, 10.99 %.
3-[(3-Methoxy-benzylidene)-amino]-2-phenyl-3H-quinazo-
lin-4-one (6a) Yield: 70 %; Rf value: 0.4; m.p. 145–
147 °C; IR (KBr, cm-1): 1682 (C=O), 1624 (C=N), 1235
Synthesis of 3-[3-(allyloxybenzylidene)-amino]-2-phenyl-
3H-quinazolin-4-one (6e) Yield: 60 %; Rf value: 0.4;
m.p.: 160–162 °C; IR (KBr, cm-1): 1685 (C=O), 1623
(C=N), 1245 (C–O); 1HNMR (300 MHz, DMSO-d6) d
(ppm): d 9.35 (s, 1H, CH=N), 8.41–7.01 (m, 13H, ArH),
6.04–6.13 (m, 1H, CH=), 5.32–5.48 (m, 2H, = CH2), 4.8
(q, 2H, J = 5.2 Hz, OCH2); 13C NMR (75 MHz, DMSO-
d6): d 170.0 (C=O), 162.7 (C–O), 162.8, 159.9 (N=C),
153.0, 146.6, 139.0, 135.0 (CH=), 130.3, 130.1, 128.2,
128.1, 127.3, 126.6, 126.0, 124.1, 121.8, 121.0, 119.3
(=CH2), 117.9, 114.9, 70.6 (OCH2); MS: m/z 382 (M?1)?;
Anal. Calcd for C24H19N3O2: C, 75.57, H, 5.02, N, 11.02;
Found: C, 75.53; H, 5.03; N, 11.07 %.
1
(C–O); H NMR (300 MHz, DMSO-d6): d 8.99 (s, 1H,
CH=N), 8.30–6.85 (m, 13H, ArH), 3.91 (m, 3H, OCH3);
13C NMR (75 MHz, DMSO-d6): d 169.7 (C=O), 164.7
(C–O), 163.9, 158.6 (N=C), 154.1, 146.4, 134.1, 130.1,
130.0, 128.9, 128.6, 127.1, 126.7, 126.2, 124.7, 121.4,
121.0, 117.2, 115.8, 68.1 (OCH); MS: m/z 356 (M?1)?;
Anal. Calcd for C22H17N3O2: C, 74.35, H, 4.82, N, 11.82;
Found: C, 74.34; H, 4.80; N, 11.80 %.
3-[(3-Ethoxy-benzylidene)-amino]-2-phenyl-3H-quinazo-
lin-4-one (6b) Yield: 75 %; m.p.: 150–152 °C; IR (KBr,
1
cm-1): 1682 (C=O), 1624 (C=N), 1230 (C–O); H NMR
3-(3-(But-3-enyloxy)benzylidene-amino)-2-phenyl-3H-qui-
nazolin-4-one (6f) Yield: 65 %; Rf value: 0.6; m.p.: 140–
145 °C; IR (KBr, cm-1): 1688 (C=O), 1626 (C=N), 1245
(C–O); 1HNMR (300 MHz, DMSO-d6) d (ppm): d 9.26 (s,
1H, CH=N), 8.26–6.85 (m, 13H, ArH), 5.85 (m, 1H,
CH=C), 5.01 (m, 2H, =CH2), 3.99 (t, 2H, OCH2), 2.54 (m,
2H, CH2); 13C NMR (75 MHz, DMSO-d6): d 167.4 (C=O),
162.8, 160.9 (C–O), 157.6 (N=C), 153.4, 146.9, 136.0
136.3 (CH=), 130.0, 129.9, 128.3, 128.1, 127.4, 126.3,
126.0, 124.2, 121.3, 121.0, 119.2, 118.0 (CH2), 115.0, 68.9
(OCH2), 36.3 (CH2); m/z 395 (M?1)?; Anal. Calcd for
C25H21N3O2: C, 75.93, H, 5.35, N, 10.63; Found: C, 75.99;
H, 5.37; N, 10.66 %.
(300 MHz, DMSO-d6): d 9.24 (s, 1H, CH=N), 8.25–6.94
(m, 13H, ArH), 4.15 (q, 2H, OCH2), 1.35 (t, 3H,
J = 6.6 Hz, CH3); 13C NMR (75 MHz, DMSO-d6): d
169.5 (C=O), 163.9 (C–O), 162.9, 158.2 (N=C), 153.8,
146.0, 139.8, 130.2, 130.0, 128.8, 128.6, 127.4, 126.5,
126.2, 124.0, 121.4, 121.2, 117.5, 115.3, 70.1 (OCH),
16.1(CH3); MS: m/z 370 (M?1)?; Anal. Calcd for
C23H19N3O2: C, 74.78, H, 5.18, N, 11.37; Found: C, 74.70;
H, 5.23; N, 11.42 %.
2-Phenyl-3-[(3-propoxy-benzylidene)-amino]-3H-quinazo-
lin-4-one (6c) Yield: 70 %; Rf value: 0.4; m.p.: 160–
162 °C; IR (KBr, cm-1): 1699 (C=O), 1620 (N=C), 1230
(C–O); 1HNMR (300 MHz, DMSO-d6) d (ppm): d 8.98 (s,
1H, CH=N), 8.36–6.87 (m, 13H, ArH), 3.98 (t, 2H,
J = 7.0 Hz OCH2), 1.78–1.88 (m, 2H, CH2), 1.04 (t, 3H,
J = 7.2 Hz, CH3); 13C NMR (75 MHz, DMSO-d6): d
169.4 (C=O), 163.5 (C–O), 162.0, 158.0 (N=C), 153.4,
146.2, 139.3, 130.1, 130.0, 128.9, 128.6, 127.2, 126.5,
126.3, 124.0, 121.9, 121.3, 116.9, 114.8, 70.3 (OCH), 22.0
(CH2), 11.1(CH3); MS: m/z 384 (M ? 1)?; Anal. Calcd for
3-[(3-Butoxy-benzylidene)-amino]-2-phenyl-3H-quinazo-
lin-4-one (6g) Yield: 68 %; Rf value: 0.3; m.p.: 160–
165 °C; IR (KBr, cm-1): 1643 (N=C), 1679 (C=O), 1245
1
(C–O); HNMR (300 MHz, DMSO-d6) d (ppm): 9.26 (s,
1H, N=CH); 8.26–6.97 (m, 13H, ArH), 4.09 (t, 2H,
J = 6.4 Hz, OCH2), 1.75(m, 2H, OCH2CH2), 1.47(m, 2H,
CH2CH3), 0.93 (t, 3H, J = 7.2 Hz, CH3); 13C NMR
(75 MHz, DMSO-d6): d 169.2 (C=O), 163.8 (C–O), 162.1,
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3285
158.0 (N=C), 153.5, 146.0, 139.2, 130.2, 130.0, 128.8,
128.7, 127.1, 126.4, 126.8, 124.2, 121.2, 121.0, 117.0,
114.5, 69.3 (OCH), 32.0 (CH2), 18.4 (CH2) 12.1(CH3);
MS: m/z 398 (M?1)?; Anal. Calcd for C25H23N3O2: C,
75.54, H, 5.83, N, 10.57; Found: C, 75.50; H, 5.87; N,
10.53 %.
tests based on MES convulsions, 60 Hz of alternating
current (50 mA) was delivered for 0.2 s by corneal elec-
trodes which had been primed with an electrolyte solution
containing an anesthetic agent (0.5 % tetracaine HCl).
Abolition of the hind limb tonic extensor spasm was
recorded as a measurement of anticonvulsant activity.
3-[(3-Benzyloxy-benzylidene)-amino]-2-phenyl-3H-quinaz-
olin-4-one (6h) Yield: 65 %; m.p.: 95–97 °C. IR (KBr,
Rotorod motor impairment screening
1
cm-1): 1643 (N=C), 1685 (C=O), 1246 (C–O); HNMR
Motor impairment is measured in mice by the rotorod test.
The mice are trained to stay on an accelerating rotorod that
rotates at six revolutions per minute. The rod diameter is
3.2 cm. Motor impairment was indicated by the inability of
the animal to maintain equilibrium on the rod for at least
1 min in each of the trials.
(300 MHz, DMSO-d6) d (ppm): 9.30 (s, 1H, N=CH), 8.25-
6.99 (m, 18H, ArH), 5.25 (s, 2H, OCH2); 13C NMR
(75 MHz DMSO-d6): d 168.7 (C=O), 166.7 (C–O), 163.0,
155.6 (N=C), 154.1, 146.3, 136.9, 134.1, 130.1, 130.0,
128.9, 128.6, 128.2, 127.1, 127.0, 126.9, 126.7, 126.2,
124.7, 121.4, 121.2, 116.0, 115.8, 68.9 (OCH2); MS: m/z
384 (M?1)?; Anal. Calcd for C28H21N3O2: C, 77.94, H,
4.91, N, 9.74; Found: C, 77.99; H, 4.96; N, 9.72 %.
CNS depression study
The forced swim method (Porsolt’s swim pool test) is
followed to study CNS depression (Porsolt et al., 1978).
Mice are placed in a chamber (diameter 45 cm, height:
20 cm) containing water up to a height of 15 cm at
25 2 °C. Two swim sessions are conducted, an initial
15 min pre-test, followed by a 5 min test session 24 h later.
The animals are administered an i.p. injection (30 mg/kg)
of the test compounds 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 are measured.
Pharmacology
Anticonvulsant screening
The anticonvulsant evaluations were performed using
reported procedures (Krall et al., 1978; Porter et al., 1984).
Male albino mice (CF-1 strain, 18-25 g) were used as
experimental animal. The compounds were suspended in
polyethylene glycol (PEG-400). All experimental protocols
were carried out with permission from the Institutional
Animal Ethics Committee (IAEC). Animals were obtained
from the Central Animal House Facility, DR. K. N. Modi
Institute of Pharmaceutical Education and Research,
Modinagar, Uttar Pradesh, India.
Results and discussion
Electroshock seizure method (MES)
Chemistry
Maximal seizures were induced by the application of
electrical current to the brain via corneal electrodes. For all
Compounds (5 and 6a–h) were prepared according to
Scheme 1. Synthesis of 2-phenyl-benzo[d][1,3]oxazin-4-one (2)
Scheme 1 Synthesis of
quinazolinone derivatives 5 and
6a–h
O
O
COOH
PhCOCl
Pyridine
NH2
OH
NH2NH2.H2O
EtOH
O
N
NH2
N
Ph
N
H
3
Ph
1
2
EtOH
GAA
O
N
O
O
N
N
N
NH2
N
3-OH-PhCHO
GAA, EtOH
N
N
DMF, K2CO3
RX
Ph
N
Ph
Ph
OR
4
HO
6a-h
5
a; R = CH3, b; R = C2H5, c; R = C3H7, d; R = iso-propyl, e; R = allyl, f; R = but-3-enyl, g; R =
n-butyl h; R = benzyl.
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Med Chem Res (2013) 22:3282–3288
involves condensation of anthranilic acid (1) and benzoyl
chloride in the presence of pyridine. Compound 2 was
refluxed with hydrazine hydrate in ethanol and yielded
intermediate 3. Further, the intermediate 3 was dehydrated
with catalytic amount of GAA in ethanol and yielded 3-
amino-2-phenyl-1H-quinazolin-4-one (4) with a good
yield. Compound 4 was treated with 3-hydroxy benzalde-
hyde and small amount of GAA in ethanol to afford schiff
base derivative 5. Finally, synthesis of 3-[(3-substituted-
benylidene)-amino]-2-phenyl-3H-quinazolin-4-one (6a-h)
were carried out by reacting 3-[(3-Hydroxy-benzylidene)-
amino]-2-phenyl-3H-quinazolin-4-one (5) with various
alkyl halide in the presence of anhydrous K2CO3 in DMF.
The intermediates (3, 4, and 5) and final compounds
6a–h were confirmed by FT-IR, 1HNMR, and mass
spectroscopy.
compounds. Thus, the substitution by schiff base moiety
would be synergistic. The alkyloxy and phenyl moieties (in
2nd position) were also introduced in the structure to
increase the lipophilicity of the molecule. Therefore, in the
present project first we sought to synthesis the designed
molecules and then their anticonvulsant evaluation; finally
establishing the structure activity relationship.
Pharmacology
Anticonvulsant activity and motor impairment
Synthesized Quinazolinone derivatives were screened for
their anticonvulsant activity against standard models MES
(maximal electroshock seizure test) for their ability to
reduce seizure spread. Motor impairment screening was
also carried out by rotorod test method. The anticonvulsant
activity was reported after 0.5 and 4.0 h time intervals at
dose levels of 30, 100, and 300 mg/kg body weight. The
CNS depressant was studied at a dose level of 100 mg/kg
body weight. Phenytoin and Carbamazepine were used as
standard drugs.
Yogeeswari et al. (2005) have proposed the four crucial
structural components for anticonvulsant activity like (i)
aryl ring center or the lipophilic group (A), (ii) an electron
donor atom (D), (iii) a hydrogen bond acceptor (HA), and
(iv) a hydrogen bond donor (HD). The proposed four-point
pharmacophore model resembles with synthesized qui-
nazolinone-schiff base derivatives and that of standard
anticonvulsants as depicted in Fig. 1.
The anticonvulsant data of this series (5, 6a–h) are
summarized in Table 1; compound 6h showed protection
at maximum dose (300 mg/kg) after 4.0 h while com-
pounds 6d and 6e showed protection at a maximum dose
(300 mg/kg) after 0.5 and 4.0 h. Compounds 6f and 6g
showed protection at a 100 mg/kg at 4.0 h and at a dose of
300 mg/kg at 0.5 h. Compounds 5 and 6a showed protec-
tion at a 100 mg/kg at 4.0 h. Compound 6b showed the
activity at the dose of 100 mg/kg at 0.5 and 4.0 h. Com-
pound 6c showed the activity at the dose of 100 mg/kg at
The above-proposed model assists us to perform an
effective and simple synthesis of 2-phenyl-3-(3-(sub-
stituted-benzylideneamino)-quinazolin-4(3H)-one, where
quinazolin-one would be an aryl ring center and to explore
if the inclusion of schiff base (might be biosteric replace-
ment with aryl semicarbazone) at the 3rd position could be
an additional feature as pharmacophoric hybrid that is able
to improve the pharmacological profile of quinazolinone
Fig. 1 Development of four-
point pharmacophore model,
R-aryl ring center or lipophilic
group; D-An electron donor
atom; HA-A hydrogen bond
R
O
D
O
D
O
HD
H
D O
H
O
acceptor; HD-A hydrogen bond
donor
N
N
H
N
A
A
HA
N
N N
S
A
HD
H
HA
N
Cl HD H
HA
Aryl semicarbazone
Quinazolone-schiff base derivative
Ralitoline
HA
D
O
D
H
D
N
O
S
O
OH N
N
H
A
A
HD
N
H
H
HD
A
N
H N
HD
2
Cl
O
HA
O
HA
F
Carbamazipine
Zonisamide
Progabide
123

Med Chem Res (2013) 22:3282–3288
3287
Table 1 Anticonvulsant and motor impairment screening of synthe-
sized compounds (5, 6a–h)
Table 2 CNS depressant study of the selected compounds by Por-
solt’s forced swim pool test
Compound
R
MESa
Motor impt.a
Compounda
R
Duration of
immobility(s)
(mean SEM)b
% Increased
of immobility
0.5 h 4.0 h 0.5 h 4.0 h
5
H
–
–
100
100
100
30
–
–
–
–
6b
CH2CH3
68.3 1.16*
80.2 1.15*
29.60
52.18
110.81
56.35
–
6a
CH3
6c
CH2CH2CH3
6b
CH2CH3
n-CH2CH2CH3
CH(CH3)2
CH2=CHCH2
100
100
300
300
–
–
6f
CH2(CH2)2CH3 111.1 1.89*
82.4 0.94
6c
–
–
Carbamazepine
6d
300
300
100
100
300
–
–
–
Control
52.7 0.70
6e
–
–
a
The compounds were tested at a dose of 100 mg/kg (i.p.). Each
value represents the mean SEM of six mice. The CNS depressant
effect was compared with respect to the standard drug. * p \ 0.0001
6f
n-CH2(CH2)2CH3 300
–
–
6g
CH2=CHCH2CH2 300
–
–
b
6h
CH2C6H5
–
–
–
300
–
Data was analyzed by unpaired student’s t test
Control
–
Phenytoinb
Carbamazepinb
a
30
30
30
–
100
100
The most active compounds of this study were found to
be 6b and 6c as they are effective in both 0.5 and 4.0 h
time interval at lower dose 100 and 30 mg/kg, respectively,
and show no motor impairment effect. The compounds 6b
and 6c also showed reduced CNS depressant effect in
comparison to the standard drug carbamazepine.
30
300
Doses of 30, 100, and 300 mg/kg were administered; the figures in
the table indicate the minimum dose whereby bioactivity was dem-
onstrated in half or more of mice. The animals were examined 0.5 and
4.0 h after injection was made. The dash indicates an absence of
activity at maximum dose administered
b
Activity reported (show 100 % protection at respective dose)
0.5 h and at dose 30 mg/kg at 4.0 h. The compounds 6b
and 6c having R = ethyl and n-propyl groups, respectively,
were found to be the most active of the series showing
activity both at 0.5 and 4.0 h at lower doses of 100 mg/kg
and 30 mg/kg, respectively. In the rotarod motor impair-
ment screening, compounds did not show any motor
impairment even at even maximum dose of 300 mg/kg
except compound 6h, having R = benzyl group, which
showed motor impairment at 300 mg/kg dose after 4.0 h.
This motor impairment might be due to the presence of
bulkier aromatic group.
Conclusion
On the basis of the above observation it can be concluded
that as the aliphatic straight chain increases from H to
n-propyl in compound 5, 6a–c, and 6f, lipophilicity of
compound also increases that lead to gradually enhance-
ment in the blood brain barrier (BBB) crossing capacity of
the compounds and potency increase up to n-propyl grad-
ually than decrease in n-butyl, it may be due to excess of
lipophilicity of n-butyl derivative. However, when R was
replaced with branched chain, unsaturated chain, or bulkier
groups like iso-propyl, allyl, benzyl, etc. groups, the
potency decreased, which might be due to steric hindrance
to binding the additional bulkier groups and lipophilicity of
the compounds also decreases on incorporation of saturated
chain which leads to reduction in the BBB crossing
capacity of the compounds and, therefore, anticonvulsant
activity decrease of having branched, unsaturated, and
bulkier groups.
CNS depressant activity
After anticonvulsant activity some significant compounds
were selected and tested for their CNS depressant activity.
CNS depressant effect of the compounds was determined
by Porsolt’s force swim pool method. The CNS depressant
activity was done at a dose level of 100 mg/kg body
weight, and Carbamazepine was used as the standard drug.
Selected compounds i.e., 6b, 6c, and 6f having signifi-
cant anticonvulsant activities were tested for their CNS
depressant effect. The compounds showed 29.60, 52.18,
and 110.81 % increase in immobility time with respect to
control whereas the standard drug carbamazepine showed
56.35 % increase in the immobility time (Table 2). Thus it
was observed that compound 6b (29.60 %) and 6c (52.18)
showed less CNS depressant effect in comparison to
carbamazepine.
On the bases of the above study, the activity may be due
to the presence of adequate long and straight aliphatic
chain i.e., ethyl and propyl that provide adequate lipo-
philicity and well fitted to receptor site.
Acknowledgments Authors are grateful to The Director, Faculty of
Pharmacy, Dr. K. N. Modi Institute of Pharmaceutical Education and
Research, Modinagar, Uttar Pradesh, for laboratory facilities. Authors
are also thankful to Mr. Shamsuzzaman, Department of Pharmacol-
ogy, V. P. Chest Institute, Delhi University, New Delhi, India for their
cordial assistance in performing biological activities.
123

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Med Chem Res (2013) 22:3282–3288
Leppik IE (1994) Antiepileptic drugs in development: prospects for
the near future. Epilepsia 35(S4):29–40
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