Design and evaluation of new hybrid pharmacophore quinazolino-tetrazoles as anticonvulsant strategy

Article abstract of DOI:10.1007/s00044-013-0630-4

The anticonvulsant study of 25 newly synthesized quinazolin-4(3H)-one substituted 1H and 2H-tetrazoles (6a-6d, 7a-7b, 8a-8i, 8a′-8i′) was executed. The study employing the maximal electroshock and subcutaneous pentylenetetrazole (scPTZ) screens, the 'gold standards' in the preliminary anticonvulsant breakthrough and the neurotoxicity study applying the rotorod test unveiled a triad of compounds 6c, 7b and 8i′ as the looms amongst the compendium of synthesized compounds. The quantification data of these compounds following oral administration in rats showcased 7b to endorse a remarkable position in the MES screen with a protective indice (PI) of >39.67 and 6c in the scPTZ delineating a PI > 3.10, respectively. All the potent compounds were destitute of toxicity.

Full text of DOI:10.1007/s00044-013-0630-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0630-4
ORIGINAL RESEARCH
Design and evaluation of new hybrid pharmacophore
quinazolino-tetrazoles as anticonvulsant strategy
•
Sachin Malik Suroor A. Khan
Received: 26 January 2013 / Accepted: 14 May 2013
Ó Springer Science+Business Media New York 2013
Abstract The anticonvulsant study of 25 newly synthe-
sized quinazolin-4(3H)-one substituted 1H and 2H-tetrazoles
(6a–6d, 7a–7b, 8a–8i, 8a0–8i0) was executed. The study
employing the maximal electroshock and subcutaneous
pentylenetetrazole (scPTZ) screens, the ‘gold standards’ in
the preliminary anticonvulsant breakthrough and the neuro-
toxicity study applying the rotorod test unveiled a triad of
compounds 6c, 7b and 8i0 as the looms amongst the com-
pendium of synthesized compounds. The quantification data
of these compounds following oral administration in rats
showcased 7b to endorse a remarkable position in the MES
screen with a protective indice (PI) of[39.67 and 6c in the
scPTZ delineating a PI [ 3.10, respectively. All the potent
compounds were destitute of toxicity.
substantial number of the patients (Bell and Sander, 2002;
Lopes Lima, 2000; Perucca, 2002; Berk et al., 2001). In spite
of the prominent therapeutic arsenal of old and new AEDs,
unfortunately it is estimated that up to 30 % of affected
population are still immune to available medication
(Holmes, 2007; Perucca et al., 2007; Smith et al., 2007).
Moreover, many AEDs have grievous side effects, such as
ataxia, drowsiness, gingival hyperplasia, gastrointestinal
disturbances, along with dose-related toxicity and peculiar
adverse effects that wander in harshness from minimal brain
impairment and megaloblastic anaemia to death from
aplastic anaemia or hepatic failure (Spear, 2001; Brown and
Holmes, 2001; Kramer, 2001). These confinements with
conventional antiepileptic drugs necessitate the need for the
development of more efficacious and safer antiepileptic
drugs.
Keywords Quinazolin-4(3H)-one ꢀ Tetrazoles ꢀ
Anticonvulsant activity ꢀ Hepatic toxicity
One of the most frequently encountered heterocycles in
medicinal chemistry is 4(3H)-quinazolinones, which posses
various pharmacological activities like antifungal (Tiwari
et al., 2007), antibacterial (Grover and Kini, 2006), anti-
tumor (Cao et al., 2005), anti-inflammatory (Giri et al.,
2009), anticonvulsant (El-Helby and AbdelWahab 2003;
Kadi et al., 2006; Jatav et al., 2008), analgesic (VanZyl,
2001; Kumar et al., 2003) and antitubercular (Mohamed
et al., 2004; Mohamed et al., 2005). A literature sight
exposed that the presence of a substituted aromatic ring at
position 3 and a methyl group at position 2 on quinazolin-
4(3H)-one nucleus is an essential requirement for CNS
depressant and antiepileptic activities (El-Azab and ElTa-
hir, 2012; El-Azab et al., 2011). Quinazolin-4(3H)-one
constitutes a good template for the preparation of some
new anticonvulsant agents, since such a heterocyclic sys-
tem has the required pharmacophoric moiety. Methaqua-
lone, a crucial landmark in the area of synthetic
anticonvulsants owned quinazoline core responsible for its
Introduction
Epilepsy is a major neurological condition that strikes all
populations (Hauser et al., 1991) represented by paroxysmal
cerebral dysrhythmia, manifested as brief episodes (sei-
zures) of loss or disturbance of consciousness, often fol-
lowed by convulsions (Fisher et al., 2005). The past decades
have endorsed many approaches in the evolution of new
strategies for the treatment of epilepsy, mainly focused in
the prevention of seizures. The antiepileptic drugs (AEDs)
presently employed provides adequate seizure control in a
S. Malik ꢀ S. A. Khan (&)
Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Jamia Hamdard, New Delhi 110062, India
e-mail: sakhanpchem@gmail.com
123

Med Chem Res
activity (Gujral et al., 1957). Its 3-(2-chlorophenyl)-2-
methyl-4(3H)-quinazolinone analogue (Mecloqualone) was
found to possess marked anticonvulsant action, 1.5 times
more potent than phenytoin sodium (DPH) against elec-
troshock induced convulsions and 10 times more potent
than Troxidone against pentylenetetrazol induced seizures
(Bhaduri et al., 1964; Salimath et al., 1956). Interestingly,
a series of 3-substituted quinazolinones structurally related
to methaqualone showed good protection against maximal
electroshock and subcutaneous Metrazol induced seizures
(Wolfe et al., 1990; Aziza, 1997).
comprising alkoxy tetrazole with carbonyl, sulfonyl, aryl,
alkyl pyridinyl moieties were designed, synthesized and
evaluated for anticonvulsant activity.
Results and discussion
Chemistry
Present study was undertaken to synthesize some novel quin-
azol-4(3H)-one embedded tetrazole with aromatic and het-
eroaromatic nuclei derivatives, and to investigate their
probable anticonvulsant effect. Target compounds were
obtained in five-step reaction process, outlined in Scheme 1
and 2. 8-hydroxy-2-methyl-3-o-tolylquinazolin-4(3H)-one (3)
first key intermediate was obtained by the reaction of 3-hy-
droxyanthranilic acid with acetic anhydride followed by
treatment with o-toludine in anhydrous pyridine to afford 8-
acetyloxy-2-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone
(2), which was subjected to catalytic hydrolysis by the reaction
with potassium carbonate in methanol to give compound (3).
Alkylation of the 8-hydroxy-2-methyl-3-o-tolylquinazolin-
4(3H)-one (3) with chloroacetonitrile under basic conditions
gave the nitriles i.e. 2-(2-methyl-4-oxo-3-o-tolyl-3,4-dihy-
droquinazolin-8-yloxy)acetonitrile (4) in good yield. The tet-
razole moiety was prepared by heating the nitrile with sodium
azide in DMF in presence of triethyl ammonium chloride. The
proposed mechanism involves a nucleophilic attack of azide
ion on the carbon of the nitrile group, followed by ring closure
of the imino azide to form the tetrazole ring. The tetrazole ring
in 8-((1H-tetrazol-5-yl) methoxy)-2-methyl-3-o-tolylquinazo-
lin-4(3H)-one (5) was established by direct [2 ? 3] cycload-
dition of azide with nitrile derivative (4). Subsequent acylation
and alkylation was performed with different benzoyl chloride,
benzenesulfonyl chloride and benzyl chloride derivatives
under basic conditions to afford designed compounds. 8-((2-
benzoyl-substituted-2H-tetrazol-5-yl)-methoxy)-2-methyl-3-
o-tolylquinazolin-4(3H)-one (6a–6d) was prepared with dif-
ferent benzoyl chloride under basic conditions, until odour of
acid chloride disappeared. Similar process was followed for
synthesis of 2-methyl-8-((2-(phenyl substituted-sulfonyl)-2H-
tetrazol-5-yl) methoxy)-3-o-tolylquinazolin-4(3H)-one (7a, 7b)
using different benzenesulfonyl chloride derivatives under
more basic conditions than benzyl chlorides. In both
acylation process electrophiles attack the N-2 position of
tetrazole and form 2,5-disubstituted tetrazoles, which is
confirmed from the thermal decomposition to form Huigen
product. Tetrazole rings are readily converted into the
N-benzyl derivatives at room temperature, using 1.5 equiva-
lents of benzyl chloride in triethylamine and acetonitrile, to
form regioisomeric mixture of 1,5-disubstituted tetrazoles
(8a0–8i0) and 2,5-disubstituted tetrazoles (8a–8i), which are
separated by column chromatography in varied yields.
Similarly, tetrazoles belong to the privileged heterocy-
clic scaffolds, in the modern medicinal chemistry as they
have a wide range of biological activities admitting anti-
convulsant (Sun et al., 2010a, b; Alhano et al., 2006),
antitubercular (Chitra et al., 2011), antiemetic (Armour
et al., 1996), antiamoebic (Wani et al., 2012), antihista-
minic (Pellicciari et al., 1999), antihypertensive (Nicolai
et al., 1995) and antidepressant activities (Deng et al.,
2010; Wang et al., 2009; Beghi et al., 2004). The tetrazole
nuclei in YKP3089 a novel compound with broad-spectrum
anticonvulsant activity under clinical development (Phase
II studies) at SK Life Science having good tolerability,
possibility of once daily dosing and broad spectrum
activity in animal models of epilepsy has focused consid-
erable interest (Bialer et al., 2010).
Tetrazoles generally do not exhibit pharmacological
activity, however, many of its derivatives possess interesting
biological activities due to metabolically stable surrogates for
carboxylic acids, and offer a more favourable pharmacoki-
netic profile due to their lipophilic spacer property (Butler,
1996; Juby et al., 1968; Chiu et al., 1989; Furkawa et al.,
1982; Koldobskii and Kharbash, 2003; O’Neill et al., 1998;
Liljebris et al., 2002; MDDR database, 2001). Tetrazoles
exhibit a planar structure. Hansch showed that anionic tetra-
zoles are almost 10 times more lipophilic than the corre-
sponding carboxylate, an important factor in allowing the
molecule to pass through cell membranes (Peters et al., 2001;
Kubo et al., 1993). Hydrogen bonding capability of tetrazolic
anions with receptor recognition sites is a key interaction for
enhanced binding affinity (Holland and Pereira, 1967).
Moreover, all the designed compounds comprised of the
four pharmacophoric elements that are necessary for good
anticonvulsant activity suggested by Pandeya et al. as
manifested in many currently used antiepileptic drugs.
These are hydrophobic domain, hydrogen bonding domain,
electron donor moiety and distal hydrophobic domain
(Pandeya et al., 2000).
In view of these points, it was thought worthwhile to
prepare a new hybrid that clubbed both quinazolin-4(3H)-
one and substituted tetrazoles (Fig. 1), having high lipid
solubility in hope of developing new potent and safer
compounds. Herein, a new series of methaqualone analogue
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Med Chem Res
Fig. 1 Structure of biologically
active anticonvulsant agents and
rationally designed template for
targeted compound (6a–6d, 7a–
7b, 8a–8i, 8a0–8i0)
H2NOC
N
Cl
O
N
O
N
N
N
N
O
N
N
N
O
YKP-3089
N
Methaqualone
N
N
Ar
(7a-7b)
X
Designed Compounds
8a-8i
8a'-8i'
CO, SO2 , CH2
Lipophillic groups
(6a-6d)
The most common nucleophile type reactions at the tet-
razole nitrogens arise from the acidity of the ring N–H bond.
The tetrazolic acids form stable anions when treated with
bases, and are more reactive than neutral tetrazoles towards
alkylating agents. The product is a mixture of 1N and 2N-
alkyl isomers (Scheme 3), the relative proportions of which
depend upon the conditions of the alkylation, the steric
requirements of the alkylating agent and the influence of the
5-substituent. The regioisomers can be distinguished with a
high reliability and generally they can be isolated in good
yields by simple chromatography on silica gel. In N-disub-
stituted tetrazoles series, the more polar 1,5-disubstituted
form (high dipole moment) usually has a higher melting point
or boiling point than the corresponding 2,5-disubstituted
isomer (lower dipole moment). Furthermore, 1H NMR studies
studies of disubstituted tetrazoles have shown that protons of
CH2 group bonded to N1 of 1,5-disubstituted tetrazoles are
more shielded than the corresponding protons of 2,5-disub-
stituted tetrazoles. Moreover, their 13C NMR spectra have
shown that the tetrazole-C5 carbon atom of 1,5-disubstituted
tetrazoles is more shielded than the tallying carbon of the 2,5-
disubstituted tetrazoles (May and Abell, 2001; Bethel et al.,
1999; Byard and Herbert, 1999). Based on these accounted
observations, compounds 8a0–8i0 was assigned as 1,5-disub-
stituted tetrazoles since its 1H NMR spectrum displayed sig-
nals for N–CH2 protons between d 5.25–5.50 ppm, while its
13C NMR spectrum displayed C5 resonance at around d
150 ppm. Meanwhile compounds 8a–8i was designated as
1
2,5-disubstituted tetrazoles as evidenced from its H NMR
that exhibited signals for N–CH2 protons between d
5.85–6.20 ppm, whereas, its 13C NMR spectrum showed
signals for tetrazole-C5 atom at around d 160 ppm. The
physical and elemental analyses data for titled compounds are
summarized in Table 1. Moreover, the structures of all the
O
N
O
COOH
Ac2O
K2CO3
MeOH
N
N
NH2
N
OH
OAc
OH
CH3
1
2
3
NH2
3- Hydroxy
K2CO3
CH3COCH3
Anthranilic Acid
CNCH2Cl
O
N
N
N
NaN3
DMF
N
O
N
O
OCH2CN
NH
N N
4
5
Scheme 1 Synthetic scheme for the key intermediate 8-((1H-tetrazol-5-yl) methoxy)-2-methyl-3-o-tolylquinazolin-4(3H)-one (5)
123

Med Chem Res
N
N
O
N
O
N
N
N
O
N N
O
Ar
C
O
6a-6d
N
N N
N
Ar-COCl
O
10 % NaHCO3
S
O
Ar-SO2Cl
20 % NaHCO3
Ar
7a-7b
15
6a Ar = C6H5
6b Ar = 4-NO2C6H4
6c
17
16
14
13
2
3
N
7a
Ar = 4-CH3C6H4
N 1
11
O
5
Ar = 4-NH2C6H4
6d Ar = 4-OHC6H4
19
12
18
7b Ar = 4-NH2C6H4
9
10
O
20
21
4
8
5
272N NH
N N
25
6
23
24
1'
Ar-CH2Cl
NEt3, CH3CN
6'
5'
2'
3'
Ar -
4'
N
N
N
N
O
+
O
N
O
Ar
O
8a, 8a' Ar = C6H5
8b, 8b' Ar = 2-CH3C6H4
8c, 8c'
N
N N
N
N
N N
Ar = 2-ClC6H4
Ar
8d, 8d' Ar = 3-ClC6H4
8e, 8e' Ar = 4-ClC6H4
8a'-8i'
8a-8i
8f, 8f'
Ar = 3,4-Cl2C6H3
8g, 8g' Ar = 2-pyridyl
8h, 8h' Ar = 3-pyridyl
8i, 8i'
Ar = 4-pyridyl
Scheme 2 Synthesis of the final compounds (6a–6d, 7a–7b, 8a–8i, 8a0–8i0)
synthesized compounds are established from its IR, 1H NMR,
13C NMR, mass and elemental analysis.
drug development (ADD) program protocol (Rogawski and
Loscher, 2004). The pre-clinical Phase I evaluation was
executed using the two ‘gold standards’ (White, 2003)
anticonvulsant models namely the maximal electroshock
seizure (MES) test and the subcutaneous pentylenetetrazole
(scPTZ) test. Neurotoxicity of the active compounds was
ascertained using the minimal motor impairment-Rotorod
Pharmacology
The newly synthesized compounds were evaluated for
anticonvulsant screening based on the NIH anticonvulsant
123

Med Chem Res
H
N
R'
R
R
R
N
N
Base
R
R
N
N
N
N
N
R'X
N
NH
N
N
N
N
R'
N
+
N
N
N
N
N
Scheme 3 Alkylation to tetrazoles to form a mixture of 1,5 and 2,5-disubstituted tetrazoles
test. The MES test is linked with the electrical induction of
the seizure, whereas PTZ test involves a chemical induc-
tion to generate the convulsion. The test compounds were
administered intraperitoneally (i.p.) into the mice at the
doses of 30, 100 and 300 mg/kg in the MES screen,
whereas 100 and 300 mg/kg in the scPTZ screen. Phenyt-
oin was picked out as standard drug in the MES and
minimal motor impairment test, whereas ethosuximide was
selected for the scPTZ screening. The evaluation was
carried out at two time intervals of 0.5 and 4.0 h,
respectively.
The minimal motor impairment was performed using
rotorod test in the compounds exhibiting protectivity
against MES and scPTZ induced convulsions. The com-
pound 6a, 6c, 7b, 8i and 8i0 were found to be devoid of any
neurotoxicity even at the maximum dose, thereby, con-
sidering it to be much safer than the standard drug phe-
nytoin. Compound 6d, 8g and 8h gave equivalent
neurotoxicity profile compared to phenytoin at 0.5 h, but
the increase in the magnitude of dose indicated a decrease
in toxicity after 4.0 h duration, suggesting it to be less toxic
than the standard drug after prolonged absorption. The
compound 5, 8g0 and 8h0 had minimal motor impairment
dose equivalent to the standard drug phenytoin (Table 2).
In accord to the Anticonvulsant Screening Project (ASP)
disposition, the upshots of the prelude anticonvulsant
screening in mice, compounds 6c, 7b and 8i0 were selected
for canvassing their anticonvulsant effect (MES and scPTZ
screen) after oral administration into rats at a dose of 30
and 50 mg/kg, respectively as the ability to inhibit epilepsy
by oral route is a valuable property for development as
drug candidate. The outcomes are arrayed in Table 3 and
Table 4.
The MES test for generalized tonic–clonic seizure eval-
uation keyed out some clinical candidates that forbade sei-
zure spread. Amongst the plethora of the synthesized
compounds, four compounds 6a, 6c, 7b and 8i0, exhibited
significantly active profile against the electrically induced
seizures at a dose of 30 mg/kg at 0.5 h duration. Compound
7b upheld at the same dose after 4.0 h, whereas, 6a, 6c and
8i0 were active at a higher dose of 100 mg/kg, rendering
rapid onset and shorter duration of action of the triad at the
lower dose. The compounds 5, 6d, 8g and 8h0 revealed
protection at the dose level of 100 mg/kg at 0.5 h. At 4.0 h
compound 5 persisted to show anti-MES protection at the
same dose, whereas, compounds 6d and 8h0 indicated to
prevent the seizure spread at a higher dose of 300 mg/kg.
The compound 8g, 8g0, 8h and 8i with rapid onset provided
in cessation of activity at 4.0 h duration. The remaining
compounds showed anticonvulsant activity at the maximum
administered dose of 300 mg/kg at 0.5 h with loss in activity
at 4.0 h, except compound 7a that retained its similar profile
at the latter reported time (Table 2).
The data illustrated one peak of 100 % protection at
0.5 h like phenytoin and succeeded by 50 % at 0.25, 1, 2
and 4 h for 7b proposing it to be the most active of the
series, thereby, retaining the anticonvulsant potential after
prolonged interval in MES screen. The accompanying
compound 6c attained a maximum of 75 % protection at
0.5 h, followed by a decrease up to 25 % after prolonged
administration. The orally dosed compound 8i0 achieved
merely 50 % protection in MES test an hour after admin-
istration. Likewise, the scPTZ study of 8i0 analyzed a peak
of 50 % protection at 0.5 and 1 h, compared to 25 % at 2 h
and no protection at 4 h, respectively. It remarked 8i0 to
have slow absorption, but rapid metabolism against PTZ
induced seizures. The compounds 6c and 7b were repre-
sented by retarded absorption, and merely 25 % protection
at 2 h against oral induction in scPTZ test with the con-
tinuance of 25 % protection for 6c, and an increase to 50 %
for 7b after 4 h duration.
The compounds portraying better anticonvulsant profile
in the MES screen were further challenged by chemically
induction of seizures in the scPTZ test. The compounds 5,
6c, 6d, 7b and 8i0 raised the seizure threshold at a dose of
100 mg/kg after 0.5 h interval. Interestingly, 6c depicted
activity at the same dose at 4.0 h as well marking it as the
most efficient compound of the series. The compounds 7b
and 8i0 rendered anti-scPTZ action at a higher dose of
300 mg/kg equating the effect of the reference drug etho-
suximide. The compounds 5 and 6d ensued in cessation of
activity at 4.0 h duration. The compounds 6a, 8g, 8g0, 8h,
8h0 and 8i established protection against the scPTZ induced
convulsions at the maximum dose of 300 mg/kg after 0.5 h
leading to loss in activity at 4.0 h, except 8g0 and 8h0 that
preserved its activity at 300 mg/kg after 4.0 h (Table 2).
The MES protection graph of the compounds 6c, 7b and
8i0 after oral administration is revelatory of the fact of
delayed but sustained absorption of these compounds after
prolonged duration of time. The scPTZ oral administration
protection indices binned 8i0 as promising candidate having
comparable activity to the standard drug ethosuximide.
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Med Chem Res
Table 1 Physicochemical data
of synthesized compounds (4, 5,
6a–6d, 7a–7b, 8a–8i, 8a0–8i0)
Compd. no.
Mol. formula (Mol. weight)
Yielda (%)
M.p. (°C)
Elemental analysesb
Calculated/found (%)
C
H
N
4
C18H15N3O2
(305.33)
71.55
55.45
75.88
66.66
70.35
64.45
72.20
82.25
105–108
260–265
95–98
70.81
70.82
62.06
62.01
66.36
66.34
60.36
60.33
64.23
64.20
64.10
64.07
59.75
59.77
57.25
57.22
68.48
68.49
69.01
68.98
63.49
63.48
63.49
63.50
63.49
63.49
59.18
59.20
65.09
65.11
65.09
65.12
65.09
65.08
4.95
4.92
4.63
4.42
4.46
4.48
3.85
3.88
4.53
4.55
4.30
4.33
4.41
4.38
4.20
4.22
5.06
5.04
5.35
5.36
4.48
4.50
4.48
4.47
4.48
4.47
3.97
3.96
4.27
4.25
4.27
4.25
4.27
4.26
13.76
13.77
24.12
24.10
18.57
18.55
19.71
19.72
20.97
20.95
17.94
17.93
16.72
16.70
19.47
19.45
19.17
19.19
18.57
18.57
17.77
17.76
17.77
17.80
17.77
17.76
16.56
16.60
23.10
23.14
23.10
23.07
23.10
23.08
5
C
18H16N6O2
(348.36)
25H20N6O3
(452.46)
25H19N7O5
(497.46)
25H21N7O3
(467.48)
25H20N6O4
(468.46)
25H22N6O4S
(502.54)
24H21N7O4S
6a
C
6b
C
80–84
6c
C
220–224
167–170
180–182
242–246
6d
C
7a
C
7b
C
(503.53)
8a/8a0
8b/8b0
8c/8c0
8d/8d0
8e/8e0
8f/8f0
8g/8g0
8h/8h0
8i/8i0
C25H22N6O2
(438.48)
56.66/
28.55
48.80
30.50
40.85
32.25
38.70
25.45
52.48
32.40
45.20
22.50
42.20
26.60
35.80
25.58
60.30
32.20
108–110/
132–134
150–155/
190–192
155–158
220–223
180–182
215–216
200–204
235–238
170–172
204–210
160–163
210–212
192–195
226–229
220–222
252–256
C26H24N6O2
(452.51)
C25H21ClN6O2
(472.93)
C25H21ClN6O2
(472.93)
C25H21ClN6O2
(472.93)
C25H20Cl2N6O2
(507.37)
C23H18N7O2
(424.43)
C23H18N7O2
(424.43)
a
Solvent for recrystallization
b
Elemental analyses for C, H
and N were within 0.4 % of
the theoretical values
C23H18N7O2
(424.43)
The phase II quantitative estimation in the MES and
scPTZ screen for the orally administered rats was estab-
lished through the investigation of the median effective
dose (ED50) and median toxic dose (TD50) at the ante-
cedently gauged time of peak effect (TPE). An insight of
the quantification data of MES screen plied compound 7b
more potent than phenytoin, as manifested from its pro-
tective indice (TD50/ED50) of [39.67. In the scPTZ
attainments equalizing, the effect of standard drug etho-
suximide (PI [ 3.0), 6c fended against the chemically
induced seizures thereby making a remarkable decrease in
the ED50 to 10.90 mg/kg and TD50[150 mg/kg, ensuing in
a comparable of protection index of [3.10. However, 8i0
depicted a protective window lesser than that of phenytoin
and ethosuximide chosen as reference drugs in the MES
and scPTZ screen, respectively (Table 5).
The barren from major limitation of hepatotoxicity in
anticonvulsant drugs was provided through the estimation
of serum glutamate oxaloacetate transaminase (SGOT) and
serum glutamate pyruvate transaminase (SGPT) after
chronic administration of 6c, 7b and 8i0 to rats for 2 weeks.
The candidates did not figure any significant increase up to
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Med Chem Res
Table 2 Pharmacological
screening (Phase I) of the
synthesized compounds
Compd.
Intraperitoneal injection in micea
MESb
0.5 h
scPTZc
NTd
0.5
4 h
0.5 h
4 h
4 h
5
100
30
100
100
–
100
300
X
–
100
300
X
100
300
X
6a
–
6b
300
30
X
6c
100
300
300
30
–
100
100
X
100
–
300
100
X
300
300
X
6d
100
300
30
Negative control group received
0.9 % saline (10 mL/kg) which
showed zero % protection
7a
X
7b
100
X
300
X
300
X
300
X
a
Number of animal used = 4,
8a
8a0
300
300
300
300
300
300
300
300
300
300
300
300
100
100
100
100
100
30
Doses of 30, 100 and 300 mg/kg
were administered. The figure in
the table indicates the minimum
dose whereby, bioactivity was
demonstrated in half or more of
the mice. The animals were
examined at 0.5 and 4 h. A (–)
dash indicates the absence of
anticonvulsant activity and
neurotoxicity at the maximum
dose administered (300 mg/kg).
X indicates the compound not
tested against anticonvulsant
activity and neurotoxicity
–
X
X
X
X
8b
8b0
–
X
X
X
X
–
X
X
X
X
8c
8c0
–
X
X
X
X
–
X
X
X
X
8d
8d0
–
X
X
X
X
–
X
X
X
X
8e
8e0
–
X
X
X
X
–
X
X
X
X
8f
8f0
–
X
X
X
X
–
X
X
X
X
b
Maximal electroshock test
8g
8g0
–
300
300
300
300
300
100
–
–
100
100
100
100
300
300
100
–
300
100
300
100
300
300
100
–
c
Subcutaneous
pentylenetetrazole test
–
300
–
8h
8h0
–
d
Neurotoxicity screening-
rotorod test
300
–
300
–
8i
8i0
e
Reference drugs, data for
100
30
–
300
–
phenytoin and ethosuximide
were used as positive control,
Ref. (Thirumurugan et al.,
2006)
Phenytoine
Ethosuximidee
30
–
100
300
Table 3 Evaluation of selected compounds in MES test after oral
administration (30 mg/kg) to rats
Table 4 Evaluation of selected compounds scPTZ test after oral
administration (50 mg/kg) to rats
Compd.
Oral administration to ratsa (h)
Compd.
Oral administration to ratsa (h)
0.25
0.5
1.0
2.0
4.0
0.25
0.5
1.0
2.0
4.0
6c
1
2
0
1
3
4
1
4
2
2
2
3
1
2
1
3
1
2
1
3
6c
0
0
0
0
0
0
2
2
0
0
2
1
1
1
1
1
1
2
0
0
7b
8i0
7b
8i0
Phenytoinb
Ethosuximideb
a
a
Figure indicate the number of rats out of four which are protected
Figure indicate the number of rats out of four which are protected
b
b
Reference drug, data for phenytoin, Ref. (Yogeeswari et al., 2005)
Reference drug, data for ethosuximide Ref. (Thirumurugan et al.,
2006)
95 % level of significance for these enzymes compared to
the control as well as the standard drug phenytoin Table 6.
The in vivo data in rats supported absorption of com-
pounds from gastrointestinal tract and also their penetration
to central nervous system. The inhibition of electrically
induced seizures that is characteristic for phenytoin and
phenytoin-like drugs may suggest the influence of com-
pound on voltage depended Na? channels, as the most
credible mechanism of antiepileptic action, and provide
more insights for the anticonvulsant effects of these new
analogues against convulsant-induced seizures, which will
be considered extensively in our future study.
123

Med Chem Res
Table 5 Quantification studies (Phase II) of selected compounds in rats after oral administration
TPE (h)a
PId
b
MES ED50 (mg/kg)
b
scPTZ ED50 (mg/kg)
c
NT TD50 (mg/kg)
Compd.
6c
2
10.90 (8.72–25.90)
4.93 (3.80–7.40)
48.35 (40.50–100.20)
72.30 (45.60–90.80)
[100
[150
[13.76 (MES)
[3.10 (scPTZ)
[39.67 (MES)
[2.71 (scPTZ)
[15.51 (MES)
[2 (scPTZ)
7b
8i0
4
1
195.57 (163.36–210.55)
12.90 (10.72–25.10)
[200
Phenytoine
Ethosuximidef
1
2
28.1 (27.7–35.20)
[500
167.0 (116.0–237.0)
[1000
[500
[35.58 (MES)
[3.0 (scPTZ)
[500
a
Time to peak effect
b
ED50—median effective dose required to assure anticonvulsant protection in 50 % animals
TD50—median toxic dose eliciting minimal neurological toxicity in 50 % animals
c
d
e
f
PI—protective index (TD50/ED50
)
Reference drug, data for phenytoin, Ref. (Porter et al., 1984)
Reference drug, data for ethosuximide, Ref. (White et al., 2002)
Table 6 Effect of selected compounds on serum levels of liver
transaminases in rats
the favored compounds 6c and 7b auspicated the substituent
effect of the synthesized compounds. Whilst, the substitution
of electron donating and electron withdrawing groups did
not ascribed to anticonvulsant potentiating effect in the 2,5-
substituted 8a–8f and 1,5-substituted 8a0–8f0, the majorly
role was played by the heterocyclic pyridinyl moiety colli-
gated through the alkyl linkage to the tetrazole nuclei.
Moreover, the 4-pyridinyl analogue 8i0 accounted for owing
the substantial anticonvulsant potential than the congeners of
the group.
Compd.a
SGPTb,e (units/mL)
SGOTc,e (units/mL)
Controld
46.2 5.20
44.6 4.32
43.3 4.70
45.1 6.20
52.6 3.48
73.2 5.96
64.8 5.25
70.2 4.70
73.1 5.75
84.1 6.50
6c
7b
8i0
Phenytoin
Reference drug, phenytoin tested at 25 mg/kg oral for 14 days
a
The compounds were tested at a dose of 30 mg/kg oral for 14 days
b
Denotes serum glutamate oxaloacetate transaminase
c
Denotes serum glutamate pyruvate transaminase
Experimental
d
Control animals (six rats) were treated with 0.5 % methylcellulose
for 14 days
Chemistry
e
Each value represents the mean SEM of six rats, not significant
from the control value at p \ 0.05 (student’s t test)
All reagents were used as purchased from commercial
suppliers like Merck India Ltd., S.D Fine Chemicals,
Sigma Aldrich and Qualigens and were used without
purification. The purity and homogeneity of the compounds
were assessed by the thin-layer chromatography (TLC)
performed on Merck silica gel 60 F254 aluminum sheets.
Melting points were determined in one end open capillary
tubes on Buchi 530 melting point apparatus and are
uncorrected. Elemental data of C, H, and N were within
0.4 % of the theoretical value as determined by Perkin
Elmer Model 240 analyzer. The Infrared Spectra of com-
pounds were recorded on Perkin Elmer Spectrum BX-II
Spectrophotometer using KBr pellets are represented by
the following abbreviations: s (strong), m (medium),
Conclusion
The jibing of the chemical structure and the ascertained
biological activity of the probed compound, it was observed
that from the inventory of 25 examined compounds, 6c, 7b
and 8i0 proved to be of clinical significance. The quinaz-
olinone nuclei dissembled as the mainstay for the persuading
the anticonvulsant activity. The introduction of the benzyl-
oxy tetrazole moiety as the core fragment synergized the
activity. The presence of the free carbonyl (6a–6d) and
sulphonyl group (7a–8b) attributed to the amplification of
the anticonvulsant stimulus. Moreover, it is clear that that
good anticonvulsant activity was confined to compounds
containing free oxygen functionality. The ameliorating
amino fragment at the para position of the benzene moiety in
1
w (weak) and br (broad) absorption bands. H NMR and
13C NMR spectra of DMSO-d6/CDCl3 solutions were,
respectively, recorded at 400 MHz with Bruker model
DRX 400 NMR Spectrometer using TMS [(CH3)4Si] as
123

Med Chem Res
internal standard. Signal multiplicities are represented by
the following abbreviations: s (singlet), br s (broad singlet),
d (doublet), t (triplet), and m (multiplet). Chemical shifts
are reported in d values (ppm) relative to TMS d = 0. The
Mass Spectra was recorded on a Waters Micro-mass ZQ
2000 Spectrophotometer. The structures were confirmed by
After cooling, the reaction mixture was filtered and evapo-
rated rendering colourless crystals of 2-(2-methyl-4-oxo-3-o-
tolyl-3,4-dihydroquinazolin-8-yloxy) acetonitrile (4). IR
(KBr) tmax (cm-1): 3050, 3040 (s, Ar C–Hstr), 2229 (s,
C:Nstr), 1680 (s, cyclic C=Ostr), 1523 (w, C=Nstr), 1454,
1433 (w, Ar C=Cstr), 1291 (s, C–Ostr); 1H NMR (d) CDCl3:
2.21 (s, 3H, CH3 of quinazoline), 2.35 (s, 3H, Ar–CH3), 4.90
(s, 2H, OCH2), 6.95 (d, 1H, J = 7.0 Hz), 7.20–7.45 (m, 3H),
7.55 (d, 1H, J = 7.0 Hz), 7.70 (d, 1H, J = 7.5 Hz), 8.20 (d,
1H, J = 8.0 Hz); 13C NMR (d) CDCl3: 18.2 (C-18), 24.5 (C-
17), 54.5 (OCH2CN), 115.7 (OCH2CN), 121.5 (C-10), 122.8
(C-5), 124.6(C-6), 126.5(C-16), 127.3 (C-7), 129.2(C-14 and
C-15), 132.5 (C-13), 134.3 (C-12), 136.6 (C-11), 146.5 (C-9),
152.2 (C-8), 155.2 (C-2), 162.4(C-4); MS (m/z): 306.11
(M? ? 1).
1
both spectral (IR, H NMR, 13C NMR, MS) and elemental
analyses.
2-methyl-4-oxo-3-o-tolyl-3,4-dihydroquinazolin-8-yl
acetate (2)
The synthesis of 2-methyl-4-oxo-3-o-tolyl-3,4-dihydroqui-
nazolin-8-yl acetate (2) was carried out according to repor-
ted procedure (El-Azab et al., 2011). Yield 83.50 %; m.p.:
130–132 °C; IR (KBr) tmax (cm-1): 3120, 3100 (s, Ar C–
Hstr), 2830 (s, CH3, C–Hstr), 1740 (s, Ar C=Ostr), 1720 (s,
cyclic C=Ostr), 1522 (w, C=Nstr), 1445 (w, Ar C=Cstr), 1220,
1055 (s, C–Ostr); 1H NMR (d) CDCl3: 2.08 (s, 3H), 2.10 (s,
3H), 2.30 (s, 3H), 7.05 (d, 1H, J = 7.5 Hz), 7.25–7.45 (m,
3H), 7.52 (d, 1H, J = 8.2. Hz), 7.68 (d, 1H, J = 7.5 Hz),
8.15 (d, 1H, J = 8.2 Hz); 13C NMR (d) CDCl3: 17.5 (C-18),
20.4 (OCOCH3), 25.8 (C-17), 121.1 (C-10), 122.4 (C-5),
124.5 (C-6), 126.6 (C-16), 127.5 (C-7), 127.8 (C-14 and
C-15), 131.3 (C-13), 134.5 (C-12), 136.6 (C-11), 141.5 (C-
8), 146.7 (C-9), 155.4 (C-2), 161.1 (C-4), 168.8 (OCOCH3);
MS (m/z): 309.45 (M? ? 1).
8-((1H-tetrazol-5-yl) methoxy)-2-methyl-3-o-
tolylquinazolin-4(3H)-one (5)
A mixture of 2-(2-methyl-4-oxo-3-o-tolyl-3,4-dihydroquina-
zolin-8-yloxy)acetonitrile (4) (428.4 mg, 1.40 mmol) and
sodium azide (194 mg, 2.99 mmol) in dry DMF (10 mL) was
stirred in a sealed flask at 80 °C for 4 days. The reaction
mixture was concentrated under reduced pressure, H2O added
(10 mL) and acidified to pH 3 with 2 M HCl. The aqueous
phase was extracted with Et2O and the organic phase washed
with aqueous saturated CaCl2. After drying, evaporation and
column chromatography [toluene–EtOAc–AcOH (24:24:2)]
followed by recrystallization (EtOAc–light petroleum) gave 5
ascolourless crystals. IR(KBr)tmax (cm-1):3115, 3097(s, Ar
C–Hstr), 2929 (s, CH3, C–Hstr), 2700–2500 (br m, N–Hstr),
1724 (s, cyclic C=Ostr), 1623 (w, C=Nstr), 1550 (w, N=N–Nstr,
8-hydroxy-2-methyl-3-o-tolylquinazolin-4(3H)-one (3)
The synthesis of 2-methyl-4-oxo-3-o-tolyl-3,4-dihydroqui-
nazolin-8-yl acetate (3) was carried out according to repor-
ted procedure (El-Azab et al., 2011). Yield 73.25 %; m.p.:
160–165 °C; IR (KBr) tmax (cm-1): 3540 (s, O–Hstr), 3150,
3120 (s, Ar C–Hstr), 2850 (s, CH3, C–Hstr), 1710 (s, cyclic
1
tetrazole), 1450, 1440 (w, Ar C=Cstr), 1250 (s, C–Ostr); H
NMR (d) DMSO-d6 : 2.19(s, 3H, CH3 ofquinazoline), 2.70(s,
3H, Ar-CH3), 4.60 (s, 2H, OCH2), 7.05 (d, 1H, J = 8.0 Hz),
7.20–7.55 (m, 3H), 7.75 (d, 1H, J = 8.0 Hz), 7.90 (d, 1H,
J = 8.5 Hz), 8.20 (d, 1H, J = 8.0 Hz), 12.80 (br s, NH of
tetrazole, D2O exchangeable); 13C NMR (d) CDCl3: 17.6 (C-
18), 23.8(C-17),68.8(C-20), 120.9(C-10), 122.4(C-5),125.6
(C-6), 126.4 (C-16), 127.2 (C-7), 128.4 (C-14 and C-15),
133.1 (C-13), 135.1 (C-12), 138.2 (C-11), 145.5 (C-9), 150.2
(C-8), 154.4 (C-21), 156.2 (C-2), 162.5 (C-4); MS (m/z):
349.20 (M? ? 1).
1
C=Ostr), 1525 (w, C=Nstr), 1460, 1445 (w, Ar C=Cstr); H
NMR (d) CDCl3: 2.15 (s, 3H), 2.32 (s, 3H), 7.10 (d, 1H,
J = 7.0 Hz), 7.25–7.40 (m, 3H), 7.62 (d, 1H, J = 7.5 Hz),
7.70 (d, 1H, J = 7.5 Hz), 8.10 (d, 1H, J = 7.5 Hz), 11.20
(br s, 1H, OH); 13C NMR (d) CDCl3: 17.1 (C-18), 25.5 (C-
17), 121.5 (C-10), 121.8 (C-5), 125.1 (C-6), 126.4 (C-16),
127.1 (C-7), 128.4 (C-14 and C-15), 131.5 (C-13), 135.1 (C-
12), 137.1 (C-11), 145.5 (C-9), 150.1 (C-8), 154.4 (C-2),
160.5 (C-4); MS (m/z): 267.35 (M? ? 1).
General procedure for the synthesis of compounds
2-(2-methyl-4-oxo-3-o-tolyl-3,4-dihydroquinazolin-8-
yloxy)acetonitrile (4)
(6a-6d)
8-((1H-tetrazol-5-yl) methoxy)-2-methyl-3-o-tolylquinazo-
lin-4(3H)-one (5) (543.7 mg, 1.5 mmol) (5) was processed
with substituted benzoyl chloride [6a/6b/6c/6d 210.5
(0.25 mL)/278/233.3/234(0.32 mL)mg, 1.5 mmol] in10 mL
of10 %sodiumbicarbonatesolution. Themixturewasshaken
vigorously until the odour of aromatic acid chloride had
Amixtureof8-hydroxy-2-methyl-3-o-tolylquinazolin-4(3H)-
one (3) (585.2 mg, 2.2 mmol) and K2CO3 (615 mg,
4.5 mmol) in acetone (60 mL) was stirred at room tempera-
ture for 30 min. Chloroacetonitrile (423 lL, 6.7 mmol) was
slowly added and stirring was continued for 18 h at 50 °C.
123

Med Chem Res
disappeared. The solids separated out and were filtered and
dried. Recrystallization of the dried compounds from aqueous
ethanol yielded compounds 6a–6d.
exchangeable), 6.77 (d, 2H, J = 10 Hz), 7.0 (d, 1H,
J = 7.5 Hz), 7.20 (d, 2H, J = 10 Hz), 7.30-7.65 (m, 3H),
7.70 (d, 1H, J = 7.5 Hz), 7.90 (d, 1H, J = 8.0 Hz), 8.20
(d, 1H, J = 8.0 Hz); 13C NMR (d) DMSO-d6 : 17.8 (C-18),
23.5 (C-17), 69.9 (C-20), 116.2 (C-30 and C-50), 121.1 (C-
10), 122.3 (C-5), 124.9 (C-6), 125.6 (C-16), 127.1 (C-7),
127.5 (C-20 and C-60), 129.4 (C-14 and C-15), 130.2 (C-10),
131.4 (C-13), 133.2 (C-12), 135.5 (C-11), 140.4 (C-9),
150.5 (C-8), 152.6 (C-40), 154.2 (C-2), 161.1 (C-21), 163.5
(C-4), 170.5 (C=O of benzoyl); MS (m/z): 468.54 (M? ? 1).
8-((2-benzoyl-2H-tetrazol-5-yl) methoxy)-2-methyl-3-
o-tolylquinazolin-4(3H)-one (6a)
IR (KBr) tmax (cm-1): 3145, 3120 (s, Ar C–Hstr), 2950 (s,
CH3, C–Hstr), 1730 (s, cyclic C=Ostr), 1650 (s, Ar C=Ostr),
1610 (w, C=Nstr), 1510 (w, N=N–Nstr, tetrazole), 1420 (w,
Ar C=Cstr), 1210 (s, C–Ostr); 1H NMR (d) DMSO-d6 : 2.15
(s, 3H, CH3 of quinazoline), 2.45 (s, 3H, Ar–CH3), 4.50
(s, 2H, OCH2), 7.0 (d, 1H, J = 7.0 Hz), 7.20–7.55 (m, 6H),
7.65 (d, 2H), 7.70 (d, 1H, J = 7.0 Hz), 8.0 (d, 1H,
J = 7.5 Hz), 8.30 (d, 1H, J = 8.0 Hz); 13C NMR (d)
DMSO-d6 : 17.2 (C-18), 24.3 (C-17), 68.5 (C-20), 120.8
(C-10), 122.7 (C-5), 125.1 (C-6), 126.2 (C-16), 127.1 (C-
7), 128.7 (C-14 and C-15), 129.7 (C-30 and C-50), 130.4 (C-
10), 130.8 (C-20 and C-60), 133.2 (C-13), 134.2 (C-40), 135.1
(C-12), 136.6 (C-11), 143.8 (C-9), 152.1 (C-8), 154.3 (C-
2), 161.6 (C-21), 162.2 (C-4), 169.3 (C=O of benzoyl); MS
(m/z): 453.33 (M? ? 1).
8-((2-(4-hydroxybenzoyl)-2H-tetrazol-5-yl) methoxy)-
2-methyl-3-o-tolylquinazolin-4(3H)-one (6d)
IR (KBr) tmax (cm-1): 3580 (s, O–Hstr), 3150, 3120 (s, Ar
C–Hstr), 2870 (s, CH3, C–Hstr),1900–1600 (w, overtones,
Ar C–Hstr), 1750 (s, cyclic C=Ostr), 1685 (s, Ar C=Ostr),
1620 (w, C=Nstr), 1510 (w, N=N–Nstr, tetrazole), 1460 (w,
Ar C=Cstr), 1210 (s, C–Ostr); 1H NMR (d) DMSO-d6 : 2.30
(s, 3H, CH3 of quinazoline), 2.50 (s, 3H, Ar–CH3), 4.44 (s,
2H, OCH2), 7.10 (d, 1H, J = 7.5 Hz), 7.20 (d, 2H,
J = 8.2 Hz), 7.30–7.65 (m, 3H), 7.78 (d, 1H, J = 7.5 Hz),
7.85 (d, 1H, J = 7.5 Hz), 7.95 (d, 2H, J = 8.2 Hz), 8.20
(d, 1H, J = 8.0 Hz), 11.02 (br s, 1H, OH); 13C NMR (d)
DMSO-d6 : 18.8 (C-18), 26.2 (C-17), 67.9 (C-20), 119.2
(C-30 and C-50), 121.7 (C-10), 122.4 (C-5), 123.8 (C-6),
125.5 (C-16), 126.9 (C-7), 128.1 (C-10), 129.6 (C-14 and
C-15), 130.5 (C-20 and C-60), 131.7 (C-13), 134.2 (C-12),
136.2 (C-11), 145.2 (C-9), 152.2 (C-8), 154.1 (C-40), 156.5
(C-2), 160.5 (C-21), 162.8 (C-4), 169.6 (C=O of benzoyl);
MS (m/z): 469.24 (M? ? 1).
2-methyl-8-((2-(4-nitrobenzoyl)-2H-tetrazol-5-yl)
methoxy)-3-o-tolylquinazolin-4(3H)-one (6b)
IR (KBr) tmax (cm-1): 3156, 3100 (s, Ar C–Hstr), 2932 (s,
CH3, C–Hstr), 1760 (s, cyclic C=Ostr), 1680 (s, Ar C=Ostr),
1600 (w, C=Nstr), 1526, 1339 (s, asymmetric and sym-
metric NO2 str), 1490 (w, N=N–Nstr, tetrazole), 1420, 1400
1
(w, Ar C=Cstr), 1215 (s, C–Ostr); H NMR (d) DMSO-d6 :
2.25 (s, 3H, CH3 of quinazoline), 2.55 (s, 3H, Ar–CH3),
4.66 (s, 2H, OCH2), 7.10 (d, 1H, J = 7.5 Hz), 7.20–7.65
(m, 3H), 7.80 (d, 1H, J = 7.5 Hz), 7.90 (d, 1H,
J = 7.0 Hz), 8.30 (d, 1H, J = 8.0 Hz), 8.35 (d, 2H,
J = 12.0 Hz), 8.43 (d, 2H, J = 12.0 Hz); 13C NMR (d)
DMSO-d6 : 18.5 (C-18), 26.1 (C-17), 69.3 (C-20), 120.7
(C-10), 121.8 (C-5), 125.2 (C-6), 126.4 (C-16), 126.7 (C-30
and C-50), 127.1 (C-7), 128.2 (C-20 and C-60), 128.6 (C-14
and C-15), 130.4 (C-40), 131.9 (C-13), 133.2 (C-12), 135.5
(C-11), 136.4 (C-10), 142.3 (C-9), 151.5 (C-8), 153.3 (C-2),
160.6 (C-21), 161.2 (C-4), 170.3 (C=O of benzoyl); MS
(m/z): 498.21 (M? ? 1).
General procedure for the synthesis of compounds
(7a, 7b)
8-((1H-tetrazol-5-yl)methoxy)-2-methyl-3-o-tolylquinazolin-
4(3H)-one (543.7 mg, 1.5 mmol) (5) was treated with substi-
tuted benzenesulfonyl chloride (7a/7b 285.9/287.4 mg,
1.5 mmol) in 10 mL of 20 % sodium bicarbonate solution.
The mixture was shaken vigorously until the odour of aromatic
acid chloride had disappeared. The solids separated out and
were filtered and dried. Recrystallization of the dried com-
pounds from aqueous ethanol yielded compounds 7a, 7b.
8-((2-(4-aminobenzoyl)-2H-tetrazol-5-yl) methoxy)-2-
2-methyl-3-o-tolyl-8-((2-tosyl-2H-tetrazol-5-yl)
methoxy) quinazolin-4(3H)-one (7a)
methyl-3-o-tolylquinazolin-4(3H)-one (6c)
IR (KBr) tmax (cm-1): 3365 (s, N–Hstr), 3150, 3100 (s, Ar
C–Hstr), 2890 (s, CH3, C–Hstr), 1750 (s, cyclic C=Ostr),
1695 (s, Ar C=Ostr), 1610 (w, C=Nstr), 1550 (w, N=N–Nstr,
IR (KBr) tmax (cm-1): 3145, 3120 (s, Ar C–Hstr), 2930 (s,
CH3, C–Hstr), 1950–1600 (w, overtones, Ar C–Hstr), 1720 (s,
cyclic C=Ostr), 1600 (w, C=Nstr), 1470 (w, N=N–Nstr, tet-
razole), 1440 (w, Ar C=Cstr), 1297, 1151 (s, asymmetric and
symmetric SO2str), 1205 (s, C–Ostr); 1H NMR (d) DMSO-d6 :
2.25 (s, 3H, CH3 of quinazoline), 2.45 (s, 3H, Ar–CH3),
1
tetrazole), 1440 (w, Ar C=Cstr), 1220 (s, C–Ostr); H NMR
(d) DMSO-d6 : 2.20 (s, 3H, CH3 of quinazoline), 2.55 (s,
3H, Ar–CH3), 4.30 (s, 2H, OCH2), 4.80 (s, 2H, NH2, D2O
123

Med Chem Res
2.65 (s, 3H, Ar–CH3), 4.55 (s, 2H, OCH2), 6.90 (d, 1H,
J = 7.5 Hz), 7.10–7.40 (m, 3H), 7.35 (d, 2H, J = 8.5 Hz),
7.50 (d, 2H, J = 7.5 Hz), 7.78 (d, 1H, J = 7.5 Hz), 7.90
(d, 1H, J = 8.0 Hz), 8.20 (d, 1H, J = 8.0 Hz); 13C NMR
(d) DMSO-d6 : 18.4 (C-18), 22.3 (40-CH3C6H4), 24.6 (C-
17), 65.2 (C-20), 121.4 (C-10), 122.5 (C-5), 125.2 (C-6),
126.6 (C-16), 127.5 (C-7), 128.2 (C-20 and C-60), 129.2 (C-
14 and C-15), 130.5 (C-30 and C-50), 131.2 (C-13), 133.2
(C-12), 135.1 (C-11), 136.6 (C-10), 138.2 (C-40), 142.2 (C-
9), 151.1 (C-8), 153.6 (C-2), 160.6 (C-21), 164.2 (C-4); MS
(m/z): 503.42 (M? ? 1).
tetrazoles were separated by column chromatography (TLC
conditions) to give 1,5-disubstitued tetrazole as awhite fluffy
powder and 2,5-disubstituted tetrazole as white crystalline
solid. Both were recrystallized from ethyl acetate/hexane.
8-((2-benzyl-2H-tetrazol-5-yl) methoxy)-2-methyl-3-o-
tolylquinazolin-4(3H)-one (8a)
IR (KBr) tmax (cm-1): 3154, 3100 (w, Ar C–Hstr), 2920 (s,
CH3, C–Hstr), 1695 (s, cyclic C=Ostr), 1620 (w, C=Nstr),
1525 (w, N=N–Nstr, tetrazole), 1440, 1420 (w, Ar C=Cstr),
1215 (s, C–Ostr); 1H NMR (d) DMSO-d6 : 2.20 (s, 3H, CH3
of quinazoline), 2.35 (s, 3H, Ar–CH3), 4.32 (s, 2H, OCH2),
6.15 (s, 2H, N–CH2), 7.10 (d, 1H, J = 7.0 Hz), 7.20-7.55
(m, 6H), 7.70 (d, 1H, J = 7.0 Hz), 7.85 (d, 2H), 8.10 (d,
1H, J = 7.5 Hz), 8.30 (d, 1H, J = 8.0 Hz); 13C NMR (d)
DMSO-d6 : 17.8 (C-18), 23.6 (C-17), 56.8 (–CH2 of ben-
zyl), 70.8 (C-20), 120.8 (C-10), 121.2 (C-5), 124.5 (C-6),
125.3 (C-40)126.4 (C-16), 126.8 (C-20 and C-60), 127.5
(C-7), 128.5 (C-30 and C-50), 129.5 (C-14 and C-15), 131.3
(C-13), 134.4 (C-12), 134.8 (C-10), 136.5 (C-11), 145.5
(C-9), 150.8 (C-8), 153.2 (C-2), 161.1 (C-21), 163.2 (C-4);
MS (m/z): 439.50 (M? ? 1).
8-((2-(4-aminophenylsulfonyl)-2H-tetrazol-5-yl)
methoxy)-2-methyl-3-o-tolylquinazolin-4(3H)-one (7b)
IR (KBr) tmax (cm-1): 3415 (s, N–Hstr), 3150, 3110 (s, Ar
C–Hstr), 2800 (s, CH3, C–Hstr), 1730 (s, cyclic C=Ostr), 1610
(w, C=Nstr), 1520 (w, N=N–Nstr, tetrazole), 1440, 1430 (w, Ar
C=Cstr), 1285, 1120 (s, asymmetric and symmetric SO2str),
1205 (s, C–Ostr); 1H NMR (d) DMSO-d6 : 2.15 (s, 3H, CH3 of
quinazoline), 2.45 (s, 3H, Ar–CH3), 4.30 (s, 2H, OCH2), 4.54
(s, 2H, NH2, D2O exchangeable), 6.70 (d, 2H, J = 10 Hz), 7.0
(d, 1H, J = 7.0 Hz), 7.25 (d, 2H, J = 10 Hz), 7.30–7.55 (m,
3H), 7.80 (d, 1H, J = 7.0 Hz), 7.98 (d, 1H, J = 8.0 Hz), 8.25
(d, 1H, J = 8.0 Hz); 13C NMR (d) DMSO-d6 : 17.8 (C-18),
23.5 (C-17), 69.9 (C-20), 116.2 (C-30 and C-50), 121.1 (C-10),
122.3 (C-5), 124.9 (C-6), 125.8 (C-16), 127.4 (C-7), 129.4
(C-14 and C-15), 130.2 (C-20 and C-60), 131.4 (C-13), 131.7
(C-12), 135.5 (C-11), 137.6 (C-10), 142.5 (C-9), 150.5 (C-8),
152.6 (C-40), 154.2 (C-2), 161.1 (C-21), 163.5 (C-4); MS (m/
z): 504.44 (M? ? 1).
8-((1-benzyl-1H-tetrazol-5-yl) methoxy)-2-methyl-3-o-
tolylquinazolin-4(3H)-one (8a0)
IR (KBr) tmax (cm-1): 3100 (w, Ar C–Hstr), 2950 (s, CH3,
C–Hstr), 1680 (s, cyclic C=Ostr), 1610 (w, C=Nstr), 1515 (w,
N=N–Nstr, tetrazole), 1420 (w, Ar C=Cstr), 1230 (s, C–Ostr);
1H NMR (d) DMSO-d6 : 2.11 (s, 3H, CH3 of quinazoline),
2.40 (s, 3H, Ar–CH3), 4.55 (s, 2H, OCH2), 5.50 (s, 2H, N–
CH2), 7.20 (d, 1H, J = 7.5 Hz), 7.25-7.55 (m, 6H), 7.65 (d,
1H, J = 7.5 Hz), 7.80 (d, 2H), 8.0 (d, 1H, J = 8.0 Hz), 8.25
(d, 1H, J = 8.0 Hz); 13C NMR (d) DMSO-d6 : 18.5 (C-18),
24.1(C-17), 50.5 (–CH2 of benzyl), 66.8 (C-20), 120.5 (C-
10), 121.2 (C-5), 123.4 (C-6), 125.5 (C-40), 126.2 (C-16),
126.9 (C-20 and C-60), 127.1 (C-7), 128.1 (C-30 and C-50),
129.2 (C-14 and C-15), 130.4 (C-13), 133.4 (C-12), 134.4
(C-10), 136.2 (C-11), 142.7 (C-9), 151.2 (C-8), 152.2 (C-21),
153.6 (C-2), 161.5 (C-4); MS (m/z): 439.25 (M? ? 1).
General procedure for the synthesis of compounds (8a–
8i, 8a0–8i0)
To an oven-dried, round-bottomed flask under dry atmosphere
were added 8-((1H-tetrazol-5-yl) methoxy)-2-methyl-3-o-tol-
ylquinazolin-4(3H)-one (543.7 mg, 1.5 mmol) (5) and
substituted aromatic and heteroaromatic methyl chloride
[8a–8a0(189.8 mg)/8b–8b0(210.9 mg)/(8c–8c0)–(8e–8e0)
(241.5 mg)/8f–8f0(293.2 mg)/(8g–8g0)–(8i–8i0) (191.3 mg),
1.5 mmol]. The flask was sealed with a rubber septum.
Anhydrous acetonitrile (10 mL) was added via syringe to
form white slurry. Triethylamine (0.32 mL, 230 mg,
2.3 mmol) was added via syringe, and the mixture was stir-
red at room temperature for 24 h. The reaction was moni-
tored by TLC (silica gel/1:1 ethyl acetate:hexane; 2,5-
disubstituted product (8a–8i) Rf—0.4, 1,5-disubstituted
product (8a0–8i0) Rf—0.3). Brine (15 mL) was added to
quench the reaction and the mixture was transferred to a
separatory funnel and then extracted with ethyl acetate. The
combined organic extracts were dried over sodium sulphate,
filtered and concentrated. The regioisomeric disubstituted
2-methyl-8-((2-(2-methylbenzyl)-2H-tetrazol-5-yl)
methoxy)-3-o-tolylquinazolin-4(3H)-one (8b)
IR (KBr) tmax (cm-1): 3140, 3100 (s, Ar C–Hstr), 2930 (s,
CH3, C–Hstr), 1950–1600 (w, overtones, Ar C–Hstr), 1680
(s, cyclic C=Ostr), 1620 (w, C=Nstr), 1475 (w, N=N–Nstr,
tetrazole), 1445 (w, Ar C=Cstr), 1205 (s, C–Ostr), 746 (w,
1
Phenyl C–Hstr); H NMR (d) DMSO-d6 : 2.25 (s, 3H, CH3
of quinazoline), 2.30 (s, 3H, Ar–CH3), 2.50 (s, 3H, Ar–
CH3), 4.65 (s, 2H, OCH2), 6.20 (s, 2H, N–CH2), 6.95 (d,
1H, J = 7.0 Hz), 7.10-7.40 (m, 5H), 7.60 (d, 2H,
123

Med Chem Res
8-((1-(2-chlorobenzyl)-1H-tetrazol-5-yl) methoxy)-2-
methyl-3-o-tolylquinazolin-4(3H)-one (8c0)
J = 7.8 Hz), 7.78 (d, 1H, J = 7.0 Hz), 7.90 (d, 1H,
J = 8.0 Hz), 8.20 (d, 1H, J = 8.0 Hz); 13C NMR (d)
DMSO-d6 : 17.5 (C-18), 20.5 (2-CH3C6H4), 24.7 (C-17)
56.2 (C-20), 73.1 (–CH2 of benzyl), 120.2 (C-10), 121.4
(C-5), 123.8 (C-20), 124.6 (C-6), 125.9 (C-50), 126.8
(C-16), 127.5 (C-7), 128.3 (C-14 and C-15), 129.1 (C-30),
130.3 (C-40), 131.3 (C-60), 131.5 (C-13), 133.2 (C-12),
135.6 (C-11), 137.6 (C-10), 144.4 (C-9), 149.8 (C-8), 152.2
(C-2), 160.2 (C-21), 162.5 (C-4); MS (m/z): 453.33
(M? ? 1).
IR (KBr) tmax (cm-1): 3119 (s, Ar C–Hstr), 2925 (s, CH3,
C–Hstr), 1737 (s, cyclic C=Ostr), 1625 (w, C=Nstr), 1550 (w,
N=N–Nstr, tetrazole), 1205 (s, C–Ostr), 740 (w, Ar C–Cl);
1H NMR (d) DMSO-d6 : 2.25 (s, 3H, CH3 of quinazoline),
2.35 (s, 3H, Ar–CH3), 4.40 (s, 2H, OCH2), 5.30 (s, 2H, N–
CH2), 7.10 (d, 1H, J = 7.0 Hz), 7.10–7.55 (m, 5H), 7.70
(d, 1H, J = 7.0 Hz), 7.84 (d, 2H, J = 7.8 Hz), 7.90 (d, 1H,
J = 8.5 Hz), 8.15 (d, 1H, J = 8.0 Hz); 13C NMR (d)
DMSO-d6 : 17.6 (C-18), 24.2 (C-17), 51.3 (C-20), 66.7
(-CH2of benzyl), 120.8 (C-10), 122.4 (C-5), 124.5 (C-6),
124.5 (C-20), 126.4 (C-16), 127.2 (C-7), 127.5 (C-50), 128.3
(C-14 and C-15), 130.2 (C-40) 131.4 (C-30), 131.6 (C-13),
132.5 (C-60), 132.9 (C-10), 134.5 (C-12), 135.5 (C-11),
143.2 (C-9), 148.8 (C-8), 152.2 (C-21), 154.4 (C-2), 160.8
(C-4); MS (m/z): 473.50 (M? ? 1 for 35Cl), 474.85
(M? ? 1 for 37Cl).
2-methyl-8-((1-(2-methylbenzyl)-1H-tetrazol-5-yl)
methoxy)-3-o-tolylquinazolin-4(3H)-one (8b0)
IR (KBr) tmax (cm-1): 3150, 3120 (s, Ar C–Hstr), 2900 (s,
CH3, C–Hstr), 1900–1600 (w, overtones, Ar C–Hstr), 1640
(s, cyclic C=Ostr), 1610 (w, C=Nstr), 1510 (w, N=N–Nstr,
tetrazole), 1445, 1414 (w, Ar C=Cstr), 1220 (s, C–Ostr), 740
1
(w, Phenyl C–Hstr); H NMR (d) DMSO-d6 : 2.15 (s, 3H,
CH3 of quinazoline), 2.25 (s, 3H, Ar–CH3), 2.64 (s, 3H,
Ar–CH3), 4.60 (s, 2H, OCH2), 5.40 (s, 2H, N–CH2), 7.15
(d, 1H, J = 7.5 Hz), 7.25–7.45 (m, 5H), 7.65 (d, 2H,
J = 8.1 Hz), 7.78 (d, 1H, J = 7.5 Hz), 7.84 (d, 1H,
J = 8.5 Hz), 8.22 (d, 1H, J = 8.0 Hz); 13C NMR (d)
DMSO-d6 : 17.2 (C-18), 21.1 (2-CH3C6H4), 24.2 (C-17),
51.4 (C-20), 66.1 (–CH2 of benzyl), 120.5 (C-10), 121.1
(C-5), 123.5 (C-20), 124.4 (C-6), 125.9 (C-50), 126.6 (C-
16), 127.1 (C-7), 128.6 (C-14 and C-15), 129.1 (C-30),
130.5 (C-40), 131.3 (C-60), 131.8 (C-13), 133.4 (C-12),
135.3 (C-11), 137.2 (C-10), 145.4 (C-9), 150.2 (C-8), 152.2
(C-21), 153.5 (C-2), 162.6 (C-4); MS (m/z): 453.32
(M? ? 1).
8-((2-(3-chlorobenzyl)-2H-tetrazol-5-yl) methoxy)-2-
methyl-3-o-tolylquinazolin-4(3H)-one (8d)
IR (KBr) tmax (cm-1): 3096 (s, Ar C–Hstr), 2885 (s, CH3,
C–Hstr), 1712 (s, cyclic C=Ostr), 1636 (w, C=Nstr), 1525 (w,
N=N–Nstr, tetrazole), 1210 (s, C–Ostr), 820 (w, Ar C–Cl);
1H NMR (d) DMSO-d6 : 2.10 (s, 3H, CH3 of quinazoline),
2.34 (s, 3H, Ar–CH3), 4.53 (s, 2H, OCH2), 5.95 (s, 2H, N–
CH2), 7.05 (d, 1H, J = 7.5 Hz), 7.10–7.45 (m, 4H), 7.50
(d, 1H, J = 7.5 Hz), 7.63 (s, 1H), 7.82 (d, 2H,
J = 7.8 Hz), 7.91 (d, 1H, J = 8.0 Hz), 8.18 (d, 1H,
J = 8.5 Hz); 13C NMR (d) DMSO-d6 : 18.5 (C-18), 25.1
(C-17), 57.2 (C-20), 72.2 (–CH2 of benzyl), 120.5 (C-10),
122.4 (C-5), 124.5 (C-6), 125.2 (C-40), 126.2 (C-16), 127.0
(C-7), 127.2 (C-60), 128.8 (C-14 and C-15), 129.2 (C-20),
129.8 (C-50), 131.1 (C-13), 132.3 (C-10), 134.6 (C-30),
134.9 (C-12), 136.5 (C-11), 142.5 (C-9), 149.4 (C-8), 153.3
(C-2), 160.5 (C-21), 161.5 (C-4); MS (m/z): 473.85
(M? ? 1 for 35Cl), 474.95 (M? ? 1 for 37Cl).
8-((2-(2-chlorobenzyl)-2H-tetrazol-5-yl) methoxy)-2-
methyl-3-o-tolylquinazolin-4(3H)-one (8c)
IR (KBr) tmax (cm-1): 3142, 3115 (s, Ar C–Hstr), 2950 (s,
CH3, C–Hstr), 1748 (s, cyclic C=Ostr), 1634 (w, C=Nstr),
1555 (w, N=N–Nstr, tetrazole), 1200 (s, C–Ostr), 746 (w, Ar
1
C–Cl); H NMR (d) DMSO-d6 : 2.22 (s, 3H, CH3 of qui-
8-((1-(3-chlorobenzyl)-1H-tetrazol-5-yl) methoxy)-2-
methyl-3-o-tolylquinazolin-4(3H)-one (8d0)
nazoline), 2.44 (s, 3H, Ar–CH3), 4.65 (s, 2H, OCH2), 5.90
(s, 2H, N–CH2), 7.15 (d, 1H, J = 7.5 Hz), 7.10-7.55 (m,
5H), 7.70 (d, 1H, J = 7.5 Hz), 7.80 (d, 2H, J = 8.2 Hz),
7.90 (d, 1H, J = 8.5 Hz), 8.10 (d, 1H, J = 8.0 Hz); 13C
NMR (d) DMSO-d6 : 18.6 (C-18), 25.2 (C-17), 57.3 (C-
21), 70.7 (–CH2 of benzyl), 121.2 (C-10), 122.5 (C-5),
124.4 (C-6), 124.7 (C-20), 126.3 (C-16), 127.3 (C-7), 127.5
(C-50), 127.9 (C-14 and C-15), 129.8 (C-40), 131.3 (C-13),
131.7 (C-30), 132.5 (C-60), 133.4 (C-10), 134.6 (C-12),
135.5 (C-11), 144.2 (C-9), 148.8 (C-8), 152.2 (C-2), 158.8
(C-21), 162.5 (C-4); MS (m/z): 473.55 (M? ? 1 for 35Cl),
474.80 (M? ? 1 for 37Cl).
IR (KBr) tmax (cm-1): 3060 (s, Ar C–Hstr), 2935 (s, CH3,
C–Hstr), 1702 (s, cyclic C=Ostr), 1626 (w, C=Nstr), 1515 (w,
N=N–Nstr, tetrazole), 1205 (s, C–Ostr), 822 (w, Ar C–Cl);
1H NMR (d) DMSO-d6 : 2.12 (s, 3H, CH3 of quinazoline),
2.32 (s, 3H, Ar–CH3), 4.52 (s, 2H, OCH2), 5.40 (s, 2H, N–
CH2), 7.08 (d, 1H, J = 7.5 Hz), 7.10–7.45 (m, 4H), 7.53
(d, 1H, J = 7.5 Hz), 7.65 (s, 1H), 7.81(d, 2H, J = 8.2 Hz),
7.90 (d, 1H, J = 8.0 Hz), 8.10 (d, 1H, J = 8.5 Hz); 13C
NMR (d) DMSO-d6 : 17.5 (C-18), 24.5 (C-17), 49.2 (C-
20), 68.5 (–CH2 of benzyl), 120.8 (C-10), 122.6 (C-5),
123

Med Chem Res
1
124.1 (C-6), 125.8 (C-40), 126.8 (C-16), 127.1 (C-60), 127.6
(C-7), 128.4 (C-14 and C-15), 129.5 (C-20), 129.7 (C-50),
131.4 (C-13), 132.5 (C-10), 134.4 (C-12), 135.1 (C-30),
136.2 (C-11), 143.5 (C-9), 148.6 (C-8), 150.0 (C-21), 152.5
(C-2), 163.4 (C-4); MS (m/z): 473.65 (M? ? 1 for 35Cl),
474.75 (M? ? 1 for 37Cl).
C–Cl); H NMR (d) DMSO-d6 : 2.19 (s, 3H, CH3 of qui-
nazoline), 2.38 (s, 3H, Ar–CH3), 4.70 (s, 2H, OCH2), 5.95
(s, 2H, N–CH2), 7.05 (d, 1H, J = 7.0 Hz), 7.15 (d, 1H,
J = 7.8 Hz), 7.18-7.55 (m, 3H), 7.62 (d, 1H, J = 7.0 Hz),
7.78 (s, 2H), 7.95 (d, 1H, J = 8.0 Hz), 8.10 (d, 1H,
J = 7.8 Hz), 8.15 (d, 1H, J = 8.0 Hz); 13C NMR (d)
DMSO-d6 : 17.5 (C-18), 24.2 (C-17), 55.8 (C-20), 70.5
(–CH2 of benzyl), 121.2 (C-10), 122.5 (C-5), 124.4 (C-6),
126.5 (C-16), 127.0 (C-7), 127.9 (C-14 and C-15), 128.5
(C-60), 129.2 (C-40), 130.0 (C-20), 130.5 (C-50), 130.8
(C-13), 132.5 (C-30), 134.6 (C-12), 135.1 (C-10), 136.5 (C-
11), 145.5 (C-9), 151.6 (C-8), 153.3 (C-2), 160.0 (C-21),
162.6 (C-4); MS (m/z): 473.25 (M? ? 1 for 35,35Cl),
474.95 (M? ? 1 for 35,37Cl), 476.33 (M? ? 1 for 37,37Cl).
8-((2-(4-chlorobenzyl)-2H-tetrazol-5-yl) methoxy)-2-
methyl-3-o-tolylquinazolin-4(3H)-one (8e)
IR (KBr) tmax (cm-1): 3133 (s, Ar C–Hstr), 2927 (s, CH3,
C–Hstr), 1749 (s, cyclic C=Ostr), 1624 (w, C=Nstr), 1530 (w,
N=N–Nstr, tetrazole), 1195 (s, C–Ostr), 846 (w, Ar C–Cl);
1H NMR (d) DMSO-d6 : 2.14 (s, 3H, CH3 of quinazoline),
2.45 (s, 3H, Ar–CH3), 4.60 (s, 2H, OCH2), 6.12 (s, 2H, N–
CH2), 7.10 (d, 1H, J = 7.5 Hz), 7.10–7.45 (m, 3H), 7.66
(d, 1H, J = 7.5 Hz), 7.70 (d, 2H, J = 8.8 Hz), 7.95 (d, 1H,
J = 8.0 Hz), 8.10 (d, 2H, J = 8.8 Hz), 8.18 (d, 1H,
J = 8.0 Hz); 13C NMR (d) DMSO-d6 : 16.9 (C-18), 22.8
(C-17), 57.1 (C-20), 71.6 (–CH2 of benzyl), 121.4 (C-10),
122.5 (C-5), 124.5 (C-6), 126.6 (C-16), 127.6 (C-7), 128.1
(C-14 and C-15), 128.5 (C-30 and C-50), 130.0 (C-20 and
C-60), 131.5 (C-40), 132.2 (C-13), 133.5 (C-12), 134.6 (C-
10), 135.5 (C-11), 145.5 (C-9), 150.5 (C-8), 152.2 (C-2),
161.1 (C-21), 162.5 (C-4); MS (m/z): 473.90 (M? ? 1 for
35Cl), 475.10 (M? ? 1 for 37Cl).
8-((1-(3,4-dichlorobenzyl)-1H-tetrazol-5-yl)methoxy)-
2-methyl-3-o-tolylquinazolin-4(3H)-one (8f0)
IR (KBr) tmax (cm-1): 3107 (s, Ar C–Hstr), 2942 (s, CH3,
C–Hstr), 1725 (s, cyclic C=Ostr), 1625 (w, C=Nstr), 1523 (w,
N=N–Nstr, tetrazole), 1211 (s, C–Ostr), 848, 824 (w, Ar C–
1
Cl); H NMR (d) DMSO-d6 : 2.16 (s, 3H, CH3 of qui-
nazoline), 2.40 (s, 3H, Ar–CH3), 4.52 (s, 2H, OCH2), 5.35
(s, 2H, N–CH2), 7.04 (d, 1H, J = 7.0 Hz), 7.14 (d, 1H,
J = 7.8 Hz), 7.18-7.55 (m, 3H), 7.60 (d, 1H, J = 7.0 Hz),
7.75 (s, 2H), 7.95 (d, 1H, J = 8.5 Hz), 8.15 (d, 1H,
J = 7.8 Hz), 8.25 (d, 1H, J = 8.0 Hz); 13C NMR (d)
DMSO-d6 : 17.1 (C-18), 25.2 (C-17), 50.5 (C-20), 67.5
(–CH2 of benzyl), 120.9 (C-10), 122.2 (C-5), 124.5 (C-6),
126.5 (C-16), 127.4 (C-7), 128.2 (C-60), 128.7 (C-14 and
C-15), 129.5 (C-40), 130.2 (C-20), 130.5 (C-50), 131.2 (C-
13), 132.5 (C-30), 133.9 (C-12), 135.4 (C-10), 136.3 (C-11),
144.5 (C-9), 150.2 (C-20), 151.3 (C-8), 154.0 (C-2), 161.5
(C-4); MS (m/z): 473.35 (M? ? 1 for 35,35Cl), 474.88
(M? ? 1 for 35,37Cl), 476.20 (M? ? 1 for 37,37Cl).
8-((1-(4-chlorobenzyl)-1H-tetrazol-5-yl) methoxy)-2-
methyl-3-o-tolylquinazolin-4(3H)-one (8e0)
IR (KBr) tmax (cm-1): 3138 (s, Ar C–Hstr), 2957 (s, CH3,
C–Hstr), 1746 (s, cyclic C=Ostr), 1645 (w, C=Nstr), 1510 (w,
N=N–Nstr, tetrazole), 1232 (s, C–Ostr), 852 (w, Ar C–Cl);
1H NMR (d) DMSO-d6 : 2.24 (s, 3H, CH3 of quinazoline),
2.46 (s, 3H, Ar–CH3), 4.68 (s, 2H, OCH2), 5.50 (s, 2H, N–
CH2), 7.10 (d, 1H, J = 7.5 Hz), 7.10-7.45 (m, 3H), 7.60 (d,
1H, J = 7.5 Hz), 7.72 (d, 2H, J = 8.8 Hz), 7.92 (d, 1H,
J = 8.0 Hz), 8.05 (d, 2H, J = 8.8 Hz), 8.15 (d, 1H,
J = 8.0 Hz); 13C NMR (d) DMSO-d6 : 17.8 (C-18), 22.5
(C-17), 51.5 (C-20), 68.6 (–CH2 of benzyl), 120.8 (C-10),
122.2 (C-5), 124.5 (C-6), 126.6 (C-16), 127.5 (C-7), 128.2
(C-14 and C-15), 128.5 (C-30 and C-50), 130.1 (C-20 and
C-60), 131.5 (C-40), 131.9 (C-13), 133.8 (C-12), 134.6 (C-
10), 135.7 (C-11), 142.5 (C-9), 149.6 (C-8), 150.2 (C-21),
153.6 (C-2), 160.8 (C-4); MS (m/z): 473.70 (M? ? 1 for
35Cl), 474.45 (M? ? 1 for 37Cl).
2-methyl-8-((2-(pyridin-2-ylmethyl)-2H-tetrazol-5-yl)
methoxy)-3-o-tolylquinazolin-4(3H)-one (8g)
IR (KBr) tmax (cm-1): 3097, 3092 (s, Ar C–Hstr), 2920 (s,
CH3, C–Hstr), 1744 (s, cyclic C=Ostr), 1620 (w, C=Nstr),
1510 (w, N=N–Nstr, tetrazole), 1450 (w, Ar C=Cstr), 1250 (s,
1
C–Ostr), 796, 744 (s, pyridine); H NMR (d) DMSO-d6 :
2.19 (s, 3H, CH3 of quinazoline), 2.50 (s, 3H, Ar–CH3), 4.58
(s, 2H, OCH2), 6.00 (s, 2H, N–CH2), 7.05 (d, 1H,
J = 8.0 Hz), 7.20–7.55 (m, 3H), 7.65 (d, 1H, J = 8.0 Hz),
7.90 (d, 1H, J = 8.5 Hz), 8.05 (t, 2H, J = 7.7, 4.8, 1.7 Hz),
8.10 (d, 1H, J = 8.0 Hz), 8.21 (d, 1H, J = 7.8 Hz), 8.65 (d,
1H, J = 4.8 Hz); 13C NMR (d) DMSO-d6 : 17.5 (C-18),
23.5 (C-17), 57.2 (C-20), 72.2 (–CH2 of pyridin-2-yl
methyl)), 121.2 (C-10), 122.4 (C-5), 122.7 (C-40), 124.6 (C-
6), 125.6 (C-50), 126.5 (C-16), 127.5 (C-7), 128.9 (C-14 and
C-15), 131.5 (C-13), 134.4 (C-12), 136.5 (C-11), 137.5
8-((2-(3,4-dichlorobenzyl)-2H-tetrazol-5-yl)methoxy)-
2-methyl-3-o-tolylquinazolin-4(3H) one (8f)
IR (KBr) tmax (cm-1): 3127 (s, Ar C–Hstr), 2947 (s, CH3,
C–Hstr), 1745 (s, cyclic C=Ostr), 1628 (w, C=Nstr), 1553 (w,
N=N–Nstr, tetrazole), 1215 (s, C–Ostr), 846, 825 (w, Ar
123

Med Chem Res
(C-60), 143.3 (C-10), 146.2 (C-9), 148.6 (C-30), 150.5 (C-8),
152.5 (C-2), 160.0 (C-21), 162.5 (C-4); MS (m/z): 425.50
(M? ? 1).
(d, 1H, J = 7.0 Hz), 7.75 (t, 1H, J = 7.8, 4.9 Hz), 7.85 (d,
1H, J = 8.0 Hz), 8.15 (d, 1H, J = 8.0 Hz), 8.30 (d, 1H,
J = 7.8 Hz), 8.55 (d, 1H, J = 4.8 Hz), 8.68 (s, 1H); 13C
NMR (d) DMSO-d6 : 17.5 (C-18), 23.6 (C-17), 51.5 (C-20),
68.8 (–CH2 of pyridin-3-yl methyl), 120.8 (C-10), 121.5
(C-10), 122.8 (C-5), 124.0 (C-50), 124.6 (C-6), 126.2 (C-16),
127.2 (C-7), 129.7 (C-14 and C-15), 131.5 (C-60), 132.4
(C-13), 135.0 (C-12), 135.7 (C-11), 144.5 (C-9), 146.6
(C-20), 150.3 (C-40), 152.2 (C-21), 152.8 (C-8), 156.6 (C-2),
162.6 (C-4); MS (m/z): 425.25 (M? ? 1).
2-methyl-8-((1-(pyridin-2-ylmethyl)-1H-tetrazol-5-yl)
methoxy)-3-o-tolylquinazolin-4(3H)-one (8g0)
IR (KBr) tmax (cm-1): 3079 (s, Ar C–Hstr), 2938 (s, CH3, C–
Hstr), 1704 (s, cyclic C=Ostr), 1623 (w, C=Nstr), 1528 (w,
N=N–Nstr, tetrazole), 1460 (w, Ar C=Cstr), 1208 (s, C–Ostr),
786, 742 (s, pyridine); 1H NMR (d) DMSO-d6 : 2.24 (s, 3H,
CH3 of quinazoline), 2.56 (s, 3H, Ar–CH3), 4.54 (s, 2H,
OCH2), 5.33 (s, 2H, N–CH2), 7.02 (d, 1H, J = 8.0 Hz),
7.20–7.55 (m, 3H), 7.60 (d, 1H, J = 8.0 Hz), 7.88 (d, 1H,
J = 8.5 Hz), 8.08 (t, 2H, J = 7.7, 4.8, 1.3 Hz), 8.15 (d, 1H,
J = 8.5 Hz), 8.25 (d, 1H, J = 7.8 Hz), 8.60 (d, 1H,
J = 4.5 Hz); 13C NMR (d) DMSO-d6 : 17.2 (C-18), 23.8 (C-
17), 52.2 (C-20), 69.5 (–CH2 of pyridin-2-yl methyl), 120.9
(C-10), 122.5 (C-5), 122.7 (C-40), 124.6 (C-6), 125.5 (C-50),
126.5 (C-16), 127.8 (C-7), 128.2 (C-14 and C-15), 131.3 (C-
13), 134.6 (C-12), 135.8 (C-11), 137.7 (C-60), 142.5 (C-10),
144.4(C-9),148.9(C-30),150.0(C-8), 152.5(C-21), 154.2(C-
2), 161.4 (C-4); MS (m/z): 425.24 (M? ? 1).
2-methyl-8-((2-(pyridin-4-ylmethyl)-2H-tetrazol-5-yl)
methoxy)-3-o-tolylquinazolin-4(3H) one (8i)
IR (KBr) tmax (cm-1): 3188 (s, Ar C–Hstr), 2950 (s, CH3,
C–Hstr), 1705 (s, cyclic C=Ostr), 1640 (w, C=Nstr), 1520 (w,
N=N–Nstr, tetrazole), 1202 (s,C–Ostr); 1HNMR(d)DMSO-d6 :
2.20 (s, 3H, CH3 of quinazoline), 2.51 (s, 3H, Ar–CH3), 4.53
(s, 2H, OCH2), 5.85 (s, 2H, N–CH2), 7.10 (d, 1H,
J = 7.0 Hz), 7.10-7.45 (m, 3H), 7.55 (d, 1H, J = 7.0 Hz),
7.78 (d, 2H, J = 6.0 Hz), 7.92 (d, 1H, J = 8.0 Hz), 8.15
(d, 1H, J = 8.0 Hz), 8.45 (d, 2H, J = 6.0 Hz); 13C NMR (d)
DMSO-d6 : 17.3 (C-18), 24.4 (C-17), 55.5 (C-20), 73.5 (–CH2
of pyridin-4-yl methyl), 120.6 (C-20), 121.3 (C-10), 122.5
(C-5), 124.7(C-6), 126.6(C-16), 127.5 (C-7), 127.8(C-14 and
C-15), 130.8 (C-13), 134.4 (C-12), 136.6 (C-11), 138.5 (C-10),
146.5 (C-9), 148.5 (C-30), 150.0 (C-8), 152.5 (C-2), 159.6
(C-21), 164.0 (C-4); MS (m/z): 425.11 (M? ? 1).
2-methyl-8-((2-(pyridin-3-ylmethyl)-2H-tetrazol-5-yl)
methoxy)-3-o-tolylquinazolin-4(3H) one (8h)
IR (KBr) tmax (cm-1): 3095, 3086 (s, Ar C–Hstr), 2920 (s,
CH3, C–Hstr), 1704 (s, cyclic C=Ostr), 1635 (w, C=Nstr), 1528
(w, N=N–Nstr, tetrazole), 1480 (w, Ar C=Cstr), 1220 (s,
2-methyl-8-((1-(pyridin-4-ylmethyl)-1H-tetrazol-5-yl)
methoxy)-3-o-tolylquinazolin-4(3H)-one (8i0)
1
C–Ostr); H NMR (d) DMSO-d6 : 2.10 (s, 3H, CH3 of qui-
nazoline), 2.36 (s, 3H, Ar–CH3), 4.68 (s, 2H, OCH2), 6.10 (s,
2H, N–CH2), 7.05 (d, 1H, J = 7.0 Hz), 7.20–7.45 (m, 3H),
7.60 (d, 1H, J = 7.0 Hz), 7.77 (t, 1H, J = 7.9, 4.9 Hz), 7.90
(d, 1H, J = 8.5 Hz), 8.10 (d, 1H, J = 8.0 Hz), 8.35 (d, 1H,
J = 7.9 Hz), 8.45 (d, 1H, J = 4.9 Hz), 8.75 (s, 1H); 13C
NMR (d) DMSO-d6 : 18.5 (C-18), 24.5 (C-17), 57.6 (C-20),
70.8 (–CH2 of pyridin-3-yl methyl), 121.2 (C-10), 121.8 (C-
10), 122.5 (C-5), 124.4 (C-6), 126.4 (C-50), 127.0 (C-16),
127.5 (C-7), 129.6 (C-14 and C-15), 131.2 (C-60), 131.8 (C-
13), 135.0 (C-12), 135.8 (C-11), 145.5 (C-9), 147.6 (C-20),
150.0 (C-40), 152.5 (C-8), 157.4 (C-2), 160.4 (C-21), 163.6
(C-4); MS (m/z): 425.10 (M? ? 1).
IR(KBr)tmax (cm-1):3120, 3055(s, ArC–Hstr), 2910(s, CH3,
C–Hstr), 1725 (s, cyclic C=Ostr), 1635 (w, C=Nstr), 1545 (w,
N=N–Nstr, tetrazole), 1230 (s,C–Ostr); 1HNMR(d)DMSO-d6 :
2.22 (s, 3H, CH3 of quinazoline), 2.37 (s, 3H, Ar–CH3), 4.59
(s, 2H, OCH2), 5.25 (s, 2H, N–CH2), 7.05 (d, 1H,
J = 7.5 Hz), 7.10–7.40 (m, 3H), 7.55 (d, 1H, J = 7.5 Hz),
7.80 (d, 2H, J = 6.5 Hz), 7.90 (d, 1H, J = 8.0 Hz), 8.25
(d, 1H, J = 8.0 Hz), 8.40 (d, 2H, J = 6.5 Hz); 13C NMR (d)
DMSO-d6 : 17.5 (C-18), 23.4 (C-17), 50.5 (C-20), 68.6 (–CH2
of pyridin-4-yl methyl), 120.8 (C-20), 121.5 (C-10), 122.2 (C-
5), 124.0 (C-6), 125.8 (C-16), 127.0 (C-7), 127.6 (C-14 and
C-15), 131.5 (C-13), 133.3 (C-12), 135.6 (C-11), 138.8 (C-10),
145.5 (C-9), 147.7 (C-30), 150.6 (C-8), 151.5 (C-21), 152.7
(C-2), 160.6 (C-4); MS (m/z): 425.30 (M? ? 1).
2-methyl-8-((1-(pyridin-3-ylmethyl)-1H-tetrazol-5-yl)
methoxy)-3-o-tolylquinazolin-4(3H) one (8h0)
IR (KBr) tmax (cm-1): 3108 (s, Ar C–Hstr), 2926 (s, CH3,
C–Hstr), 1714 (s, cyclic C=Ostr), 1644 (w, C=Nstr), 1521(w,
N=N–Nstr, tetrazole), 1485 (w, Ar C=Cstr), 1195 (s, C–Ostr);
1H NMR (d) DMSO-d6 : 2.20 (s, 3H, CH3 of quinazoline),
2.35 (s, 3H, Ar–CH3), 4.78 (s, 2H, OCH2), 5.42 (s, 2H,
N–CH2), 7.02 (d, 1H, J = 7.0 Hz), 7.20-7.45 (m, 3H), 7.55
Pharmacology
Albino Rat (Wistar, 150–200 g), Albino mice (Swiss,
25–30 g) were used in groups as experimental animals. The
test compounds and standard drug were suspended in
Tween 80 (1 %) or in a 0.5 % methyl cellulose-water
123

Med Chem Res
mixture and administered intraperitoneally. Animals were
housed in wire-mesh cages under the laboratory conditions
(26 2 °C), 12–12 h light/dark. Animals were allowed to
acclimatize with free access to food and water for a 24 h
period before testing. All the experimental protocols were
carried out with the permission of the Institutional Animal
Ethics Committee (IAEC). Animals were obtained from the
Central Animal House Facility (173/CPCSEA, 28 Jan.,
2000), Jamia Hamdard, New Delhi, India.
protection or minimal neurotoxicity. From the plot of the
data obtained, the respective ED50 and TD50 values, 95 %
confidence intervals, slope of the regression line and
standard error of the slope were calculated by means of a
computer program (Litchfield and Wilcoxon, 1949).
Hepatotoxicity studies
The animals were divided into groups of six, and the
control group received a basal diet and vehicle. Other
groups were administered the test drug in a dose of 30 mg/
kg/day oral (in PEG 400 or 2 % methylcellulose) for
14 days. After the specified period, each animal was
anaesthetized by anaesthetic ether, and blood was collected
by cardiac puncture to assess the transaminase activity. The
in vitro determination of transaminase activity was carried
out according to the 2,4-dinitrophenyl hydrazine method
using SPAN diagnostic reagent kits (Nydick et al., 1955;
Reitman and Frankel, 1957).
Maximal electroshock test (MES)
In the MES screen, an electrical stimulus of 0.2 s in duration
(50 mA in mice and 150 mA in rat at 60 Hz) is delivered via
corneal electrodes primed with an electrolyte solution con-
taining an anaesthetic agent (Krall et al., 1978).
Subcutaneous pentylenetetrazole seizure test (scPTZ)
This screen utilizes a dose of pentylenetetrazole (85 mg/kg
in mice and 70 mg/kg in rats) that produces clonic seizures
lasting for a period of at least 5 s in 97 % (CD97) of animals
tested. At the anticipated time of testing, the convulsant is
administered subcutaneously. All the compounds were
injected intraperitoneally into mice at the dose levels of 30,
100 and 300 mg/kg, with anticonvulsant activity and
neurotoxicity assessment at 0.5 and 4 h after administration.
Selected derivatives were administrated orally into rats
using four animals at a fixed dose of 30 (MES test) and
50 mg/kg (scPTZ test). This screen discloses the time of
onset, the approximate time of peak effect (TPE) and the
duration of anticonvulsant activity. For both doses the
motor impairment was studied in parallel. Rats were tested
at five time periods ranging from one quarter to 4 h post
substance administration (Clark et al., 1984).
Acknowledgments The authors are thankful to Jamia Hamdard
New Delhi, India for providing facility for research work. The author
is thankful to IIT Delhi and CDRI Lucknow for spectral and ele-
mental data along with Fortis Hospital for Liver toxicity studies. One
of the authors (Sachin Malik) expresses thanks to Central Scientific
Industrial Research (CSIR) New Delhi, India for the award of Senior
Research Fellowship (SRF) as financial assistance.
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