Design, synthesis, and anticonvulsant activity of novel quinazolinone analogues

Article abstract of DOI:10.1007/s00044-010-9465-4

A number of 2-substituted and 2,3-disubstituted quinazolinone analogues have been synthesized. Their structures have been elucidated on the basis of elemental analyses and spectroscopic studies (IR, ¹H NMR, and MS). An evaluation of the anticon

Full text of DOI:10.1007/s00044-010-9465-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1280–1286
DOI 10.1007/s00044-010-9465-4
ORIGINAL RESEARCH
Design, synthesis, and anticonvulsant activity of novel
quinazolinone analogues
•
Nagwa M. Abdel Gawad Hanan Hanna Georgey
•
•
Riham M. Youssef Nehad A. El Sayed
Received: 13 June 2010 / Accepted: 1 October 2010 / Published online: 24 October 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A number of 2-substituted and 2,3-disubstituted
quinazolinone analogues have been synthesized. Their
structures have been elucidated on the basis of elemental
analyses and spectroscopic studies (IR, 1H NMR, and MS).
An evaluation of the anticonvulsant activity of the prepared
compounds has indicated that some of them exhibit mod-
erate to significant activity, compared to diazepam and
phenobarbital standards.
In continuation to the efforts done toward the synthesis
of potential molecules as anticonvulsant agents, our aim
was to synthesize new 2-substituted quinazolinone deriv-
atives 2–4 a–c, and 2,3-disubstituted quinazolinones 6, 7,
10 a–d, 13, 14 a, b, 15 a, b and evaluate their anticon-
vulsant potency. It was of special importance to incorporate
some moieties that were reported to potentiate the anti-
convulsant activity such as pyridazine ring (El-Helby and
Wahab, 2003), diphenyl hydantoin moiety (Hudkins et al.,
1997), valproate moiety (Luchowska et al., 2002), thiadi-
azole ring (Dogan et al., 2002), benzylidene group (Aziza
et al., 1994), and pyrazole ring (Abdel-Aziz et al., 2009) to
furnish the target compounds. Moreover, the choice of
substituents was based on their relatively high lipophilicity
as indicated from their log P values to pass the blood-brain
barrier aiming to have strong anticonvulsant activity.
Keywords Quinazolinones ꢀ Thiadiazole ꢀ Benzylidene ꢀ
Pyrazole ꢀ Triazole ꢀ Anticonvulsant activity
Introduction
The quinazolinone nucleus and its derivatives have been
extensively studied because of their wide range of phar-
macological activities. They were found to be effective as
analgesic, anti-inflammatory (Alagarsamy et al., 2007),
antihyperlipidemic (Refaie et al., 2005), antihypertensive
(Xue et al., 2004), antihyperglycemic (Ram et al., 2003),
and anticancer (Al-Obaid et al., 2009) agents. Specifically,
the 3H-quinazolin-4-one derivatives are widely known as
anticonvulsant agents as shown in compounds I, II (Misra
et al., 1980; Guan et al., 2007). Moreover, few reports
concerning the anticonvulsant activity of substituted qui-
nazolinones exemplified by III, IV have been recorded
(El-Helby and Wahab, 2003).
R
HN
S
O
N
N
O
N
N
Br
N
N
N
Ar
Br
II
I
R= C6H5, 4-OCH3 C6H4, 4-Cl C6H4
Ar= C6H5, 4-OCH3 C6H4, 4-CH3 C6H4
Cl
Cl
O
O
I
I
N
N
N
O
S
N
O
S
N. M. Abdel Gawad ꢀ H. H. Georgey (&) ꢀ
R. M. Youssef ꢀ N. A. El Sayed
HN
HN
N
Pharmaceutical Chemistry Department, Faculty of Pharmacy,
Cairo University, Kasr El-Eini Street, 11562 Cairo, Egypt
e-mail: Hanan-Hanna@hotmail.com
N
H
O
IV
III
123

Med Chem Res (2011) 20:1280–1286
Results and discussion
Chemistry
1281
Moreover, the 2-hydrazinyl-3-phenylquinazolin-4(3H)-one
11 (Alagarsamy et al., 2007) was reacted with the freshly
prepared ethoxy methylene malononitrile 12 (Akio, 1957)
to give the pyrazolo derivative 13 (Scheme 4). Finally, the
benzylidene containing compounds 14 a–c were synthe-
sized via the reaction of 2-hydrazinyl-3-phenylquinazolin-
4(3H)-one 11 with various aromatic aldehydes. Also, these
prepared compounds 14 a–c were subjected to further
cyclization to furnish the triazolo derivatives 15 a–c
(Scheme 5).
The bromomethyl quinazoline derivative 1, prepared
according to reported procedure (Spirkova et al., 1999),
was reacted with sodium phenytoin, sodium valproate, and
amino thiadiazoles to afford compounds 2, 3 and 4 a–c,
respectively (Scheme 1). In another pathway, the target
piperazine and pyridazine containing compounds 6 and 7,
respectively were obtained through the cyclization of the
acetohydrazide derivative 5 with chloroacetyl chloride
and benzoin respectively (Scheme 2). Furthermore, the
3-substituted-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones 8
a, b were synthesized according to the reported method
(El-Helby and Wahab, 2003; Lakhan and Srivastava, 1993)
and then reacted with the appropriate freshly prepared
substituted phenacyl bromides 9 i–iii (Wei et al., 2006; Lee
et al., 2004) to yield compounds 10 a–d (Scheme 3).
Anticonvulsant screening
It was done using pentylene tetrazole PTZ-induced (car-
diazole) seizures in mice in doses 50–150 mg/kg body
weight (Fisher, 1989). The results are shown in Table 1.
From the obtained results, it was observed that all the
screened compounds showed lower activity than the ref-
erence standards tested. It was noticed that in compounds
Scheme 1 Reaction conditions:
a phenytoin sodium, absolute
ethanol, reflux, 72 h; b sodium
valproate, absolute ethanol,
reflux, 48 h; c substituted
O
NH
O
CH2N
N
NH
thiadiazoles, absolute ethanol,
anhydrous K2CO3, reflux, 48 h
O
2
a
O
O
N
Cpd
4 a
4 b
4 c
R1
Cl
OCH3
N (CH3)2
b
NH
CH2O
NH
CH2Br
N
O
1
3
O
c
NH
CH2NH
S
N
R1
N
N
4 a - c
O
O
O
N
N
b
N
a
N
O
S
N
O
S
N
NHNH2
N
5
S
O
HN
HN
N
H
O
6
7
Scheme 2 Reaction conditions: a chloroacetylchloride, dry DMF, stir, 2 h, and reflux, 5 h; b benzoin, absolute ethanol, glacial acetic acid,
reflux, 4 h
123

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Med Chem Res (2011) 20:1280–1286
Cpd
10 a
10 b
10 c
10 d
R1
R2
Cl
Br
Br
OCH3
C6H5
C2H5
C6H5
C6H5
O
O
N
Br
R1
S
R2
R1
S
N
N
O
9 i- iii
O
N
H
8 a, b
a
10 a-d
R2
Scheme 3 Reaction conditions: a substituted phenacyl bromides, dry acetone, anhydrous K2CO3, reflux, 24 h
Scheme 4 Reaction conditions:
a absolute ethanol, reflux, 15 h
O
N
CN
O
H5C2OCH
N
CN
N
N
N
12
a
N
NHNH2
H2N
11
CN
13
O
N
O
O
N
b
N
N
a
N
N
N
N
NHNH2
N
N
CH
R1
H
11
Cpd
14, 15 a
14, 15 b
R1
Cl
OCH3 OCH3
R2
H
R2
14 a, b
R1
R2
15 a, b
Scheme 5 Reaction Conditions: a aromatic aldehyde, absolute ethanol, few drops piperidine, reflux, 8 h; b glacial acetic acid, anhydrous sodium
acetate, reflux, 4h
10 a–d, the highest anticonvulsant activity was shown in
the compound 10 c that bear a bromo substituent which is
in coordinate with its log P value because the bromo
derivative had higher lipophilic character than the other
compared derivatives. Moreover, both compounds 6 and 7
containing piperazine or pyridazine moiety showed nearly
the same activity as declared from their PD50 results; the
dose of the drug that protects 50% of the animals chal-
lenged. In addition, compound 13 showed anticonvulsant
activity with PD50 equals to 90 mg/kg. Interestingly, it
was drawn from the listed results that the chloro analogue
14 a showed better activity than the dimethoxy derivative
14 b which was also in conformity with their log P values
that showed that the chloro derivative was more lipophilic
than its dimethoxy analogue. This revealed that the
electron withdrawing group imparts maximum activity
and that the electron donating group markedly decreases
the anticonvulsant efficacy. It is worthwhile to note that
the tricyclic ring systems 15 a, b displayed weak anti-
convulsant effect compared to their uncyclized counter-
parts 14 a, b indicating that the cyclization process was
unfavorable to the anticonvulsant efficacy and that the
lipophilic character decreased upon cyclization as
declared from their log P values. Finally, it was con-
cluded that the quinazolone containing a phenytoin moi-
ety 2 was twice more active than that having a valproate
moiety 3. Concerning compounds 4 a–c, it was found that
the chloro substituent showed the highest activity
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Table 1 Anticonvulsant
activity of the synthesized
compounds
Compound
50 mg/kg
100 mg/kg
150 mg/kg
PD50 (mg/kg)
Log P
2
50
87.5
100
53
111
53
111
62
66
68
80
86
78
85
90
50
83
64
160
2
2.93
3.39
4.17
3.48
3.89
2.13
6.40
5.50
4.45
5.77
4.82
3.01
5.53
4.72
5.25
4.44
3.18
1.36
3
25
50
62.5
4a
50
100
100
4b
25
37.5
50
4c
37.5
75
100
6
37.5
62.5
100
7
37.5
62.5
87.5
10a
25
62.5
87.5
10b
37.5
50
87.5
10c
37.5
50
100
10d
37.5
50
87.5
13
25
50
87.5
14a
50
100
100
14b
25
62.5
87.5
15a
37.5
62.5
100
15b
12.5
37.5
50
Diazepam
Phenobarbital
25 (1 mg/kg)
37.5 (10 mg/kg)
50 (2 mg/kg)
50 (15 mg/kg)
75 (3 mg/kg)
62.5 (20 mg/kg)
16
compared to N (CH3)2 followed by the OCH3 group
confirming our previous concept.
spectrophotometer. The chemical shifts were expressed in
d ppm units using trimethylsilane as an internal standard.
The exchangeable protons OH, NH, and NH2 were
exchanged by D2O. Mass Spectra were done on Shimadzu
Qp-2010 plus. All the reactions were monitored by thin
layer chromatography. Silica gel/TLC-cards DC-Alufolien-
Kieselgel with fluorescent indicator 254 nm, layer thick-
ness 0.2 mm, 20 9 20 cm aluminum cards were used.
Petroleum ether: ethyl acetate (1:1) or (1:2) was the
adopted solvent system. Chemical name was done applying
the IUPAC system for nomenclature using Chem. Draw
Ultra program version 9.
Conclusion
The anticonvulsant screening revealed that the electron
withdrawing groups made a positive impact on the activity
when compared to the electron donating ones. Also, it was
evident that the cyclization process led to unfavorable
results. Moreover, it was found that the phenytoin moiety
increased the activity of the quinazolone derivative while
the valproate moiety inhibited it based on their PD50
results.
Preparation of 2-(bromomethyl)quinazolin-4(3H)-one (1)
(Spirkova et al., 1999)
Experimental
Synthesis of 3-(4-Oxo-3,4-dihydro-quinazolin-2-ylmethyl)-
5,5-diphenyl-imidazolidine-2,4-dione (2) A mixture of
2-(bromomethyl) quinazolin-4(3H)-one 1 (2.39 g, 10 mmol)
and sodium phenytoin (2.77 g, 10 mmol) was refluxed in
absolute ethanol (30 ml) for 72 h. The reaction mixture
was filtered while hot, the filtrate was evaporated to dry-
ness under vacuum, and the obtained solid was crystallized
from acetone, (68% yield), m.p. 251–252°C, IR (KBr,
cm-1): 3270, 3210 (2 NHs), 3066 (CH aromatic), 2923,
2857 (CH aliphatic), 1772, 1724, 1673 (C=Os), 1617 (NH
Chemistry
Melting points were carried out by the open capillary tube
method using a Gallenkamp digital melting point Griffin
apparatus 1901, and they are uncorrected. Elemental
Microanalyses were carried out using Heraew and Vario El
III (elemntar), CHNS analyzer (Germany) at the Micro
Analytical Center, Faculty of Science, Cairo University.
Infrared Spectra were done on Bruker FT-IR spectropho-
tometer Vector 22, Schimadzu 435, Perkin-Elmer 457 and
Jasco FT IR plus 460 Japan, and expressed in wave number
1
bending), 1444, 1402 (C=C), H NMR (CDCl3: d, ppm):
4.76 (s, 2H, CH2), 6.99–8.17 (m, 14H, CHs aromatic), 8.70
(s, 1H, NH), 11.54 (s, 1H, NH), MS (m/z) : 410 (M?, 0.82);
Anal. Calcd. For C24H18N4O3: C, 70.23; H, 4.42; N,
13.65%. Found: C, 70.46; H, 4.60; N, 13.69%.
(cm-1), using potassium bromide disks. H NMR Spectra
1
were carried out using a Varian Gemini 200 MHz
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Med Chem Res (2011) 20:1280–1286
Synthesis of 2-propyl-pentanoic acid 4-oxo-3,4-dihydro-
quinazolin-2-ylmethyl ester (3) A mixture of 2-(bromo-
methyl) quinazolin-4(3H)-one 1 (2.39 g, 10 mmol) and
sodium valproate (1.66 g, 10 mmol) was refluxed in
absolute ethanol (30 ml) for 48 h. The reaction mixture
was filtered while hot; the filtrate was evaporated to dry-
ness under vacuum and the obtained solid residue was
crystallized from acetone, (52% yield), m.p. 85–87°C, IR
(KBr, cm-1): 3392 (NH), 3040 (CH aromatic), 2928, 2866
(CH aliphatic), 1747, 1659 (C=Os), 1616 (NH bending),
Anal. Calcd. For C19H18N6OS: C, 60.30; H, 4.79; N,
22.21%. Found: C, 60.99; H, 4.99; N, 22.48%.
Preparation of 2-(4-oxo-3-phenyl-3,4-dihydroquinazolin-
2-ylthio)acetohydrazide (5) (Gursoy and Karalı, 2003)
¨
Synthesis of 4-(4-oxo-3-phenyl-3,4-dihydroquinazolin-
mixture of the
2-ylthio)pyridazin-3,6-dione (6)
A
acetohydrazide derivative 5 (3.26 g, 10 mmol) and chlo-
roacetylchloride (1.69 g, 1.21 ml, 15 mmol) was stirred in
dry DMF (15 mL) for 2 h at room temperature. The reaction
mixture was then refluxed for another 5 h and poured onto
crushed ice. The separated solid was filtered, washed with
water, dried, and crystallized from acetone, (52% yield),
m.p. 93–95°C; IR (KBr, cm-1): 3466 (br, NHs), 3062 (CH
aromatic), 2982, 2925 (CH aliphatic), 1741, 1685 (C=O s),
1606 (NH bending), 1576, 1550 (C=C); 1H NMR (DMSO-
d6: d, ppm): d 3.98 (t, 1H, CH, J = 13.2 Hz), 4.74 (d, 2H,
CH2, J = 13.6 Hz), 7.08–8.03 (m, 9H, CHs aromatic),
10.44, 11.60 (2s, 2H, 2NHs,); MS (m/z) : 368 (M ? 2,
0.01); Anal. Calcd. For C18H14N4O3S: C, 59.01; H, 3.85;
N, 15.29%. Found: C, 59.68; H, 3.38; N, 15.50%.
1
1580, 1466 (C=C); H NMR (DMSO-d6: d, ppm): 0.89
(t, 6H, 2 CH3, J = 6.00 Hz), 1.49 (m, 8H, 4 CH2), 2.52
(m, H, CH), 5.00 (s, 2H, OCH2), 7.49–8.14 (m, 4H, CHs
aromatic), 12.46 (s, 1H, NH,), MS (m/z) : 303 (M ? 1,
1.89); Anal. Calcd. For C17H22N2O3: C, 67.53; H, 7.33; N,
9.26%. Found: C, 67.45; H, 7.50; N, 9.20%.
Synthesis of 2-{[5-(4-substituted phenyl)-[1,3,4]thiadiazol-
2-ylamino]-methyl}-3H-quinazolin-4-ones (4 a–c)
A
mixture of 2-(bromomethyl) quinazolin-4(3H)-one 1 (2.39
g, 10 mmol) and 2-amino-5-aryl-10,30,40-thiadiazoles
(10 mmol) was refluxed in absolute ethanol (30 ml) in the
presence of anhydrous potassium carbonate (1.37 g,
10 mmol) for 48 h. The reaction mixture was filtered while
hot; the filtrate was evaporated to dryness under vacuum
and the obtained solid was crystallized from methanol.
2-{[5-(4-chlorophenyl)-[1,3,4]thiadiazol-2-ylamino]-
Synthesis of 2-(3-oxo-5,6-diphenyl-2,3,4,5-tetrahydropyridazin-
4-ylthio)-3-phenyl quinazolin-4(3H)-one (7) A mixture of
the acetohydrazide derivative 5 (3.26 g, 10 mmol) and
benzoin (2.12 g, 10 mmol) was refluxed in absolute etha-
nol (20 mL) containing few drops of glacial acetic acid for
8 h. The reaction mixture was cooled, and the obtained
solid was filtered, dried, and crystallized from acetone,
(48% yield), m.p. 240–241°C; IR (KBr, cm-1): 3289 (NH),
3061 (CH aromatic), 2922, 2859 (CH aliphatic), 1666 (br,
methyl}-3H-quinazolin-4-one (4 a): (68% yield), m.p.
192–193°C; IR (KBr, cm-1): 3284 (br, NHs), 3050 (CH
aromatic), 2922, 2852 (CH aliphatic), 1670 (C=O), 1611
1
(NH bending), 1575, 1510(C=C), 769 (C–Cl); H NMR
(DMSO-d6: d, ppm): 4.06 (s, 2H, CH2), 7.50–8.13 (m, 10H,
8 CHs aromatic ? 2NHs); Anal. Calcd. For C17H12
ClN5OS: C, 55.21; H, 3.27; N, 18.94%. Found: C, 54.90;
H, 3.50; N, 18.82%.
1
C=Os), 1603 (NH bending), 1547, 1482 (C=C); H NMR
(DMSO-d6: d, ppm): 5.11(s, 1H, C4H pyridazine), 6.15
(s, 1H, C5H pyridazine), 7.13–8.15 (m, 19H, CHs aromatic),
9.46 (s, 1H, NH); MS (m/z) : 499 (M - 3, 1.54); Anal.
Calcd. For C30H22N4O2S: C, 71.69; H, 4.41; N, 11.15%.
Found: C, 71.80; H, 4.00; N, 10.90%.
2-{[5-(4-methoxyphenyl)-[1,3,4]thiadiazol-2-ylamino]-
methyl}-3H-quinazolin-4-one (4 b)2-{[5-(4-methoxy-
phenyl)-[1,3,4]thiadiazol-2-ylamino]-methyl}-3H-quinazo-
lin-4-one (4 b): (60% yield), m.p. 235–237°C; IR (KBr,
cm-1): 3270 (br, NHs), 3085 (CH aromatic), 2958, 2921
(CH aliphatic), 1632 (C=O), 1567 (NH bending), 1512,
Preparation of 3-substituted-2-thioxo-2,3-
dihydroquinazolin-4(1H)-ones (8 a, b)
1
1462 (C=C); H NMR (DMSO-d6: d, ppm): 4.26 (s, 2H,
CH2), 7.50–8.13 (m, 8H, CHs aromatic), 8.54, 9.39 (2s, 2H,
2NHs); MS (m/z) : 368 (M ? 3, 0.01); Anal. Calcd. For
C18H15N5O2S: C, 59.16; H, 4.14; N, 19.17%. Found: C,
59.44; H, 4.04; N, 19.07%.
(El-Helby and Wahab, 2003; Lakhan and Srivastava, 1993)
Preparation of 2-bromo-1-(4-substituted-phenyl)ethanones
(9 i–iii) (Wei et al., 2006; Lee et al., 2004)
2-{[5-(4-dimethylaminophenyl)-[1,3,4]thiadiazol-2-yla-
mino]-methyl}-3H-quinazolin-4-one (4 c): (57% yield),
m.p. 145–147°C; IR (KBr, cm-1): 3388 (br, NHs), 3049
(CH aromatic), 2919, 2818 (CH aliphatic), 1660 (C=O),
1597 (NH bending), 1543, 1467 (C=C); 1H NMR (DMSO-
d6: d, ppm): 3.07 (s, 6H, 2CH3), 3.87 (s, 2H, CH2),
6.82–7.74 (m, 8H, CHs aromatic), 9.67 (s, 2H, 2NHs);
Synthesis of 2-(2-(4-substituted-phenyl)-2-oxoethylthio)-
3-substituted quinazolin-4(3H)-ones (10 a–d) A mixture
of 2-thioxo dihydroquinazolinones 8 a–d (10 mmol) and
the appropriate freshly prepared substituted phenacyl bro-
mide 9 i–iii (10 mmol) was refluxed in dry acetone (30 ml)
in the presence of anhydrous potassium carbonate (1.37 g,
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Med Chem Res (2011) 20:1280–1286
1285
10 mmol) for 24 h. The reaction mixture was then filtered
while hot, and the filtrate was evaporated to dryness. The
obtained solid was crystallized from acetone.
2921, 2853 (CH aliphatic), 2194 (CN), 1725, (C=O), 1651
1
(NH bending), 1534, 1489 (C=C); H NMR (DMSO-d6: d,
ppm): 6.95–8.45 (m, 10H, CHs aromatic), 9.88 (s, 2H,
NH2); MS (m/z): 327 (M - 1, 0.68); Anal. Calcd. For
C18H12N6O: C, 65.85; H, 3.68; N, 25.60%. Found: C,
65.98; H, 3.74; N, 25.78%.
2-(2-(4-Chlorophenyl)-2-oxoethylthio)-3-phenylquinaz-
olin-4(3H)-one (10 a): (70% yield), m.p. 195–197°C; IR
(KBr, cm-1): 3061 (CH aromatic), 2922, 2852 (CH ali-
phatic), 1722, 1663 (C=Os), 1548, 1490 (C=C), 754
1
(C–Cl); H NMR (CDCl3: d, ppm): 4.65 (s, 2H, SCH2),
Synthesis of 2-(2-(3,4-disubstituted benzylidene)hydrazi-
nyl)-3-phenylquinazolin-4(3H)-ones (14 a, b) A mixture
of 2-hydrazinyl-3-phenylquinazolin-4(3H)-one 11 (2.52 g,
10 mmol) and the appropriate aromatic aldehydes (10
mmol) was refluxed in absolute ethanol (30 ml) in the
presence of few drops of piperidine for 8 h. The reaction
mixture was filtered while hot; the filtrate was evaporated
to dryness under vacuum and the obtained solid residue
was crystallized from ethanol.
6.94–8.14 (m, 13H, CHs aromatic); Anal. Calcd. For
C22H15ClN2O2S: C, 64.94; H, 3.72; N, 6.88%. Found: C,
65.00; H, 3.90; N, 6.58%.
2-(2-(4-Bromophenyl)-2-oxoethylthio)-3-ethylquinazo-
lin-4(3H)-one (10 b): (70% yield), m.p. 153–154°C; IR
(KBr, cm-1): 3061 (CH aromatic), 2955, 2919 (CH ali-
phatic), 1665 (br, C=Os), 1584, 1510 (C=C), 696 (C–Br);
1H NMR (CDCl3: d, ppm): 1.23 (t, 3H, CH3CH2, J = 8.39
Hz), 2.53 (s, 2H, SCH2), 4.5 (q, 2H, CH3CH2, J = 7.79
Hz), 7.18–8.23 (m, 8H, CHs aromatic); Anal. Calcd. For
C18H15BrN2O2S: C, 53.61; H, 3.75; N, 6.95%. Found: C,
53.51; H, 3.79; N, 6.88%.
2-(2-(4-Chlorobenzylidene)hydrazinyl)-3-phenylquinaz-
olin-4(3H)-one (14 a): (59% yield), m.p. 140–142°C; IR
(KBr, cm-1): 3324 (NH), 3058 (CH aromatic), 2921, 2853
(CH aliphatic), 1672 (C=O), 1616 (NH bending), 1575,
1
2-(2-(4-Bromophenyl)-2-oxoethylthio)-3-phenylquinaz-
olin-4(3H)-one (10 c): (73% yield), m.p. 117–118°C; IR
(KBr, cm-1): 3059 (CH aromatic), 2920, 2851 (CH ali-
phatic), 1684 (br, C=Os), 1584, 1530 (C=C), 695 (C–Br);
1H NMR (DMSO-d6: d, ppm): 5.67(s, 2H, SCH2),
6.58–8.02 (m, 13H, CHs aromatic); MS (m/z) : 450 (M -
1, 0.37); Anal. Calcd. For C22H15BrN2O2S: C, 58.55; H,
3.35; N, 6.21%. Found: C, 58.70; H, 3.30; N, 5.90%.
2-(2-(4-Methoxyphenyl)-2-oxoethylthio)-3-phenylqui-
nazolin-4(3H)-one (10 d): (70% yield), m.p. 174–175°C;
IR (KBr, cm-1): 3059 (CH aromatic), 2955, 2920 (CH
1510 (C=C), 752 (C–Cl); H NMR (CDCl3: d, ppm): 4.65
(s, 1H, NH), 7.26–8.60 (m, 13H, CHs aromatic), 9.51 (s,
IH, CH); Anal. Calcd. For C21H15ClN4O: C, 67.29; H,
4.03; N, 14.95%. Found: C, 66.87; H, 4.46; N, 15.05%.
2-(2-(3,4-Dimethoxybenzylidene)hydrazinyl)-3-phenyl-
quinazolin-4(3H)-one (14 b): (62% yield), m.p.
263–265°C; IR (KBr, cm-1): 3287 (NH), 3059 (CH aro-
matic), 2920, 2854 (CH aliphatic), 1663 (C=O), 1593 (NH
bending), 1520, 1466(C=C); 1H NMR (DMSO-d6: d, ppm):
3.89, 3.92 (2s, 6H, 2OCH3), 5.50 (s, 1H, NH), 6.66–7.94
(m, 12H, CHs aromatic), 9.91 (s, IH, CH); MS (m/z): 401
(M ? 1, 2.13); Anal. Calcd. For C23H20N4O3: C, 68.99; H,
5.03; N, 13.99%. Found: C, 68.55; H, 4.78; N, 14.36%.
1
aliphatic), 1680 (br, C=Os), 1546, 1511 (C=C); H NMR
(DMSO-d6: d, ppm): 3.84(s, 3H, OCH3), 5.55(s, 2H,
SCH2), 7.05–8.05 (m, 13H, CHs aromatic); Anal. Calcd.
For C23H18N2O3S: C, 68.64; H, 4.51; N, 6.96%. Found: C,
68.75; H, 4.55; N, 6.58%.
Synthesis of 1-substituted-4-phenyl-[1,2,4]triazolo[4,
3-a]quinazolin-5(4H)-ones (15 a, b) A solution of 2-(2-
(4-substituted benzylidene) hydrazinyl)-3-phenylquinazo-
lin-4(3H)-ones 14 a, b (10 mmol) in glacial acetic acid
(15 ml) was refluxed for 4 h in the presence of anhydrous
sodium acetate (1.5 g). The reaction mixture was then fil-
tered while hot, and the filtrate was poured onto ice/water
mixture. The obtained solid was crystallized from ethanol.
1-(4-Chlorophenyl)-4-Phenyl-[1,2,4]Triazolo[4,3-
Preparation of 2-hydrazinyl-3-phenylquinazolin-4(3H)-
one 11 (Alagarsamy et al., 2007)
Preparation of ethoxy methylene malononitrile 12 (Akio,
1957)
Synthesis of 5-amino-1-(4-oxo-3-phenyl-3,4-dihydroqui-
nazolin-2-yl)-1H-pyrazole-4-carbonitrile (13) To a solu-
tion of 2-hydrazinyl-3-phenylquinazolin-4(3H)-one 11
(0.76 g, 3 mmol) in absolute ethanol (20 mL), ethoxy
methylene malononitrile 12 (0.36 g, 3 mmol) was added
gradually and the reaction mixture was refluxed for 15 h.
The solution was concentrated to half its volume; the
resulting solid was filtered off, washed with ethanol, and
crystallized from acetone, (62% yield), m.p. 235–237°C;
IR (KBr, cm-1): 3244, 3205 (NH2), 3062 (CH aromatic),
a]Quinazolin-5(4H)-one (15 a): (42% yield), m.p.
190–192°C; IR (KBr, cm-1): 3065 (CH aromatic), 2927,
2863 (CH aliphatic), 1673 (C=O), 1597, 1555(C=C), 760
(C–Cl); 1H NMR (DMSO-d6: d, ppm): 7.06–8.11 (m, 13H,
CHs aromatic); MS (m/z) : 296 (M?, 0.89), 294 (M - 2,
2.15); Anal. Calcd. For C15H9ClN4O: C, 60.72; H, 3.06; N,
18.88%. Found: C, 60.60; H, 3.10; N, 18.68%.
1-(3,4-Dimethoxyphenyl)-4-phenyl-[1,2,4]triazolo[4,3-
a]quinazolin-5(4H)-one (15 b): (48% yield), m.p.
238–240°C; IR (KBr, cm-1): 3062 (CH aromatic), 2933,
123

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Med Chem Res (2011) 20:1280–1286
1
Al-Obaid AM, Abdel-Hamide SG, El-Kashef HA, Abdel-Aziz AAM,
El-Azab AS, Al-Khamees HA, El-Subbagh HI (2009) Synthesis,
in vitro antitumor activity and molecular modeling study of
certain 2-thieno-4(3H)-quinazolinone analogs. Eur J Med Chem
44:2379–2391
2843 (CH aliphatic), 1683 (C=O), 1604, 1550(C=C); H
NMR (DMSO-d6: d, ppm): 3.61, 3.84 (2s, 6H, 2OCH3),
7.06–8.32 (m, 12H, CHs aromatic); Anal. Calcd. For
C23H18N4O3: C, 69.34; H, 4.55; N, 14.06%. Found: C,
69.58; H, 4.06; N, 14.29%.
Aziza MA, Ibrahim MK, El-Helby AG (1994) Synthesis of novel
2-styryl-3-benzylideneimino 4(3H) quinazolone derivatives of
expected anticonvulsant activity. Azhar J Pharm Sci 34:66–73
Dogan HN, Duran A, Rollas S, Sener G, Uysal MK, Gu¨len D (2002)
Synthesis of new 2,5-Disubstituted-1,3,4-thiadiazoles and pre-
liminary evaluation of anticonvulsant and antimicrobial activi-
ties. Bioorg Med Chem 10:2893–2898
Anticonvulsant screening
The newly synthesized compounds were evaluated for their
anticonvulsant activity using pentylene tetrazole PTZ-
induced (cardiazole) seizures in mice in doses 50–150 mg/
kg body weight. They were suspended in water and few
drops of propylene glycol, injected intraperitoneal, and each
compound was tested for at least three various doses. Each
dose was tested on a group of eight mice, and statistical
analysis was done to interpret the results. The control ani-
mals were injected with vehicle only. The animals were
injected with cardiazole in a dose of 70 mg/kg 1 hour after
they were injected with the tested compounds. The animals
were observed for the following 30 min for the appearance
of seizures [Fisher, 1989]. Animals showing no threshold
convulsions during the period of 30 min were protected.
Diazepam in doses 1, 2, and 3 mg/kg and phenobarbital
sodium in doses 10, 15, and 20 mg/kg were used as refer-
ence drugs to cover all types of convulsions. The number of
protected animals in each group was recorded, the per-
centage of protection was recorded for all the three tested
doses, and the values are tabulated in Table 1 together with
the tested compounds PD50 and their log P values.
El-Helby AG, Wahab MH (2003) Design and synthesis of some new
derivatives of 3H-quinazolin-4-one with promising anticonvul-
sant activity. Acta Pharm 53:127–137
Fisher RS (1989) Animal models of the epilepsies. Brain Res Rev
14:245–278
Guan L, Jin Q, Tian G, Chai K, Quan Z (2007) Synthesis of some
quinoline-2(1H)-one and 1,2,4-triazolo [4,3-a] quinoline deriv-
atives as potent anticonvulsants. J Pharm Pharm Sci 10:254–262
Gu¨rsoy A, Karalı N (2003) Synthesis and primary cytotoxicity
evaluation of 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercapto-
acetyl]hydrazono]-1H–2-indolinones. Eur J Med Chem 38:
633–643
Hudkins RL, DeHaven-Hudkins DL, Doukas P (1997) Design of dual
acting anticonvulsant-antimuscarinic succinimide and hydantoin
derivatives. Bioorg Med Chem Lett 7:979–984
Lakhan R, Srivastava M (1993) A convenient preparation of 2-thioxo-
4(3H)-quinazolinones. Proc Ind Acad Sci 105:11–17
Lee JC, Park JY, Yoon SY, Bae YH, Lee Seung J (2004) Efficient
microwave induced direct a-halogenation of carbonyl com-
pounds. Tetrahedron Lett 45(1):191–193
Luchowska E, Luchowski P, Wielosz M, Kleinrok ZC, Czuczwar
SCJ, Urban0ska Ewa M (2002) Propranolol and metoprolol
enhance the anticonvulsant action of valproate and diazepam
against maximal electroshock. Pharmacol Biochem Behav
71:223–231
Misra VS, Gupta PN, Pandey RN (1980) Synthesis of 2-phenyl/
methyl-3-[o-,m-or p-(benzimidazol-20-yl) phenyl]-6 or 6, 8-
substituted/unsubstituted quinazoline (3H)-4-ones. Pharmazie
35:400–401
Ram VJ, Farhanullah, Tripathi BK, Srivastava AK (2003) Synthesis
and antihyperglycemic activity of suitably functionalized 3H-
quinazolin-4-ones. Bioorg Med Chem 11:2439–2444
Refaie FM, Esmat AY, Abdel-Gawad SM, Ibrahim AM, Mohamed
MA (2005) The antihyperlipidemic activities of 4(3H) quinaz-
olinone and two halogenated derivatives in rats. Lipids Health
Dis 4:22–32
Acknowledgments The authors introduce their great thanks to the
Pharmacology Department, Faculty of Pharmacy, Cairo University
for their valuable help in screening the anticonvulsant activity of the
tested compounds.
References
Abdel-Aziz M, Abuo-Rahma GEDA, Hassan AA (2009) Synthesis of
novel pyrazole derivatives and evaluation of their antidepressant
and anticonvulsant activities. Eur J Med Chem 44:3480–3487
Akio I (1957) Takamine Kenkyusho, 9, 21 Though Chem. Abstract
(1961) 55:1439d
Alagarsamy V, Solomon VR, Dhanabal K (2007) Synthesis and
pharmacological evaluation of some 3-phenyl-2-substituted-3H-
quinazolin-4-one as analgesic, anti-inflammatory agents. Biorg
Med Chem 15:235–241
Spirkova K, Stankovsky S, Mrvova A, Cipak L (1999) Synthesis and
biological activity of some 2-substituted quinazolin-4-ones.
Chem Papers 53:272–275
Wei Q, Zhang S, Gao J, Li W, Xu L, Yu Z (2006) Synthesis and
QSAR studies of novel triazole compounds containing thioamide
as potential antifungal agents. Bioorg Med Chem 14:7146–7153
ˇ
Xue S, McKenna J, Shieh W-C, Repic O (2004) A facile synthesis of
C2, N3-disubstituted-4-quinazolone. J Org Chem 69:6474–6477
123