Synthesis and anticonvulsant evaluation of some new 2,3,8-trisubstituted- 4(3H)-quinazoline derivatives

Article abstract of DOI:10.1016/j.bmcl.2011.11.007

A new series of 2,3,8-trisubstituted-4(3H)-quinazoline derivatives were synthesized, evaluated for their anticonvulsant activity against electrically (MES) and chemically (PTZ, picrotoxin and Strychnine) induced seizures and compared with the standard drugs methaqualone and sodium valproate. Compounds 3, 17 and 22 proved to be the most potent compounds of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test as compared with the reference drugs. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs.

Full text of DOI:10.1016/j.bmcl.2011.11.007

Bioorganic & Medicinal Chemistry Letters 22 (2012) 327–333
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and anticonvulsant evaluation of some new
2,3,8-trisubstituted-4(3H)-quinazoline derivatives
Adel S. El-Azab a,c, , Kamal E.H. ElTahir b
⇑
a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
b Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
c Department of Organic Chemistry, College of Pharmacy, Al-Azhar University, Nasr City, Cairo 11884, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of 2,3,8-trisubstituted-4(3H)-quinazoline derivatives were synthesized, evaluated for their
anticonvulsant activity against electrically (MES) and chemically (PTZ, picrotoxin and Strychnine)
induced seizures and compared with the standard drugs methaqualone and sodium valproate. Com-
pounds 3, 17 and 22 proved to be the most potent compounds of this series with relatively low neuro-
toxicity and low toxicity in the median lethal dose test as compared with the reference drugs. The
obtained results showed that the most active compounds could be useful as a template for future design,
modification and investigation to produce more active analogs.
Received 10 September 2011
Revised 16 October 2011
Accepted 2 November 2011
Available online 16 November 2011
Keywords:
Synthesis
Quinazoline
Anticonvulsant
Neurotoxicity
Ó 2011 Elsevier Ltd. All rights reserved.
Epilepsy is one of the most common neurological disorders,
affecting about 1% of the world’s population. Many efforts devoted
in the recent years for the development of novel therapeutics re-
sulted in the availability of several newer drugs as promising anti-
convulsants.1,2 However, the currently available anticonvulsants
are effective in reducing the severity and number of seizures in less
than 70% of patients. Moreover, their usage is associated with
undesirable numerous side effects.2–6 Therefore, continued search
for safer and more effective anticonvulsants is urgently necessary.
One of the most frequently encountered heterocycles in medicinal
chemistry is 4(3H)-quinazolinones, which have diverse pharmaco-
logical activities like anti-tumor,7,8 anti-inflammatory,9 anticon-
vulsants,10,11 and antimicrobial activities.12,13
A literature survey revealed that the presence of a methyl group
at position 2 and a substituted aromatic ring at position 3 are nec-
essary requirement for the CNS depression and anticonvulsant
activities of compounds such as methaqualone, etaqualone, mec-
loqualone, mebroqualone and afloqualone (Fig. 1).
Figure 1 represents the similarities between the reported CNS
active agent’s quinazolinones and our designed compounds.
Methaqualone was an important landmark in the field of syn-
thetic anticonvulsant, possessed quinazoline core which was
responsible for its activity.14 The 6-chloro analog of methaqualone
(mecloqualone) was found to possess marked anticonvulsant ac-
tion, 1.5 times more potent than phenytoin sodium (DPH) against
electroshock induced convulsions and 10 times more potent than
Troxidone against pentylenetetrazol induced seizures.15,16
Moreover, a series of 3-substituted quinazolinones I–II (Fig. 1),
structurally related to methaqualone showed good protection
against maximal electroshock and subcutaneous Metrazol
induced-seizures.17,18 In spite of the fact that literately hundreds
of quinazolinones related to compound methaqualone have been
synthesized and tested for their anticonvulsant activity, none of
those drugs are currently used. A persistent problem with these
compounds arises from the fact that, nearly every derivative tested
in combined neurotoxicity and anticonvulsant screenings exhib-
ited neurotoxicity values (TD50’s) that are less than or only slightly
higher than the effective doses (ED50’s), consequently, the protec-
tive index (PI) corresponding to TD50/ED50 is too low.15,16
In view of the previous rationale and in continuation of an
ongoing program aiming at finding new structure leads with po-
tential anticonvulsant activities,19 a new series of 4(3H)-quinazo-
line pharmacophore was designed with substituted moieties
possesses different electronic environment in hope of developing
potent and safe new effective compounds. In such fashion, substi-
tuted 4(3H)-quinazoline was designed to accommodate an ester
function at position 8 that used to synthesize compounds of types
B and C. The acetic acid hydrazide function at position 8 was used
to introduce an arylidine moiety D, phenyl ring of arylidine con-
taining electron donating or electron withdrawing group in order
to investigate their electronic effect on activity and unsubstituted
arylidine was converted into phenylthiazolidin-4-one moiety E.
⇑
Corresponding author. Address: Department of Pharmaceutical Chemistry,
College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi
Arabia. Fax: +966 1 467 6383.
E-mail address: adelazaba@yahoo.com (A.S. El-Azab).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.007

328
A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 327–333
R
N
O
N
R
N
O
N
O
N
O
N
H2N
N
N
F
O
N
Afaqualone
Methaqualone R=CH3
Etaloqualone R=C2H5
Mecloqualone R=Cl
Mebroqualone R=Br
Methylmethaqualone
I: R=CH3
II:R=Cl
O
N
O
N
O
N
O
N
N
N
N
N
N
R
OCH2CONHN
OCH2COR
OCH2CONHR
O
O
x
C
A
B
D
O
N
O
N
N
O
N
O
N
O
O
N
OCH2
N
N
O
R
OCH2CON
N
O
OCH2CONH N
S
O
H
O
H
X
N
Ph
NH
HN
N
SH
F
G
E
H
Figure 1. Reported15,16 and designed quinazolines as anticonvulsant (A–H).
In additions, acetic acid hydrazide function was used to commence
benzoyl moiety A, cyclic imides with different substituent’s F and
oxypyrazolidin-3,5-dione G. On the other hand, substituted
4(3H)-quinazoline was deliberate to acclimatize an potassium
hydrazinecarbodithioate function at position 8 that accustomed
to synthesize isosteric compounds of types H (Fig. 1). The objective
of forming these hybrids is an attempt to reach an active anticon-
vulsant agent without neurotoxicity.
potassium carbonate at room temperature to afford quantitative
yield of ethyl 2-[3,4-dihydro-2-methyl-3-(2-methylphenyl)-4-oxo-
quinazolin-8-yloxy]acetate (2), which was treated with hydrazine
hydrate in ethanol at room temperature to furnish 2-[3,4-dihy-
dro-2-methyl-3-(2-methylphenyl)-4-oxoquinazolin-8-yloxy]acetic
acid hydrazide (3) as a key intermediate in 90% yield. Ester 2 was
reacted with semicarbazide and/or thiocarbohydrazide in anhy-
drous pyridine to give 2-[2-(2-methyl-3-(2-methylphenyl)-4(3H)-
quinazolin-8-yloxy)acetyl]hydrazinecarboxamide (4) and N0-(hyd-
razinecarbonothioyl)-2-[(2-methyl-3-(2-methylphenyl)-4(3H)-qui-
nazolin-8-yloxy)acetyl]acetohydrazide (5) in 61 and 64% yield,
The synthetic strategy to prepare the target compounds 2–25 is
depicted in schemes 1–3. 8-Hydroxyquinazoline 1 was reacted
with ethylbromoacetate in dry acetone in the presence of
O
N
O
O
N
N
N
N
ethylbromoacetate
acetone, K2CO3
2-ethanolamine
pyridine, reflux
N
OCH2CONHCH2CH2OH
OCH2COOEt
OH
1
6
2
X
RNHCNHNH2
pyridine, reflux
R=H, NH2
conc.
H2SO4, r.t
H
t
.
N
r
,
H
H
N
O
X=O, S
t
E
O
N
N
O
N
O
N
N
X
N
OCH2
OCH2CONHNH2
OCH2CONHNHCNHR
O
N
3
R
X
no.
4
5
H
NH2
O
S
7
Scheme 1. Synthesis and reaction of Ester 2.

A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 327–333
329
O
N
O
O
N
N
SHCH2COOH
N
N
O
N
benzene, reflux
R
N
OCH2CONHNHCOPh
OCH2CONHN
OCH2CONH
S
8
x
Ph
13
no.
x
R
BzCl, TEA
CH2Cl2
9
H
CH
CH
CH
N
10
11
12
OMe
F
H
O
O
N
N
O
N
N
ClCOOEt, r.t
CH2Cl2, TEA
NH2NH2
EtOH, r.t
N
N
OCH2CONHNHCOOEt
OCH2CONHNHCONHNH2
OCH2CONHNH2
3
17
19
NaOEt, EtOH
reflux
X
substituted phthalic
anhydride, AcOH, reflux
haeting above
melting point
O
N
O
O
N
N
N
N
N
O
O
OCH2CONH
OCH2
O
N
O
N
N
NH
NH
O
NH
HN
R
R
R
14 R=H
15 R=Br
16 R=Cl
O
20
R
18
Scheme 2. Reaction of acid hydrazide 3.
O
N
N
O
N
O
N
KOH, CS2,
EtOH, r.t
CH3I,
N
S
N
S
EtOH, r.t
OCH2CONHNH2
OCH2CONHNHCSK
OCH2CONHNHCSCH3
3
21
22
1-KOH,CS2
2-NH2NH2,
EtOH, r.t
2
4
O
O
N
O
N
N
N
O
N
N
N
NH2NH2
OCH2
OCH2
OCH2
EtOH, reflux
NH2
SH
N
S
N
O
N
N
S
N
N
N
OCH2CONHNHCNHNH2
N
SH
24
Scheme 3. Synthesiis and reaction of potassium hydrazinecarbodithioate 21.
SH
23
25
5
respectively. Compound 5 was also obtained in another pathway,
(in 78% yield); on treatment of 3 with carbon disulfide in ethanolic
potassium hydroxide followed by treating with hydrazine hydrate.
Treatment of 2 with 2-ethanolamine in boiling anhydrous pyridine
furnished N-[(2-hydroxyethyl)-2-(2-methyl-3-(2-methylphenyl)-
4(3H)-quinazolin-8-yloxy)]acetamide (6) in 73% yield, which was

330
A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 327–333
Table 1
subjected to acid dehydrative cyclization by the action of concen-
trated H2SO4 at room temperature to yield 8-(4,5-dihydrooxazol-
2-yl)methoxy)-2-methyl-3-o-tolylquinazolin-4(3H)-one (7) in
44% yield (Scheme 1).
Preliminary anticonvulsant activity of the new synthesized compounds (0.5 mmol/
kg), valproate (300 mg/kg) and methaqualone (200 mg/kg)
Compound no.
PTZ (% of protection)
MES (% of protection)
Acid hydrazide 3 was treated with benzoyl chloride in dichloro-
methane in the presence of triethylamine at room temperature to
furnish N-[2-(2-methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-
yloxy)acetyl]benzohydrazide (8) in 90% yield.
Valproate
Methaqualone
3
4
100
100
100
50
100
100
50
0.0
33
5
66
Hydrazones 9–12 was obtained in 69–74% yields, on reaction of
3 with various aldehydes in boiling methanol, compound 9 was
subjected to cyclization via reaction with thioglycolic acid in anhy-
drous benzene to afford [2-(2-methyl)-3-(2-methylphenyl)-4(3H)-
quinazolin-8-yloxy)-N-(2-phenylthiazolidin-4-on-3-yl)] acetamide
(13) in 63% yield. Acid hydrazide 3 was reacted with various anhy-
drides in glacial acetic acid in the presence of anhydrous sodium
acetate to give the corresponding N-(substituted-1,3-dioxoisoindo-
lin-2-yl)acetamides 14–16 in 84–89% yields, respectively. On the
other hand, the reaction of 3 with ethylchloroformate in anhydrous
pyridine gave ethyl-2-[2-(2-methyl)-3-(2-methylphenyl)-4(3H)-
quinazolin-8-yloxy)acetyl]hydrazincarboxylate (17) in 88% yield,
which was subjected to cyclization with sodium ethoxide in boil-
ing ethanol to afford 4-[(2-methyl)-3-(2-methylphenyl)-4(3H)-
quinazolin-8-yloxy)pyrazolidin-3,5-dione (18) in 59% yield.
Hydrazincarboxylate 17 was treated with hydrazine hydarate in
ethanol at room temperature to furnish the corresponding acid
hydrazide 19 in 87% yield, an attempt to cyclize 19 to 1,2,4,5-tetra-
zin-3-one derivative 20 was failed (Scheme 2).
6
9
50
50
33
66
100
50
100
0.0
0.0
0.0
50
100
0.0
100
10
11
17
19
22
PTZ = pentylenetetrazol, MES = maximal electroshock test.
compound 5 exhibited 33% protection. Nevertheless, none of all
synthesized compounds exhibited any potency towards anti-
strychnine and/or picrotoxine activity at the same dose levels.
As a result of preliminary screening, the most active compounds
3, 17 and 22 were subjected to further investigations at different
doses for quantification of their anticonvulsant activity (indicated
by ED50) and neurotoxicity (indicated by TD50) in mice (Table 2).
The selected compounds 3, 17 and 22 were exhibited anticonvul-
sant activity against PTZ-induced seizure with ED50 values of 98,
160 and 150 mg/kg, respectively. Methaqualone and valproate
were used as reference drugs and these compounds produced
ED50 values of 200 and 300 mg/kg, respectively. Interestingly, the
ED50 values of the selected compounds were found to be smaller
compared to the reference anticonvulsant drugs at molar doses.
The protective index (ED50/TD50) is considered to be an index
representing the margin of safety and tolerability between anti-
convulsant doses and doses of anticonvulsant drugs exerting acute
adverse effects (e.g., sedation, motor coordination impairment,
ataxia or other neurotoxic manifestations.23 Evaluation of the
acute adverse effect profile (TD50) of compounds27 3, 17 and 22 re-
vealed that these agents exerted low neurological deficit (Table 2).
The protective index values of the selected compounds (2.72, 2.61
and 1.91) were higher than or equal to the reference drugs as com-
pared to 2.0 for methaqualone and 1.50 for valproate. It is obvious
that the protective index values for these selected compounds re-
vealed a difference between the doses producing neurotoxic action
(TD50) and those exerting anti-PTZ (ED50) actions in mice. The pres-
ent results are in agreement with the results of the anticonvulsant
study of 2-substituted 3-aryl-4(3H)-quinazolinones in mice by
Wolfe et al.17 (Wolfe et al., 1990). Wolfe and colleagues reported
that the series of 4(3H)-quinazolinones which possessing 3-o-tolyl
and 3-o-chlorophenyl groups showed good protection against MES
and PTZ induced seizures, combined with relatively low neurotox-
icity after i.p. administration 4(3H)-quinazolinones in mice.
Compounds 3, 17 and 22 revealed LD50 values of 1000, 418 and
501 mg/kg with therapeutic index (LD50/ED50) values 10.2, 1.53
and 3.34. It is worthwhile to note that the therapeutic index of
the selected compounds was found to be equal or higher as
compared to the reference anticonvulsant drugs at molar doses
(Table 2). The results of the seizure induction screening methods
in the current study showed that some new quinazolines were
effective in controlling the seizures induced by PTZ and MES but
failed to control those induced by strychnine and picrotoxin. This
effect is similar to that of 4(3H)-quinazolinones, which have
anticonvulsant effects on seizures induced by MES and PTZ and
are ineffective against strychnine-induced seizures in mice.18
It has been reported that the convulsants induce seizures by
Moreover, acid hydrazide 3 was treated with carbon disulfide in
ethanolic potassium hydroxide to afford potassium 2-[2-(2-
methyl-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)acetyl]hy-
drazinecarbodithioate (21) as a key intermediate in 92% yield.
Compound 21 was alkylated with methyl iodide to give methyl-2-
[2-(2-methyl-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)acetyl]
hydrazinecarbodithioate (22) in
a quantitative yield. 8-[(5-
mercapto-1,3,4-thiadiazol-2-yl)methoxy]-2-methyl-3-(2-methyl-
phenyl)-4(3H)-quinazolinone (23) was obtained in 55% yield on
cyclization of 21 via the action of concentrated H2SO4 at room
temperature.
Cyclization of compound 21 with boiling ethanol produced 8-
(5-Mercapto-1,3,4-oxadiazol-2-yl)methoxy)-[2-methyl-3-(2-methyl-
phenyl)]-4(3H)-quinazolinone (24) in 86% yield, which was treated
with ethanolic solution of hydrazine hydrate to furnish 8-[(4-ami-
no-5-mercapto-4H-1,2,4-triazol-3-yl)methoxy-2-methyl-3-(2-me-
thylphenyl)]-4(3H)-quinazolinone (25) in 76% yield. Compound 25
was also obtained by heating compound 5 in boiling ethanol
(Scheme 3).
The anticonvulsant activity and the acute neurotoxicity of the
new synthesized compounds were evaluated by the use of stan-
dard techniques.20 21
The preliminary screening was performed at
,
0.5 mmol/kg of all synthesized compounds (2–25) by using of
pentylenetetrazole (PTZ), picrotoxin, strychnine induced and max-
imal electroshock seizure (MES) model of seizures. The MES test is
associated with the electrical induction of the seizure, whereas
PTZ, picrotoxin and strychnine methods involve a chemical induc-
tion to generate the convulsion.22
The initial anticonvulsant evaluation showed that some of these
compounds are inactive; however compounds 3, 4, 5, 6, 9, 10, 11,
17, 19 and 22 were active against PTZ at 0.5 mmol/kg, among
which compounds 3, 17 and 22 were presented 100% protection,
compounds 5 and 11 was presented 66% protection, compounds
4, 6, 9 and 19 presented 50% protection, while compound 10 was
presented 33% protection (Table 1). Compounds 3, 5, 11, 17 and
22 exhibited anticonvulsant activity against MES-induced seizure
at the dose of 0.5 mmol/kg. The most active of these compounds
were 17 and 22 which presented 100% protection. The remaining
two compounds 3 and 11 exhibited anti-MES effect by 50%, while
inhibiting
c-aminobutyric acid (GABA) neurotransmission (such

A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 327–333
331
Table 2
Comparison of the anticonvulsant activity (ED50), acute neurotoxic effects (TD50), median lethal dose (LD50), therapeutic and protective indexes of the most promising
anticonvulsant new synthesized compounds, sodium valproate and methaqualone in mice
Compound No.
ED50 (mgl/kg)
TD50 (mg/kg)
LD50 (mg/kg)
Therapeutic index
Protective index
Valproate
Methaqualone
300
200
98
160
150
450
400
267
246
287
500
500
1000
418
1.66
2.50
10.20
1.53
1.50
2.00
2.72
2.61
1.91
3
17
22
501
3.34
ED50 = median effective dose providing anticonvulsant protection in 50% of mice against pentylenetetrazole (PTZ) induced seizures.
TD50 = median toxic dose producing minimal neurological toxicity in 50% of mice subjected to the Chimney test.
LD50 = median lethal dose that causes 50% mortality in mice.
Therapeutic index = LD50/ED50
Protective index = TD50/ED50
.
.
as PTZ), GABAA-antagonist GABAA receptor agonist by increasing
chloride influx via brain chloride channel (such as picrotoxin) or
directly antagonizes the inhibitory spinal reflexes of glycine (such
as strychnine).24–26 Generally, in the MES test, one can determine
the anti-seizure effects of agents or drugs that suppress tonic-
clonic seizures by suggesting that those compounds possess the
ability to prevent the spread of seizure discharge throughout neu-
ronal tissues and to raise seizure threshold.23 On account of their
partial effectiveness, it is difficult to report that our synthesized
compounds as having anticonvulsant effects via influencing
glycine neurotransmission. However, most of our new compounds
can control the seizures induced by PTZ and MES this might sug-
gest that these compounds exhibit a broad spectrum of anticonvul-
sant activity in animal models of partial and generalized epilepsy
via GABA activation. In addition, more detailed study on the GABA
pathways and the neurotransmitter levels might be interesting and
might provide more insights for the anticonvulsant effects of these
new 4(3H)-quinazolines against convalsants induced seizures,
which will be considered extensively in our future study. However,
at present some of the new synthesized compounds have relatively
potent anticonvulsant effects combined with relatively low
neurotoxicity.
The anticonvulsant activity of the newly synthesized com-
pounds27 revealed that compounds having acetic acid hydrazide
fragments at position 8 possess significant anticonvulsant activity
such as compounds 3, 17 and 22. Compounds containing acid
hydrazide moieties such as 3 were more potent as compared to
the parent ester 2. Interestingly, cyclization of acid hydrazide 3
into the corresponding amides such as compounds 13–16 inhibits
the anticonvulsant activity, such phenomenon suggests that the
importance of open chain of acetic acid hydrazide for the anticon-
vulsant activity.
O
N
O
N
O
N
N
N
N
O
O
O
O
O
O
H
N
H
O
NH2
N
S
N
H
N
H
N
H
O
S
3
17
22
Figure 2. The most active anticonvulsant activity. Compounds 3, 17 and 22 showed
100% protection against PTZ -induced seizures and 50%, 100%, 100% protection
against MES-induced tonic extension, respectively.
In conclusion, the present study, new derivatives of 4(3H)-qui-
nazolinones were synthesized and evaluated for their anticonvul-
sant activity in mice. The results of this study demonstrated that
some 8-substituted-4(3H)-quinazolinones derivatives possess a
good anticonvulsant activity, specially, compounds 3, 17 and 22
showed better anticonvulsant activity and much lower toxicity
compared with the reference drugs (Fig. 2). The obtained results
showed that compounds 3, 17 and 22 could be useful as a template
for future design, modification and investigation to produce more
active analogs.
Acknowledgment
The authors extend their appreciation to the Deanship of Scien-
tific Research at King Saud University for funding the work through
the research group project No. RGP-VPP-163.
On the other hand, replacement of amide moieties such as com-
pounds 14–16 with benzylidine moiety such as compounds 9–11
increase the anticonvulsant activity. It is clear that the presence
of electron withdrawing group at aromatic ring of benzylidine en-
hance the activity compared with unsubstituted or electron donat-
ing group in phenyl ring, for examples compound 11 is more active
than compounds 9 and 10.
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El-Azab, A. S.; Abdel-Hamide, S. G.; Al-Omar, M. A.; Al-Obaid, A. M.; El-
Subbagh, H. I. Bioorg. Med. Chem. 2010, 18, 2849.
13. El-Azab, A. S. Phosphorus, Sulfur Silicon Relat. Elem. 2007, 183, 333.
14. Gujral, M. L.; Sareen, K. N.; Kohli, R. P. Ind. J. Med. Res. 1957, 45, 20711.

332
A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 327–333
15. Bhaduri, A. P.; Khanna, N. M.; Dhar, M. L. Ind. J. Chem. 1964, 2, 159.
16. Salimath, S. R.; Patel, Shah,N. M. J. Ind. Chem. Soc. 1956, 33, 140.
17. Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.; Greenwood, T. D. J.
Med. Chem. 1990, 33(1), 161.
C25H22N4O4: MS (70 eV): m/z = 442.
N-Arylidine-[2-(2-methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)]
acetohydrazide (9–12)
A solution of acid hydrazide 3 (2 mmol, 676 mg) in methanol (10 mL) and the
appropriate aldehyde (2 mmol) was refluxed for 12–15 h. The reaction mixture
was filtered and deride.
18. Aziza, M. A. Az. J. Pharm. Sci. 1997, 19, 129135.
19. El-Azab, A. S.; Kamal, E. H.; Attia, S. M. Monatsh. Chem. 2011, 142, 837–848.
20. Krall, R. L.; Penry, J. K.; White, B. G.; Kupferberg, H. J.; Swinyard, E. A. Epilepsia.
1978, 19, 409.
21. Poter, R. J.; Cereghino, J. J.; Gladding, G. D.; Hessie, B. J.; Kupferberg, H. J.;
Scoville, B. Cleveland Clin. 1984, Q 51, 293.
22. Vogel, H. G. In Drug Discovery and Evaluation; Vogel, H. G., Vogel, W. H., Eds.,
2nd ed.; Pharmacological assays; Springer: Berlin, 2002; pp 422–488.
23. Löscher, W.; Nolting, B. Epilepsy Res. 1991, 9(1), 1.
N-Benzylidine-[2-(2-methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)]
acetohydrazide (9)
Yield 72%, yellow oil; 1H NMR (CDCl3): d 9.99 (s, 1H, exchangeable), 8.37 (s, 1H),
7.97–7.85 (m, 3H), 7.70–7.60 (m, 3H), 7.53–7.11 (m, 6H), 4.87 (s, 2H), 2.08 (s, 3H),
2.09 (s, 3H). 13C NMR (CDCl3): d 17.3, 23.9, 70.4, 119.6, 121.1, 122.2, 127.2, 128.5,
129.7, 130.6, 131.6, 133.7, 134.4, 135.3, 145.7, 149.8, 152.6, 154.7, 161.0, 161.4,
164.7, 169.9. C25H22N4O3: MS (70 eV): m/z = 425.
24. Olsen, R. W. J. Neurochem. 1981, 27, 1.
25. J. Physiol. Pharmacol. 1988, 66, 1135.
26. Okada, R.; Negishi, H. Brain. Res. 1989, 480, 383.
N’-(2-Methoxybenzylidene)-[2-(2-methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-
8-yloxy)]acetohydrazide (10)
Yield 74%, mp: 133–5 °C; 1H NMR (DMSO-d6): d 11.73 (s, 1H, exchangeable), 8.37
27. General: Melting points were recorded on Barnstead 9100 Electrothermal
melting apparatus. IR spectra were recorded on a Perkin–Elmer spectrometer.
1H NMR and 13C NMR was recorded in DMSO-d6 and/or CDCl3 on a Jeol 500 MHz
instrument using TMS as internal standard (chemical shifts in d ppm). Mass
spectra were recorded on a Shimadzu PQ-5000 GC–MS apparatus. Solvent
evaporation was performed under reduced pressure using Buchan Rotatory
Evaporator unless otherwise stated. TLC was performed on precoated silica gel
plates (60-F254, 0.2 mm), manufactured by EM Sciences, Inc, and shortwave UV
(254) nm was used to detect the UV absorbing compounds (CH2Cl2/EtOH 10:1).
Compound 2 and 3 were synthesized according to reported method.19
2-[(2-Methyl-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)]substituted
acetohydrazide (4–5)
(s, 1H), 7.86–6.99 (m, 11H), 4.89 (s, 2H), 3.84 (S, 3H), 2.09 (s, 3H), 2.03 (s, 3H). 13
C
NMR (DMSO-d6): d 17.3, 24.0, 69.5, 56.2, 117.1, 118.2, 121.2, 122.5, 126.1, 127.1,
128.8, 129.7, 131.5, 131.9, 135.5, 140.1, 143.8, 153.2, 153.5, 153.6, 158.1, 158.3,
161.0, 161.1, 163.3, 169.2. C26H24N4O4: MS (70 eV): m/z = 456 (M+1).
N0-(2-Fluorobenzylidene)-[2-(2-methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-
yloxy)]acetohydrazide (11)
Yield 70%, mp: 120–2 °C; 1H NMR (CDCl3): d 11.64 (s, 1H, exchangeable), 8.56 (s,
1H), 8.16–8.01 (m, 2H), 7.48–7.37 (m, 6H), 7.22–7.02 (m, 3H), 4.95 (s, 2H), 2.31 (s,
3H), 2.14 (s, 3H). 13C NMR (CDCl3): d 17.3, 24.0, 71.2, 115.5, 115.6, 120.7, 121.6,
122.3, 124.6, 127.2, 127.3, 127.8, 129.9, 131.7, 132.2, 135.3, 136.4, 142.1, 14.2,
152.9, 155.1, 160.5, 161.0, 162.5, 165.1. C25H21FN4O3: MS (70 eV): m/z = 443.
2-(2-Methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)-N-(pyridine-4-
ylmethylene)acetohydrazide (12)
A
mixture of ester 2 (2 mmol, 704 mg) and semicarbazide and/or
thiocarbohydrazide (3 mmol) in pyridine (10 mL) was heated under reflux for
12 h. The reaction mixture was cooled, the solvent was removed under reduced
pressure; the residue was triturated with water and filtered. The solid obtained
was dried and recrystallized from ethanol.
Yield 69%, mp: 114–6 °C; 1H NMR (DMSO-d6): d 11.94 (s, 1H, exchangeable), 8.88
(s, 1H), 8.69 (d, 2H, J = 3.5 Hz), 8.37 (d, 1H, J = 4.0 Hz), 8.03–7.18 (m, 8H), 5.44 (s,
2H), 2.10 (s, 3H), 2.04 (s, 3H). 13C NMR (DMSO-d6): d 17.3, 24.0, 69.5, 119.4, 121.4,
121.5, 122.1, 122.6, 127.0, 127.9, 128.8, 129.8, 135.5, 137.4, 138.4, 142.0, 146.0,
149.8, 150.7, 151.6, 161.0, 161.1, 165.3, 169.7. C24H21N5O3: MS (70 eV): m/
z = 427.
2-[(2-(2-Methyl-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)acetyl)]
hydrazincarboxamide (4)
Yield 61%, mp: 70–2 °C; 1H NMR (CDCl3): d 7.95 (d, 1H, J = 8.0 Hz), 7.41–7.36 (m,
5H), 7.17–7.15 (m, 2H), 4.95 (s, 2H), 3.84(s, 2H), 2.25(s, 3H), 2.13(s, 3H). 13C NMR
(CDCl3): d 17.3, 24.1, 66.7, 117.1, 120.1, 122.3, 126.5, 127.6, 127.9, 129.6, 131.5,
135.3, 136.8, 138.6, 152.4, 154.0, 161.3, 169.1. C19H19N5O4: MS (70 eV): m/
z = 396 (Mꢀ1).
2-(2-Methyl-4-oxo-3-o-tolyl-3,4-dihydroquinazolin-8-yloxy)-N-(4-oxo-2-
phenylthiazolidin-3-yl)acetamide (13)
A solution of N-Benzylidine 9 (1 mmol, 426 mg) in dry benzene (10 mL) was
refluxed for6 hwith thiglycolic acid(3 mmol, 271 mg). Thereaction mixturewas
cooled, the solvent was removed under reduced pressure; the residue was
neutralized with 10% sodium carbonate solution. The solid obtained was filtered,
dried and recrystallized from acetic acid. Insoluble in any solvent MS (70 eV): m/
z = 500. Anal. Calcd for C27H24N4O4S (500.15) C, 64.78, H, 4.83, N, 11.19. Found C,
64.70, H, 4.93, N, 11.10.
N-(Substituted-1,3-dioxoisoindolin-2-yl)-[2-(2-methyl)-3-(2-methylphenyl)-
4(3H)- quinazolin-8-yloxy)]acetamide (14–16)
Equimolar amount of acid hydrazide 3 (2 mmol, 676 mg) and the appropriate
anhydride was refluxed in glacial acetic acid (15 mL) containing anhydrous
sodium acetate (5 mmol, 295 mg) for 10–12 h. The reaction mixture was filtered,
washed with water and deride.
N0-Hydrazinecarbonothioyl-2-[(2-methyl-3-(2-methylphenyl)-4(3H)-quinazolin-
8-yloxy)acetyl]acetohydrazide (5)
Yield 78%, mp: 126–8 °C; 1H NMR (DMSO-d6): d 8.66 (s, 1H, exchangeable), 7.72
(d, 1H, J = 7.0 Hz), 7.54–7.09 (m, 6H), 4.7 (s, 2H), 3.92–3.69 (br.s, 4H,
exchangeable), 2.11 (s, 3H), 2.02 (s, 3H). 13C NMR (DMSO-d6): d 17.3, 24.1,
69.1, 119.2, 119.5, 122.0, 127.3, 127.9, 128.8, 129.9, 131.6, 135.4, 137.2, 138.9,
153.5, 154.1, 161.0, 167.3, 182.0. C19H20N6O: MS (70 eV): m/z = 413 (M+1).
Pathway B for compound (5)
A solution potassium dithioate 22 (1 mmol, 452 mg) in absolute ethanol (10 mL)
was refluxed for 3 h, the reaction mixture was cooled and the solvent was
removed under reduced pressure. The residue was dissolved in water,
neutralized with 10% HCl; the solid obtained was filtered and dried.
N-[(2-Hydroxyethyl)-2-(2-methyl-3-(2-methylphenyl)-4(3H)-quinazolin-8-
yloxy)]acetamide (6)
N-(1,3-Dioxoisoindolin-2-yl)-[2-(2-methyl)-3-(2-methylphenyl)-4(3H)-
quinazolin-8-yloxy)]acetamide (14)
Yield 86%, mp: 160–2 °C; 1H NMR (CDCl3): d 11.71 (s, 1H, exchangeable), 8.00–
7.76 (m, 5H), 7.47–7.38 (m, 5H), 7.18 (d, 1H, J = 7.0 Hz), 5.01 (s, 2H), 2.11 (s, 3H),
2.09 (s, 3H). 13C NMR (CDCl3): d 17.3, 23.5, 71.1, 121.6, 122.2, 123.9, 124.4, 127.3,
127.8, 129.8, 130.0, 130.2, 131.6, 134.6, 135.1, 135.2, 136.3, 138.9, 152.9, 155.2,
160.8, 163.4, 164.9, 167.8. C26H20N4O5: MS (70 eV): m/z = 468.
[2-(2-Methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy-N-(4,5,6,7-
tetrabromo-1,3-dioxoisoindolin-2-yl)]acetamide (15)
A mixture of ester 2 (5 mmol, 1.76 g) and ethanolamine (6 mmol, 366 mg) in
pyridine (20 mL) was heated under reflux for 8 h. The reaction mixture was
cooled, the solvent was removed under reduced pressure; the residue was
triturated with water. The solid obtained was filtered, dried.
Yield 73%, mp: 137–9 °C; 1H NMR (DMSO-d6): d 8.74 (s, 1H, exchangeable), 7.71
(d, 1H, J = 7.5 Hz), 7.43–7.34 (m, 5H), 7.15 (d, 1H, J = 7.0 Hz), 4.62 (s, 2H), 4.06 (s,
1H, exchangeable), 3.49 (t, 2H, J = 5.0 Hz), 3.27 (t, 2H, J = 5.0 Hz), 2.13(s, 3H), 2.04
(s, 3H).
Yield 89%, mp: 283–5 °C; 1H NMR (DMSO-d6): d 7.73 (d, 1H, J = 7.5 Hz), 7.51–7.37
(m, 6H), 5.01 (s, 2H), 2.11 (s, 3H), 2.03 (s, 3H). 13C NMR (DMSO-d6): d 17.3, 24.0,
68.6, 119.0, 119.4, 121.4, 122.0, 127.2, 127.9, 128.8, 129.6, 129.8, 131.5, 135.5,
137.2, 137.6, 138.7, 153.2, 154.0, 160.9, 161.6, 168.7, 172.6. C26H16Br4N4O5: MS
(70 eV): m/z (MꢀC8Br4NO2) = 462.
13C NMR (DMSO-d6): d 17.3, 24.1, 41.7, 60.2, 70.2, 119.6, 119.8, 122.0, 127.3,
127.8, 128.7, 129.8, 131.5, 135.4, 137.2, 139.0, 153.4, 154.2, 160.2, 168.3.
C20H21N3O4: MS (70 eV): m/z = 367.
[2-(2-Methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)]-N-(4,5,6,7-
tetrachloro-1,3-dioxoisoindolin-2-yl)]acetamide (16)
8-(4,5-dihydrooxazol-2-yl)methoxy)-2-methyl-3-o-tolylquinazolin-4(3H)-one (7)
A
mixture of N-[(2-hydroxyethyl)-2-[(2-methyl-3-(2-methylphenyl)-4(3H)-
Yield 84%, mp: 273–5 °C; 1H NMR (DMSO-d6): d 11.35 (s, 1H, exchangeable),
quinazolin-8-yloxy)]acetamide (6) (2 mmol, 708 mg) and conc. H2SO4 (3 mL)
was stirred at room temperature for 12 h. The reaction mixture was neutralized
with 20% KHCO3 solution, filtered, washed with water, dried and recrystallized
from ethanol.
7.79–7.77 (m, 1H), 7.49–7.37 (m, 6H), 5.12 (s, 2H), 2.11 (s, 3H), 2.04 (s, 3H). 13
C
NMR (DMSO-d6):d17.3, 24.0, 68.5, 119.7, 119.9, 122.2, 126.6, 127.2, 127.9, 128.8,
129.4, 129.9, 131.6, 135.5, 137.2, 139.0, 139.8, 153.1, 154.1, 160.9, 161.0, 168.1.
C
26H16Cl4N4O5: MS (70 eV): m/z = 606.
Yield 44%, mp: 147–9 °C; 1H NMR (DMSO-d6): d 8.51 (s, 1H), 7.73 (m, 1H), 7.44–
7.38 (m, 4H), 7.17 (s, 1H), 4.71 (s, 2H), 3.81 (t, 2H, J = 5.0 Hz), 3.38 (t, 2H,
J = 5.0 Hz), 2.13 (s, 3H), 2.02 (s, 3H). 13C NMR (DMSO-d6): d 17.3, 24.1, 39.0, 64.9,
69.9, 119.6, 119.7, 122.0, 127.3, 127.9, 128.8, 129.8, 131.5, 135.4, 137.2, 138.9,
153.4, 154.4, 161.0, 168.5. C20H19N3O3: MS (70 eV): m/z = 351.
Ethyl-2-[2-(2-methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-
yloxy)acetyl]hydrazinecarboxylate (17)
A
mixture of acid hydrazide 3 (3 mmol, 1.014 g) and ethylchloroformate
(4 mmol, 432 mg) in pyridine (20 mL) was refluxed for 8 h. The reaction
mixture was cooled, the solvent was removed under reduced pressure; the
residue was triturated with water, filtered the solid obtained was dried and
recrystallized from ethanol.
N-[2-(2-Methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)acetyl]benzohyd-
razide (8)
To stirred solution of acid hydrazide 3 (3 mmol, 1.014 mg) in dichloromethane
(20 mL) containing triethylamine (5 mmol, 505 mg), benzoylchloride (3 mmol,
422 mg) was added and the reaction mixture was stirred at room temperature
for 7 h. The reaction mixture was filtered and the solvent was evaporated under
reduced pressure, the solid obtained was washed with water, filtered, dried and
recrystallized from ethanol.
Yield 88%, mp: < 350 °C; 1H NMR (CDCl3): d 10.76 (s, 1H, NHC@O), 8.02 (m, 1H),
7.46–7.38 (m, 5H), 7.17 (d, 1H, J = 7.5 Hz), 6.96 (s, 1H, NH–C@O), 4.85 (s, 2H), 4.16
(q, 2H, J = 7.0 Hz), 2.2 (s, 3H), 2.11(s, 3H), 1.23 (t, 3H, J = 2.5 Hz). 13C NMR (CDCl3):
d 14.4, 17.3, 23.8, 62.14, 71.9, 121.8, 121.9, 127.1, 129.8, 131.7, 135.3, 136.5,
139.4, 151.6, 153.2, 155.1, 150.1, 161.0, 167.7, 168.4. C21H22N4O5: MS (70 eV): m/
z = 411 (M+1).
Yield 90%, mp: 212–4 °C; 1H NMR (DMSO-d6): d 12.0 (s, 1H, exchangeable), 10.55
(s, 1H, exchangeable), 7.96–7.37 (m, 12H), 5.05 (s, 2H), 2.04 (s, 3H), 2.02 (s, 3H).
4-[(2-Methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)]pyrazolidin-3,5-
dione (18)

A. S. El-Azab, K. E. H. ElTahir / Bioorg. Med. Chem. Lett. 22 (2012) 327–333
333
A hydrazine carboxylate 17 (1 mmol, 410 mg) was refluxed in absolute ethanol
(10 mL) containing sodium metal (1 mmol, 23 mg) for 6 h. The reaction mixture
was cooled, the solvent was removed under reduced pressure; the residue was
triturated with water, filtered, the solid obtained was dried and recrystallized
ethanol. Yield 59%, mp: 126–8 °C; 1H NMR (DMSO-d6): d 7.67 (dd, 1H, J = 3.0 Hz,
2.5), 7.47–7.38 (m, 5H), 7.33 (d, 1H, J = 7.5 Hz), 4.49 (s, 1H), 3.60 (s, 1H,
exchangeable), 3.56 (s, 1H exchangeable), 2.13 (s, 3H), 2.01 (s, 3H). 13C NMR
(DMSO-d6): d 17.2, 23.8, 116.8, 118.1, 121.6, 127.4, 127.5, 127.9, 128.7, 129.8,
131.6, 135.4, 137.2, 138.0, 153.0, 154.7, 155.4, 155.5, 161.0. C19H16N4O4: MS
(70 eV): m/z = 365 (M+1).
137.2, 147.4, 152.2, 155.9, 160.8, 166.9. C19H18N6O2S: MS (70 eV): m/z = 395
(M+1).
Adult male white Swiss albino mice weighing 20–25 g (10–12 weeks old) were
obtained from Experimental Animal Care Centre, College of Pharmacy, King Saud
University. The animals were maintained under standard conditions of
humidity, temperature (25 2 °C) and light (12 h light/12 h dark). They were
fed with a standard mice pellet diet and had free access to water. All animal
experimentation described in the manuscript was conducted in accord with
accepted standards of humane animal care in accordance with the King Saud
University guidelines and the legal requirements in Kingdom of Saudi Arabia.
Each treatment group and vehicle control group consisted of six animals.
Theanticonvulsantactivity of allsynthesized compoundswere evaluated byfour
models namely, pentylentetrazole (PTZ), picrotoxin, strychnine and maximal
electroshock (MES) models.22 The test compounds were dissolved 10% DMSO
and injected intraperitoneally (i.p.) at dose of 0.5 mmol/kg 30 minutes before
seizures induction. Sodium valproate (300 mg/kg) and methaqualone (200 mg/
kg) were used as reference drugs (In the MES test, seizures were elicited with a
75-Hzalternating current of 99 mAintensity inmice. The current was applied via
ear electrodes for 2 s. Protection against the spread of MES-induced seizures was
defined as the abolition of the hind leg and tonic maximal extension component
of the seizure.28 The PTZ test was carried out by the i.p. injection of a convulsing
dose of PTZ (100 mg/kg). Seizures and tonic-clonic convulsions, hypnosis and
death were recorded. As with PTZ, the chemo-convulsion’s picrotoxin and
strychnine were administered i.p. to mice in a dose eliciting convulsions in 100%
of control mice. The doses needed were 8 and 1.5 mg/kg, respectively. With
picrotoxin, suppression of clonic-tonic episodes and death were used as the
endpoints. With strychnine, animals not experiencing any tonic seizure
components were counted as being protected. The three promising
compounds 3, 17 and 22 at different doses were further evaluated in PTZ
model in order to determine their protective and therapeutic indexes. Groups of
6 mice each were given a range of i.p. doses of the selected drug until at least four
points were established in the range of 10-90% seizure protection or minimal
observed neurotoxicity. From the plots of these data, the respective ED50 and
TD50 values, slopes of the regression line and the standard error were calculated
using a computer program based on the method described by Finney.29 The dose
of tested compounds that prevented 50% of the treated animals from PTZ-
induced clonic convulsion was calculated (ED50). Observation time with all
convulsants was 60 min for convulsions and death. The animals that showed no
convulsion within one hour after convulsive drug administration were
considered to be protected.30
N0-[(Hydrazinecarbonyl)-2-[(2-methyl-3-(2-methylphenyl)-4(3H)-quinazolin-8-
yloxy)]acetohydrazide (19)
A mixture of hydrazine carboxylate 17 (2 mmol, 820 mg) hydrazine hydrate
(5 mmol, 250 mg) in absolute ethanol (50 mL) was stirred at room temperature
for 8 h. The reaction mixture was filtered and dried. Yield 78%, mp: 115–7 °C; 1
H
NMR (DMSO-d6): d 9.56 (s, 1H, exchangeable), 7.75–7.71 (m, 1H), 7.47–7.34 (m,
6H), 4.73 (s, 2H), 4.42 (s, 2H exchangeable), 3.39 (s, 1H, exchangeable), 2.07 (s,
3H), 2.04 (s, 3H). 13C NMR (DMSO-d6): d 17.3, 24.1, 69.3, 119.5, 122.0, 127.2,
127.9, 128.8, 129.8, 131.5, 135.5, 137.2, 139.0, 153.6, 154.0, 161.0, 167.2, 167.3.
C
19H20N6O4: MS (70 eV): m/z = 397 (M+1).
Potassium-2-[2-(2-methyl-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)acetyl]
hydrazinecarbodithioate (21)
To stirred solution of acid hydrazide 3 (3 mmol, 1.014 mg) in absolute ethanol
(20 mL) containing potassium hydroxide (5 mmol, 280 mg), carbon disulfide
was added and the reaction mixture was stirred at room temperature for 3 h. The
reaction mixture was filtered and used without further purification.
Methyl-2-[2-(2-methyl-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)acetyl]
hydrazinecarbodithioate (22)
To stirred solution of potassium dithioate 21 (1 mmol, 452 mg) in absolute
ethanol (10 mL), methyl iodide was added and the reaction mixture was stirred
at room temperature for 2 h. The solvent was removed under reduced pressure,
washed with water, filtered, dried and recrystallized from ethanol.
Yield 100%, mp: 266–8 °C1H NMR (DMSO-d6): d 10.64 (s, 1H), 7.70–7.20 (m, 7H),
4.87 (s, 2H), 2.43 (s, 3H), 2.08 (s, 3H), 2.01 (s, 3H). 13C NMR (DMSO-d6): d 17.3,
24.0, 66.4, 86.3, 117.2, 118.4, 119.3, 122.0, 127.8, 128.8, 129.8, 131.5, 135.4,
137.3, 138.7, 152.8, 154.1, 154.9, 160.9, 163.5. C20H20N4O3S2: MS (70 eV): m/
z = 427 (Mꢀ1).
8-[(5-mercapto-1,3,4-thiadiazol-2-yl)methoxy]-2-methyl-3-(2-methylphenyl)-
4(3H)-quinazolinone (23)
A mixture of potassium dithioate 21 (2 mmol, 904 mg) and conc. H2SO4 (5 mL)
was stirred at room temperature for 12 h. The reaction mixture was neutralized
with 20% KHCO3 solution, the solid obtained was filtered, washed with water,
dried and recrystallized from ethanol. Yield 55%, mp: 334–6 °C; MS (70 eV): m/
z = 396. (Insoluble in any solvents). Anal. Calcd for C19H16N4O2S2 (396.5) C, 57.56,
H, 4.07, N, 14.13. Found C, 57.70, H, 3.98, N, 14.10.
The acute neurotoxicity of the selected compounds was evaluated in mice using
the chimney test.31 Here, motor impairment was indicated by the inability of the
micetoclimbbackward upthetube within30 s. Tested animalsweregivenani.p.
injection of the selected compounds in various doses 30 min before the test. The
neurotoxic effects of the tested compounds were expressed as their median toxic
doses (TD50 values), representing the doses at which the investigated
compounds impaired motor coordination in 50% of the animals.
8-(5-Mercapto-1,3,4-oxadiazol-2-yl)methoxy)-[2-methyl-3-(2-methylphenyl)]-
4(3H)- quinazolinone (24)
A solution of potassium dithioate 21 (1 mmol, 452 mg) in ethanol (10 mL) was
refluxed for 4 h, the reaction mixture was cooled and the solvent was evaporated
under reduced pressure. The residue was dissolved in water, neutralized with
10% HCl; the solid obtained was filtered, washed with water and dried. Yield 86%,
mp: 144–6 °C; 1H NMR (DMSO-d6): d 7.72 (d, 1H, J = 8.0 Hz), 7.54 (d, 1H,
J = 8.0 Hz), 7.46–7.36 (m, 5H), 5.29(s, 1H, exchangeable), 2.09(s, 3H), 2.02 (s, 3H).
13C NMR (DMSO-d6): d 17.3, 24.0, 61.3, 118.1, 119.2, 122.1, 127.1, 127.8, 128.8,
129.8, 131.5, 137.3, 138.8, 152.7, 153.8, 159.3, 161.0, 180.5. C19H16N4O3S: MS
(70 eV): m/z = 382.
The protective index for the selected compounds was calculated by dividing the
TD50 value, as determined in the chimney test, by the respective ED50 value, as
determined in the PTZ test. The protective index is considered to be an index
representing the margin of safety and tolerability between ED50 and TD50.
32 The
median lethal dose (LD50), the dose of the selected compounds that causes 50%
mortality in mice was determined from dose-response curves with at least 4
doses by the method of Litchfield and Wilcoxon.33 Therapeutic index, ratio of the
dose producing toxicity in 50% of animals to the dose needed to produce the
desired 50% therapeutic response was then calculated.
8-(4-Amino-5-mercapto-4H-1,2,4-triazol-3-yl)methoxy-[2-methyl-3-(2-methyl-
phenyl)]-4(3H)-quinazolinone (25)
28. Everett, G. M.; Richards, R. K. J. Pharmacol. Exp. Ther. 1952, 106, 303.
29. Finney, D. J. Probit Analysis, 3rd ed.; Cambridge University Press: London, 1971.
30. White, H. S.; Woodhead, J. H.; Franklin, M. R.; Swinyard, E. A.; Wolf, H. H. In
Antiepileptic Drugs; Levy, R. H., Mattson, R. H., Meldrum, B. S., Eds., 4th ed.;
Raven: NewYork, 1995; pp 99–121.
31. Suárez, A.; Echandi, M. M.; Ulate, G.; Cicció, J. F. Rev. Biol. Trop. 2003, 51(1), 247.
32. Luszczki, J. J.; Wojda, E.; Andres-Mach, M.; Cisowski, W.; Glensk, M.; Glowniak,
K.; Czuczwar, S. J. Epilepsy Res. 2009, 85, 293.
A solution of potassium dithioate 21 (1 mmol, 452 mg) in ethanol (10 mL)
containing hydrazine hydrate (5 mmol, 250 mg) was refluxed for 6 h, the
reaction mixture was cooled and the solvent was evaporated under reduced
pressure. The residue was dissolved in water, neutralized with 10% HCl, the solid
obtained was filtered, washed with water and dried. Yield 76%, mp: 157–9 °C; 1
H
NMR (CDCl3): 15.28 (s, 1H), 7.90 (d, 1H, J = 7.5 Hz), 7.44–7.19 (m, 5H), 7.08 (d, 1H,
J = 7.5 Hz), 5.31 (s, 2H), 5.10 (s, 2H), 2.16 (s, 3H), 2.05 (s, 3H). 13C NMR (CDCl3): d
17.5, 22.1, 59.5, 114.6, 119.7, 122.1, 127.2, 127.8, 129.9, 131.7, 135.3, 136.1,
33. Litchfield, J.; Wilcoxon, F. J. Pharmacol. Exp. Ther. 1949, 96, 99. 84, Q 51, 293–
305.