Synthesis and CNS depressant activity of some novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones

Article abstract of DOI:10.1016/j.ejmech.2007.02.004

A series of novel 3-[5-substituted phenyl-1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones were synthesized and evaluated for anticonvulsant, sedative-hypnotic and CNS depressant activities. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight 2-styrylquinazolin-4(3H)-one derivatives were examined in the maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. Out of eighteen compounds only 4a, 4d, 4e, 4j and 4k showed anticonvulsant activity in one or more test models. All except 4e and 4f exhibited significant sedative-hypnotic activity via actophotometer screen. CNS depressant activity screened with the help of the forced swim pool method resulted into some potent compounds. From the experimental observation it can be concluded that synthesized compounds exhibited relatively better sedative-hypnotic and CNS depressant activities.

Full text of DOI:10.1016/j.ejmech.2007.02.004

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European Journal of Medicinal Chemistry 43 (2008) 135e141
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and CNS depressant activity of some novel 3-[5-substituted
1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H )-ones
b
Varsha Jatav a, Pradeep Mishra a, Sushil Kashaw a, , J.P. Stables
*
a Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, Dr. H.S.G. University, Sagar, M.P. 470003, India
b Preclinical Pharmacology Section, Epilepsy Branch, National Institutes of Health, Bethesda 20892-9020, USA
Received 14 November 2006; received in revised form 11 February 2007; accepted 12 February 2007
Available online 25 February 2007
Abstract
A series of novel 3-[5-substituted phenyl-1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H )-ones were synthesized and evaluated for
anticonvulsant, sedative-hypnotic and CNS depressant activities. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight
2-styrylquinazolin-4(3H )-one derivatives were examined in the maximal electroshock induced seizures (MES) and subcutaneous pentylenete-
trazole (scPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. Out of eighteen compounds only 4a,
4d, 4e, 4j and 4k showed anticonvulsant activity in one or more test models. All except 4e and 4f exhibited significant sedative-hypnotic activity
via actophotometer screen. CNS depressant activity screened with the help of the forced swim pool method resulted into some potent com-
pounds. From the experimental observation it can be concluded that synthesized compounds exhibited relatively better sedative-hypnotic and
CNS depressant activities.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: 4(3H )-Quinazolinones; MES; Subcutaneous pentylenetetrazole induced seizure
1. Introduction
reports in the literature our attention was drawn to the earlier
discovery by Boltze et al. [5] and Wolfe et al. [6] that modifica-
tion of methyl group by some other chemical moiety yielded
structural analogues with anticonvulsant activity. Medicinal
chemists over the years have substituted different heterocyclic
rings at position 3 of the 4(3H )-quinazolinone to get potent
CNS acting drugs. 1,3,4-Thiadiazoles nucleus itself exhibits
anticonvulsant, sedative-hypnotic and CNS neurotoxicity activ-
ities [7]. In hope of getting synergistic response of 4(3H )-
quinazolinone nucleus itself, substitution of 1,3,4-thiadiazoles
nucleus at third position and chemically modifying second posi-
tion of 4(3H )-quinazolinone, the present paper reports on the
synthesis, anticonvulsant, neurotoxicity, CNS depressant activ-
ity and behavioral study of 18 new 3-(103040thiadiazol-2-yl)-
2-styrylquinazolin-4(3H )-ones.
One of the most frequently encountered heterocycles in me-
dicinal chemistry is 4(3H )-quinazolinone with wide applica-
tions including anticonvulsant, sedative, tranquilizer, analgesic,
antimicrobial, anesthetic, anticancer, antihypertensive, anti-
inflammatory, diuretic and muscle relaxant properties [1e4].
Literature survey revealed that the presence of substituted
aromatic ring at position 3 and methyl group at position 2 are
necessary requirement for the central nervous system (CNS)
depression and anticonvulsant activities. In spite of the fact
that literally hundreds of quinazolinones related to 2-methyl-
3-o-tolyl-4(3H )-quinazolinone (methaqualone) have been syn-
thesized and tested for central nervous system (CNS) depression
and anticonvulsant activities, none of the drugs currently in use
contain the 4(3H )-quinazolinone ring system. Among the few
2. Chemistry
Thesynthesisof3-(103040-Thiadiazolyl)-2-methylquinazolin-
4(3H )-one is accomplished as shown in Figs. 1 and 2.
* Corresponding author. Tel.: þ91 7582240757; fax: þ91 7582244094.
E-mail address: sushilkashaw@gmail.com (S. Kashaw).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.02.004

136
V. Jatav et al. / European Journal of Medicinal Chemistry 43 (2008) 135e141
N
N
O
(IV)
COOH
NH2
H2N
R
S
(CH3CO)2O
O
in GAA
N
CH3
1
2
O
O
N
N
N
N
N
N
ArCHO
in GAA
N
S
R
S
R
N
CH3
Ar
4
3
Fig. 1. Scheme for the synthesis of title compounds.
Fe+++
N
N
Step -1
NNHCSNH2
RCH
RCHO + H2NNHCSNH2
-H2O
Step 2
R
S
IV
NH2
I
II
III
Fig. 2. Scheme for the synthesis of 2-amino-5-aryl-1,3,4-thiadiazoles.
3-(103040-Thiadiazolyl)-2-styrylquinazolin was synthesized by
3-step procedure, whereas 3-(103040-thiadiazolyl)-2-styryl-
quinazolin 4 obtained by refluxing equimolar amount of
3-(103040-thiadiazolyl)-2-methyl quinazolin and aromatic al-
dehyde in glacial acetic acid. The structures of the new
compounds were elucidated by analytical and spectroscopic
measurements.
The IR spectra showed the C]O peak at 1701 cmꢀ1, C]O
stretching at 1580 and C]C stretching (Alkene) vibration at
1630 cmꢀ1. The 13C NMR depicted spectrum at (C-2) 162.4,
Table 1
Physical data of 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H )-ones
O
N
N
N
R
S
N
Ar
Code No.
Ar
R
Yield (%)
M.p. (ꢁC)
Molecular formulaa
Rf
Log pb
4a
4b
4c
4d
4e
4f
eC6H5
eC6H5
eC6H5
50
48
47
42
43
25
30
35
30
32
38
27
30
33
35
38
38
28
198
200
C24H18N4OS
C25H20N4O2S
C25H20N4OS
C24H17ClN4OS
C24H17ClN4OS
C26H20N4OS
C25H20N4O2S
C26H22N4O3S
C26H22N4O2S
C25H17ClN4O2S
C25H17ClN4O2S
C27H20N4O2S
C25H18N4OS
C26H22N4O2S
C26H20N4OS
C25H17ClN4OS
C25H17ClN4OS
C27H20N4OS
0.61
0.66
0.71
0.84
0.81
0.58
0.63
0.59
0.58
0.85
0.82
0.79
0.75
0.76
0.63
0.81
0.83
0.78
3.68
3.73
4.17
4.39
4.39
3.87
3.59
3.65
4.09
4.31
4.31
3.87
4.17
4.23
4.67
4.89
4.89
4.37
p-OCH3C6H4
p-CH3C6H4
p-ClC6H4
eC6H5
eC6H5
208
220
eC6H5
eC6H5
m-ClC6H4
eCH]CHC6H4
eC6H5
220
206
4g
4h
4i
p-OCH3C6H4
p-OCH3C6H4
p-OCH3C6H4
p-OCH3C6H4
p-OCH3C6H4
p-OCH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
232
230
p-OCH3C6H4
p-CH3C6H4
p-ClC6H4
226
4j
>250c
>250c
225
4k
4l
m-ClC6H4
eCH]CHC6H4
eC6H5
4m
4n
4o
4p
4q
4r
a
206
226
p-OCH3C6H4
p-CH3C6H4
p-ClC6H4
m-ClC6H4
eCH]CHC6H4
224
212
210
242
Elemental analyses for C, H, N were within ꢂ0.4% of the theoretical value.
Log p was generated using hyperchem.
Melting point of the compound at their decomposition.
b
c

V. Jatav et al. / European Journal of Medicinal Chemistry 43 (2008) 135e141
137
(C-4) 168.3, (C-11) 112 and (C-12) 136. Thin layer chromatog-
raphy (TLC) was run throughout the reaction to optimize the re-
action for purity and completion. The physicochemical data for
the newly synthesized compounds are presented in Table 1.
3-(103040-Thiadiazolyl)-2-methyl quinazolinones [8e10]
were obtained by refluxing 2-methylbenzoxazin-4(3H )-one 2
[11] with the amine derivative IV according to Fig. 1. The
amino derivative IV [12e15] was obtained by the oxidative
cyclization of thiosemicarbazone III (through condensation
of aromatic aldehyde I and thiosemicarbazide II) in the pres-
ence of ferric chloride according to the scheme given in Fig. 2.
screened for their CNS behavioral activity in mice using acto-
photometer and Porsolt’s swim pool test in rats and results are
presented in Tables 3 and 4.
4. Results and discussions
Initial anticonvulsant activity and neurotoxicity data for the
quinazolinone analogs are reported in Table 2, along with the
literature data on phenytoin, carbamazepine, sodium val-
proate, phenobarbital and ethosuximide [16e18]. In this series
all the quinazolinone analogs showed more potent sedative-
hypnotic and CNS depressant activities than anticonvulsant
activity. In the earlier reports it was highlighted that the pres-
ence of electron rich atom/group attached at the para position
of the aryl ring showed increased potency in the MES screen
[19,20]. Compounds 4a, 4d, 4e, 4j, 4k and 4p were found to
exhibit anticonvulsant activity in MES screen, however, com-
pound 4a showed potency similar to standard drug (phenytoin,
carbamazepine) without any neurotoxicity. All the synthesized
compounds were active in MES screen for a long duration of
time (after 4 h). Compound 4d displayed activity in the MES
screen after 0.5 h (100 mg/kg) and 4 h (100 mg/kg) while it
was active at both 0.5 h (300 mg/kg) and 4 h (300 mg/kg) in
the scPTZ test. This compound exhibited rapid onset of action
and long duration of activity. Compounds 4b, 4c, 4f, 4g, 4h,
4l, 4m, 4n, 4o and 4r did not show any activity in MES as
well as in scPTZ after 0.5 h. Compounds 4e, 4f, 4g and 4h
showed neurotoxicity after 0.5 h at 300 mg/kg body weight.
3. Pharmacology
The new derivatives obtained from the reaction sequence
were injected intraperitoneally into mice and evaluated in
the maximal electroshock (MES), subcutaneous pentylenete-
trazole (scPTZ) and neurotoxicity screens, using doses of 30,
100 and 300 mg/kg at two different time intervals. These
data are presented in Table 2. These compounds were also
Table 2
Anticonvulsant activity and minimal motor impairment of 3-[5-substituted
1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H )-ones
Code no.
Intraperitoneal injection in micea
MES screen scPTZ screen
Neurotoxicity screen
0.5 h
4 h
0.5 h
4 h
0.5 h
4 h
4a
4b
30
e
e
e
eb
e
e
e
e
e
e
e
Table 3
Behavioral study of 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazo-
4c
4d
e
e
e
e
e
e
100
e
100
100
e
300
e
300
e
e
e
e
line-4(3H )-ones
4e
300c
300
100d
300
e
Compounda Activity scoreb
% Inhi-
bition
4f
4g
e
e
e
e
e
e
e
e
e
e
e
e
e
e
Control
(24 h prior)
Post treatment
0.5 h After
4h
4i
1 h After
e
e
300
300e
e
e
e
4j
4k
e
300
300
e
300
e
e
e
e
4a
4b
4c
4d
4e
4f
559.32 ꢂ 20.78 472.31 ꢂ 26.78
416.04 ꢂ 11.26 381.82 ꢂ 9.69
249.45 ꢂ 11.69
266.36 ꢂ 11.89
55
36
e
e
e
e
e
e
4l
4m
e
442.24 ꢂ 10.42 531.00 ꢂ 17.22NS 467.00 ꢂ 21.11NS e
e
e
e
e
e
e
418.10 ꢂ 9.97 250.62 ꢂ 10.30
454.16 ꢂ 10.62 319.57 ꢂ 9.66
454.72 ꢂ 20.52 372.87 ꢂ 2.21
467.63 ꢂ 8.89 419.24 ꢂ 6.12
442.82 ꢂ 21.24 308.13 ꢂ 7.25
398.46 ꢂ 26.18 315.46 ꢂ 4.56
410.52 ꢂ 10.62 306.98 ꢂ 21.13
324.76 ꢂ 27.73 292.39 ꢂ 29.87
468.62 ꢂ 13.38 362.37 ꢂ 11.02
420.86 ꢂ 30.22 353.52 ꢂ 6.77
397.92 ꢂ 10.80 272.19 ꢂ 2.11
328.16 ꢂ 32.96 291.39 ꢂ 1.02
435.72 ꢂ 22.66 373.56 ꢂ 2.35
376.34 ꢂ 32.75 298.67 ꢂ 7.35
384.52 ꢂ 15.66 310.32 ꢂ 2.44
132.04 ꢂ 12.16
165.52 ꢂ 12.70
68
63
4n
4o
e
e
e
e
e
e
e
e
e
300
e
e
e
e
e
e
e
ee
e
489.92 ꢂ 11.63NS e
4p
4q
4g
4h
4i
210.24 ꢂ 12.62
180.30 ꢂ 12.05
142.19 ꢂ 13.28
155.31 ꢂ 17.30
110.45 ꢂ 11.25
228.32 ꢂ 26.72
185.15 ꢂ 31.79
137.19 ꢂ 32.84
92.20 ꢂ 34.91
153.08 ꢂ 10.90
128.94 ꢂ 26.37
123.32 ꢂ 38.13
164.10 ꢂ 30.11
55
59
64
62
66
51
55
65
71
64
65
67
70
e
300
e
300
e
e
e
4r
e
e
e
e
Phenytoinf
Carbamazepinef
Sodium vaporatef
Phenobarbitalsf
Ethosuximidef
a
30
30
e
30
100
e
e
e
300
e
100
100
e
100
300
e
4j
100
300
30
300
4k
4l
100
e
30
e
300
e
100
e
300
e
4m
4n
4o
4p
4q
4r
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 animal was examined 0.5 and 4 h after injections were
made the dash(e) indicates an absence of activity at maximum dose adminis-
tered (300 mg/kg).
Phenytoinc 546.40 ꢂ 31.12 251.02 ꢂ 12.32
b
a
Died during test at 300 mg/kg without seizure.
Neurotoxicity at 100 mg/kg (0.25 h, 1 h).
The compound were tested at a dose of 100 mg/kg (i.p.).
Each score represents the mean ꢂ SEM of six mice, significantly different
c
b
d
Loss of righting reflux.
At 100 mg/kg after 0.25 h, 3/5 and after 1 h 4/5 mice were protected.
Data from Refs. [9e11].
from the control score at <0.02 and NS indicate not significant at p > 0.02
(student’s t test).
e
f
c
Tested at 25 mg/kg p.o.

138
V. Jatav et al. / European Journal of Medicinal Chemistry 43 (2008) 135e141
Table 4
CNS study on 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-
4(3H )-ones by forced swim pool test
a similar study using swim pool test, the immobility time after
administration of the test compounds were compared with car-
bamazepine (Table 4). Except for 4c, 4g and 4l other tested
compounds were found to exhibit potent CNS depressant activ-
ity ( p < 0.05) as indicated by increased immobility time.
Present study explored that substitution of 1,3,4-thiadia-
zoles at third position and styryl moiety at second position
of 4(3H )-quinazolinone leads to the development of new
chemical entities with potent sedative-hypnotic and CNS
depressant activities as compared to anticonvulsant activity.
Compounda
Immobility timeb (s)
Control (24 h prior)
Post treatment (60 min after)
PEG
4a
174.67 ꢂ 14.72
135.42 ꢂ 9.87
97.12 ꢂ 6.29
178 .53 ꢂ 12.32 NS
200.30 ꢂ 11.69
130.37 ꢂ 10.32
172.00 ꢂ 12.49NS
163.30 ꢂ 12.06
197.60 ꢂ 12.94
172.72 ꢂ 11.62
120.83 ꢂ 10.91NS
110.60 ꢂ 12.72
208.72 ꢂ 10.12
182.24 ꢂ 11.24
179.07 ꢂ 12.86
118.43 ꢂ 11.10NS
120.56 ꢂ 10.98
187.16 ꢂ 12.36
210.70 ꢂ 13.42
74.63 ꢂ 13.63
4b
4c
154.62 ꢂ 11.23
88.65 ꢂ 10.92
108.19 ꢂ 7.31
125.63 ꢂ 8.81
114.33 ꢂ 7.24
57.66 ꢂ 11.19
187.19 ꢂ 10.68
101.04 ꢂ 12.05
134.38 ꢂ 13.29
107.97 ꢂ 12.62
63.42 ꢂ 12.16
119.37 ꢂ 11.89
136.18 ꢂ 11.69
49.10 ꢂ 13.72
134.93 ꢂ 17.30
172.17 ꢂ 13.89
138.82 ꢂ 15.09
4d
4e
4f
4g
5. Experimental protocol
4h
4i
4j
4k
5.1. Chemistry
4l
4m
Melting points were determined in one end open capillary
tubes on a Buchi 530 melting point apparatus and are uncor-
rected. Infrared (IR) spectra were recorded for the compounds
on Perkin Elmer Spectrum RXI Spectrophotometer in KBr.
4n
4o
4p
4q
1
13C nuclear magnetic resonance (13C NMR) and H nuclear
198.05 ꢂ 14.08
218.29 ꢂ 10.93
240.30 ꢂ 14.10
4r
Carbamazepinec
magnetic resonance (1H NMR) spectra were recorded for the
compounds on Advance bruker (300 MHz) instrument. Chem-
ical shifts are reported in parts per million (ppm) using tetra-
methylsilane (TMS) as an internal standard. Elemental
analysis (C, N and S) was undertaken with Elemental vario
EL III Carlo Erba 1108 analyzer. The purity of the compounds
was confirmed by thin layer chromatography using silica gel
glass plates and a solvent system of benzene:ethanol (8:2).
The spots were developed in iodine chamber and visualized
under ultra violet lamp. The log p values were determined us-
ing Hyperchem and Chemdraw software.
a
The compounds were tested at a dose of 100 mg/kg (i.p.).
Each value represent the mean ꢂ SEM of six rats significantly different
b
from the control at p < 0.05 and NS denotes not significant at p < 0.05
(student’s t test).
c
Tested at 30 mg/kg (i.p.).
The most active compound in the scPTZ test, a test used to
identify compound that elevates seizure threshold, were 4j
and 4q.
Experimental results indicated that our compound exhibited
better sedative-hypnotic and CNS depressant activities as com-
pared to anticonvulsant activity. All the compounds were
screened for behavior study and CNS depressant activity. In
the behavioral study using actophotometer scoring technique,
compounds showed decrease in locomotor activity between
36% and 71% where 36% was the lowest and 71% was the max-
imal decrease in locomotor activity when compared to phenyt-
oin as reported in Table 3. Compound 4o was equipotent to
phenytoin in decreasing % locomotor activity. All the com-
pounds except 4b exhibited more than 50% decrease in locomo-
tor activity ( p < 0.02) after 1 h. Generally compounds
possessing higher log p value showed higher decrease in loco-
motor activity. Bulkier compounds are more lipophilic and
can cross blood brain barrier to exert their effect at CNS. In
5.1.1. Synthesis of 2-amino 5-aryl 103040-thiadiazole [5e8]
2-Amino-5-aryl 103040-thiadiazole was synthesized follow-
ing two steps.
Step 1: synthesis of thiosemicarbazones
Aromatic aldehyde I (0.2 M) in warm alcohol (300 mL)
and thiosemicarbazide II (0.2 M) in warm water (300 mL)
were mixed slowly with continuous stirring. The product sep-
arated immediately on cooling which was filtered with suction,
dried and recrystallised in 75% ethanol to yield III. Physico-
chemical properties are presented in Table 5.
Table 5
Physico-chemical data of thiosemicarbazone ReCH]NNHCSNH2
S. No.
R
Yield Solvent recrystallize M.P. (ꢁC) Molecular
formula
Molecular IR (cmꢀ1
weight
)
1H NMR (ppm)
1
2
3
4
5
6
C6H5
92%
85%
95%
90%
90%
80%
Aq. ethanol (50%)
Ethanol
159
170
160
207
206
185
C8H9N3S
C9H4N3OS
C9H4N3S
179.25
209.27
193.27
3350 (NH2), 3320 (NH) 2.0 (NH2), 2.0 (NH)
p-OCH3C6H4
p-CH3C6H4
p-ClC6H4
m-ClC6H4
-CH=CHC6H4
3362 (NH2), 3315 (NH) 2.0 (NH2), 2.0 (NH), 3.73 (CH3)
3294 (NH2), 3140 (NH) 2.0 (NH2), 2.0 (NH), 2.35 (CH3)
3315 (NH2), 3326 (NH) 2.0 (NH2), 2.0 (NH)
Aq. ethanol (50%)
Ethanol
C8H8ClN3S 213.69
C8H8ClN3S 213.69
Aq. ethanol (50%)
Ethanol
3340 (NH2), 3326 (NH) 2.0 (NH2), 2.0 (NH)
3350 (NH2), 3321 (NH) 2.0 (NH2), 5.6 (CH1), 6.6 (CH2)
C10H11N3S
205.28
1
2

V. Jatav et al. / European Journal of Medicinal Chemistry 43 (2008) 135e141
139
Step-2: synthesis of 2-amino-5-aryl 103040-thiadiazoles
4e
IR (cmꢀ1) 1700 (C]O), 1614 (C]C) Alkene, 1555 (C]N), 1326
(CN), 760 (CS); 13C NMR (d) 160.2 (C-2), 168.8 (C-4), 112 (C-11),
136 (C-12), 137.9 (C-100), 134 (C-13); 1H NMR (300 MHz, d) 5.12 (d,
1H, olefinic CH, J ¼ 15.4 Hz), 6.41e7.49 (a set of signals, 13H,
aromatic protons and olefinic CH).
Thiosemicarbazone III (0.05 M) was suspended in 300 ml
warm water, FeCl3 (0.15 M) in 300 ml water was added quan-
titatively, slowly with constant stirring. The contents were
heated at 80e90 ꢁC for 45 min. Solution was filtered hot
and then citric acid (0.11 M) and sodium citrate (0.05 M)
were added. The resulting mixture was divided into 4 parts
and each part was neutralized separately with ammonia
(10%). The required amine separated out, filtered with suction,
dried and recrystallised with appropriate solvent. Physico-
chemical properties are reported in Table 6.
4f
IR (cmꢀ1) 1737 (C]O), 1610 (C]C) Alkene, 1532 (C]N), 1269
(CN), 733 (CS); 13C NMR (d) 167 (C-2), 168.9 (C-4), 112 (C-4), 136
(C-12), 134 (C-100), 134 (C-13), 125 (CA), 130 (CB); 1H NMR
(300 MHz, d) 5.60 (d, 1H, olefinic CH, J ¼ 15.6 Hz), 6.99 (d, 2H,
olefinic CH), 6.78e8.01 (a set of signals, 14H, aromatic protons and
olefinic CH).
IR (cmꢀ1) 1700 (C]O), 1620 (C]C) Alkene, 1542 (C]N), 1274 (CN),
740 (CS); 13C NMR(d) 158.8 (C-2), 168.6 (C-4), 112 (C-11), 136(C-12),
136.5 (C-100), 134.5 (C-13), 56 (CA); 1H NMR (300 MHz, d) 3.84 (s, 3H,
CH3), 5.82 (d, 1H, olefinic CH, J ¼ 14.4 Hz), 6.72e7.94 (a set of signals,
13H, aromatic protons and olefinic CH).
IR (cmꢀ1) 1739 (C]O), 1642 (C]C) Alkene, 1542 (C]N), 1334
(CN), 759 (CS); 13C NMR (d) 167 (C-2), 168.6 (C-4), 112 (C-11), 136
(C-12), 128.8 (C-100), 131.4 (C-13), 55.5 (CA), 56 (CB); 1H NMR
(300 MHz, d) 3.63 (s, 3H, CH3), 3.72 (s, 3H, CH3), 5.76 (d, 1H,
olefinic CH, J ¼ 15.0 Hz), 6.60e7.86 (a set of signals, 12H, aromatic
protons and olefinic CH).
IR (cmꢀ1) 1701 (C]O), 1637 (C]C) Alkene, 1530 (C]N), 1267
(CN), 774 (CS); 13C NMR (d) 165 (C-2), 168 (C-4), 112 (C-11), 136
(C-12), 133.5 (C-100), 131.4 (C-13), 21.4 (CA), 56 (CB); 1H NMR
(300 MHz, d) 2.32 (s, 3H, CH3), 3.74 (s, 3H, CH3), 5.85 (d, 1H,
olefinic CH, J ¼ 15.2 Hz), 6.74e7.10 (a set of signals, 12H, aromatic
protons and olefinic CH).
4g
4h
5.1.2. Synthesis of 2-methyl-3-(103040-thiadiazole-20-yl)-
4(3H )-quinazolinone[21]
Anthranilic acid 1 (0.01 M) and acetic anhydride were re-
fluxed under anhydrous condition for 4 h. Excess of acetic an-
hydride was distilled off under reduced pressure. To the
mixture obtained, amines IV (0.01 M) in glacial acetic acid
was added and refluxed for 4 h. Obtained reaction mixture
was poured into crushed ice and left overnight. The solid
which separated out was filtered, washed thoroughly with
cold distilled water, dried and recrystallised from hot ethanol.
The yield, melting point and other physical properties of syn-
thesized compound are recorded in Table 7.
4i
4j
IR (cmꢀ1) 1734 (C]O), 1634 (C]C) Alkene, 1542 (C]N), 1293
(CN), 658 (CS); 13C NMR (d) 167 (C-2), 168.7 (C-4), 112 (C-11),
135.8 (C-12), 134.6 (C-100), 131.4 (C-13), 56 (CA); 1H NMR
(300 MHz, d) 3.80 (s, 3H, CH3), 5.62 (d, 1H, olefinic CH,
J ¼ 15.6 Hz), 6.51e7.89 (a set of signals, 12H, aromatic protons
and olefinic CH).
5.1.3. Synthesis of title compound
The title compounds were synthesized by following the
procedure reported earlier [11,22e26]. A solution of 3
(0.01 M) and opportune benzaldehyde (0.01 M) were reacted
with glacial acetic acid (10 ml) and refluxed for 12 h.
4k
4l
IR (cmꢀ1) 1700 (C]O), 1630 (C]C) Alkene, 1560 (C]N), 1348
(CN), 591 (CS); 13C NMR (d) 165 (C-2), 168.6 (C-4), 112 (C-11), 136
(C-12), 137.9 (C-100), 131.6 (C-13), 56 (CA); 1H NMR (300 MHz, d)
3.46 (s, 3H, CH3), 5.43 (d, 1H, olefinic CH, J ¼ 15.4 Hz), 6.65e7.96 (a
set of signals, 12H, aromatic protons and olefinic CH).
The solid
4 which separated out was filtered with
IR (cmꢀ1) 1708 (C]O), 1608 (C]C) Alkene, 1505 (C]N), 1278
(CN), 620 (CS); 13C NMR (d) 167 (C-2), 168 (C-4), 112 (C-11), 136.5
(C-12), 134.9 (C-100), 131.6 (C-13), 124.2 (CA), 129.2 (CB), 56 (CC);
1H NMR (300 MHz, d) 3.57 (s, 3H, CH3), 5.66 (d, 1H, olefinic CH,
J ¼ 15.2 Hz), 7.01 (d, 2H, olefinic CH), 6.72e8.12 (a set of signals,
13H, aromatic protons and olefinic CH).
suction and recrystallised from dimethylformamide to
give pure compound. The physical data of the styryl quinazo-
linone are given in Table 1. The IR spectra, 13C NMR spectra
1
and H NMR spectra of the title compounds are as follows:
4m
4n
IR (cmꢀ1) 1701 (C]O), 1693 (C]C) Alkene, 1562 (C]N), 1274
(CN), 761 (CS); 13C NMR (d) 164 (C-2), 165 (C-4), 112 (C-11), 136
1
(C-12), 136.5 (C-100), 131.9 (C-13), 20.9 (CA); H NMR (300 MHz, d)
4a
4b
IR (cmꢀ1) 1693 (C]O), 1650 (C]C) Alkene, 1530 (C]N), 1317
(CN), 688 (CS); 13C NMR (300 MHz, d) 168 (C-4), 162.4 (C-2), 112
2.36 (s, 3H, CH3), 5.60 (d, 1H, olefinic CH, J ¼ 15.2 Hz), 6.66e7.90
(a set of signals, 13H, aromatic protons and olefinic CH).
IR (cmꢀ1) 1703 (C]O), 1609 (C]C) Alkene, 1559 (C]N), 1251
(CN), 615 (CS); 13C NMR (d) 161.4 (C-2), 168 (C-4), 112 (C-11), 136
(C-12), 128.5 (C-100), 131.9 (C-13), 55.4 (CA), 22 (CB); 1H NMR
(300 MHz, d) 2.30 (s, 3H, CH3), 3.74 (s, 3H, CH3), 5.64 (d, 1H,
olefinic CH, J ¼ 15.2 Hz), 6.68e7.89 (a set of signals, 12H, aromatic
protons and olefinic CH).
IR (cmꢀ1) 1612 (C]O), 1650 (C]C) Alkene, 1520 (C]N), 1313
(CN), 615 (CS); 13C NMR (d) 165 (C-2), 168 (C-4), 112 (C-11), 136
(C-12), 134.6 (C-100), 131.4 (C-13), 50.5 (CA), 20.9 (CB); 1H NMR
(300 MHz, d) 2.30 (s, 3H, CH3), 2.34 (s, 3H, CH3), 5.58 (d, 1H,
olefinic CH, J ¼ 15.4 Hz), 6.87e8.10 (a set of signals, 12H, aromatic
protons and olefinic CH).
IR (cmꢀ1) 1693 (C]O), 1610 (C]C) Alkene, 1590 (C]N), 1316
(CN), 667 (CS); 13C NMR (d) 158.6 (C-2), 168.7 (C-4), 112 (C-11),
136 (C-12), 135.1 (C-100), 131.6 (C-13), 22.4 (CA), 131.9 (CB); 1H
NMR (300 MHz, d) 2.40 (s, 3H, CH3), 5.76 (d, 1H, olefinic CH,
J ¼ 15.2 Hz), 6.54e7.94 (a set of signals, 12H, aromatic protons and
olefinic CH).
1
(C-11), 136 (C-12), 136.5 (C-100), 135 (C-18); H NMR (300 MHz, d)
5.16 (d, 1H, olefinic CH, J ¼ 15.2 Hz), 6.6e7.92 (a set of signals, 14H,
aromatic protons and olefinic CH).
IR (cmꢀ1) 1700 (C]O), 1611 (C]C) Alkene, 1520 (C]N), 1313
(CN), 675 (CS); 13C NMR (300 MHz, d) 161 (C-2), 161.5 (C-4), 114.7
(C-11), 136 (C-12), 136.5 (C-100), 134 (C-13), 55.4 (CA); 1H NMR
(300 MHz, d) 3.73 (s, 3H, CH3), 5.74 (d, 1H, olefinic CH,
J ¼ 15.5 Hz), 6.83e8.00 (a set of signals, 13H, aromatic protons and
olefinic CH).
4o
4p
4c
IR (cmꢀ1) 1691 (C]O), 1640 (C]C) Alkene, 1530 (C]N), 1275
(CN), 773 (CS); 13C NMR (d) 165 (C-2), 168 (C-4), 112 (C-11), 136
(C-12), 133.5 (C-100), 134.9 (C-13), 21.4 (CA); 1H NMR (300 MHz, d)
2.35 (s, 3H, CH3), 5.84 (d, 1H, olefinic CH, J ¼ 15.2 Hz), 6.12e7.85 (a
set of signals, 13H, aromatic protons and olefinic CH).
IR (cmꢀ1) 1700 (C]O), 1668 (C]C) Alkene, 1591 (C]N), 1326
(CN), 752 (CS); 13C NMR (d) 165 (C-2), 168 (C-4), 112 (C-11), 136.4
(C-12), 134.6 (C-100), 135 (C-13); 1H NMR (300 MHz, d) 5.52 (d, 1H,
olefinic CH, J ¼ 15.2 Hz), 6.80e7.48 (a set of signals, 13H, aromatic
protons and olefinic CH).
4d

140
V. Jatav et al. / European Journal of Medicinal Chemistry 43 (2008) 135e141
4q
IR (cmꢀ1) 1695 (C]O), 1610 (C]C) Alkene, 1530 (C]N), 1322
weight for rats at doses of 30, 100, 300 mg/kg to one to four
animals. Activity was established using the MES and scPTZ
test and these data are presented in Table 2.
(CN), 618 (CS); 13C NMR (d) 160.1 (C-2), 168.7 (C-4), 112 (C-11),
136 (C-12), 137.9 (C-100), 131.1 (C-13), 12.3 (CA); 1H NMR
(300 MHz, d) 2.32 (s, 3H, CH3), 5.67 (d, 1H, olefinic CH,
J ¼ 15.6 Hz), 6.76e7.49 (a set of signals, 12H, aromatic protons and
olefinic CH).
5.2.2. Neurotoxicity screening
4r
IR (cmꢀ1) 1708 (C]O), 1600 (C]C) Alkene, 1520 (C]N), 1311
(CN), 633 (CS); 13C NMR (d) 161.6 (C-2), 168.6 (C-4), 112 (C-11),
136.4 (C-12), 135.4 (C-100), 131.9 (C-13), 124.8 (CA), 130.8 (CB), 22.4
(CC); 1H NMR (300 MHz, d) 2.35 (s, 3H, CH3), 5.63 (d, 1H, olefinic
CH, J ¼ 15.4 Hz), 6.93 (d, 2H, olefinic CH), 6.70e7.99 (a set of
signals, 13H, aromatic protons and olefinic CH).
Minimal motor impairment [31] was measured in mice by
the rotorod test. The mice were trained to stay on an acceler-
ating rotorod that rotated at six revolutions per minute. The
rod diameter was 3.2 cm. Neurotoxicity was indicated by the
inability of the animal to maintain equilibrium on the rod
for at least 1 min in each of the three trials.
5.2. Pharmacology
5.2.3. Behavioral testing
The anticonvulsant evaluation was undertaken using re-
ported procedure [27e30]. Male albino mice (CF-1 strain
or swiss, 18e25 g) and rats (SpragueeDawley or Wistar,
100e150 g) were used as experimental animals. The tested
compounds were suspended in polyethylene glycol 400.
The titled compounds (100 mg/kg) were screened for
their behavioral effect using actophotometer [32] at 30 min
and 1 h after drug administration. The behavior of animals
inside the photocell was recorded as a digital score. Increased
scores suggest good behavioral activity. The activity of the
compounds were at maximum at 1 h, therefore, the activity
values at 1 h were used to calculate % decrease in locomo-
tor activity. The control group animals were administered
PEG 400. The observations are tabulated as Table 3.
5.2.1. Anticonvulsant screening
Initially all the compounds were administered i.p. in a vol-
ume of 0.01 ml/g body weight for mice and 0.004 ml/g body
Table 6
Physico-chemical data of 2-amino-5-aryl 1,3,4-thiadiazole
N
N
R
NH2
S
S. No.
R
Yield
Solvent recrystallize
M.P. (ꢁC)
Molecular
formula
Molecular
weight
IR (cmꢀ1
)
1H NMR (ppm)
1
2
3
4
5
C6H5
65%
60%
62%
70%
70%
Aq. ethanol (25%)
Aq. ethanol (50%)
Aq. ethanol (25%)
Aq. ethanol (50%)
Aq. ethanol (50%)
224
210
215
227
226
C8H7N3S
C9H9N3OS
C9H9N3S
177.23
207.26
191.26
211.67
211.67
3496 (NH2)
3500 (NH2)
3450 (NH2)
3452 (NH2)
3466 (NH2)
4.0 (NH2)
p-OCH3C6H5
p-CH3C6H4
p-ClC6H4
m-ClC6H4
4.0 (NH2), 3.73 (OCH3)
4.0 (NH2), 2.35 (CH3)
4.0 (NH2)
C8H6ClN3S
C8H6ClN3S
4.0 (NH2)
4.0 (NH2), 6.9 (CH1), 6.9
(CH2)
-CH=CHC6H4
6
60%
Aq. ethanol
220
C8H8N3S
202.27
3490 (NH2)
1
2
Table 7
Physicochemical properties of 3-[5-substituted 1,3,4-thiadiazole-2-yl] quinazoline-4(3H )-ones
O
N
N
4
3
N
R
S
2
N
1
CH3
CA
S. No.
1
R
Yield
60%
M.P. (ꢁC)
Molecular formula
C17H12N4SO
Molecular weight
320.38
IR (cmꢀ1
)
13C NMR (ppm)
C6H5
172e174
1693 (C]O)
164 (C-2), 173 (C-4), 17.4
(CA)
p-OCH3C6H4
2
3
4
5
6
60%
58%
55%
55%
50%
185e187
180e182
189e190
188e190
176e177
C18H14N4SO2
C18H14N4SO
C17H11N4SOCl
C17H11N4SOCl
C19H13N4SO
350.40
334.40
354.82
354.5
1701 (C]O)
1700 (C]O)
1695 (C]O)
1705 (C]O)
1692 (C]O)
164 (C-2), 173 (C-4), 17.4
(CA), 56 (CB)
CB
p-CH3C6H4
164 (C-2), 173 (C-4), 17.4
(CA), 20.9 (CB)
CB
p-ClC6H4
m-ClC6H4
164 (C-2), 173 (C-4), 17.4
(CA)
164 (C-2), 173 (C-4), 17.4
(CA)
CH=CHC6H4
CB CC
346.41
164 (C-2), 173 (C-4), 17.4
(CA), 124.8 (CB), 130.8 (CC)

V. Jatav et al. / European Journal of Medicinal Chemistry 43 (2008) 135e141
[12] G. Young, W. Eyre, J. Chem. Soc. 54 (1901) 162.
141
5.2.4. CNS depressant activity
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Am. Chem. Soc. 73 (1957) 906.
The forced swim pool method described earlier [33] was
followed. Wistar rats were placed in chamber (diameter
45 cm, height 20 cm) containing water up to a height of
15 cm at 25 ꢂ 2 ꢁC. Two swim sessions were conducted an
initial 15 min pretest, followed by a 5 min test session 24 h
later. The animals were drug administrated (100 mg/kg) the
test compound i.p. 30 min before the test session. The period
of immobility (passive floating without struggling, making
only those movements which are necessary to keep its head
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