Synthesis and pharmacological screening of some novel chalconyl derivatives of substituted phenyl semicarbazide

Article abstract of DOI:10.1007/s00044-009-9277-6

In the present study, we have synthesized chalcone and semicarbazide-linked chalonyl derivatives and the titled compounds confirmed by MS, IR, and 1H NMR techniques. The anticonvulsant activity was determined by maximal electroshock (MES) induced seizure method. A majority of the compounds exhibited significant anticonvulsant activity after intraperitoneal administration. The results show the importance of hydrogen bonding for activity. In the present study 5e, 5h, 5i, 6e, 6h, and 6i emerged as the most active molecules, showed significant anticonvulsant of activity. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-009-9277-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:74–80
DOI 10.1007/s00044-009-9277-6
ORIGINAL RESEARCH
Synthesis and pharmacological screening of some novel chalconyl
derivatives of substituted phenyl semicarbazide
•
Hemendra Pratap Singh S. N. Pandeya
•
•
C. S. Chauhan Chandra Shekhar Sharma
Received: 5 May 2009 / Accepted: 3 December 2009 / Published online: 25 December 2009
Ó Springer Science+Business Media, LLC 2010
Abstract In the present study, we have synthesized
chalcone and semicarbazide-linked chalonyl derivatives
patients are poorly treated with the available antiepileptic
drugs (AEDs). Moreover, many AEDs have serious side
effects (Meador, 2003; Lin and Kadaba, 1997) and lifelong
medication may be required. Hence, with all of these fac-
tors in mind, it has been suggested that the focus of epi-
lepsy research should be directed to identifying the
underlying mechanism of epileptogenesis and the sub-
sequent ‘‘expression’’ of seizure activity, rather than
resorting primarily to symptom control, that is, mere sup-
pression of seizures (Yogeeswari et al., 2004).
1
and the titled compounds confirmed by MS, IR, and H
NMR techniques. The anticonvulsant activity was deter-
mined by maximal electroshock (MES) induced seizure
method. A majority of the compounds exhibited significant
anticonvulsant activity after intraperitoneal administration.
The results show the importance of hydrogen bonding for
activity. In the present study 5e, 5h, 5i, 6e, 6h, and 6i
emerged as the most active molecules, showed significant
anticonvulsant of activity.
Semicarbazone and chalcones (Awasthi et al., 2009;
Pati et al., 2005; Gopalakrishnan et al., 2007) are itself
versatile nucleus of various activities. In our present
research work we have used the hybridization of pharma-
cophore technique of drug design and fused both the
nucleus to form a novel pharmacophore ‘chalconesemic-
arbazone’. We have also designed a synthetic scheme to
synthesize this pharmacophore moiety and its derivatives
and done pharmacological screening as anticonvulsant.
Keywords Chalcones ꢀ Anticonvulsant ꢀ Semicarbazide
Introduction
Epilepsy is a collective term that includes over 40 different
types of human seizure disorders (McCormick and Con-
treras 2001). Approximately 1% of the world population at
any one time ([50 million people worldwide) is afflicted
with this serious neurological disorder (McNamara, 2001).
Conventional antiepileptic drugs (AEDs) are widely pre-
scribed but induce a range of side effects. Furthermore,
there is a significant group of patients (20–30%) resistant to
the currently available therapeutic agents. Although the
current drugs provide adequate seizure control in many
patients, it is roughly estimated that up to 28–30% of
Materials and methods
Chemistry
Melting points were measured in open capillary tubes on a
Buchi 530 melting point apparatus and were uncorrected.
Infrared (IR) and proton nuclear magnetic resonance (1H
NMR) spectra were recorded for the compounds on Jasco
IR Report 100 (KBr) and Brucker Advance (300 MHz)
instruments, respectively. Chemical shifts are reported in
parts per million (ppm) using tetramethylsilane (TMS) as
an internal standard. All exchangeable protons were con-
firmed by addition of D2O. Mass spectra were measured
with a Shimadzu GC–MS-QP5000 spectrophotometer.
H. P. Singh (&) ꢀ C. S. Chauhan ꢀ C. S. Sharma
B N College of Pharmacy, Udaipur, Rajasthan, India
e-mail: hps_medicinalchemistry00@yahoo.co.in
S. N. Pandeya
Saroj Institute of Pharmacy, Lucknow, UP, India
123

Med Chem Res (2011) 20:74–80
75
1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (4a)
Only molecular ions (M?) peaks are given. Elemental
analysis (C, H, and N) was undertaken with a Perkin-Elmer
model 240C analyzer, and all analyses were consistent with
theoretical values (within 0.4%) unless indicated. The
homogeneity of the compounds was monitored by
ascending thin-layer chromatography (TLC) on silica gel G
(Merck) coated aluminum plates, visualized by iodine
vapor (Fig. 1).
1H-NMR (d/ppm in CDCl3): 5.0 (s, 1H, 20-OH), 7.14 (dd,
J = 7.9, 1.8 Hz, 1H, 400-H), 7.21 (d, J 7.9 Hz, 2H, 300, 5-H00),
7.30 (d, J = 7.9 Hz, 2H, 200, 600-H), 7.56 (s, 1H, –CH=CH–),
7.64 (m, J 8.3 Hz, 4H, Ar–H), 7.90 (s, 1H, –CH=CH–). IR
(KBr/cm-1): 3480(–OH), 1748–1716 (–CO), 1670 (–CH=CH–),
1616, 1558 (aromatic), 754, 697 (monosubstituted benzene).
1-(2-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one
(4b)
Synthesis of substituted chalcone derivatives
Substituted benzaldehydes (0.012 mol) were added to a
mixture of substituted acetophenones (0.01 mol) in 25 ml
of ethanol in a 200 ml beaker. The content of the beaker
was mixed well and to that 10 ml of 10% potassium
hydroxide solution was added and stirred vigorously at
25°C until the mixture was so thick that stirring was no
longer effective (3–4 h). After the completion of the stir-
ring, the reaction mixture was kept in a refrigerator over-
night. The reaction mixture was then diluted with ice-cold
water (50 ml), acidified with 10% aqueous hydrochloric
acid to precipitate the chalcones. The product was filtered
with suction on a Buchner funnel, washed with cold water
until the washings were neutral to litmus and then washed
with 10 ml of ice-cold rectified spirit. The dried product
was recrystallized from chloroform. The structure and
physicochemical properties of the synthesized chalcone
derivatives are given in Table 1.
1H-NMR (d/ppm in CDCl3): 5.0 (s, 1H, 20-OH), 5.1 (s, 1H,
400-OH), 6.68 (d, J = 7.9 Hz, 2H, 300, 500-H), 7.13 (d,
J = 8.0 Hz, 2H, 200, 600-H), 7.64–6.92 (m, J = 8.3 Hz, 4H,
Ar–H), 7.56 (s, 1H, –CH=CH–), 7.90 (s, 1H, –CH=CH–),
IR (KBr/cm-1): 3480, 3345 (–OH),1771, 1732 (–CO),
1682 (–CH=CH–), 1603, 1575 (aromatic), 834 (p-disub-
stituted benzene).
1-(2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one
(4c)
1H-NMR (d/ppm in CDCl3): 3.73 (s, 3H, 400-OCH3), 5.0 (s,
1H, 20-OH), 6.72 (d, J = 7.9 Hz, 2H, 300, 500-H), 7.19 (d,
J = 7.9 Hz, 2H, 200,600-H), 7.56 (s, 1H, –CH=CH–),
7.64–6.92 (m, J = 8.1 Hz, 4H, Ar–H), 7.90 (s, 1H,
–CH=CH–), IR (KBr/cm-1): 3480, 3446 (–OH), 1748,
1716 (–CO), 1670 (–CH=CH–), 1605, 1575 (aromatic),
834 (p-disubstituted benzene).
Compounds 4a–4j gave positive test for chalcone and
positive ferric chloride test.
Fig. 1 Scheme for synthesis of
chalcones and its semicarbazide
derivatives
O
NH2
NaCNO
NH2
R
N
H
R
GAA
1
NH2NH2
R = 4-F/4-Br
2
O
R2
NH2
N
N
H
H
R
Con HCl
3
H
N
N
H
+
N
R1
O
O
R
5a-5j
6a-6j
R1
R2
4a-4j
KOH
O
H
CH3
O
R1
+
R2
123

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Med Chem Res (2011) 20:74–80
Table 1 Structure and physicochemical properties of chalcone derivatives
Comp. code
R1
R2
Mol. formula
Mp (°C)
Yield (%)
Rf value
4a
4b
4c
4d
4e
4f
H
H
400-OH
C15H12O2
C15H12O3
C16H14O3
C17H17NO2
C15H12O4
C17H17NO3
C15H12O3
C15H12O4
C15H12O4
C16H14O4
89
164
135
155
216
174
166
218
208
152
85
85
85
85
90
90
85
85
85
85
0.80
0.83
0.82
0.78
0.85
0.81
0.86
0.84
0.87
0.79
H
H
400-OCH3
400-N(CH3)2
600-OH
400-N(CH3)2
600-OH
600-OH
400-OH
400-OCH3
H
40-OH
40-OH
H
50OH
50OH
50OH
4g
4h
4i
4j
Solvent system (n-hexane: ethyl acetate 9:1)
1.8 Hz, 1H, 400-H), 7.21 (d, J = 7.9 Hz, 2H, 300, 500-H),
7.30 (s, 1H, 200-H), 7.56 (s, 1H, –CH=CH–), 7.90 (s, 1H,
–CH=CH–), IR (KBr/cm-1): 3391, 3209 (–OH), 1748,
1698 (–CO), 1653 (–CH=CH–), 1623, 1576 (aromatic),
728, 697 (monosubstituted benzene)s.
3-[4-(dimethylamino)phenyl]-1-(2-hydroxyphenyl)prop-2-
en-1-one (4d)
1H-NMR (d/ppm in CDCl3): 2.8 (s, 6H, 400-NMe2), 5.0 (s,
1H, 20-OH), 6.54 (d, J = 7.9 Hz, 2H, 300, 500-H), 7.12 (d,
J = 8.0 Hz, 2H, 200, 600-H), 7.56 (s, 1H, –CH=CH–),
7.64–6.92 (m, J = 7.9 Hz, 4H, Ar–H), 7.90 (s, 1H,
–CH=CH–), IR (KBr/cm-1): 3480, 3446 (–OH),1748, 1716
(–CO), 1670 (–CH=CH–), 1621, 1558, 1521 (aromatic),
1312 (C–N stretching in Ar amines), 835 (p-disubstituted
benzene).
1-(2,5-dihydroxyphenyl)-3-(2-hydroxyphenyl)prop-2-en-1-
one (4h)
1H-NMR (d/ppm in CDCl3): 5.0 (s, 3H, 20, 50, 600-OH), 6.68
(d, J = 7.9 Hz, 1H, 30-H), 6.77 (dd, J = 7.9, 1.8 Hz, 1H,
60-H), 6.97 (dd, J = 7.9, 1.8 Hz, 1H, 40-H), 7.11–6.75 (m, J
8.3 Hz, 4H, Ar–H), 7.39 (s, 1H, –CH=CH–), 8.17 (s, 1H,
–CH=CH–), IR (KBr/cm-1): 3446 (–OH), 1748, 1698
(–CO), 1670, 1652 (–CH=CH–), 1616, 1540 (aromatic),
714, 673 (monosubstituted benzene).
1-(2,4-dihydroxyphenyl)-3-(2-hydroxyphenyl)prop-2-en-1-
one (4e)
1H-NMR (d/ppm in CDCl3): 5.0 (s, 3H, 20, 40, 600-OH), 6.68
(d, J = 7.9 Hz, 2H, 300, 500-H), 7.13 (d, J = 7.9 Hz, 2H, 200,
400-H), 7.39 (s, 1H, –CH=CH–), 7.47–6.39 (m, J = 8.2 Hz,
3H, Ar–H), 8.17 (s, 1H, –CH=CH–), IR (KBr/cm-1): 3841
(–OH), 1732, 1698 (–CO), 1670 (–CH=CH–), 1616, 1558
(aromatic), 727, 652 (monosubstituted benzene).
1-(2,5-dihydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-
one (4i)
1H-NMR (d/ppm in CDCl3): 5.0 (s, 3H, 20, 50, 400-OH), 6.68
(d, J = 7.9 Hz, 2H, 300, 500-H), 7.11–6.75 (m, J = 8.3 Hz,
3H, Ar–H), 7.13 (d, J = 7.9 Hz, 2H, 200, 600-H), 7.56 (s,
1H, –CH=CH–), 7.90 (s, 1H, –CH=CH–), IR (KBr/cm-1):
3244 (–OH), 1732, 1698 (–CO), 1683 (–CH=CH–), 1646,
1557 (aromatic), 834 (p-disubstituted benzene).
1-(2,4-dihydroxyphenyl)-3-[4-(dimethylamino)phenyl]
prop-2-en-1-one (4f)
1H-NMR (d/ppm in CDCl3): 2.85 (s, 6H, 400-NMe2), 5.0 (s,
2H, 20, 40-OH), 6.54 (d, J = 7.9 Hz, 2H, 300, 500-H), 7.12 (d,
J = 7.9 Hz, 2H, 200, 600-H), 7.56 (s, 1H, –CH=CH–),
7.47–6.39 (m, J 8.1 Hz, 3H, Ar–H), 7.90 (s, 1H, –CH=CH–),
IR (KBr/cm-1): 3480 (–OH), 1748, 1697 (–CO), 1670
(–CH=CH–), 1616, 1540 (aromatic), 1316 (C–N stretching
in Ar amines), 824 (p-disubstituted benzene).
1-(2,5-dihydroxyphenyl)-3-[4-(dimethylamino)phenyl]
prop-2-en-1-one (4j)
1H-NMR (d/ppm in CDCl3): 3.73 (s, 3H, 400 –OCH3), 5.0
(s, 2H, 20, 50-OH), 6.72 (d, J = 7.9 Hz, 2H, 300, 500-H),
7.11–6.75 (m, J = 8.3 Hz, 3H, Ar–H), 7.19 (d,
J = 7.9 Hz, 2H, 200, 600-H), 7.56 (s, 1H, –CH=CH–), 7.90
(s, 1H, –CH=CH–), IR (KBr/cm-1): 3244 (–OH), 1732,
1716 (–CO), 1683 (–CH=CH–), 1577, 1540 (aromatic),
834 (p-disubstituted benzene).
1,3-bis(2-hydroxyphenyl)prop-2-en-1-one (4g)
1H-NMR (d/ppm in CDCl3): 5.0 (s, 2H, 20, 600-OH),
7.11–6.75 (m, J = 8.2 Hz, 4H, Ar–H), 7.14 (dd, J = 7.9,
123

Med Chem Res (2011) 20:74–80
77
Synthesis of substituted phenyl urea (2)
Elemental analysis cal/fou (%) C (60.56/60.32), H (4.16/
3.98), N (9.63/9.42).
The phenyl ureas were synthesized according to the
reported procedure (Yogeeswari et al., 2004). Substituted
aniline (0.1 mol) was dissolved in 20 ml of glacial acetic
acid and 10 ml of water. To this, 0.1 mol of sodium cya-
nate (6.5 g) in 80 ml of warm water was added with con-
tinuous stirring. The reaction mixture was allowed to cool
for 30 min, filtered, dried and recrystallized with boiling
water to yield (2). IR (KBr/cm-1) 3451, 1666, 844, 1H-
NMR (d/ppm in CDCl3): 7.17–7.63 (m, J = 8.2 Hz, 3H,
Ar–H), 8.35 (s, 1H, ArNH, D2O exchangeable), 9.47 (s,
2H, CONH2, D2O exchangeable).
4-(4-bromphenyl)-1-[1-(2-hydroxyphenyl)-3-(4-
hydroxyphenyl)allylidene]semicarbazide (5b)
1H-NMR (d/ppm in CDCl3): 4.9 (s, 1H, 2-OH), 5.2 (s, 1H,
4-OH), 7.3–7.64 (m, J = 8.4 Hz, 11H, Ar–H) 7.8 (s, 1H,
–CH=CH–), 8.0 (s, 1H, –CH=CH–), 8.44 (s, 1H, ArNH,
D2O exchangeable), 9.8 (s, 1H, CONH, D2O exchange-
able); IR (KBr/cm-1): 3455 (NH), 3475(–OH), 3310–3245
(CONH), 1675 (–CH=CH–),1594 (C–N), 1615, 1556
(aromatic), 750, 695 (monosubstituted benzene); MS, m/z
451; Elemental analysis, cal/fou (%) C (58.42/58.24), H
(4.01/3.88), N (9.29/8.96).
Synthesis of substituted phenyl semicarbazide (3)
Equimolar quantities (0.05 mol) of above synthesized
phenyl ureas (2) and hydrazine hydrate (2.5 ml) in ethanol
were refluxed for 27 h with continuous stirring. The two-
third volume of ethanol was distilled by vacuum distillation
unit and then poured into ice. The resultant precipitate was
filtered, washed with water and dried. The solid thus
obtained was recrystallized with 50 ml of 90% alcohol.
1H-NMR (d/ppm in CDCl3): 5.46 (s, 2H, NH2, D2O
exchangeable), 7.12–7.64 (m, J = 8.3 Hz, 4H, Ar–H), 8.34
(s, 1H, ArNH, D2O exchangeable), 9.42 (bs, 1H, NHNH2,
D2O exchangeable); IR (KBr/cm-1) 3250, 3038, 2854,
1718, 1620–1555, 1278, 690.
4-(4-bromophenyl)-1-[1-(2-hydroxyphenyl)-3-(4-
methoxyphenyl)allylidene] semicarbazide (5c)
1H-NMR (d/ppm in CDCl3): 4.7 (s, 1H, 2-OH), 3.88 (s,
3H, 4-OCH3),7.12–7.85 (m, J = 8.3 Hz, 11H, Ar–H), 7.98
(s, 1H, –CH=CH–), 8.35 (s, 1H, –CH=CH–), 8.87 (s, 1H,
ArNH, D2O exchangeable), 9.86 (s, 1H, CONH, D2O
exchangeable); IR (KBr/cm-1): 3458 (NH), 3478 (–OH),
3310–3243 (CONH), 1677 (–CH=CH–),1587 (C–N), 1626,
1555 (aromatic), 758, 687 (monosubstituted benzene); MS,
m/z 465; Elemental analysis cal/fou (%) C (59.24/59.13), H
(4.32/4.14), N (9.01/8.92).
General method for the synthesis of substituted phenyl
semicarbazidechalcones
1-[3-{4-(dimethylamino)phenyl}-1-(2-
hydroxyphenyl)allylidene]-4-(4-bromophenyl)
semicarbazide (5d)
To
a solution of above phenyl semicarbazide (3)
1H-NMR (d/ppm in CDCl3): 2.82 (s, 6H, 400-NMe2), 5.21
(s, 1H, 20-OH), 6.59 (d, J = 7.9 Hz, 2H, 300, 500-H), 7.14 (d,
J = 8.0 Hz, 2H, 200, 600-H), 7.58 (s, 1H, –CH=CH–),
7.54–6.92 (m, J = 7.9 Hz, 4H, Ar–H), 7.88 (s, 1H,
–CH=CH–), 8.46 (s, 1H, ArNH, D2O exchangeable), 9.84
(s, 1H, CONH, D2O exchangeable); IR (KBr/cm-1): 3480,
3446 (–OH), 1748, 1716 (–CO), 1670 (–CH=CH–), 1621,
1558, 1521 (aromatic), 1312 (C–N stretching in Ar
amines), 835 (p-disubstituted benzene). MS, m/z 478;
Elemental analysis, cal/fou (%) C (60.13/60.11), H (4.84/
4.78), N (11.69/11.62).
(0.005 mol) in 25 ml of ethanol was added in an equimolar
quantity of previously dissolved appropriate chalcone
derivative in ethanol. Then few drops of Con. hydrochloric
acid were added and stirred for 4–5 h. Then reaction
mixture was poured into ice and the precipitate, so obtained
was filtered, washed with water. The crude solid was dried
and recrystallized with hot ethanol. The structures and
physicochemical properties of the synthesized title com-
pounds are given in Table 2.
4-(4-bromophenyl)-1-[1-(2-hydroxyphenyl)-3-
phenylallylidene]semicarbazide (5a)
1-[1-(2,4-dihydroxyphenyl)-3-(2-
hydroxyphenyl)allylidene]-4-(4-bromophenyl)
semicarbazide (5e)
1H-NMR (d/ppm in CDCl3): 4.70 (s, 1H, 2-OH), 7.30–7.70
(m, J = 8.26 Hz, 13H, Ar–H) 7.91 (s, 1H, –CH=CH–),
8.32 (s, 1H, –CH=CH–), 6.56 (s, 1H, ArNH, D2O
exchangeable), 9.78 (s, 1H, CONH, D2O exchangeable); IR
(KBr/cm-1): 3431 (NH), 3478(–OH), 3315–3235 (CONH),
1674 (–CH=CH–),1599 (C–N), 1613, 1560 (aromatic),
755, 698 (monosubstituted benzene); MS, m/z 435;
1H-NMR (d/ppm in CDCl3): 5.1 (s, 1H, 2-OH), 5.3 (s, 1H,
4-OH), 6.4 (s, 1H, 6-OH), 7.22–7.58 (m, J = 8.5 Hz, 10H,
Ar–H) 7.88 (s, 1H, –CH=CH–), 8.4 (s, 1H, –CH=CH–),
8.77 (s, 1H, ArNH, D2O exchangeable), 9.85 (s, 1H,
123

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Med Chem Res (2011) 20:74–80
Table 2 Structure and physicochemical properties of synthesized title compounds
Comp. code
R
R1
R2
Mol. formula
Mp (°C)
Yield (%)
Rf value
5a
5b
5c
5d
5e
5f
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-F
H
H
400-OH
C22H18BrN3O2
C22H18BrN3O3
C23H20BrN3O3
C24H23BrN4O2
C22H18BrN3O4
C24H23BrN4O3
C22H18BrN3O3
C22H18BrN3O4
C22H18BrN3O4
C23H20BrN3O4
123
128
137
126
116
163
146
126
134
163
142
120
153
165
126
151
149
181
187
166
59
65
65
58
65
50
63
60
56
57
59
65
65
58
65
50
63
60
56
57
0.77
0.70
0.64
0.56
0.62
0.68
0.54
0.62
0.69
0.52
0.67
0.72
0.65
0.50
0.61
0.78
0.53
0.71
0.66
0.59
H
H
400-OCH3
400-N(CH3)2
600-OH
400-N(CH3)2
600-OH
600-OH
400-OH
400-OCH3
H
40-OH
40-OH
H
50OH
50OH
50OH
H
5g
5h
5i
5j
6a
6b
6c
6d
6e
6f
H
400-OH
C22H18FN3O2
4-F
H
C22H18FN3O3
C23H20FN3O3
C24H23FN4O2
C22H18FN3O4
C24H23FN4O3
C22H18FN3O3
C22H18FN3O4
C22H18FN3O4
C23H20FN3O4
4-F
H
400-OCH3
400-N(CH3)2
600-OH
400-N(CH3)2
600-OH
600-OH
400-OH
400-OCH3
4-F
H
4-F
40-OH
40-OH
H
50OH
50OH
50OH
4-F
6g
6h
6i
4-F
4-F
4-F
6j
4-F
Solvent system (Chloroform: methanol 9:1)
CONH, D2O exchangeable); IR (KBr/cm-1): 3453 (NH),
3482 (–OH), 3314–3242 (CONH), 1667 (–CH=CH–),1594
(C–N), 1618, 1552 (aromatic), 758, 687 (monosubstituted
benzene); MS, m/z 467; Elemental analysis cal/fou (%) C
(56.42/56.24), H (3.87/3.44), N (8.98/8.66).
–CH=CH–), 6.70 (s, 1H, ArNH, D2O exchangeable), 9.98
(s, 1H, CONH, D2O exchangeable); IR (KBr/cm-1): 3453
(NH), 3483(–OH), 3308–3238 (CONH), 1685 (–CH=CH–),
1594 (C–N), 1614, 1547 (aromatic), 756, 687 (monosub-
stituted benzene); MS, m/z 480; Elemental analysis cal/fou
(%) C (57.27/57.24), H (4.18/4.02), N (8.71/8.58).
1-[1-(2,5-dihydroxyphenyl)-3-(2-
hydroxyphenyl)allylidene]-4-(4-bromophenyl)
semicarbazide (5h)
4-(4-fluorophenyl)-1-[1-(2-hydroxyphenyl)-3-
phenylallylidene]semicarbazide (6a)
1H-NMR (d/ppm in CDCl3): 5.31 (s, 1H, 2-OH), 4.9 (s, 1H,
4-OH), 5.6 (s, 1H, 6-OH) 7.20–7.74 (m, J = 8.4 Hz, 11H,
Ar–H) 7.86 (s, 1H, –CH=CH–), 8.17 (s, 1H, –CH=CH–),
6.47 (s, 1H, ArNH, D2O exchangeable), 9.60 (s, 1H,
CONH, D2O exchangeable); IR (KBr/cm-1): 3465 (NH),
3475(–OH), 3310–3250 (CONH), 1677 (–CH=CH–),1595
(C–N), 1619, 1557 (aromatic), 754, 690 (monosubstituted
benzene); MS, m/z 467; Elemental analysis cal/fou (%) C
(56.42/56.32), H (3.87/3.72), N (8.97/8.78).
1H-NMR (d/ppm in CDCl3): 4.72 (s, 1H, 2-OH), 7.28–7.72
(m, 13H, Ar–H) 7.92 (s, 1H, –CH=CH–), 8.32 (s, 1H,
–CH=CH–), 6.56 (s, 1H, ArNH, D2O exchangeable), 9.88
(s, 1H, CONH, D2O exchangeable); IR (KBr/cm-1): 3432
(NH), 3480(–OH), 3325–3236 (CONH), 1674 (–CH=CH–),
1592 (C–N), 1614, 1560 (aromatic), 756, 692 (monosub-
stituted benzene); MS, m/z 374; Elemental analysis cal/fou
(%) C (70.39/70.32), H (4.83/4.78), N (11.19/11.02).
4-(4-fluorophenyl)-1-[1-(2-hydroxyphenyl)-3-(4-
hydroxyphenyl)allylidene]semicarbazide (6b)
1-[1-(2,5-dihydroxyphenyl)-3-(4-
methoxyphenyl)allylidene]-4-(4-bromophenyl)
semicarbazide (5j)
1H-NMR (d/ppm in CDCl3): 4.91 (s, 1H, 2-OH), 5.21 (s,
1H, 4-OH), 7.3–7.64 (m, J = 8.4 Hz, 11H, Ar–H) 7.79 (s,
1H, –CH=CH–), 8.1 (s, 1H, –CH=CH–), 8.43 (s, 1H,
ArNH, D2O exchangeable), 9.84 (s, 1H, CONH, D2O
exchangeable); IR (KBr/cm-1): 3458 (NH), 3474(–OH),
1H-NMR (d/ppm in CDCl3): 3.77 (s, 3H, 4-OCH3), 5.3 (s,
1H, 2-OH), 5.64 (s, 1H, 5-OH), 7.15–7.75 (m, J = 8.3 Hz,
11H, Ar–H), 7.82 (s, 1H, –CH=CH–), 7.94 (s, 1H,
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Med Chem Res (2011) 20:74–80
79
3310–3241 (CONH), 1675 (–CH=CH–),1598 (C–N), 1614,
1558 (aromatic), 745, 685 (monosubstituted benzene); MS,
m/z 390; Elemental analysis, cal/fou (%) C (67.51/67.24),
H (4.64/6.58), N (10.74/10.67).
Swinyard and Brown, 1952). The electroshock assay in
mice is used primarily as an indication for compounds
which are effective in grand mal epilepsy. Tonic hind limb
extensions are evoked by electric stimuli which are sup-
pressed by anti-epileptics. The behavioral and electro-
graphic seizures generated in this model are consistent with
the human disorder. Albino mice of either sex weighing
20–25 g were housed in 22 groups of six each and accli-
matized to their environment for at least 2 days before the
experiments. The animals were allowed to free access to
tap water before being tested and to standard commercial
mice pellets. The test compounds were dissolved in DMSO
as a vehicle and were administered intra peritoneal. Control
animals were injected with vehicle only. Phenytoin
(25 mg/kg, i.p.) was injected to the animals of standard
group. This dose was determined on the basis of a pilot
experiment in which it produced tonic-clonic convulsions
without being fatal. Abolition of the hind limb tonic
extensor component indicates the test compound’s ability
to inhibit MES-induced seizure spread (Toman et al.,
1964). An apparatus with corneal or ear electrodes is used
to deliver the stimuli. The intensity of stimulus is 50 mA;
50 Hz for 0.2 s has been used. After 30 min of dose
administration, the electric shock was given to the mice of
all the different groups as above defined method. Under
these conditions all vehicle treated mice show the charac-
teristic extensor tonus. The animals are observed closely
for 2 min. Disappearance of the hind leg extensor tonic
convulsion is used as positive criterion. Percent of inhibi-
tion of seizures relative to controls is calculated.
4-(4-fluorophenyl)-1-[1-(2-hydroxyphenyl)-3-(4-
methoxyphenyl)allylidene] semicarbazide (6c)
1H-NMR (d/ppm in CDCl3): 4.73 (s, 1H, 2-OH), 3.82 (s,
3H, 4-OCH3),7.18–7.86 (m, 11H, Ar–H), 7.96 (s, 1H,
–CH=CH–), 8.35 (s, 1H, –CH=CH–), 8.89 (s, 1H, ArNH,
D2O exchangeable), 9.85 (s, 1H, CONH, D2O exchange-
able); IR (KBr/cm-1): 3456 (NH), 3468 (–OH), 3310–3245
(CONH), 1678 (–CH=CH–),1588 (C–N), 1628, 1557
(aromatic), 758, 687 (monosubstituted benzene); MS, m/z
404; Elemental analysis cal/fou (%) C (68.14/68.13), H
(4.97/4.78), N (10.36/10.32).
1-[3-{4-(dimethylamino)phenyl}-1-(2-
hydroxyphenyl)allylidene]-4-(4-fluorophenyl)
semicarbazide (6d)
1H-NMR (d/ppm in CDCl3): 2.84 (s, 6H, 400-NMe2), 5.11
(s, 1H, 20-OH), 6.58 (d, J = 7.9 Hz, 2H, 300, 500-H), 7.14 (d,
J = 8.0 Hz, 2H, 200, 600-H), 7.58 (s, 1H, –CH=CH–),
7.54–6.92 (m, J = 7.9 Hz, 4H, Ar–H), 7.88 (s, 1H,
–CH=CH–), 8.46 (s, 1H, ArNH, D2O exchangeable), 9.84
(s, 1H, CONH, D2O exchangeable); IR (KBr/cm-1): 3480,
3446 (–OH), 1748, 1716 (–CO), 1670 (–CH=CH–), 1621,
1558, 1521 (aromatic), 1312 (C–N stretching in Ar
amines), 835 (p-disubstituted benzene). MS, m/z 417;
Elemental analysis, cal/fou (%) C (68.88/68.74), H (5.54/
5.48), N (13.39/13.37).
Results and discussion
1-[1-(2,5-dihydroxyphenyl)-3-(4-
methoxyphenyl)allylidene]-4-(4-fluorophenyl)
semicarbazide (6j)
The synthesized titled compounds (5a–6j), obtained from
the reaction sequence were injected intraperitoneally into
mice and evaluated as anticonvulsant in the maximal
electroshock (MES), using doses of 30 mg/kg. These
observed data are presented in Table 3. All the compounds
showed anti-MES activity indicative of their ability to
prevent seizure spread. All the compounds showed pro-
tection against MES model at 30 mg/kg more or less
depending upon the substitutions. When the observed
results compared, it observed that the 4-fluoro substituted
compounds showed more protection from seizures in
comparison to the 4-bromo substituted compounds. This
may be due to increased lipophilicity of fluoro substituted
compounds. The substitution with different substituents on
the phenyl of the aldehydic and acetophenic group of
chalcone moiety plays an important role in protection of
seizures. When the phenyl group of aldehydic and ace-
tophenic moiety of chalcone is substituted with –OH group
(compound 5b, 5e, 5f, 5g, 5h, 5i, 6b, 6e, 6f, 6g, 6h, and 6i)
1H-NMR (d/ppm in CDCl3): 3.79 (s, 3H, 4-OCH3), 5.34 (s,
1H, 2-OH), 5.59 (s, 1H, 5-OH), 7.25–7.75 (m, 11H, Ar–H),
7.86 (s, 1H, –CH=CH–), 7.98 (s, 1H, –CH=CH–), 6.75 (s,
1H, ArNH, D2O exchangeable), 9.92 (s, 1H, CONH, D2O
exchangeable); IR (KBr/cm-1): 3457 (NH), 3487(–OH),
3308–3238 (CONH), 1688 (–CH=CH–),1597 (C–N), 1624,
1549 (aromatic), 756, 687 (monosubstituted benzene); MS,
m/z 420; Elemental analysis cal/fou (%) C (65.55/65.28), H
(4.78/4.76), N (9.97/9.77).
Pharmacological screening
All the synthesized compounds were screened for their
anticonvulsant activity by MES method (Ellison et al.,
1978; Rastogi and Ticku, 1996; Sohn et al., 1970;
123

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Med Chem Res (2011) 20:74–80
6g). The compounds with no substitution or less substitu-
tion (5a, 6a) were showed very less protection in com-
parison to the substituted compounds.
Table 3 Pharmacological screening as anticonvulsant of synthesized
compounds
Comp. no
Dosea
(mg/kg)
Mean SEMb
Protection Potency
(%)
So, on the bases of the observed result it was concluded
that, the substitutions favor the activity but the bulkier
substitution on the compounds showed lesser protection
may be due to the improper attachment with the receptors.
But in case of –OH substitution the activity increases with
the increased number of substitution may be due to the
increased hydrogen bonding. To find the exact mechanism
of the synthesized titled compounds further research is
going on in our lab at molecular level.
Normal control
–
25
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
8.98 0.0600
–
–
Phenytoin
5a
5b
5c
1.8 0.1183*** 79.95
6.95 0.0494 22.60
100
28.26
2.88 0.0122*** 67.92
4.6 0.0199*** 51.44
6.2 0.1844*** 30.95
2.43 0.1493*** 72.93
84.95
64.34
38.71
91.21
30.35
81.06
94
5d
5e
5f
6.8 0.0494*
24.27
Acknowledgments The authors deeply appreciate the assistance of
Department of Pharmacology, B N College of Pharmacy, Udaipur,
India in the pharmacological screening of the synthesized compounds.
5g
5h
5i
3.167 0.0122*** 64.81
2.23 0.0199*** 75.16
2.101 0.1844*** 76.61
5.417 0.1493*** 39.75
95.82
49.71
28.96
87.74
66.42
45.26
92.62
37.04
83.56
94.98
99.72
56.54
5j
6a
6b
6c
6.90 0.0494
23.16
References
2.68 0.0122*** 70.15
4.21 0.0199*** 53.11
5.73 0.1844*** 36.19
2.33 0.1493** 74.05
Awasthi SK, Mishra N, Kumar B, Sharma M, Bhattacharya A, Mishra
LC, Bhasin VK (2009) Potent antimalarial activity of newly
synthesized substituted chalcone analogs in vitro. Med Chem
Res 18(6):407–420
Ellison G, Eison MS, Huberman HS, Daniel F (1978) Long-term
changes in dopaminergic innervation of caudate nucleus after
continuous amphetamine administration. Science 201:276–278
Gopalakrishnan M, Thanusu J, Kanagarajan V (2007) Synthesis and
biological evaluation of 5,7-diaryl-4,4-dimethyl-4,5,6,7-tetrahy-
dropyridino[3,4-d]-1,2,3-thiadiazoles. Med Chem Res 16(7–9):
392–401
6d
6e
6f
6.32 0.0494
29.62
6g
6h
6i
2.98 0.0122*** 66.81
2.16 0.0199*** 75.94
1.82 0.1844*** 79.73
4.92 0.1493*** 45.21
6j
a
The compounds were tested at a dose of 30 mg/kg (i.p.)
Lin Z, Kadaba PK (1997) Molecular targets for the rational design of
antiepileptic drugs and related neuroprotective agents. Med Res
Rev 17:537–572
b
Each value represents the mean SEM of six rats significantly
different from the control
McCormick DA, Contreras D (2001) On the cellular and network
bases of epileptic seizures. Annu Rev Physiol 1(63):815–846
McNamara OJ (2001) Pharmacological basis of therapeutics. In:
* P \ 0.05, ** P \ 0.01, and *** P \ 0.001 when compared to
control group (Dunnett’s post hoc test)
Hardman JG, Limbird
pp 521–548
L (eds) McGraw-Hill, New York,
the compounds exhibited better activity in comparison to
substitution with other as methoxy (5c, 5j, 6c, and 6j) and
p-dimethyl amino groups (compound 5d, 5f, 6d, and 6f),
may be due to increased hydrogen bonding interactions
with the receptors. The hydroxyl group at position 2 in
acetophenic moiety is very important for retention of the
anticonvulsant activity. But the variation in position of
hydroxyl substitution on the aldehydic and acetophenic
moiety, also affect the potency of the compounds. It was
observed that in the di-hydroxyl-substituted compounds,
–OH at 5 position in acetophenic and 4 position in alde-
hydic position (5i, 6i) was more favorable for the activity
in comparison to the 5 and 6 position, respectively (5h, 6h).
When mono substitution was done with only one –OH
group at position 4 (5b, 6b) and 6 (5g, 6g), the results
showed that the compounds substituted at 4 (5b, 6b) were
showed more protection in comparison to position 6 (5g,
Meador KJ (2003) Newer anticonvulsants: dosing strategies and
cognition in treating patients with mood disorders and epilepsy.
J Clin Psychiatry 64:30–34
Pati HN, Holt HL, LeBlanc R, Dickson J, Stewart M, Brown T, Lee
M (2005) Synthesis and cytotoxic properties of nitro- and
aminochalcones. Med Chem Res 14(1):19–25
Rastogi SA, Ticku MK (1996) Involvement of a GABA-ergic
mechanism in the anticonvulsant effect of phenobarbital against
maximal electroshock-induced seizures in rats. Pharmacol Bio-
chem Behav 222:141–146
Sohn YJ, Levitt B, Raines A (1970) Anticonvulsant properties of
diphenylthiohydantoin. Arch Int Pharmacodyn 188:284–289
Swinyard EA, Brown WC, Goodman LS (1952) Comparative assay of
antiepileptic drugs in mice and rats. Pharmacol Exp Ther
106:319–330
Toman JEP, Nodin JH, Siegler PE (1964) Animal techniques for
evaluating anticonvulsants. Year Book Med Publ 1:348–352
Yogeeswari P, Raghavendran J, Thirumurugan R, Saxena A, Sriram
D (2004) Sodium valproate stimulates potassium and chloride
urinary excretion in rats: gender differences. Curr Drug Targets
5:553–568
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