Synthesis and anticonvulsant activity of some ω-(1H-1-imidazolyl)-N- phenylalkanoic acid amide derivatives

Article abstract of DOI:10.1016/S0014-827X(01)01197-1

In this study, 15 ω-(1H-imidazol-1-yl)-N-phenylacetamide, propionamide and butyramide derivatives having methoxyl, methyl, nitro and chloro in ortho position of N-phenyl ring or without any substituent have been realized by two-step synthesis. Their antic

Full text of DOI:10.1016/S0014-827X(01)01197-1

Il Farmaco 000 (2002) 201–206
www.elsevier.com/locate/farmac
Synthesis and anticonvulsant activity of some
v-(1H-1-imidazolyl)-N-phenylalkanoic acid amide derivatives
b
Zeynep Aktu¨rk a, Fatma Kılıc¸ , Kevser Erol b, Varol Pabuc¸cuog˘lu a,*
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege Uni6ersity Borno6a, Izmir 35100, Turkey
b Faculty of Medicine, Osmangazi Uni6ersity, Department of Pharmacology, Eskis¸ehir, Turkey
Received 10 July 2001; accepted 27 October 2001
Abstract
In this study, 15 v-(1H-imidazol-1-yl)-N-phenylacetamide, propionamide and butyramide derivatives having methoxyl, methyl,
nitro and chloro in ortho position of N-phenyl ring or without any substituent have been realized by two-step synthesis. Their
anticonvulsant activity was determined against seizures induced by maximal electroshock (MES). The most active compound in
´
the series was 2-(1H-imidazol-1-yl)-N-(o-chlorophenyl)acetamide. © 2002 Editions scientifiques et me´dicales Elsevier SAS. All
rights reserved.
Keywords: Anticonvulsant; MES; Imidazole; Anilide
1. Introduction
substitution pattern and nature of substituent(s) on
N-phenyl ring is of vital importance for anticonvulsant
activity [9,13]. It seems that o-substitution on N-phenyl
ring is essential.
Epilepsy is one of the most common neurological
diseases. It is a chronic and often progressive disorder
characterized by recurrent transient attacks which are
caused by an abnormal discharge of cerebral neurons
[1,2]. At least 50 million people worldwide are suffering
from epilepsy, it being the second leading neurological
disorder after stroke. Despite the optimal use of availa-
ble antiepileptic drugs, the treatment is not satisfactory
in preventing seizures completely [3–6]. The second
handicap in treatment of epilepsy is the notable adverse
effects of current antiepileptic drugs. Therefore, the
need for safer and more effective new antiepileptic
drugs is well known [1,6].
8
Ustu¨nes et al., inspired by the structures of Denzimol
and Nafimidone (Fig. 2), of which the clinical develop-
ments were stopped [14], have reported the anticonvul-
Numerous compounds are synthesized each year to
determine anticonvulsant properties. One of the struc-
tures among the compounds studied for anticonvulsant
activity is anilide nucleus. It is known that anilide
function yields potent anticonvulsant compounds such
as Ameltolide [7], Ralitoline [8], D2916 [9], certain
N-phenylphthalimides [10,11] and N-(2,6-dimethyl-
phenyl)-2-piperidinecarboxamide [12] (Fig. 1). Struc-
ture–activity studies of anilide derivatives revealed that
Fig. 1. Potent anticonvulsant compounds bearing anilide function.
* Corresponding author.
E-mail address: papuccuogluv@pharm.ege.edu.tr (V. Pabuc¸cuog˘lu).
Fig. 2. Chemical structures of Denzimol and Nafimidone.
´
0014-827X/02/$ - see front matter © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S0014-827X(01)01197-1

202
Z. Aktu¨rk et al. / Il Farmaco 57 (2002) 201–206
Fig. 3. Chemical structure of title compounds to be synthesized.
sant profiles of three compounds having the basic struc-
tures v-(1H-imidazol-1-yl)-N-(p-tolyl)acetamide, pro-
panamide and butyramide in a preliminary study [15].
According to their results, the anticonvulsant activities
of these compounds against MES test were comparable
to or less than that of phenobarbital. On the other
hand, in a study on N-arylazole acetamide derivatives,
Scheme 1. Synthesis of compounds.
3.1.1. Synthesis of ꢀ-chloroanilide deri6ati6es (1a–15a)
Aniline or o-substituted aniline (0.066 mol) was dis-
solved in 25 ml glacial acetic acid. v-Chloroacyl chlo-
ride (2-chloroacetyl chloride, 3-chloropropionyl
chloride and 4-chlorobutyryl chloride) (0.074 mol) was
added dropwise to this solution while cooling in an
ice-bath. The reaction mixture was stirred in ice-bath
for 30 min and 1 h at room temperature. The mixture
was poured into saturated sodium acetate solution. The
precipitate was filtered, washed with cold water and
purified by crystallization. Yields, melting points and
1H NMR spectral data are presented in Table 1.
8
Ozkanli et al. stated that 2-(1H-imidazol-1-yl)-N-
phenylacetamide shows anti-MES activity at 100 mg/kg
dose in mice [16].
These findings have prompted us to refocus on v-
(1H-imidazol-1-yl)-N-phenylalkanoic
acid
amide
derivatives to explore the possible effect of o-substitu-
tion on N-phenyl ring for anticonvulsant activity.
The compounds synthesized are presented in Fig. 3.
2. Chemistry
v-(1H-Imidazol-1-yl)-N-(o-substitutedphenyl
or
3.1.2. Synthesis of ꢀ-(1H-1-imidazolyl)-N-phenyl-
alkanoic acid amide deri6ati6es (1–15)
phenyl)acetamides, propanamides and butyramides
which were evaluated for anticonvulsant activity, were
prepared by two-step synthesis. As illustrated in
Scheme 1, in the first step, v-chloroanilides were pre-
pared by reacting v-chloroacyl chloride with o-substi-
tuted anilines or aniline. In the second step,
v-chloroanilides were condensed with imidazole to fur-
nish the title compounds 1–15 (Table 2). The title
compounds except compound 1 are novel.
v-Chloroanilides (0.002 mol) and imidazole (0.01
mol) in a suitable solvent were refluxed under nitrogen
(solvents and reflux times are listed in Table 2.). After
the reaction was completed, solvent was removed under
vacuo. Residue was dissolved in chloroform and
washed with water twice. Organic phase, after drying
over anhydrous sodium sulfate, evaporated to dryness.
Residue was purified by crystallization (yields and mel-
ting points are given in Table 2.).
3. Experimental
3.2. Pharmacology
3.1. Chemistry
All experiments for animal testing were approved by
Osman Gazi University, School of Medicine, Animal
Use and Care Committee. All compounds were tested
for anticonvulsant activity with female albino mice
weighing 25–35 g. The animals were housed in colony
cages under standard laboratory conditions with free
access to chow pellets and top water. Seizures were
induced by means of 60 Hz current of 60 mA delivered
through ear electrodes (Hugo Basile). The stimulus
duration was 0.2 s and pulse width was 0.4. The
criterion to indicate the convulsive response was the
tonic extension of hind limbs. Eight animals were used
in each group. All the compounds were dissolved in
dimethyl sulfoxide (DMSO) and injected intraperi-
Melting points were determined on a Buchi 510
Melting point apparatus and are uncorrected. The IR
spectra of compounds were recorded as potassium bro-
mide pellets on a Jasco FT/IR-400 spectrometer. The
1H NMR spectra were recorded on a Bruker DPX-400
FT-NMR in CHCl3-d1 as solvent. Chemical shifts were
reported in parts per million (l). Mass spectra (EI)
were measured on a Mikromass VG Platform-II spec-
trometer. Elemental analyses for C,H and N were per-
:
formed by TUBITAK Analytical Laboratory Ankara,
Turkey. The analytical results for the elements were
within 90.4% of theoretical values.

Z. Aktu¨rk et al. / Il Farmaco 57 (2002) 201–206
203
toneally to the animals at 100 and 30 mg/kg (only for
compounds 8 and 10) doses in approximately 0.1 ml
volume. 0.1 ml DMSO were given to the control ani-
mals. The tests were performed 30 min after the injec-
tion of the compounds.
having methoxyl, methyl, nitro and chloro in ortho
position of N-phenyl ring or without any substituent
were obtained by two-step synthesis. Chemical struc-
tures of title compounds were confirmed by elemental
1
analysis, H NMR, IR and EIMS data.
Minimal neurotoxicity was measured by using the
rotarod test aparat (Commat MAY RR9612, Ankara,
Turkey). Mice were placed on a 3.5 cm diameter
knurled plastic rod rotating at 6 rpm after the adminis-
tration of the compounds and their ability to maintain
their balance was tested. Neurological deficit was indi-
cated by the inability of the animal to maintain its
equilibrium for 1 min on the rotating rod in each three
In IR spectra, all title compounds had NꢀH and CꢁO
stretching bands in the region of 3341–3103 and 1695–
1665 cm−1, respectively, indicating the presence of an
1
anilide structure (Table 3). H NMR spectra showed
that aliphatic and aromatic protons resonated at ex-
pected frequencies and displayed similar splitting pat-
terns for individual compound (Table 4). The chemical
shifts of N-phenyl protons, in each compound, were
relatively different depending on the nature of sub-
stituent. The structures of title compounds were further
verified by EIMS spectra where the m/z values of
molecular ion peaks were in complete agreement with
the calculated molecular weight for individual com-
pounds (Table 3). The mass spectra of chloro analogs
10–12, also had the [M+2]+ ions which were less than
50% of the corresponding molecular ions as expected.
2
trials [17]. Fisher’s exact  test was used for statistical
analysis.
4. Results
In this study, 15 v-(1H-imidazol-1-yl)-N-phenylace-
tamide, propionamide and butyramide derivatives
Table 1
Yields, melting points and 1H NMR data of compounds 1a–15a
Comp.
n
R
Yield (%)
m.p. (°C)
1H NMR
1a
2a
3a
1
2
3
H
H
H
74
43
44
131–133 a
4.21 (s, 2H), 7.20 (td, 1H), 7.38 (td, 2H), 7.58 (dd, 2H), 8.52 (br.s, NH)
2.83 (t, 2H), 3.89 (t, 2H), 7.15 (t, 1H), 7.34 (t, 2H), 7.54 (d, 2H), 7.58 (br.s, NH)
2.21 (quin, 2H), 2.57 (t, 2H), 3.67 (t, 2H), 7.13 (t, 1H), 7.33 (t, 2H), 7.51 (br.s, NH),
7.52 (d, 2H)
113 a
59–61 a
4a
5a
6a
7a
8a
9a
1
2
3
1
2
3
CH3
CH3
CH3
59
36
39
106 a
75 a
73 a
61 b
78 b
75 b
2.33 (s, 3H), 4.25 (s, 2H), 7.15 (td, 1H), 7.23–7.26 (m, 2H), 7.90 (d, 1H), 8.10 (br.s,
NH)
2.28 (s, 3H), 2.85 (t, 2H), 3.90 (t, 2H), 7.12 (t, 1H), 7.20–7.24 (m, 2H), 7.26 (br.s, NH),
7.73 (d, 1H)
2.22 (quin, 2H), 2.28 (s, 3H), 2.60 (t, 2H), 3.69 (t, 2H), 7.10–7.12 (m, 2H), 7.20–7.24
(m, 2H), 7.77 (d, 1H)
3.93 (s, 3H), 4.21 (s, 2H), 6.93 (d, 1H), 7.00 (t, 1H), 7.12 (td, 1H), 8.36 (d, 1H), 8.96
(br.s, NH)
2.88 (t, 2H), 3.91 (t, 2H), 3.91 (s, 3H), 6.90 (dd, 1H), 6.99 (td, 1H), 7.08 (td, 1H), 7.90
(br.s, NH), 8.39 (dd, 1H)
2.23 (quin, 2H), 2.61 (t, 2H), 3.69 (t, 2H), 3.90 (s, 3H), 6.90 (dd, 1H), 6.97 (td, 1H),
7.06 (td, 1H), 7.83 ( br.s, NH), 8.37 (d, 1H)
4.26 (s, 2H), 7.12 (td, 1H), 7.32 (td, 1H), 7.42 (dd, 1H), 8.38 (dd, 1H), 8.96 (br.s, NH)
2.92 (t, 2H), 3.91 (t, 2H), 7.08 (td, 1H), 7.30 (td, 1H), 7.40 (dd, 1H), 7.77 (br.s, NH),
8.39 (d, 1H)
2.24 (quin, 2H), 2.66 (t, 2H), 3.70 (t, 2H), 7.07 (td, 1H), 7.30 (td, 1H), 7.39 (dd, 1H),
7.68 (br.s, NH), 8.37 (d, 1H)
OCH3 88
OCH3 88
OCH3 97
10a
11a
1
2
Cl
Cl
56
47
70–71 a
82–83 a
12a
3
Cl
36
62–64 a
13a
14a
1
2
NO2
NO2
45
46
83–86 a
80–84 a
4.27 (s, 2H), 7.28 (td, 1H), 7.71 (td, 1H), 8.27 (dd, 1H), 8.78 (dd, 1H), 11.37 (br.s, NH)
2.97 (t, 2H), 3.91 (t, 2H), 7.23 (td, 1H), 7.68 (td, 1H), 8.24 (dd, 1H), 8.80 (dd, 1H),
10.45 (br.s, NH)
2.25 (quin, 2H), 2.72 (t, 2H), 3.69 (t, 2H), 7.21 (td, 1H), 7.67 (td, 1H), 8.24 (dd, 1H),
8.79 (dd, 1H), 10.41 (br.s, NH)
15a
3
NO2
40
61 a
a Ethanol/water.
b Ethyl acetate/hexane.

204
Z. Aktu¨rk et al. / Il Farmaco 57 (2002) 201–206
Table 2
Reflux times, yields, melting points and elemental analysis of title compounds
Comp.
n
R
Reflux time (h)
Yield (%)
m.p. (°C)
Empirical formula
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
H
H
H
CH3
CH3
CH3
OCH3
OCH3
OCH3
Cl
Cl
Cl
NO2
NO2
NO2
1 a
2 b
1 b
2 a
49
60
68
31
44
43
27
29
23
60
45
51
60
60
54
139 c
C11H11N3O
C12H13N3O
C13H15N3O
C12H13N3O
C13H15N3O
C14H17N3O
C12H13N3O2
C13H15N3O2
C14H17N3O2
C11H10ClN3O
C12H12ClN3O
C13H14ClN3O
C11H10N4O3
C12H12N4O3
C13H14N4O3
151–153 c
128–132 c
169–171 c
119 c
5 b
20 b
2 a
68–70 d
113 d
2 b
8 b
2 a
93–96 c
82–84 d
159 c
4 b
20 b
3 a
118 c
93–94 d
166–168 c
131–133 c
118 d
3 b
4 b
a Benzene.
b Toluene.
c Methanol/water.
d Ethyl acetate/hexane.
Table 3
IR and EIMS data of title compounds
Comp. IR (cm−1
)
EIMS m/z (% intensity)
1
2
3
4
5
3267–3137, 1670 202 (80, M++1), 201 (57, M+), 174 (28), 82 (77), 81 (100), 54 (56).
3240–3122, 1685 216 (100, M++1), 215 (25, M+), 96 (23), 95 (17), 81 (32), 68 (11), 54 (24).
3290–3110, 1680 230 (100, M++1), 229 (26, M+), 162 (29), 137 (9), 110 (64), 109 (34), 95 (57), 82 (50), 81 (24), 54 (22).
3270–3115, 1665 216 (100, M++1), 215 (48, M+), 120 (21), 107 (26), 106 (33), 91 (38), 82 (79), 81 (85), 54 (42).
3235–3105, 1685 230 (100, M++1), 229 (19, M+), 123 (21), 107 (72), 106 (51), 96 (12), 95 (39), 81 (39), 69 (46), 68 (21), 54
(25).
6
3230–3104, 1685 244 (50, M++1), 243 (26, M+), 137 (25), 110 (40), 109 (42), 107 (74), 106 (83), 95 (60), 82 (100), 81 (44), 69
(54), 54(34).
7
8
9
3270–3106, 1670 232 (94, M++1), 231 (64, M+), 82 (100), 81 (81), 54 (31).
3220–3112, 1675 246 (52, M++1), 245 (29, M+), 123 (87), 108 (100), 96 (78), 95 (42), 81 (62), 68 (38), 55 (38), 54 (41).
3230–3112, 1680 260 (99, M++1), 259 (32, M+), 192 (30), 137 (10), 110 (57), 109 (40), 108 (71), 95 (58), 82 (100), 81 (37), 54
(31).
10
11
3255–3112, 1670 238 (24, M++2), 237 (17, M++1), 236 (70, M+), 200 (45), 82 (63), 81 (100), 54 (53).
3230–3103, 1685 252 (32, M++2), 251 (17, M++1), 250 (96, M+), 127 (18) 123 (4), 96 (9), 95 (12), 81 (46), 68 (16), 54 (49),
37 (34), 35 (100).
12
3270–3107, 1685 266 (30, M++2), 265 (20, M++1), 264 (91, M+), 196 (31), 137 (27), 134 (26), 127 (52), 110 (100), 95 (93), 82
(71), 81 (41), 54 (38).
13
14
15
3341–3111, 1695 247 (21, M++1), 246 (7, M+), 82 (45), 81 (100), 54 (74).
3140–3115, 1685 261 (5, M++1), 260 (1, M+), 95 (9), 91 (20), 90 (22), 81 (57), 68 (25), 54 (100).
3235–3114, 1690 275 (7, M++1), 274 (2, M+), 137 (15), 110 (14), 109 (11), 95 (64), 82 (31), 81 (52), 68 (12), 54 (74), 41 (100).
The anticonvulsant activities of the title compounds
displaying statistically significant activity were further
tested at 30 mg/kg dose level. All the compounds at
doses studied showed no neurotoxicity according to
rotarod test. Preliminary screening results are presented
in Table 5.
were determined against maximal electroshock seizures
(MES) induced 30 min after administration of the
compounds. For this purpose, each compound was,
first, tested at 100 mg/kg dose level and the compounds

Z. Aktu¨rk et al. / Il Farmaco 57 (2002) 201–206
205
5. Discussion
chlorophenyl)acetamide (10), followed by 2-(1H-imida-
zol-1-yl)-N-(o-methoxyphenyl)propionamide (8) as the
second one.
Concerning acetamide derivatives, among the sub-
stituents studied, chloro is the only one that yields
compound 10 with a higher anti-MES activity in com-
parison to unsubstituted acetamide derivative 1 (see
Table 5). o-Tolyl derivative 4 in acetamide series shows
no activity at 100 mg/kg dose, whereas 2-methyl or
The anticonvulsant activity results obtained from the
MES test (Table 5) indicate that the acetamides, in
general, are considerably more active than the propio-
namide and butyramide counterparts, and the nature of
o-substituent on N-phenyl ring is an important factor
in determining anticonvulsant potency. The most active
compound in the series is 2-(1H-imidazol-1-yl)-N-(o-
Table 4
1H NMR data of title compounds
Comp.
1H NMR
1
2
3
4.85 (s, 2H, a-H), 7.09 (s, 1H, H-5%), 7.16 (t, 1H, J=7.4, H-4), 7.23 (s, 1H, H-4%), 7.33 (t, 2H, J=7.9, H-3 and H-5),
7.46 (d, 2H, J=7.9, H-2 and H-6), 7.60 (s, 1H, H-2%), 7.78 (br.s, NH)
2.80 (t, 2H, J=6.3, a-H), 4.37 (t, 2H, J=6.3, b-H), 6.99 (s, 1H, H-5%), 7.03 (s, 1H, H-4%), 7.13 (t, 1H, J=7.4, H-4),
7.32 (t, 2H, J=7.9, H-3 and H-4), 7.34 (s, 1H, H-2%), 7.54 (d, 2H, J=8, H-2 and H-6), 8.75 (br.s, NH).
2.21 (quin, 2H, J=6.6, b-H), 2.34 (t, 2H, J=7, a-H), 4.07 (t, 2H, J=6.3, g-H), 6.94 (s,1H, H-5%) 7.03 (s, 1H, H-4%),
7.09 (t, 1H, J=7.4, H-4), 7.30 (t, 2H, J=7.9, H-3 and H-5), 7.41 (s, 1H,H-2%) 7.59 (d, 2H, J=7.8, H-2 and H-6), 9.65
(br.s, NH).
4
5
6
2.01 (s, 3H, CH3), 4.87 (s, 2H, a-H), 6.9 (br.s, NH), 7.11 (s, 1H, H-5%), 7.11–7.27 (m, 2H, H-5 a and H-3), 7.23 (t, 1H,
J=7.6, H-4 a), 7.28 (s, 1H, H-4%), 7.68 (s, 1H, H-2%), 7.86 (d, 1H, J=8, H-6).
2.17 (s, 3H, CH3), 2.84 (t, 2H, J=6.3, a-H), 4.40 (t, 2H, J=6.3, b-H), 7.00 (s, 1H, H-5%), 7.05 (s, 1H, H-4%), 7.13 (t,
1H, J=7.4, H-4 a), 7.18–7.23 (m, 2H, H-3 and H-5 a), 7.47 (s, 1H, H-2%), 7.60 (br.s, NH), 7.62 (d, 1H, J=7.9, H-6).
2.19 (quin, 2H, J=6.8, b-H), 2.24 (s, 3H, CH3), 2.35 (t, 2H, J=6.9, a-H), 4.06 (t, 2H, J=6.6, g-H), 6.93 (s, 1H, H-5%),
7.03 (s, 1H, H-4%), 7.11 (t, 1H, J=7.4, H-4 a), 7.18–7.21 (m, 2H, H-3 and H-5 a), 7.43 (s, 1H, H-2%), 7.62 (d, 1H,
J=7.8, H-6), 8.15 (br.s, NH).
7
3.76 (s, 3H, OCH3), 4.82 (s, 2H, a-H), 6.84 (dd, 1H, J=8.2, 0.9, H-3), 6.96 (td, 1H, J=7.8, 1.1, H-5 a), 7.07 (s, 1H,
H-5%), 7.08 (td, 1H, J=7.8, 1.5, H-4 a), 7.24 (s, 1H, H-4%), 7.62 (s, 1H, H-2%) 7.79 (br.s, NH), 8.29 (dd, 1H, J=8.0, 1.4,
H-6).
8
2.84 (t, 2H, J=6.5, a-H), 3.86 (s, 3H, OCH3), 4.40 (t, 2H, J=6.5, b-H), 6.88 (dd, 1H, J=8.1, 1.1, H-3), 6.97 (td, 1H,
J=6.9, 1.2, H-5 a), 6.99 (s, 1H, H-5%), 7.04 (s, 1H, H-4%), 7.06 (td, 1H, J=7.4, 1.4, H-4 a), 7.54 (s, 1H, H-2%), 7.78 (br.s,
NH), 8.32 (dd, 1H, J=8.0, 1.4, H-6).
9
2.20 (quin, 2H, J=6.8, b-H), 2.35 (t, 2H, J=7.0, a-H), 3.78 (s, 3H, OCH3), 4.08 (t, 2H, J=6.8, g-H), 6.89 (dd, 1H,
J=8.1, 1.1, H-3), 6.96 (s, 1H, H-5%), 6.97 (td, 1H, J=8.0, 1.2, H-5 a), 7.06 (td, 1H, J=7.9, 1.4, H-4 a), 7.08 (s, 1H,
H-4%), 7.50 (s, 1H, H-2%), 7.78 (br.s, NH), 8.33 (dd, 1H, J=7.9, 1.3, H-6).
10
4.88 (s, 2H, a-H), 7.10 (td, 1H, J=7.7,1.4, H-5 a), 7.11 (s, 1H, H-5%), 7.28 (s, 1H, H-4%), 7.30 (td, 1H, J=7.8, 1.3,
H-4 a), 7.35 (dd, 1H, J=8.0, 1.2, H-3), 7.64 (br.s, NH), 7.67 (s, 1H, H-2%), 8.33 (d, 1H, J=7.4, H-6) 2.89 (t, 2H,
J=6.4, a-H), 4.40 (t, 2H, J=6.4, b-H), 6.99 (s, 1H, H-5%), 7.05 (s, 1H, H-4%), 7.08 (t, 1H, J=7.8, H-5 a), 7.28 (td, 1H,
J=7.9, 1.3, H-4 a), 7.37 (dd, 1H, J=7.5, 1.0, H-3), 7.52 (s, 1H, H-2%), 7.91 (br.s, NH), 8.24 (d, 1H, J=8.1, H-6).
2.89 (t, 2H, J=6.4, a-H), 4.40 (t, 2H, J=6.4, b-H), 6.99 (s, 1H, H-5%), 7.05 (s, 1H, H-4%), 7.08 (t, 1H, J=7.8, H-5 a),
7.28 (td, 1H, J=7.9, 1.3, H-4a), 7.37 (dd, 1H, J=7.5, 1.0, H-3), 7.52 (s, 1H, H-2%), 7.91 (br.s, NH), 8.24 (d, 1H,
J=8.1, H-6).
2.22 (quin, 2H, J=6.8, b-H), 2.41 (t, 2H, J=6.8, a-H), 4.09 (t, 2H, J=6.8, g-H), 6.95 (s, 1H, H-5%), 7.05–7.09 (m, 1H,
H-5 a), 7.08 (s, 1H, H-4%), 7.28 (td, 1H, J=7.9, 1.4, H-4 a), 7.38 (dd, 1H, J=8.0, 1.3, H-3), 7.50 (s, 1H, H-2%), 7.87
(br.s, NH), 8.27 (d, 1H, J=8.1, H-6).
4.91 (s, 2H, a-H), 7.09 (t, 1H, J=1.2, H-5%), 7.26 (t, 1H, J=1.1, H-4%), 7.27 (td, 1H, J=7.8, 1.4, H-4), 7.66 (s, 1H,
H-2%), 7.69 (td, 1H, J=7.9, 1.5, H-5), 8.22 (dd, 1H, J=8.5, 1.5, H-3), 8.74 (dd, 1H, J=8.5, 1.2, H-6), 10.43 (br.s,
NH).
2.97 (t, 2H, J=6.3, a-H), 4.43 (t, 2H, J=6.3, b-H), 7.01 (d, 1H, J=1.2, H-5%), 7.07 (s, 1H,H-4%), 7.23 (td, 1H, J=7.9,
1.3, H-4), 7.57 (s, 1H, H-2%), 7.68 (td, 1H, J=7.9, 1.5, H-5), 8.23 (dd, 1H, J=8.4, 1.5, H-3), 8.74 (dd, 1H, J=8.5, 1.0,
H-6), 10.36 (br.s, NH).
11
12
13
14
15
2.24 (quin, 2H, J=7.0, b-H), 2.49 (t, 2H, J=7.0, a-H), 4.11 (t, 2H, J=7.0, g-H), 6.97 (s, 1H, H-5%), 7.09 (s, 1H, H-4%),
7.21 (td, 1H, J=7.9, 1.1, H-4), 7.52 (s, 1H, H-2%), 7.67 (td, 1H, J=7.9, 1.4, H-5), 8.22 (dd, 1H, J=8.5, 1.2, H-3), 8.72
(d, 1H, J=8.5, H-6), 10.36 (br.s, NH).
a Interchangeable.

206
Z. Aktu¨rk et al. / Il Farmaco 57 (2002) 201–206
Table 5
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Wiley-VCH, New York, 1997, pp. 589–593.
MES-test screening data in mice of title compounds
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(Ed.), Burger’s Medicinal Chemistry and Drug Discovery-3, 5th
ed., Willey, New York, 1996, pp. 175–260.
Comp.
100 mg/kg a
30 mg/kg a
1
2
3
5/8
2/8
2/8
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commonly used antiepileptic drugs, Pharmacol. Therap. 90
(2001) 21–34.
4
5
0/8
2/8
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Epilepsy Res. 45 (2001) 3–6.
6
7
8
9
10
11
12
13
14
15
3/8
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antiepileptic drugs and related neuroprotective agents, Med. Res.
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5/8 *
6/8 **
5/8 *
7/8 **
1/8
3/8
5/8 *
3/8
4/8 *
6/8 **
2/8
a Protected animals to tested animals.
* PB0.05.
** PB0.01.
2,6-dimethyl substitution on anilide structures were
known to yield active anticonvulsant compounds [9,18].
Anti-MES activity of o-tolyl derivatives (6, 7) in propio-
namide and butyramide series is increased gradually,
but it is still lower than that of 1. In propionamide and
butyramide series, methoxyl is a unique substituent
which leads to compounds 8 and 9 with slightly better
or equal activity compared with 1.
In conclusion, these results revealed that further de-
tailed studies on this group of compounds are needed
for determining substitution pattern and the nature of
substituent(s) to optimize the anticonvulsant activity.
Our effort will continue to do so.
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145–162.
8
8
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This study was supported by research grants from
Ege University (project number: 98/Ecz/18) and the
Turkish Scientific and Technical Research Council
(TUBITAK; project number: SBAG/AYD 284).
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