The synthesis and anticonvulsant activity of some omega-phthalimido-N-phenylacetamide and propionamide derivatives.

Article abstract of DOI:10.1002/ardp.200300823

In this study, by combining anilide and N', N'-phthaloylglycinamide pharmacophores which are known to produce potent anticonvulsant compounds, sixteen omega-phthalimido-N-phenylacetamide and propionamide derivatives bearing substituents at positions 2 or 2, 6 on N-phenyl ring have been synthesized. The structural confirmation of the title compounds was achieved by interpretation of spectral and analytical data. The anticonvulsant activity of the title compounds was determined against maximal electroshock seizure at 100 mg/kg dose level in mice. The preliminary screening results indicated that omega-phthalimido-N-phenylacetamide and propionamide nuclei have pronounced anticonvulsant activity against maximal electroshock seizure.

Full text of DOI:10.1002/ardp.200300823

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 105−111
Synthesis and Activity of Amide Derivatives 105
Zeynep Soyera,
The Synthesis and Anticonvulsant Activity of
some ω-Phthalimido-N-phenylacetamide and
Propionamide Derivatives
Fatma Sultan Kılıcb,
Kevser Erolb,
Varol Pabuccuoglua
a Department of
In this study, by combining anilide and NЈ,NЈ-phthaloylglycinamide pharmaco-
phores which are known to produce potent anticonvulsant compounds, sixteen
ω-phthalimido-N-phenylacetamide and propionamide derivatives bearing sub-
stituents at positions 2 or 2,6 on N-phenyl ring have been synthesized. The
structural confirmation of the title compounds was achieved by interpretation of
spectral and analytical data. The anticonvulsant activity of the title compounds
was determined against maximal electroshock seizure at 100 mg/kg dose level
in mice. The preliminary screening results indicated that ω-phthalimido-N-phe-
nylacetamide and propionamide nuclei have pronounced anticonvulsant activity
against maximal electroshock seizure.
Pharmaceutical Chemistry,
Faculty of Pharmacy, Ege
University Bornova, Izmir
35100, Turkey
b Department of Pharmacology,
Faculty of Medicine,
Osmangazi University,
Eskis᝺ehir, Turkey
Keywords: Anticonvulsant; MES; Anilide; 2-Phthalimidoacetamide; 3-Phthalimi-
dopropionamide
Received: June 13, 2003; Accepted: September 18, 2003 [FP823]
DOI 10.1002/ardp.200300823
Introduction
phthaloylGABA have been published [9]. They re-
ported that phthaloylglycine N-monoalkylamides are
Electrophysiologically epileptic seizures are evoked by
excessive neuronal discharge in the brain. Imbalance
between inhibitory and excitatory processes followed
by over-excitation in the brain leads to epileptic sei-
zures [1]. Therefore, inhibition of excitation or enhance-
ment of inhibition in the brain is the ultimate goal for
anticonvulsive drug therapy. Thus, excitatory or inhibi-
tory neurotransmission is the prevalent target for de-
signing new anticonvulsants [2Ϫ4] GABAergic and
glutamatergic systems and their receptor sites are the
examples of such targets [1Ϫ3, 5]. It is also known
that glycine is one of the most important inhibitory
neurotransmitters in the brain. Meanwhile, it plays an
important role as a “coagonist of glutamate” at glycine
modulatory sites of NMDA receptors [1, 5]. Therefore,
glycine is of importance as one of the starting points
for the development of new anticonvulsants. Some of
the glycine derivatives such as milacemide (N-pentyl-
glycinamide), valrocemide (valproylglycinamide), and
NЈ,NЈ-phthaloylglycinamide, are known to have potent
anticonvulsant activity [6Ϫ8]. Salach et al. reported
that NЈ,NЈ-phthaloylglycinamide and its N-alkyl anal-
ogs designed as probable prodrug of glycinamide
have anticonvulsant activity on their own [8]. In a re-
cent study conducted by Usifoh et al. the synthesis
and anticonvulsant activity of N-alkyl amides of NЈ,NЈ-
phthaloylglycine, NЈ,NЈ-phthaloyl-β-alanine and NЈ,NЈ-
more active than the corresponding derivatives con-
taining GABA in maximal electroshock seizure (MES),
and NЈ,NЈ-phthaloyl-β-alanine amides are essentially
inactive. According to the authors “NЈ,NЈ-phthaloylgly-
cine amides might represent a new class of antiepilep-
tic drugs” [9].
Anilide is the other pharmacophore moiety known to
produce potent anticonvulsant drugs such as ameltol-
ide [4-amino-N-(2,6-dimethylphenyl)benzamide] [10],
ralitoline [(Z)-N-(2-chloro-6-methylphenyl)-(3-methyl-
4-oxothiazolidine-2-ylidene)acetamide] [11] and cer-
tain N-phenylphthalimides [12, 13]. Anti-MES activity
of anilides is directly influenced by the nature and pat-
tern of substitution on the N-phenyl ring. Optimum ac-
tivity was found with small and lipophilic substituents
at positions 2 or 2 and 6 of the N-phenyl ring [14-16].
These results encouraged us to combine anilide and
phthaloylglycinamide pharmacophores to explore pos-
sible anti-MES-active 2-phthalimido-N-phenylacet-
amide derivatives as glycinamide analogs. Our litera-
ture survey revealed that certain 2-phthalimido-N-phe-
nylacetamide derivatives with different substituents at
position 2 and/or 3 and/or 4 of the N-phenyl ring have
been evaluated once against pentylenetetrazole-in-
duced convulsions [17]. To our knowledge this is the
only report available about anticonvulsant activity of
phthaloylglycinanilide in the literature.
Correspondence: Varol Pabuccuoglu, Department of Phar-
maceutical Chemistry, Faculty of Pharmacy, Ege University
Bornova, Izmir 35100, Turkey. Phone: +90 232 3399931, Fax:
+90 232 3885258; e-mail: papuccuogluv@pharm.ege.edu.tr
In this study, we designed a group of 2-phthalimido-N-
phenylacetamide and 3-phthalimido-N-phenylpropion-
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106 Pabuccuoglu et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 105−111
Scheme 1. Synthesis of the compounds.
Table 1. Reflux time, yield, melting point and formula
of title compounds.
Figure 1. The title compounds designed.
Comp. Reflux
No Time (h) (%)
Yield M.p. (°C)
Formula
amide derivatives with substituents at positions 2 or 2
and 6 of the N-phenyl ring (Figure 1). Our aim was to
investigate the anti-MES activity of ω-phthalimido-N-
phenylacetamide and propionamide pharmacophore
and the possible effects of the substitutions at posi-
tions 2 or 2 and 6 of the N-phenyl ring.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4
5
3
5
4
5
4
5
4
5
4
5
5
5
4
5
73
69
76
73
68
78
87
57
70
55
53
64
77
71
52
41
224a
188b
234c
194
C16H12N2O3
C17H14N2O3
C16H11ClN2O3
C17H13ClN2O3
C17H14N2O3
C18H16N2O3
C17H14N2O4
C18H16N2O4
C19H18N2O3
C20H20N2O3
C16H10Cl2N2O3
C17H12Cl2N2O3
248d
200
202e
166
226
167
307
Results and discussion
Chemistry
In this study, sixteen ω-phthalimido-N-phenylacet-
amide and propionamide derivatives have been syn-
thesized to evaluate anti-MES activity. The synthesis
of the title compounds has been realized in two steps
(Scheme 1). In the first step, ω-chloroanilides were
prepared by reacting ω-chloroacyl chloride (2-chlo-
roacetyl and 3-chloropropionyl chloride) with appropri-
ately substituted anilines. In the second step, these
intermediates were refluxed with phthalimide potas-
sium salt in DMF according to the method reported by
Schapira et al. [18]. The reflux times, yields and melt-
ing points are reported in Table 1. The structures of
the title compounds were confirmed by spectral (IR,
1H and 13C NMR and EIMS) and elemental analysis
(see Table 1, 2, and 3). The seven derivatives of the
title compounds, namely 1 [17Ϫ19], 2 [20], 3 [17], 5
[17, 21], 7 [17], 13 [22] and 14 [23], were reported
previously. However, except for compound 1 their de-
tailed spectral data have not been described in the lit-
erature.
238
285Ϫ286f C18H16N2O3
254g
295
227
C19H18N2O3
C17H13ClN2O3
C18H15ClN2O3
a
b
c
d
e
f
220Ϫ227 °C Ref [19], 232 °C Ref [17], 231 °C Ref [18].
193Ϫ194 °C Ref [20].
245 °C Ref [17].
242 °C Ref [17], 265-266 °C Ref [21].
240 °C Ref [17].
288Ϫ291 °C Ref [22].
g
253Ϫ254.5 °C Ref [23].
were observed between 3321Ϫ3242 cmϪ1 and
1650Ϫ1675 cmϪ1, respectively. Two additional bands
appeared at around 1770 and 1720 cmϪ1 in spectra
indicating the presence of phthalimide carbonyl
groups.
With regard to IR data, diagnostic vibrational bands
were provided by anilide and phthalimide moieties.
N-H and C=O stretching bands of anilide chromofore
1H NMR spectra of the title compounds were consist-
ent with expected resonance signals in terms of
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 105−111
Table 2. IR and EIMS data of title compounds.
Synthesis and Activity of Amide Derivatives 107
Comp.
No
IR (cm؊1
)
EIMS m/z (% intensity)
1
2
3
3279, 1773, 1727, 1667
3301, 1771,1725, 1655
3255, 1770, 1728, 1667
280 (M+, 19), 160 (100), 132 (21), 104 (34), 93 (9), 92 (50), 76 (67)
294 (M+, 8), 202 (18), 160 (11), 93 (100), 76 (29)
316 ( [M+2]+, 2), 314 (M+, 10), 279 (51), 160 (90), 159 (95), 132
(30), 126 (63), 104 (78), 99 (45), 90 (36), 83 (19), 77 (100)
328 (M+, 3), 293 (20), 202 (31), 160 (100), 126 (69), 104 (32),
99 (14), 76 (43)
4
3288, 1773, 1717, 1657
3275, 1771, 1728, 1661
3291, 1773, 1727, 1650
3296, 1775, 1725, 1672
3321, 1773, 1716, 1656
3256, 1773, 1723, 1657
3261, 1772, 1718, 1657
3242, 1777, 1724, 1675
3246, 1770, 1705, 1665
3254, 1777, 1720, 1663
3271, 1772, 1721, 1653
3251, 1774, 1726, 1672
3260, 1771, 1721, 1664
5
294 (M+, 11), 160 (100), 133 (44), 106 (90), 104 (39), 91 (15),
78 (33) 76 (46)
6
308 (M+, 19), 202 (19), 160 (100), 107 (52), 106 (87), 104 (23),
76 (30)
7
310 (M+, 84), 161 (66), 160 (89), 132 (20), 123 (100), 108 (32),
104 (45), 85 (29), 83 (46), 76 (41)
8
324 (M+, 40), 202 (14), 160 (100), 123 (59), 122 (94), 108 (87),
106 (87), 104 (28), 92 (26), 80 (28), 75 (48)
322 (M+, 2), 162 (100), 160 (3), 132 (18), 117 (15), 104 (26), 82
(18), 76 (30)
9
10
11
12
13
14
15
16
336 (M+, 10), 202 (18), 162 (19), 160 (100), 134 (78), 120 (53),
104 (16), 91 (11), 85 (13), 82 (27), 76 (50)
315 (2), 314 (4), 312 (7), 160 (100), 134 (6), 133 (21), 132 (19),
104 (41), 77 (37)
329 (4), 327 (8), 202 (34), 163 (16), 160 (100), 132 (5), 130 (7),
76 (20)
308(M+, 8), 160 (100), 148 (81), 132 (22), 120 (52), 104 (43), 91
(19), 76 (52)
322 (M+, 20), 202 (31), 160 (100), 121 (88), 104 (16),
91 (11), 77 (16), 76 (23)
330 ( [M+2]+, 2), 328 (M+, 6), 160 (100), 141 (9), 140 (14), 132
(10), 104 (35), 82 (13), 77 (19), 76 (33)
307 (60), 202 (23), 160 (100), 140 (46), 104 (21), 76 (43)
chemical shifts and integrations. The chemical shifts
and splitting patterns of N-phenyl protons in each com-
pound differed depending on the nature of the sub-
stituents and substitution patterns. In decoupled
13C NMR spectra, the resonance signals did not
account for the total number of carbon atoms in indi-
vidual compounds, since as expected certain signals
represent more than one carbon atom (Table 2).
either the phthalimide or the anilide portion of the mol-
ecule. The m/z 160 ion [C9H6NO2]+ derived from the
phthalimide portion through α-cleavage of amide re-
sults in the base peak of the title compounds, except
for compounds 2, 3, 7 and 9 the base peaks of which
were obviously derived from the aniline portion of the
molecule.
The molecular ion peaks of the title compounds, ex-
cept for compounds 11, 12 and 16, are in complete
agreement with the calculated molecular weights. The
aforementioned compounds 11, 12 and 16 bearing
chloro as a common substituent did not produce any
molecular ion, but furnished [M-Cl]+ ions derived by
loss of one chlorine atom from the molecule. The main
fragmentation seems to occur at the α-position of am-
ide carbonyl (α-cleavage) to furnish ions derived from
Anticonvulsant activity
The anticonvulsant activity of the title compounds was
evaluated against maximal electroshock seizures in-
duced 0.5 or 4 h after administration of single dose
levels (100 mg/kg) in mice. The Rotarod test was used
to demonstrate the possible neurotoxicity. The anti-
convulsant and neurotoxicity screening data are pre-
sented in Table 4. According to the rotarod test none
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108 Pabuccuoglu et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 105−111
Table 3. NMR Data of title compounds.
Comp.
NMR
1H NMR: 4.43 (s, 2H, CH2), 6.98 (td, 1H, J = 7.4, 1.0, H-4), 7.19 (td, 2H, J = 7.6, 1.8, H-3 and H-5),
1
7.49 (dd, 2H, J = 7.6, 1.0, H-2 and H-6), 7.70Ϫ7.72 (m, 2H, Pht-H), 7.79Ϫ7.81 (m, 2H, Pht-H),
9.93 (brs, 1H, NH).
13C NMR: 41.6, 120.1, 124.1, 124.5, 129.7, 132.5, 135.5, 139.4, 165.6, 168.4.
2
1H NMR: 2.97 (t, 2H, J = 7.3, α-CH2), 4.23 (t, 2H, J = 7.3, β-CH2),7.23 (t, 1H, J = 7.4, H-4), 7.46 (t,
2H, J = 7.9, H-3 and H-5), 7.76 (d, 2H, J = 7.8, H-2 and H-6), 7.97Ϫ8.00 (m, 2H, Pht-H), 8.03Ϫ8.06
(m, 2H, Pht-H), 9.93 (brs, 1H, NH).
13C NMR: 29.5, 30.4, 114.8, 118.2, 118.4, 123.6, 127.1, 129.3, 134.2, 162.8, 163.7.
3
4
1H NMR: 4.59 (s, 2H, CH2), 7.15 (td, 1H, J = 7.7, 1.4, H-4*), 7.27 (td, 1H, J = 7.3, 1.3, H-5*), 7.43 (dd,
1H, J = 8.0, 1.3, H-3), 7.80Ϫ7.86 (m, 3H, Pht-H and H-6), 7.88Ϫ7.91 (m, 2H Pht-H), 9.75 (brs, 1H, NH).
13C NMR: 41.4, 124.1, 127.0, 127.5, 128.4, 130.4, 132.6,135.2, 135.5, 166.3, 168.3.
1H NMR: 2.80 (t, 2H, J = 7.0, α-CH2), 3.97 (t, 2H, J = 7.0, β-CH2), 7.10 (td, 1H, J = 7.7, 1.5, H-4*), 7.23
(td, 1H, J = 7.7, 1.4, H-5*), 7.35 (dd, 1H, J = 8.0, 1.4, H-3), 7.72 (dd, 1H, J = 7.9, 1.4, H-6), 7.76Ϫ7.79
(m, 2H,Pht-H), 7.80Ϫ7.84 (m, 2H,Pht-H), 9.39 (brs, N-H).
13C NMR: 35.2, 35.4, 123.9, 127.3, 127.6, 127.8, 128.1, 130.2, 132.6, 135.2, 135.6, 168.5, 169.9
1H NMR: 2.21 (s, 3H, CH3), 4.46 (s, 2H, CH2), 7.03Ϫ7.09 (m, 2H, H-4 and H-5), 7.14 (dd, 1H, J = 7.3,
0.9, H-3), 7.34 (dd, 1H, J = 7.4, 1.0, H-6), 7.77Ϫ7.80 (m, 2H, Pht-H), 7.82Ϫ7.86 (m, 2H, Pht-H), 9.54
(brs, N-H).
5
6
13C NMR: 18.6, 41.4, 124.1, 125.9, 126.4, 126.9, 131.2, 132.6, 132.9, 135.5, 136.6, 165.9, 168.2.
1H NMR: 2.13 (s, 3H, CH3), 2.71 (t, 2H, J = 7.0, α-H), 3.94 (t, 2H, J = 7.1, β-H), 7.00 (t, 1H, J = 7.2,
H-4), 7.08Ϫ7.10 (m, 2H, H-3 and H-5), 7.31 (d, 1H, J = 7.7, H-6), 7.75Ϫ7.77 (m, 2H, Pht-H),
7.80Ϫ7.82 (m, 2H, Pht-H), 9.26(brs, N-H).
13C NMR: 18.5, 35.4, 123.9, 126.0, 126.2, 126.7, 131.0, 132.6, 132.7, 135.2, 137.0, 168.5, 169.9
7
1H NMR: 3.86 (s, 3H, OCH3), 4.53 (s, 2H, CH2), 6.82 (t, 1H, J = 7.7, H-5*), 6.94 (dd, 1H, J = 7.2, 1.0,
H-3), 7.01 (t, 1H, J = 7.7, H-4*), 7.77Ϫ7.79 (m, 2H, Pht-H), 7.83Ϫ7.85 (m, 2H, Pht-H), 7.93 (d, 1H,
J = 7.8, H-6), 9.40 (brs, N-H).
13C NMR: 41.6, 56.6, 112.2, 121.1, 122.7, 124.1, 125.6, 127.7, 132.5, 135.5, 150.5, 165.8, 168.4
8
1H NMR: 2.89 (t, 2H, J = 7.4, α-H), 3.88 (s, 3H, OCH3), 4.16 (t, 2H, J = 7.4, β-H), 6.89 (dd, 1H, J = 8.1,
1.3, H-3), 6.98 (td, 1H, J = 7.8, 1.3, H-5*), 7.07 (td, 1H, J = 7.8, 1.4, H-4*), 7.74-7.78 (m, 2H, Pht-H),
7.87Ϫ7.91 (m, 2H, Pht-H), 7.81 (brs, N-H), 8.37 (d, 1H, J = 7.6, H-6).
13C NMR: 35.2, 35.6, 56.4, 112.1, 121.0, 123.5, 123.9, 125.4, 127.9, 132.6, 135.2, 150.8, 168.5, 169.7
9
1H NMR: 1.16 (d, 6H, J = 6.8, CH3), 3.18Ϫ3.21 (m, 1H, CH), 4.46 (s, 2H, CH2), 7.09 (t, 1H, J = 7.4,
H-4*), 7.15 (t, 1H, J = 7.2, H-5*), 7.23 (d, 1H, J = 7.4, H-3**), 7.25 (d, 1H, J = 7.7, H-6**), 7.77Ϫ7.79
(m, 2H, Pht-H), 7.84-7.86 (m, 2H, Pht-H), 9.56 (brs, NH).
13C NMR: 18.6, 22.8, 73.7, 118.5, 121.1, 121.9, 122.0, 127.5, 129.4, 138.7, 161.0, 163.0.
10
1H NMR: 1.04 (d, 6H, J = 6.8, CH3), 2.71 (t, 2H, J = 6.9, α-H), 3.01Ϫ3.05 (m, 1H, CH), 3.93 (t, 2H, J =
6.9, β-H), 7.05Ϫ7.13 (m, 2H, H-4 and H-5), 7.17Ϫ7.22 (m, 2H, H-3 and H-6), 7.76Ϫ7.79 (m, 2H,
Pht-H), 7.80Ϫ7.83 (m, 2H, Pht-H), 9.30 (brs, NH).
13C NMR: 24.0, 27.9, 35.2, 35.4, 123.9, 126.3, 126.5, 127.1, 127.9, 132.6, 135.2, 135.5, 144.2,
168.5, 169.9.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 105−111
Table 3. (continued).
Synthesis and Activity of Amide Derivatives 109
Comp.
NMR
1H NMR: 4.30 (s, 2H, CH2), 6.99 (t, 1H, J = 7.8, H-4), 7.15 (d, 2H, J = 8.1, H-3 and H-5), 7.54Ϫ7.57
11
12
13
14
15
16
(m, 2H, Pht-H), 7.61Ϫ7.64 (m, 2H, Pht-H), 9.82 (brs, NH).
13C NMR: 31.5, 124.1, 129.4, 130.3, 132.6, 133.2, 134.5, 135.5, 166.1, 168.2
1H NMR: 2.79 (t, 2H, J = 7.4, α-H), 3.95 (t, 2H, J = 7.3, β-H), 7.11 (t, 1H, J = 8.1, H-4), 7.27 (d, 2H,
J = 8.1, H-3 and H-5), 7.67Ϫ7.70 (m, 2H, Pht-H), 7.74Ϫ7.77 (m, 2H, Pht-H), 9.58 (brs, NH).
13C NMR: 34.1, 35.0, 123.8, 129.3, 130.0, 132.7, 133.7, 134.5, 135.2, 168.5, 169.3.
1H NMR: 1.96 (s, 6H, CH3), 4.24 (s, 2H, CH2), 6.75-6.82 (m, 3H, H-3, H-4 and H-5), 7.55Ϫ7.57 (m,
2H, Pht-H), 7.62Ϫ7.64 (m, 2H, Pht-H), 9.23 (brs, NH).
13C NMR: 13.3, 35.7, 118.3, 121.9, 122.8, 127.3, 129.3, 129.6, 130.6, 160.1, 162.7
1H NMR: 1.90 (s, 6H, CH3), 2.59 (t, 2H, J = 7.3, α-H), 3.79 (t, 2H, J = 7.3, β-H), 6.76Ϫ6.83 (m, 3H,
H-3, H-4 and H-5), 7.55Ϫ7.57 (m, 2H, Pht-H), 7.61Ϫ7.68 (m, 2H, Pht-H), 8.94 (brs, NH).
13C NMR: 13.4, 29.2, 29.8, 118.2, 121.7, 122.9, 127.2, 129.3, 130.1, 130.2, 130.5, 162.9, 163.5
1H NMR: 2.17 (s, 3H, CH3), 4.45 (s, 2H, CH2), 7.07Ϫ7.10 (m, 2H, H-5* and H-4*), 7.16 (dd, 1H,
J = 6.7, 2.7, H-3*), 7.72Ϫ7.75 (m, 2H, Pht-H), 7.79Ϫ7.82 (m, 2H, Pht-H), 9.60 (brs, NH).
13C NMR: 19.0, 41.0, 124.1, 127.8, 129.0, 129.9, 132.5, 132.7, 134.0, 135.4, 139.2, 165.9, 168.3
1H NMR: 2.13 (s, 3H, CH3), 2.80 (t, 2H, J = 7.6, α-H), 3.99 (t, 2H, J = 7.4, β-H), 7.01Ϫ7.03 (m, 2H,
H-4 and H-5), 7.13 (dd, 1H, J = 7.4, 2.4, H-3), 7.75Ϫ7.77 (m, 2H, Pht-H), 7.65Ϫ7.67 (m, 2H,
Pht-H), 9.05 (brs, NH).
13C NMR: 13.8, 29.2, 29.7, 118.1, 118.2, 122.1, 122.9, 124.0, 127.3, 128.2, 128.9, 129.2, 129.3,
133.6, 162.9, 163.8.
*
Interchangeable.
of the compounds showed neurotoxicity at the applied
dose. Preliminary screening results indicated that the
title compounds have pronounced anti-MES activity.
The derivatives bearing substituents at the ortho posi-
tion on the N-phenyl ring in both acetamides and pro-
pionamides, except isopropyl substituted ones (com-
pound 9 and 10), provided better protection at 4 h than
at 0.5 h. However, 2,6-disubstituted and 2-isopropyl
substituted compounds did not follow similar trends
and their activity did not differ significantly depending
on the time of administration. The most active com-
pounds in the acetamide series are compound 3 and
compound 7. The rest of the acetamide derivatives did
not produce compounds superior to compound 1
which did not have any substituent on the N-phenyl
ring. With regard to propionamide derivatives, the
most active compound is compound 2 followed by
compounds 6 and 10. Surprisingly, in the propionam-
ide series, the substituents studied did not create com-
pounds with superior activity compared to the unsub-
stituted propionamide derivative (compound 2). The
compounds displaying statistically significant activity
were 2, 3, 6, 7 and 10 in both series. Compound 1, 3,
5 and 7 have been evaluated previously against pen-
tylene-tetrazole-induced tonic-convulsions predicting
activity on absence seizures. Compound 7, one of the
most active compounds against MES in this study, has
been found inactive, and the others have shown 33%
protection at 100 mg/kg dose level in frogs [17].
As mentioned in the introduction, Usifoh et al. reported
that aliphatic amides of NЈ,NЈ-phthaloyl-β-alanine (cor-
responding to our propionamide derivatives) were es-
sentially inactive in the MES test [9]. In contrast to this,
our study revealed that N-phenyl substituted amides
of NЈ,NЈ-phthaloyl-β-alanine nucleus have a definite
anticonvulsant activity against MES.
Experimental
Chemistry
Melting points were determined on a Buchi 510 Melting point
apparatus and are uncorrected. The IR spectra of com-
pounds were recorded as potassium bromide pellets on a
Jasco FT/IR-400 spectrometer. The NMR spectra were re-
corded on a Bruker DPX-400 FT-NMR using a CDCl3/DMSO-
d6 mixture (0.6 mL /4 drops) as solvent. Chemical shifts were
reported in parts per million (δ). J values were given in Hz.
Mass spectra (EI) were measured on a Mikromass VG Plat-
form-II spectrometer. Elemental analyses (C, H and N) were
performed by TUBITAK Analytical Laboratory Ankara, Turkey.
The analytical results for the elements were within 0.4 %
of theoretical values.
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110 Pabuccuoglu et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 105−111
temperature was maintained at 20 1 °C under conditions
of a 12-hours light and dark schedule. Before the experiments
mice were allowed 1 wk of adaptation. They were used only
once. The experiments were performed between 9 and 12
am in the morning.
Table 4. Anticonvulsant and neurotoxicity screening
data of title compouds at 100 mg/kg dose in mice.
Comp
MESa
Toxicityb
0.5 h
0.5 hc
4 hc
4 h
All title compounds were suspended in 0.5 % methylcellulose
and injected intraperitoneally at 100 mg/kg doses. 0.1 mL
methylcellulose was given intraperitoneally to control ani-
mals. The rotarod test was carried out to determine minimal
neurotoxicity before the experiments. Maximal electroshock
seizures (MES) were induced 0.5 h or 4 h after administration
of title compounds, by application of a 60 Hz current of 60
mA and 0.4 pulse witdh for 0.2 s via ear electrodes by using
a Ugo Basile electroshock device. The anticonvulsive activity
of the compounds was evaluated by defining the abolition of
the hind-leg tonic maximal extension component of the sei-
zure [25]. FisherЈs exact X2 test was used for statistical analy-
sis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1/4
3/4
1/4
2/4
2/4
2/4
3/4
2/4
3/4
3/4
2/4
2/4
3/4
3/4
3/4
3/4
3/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/8
0/8
0/4
0/4
0/0
0/4
0/4
0/4
0/8
0/4
0/4
0/4
0/4
0/4
0/4
8/8**
8/8**
3/4
3/4
7/8*
7/8*
2/4
3/4
7/8*
2/4
3/4
3/4
2/4
3/4
Acknowledgments
This study was supported by research grants from Ege
University (project number: 2000/Ecz/15) and The
Scientific and Technical Research Council of Turkey
(TUBITAK; project number: SBAG/AYD 359).
3/4
a
protected animals to tested animals.
animals exhibited neurotoxicity to tested animals.
Control group: 6/8.
b
c
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