Synthesis and anticonvulsant activity of some N-phenyl-2- phtalimidoethanesulfonamide derivatives

Article abstract of DOI:10.1002/ardp.200700166

In this study, inspired by the structures of the taltrimide, 2-phthalimidoethanesulphonamide, and the anilide pharmacophore known to be synthetically produced anticonvulsant compounds, fifteen N-phenyl-2- phtalimidoethanesulfonamide derivatives bearing substituents with diverse electronic and hydrophobic features on N-phenyl ring were 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 in mice at a dose level of 100 mg/kg. The preliminary screening results indicated that the exchange of the N-isopropyl moiety for an N-phenyl ring in the taltrimide molecule abolished the anticonvulsant activity. However, introducing certain substituents, such as nitro, methyl, and chloro, into the N-phenyl ring lead to more active compounds in comparison to the unsubstituted derivatives.

Full text of DOI:10.1002/ardp.200700166

656
Arch. Pharm. Chem. Life Sci. 2007, 340, 656–660
Full Paper
Synthesis and Anticonvulsant Activity of Some N-Phenyl-2-
phtalimidoethanesulfonamide Derivatives
Ozlem Akgul1, Fatma Sultan Kilic2, Kevser Erol2, and Varol Pabuccuoglu1
1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University Bornova, Izmir, Turkey
2 Department of Pharmacology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
In this study, inspired by the structures of the taltrimide, 2-phthalimidoethanesulphonamide,
and the anilide pharmacophore known to be synthetically produced anticonvulsant com-
pounds, fifteen N-phenyl-2-phtalimidoethanesulfonamide derivatives bearing substituents with
diverse electronic and hydrophobic features on N-phenyl ring were 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 elec-
troshock seizure in mice at a dose level of 100 mg/kg. The preliminary screening results indi-
cated that the exchange of the N-isopropyl moiety for an N-phenyl ring in the taltrimide mole-
cule abolished the anticonvulsant activity. However, introducing certain substituents, such as
nitro, methyl, and chloro, into the N-phenyl ring lead to more active compounds in comparison
to the unsubstituted derivatives.
Keywords: Anticonvulsant / MES / N-Phenyl-2-phtalimidoethanesulfonamide / Taurine / Taltrimide /
Received: June 29, 2007; accepted: August 21, 2007
DOI 10.1002/ardp.200700166
Supporting Information for this article is available from the author or on the WWW under http://www.wiley-vch.de/
contents/jc_2019/200700166_s.pdf
The inhibition of excitation or enhancement of inhibi-
Introduction
tion in the brain is the ultimate goal for anticonvulsant
drug therapy, since the imbalance between inhibitory
and excitatory processes followed by over-excitation in
the brain leads to epileptic seizure [3, 5, 6]. Therefore, the
inhibitor amino acids in the central nervous system
become the natural prevalent targets for designing new
anticonvulsants [7].
Besides the major inhibitor amino acids GABA and gly-
cine, taurine, as an inhibitor amino acid, modulates the
excitatory and inhibitory neurotransmission leading to
enhanced inhibition [8–10]. Taurine is known to have
anti-epileptic activity, but it has clinically no application
yet [8, 11]. Its hydrophilic nature leading to uncertain
pharmacokinetics prevents its use for therapeutic pur-
poses [8]. Attempts for more lipophilic taurine analogs
yielded N-isopropyl-2-phthalimidoethane sulfonamide, a
potent anticonvulsant compound known as taltrimide
[8, 12, 13]. In animal experiments, the anticonvulsive
effects of taltrimide (in both tests of MES and PST) have
Epilepsy requires long-term efficient therapy without
unwanted side effects, so the development of new anti-
epileptic drugs (AEDs) with approved therapeutic proper-
ties is as an important challenge for medicinal chemis-
try, since epilepsy is one of the most common neurologi-
cal diseases [1–3]. Clinically available AEDs have certain
disadvantages such as notable adverse effects and ineffi-
cient therapy in some seizure types [3, 4]. The need for
new anti-epileptic drugs with different modes of action
than those of the available ones seems essential for satis-
factory results [4].
Correspondence: Varol Pabuccuoglu, Pharmaceutical Chemistry De-
partment, Faculty of Pharmacy, Ege University, Bornova 35100, Izmir,
Turkey.
E-mail: Varol.pabuccuoglu@ege.edu.tr
Fax: +90 232 388-5258
Abbreviations: anti-epileptic drugs (AEDs); maximal electroshock seiz-
ure (MES); anticonvulsant screening project (ASP)
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Arch. Pharm. Chem. Life Sci. 2007, 340, 656–660
Anticonvulsant N-phenyl-2-phtalimidoethanesulfonamides
657
not been confirmed in clinical studies, and during the
taltrimide treatment, the frequency of seizures has been
increased indicating the possible proconvulsive behavior
[14]. On the other hand, in a recent study, N-valproyltaur-
inamide has been reported as promising AED candidate
for further experimental epilepsy models [15].
The data summarized above encourage us to investi-
gate the N-phenyl derivatives of 2-phthalimidotaurina-
mide as potential anticonvulsants since the anilide phar-
macophore with small and lipophilic substituents on the
N-phenyl ring is known to produce potent anticonvul-
sants [16–18].
Results and discussion
Chemistry
In this study, fifteen N-phenyl-2-phtalimidoethanesulfo-
namide derivatives have been synthesized to evaluate
anti-MES activity. The synthesis of the title compounds
was performed in three steps according to the method
reported by Winterbottom et al. [19]. As illustrated in
Scheme 1, in the first step, the reaction of 2-aminoethane
sulfonic acid (taurine) with phthalic anhydride and
Scheme 1. Synthesis of the presented compounds.
potassium acetate in acetic acid solution furnished 2-
phthalimidoethanesulfonic acid potassium salt. In the
second step, potassium salt was transformed to the corre-
sponding sulfonyl chloride derivative with phosphorus
pentachloride. The reactions of sulfonyl chloride deriv-
Table 1. Yield, melting point, formula, IR, and API-MS data of title compounds.
Comp
Yield (%) Mp (8C)
Formula
IR (cm– 1
)
API-MS m/z (% intensity)
1
2
60
19
136–138a) C16H14N2O4S
3248, 1768, 1699, 1362, 1142
3265, 1771, 1716, 1370, 1147
331 (1, [M+1]+), 174 (100)
362 (2, [M+2]+), 361 (10, [M+1]
+), 174 (100)
154
C17H16N2O5S
3
4
25
12
118
C17H16N2O5S
C17H16N2O5S
3244, 1770, 1700, 1362, 1143
3252, 1776, 1718, 1359, 1146
361 (6, [M+1]+), 174 (100)
362 (6, [M+2]+), 361 (31, [M+1]
+), 297 (100)
142b)
5
6
7
43
15
21
174
122
165c)
C17H16N2O4S
C17H16N2O4S
C17H16N2O4S
3278, 1770, 1716, 1365, 1149
3266, 1775, 1702, 1366, 1147
3326, 1773, 1721, 1369, 1143
345 (3, [M+1]+), 174 (100)
345 (3, [M+1]+), 174 (100)
346 (5, [M+2]+), 345 (22, [M+1]
+), 174 (100)
8
9
25
32
20
31
53
222
C16H13N3O6S
3270, 1774, 1707, 1525, 1390,
1346, 1153
3201, 1772, 1707, 1519, 1362,
1336, 1147
376 (6, [M+1] +), 270 (100)
208d)
162
C16H13N3O6S
376 (1, [M+1]+), 174 (100)
10
11
12
C16H13ClN2O4S
C16H13ClN2O4S
C16H13ClN2O4S
3249, 1773, 1717, 1399, 1148
366 (0.2, [M+2]+), 365 (1,
[M+1]+), 174 (100)
128
3268, 1764, 1711, 1367, 1148
3321, 1773, 1719, 1367, 1143
366 (0.4, [M+1]+), 365 (2,
[M+1]+), 174 (100)
150e)
366 (1, [M+2]+), 365 (3, [M+1]
+), 174 (100)
13
14
15
13
18
18
144
189
128
C19H20N2O4S
C18H18N2O4S
C18H18N2O4S
3267, 1770, 1713, 1365, 1144
3278, 1775, 1719, 1363, 1140
3312, 1769, 1700, 1366, 1140
373 (13, [M+1] +), 174 (100)
359 (10, [M+1] +), 174 (100)
359 (5, [M+1] +), 174 (100)
a)
1418C from etanol, Ref [19].
148–1498C from aqueous acetic acid, Ref [19].
168–1708C from ethanol, Ref [19].
214.5–215.58C from aqueous acetic acid, Ref [19].
154–1558C from aqueous acetic acid, Ref [19].
b)
c)
d)
e)
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658
O. Akgul et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 656–660
Table 2. NMR data of title compounds.
Compound
NMR
1
2
1H NMR (CDCl3) d 7.86 (2H, dd, J= 2.7, 5.5 Hz, H-49, H-79), 7.73 (2H, dd, J= 3.1, 5.5 Hz, H-59, H-69), 7.25–7.33 (4H, m, H-2,
H-3, H-5, H-6), 7.15–7.17 (1H, m, H-4), 7.07 (brs, NH), 4.08 (2H, t, J= 5.9 Hz, a-CH2), 3.45 (2H, t, J= 5.9 Hz, b-CH2) ppm.
1H NMR (CDCl3) d 7.84 (2H, dd, J= 3.1, 5.5 Hz, H-49, H-79), 7.72 (2H, dd, J= 3.1, 5.5 Hz, H-59, H-69), 7.53 (1H, dd, J= 1.6,
7.8 Hz, H-3*), 7.16 (brs, NH), 7.12 (1H, td, J= 1.6, 7.8 Hz, H-4**), 6.94 (1H, t, J= 7.8 Hz, H-5**), 6.89 (1H, d, J= 8.1 Hz, H-
6*), 4.14 (2H, t, J= 6.2 Hz, a-CH2), 3.91 (3H, s, OCH3), 3.41 (2H, t, J= 6.2 Hz, b-CH2) ppm.
5
1H NMR (CDCl3) d 7.85 (2H, dd, J= 3.1, 5.5 Hz, H-49, H-79), 7.73 (2H, dd, J= 3.1, 5.5 Hz, H-59, H-69), 7.46 (1H, d, J= 7.8 Hz,
H-3*), 7.21–7.18 (2H, m, H-5**, H-6*), 7.06 (1H, t, J= 7.4 Hz, H-4**), 6.65 (brs, NH), 4.12 (2H, t, J= 6.0 Hz, a-CH2), 3.53
(2H, t, J= 6.2 Hz, b-CH2), 2.43 (3H, s, CH3) ppm.
8
9
1H NMR (DMSO-d6) d 10.55 (brs, NH), 7.96–7.95 (1H, m, H-4), 7.91–7.88 (1H, m, H-6), 7.8 (4H, m, H-49, H-59, H-69, H-79),
7.59–7.57 (2H, m, H-2, H-5), 3.95 (2H, t, J= 7 Hz, a-CH2), 3.55 (2H, t, J= 7.2 Hz, b-CH2) ppm.
1H NMR (CDCl3) d 8.19 (2H, d, J= 9 Hz, H-3, H-59), 7.86 (2H, dd, J= 3.1, 6.25 Hz, H-4, H-79), 7.76 (2H, dd, J= 3.1, 5.6 Hz, H-
59, H-69), 7.64 (brs, NH), 7.41(2H, dd, J= 1.95, 8.97 Hz, H-2, H-6), 4.07 (2H, t, J= 5.9 Hz, a-CH2), 3.55 (2H, t, J= 5.9 Hz, b-
CH2) ppm.
10
1H NMR (CDCl3) d 7.85 (2H, dd, J= 3.1, 5.5 Hz, H-49, H-79), 7.73 (2H, dd, J= 3.1, 5.5 Hz, H-59, H-69), 7.66 (1H, dd, J= 1.6,
8.2 Hz, H-3), 7.39 (1H, dd, J= 1.6, 8.19 Hz, H-6), 7.3–7.26 (1H, m, H-4*), 7.22 (brs, NH), 7.09 (1H, td, J= 1.6, 7.8 Hz, H-5*),
4.18 (2H, t, J= 6.2 Hz, a-CH2), 3.49 (2H, t, J= 6.2 Hz, b-CH2) ppm.
14
1H NMR (CDCl3) d 7.88 (2H, dd, J= 2.7, 5.5 Hz, H-49, H-79), 7.74 (2H, dd, J= 3.1, 5.5 Hz, H-59, H-69), 7.10–7.09 (3H, m, H-3,
H-4, H-5), 6.26 (brs, NH), 4.35 (2H, t, J= 6.24 Hz, a-CH2), 3.54 (2H, t, J= 6.24 Hz, b-CH2), 2.41 (6H, s, CH3) ppm.
* Interchangeable
ative and appropriated anilines in the third step yielded different chemical shifts with expected splitting pat-
the title compounds. The structures of the title com- terns. The representative examples of NMR data of the
pounds were confirmed by spectral (IR, 1H-NMR, and title compounds are summarized at Table 2.
APCI (atmospheric pressure chemical ionization)-MS) and
The mass spectra of the title compounds were recorded
elemental analysis. The yields, melting points, and for- according to the APCI technique and interpreted for the
mulas of title compounds are reported in Table 1. The positive ionization (Table 1). The [M+H]+ ions of the title
title compounds except compound 1, 4, 7, 9, and 12, compounds were in complete agreement with the calcu-
which were reported as potential antibacterials and anti- lated molecular weights. The main fragmentation seems
malarials by Winterbottom et al., are novel [19]. Taltri- to occur at the sulfonamide function to give the m/z 238
mide was also synthesized according to the method ion [C10H8NO4S]+ and m/z 174 ion [C10H8NO2]+ as base peaks
reported in the literature and its spectral data is consis- in title compounds except compounds 4 and 8.
tent with the data reported [20].
The presence of vibrational bands resulting from Pharmacology
phthalimide and sulfonamide moieties are the confirma- According to the Anticonvulsant Screening Project (ASP),
tive frequencies for title compounds in the IR spectra two convulsant test, maximal electroshock (MES) and
(Table 1). C=O stretching bands of phthalimide moiety pentylenetetrazole (ScPTZ), are used for primary evalua-
were observed between 1700–1776 cm– 1 as a doublet tion for anticonvulsant activity and the rotarod test is for
arising from the vibrational interaction [21]. N-H and SO2 primary toxicity screening. The MES test is a model for
stretching bands providing the confirmation of sulfona- generalized tonic-clonic seizures and represents those
mide group were detected between 3201–3326 and compounds, which prevent seizure spread [22]. Since tal-
1140–1399 cm– 1, respectively.
trimide and anticonvulsant anilides are more active in
1H-NMR data of title compounds were totally in agree- the MES test, the anticonvulsant activity of title com-
ment with the expected resonance signals in terms of pounds was evaluated against maximal electroshock seiz-
chemical shifts and integrations. Depending on the ures induced 0.5 or 4 h after administration of single
nature of the substituents and substitution patterns on dose level (100 mg/kg) in mice. The rotarod test was used
N-phenyl ring, the aromatic protons were observed in for determining possible neurotoxicity. The anticonvul-
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Arch. Pharm. Chem. Life Sci. 2007, 340, 656–660
Anticonvulsant N-phenyl-2-phtalimidoethanesulfonamides
659
Table 3. Anticonvulsant and neurotoxicity screening data of title
compounds at 100 mg/kg dose in mice.
In a recent study, the 2-phthalimido-N-phenylpropana-
mide nucleus has been reported to have anticonvulsant
activity against MES test without any neurotoxicity [23].
Exchanging the carbonyl group with sulfonyl in the 2-
phthalimido-N-phenylpropanamide nucleus leads to N-
phenyl-2-phtalimidoethanesulfonamide derivatives. The
results obtained in this study revealed that such non-clas-
sic isosteric replacement not only reduced the anticon-
vulsant activity but also increased the neurotoxicity.
Comp
MESa)
4 h
Toxicityb)
4 h
0.5 h
0.5 h
Control
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1/4
0/4
1/4
1/4
0/4
0/4
0/4
0/4
3/4
0/4
3/4
1/4
1/4
0/4
2/4
1/4
2/4
1/4
0/4
1/4
0/4
1/4
3/4
2/4
1/4
2/4
3/4
1/4
1/4
1/4
0/4
3/4
0/4
0/4
0/4
0/4
1/4
0/4
0/4
2/4
1/4
0/4
0/4
0/4
2/4
1/4
1/4
1/4
0/4
4/4c)
0/4
2/4
1/4
1/4
0/4
4/4c)
1/4
0/4
0/4
0/4
0/4
1/4
3/4
0/4
1/4
1/4
0/4
1/4
This study was supported by research grants from (Project
number: 2003/ECZ/005) and The Scientific and Technological
Research Council of Turkey (TUBITAK; Project number: SBAG-
HD-133).
The authors have declared no conflict of interest.
Taltrimide
Experimental
a)
Protected animals to tested animals.
Animals exhibited neurotoxicity to tested animals.
p a 0.05.
b)
c)
Chemistry
Melting points were determined on a Bꢀchi 510 melting point
apparatus (Bꢀchi Labortechnik, Flawil, Switzerland) and are
uncorrected. The IR spectra of compounds were recorded as a
potassium bromide pellets on a Jasco FT/IR-400 spectrometer
(Jasco, Tokyo, Japan). The NMR spectra were recorded on a Varian
AS 400 Mercury Plus NMR (Varian Inc., Palo Alto, CA, USA).
Chemical shifts were reported in parts per million (d). J values
were given in Hz. Mass spectra (APCI; atmospheric pressure
chemical ionization) were measured on an Agilent 1100 MSD
spectrometer (Agilent, Palo Alto, CA, USA). Elemental analyses
(C, H and N) were performed by TUBITAK Analytical Laboratory
Ankara, Turkey.
sant and neurotoxicity screening data are presented in
Table 3.
The replacement of N-isopropyl with N-phenyl ring in
taltrimide molecule (compound 1) abolished the anticon-
vulsant activity. Introducing small lipophilic substitu-
ents on the N-phenyl ring in compound 1 provided lim-
ited contribution to anticonvulsant activity depending
on the nature and the position of the substituents. The
activity screening data revealed that compounds 8 and
10 are more and compound 14 is equal active at 0.5 h in
comparison to taltrimide. Under the set of studied sub-
stituents on N-phenyl ring, chloro in ortho position and
nitro in meta position gave the best results at 0.5 h pro-
ducing more active compounds than taltrimide (com-
pounds 8 and 10). Their activity was diminished at 4 h.
On the other hand, positive contribution of methyl
group to anticonvulsant activity became apparent in
compounds 5 and 14 at 4 h. A similar situation was
observed with compound 9 having a nitro substituent on
para position at 4 h. Those compounds except compound
14 were inactive at 0.5 h. One methyl substitution in the
ortho position increased the neurotoxicity dramatically
leading to the most neurotoxic compound in the series
(compound 5), whereas dimethyl substitution did not fol-
low a similar pattern (compound 14). None of the com-
pounds synthesized presented equal activity to taltri-
mide at 4 h.
Synthesis of the potassium salt of 2-phthalimidoethane-
sulfonic acid
A suspension of 1.36 mol of taurine and 1.45 mol of anhydrous
potassium acetate in 475 mL of acetic acid was refluxed for ten
minutes, then, 1.45 mol of phthalic anhydride was added. The
reaction mixture was refluxed with stirring for additional two
and half hour. At the end of the reaction, a white precipitation
was formed. After cooling in an ice-bath with continued stirring,
the white product was filtered off, washed with acetic acid fol-
lowed by alcohol, and purified by crystallization from water.
Synthesis of 2-phthalimidoethanesulfonyl chloride
The potassium salt of 2-phthalimidoethanesulfonic acid
(0.015 mol) was suspended in 22 mL of benzene. The excess of
benzene (approximately 4 mL) was removed under vacuum.
Phosphorus pentachloride (0.0132 mol) of was added to the mix-
ture and refluxed by stirring for one hour. After adding another
0.0132 mol of phosphorus pentachloride, the reaction was con-
tinued to reflux for an additional one and a half hour. The reac-
tion mixture was evaporated to dryness. The residue was washed
with cold water. The crude product was crystallized from
dichloromethane : ethanol mixture (1 : 1).
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O. Akgul et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 656–660
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portions to 0.01 mol of the aniline dissolved in 0.1 mol of dry
pyridine by cooling in an ice bath. After treating the mixture in
an ice bath for half an hour and stirring the mixture at room
temperature for an additional half hour. The mixture was
poured into dilute hydrochloric acid solution. The precipitated
product, after washing with water, was crystallized from acetic
acid : water mixture (1 : 1).
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Pharmacology
Eskisehir Osmangazi University, School of Medicine, Animal Use
and Care Committee approved all the experiments for animal
testing. Male swiss albino mice weighing 30–40 g were used.
Laboratory temperature was maintained at 20 l 18C under con-
ditions of a 12-hours light-and-dark schedule. Before the experi-
ments, mice were allowed one week of adaptation. They were
used only once. The experiments were performed between 9 and
12 am in the morning.
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and injected intraperitoneally to the animals at 100 mg/kg
doses. Methylcellulose 0.1 mL was given intraperitoneally to the
control animals. The rotarod test was carried out to determine
minimal neurotoxicity before the experiments. Maximal electro-
shock seizures (MES) were induced 0.5 or 4 h after administra-
tion of the title compounds, by application of a 60 Hz current of
60 mA and 0.4 pulse width for 0.2 s via ear electrodes by using
Ugo Basile electroshock device (Ugo Basile, Italy). The anticonvul-
sive activity of the compounds was evaluated by defining as the
abolition of the hind-leg the tonic maximal extension compo-
nent of the seizure [24]. Fischer's exact v2 test was used for statis-
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