Design and Synthesis of Novel Phenylpiperazine Derivatives as Potential Anticonvulsant Agents

Article abstract of DOI:10.1002/ardp.201500272

Eighteen new 5-benzylidene-3-(4-arylpiperazin-1-ylmethyl)-2-thioxo-imidazolidin-4-ones were designed as hybrid structures from previously reported anticonvulsant compounds, synthesized and tested for anticonvulsant activity. Initial anticonvulsant screeni

Full text of DOI:10.1002/ardp.201500272

RCHH HARM
A P
Arch. Pharm. Chem. Life Sci. 2015, 348, 868–874
Archiv der Pharmazie
Full Paper
Design and Synthesis of Novel Phenylpiperazine Derivatives as
Potential Anticonvulsant Agents
Monica M. W. Habib1, Mohamed A. O. Abdelfattah1,2, and Ashraf H. Abadi1
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University
in Cairo, Cairo, Egypt
American University of The Middle East, Egaila, Kuwait
2
Eighteen new 5-benzylidene-3-(4-arylpiperazin-1-ylmethyl)-2-thioxo-imidazolidin-4-ones were
designed as hybrid structures from previously reported anticonvulsant compounds, synthesized and
tested for anticonvulsant activity. Initial anticonvulsant screening was performed using the strychnine
(2 mg/kg IP) potent generalized-induced seizure and pentylenetetrazole (PTZ) (60 mg/kg IP) acute
clonic-induced convulsion screens in mice. All the molecules were found to be effective in at least
one seizure model, compounds 10, 13, 15, 17, and 18 were active against both types of seizures
induced. Compound 13 turned out to be the most active candidate within the strychnine model,
having an average survival time of 6 min close to that of the positive control phenytoin, while
compound 8 showed 100% protection from the induced PTZ seizures, resembling the protection of
the positive control phenobarbital. Initial SAR studies for anticonvulsant activity are discussed.
Keywords: 2-Thiohydantoin / Anticonvulsant / Epilepsy / Phenylpiperazine
Received: August 4, 2015; Revised: September 22, 2015; Accepted: September 28, 2015
DOI 10.1002/ardp.201500272
The 2-thiohydantoins had marked an anticonvulsant activity
Introduction
which prompted the preparation of several series of
substituted-2-thiohydantoins for evaluation as anticonvul-
sants. They are thought to be of general interest as
anticonvulsants because structural requirements for optimal
anticonvulsant activity in the 2-thiohydantoin compounds
were found to differ greatly from those of the hydantoins,
where the 2-thiohydantoin compounds have greater protec-
tive effect against convulsions [5].
Epilepsy is a disease of complex nature and of different
etiology. It is a devastating neurological disorder that afflicts
approximately 50 million people worldwide [1]. For epilepsy
treatment, nearly 95% of clinically available drugs were
approved before 1985 and they could provide satisfactory
seizure control for 60–70% of patients [2]. In recent times,
several new drugs have emerged to treat epilepsy. Although
these drugs have shown to be effective in controlling the
seizures, their efficacy does not appear to be superior to that
of the established antiepileptic drugs as phenytoin [3].
However phenytoin II (Fig. 1) continues to create significant
side effects and toxicity due to its narrow therapeutic index,
high degree of serum protein binding, nonlinear elimination
pharmacokinetics, and considerable individual variations in
metabolism [4].
N-Phenylpiperazine compounds constitute a very large
chemical class and some of these compounds have the ability
to cross the blood–brain barrier due to the small size and the
lipophilic nature of their molecules. Thus, some N-phenyl-
piperazine derivatives promote activity upon the central
nervous system and are used in the treatment of various
mental disorders, including anxiety disorders [6], Alzheimer’s
disease [7], psychosis [8], and depression [9]. Besides, a lot of
compounds with N-phenylpiperazine moiety were tested for
their anticonvulsant properties, where most of them were
reported to display protection against different types of
induced seizures [10].
Correspondence: Prof. Ashraf H. Abadi, Department of Pharma-
ceutical Chemistry, Faculty of Pharmacy and Biotechnology,
German University in Cairo, Cairo 11835, Egypt.
E-mail: ashraf.abadi@guc.edu.eg
Based on the literature review, the phenylpiperazine
derivative N-[(4-arylpiperazin-1-yl)-methyl]-3-arylpyrrolidine-
2,5-dione I and the 2-thiohydantoin derivative 3-(alkyl/aryl)-
5,5-diphenyl-2-thioxoimidazolidine-4-one III (Fig. 1) were
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Arch. Pharm. Chem. Life Sci. 2015, 348, 868–874
Phenylpiperazine Derivatives as Potential Anticonvulsant Agents
Archiv der Pharmazie
Infrared spectra showed weak broad band at 3156–3375 cmꢀ1
,
corresponding to (–NH) stretching and sharp bands at 1708–
1739 cmꢀ1, corresponding to (–C O) stretching.
–
–
Mass spectra confirmed the molecular weight of the
synthesized compounds. The molecular ion peaks confirmed
the molecular weight of the synthesized compounds. The
isotopic pattern was used to confirm the presence of chloro-
and bromo-substituent.
Compounds having chlorine or bromine showed two ion
peaks (Mþ and Mþþ2) with peak heights ratio of 3:1 and 1:1 in
case of chlorine and bromine containing compounds,
respectively.
In the 1H NMR spectra, two significant singlet peaks were
common in all the spectra of the synthesized compounds. The
first one corresponds to the proton of the benzylidene moiety
in the range from 6.63 to 7.08 ppm, which confirmed the
success of the Knoevenagel condensation. The second
corresponds to the two protons of the methylene carbon
linking the phenylpiperazine and the thiohydantoin units in
the range from 4.95 to 5.45 ppm, which confirmed success of
Mannich addition. The presence of two multiplets of four
protons each in the range from 2.7 to 4.0 ppm confirmed the
presence of the piperazine ring.
Figure 1. Anticonvulsant candidates for the new hybrid
synthesized scaffold.
found to show significant anticonvulsant activity [5a, 10a, 11].
In this study, we report the synthesis and the pharmacological
evaluation of novel anticonvulsant analogs through structure
modification rather than a mechanism-driven design because
of the complex nature of epilepsy, gathering the important
features in these candidates to satisfy the criteria required for
the anticonvulsant activity [10b] having two different
nitrogen heteroatomic systems (a 2-thiohydantoin and a
piperazine ring), two phenyl rings (one at the 5-arylidene
thiohydantoin intermediate and the other at the N-phenyl-
piperazine) and the carbonyl group found at the 2-thiohy-
Anticonvulsant activity
The brain uptake of drugs is generally related to the drug
lipophilicity, which can be expressed as the log P [12]; the log
P-values of all the synthesized compounds were calculated
(Table 1) and were found to be greater than 2.
A potent generalized seizure model can be produced by IP
injection of strychnine, interacting with GABA-benzodiaze-
dantoin
giving
a
5-benzylidene-3-(4-aryl-piperazin-1-
ylmethyl)-2-thioxo-imidazolidin-4-one scaffold IV (Fig. 1).
The newly synthesized compounds were tested for anticon-
vulsant activity against chemically induced convulsion using
strychnine and PTZ as positive controls.
pine receptors [13], and serving as a noncompetitive
inhibitor on the glycine receptors [14]; phenytoin was used
as a positive control inhibiting the voltage-dependent Naþ
channels [12].
Tendency of increased survival time compared to the
strychnine-treated group was observed; besides, compounds
4, 10, 11, 13, 15, 16, 17, and 18 showed to be statistically
significant on comparing them to that of the positive control
phenytoin considering the standard deviation of the survival
time (Table 1); the presence of p-chloro substituent on the
benzylidene moiety (compounds 9–16) has increased the
activity of the majority of the compounds on being compared
to their congeners without p-chloro substituent (compounds
1–8), and this is obvious when comparing compounds 10, 11,
13, 15, and 16 to compounds 2, 3, 5, 7, and 8, respectively.
Studying the presence of bulkier more lipophilic halogen like
bromine in the same position of p-chloro substituent on the
benzylidene moiety (compound 17) has indeed shown 2.5-
fold elongation in the average survival time following
strychnine injection when compared to its previously synthe-
sized analogs, compounds 1 and 9. Studying the effect of the
presence of two oxygenated substituents on the developed
scaffold, compound 18 having p-OMe and 2-OH substituent
on the benzylidene and phenylpierazine units, respectively,
Results and discussion
Chemistry
The general synthesis of 5-benzylidene-3-(4-aryl-piperazin-1-
ylmethyl)-2-thioxoimidazolidin-4-one derivatives is illustrated
in Scheme 1. The final products were obtained in two steps:
Knoevenagel condensation reaction between a benzalde-
hyde derivative and 2-thiohydantoin with piperidine as the
catalyst giving the intermediate 5-arylidene thiohydantoin
derivatives. Mannich bases are then synthesized from those
intermediates, when the latter were allowed to react with
formaldehyde and aryl piperazines in ethanol at room
temperature overnight, 5-benzylidene-3-(4-aryl-piperazin-1-
ylmethyl)-2-thiohydantoin derivatives 1–18 were obtained.
The structural elucidation of all synthesized compounds
was done via different spectroscopic analytical techniques,
such as FT-IR spectroscopy, electron impact mass spectrome-
try, 1H NMR spectroscopy, and elemental analysis.
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Arch. Pharm. Chem. Life Sci. 2015, 348, 868–874
M. M. W. Habib et al.
Archiv der Pharmazie
Scheme 1. General scheme for the new synthesized scaffold.
did not show better activity than compound 13 and kept an
average survival time following strychnine injection of 4 min.
On the other hand, PTZ is a central nervous system
stimulant. Acute clonic convulsions resulting from the sub-
maximal dose of PTZ (60 mg/kg IP) is analogous to petit mal
type convulsions (absence seizures) in man [15]. PTZ is a
GABAA receptor antagonist that reduces the chloride
conductance; PTZ-induced seizures could be blocked by
phenobarbital that was used as a positive control [16]. Most
of the compounds have shown a percentage protection
ranging from 33% up to 100% (Table 2), where the protected
mice showed no convulsions within an observation time of
30 min.
Presence of p-chloro substituent on the benzylidene moiety
(compounds 9–16) again has increased and enhanced the
activity when compared to their congeners with no p-chloro
substituent. This is obvious when comparing compounds 9, 10,
11 to compounds 1, 2, and 3. Compound 17 bearing a p-Br
substituent on the benzylidene moiety and a bare phenyl-
piperazine unit has shown 83% protection against the acute
clonic convulsions induced by the injected PTZ dose versus 33
and 50% protection shown by its analogs, compounds 1 and 9,
respectively.
Compound 18 bearing two oxygenated substituents on its
scaffold showed similar percentage protection of 83% to its
analog compound 13.
Conclusion
Eighteen novel compounds were synthesized as novel
anticonvulsant analogs of a hybrid structure from previously
reported anticonvulsant compounds. The synthesized com-
pounds have Log P-values greater than 2, indicating the
relative lipophilicity of these candidates which may affect
their brain uptake. The compounds proved to be potential
anticonvulsant agents through the two in vivo screening tests,
strychnine and PTZ-induced convulsions.
For the strychnine-induced potent generalized seizures
model, all the compounds have shown tendency of increased
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Arch. Pharm. Chem. Life Sci. 2015, 348, 868–874
Phenylpiperazine Derivatives as Potential Anticonvulsant Agents
Archiv der Pharmazie
Table 1. Anticonvulsant activity of the tested compounds
at a dose of 100 mg/kg prior to using strychnine 2 mg/kg,
and their log P-values.
compounds showed percentage protection from convulsions
that ranged from 33 to 100%, where compound 8 showed
100% protection from the induced seizures. Based on the
structural features of the highly active candidates in both
models, we can conclude that the presence of a bulky halogen
in the size of bromine or chlorine on the para position of the
benzylidene moiety located on position 5 of the thiohydan-
toin core and ortho-oxygenated substituent on the phenyl-
piperazines unit linked to position 3 via methylene carbon
would ensure optimum activity of the candidates bearing this
novel chemical scaffold.
Survival time
(min ꢁ SD)
Compound
Log P
Strychnine
Phenytoin
1
2
3
4
5
6
0.63
2.14
3.58
4.13
3.73
3.73
2.84
2.84
3.45
3.79
4.13
4.69
4.29
4.29
3.74
3.74
4.01
4.35
4.4
2.53 ꢁ 0.9
6.83 ꢁ 0.98
1.63 ꢁ 1.11
3.02 ꢁ 1.86
2.58 ꢁ0.73
3.84 ꢁ 3.29
2.97 ꢁ 1.56
2.82 ꢁ 0.74
3.24 ꢁ 1.34
2.13 ꢁ 0.95
1.57 ꢁ 0.55
4.66 ꢁ 2.94
4.29 ꢁ 2.89
2.63 ꢁ 1.36
6.06 ꢁ 3.02
2.48 ꢁ 0.74
3.88 ꢁ 1.83
4.32 ꢁ 1.56
4.22 ꢁ 3.28
4.13 ꢁ 3.84
Experimental
7
8
9
Chemistry
10
11
12
13
14
15
16
17
18
All starting materials were obtained from Sigma–Aldrich and
all organic solvents used were obtained from El-Gomhuoria
Company and were of pure analytical grade used without
further purification. Melting points (°C) were determined by
open capillary tube method using Buchi B-540 mp apparatus
and were uncorrected. Elemental microanalyses were per-
formed at the Micro-Analytical Center, Faculty of Science,
Cairo University, values were within ꢁ0.4% of the theoretical
ones unless otherwise indicated. The IR spectra were recorded
on Alpha FT-IR spectrophotometer. The 1H NMR spectra, in
CDCl3 or DMSO-d6 as a solvent, were recorded on Varian
Mercury spectrophotometer at 300 MHz. Chemical shifts are
reported as d (ppm) relative to tetramethylsilane (TMS) as
internal standard. Mass spectra were performed by gas
chromatography method on Shimadzu Qp-2010 Plus, by
electron ionization mode at potential of 70 eV. The progress
of the reaction was monitored by TLC using fluorescent
precoated silica gel plates and detection of the components
was made by short ultraviolet light at l ¼ 254 nm and
methylene chloride/methanol (95:5) as the eluting system.
3.06
survival time compared to the strychnine-treated group with
a statistical significance for most of the compounds on
comparing them to the phenytoin-treated group, where
compound 13 showed to be the most active candidate with an
average survival time of 6 min. While for the PTZ-induced
acute clonic convulsions model, most of the synthesized
Table 2. Anticonvulsant activity of the tested compounds
at a dose of 100 mg/kg prior using PTZ.
Compound
Protection (%)
General procedure for the synthesis of 5-benzylidene-3-(4-
aryl-piperazin-1-ylmethyl)-2-thioxo-imidazolidin-4-one
derivatives 1–18
Phenobarbital
1
2
3
4
5
6
7
100
33
0
An equimolar reaction between thiohydantoin, an aromatic
aldehyde and piperidine (five drops) in water (30 mL) were
stirred and refluxed at 70°C for 8–9 h. The precipitated
product was filtered, dried, and subjected to column
chromatography on silica gel for further purification, using
a mixture of methylene chloride/methanol (95:5) as the
eluent. Every intermediate together with formaldehyde
(1 mL, 35% solution) and an N-arylpiperazine in absolute
ethanol (30 mL) were left over night stirring at room
temperature. The resulting residual solid was crystallized
from aqueous ethanol to give the expected structure.
0
33
83
66
66
100
50
83
50
33
83
83
83
50
83
83
8
9
10
11
12
13
14
15
16
17
18
5-Benzylidene-3-(4-phenylpiperazin-1-ylmethyl)-2-
thioxoimidazolidin-4-one (1)
Yellow solid. Yield: 76%; mp 191–193°C; TLC: Rf ¼ 0.68; IR:
3246 (NH), 2826, 2942 (CH ), 1731 (C O). 1H NMR (300 Hz,
–
–
2
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Arch. Pharm. Chem. Life Sci. 2015, 348, 868–874
M. M. W. Habib et al.
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CDCl3) d: 2.94–2.96 (m, 4H, piperazine), 3.17–3.18 (m, 4H,
piperazine), 4.97 (s, 2H, CH2), 6.75 (s, 1H, CH), 6.76–7.48 (m,
10H, aromatic), 8.72 (s, brs, 1H, NH). EI-MS: m/z (%) 377.90,
Mþ, (0.56). Anal. calcd. for C21H22N4OS (378.49): C: 66.64, H:
5.86, N: 14.80; Found: C: 66.86, H: 5.15, N: 14.53.
5-Benzylidene-3-[4-(2-methoxyphenyl)-piperazin-1-
ylmethyl]-2-thioxoimidazolidin-4-one (7)
Brown solid. Yield: 90%; mp 135–137°C; TLC: Rf ¼ 0.33; IR:
3332 (NH), 2827, 2921 (CH ), 1724 (C O). 1H NMR (300 Hz,
–
–
2
CDCl3) d: 3.42–3.43 (m, 4H, piperazine), 3.85–3.87 (m, 4H,
piperazine), 3.88 (s, 3H, OCH3), 5.44 (s, 2H, CH2), 6.70 (s, 1H,
CH), 6.80–7.48 (m, 9H, aromatic), 9.83 (s, brs, 1H, NH). EI-MS:
m/z (%) 407.90, Mþ, (15.55). Anal. calcd. for C22H24N4O2S
(408.52): C: 64.68, H: 5.92, N: 13.71; Found: C: 64.21, H: 5.52, N:
13.96.
5-Benzylidene-3-[4-(2-chlorophenyl)-piperazin-1-
ylmethyl]-2-thioxoimidazolidin-4-one (2)
Brown solid. Yield: 79%; mp 218–220°C; TLC: Rf ¼ 0.31; IR:
3334 (NH), 2813, 2930 (CH ), 1720 (C O). 1H NMR (300 Hz,
–
–
2
CDCl3) d: 3.39–3.41 (m, 4H, piperazine), 3.44–3.46 (m, 4H,
piperazine), 5.44 (s, 2H, CH2), 6.71 (s, 1H, CH), 6.81–7.48 (m, 9H,
aromatic), 9.88 (s, brs, 1H, NH). EI-MS: m/z (%) 412.00, Mþ,
(28.57) and 414.00, Mþþ2, (22.71). Anal. calcd. for
5-Benzylidene-3-[4-(2-ethoxyphenyl)-piperazin-1-
ylmethyl]-2-thioxoimidazolidin-4-one (8)
Brown solid. Yield: 71%; mp 179–181°C; TLC: Rf ¼ 0.36; 1H
NMR (300 Hz, CDCl3) d: 1.44–1.46 (t, 3H, OCH2CH3), 3.42–3.44
(m, 4H, piperazine), 3.59–3.61 (m, 4H, piperazine), 4.07–4.09
(q, 2H, OCH2CH3), 5.43 (s, 2H, CH2), 6.77 (s, 1H, CH), 6.81–7.49
(m, 9H, aromatic), 8.77 (s, brs, 1H, NH). EI-MS: m/z (%) 421.00,
Mþ, (44.29). Anal. calcd. for C23H26N4O2S (422.54): C: 65.38, H:
6.20, N: 13.26; Found: C: 65.72, H: 6.63, N: 13.23.
C
21H21ClN4OS (412.94): C: 61.08, H: 5.13, N: 13.57; Found: C:
61.25, H: 5.15, N: 13.53.
5-Benzylidene-3-[4-(2-fluorophenyl)-piperazin-1-
ylmethyl]-2-thioxoimidazolidin-4-one (3)
Orange solid. Yield: 83%; mp 188–190°C; TLC: Rf ¼ 0.33; IR:
3375 (NH), 2823, 2951 (CH ), 1710 (C O). 1H NMR (300 Hz,
–
–
2
CDCl3) d: 2.98–2.99 (m, 4H, piperazine), 3.08–3.09 (m, 4H,
piperazine), 4.98 (s, 2H, CH2), 6.76 (s, 1H, CH), 6.92–7.52 (m, 9H,
aromatic). EI-MS: m/z (%) 395.80, Mþ, (21.80). Anal. calcd. for
5-(4-Chlorobenzylidene)-3-(4-phenylpiperazin-1-
ylmethyl)-2-thioxo-imidazolidin-4-one (9)
Bright yellow solid. Yield: 69%; mp 184–186°C; TLC: Rf ¼ 0.50;
1
–
C
21H21FN4OS (396.48): C: 63.62, H: 5.34, N: 14.13; Found: C:
IR: 3223 (NH), 2824, 2946 (CH ), 1710 (C O). H NMR (300 Hz,
–
2
63.89, H: 5.53, N: 14.47.
CDCl3) d: 3.17–3.20 (m, 4H, piperazine), 3.92–3.96 (m, 4H,
piperazine), 4.97 (s, 2H, CH2), 6.71 (s, 1H, CH), 6.84–7.47 (m, 9H,
aromatic). EI-MS: m/z (%) 412.10, Mþ, (1.70). Anal. calcd. for
5-Benzylidene-3-[4-(4-fluorophenyl)-piperazin-1-
ylmethyl]-2-thioxoimidazolidin-4-one (4)
C
21H21ClN4OS (412.94): C: 61.08, H: 5.13, N: 13.57; Found: C:
Yellow solid. Yield: 95%; mp 205–207°C; TLC: Rf ¼ 0.62; IR:
61.35, H: 5.42, N: 13.39.
3226 (NH), 2818, 2951 (CH ), 1708 (C O). 1H NMR (300 Hz,
–
–
2
CDCl3) d: 2.93–2.96 (m, 4H, piperazine), 3.08–3.11 (m, 4H,
piperazine), 4.97 (s, 2H, CH2), 6.75 (s, 1H, CH), 6.83–7.51 (m, 9H,
aromatic), 8.73 (s, brs, 1H, NH). EI-MS: m/z (%) 395.90, Mþ,
(0.42). Anal. calcd. for C21H21FN4OS (396.48): C: 63.62, H: 5.34,
N: 14.13; Found: C: 63.24, H: 5.59, N: 14.44.
5-(4-Chlorobenzylidene-3-[4-(2-chlorophenyl)-piperazin-
1-ylmethyl]-2-thioxoimidazolidin-4-one (10)
Brown solid. Yield: 64%; mp 146–148°C; TLC: Rf ¼ 0.34; IR:
3267 (NH), 2811, 2930 (CH ), 1727 (C O). 1H NMR (300 Hz,
–
–
2
CDCl3) d: 3.15–3.17 (m, 4H, piperazine), 3.21–3.23 (m, 4H,
piperazine), 6.47 (s, 2H, CH2), 7.08 (s, 1H, CH), 7.12–7.77 (m, 8H,
aromatic). EI-MS: m/z (%) 447.00, Mþ, (67.62) and 449.00,
Mþþ2, (49.52). Anal. calcd. for C21H20Cl2N4OS (447.38): C:
56.38, H: 4.51, N: 12.52; Found: C: 56.71, H: 4.61, N: 12.05.
5-Benzylidene-3-[4-(2-hydroxyphenyl)-piperazin-1-
ylmethyl]-2-thioxoimidazolidin-4-one (5)
Red solid. Yield: 75%; mp 112–114°C; TLC: Rf ¼ 0.48; IR: 3343
1
–
(NH), 2825, 2945 (CH ), 1739 (C O). H NMR (300 Hz, CDCl ) d:
–
2
3
2.75–2.96 (m, 4H, piperazine), 3.72–3.76 (m, 4H, piperazine),
5.45 (s, 2H, CH2), 6.74 (s, 1H, CH), 6.88–7.47 (m, 9H, aromatic).
EIMS: m/z (%) 394.00, Mþ, (64.04). Anal. calcd. for
5-(4-Chlorobenzylidene)-3-[4-(2-fluorophenyl)-piperazin-
1-ylmethyl]-2-thioxoimidazolidin-4-one (11)
Yellowish brown solid. Yield: 66%; mp 193–195°C; TLC:
–
C
21H22N4O2S (394.49): C: 63.94, H: 5.62, N: 14.20; Found: C:
R ¼ 0.45; IR: 3373 (NH), 2818, 2948 (CH ), 1707 (C O). 1H
–
f
2
63.90, H: 5.79, N: 14.52.
NMR (300 Hz, DMSO) d: 2.79–2.81 (m, 4H, piperazine), 2.97–
2.99 (m, 4H, piperazine), 4.79 (s, 2H, CH2), 6.63 (s, 1H, CH),
6.96–7.82 (m, 8H, aromatic). EI-MS: m/z (%) 430.00, Mþ,
(30.57) and 432.00, Mþþ2, (19.62). Anal. calcd. for
5-Benzylidene-3-[4-(4-hydroxyphenyl)-piperazin-1-
ylmethyl]-2-thioxoimidazolidin-4-one (6)
Red solid. Yield: 68%; mp 180–182°C; TLC: Rf ¼ 0.40; IR: 3342
C21H20ClFN4OS (430.93): C: 58.53, H: 4.68, N: 13.00; Found:
1
–
(NH), 2819, 2944 (CH ), 1726 (C O). H NMR (300 Hz, CDCl ) d:
C: 58.83, H: 4.85, N: 12.78.
–
2
3
2.72–2.95 (m, 4H, piperazine), 3.72–3.77 (m, 4H, piperazine),
5.44 (s, 2H, CH2), 6.64 (s, 1H, CH), 6.78–7.46 (m, 9H, aromatic).
EIMS: m/z (%) 394.90, Mþ, (66.67). Anal. calcd. for
5-(4-Chlorobenzylidene)-3-[4-(4-fluorophenyl)-piperazin-
1-ylmethyl]-2-thioxoimidazolidin-4-one (12)
C
21H22N4O2S (394.49): C: 63.94, H: 5.62, N: 14.20; Found: C:
Yellow solid. Yield: 76%; mp 195–197°C; TLC: Rf ¼ 0.43; IR:
3349 (NH), 2827, 2955 (CH ), 1713 (C O). 1H NMR (300 Hz,
–
–
63.64, H: 5.32, N: 14.41.
2
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Phenylpiperazine Derivatives as Potential Anticonvulsant Agents
Archiv der Pharmazie
CDCl3) d: 2.92–2.95 (m, 4H, piperazine), 3.07–3.11 (m, 4H,
piperazine), 4.96 (s, 2H, CH2), 6.675 (s, 1H, CH), 6.83–7.46
(m, 8H, aromatic). EI-MS: m/z (%) 429.90, Mþ, (73.58) and
431.9, Mþþ2, (66.04). Anal. calcd. for C21H20ClFN4OS
(430.93): C: 58.53, H: 4.68, N: 13.00; Found: C: 58.25, H:
4.58, N: 12.63.
(46.85) and 458.00, Mþþ2, (56.76). Anal. calcd. for
C
21H21BrN4OS (457.39): C: 55.14, H: 4.63, N: 12.25; Found:
C: 55.55, H: 4.23, N: 11.85.
3-[4-(2-Hydroxyphenyl)-piperazin-1-ylmethyl]-5-(4-
methoxybenzylidene)-2-thioxoimidazolidin-4-one (18)
1
Red solid. Yield: 67%; mp 129–131°C; TLC: Rf ¼ 0.26; H NMR
5-(4-Chlorobenzylidene)-3-[4-(2-hydroxyphenyl)-
piperazin-1-ylmethyl]-2-thioxoimidazolidin-4-one (13)
(300 Hz, CDCl3) d: 22.95–2.97 (m, 4H, piperazine), 3.39–3.41 (m,
4H, piperazine), 3.88 (s, 3H, OCH3), 5.43 (s, 2H, CH2), 6.68 (s, 1H,
CH), 6.77–7.40 (m, 8H, aromatic). EI-MS: m/z (%) 424.00, Mþ,
(0.5). Anal. calcd. for C22H24N4O3S (424.52): C: 62.24, H: 5.70, N:
13.20; Found: C: 62.67, H: 5.5, N: 12.95.
Dark yellow solid. Yield: 51%; mp 179–181°C; TLC: Rf ¼ 0.45;
1
–
IR: 3375 (NH), 2816, 2934 (CH ), 1736 (C O). H NMR (300 Hz,
–
2
CDCl3) d: 2.79–3.14 (m, 4H, piperazine), 3.72–3.76 (m, 4H,
piperazine), 5.44 (s, 2H, CH2), 6.65 (s, 1H, CH), 6.72–7.54 (m, 8H,
aromatic). EI-MS: m/z (%) 429.00, Mþ, (37.84) and 431.00,
Mþþ2, (31.35). Anal. calcd. for C21H21ClN4O2S (428.94): C:
58.80, H: 4.93, N: 13.06; Found: C: 58.83, H: 5.05, N: 13.39.
Determination of partition coefficient
(log P)
The Log P-values of the synthesized compounds were
calculated by ChemDraw Ultra 7.0.1 software.
5-(4-Chlorobenzylidene)-3-[4-(4-hydroxyphenyl)-
piperazin-1-ylmethyl]-2-thioxoimidazolidin-4-one (14)
Anticonvulsant screening
The 18 synthesized compounds 1–18 were evaluated for
anticonvulsant activity against PTZ and strychnine-induced
seizures in mice.
Red solid. Yield: 82%; mp 140–142°C; TLC: Rf ¼ 0.50; IR: 3178
1
–
(NH), 2820, 2947 (CH ), 1726 (C O). H NMR (300 Hz, CDCl ) d:
–
2
3
2.71–3.04 (m, 4H, piperazine), 3.72–3.75 (m, 4H, piperazine),
5.44 (s, 2H, CH2), 6.64 (s, 1H, CH), 6.67–7.46 (m, 8H, aromatic).
EIMS: m/z (%) 429.00, Mþ, (20.00) and 431.00, Mþþ2, (18.97).
Anal. calcd. for C21H21ClN4O2S (428.94): C: 58.80, H: 4.93, N:
13.06; Found: C: 58.46, H: 4.63, N: 12.79.
Strychnine seizure pattern test
Male albino mice weighing 18–25 g were housed in groups
of six. The animals were acclimated to their environment for
at least 2 days before the experiments and were allowed
free access to food and water before being tested. The mice
were divided into negative control group, strychnine group,
positive control group, and 18 test groups; each group
consisted of six animals. The negative control group
received 2% Tween 80 in water at a dose of 10 mL/kg IP,
which is used as the vehicle for suspending all the tested
drugs and compounds. The strychnine group received
strychnine at a dose of 2 mg/kg IP. The positive control
group received phenytoin at the dose of 100 mg/kg IP,
45 min before IP injection of strychnine (2 mg/kg IP). The test
groups received the test compounds at the dose of 100 mg/
kg IP, 45 min before IP injection of strychnine (2 mg/kg). The
mice were observed and the average survival time was
recorded [12, 17].
5-(4-Chlorobenzylidene)-3-[4-(2-methoxyphenyl)-
piperazin-1-ylmethyl]-2-thioxoimidazolidin-4-one (15)
Dark brown semisolid. Yield: 64%; TLC: Rf ¼ 0.47; 1H NMR
(300 Hz, CDCl3) d: 3.41–3.43 (m, 4H, piperazine), 3.61–3.63 (m,
4H, piperazine), 3.88 (s, 3H, OCH3), 5.43 (s, 2H, CH2), 6.71 (s, 1H,
CH), 6.88–7.44 (m, 8H, aromatic), 9.80 (s, brs, 1H, NH). EI-MS:
m/z (%) 442.00, Mþ, (60.00) and 444.00, Mþþ2, (56.84). Anal.
calcd. for C22H23ClN4O2S (442.96): C: 59.65, H: 5.23, N: 12.65;
Found: C: 59.73, H: 4.92, N: 12.49.
5-(4-Chlorobenzylidene)-3-[4-(2-ethoxyphenyl)-piperazin-
1-ylmethyl]-2-thioxoimidazolidin-4-one (16)
Dark brown semisolid. Yield: 61%; TLC: Rf ¼ 0.42; 1H NMR
(300 Hz, CDCl3) d: 1.43–147 (t, 3H, OCH2CH3), 3.34–3.36 (m, 4H,
piperazine), 3.35–3.52 (m, 4H, piperazine), 4.04–4.08 (q, 2H,
OCH2CH3), 5.43 (s, 2H, CH2), 6.86 (s, 1H, CH), 6.89–7.44 (m, 8H,
aromatic), 9.80 (s, brs, 1H, NH). EI-MS: m/z (%) 456.00, Mþ,
(70.48) and 458.00, Mþþ2, (11.43). Anal. calcd. for
PTZ seizure pattern test
Male albino mice, weighing 18–25 g were divided into
positive control group and 18 test groups (n ¼ 6 per group).
The positive control group received phenobarbital at the dose
of 30 mg/kg IP 1 h before the administration of PTZ at the dose
of 60 mg/kg IP. The test groups received the testing
compounds at the dose of 100 mg/kg IP before the PTZ
administration. Animals devoid of clonic convulsions were
considered to be protected and results were represented as
percentage protection [12, 18].
C
23H25ClN4O2S (456.99): C: 60.45, H: 5.51, N: 12.26; Found:
C: 60.32, H: 5.44, N: 12.10.
5-(4-Bromobenzylidene)-3-(4-phenylpiperazin-1-
ylmethyl)-2-thioxoimidazolidin-4-one (17)
Bright yellow solid. Yield: 56%; mp 218–220°C; TLC:
R ¼ 0.46; IR: 3226 (NH), 2823, 2948 (CH ), 1707 (C O). 1H
–
–
f
2
NMR (300 Hz, DMSO) d: 2.76–2.78 (m, 4H, piperazine), 3.07–
3.09 (m, 4H, piperazine), 4.78 (s, 2H, CH2), 6.60 (s, 1H, CH),
6.90–7.66 (m, 9H, aromatic). EI-MS: m/z (%) 456.00, Mþ,
The authors have declared no conflicts of interest.
ß 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2015, 348, 868–874
M. M. W. Habib et al.
Archiv der Pharmazie
[9] G. I. Papakostas, M. Fava, Eur. Psychiat 2007, 22,
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