Synthesis of Novel Triazolyl/Oxadiazolyl/Thiadiazolyl-Piperazine as Potential Anticonvulsant Agents

Article abstract of DOI:10.1055/a-1291-7554

Reaction of piperazine with chloroacetylchloride in dry acetone yield compound 1, which on reaction with hydrazine hydrate yielded compound 2, which was further reacted with various substituted phenylisothiocyanates in absolute alcohol to afford compounds

Full text of DOI:10.1055/a-1291-7554

Published online: 2021-01-12
Thieme
Original Article
Synthesis of Novel Triazolyl/Oxadiazolyl/Thiadiazolyl-Piperazine as
Potential Anticonvulsant Agents
Author
Archana
AbstrAct
Affiliation
Medicinal Chemistry Laboratory, Department of Chemistry,
Meerut College, Meerut, Uttar Pradesh, India
Reaction of piperazine with chloroacetylchloride in dry acetone
yield compound 1 , which on reaction with hydrazine hydrate
yielded compound 2, which was further reacted with various sub-
stituted phenylisothiocyanates in absolute alcohol to afford com-
pounds 3–8 i.e. 2-(carbazolylacetyl)-N-(substitutedphenyl)-hy-
drazinepiperazinothioamides. Compounds 3–8 on reaction
with aqueous NaOH, ethanolic NaOH and conc. H2SO4 afford
triazoles 9–14, oxadiazoles 15–20 and thiadiazoles 21–26 re-
spectively. Twenty four newly synthesized compounds were
evaluated for their anticonvulsant activity and acute toxicity.
The structures of these compounds were established on the
basis of analytical and spectral data.
Key words
antiepileptic drugs, drug research, pharmacology
received
accepted
27.06.2020
12.10.2020
published online 12.01.2021
Bibliography
Drug Res 2021; 71: 199–203
DOI 10.1055/a-1291-7554
ISSN 2194-9379
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG, Rüdigerstraße 14,
70469 Stuttgart, Germany
Correspondence
Dr. Archana
Medicinal Chemistry Laboratory, Department of Chemistry,
Meerut College
Meerut 250001
Uttar Pradesh
India
Tel.: 9412208444, Fax: 9458406049
archanachemistrymcm@gmail.com
Introduction
Moreover, various versatile pharmacophores such as triazoles [11–14],
oxadiazoles [15–19] and thiadiazoles [20–22] possess anticonvulsant
activity. Several scientists have also elucidated that the modifica-
tions at 1st or 4th position in piperazine nucleus by different heter-
ocyclic moieties yielded potent anticonvulsant agents. This fact is
utilized in the present work and various new compounds have been
synthesized by in- corporating triazoles, oxadiazoles and thiadia-
zoles at 1st position of piperazine with the aim to synthesize more
potent and safer anticonvulsant agents.
Epilepsy is a disorder of brain, in which nerve cells actually in the
brain is disturbed, causing seizures. Different groups of pharmaco-
logical agents used in the treatment of epileptic seizures are called
anticonvulsant agents. Currently available drugs are helpful in
approximately 60–70 % patients. Moreover, drugs used for the
treatment of epilepsy are associated with a number of adverse
reactions causing various side effects. Therefore, the need of the
day is to search new chemical entities for the treatment of epilepsy
with greater efficacy and fewer side effects.
Heterocyclic compounds forms the backbone for the discovery
of many bioactive compounds. Chemical literature survey reveals
that piperazine derivatives are biologically versatile compounds
which possess potent antifungal [1, 2], antimicrobial [3, 4], antihis-
tamine [5], antipsychotic [6, 7], anticonvulsant [8–10] properties.
Materials and Methods
All the melting points are taken in open capillary and are uncor-
rected. Analytical thin layer chromatography was performed on
silica gel-G plate (0.25 mm thickness ) and visualized under UV
Archana. Piperazine as Anticonvulsant Agent… Drug Res 2021; 71: 199–203 | © 2021. Thieme. All rights reserved.
199

Thieme
Original Article
was refluxed for 20–22 hours. After completion of the reaction, excess
of ethanol was distilled off till a small volume was left. On cooling, crys-
tals of 2-phenylpiperazinyl acetohydrazides (2) were formed. The crys-
tals so obtained were filtered and recrystallized from methanol. The
physical and analytical data of compound 2 is given in ▶table 1.
IR vmax (KBr, cm-1):3030 (aromatic C-H),2128 (C-N), 1690 (C=O ), 3370
(NH), 1616. 1H-NMR δ (CDCl3 and DMSO-d6): 3.70 (s, 2H, -NCH2),
6.55–7.56 (m, 5H, Ar-H), 8.30 (d, 2H, NH2), 8.40 (t, 1H, NH), 2.60 (m,
5H, 4x-CH2 of piperazine) (ppm). MS: m/z 234.
Synthesis of 2-(phenyl piperazinyl acetyl)-N-(2’-bromophenyl)-
hydrazinecarbothioamide (3) : A mixture of 2-phenylpiperazinyl
acetohydrazide (2) (0.3 mole) and 2-bromophenylisothiocyanate
(0.3 mole) in 30 ml of absolute ethanol was refluxed for 5–6 hours.
After completion of the reaction, the reaction mixture was concen-
trated and kept overnight at room temperature. The needle shaped
crystals thus obtained were purified by recrystallization with pe-
troleum ether to furnish compound 3. The physical and analytical
data of compound 3 is given in ▶table 1. IR vmax (KBr, cm-1): 3029
(aromatic C-H ), 2135 (-CN ),1693 (C=O), 3375 (NH), 1130 (C=S),
611 (C-Br). 1H-NMR δ (CDCl3 and DMSO-d6): 3.70 (s, 2H, -NCH2),
7.30–8.40 (m, 9H, Ar-H), 8.70 (d, 1H, CONH), 8.74 (d, 1H,
NHC = S),8.90 (s, 1H, NH-Ar), 2.62 (m, 5H, 4x-CH2 of piperazine)
(ppm). MS: m/z 448.
Other compounds (4–8) of this step were also prepared simi-
larly. Their physical and analytical data are given in ▶table 1.
Synthesis of 3-(phenyl piperazinyl methylene)-4-(2’-
bromophenyl)-1,2,4-triazol-5(4H)-thione (9) : A mixture of com-
pound 3 (0.04 mole) and 30 ml of 2% NaOH solution was refluxed
for 6 hours. After completion of the reaction, the reaction mixture
was filtered and the filtrate was neutralized with conc. HCl drop-
wise till pH was adjusted to 7. The mixture was kept aside for a few
minutes. The distinctive precipitate thus obtained was filtered,
washed with water and recrystallized from petroleum ether to give
compound 9. The physical and analytical data of compound 9 is
given in ▶table 1. IR vmax (KBr, cm-1): 3041 (aromatic C-H ), 2160
(-CN ), 3440 (NH), 1265 (C = S), 614 (C-Br). 1H-NMR δ (CDCl3 and
DMSO-d6): 4.16 (s, 2H, -NCH2), 6.83–7.95 (m, 9H, Ar-H), 10.64 (s,
1H, NH of triazole), 8.74 (d, 1H, NHC= S),8.90 (s, 1H, NH-Ar), 2.65
(m, 5H, 4x-CH2 of piperazine) (ppm). MS: m/z 431.
Other compounds (10–14) of this step were also prepared sim-
ilarly. Their physical and analytical data are given in ▶table 1.
Synthesis of 5-(phenyl piperazinyl methylene)-2-(2’-
bromophenyl)-oxadiazole (15) : A solution of compound 3 (0.04
mole) in 25 ml ethanol and sodium hydroxide solution (4 ml) was
cooled under continuous stirring for 30 minutes. To this mixture,
iodine in KI (5 %) was added drop-wise till the colour of iodine per-
sisted at room temperature. After that the mixture was refluxed for
2 hours. After completion of the reaction, the mixture was poured
onto crushed ice. The solid thus obtained was washed with sodium
thiosulphate solution and recrystallized from methanol to give
compound 15. The physical and analytical data of compound 15 is
given in ▶table 1. IR vmax (KBr, cm-1): 299 (aromatic C-H), 2180
(-CN ), 3460 (NH), 1009 (C-O-C), 613 (C-Br). 1H-NMR δ (CDCl3 and
DMSO-d6): 4.13 (s, 2H, -NCH2), 6.90–8.05 (m, 9H, Ar-H), 8.83 (s, 1H,
NH-Ar), 2.65 (m, 5H, 4x-CH2 of piperazine) (ppm). MS: m/z 415.
Other compounds (16–20) of this step were also prepared sim-
ilarly. Their physical and analytical data are given in ▶table 1.
▶Fig. 1 Synthetic route for the synthesis of compounds 1–26.
light, and/or by spraying with 5% solution of phosphomolybdic acid
(PMA) in ethanol, followed by charring with a heat gun. The IR spec-
tra were recorded on Beckman Acculab-10 spectrophotometer
(γmax in cm-1). 1H-NMR was recorded on Varian NMR 500 instru-
ment at 500 MHz. Chemical shifts were reported in parts per mil-
lion (ppm) relative to tetramethylsilane (TMS), which was used as
internal and external standards for 1H-NMR. Mass Shimadzu 2010s
mass spectrometer was used for recording mass spetra. Synthetic
route for the synthesis of compounds 1 to 26 is depicted in ▶Fig. 1.
Synthesis of N- ethyl phenylpiperazinylacetate (1) : Ethyl chloro
acetate (1.0 mole) was added to a solution of phenyl piperazine
(1.0 mole) in dry acetone (100ml) in presence of anhydrous K2CO3
(8 gm) with constant stirring. The mixture thus obtained was re-
fluxed on a water bath for about 13 hours. The solid mass thus ob-
tained was filtered, dried and recrystallized from ethanol to afford
compound 1. The physical and analytical data of compound 1 is
given in ▶table 1. IR vmax (KBr, cm-1):3040 (aromatic C-H), 2130
(C-N), 1680 (C=O ester). 1H-NMR δ (CDCl3 and DMSO-d6): 3.75 (s,
2H, -NCH2), 6.69–7.76 (m, 5H, Ar-H), 1.26 (t, 3H, COOCH2CH3), 4.20
(q, 2H, COOCH2CH3), 2.62 (m, 5H, 4x-CH2 of piperazine) (ppm). MS:
m/z 248 .
Synthesis of 2-phenylpiperazinyl acetohydrazide (2) : Compound
1 (0.4 mole) was added to hydrazine hydrate (15ml) taken in round
bottom flask. Sufficient quantity of dry ethanol was added to dilute
the contents till a clear solution was obtained. The reaction mixture
Archana. Piperazine as Anticonvulsant Agent… Drug Res 2021; 71: 199–203 | © 2021. Thieme. All rights reserved.
200

▶table 1 Physical and analytical data of compounds 1-26.
comp. No.
r
M.P. °c
recryst. solvent
Yield (%) Molecular Formula
calcd. (Found) %
c
H
N
1
2
−
128
145
180
185
178
177
178
176
170
200
202
205
203
210
215
222
218
214
210
218
225
226
224
228
222
214
Ethanol
80
84
76
78
77
76
79
74
72
74
72
70
73
66
73
67
70
75
72
71
62
68
65
64
62
67
C14H20N2O2
12H18N4O
67.74 (67.72)
61.53 (61.55)
50.89 (50.91)
76.66 (76.63)
60.15 (60.12)
60.15 (60.18)
70.98 (70.96)
70.98 (70.97)
52.90 (52.87)
58.99 (59.00)
62.82 (62.79)
62.82 (62.80)
66.31 (66.29)
66.31 (66.33)
54.93 (54.90)
61.53 (61.55)
65.57 (65.55)
65.57 (65.60)
69.23 (69.20)
69.23 (69.26)
52.90 (52.89)
58.99 (58.97)
62.82 (62.80)
62.82 (62.85)
66.31 (66.28)
66.31 (66.29)
8.06 (8.08)
7.69 (7.71)
4.91 (4.89)
5.45 (4.47)
6.26 (6.24)
6.26 (6.28)
7.60 (7.58)
7.60 (7.62)
4.87 (4.90)
5.43 (5.45)
6.28 (6.30)
6.28 (6.27)
6.84 (6.86)
6.84 (6.86)
5.06 (5.04)
5.66 (5.68)
6.55 (6.52)
6.55 (6.57)
7.14 (7.16)
7.14 (7.13)
4.87 (4.90)
5.43 (5.45)
6.28 (6.31)
6.28 (6.27)
6.84 (6.81)
6.84 (6.86)
11.29 (11.31)
23.93 (23.95)
15.62 (15.59)
17.34 (17.35)
17.54 (17.56)
17.54 (17.52)
7.88 (7.90)
−
Methanol
pet. ether
acetone
C
3
2-Br
C19H22N5OSBr
C19H22N5OSCl
C20H25N5O2S
C20H25N5O2S
C21H27N2OS
C21H27N2OS
C19H21N5SBr
C19H21N5SCl
C20H24N5OS
C20H24N5OS
C21H26N5S
4
4-Cl
5
2-OCH3
4-OCH3
2-C2H5
4-C2H5
2-Br
Ethanol
6
DMF-water
Ethanol
7
8
Ethanol
7.88 (7.91)
9
pet ether
Ethanol
16.24 (16.26)
18.11 (18.09)
18.32 (18.29)
18.32 (18.31)
18.42 (18.40)
18.42 (18.39)
16.86 (16.84)
18.89 (18.86)
19.12 (19.09)
19.12 (19.15)
19.23 (19.20)
19.23 (19.25)
16.24 (16.22)
18.11 (18.08)
18.32 (18.30)
18.32 (18.33)
18.42 (18.40)
18.42 (18.44)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4-Cl
2-OCH3
4-OCH3
2-C2H5
4-C2H5
2-Br
DMF-water
Methanol
DMF-water
acetone
C21H21N5S
methanol
acetone
C19H22N5OBr
C19H22N5OCl
C20H25N5O2
C20H25N5O2
C21H27N5O
4-Cl
2-OCH3
4-OCH3
2-C2H5
4-C2H5
2-Br
DMF-water
Ethanol
acetone
pet. ether
DMF-water
DMF-water
ethanol
C21H27N5O
C19H22N5SBr
C19H22N5SCl
C20H25N5OS
C20H25N5OS
C21H27N5S
4-Cl
2-OCH3
4-OCH3
2-C2H5
4-C2H5
DMF-water
methanol
ethanol
C21H27N5S
C, H, N were within ± 0.4 %.
Synthesisof5-(phenylpiperazinylmethylene)-2-(2’-bromophenyl)-
thiadiazole (21) : Concentrated sulphuric acid (15 ml) was placed
in a conical flask and compound 3 (0.04 mole ) was added in small
portions over a period of 2 hours with constant stirring while main-
taining the temperature at about 0–5 0C. When the reaction was
completed, the mixture was poured onto crushed ice. Precipitated
solid thus obtained was filtered, washed with water, dried at room
temperature and recrystallized from DMF-water to furnish com-
pound 21. The physical and analytical data of compound 21 is given
in ▶table 1. IR vmax (KBr, cm-1): 299 (aromatic C-H), 2180 (-CN ),
3460 (NH), 1009 (C-O-C), 613 (C-Br). 1H-NMR δ (CDCl3 and DM-
SO-d6): 4.13 (s, 2H, -NCH2), 6.90–8.05 (m, 9H, Ar-H), 8.83 (s, 1H,
NH-Ar), 2.65 (m, 5H, 4x-CH2 of piperazine) (ppm). MS: m/z 431.
Other compounds (22–26) of this step were also prepared sim-
ilarly. Their physical and analytical data are given in ▶table 1.
doses of test drugs and phenytoin sodium 30 mg/kg i.p. The rats
were subjected to a shock of 150 M.A. by convulsiometer after 1
hour of drug treatment through ear electrodes for 0.2 s. The pres-
ence or absence of extensor response was noted. Animals in which
extensor response was abolished were taken as protected rats. The
results are depicted in ▶table 2
Acute toxicity
Acute toxicity in mice was investigated in mice by following the
method of Smith [24] and the results are depicted in ▶table 2.
Results
Anticonvulsant activity in rats
In the maximal electroshock induced seizure test (MES), out of 24
compounds tested, compounds 9, 15, 21 and 23 exhibited most
potent activity with 80%, 80%, 80% and 90% inhibition of seizures
respectively. The results are depicted in ▶table 2.
Pharmacology
Anticonvulsant activity- supra maximal electroshock seizure pat-
tern test (SMES)
Method of Tomen et al. [23] was used for performing the anti-
convulsant activity. Rats of Charles Foster strain were used . Rats
of both the sex weighing between 90 to 120 grams were used. Ac-
tivity was performed by dividing the rats into groups. Each group
contains 10 animals (rats).The rats were treated with different
Acute toxicity in mice
All the compounds 3–26, were also evaluated for acute toxicity. All
compounds showed good value of greater than 1000 mg/kg i.p.
Archana. Piperazine as Anticonvulsant Agent… Drug Res 2021; 71: 199–203 | © 2021. Thieme. All rights reserved.
201

Thieme
Original Article
▶table 2 Pharmacological data of compounds (3-26).
4 position of phenyl ring showed moderate protection of 50 %
against seizures. Compounds 7 and 8 substituted with ethoxy
group at 2nd and 4th position of phenylgroup showed least protec-
tion of 40 %.
compound
Acute toxicity
Anticonvulsant activity
ALD50 (mg/kg
i.p.)
Dose (mg/kg
%inhibition
of seizures
i.p.)
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
7.5
15
30
30
30
30
30
2.0 ml
Further, the series was characterized by its trifurcation which
leads to the synthesis of triazoles (9–14), oxadiazole (15–20) and
thiadiazoles (21–26). Studying the anticonvulsant activity of tria-
zoles (9–14) it was noticed that compound 9 having substitution
with bromo group at 2nd position of phenyl ring showed good pro-
tection of 80 % against seizures which is equipotent to standard
drug phenytoin sodiyum (80%). Compounds 4 and 5 having chloro
and methoxy group at 4th and 2nd position of phenyl ring respec-
tively also showed good protection of 70%. At the same time 60%
inhibition of seizures was shown by compounds 12, 13 and 14 hav-
ing substitution with 4-methoxy, 2-ethoxy and 4-ethoxy groups on
phenyl ring.
Compounds (15–20) having different substituted oxadiazole
moiety on phenyl piperazine have shown varying degree (50–80%)
of anticonvulsant activity. However, the effect of different substi-
tutions was found to be similar with that of compounds (9–14).
Moreover, the compounds (21–26) having different substituted
thiadiazole moiety on phenyl piperazine ring showed good anti-
convulsant response ranging from 60 % to 90 %. Compound 23,
substituted with methoxy group at 2nd position of phenyl ring
showed maximum anticonvulsant response of 90 % and was found
more potent than standard drug-phenytoin sodium, which pro-
vides 80% inhibition of seizures. Considering the potentiality of this
compound, it was studied in detail at three graded dose of 7.5, 15
and 30mg/kg i.p. and showed protection of 40, 60 and 90% respec-
tively at these dose levels. Compound 21, (with bromo group at 2nd
position of phenyl ring ) also exhibit activity equipotent to stand-
ard drug i. e. 80 %. 70 % Inhibition of seizures was shown by com-
pounds 16 and 18 substituted with chloro group and methoxy
group respectively at 4th position of phenyl ring. Compounds 25
and 26 substituted with ethoxy group at 2nd and 4th position of phe-
nyl group were found to be least potent (60%) among thiadiazoles
synthesized.
3
4
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 2000
60**
50*
5
60**
50*
6
7
40*
8
40*
9
80***
70***
70***
60**
60**
60**
80***
70***
70***
60**
60**
60**
80***
80***
40*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
60**
90***
70***
60**
60**
80***
0
24
> 1000
> 1000
> 1000
25
26
Phenytoin sodium
Propylene glycol
* p < 0.05, ** p < 0.01, ***p < 0.001.
thereby suggesting a good safety margin. Compound 23, exhibit
exceptionally high value of ALD50 greater than 2000 mg/kg i.p.
Conclusion
From this study, we may conclude:
Pharmacology
1. Compounds with thiadiazole moiety (21–26) showed more potent
anticonvulsant activity in comparison to their corresponding tria-
zoles (9–14) an oxadiazoles (15–20).
2. Compounds having bromo group at 2nd position of phenyl
group was found to be beneficial for anticonvulsant activity.
3. Presence of methoxy group at 2nd position of phenyl group
enhanced anticonvulsant potential when present in thiadiazole,
which was not found to enhance activity when present in triazole
and oxadiazole.
The newly synthesized compounds i. e. compounds (3–8), (9–14),
(15–20) and (21–26) were studied for anticonvulsant activity at a
dose of 30 mg/kg i.p. These compounds were also evaluated for
approximate lethal dose (ALD50). The results of these activities are
depicted in ▶table 2.
Compounds (3–8) i.e 2-(phenyl piperazinyl acetyl)-N-(substi-
tutedphenyl)-hydrazinecarbothioamides showed varying degree
of protection ranging from 40 % to 60 % against seizures produced
by maximal electroshock. Results of anticonvulsant activity shows
that compound 3 and compound 5 substituted with bromo and
methoxy group respectively at 2nd position of phenyl ring showed
appreciable protection of 60% against convulsions. Compounds 4
and 6 substituted with chloro and methoxy groups respectively at
Conflict of Interest
There is no conflict of interest.
Archana. Piperazine as Anticonvulsant Agent… Drug Res 2021; 71: 199–203 | © 2021. Thieme. All rights reserved.
202

References
[13] Deng XQ, Song MX, Zheng Y et al. Design, synthesis and evaluation of
the antidepressant and anticonvulsant activities of triazole-containing
quinolinones. Eur J Med Chem 2014; 73: 217–224
[1] Suryanshi HR, Rathore MM. Synthesis and biological activities of
piperazine derivatives as antimicrobial and antifungal agents. Org
Commun 2017; 10: 228–238
[14] Kapron B, Czarnomysy R, Wysokiniski M et al. 1,2,4-Triazole-based
anticonvulsant agents with additional ROS scavenging activity are
effective in a model of pharmacoresistant epilepsy. J Enzyme Inhibition
and Med Chem 2020; 35: 993–1002
[2] Chandrika NT, Shrestha SK, Ngo HX et al. Alkylated piperazines and
piperazine-azole hybrids as antifungal agents. J Med Chem 2018; 61:
158–173
[15] Almmasirad A, Tabatabai SA, Faizi M et al. Synthesis and anticonvulsant
activity of new 2-substituted -5-[2-(2-fluorophenoxyphenyl)
phenyl]-1,3,4-oxadiazoles and 1,2,4-triazoles. Bioorg Med Chem 2004;
14: 6057–6059
[3] Chaudhary PK, Verma AK, Singh D et al. Synthesis and antimicrobial
activity of N-alkyl and N-aryl piperazine derivatives. Bio Med Chem
2006; 14: 1818–1826
[16] Zarghi A, Tabatabai SA, Faizi M et al. Synthesis and anticonvulsant of
new 2-substituted-5(2-benzyloxyphenyl)-1,3,4-oxadiazoles. Bioorg
Med Chem Lett 2005; 15: 3126–3129
[4] Mallesha L, Mohana KN. Synthesis, antimicrobial and antioxidant
activities of 1-(1,4-benzodioxane-2-carbonyl) piperazine derivatives.
Eur J Chem 2011; 2: 193–199
[17] Zarghi A, Hamedi S, Tootooni F et al. Synthesis and pharmacological
evaluation of new 2-substituted-5-{2-[(2-halobenzyl)thiophenyl}-1,3,4-
oxadiazoles as anticonvulsant agents. Sci Pharm 2008; 76: 185–201
[5] Choo HYP, Chung BJ, Chung SH. Synthesis of piperazine derivatives
and evaluation of their antihistamine and antibradykinin effects.
Bioorg Med Chem Lett 1999; 9: 2727–2730
[18] Almasirad A, Vousooghi N, Tabatabai SA et al. Shafiee A. Synthesis,
anticonvulsant and muscle reluctant activities of substituted
1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole. Acta Chimica
Solvenica 2007; 54: 317–324
[6] Howard HR, Lowe JA, Seeger TF et al. 3-Benzisothiazolylpiperazine
derivatives as potential atypical antipsychotic agents. J Med Chem
1996; 39: 143–148
[7] Chen Y, XU X, Liu X et al. Synthesis and evaluation of a series of
2-substituted-5-thiopropylpiperazine (piperidine)-1,3,4- oxadiazoles
derivatives as atypical antipsychotics 2012; 7: 1–10
[19] Nazar S, Siddiqui N, Alam O. Recent progress of 1,3,4-oxadiazoles as
anticonvulsants: Future horizons. Archiv der Pharmazie 2020; 353:
1–12
[8] Mukherjee D, Mukhopadhyay A, Bhat KS et al. characterization and
anticonvulsant activity of substituted 4-chloro-2-(piperazin-1-yl )
quinazolines. Int J Pharm Pharm Sci 2014; 6: 567–571
[20] Foroumadi A, Sheibani V, Sakhteman A et al. Synthesis and anticonvul-
sant activity of novel 2-amino-5-[4-chloro-2-(2-chlorophenoxy)
phenyl]-1,3,4-thiadiazole derivatives. Daru 2007; 15: 89–93
[9] Kaminski K, Wiklik B, Obniska J. Synthesis and anticonvulsant activity
of new N-phenyl-2-(4-phenylpiperazin-1-yl) acetaminde derivatives.
Med Chem Res 2015; 24: 3047–3061
[21] Sarafroz M, Khatoon Y, Ahmad N et al. Synthesis, characterization and
anticonvulsant activity of novel fused 1,2,4-triazolo-1,3,4-thiadiazoles.
Oriental J Chem 2019; 35: 64–70
[10] Kaminski K, Rzepka S, Obniska J. Synthesis and anticonvulsant activity
of new 1-[2-oxo-2(4-phenylpiperazin-1-yl) ethyl] pyrrolidine-2,5-
diones. Bioorg Med Chem Lett 2011; 21: 5800–5803
[22] Toolabi M, Khoramjouy M, Aghcheli A et al. Synthesis and radioligand-
binding assay of 2,5-disubstituted thiadiazoles and evaluation of their
anticonvulsant activities. Arch Pharm 2020; e2000066: 1–9
[11] Plech T, Kapron B, Luszczki JJ et al. Studies on the anticonvulsant activity
and influence on GABA-ergic neuro-transmission of 1,2,4-triazole-
3-thionebased compounds. Molecules 2014; 19: 11279–11299
[23] Toman JEP, Swinyard EA, Goodman LS. Properties of maximal seizures
and their alteration by their anticonvulsant drugs and other agents.
J Neurophysiol 1946; 9: 231–240
[12] Plech T, Luszczki JJ, Wujec M et al. Synthesis, characterization and
preliminary anticonvulsant evaluation of some 4-alkyl-1,2,4-triazoles.
Eur J Med Chem 2013; 60: 208–215
[24] Smith QE. In: Pharmacological screening tests progress in medicinal
chemistry-1, Butterwort’s London. Medicinal Chem 1960; 1: 1–33
Archana. Piperazine as Anticonvulsant Agent… Drug Res 2021; 71: 199–203 | © 2021. Thieme. All rights reserved.
203