Synthesis, evaluation, and molecular properties prediction of substituted cinnamoylpiperazine derivatives as potential antinociceptive and anticonvulsive agents

Article abstract of DOI:10.1007/s00044-018-2175-z

A series of novel cinnamoylpiperazine derivatives (5a–5l) were synthesized as potential antinociceptive, and anticonvulsive agents. Various heterocyclic systems like piperidine, morpholine, piperazine, and N-arylpiperazine were combined with cinnamoyl or methylenedioxy cinnamoyl moieties to obtain a series of constrained analogs of cinnamides. Of these, compound 5e possessing 4-fluorophenyl substitution on the piperazine ring exhibited good antinociceptive activity in capsaicin and formalin-induced nociception methods, and also significant anticonvulsant activity in pentylenetetrazole and maximal electroshock-induced seizure methods. Further, all the derivatives were studied for molecular and preadmet properties. The activities of compound 5e were supported by molecular and preadmet properties for its in silico oral bioavailability and drug-likeness.

Full text of DOI:10.1007/s00044-018-2175-z

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-018-2175-z
ORIGINAL RESEARCH
Synthesis, evaluation, and molecular properties prediction of
substituted cinnamoylpiperazine derivatives as potential
antinociceptive and anticonvulsive agents
Gummalla Prasanthi1,2 Kvsrg Prasad1 Koganti Bharathi1
●
●
Received: 11 July 2016 / Accepted: 24 March 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
A series of novel cinnamoylpiperazine derivatives (5a–5l) were synthesized as potential antinociceptive, and anticonvulsive
agents. Various heterocyclic systems like piperidine, morpholine, piperazine, and N-arylpiperazine were combined with
cinnamoyl or methylenedioxy cinnamoyl moieties to obtain a series of constrained analogs of cinnamides. Of these,
compound 5e possessing 4-fluorophenyl substitution on the piperazine ring exhibited good antinociceptive activity in
capsaicin and formalin-induced nociception methods, and also significant anticonvulsant activity in pentylenetetrazole and
maximal electroshock-induced seizure methods. Further, all the derivatives were studied for molecular and preadmet
properties. The activities of compound 5e were supported by molecular and preadmet properties for its in silico oral
bioavailability and drug-likeness.
●
●
●
Keywords Cinnamoylpiperazines Capsaicin-induced nociception anticonvulsant activity drug-likeness
Introduction
epilepsy is one of the prominent goals in biomedical
research. There is an abundant evidence of oxidative injury
in animal models of epilepsy and nociceptive pain. There-
fore, antioxidant therapy aimed at reducing oxidative stress
has received considerable attention in the treatment of epi-
lepsy and pain (Salat et al. 2012; Azam et al. 2010).
Epilepsy and neuropathic pain are disorders characterized
by either inappropriate spontaneous neuronal activity or
excessive neuronal activity in response to physiological
stimuli. These disorders are currently managed by drugs
that are capable of dampening neuronal excitability
(Wickenden et al. 2004). Drugs commonly used for epi-
leptic therapy like gabapentin and carbamazepine are
approved for the treatment of neuropathic pain. Lamotrigine
has also demonstrated efficacy in clinical trials (Eisenberg
et al. 2001). Pharmacological and clinical studies have
documented the pathophysiological similarities in epilepsy
and neuropathic pain models (Dickenson et al. 2002; Bar-
uah et al. 2012; Rapacz et al. 2016). Hence, the identifica-
tion of compounds able to treat both nociceptive pain and
Research efforts made a long history of cinnamide
derivatives with various biological properties, such as
antineoplastic, antifungal, antimycobacterial, antic-
onvulsant, and antinociceptive activities (De et al. 2011;
Xiao et al. 2011; Kakwani et al. 2011; Gunia et al. 2012;
Tamiz et al. 1999). N-aryl cinnamides like SB 366791,
AMG 9810, and AMG 3047 were claimed to be potent and
important classes of transient receptor potential vanilloid 1
(Trpv1) antagonists (Fig. 1) (Doherty et al. 2005; Wu et al.
2008a). In addition, there are many reports suggesting the
anticonvulsant activity of derivatives of (E) and (Z) m-
(trifluoromethyl)-α, β-dimethyl cinnamides (1) and ami-
noalkanol derivatives of α-phenylcinnamic acid (2) (Fig. 1)
(Balsamo et al. 1981; Gunthorpe et al. 2004). On the other
hand, certain N-arylpiperazines linked to the other aromatic
system via amide linkage as constrained urea such as N-(4-
tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-car-
boxamide (BCTC) were reported to exhibit Trpv1 antag-
onistic activity (Pomonis et al. 2003; Tafesse et al. 2004).
* Gummalla Prasanthi
prasanthi.gummalla@yahoo.com
1
Sri Padmavati Mahila Visvavidyalayam (Women’s University),
Tirupati 517502, India
2
Annamacharya College of Pharmacy, Rajampet, Kadapa, Andra
Pradesh, India

Medicinal Chemistry Research
O
CH3
CH
Fig. 1 Various cinnamide and
arylpiperazine derivatives as
lead molecules
OH
F
N
H
C
F
H2N
H2
Ph
O
C
F
(1)
(2)
Cl
H
N
H
N
O
O
O
O
OCH3
SB-366791
AMG9810
F
F
F
Cl
O
H
N
N
N
N
NH
N
O
BCTC
OH
AMG3047
Literature survey revealed that one of the important core
fragments possessing nitrogen-containing heterocyclic sys-
tems attached to another aromatic system via a carbonyl or
methylenyl group is an essential feature for antiepileptic and
antinociceptive activities (Obniska et al. 2010; Abou-Seri
et al. 2011). Based on the previous findings, BCTC, SB-
366791, AMG 9810, and AMG 3047 were chosen as lead
compounds in the present study for further hybrid phar-
macophore approaches, and combined the potential scaf-
folds into a novel hybrid molecule aiming to enhance their
activity. Therefore, we have designed and synthesized a
series of cinnamide derivatives containing morpholinyl,
piperidinyl, piperazinyl, and N-arylpiperazinyl moieties as
constrained carboxamide analogs with promising biological
activities.
chloride formation which was further treated with second-
ary amines like piperidine, morpholine, piperazine, or sub-
stituted piperazine by the dehydrohalogenation reaction,
affording the title compounds 5a–5l as depicted in Scheme
1 (Wu et al. 2008b). The structure of the compounds was
1
confirmed by IR, H NMR, mass, and elemental analysis.
The IR spectra of the compounds showed a broad band in
the range of 1655–1640 cm−1 assignable to the C=O
stretching in the amide functional group and a band at
1640–1610 cm−1 indicating the C=C stretching in the cin-
namoyl group. The mass spectra of the compounds showed
the corresponding molecular ion peaks, and the elemental
analysis for the compounds is within the limits of 0.4% of
theoretical value.
1
The H NMR spectrum of the compounds supported the
structures of 5a–5l. These compounds showed a doublet in
the region of 6.3–7.6 ppm due to alkenyl protons of the
cinnamoyl moiety (J = 12.0–15.8 Hz), a broad doublet or a
triplet in the region of 2.1–2.8 ppm, and 3.2–3.9 ppm
indicated the protons of the heterocyclic substitutions like
piperidinyl, morpholinyl, and piperazinyl substitutions. A
multiplet in the region of 6.5–7.5 ppm indicated the
Results and discussion
Chemistry
Synthesis of substituted cinnamoylpiperazine derivatives
was carried out by simple and feasible procedures via acid

Medicinal Chemistry Research
R1
R2
COCl
R1
R2
COOH
(i)
(3) R1=R2=H
(4) R1; R2= -OCH2O-
(1) R1=R2=H
(2) R1; R2= -OCH2O-
(ii)
O
R1
R2
N
X
X=NH/ CH2/ O/ NAr
5a-5i = R1=R2=H
R1; R2= -OCH2O-
5j-5l =
compound
R1=R2
X
compound
R1=R2
H
X
5a
5b
5c
5d
5e
5f
H
H
H
H
H
H
CH2
O
5g
5h
5i
N-4-NO2-Ph
N-Pyridin-2-yl
N-Pyrimidin-2-yl
N-Ph
H
NH
N-Ph
H
5j
-OCH2O-
-OCH2O-
-OCH2O-
N-4-F-Ph
5k
5l
N-4-F-Ph
N-4-Cl-Ph
N-Pyridin-2-yl
Scheme 1 Synthetic protocol of the target compounds 5a–5l. Reagents and conditions: (i) thionylchloride, CH2Cl2, stirring, 5 h, rt (ii) acetone,
triethylamine, 2° amine, stirring,10–12 h, rt
aromatic protons present in the phenyl ring of the cinna-
moyl moiety.
position of piperazine also showed promising activity (61.7
and 64.7%).
Perusal of the data showed that introduction of mor-
pholinyl, piperidinyl, or piperazinyl ring systems attached to
the cinnamoyl moiety showed pronounced influence on
antinociceptive activity. Piperazinyl-substituted cinnamides
were found to be more potent when compared to com-
pounds containing morpholinyl or piperidinyl ring systems.
The presence of the phenyl group at the fourth position of
the piperazinyl moiety seems to be essential for the activity.
Further, substitution of the phenyl ring by electron-
withdrawing fluorine or chlorine atoms resulted in
increase in activity. Replacement of the N-phenyl ring in 5d
with pyridin-2-yl and pyrimidin-2-yl as in 5h and 5i
resulted in a drastic decrease in activity. Compounds 5j, 5k,
and 5l are structurally related to 5d, 5f, and 5h, respectively,
and showed decreased antinociceptive activity, which may
be due to the presence of 3,4-methylenedioxy groups
Pharmacology
The profile of antinociceptive activity of the compounds
5a–5l was evaluated in capsaicin-induced and formalin-
induced nociceptive methods after oral administration of the
compounds to the male Swiss albino mice at the dose of
10 mg/kg and observations were made after 1 h (Table 1)
(Rossato et al. 2011). Compounds 5a–5h, 5j, and 5k
exhibited significant activity in capsaicin-induced nocicep-
tion except 5i and 5l. Compound 5e with 4-fluorophenyl
substitution exhibited the highest activity (73.5%),
which may be due to the presence of electron-withdrawing
p-fluoro substitution present on the phenyl ring of the
piperazinyl moiety. Compounds 5d and 5f possessing
phenyl and 4-chlorophenyl substitutions at the fourth

Medicinal Chemistry Research
Table 1 Antinociceptive activity of derivatives of cinnamoylpiperazines (5a–5l) by capsaicin and formalin-induced methods at the dose of 10 mg/
kg, p.o
Compound Capsaicin-induced methoda
Formalin-induced methodb
Number of flinches Percentage
Number of paw
licking during
0–5 min (mean
SEM)
Percentage
protection during
0–5 min
Number of paw licking Percentage
(mean SEM)
protection
during 15–30 min
protection during
(mean SEM)
15–30 min
5a
12 0.70*
29.41
47.05
52.94
61.76
73.52
64.70
41.14
29.41
28.41
13.17 1.400**
10.33 1.256**
9.66 0.765**
11.50 1.285**
8.83 1.400**
9.50 0.428**
11.33 0.557**
15.0 0.8563**
15.50 0.716**
12.67 0.4216**
9.50 0.428**
15.83 0.792**
5.33 1.174**
21.67 0.9888
39.2
52.3
55.4
46.9
59.2
56.1
47.7
30.7
28.4
41.5
56.1
26.9
75.4
–
6.0 0.8563***
2.3 0.6667**
3.3 0.557**
5.5 1.147***
4.0 0.3651****
5.1 0.307***
5.8 0.307***
5.5 0.4282***
6.1 0.307***
4.6 0.4216***
4.1 0.307*
16.2
67.8
53.9
23.1
44.1
28.7
18.9
23.1
14.8
35.7
42.7
16.2
86.0
–
5b
9.0 1.41**
8.0 1.41**
6.5 0.99**
4.5 1.53**
6.0 0.70**
10 1.15****
12 1.41*
5c
5d
5e
5f
5g
5h
5i
12.17 2.574***
5j
10.5 0.9916**** 38.23
5k
7.16 0.5270**
15.5 0.9916***
–
57.88
8.8
–
5l
6.0 0.365***
1.0 0.2713**
7.1 0.6009
Tramadol
Control
17 1.698
–
aTest compounds were given 1 h before the capsaicin administration (1 nmol/paw, subplantar). Number of flinches was measured for 5 min. All the
values were expressed as mean SEM. ANOVA was followed by Dunnet’s method
bTest compounds were given 1 h before the formalin administration (2.5%, intraplantar). Number of paw lickings was measured for 5 min (early
phase) and 15–30 min (late phase). All the values were expressed as mean SEM. ANOVA was followed by Dunnet’s method
*P < 0.05 vs. control, **P < 0.0001 vs. control, ***P > 0.05 vs. control, ****P > 0.0001 vs. control
additionally present on the phenyl ring of the cinnamoyl
moiety.
pentylenetetrazole-induced and maximal electroshock-
induced methods (Table 2) (Obniska et al. 2010; Subudhi
et al. 2009). Compound 5e possessing p-fluorophenyl sub-
stitution on the piperazine ring exhibited a good latency
period against the pentylenetetrazole-induced seizures and
is comparable to the standard drug, diazepam. Compounds
5b, 5d, and 5e exhibited maximum protection against
mortality and are comparable to the standard drug,
diazepam.
In the case of maximal electroshock-induced method, all
the compounds 5b, 5d, 5e, and 5f showed significant pro-
tection. Compounds with morpholinyl, phenyl, 4-fluor-
ophenyl, and 4-chlorophenyl substitutions as in 5b, 5d, 5e,
and 5f, respectively, showed less limb-extension period and
pronounced seizure inhibitory activity (71.8, 65.3, 74.3, and
61.5%), and are comparable to the standard drug, phenytoin
(64.1%) except compound 5f.
In formalin-induced nociception methods, all compounds
5a–5l exhibited significant activity. Replacement of the
morpholinyl moiety in 5b with piperazinyl substitution as in
5c increased the activity, which may be due to specific
interaction of free NH with the target site. The presence of
the phenyl ring at the fourth position of piperazine as in 5d
decreased the activity, whereas 4-fluorophenyl (5e and 5k)
and 4-chlorophenyl groups (5f) exhibited good anti-
nociceptive activity. However, the activity of these com-
pounds is not comparable to tramadol in formalin-induced
nociception assay.
The second phase of formalin-induced nociception
indicates anti-inflammatory response. Compounds 5b, 5c,
5e, and 5k exhibited significant activity. Out of these,
compound 5b possessing the morpholine ring showed good
anti-inflammatory activity. Compounds containing the free
piperazine ring also showed good activity, followed by 4-
fluorophenyl piperazinyl substitution. However, the activ-
ity of these compounds is less than tramadol. Other com-
pounds did not exhibit significant anti-inflammatory
response.
Calculation of molecular properties
Drug-likeness is a qualitative concept, estimated from the
molecular properties that affect their absorption, distribu-
tion, metabolism, and excretion (ADME) of a compound by
using Molinspiration software for the compounds under
The antiepileptic profile of the compounds selectivity 5b,
5d, 5e, and 5f was evaluated by two methods, subcutaneous

Medicinal Chemistry Research
Table 2 Anticonvulsant activity of the selective cinnamoylpiperazine derivatives in PTZ and MES methods at the dose of 10 mg/kg, p.o
Compound
PTZ methoda
MES methodb
Latency period
mean SEM
Percentage protection
against mortality
Duration of limb-
extension mean SEM
Percentage
protection
5b
220 25.30***
235 23.73***
210 32.86***
300 0***
100
100
100
33.3
100
–
7.333 0.9189***
71.8
65.3
74.3
61.5
–
5d
9 0.3651***
5e
6.667 1.282***
10 0.9661***
–
5f
Diazepam
Phenytoin
Control
300 00.0***
–
9.333 0.5578***
26 3.120
64.1
–
77.33 5.731
–
aLatency period was measured 1 min after the PTZ administration. Test compounds were administered 1 h before the PTZ administration (80 mg/
kg)
bDuration of limb-extension was measured by inducing the electroconvulsive seizures. (Drug was administered 1 h before inducing the
electroconvulsive seizures (150 m.amp, 0.2 s)). All the values were expressed as mean SEM. One-way analysis of variance (ANOVA) was
followed by Dunnet’s method
***P < 0.0001 vs. control, nsP > 0.05 vs control
Table 3 Prediction of molecular properties for the cinnamoylpiperazine derivatives (5a–5l)
Compound
cLogP
M.Wt
nON
nNHOHH
Volume
nViola-ions
nrotb
TPSA
%ABS
5a
5b
5c
5d
5e
5f
2.923
1.861
1.311
3.604
3.767
4.281
3.562
2.704
2.318
3.494
3.657
2.208
215
217
216
292
310
326
337
293
294
336
354
338
2
3
3
3
3
3
6
4
5
5
5
7
0
0
1
0
0
0
0
0
0
0
0
0
216.39
208.57
211.99
283.78
288.71
297.32
307.12
279.62
275.47
307.71
312.64
299.40
0
0
0
0
0
0
0
0
0
0
0
0
2
2
2
3
3
3
4
3
3
3
3
3
20.3
101.9
98.8
97.8
100
29.5
32.3
23.547
23.547
23.547
69.371
36.439
49.331
42.015
42.015
67.799
100
100
5g
5h
5i
85
96.4
91.9
94.5
94.5
85.6
5j
5k
5l
%ABS percentage of absorption, MW molecular weight, (nOHNH) HBD number of H-bond donors, (nON) HBA number of H-bond acceptors, MR
molar refractivity, nrotb number of rotatable bonds, TPSA topological polar surface area
study (http://www.molinspiration.com/services/properties.
html). Molecular descriptors such as partition coefficient
(log P), molecular weight (MW), or hydrogen bond
acceptors and donors in a molecule indicate membrane
permeability and bioavailability (Ahsan et al. 2011). The
number of rotatable bonds explains the conformational
changes and flexibility of molecules, and for binding to the
receptors. It was reported that the number of rotatable bonds
should be ≤10 to pass the oral bioavailability (Veber et al.
2002). Compounds 5a–5l possess 2–4 rotatable bonds and
therefore, exhibit optimum conformational flexibility.
Topological polar surface area (TPSA) is a very useful
parameter to predict the transport properties of drugs like
intestinal absorption and blood–brain barrier penetration
(Zhao et al. 2002). TPSA and volume are inversely pro-
portional to the percentage of absorption (%ABS) and cal-
culated using the equation: %ABS = 109 0.345 × TPSA
(Menenzes et al. 2011). It was observed that all the title
compounds exhibited good %absorption ranging from 85 to
100% (Table 3). The Lipinski’s rule-of five states that most
molecules with good membrane permeability have log P ≤
5, molecular weight ≤ 500, number of hydrogen bond
acceptors ≤ 10, and number of hydrogen bond donors ≤ 5 is
widely used as a filter for drug-likeness [Lipinski et al.
1997; Prasanthi et al. 2013]. Furthermore, none of the
compounds violated Lipinski’s parameters, making them
potentially promising agents for antinociceptive and anti-
epileptic therapies.

Medicinal Chemistry Research
Table 4 Calculation of ADME properties for the cinnamoylpiperazine
derivatives (5a–5l)
substitution on the piperazine ring of cinnamoylpiperazine
derivatives may be a desirable feature for antinociceptive,
and anticonvulsant activities. Molecular properties predic-
tion data of compound 5e also support for drug-likeness and
oral bioavailability.
Compound HIA (%) In vitro
MDCK
iPPB C
brain
Caco2 (nm/s) (nm/s)
/Cblood
5a
5b
5c
5d
5e
5f
100
100
95.7
100
100
100
96.0
98.5
97.3
97.8
97.8
97.7
49.10
52.68
39.25
56.45
57.0
69.60
296.33
161.82
185.79
44.7
83.47 0.290
64.34 0.766
21.77 0.086
97.07 0.857
92.20 0.610
89.70 1.30
33.70 0.030
58.30 0.160
44.02 0.070
60.25 0.29
69.4 0.30
80.96 0.18
Materials and methods
General
21.81
21.0
1.72
5g
5h
5i
0.51
Aldehydes and esters were procured from Sigma-Aldrich
and Merck chemicals. All other chemicals are of AR grade.
Purity of the samples was monitored by TLC analysis using
precoated aluminum plates (Merck), coated with silica gel
(Kieselgel 60) with F254 indicator. Melting points were
determined in open capillaries using Analab melting-point
apparatus and were uncorrected. IR spectra were recorded
as KBr pellets on a Jasco FTIR (FTIR-4100) spectro-
photometer. 1H NMR spectra were carried out on Jeol-400-
MHz NMR spectrophotometer (JNM-400) using TMS as
the internal reference. Chemical shifts (δ values are given in
parts per million (ppm) using CDCl3 as a solvent and
coupling constants (J) in Hz). Splitting patterns are desig-
nated as follows: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet. Mass spectral data were obtained on LCMS
(Shimadzu) APCI model LC-2010 EV.
21.0
0.70
21.0
0.54
5j
21.09
21.09
53.39
0.67
5k
5l
0.56
33.83
HIA (%) percentage of human intestinal absorption, PCaco2 (nm/s)
Caco2 cell permeability in nm/s, PMDCK (nm/s) Madin–Darby canine
kidney cell permeability in nm/s, PPB (%) in vitro plasma protein
binding (percentage), BB (Cbrain/Cblood) in vivo blood–brain barrier
penetration
The absorption and distribution parameters like oral
bioavailability, in vitro plasma protein binding, and
blood–brain barrier penetration were calculated from pre-
ADME predictor, a molecular descriptor tool (http://www.
preadmet.bmdc.org/index.php). Oral drug absorption can be
predicted using in vitro models like human intestinal
absorption (%HIA), Caco2 cell (PCaco2), and MDCK cell
(PMDCK) permeabilities (Table 4). Compounds 5a–5l
showed %HIA ranging from 96 to 100%, and optimum
Caco2 cell permeability (4–70 nm/s), while compounds 5a–
5e and 5l displayed optimum MDCK cell permeability
(25–500 nm/s). Compounds 5a–5f and 5l showed optimum
penetration into CNS via the blood–brain barrier. The sig-
nificance of 4-fluorophenyl substitution on the piperazinyl
moiety in 5e is further supported by the molecular and
preADME predictions. This substitution displayed optimum
log P, MDCK, and Caco2 cell permeabilities, and CNS
penetrations than other substitutions, and good percentage
of human intestinal absorption, thus suggesting good oral
bioavailability and its drug-likeness.
Elemental analyses were performed on Perkin Elmer
2400 C, H, and N elemental analyzer.
General method for the synthesis of compounds 5a–5l
A total of 10 mmol of cinnamoyl chloride (3) or (methyle-
nedioxy)cinnamoyl chloride (4) was dissolved in a suitable
quantity of acetone, 10 mmol of different secondary amines,
and 2–3 drops of triethylamine were added at room tem-
perature and continuously stirred for 10–12 h to obtain the
compounds 5a–5l. Completion of the reaction was mon-
itored by TLC plates (Abou-Seri et al. 2011).
Synthesis of cinnamoyl chloride (3) or (methylenedioxy)
cinnamoyl chloride (4)
A total of 10 mmol of cinnamic acid (1, 1.66 g) or
10.9 mmol of (methylenedioxy)cinnamic acid, i.e., (E)-3-
(benzo[d][1,3]dioxol-6-yl)acrylic acid (2, 2.1 g) dissolved
in dichloromethane, and 10 mmol of thionylchloride was
added at room temperature and allowed for stirring for 5 h.
After the completion of the reaction, excess of thio-
nylchloride was removed by distillation to obtain compound
3 or 4. These compounds were used without further pur-
ification for the next step.
Conclusions
In summary, a series of novel cinnamide derivatives were
synthesized successfully by combining the two pharmaco-
phoric core fragments. The present study revealed that
compound 5e showed promising antinociceptive and
anticonvulsant activities. The presence of 4-fluorophenyl

Medicinal Chemistry Research
3-Phenyl-1-(piperidin-1-yl) prop-2-en-1-one (5a) A total of
1.66 g of cinnamoyl chloride (3, 10 mmol) was dissolved in
acetone, 1 ml of (10 mmol) piperidine, and 2–3 drops of
triethylamine were added at room temperature with con-
tinuous stirring for 10–12 h to obtain compound 5a as white
color powder with 58% yield. m.p. 143–144 °C. Rf: 0.22. IR
(KBr, νmax, cm−1): 3095, 3080, and 3060 (Ar C–H str),
3029 (trans=CH str), 1652 (amide C=O str), and 1631
Calc. for C13H16N2O: C, 72.19; H, 7.46; N, 12.95; O, 7.40.
Found: C, 72.16; H, 7.48; N, 12.94; O, 7.42.
3-Phenyl-1-(4-phenylpiperazin-1-yl) prop-2-en-1-one (5d)
A total of 1.62 g (10 mmol) of N-phenylpiperazine was
added and proceeded as in 5a to obtain compound 5d as
shiny white crystalline flakes, yield 78%. m.p. 146–147 °C.
Rf: 0.29. IR (KBr, νmax, cm−1): 3098 and 3063 (Ar C–H str),
3027 (trans=CH str), and 1638 (amide, C=O str). 1H NMR
(400 MHz, CDCl3) δ (ppm): 3.28–3.36 (br d, 4 H, J =
4.1 Hz, 4CH2 of piperazine), 3.59–3.67 (br d, 4 H, J =
4.1 Hz, 4CH2 of piperazine), 6.79 (d, 1 H, J = 15.8 Hz,
–CH=CH–C6H5), 6.89–7.49 (m, 10 H, Ar–H), and
7.51–7.55 (d, 1 H, J = 15.8 Hz, –CH=CH–C6H5). APCI-
MS: m/z = 292.1 (M)+. Anal. Calc. for C19H20N2O: C,
78.05; H, 6.89; N, 9.58; O, 5.48. Found: C, 78.06; H, 6.88;
N, 9.56; O, 5.50.
1
(trans C=C str). H NMR (400 MHz, CDCl3) δ (ppm):
2.45–2.55 (dt, 6 H, J = 4.7 Hz, 3CH2 of piperidine), 3.4 (t,
4 H, J = 4.7 Hz, 2CH2 of piperidine), 6.35–6.45 (d, 1 H, J
= 15.6 Hz, –CH=CH– of the cinnamoyl group), and
7.35–7.45 (d, 1 H, J = 15.6 Hz, –CH=CH– of the cinna-
moyl group). APCI-MS: m/z = 215.9 (M + H)+. Anal.
Calc. for C14H17NO: C, 78.10; H, 7.96; N, 6.51; O, 7.43.
Found: C, 78.12; H, 7.94; N, 6.50; O, 7.44.
1-Morpholino-3-phenyl-prop-2-en-1-one (5b) A total of
1.66 g of compound 3 was dissolved in acetone, 1 ml of
(10 mmol) morpholine, and proceeded as in 5a to obtain
compound 5b as white crystalline powder, yield 57%. m.p
148–149 °C. Rf: 0.28, IR (KBr, νmax, cm−1): 3075 and 3056
(Ar C–H str), 3012 (trans=CH str), 2987 (C–H str), 1652
(amide C=O str), and 1631 (trans C=C str). 1H NMR
(400 MHz, CDCl3) δ (ppm): 2.95–3.05 (dt, 4 H, J = 5.2 Hz,
2CH2 of morpholine), 3.45–3.55 (t, 4 H, J = 5.2 Hz, 2CH2
of morpholine), 6.35–6.45 (d, 1 H, J = 14.8 Hz, –CH=CH–
of the cinnamoyl group), and 7.35–7.45 (d, 1 H, J =
14.8 Hz, –CH=CH– of the cinnamoyl group). APCI-MS:
1-(4-(4-Fluorophenyl) piperazin-1-yl)-3-phenyl-prop-2-en-1-
one (5e) A total of 1.82 g (10 mmol) of N-(4-florophenyl)-
piperazine was added and proceeded as in 5a to obtain
compound 5e. It was obtained as white silky powder, yield
72%. m.p. 142–143 °C. Rf: 0.21. IR (KBr, νmax, cm−1):
3097 and 3070 (Ar C–H str), 3024 (trans=C–H str), 2994,
2950, and 2893 (alkyl CH2 C–H str), and 1641 (amide C=O
str). 1H NMR (400 MHz, CDCl3) δ (ppm): 3.08–3.19 (br d,
4 H, J = 4.2 Hz, 4CH2 of piperazine), 3.51–3.62 (br d, 4 H,
J = 4.2 Hz, 4CH2 of piperazine), 6.35–6.45 (dd, 1 H, J =
13.8 Hz, –CH=CH–C6H5), 6.5–7.65 (m, 9 H, J = 7.29 Hz,
J = 8.1 Hz Ar–H), and 7.3–7.4 (dd, 1 H, J = 13.8 Hz,
–CH=CH–C6H5). APCI-MS: m/z = 310.3 (M)+, 292.1
(C19H19N2O)+. Anal. Calc. for C19H19FN2O: C, 73.53; H,
6.17; F, 6.12; N, 9.03; O, 5.15. Found: C, 73.51; H, 6.18; F,
6.11; N, 9.04; O, 5.16.
m/z = 216.9 (M)+, 218.9 (M + 2 H)+ Anal. Calc. for
.
C13H15NO2: C, 71.87; H, 6.96; N, 6.44; O, 14.73. Found: C,
71.88; H, 6.94; N, 6.43; O, 14.75.
3-Phenyl-1-(piperazin-1-yl) prop-2-en-1-one (5c) A total of
1.86 g (10 mmol) of N-boc-piperazine was added and pro-
ceeded as in 5a. The obtained compound was subjected for
the deprotection and produced the compound 5c as white
crystalline powder. Deprotection: The product obtained was
dissolved in 6 N HCl (60 ml) and washed with ether three to
four times each of 50 ml of quantity. The aqueous phase
was basified with potassium hydroxide pellets and adjusted
the pH to 11. It was then extracted with ethyl acetate, each
quantity of 100 ml for three to four times. The combined
organic phases were dried over Na2SO4 and concentrated to
get compound 5c in 58% yield. m.p 180–181 °C. Rf: 0.23.
IR (KBr, νmax, cm−1): 3095 and 3060 (Ar C–H str), 3029
(trans=CH str), 1638 (amide C=O str), and 1599 (Ar C–C
str). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.30–2.45 (br d,
4 H, J = 4.2 Hz, 2CH2 of piperazine), 3.4–3.6 (br t, 4 H, J
= 4.2 Hz, 2CH2 of piperazine), 5.65–5.90 (br s, 1 H, NH of
piperazine), 6.5 (d, 1 H, J = 12.5 Hz, –CH=CH–C6H5),
7.12–7.35 (m, 5 H, Ar–H), and 7.6 (d, 1 H, J = 12.5 Hz,
1-(4-(4-Chlorophenyl) piperazin-1-yl)-3-phenyl-prop-2-en-1-
one (5f) A total of 1.96 g (0.01 mol) of N-(4-chlor-
ophenyl)-piperazine was added and proceeded as in 5a to
obtain compound 5f. It was obtained as white silky crystals,
yield 71%. m.p. 155–156 °C, Rf: 0.25. IR (KBr, νmax, cm
−1): 3091 and 3057 (Ar C–H str), 3024 (trans=C–H str),
2984 and 2943 (alkyl CH2 C–H str), and 1641 (amide C=O
str). 1H NMR (400 MHz, CDCl3) δ (ppm): 3.12–3.24 (br d,
4 H, J = 4.2 Hz, 4CH2 of piperazine), 3.48–3.59 (br d, 4 H,
J = 4.2 Hz, 4CH2 of piperazine), 6.25–6.35 (dd, 1 H, J =
12.2 Hz, –CH=CH–C6H5), 6.45–7.45 (m, 9 H, Ar–H), and
7.35–7.45 (dd, 1 H, J = 12.2 Hz, –CH=CH–C6H5). APCI-
MS: m/z = 326.9 (M)+. Anal. Calc. for C19H19ClN2O: C,
69.83; H, 5.86; Cl, 10.85; N, 8.56; O, 4.90. Found: C,
69.81; H, 5.86; Cl, 10.87; N, 8.55; O, 4.91.
1-(4-(4-Nitrophenyl) piperazin-1-yl)-3-phenyl-prop-2-en-1-
one (5g) A total of 2.07 g (0.01 mol) of N-(4-
–CH=CH–C6H5). APCI-MS: m/z = 216.9 (M + H)+ Anal.
.

Medicinal Chemistry Research
nitrophenyl)-piperazine was used to obtain compound 5g
and appeared as pale-yellow color, yield 67%. m.p.
175–176 °C, Rf: 0.25. IR (KBr, νmax, cm−1): 3086 (Ar C–H
str), 3020 (trans=C–H str), 2989 and 2933 (alkyl CH2 C–H
str), and 1645 (amide C=O str). 1H NMR (400 MHz,
CDCl3) δ (ppm): 3.10–3.22 (br d, 4 H, J = 4.2 Hz, 4CH2 of
piperazine), 3.40–3.55 (br d, 4 H, J = 4.2 Hz, 4CH2 of
3.75–3.90 (br d, 4 H, J = 5.7 Hz, 2CH2 of piperazine), 5.85
(s, 2 H, CH2 of –OCH2–O), 6.35–6.45 (d, 1 H, J = 15.8 Hz,
CH gp of –CH=CH–C6H5), 7.55–7.65 (d, 1 H, J = 15.8 Hz,
CH gp of –CH=CH–C6H5), and 6.85–7.45 (m, 8 H, Ar–H).
APCI-MS: m/z = 335.9 (M)+, 215.0 (C13H15N2O)+ Anal.
.
Calc. for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33; O, 14.27.
Found: C, 71.40; H, 5.60; N, 8.32; O, 14.28.
piperazine),
6.20–6.35
(dd,
1 H,
J = 12.5 Hz,
–CH=CH–C6H5), 6.45–7.45 (m, 9 H, Ar–H), and
7.35–7.45 (dd, 1 H, J = 12.5 Hz, –CH=CH–C6H5). APCI-
MS: m/z = 337.1 (M)+. Anal. Calc. for C19H19N3O3: C,
67.64; H, 5.68; N, 12.46; O, 14.22. Found: C, 67.63; H,
5.69; N, 12.45; O, 14.23.
3-(Benzo[d][1,3]-dioxol-6-yl)-1-(4-(4-fluorophenyl)-pipera-
zin-1-yl)-prop-2-en-1-one (5k) A total of 1.82 g (10 mmol)
of N-(4-fluorophenyl)-piperazine was used and proceeded
as in 5j to obtain compound 5k as white powder with 60%
yield. m.p. 250–251 °C. Rf: 0.24. IR (KBr, νmax, cm−1):
3058 (Ar C–H str), 2964 (C–H str in CH2), and 1638 (amide
C=O str). 1H NMR (400 MHz, CDCl3) δ (ppm): 3.1–3.2 (t,
4 H, J = 4.2 Hz, 2CH2 of piperazine), 3.65–3.80 (br d, 4 H,
J = 4.9 Hz, 2CH2 of piperazine), 5.9 (s, 2 H, CH2 of
–OCH2–O), 6.65–6.75 (d, 1 H, J = 15.3 Hz, CH of
–CH=CH–C6H5), 7.55–7.70 (d, 1 H, J = 15.3 Hz, CH of
–CH=CH–C6H5), and 7.05–7.45 (m, 7 H, Ar–H). APCI-
3-Phenyl-1-(4-(pyridin-2-yl) piperazin-1-yl)-prop-2-en-1-one
(5h) A total of 1.63 g (10 mmol) of N-(pyridin-2-yl)-
piperazine was used to obtain compound 5h and appeared
as white crystals, yield 64%. m.p. 125–126 °C. Rf: 0.27. IR
(KBr, νmax, cm−1): 3094 and 3076 (Ar C–H str), 1625
1
(amide C=O str). H NMR (400 MHz, CDCl3) δ (ppm):
2.15–2.25 (t, 4 H, J = 4.2 Hz, 2CH2 of piperazine), 3.8–3.9
(t, 4 H, J = 4.2 Hz, 2CH2 of piperazine), 6.35–6.45 (d, 1 H,
J = 14.5 Hz, –CH=CH–C6H5), 6.9–8.1 (m, 9 H, J =
7.35 Hz, J = 7.9 Hz, Ar–H), and 7.6–7.7 (d, 1 H, J =
14.5 Hz, –CH=CH–C6H5). APCI-MS: m/z = 292.9 (M)+,
214.9 (M + 2 H)+. Anal. Calc. for C18H19N3O: C, 73.69; H,
6.53; N, 14.32; O, 5.45. Found: C, 73.68; H, 6.54; N, 14.31;
O, 5.47.
MS: m/z = 354.9 (M + H)+ Anal. Calc. for C20H19FN2O3:
.
C, 67.79; H, 5.40; F, 5.36; N, 7.91; O, 13.54. Found: C,
67.79; H, 5.41; F, 5.35; N, 7.90; O, 13.55.
3-(Benzo[d][1,3]-dioxol-6-yl)-1-(4-(pyridin-2-yl)-piperazin-1-
yl)-prop-2-en-1-one (5l) A total of 1.63 g (10 mmol) of N-
(pyridin-2-yl)-piperazine was used in 5j procedure to obtain
compound 5l. It was obtained as white powder with 60%
yield. m.p. 249–250 °C. Rf :0.25. IR (KBr, νmax, cm−1):
3064 (Ar C–H str), 2973 (C–H str, CH2), and 1625 (amide
C=O str). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.15–2.25
(t, 4 H, J = 4.2 Hz, 2CH2 of piperazine), 3.8–3.9 (t, 4 H, J
= 4.2 Hz, 2CH2 of piperazine), 5.35 (s, 2 H, CH2 of
3-Phenyl-1-(4-(pyrimidin-2-yl) piperazin-1-yl)-prop-2-en-1-
one (5i) A total of 1.64 g (10 mmol) of N-(pyrimidin-2-
yl)-piperazine was used in the 5a procedure to obtain
compound 5i as dull white color crystals, yield 68%. m.p
140–141 °C. Rf: 0.28. IR (KBr, νmax, cm−1): 3079 and 3072
(Ar C–H str), 2926 (C–H str, CH2), and 1625 (amide C=O
str). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.15–2.25 (t, 4 H,
J = 4.5 Hz, 2CH2 of piperazine), 3.8–3.9 (t, 4 H, J = 4.5 Hz,
2CH2 of piperazine), 6.35–6.45 (d, 1 H, J = 14.2 Hz,
–CH=CH–C6H5), 6.8–8.1 (m, 9 H, Ar–H), and 7.6–7.7 (d,
1 H, J = 14.2 Hz, –CH=CH–C6H5). APCI-MS: m/z = 293.9
(M)+. Anal. Calc. for C17H18N4O: C, 69.37; H, 6.16; N,
19.03; O, 5.44. Found: C, 69.37; H, 6.15; N, 19.02; O, 5.46.
–OCH2–O),
6.35–6.45
(d,
1 H,
J = 14.5 Hz,
–CH=CH–C6H5), 6.9–8.1 (m, 9 H, J = 7.35 Hz, J = 7.9 Hz,
Ar–H), and 7.6–7.7 (d, 1 H, J = 14.5 Hz, –CH=CH–C6H5).
APCI-MS: m/z = 336.9 (M)+. Anal. Calc. for C19H19N3O3:
C, 67.64; H, 5.68; N, 12.46; O, 14.22. Found: C, 67.65; H,
5.66; N, 12.45; O, 14.24.
Pharmacology
Experimental animals
3-(Benzo[d]
[1,3]-dioxol-6-yl)-1-(4-phenyl)piperazin-1-yl)
prop-2-en-1-one (5j) A total of 2.1 g (10 mmol) of com-
pound 4 was dissolved in acetone, 1.62 g (10 mmol) of N-
(phenyl)-piperazine, and 2–3 drops of triethylamine were
added at room temperature with continuous stirring for
10–12 h to obtain compound 5j and appeared as white
powder with 66% yield. m.p. 252–253 °C. Rf: 0.23. IR
(KBr, νmax, cm−1): 3098 and 3075 (Ar C–H str), 1638
Male Swiss albino mice (18–22 g) and male Wistar rats
(150–200 g) were used as experimental animals and were
obtained from King Institute of Preventive Medicine,
Guindy, Chennai-32. The animals were acclimatized at the
temperature 23 2 °C with a natural 12:12 h light/dark
cycle in the polypropylene cages. They were fed ad libitum
with balanced rodent pellet diet and water throughout the
experimental period. The animals were sheltered for 1 week
and prior to the experiment, they were acclimatized to
1
(amide C=O str). H NMR (400 MHz, CDCl3) δ (ppm):
3.1–3.3 (br d, 4 H, J = 5.7 Hz, 2CH2 of piperazine),

Medicinal Chemistry Research
laboratory temperature. The protocol was approved by the
Institutional Animal Ethics Committee (IAEC) of Anna-
macharya College of Pharmacy, Rajampet, India constituted
for the purpose as per CPSCEA guidelines (1220/a/08/
CPCSEA/ANCP/06).
were divided into six groups of six rats each. Group 1 was
the control group-received vehicle; Group 2 received 5 mg/
kg body weight of diazepam; and Groups 3–6 received the
test compounds 5b, 5d, 5e, and 5f, respectively (10 mg/kg
body weight), which were prepared by suspension in 0.5%
sodium carboxymethylcellulose. All the drugs were admi-
nistered 1 h prior to the PTZ administration and the latency
period of the seizures, and the mortality was observed.
Acute toxicity studies
The study was conducted as per OECD-425 guidelines for
testing of chemicals acute oral toxicity and used to fix the safe
dose for the compounds 5a–5l. Swiss albino mice were divi-
ded into 14 groups, each containing five animals. Drugs were
administered by oral route in different concentrations (2000,
1000, 500, 250, 100, 50, 20, and 10 mg/kg body weight). The
animals were observed for their death over a period of 7 days.
The LD50 values were calculated by the up-and-down method,
and the dose was fixed as 10 mg/kg body weight.
The maximal electric shock test The anticonvulsant
property of the drug in this model was assessed by its ability
to protect against maximal electric shock-induced convul-
sions. Male Wistar rats were divided into six groups of six
rats each. Group 1 was the control group-received vehicle;
Group 2 received 30 mg/kg body weight of phenytoin; and
Groups 3–6 received the test compounds 5b, 5d, 5e, and 5f,
respectively (10 mg/kg body weight). Maximal electric
shock of 150 mA of current for 0.2 s was applied through
corneal electrodes to induce convulsions in the control,
standard, and test compounds-treated animals.
Evaluation of antinociceptive activity
Capsaicin-induced nociceptive assay Male Swiss mice
(18–22 g) were used for the method and followed the
adaptation to the experimental conditions. An aliquot of 20
µl of capsaicin (1 nmol/paw) was injected subplantarly to
the right hind paw, and the total number of flinchings of the
injected paw was measured individually for 5 min and used
as a measurement of nociception. The animals were treated
with control and test compounds 5a–5l using oral gavages
(10 mg/kg) 1 h prior to capsaicin injection.
Statistical analysis
The results of antinociceptive and anticonvulsant activities
were expressed as mean SEM. The statistical significance
of the differences between the groups was analyzed by one-
way analysis of variance (ANOVA) followed by Dunnett’s
multiple-comparison test.
Calculation of molecular and ADME properties
Method for formalin-induced nociception method The
mice were divided into 14 groups, each containing six ani-
mals. Group 1 was the control group-received vehicle; Group
2 received tramadol injection (5 mg/kg, s.c.); and Groups
3–14 received the test compounds 5a–5l (10 mg/kg, p.o),
respectively, 1 h prior to the formalin injection. Animals were
injected intraplantarly with 20 μl of 2.5% formalin solution
(0.92% of formaldehyde, made up in saline solution 137 mM
NaCl). Mice were immediately placed in a glass cylinder
20 cm in diameter and observed from 0 to 30 min following
formalin injection. The amount of time spent licking the
injected paw was measured with a digital timer and was
considered as the indication of nociception. The first phase of
the nociceptive response normally peaked 5 min after the
formalin injection and the second phase 15–30 min after the
formalin injection, representing the neurogenic and inflam-
matory nociceptive responses, respectively.
The molecular properties like TPSA, cLogP, number of
rotatable bonds, and violations of Lipinski’s rule-of-five
were calculated using Molinspiration online property cal-
culator tool kit. The TPSA was used to calculate the per-
centage of absorption (%ABS) according to the equation: %
ABS = 109–[0.345 × TPSA]. In vitro plasma protein bind-
ing values were obtained from the ADME calculator.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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