Synthesis, computational studies and preliminary pharmacological evaluation of 2-[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides as potential antipsychotics

Article abstract of DOI:10.1016/j.ejmech.2011.07.028

A series of 2-[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides have been synthesized and the target compounds (3a-j) were evaluated for atypical antipsychotic activity in apomorphine induced climbing, 5-HTP induced head twitches behavior and catalepsy studies in mice. The physicochemical similarity of the target compounds with respect to standard drugs clozapine, ketanserin and risperidone was calculated by using software programs. Among them, compound 3e showed maximum atypical antipsychotic like profile.

Full text of DOI:10.1016/j.ejmech.2011.07.028

European Journal of Medicinal Chemistry 46 (2011) 4753e4759
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
Synthesis, computational studies and preliminary pharmacological evaluation
of 2e[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides as potential
antipsychotics
,
a
b
Sushil Kumar a , A.K. Wahi , Ranjit Singh
*
a Drug Design & Medicinal Chemistry Research Laboratory, College of Pharmacy, IFTM, Moradabad-244001, UP, India
b School of Pharmaceutical Sciences, Shobhit University, Meerut, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides have been synthesized and
the target compounds (3aej) were evaluated for atypical antipsychotic activity in apomorphine induced
climbing, 5-HTP induced head twitches behavior and catalepsy studies in mice. The physicochemical
similarity of the target compounds with respect to standard drugs clozapine, ketanserin and risperidone
was calculated by using software programs. Among them, compound 3e showed maximum atypical
antipsychotic like profile.
Received 19 July 2010
Received in revised form
15 July 2011
Accepted 16 July 2011
Available online 22 July 2011
Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords:
N, N-diphenylacetamide
Arylpiperazines
Computational studies
Antipsychotic activity
Dopamine and Serotonin antagonists
1. Introduction
serotonin 5-HT2 and dopamine D2 receptor antagonism to play
critical role in the mechanism of action of atypical antipsychotic
Schizophrenia is a complex psychological disorder affecting
about 1% of the population worldwide [1,2]. The use of classical
antipsychotics (phenothiazines, haloperidol, etc.) for the treatment
of schizophrenia is associated with severe mechanism related side
effects including induction of acute extra pyramidal symptoms
[3,4]. Classical or typical antipsychotics share the ability to block D2
dopamine receptor and their effectiveness in the treatment of
positive symptoms of schizophrenia [5]. The adverse effects pre-
sented by classical antipsychotics, along with their ineffectiveness
in the treatment of negative symptoms of schizophrenia has
encouraged the search for atypical antipsychotic drugs. It has been
observed that clozapine and other antipsychotic drugs which show
a reduced propensity for the development of EPS have demon-
strated a higher affinity for the 5-HT2 receptor than the D2 receptor
[6]. The mechanism of their action is still controversial, since
there are several models explaining ‘atypicality’ by specific drug
action on subclasses of serotonergic, glutamatergic, muscarinic or
drugs. This so-called ‘serotonin-dopamine’ hypothesis has become
a useful model for developing new antipsychotics to achieve
superior efficacy with a lower incidence of extra pyramidal side
effects compared to classical antipsychotics [7,8]. This model
suggests the ratio of 5-HT2A to D2 receptor affinities to be the major
determinant of a drug’s possibility to behave as an atypical
antipsychotic [9]. Arylpiperazine derivatives display diverse phar-
macological activity which can be mediated by different subpop-
ulations of serotonin, dopamine and aderenergic receptors [10e15].
Their general chemical structure consists of the arylpiperazine
moiety connected by an alkyl chain with the terminal amide or
imide fragment (Chart 1) [16e21]. In view of these observations, we
herein report the synthesis, computational studies of some new
arylpiperazines and evaluate them for a possible atypical antipsy-
chotic potential.
2. Results and discussion
a
-adrenergic receptors. It was hypothesized that a combination of
2.1. Synthesis of compounds
The new arylpiperazines were prepared using the pathway
shown in Scheme 1. The substituent of the compounds is given in
* Corresponding author. Tel.: þ91 591 2360817; fax: þ91 591 2360818.
E-mail address: sushilmpharm@rediffmail.com (S. Kumar).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.07.028

4754
Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 4753e4759
O
N
N
N
N
N
O
OH
Buspirone
O
O
F
N
N
NH
Flesinoxan
OCH3
O
N
N
O
NH
CH2
N
N
Ar
n
X
WAY-100135
1
OCH3
N
N
O
N
N
WAY-100635
Chart 1. Structure of some amide and imides based arylpiperazines.
Table 1. The target compounds (3aej) were prepared by a two-step
procedure: chloroacetylation of diphenylamine (1) in toluene, fol-
lowed by condensation of intermediate (2) with substituted phe-
nylpiperazines in acetonitrile in the presence of K2CO3 and KI as
catalyst. All the reactions were monitored by TLC. The target
compounds were obtained in good yields (46e76%). The structural
assignments to new compounds were based through analytical and
spectroscopic data. In the IR spectrum of compound 2 a peak at
1678 cmꢀ1 assigned to C]O str and the appearance of a new band
at 695 cmꢀ1 due to CeCl str along with the absence of band at
3240 cmꢀ1 due to NH str. The NMR spectrum showed a character-
2.2. Computation of physicochemical properties
A set of molecular parameters was computed for the target
compounds as well as three standard drugs clozapine, ketanserin
and risperidone using Chem 3D Ultra version, 11.0, and Chem Silico
online free software are shown in Table 2. The important molecular
parameters for antipsychotics are bloodebrain barrier (BBB), log P
and topological polar surface area (TPSA) [22,23]. Literature review
suggested that TPSA is a measure of a molecule’s hydrogen bonding
capacity and its value should not exceed certain limit if the
compound is intended to be CNS active. Two differing limits have
been proposed: van de Waterbeemed et al. [24] suggested a limit of
90 A2, where, Kelder et al. [25] suggested 60e70 A2. The TPSA value
for test compounds were well within these limits (26.79e78.60)
which shows that these compounds have a potential to effectively
cross the bloodebrain barrier. The log BB values (0.01e0.41) and
log P values (4.04e5.6) for the compounds were noted and sug-
gesting that these have an excellent potential for CNS activity.
istic singlet peak at
d 4.02 indicated its formation. The target
compounds (3aej) were confirmed by the absence of CeCl str at
695 cmꢀ1, presence of C]O str at 1673e1685 cmꢀ1, CeN str
(aliphatic) at 1217e1237 cmꢀ1, CeN str (aromatic) at 1448e1496
and by the presence of singlet proton at d 4.47e4.58 (2H, COCH2) in
the proton NMR. Mass spectra of the target compounds exhibited
characteristic M þ 1 peak.

Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 4753e4759
4755
NCOCH2Cl
i
ClCOCH2Cl
NH
R
(2)
(1)
ii
N
NH
N
N
NCOCH2
R
(3a-j)
Scheme 1. Synthesis of the target compounds. Reagents and condition: (i) toluene, reflux, 4 h (ii) Acetonitrile, K2CO3, KI.
2.3. Similarity calculations
2.4. Preliminary pharmacological evaluation for atypical
antipsychotic effect
The physicochemical similarity of the target compounds was
calculated with respect to the standard drugs [26] and is shown in
Table 3.
Firstly, the distance di of a particular target compound j to drug
molecules e.g., clozapine was calculated by the formula:
All the target compounds were subjected to preliminary phar-
macological evaluation to determine their ability to inhibition of
apomorphine induced climbing behavior, inhibition of 5-hydroxy
tryptophan (5-HTP) induced head twitches behavior [27e30] and
catalepsy studies [31e33]. Prior permission of the Animal Ethics
Committee was obtained and all experiments were conducted
according to the approved protocol (837/ac/04/CPCSEA). Clozapine
and haloperidol groups were employed as standard (positive
control). Statistical analysis of the results in the test group was done
by comparison with the results in the control group employing
non-parametric Kruskal Wallis test or one way ANOVA (Jandel
Sigmastat version 2.0). Level of significance was fixed at p < 0.05.
The results from the pharmacological evaluation of the target
compounds are given in Table 4 and depicted graphically in
Figs. 1e3. All ligands showed significant interactions with the
dopamine and serotonin receptors, which were found to be
dependent, fundamentally on the substitution of N-aryl group of
piperazines. With respect to dopamine receptor, the compounds 3e
and 3f (ED50 ¼ 8.2 and 10.0 mg/kg, respectively) possessing
methoxy group at ortho and meta position of aryl group of piper-
azine showed statistically significant reversal of apomorphine
induced climbing behavior than chloro, trifluoromethyl and
dichloro analogs 3g, 3d and 3h (ED50 ¼ 16.5, 21.3 and 24.0 mg/kg,
respectively). The analogs 3a and 3i (ED50 ¼ 20.5 and 13.4 mg/kg,
respectively) exhibited a modest interaction for dopamine receptor.
Significant reduction in activity was observed, when methyl,
dimethyl and nitro group was present at aryl moiety of piperazine
3b, 3c and 3j (ED50 > 20, 28.5, and 30.0 mg/kg, respectively).
Regarding the inhibition of 5-HTP induced head twitches study
showed that ortho and meta-methoxy analogs 3e and 3f
(ED50 ¼ 12.7 and 15.5 mg/kg, respectively) produced significant
activity than chloro, trifluoromethyl and dichloro analogs 3g, 3d
and 3h (ED50 ¼ 18.0, 30.0 and >20.0 mg/kg, respectively). The
n
X
ꢀ
ꢁ
di2
¼
1 ꢀ Xi;j=Xi;std 2=n
j ¼ 1
where, Xi,j is the value of molecular parameter ‘i’ for compound ‘j’,
i,std is the value of the same molecular parameter for the standard
X
drug, e.g., clozapine, ketanserin and risperidone. Then, the simi-
larity of compound ‘j’ to the standard drug was calculated as:
Similarity (%) ¼ (1 ꢀ R) ꢁ 100. where R ¼ Od2 is the quadratic
mean (root mean square), a measure of central tendency. Similarity
of target compounds was noted less with respect to clozapine.
However, a much higher similarity was found with respect to
ketanserin and risperidone. Among them, compounds 3e and 3f
showed maximum structural similarity with respect to risperidone
(86.33% and 86.39%).
Table 1
Substituent of compounds 3aej.
Cpd. no.
Cpd. code
R
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
4-CH3
2,3-CH3
3-CF3
2-OCH3
3-OCH3
3-Cl
3,4-Cl
4-F
4-NO2
3j

4756
Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 4753e4759
Table 2
Calculation of molecular properties for target compounds and standard drugs.
Cpd. code
Log BBj
Log P
M.Wa
MRb
SASc (A2)
MSAd (A2)
SEVe (A2)
TPSAf
MTIg
WIh
Ovi
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
0.25
0.36
0.39
0.41
0.21
0.27
0.32
0.33
0.31
0.01
0.75
ꢀ0.48
ꢀ0.20
4.49
4.98
5.46
5.41
4.36
4.36
5.05
5.60
4.65
4.04
3.71
2.37
2.10
371.47
385.50
399.53
439.47
401.50
401.50
405.92
440.36
389.47
416.47
326.82
395.43
410.48
113.32
119.22
125.12
119.83
120.57
120.57
117.93
122.53
113.73
119.57
94.58
641.894
582.422
679.816
690.253
676.270
687.020
666.463
686.713
648.109
686.144
508.991
589.340
690.021
344.355
313.211
371.123
373.577
367.637
370.267
359.201
372.494
348.009
371.220
259.124
298.729
375.090
308.409
291.582
336.247
335.839
333.074
331.754
322.774
336.839
311.631
332.383
215.892
253.386
351.810
26.79
26.79
26.79
26.79
36.02
36.02
26.79
26.79
26.79
78.60
30.87
69.72
57.50
17130
19148
20677
22826
20277
20575
18269
19519
18374
22209
8127
2193
2450
2644
3226
2648
2692
2428
2688
2450
3024
1082
2596
2793
1.5599
1.4729
1.5870
1.5988
1.5821
1.5976
1.5785
1.5910
1.5655
1.5997
1.4889
1.5420
1.5563
CLZk
KETl
RISm
106.67
114.21
18646
20311
a
Molecular weight.
Molar refractivity.
b
c
Connolly solvent accessible surface area.
Connolly molecular surface area.
Connolly solvent excluded volume.
Topological polar surface area.
Molecular topological index.
Wienner index.
Ovality.
Calcd. online [35].
Clozapine.
Ketanserin.
d
e
f
g
h
i
j
k
l
m
Risperidone.
fluoro analog 3i (ED50 ¼ 20.0 mg/kg) exhibited a modest interaction
for serotonin receptor than the methyl, dimethyl analogs 3b and 3c
(ED50 ¼ 31.2 and >30.0 mg/kg, respectively) suggesting a potential
steric effect of the phenyl ring in the binding site. Nitro analog 3j
(ED50 > 40.0 mg/kg) showed lowest activity with serotonin
receptor. The catalepsy results showed all the new compounds
were less cataleptogenic than haloperidol. Among them, methoxy
analogs 3e and 3f (ED50 ¼ 50.4 and 55.5 mg/kg, respectively)
exhibited lower propensity to produce catalepsy.
catalepsy. Moreover, TPSA, log BB, log P values suggested that this
compound has the potential to penetrate the bloodebrain barrier
and showed good similarity with respect to standard drugs,
particularly risperidone. Further studies on this lead including
in vitro assays are required for the refinement of the atypical
antipsychotic activity.
4. Experimental
Melting points of the synthesized compounds were determined
by open capillary method and are uncorrected. The IR spectra of
synthesized compounds were recorded in potassium bromide discs
on Perkin Elmer RX1. The 1H and 13C NMR spectra were recorded on
a Bruker DRX-300 spectrophometer (1H at 300 MHz and 13C at
75 MHz) in CDCl3 containing TMS as an internal standard. The
signals are quoted as follows: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; bs, broad singlet and are expressed in d ppm.
Elemental analyses were performed on Perkin Elmer 2400 analyzer.
The mass spectra were recorded on a Micromass Quattro II triple
3. Conclusion
A new series of arylpiperazines have been synthesized and their
preliminary pharmacological evaluation has shown potential
atypical antipsychotic effect in animal models. However, in vivo
results are insufficient for prediction of an atypical antipsychotic
profile with similar to clozapine. Among the compounds, 3e has
shown potent atypical antipsychotic activity probably by inhibition
of dopamine D2 and serotonin 5-HT2 receptors and low induction of
Table 3
Table 4
Similarity values of target compounds with respect to the standard drugs.
Potential for atypical antipsychotic activity in vivo.
Cpd.Code.
Similaritya,b (in %) to
Clozapine
Cpd. code
Inhibition of
Inhibition of
Induction of
Ketanserin
Risperidone
apomorphine induced 5-HTP induced head catalepsy
climbing behavior
(ED50, mg/kg, i.p.)
twitches behavior
(ED50, mg/kg, i.p.)
(ED50, mg/kg, i.p.)
3a
3b
3c
3d
3e
3f
3g
3h
3i
41.72
32.69
18.99
0.22
20.44
16.61
31.70
20.78
32.24
8.15
75.10
77.01
72.37
70.12
76.74
76.45
74.29
72.28
75.57
81.27
77.86
77.91
80.61
79.56
86.33
86.39
79.90
80.61
79.56
86.04
3a
3b
3c
3d
3e
3f
3g
3h
20.5
>20
28.5
21.3
8.2
10.0
16.5
24.0
13.4
30.0
8.7
27.0
31.2
>30
30.0
12.7
15.5
18.0
>20
20.0
>40
2.8
50
>40
>40
48.0
50.4
55.4
48.4
45
>40
>40
e
nda
3j
3i
3j
a
(1 ꢀ R) ꢁ 100 where R ¼ quadratic mean (root mean square mean).
b
Calcd. from physicochemical properties: molecular weight; molar refractivity;
Clozapine
Haloperidol
Connolly solvent accessible surface area; Connolly molecular surface area; Connolly
solvent excluded volume; topological polar surface area; molecular topological
index; Wiener index.
e
e
a
nd: Not determined, 1mg/kg dose was used.

Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 4753e4759
4757
16
14
12
10
8
6
4
2
14
12
10
8
30
60
90
6
120
240
4
2
0
0
l
l
e
o
d
3f
3i
3j
3f
3i
3j
ro
n
i
3a
3b
3c
Synthesized compounds
3d
3e
3g
3h
3a
3b
3c
3d
3e
3g
3h
t
i
r
n
p
e
p
a
z
Co
o
o
Synthesized compounds
l
Cl
Ha
Fig. 1. The effect of synthesized compounds (3aej) on climbing behavior induced by
apomorphine (2.5 mg/kg, i.p.). Each column represents the mean ꢃ SEM of total
climbing score for groups of six mice assessed at 5 min intervals for 20 min, starting
10 min after apomorphine treatment. A score 20 is the maximum possible. Clozapine
(ED50 8.7 mg/kg, i.p) was used for comparison with respect to test compounds (3aej).
p < 0.05.
Fig. 3. Induction of catalepsy of synthesized compounds (3aej). Haloperidol (1.0 mg/
kg, i.p) was used for comparison with respect to test compounds. Results are expressed
as the mean ꢃ SEM. (n ¼ 6), p < 0.05.
4.1.2.1. 2-[4-(Phenyl) piperazin-1-yl] N, N-diphenyl acetamide
(3a). Yield: 76%. mp: 125e127 ꢂC. Rf ¼ 0.34 (Hexane/EtOAc 2:1). IR
(KBr, cmꢀ1): 3056, 2826, 1673, 1448, 1237. 1H NMR (300 MHz;
quadrupole mass spectrometer. All reagents were of commercial
quality and were used without further purification. The reactions
progress was monitored by thin-layer chromatography (TLC) using
silica gel G and spots were visualized in an iodine chamber.
CDCl3)
4.56 (s, 2H, COCH2); 6.80e6.90 (m, 6H, AreH); 7.20e7.54 (m, 9H,
AreH). 13C NMR (75 MHz, CDCl3
): 48.92, 53.15, 76.58, 115.91,
d: 2.64e2.67 (m, 4H, pip ring); 3.15e3.66 (m, 4H, pip ring);
d
116.62, 119.50, 120.25, 127.13, 128.97, 142.31, 151.19, 154.64, 169.29.
MS (EI, m/z): 372.2 (M þ 1). Anal.Calcd.for C24H25N3O: C, 77.60; H,
6.78; N, 11.31. Found: C, 77.66; H, 6.74; N, 11.35.
4.1. Synthesis of compounds
4.1.1. Synthesis of 2-chloro-N, N-diphenylacetamide (2)
4.1.2.2. 2-[4-(4-Methylphenyl) piperazin-1-yl] N, N-diphenylaceta-
mide (3b). Yield: 72%. mp: 86e88 ꢂC. Rf ¼ 0.28 (Hexane/EtOAc 2:1).
IR (KBr, cmꢀ1): 3014, 2826, 1674, 1453, 1218. 1H NMR (300 MHz;
Diphenylamine (6.76 g, 0.04 mol) was dissolved in toluene
(200 ml) in a 250 ml round bottom flask and chloroacetylchloride
(3.18 ml, 0.04 mol) was added. The reaction mixture was refluxed
for 4 h. A total of 400 ml of water was then added to the reaction
mixture and kept overnight for precipitation of the product, which
was filtered, washed with water, dried and recrystallized from
ethanol [34]. Yield: 73.49 %. mp: 116e118 ꢂC. Rf ¼ 0.44 (Hexane/
EtOAc 5:1). IR (KBr, cmꢀ1): 3005, 2942, 1678, 1364, 1263, 695. 1H
CDCl3) d: 2.25 (s, 3H, CH3); 2.69e2.97 (m, 4H, pip ring); 3.12- 3.77
(m, 4H, pip ring); 4.47 (s, 2H, COCH2); 6.65e6.72 (m, 6H, AreH);
7.10e7.48 (m, 8H, AreH). MS (EI, m/z): 386.2 (M þ 1). Anal.Calcd.for
C25H27N3O: C, 77.89; H, 7.06; N, 10.90. Found: C, 77.85; H, 7.09; N,
10.94.
NMR (300 MHz; CDCl3) d: 4.02 (s, 2H); 7.26e7.39 (m, 10H, AreH).
4.1.2.3. 2-[4-(2,3-Dimethylphenyl)piperazin-1-yl] N, N-diphenylace-
tamide (3c). Yield: 60%. mp: 107e109 ꢂC. Rf ¼ 0.26 (Hexane/EtOAc
2:1). IR (KBr, cmꢀ1): 3012, 2820, 1675, 1490, 1219. 1H NMR
4.1.2. General procedure for the synthesis of 3aej
2-Chloro-N, N-diphenylacetamide (1.22 g, 0.005 mol) was dis-
solved in acetonitrile (100 ml) in a 250 ml round bottom flask,
anhydrous K2CO3 (0.69 g, 0.005 mol), appropriate arylpiperazine
(0.005 mol) and catalytic amount of potassium iodide were added.
The above mixture was allowed to reflux with continuous stirring
on magnetic stirrer for 10 h. After completion of reaction the
solvent was removed by vacuum distillation and residue was dis-
solved in 1:1 mixture of chloroform and water. The organic layer
was separated, washed with brine and dried over MgSO4, removal
of the solvent afforded target compounds 3aej.
(300 MHz; CDCl3) d: 2.18 (s, 3H, CH3); 2.24 (s, 3H, CH3); 2.35e2.94
(m, 4H, pip ring); 3.05e3.97 (m, 4H, pip ring); 4.57 (s, 2H, COCH2);
6.64e6.87 (m, 5H, AreH); 7.18e7.56 (m, 8H, AreH). MS(EI, m/z):
400.2 (M þ 1). Anal. Calcd. for C26H29N3O: C, 78.16; H, 7.32; N,10.52.
Found: C, 77.19; H, 7.37; N, 10.49.
4.1.2.4. 2-[4-(3-Trifluoromethylphenyl) piperazin-1-yl] N, N-diphe-
nylacetamide (3d). Yield: 57%. mp: 60e62 ꢂC. Rf ¼ 0.27 (Hexane/
EtOAc 2:1). IR (KBr, cmꢀ1): 3016, 2828, 1674, 1490, 1218. 1H NMR
(300 MHz; CDCl3) d: 2.64e2.67 (m, 4H, pip ring); 3.15e3.66 (m, 4H,
pip ring); 4.56 (s, 2H, COCH2); 6.65e6.80 (m, 6H, AreH); 7.21e7.35
(m, 8H, AreH). MS (EI, m/z): 440.1 (M þ 1). Anal. Calcd. for
C25H24F3N3O: C, 68.32; H, 5.50; N, 9.56. Found: C, 68.36; H, 5.54; N,
9.52.
8
7
6
5
4
3
2
1
0
4.1.2.5. 2-[4-(2-Methoxyphenyl) piperazin-1-yl] N, N-diphenylaceta-
mide (3e). Yield: 48%. mp: 79e81 ꢂC. Rf ¼ 0.22 (Hexane/EtOAc 2:1).
IR (KBr, cmꢀ1): 3083, 2822, 1685, 1493, 1218. 1H NMR (300 MHz;
CDCl3) d: 2.64e2.68 (m, 4H, pip ring); 3.15e3.20 (m, 4H, pip ring);
3.78 (s, 3H, OCH3); 4.57 (s, 2H, COCH2); 6.39e6.52 (m, 6H, AreH);
7.04e7.37 (m, 8H, AreH); MS (EI, m/z): 402.2 (M þ 1). Anal.Calcd.for
C25H27N3O2: C, 74.79; H, 6.78; N, 10.47. Found: C, 74.75; H, 6.74; N,
10.49.
e
ol
3f
3i
3j
r
n
i
3a
3b
3c
3d
3e
3g
3h
p
nt
a
z
Co
Synthesized compounds
lo
C
Fig. 2. The effect of synthesized compounds (3aej) on the 5-HTP (50 mg/kg, i.p.)
induced head twitches behavior. Each column represents the mean ꢃ SEM of total
score for groups of six mice assessed at 10 min intervals for 30 min, starting 20 min
after the 5-HTP treatment. A score 8 is the maximum possible. Clozapine (ED50 2.8 mg/
kg, i.p) was used for comparison with respect to test compounds (3aej). p < 0.05.
4.1.2.6. 2-[4-(3-Methoxyphenyl) piperazin-1-yl] N, N-diphenylaceta-
mide (3f). Yield: 46%. mp: 110e112 ꢂC. Rf ¼ 0.24 (Hexane/EtOAc
2:1). IR (KBr, cmꢀ1): 3083, 2822, 1685, 1493, 1218. 1H NMR

4758
Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 4753e4759
(300 MHz; CDCl3 d): 2.64e2.68 (m, 4H, pip ring); 3.15e3.20 (m, 4H,
pip ring); 3.77 (s, 3H, OCH3); 4.57 (s, 2H, COCH2); 6.39e6.52 (m, 6H,
AreH); 7.04e7.37 (m, 8H, AreH); MS (EI, m/z): 402.2 (M þ 1). Anal.
Calcd. for C25H27N3O2: C, 74.79; H, 6.78; N, 10.47. Found: C, 74.75; H,
6.79; N, 10.51.
of 5-HTP. Thirty minutes later, the test compound was adminis-
tered. After a further 30 min, the mice received 5-HTP (50 mg/kg,
i.p). The mice were returned to the test cages and then head
twitches were assessed at 10 min intervals for 30 min, starting
20 min after the 5-HTP treatment. Head twitches were monitored
using the following scoring system: 0, absent; 1, moderate; 2,
marked (Fig. 2). A maximum of 8 score is possible. An observer
made all observations unaware of the specific drug treatments.
4.1.2.7. 2-[4-(3-Chlorophenyl) piperazin-1-yl] N, N-diphenylaceta-
mide (3g). Yield: 56%. mp: 102e104 ꢂC. Rf ¼ 0.32 (Hexane/EtOAc
2:1). IR (KBr, cmꢀ1): 3016, 2828, 1674, 1490, 1218. 1H NMR
(300 MHz; CDCl3)
d: 2.63e2.66 (m, 4H, pip ring); 3.15e3.20 (m, 4H,
4.2.3. Catalepsy
pip ring); 4.54 (s, 2H, COCH2); 6.73e6.98 (m, 6H, AreH); 7.20e7.36
(m, 8H, AreH). MS (EI, m/z): 406.1 (M þ 1). Anal. Calcd. for
C24H24ClN3O: C, 71.01; H, 5.96; N, 10.35. Found: 71.07; H, 5.99; N,
10.39.
Catalepsy was induced in albino mice (n ¼ 6) with haloperidol
(1.0 mg/kg, i.p) and was assessed at 30 min intervals until 120 min
and at the end of 240 min by means of a standard bar test. Catalepsy
was assessed in terms of the time (s) for which the mouse main-
tained an imposed position with both front limbs extended and
resting on a 4 cm high wooden bar (1.0 cm diameter). The endpoint
of catalepsy was considered to occur when both front paws were
removed from the bar or if the animal moved its head in an
exploratory manner. Severity of the cataleptic behavior was scored
as 1 if maintained the imposed posture for at least 20 s and every
additional 20 s one extra point was given (Fig. 3). A cut-off time of
1100 s was applied during the recording of observations. The
animals were returned to their individual home cages in between
determinations. All observations were made between 10.00 and
16.00 hrs in a quiet room at 23e25 ꢂC. The animals in the test group
were administered with test drugs instead of haloperidol and the
remaining procedure for assessment of catalepsy was same as
mentioned above.
4.1.2.8. 2-[4-(3, 4-Dichlorophenyl) piperazin-1-yl] N, N-diphenyla-
cetamide (3h). Yield: 51%. mp: 80e82 ꢂC. Rf ¼ 0.29 (Hexane/EtOAc
2:1). IR (KBr, cmꢀ1): 3016, 2829, 1675, 1480, 1219. 1H NMR
(300 MHz; CDCl3) d: 2.60e2.66 (m, 4H, pip ring); 3.14e20 (m, 4H,
pip ring); 4.50 (s, 2H, COCH2); 6.68e6.98 (m, 6H, AreH); 7.23e7.48
(m, 7H, AreH). MS (EI, m/z): 440.1 (M þ 1). Anal. Calcd. for
C24H23Cl2N3O: C, 65.46; H, 5.26; N, 9.54. Found: C, 65.42; H, 5.28; N,
9.58.
4.1.2.9. 2-[4-(4-Fluorophenyl) piperazin-1-yl] N, N-diphenylaceta-
mide (3i). Yield: 49%. mp: 96e98 ꢂC. Rf ¼ 0.21 (Hexane/EtOAc 2:1).
IR (KBr, cmꢀ1): 3021, 2840, 1674, 1480, 1217. 1H NMR (300 MHz;
CDCl3) d: 2.68e2.71 (m, 4H, pip ring); 3.09e3.34 (m, 4H, pip ring);
4.54 (s, 2H, COCH2); 6.67e7.02 (m, 6H, AreH); 7.18e7.48 (m, 8H,
AreH). MS (EI, m/z): 390.1 (M þ 1). Anal. Calcd. for C24H24FN3O: C,
74.01; H, 6.21; N, 10.79. Found: C, 74.05; H, 6.24; N, 10.77.
Acknowledgement
The authors are grateful to Prof. R. M. Dubey, Managing Director,
IFTM, Moradabad, for providing the research facilities and also
thankful to CDRI, Lucknow for spectral analysis. This work is a part
of work done for Ph.D. degree of Shobhit University.
4.1.2.10. 2-[4-(4-Nitrophenyl) piperazin-1-yl] N, N-diphenylaceta-
mide (3j). Yield: 47%. mp: 134e136 ꢂC. Rf ¼ 0.30 (Hexane/EtOAc
2:1). IR (KBr, cmꢀ1): 3020, 2848, 1673, 1496, 1217. 1H NMR
(300 MHz; CDCl3) d: 2.68e2.71 (m, 4H, pip ring); 3.19e3.43 (m, 4H,
pip ring); 4.58 (s, 2H, COCH2); 6.76e6.98 (m, 6H, AreH); 7.10e8.17
(m, 8H, AreH). MS (EI, m/z): 417.1 (M þ 1). Anal. Calcd. for
C24H24N4O3: C, 69.21; H, 5.81; N, 13.45. Found: C, 69.25; H, 5.84; N,
13.48.
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