Design, synthesis, pharmacological evaluation and computational studies of 1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]ethanones as potential antipsychotics

Article abstract of DOI:10.1016/j.ejmech.2013.12.043

This article describes the design of biphenyl moiety linked with aryl piperazine and syntheses of fourteen 1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]ethanone derivatives along with their pharmacological evaluation for antipsychotic activity and computational studies including quantitative structure activity relationship (QSAR) and descriptor based similarity study. All compounds were found to exhibit considerable anti-dopaminergic and anti-serotonergic activity in behavioural models. Among all derivatives, compound 1-(biphenyl-4-yl)-2-[4-(2-methoxyphenyl)-piperazin-1- yl]ethanone (3c) and 1-(biphenyl-4-yl)-2-[4-(2,3-dichlorophenyl)-piperazin-1-yl] ethanone (3k) showed impressive antipsychotic profile with lower potency for catalepsy induction. These results were found to be sturdily matching with docking study in designing of compounds with homology model of human dopamine D₂ receptor. Also the QSAR study strongly supports the obtained results.

Full text of DOI:10.1016/j.ejmech.2013.12.043

European Journal of Medicinal Chemistry 74 (2014) 358e365
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis, pharmacological evaluation and computational
studies of 1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]
ethanones as potential antipsychotics
*
Sharad H. Bhosale , Ashish M. Kanhed, Radha Charan Dash, Mugdha R. Suryawanshi,
K.R. Mahadik
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Pune 411038, India
a r t i c l e i n f o
a b s t r a c t
Article history:
This article describes the design of biphenyl moiety linked with aryl piperazine and syntheses of fourteen
1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]ethanone derivatives along with their phar-
macological evaluation for antipsychotic activity and computational studies including quantitative
structure activity relationship (QSAR) and descriptor based similarity study. All compounds were found
to exhibit considerable anti-dopaminergic and anti-serotonergic activity in behavioural models. Among
all derivatives, compound 1-(biphenyl-4-yl)-2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethanone (3c) and
1-(biphenyl-4-yl)-2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]ethanone (3k) showed impressive antipsy-
chotic profile with lower potency for catalepsy induction. These results were found to be sturdily
matching with docking study in designing of compounds with homology model of human dopamine D2
receptor. Also the QSAR study strongly supports the obtained results.
Received 17 April 2013
Received in revised form
2 October 2013
Accepted 23 December 2013
Available online 11 January 2014
Keywords:
Antipsychotic
1-(Biphenyl-4-yl)-2-[4-(substituted
phenyl)-piperazin-1-yl]ethanones
Pharmacological evaluation
QSAR
Ó 2014 Elsevier Masson SAS. All rights reserved.
Descriptor based similarity study
1. Introduction
of the brain [4]. Other side effects of these typical antipsychotics
include hyperprolactinemia, sexual disturbances, malignant
Schizophrenia is the overwhelming mental disorder character-
ized by severe distortions of reality and disturbances in perception,
intellectual performance, behaviour and motor activities [1]. The
symptoms of schizophrenia are categorized in to positive symp-
toms which include delusion, hallucination, illusion and negative
symptoms that include apathy, reduced motivation, and alogia [2].
Various typical antipsychotics like chlorpromazine, haloperidol
have been introduced which showed improvement in positive
symptoms of schizophrenia by blocking dopaminergic trans-
mission in the brain [3]. This non-selective inhibition of dopamine
not only reduces psychoses symptoms, but also creates extrapyra-
midal symptoms (EPS) like Parkinsonism and tardive dyskinesia as
side effects due to blockade of dopaminergic activity in motor areas
neuroleptic syndromes and cardiac arrhythmias [5]. In search of
new antipsychotic agents to treat either types of symptoms of
schizophrenia and to obtain broader efficacy, second generation or
atypical antipsychotics like clozapine, ziprasidone, aripiprazole
were introduced. It was believed that the newer atypical antipsy-
chotics are effective against both positive and negative symptoms
of schizophrenia by blocking dopaminergic as well as serotonergic
neurotransmission in brain [6,7]. But these atypical antipsychotics,
on chronic medication, have limitations like substantial weight
gain, agranulocytosis, blood dyscrasias and hyperglycemia [8e10].
In 2007 Bifeprunox, was filed with US-FDA for its potential
atypical antipsychotic activity. In fact Bifeprunox has better anti-
dopaminergic and anti-serotonergic activity than many of the
other atypical antipsychotics. Previously many molecular modifi-
cations of parent bifeprunox have been performed and tested for
their antipsychotic profile [11]. Various substituted phenyl pipera-
zines were also reported for anti-dopaminergic and anti-
serotonergic activity with less EPS induction [12,13]. Furthermore,
biphenyl has been reported to comprise with diverse biological
activities like, anti-inflammatory [14], nitric oxide synthase inhib-
itor [15], anti-diabetics [16], and fungicidal activity [17]. Here we
Abbreviations: QSAR, quantitative structure activity relationship; EPS, extrapy-
ramidal symptoms; GPCR, G-protein coupled receptors; DMF, N,N-dimethyl form-
amide; 5-HTP, DL-5-hydroxytryptophan; EA, electron affinity; BBB, blood brain
barrier; QPlogBB, predicted brain/blood partition coefficient; WFI, water for injec-
tion; i.p, intraperitoneal.
* Corresponding author. Tel.: þ91 9011032735; fax: þ91 20 25439383.
E-mail address: shbhosale2859@gmail.com (S.H. Bhosale).
0223-5234/$ e see front matter Ó 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.12.043

S.H. Bhosale et al. / European Journal of Medicinal Chemistry 74 (2014) 358e365
359
have designed hybrid structure with biphenyl and aryl-piperazine
moiety with acetyl linker (Fig. 1). In previous study our group has
reported the homology model for human dopamine D2 receptor
and here we used same for docking of designed molecules [18].
While designing the molecule we considered various factors
required for receptor affinity such as; i) the presence of nitrogen
attached with aliphatic chain which gets protonated and becomes
quaternary in physiological conditions to produce hydrogen
bonding with dopamine receptor, ii) the presence of hydrophobic
groups to bind with two hydrophobic microdomain of 7-
transmembrane GPCR [18]. On design, we conceived it interesting
to evaluate anti-dopaminergic and anti-serotonergic activity along
with catalepsy profile of designed biphenyl moiety linked with
substituted aryl piperazine by acetyl linker.
Fig. 2. Glide XP docking of compound 3c docked in active site of D2 receptor.
2. Results and discussion
derivatives were in the range of 62e85% after recrystallization in
ethanolewater.
2.1. Docking study
The compounds were docked on 3D structure of human D2 re-
ceptor using Glide XP docking. The binding mode of most active
compound (3c) is shown in Fig. 2. The nitrogen of piperazine
attached to the aliphatic chain protonates at physiological pH and it
showed hydrogen bonding interaction with the carboxylate ion of
Asp85 residue. The distance between the charged nitrogen and
2.3. Pharmacology
The inhibition of apomorphine induced climbing behaviour and
inhibition of DL-5-Hydroxytryptophan (5-HTP) induced head
twitches model along with haloperidol induced catalepsy model
was used for the in-vivo evaluation of antipsychotic potential of
synthesized derivatives. Taking compound 3n as lead, various
substitutions were made on aryl ring and the behavioural studies
were performed. All the biological data statistically analysed and
represented as percentage inhibition in Table 1.
Central anti-dopaminergic activity for all compounds was
assessed by their ability to inhibit apomorphine induced climbing
behaviour. By and large, antidopaminergic activity exhibited by
ortho substituted derivatives was found more than meta and para
substituted derivatives. Presence of chloro (3a), methyl (3b) on aryl
ring resulted in increase in anti-dopaminergic activity as compared
to lead (3n). While substitution methoxy (3c) at ortho position
significantly reversed the apomorphine induced climbing behav-
iour. Further presence of methyl (3e) at meta position slightly
improved the anti-dopaminergic activity. Whereas chloro (3d) and
trifluoromethyl (3f) substitution at meta position exhibited reduc-
tion in the anti-dopaminergic activity. Replacement of hydrogen at
para position with halogens (3g and 3h) decreased the anti-
dopaminergic activity. Whereas replacement with methyl (3i)
ꢀ
Asp85 carboxylate ion was found to be w1.47 A. Further, the hy-
drophobic interaction of aryl piperazine ring of ligand with Val82,
Ile137, Val161 and Trp357 of receptor stabilized the complex.
Additionally, the biphenyl moiety was found to be stabilized by
Val62 and Trp384.
2.2. Chemistry
The scheme for the synthesis of titled compounds 1-(biphenyl-
4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]-ethanones (3ae
3n) is depicted in Scheme 1. Compound 1-(biphenyl-4-yl)-2-
chloroethanone (2) was prepared by FriedeleCrafts acylation of
biphenyl (1) with chloroacetyl chloride in presence of anhydrous
AlCl3 in carbon disulphide (CS2). Synthesis of derivatives 3ae3n
was accomplished by reacting 2 with various substituted aryl pi-
perazines in N,N-dimethyl formamide (DMF) and K2CO3. Structures
were confirmed on the basis of elemental analysis, IR, 1H NMR, 13
NMR and mass spectroscopy (ESI). The yields of synthesized
C
Fig. 1. Planned modification and newly designed antipsychotic molecule.

360
S.H. Bhosale et al. / European Journal of Medicinal Chemistry 74 (2014) 358e365
Scheme 1. (a) CS2, AlCl3, reflux 1 h; (b) DMF, K2CO3, heat 60 ꢂC (4e6 h).
and methoxy (3j) at para position barely increased the anti-
dopaminergic activity. As far as di-substituted derivatives are
concerned, an appreciable increase in anti-dopaminergic activity
was observed in ortho-meta di-substituted compounds bearing
steric and hydrophobic moieties as in 3k and 3l. But in metaepara
di-halo substituted compounds, remarkably decrease in the anti-
dopaminergic activity was observed (3m).
compounds, compound 3j showed high catalepsy induction.
Overall from the pharmacological evaluation of synthesized de-
rivatives for antipsychotic activity, the compound 1-(biphenyl-4-
yl)-2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethanone (3c) and 1-
(biphenyl-4-yl)-2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]etha-
none (3k) showed impressive atypical antipsychotic profile with
lower potency for catalepsy induction.
In the assessment of anti-serotonergic activity, all derivatives
showed increased anti-serotonergic activity except 3b and 3h
which showed decrease in activity as compared to lead 3n. Com-
pound 3c showed good anti-serotonergic activity. In catalepsy in-
duction study on albino mice, it was observed that compound 3c,
3k and 3l showed minimum catalepsy induction but comparatively
not less than standard aripiprazole. Among all synthesized
2.4. Computational studies
2.4.1. Quantitative structure activity relationship study (QSAR)
The QSAR model was generated for antidopaminergic potential.
As all the descriptors are not important for specific model gener-
ation, and hence to select the optimal set of descriptors, we used
systematic variable selection leave one out (LOO) method in step-
wise forward manner for the selection of descriptors. The QSAR
result for antidopaminergic potential produced highly predictive
model that has excellent r2 ¼ 0.95. Further the developed model
showed rc2v ¼ 0.8971 and F value 104.5 indicating the model is very
well validated and explained. The two best descriptors selected on
the basis of importance in biological activity were electron affinity
(EA) (eV) and predicted brain/blood partition coefficient (QPlogBB).
From the QSAR study, the statistically significant equation
derived was,
Table 1
Various synthesized compounds with in vivo pharmacological data at the dose of
15 mg/kg in male albino mice.
Compd.
R
%Inhibition of
climbing
behaviour
%Inhibition of
head twitches
%Catalepsy
induction
BA ¼ 4:9879ðꢀ0:2612Þ þ 0:2968ðꢀ0:0749Þ
QPlogBB ꢁ 4:2743ðꢀ0:3363Þ EAðeVÞ:
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
Arp
2-Cl
38.25
38.54
53.44
29.92
33.59
26.38
26.36
23.45
33.28
32.93
42.83
40.72
25.71
31.90
61.10
35.21
26.68
61.28
32.57
29.61
32.57
29.22
24.51
29.83
36.12
38.31
35.39
38.78
27.98
94.49
42.31
35.84
29.43
31.84
33.82
31.84
35.17
30.48
38.66
59.28
28.97
29.87
30.50
34.53
26.86
N ¼ number of compounds ¼ 14; r2 ¼ 0:95; s ¼ 0:0248;
F ¼ 104:5; rc2v ¼ 0:8971:
2-CH3
2-OCH3
3-Cl
3-CH3
3-CF3
4-Cl
From the equation it was observed that, electron affinity (EA)
correlated negatively with biological activity, however contributed
more than QPlogBB towards biological activity. Relatively greater
activity in compounds 3b, 3c, 3i and 3l (groups- 2-CH3, 2-OCH3, 4-
CH3, 2,3-diCH3 respectively) can be attributed to lower EA of these
compounds since these are having electron releasing groups and
thus increase electron availability in phenyl ring. On the contrary
the electron affinity in the compounds 3f, 3h and 3m (groups e 3-
CF3, 4-F, 3,4-diCl) is more and resulted into relatively diminished
activity. The second parameter QPlogBB contributed relatively less
in the above QSAR but positively correlated with biological activity
4-F
4-CH3
4-OCH3
2,3-diCl
2,3-diCH3
3,4-diCl
H
Number of animal used per group n ¼ 6, p < 0.05. Arp ¼ aripiprazole.
Compound that showed better result among all the synthesized compounds were
highlighted in bold.

S.H. Bhosale et al. / European Journal of Medicinal Chemistry 74 (2014) 358e365
361
Table 2
BBB permeation are logP, molecular weight, molecular volume and
molecular surface area. Here we used Schrodinger suite 2009 to
carry out the similarity study between synthesized compounds in
test set and four standard drugs (aripiprazole, paliperidone,
ketanserin and sertindole) in probe set by using Tanimoto associ-
ation coefficient (Table 3). The physiochemical properties of com-
pounds 3c, 3f, 3j, 3k and 3m showed good similarity with
aripiprazole, ketanserin, paliperidone and sertindole; and com-
pounds 3h and 3n showed less similarity. Interestingly the com-
pounds 3c and 3k which showed high physiochemical similarity
with all the probe molecules than other test molecules, also
showed good antipsychotic potential.
LIC ¼ experimental %inhibition of climbing behavior, PIC ¼ predicted %inhibition of
climbing behaviour. EA ¼ electron affinity, QPlogBB ¼ predicted brain/blood parti-
tion coefficient.
Compound
R
LIC
PIC
Residual
EA (eV) QPlogBB
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
2-Cl
1.5828
1.5860
1.7279
1.4760
1.5263
1.4213
1.4210
1.3702
1.5223
1.5176
1.6318
1.6099
1.4101
1.5039
1. 6020
1.5900
1.6900
1.4930
1.4950
1.4000
1.4410
1.3720
1.5440
1.5340
1.6570
1.6160
1.3730
1.5000
ꢁ0.0192
ꢁ0.0040
0.0379
0.804
0.799
0.771
0.853
0.822
0.886
0.853
0.863
0.82
0.475
0.344
0.274
0.495
0.316
0.597
0.524
0.468
0.346
0.286
0.619
0.341
0.632
0.356
2-CH3
2-OCH3
3-Cl
3-CH3
3-CF3
4-Cl
ꢁ0.0170
0.0313
0.0213
ꢁ0.0200
ꢁ0.0018
ꢁ0.0217
ꢁ0.0164
ꢁ0.0252
ꢁ0.0061
0.0371
4-F
4-CH3
4-OCH3
2,3-diCl
2,3-diCH3
3,4-diCl
H
0.823
0.852
0.81
3. Conclusion
0.874
0.826
In conclusion, we designed and synthesized a series of fourteen
derivatives of 1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piper-
azin-1-yl]ethanone and their structures were confirmed by physi-
cochemical and spectral analysis. The strategy chosen for the current
study was to combine pharmacophoric key features from biphenyl
and aryl piperazine using acetyl linkage to explore atypical anti-
psychotic profile of the resultant compounds. The pharmacological
study revealed that all derivatives possess considerable anti-
dopaminergic and anti-serotonergic activity. Among all synthe-
sized derivatives compound 1-(biphenyl-4-yl)-2-[4-(2-methoxy
phenyl)-piperazin-1-yl]ethanone (3c) and 1-(biphenyl-4-yl)-2-[4-
(2,3-dichlorophenyl)-piperazin-1-yl]ethanone (3k) showed im
pressive antipsychotic profile with lower potency for catalepsy in-
duction. From the QSAR study of synthesized derivatives, the
resulting equation correlated between two variables (QPlogBB
positively and EA negatively) and antidopaminergic activity. Further
more a descriptor based similarity study was carried out to study
blood brain permeation ability of synthesized compounds with
standard antipsychotic drugs. From the resultant Tanimoto similarity
index, compound 3c and 3k showed good similarity with the stan-
dard atypical antipsychotic drugs and also found to have good
antipsychotic potential.
0.0039
(data for EA and QPlogBB is shown in Table 2). The bloodebrain
barrier (BBB) permeability is an important absorption, distribution,
metabolism and excretion (ADME) property and crossing the
bloodebrain barrier is a compulsory step for drug distribution.
Several drug targets are located in the central nervous system (CNS)
within the brain. The bloodebrain barrier is a distinctive mem-
branous barrier that tightly isolates the brain from the circulating
blood [19]. Thus, the bloodebrain partition coefficient (logBB) is a
determining factor for the efficacy of central nervous system-acting
drugs. However various physiochemical properties involved in
QPlogBB permeation are logP, molecular weight, molecular volume
and molecular surface area and so QPlogBB is a contribution of
multi molecular and physical properties of the molecules. As the
molecular and physical property of the derivatives vary according
to structural diversity, it is very difficult to interpret it at molecular
level. This QSAR study supports the postulation of design and the
results from the behavioural models obtained. The graph for actual
activity verses predicted is shown in Fig. 3.
2.4.2. Similarity study
4. Experimental
Further the descriptor based similarity study was performed
between the synthesized compounds and standard antipsychotic
drugs for blood brain barrier permeation analysis. The chemical
similarity study is helpful to compare the biological similarity be-
tween the set of test and probe molecules. To cross the blood brain
barrier (BBB) and exhibit the central nervous system activity the
antipsychotic agents should possess the fundamental physico-
chemical features. Various physiochemical properties involved in
4.1. Docking study
Various substitutions were made on aryl part of aryl piperazine
considering the unsubstituted compound 3n as lead. We used the
homology model of human dopamine D2 receptor, previously re-
ported by us [18], for the docking study of designed molecules.
Table 3
Tanimoto similarity study of synthesized compounds with respect to standard
drugs.
Compound
Aripiprazole
Ketanserin
Paliperidone
Sertindole
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
0.3243
0.3098
0.7291
0.4418
0.5424
0.6421
0.4359
0.1262
0.5421
0.7428
0.6850
0.6284
0.6908
0.0574
0.2505
0.4243
0.5564
0.3618
0.3939
0.4542
0.5124
0.1738
0.3942
0.6102
0.4082
0.3864
0.4155
0.2765
0.2872
0.2635
0.6332
0.3854
0.4708
0.6577
0.3805
0.1138
0.4705
0.6361
0.6348
0.5726
0.6614
0.0464
0.5018
0.4615
0.6373
0.5882
0.5829
0.8724
0.5952
0.1669
0.5866
0.6088
0.9029
0.7541
0.9710
0.0000
Fig. 3. Correlation graph between LIC (experimental) and PIC (predicted) of the syn-
thesized compounds.

362
S.H. Bhosale et al. / European Journal of Medicinal Chemistry 74 (2014) 358e365
Docking studies were performed using Glide module from Schrö-
dinger suit 2009 [20]. As it performs grid-based ligand docking,
grid was generated with the help of receptor grid generation tool of
Glide by keeping all parameters at standard. The structures of
molecules were generated within MAESTRO and exhaustive
conformational search was carried out using OPLS_2005 force field.
These structures then XP docked on the receptor grid for binding
evaluation study by keeping all parameters to their standard value.
m/z 391.15 (Mþ H). 13C NMR (
d ppm CDCl3): 49.3 (ArNeCH2e, ArNe
CH2e of pyrazine); 52.61 (NeCH2e, NeCH2e of pyrazine at
aliphatic site), 65.50 (aliphatic eCH2e); 114.61, 119.58, 123.47,
127.73 (5C), 127.61, 129.10 (4C), 129.68, 134.63, 138.80, 146.80,
150.72(Aromatic C); 195.80 (eC]O).
4.2.4. 1-(Biphenyl-4-yl)-2-(4-o-tolylpiperazin-1-yl)ethanone (3b)
Yield: 64%. mp: 100e101 ꢂC. Elemental analysis: Calcd. C, 81.05;
H, 7.07; N, 7.56; O, 4.32.; found: C, 81.09; H, 7.06; N, 7.58; O, 4.31. IR
4.2. Synthesis
(cmꢁ1): 3060, 2949, 2821, 1684, 1601. 1H NMR (
d ppm CDCl3): 2.34
(s, 3H, AreCH3); 2.71e2.8 (t, 4H, eCH2eNe(CH2)2, J ¼ 4.9); 3.28e
Completion of reaction was monitored by thin layer chroma-
tography on Merck pre coated silica gel F254 plates. The melting
points of synthesized compounds were checked on Veego VMP e D
digital melting point apparatus by open capillary method and are
uncorrected. The IR spectra of synthesized compounds were
3.32 (t, 4H, ArNe(CH2)2, J ¼ 5.2); 3.87 (s, 2H, eCH2); 6.69e8.1 (m
13H ArH). 13C NMR (
d ppm CDCl3): 14.27 (AreCH3); 50.04 (ArNe
CH2e, ArNeCH2e of pyrazine); 52.94 (NeCH2e, NeCH2e of pyr-
azine at aliphatic site), 64.62 (aliphatic eCH2e); 113.28, 117.05,
120.75, 123.67, 125.58, 127.45 (5C), 128.43, 128.34 (4C), 134.76,
138.79, 146.24, 149.26 (Aromatic C); 195.40 (eC]O).
recorded on Jasco FTIR 4100 in potassium bromide. The 1H NMR, 13
C
NMR and 13C DEPT-135 spectra were recorded in CDCl3 using NMR
Varian Mercury plus 300 MHz using tetra methyl silane (TMS) as
internal standard. The mass spectra of compounds were recorded
on 410 Prostar Binary LC with 500 MS IT PDA detector. Elemental
analysis was performed on FLASH EA 1112, Thermo-Finnigan and
indicated with the element symbol. The elemental analyses were
within ꢀ0.4% of the theoretical values.
4.2.5. 1-(Biphenyl-4-yl)-2-[4-(2-methoxyphenyl)-piperazin-1-yl]
ethanone (3c)
Yield: 74%. mp: 78e80 ꢂC. Elemental analysis: Calcd. C, 77.69; H,
6.78; N, 7.25; O, 8.28.; found: C, 77.72; H, 6.77; N, 7.28; O, 8.25. IR
(cmꢁ1): 3060, 2938, 2818, 1681, 1601. 1H NMR (
d ppm CDCl3): 2.7e
2.8 (t, 4H, eCH2eNe(CH2)2, J ¼ 5.3); 3.28e3.33 (t, 4H, ArNe(CH2)2,
J ¼ 5.2); 3.87 (s, 3H, eOCH3); 3.91 (s, 2H, eCH2); 6.72e8.11 (m, 13H,
4.2.1. Synthesis of 1-biphenyl-4-yl-2-chloroethanone (2)
ArH). 13C NMR (
d ppm CDCl3): 49.94 (ArNeCH2e, ArNeCH2e of
In a 250 mL three neck flask (attached with reflux condenser
and dropping funnel on a mechanical stirrer) 0.02 mol of biphenyl,
0.023 mol of finely powdered anhydrous AlCl3, and 30 mL of carbon
disulphide (CS2) was placed for stirring. From the dropping funnel
0.02 mol of chloroacetyl chloride was added drop wise over a
period of 20 min and reflux of mixture was started while adding.
The mouth of both condenser and funnel was closed with calcium
chloride guard tube. After addition of CS2 the reaction was
continued for 1 h with reflux. The reaction mixture was cooled and
poured slowly on crushed ice containing concentrated hydrochloric
acid. This mixture was stirred for 15 min and the product was
filtered and washed with water to remove traces of hydrochloric
acid. Washing of petroleum ether was given to final product in
order to remove any remaining biphenyl and finally recrystallised
by ethanol water to get pure compound 2.
pyrazine); 53.36 (NeCH2e, NeCH2e of pyrazine at aliphatic site);
54.90 (AreOeCH3); 64.54 (aliphatic eCH2e); 113.73, 115.27, 119.62,
120.43, 127.20 (5C), 129.16 (4C), 134.65, 138.90, 142.38, 143.82,
145.92 (Aromatic C); 195.67 (eC]O).
4.2.6. 1-(Biphenyl-4-yl)-2-[4-(3-chlorophenyl)-piperazin-1-yl]
ethanone (3d)
Yield: 83%. mp: 136e138 ꢂC. Elemental analysis: Calcd. C, 73.74;
H, 5.93; N, 7.17; O, 4.09.; found: C, 73.68; H, 5.91; N, 7.15; O, 4.10. IR
(cmꢁ1): 3031, 2972, 2911, 2842, 1686, 1598, 767. 1H NMR (
d ppm
CDCl3): 2.7e2.8 (t, 4H, eCH2eNe(CH2)2, J ¼ 4.6); 3.28 (t, 4H, ArNe
(CH2)2, J ¼ 5.1); 3.91 (s, 2H, eCH2); 7.12e8.11 (m,13H, ArH). 13C NMR
(d ppm CDCl3): 50.13 (ArNeCH2e, ArNeCH2e of pyrazine); 52.62
(NeCH2e, NeCH2e of pyrazine at aliphatic site), 64.51 (aliphatic e
CH2e); 112.34, 114.73, 122.43, 127.31 (5C), 128.54 (4C), 129.72,
134.33,134.58,139.86, 145.92, 149.42 (Aromatic C); 195.78 (eC]O).
Yield: 91%. Mp: 127e128 ꢂC. Molecular formula: C14H11ClO
(230). Elemental analysis: Calcd. C, 72.89; H, 4.81; O, 6.94.; found: C,
72.84; H, 4.80; O, 6.96. IR (cmꢁ1): 3046, 2943, 1691, 1601, 1H NMR (
d
4.2.7. 1-(Biphenyl-4-yl)-2-(4-m-tolyl-piperazin-1-yl)ethanone (3e)
Yield: 84%. mp: 130e132 ꢂC. Elemental analysis: Calcd. C, 81.05;
H, 7.07; N, 7.56; O, 4.32.; found: C, 81.12; H, 7.08; N, 7.54; O, 4.33. IR
ppm CDCl3): 4.75 (s, 2H, CH2e in acyl side chain); 7.63e7.65 (d, C2,6
0
0
aromatic, J ¼ 6.9, 2H); 7.71e7.74 (d, C2 ,6 aromatic, J ¼ 8.4, 2H);
7.45e7.55 (m, C3 ,4 ,5 ; aromatic 3H); 8.03e8.06 (d, C3,5 aromatic,
J ¼ 8.4, 2H).
(cmꢁ1): 3060, 3034, 2965, 2828, 1689, 1601. 1H NMR (
d ppm CDCl3):
0
0
0
2.31 (s, 3H, AreCH3); 2.7e2.8 (t, 4H, eCH2eNe(CH2)2, J ¼ 4.8);
3.26e3.29 (t, 4H, ArNe(CH2)2, J ¼ 4.7); 3.91 (s, 2H, eCH2); 6.66e
4.2.2. General procedure for syntheses of compound 3ae3n
A mixture of 2 (0.0026 mol), aryl piperazine (0.0026 mol) and
anhydrous potassium carbonate (0.0026 mol) was added to reac-
tion flask and heated in DMF for 4e6 h with stirring at 60 ꢂC. The
reaction was carried out by pouring the mixture in ice cold water.
This mixture was filtered under vacuum and the product was
washed with water. All the compounds were recrystallised from
ethanolewater system.
8.11 (m, 13H, ArH). MS (ESI): m/z 371.2 (Mþ H). 13C NMR (
d ppm
CDCl3): 21.75 (AreCH3); 49.15 (ArNeCH2e, ArNeCH2e of pyr-
azine); 53.61 (NeCH2e, NeCH2e of pyrazine at aliphatic site), 64.50
(aliphatic eCH2e); 113.31, 117.05, 120.75, 127.26 (5C), 128.76,128.96
(4C), 134.71, 138.81, 139.84, 146.04, 151.32 (Aromatic C); 195.87 (e
C]O). DEPT-135 (CDCl3): CH2 negative peaks: 49.16 (2C), 53.62
(2C), 64.54; CH and CH3 Positive peaks: 21.75, 113.30, 117.04, 120.74,
127.25 (5C), 128.76 and 128.96 (4C).
4.2.3. 1-(Biphenyl-4-yl)-2-[4-(2-chlorophenyl)-piperazin-1-yl]
ethanone (3a)
4.2.8. 1-(Biphenyl-4-yl)-2-[4-(3-trifluromethylphenyl)-piperazin-
1-yl]ethanone (3f)
Yield: 83%. mp: 100e102 ꢂC. Elemental analysis: Calcd. C, 73.74;
H, 5.93; N, 7.17; O, 4.09.; found: C, 73.81; H, 5.91; N, 7.15; O, 4.10. IR
Yield: 82%. mp: 130e135 ꢂC. Elemental analysis: Calcd. C, 70.74;
H, 5.46; N, 6.60; O, 3.77.; found: C, 70.81; H, 5.45; N, 6.62; O, 3.76. IR
(cmꢁ1): 3064, 2942, 2827, 1682, 1603, 793. 1H NMR (
d
ppm CDCl3):
(cmꢁ1): 3088, 2993, 2954, 2840, 1691, 1604. 1H NMR (
d ppm CDCl3):
2.7e2.82 (t, 4H, eCH2eNe(CH2)2, J ¼ 4.5); 3.2e3.3 (t, 4H, ArNe
2.79e2.83 (t, 4H, eCH2eNe(CH2)2, J ¼ 4.5); 3.31e3.34 (t, 4H, ArNe
(CH2)2, J ¼ 4.6); 3.9 (s, 2H, eCH2); 6.5e8.11 (m, 13H, ArH). MS (ESI):
(CH2)2, J ¼ 4.6); 3.922 (s, 2H, eCH2); 7.06e8.1 (m, 13H, ArH). MS

S.H. Bhosale et al. / European Journal of Medicinal Chemistry 74 (2014) 358e365
363
(ESI):m/z 425.2 (Mþ H). 13C NMR (
d
ppm CDCl3): 49.73 (ArNeCH2e,
(CH2)2, J ¼ 4.6); 3.89 (s, 2H, eCH2); 6.8e8.11 (m, 12H, ArH). MS
ArNeCH2e of pyrazine); 52.53 (NeCH2e, NeCH2e of pyrazine at
aliphatic site), 64.63 (aliphatic eCH2e); 121.26 (AreCF3); 108.10,
116.79, 122.26, 127.54 (5C), 128.81, 129.36 (4C), 131.15, 134.56,
139.69, 146.12, 150.10 (Aromatic C); 195.56 (eC]O).
(ESI): m/z 425.1 (Mþ H), 426.1 (M þ 2), 427.1 (M þ 4). 13C NMR (
d
ppm CDCl3): 49.36 (ArNeCH2e, ArNeCH2e of pyrazine); 52.18 (Ne
CH2e, NeCH2e of pyrazine at aliphatic site); 64.58 (aliphatic e
CH2e); 118.92, 120.75, 121.72, 127.47 (5C), 128.73, 128.87 (4C),
131.48, 134.83, 139.86, 146.12, 151.29 (Aromatic C); 195.76 (eC]O).
4.2.9. 1-(Biphenyl-4-yl)-2-[4-(4-chlorophenyl)-piperazin-1-yl]
ethanone (3g)
4.2.14. 1-(Biphenyl-4-yl)-2-[4-(2,3-dimethylphenyl)-piperazin-1-
yl]ethanone (3l)
Yield: 79%. mp: 168e170 ꢂC. Elemental analysis: Calcd. C, 73.74;
H, 5.93; N, 7.17; O, 4.09.; found: C, 73.69; H, 5.91; N, 7.15; O, 4.08. IR
Yield: 77%. mp: 108e110 ꢂC. Elemental analysis: Calcd. C, 81.21;
H, 7.34; N, 7.29; O, 4.16.; found: C, 81.15; H, 7.31; N, 7.30; O, 4.18. IR
(cmꢁ1): 3088, 3034, 2966, 2839, 1689, 1599, 758. 1H NMR (
d ppm
CDCl3): 2.81e2.83 (t, 4H, eCH2eNe(CH2)2, J ¼ 4.9); 3.24e3.27 (t,
(cmꢁ1): 3059, 2941, 2820, 1684, 1597. 1H NMR (
d ppm CDCl3): 2.32e
4H, ArNe(CH2)2, J ¼ 4.8); 3.93 (s, 2H, eCH2); 6.84e8.1 (m, 13H,
2.4 (m, 6H, Are(CH3)2); 2.7e2.8 (t, 4H, eCH2eNe(CH2)2, J ¼ 4.6);
ArH). 13C NMR (
d ppm CDCl3): 49.68 (ArNeCH2e, ArNeCH2e of
3.28 (t, 4H, ArNe(CH2)2, J ¼ 4.8); 3.9 (s, 2H, eCH2); 6.7e8.11 (m,
pyrazine); 53.49 (NeCH2e, NeCH2e of pyrazine at aliphatic site),
64.47 (aliphatic eCH2e); 114.68 (2C), 119.70 (2C), 127.42 (5C),
129.17 (4C), 134.69, 139.82, 146.06, 146.89, 147.68 (Aromatic C);
195.77 (eC]O).
12H, ArH). MS (ESI): m/z 385.2 (Mþ H). 13C NMR (
d ppm CDCl3):
11.30, 16.87 (AreCH3); 49.86 (ArNeCH2e, ArNeCH2e of pyrazine);
52.67 (NeCH2e, NeCH2e of pyrazine at aliphatic site); 64.48
(aliphatic eCH2e); 112.32, 119.43, 124.32, 127.89, 127.56 (5C),
128.21 (4C), 133.93, 137.39, 139.32, 146.33, 148.70 (Aromatic C);
195.45 (eC]O).
4.2.10. 1-(Biphenyl-4-yl)-2-[4-(4-flurophenyl)-piperazin-1-yl]
ethanone (3h)
Yield: 81%. mp: 165e170 ꢂC. Elemental analysis: Calcd. C, 76.98;
H, 6.19; N, 7.48; O, 4.27.; found: C, 77.02; H, 6.20; N, 7.46; O, 4.28. IR
4.2.15. 1-(Biphenyl-4-yl)-2-[4-(3,4-dichlorophenyl)-piperazin-1-yl]
ethanone (3m)
(cmꢁ1): 3063, 2965, 2928, 2835, 1687, 1600. 1H NMR (
d
ppm CDCl3):
Yield: 74%. mp: 145e147 ꢂC. Elemental analysis: Calcd. C, 67.77;
H, 5.21; N, 6.59; O, 3.76.; found: C, 67.82; H, 5.19; N, 6.60; O, 3.75. IR
2.78e2.81 (t, 4H, eCH2eNe(CH2)2, J ¼ 5.2); 3.19e3.22 (t, 4H, ArNe
(CH2)2, J ¼ 5.3); 3.91 (s, 2H, eCH2); 6.86e8.11 (m, 13H, ArH). MS
(cmꢁ1): 3088, 3032, 2965, 2831, 1686, 1601, 762. 1H NMR (
d ppm
(ESI): m/z 375.2 (Mþ H). 13C NMR (
d
ppm CDCl3): 50.08 (ArNeCH2e,
CDCl3): 2.68e2.8 (t, 4H, eCH2eNe(CH2)2, J ¼ 5.1); 3.3 (t, 4H, ArNe
ArNeCH2e of pyrazine); 53.54 (NeCH2e, NeCH2e of pyrazine at
aliphatic site), 64.43 (aliphatic eCH2e); 115.61 (2C), 117.97 (2C),
127.26 (5C), 128.97 (4C), 134.69, 139.82, 146.06, 147.92, 156.29 (Ar-
omatic C); 195.81 (eC]O). DEPT-135 (CDCl3): CH2 negative peaks:
50.08 (2C), 53.55 (2C), 64.45; CH and CH3 Positive peaks: 115.60
(2C), 117.89 (2C), 127.22 (5C), and 128.97 (4C).
(CH2)2, J ¼ 4.9); 3.89 (s, 2H, eCH2); 6.8e8.11 (m, 12H, ArH). 13C NMR
(d ppm CDCl3): 49.43 (ArNeCH2e, ArNeCH2e of pyrazine); 52.57
(NeCH2e, NeCH2e of pyrazine at aliphatic site); 64.73 (aliphatic e
CH2e); 112.42, 114.23, 124.58, 148.56, 127.62 (5C), 128.63 (4C),
131.59, 133.82, 134.63, 139.57, 146.12 (Aromatic C); 195.68 (eC]O).
4.2.16. 1-(Biphenyl-4-yl)-2-(4-phenyl-piperazin-1-yl)ethanone
(3n)
4.2.11. 1-(Biphenyl-4-yl)-2-(4-p-tolyl-piperazin-1-yl)ethanone (3i)
Yield: 62%. mp: 148e150 ꢂC. Elemental analysis: Calcd. C, 81.05;
H, 7.07; N, 7.56; O, 4.32.; found: C, 80.99; H, 7.09; N, 7.58; O, 4.30. IR
Yield: 84%. mp: 180e184 ꢂC. Elemental analysis: Calcd. C, 80.87;
H, 6.79; N, 7.86; O, 4.49.; found: C, 80.91; H, 6.81; N, 7.84; O, 4.50. IR
(cmꢁ1): 3044, 2964, 2836, 1687, 1605. 1H NMR (
d
ppm CDCl3): 2.32
(cmꢁ1): 3096, 3060, 2960, 2844,1686,1602. 1H NMR (
d ppm CDCl3):
(s, 3H, AreCH3); 2.7e2.8 (t, 4H, eCH2eNe(CH2)2, J ¼ 5.4); 3.25e
2.78e2.82 (t, 4H, eCH2eNe(CH2)2, J ¼ 4.95); 3.28e3.31 (t, 4H,
3.29 (t, 4H, ArNe(CH2)2, J ¼ 5.4); 3.9 (s, 2H, eCH2); 6.7e8.11 (m,
ArNe(CH2)2, J ¼ 4.9); 3.91 (s, 2H, eCH2); 6.93e8.1 (m,14H, ArH). MS
13H, ArH). 13C NMR (
d
ppm CDCl3): 22.16 (AreCH3); 49.82 (ArNe
(ESI): m/z 357.2 (Mþ H). 13C NMR (
d ppm CDCl3): 49.56 (ArNeCH2e,
CH2e, ArNeCH2e of pyrazine); 52.92 (NeCH2e, NeCH2e of pyr-
azine at aliphatic site), 64.73 (aliphatic eCH2e); 113.98(2C), 126.82,
127.69 (5C), 129.21 (4C), 130.32 (2C), 134.73, 139.64, 146.23, 147.24
(Aromatic C); 195.54 (eC]O).
ArNeCH2e of pyrazine); 53.26 (NeCH2e, NeCH2e of pyrazine at
aliphatic site); 63.73 (aliphatic eCH2e); 114.43 (2C), 119.23, 124.58,
127.62 (4C), 128.90 (6C), 133.85,138.47, 145.83, 148.56 (Aromatic C);
194.86 (eC]O).
4.2.12. 1-(Biphenyl-4-yl)-2-[4-(4-methoxyphenyl)-piperazin-1-yl]
ethanone (3j)
4.3. Pharmacology
Yield: 63%. mp: 150e152 ꢂC. Elemental analysis: Calcd. C, 77.69;
H, 6.78; N, 7.25; O, 8.28.; found: C, 77.74; H, 6.75; N, 7.28; O, 8.30. IR
4.3.1. Experimental groups
Male albino mice (weight range of 20e25 g) procured from
Serum Institute of India, Pune were used for experimental study.
The animals were kept in suitable environmental condition
(22 ꢀ 2ꢂ C with 12 h light/dark cycle) and fed with standard food
pellets. For experiment purpose three groups of animals as control,
test and standard, each with 6 animals were made. All the doses
were calculated on body weight basis and were prepared in water
for injection (WFI). Route of administration was i.p. except wher-
ever mentioned. Aripiprazole was used as standard for experi-
mental study. Institutional animal ethical committee, Poona
College of pharmacy approved all animal experiments.
(cmꢁ1): 3033, 3000, 2947, 2834, 1684, 1601. 1H NMR (
d ppm CDCl3):
2.7e2.8 (t, 4H, eCH2eNe(CH2)2, J ¼ 5.1); 3.26e3.3 (t, 4H, ArNe
(CH2)2, J ¼ 5.2); 3.83 (s, 3H, eOCH3); 3.88 (s, 2H, eCH2); 6.72e8.1
(m, 13H, ArH). 13C NMR (
d ppm CDCl3): 55.66 (AreOeCH3); 49.73
(ArNeCH2e, ArNeCH2e of pyrazine); 52.86 (NeCH2e, NeCH2e of
pyrazine at aliphatic site), 64.53 (aliphatic eCH2e); 114.96(2C),
115.10(2C), 127.48 (5C), 129.24 (4C), 134.46, 139.45, 146.18, 147.83,
148.28 (Aromatic C); 195.69 (eC]O).
4.2.13. 1-(Biphenyl-4-yl)-2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]
ethanone (3k)
Yield: 85%. mp: 155e160 ꢂC. Elemental analysis: Calcd. C, 67.77;
H, 5.21; N, 6.59; O, 3.76.; found: C, 67.82; H, 5.20; N, 6.61; O, 3.77. IR
4.3.2. Inhibition of apomorphine induced climbing behaviour
Administration of apomorphine to mice results in an unusual
climbing behaviour characterized initially by rearing and then full-
climbing activity, predominantly mediated by the mesolimbic
(cmꢁ1): 3062, 2946, 2832, 1687, 1581, 769. 1H NMR (
d
ppm CDCl3):
2.7e2.8 (t, 4H, eCH2eNe(CH2)2, J ¼ 4.5); 3.2e3.5 (t, 4H, ArNe

364
S.H. Bhosale et al. / European Journal of Medicinal Chemistry 74 (2014) 358e365
dopamine system. On the basis of this test, the relative antipsy-
chotic potential of the synthesized compounds has been deter-
mined. Climbing behaviour was assessed in the animals by placing
them individually in the cylindrical wire mesh cage (height 18 cm,
diameter 14 cm). Five minutes after administration of apomorphine
(1.0 mg/kg) (intraperitoneal; i.p), standard or test compound was
administered at 15 mg/kg dose by i.p. route. After 10 min climbing
behaviour was assessed at 5-min intervals for 30 min. In standard
group, animal received aripiprazole at dose of 15 mg/kg [21].
calculated by using QikProp module within Schrödinger suite [26].
To derive QSAR models, the QikProp calculated descriptors were
used as independent variables and the BA as the dependent vari-
able. All the statistical work was done in Strike module [27]. Cross-
validated multiple linear regressions (MLR) method of leave one
out (LOO) was performed to generate QSAR equation. The QSAR
equation for antipsychotic potential was evaluated by cross vali-
dated correlation coefficient ðrc2vÞ, standard error of estimation (s),
F-test (F) and correlation coefficient (r2).
4.3.3. Antagonism of 5-HTP induced head twitches
4.5.2. Similarity study
5-HTP was used as the precursor of serotonin. In mice because of
5-HTP, the characteristic symptom of head-twitches is observed.
Antagonism of head twitches induced by 5-HTP in mice indicates
anti-serotonergic activity. Each animal in the control group was
injected with WFI. After 30 min the animals were injected with
carbidopa solution (25 mg/kg) prepared in WFI. It was followed by
administration of 5-HTP solution (100 mg/kg, i.v.) after 30 min. The
numbers of head twitches were counted for a period of 5 min which
was followed by an interval of 5 min before the next count. Head
twitches were counted for a period of 1 h. For test compounds each
animal was administered at 15 mg/kg dose after 30 min followed by
5-HTP solution and carbidopa. Head twitches were counted similar
to control group. In standard group, animal received aripiprazole at
dose of 15 mg/kg [22].
In the present study we performed the similarity study of 14
synthesized derivatives (test molecules) along with four standard
drugs aripiprazole, sertindole, ketanserin and paliperidone (probe
molecules). All the computational studies were performed using
MAESTRO, graphical user interface for Schrödinger suite 2009. The
3D structure of molecules was built using ‘build’ module within
Schrödinger. The various physicochemical properties such as log P,
molecular weight, solvent accessible surface area and molecular
volume were calculated by using QikProp module within Schrö-
dinger suite as these properties of the antipsychotic drugs are
responsible to cross BBB. The descriptor-based similarity study was
done in Strike module. The similarity study was carried out using
tanimoto association coefficient, which gives the similarity values
in scale from 0 to 1. The tanimoto distance metric is a normalized
measure of the similarity in descriptor space between a test
molecule and a probe molecule. Similarities lie between one and
zero with a value of one indicating identical molecules and a value
of zero indicating completely dissimilar molecules.
4.3.4. Haloperidol induced catalepsy
It has been noticed that catalepsy in rodent is a model predictive
of EPS in human. Animals in the control group were administered
with haloperidol (1 mg/kg), which was taken as the prototype of
typical antipsychotics as result catalepsy was induced in the ani-
mals. Assessment of catalepsy was done by placing the forepaws of
mice on a horizontal bar (2 mm in diameter) kept at a height of
2.5 cm from the platform with hind paws resting on the platform.
The evaluation of haloperidol induced catalepsy was done by
recording the time span for which the mice retained their forepaws
on the horizontal bar during the observation periods of 5 min. The
animals in the test group were administered with test drug instead
of haloperidol and the remaining procedure for assessment of
catalepsy was same as mentioned above [23].
Acknowledgement
The authors are thankful to Serum Institute of India (SII), Pune
for providing animals for experimental work.
Appendix A. Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.ejmech.2013.12.
043. These data include MOL files and InChIKeys of the most
important compounds described in this article.
4.4. Statistical analysis
The data obtained from the above studies was analysed to one
way analysis of variance (ANOVA) for determining the significant
difference between the groups. The inter group significance or post
hoc comparison was analysed using Dunnet’s t test. P values <0.05
were considered to be significant. All the values were expressed as
percentage inhibition of respective behaviour model relative to
control group.
References
[1] J.S. Mayer, L.F. Quenzer, Psychopharmacology: Drugs, the Brain and Behavior,
Sinauer Associates Inc., Sunderland, Massachusetts, USA, 2005.
[2] B. Capuano, I.T. Crosby, E.J. Lloyd, Schizophrenia: genesis, receptorology and
current therapeutics, Curr. Med. Chem. 9 (5) (2002) 521e548.
[3] S. Aldridge, Magic Molecules: How Drugs Works, Cambridge University Press,
1998.
[4] S. Wu, R. Gao, Q. Xing, H. Li, Y. Shen, N. Gu, G. Feng, L. He, Association of DRD2
polymorphisms and chlorpromazine-induced extrapyramidal syndrome in
Chinese schizophrenic patients, Acta Pharmacol. Sin. 27 (8) (2006) 966e970.
[5] A. Wieck, P. Haddad, Hyperprolactinaemia caused by antipsychotic drugs, BMJ
324 (7332) (2002) 250e252.
[6] B.H. Hansen, B.V. Christensen, F.C. Gronvald, J.P. Mongensen, Mesolimbic se-
lective antipsychotic arylcarbamates, Eur. J. Med. Chem. 33 (11) (1998) 839e
858.
[7] S. Kapur, G. Remington, Serotonin-dopamine interaction and its relevance to
schizophrenia, Am. J. Psychiatry 153 (1996) 466e476.
[8] D.A. Wirshing, W.C. Wirshing, L. Kysar, M.A. Berisford, D. Goldstein, J. Pashdag,
J. Mintz, S.R. Marder, Novel antipsychotics: comparison of weight gain lia-
bilities, J. Clin. Psychiatry 60 (6) (1999) 358e363.
[9] M. Lorenz, W.E. Evering, A. Provencher, J.T. Blue, H.B. Lewis, J.R. Hazelette,
P. Rajagopalan, P.C. Meunier, B.D. Car, Atypical antipsychotic-induced neu-
tropenia in dogs, Toxicol. Appl. Pharmacol. 155 (3) (1999) 227e236.
[10] J.A. Lowe, T.F. Seeger, A.A. Nagel, H.R. Howard, P.A. Seymour, J.H. .Heym,
F.E. Ewing, M.E. Newman, A.W. Schmidt, J.S. Furman, 1-Naphthylpiperazine
derivatives as potential atypical antipsychotic agents, J. Med. Chem. 34 (6)
(1991) 1860e1866.
4.5. Computational studies
4.5.1. QSAR Study
In the present study 14 derivatives and their corresponding
antipsychotic potential were used for QSAR generation. All the
computational studies were performed using maestro, graphical
user interface for Schrödinger suite 2009 [24]. The 3D structure of
molecules was built using ‘build’ module within Schrödinger. All
the structures were minimized using MacroModel by OPLS_2005
with PowelleReeves conjugate gradient convergence criterion of
0.05 kcal/mol force field at a maximum of 3500 iteration. An 8 A0
and 20 A0 cut-off was applied for both van der Waals interactions
and electrostatic energies respectively [25]. Physically significant
descriptors and pharmaceutically relevant properties were

S.H. Bhosale et al. / European Journal of Medicinal Chemistry 74 (2014) 358e365
365
[11] R.W. Feenstra, J. Moes, J.J. Hofma, H. Kling, W. Kuipers, S.K. Long, M.M. Tulp,
New 1-aryl-4-(biarylmethylene)piperazines as potential atypical antipsy-
chotics sharing dopamine D2-receptor and serotonin 5-HT1A-receptor affin-
ities, Bioorg. Med. Chem. Lett. 11 (2001) 2345e2349.
[12] G.E. Martin, R.J. Elgin, J.R. Mathiasen, C.B. Davis, J.M. Kesslick, W.J. Baldy,
R.P. Shank, D.L. DiStefano, C.L. Fedde, M.K. Scott, Activity of aromatic
substituted phenylpiperazines lacking affinity for dopamine binding sites in a
preclinical test of antipsychotic efficacy, J. Med. Chem. 32 (5) (1989) 1052e
1056.
[13] S. Butini, S. Gemma, G. Campiani, S. Franceschini, F. Trotta, M. Borriello,
N. Ceres, S. Ros, S.S. Coccone, M. Bernetti, M. De Angelis, M. Brindisi, V. Nacci,
I. Fiorini, E. Novellino, A. Cagnotto, T. Mennini, K. Sandager-Nielsen,
J.T. Andreasen, J. Scheel-Kruger, J.D. Mikkelsen, C. Fattorusso, Discovery of a
new class of potential multifunctional atypical antipsychotic agents targeting
dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis,
and effects on behaviour, J. Med. Chem. 52 (1) (2009) 151e169.
[14] A. Deep, S. Jain, P.C. Sharma, Synthesis and anti-inflammatory activity of some
novel biphenyl-4-carboxylic acid 5-(arylidene)-2-(aryl)-4-oxothiazolidin-3-yl
amides, Acta Pol. Pharm. 67 (1) (2010) 63e67.
[17] M.G. Setzu, G. Stefancich, P. LaColla, S. Castellano, Synthesis and antifungal
properties of N-[(1,10-biphenyl)-4-ylmethyl]-1H-imidazol-1-amine de-
rivatives, Farmaco 57 (12) (2002) 1015e1018.
[18] R.C. Dash, S.H. Bhosale, S.M. Shelke, M.R. Suryawanshi, A.M. Kanhed,
K.R. Mahadik, Scaffold hopping for identification of novel D2 antagonist based
on 3D pharmacophore modelling of illoperidone analogs, Mol. Diversity 16 (2)
(2012) 367e375.
[19] N. Bodor, P. Buchwald, Recent advances in the brain targeting of neuro-
pharmaceuticals by chemical delivery systems, Adv. Drug. Delivery Rev. 36
(1999) 229e254.
[20] Glide, Version 5.5 Schrödinger, LLC, New York, NY, 2009.
[21] S.R. Kesten, T.G. Heffner, S.J. Johnson, T.A. Pugsley, J.L. Wright, L.D. Wise,
Design, synthesis, and evaluation of chromen-2-ones as potent and selective
human dopamine D4 antagonists, J. Med. Chem. 42 (18) (1999) 3718e3725.
[22] H.G. Vogel, Drug Discovery and Evaluation: Pharmacological Assay, Springer-
Verlag Berlin Heidelberg, New York, 2002.
[23] R.T. Khisti, S.N. Mandhane, C.T. Chopde, The neurosteroid 3 alpha-hydroxy-5
alpha-pregnan-20-one induces catalepsy in mice, Neurosci. Lett. 251 (2)
(1998) 85e88.
[15] R. Sharma, P.S. Kodavanti, In vitro effects of polychlorinated biphenyls and
hydroxy metabolites on nitric oxide synthases in rat brain, Toxicol. Appl.
Pharmacol. 178 (2002) 127e136.
[16] N. Sachan, S. Thareja, R. Agarwal, S.S. Kadam, V.M. Kulkarni, Substituted
biphenyl ethanones as antidiabetic agents: synthesis and in-vivo screening,
Int. J. PharmTech Res. 1 (4) (2009) 1625e1631.
[24] MAESTRO, Version 9.0, Schrödinger, LLC, New York, NY, 2009.
[25] MacroModel, Version 9.7, Schrödinger, LLC, New York, NY, 2009.
[26] QikProp, Version 3.2, Schrödinger, LLC, New York, NY, 2009.
[27] Strike, Version 1.8, Schrödinger, LLC, New York, NY, 2009.