Synthesis and computational studies on aryloxypropyl piperazine derivatives as potential atypical antipsychotic agents

Article abstract of DOI:10.2174/157018012799079725

A series of aryloxypropyl derivatives have been synthesized and evaluated for atypical antipsychotic activity in apomorphine induced mesh climbing and stereotypy assays in mice and the compounds displayed good efficacy coupled with an atypical profile. In

Full text of DOI:10.2174/157018012799079725

218
Letters in Drug Design & Discovery, 2012, 9, 218-224
Synthesis and Computational Studies on Aryloxypropyl Piperazine
Derivatives as Potential Atypical Antipsychotic Agents
Alka Bali*, Abhishek Bhalla, Suman Bala and Rajesh Kumar
University Institute of Pharmaceutical Sciences, UGC Center of Advanced Study, Panjab University, Chandigarh, 160
014, India
Received July 08, 2011: Revised November 02, 2011: Accepted November 02, 2011
Abstract: A series of aryloxypropyl derivatives have been synthesized and evaluated for atypical antipsychotic activity in
apomorphine induced mesh climbing and stereotypy assays in mice and the compounds displayed good efficacy coupled
with an atypical profile. Investigation of the selected physicochemical parameters important for CNS activity suggested a
good potential for CNS activity. All compounds showed excellent compliance with lipinski’s rules for oral and CNS
activity. Good physicochemical similarity was noted for the test compounds with respect to standard drugs and good brain
permeation was suggested by their log BB values computed through an online software program.
Keywords: Atypical antipsychotics, CNS agents, Lipinski rules, Log BB, Aryloxypiperazines, Piperazine.
1. INTRODUCTION
development of atypical antipsychotics, viz dopaminergic
[12,13], serotonergic [14, 15] and several others [16-18]
suggest that the strategies of "intramolecular polypharmacy,"
in which a single drug possesses the capacity to affect
multiple receptor types should to be more relevant in this
regard. Further, each atypical possesses a unique portfolio of
activities at receptors that may contribute to therapeutic
effects or side effects [19]. Hence, behavioural tests based
upon locomotor activity and stereotyped behaviour induced
by a dopaminergic agonist (e.g., apomorphine) have been
widely used to assess atypical antipsychotic profile. In these
models, a significant reversal of the locomotor activity
(mesh climbing behaviour) induced by a dopaminergic
agonist like apomorphine is indicative of a potential
antipsychotic profile arising from dopaminergic blockade in
the mesolimbic areas of the brain. Further, the inability of
the compound to reverse the apomorphine induced
stereotyped behaviour suggests a low propensity to cause
extrapyramidal symptoms by sparing the nigrostriatal system
[20]. We had recently reported a series of quinoliloxypropyl
piperazines and 1, 4-diaryl substituted piperazine derivatives
[21-22] as potential atypical antipsychotics bearing acetyl
substituent on the phenyl ring. We found it worthwhile to
extend the series further by replacing COCH3 group with
other H-bond acceptor groups (methoxy/CHO) and
investigate the resultant effect on their pharmacological
activity in the same animal models to extend the structure
activity relationships. In this paper, we therefore, report the
synthesis, pharmacological evaluation and computational
studies on the aryloxypiperazine series of compounds
bearing methoxy/CHO substituents in place of COCH3
group. Since, the compounds were intended to be CNS
active, their potential to cross the blood brain barrier was
computed through an online software program in terms of
their log BB values. The physicochemical and steric
similarity between standard drugs clozapine, ketanserin,
ziprasidone and risperidone and the new analogs was
Schizophrenia is a complex psychological disorder
afflicting nearly 24 million people worldwide which
accounts for 1% of the population worldwide [1].
Neurochemical and/or anatomical abnormalities in the
central nervous system (CNS) are proposed to be the
underlying cause of this disorder [2]. Although, multiple
approaches have been explored as research and development
tools [3], yet, the dopaminergic hypothesis of schizophrenia
has dominated the drug development in this field [4]. The
activity of classical or typical antipsychotics such as
haloperidol to alleviate the positive symptoms of the disease
is related to their ability to block D2 receptors in the
mesocorticolimbic system, and the intensity of their
mechanism related side effects i.e. muscular rigidity,
bradykinesia, akathesia and galactorroea (due to increased
prolactin release) is closely correlated with their ability to
block the dopaminergic receptors in the nigrostriatal
pathway [5, 6]. The dibenzodiazepine derivative clozapine
[7], considered as the prototype of the new group of non-
classical or atypical antipsychotics is indicated for patients
refractory to conventional antipsychotics. Atypical
antipsychotics possess a superior profile over conventional
neuroleptics in being nearly devoid of extrapyramidal side
effects and in being effective in alleviation of negative
symptoms of the disease. Many, but not all, atypicals have
been found to improve cognitive function, which could be
their most important advantage with regard to efficacy [8].
However, their hematological safety, metabolic and other
adverse effects [9-11] have been the cause of constant
concern in context of their therapeutic importance. The
complex etiology of schizophrenia arises from the
multireceptor involvement in the disease. The numerous
receptor binding approaches being followed for the
*Address correspondence to this author at the University Institute of
Pharmaceutical Sciences, UGC Center of Advanced Study, Panjab
University, Chandigarh,160 014, India; Tel: 91-172-2534104 ; Fax: 91-172-
541142; E-mail: alka.bali@rediffmail.com, alkaa.bali@gmail.com
calculated from
a set of physicochemical properties
computed using software programs.
© 2012 Bentham Science Publishers
1875-628X/12 $58.00+.00

Aryloxypiperazines as Potential Atypical Antipsychotics
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 2 219
OCH2CH2CH2Cl
R
a
HO
R
R
+
3
4
9
o-OCH3
p-OCH3
o-CHO
ClCH2CH2CH2Br
10 p-CHO
N
Cl
b
NH
c
Cl
Cl
1
2
o-Cl
p-Cl
N
N
Cl
Cl
p-
o-
o-
p-
p-
o-
o-
p-
O
R
5
6
7
8
p-OCH3
p-OCH3
o-OCH3
o-OCH3
11 o-CHO
12 o-CHO
13 p-CHO
14 p-CHO
Scheme 1. Synthetic scheme for preparation of the final compounds 5-8 and 11-14.
Reagents and conditions: (a) K2CO3, 16-18 h (b) piperazine (twice molar quantity), abs. EtOH, (c) K2CO3, DMF, 700C, 3-10 h reflux
2. RESULTS AND DISCUSSION
2.1. Synthesis
and 4- hydroxybenzaldehydes were similarly reacted with 1-
bromo-3-chloropropane and potassium carbonate in acetone
to prepare their 3-chloropropyl ether derivatives 2- and 4-
(3- chloropropoxy)benzaldehydes 9 and 10. The final
target compounds X’-[3-{4-(X-chlorobenzyl)piperazin-1-
yl}propoxy] benzaldehydes (11-14) were prepared by
coupling of 9 and 10 with the the respective chlorobenzyl
piperazines 1 and 2 in dimethyl formamide. All the reactions
were monitored by TLC and the final products were purified
by column chromatography and characterized through UV,
IR, NMR and mass spectroscopic data.
The synthetic scheme followed for the preparation of the
final compounds and their chemical structures are given in
Scheme 1. The first step was the preparation of 2- and 4-
chlorobenzyl piperazines 1 and 2 by reaction of the
corresponding chlorobenzyl chlorides with piperazine in
absolute ethanol at room temperature. In these reactions, the
formation of the respective disubstituted derivatives, viz 1,4-
bis-(2- or 4- chlorobenzyl) piperazines was minimized by
using half molar quantity of chlorobenzyl chloride, as
compared to the piperazine. The compounds 1 and 2 were
obtained in good yields (80-85%) and the disubstituted
compounds (nearly 2.5% yields) were removed from the
products by filtration. In the second step, 2- or 4-
2.2. Preliminary Evaluation for Atypical Antipsychotic
Effect
Amongst the established animal behavioural models, the
inhibition of apomorphine induced climbing response in
mice coupled with a weak or no inhibition of apomorphine
induced stereotypy has been an accepted model for atypical
profile. Prior permission of the Institutional Animal Ethics
Committee (IAEC) was obtained and all experiments were
conducted according to the approved protocol. The final
compounds were evaluated for their ability to antagonize
apomorphine induced mesh climbing behaviour (indicative
of dopaminergic antagonism in mesocorticolimbic pathway
associated with antipsychotic effect) and apomorphine
methoxyphenols
were
refluxed
with
1-bromo-3-
chloropropane with potassium carbonate in acetone by
variation of our previously reported procedure [21] yielding
their corresponding 3-chloropropyl ether derivatives 3 and 4.
The
final
compounds
1-(X-chlorobenzyl)-4-(3-(X’-
methoxyphenoxy)propyl) piperazines 5 – 8 were obtained in
good yields (65-70%) by coupling reaction of the
corresponding chlorobenzyl piperazines 1 and 2 with the
chloropropyl ether derivatives 3 and 4 in dimethylformamide
at a temperature of 700C. Further, the starting compounds 2-

220 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 2
Bali et al.
induced stereotypy (characteristic of antagonism in
nigrostriatal system linked to extrapyramidal symptoms) in
mice. Initial titration at different dose levels was done for
selection of doses and three dose levels were employed for
all the tested compounds. Clozapine was employed as a
standard drug (positive control) in three dose levels of 2.5,
5.0 and 7.5 mg/kg. A 0.1% solution of the surfactant Tween
80 prepared in distilled water was used as a vehicle to
dissolve the target compounds. 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 (p < 0.001) and
TUKEY test (p<0.05) (Jandel Sigmastat version 2.0). The
results from the pharmacological evaluation of the target
compounds are given in Tables 1 and 2 and depicted
graphically in Figs. (1 and 2). A statistically significant
reversal of apomorphine induced mesh climbing was noted
for the test compounds 5-8 and 11-14. Except for compound
11, all other compounds did not produce a statistically
significant reversal of apomorphine induced stereotypy.
Negative results in stereotypy assay imply that nigrostriatal
regions of the brain are being spared by the drug and this
suggests the presence of a potential atypical profile.
Compound 11, on the other hand, displayed a conventional
or ‘typical’ profile. In our previous studies, efficacy of the o-
COCH3 derivatives (ED50 values 10.0 and 10.5 mg kg-1
respectively) had been found to be much higher than their p-
COCH3 analogs (ED50 values 50.0 and 23.0 mg kg-1
respectively) and differences were noted in terms of atypical
profile also, however, interestingly, this differentiation was
not seen in case of the methoxy/CHO analogs with para- and
ortho- analogs displaying very similar efficacies in the mesh
climbing assay. The position of the substituents seems to be
playing very little role in determining an atypical profile in
this compound series. Considering the fact that both OCH3
and CHO groups are electronically similar to acetyl group
and can possibly show similar interactions with the target
site(s), these differences may be attributed to their smaller
steric bulk than acetyl moiety which seems to delineate the
atypical profile from the position of the substituent on the
phenyl ring. Moreover, the ED50 values of the compounds
(calculated from the plot of log dose vs response at three
dose levels) ranged from 3.1-5.7 mg kg-1. These values are
much lower in comparison with the values for the
corresponding acetyl derivatives reported earlier (ED50
values 10.0 and 50.0 mg kg-1) [22]. In order to correlate this
enhanced efficacy with the change in the chemical structure,
selected molecular parameters were calculated for the target
compounds and some atypical antipsychotic drugs using
Chem3D Pro 12.0 (Table 3) and online softwares.
Lipophilicity (ClogP) has been identified as important
determinants for membrane permeability as well as blood
brain barrier penetration. The values of ClogP for most of
our test compounds were in the range (3.806-3.933) close to
that of marketed CNS drugs. Further, the calculated log P
values of the methoxy/CHO analogs (3.806-3.933) and their
log BB values (0.27-0.53) were found to be quite close to the
corresponding values for the COCH3 derivatives (log P 3.371
and logBB 0.24-0.34). This signifies similarity in solubility
profiles, permeability characteristics and BBB penetration
potential of the methoxy/CHO and COCH3 analogs. In this
light, the observed differences in the activities of may be
significantly (if not solely) attributable to the differences in
chemical structures. Besides lipophilicity, several other
molecular parameters have also been correlated with CNS
activity, e.g.,cutoff limits have been given for molecular
weights of CNS drugs for efficient BBB penetration. Mean
value of MW for marketed CNS drugs is 310. Levin [23] and
Van de Waterbeemd [24] have suggested these limits as 400
and 450 respectively and values (363-375) for all our
compounds fall within these limits. Similarly, literature
reports suggest that TPSA is a measure of a molecule’s
hydrogen bonding capacity and its value should not exceed a
certain limit if the compound is intended to be CNS active.
The values for these limits proposed are 60-70 A˚2 [25] and
should not exceed 90 A˚2. The TPSA values for our test
compounds were found to be well within these limits (32.78
- 49.85) which shows that all the test compounds have a
potential to effectively cross the blood brain barrier.
According to Lipinski’s “Rule of five” [26], a good
absorption and permeability is likely if MW is ꢀ500; LogP is
ꢀ5; number of hydrogen bond donors (expressed as the sum
of OHs and NHs) ꢀ5 and number of hydrogen bond
acceptors (expressed as the sum of Ns and Os) ꢀ10 and
number of rotatable bonds ꢀ10. These rules get more
stringent for good CNS penetration as molecular weight
ꢀ400; Log P ꢀ 5; number of hydrogen bond donors ꢀ3 and
number of hydrogen bond acceptors ꢀ7. As evident from
Table 3, all compounds comply well with these rules.
Recently, several computational methods have been worked
out to assess blood brain barrier penetration of compounds
with overall accuracies ranging from 75% to 97% [27]. We
calculated the log BB values for our target compounds using
an online software program based on topological descriptors
[28] (Table 3). The values were also determined for the
selection of antipsychotics for comparison. Experimental
values of log BB published cover the range from about _2.00
to +1.04. Literature reports suggest that log BB values
greater than 0.30 result for the compounds which are able to
cross the BBB readily. In comparison, log BB values below -
1.00 signify a poor distribution to the brain [29]. The Log
BB values for our present compound series (0.27 to 0.53)
suggests an excellent potential for blood brain barrier
penetration.
3. EXPERIMENTAL SECTION
The melting points reported are uncorrected. The Infrared
spectra of these compounds were recorded in KBr pellets on
Perkin Elmer PE RX 1 FTIR spectrophotometer. Proton
NMR was recorded on Bruker Avance-II, 400 MHz
instrument. For NMR, solutions were made in deuterated
chloroform containing tetramethylsilane as internal
reference. For mass spectra, solutions were made in HPLC
grade methanol. Reactions were monitored and the
homogeneity of the products was checked by TLC.
Anhydrous sodium sulfate and anhydrous calcium chloride
were used for drying solvent extracts.
3.1. General Procedure for Synthesis
A suspension of potassium carbonate (0.647g, 4.7mmol)
was prepared in 5ml of DMF and 1-(X-chlorobenzyl)
piperazines (4.7 mmol) were added with stirring. To the

Aryloxypiperazines as Potential Atypical Antipsychotics
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 2 221
Table 1. Chemical Structures and Pharmacological Evaluation of the Compounds for Atypical Antipsychotic Profile
R1
O
R
N
N
R2
Compound
R
R1
R2
ED50(mg/kg)
Log ED50
Reversal of
Reversal of
apomorphine
apomorphine
induced mesh
climbinga
induced stereotypya
(mesh
climbing)
5
p-OCH3
p-OCH3
o-OCH3
o-OCH3
o-CHO
o-CHO
p-CHO
p-CHO
-
Cl
H
H
Cl
Cl
H
H
Cl
-
H
Cl
Cl
H
H
Cl
Cl
H
-
+
+
+
+
+
+
+
+
+
_
_
_
_
+
_
_
_
_
3.10
3.10
5.01
5.20
5.70
4.50
4.60
5.00
3.01
0.49
0.49
6
7
0.70
8
0.72
11
12
0.755
0.653
0.662
0.698
0.479
13
14
Clozapine
aStatistically significant reduction compared to control assessed by one way ANOVA (p < 0.001) and TUKEY test (p<0.05).
Table 2. Mean Score in Apomorphine Induced Mesh Climbing and Stereotypy
Treatment
Average score at time (min)
20
10
15
25
30
C
St
C
St
C
St
C
St
C
St
Naïve
7.0 ±0.45
8.8 ±0.37
5.4±0.22b
4.0±0.31
8.0±0.31
8.4±0.10
6.0±0.31b
7.8±0.37
5.2±0.09b
3.0±0.31
8.2±0.37
7.8±0.17
6.0±0.55
8.2±0.37
6.0±0.14b
3.2±0.20
8.2±0.17
8.2±0.17
5.4±0.51
7.6±0.24
5.0±0.20b
2.2±0.20
8.4±0.24
8.2±0.09
5.8±0.37
8.0±0.32
5.0±0.14b
1.4±0.51
8.2±0.20
7.6±0.17
Control
Clozapine
(7.5mg/kg)
5 (7.5mg/kg)
6 (10mg/kg)
7 (10mg/kg)
8 (10mg/kg)
11(10mg/kg)
12(10mg/kg)
13(7.5mg/kg)
14(10mg/kg)
5.4±0.24a
5.0±0.45a
5.4±0.10b
4.8±0.09b
4.8±0.37a
4.6±0.59a
5.0±.44a
8.2±0.20
7.8±0.20
8.0±0.18
8.2±0.11
4.0±0.31a
8.0±0.54
7.6±0.73
8.0±0.54
4.2±0.29a
5.0±0.31a
5.4±0.18b
4.8±0.21b
4.6±0.24a
4.8±0.58a
4.0±0.31a
6.2±0.58a
8.4±0.24
8.0±0.31
7.8±0.20
7.8±0.17
3.2±0.19a
6.8±0.73
7.8±0.66a
6.6±1.0
4.2±0.20a
4.4±0.40a
5.2±0.09b
5.1±0.11b
4.6±0.24a
4.4±0.54a
4.4±0.24a
5.0±.54 a
7.4±0.24
8.0±0.31
7.6±0.11
8.0±0.14
3.2±0.37
7.8±0.73
7.6±0.81
8.2±0.20
4.6±0.24a
4.4±0.24a
4.8±0.09b
4.4±0.11b
5.2±0.37 a
4.4±0.48 a
4.8±0.37 a
5.2±0.48 a
7.4±0.24
7.9±0.20
8.4±0.22
7.8±0.09
4.0±0.31a
7.0±0.44
7.8±0.37
6.8±0.48
3.8±0.37a
4.0±0.31b
5.4±0.17b
4.0±0.14b
4.8±0.37 a
5.0 ±0.37 a
4.6±0.51 a
5.2 ±0.37 a
7.6±0.20
7.8±0.20
7.9±0.11
7.2±0.17
3.6±0.24a
7.6±0.51
7.6±0.54
7.4±0.37
6.6±0.59a
Readings shown are at highest dose level.
All values are expressed as mean + S.E.M. (n=5); a significantly different from control at p < 0.001 (one way ANOVA).
bSignificantly different from control at P< 0.05 (TUKEY test).
C: Apomorphine Induced mesh climbing St: Apomorphine Induced stereotypy.
resulting suspension, a solution of X-(3-chloropropoxy)
benzaldehyde/X-(3-chloropropoxy)anisole (3.1 mmol) in
DMF (5ml) was added dropwise with stirring. The solution
was heated at a temperature of 70-800C for 3-10 hours and
filtered. The filtrate was added to 60ml water. The resulting
solution was extracted with chloroform; the chloroform layer
was washed with saline and dried over anhydrous sodium
sulphate. Removal of the solvent under vacuum afforded the
crude product which was purified by column
chromatography using silica gel (60-80 mesh), employing
petroleum ether along with varying amounts of ethyl acetate
and methanol as solvent.

222 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 2
Bali et al.
10
9
Control
8
Clozapine
7
5
6
6
5
7
4
8
3
11
12
13
14
2
1
0
10
15
20
25
30
Time in minutes
Fig. (1). Mean Score of Compounds in Apomorphine Induced Mesh Climbing Assay.
9
8
7
6
5
4
3
2
1
0
Control
Clozapine
5
6
7
8
11
12
13
14
10
15
20
25
25
Time in minutes
Fig. (2). Mean Score of Compounds in Apomorphine Induced Mesh Climbing Assay.
Table 3. Calculation of Molecular Properties and Log BB Values for Target Compounds and Standard Drugs
Comp.
No.
M.Wa
MRb
SASc
(A2 )
SAd
(A2 )
SEVe
(A3 )
Ovality LogP TPSAf MTIg WIh
(A2 )
LRn
Log
No. of H-
bond
acceptors
No. of
H-
bond
donors
BBm
5
6
0.27
0.34
0.38
0.38
0.42
0.28
0.53
0.36
0.75
0.89
374.904 107.336 638.022 315.156 250.283
374.904 107.336 704.482 373.796 335.239
1.590
1.602
1.562
1.564
1.59
3.933
3.933
3.933
3.933
3.806
3.806
3.806
3.806
3.707
2.368
4.668
2.100
24.94
24.79
25.94
25.94
32.78
32.78
32.78
32.78
30.87
69.72
47.94
16370 2239
16192 2201
15716 2129
15894 2167
16324 2239
16146 2201
15848 2167
15640 2120
4
4
4
4
4
4
4
4
4
5
5
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
7
374.91
374.91
372.89
372.89
372.89
372.89
362.82
107.110 667.307 361.880 341.326
107.110 680.115 362.361 335.864
107.464 693.423 367.319 327.561
107.464 674.845 360.416 327.807
107.464 686.365 366.416 328.771
8
11
12
1.57
13
1.591
1.583
1.473
1.574
1.590
1.590
14
107.464 680.698
360.28
328.628
CLZi
KETj
ZIPk
RISl
95.226 506.405 256.884 216.638
8127
1082
395.427 106.778 609.934 311.188 261.484
18646 2596
16979 2344
20311 2793
-0.08 412.936 116.981 625.053 320.158 268.640
-0.20
484.00
114.60
631.449 324.651 274.282
57.5
6
b
c
d
e
f
aMolecular weight; Molar refractivity; Connolly solvent accessible surface area; Connolly molecular surface area; Connolly solvent excluded volume; Topological polar surface
area; gMolecular topological index; hWiener index; iClozapine; jKetanserine; kZiprasidone; lRisperidone; mCalcd. Online27); nViolations from Lipinski’s rules of five (CNS drugs).

Aryloxypiperazines as Potential Atypical Antipsychotics
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 2 223
1-(4-chlorobenzyl)-4-(3-(4-methoxyphenoxy)propyl)pipera-
zine (5)
(2H, m), 4.23 (2H, t, J=7.2 Hz), 3.70 (2H, s), 3.40 (2H, t,
J=7.2 Hz), 2.67 (8H, m, broadened), 2.04 (2H, quintet, J=7.2
Hz). FTIR (KBr) cm-1: 3062, 2941, 2839, 1699, 1590, 1253,
1155, 1061, 1010, 946, 821 and 753. MS [EI, m/z (relative
intensity)]: 375 (8.9) [M+2], 373 (26.8) [M. +], 125 (100)
Reaction condition, 3 h. Yellowish solid; Yield 67.2%,
mp 228-2300C. 1H-NMR (400 MHz; CDCl3) ꢀ: 7.38 (2H, dd,
J=7.0 Hz, 1.5 Hz), 7.26 (2H, dd, J=7.0 Hz, 1.5 Hz), 6.73
(4H, m), 3.86 (2H, t, J=6.4 Hz), 3.66 (3H, s), 3.54 (2H, s),
2.46 (10H, m), 1.89 (2H, quintet, J=7.4 Hz). FTIR (KBr) cm-
1: 3050, 2940, 2811, 1504, 1458, 1229, 1152, 1090, 1011,
943, 828, 768. MS [EI, m/z (relative intensity)]: 377 (9.7)
+
[ClC6H4CH2 ].
4-[3-{4-(2-chlorobenzyl)piperazin-1-yl}propoxy]benzalde-
hydes (13)
Light yellow solid; Yield 75.6%, mp 205-2070C. 1H-
NMR (400 MHz; CDCl3) ꢀ: 9.87 (1H, s), 7.89 (2H, d, J=8.6
Hz), 7.48 (1H, dd, J=7.2 Hz, 1.4 Hz), 7.39 (1H, dd, J=7.2
Hz, 1.4 Hz), 7.20 (2H, m), 7.00 (2H, d, J=8.6 Hz), 4.30 (2H,
t, J=7.0 Hz), 4.15 (2H, t, J=7.0 Hz), 3.54 (2H, s), 2.56 (8H,
m, broadened), 2.00 (2H, quintet, J=7.0 Hz). FTIR (KBr)
cm-1: 3063, 2940, 2811, 1669, 1600, 1509, 1393, 1256, 1159,
1049, 1011, 947, 832 and 754. MS [EI, m/z (relative
intensity)]: 375 (6.8) [M+2], 373 (20.2) [M. +], 125 (100)
+
[M+2], 375 (25.2) [M. +], 125 (100) [ClC6H4CH2 ].
1-(2-chlorobenzyl)-4-(3-(4-methoxyphenoxy)propyl)pipera-
zine (6)
Reaction condition, 3 h. Yellowish solid; Yield 67.2%,
mp 212-2140C. 1H-NMR (400 MHz; CDCl3) ꢀ: 7.38 (1H, dd,
J=7.0 Hz, 1.4 Hz), 7.25 (1H, dd, J=7.0 Hz, 1.4 Hz), 7.10
(2H, m), 6.73 (4H, m), 3.86 (2H, t, J=6.4 Hz), 3.66 (3H, s),
3.54 (2H, s), 2.46 (10H, m), 1.89 (2H, quintet, J=7.4 Hz).
FTIR (KBr) cm-1: 3063, 2941, 2811, 1507, 1444, 1231,
1155, 1041, 1011, 947, 826, 753. MS [EI, m/z (relative
intensity)]: 377 (7.8) [M+2], 375 (23.6) [M. +], 125 (100)
+
[ClC6H4CH2 ].
4-[3-{4-(4-chlorobenzyl)piperazin-1-yl}propoxy]benzalde-
hydes (14)
+
[ClC6H4CH2 ].
Light yellow solid; Yield 72.4%, mp 235-2370C. 1H-
NMR (400 MHz; CDCl3) ꢀ: 9.87 (1H, s), 7.80 (2H, d, J=8.0
Hz), 7.27 (4H, m), 6.98 (2H, d, J=8.0 Hz), 3.56 (2H, t, J=6.8
Hz), 3.50 (2H, s), 3.30 (2H, t, J=7.0 Hz), 2.46 (8H, m,
broadened), 2.01 (2H, quintet, J=7.0 Hz). FTIR (KBr) cm-1:
3065, 2942, 2814, 1687, 1599, 1404, 1256, 1159, 1088,
1012, 951, 834 and 690. MS [EI, m/z (relative intensity)]:
1-(2-chlorobenzyl)-4-(3-(2-methoxyphenoxy)propyl)pipera-
zine (7)
Reaction condition, 6 h. Yellowish solid; Yield 62.0%,
mp 190-1920C. 1H-NMR (400 MHz; CDCl3) ꢀ: 7.46 (1H, dd,
J=6.30 Hz, 1.68 Hz), 7.34 (1H, dd, J=6.28 Hz, 1.68 Hz),
7.18 (2H, m), 6.90 (4H, m), 4.10 (2H, t, J=6.20 Hz), 3.85
(3H, s), 3.64 (2H, s), 2.60 (10H, m, broadened), 2.34 (2H,
quintet, J=6.8 Hz). FTIR (KBr) cm-1: 3063, 2935, 2880,
1507, 1458, 1252, 1122, 1020, 1011, 947, 826, 753. MS [EI,
m/z (relative intensity)]: 377 (40.7) [M+2], 375 (100) [M. +].
+
375 (7.0) [M+2], 373 (24.2) [M. +], 125 (100) [ClC6H4CH2 ].
3.2. Atypical Antipsychotic Activity
Albino lyka mice (6 mice in each group) of either sex
(26-38 g) were habituated by individually placing in a
circular cage made of wire mesh of diameter 13 cm and
height 14 cm. Mice in the test groups, control groups and
clozapine groups were injected with the test compound,
normal saline and clozapine intraperitoneally and returned to
the home cage. After a gap of ten minutes, apomorphine (2.5
mg/kg) was injected intraperitoneally. Mesh climbing
behaviour was noted for the naïve or untreated group at the
start and then, readings were noted at 10, 15, 20, 25 and 30
min. after the apomorphine injection by placing the mice in
the mesh cage for 60 seconds. Severity of the climbing
behaviour was scored as: 1 (one, two or three paws on the
mesh) and 2 (all four paws on the mesh). The same albino
lyka mice employed in the mesh climbing assay were used
for the stereotypy assay and response was noted similarly at
10, 15, 20, 25 and 30 min. after apomorphine injection by
placing the animal in an inverted 500 ml beaker for 60
seconds. Scoring of stereotypy was done as: 1 (rearing,
sniffing, grooming) and 2 (licking, biting).
1-(4-chlorobenzyl)-4-(3-(2-methoxyphenoxy)propyl)pipera-
zine (8)
Reaction condition, 6 h. Yellowish solid; Yield 62.0%,
1
mp 190-1920C. H-NMR (400 MHz; CDCl3) ꢀ: 7.26 (4H,
m), 6.91 (4H, m), 4.17 (2H, t, J=6.10 Hz), 3.86 (3H, s), 3.45
(2H, s), 2.60 (10H, m, broadened), 2.30 (2H, quintet, J=6.1
Hz). FTIR (KBr) cm-1: 3063, 2932, 2879, 1508, 1457, 1252,
1122, 1052, 1020, 943, 826, 741. MS [EI, m/z (relative
intensity)]: 377 (26.5) [M+2], 375 (100) [M. +].
2-[3-{4-(4-chlorobenzyl)piperazin-1-yl}propoxy]benzalde-
hydes (11)
1
Creamy white solid; Yield 74.6%, mp 225-2270C. H-
NMR (400 MHz; CDCl3) ꢀ: 10.49 (1H, s), 7.84 (1H, dd,
J=8.0 Hz, 1.8 Hz), 7.54 (1H, m), 7.25 (4H, m), 7.00 (2H, m),
4.25 (2H, t, J=7.2 Hz), 3.60 (2H, s), 2.60 (2H, t, J=7.2 Hz),
2.50 (8H, m, broadened), 2.04 (2H, quintet, J=7.2 Hz). FTIR
(KBr) cm-1: 3062, 2941, 2839, 1699, 1590, 1253, 1155,
1061, 1010, 946, 821 and 753. MS [EI, m/z (relative
intensity)]: 375 (6.8) [M+2], 373 (20.6) [M. +], 125 (100)
+
[ClC6H4CH2 ].
4. CONCLUSION
2-[3-{4-(2-chlorobenzyl)piperazin-1-yl}propoxy]benzalde-
hydes (12)
Light yellow solid; Yield 77.6%, mp 205-2070C. 1H-
NMR (400 MHz; CDCl3) ꢀ: 10.50 (s, 1H), 7.84 (1H, dd,
J=8.0 Hz, 1.8 Hz), 7.60 (1H, dd, J=8.0 Hz, 1.8 Hz), 7.50
(1H, dd, J=8.0 Hz, 1.8 Hz), 7.35 (1H, m), 7.25 (2H, m), 6.90
A
series of aryloxypiperazines having OCH3/CHO
substituents have been synthesized and a potential atypical
antipsychotic effect was noted in the compounds 5-8 and 11-
14. Excellent efficacy was observed which was comparable
to clozapine. The results further strengthen our previous
hypothesis that in our compound series, the presence of

224 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 2
Bali et al.
selective dopamine D3-receptor antagonists: Quinolin(di)one and
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Galici, R.; Boggs, J.D.; Miller, K.L.; Bonaventure, P.; Atack, J.R.
Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse
models predictive of antipsychotic-like activity. Behav.
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Stephane, C.; Bourdiol, N.; Lacharme, V.; Newman-Tancredi, A.;
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hydrogen bond acceptor substituents on the phenyl ring is
important for antipsychotic activity. Further, smaller size of
the substituents seems to reduce the tendency of the
compounds to bind to nigrostriatal regions. The
computational studies suggest a good correlation between
activity profile and the chemical structures. The values of the
various computed parameters e.g., log BB values (_2.00 -
1.04), TPSA (24.79 – 32.78) and log P (3.806-3.933) for the
test compounds indicate a good potential to penetrate the
blood brain barrier and an excellent compliance with
lipinski’s rules for CNS activity.
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ACKNOWLEDGEMENTS
The research grant provided by the University Grants
Commission is duly acknowledged.
CONFLICT OF INTEREST
Discovery
yl)piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-
methylethoxy)phenyl]methanone (RG1678), promising novel
of
[4-(3-Fluoro-5-trifluoromethyl-
pyridine-2-
The authors declare no conflict of interest.
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