Synthesis, evaluation and computational studies on a series of acetophenone based 1-(aryloxypropyl)-4-(chloroaryl) piperazines as potential atypical antipsychotics

Article abstract of DOI:10.1016/j.ejmech.2010.02.008

A series of 1-(aryloxypropyl)-4-(chloroaryl) piperazines have been synthesized and the target compounds evaluated for atypical antipsychotic activity in apomorphine induced mesh climbing and stereotypy assays in mice. The compounds 11 and 12 have emerged

Full text of DOI:10.1016/j.ejmech.2010.02.008

European Journal of Medicinal Chemistry 45 (2010) 2656e2662
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, evaluation and computational studies on a series of acetophenone
based 1-(aryloxypropyl)-4-(chloroaryl) piperazines as potential
atypical antipsychotics
*
Alka Bali , Komal Sharma, Abhishek Bhalla, Suman Bala, Dinesh Reddy, Anant Singh, Anil Kumar
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, 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 1-(aryloxypropyl)-4-(chloroaryl) piperazines have been synthesized and the target
Received 12 September 2009
Received in revised form
24 January 2010
Accepted 2 February 2010
Available online 10 February 2010
compounds evaluated for atypical antipsychotic activity in apomorphine induced mesh climbing and
stereotypy assays in mice. The compounds 11 and 12 have emerged as important lead compounds
showing potential atypical antipsychotic profile. The physicochemical similarity of the new analogs with
respect to standard drugs clozapine, ketanserin, ziprasidone and risperidone was assessed by calculating
from a set of 10 physicochemical properties using software programs. The test compounds demonstrated
good similarity values with respect to the standard drugs. The potential of these compounds to penetrate
the blood brain barrier (log BB) was computed through an online software program and the values
obtained for the compounds suggest a good brain permeation.
Keywords:
Atypical antipsychotics
1,4-Diaryl substituted piperazine derivatives
Physicochemical similarity
Log BB
Ó 2010 Elsevier Masson SAS. All rights reserved.
CNS agents
1. Introduction
the disease. Unfortunately, its therapeutic use has been hampered
by serious side effects particularly, agranulocytosis (1e3%) [8],
Schizophrenia is a psychological disorder with unknown aeti-
ology afflicting about 1% of the population worldwide [1]. The
classical or ‘typical’ neuroleptics such as chlorpromazine, haloper-
idol, fluphenazine have been postulated to alleviate the active or
positive symptoms of the disease [2,3] through inhibition of the
postsynaptic dopaminergic transmission in mesolimbic areas of
brain associated with integration of emotions and behaviour [4].
However, their actions in the nigrostriatal regions of the brain
associated with locomotor coordination results in severe mecha-
nism related side effects including parkinsonism and akathesia
(extrapyramidal symptoms), tardive dyskinesia and galactorrhoea
(due to increased prolactin release) [5,6].
The introduction of clozapine, a dibenzodiazepine derivative [7]
for treatment-resistant schizophrenia gave rise to a new group of
atypical or non-classical antipsychotics. Clozapine was the first
compound to demonstrate a superior profile over conventional
neuroleptics. It is nearly devoid of extrapyramidal side effects and
moreover, it is also effective in alleviation of negative symptoms of
sialorrhoea (30%), metabolic effects [9], orthostatic hypotension
and tachycardia attributed to its high affinity for a multitude of CNS
receptors [10].
Several dopaminergic [11,12] and serotonergic approaches
[13e15], besides others [16e18] have been investigated for the
development of atypical antipsychotics, however, their exact
significance is not clear yet. In animal models, it is widely accepted
that atypical antipsychotics are identified by their inhibition of
apomorphine induced climbing response (indicative of action in
mesocorticolimbic region associated with integration of emotions
and behaviour; antipsychotic effect) along with weak or no inhi-
bition of apomorphine induced stereotypy (sparing the nigros-
triatal system associated with locomotor coordination; reduced
extrapyramidal side effect liability) [19].
We had recently reported a series of quinoliloxypropyl pipera-
zines [20] where the quinolin-8-yl derivative 1a (Fig. 1) had
emerged as an important lead compound as a potential atypical
antipsychotic. As U.S. EPA has classified quinoline as a Group C
carcinogen and it is considered “likely to be carcinogenic in
humans” in accordance with the EPA's proposed guidelines for
carcinogenic risk assessment (U.S. EPA, 1996a), in this paper, we
report the synthesis, pharmacological evaluation and 2D similarity
* Corresponding author. Tel.: þ91 172 2534104; fax: þ91 172 541142.
E-mail address: alka.bali@rediffmail.com (A. Bali).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.02.008

A. Bali et al. / European Journal of Medicinal Chemistry 45 (2010) 2656e2662
2657
3e6 were also obtained in good yields (80e85%) by reaction of their
corresponding aryl/aroyl chlorides (0.01 M) with piperazine
(0.02 M) from our previously reported procedure [20]. In these
reactions, two disubstituted by-products, 7e8 were also obtained
in very low yields (nearly 2.5%) which could be separated by
filtration. Their yield was increased to nearly 75e77% by using
twice molar quantities of the chlorobenzyl chlorides compared to
piperazine. The final target compounds X-[3-{4-(X0-chlorobenzyl)
piperazin-1-yl}propoxy] phenylethanones (9e12) and X-[3-{4-(X0-
chlorobenzoyl) piperazin-1-yl}propoxy] phenylethanones (13e16)
were prepared by reacting the corresponding 3-chloropropyl ether
derivatives with the chlorobenzyl piperazines/chlorobenzoyl
piperazines in dimethyl formamide. All the reactions were moni-
tored by TLC. The final products were purified by column chro-
matography and characterized through spectroscopic data.
N
N
Cl
N
O
1a
Fig. 1. Quinoline based lead compound with atypical antipsychotic profile.
studies on another novel series of 1,4-diaryl substituted piperazine
derivatives which incorporate an acetophenone system as
a replacement for the quinoline system. The physicochemical and
steric similarity between standard drugs clozapine, ketanserin,
ziprasidone and risperidone and the new analogs designed was
calculated from a set of 10 physicochemical properties computed
using software programs. 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.
2.2. Preliminary pharmacological evaluation for atypical
antipsychotic effect
In animal models, the atypical antipsychotics are identified by
their inhibition of apomorphine induced climbing response (indica-
tive of dopaminergic antagonism in mesocorticolimbic pathway
associatedwithantipsychoticeffect) alongwithweak or noinhibition
of apomorphine induced stereotypy (characteristic of antagonism in
nigrostriatal system linked to extrapyramidal symptoms) [19].
All the target compounds were subjected to preliminary phar-
macological evaluation to determine their ability to antagonize
apomorphine induced mesh climbing behaviour and apomorphine
induced stereotypy in mice. Prior permission of the Animal Ethics
Committee was obtained and all experiments were conducted
according to the approved protocol. Doses were selected by initial
titration at different dose levels. Clozapine group was employed as
2. Results and discussion
2.1. Synthesis of compounds
Synthetic scheme for preparation of target compounds is
summarized in Fig. 2. In the first step, 2-, 3- or 4-hydroxy aceto-
phenones were converted to their 3-chloropropyl ether derivatives
1 and 2 by refluxing with 1-bromo-3-chloropropane and potassium
carbonate in acetone by variation of a previously reported proce-
dure [21]. The o- and p-chloro benzyl/chlorobenzoyl piperazines
OCH2CH2CH2Cl
a
COCH3
HO
COCH3
ClCH2CH2CH2Br
1
2
p-COCH3
o-COCH3
X
N
X
b
Cl
Cl
NH
X = CH2, C=O
c
Cl
Cl
X
3
4
5
6
o-
p-
o-
p-
CH2
CH2
C=O
C=O
d
X
N
X
N
Cl
X
N
Cl
X
Cl
7
8
o-
p-
CH2
CH2
N
Cl
O
9-16
COCH3
Fig. 2. Synthetic scheme for preparation of the target compounds. Reagents and conditions: (a) K2CO3, 16-18 h (b) piperazine (twice molar quantity), abs. EtOH, (c) K2CO3, DMF,
70ꢀC, 3-10 h reflux (d) piperazine (half molar quantity), abs. EtOH.

2658
A. Bali et al. / European Journal of Medicinal Chemistry 45 (2010) 2656e2662
a 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 values obtained for selected molecular parameters computed
for the test compounds and standard drugs are shown in Table 3.
Since, antipsychotics are essentially intended to act on CNS target
sites, the blood brain barrier (BBB) must be crossed for their effect to
be exerted. Important molecular descriptors used to predict BBB
penetration are molecular surface area parameters (e.g., topological
polar surface area TPSA), log P and volume parameters. Steric and
molecular surface descriptors computed include Connolly Solvent
The results from the pharmacological evaluation of the target
compounds are given in Tables 1 and 2 and depicted graphically in
Figs. 3 and 4. The test compounds 9, 10, 11 and 12 possessing
chlorobenzyl system and the disubstituted by-products 7 and 8
produced statistically significant reversal of apomorphine induced
mesh climbing indicating potential antipsychotic effect. However,
the compounds 9, 10, 7 and 8 also reversed apomorphine induced
stereotypy signifying that these are also acting in nigrostriatal
regions of the brain and hence, lacking an atypical profile. In
comparison, the activity in mesh climbing assay for the compounds
11 and 12 was coupled with negative results in stereotypy assay,
thus implying that these have potential atypical antipsychotic
profile. The results with 11 and 12 correlate quite well with our
earlier findings with quinoline based derivatives. Both these
compounds possess an o-acetyl function in which, the carbonyl
function is in a similar orientation as the quinoline nitrogen in the
8-substituted quinolyl derivative 1a (Fig. 1), the lead compound
from our earlier series. The replacement of quinoline by aceto-
phenone system has also resulted in an improved potency. The
o-acetyl analog of 1a had and ED50 value of 10.5 mg kgꢁ1 whereas,
1a was effective at much higher doses (80 mg kgꢁ1). Other
compounds have shown ED50 values ranging from 10.0 to
50.0 mg kgꢁ1. The o-COCH3 based compounds 11 and 12 (ED50
values 10.0 and 10.5 mg kgꢁ1, respectively) were found to be 2e5
times more potent than their p-COCH3 analogs 9 and 10 (ED50
values 50.0 and 23.0 mg kgꢁ1, respectively). Interestingly, the four
chlorobenzoyl based compounds 13, 14, 15 and 16 did not produce
statistically significant reversal of apomorphine induced mesh
climbing at p < 0.05, but these caused statistically significant
reversal in the stereotypy assay. This was also seen in the quinoline
based compounds and suggests that these may be only having
the potential to bind to nigrostriatal areas of the brain instead of the
desired action in the mesocorticolimbic region.
2
ꢀ
Accessible Surface Area SAS (A ), Connolly Molecular Surface Area
2
ꢀ
3
ꢀ
MS (A ), Connolly Solvent Excluded Volume SEV (A ) and Ovality.
Global physicochemical properties computed were hydrophobic
parameter log P and molecular weight MW (atomic mass units).
Topological polar surface area, TPSA, which is a recognized param-
eter for prediction of drug transport properties (in this case, BBB
penetration), was also determined. Other parameters were Molec-
ular Topological Index MTI and Wiener Index WI.
Literature reports suggest 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 Waterbeemd et al. [22] suggest
2
ꢀ
a limit of 90 A , whereas, Kelder et al. [23] have a lower limit of
2
ꢀ
60e70 A . The TPSA values for test compounds were well within
these limits (6.48e49.85) which shows that these compounds have
a potential to effectively cross the blood brain barrier. Further,
lipophilicity correlates positively with BBB penetration and the
values of C log P for most of our test compounds were in the range
(2.807e4.581) close to that of marketed CNS drugs.
2.4. Similarity calculations
The physicochemical and steric similarity of the target
compounds was calculated with respect to the standard drugs
[24,25]. Firstly, the distance di of a particular target compound j to
drug molecules e.g., clozapine was calculated by the formula:
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
2.3. Computation of physicochemical properties
drug, e.g., clozapine, risperidone, etc. Then, the similarity of
compound ‘j’ to the standard drug was calculated as:
A set of 10 molecular parameters was computed for the target
compounds as well as for four standard drugs clozapine, risper-
idone, ziprasidone and ketanserin using Chem3D Ultra version 11.0.
Similarity ð%Þ [ ð1 L RÞ 3 100
Table 1
Pharmacological evaluation for atypical antipsychotic profile.
R1
R2
(X)
R2
R1
R1
R2
(X)
O
R
N
N
N
N
(X)
A
B
Comp. no.
Structure type
R
R1
R2
X
Reversal of apomorphine
induced mesh climbinga
Reversal of apomorphine
induced stereotypya
ED50 (mg/kg)
(mesh climbing)
Log ED50
9
A
A
A
A
A
A
A
A
B
B
p-COCH3
p-COCH3
o-COCH3
o-COCH3
p-COCH3
p-COCH3
o-COCH3
o-COCH3
e
Cl
H
Cl
H
Cl
H
Cl
H
Cl
H
H
Cl
H
Cl
H
Cl
H
Cl
H
Cl
CH2
CH2
CH2
CH2
C]O
C]O
C]O
C]O
CH2
þ
þ
þ
þ
_
_
_
_
þ
þ
_
50.0
23.0
10.0
10.5
e
1.70
1.36
1.00
1.02
e
10
11
12
13
14
15
16
7
_
þ
þ
þ
þ
þ
þ
e
e
e
e
e
e
þ
10.5
7.2
1.02
0.86
8
e
CH2
þ
aStatistically significant reduction compared to control at p < 0.05.

A. Bali et al. / European Journal of Medicinal Chemistry 45 (2010) 2656e2662
2659
Table 2
Mean score in apomorphine induced mesh climbing and stereotypy.
Treatment
Average score at time (min)
10
15
C
20
C
25
C
30
C
C
St
St
St
St
St
Naïve
Control
Clozapine
9
10
11
12
13
14
15
16
7
7.0 ꢂ 0.45
8.8 ꢂ 0.37
2.2 ꢂ 0.2a
2.8 ꢂ 0.5a
3.0 ꢂ 0.3a
3.4 ꢂ 0.24a
3.2 ꢂ 0.37a
7.8 ꢂ 0.24
7.8 ꢂ 0.45
8.2 ꢂ 0.37
7.2 ꢂ 0.50
5.6 ꢂ 0.24a
6.2 ꢂ 0.37a
4.0 ꢂ 0.31
5 ꢂ 0.0.31
4.0 ꢂ 0.31
3.2 ꢂ 0.60a
3.0 ꢂ 0.30a
3.8 ꢂ 0.37
4.2 ꢂ 0.37
3.2 ꢂ 0.60a
3.0 ꢂ 0.30a
3.2 ꢂ 0.60a
3.2 ꢂ 0.25a
4.6 ꢂ 0.24a
2.6 ꢂ 0.24a
6.0 ꢂ 0.31
7.8 ꢂ 0.37
2.2 ꢂ 0.37a
2.4 ꢂ 0.24a
2.8 ꢂ 0.37a
2.2 ꢂ 0.37a
3.6 ꢂ 0.50a
7.4 ꢂ 0.37
6.8 ꢂ 0.24
7.4 ꢂ 0.25
7.2 ꢂ 0.31
3.4 ꢂ 0.37a
6.2 ꢂ 0.37
3.0 ꢂ 0.31
4.2 ꢂ 0.37
4.6 ꢂ 0.24
2.4 ꢂ 0.50a
2.4 ꢂ 0.25a
3.6 ꢂ 0.24
3.6 ꢂ 0.24
2.6 ꢂ 0.30a
3.0 ꢂ 0.20a
2.8 ꢂ 0.40a
3.0 ꢂ 0.20a
3.8 ꢂ 0.20a
2.2 ꢂ 0.2a
6.0 ꢂ 0.55
8.2 ꢂ 0.37
3.2 ꢂ 0.31a
1.0 ꢂ 0.30a
1.0 ꢂ 0.45a
2.4 ꢂ 0.24a
3.2 ꢂ 0.60a
7.2 ꢂ 0.45
7.0 ꢂ 0.30
6.8 ꢂ 0.31
7.0 ꢂ 0.45
2.2 ꢂ 0.37a
6 ꢂ 0.45a
3.2 ꢂ 0.2
5.4 ꢂ 0.51
7.6 ꢂ 0.24
2.8 ꢂ 0.37a
0.6 ꢂ 0.40a
3.2 ꢂ 0.37a
2.2 ꢂ 0.20a
3.4 ꢂ 0.60a
7.6 ꢂ 0.37
7.0 ꢂ 0.30
7.0 ꢂ 0.45
7.0 ꢂ 0.24
1.2 ꢂ 0.40a
6.0 ꢂ 0.31a
2.2 ꢂ 0.2
5.8 ꢂ 0.37
8.0 ꢂ 0.32
2.4 ꢂ 0.24a
0.4 ꢂ 0.24a
0.4 ꢂ 0.25a
1.6 ꢂ 0.24a
2.0 ꢂ 0.45a
7.4 ꢂ 0.24
7.0 ꢂ 0.24
6.8 ꢂ 0.24
7.0 ꢂ 0.24
1.0 ꢂ 0.30a
5.6 ꢂ 0.4a
1.4 ꢂ 0.51
4.2 ꢂ 0.2
4.2 ꢂ 0.37
3.8 ꢂ 0.37
2.4 ꢂ 0.24a
1.6 ꢂ 0.25a
3.6 ꢂ 0.24
3.6 ꢂ 0.24
2.2 ꢂ 0.40a
2.4 ꢂ 0.25a
2.4 ꢂ 0.30a
2.4 ꢂ 0.24a
3.4 ꢂ 0.24a
2.2 ꢂ 0.2a
3.6 ꢂ 0.24
3.6 ꢂ 0.24
2.2 ꢂ 0.20a
1.4 ꢂ 0.25a
3.2 ꢂ 0.20
4.0 ꢂ 0.31
2.2 ꢂ 0.60a
2.0 ꢂ 0.20a
1.8 ꢂ 0.20a
2.0 ꢂ 0.20a
3.0 ꢂ 0.20a
2.4 ꢂ 0.24a
3.6 ꢂ 0.24
2.2 ꢂ 0.30a
0.4 ꢂ 0.24a
3.0 ꢂ 0.30
3.8 ꢂ 0.37
1.8 ꢂ 0.30a
1.6 ꢂ 0.30a
1.4 ꢂ 0.24a
1.4 ꢂ 0.30a
3.0 ꢂ 0.20a
2.4 ꢂ 0.24a
8
All values are expressed as mean ꢂ S.E.M. (n ¼ 5).
aSignificantly different from control at p < 0.05. C: apomorphine induced mesh climbing St: apomorphine induced stereotypy.
where R ¼ Od2 is the quadratic mean (root mean square), a measure
of central tendency. The calculation results obtained for assessment
of the structural similarity of the prepared compounds to standard
drugs are presented in Table 4. The compounds 9e16 showed good
physicochemical similarity to drugs with extended chain structure
as risperidone, ziprasidone and ketanserin (82e99%) and very less
similarity to the fused system dibenzodiazepine derivative cloza-
pine (29e40%). Interestingly, the two by-products 7 and 8 showed
very good similarity with respect to clozapine (90e99%) and not to
the other drugs. The compounds 11 and 12 displaying an atypical
profile showed maximum similarity to risperidone (92e94%)
poorly distributed to the brain [28]. The log BB values for the
compounds 7e12 (0.24e0.70) were found to be greater than or
approaching 0.30, suggesting that these have an excellent potential
for blood brain barrier penetration. The chlorobenzoyl derivatives
13e16 had values ranging from ꢁ0.11 to ꢁ0.06 suggesting
a moderate blood brain barrier penetration.
3. Conclusion
A series of arylpiperazine derivatives have been synthesized and
their preliminary pharmacological evaluation has shown potential
atypical antipsychotic effect in compounds 11 and 12. Test
compounds have shown good similarity with respect to the stan-
dard drugs, particularly, risperidone. The log BB values and values
of the molecular parameters important for blood brain barrier
penetration, i.e., TPSA (6.48e32.78) and log P (3.371e4.581)
computed for the test compounds indicate that these have a good
potential to penetrate the blood brain barrier and show CNS
activity.
2.5. Calculation of blood brain barrier penetration (log BB values)
Several computational methods have been employed for the
prediction of blood brain barrier penetration potential of
compounds with overall accuracies from 75 to 97% [26]. We
assessed our compounds for likely permeation of BBB by calculating
the log BB values for these using an online software program based
on topological descriptors [27] (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 þ1.04. Within this range, compounds with log BB > 0.30
cross the BBB readily, while compounds with a log BB < ꢁ1.00 are
4. Experimental protocols
Infrared spectra were recorded in KBr pellets on Perkin Elmer
RX 1 spectrophotometer. Proton NMR was recorded on Bruker
Avance-II, 400 MHz instrument. For NMR, solutions were made in
deuterated chloroform and deuterated chloroform employing
Fig. 3. Mean score in apomorphine induced mesh climbing assay.
Fig. 4. Mean score in apomorphine induced stereotypy assay.

2660
A. Bali et al. / European Journal of Medicinal Chemistry 45 (2010) 2656e2662
Table 3
Calculation of molecular properties and log BB values for target compounds and standard drugs.
Comp. no.
Log BBm
M.W.a
MRb
SASc (A2)
SAd (A2)
SEVe (A3)
Ovality
Log P
TPSAf (A2)
MTIg
WIh
9
0.34
0.27
0.26
386.915
386.915
386.915
386.915
400.907
400.907
400.907
400.907
335.271
325.71
111.276
111.276
111.276
111.276
111.107
111.107
111.107
111.107
94.873
94.873
95.226
106.778
116.981
114.60
723.150
716.880
715.203
698.663
688.390
673.504
687.387
662.370
552.279
537.865
506.405
609.934
625.053
631.449
385.098
382.851
383.819
377.712
380.493
375.443
380.311
372.948
273.796
270.143
256.884
311.188
320.158
324.651
344.504
344.232
345.601
345.068
344.781
347.453
344.874
348.850
225.847
226.680
216.638
261.484
268.640
274.282
1.598
1.612
1.611
1.588
1.600
1.571
1.599
1.556
1.527
1.503
1.473
1.574
1.590
1.590
3.371
3.371
3.371
3.371
2.807
2.807
2.807
2.807
4.581
4.581
3.707
2.368
4.668
2.100
32.78
32.78
32.78
32.78
49.85
49.85
49.85
49.85
06.48
06.48
30.87
69.72
47.94
57.5
18,276
18,088
17,526
17,338
19,361
19,167
18,579
18,385
9180
8900
8127
18,646
16,979
20,311
2494
2454
2386
2346
2686
2644
2572
2530
1271
1211
1082
2596
2344
2793
10
11
12
13
14
15
16
7
0.24
ꢁ0.06
ꢁ0.11
ꢁ0.10
ꢁ0.07
0.67
0.70
0.75
0.89
8
CLZi
KETj
ZIPk
RISl
362.82
395.427
412.936
484.00
ꢁ0.08
ꢁ0.20
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.
Wiener index.
d
e
f
g
h
i
Clozapine.
Ketanserine.
Ziprasidone.
Risperidone.
j
k
l
m
Calcd. online (Ref. [27]).
tetramethylsilane as internal reference. Mass spectra were obtained
with Vg-11-250 J70S spectrometer at 70 eV using electron ioniza-
tion (EI source). For mass spectra, solutions were made in HPLC
grade methanol.
1H); 6.98 (m, 1H); 6.92 (dd, 1H, J ¼ 9.0 Hz, 2.0 Hz); 3.71 (t, 2H,
J ¼ 8.0 Hz); 3.57 (t, 2H, J ¼ 8.0 Hz); 2.62 (s, 3H); 2.30 (quintet, 2H,
J ¼ 8.0 Hz). MS [EI, m/z (relative intensity)]: 214 (8.8) [M þ 2], 212
(25.2) [Mþ], 125(100) [CleC6H4eCH2], 89. Melting point: 70e72 ꢀC.
Yield 80.2%.
4.1.1.2. 1-[4-(3-chloropropoxy)phenyl]ethanone (2). IR (KBr, cmꢁ1):
4.1. Synthesis of compounds
3057, 2944, 2800, 1673, 1599, 1510, 1441, 1259, 1166, 836 and 695.
1H NMR (400 MHz; CDCl3,
d
, J): 7.92 (d, 2H, J ¼ 7.0 Hz); 6.93 (d, 2H,
4.1.1. Preparation of 1-[X-(3-chloropropoxy)phenyl]ethanones
(1e2)
J ¼ 7.0 Hz); 4.18 (t, 2H, J ¼ 8.0 Hz); 3.73 (t, 2H, J ¼ 8.0 Hz); 2.55 (s,
3H); 2.26 (quintet, 2H, J ¼ 8.0 Hz). MS [EI, m/z (relative intensity)]:
214 (8.5) [M þ 2], 212 (23.4) [Mþ], 125(100) [CleC6H4eCH2], 89.
Melting point: 69e71 ꢀC. Yield 81.2%.
Mixture of 2- or 4-hydroxyacetophenone (4.5 g, 0.033 M),
1-bromo-3-chloropropane (10 ml, 0.10 M) and anhydrous potas-
sium carbonate (6.91 g, 0.05 M) in 70 ml of acetone was heated
under reflux for 16e18 h. After removal of solid material by
filtration, the solvent was evaporated under vacuum yielding the
1-[X-(3-chloropropoxy) phenyl]ethanones.
4.1.2. Preparation of 1-(X-chlorobenzyl)-piperazine (3e4), the
corresponding benzoyl derivatives (5e6) and disubstituted
derivatives 7e8
4.1.1.1. 1-[2-(3-chloropropoxy)phenyl]ethanone (1). IR (KBr, cmꢁ1):
To the solution of piperazine (1.72 g, 20 mmol) in absolute
ethanol(10 ml), the corresponding chlorobenzoyl- and chlorobenzyl
chlorides (10 mmol) were added dropwise and the reaction was
allowed to proceed for 4e6 h at room temperature. To the contents
of the reaction mixture,100 ml of distilled water was then added and
the precipitated disubstituted by-products were filtered out.
Removal of the solvent under vacuum afforded the crude product
which was recrystallized from methanol to obtain crystals of the
purecompounds. Theuse ofchlorobenzyl chlorides (40mmol) in the
same procedure afforded mainly the by-products 7e8.
3050, 2969, 1641, 1487, 1447, 1242,1221, 1069, 1028, 835 and 619. 1H
NMR (400 MHz; CDCl3,
d, J): 7.74 (dd, 1H, J ¼ 9.0 Hz, 2.0 Hz); 7.47(m,
Table 4
Similarity values of target compounds with respect to the standard drugs.
Compd. no.
Similaritya,b(in %) to
Clozapine
Ketanserine
Ziprasidone
Risperidone
9
33.80
39.30
35.20
40.25
27.19
28.78
31.25
31.25
99.83
89.93
97.26
96.69
83.50
82.08
83.39
84.91
82.85
82.85
48.23
44.29
98.37
98.62
81.90
82.36
82.22
82.60
82.92
82.92
16.58
12.20
91.33
90.53
92.14
94.50
83.95
84.01
83.68
83.68
23.29
45.05
10
11
12
13
14
15
16
7
4.1.2.1. 1-(2-Chlorobenzyl)-piperazine
3500e3200, 3063, 2940, 2813, 1610, 1443, 1135, 1051, 754 and 683.
1H NMR (400 MHz; CDCl3,
(3). IR
(KBr,
cmꢁ1):
d, J): 7.43 (dd, 1H, J ¼ 9.0 Hz, 2.0 Hz); 7.34
(dd, 1H, J ¼ 9 Hz, 2 Hz); 7.20 (m, 2H); 3.61 (s, 2H); 2.54 (t, 4H,
J ¼ 6.0 Hz); 2.54 (broadened m, 4H); 2.01 (br, s, 1H). MS [EI, m/z
(relative intensity)]: 212 (0.9) [M þ 2], 210 (2.3) [Mþ], 125(100)
[CleC6H4eCH2], 89. Melting point: 157 ꢀC. Yield 66.7%.
8
a
(1 ꢁ R) ꢃ 100 where R ¼ Quadratic mean (Root mean square mean).
b
Calcd. from physicochemical properties: Molecular weight; Molar refractivity;
Connolly solvent accessible surface area; Connolly molecular surface area; Connolly
solvent excluded volume; Topological polar surface area; Molecular topological
index; Wiener index.
4.1.2.2. 1-(4-Chlorobenzyl)-piperazine
3500e3200, 3017, 2938, 2804, 1609, 1475, 1426, 1186, 1090 and 661.
(4). IR
(KBr,
cmꢁ1):

A. Bali et al. / European Journal of Medicinal Chemistry 45 (2010) 2656e2662
2661
1H NMR (400 MHz; CDCl3,
d
, J): 7.27 (d, 2H, J ¼ 9.0 Hz); 7.25 (d, 2H,
1170, 1089, 1048, 956 and 836; 1H NMR (400 MHz, CDCl3): 7.93 (d,
2H, J ¼ 7.0 Hz); 7.29 (m, 4H); 6.93 (d, 2H); 4.08 (t, 2H, J ¼ 7.5 Hz);
3.48 (s, 2H); 2.5 (broadened m, 13H); 2.01 (quintet, 2H, J ¼ 7.5 Hz).
MS [EI, m/z (relative intensity)]: 388 (0.45) [M þ 2], 386 (1.04) [Mþ],
125 (100) [ClC6H4CH2]. Melting point: 289 ꢀC. Anal. Calcd. for
C20H27N2O2Cl: C, 62.18; H, 6.99; N, 7.25. Found: C, 61.24; H, 6.14; N,
7.01. Yield 67.2%.
J ¼ 9.0 Hz); 3.44 (s, 2H); 2.87 (t, 4H, J ¼ 7.0 Hz); 2.39 (broadened s,
4H); 1.83 (s, 1H, NH proton). MS [EI, m/z (relative intensity)]: 212
(0.9) [M þ 2], 210 (2.1) [Mþ], 125(100) [CleC6H4eCH2], 89. Melting
point: 150 ꢀC. Yield 60.5%.
4.1.2.3. 1-(2-Chlorobenzoyl)-piperazine (5). IR (Nujol, cmꢁ1):
3500e3150, 3100, 2940, 2900, 2850, 1679, 1595, 1450, 1230, 1100,
745 and 710; 1H NMR (400 MHz; CDCl3,
d, J): 7.57 (m, 2H); 7.42 (t,
4.1.3.3. 2-[3-{4-(4-Chlorobenzyl)-piperazin-1-yl}propoxy]phenyl
1H, J ¼ 8.0 Hz); 7.32 (dd, 1H, J ¼ 8.0 Hz, 1.8 Hz); 3.61 (broadened s,
2H), 3.41 (s, 2H); 2.86 (s, 4H); 2.08 (s, 1H, NH). MS [EI, m/z (relative
intensity)]: 226 (1.7) [M þ 2], 224 (3.5) [Mþ], 139 (30.8), 105 (100)
[C6H5CO], 85, 77. Melting point: 195 ꢀC. Yield 80.5%.
ethanone (11). IR (KBr, cmꢁ1): 3066, 2941, 2811, 1675, 1596, 1447,
1239, 1157, 1045, 828 and 754; 1H NMR (400 MHz, CDCl3):
d 7.84
(dd, 1H, J ¼ 7.0 Hz, 1.0 Hz); 7.36 (m, 1H); 7.27 (m, 2H); 7.13 (m, 2H);
6.84 (d, 2H); 4.01 (t, 2H, J ¼ 8.0 Hz), 3.60 (s, 2H), 2.67 (m, 10H), 2.46
(s, 3H); 2.04 (quintet, 2H, J ¼ 8.0 Hz). MS [EI, m/z (relative inten-
sity)]: 388 (0.25) [M þ 2], 386 (0.75) [Mþ], 125 (100) [ClC6H4CH2].
Melting point: 288 ꢀC. Anal. Calcd. for C20H27N2O2Cl: C, 62.18; H,
6.99; N, 7.25. Found: C, 61.81; H, 6.44; N, 6.96. Yield 58.8%.
4.1.2.4. 1-(4-Chlorobenzoyl)-piperazine (6). IR (Nujol, cmꢁ1):
3500e3100, 3120, 2950, 2900, 2850, 1640, 1590, 1450, 1240, 1110,
740 and 710; 1H NMR (400 MHz; CDCl3,
d, J): 7.40 (d, 2H,
J ¼ 11.0 Hz); 7.32 (d, 2H, J ¼ 11.0 Hz); 3.71 (s, 2H), 3.41 (s, 2H); 2.86
(s, 4H); 2.08 (s, 1H, NH). MS [EI, m/z (relative intensity)]: 226 (0.7)
[M þ 2], 224 (2.6) [Mþ], 139 (26.8), 105 (100) [C6H5CO], 85, 77.
Melting point: 200 ꢀC. Yield 82.6%.
4.1.3.4. 2-[3-{4-(2-Chlorobenzyl)-piperazin-1-yl}propoxy]phenyl
ethanone (12). IR (KBr, cmꢁ1): 3072, 2949, 1668, 1596, 1450, 1237,
1049, 965 and 849; 1H NMR (400 MHz, CDCl3):
d 7.70 (dd, 1H,
J ¼ 9.0 Hz, 1.5 Hz); 7.44 (m, 2H); 7.00 (m, 3H); 6.98 (m, 2H); 4.30 (t,
4H, J ¼ 8.0 Hz); 2.60 (m, 11H); 2.40 (t, 2H, J ¼ 8.0 Hz); 2.20 (quintet,
2H, J ¼ 8.0 Hz). MS [EI, m/z (relative intensity)]: 388 (0.25) [M þ 2],
386 (0.75) [Mþ], 125 (100) [ClC6H4CH2]. Melting point: 2850 ꢀC.
Anal. Calcd. for C20H27N2O2Cl: C, 62.18; H, 6.99; N, 7.25. Found: C,
61.08; H, 6.26; N, 7.07. Yield 58.8%.
4.1.2.5. 1,4-Bis(4-chlorobenzyl)piperazine (7). IR (KBr, cmꢁ1): 3061,
2941, 2800, 1665, 1442, 1129, 1013 and 694; 1H NMR (400 MHz,
CDCl3):
d 7.25 (m, 8H); 3.45 (s, 4H); 2.44 (s, 8H). MS [EI, m/z (relative
intensity)]: 338 (2.5) [M þ 4], 336 (13.2) [M þ 2], 334 (23.6) [Mþ], 125
(100) [ClC6H4CH2]. Melting point: 200 ꢀC. Anal. Calcd. for C18H20N2Cl2:
C, 64.67; H, 5.99; N, 8.38. Found: C, 63.65; H, 5.24; N, 8.04. Yield 76.2%.
4.1.3.5. 4-[3-{4-(4-Chlorobenzoyl)-piperazin-1-yl}propoxy]phenyl
ethanone (13). IR (KBr, cmꢁ1): 3066, 2941, 2811, 1675, 1596,
1447,1239, 1157, 1045, 828 and 754; 1H NMR (400 MHz, CDCl3):
4.1.2.6. 1,4-Bis(2-chlorobenzyl)piperazine (8). IR (KBr, cmꢁ1): 3063,
2945, 2801, 2761, 1441, 1128, 1010 and 695; 1H NMR (400 MHz,
CDCl3):
d
7.47 (dd, 2H, J ¼ 7.5 Hz, 1.5 Hz); 7.34 (dd, 2H, J ¼ 7.5 Hz,
d
7.75 (d, 2H, J ¼ 8.5 Hz); 7.56 (m, 2H); 7.42 (t, 1H, J ¼ 7.5 Hz); 7.34
1.5 Hz); 7.24 (m, 4H); 3.63 (s, 4H); 2.57 (broadened m, 8H). MS [EI,
m/z (relative intensity)]: 338 (2.9) [M þ 4], 336 (14.8) [M þ 2], 334
(25.6) [Mþ], 125 (100) [ClC6H4CH2]. Melting point: 210 ꢀC. Anal.
Calcd. C18H20N2Cl2: C, 64.67; H, 5.99; N, 8.38. Found: C, 64.11; H,
5.64; N, 8.18. Yield 77.5%.
(dd, 1H, J ¼ 7.5 Hz, 1.0 Hz); 6.96 (d, 2H, J ¼ 8.5 Hz); 3.95 (t, 2H,
J ¼ 8.5 Hz); 2.56e2.45 (m, 13H); 1.95 (quintet, 2H, J ¼ 8.5 Hz). MS
[EI, m/z (relative intensity)]: 402 (0.50) [M þ 2], 400 (1.30) [Mþ],139
(100) [ClC6H4CO]. Melting point: 300 ꢀC. Anal. Calcd. for
C20H25N2O3Cl: C, 60.0; H, 6.25; N, 7.00. Found: C, 59.11; H, 6.24; N,
6.67. Yield 62.8%.
4.1.3. Preparation of X-[3-{4-(X0-chlorobenzyl)-piperazin-1-yl}
propoxy]phenyl ethanones (9e12) and corresponding chlorobenzoyl
derivatives (13e16)
4.1.3.6. 4-[3-{4-(2-Chlorobenzoyl)-piperazin-1-yl}propoxy]phenyl
ethanone (14). IR (KBr, cmꢁ1): 3066, 2941, 2811, 1675, 1596,
1447,1239, 1157, 1045, 828 and 754; 1H NMR (400 MHz, CDCl3):
A suspension of potassium carbonate (0.647 g, 4.7 mmol) was
prepared in 5 ml of DMF and 1-(X-chlorobenzyl) piperazines
(4.7 mmol) were added with stirring. To the resulting suspension,
a solution of 1-[X-(3-chloropropoxy) phenyl]ethanone (3.1 mmol)
in DMF (5 ml) was added dropwise with stirring. The solution was
heated at a temperature of 70e80 ꢀC for 3e10 h and filtered. The
filtrate was added to 60 ml 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.
d
7.82 (d, 2H, J ¼ 7.5 Hz); 7.71 (d, 2H, J ¼ 8.0 Hz); 7.50 (d, 2H,
J ¼ 7.5 Hz); 7.14 (d, 2H, J ¼ 8.0 Hz); 4.01 (t, 2H, J ¼ 8.5 Hz); 2.60e2.47
(m, 13H); 2.01 (quintet, 2H, J ¼ 8.5 Hz). MS [EI, m/z (relative
intensity)]: 402 (0.52) [M þ 2], 400 (1.25) [Mþ], 139 (100)
[ClC6H4CO]. Melting point: 308 ꢀC. Anal. Calcd. for C20H25N2O3Cl: C,
60.0; H, 6.25; N, 7.00. Found: C, 58.81; H, 5.99; N, 6.28. Yield 62.8%.
4.1.3.7. 2-[3-{4-(4-Chlorobenzoyl)-piperazin-1-yl}propoxy]phenyl
ethanone (15). IR (KBr, cmꢁ1): 3066, 2941, 2811, 1675, 1596,
1447,1239, 1157, 1045, 828 and 754; 1H NMR (400 MHz, CDCl3):
d
7.60 (m, 2H); 7.42 (m, 2H); 7.31 (dd, 1H, J ¼ 7.5 Hz, 1.5 Hz); 7.28
4.1.3.1. 4-[3-{4-(4-Chlorobenzyl)-piperazin-1-yl}propoxy]phenyl
(dd, 1H, J ¼ 8.0 Hz, 1.5 Hz); 7.02 (m, 2H); 4.00 (t, 2H, J ¼ 8.5 Hz);
2.57e2.45 (m, 13H); 1.98 (quintet, 2H, J ¼ 8.5 Hz). MS [EI, m/z
(relative intensity)]: 402 (0.45) [M þ 2], 400 (1.18) [Mþ], 139 (100)
[ClC6H4CO]. Melting point: 305 ꢀC. Anal. Calcd. for C20H25N2O3Cl: C,
60.0; H, 6.25; N, 7.00. Found: C, 58.96; H, 6.14; N, 6.85. Yield 65.8%.
ethanone (9). IR (Nujol, cmꢁ1): 3064, 2943, 2880, 1675, 1441, 1254,
1171, 954 and 834; 1H NMR (400 MHz, CDCl3,
d, J): 7.90 (d, 2H,
J ¼ 7.0 Hz); 7.46 (dd, 1H, J ¼ 9.0 Hz, 1.0 Hz); 7.33 (dd, 1H, J ¼ 9.0 Hz,
1.0 Hz); 7.23 (m, 2H); 6.92 (d, 2H, J ¼ 7.0 Hz); 4.08 (t, 2H, J ¼ 7.5 Hz);
3.62 (s, 2H); 2.54 (m, 13H); 2.01 (quintet, 2H, J ¼ 7.5 Hz). MS [EI, m/z
(relative intensity)]: 388 (0.58) [M þ 2], 386 (1.75) [Mþ], 125 (100)
[ClC6H4CH2]. Melting point: 290 ꢀC; Anal. Calcd. for C20H27N2O2Cl: C,
62.18; H, 6.99; N, 7.25. Found: C, 61.79; H, 6.64; N, 7.02. Yield 67.0%.
4.1.3.8. 2-[3-{4-(2-Chlorobenzoyl)-piperazin-1-yl}propoxy]phenyl
ethanone (16). IR (KBr, cmꢁ1): 3066, 2941, 2811, 1675, 1596,
1447,1239, 1157, 1045, 828 and 754; 1H NMR (400 MHz, CDCl3):
d
7.80 (d, 2H, J ¼ 8.0 Hz); 7.57 (d, 2H, J ¼ 8.0 Hz); 7.42 (t, 1H,
4.1.3.2. 4-[3-{4-(2-Chlorobenzyl)-piperazin-1-yl}propoxy]phenyl
J ¼ 7.6 Hz); 7.25 (dd, 1H, J ¼ 7.5 Hz, 1.0 Hz); 7.10 (m, 2H); 4.04 (t, 2H,
J ¼ 9.0 Hz); 2.55e2.42 (m, 13H); 2.04 (quintet, 2H, J ¼ 9.0 Hz). MS
ethanone (10). IR (Nujol, cmꢁ1): 3020, 2940, 1674, 1599, 1451, 1256,

2662
A. Bali et al. / European Journal of Medicinal Chemistry 45 (2010) 2656e2662
[EI, m/z (relative intensity)]: 402 (0.58) [M þ 2], 400 (1.34) [Mþ],139
(100) [ClC6H4CO]. Melting point: 308 ꢀC. Anal. Calcd. for
C20H25N2O3Cl: C, 60.0; H, 6.25; N, 7.00. Found: C, 59.08; H, 5.93; N,
6.65. Yield 65.8%.
[6] B. Costall, R.J. Naylor, The importance of the ascending dopaminergic systems
to the extrapyramidal and mesolimbic brain areas for the cataleptic action of
the neuroleptic and cholinergic agents. Neuropharmacology 13 (1974)
353e364.
[7] H.Y. Meltzer, Commentary on clinical studies on the mechanism of action of
clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psycho-
pharmacology 99 (1989) S18eS27.
4.2. Preliminary pharmacological evaluation for atypical
antipsychotic effect
[8] R.W. Griffith, K. Saameli, Clozapine and agranulocytosis. Lancet
pp. 657e657.
[9] K. Melkersson, M.L. Dahl, Adverse metabolic effects associated with atypical
antipsychotics: literature review and clinical implications. Drugs 64 (2004)
701e723.
2 (1975)
4.2.1. Apomorphine induced mesh climbing assay
[10] J.T. Schwartz, A.W. Brotman, A clinical guide to antipsychotic drugs. Drugs 44
(1992) 981e992.
[11] A. Thurkauf, X. Chen, S. Zhang, Y. Gao, A. Kieltyka, J.W.F. Wasley, R. Brodbeck,
W. Greenlee, A. Ganguly, H. Zhao, 1 H-Pyrazolo-[3,4-c]cyclophepta[1,2-thio-
phenes: a unique structural class of dopamine D4 selective ligands. Bioorg.
Med. Chem. Lett. 13 (2003) 2921e2924.
[12] H. Geneste, G. Backfisch, W. Braje, J. Delzer, A. Haupt, C.W. Hutchins, L.L. King,
W. Lubisch, G. Steiner, H. Teschendorf, L. Unger, W. Wernet, Synthesis and SAR
of highly potent and selective dopamine D3-receptor antagonists: quinolin(di)
one and benzazepin(di)one derivatives. Bioorg. Med. Chem. Lett. 16 (2006)
658e662.
[13] F.C. Masaguer, E. Ravina, J.A. Fontenla, J. Brea, H. Tristan, M.I. Loza, Butyro-
phenone analogues in the carbazole series as potential atypical antipsychotics:
synthesis and determination of affinities at D2, 5-HT2A, 5-HT2B and 5-HT2C
receptors. Eur. J. Med. Chem. 35 (2000) 83e95.
Albino lyka mice (six mice in each group) of either sex (26e38 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 were injected with the test compound intraperitoneally and
returned to the home cage. Mice in the control groups were injected
with normal saline intraperitoneally and returned to the home cage.
Mice in the clozapine test groups were injected with clozapine
intraperitoneally and returned to the home cage. After a gap of
10 min, apomorphine (2.5 mg kgꢁ1) 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 s. 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).
[14] A.B. Reitz, D.J. Bennett, P.S. Blum, E.E. Codd, C.A. Maryanoff, M.E. Ortegon, M.
J. Renji, M.K. Scott, R.P. Shank, J.L. Vaught, A new arylpiperazine antipsychotic
with high D2/D3/5-HT1A/a1 adrenergic affinity and a low potential for extra-
pyramidal effects. J. Med. Chem. 37 (1994) 1060e1062.
[15] D.C. Cole, J.W. Ellingboe, W.J. Lennox, H. Mazandarani, D.L. Smith, J.R. Stock,
G. Zhang, P. Zhou, L.E. Schechter, N1-arylsulfonyl-3-(1, 2, 3, 6-tetrahydropyr-
idin-4-yl)-1H-indole derivatives are potent and selective 5-HT6 receptor
antagonists. Bioorg. Med. Chem. Lett. 15 (2005) 379e383.
4.2.2. Apomorphine induced stereotypy assay
The same albino lyka mice employed in the mesh climbing assay
were used. Each mouse was injected with either the vehicle or the
test compound or clozapine and returned to its home cage. After
a gap of 10 min, apomorphine (2.5 mg kgꢁ1) was injected. Stereo-
typy 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 s. Scoring of stereotypy was done as: 1 (rearing,
sniffing, grooming) and 2 (licking, biting). Three dose levels were
employed and doses were selected by initial titration at different
dose levels. The atypical antipsychotic drug clozapine was
employed as a separate group (positive control) for comparison.
[16] R. Xu, J.R. Lever, S.Z. Lever, Synthesis and in vitro evaluation of tetrahy-
droisoquinolinyl benzamides as ligands for
s receptors. Bioorg. Med. Chem.
Lett. 17 (2007) 2594e2597.
[17] M. Weigl, B. Wunsch, Synthesis of bridged piperazines with
s receptor affinity.
Eur. J. Med. Chem. 42 (10) (2007) 1247e1262.
[18] B. Kinkead, S. Shahid, M.J. Owens, C.B. Nemeroff, Effects of acute and sub-
chronic administration of typical and atypical antipsychotic drugs on the
neurotensin system of the rat brain. J. Pharmacol. Exp. Ther. 67 (2000) 67e73.
[19] H.G. Vogel (Ed.), Drug Discovery and Evaluation: Pharmacological Assays, third
ed. Springer, 2007, pp. 761e762.
[20] A. Bali, S. Malhotra, H. Dhir, A. Kumar, A. Sharma, Synthesis and evaluation of
1-(quinoliloxypropyl)-4-aryl piperazines for atypical antipsychotic effect.
Bioorg. Med. Chem. Lett. 19 (2009) 3041e3044.
[21] N. Muruganantham, R. Sivakumar, N. Anbalagan, V. Gunasekhran, J.T. Leonard,
Synthesis, anticonvulsant and antihypertensive activities of 8-substituted
quinoline derivatives. Biol. Pharm. Bull. 27 (2004) 1683e1687.
Acknowledgements
[22] H. van de Waterbeemd, G. Camenisch, G. Folkers, J.R. Chretien, O.A. Raevsky,
Estimation of bloodebrain barrier crossing of drugs using molecular size and
shape, and H-bonding descriptors. J. Drug Target. 6 (1998) 151e165.
[23] J. Kelder, P.D.J. Grootenhuis, D.M. Bayada, L.P.C. Delbressine, J.P. Ploemen, Polar
molecular surface as a dominating determinant for oral absorption and brain
penetration of drugs. Pharm. Res. 16 (1999) 1514e1519.
The research grant provided by University Grants Commission is
duly acknowledged.
References
[24] N. Nikolova, J. Jaworska, Approaches to measure chemical similarity
e
a review. QSAR Comb. Sci. 22 (2003) 1006e1024.
[1] M.D. Jibson, I.D. Glick, R. Tandon, Schizophrenia and other psychotic disorders.
Focus 2 (2004) 17e30.
[2] P. Seeman, H.H.M. Van Tol, Dopamine receptor pharmacology. Trends Phar-
macol. Sci. 15 (1994) 264e270.
[3] P. Seeman, Dopamine receptors: clinical correlates. in: F.E. Bloom, D.V. Kupfer
(Eds.), Psychopharmacology: The Fourth Generation of Progress. Raven Press,
New York, 1995, pp. 295e302.
[4] K.L. Davis, R.S. Kahn, G. Ko, M. Davidson, Dopamine in schizophrenia: a review
and reconceptualization. Am. J. Psychiatry 148 (1991) 1474e1486.
[5] G.M. Simpson, E.H. Pi, J.J. Sramek, Adverse effects of antipsychotic agents.
Drugs 21 (1981) 138e151.
[25] A. Bijev, D. Yaneve, A. Bocheva, G. Stoev, Ligand based design, synthesis and
preliminary in vivo screening of pyrrole derivatives as potential tricyclic anti-
inflammatory agents. Arzneim.-Forsch./Drug Res. 56 (2006) 753e759.
[26] Y.H. Zhao, M.H. Abraham,A. Ibrahim, P.V. Fish, S. Cole, M.L. Lewis, M.J. deGroot, D.
P. Reynolds, Predicting penetration across the blood brain barrier from simple
descriptors and fragmentation schemes. J. Chem. Inf. Model. 47 (2007) 170e175.
[27] <http://www.chemsilico.com/CS_prBBB/BBBhome.html>.
[28] M. Iyer, R. Mishra, Y. Han, A. Hopfinger, Predicting blood-brain partitioning of
organic drugs using membrane-interaction QSAR analysis. Pharm. Res. 19
(2002) 1611e1621.