Synthesis and evaluation of 1-(quinoliloxypropyl)-4-aryl piperazines for atypical antipsychotic effect

Article abstract of DOI:10.1016/j.bmcl.2009.04.019

A series of 1-(quinoliloxypropyl)-4-aryl-piperazines has been synthesized and the target compounds evaluated for atypical antipsychotic activity in apomorphine induced mesh climbing and stereotypic behaviour in mice. The 8-hydroxyquinoline ether derivativ

Full text of DOI:10.1016/j.bmcl.2009.04.019

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3041–3044
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of 1-(quinoliloxypropyl)-4-aryl piperazines
for atypical antipsychotic effect
b
b
a
c
Alka Bali a, , Sarika Malhotra , Himjyoti Dhir , Anil Kumar , Ajay Sharma
*
a University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160 014, India
b Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
c Division of Pharmacology, Zydus Cadila Limited, Ahmedabad, 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-(quinoliloxypropyl)-4-aryl-piperazines has been synthesized and the target compounds
evaluated for atypical antipsychotic activity in apomorphine induced mesh climbing and stereotypic
behaviour in mice. The 8-hydroxyquinoline ether derivative 14 has emerged as an important lead com-
pound showing a potential atypical antipsychotic profile. Employing appropriate physicochemical prop-
erties, the similarity of the compounds was assessed with respect to some atypical antipsychotic drugs as
clozapine, ketanserine, ziprasidone and risperidone.
Received 25 August 2008
Revised 22 March 2009
Accepted 4 April 2009
Available online 10 April 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
1-(Quinolyloxypropyl)-4-aryl-piperazines
Atypical antipsychotics
Schizophrenia
Similarity
Schizophrenia is a complex psychological disorder affecting
about 1% of the population worldwide.1 The use of classical neuro-
leptics such as chlorpromazine is associated with severe mecha-
nism related side effects including parkinsonism and akathesia
(extrapyramidal symptoms), tardive dyskinesia.2,3 Clozapine, a
dibenzodiazepine derivative,4 prototype of the so called ‘atypical
antipsychotics’ was the first compound to demonstrate a superior
profile over conventional neuroleptics, that is, being nearly devoid
of extrapyramidal side effects and alleviation of negative symp-
toms of schizophrenia. Unfortunately, its therapeutic use has been
hampered by serious side effects, for example, agranulocytosis and
sialorrhoea, attributed to its high affinity for a multitude of CNS
receptors.5,6
In this Letter, we report the synthesis and pharmacological eval-
uation of a new class of CNS active agents with a propoxyquinoline
system linked to the 4-chlorobenzyl/benzoyl piperazine ring.
Synthetic scheme for preparation of target compounds 7–14 is
summarized in Scheme 1. First step was the conversion of 6-
hydroxyquinoline and 8-hydroxyquinoline to their 3-chloropropyl
ether derivatives 1 and 2 by refluxing with 1-bromo-3-chloropro-
pane in sodium metal and absolute ethanol. The amidation reac-
tion of benzoyl chloride and 4-chlorobenzoyl chloride with
piperazine afforded the compounds 3 and 4 in 80–88% yields. Ben-
zyl piperazine and p-chlorobenzyl piperazine 5 and 6 were ob-
tained in good yields (80–85%) from reaction of their
corresponding aryl chlorides with piperazine. The final target com-
pounds 6-[3-{4-(4-X-aryl)-piperazin-1-yl}-propoxy]quinolines (7–
14) were prepared by refluxing the chloropropoxyquinolines with
the piperazine derivatives in dimethyl formamide. All the reactions
were monitored by thin layer chromatography and the products
were characterized through spectroscopic data.18 The target com-
pounds were subjected to preliminary pharmacological evaluation
to determine their ability to antagonize apomorphine induced
mesh climbing behaviour and apomorphine induced stereotypy
in mice. Doses were selected by initial titration at different dose
levels. Clozapine group was employed as a standard (positive
control).
The pertinent approaches for development of atypical antipsy-
chotics include preferential D4 versus D2 receptor affinity,7 prefer-
ential D3 versus D2 affinity,8 combined 5-HT2/D2 receptor affinity,9
5-HT1A agonism,10 dopamine autoreceptor agonism,11 sigma (
r)
receptor blockade,12 5-HT6 receptor antagonism,13 5-HT3 antago-
nism,14 partial glutamate agonists/antagonists, neurotensin agon-
ism15 or through direct animal studies.16 In animal models, the
atypical antipsychotics are identified by their inhibition of apo-
morphine induced climbing response (indicative of dopaminergic
antagonism in mesocorticolimbic pathway associated with anti-
psychotic effect) along with weak or no inhibition of apomorphine
induced stereotypy (characteristic of antagonism in nigrostriatal
system linked to extrapyramidal symptoms).17
In apomorphine induced mesh climbing assay, albino lyka mice
(six in each group) of either sex (26–38 g) were habituated by indi-
vidually placing in a circular cage made of wire mesh of diameter
13 cm and height 14 cm. Mice in the test, control and standard
groups were injected, respectively, with the test compound, nor-
* Corresponding author. Tel.: +91 172 2534104; fax: +91 172 541142.
E-mail address: alka.bali@rediffmail.com (A. Bali).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.019

3042
A. Bali et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3041–3044
OCH2CH2CH2Cl
i
HO
N
N
N
ClCH2CH2CH2Br
1-2
OCH2CH2CH2Cl
N
N
NH
NH
ii
R
R
O
N
X
N
R
N
R= H, Cl
7-14 X= CH , CO
O
2
Scheme 1. Reagents and conditions: (i) Na, EtOH, 20–24 h; (ii) DMF, 18–20 h reflux.
mal saline and clozapine intraperitoneally and returned to the
home cage. After a gap of 10 min, apomorphine (2.5 mg/kg) was in-
jected intraperitoneally. Mesh climbing behaviour was 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 behav-
iour was scored as 1 (one, two or three paws on the mesh) and 2
(all four paws on the mesh).
Apomorphine induced stereotypy assay was carried out with
the same albino lyka mice employed in the mesh climbing assay.
Stereotypy was noted at 10, 15, 20, 25 and 30 min after apomor-
phine 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).
Wallis test or one way ANOVA. Level of significance was fixed at
p < 0.05. Summary of results along with chemical structures of tar-
get compounds are given in Table 3.
Best amongst the series were 8-quinoline ether derivatives 10
and 14 (120 and 80 mg kgꢀ1 ip, respectively). In the given test dose,
both produced a statistically significant reduction in apomorphine
induced mesh climbing behaviour (H values for 10 and 14 = 9 and
68, respectively; >tabulated values) and 14 showed higher po-
tency. However, both the compounds did not reverse apomorphine
induced stereotypy at all (H values for 10 and 14 = 0.098 and 29,
respectively; <tabulated values). The 6-quinoline analogs of com-
pounds 10 and 14 (compounds 8 and 12; 25 and 5 mg kgꢀ1, respec-
tively) did not produce statistically significant decrease in either of
the assays. The benzoyl derivatives 7, 9 and 11 (25, 20 and
1 mg kgꢀ1 ip, respectively) reversed the apomorphine induced ste-
reotypy behaviour significantly (H values for 7, 9 and 11 = 5.77, 9
and 70, respectively; >tabulated values). The results show that
The final mean score results obtained in the both the assays are
given in Tables 1 and 2 and graphically depicted in Figures 1 and 2.
The test results were compared with the control group and statis-
tical analysis was carried out employing non parametric Kruskal
Table 1
Mean score of compounds in apomorphine induced mesh climbing assay
Time (min)
Mean score in compoundsa
Control
7
8
9
10
11
12
13
14
Clozapine
10
15
20
25
30
3.3
1.8
2.3
1.5
2.1
2.2
3.5
2.5
1.6
1.2
3.0
2.6
2.4
2.8
2.0
3.1
3.6
3.0
2.5
2.0
0.6
1.2
0.8
1.4
1.0
1.2
3.6
1.6
1.1
1.1
2.6
1.8
1.6
1.6
0.8
3.1
3.2
3.2
2.9
2.7
0.2
0.6
0.4
0.8
0.0
2.2
2.2
3.0
2.8
2.4
a
All values are expressed as mean SEM (n = 5).
Table 2
Mean score of compounds in apomorphine induced stereotypy assay
Time (min)
Mean score in compoundsa
Control
7
8
9
10
11
12
13
14
Clozapine
10
15
20
25
30
3.8
4.8
3.5
2.5
1.6
1.3
1.5
1.1
1.0
1.8
4.0
3.6
4.2
4.4
3.4
0.8
1.5
0.7
0.5
0.6
3.4
4.4
3.6
2.4
1.8
0.6
0.8
0.1
0.1
0.5
3.6
3.8
4.0
4.2
4.4
1.2
1.1
0.7
0.8
0.6
2.2
4.6
3.2
1.8
1.4
4.0
4.6
3.8
3.6
3.6
a
All values are expressed as mean SEM (n = 5).

A. Bali et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3041–3044
3043
the p-chloro derivatives have an increased potency over non chlo-
rinated analogs. The 8-quinoline ether system is important for
binding in mesolimbic areas as 10 and 14 have shown a profile
suggesting an atypical antipsychotic potential. In contrast, the 6-
quinoline ether system seems to selectively improve the binding
affinity in the nigrostriatal region as the 6-quinoline analogs only
cause a selective reversal of apomorphine induced stereotypy.
Further, a set of molecular parameters was computed for the
target compounds using Chem3D Ultra and their physicochemical
and steric similarity assessed with respect to standard drugs cloza-
pine, risperidone, ziprasidone and ketanserine.19 The steric and
molecular surface descriptors include connolly solvent accessible
surface area SAS (Å2), connolly molecular surface area MS (Å2),
connolly solvent excluded volume SEV (Å3) and Ovality. Global
physicochemical properties computed were hydrophobic parame-
ter log P and molecular weight MW (atomic mass units). Topolog-
ical polar surface area, TPSA, important for prediction of drug
transport properties including BBB penetration was also deter-
mined. Thereby, the distance di of a particular target compound j
to drug molecules, for example, clozapine may be presented by
the formula:
4
3.5
3
2.5
2
1.5
1
0.5
0
Control
7
8
9
10
11
12
13
10 15 20 25 30
14
Time (min)
Clozapine
Figure 1. Mean score in apomorphine induced mesh climbing assay.
Control
7
8
9
10
11
12
13
14
6
5
4
3
2
ꢀ
ꢁ
P
Xi;j
n
j¼1
1 ꢀ X
n
1
d2i ¼
i;std
0
10
15
20
25
30
where Xi,j is the value of molecular parameter i for compound j, Xi,std
is the value of same molecular parameter for the standard drug, for
example, clozapine. Then, the similarity of compound j to the stan-
dard drug was calculated as
Time (min)
Clozapine
Figure 2. Mean score in apomorphine induced stereotypy assay.
p
Similarity ð%Þ ¼ ð1 ꢀ RÞ ꢁ 100 where R ¼ d2
Table 3
R is the quadratic mean (root mean square), a measure of central
tendency. The calculation results obtained are presented in Table
4 and 5.20 Average similarity of compounds 10 and 14 to clozapine
is quiet less, that is, 56.85%. However, a much higher similarity to
other drugs was noted (90.64%; 85.5% and 76.7% with respect to
ziprasidone, risperidone and ketanserine, respectively).
Chemical structures and averaged results in pharmacological testing
[Y]
Ar
N
N
O
X
In conclusion, a new series of quinolyloxy propyl piperazine
derivatives has been investigated and two compounds 10 and 14
have shown promise as potential atypical antipsychotic agents.
Their structural similarity to representative drug examples of this
class further lends credence to these results.
Compound
no.
X
Y
Ar
Dose
(mg/kg)
Significant
mesh
climbing
Reversal in
stereotypy
7
8
9
10
11
12
13
14
H
H
H
H
Cl
Cl
Cl
Cl
C@O
CH2
6-Quinolyl
6-Quinolyl
8-Quinolyl
8-Quinolyl
6-Quinolyl
6-Quinolyl
8-Quinolyl
8-Quinolyl
25
25
20
120
1
5
5
80
ꢀ
ꢀ
ꢀ
+
ꢀ
ꢀ
ꢀ
+
+
ꢀ
C@O
CH2
C@O
CH2
C@O
CH2
+
ꢀ
+
Acknowledgments
ꢀ
+
The research grant provided by the University Grants Commis-
sion is duly acknowledged.
ꢀ
Table 4
Statistics and similarity values of test compounds to selected drug examples
Compd No.
Clozapine Ra
Ketanserine R
Ziprasidone R
Risperidone R
Similarityb,c (%) to
Ketanserine Ziprasidone
Clozapine
Risperidone
7
8
9
10
11
12
13
14
1.5385
1.202
1.469
1.167
1.848
1.593
1.808
1.467
0.1822
0.1542
0.1053
0.1178
0.5008
0.3574
0.3748
0.3487
0.0906
0.0536
0.0296
0.0719
0.2515
0.1901
0.3128
0.1153
0.1539
0.0515
0.1110
0.0359
0.3191
0.1670
0.304
53.85
20.2
46.9
67.0
84.8
59.3
80.8
46.7
81.78
84.58
89.47
88.22
49.92
64.26
62.52
65.13
90.94
94.64
97.04
92.81
74.85
80.99
68.72
88.47
84.61
94.85
88.9
96.4
68.09
83.30
69.60
74.50
0.2555
a
Quadratic mean (root mean square mean).
b
c
(1 ꢀ R) ꢁ 100.
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.

3044
A. Bali et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3041–3044
15. Kinkead, B.; Shahid, S.; Owens, M. J.; Nemeroff, C. B. J. Pharmacol. Exp. Ther.
Supplementary data
2000, 295, 67.
16. Moore, N. C.; Gershan, S. Clin. Neuropharmacol. 1989, 12, 167.
17. Drug Discovery and Evaluation: Pharmacological Assays; Vogel, H. G., Ed., 3rd ed.;
Springer, 2007; pp 761–762.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.04.019.
18. Data for selected compounds: Compound 7: IR (KBr, cmꢀ1): 3020, 1640. 1H NMR
(300 MHz, DMSO-d6): d 8.60 (d, 1H, J = 9.0 Hz), 8.10 (d, 2H, J = 9.0 Hz); 7.55–
7.45 (m, 2H); 7.44–7.38 (m, 5H); 7.10 (s, 1H); 4.30 (t, 2H, J = 6.0 Hz); 2.50 (s,
8H); 2.05–1.98 (m, 4H). MS [EI, m/z (relative intensity)]: 375 [M+], 105 (100)
[C6H5CO]. Melting point: 185 °C; Anal. Calcd for C23H25N3O2: C, 73.6; H, 6.7; N,
11.2. Found: C, 73.01; H, 6.24; N, 10.87. Yield 65%.Compound 10: IR (KBr, cmꢀ1):
3000, 1620, 1450. 1H NMR (300 MHz, CDCl3): d 8.90 (d, 1H, J = 7.8 Hz), 8.10 (d,
1H, J = 7.8 Hz); 7.55–7.45 (m, 3H), 7.33–7.28 (m, 5H); 7.20 (d, 1H, J = 6.8 Hz);
4.60 (t, 2H, J = 6.0 Hz); 3.80 (s, 2H); 2.81–2.75 (m, 8H); 2.70 (t, 2H, J = 6.5 Hz);
2.23–2.18 (m, 2H). MS [EI, m/z (relative intensity)]: 361 [M+], 91 (100)
[C6H5CH2]. Melting point: 191oC. Anal. Calcd for C23H27N3O: C, 76.45; H, 7.5; N,
11.6. Found C, 75.98; H, 6.98; N, 11.0.Yield 72.5%.Compound 11: IR (Nujol,
cmꢀ1): 3100, 1560, 1450. 1H NMR (300 MHz, CDCl3): d 8.00 (s, 1H), 7.70 (s, 1H),
7.65 (s, 1H), 7.45–7.39 (m, 7H), 3.52 (t, 6H, J = 6.0 Hz), 3.34 (t, 6H, J = 6.0 Hz),
3.12 (t, 2H, J = 6.0 Hz), 1.80 (quintet, 2H, J = 6.0 Hz); MS [EI, m/z (relative
intensity)]: 411 (M+2), 409 [M+], 105 (100) [C6H4CHO]. Melting point: 240 °C.
Anal. Calcd for C23H24N3O2Cl: C, 67.1; H, 5.8; N, 10.2. Found: C, 66.61; H, 5.32;
N, 10.02. Yield 64.8%.Compound (14) IR (Nujol, cmꢀ1): 3100, 1450; 1H NMR
(300 MHz, CDCl3): d 8.80 (d, 1H, J = 6.0 Hz), 8.23–8.17 (m, 1H), 7.50 (s, 2H), 7.35
(d, 3H, J = 8.0 Hz), 7.25 (d, 4H, J = 8.0 Hz), 4.55 (t, 2H, J = 6.0 Hz), 3.53 (s, 2H),
3.23 (t, 4H, J = 6.0 Hz), 2.78–2.72 (m, 6H), 2.90–2.86 (m, 2H); MS[EI, m/z
(relative intensity)]: 397 (M+2), 395 [M+], 210, 168, 145, 125 (100) [Cl–
C6H4CH2], 85. Melting point: 210oC. Anal. Calcd for C23H26N3OCl: C, 69.5; H,
6.5; N, 10.6. Found: C, 69.01; H, 6.32; N, 10.12. Yield 71.8%.
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