Synthesis, computational studies and preliminary pharmacological evaluation of new arylpiperazines

Article abstract of DOI:10.1155/2011/346087

A series of novel arylpiperazines were synthesized and the target compounds evaluated for atypical antipsychotic activity in apomorphine induced climbing behavior (D₂ antagonism), 5-HTP induced head twitches (5- HT _2A antagonism) and

Full text of DOI:10.1155/2011/346087

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(3), 1044-1051
http://www.e-journals.net
Synthesis, Computational Studies and Preliminary
Pharmacological Evaluation of New Arylpiperazines
SUSHIL KUMAR*, A. K. WAHI and RANJIT SINGH§
Drug Design & Medicinal Chemistry Research Laboratory
College of Pharmacy, IFTM, Moradabad-244001(U.P.), India
§School of Pharmaceutical Sciences, Shobhit University, Meerut (U.P.), India
sushilmpharm@rediffmail.com
Received 12 September 2010; Revised 30 November 2010; Accepted 15 December 2010
Abstract: A series of novel arylpiperazines were synthesized and the target
compounds evaluated for atypical antipsychotic activity in apomorphine
induced climbing behavior (D2 antagonism), 5-HTP induced head twitches (5-
HT2A antagonism) and catalepsy studies in albino mice. The physicochemical
similarity of the target compounds with respect to standard drugs clozapine,
ketanserine and risperidone was assessed by calculating from a set of
physiochemical properties using software programs. The test compounds (3a-j)
demonstrated good similarity values with respect to the standard drugs. Among
them, compound 3d has emerged as an important lead compound showing
potential atypical antipsychotic like profile.
Keywords: N-Cyclohexylacetamide, Arylpiperazines, Antipsychotic activity, 5-HT2A, D2 antagonists
Introduction
Schizophrenia has been referred to as the cancer of mental illnesses1. The vast amount of
research directed towards the treatment of schizophrenia in recent years attests to the
inadequacy of current methods of treatment and the need for new and improved therapeutic
agents. Conventional agents such as haloperidol and chlorpromazine relieve only the
positive symptoms such as delusion, hallucinations and thought disorders but ineffective in
the treatment of negative symptoms of schizophrenia. The use of typical antipsychotics for
the treatment of schizophrenia is associated with severe extrapyramidal side effects2.
Clozapine is considered atypical because it is effective in treating both the positive and
negative symptoms of schizophrenia without inducing extrapyramidal side effects. Meltzer
et al.3 suggested that in the efficacy of clozapine and other atypical antipsychotics such as
olanzapine or risperidone, the most important factor is their relative affinities for D2 and
5-HT2A receptors. Arylpiperazines have been recognized as the largest and most diverse
classes of compounds exerting actions on the central nervous system in particularly
serotonin (5-HT) and dopamine affinity4,5. Their general chemical structure consists of the
arylpiperazine moiety connected by an alkyl chain with the terminal amide or imide
fragment6. As part of our ongoing work on the development of strategies for the preparation
of new D2/5-HT2A receptor antagonists as atypical antipsychotics, we here in repot the
synthesis and preliminary pharmacological evaluation of some novel amide arylpiperazines.

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SUSHIL KUMAR et al.
Experimental
Melting points of the synthesized compounds were determined by open capillary method and
are uncorrected. The IR spectra of synthesized compounds were recorded in potassium
1
bromide discs on Perkin Elmer Spectrum RX1. The H NMR spectra were recorded on a
Bruker DRX-300 spectrophometer at 300 MHz in CDCl3 containing TMS as an internal
standard. The electrospray mass spectra were recorded on a Thermo finnigan LCQ advantage
max ion trap mass spectrometer. The reactions progress was monitored by thin-layer
chromatography (TLC) using silica gel G and spots were visualized in an iodine chamber.
Synthesis of 2-chloro-N-cyclohexylacetamide (2)
Cyclohexylamine (1) (4.61 mL, 0.04 mol) in 2 N aqueous sodium hydroxide (150 mL) at
o
0 C temperature was treated with chloroacetylchloride (3.18 mL, 0.04 mol) as a solution in
dichloromethane (100 mL). After 1 h, the layers were separated and the aqueous phase
extracted with additional portion of dichloromethane. The organic phase was combined,
washed with an aqueous solution of 1 N HCl, saturated NaHCO3, dried (Na2SO4) and
concentrated to afford 2. Yield: 75%. Mp. 100-102 oC. IR (KBr, cm-1): 3414, 3290, 3012,
1
2937, 1658, 1219, 1093, 768. H NMR (300 MHz; CDCl3 δ): 1.22-1.45 (m, 5H), 1.61-1.76
(m, 3H), 1.90-1.94 (m, 2H), 3.73-3.85 (m, 1H), 4.03 (s, 2H, COCH2), 6.44 (br s, NH).
General procedure for the synthesis of 3a-j
2-Chloro-N-cyclohexylacetamide (2) (0.87 g, 0.005 mol) was dissolved in 100 mL of
acetonitrile in a 250 mL round bottom flask. Anhydrous K2CO3 (0.69 g, 0.005 mol), catalytic
amount of potassium iodide and appropriate arylpiperazine (0.005 mol) were added into
above solution. The mixture was allowed to reflux with continuous stirring on magnetic
stirrer for 12 h. After completion of reaction the solvent was removed by vacuum distillation
and residue was dissolved in chloroform and water. An organic layer was washed with brine
and dried over MgSO4, removal of the solvent to afford the target compounds 3a-j. The
reactions are outlined in Scheme 1 and the nature of the substituents is given in Table 1.
NHCOCH2Cl
NH2
ClCOCH2Cl
i
(2)
R
ii
HN
N
(1)
R
HN COCH2
N
N
3a-j
3a-j
Scheme 1. Synthesis of the target compounds. Reagents and condition: (i) NaOH,
dichloromethane (ii) acetonitrile, K2CO3, KI.

Synthesis and Preliminary Pharmacological Evaluation
1046
Table 1. Substituents of compounds 3a-j
Compd. no.
Compd code.
R
1
2
3
H
3a
3b
3c
3d
3e
3f
3-CH3
4-CH3
2-OCH3
3-OCH3
4-OCH3
2-Cl
4
5
6
7
3g
3h
3i
8
9
10
3-Cl
4-F
4-NO2
3j
2-[4-(Phenyl) piperazin-1-yl]-N-cyclohexylacetamide (3a)
0
Yield: 0.75 g (50%). mp., 87-90 C. IR (KBr, cm-1): 3356, 3006, 2936, 1664, 1234, 1015,
1
752. H NMR (300 MHz; CDCl3 δ): 1.17-1.89 (m, 10H), 3.79- 3.82 (m,1H), 2.41 -2.86
(m, 4H, pip ring), 3.01-3.17 (m, 4H, pipring), 4.80 (s, 2H, COCH2), 6.82 -7.24 (m, 5H,
Ar-H), 7.27 (br s, NH). MS (EI) m/z: 302.3 (M+1). Rf 0.27 (Hexane: Ethylacetate 1:1).
2-[4-(3-Methylphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3b)
Yield: 0.85 g (54.14%). mp., 78-82 0C. IR (KBr, cm-1): 3246, 3006, 2938, 1660, 1234, 1015,
756. 1H NMR (300 MHz; CDCl3 δ): 1.20-1.88 (m, 10H), 3.69-3.96 (m, 1H), 2.31
(s, 3H, CH3), 2.49 -2.89 (m, 4H, pip ring), 3.11-3.23 (m, 4H, pipring), 4.72 (s, 2H, COCH2),
6.40 -8.17 (m, 4H, Ar-H), 7.27 (br s, NH). Rf : 0.23 (Hexane: Ethylacetate 1:1).
2-[4-(4-Methylphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3c)
Yield: 0.82 g (52.22%). mp., 76-80 0C. IR (KBr, cm-1): 3246, 3006, 2938, 1660, 1234, 1015,
756. 1H NMR (300 MHz; CDCl3 δ): 1.20-1.88 (m, 10H), 3.79-3.96 (m, 1H), 2.29
(s, 3H, CH3), 2.49 -2.80 (m, 4H, pip ring), 3.11-3.23 (m, 4H, pipring), 4.72 (s, 2H, COCH2),
6.40 -7.94 (m, 4H, Ar-H), 7.27 (br s, NH). Rf 0.21 (Hexane: Ethylacetate 1:1).
2-[4-(2-Methoxyphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3d)
Yield: 0.57 g (34.54%). mp., 85-89 0C. IR (KBr, cm-1): 3355, 3003, 2937, 1666, 1242, 1036,
756. 1H NMR (300 MHz; CDCl3 δ): 1.25-1.89 (m, 10H), 3.79-3.96 (m, 1H), 3.54
(s, 3H, OCH3), 2.17 -2.89 (m, 4H, pip ring), 3.10-3.42 (m, 4H, pipring), 4.69 (s, 2H,
COCH2), 6.57 -7.94 (m, 4H, Ar-H), 7.26 (br s, NH). Rf : 0.25 (Hexane: Ethylacetate 1:1).
2-[4-(3-Methoxyphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3e)
Yield: 0.50 g (30.30%). mp., 66-70 0C. IR (KBr, cm-1): 3353, 3003, 2935, 1665, 1241, 1036,
755. 1H NMR (300 MHz; CDCl3 δ): 1.25-1.89 (m, 10H), 3.79-3.96 (m, 1H), 3.54
(s, 3H, OCH3), 2.17 -2.89 (m, 4H, pip ring), 3.10-3.42 (m, 4H, pipring), 4.69 (s, 2H,
COCH2), 6.57 -7.94 (m, 4H, Ar-H), 7.26 (br s, NH). Rf : 0.39 (Hexane: Ethylacetate 1:1).
2-[4-(4-Methoxyphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3f)
Yield: 0.58 g (35.15%). mp., 94-98 0C. IR (KBr, cm-1): 3353, 3003, 2935, 1665, 1241, 1036,
755. 1H NMR (300 MHz; CDCl3 δ): 1.13-1.90 (m, 10H), 3.79-3.86 (m, 1H), 3.54
(s, 3H, OCH3), 2.67 -2.70 (m, 4H, pip ring), 3.04-3.47 (m, 4H, pipring), 4.67 (s, 2H,
COCH2), 6.77 -7.09 (m, 4H, Ar-H), 7.26 (br s, NH). Rf : 0.24 (Hexane: Ethylacetate 1:1).

1047
SUSHIL KUMAR et al.
2-[4-(2-Chlorophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3g)
Yield: 0.97 g (58.08%). mp., 72-75 0C. IR (KBr, cm-1): 3349, 3008, 2935, 1664, 1225, 1015,
1
757. H NMR (300 MHz; CDCl3 δ): 1.25-1.88 (m, 10H), 3.59- 3.81 (m, 1H), 2.14 -2.95
(m, 4H, pip ring), 3.01-3.45 (m, 4H, pipring), 4.68 (s, 2H, COCH2), 6.65 -7.94 (m, 4H, Ar-
H), 7.26 (br s, NH). Rf : 0.54 (Hexane: Ethylacetate 1:1).
2-[4-(3-Chlorophenyl) piperazin-1-yl]-N- cyclohexylacetamid (3h)
Yield: 0.95 g (56.88%). mp., 86-90 0C. IR (KBr, cm-1): 3349, 3008, 2935, 1664, 1225, 1015,
1
757. H NMR (300 MHz; CDCl3 δ): 1.25-1.88 (m, 10H), 3.59- 3.81 (m, 1H), 2.14 -2.95
(m, 4H, pip ring), 3.01-3.45 (m, 4H, pipring), 4.68 (s, 2H, COCH2), 6.65 -7.94 (m, 4H, Ar-
H), 7.26 (br s, NH). Rf : 0.47 (Hexane: Ethylacetate 1:1).
2-[4-(4-Fluorophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3i)
0
Yield: 1 g (62.89%). mp., 88-91 C. IR (KBr, cm-1): 3248, 3009, 2936, 1662, 1224, 1015,
1
756. H NMR (300 MHz; CDCl3 δ): 1.15-1.87 (m, 10H), 3.55- 3.97 (m, 1H), 2.63 -2.92
(m, 4H, pip ring), 3.10-3.45 (m, 4H, pipring), 4.82 (s, 2H, COCH2), 6.74 -7.97 (m, 4H, Ar-
H), 7.28 (br s, NH). Rf : 0.28 (Hexane: Ethylacetate 1:1).
2-[4-(4-Nitrophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3j)
0
Yield: 0.98 g (56.64%). mp., 134-136 C. IR (KBr, cm-1): 3249, 3008, 2937, 1663, 1225,
1015, 754. 1H NMR (300 MHz; CDCl3 δ): 1.18-1.91 (m, 10H), 3.55- 3.97 (m, 1H), 2.63-2.70
(m, 4H, pip ring), 3.06-3.46 (m, 4H, pipring), 4.82 (s, 2H, COCH2), 6.82 -8.13 (m, 4H,
Ar-H), 7.27 (br s, NH). Rf: 0.26 (Hexane: Ethylacetate 1:1).
Computation of physiochemical properties
A set of molecular parameters was computed for the target compounds as well as three
standard drugs clozapine, ketanserine and risperidone using Chem 3D ultra version 11.0,
Chem Silico online free software and are shown in Table 2. The important molecular
parameters for antipsychotics are blood brain barrier (BBB), log P and topological polar
surface area. Literature review suggests that TPSA is a measure of a molecule’s hydrogen
bonding capacity and its value should not exceed certain limit if the compound is intended to
be CNS active. Two differing limits have been proposed: van de Waterbeemed et al.7
suggest a limit of 90 A2, where, Kelder et al.8 suggest 60-70 A2.
Similarity calculations
The physicochemical similarity of the target compounds was calculated with respect to the
standard drugs9 and shown in Table 3. Firstly, the distance ‘di’ of a particular target
compound ‘j’ to drug molecules e.g., clozapine was calculated by the formula:
2
n
2
di
=
(1− Xi, j/Xi,std) / n
∑
j=l
Where, Xi, j is the value of molecular parameter ‘i’ for compound ‘j’, Xi, std is the value
of the same molecular parameter for the standard drug, e.g., clozapine, ketanserine and
risperidone. Then, the similarity of compound ‘j’ to the standard drug was calculated as:
Similarity (%) = (1-R) x 100. Where R =√d2 is the quadratic mean (root mean square), a
measure of central tendency.

Synthesis and Preliminary Pharmacological Evaluation
1048
Table 2. Calculation of molecular properties for 2-[4-(aryl substituted) piperazin-1-yl]-
N-cyclohexylacetamides (3a-j) and standard drugs
Compd
No.
log
BBi
SASc MSAd SEVe
(A2) (A2) (A2)
log P M.Wa MRb
TPSAf MTIg WIh
0.3
0.34
0.34
0.09
0.07
0.07
0.27
0.32
0.24
-0.87
2.47 301.43 91.17 580.26 309.45 297.08 35.58 9668 1248
2.96 315.45 97.07 611.49 328.11 313.97 35.58 10915 1408
2.96 315.45 97.07 611.47 328.10 313.96 35.58 11038 1424
2.35 331.45 98.42 633.86 336.43 311.66 44.81 11801 1559
2.35 331.45 98.42 642.35 338.88 311.45 44.81 12015 1591
2.35 331.45 98.42 644.60 339.97 311.78 44.81 12229 1623
3.03 335.87 98.78 588.70 317.12 310.21 35.58 10357 1392
3.03 335.87 95.78 604.78 324.26 311.41 35.58 10432 1408
2.63 319.42 91.58 586.41 313.07 300.27 35.58 10507 1424
3a
3b
3c
3d
3e
3f
3g
3h
3i
1.6
346.42 95.77 622.69 336.23 321.55 87.39 13142 1824
3j
CLZj 0.75
KETk -0.48
RISl -0.20
3.71 326.82 94.58 508.99 259.12 215.89 30.87 8127 1082
2.37 395.43 106.67 589.34 298.72 253.38 69.72 18646 2596
2.10 410.48 114.21 690.02 375.09 351.81 57.5 20311 2793
aMolecular weight, bMolar refractivity, cConnolly solvent accessible surface area, dConnolly
molecular surface area, eConnolly solvent excluded volume, fTopological polar surface area
gMolecular topological index, hWienner index, iCalcd.online10, jClozapine, kKetanserine, lRisperidone
Table 3. Similarity values of 2-[4-(aryl substituted)piperazin-1-yl]-N-cyclohexyl-
acetamides (3a-j) with respect to standard drugs
Similaritya,b, in % to
Compd.No
Clozapine
81.01
73.74
73.28
65.53
64.30
63.32
76.31
76.36
76.82
24.90
Ketanserine
67.40
69.62
Risperidone
64.74
70.13
3a
3b
3c
3d
3e
3f
69.84
74.29
74.63
75.00
70.36
76.03
75.39
75.89
69.70
69.65
69.42
69.71
3g
3h
3i
69.84
78.87
68.80
72.76
3j
b
a(1 - R) X 100 where R = Quadratic mean (Root mean square mean), 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
Preliminary pharmacological evaluation for atypical antipsychotic effect
All the target compounds were subjected to preliminary pharmacological evaluation to
determine their ability to antagonize apomorphine induced climbing behaviour, inhibition of
5-hydroxy tryptophan (5-HTP) induced head twitches behavior and catalepsy studies11-14
.

1049
SUSHIL KUMAR et al.
Prior permission of the animal ethics committee was obtained and all experiments were
conducted according to the approved protocol (837/ac/04/CPCSEA). Clozapine and
haloperidol groups were employed as standard (positive control). The results from the
pharmacological evaluation of the target compounds at their respective EDmin values are
depicted graphically in Figures 1, 2 and 3. EDmin of the synthesized compounds were 40mg/kg
for inhibition of apomorphine induced climbing behaviour, inhibition of 5-hydroxy tryptophan
(5-HTP) induced head twitches behavior and EDmin 80 mg/kg was for catalepsy studies.
Statistical analysis of the results in the test group was done by comparison with the results in
the control group employing one way ANOVA. Level of significance was fixed at p<0.05.
Apomorphine induced mesh climbing assay
Swiss albino mice (six mice in each group) of either sex (24-26 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, control and standard groups were injected, respectively, with test
compounds, normal saline and clozapine intraperitoneally and returned to the home cage.
After a gap of 10 min, apomorphine (2.5 mg/kg) was injected intraperitoneally. Mesh
climbing behavior was noted at 5 min intervals for up to 20 min, starting 10 min after the
apomorphine administration using the following scoring system: 0-no paws on the cage,
1-one paw on the cage, 2-two paws on the cage, 3-three paws on the cage, 4-four paws on
the cage (Figure 1). The score recorded for each animal was based on the position of the
animal at the moment it was first observed.
16
14
12
10
8
6
4
2
0
Synthesized compounds
Synthesized compounds
Figure 1. The effect of synthesized compounds (3a-j) on the apomorphine induced climbing
behavior. (Each column represents the mean SEM of total climbing score for group of six mice
assessed at 5-min intervals for 20 min, starting 10 min after apomorphine treatment. A score of
20 is the maximum possible. All values statistically significant with respect to control at p<0.05).
Antagonism of 5-hydoxytryptophan (5-HTP) induced head twitches
Swiss albino mice in the control group (n=6) was injected with pargyline (75 mg/kg, i.p) in order
to prevent the rapid degradation of 5-HTP. Thirty minutes later, the test compound was
administered. After a further 30 min, the mice received 5-HTP (50 mg/kg, s.c). The mice were
returned to the test cages and then head twitches were assessed at 10 min intervals for 30 min,
starting 20 min after the 5-HTP treatment. Head twitches were monitored using the following
scoring system, 0-absent, 1-moderate, 2-marked (fig. 2). A maximum of 8 score is possible. An
observer made all observations unaware of the specific drug treatments.

Synthesis and Preliminary Pharmacological Evaluation
1050
8
7
6
5
4
3
2
1
0
Synthesized compounds
Synthesized compounds
Figure 2. The effect of synthesized compounds (3a-j) on the 5-HTP induced head twitches
behavior. (Each column represents the mean SEM of total head twitches score for group of
six mice assessed at 10 min intervals for 30 min, starting 20 after the 5-HTP treatment. A
score of 8 is the maximum possible. All values statistically significant with respect to control
at p<0.05)
Catalepsy
Catalepsy was induced in albino mice (n=6) with haloperidol (1.0 mg/kg i.p.) and was
assessed at 30 min intervals until 120 min and at the end of 240 min by means of a standard
bar test. Catalepsy was assessed in terms of the time (sec) for which the mouse maintained
an imposed position with both front limbs extended and resting on a 4 cm high wooden bar
(1.0 cm diameter). The endpoint of catalepsy was considered to occur when both front paws
were removed from the bar or if the animal moved its head in an exploratory manner.
Severity of the cataleptic behavior was scored as 1 if maintained the imposed posture for at
least 20 sec and every additional 20 sec one extra point would be given (Figure 3).
16
14
30
12
60
10
8
90
6
120
240
4
2
0
Haloperidol
Synthesized compounds
Synthesized compounds
Figure 3. The effect of synthesized compounds (3a-j) on induction of catalepsy in mice.
Results are expressed as the mean SEM. (n=6), p<0.05.
Results ad Discussion
The target compounds (3a-j) were synthesized as outlined in Scheme 1 and obtained in good
yields (30.30-62.89%). The purity of the compounds was monitored by TLC and the
structure of the compounds was deduced on the basis of spectroscopic methods. A set of
molecular parameters and physicochemical similarity of the target compounds was
calculated with respect to the standard drugs. The compounds (3a-j) showed good structural
similarity with respect to standard drugs (24.90 - 81.01%). The results from the pharmacological

1051
SUSHIL KUMAR et al.
evaluation of the target compounds at their respective EDmin values were showed significant
reduction in apomorphine induced climbing behaviour, inhibition of 5-hydroxy tryptophan
(5-HTP) induced head twitches behavior and low propensity to induce catalepsy.
Conclusion
We have synthesized a new series of arylpiperazines and their preliminary pharmacological
evaluation has shown potential atypical antipsychotic effect. Test compounds have shown
good structural similarity with respect to the standard drugs. Among the compounds, 3d has
shown potent binding affinities for D2 and 5-HT2A receptors and low propensity to induce
catalepsy and further studies on this lead are required for the refinement of the atypical
antipsychotic activity.
Acknowledgment
The authors are grateful to the Prof. R.M. Dubey, Managing Director, IFTM, Moradabad,
for the financial assistance of this project and also thankful to the Head, sophisticated
analytical instrument facility, CDRI, Lucknow for spectral analysis. This work is a part of
work done for Ph.D. degree of Shobhit University.
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Hindawi Publishing Corporation
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
Journal of
Journal of
International Journal of
Chromatography
Journal of
Theoretical Chemistry
Catalysts
Research International
Chemistry
Spectroscopy
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
Volume 2014
Volume 2014
Volume 2014