Synthesis, computational studies, and preliminary pharmacological evaluation of new arylpiperazines as potential antipsychotics

Article abstract of DOI:10.1007/s00044-011-9630-4

A series of long-chain arylpiperazines bearing a salicylamide fragment were synthesized, and the target compounds were evaluated for atypical antipsychotic activity in apomorphine-induced climbing behavior (D₂ antagonism) and 5-HTP-induced head

Full text of DOI:10.1007/s00044-011-9630-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1218–1225
DOI 10.1007/s00044-011-9630-4
ORIGINAL RESEARCH
Synthesis, computational studies, and preliminary
pharmacological evaluation of new arylpiperazines as potential
antipsychotics
•
Sushil Kumar A. K. Wahi Ranjit Singh
•
Received: 9 April 2010 / Accepted: 18 March 2011 / Published online: 8 April 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of long-chain arylpiperazines bearing a
salicylamide fragment were synthesized, and the target
compounds were evaluated for atypical antipsychotic
activity in apomorphine-induced climbing behavior (D2
antagonism) and 5-HTP-induced head twitches (5-HT2A
antagonism) along with catalepsy studies in mice. The
physicochemical similarity values of the target compounds
with respect to standard drugs, clozapine, ketanserin, and
risperidone, were determined using software programs. The
test compounds demonstrated good similarity values with
respect to the standard drugs. The compounds 3a4 showed
maximum atypical antipsychotic like profile.
withdrawal, etc.). The use of classical (typical) neuroleptics
(e.g., haloperidol and chlorpromazine) for the treatment of
this disease is associated with severe mechanism-related
side effects, including induction of extrapyramidal symp-
toms (EPS) (Altar et al., 2003). Furthermore, these drugs
are ineffective against the negative symptoms of schizo-
phrenia. The introduction of clozapine for treatment-
resistant schizophrenia gave rise to a new group of atypical
or nonclassical antipsychotics which have no EPS and are
effective against negative symptoms (Fitton and Hell,
1990). Unfortunately, its therapeutic use has been ham-
pered by serious side effects, for example, agranulocytosis
(Griffith and Saameli, 1975). It has been observed that
clozapine and other antipsychotic drugs which show a
reduced propensity for the development of EPS have
demonstrated a higher affinity for the 5-HT2 receptor than
the D2 receptor (Meltzer, 1989). This has led to the
hypothesis that a combination of serotonin 5-HT2 and
dopamine D2 receptor antagonism play critical role in the
mechanism of action of atypical antipsychotic drugs. This
so-called serotonin-dopamine hypothesis (Meltzer et al.,
2003) has become a useful model for developing new
antipsychotics to achieve superior efficacy with a lower
incidence of extrapyramidal side effects compared to
classical antipsychotics (Kuroki et al., 2008). Arylpiper-
azine derivatives display diverse pharmacological activity
which can be mediated by different subpopulations of
serotonin, dopamine, and aderenergic receptors (Obniska
et al., 2003; Tomic et al., 2004; Kolaczkowski et al.,
2005).
Keywords Arylpiperazines ꢀ Salicylamide ꢀ
Atypical antipsychotic ꢀ 5-HT2A antagonist ꢀ D2 antagonists
Introduction
Schizophrenia is a complex psychiatric disorder that affects
approximately 1% of the population (Reynolds, 1992,
Jibson et al., 2004). The symptoms of the disease may be
divided into two broad categories: the positive symptoms,
which add to the normal psyche (aggression, hallucina-
tions, etc.) and the negative ones, which detract from the
normal psyche (e.g., flat affect, poverty of speech, social
S. Kumar (&) ꢀ A. K. Wahi
Drug Design & Medicinal Chemistry Research Laboratory,
College of Pharmacy, IFTM, Moradabad 244001, UP, India
e-mail: sushilmpharm@rediffmail.com
Their general chemical structure consists of the aryl-
piperazine moiety connected by an alkyl chain with the
terminal amide or imide fragment (Gonalez-Gomez et al.,
2003, Perrone et al., 1999; Lopez-Rodriguez et al., 2001).
As part of our ongoing study on the development of
R. Singh
School of Pharmaceutical Sciences, Shobhit University,
Meerut 250110, UP, India
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Med Chem Res (2012) 21:1218–1225
1219
2-(4-Bromobutoxy) benzamide (3c)
strategies for the preparation of new D2/5-HT2A receptor
antagonists as antipsychotics, we herein report the syn-
thesis, computational studies, and preliminary pharmaco-
logical evaluation of new amide arylpiperazines.
Yield: 4.70 g (43%); Rf: 0.67 (Ethylacetate/Methanol,
2:0.4); mp: 211–213°C; IR (cm1): 3455, 3159, 2981, 1657,
1029, 748, 1H NMR (dppm, DMSO-d6): 1.91–2.51 (m, 4H,
CH2CH2), 3.36 (t, 2H, CH2Br), 4.21 (t, 2H, OCH2), 7.80 (s,
2H, CONH2), 7.0–7.51 (m, 4H, Ar).
Materials and methods
General procedure for the synthesis of 3a1–3a6,
3b1–3b2, and 3c1–3c2
Chemistry
Melting points of the synthesized compounds were deter-
mined by open capillary method and are uncorrected. The
IR spectra of synthesized compounds were recorded in
potassium bromide disks on Schimadzu FTIR Spectro-
A mixture of 2a or 2b or 2c (5 mmol), K2CO3 (0.69 g,
5 mmol), respective substituted phenylpiperazines
(5 mmol), and a catalytic amount of potassium iodide in
anhydrous dimethylformamide (100 ml) were stirred on a
magnetic stirrer at 80°C temperature for 36 h. The reaction
mixture was poured into 150–200 ml of water, and the
precipitate was extracted with chloroform. The organic
phase was dried over Na2SO4, and the solvent was
removed. The crude products were purified by column
chromatography (Ethyl acetate/Methanol, 4:1).
1
photometer 8300. The H NMR spectra of the synthesized
compounds were recorded in DMSO using AV-300
BROKE JEOL Spectrophotometer and tetramethylsilane
(TMS) as an internal standard. Elemental analyses were
performed on Perkin Elmer 2400 analyzer. The mass
spectra were recorded on a Micromass Quattro II triple
quadrupole mass spectrometer. All the reagents were of
commercial quality and were used without further
purification.
2-[2-(4-Phenylpiperazin-1-yl) ethoxy] benzamide (3a1)
Yield: 0.50 g (23%); Rf: 0.21 (Ethylacetate/Methanol,
2:0.4); mp: 205–207°C; IR (cm-1): 3457, 3165, 2952,
1644, 1391, 1231, 1033; H NMR(DMSO-d6): 2.48–2.85
General procedure for the alkylation of salicylamide
1
(2a, 2b, and 2c)
(m, 2H, CH2N), 3.01–3.51 (m, 8H, pip ring), 4.15 (t, 2H,
CH2O), 6.88 (d, 2H, Ar–H), 6.97 (d, 2H, Ar–H), 7.01–7.37
(m, 5H, Ar–H), 7.82 (s, 2H, CONH2); MS(EI) m/z:
326(M ? 1); Anal. Calcd. for C19H23N3O2: C, 70.13; H,
7.12; N, 12.91; O, 9.83; Found: C, 70.15; H, 7.14; N,
12.95; O, 9.86.
A mixture of salicylamide (5.48 g, 0.04 mol), dihaloalkane
(1,2-dibromoethane or 1-bromo-3-chloropropane or 1,4-
dibromobutane, 0.04 mol), and K2CO3 (5.52 g, 0.04 mol)
in acetonitrile was refluxed for 8 h. The solvent was
removed under vacuum. The residue was dissolved in
CHCl3 and washed with water. The organic extract was
dried over Na2SO4. The solvent was removed, and the
residue was recrystallized from methanol and chloroform
(1:1).
2-{2-[4-(3-Methylphenyl) piperazin-1-yl] ethoxy}
benzamide (3a2)
Yield: 0.54 g (31.95%); Rf: 0.28 (Ethylacetate/Methanol,
2:0.4); mp: 189–190°C; IR (cm-1): 3458, 3163, 2889,
1648, 1390, 1228, 1033; 1H NMR (DMSO-d6): 2.31 (s, 3H,
CH3), 2.48–2.85 (m, 2H, CH2N), 3.02–3.51 (m, 8H, pip
ring), 4.15 (t, 2H, CH2O), 6.88 (d, 2H, Ar–H), 6.97 (d, 2H,
Ar–H), 7.02–7.48 (m, 4H, Ar–H), 7.82 (s, 2H, CONH2);
Anal.Calcd.for C20H25N3O2: C, 70.77; H, 7.42; N, 12.38;
O, 9.43; Found: C, 70.79; H, 7.43; N, 12.39; O, 9.41.
2-(2-Bromoethoxy) benzamide (2a)
Yield: 7.45 g (76.41%); Rf: 0.72 (Ethylacetate/Methanol,
2:0.4); mp: 199–201°C; IR (cm-1): 3455, 3159, 2961,
1657, 1029, 748; 1H NMR (DMSO-d6): 3.40 (t, 2H,
CH2Br), 4.50 (t, 2H, OCH2), 7.82 (s, 2H, CONH2),
7.0–7.50 (m, 4H, Ar).
2-{2-[4-(4-Methylphenyl) piperazin-1-yl] ethoxy}
2-(3-Chloropropoxy) benzamide (2b)
benzamide (3a3)
Yield: 5.4 g (42.18%); Rf: 0.74 (Ethylacetate/Methanol,
2:0.4); mp: 123–125°C; IR (cm-1): 3455, 3163, 2958,
1645, 1029, 749; H NMR (dppm, DMSO-d6): 1.92–2.21
(m, 2H, CH2), 3.31 (t, 2H, CH2Cl), 4.21 (t, 2H, OCH2),
Yield: 0.40 g (23.6%); Rf: 0.31 (Ethylacetate/Methanol,
2:0.4); mp:185–187°C; IR (cm-1): 3389, 3188, 2885, 1643,
1390, 1238, 1035; 1H NMR (DMSO-d6): 2.32 (s, 3H, CH3),
2.65–2.68 (m, 2H, CH2N), 3.10–3.55 (m, 8H, pip ring),
1
7.80 (s, 2H, CONH2), 7.0–7.48 (m, 4H, Ar).
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Med Chem Res (2012) 21:1218–1225
4.15 (t, 2H, CH2O), 6.88 (d, 2H, Ar–H), 6.97(d, 2H, Ar–H),
7.00–7.37 (m, 4H, Ar–H), 7.82 (s, 2H, CONH2); Anal.
Calcd. for C20H25N3O2: C, 70.79; H, 7.43; N, 12.38; O,
9.43; Found: C, 70.77; H, 7.40; N, 12.35; O, 9.40.
N, 12.38; O, 9.43; Found: C, 70.79; H, 7.43; N, 12.39; O,
9.42.
2-{3-[4-(2-Methoxyphenyl) piperazin-1-yl] propoxy}
benzamide (3b2)
2-{2-[4-(2-Methoxyphenyl) piperazin-1-yl] ethoxy}
benzamide (3a4)
Yield: 0.28 g (30.43%); Rf: 0.38 (Ethylacetate/Methanol,
2:0.4); mp: 143–145°C, IR (cm1): 3375, 3176, 2931, 1648,
1390, 1238, 1035; H NMR (dppm, DMSO-d6): 1.92–2.21
(m, 2H, CH2), 2.35–2.97 (m, 2H, CH2N), 3.00–3.59 (m,
8H, pipring), 3.97 (s, 3H, OCH3), 4.12 (t, 2H, CH2O), 6.88
(d, 2H, Ar–H), 6.98 (d, 1H, Ar–H), 7.00–7.45 (m, 5H, Ar–
H), 7.81 (s, 2H, CONH2); Anal.Calcd.for C21H27N3O3: C,
68.27; H, 7.37; N, 11.37; O, 12.99; Found C, 68.24; H,
7.39; N, 11.36; O, 12.98.
1
Yield: 0.31 g (17.5%); Rf: 0.59 (Ethylacetate/Methanol,
2:0.4); mp: 181–183°C; IR (cm-1): 3377, 3177, 2883,
1641, 1400, 1237, 1023; 1H NMR (dppm, DMSO-d6):
2.48–2.97 (m, 2H, CH2N), 3.00–3.59 (m, 8H, pipring), 3.97
(s, 3H, OCH3), 4.15 (t, 2H, CH2O), 6.88 (d, 2H, Ar–H),
6.98 (d, 1H, Ar–H), 7.00–7.32 (m, 5H, Ar–H), 7.82 (s, 2H,
CONH2); Anal.Calcd.for C20H25N3O3: C, 67.58; H, 7.09;
N, 11.82; O, 13.50; Found: C, 67.61; H, 7.13; N, 11.83; O,
13.48.
2-[4-(4-Phenylpiperazin-1-yl) butoxy] benzamide (3c1)
2-{2-[4-(3-Methoxyphenyl) piperazin-1-yl] ethoxy}
Yield: 0.24 g (27.27%); Rf: 0.39 (Ethylacetate/Methanol,
2:0.4); mp: 184–186°C, IR (cm-1): 3457, 3162, 2968,
1641, 1389, 1229, 1033; 1H NMR (dppm, DMSO-d6):
1.20–1.28 (m, 4H, CH2CH2), 2.68–2.71 (m, 2H, CH2N),
3.09–3.48 (m, 8H, pipring), 4.10 (t, 2H, CH2O), 6.88 (d,
2H, Ar–H),6.98 (d, 2H, Ar–H), 7.00–7.45 (m, 5H, Ar–H),
7.81 (s, 2H, CONH2); Anal.Calcd.for C21H27N3O2: C,
71.36; H, 7.70; N, 11.89; O, 9.05; Found: C, 71.34; H,
7.73; N, 11.86; O, 9.02.
benzamide (3a5)
Yield: 0.38 g (22.0%); Rf: 0.46 (Ethylacetate/Methanol,
2:0.4); mp: 178–180°C; IR (cm-1): 3392, 3193, 2875,
1638, 1393, 1235, 1047; 1H NMR (dppm, DMSO-d6):
2.55–2.98 (m, 2H, CH2N), 3.01–3.54 (m, 8H, pipring), 3.94
(s, 3H, OCH3), 4.15 (t, 2H, CH2O), 6.88 (d, 2H, Ar–H),
6.87 (d, 2H, Ar–H), 7.02–7.58 (m, 4H, Ar–H), 7.82 (s, 2H,
CONH2); Anal. Calcd. for C20H25N3O3: C, 67.58; H, 7.09;
N, 11.82; O, 13.50; Found: C, 67.60; H, 7.10; N, 11.83; O,
13.49.
2-{4-[4-(2-Methoxyphenyl) piperazine-1-yl] butoxy}
benzamide (3c2)
2-{2-[4-(2-Chlorophenyl) piperazin-1-yl] ethoxy}
Yield: 0.38 g (40.0%); Rf: 0.57 (Ethylacetate/Methanol,
2:0.4); mp: 175–178°C; IR (cm-1): 3457, 3160, 2968,
1641, 1387, 1229, 1031; 1H NMR (dppm, DMSO-d6):
1.24–1.28 (m, 4H, CH2CH2), 2.68–2.71 (m, 2H, CH2N),
3.09–3.48 (m, 8H, pipring), 3.86 (s, 3H, OCH3Ar), 4.10 (t,
2H, CH2O), 6.88 (d, 2H, Ar–H), 6.98 (d, 1H, Ar–H),
7.00–7.45 (m, 5H, Ar–H), 7.81 (s, 2H, CONH2); Ana-
l.Calcd.for C22H29N3O3: C, 68.90; H, 7.62; N, 10.96; O,
12.52; Found C, 68.92; H, 7.60; N,10.97; O,12.51.
benzamide (3a6)
Yield: 0.44 g (24.580%); Rf: 0.47 (Ethylacetate/Methanol,
2:0.4); mp: 154–156°C; IR (cm-1): 3457, 3162, 2887,
1644, 1389, 1229, 1033; 1H NMR (dppm, DMSO-d6):
2.47–2.97 (m, 2H, CH2N), 3.00–3.59 (m, 8H, pipring), 4.15
(t, 2H, CH2O), 6.87 (d, 2H, Ar–H), 6.99 (d, 1H, Ar–H),
7.0–7.37 (m, 5H, Ar–H), 7.82 (s, 2H, CONH2); Anal.
Calcd. for C19H22ClN3O2: C, 63.42; H, 6.16; N, 11.68; O,
8.89; Found: C, 63.43; H, 6.17; N, 11.69; O, 8.88.
Preliminary pharmacological evaluation
2-[3-(4-Phenylpiperazin-1-yl) propoxy] benzamide
All the target compounds were subjected to preliminary
pharmacological evaluation to determine their ability to
antagonize apomorphine-induced climbing behavior, inhi-
bition of 5-hydroxy tryptophan (5-HTP)-induced head
twitches behavior (Chung et al., 2002) and catalepsy
studies (Pemminati et al., 2007; Ferre et al., 1990). Prior
permission of the Animal Ethics Committee was obtained,
and all the experiments were conducted according to the
approved protocol (837/ac/04/CPCSEA). Clozapine and
haloperidol groups were employed as a standard (positive
(3b1)
Yield: 0.26 g (30.95%); Rf: 0.30 (Ethylacetate/Methanol,
2:0.4); mp: 150–152°C, IR (cm1): 3375, 3176, 2931, 1648,
1
1390, 1238, 1035; H NMR (dppm, DMSO-d6): 1.92–1.95
(m, 2H, CH2), 2.21–2.97 (m, 2H, CH2N), 3.00–3.59 (m,
8H, pipring), 4.12 (t, 2H, CH2O), 6.84 (d, 2H, Ar–H), 6.97
(d, 2H, Ar–H), 7.01–7.30 (m, 5H, Ar–H), 7.82 (s, 2H,
CONH2); Anal. Calcd. for C20H25N3O2: C, 70.77; H, 7.42;
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Med Chem Res (2012) 21:1218–1225
1221
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.
8
7
6
5
4
3
2
1
0
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 (Fig. 1). The score
recorded for each animal was based on the position of the
animal at the moment it was first observed.
Synthesized compounds
Fig. 2 Antagonism of 5-Hydoxytryptophan (5-HTP)-induced head
twitches. The effect of synthesized compounds (3a1–3a6, 3b1–3b2,
and 3c1–3c2) 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
the values are statistically significant with respect to control at
P \ 0.05
Catalepsy
Catalepsy was induced in albino mice (n = 6) with halo-
peridol (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(s) 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 it maintained the imposed
posture for at least 20 s and for every additional 20 s, one
extra point was given (Fig. 3).
Antagonism of 5-Hydoxytryptophan (5-HTP)-induced
head twitches
Swiss albino mice in the control group (n = 6) were
injected with pargyline (75 mg/kg) to prevent the rapid
degradation of 5-HTP. Thirty minutes later, the test com-
pound was administered. After a further 30 min, the mice
received 5-HTP (50 mg/kg, sc). The mice were returned to
the test cages and then head twitches were counted for
2 min at 10 min intervals for 30 min, starting 20 min after
the 5-HTP treatment (Fig. 2).
18
16
14
12
10
8
6
4
2
0
30
60
16
90
14
120
240
12
10
8
6
4
2
0
Synthesized compounds
Fig. 1 Apomorphine-induced mesh climbing assay. The effects of
synthesized compounds (3a1–3a6, 3b1–3b2, and 3c1–3c2) 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
Synthesized compounds
Fig. 3 Induction of catalepsy. The effect of synthesized compounds
(3a1–3a6, 3b1–3b2, and 3c1–3c2) on induction of catalepsy in mice.
Results are expressed as the mean SEM (n = 6). All the values are
statistically significant with respect to control at P \ 0.05
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Med Chem Res (2012) 21:1218–1225
Results and discussion
Table 1 Substituent of compounds
Cpd.
code
n
R
Synthesis
3a1
3a2
3a3
3a4
3a5
3a6
3b1
3b2
3c1
3c2
2
2
2
2
2
2
3
3
4
4
H
The new arylpiperazines were prepared using the pathway
shown in Scheme 1. The substituent of the compounds is
given in Table 1. The target compounds were prepared by a
two-step procedure: alkylation of salicylamide (1) with
dihaloalkanes (1,2-dibromoethane, 1-bromo-3-chloropro-
pane and 1,4-dibromobutane) in acetonitrile in the presence
of potassium carbonate, followed by condensation of
intermediates (2a, 2b, and 2c) with substituted phenylpip-
erazines in dimethylformamide in the presence of potas-
sium carbonate and potassium iodide as catalyst afforded
the target compounds (3a1–3a6, 3b1–3b2, and 3c1–3c2). All
the target compounds were obtained in low yield
(17.5–40%) and characterized by analytic and spectro-
scopic methods. The reaction progress was monitored by
thin-layer chromatography (TLC) using silica gel G, and
spots were visualized in an iodine chamber.
3–CH3
4–CH3
2–OCH3
3–OCH3
2–Cl
H
2–OCH3
H
2–OCH3
limits (58.8–68.03), showing that these compounds have a
potential to effectively cross the BBB. Further, lipophilic-
ity correlates positively with BBB penetration, and the
values of log P for most of our test compounds were very
close to the marketed drugs (2.52–3.2).
Computation of physicochemical properties
Similarity calculations
A set of molecular parameters was computed for the target
compounds as well as three standard drugs, clozapine,
ketanserin and risperidone, using Chem 3D Ultra version,
11.0, and Chem Silico online free software, which is shown
in Table 2. The important molecular parameters for anti-
psychotics are blood–brain barrier (BBB), log P, and
topological polar surface area (TPSA). The review of the
existing literature 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. (1998) suggested a limit of
90 A2, where, Kelder et al. (1999) suggested 60–70 A2.
The TPSA value for test compounds were well within these
The physicochemical similarity of the target compounds
was calculated with respect to the standard drugs (Bali
et al., 2010) and is shown in Table 3.
First, 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
j¼1
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, ketanserin,
and risperidone. Then, the similarity of compound ‘‘j’’ to
the standard drug was calculated as:
Scheme 1 Synthesis route of
the target compounds
CONH2
CONH2
R
Br(CH2)n
X
X=Cl,Br
HN
N
O(CH2)nX
OH
K2CO3,Acetonitrile
DMF,K2CO3,KI
n=2,3,4
(2a,2b,2c)
(1)
CONH2
R
O(CH2)n
N
N
3a1-6,3b1-2,3c1-2
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Med Chem Res (2012) 21:1218–1225
1223
Table 2 Calculation of molecular properties and log BB values for target compounds and standard drugs
Cpd. code
Log BBj
Log P
M.Wa
MRb
SASc (A2)
MSAd (A2)
SEVe (A2)
TPSAf
MTIg
WIh
Ovi
3a1
3a2
3a3
3a4
3a5
3a6
3b1
3b2
3c1
0.23
0.16
2.64
3.13
3.13
2.52
2.52
3.2
325.40
339.43
339.43
355.43
355.43
359.85
339.43
369.46
353.46
383.48
326.82
395.43
410.48
96.5
596.869
628.141
628.116
635.134
641.975
608.65
314.792
333.488
333.469
338.812
340.692
324.119
333.603
357.203
352.171
376.186
259.124
298.729
375.09
281.008
297.919
297.902
304.225
304.338
292.986
298.018
320.803
314.99
58.8
12122
13585
13722
14615
14853
12926
14070
16827
16211
19246
8127
1607
1798
1816
1978
2014
1780
1864
2274
2146
2597
1082
2596
2793
1.5172
1.5459
1.5459
1.5488
1.5570
1.5193
1.5461
1.5761
1.5730
1.6024
1.4889
1.542
102.4
58.8
0.16
102.4
58.8
-0.02
-0.15
0.16
103.75
103.75
101.11
101.1
68.03
68.02
58.8
0.18
2.75
2.62
3.2
629.429
667.699
660.925
699.174
508.991
589.34
58.8
-0.12
0.11
108.35
105.7
68.03
58.8
3c2
-0.26
0.75
3.08
3.71
2.37
2.10
112.95
94.58
338.223
215.892
253.386
351.81
68.03
30.87
69.72
57.5
CLZk
KETl
RISm
a
-0.48
-0.20
106.67
114.21
18646
20311
690.021
1.5563
Molecular weight
b
c
d
e
f
Molar refractivity
Connolly solvent accessible surface area
Connolly molecular surface area
Connolly solvent excluded volume
Topological polar surface area
Molecular topological index
Wienner index
g
h
i
Ovality
j
Calcd. online (Chemsilico.com/CS_prBBB/BBBdata.html)
k
l
Clozapine
Ketaserin
m
Risperidone
Similarity (%) = (1-R) 9 100, where R = Hd2 is the
quadratic mean (root mean square), a measure of central
tendency. The target compounds showed good structural
similarity with respect to standard drugs (13.29–92.30%).
Table 3 Similarity values of target compounds with respect to the
standard drugs
Cpd. code
Similarityab (in %) to
Clozapine
Ketanserin
Risperidone
Preliminary pharmacological evaluation
for antipsychotic effect
3a1
3a2
3a3
3a4
3a5
3a6
3b1
3b2
3c1
3c2
a
57.23
50.03
49.47
37.62
36.48
52.26
47.97
26.48
37.14
13.29
79.15
81.86
82.14
85.03
85.36
81.97
82.81
85.99
87.22
83.41
59.55
83.57
80.23
82.05
82.63
78.99
80.91
65.80
86.95
92.30
The results from the pharmacological evaluation of the
target compounds are given in Table 4 and depicted
graphically in Figs. 1, 2, and 3. All the ligands showed
significant interactions with the D2 and 5-HT2A receptors,
which were found to be dependent, fundamentally on the
substitution of the N4-aryl group of the piperazine ring. The
compounds possessing methoxy group (3a4 and 3a5) at
ortho and meta positions of aryl moiety of piperazine
produced statistically significant reversal of apomorphine-
induced climbing behavior than chloro analog (3a6). A
significant reduction in activity was observed, when methyl
group was present at meta and para positions of aryl
moiety of piperazine (3a2 and 3a3). Other compounds (3a1,
(1 - R) 9 100 where R = 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; Topo-
logical polar surface area; Molecular topological index; Wiener index
123

1224
Med Chem Res (2012) 21:1218–1225
emerged as potential atypical antipsychotic effect and
showed maximum similarity to ketanserin (85.03%).
Table 4 Potential for atypical antipsychotic activity in vivo
Cpd. code
Inhibition of
apomorphine-
induced climbing head twitches
Inhibition of
5-HTP-induced catalepsy (ED50
Induction of
,
Acknowledgment The authors are grateful to the Prof. R.M.Dubey,
Managing Director, IFTM, Moradabad, for the financial assistance to
this project. This study is a part of the research thesis submitted for
the Ph.D. degree of Shobhit University.
mg/kg, i.p.)
behavior (ED50
mg/kg, i.p.)
,
behavior (ED50,
mg/kg, i.p.)
3a1
35.3
40.0
40.5
40.0
[40
[40
[40
50.0
[40
50.8
8.7
30
50
Competing Interests The authors declare no conflict of interest.
3a2
[20
27.2
10.0
25.0
[20
[20
18.2
[40
[40
2.8
70
3a3
[80
100
[80
[80
[60
[60
[60
[70
–
3a4
3a5
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