Design, synthesis, and preliminary in vitro and in vivo pharmacological evaluation of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl] phenyl}thiazoles as atypical antipsychotic agents

Article abstract of DOI:10.1007/s00044-012-0164-1

A series of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl] phenyl} thiazoles were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were designed, synthesized, and characterized by spectral data (IR, ¹H NMR, and MS) and the purity was ascertained by microanalysis. The D₂ and 5-HT_2A affinity of the synthesized compounds was screened in vitro by radioligand displacement assays on membrane homogenates isolated from rat striatum and rat cortex, respectively. Furthermore, all the synthesized final compounds (10a-g; 11a-g; 12a-g) were screened for their in vivo pharmacological activity in Swiss albino mice. D₂ antagonism studies were performed using climbing mouse assay model and 5-HT_2A antagonism studies were performed using quipazine-induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy and 12d, 11f, and 10a were found to be the most active compounds with 5-HT_2A/D₂ ratio of 1.23077, 1.14286, and 1.12857, respectively, while the standard drug risperidone exhibited 5-HT_2A/D₂ ratio of 1.0989. Among the twenty one new chemical entities, three compounds (12d, 11f, and 10a) were found to exhibit better atypical antipsychotic activity as they were found to have higher Meltzer index than the standard drug risperidone.

Full text of DOI:10.1007/s00044-012-0164-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:1660–1673
DOI 10.1007/s00044-012-0164-1
ORIGINAL RESEARCH
Design, synthesis, and preliminary in vitro and in vivo
pharmacological evaluation of 4-{4-[2-(4-(2-substitutedquinoxalin-
3-yl)piperazin-1-yl)ethyl]phenyl}thiazoles as atypical
antipsychotic agents
•
Kondapalli Venkata Gowri Chandra Sekhar Vajja Sambasiva Rao
•
•
Winnie Deuther-Conrad Divya Sridhar Hunsur Nagendra Nagesh
•
•
•
Vellas Sreedhar Kumar Peter Brust Muthyala Murali Krishna Kumar
•
Received: 27 March 2012 / Accepted: 16 June 2012 / Published online: 1 July 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A series of 4-{4-[2-(4-(2-substitutedquinoxalin-
3-yl)piperazin-1-yl)ethyl] phenyl} thiazoles were synthe-
sized in an effort to prepare novel atypical antipsychotic
agents. The compounds were designed, synthesized, and
1.23077, 1.14286, and 1.12857, respectively, while the
standard drug risperidone exhibited 5-HT2A/D2 ratio of
1.0989. Among the twenty one new chemical entities, three
compounds (12d, 11f, and 10a) were found to exhibit better
atypical antipsychotic activity as they were found to have
higher Meltzer index than the standard drug risperidone.
1
characterized by spectral data (IR, H NMR, and MS) and
the purity was ascertained by microanalysis. The D2 and
5-HT2A affinity of the synthesized compounds was screened
in vitro by radioligand displacement assays on membrane
homogenates isolated from rat striatum and rat cortex,
respectively. Furthermore, all the synthesized final com-
pounds (10a–g; 11a–g; 12a–g) were screened for their in
vivo pharmacological activity in Swiss albino mice. D2
antagonism studies were performed using climbing mouse
assay model and 5-HT2A antagonism studies were per-
formed using quipazine-induced head twitches in mice. It
was observed that none of the new chemical entities
exhibited catalepsy and 12d, 11f, and 10a were found to be
the most active compounds with 5-HT2A/D2 ratio of
Keywords Schizophrenia ꢀ Atypical antipsychotics ꢀ
Quinoxalines ꢀ Phenyl thiazoles
Introduction
Schizophrenia is a lifelong, complex psychotic disorder
affecting around 1 % of world population (Carpenter and
Buchanan, 1994). The characteristic symptoms of the dis-
ease have been classified into positive (hallucinations,
delusions, and severe thought disorganization), negative
(alogia, anhedonia, avolition, and flattened affect), and
cognitive (slow thinking, poor concentration, poor mem-
ory, and difficulty in understanding) (Mueser and McGurk,
2004). The introduction of antipsychotics in the late 1950 s
was a major break through in the management of schizo-
phrenia and all these agents block dopamine D2 receptors
(Lewine et al., 1983). Although blockade of D2 receptors
improves the positive symptoms, it also accounts for severe
side effects such as extrapyramidal effects (EPS) (Casey,
1995), tardive dyskinesia (Marder et al., 1991), and
hyperprolactinemia (Wieck and Haddad, 2002).
K. V. G. Chandra Sekhar (&) ꢀ V. S. Rao ꢀ
H. N. Nagesh ꢀ V. S. Kumar
Department of Chemistry, Birla Institute of Technology &
Science, Pilani-Hyderabad Campus, Jawahar Nagar, Shamirpet
Mandal, Hyderabad 500 078, Andhra Pradesh, India
e-mail: kvgcs.bits@gmail.com
W. Deuther-Conrad ꢀ P. Brust
Institute of Interdisciplinary Isotope Research, Permoser Str.15,
04318 Leipzig, Germany
D. Sridhar
Department of Chemistry, Birla Institute of Technology &
Science, Pilani 333 031, Rajasthan, India
Over the past three decades, much attention regarding the
treatment of schizophrenia has focused on a new class of
antipsychotics which cause no or minimal EPS at therapeu-
tically relevant doses. These second-generation derivatives,
categorized as atypical in contrast to conventional D2
blockers, exhibit combined D2 and 5-HT2A antagonism.
M. M. K. Kumar
Department of Pharmaceutical Chemistry, College
of Pharmaceutical Sciences, Andhra University, Visakhapatnam
530 003, Andhra Pradesh, India
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Med Chem Res (2013) 22:1660–1673
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Fig. 1 Structures of some
atypical antipsychotics
developed based on Meltzer’s
classification
Compounds such as clozapine, risperidone, olanzapine, and
ziprasidone (Fig. 1) developed based on this approach
(Horacek et al., 2006). Meltzer et al. (Meltzer et al., 1989;
Roth et al., 1998) related the special clinical profile of clo-
zapine and other atypical antipsychotics to an empirical ratio,
the so-called Meltzer Index, between 5-HT2A and D2 recep-
tors (Lowe, 1994). They proposed that this ratio may be used
to discriminate atypical antipsychotics (ratio [1.12) from
classical antipsychotics (\1.09). Antagonism at 5-HT2A and
D2 receptors by these molecules is responsible for subsiding
the negative and positive symptoms of the disorder, respec-
tively (Meltzer et al., 2003; Meltzer, 2004). Experimental and
clinical studies seem to confirm the major role of the 5-HT2A
receptor for the atypical profile of the antipsychotics (Oekelen
et al., 2003; Okuyama et al., 1997). However, these com-
pounds are also not completely devoid of side effects. Side
effects caused by ‘‘atypical antipsychotics’’ are a result of
their significant binding to numerous receptors other than
required for atypical antipsychotic activity. Side effects
associated with these drugs include, weight gain (serotonergic
5-HT2C and histaminic H1 receptors blockade) (Wirshing
et al., 1999); postural or orthostatic hypotension; sedation;
dizziness (a1-adrenergic blockade); somnolence (histaminic
H1 receptor blockade); seizures (muscarinic receptor block-
ade) (Owens, 1996); newonset type2 diabetes mellitus
(Cohen, 2004); hyperlipidemia; atropine-like side effects
such as dry mouth, constipation, and urinary retention
(muscarinic M1 receptor blockade); cardiac ventricular
arrhythmias (prolongation of QT interval due to the blockade
of Ikr channels); myocarditis; insomnia; headache; and
other possible secondary cardiovascular complications
(Tamminga, 1997). Hence the search for more effective and
less toxic therapies for schizophrenia continues.
The rationale for the development of the antipsychotic
drugs recently introduced, and currently under investigation
is predominantly based on the dopamine and serotonin
hypotheses of schizophrenia (Graham et al., 2008; Garzya
et al., 2007). In continuation of our quest for novel atypical
antipsychotics (Chandra Sekhar et al., 2008, 2009, 2011), we
synthesized 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)pip-
erazin-1-yl)ethyl]phenyl}thiazole derivatives and evaluated
them for their in vitro and in vivo pharmacological activity.
The strategy of Ariens has been employed for the design
of the compounds (Ariens et al., 1979). Ariens strategy in
brief, involves modification of the structure of a receptor
agonist; in this case, dopamine, with a large lipophilic
group on the amino position, binds to the accessory binding
site adjacent to the agonist binding site and transforms the
agonist into an antagonist (Figs. 2, 3). Using this strategy,
the currently marketed drug ziprasidone was developed
Fig. 2 Conversion of dopamine
agonist into an antagonist
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Med Chem Res (2013) 22:1660–1673
Fig. 3 Model of D2 receptor, based on studies of the b-adrenergic receptor, showing proposed agonist and antagonist binding used in receptor
antagonist design (Lowe et al. 1991)
(Howard et al., 1996). We adapted this strategy and
employed piperazinyl quinoxalines, which have affinity
toward serotonin receptors (Monge et al., 1993; Lumma Jr.
et al., 1981) as one portion of the molecule and chlor-
oethylphenylthiazoles was selected as the other portion as
Pfizer group has come up with potent atypical antipsy-
chotics using the heterocycle 1-Naphthyl piperazine.
(Lowe et al., 1991).
in ethanol afforded 2,3-dihydroxyquinoxaline (2) (Hinsberg
and Pollak, 1896). Chlorination of dihydroxy compound
with phosphorous oxychloride yielded 2,3-dichloroquinox-
aline (3) (Reddy Sastry et al., 1991). The chloro compound in
the presence of anhydrous sodium carbonate on reaction with
anhydrous piperazine gave 2-chloro-3-piperazinyl quinox-
aline (4) (Scheme 2).
Synthesis of compound 6 is depicted in Scheme 3.
Compound 3 on stirring with methanol in the presence of
phase transfer catalyst—benzyltriethylammonium chloride
at room temperature yielded compound 5 (Krishnan and
Srinivasulu, 2000). 2-chloro-3-methoxyquinoxaline (5) on
stirring at room temperature with anhydrous piperazine in
the presence of acetonitrile gave 2-methoxy-3-piper-
azinylquinoxaline (6).
Results and discussion
The synthetic steps of the new compounds are summarized in
Schemes 1, 2, 3, 4, and 5. 2- and 5-substituted chlor-
oethylphenylthiazoles (1a–g) were prepared according to the
literature protocol with modifications in some steps
(Scheme 1) (Lowe et al., 1991). Equimolar amounts of
o-phenylenediamine and diethyloxalate on refluxing for 6 h
Scheme 4 illustrates the preparation of compound 9, which
was according to the literature (Lumma Jr. et al., 1981).
Refluxing equimolar amounts of n-butyl glyoxalate and
Scheme 1 Synthesis of
chloroethylphenylthiazoles
(1a–g)
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1663
Scheme 2 Synthesis of 2-chloro-3-piperazinyl quinoxaline (4)
Scheme 3 Synthesis of 2-methoxy-3-piperazinylquinoxaline (6)
o-phenylenediamine in ethanol yielded 2-hydroxyquinoxa-
line (7), which on further chlorination with phosphorous
oxychloride gave the chloro derivative (8). 2-chloroquinoxa-
line(8) was further converted to2-piperazinylquinoxaline (9).
Preparation of the final compounds is outlined in
Scheme 5. Equimolar amounts of 4, 6, or 9 and any one of
the compounds 1a–g along with 2.125 equivalents of
anhydrous Na2CO3 and catalytic amount of KI (2 mg) in
DMF as solvent when refluxed for 48 h afforded the title
compounds (10 a–g; 11a–g; 12a–g). All the synthesized
and HRMS) and elemental analysis data. Infrared analysis of
the final compounds showed strong peaks at *3440 cm-1
(NH stretch); *3065 cm-1 (aromatic C–H stretch);
*2825 cm-1 (aliphatic C–H stretch); *710 cm-1 (C–S–C
stretch); *1610 cm-1
(aromatic
C=C
stretch);
*1640 cm-1 (C=N ring stretch); *1100 cm-1 (aliphatic
C–O stretch for 11a–g); *1260 cm-1 (aliphatic C–N
stretch); *810 cm-1 (para disubstituted benzene);
*770 cm-1 (C–Cl stretch for 10a–g). In 1H-NMR spectra,
methylene protons (cyclic) adjacent to N1 nitrogen of
piperazine showed triplet in the range of d 3.06–3.21,
1
compounds were characterized by spectral (IR, H NMR,
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Med Chem Res (2013) 22:1660–1673
Scheme 4 Synthesis of 2-piperazinylquinoxaline (9)
Scheme 5 Synthesis of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl] phenyl} thiazoles (10a–g; 11a–g; 12a–g)
whereas methylene protons (cyclic) adjacent to N4 nitrogen
of piperazine showed triplet in the range of d 2.59–2.68. The
final compounds showed the 1H-NMR signals at d 7.18–8.19
(for the aromatic protons as a multiplet) and d 2.61–2.69 (for
four protons of the ethyl linker as multiplet). Elemental
(CHNS) analysis indicated that the calculated and observed
values were within the acceptable limits ( 0.4 %).
assays on membrane homogenates isolated from rat stria-
tum and rat cortex, respectively. For D2 affinity test, striatal
membranes were incubated with 0.5 nM [3H]spiperone
(101 Ci/mmol; Amersham) and 10 or 100 lM of the NCEs
in 50 mM TRIS–HCl, pH 7.4, at 21 °C for 60 min. Non-
specific binding of [3H]spiperone was determined with
10 lM haloperidol and accounted for 30 % of the total
binding. For 5-HT2A affinity test, cortical membranes were
incubated with 0.6 nM [3H]ketanserin (67 Ci/mmol; Perkin
Elmer) and 10 lM of the NCEs in 50 mM TRIS–HCl, pH
7.4, at 21 °C for 90 min. Nonspecific binding of
[3H]ketanserin was determined with 10 lM mianserin and
accounted for 20 % of the total binding. The incubation
was terminated by rapid filtration on a Brandel cell har-
vester, and filter-bound radioactivity was measured by
Receptor binding studies
In vitro pharmacological studies
The D2 and 5-HT2A affinity of the new chemical entities
(NCEs) was screened in vitro by radioligand displacement
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Med Chem Res (2013) 22:1660–1673
1665
Table 1 Results of radioligand displacement on D2 ([3H]spiperone-
labeled rat striatum) and 5-HT2A ([3H]ketanserin-labeled rat cortex)
of the final compounds (10a–g; 11a–g; 12a–g)
Apomorphine induced cage-climbing behavior in mice by a
test compound is an indication of mesolimbic dopaminergic
D2 receptor antagonism (Costall et al., 1978).
S. no. Code
R
Z
R0
D2%
displacement displacement
at 100 lM at 10 lM
(mean; n = 2) (mean; n = 2)
5-HT2A %
Pharmacokinetic studies carried out showed that the
exposure at 10 mg/kg dose was similar to the exposure of
several atypical antipsychotics at therapeutically relevant
doses, and hence this dose was chosen to carry out the in vivo
pharmacological tests. The effect of pretreatment with
10 mg/kg dose of the test compounds on apomorphine
(0.5 mg/kg s.c.) induced cage-climbing behavior was stud-
ied by the literature method (Costall et al., 1978). Haloper-
idol (1.0 mg/kg i.p.) was used as control as it completely
inhibited the climbing induced by apomorphine. Inhibition
or reversal of quipazine-induced head twitches in mice by the
test molecule (10 mg/kg dose) is an indication of central
serotonergic 5-HT2A receptor antagonism and this behavior
was studied by the literature method (Malick et al., 1977).
Risperidone (0.6 mg/kg i.p) was used as control as it com-
pletely inhibits quipazine-induced head twitches in mice.
Cataleptic effect of NCEs was evaluated and scoring was
done according to the literature method (Joshi et al., 1979).
1
10a NH2
10b NHCH3
10c NH2
10d OH
H
H
Cl
Cl
0
0
0
0
0
0
0
4
2
14
0
3
CH3 Cl
Cl
CH3 Cl
4
H
0
5
10e CH3
31
31
30
49
58
nd
28
nd
nd
68
51
57
58
22
nd
nd
63
6
10f
NHCH3 CH3 Cl
7
10g CH3
11a NH2
11b NHCH3
11c NH2
11d OH
H
H
H
Cl
8
OMe 24
OMe 40
9
10
11
12
13
14
15
16
17
18
19
20
21
CH3 OMe nd
OMe
CH3 OMe nd
H
0
11e CH3
11f
NHCH3 CH3 OMe nd
11g CH3
12a NH2
12b NHCH3
12c NH2
12d OH
H
OMe 82
H
H
H
H
H
H
H
H
26
0
In vivo Pharmacological Studies
H
CH3
H
0
Percentage inhibition (expressed as mean (l) standard
error mean (S.E.M.)), in antagonizing dopamine D2
receptors, is calculated at 10, 20, and 30 min after injecting
apomorphine hydrochloride and the results obtained are
detailed in Table 2. The results clearly indicate that all the
NCEs have the capability of antagonizing mesolimbic
dopaminergic D2 receptors with % inhibition varying
between 25 and 95 % at the studied dose level. A maxi-
mum of 95 % inhibition was observed for 10f and 12c,
while a minimum of 25 % inhibition was observed for 12b
and 12e. Percentage inhibition (expressed as mean
(l) standard error mean (SEM) in antagonizing central
serotonergic 5-HT2A receptors is calculated and the results
obtained are detailed in Table 2 as per the literature pro-
tocol (Lee et al., 2003). The results clearly indicate that all
the NCEs have the capability of antagonizing central
serotonergic 5-HT2A receptors with % inhibition varying
between 12 % and 86 % at the studied dose level. A
maximum of 86 % inhibition was observed for 10c, while a
minimum of 12 % inhibition was observed for 11a.
0
12e CH3
CH3
nd
nd
30
12f
NHCH3 CH3
12g CH3
H
nd Not determined
liquid scintillation counting. All assays were performed in
triplicate and repeated twice. The aim of this study is to
synthesize new second-generation antipsychotics, which
exhibit combined D2 and 5-HT2A antagonism. At 100 lM, 5
out of 16 NCEs displaced 80–24 % of the D2-specific radi-
otracer, while at 10 lM no inhibition was found. Regarding
the 5-HT2A affinity in the 11 and 12 series all NCEs inves-
tigated and in the 10 series 3 out of the 7 NCEs investigated
displaced 68–22 % of the 5-HT2A-specific radiotracer at
10 lM. The results with respect to the 5-HT2A receptor
indicate a clear interaction of nearly all NCEs with the or-
thosteric binding site of this target at pharmacologically
relevant concentrations. In vitro findings are tabulated in
Table 1. The observed stronger 5-HT2A receptor affinity of
most derivatives is in accordance with the expected atypical
profile of the new antipsychotics.
Average cataleptic time calculated after injecting NCEs at
tth hour for all the final compounds is outlined in Table 2.
The table also describes the maximum average cataleptic
time and the maximum average score for each compound.
The results tabulated in Table 3 clearly indicate that the
maximum average cataleptic score observed is either 0 or 1
for the NCEs at studied dose level indicating that most of the
compounds are noncataleptic. Among the final compounds,
10c and 10d exhibited maximum score of 1 each indicating
The Institutional Animal Ethics Committee of the Birla
Institute of Technology and Science, Pilani, India, approved
experimentation on animals (Protocol No. IAEC/RES/11/2).
Swiss albino mice (25–30 g) of either sex obtained from
Hissar Agricultural University, Haryana, India were used
for the pharmacological studies. Inhibition or reversal of
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Med Chem Res (2013) 22:1660–1673
Table 2 Results of D2 and 5-HT2A antagonism and catalepsy test of the final compounds (10a–g; 11a–g; 12a–g)
S. no.
Code
% D2 inhibition (mean SEM)
% 5-HT2A inhibition
(mean SEM)
Max. average
cataleptic
time (s)
Max. average
cataleptic
score
10th Min
20th Min
30th Min
1
10a
10b
10c
10d
10e
10f
65 10
60 10
80 6.12
60 10
60 10
60 10
70 9.35
80 12.25
65 10
79 6.90
41 2.78
86 2.78
58 3.65
51 5.55
81 2.78
62 1.67
12 2.78
51 3.74
60 2.37
67 2.78
65 8.53
80 5.02
62 11.23
15 2.78
36 6.26
31 2.37
80 3.74
32 4.95
55 5.98
77 4.10
18.24
3.96
23.5
28.25
9.25
8.12
3.25
14.12
10.67
10.78
7.90
11.25
3.12
6.25
9.21
9.32
2.64
3.19
9.32
3.88
5.17
2.54
0
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
80 12.25
80 6.12
60 10
3
4
50 5.81
80 12.25
70 12.25
75 11.18
65 10
5
60 10
6
95
5
95
5
7
10g
11a
11b
11c
11d
11e
11f
80 12.25
60 10
65 6.12
60 6.96
85 6.12
80 12.25
60 10
8
9
60 10
65 8.71
65 8.71
60 10
10
65 10
11
65 6.12
85 6.12
60 10
12
70 9.35
50 5.81
70 12.25
75 11.18
65 6.12
70 12.25
65 6.12
65 6.96
60 10
13
14
11g
12a
12b
12c
12d
12e
12f
85 10
15
60 10
16
25 5.81
50
5
17
95
5
80 12.25
65 10
60 10
18
60 8.71
25 5.81
60 10
65 10
19
50 5.81
75 7.91
55 6.58
70 12.25
65 10
20
21
12g
75 11.18
85 10
Risperidone
91
5
91
5
90
5
100
0
that these compounds exhibit slight catalepsy. Hence, it can
be concluded that all NCEs except 10c and 10d do not
antagonize nigrostriatal dopaminergic D2 receptors.
reactions were monitored and the purity of the compounds
was checked by ascending thin layer chromatography
(TLC) on silica gel-coated aluminum plates (Merck 60
F254, 0.25 mm) using mixture of chloroform and methanol
and the spots were visualized under ultra violet light at 254
and 366 nm. Infra red (IR) spectra were recorded in KBr
pellets on Schimadzu IR Prestige-21 FT-IR spectropho-
tometer (cm-1). 1H-NMR spectra were obtained from
Bruker DRX300 spectrometer using tetramethylsilane as
internal standard [chemical shifts in d, parts per million
(ppm)], mass spectra on a VG-70-S mass spectrometer and
elemental analysis on a Perkin Elmer 2400 CHNS ele-
mental analyzer. All compounds showed [95 % purity.
2-chloro-3-piperazinylquinoxaline (4): A mixture of
2,3–dichloroquinoxaline (4.97 g, 25 mmol), anhydrous
piperazine (10 g, 116 mmol), and anhydrous sodium car-
bonate (5 g, 47 mmol) in 75 ml of n-butanol was initially
stirred for 2 h at room temperature and then refluxed
for 20 h in oil bath. The reaction mixture was cooled
and concentrated in vacuo to yield light yellow solid
which is recrystallised with ethanol to yield 84 % (5.22 g)
of 2-chloro-3-piperazinyl quinoxaline (4) melting at
Although none of the NCEs tested inhibited either the
specific binding of the 5-HT2A ligand [3H]ketanserine or the
D2 ligand [3H]spiperone up to 1 lM in vitro (Table 1), in
vivo pharmacological data clearly indicate an atypical anti-
psychotic efficacy of the NCEs. This inconsistency might be
attributed to the difference in the extent of uptake or distri-
bution of NCEs into the target cells. The difference in the
uptake or distribution into the cells could be because of the
mechanism involved in the transportation of the NCEs such
as carrier-mediated transport in the in vivo studies, while
such mechanism might be absent in case of in vitro studies
(Goodman and Gilman’s, 2006; Chandra Sekhar et al.,
2011). Further studies are in progress in our laboratory to
determine the exact mechanism of action of the NCEs.
Experimental
Chemistry
1
130–132 °C. H NMR (DMSO-d6) (d) ppm: 2.52–2.63 (t,
Melting points were determined in open capillaries using
Bu¨chi 530 melting point apparatus without correction. The
4H, J = 4.8 Hz, N4(CH2)2); 3.10–3.16 (t, 4H, J = 4.8 Hz,
N1(CH2)2); 5.26 (s, 1H, NH); 7.63–8.07 (m, 4H, Ar–H). IR
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Med Chem Res (2013) 22:1660–1673
1667
7.63–8.07 (m, 4H, Ar–H). IR (KBr, m) cm-1: 3343 (NH
stretch); 3057, 3024 (aromatic C–H stretch), 2875, 2855
(aliphatic C–H stretch); 1652, 1608 (aromatic C=C
stretch); 1589 (C=N ring stretch); 1060 (C–O stretch); 740
(ortho substituted). HRMS (ESI) calcd for C13H16N4O
[M ? H]?: 244.1337; found: 244.1329. Anal. calculated
for C13H16N4O: C 63.91, H 6.60, N 22.93; found: C 63.76,
H 6.48, N 22.76.
Table 3 Summary of results of in vivo pharmacological studies of
the final compounds (10a–g; 11a–g; 12a–g)
S. no. Code % 5-HT2A
inhibition
% Max. D2 5-HT2A
inhibition
/
Max. avg.
D2 ratio cataleptic
score
1
10a
10b
10c
10d
10e
10f
79 6.90
41 2.78
86 2.78
58 3.65
51 5.55
81 2.78
62 1.67
12 2.78
51 3.74
60 2.37
67 2.78
65 8.53
80 5.02
70 9.35
1.12857
0
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
80 12.25 0.51250
3
80 6.12
60 10
1.07500
0.96667
Syntheses of (10a–g; 11a–g; 12a–g): The procedure
described by Lowe III et al., (1991) was adapted for this
preparation. In a 10 ml round bottom flask equipped with a
reflux condenser and N2 inlet, equimolar amounts
(0.05 mmol) of 2-chloro-3-piperazinylquinoxaline (4),
2-methoxy-3-piperazinylquinoxaline (6) or 2-piperazinyl-
quinoxaline (9) and respective chloroethylphenylthiazole
(1a–g); and sodium carbonate (0.1174 g, 1.11 mmol) and
potassium iodide (2 mg) in 2 ml of DMF were placed. The
reaction mixture was refluxed for 48 h. Once the reaction
showed completion on TLC (9:1 CHCl3, MeOH as mobile
phase), the cooled reaction mixture was poured into ice-
water mixture and the precipitate was filtered, washed with
water, and recrystallised in suitable solvents to afford the
pure final compounds 10a–g; 11a–d and g; 12a–d and
g. For compounds 11e, 11f, 12e, and 12f, once the reaction
showed completion on TLC (9:1 CHCl3, MeOH as mobile
phase), the cooled reaction mixture was poured into ice-
water mixture and the compound was extracted using
ethylacetate (3 9 5 mL). Combined organic layers were
washed with saturated aqueous brine solution (5 mL) and
dried over anhydrous Na2SO4. Solvent was evaporated
under reduced pressure using rotary evaporator and the
resultant residue was chromatographed on silica gel
(230–400 mesh) using 3 % MeOH in CHCl3 as eluent to
afford oily title compound (11e, 11f, 12e, and 12f).
4
5
80 12.25 0.63750
95 0.85260
80 12.25 0.77500
6
5
7
10g
11a
11b
11c
11d
11e
11f
8
65 10
0.18462
0.60000
9
85 6.12
10
11
12
13
14
15
16
17
18
19
20
21
80 12.25 0.75000
65 6.12
85 6.12
1.03077
0.76470
70 12.25 1.14286
62 11.23 85 10 0.72941
75 11.18 0.20000
11g
12a
12b
12c
12d
12e
12f
15 2.78
36 6.26
31 2.37
80 3.74
32 4.95
55 5.98
77 4.10
60 10
95
65 10
0.60000
0.32632
1.23077
5
70 12.25 0.45714
75 7.91
85 10
0.73333
0.90589
1.09890
12g
Risperidone
100
0
91
5
(KBr, m) cm-1: 3340 (NH stretch); 3065, 3015 (aromatic
C–H stretch); 2825, 2758 (aliphatic C–H stretch); 1644,
1608 (aromatic C=C stretch); 1596 (C=N ring stretch); 760
(C–Cl stretch); 735 (ortho substituted). HRMS (ESI) calcd
for C12H13ClN4 [M ? H]?: 248.0432; found: 248.0419.
Anal. calculated for C12H13ClN4: C 57.95, H 5.27, N
22.53; found: C 57.76, H 5.19, N 22.47.
{4-[2-(4-(2-chloroquinoxalin-3-yl)piperazin-1-
yl]ethyl)phenyl}-thiazol-2-amine (10a)
2-methoxy-3-piperazinylquinoxaline (6): A mixture of
2-chloro-3-methoxyquinoxaline (3.9 g, 20 mmol) and
anhydrous piperazine (5.184 g, 60 mmol) in 30 mL of
acetonitrile was stirred at room temperature for 5 h. Once
the reaction showed completion on TLC (9:1 CHCl3,
MeOH as mobile phase), the reaction mixture was poured
into ice-water mixture and extracted with 3 9 50 mL
portions of ethyl actetate. The combined organic layers
were dried over anhydrous sodium sulfate and concentrated
in vacuo to yield 2-methoxy-3-piperazinylquinoxaline (6),
which is recrystallised from ethanol to afford 84 % (4.1 g)
of 2-methoxy-3-piperazinylquinoxaline (6) melting at
80–82 °C. 1H NMR (DMSO-d6) (d) ppm: 2.47–2.56 (t, 4H,
J = 4.8 Hz, N4(CH2)2); 3.13–3.18 (t, 4H, J = 4.8 Hz,
N1(CH2)2); 3.68 (s, 3H, OCH3); 5.26 (s, 1H, NH);
Recrystallisation Solvent: Ethanol.
% Yield: 77 %
(0.174 g); mp: 162–164 °C. 1H NMR (DMSO-d6) (d) ppm:
2.59–2.63 (t, 4H, J = 4.8 Hz, N4(CH2)2); 2.65–2.69 (m,
4H, (CH2)2); 3.16–3.19 (t, 4H, J = 4.8 Hz, N1(CH2)2);
3.84 (s, 2H, NH2); 6.95 (s, 1H, thiazole); 7.18–8.07 (m, 8H,
Ar–H). IR (KBr, m) cm-1: 3440, 3410 (NH stretch); 3065,
3027 (aromatic C–H stretch); 2825, 2758 (aliphatic C–H
stretch); 1638 (C=N ring stretch); 1608, 1596 (aromatic
C=C stretch); 1259 (aliphatic C–N stretch), 810 (para
disubstituted benzene); 770 (C–Cl stretch), 708 (aromatic
C–H bending). HRMS (ESI) calcd for C23H23ClN6S
[M ? H]?: 450.1426; found: 450.1417; Anal. calculated
for C23H23ClN6S: C 61.25, H 5.14, N 18.63, S 7.11; found:
C 61.11, H 5.19, N 18.45, S 7.05.
123

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Med Chem Res (2013) 22:1660–1673
4-{4-[2-(4-(2-chloroquinoxalin-3-yl)piperazin-1-
yl)ethyl]phenyl}-N-methylthiazol-2-amine (10b)
2-{4-[4-(2,5-dimethylthiazol-4-yl)phenethyl]piperazin-1-
yl}-3-chloroquinoxaline (10e)
Recrystallisation Solvent: Methanol. % Yield: 79 %
(0.181 g); mp: 140–142 °C. 1H NMR (DMSO-d6) (d) ppm:
2.49 (s, 3H, NHCH3); 2.53–2.62 (t, 4H, J = 4.9 Hz,
N4(CH2)2); 2.67–2.72 (m, 4H, (CH2)2); 3.11–3.17 (t, 4H,
J = 4.9 Hz, N1(CH2)2); 4.02 (s, 1H, NHCH3); 6.61 (s, 1H,
Recrystallisation Solvent: Ethanol–water. % Yield: 52 %
1
(0.12 g); mp: 90–92 °C. H NMR (DMSO-d6) (d) ppm:
2.39 (s, 3H, 5-CH3); 2.52–2.58 (m, 4H, (CH2)2); 2.61–2.66
(t, 4H, J = 4.8 Hz, N4(CH2)2); 2.76 (s, 3H, 2-CH3);
3.18–3.24 (t, 4H, J = 4.8 Hz, N1(CH2)2); 7.25–8.20 (m,
8H, Ar–H). IR (KBr, m) cm-1: 3065, 3027 (aromatic C–H
stretch); 2842, 2753 (aliphatic C–H stretch); 1647 (C–S
stretch); 1603, 1590 (aromatic C=C stretch); 1261 (ali-
phatic C–N stretch); 823 (para disubstituted benzene); 759
(C–Cl stretch), 705 (aromatic C–H bending). HRMS (ESI)
calcd for C25H26ClN5S [M ? H]?: 463.1256; found:
463.1249; Anal. calculated for C25H26ClN5S: C 64.71, H
5.65, N 15.09, S 6.91; found: C 64.65, H 5.56, N 14.99, S
6.85.
thiazole); 7.21-8.16 (m, 8H, Ar–H). IR (KBr, m) cm-1
:
3335 (NH stretch); 3054, 3015 (aromatic C–H stretch);
2856, 2745 (aliphatic C–H stretch); 1632 (C–S stretch);
1605, 1575 (aromatic C=C stretch); 1257 (aliphatic C–N
stretch); 815 (para disubstituted benzene); 758 (C–Cl
stretch), 705 (aromatic C–H bending). HRMS (ESI) calcd
for C24H25ClN6S [M ? H]?: 464.1322; found: 464.1318;
Anal. calculated for C24H25ClN6S: C 61.99, H 5.42, N
18.07, S 6.90; found: C 61.91, H 5.41, N 18.05, S 6.85.
2-{4-[2-(4-(2-chloroquinoxalin-3-yl)piperazin-1-
yl)ethyl]phenyl}-5-methylthiazol-2-amine (10c)
4-{4-[2-(4-(2-chloroquinoxalin-3-yl)piperazin-1-
yl)ethyl]phenyl}-N,5-dimethylthiazol-2-amine (10f)
Recrystallisation Solvent: Ethanol.
%
Yield: 79 %
Recrystallisation Solvent: Ethanol.
% Yield: 45 %
(0.183 g); mp: 158–160 °C. 1H NMR (DMSO-d6) (d) ppm:
2.35 (s, 3H, CH3); 2.48–2.56 (t, 4H, J = 4.9 Hz,
N4(CH2)2); 2.61-2.67 (m, 4H, (CH2)2); 3.09-3.15 (t, 4H,
J = 4.9 Hz, N1(CH2)2); 3.77 (s, 2H, NH2); 7.19–8.05 (m,
8H, Ar–H). IR (KBr, m) cm-1: 3428, 3407 (NH stretch),
3020, 2895 (aromatic C–H stretch); 2810 (aliphatic C–H
stretch); 1640, 1602 (aromatic C=C stretch); 1260 (ali-
phatic C–N stretch), 817 (para disubstituted benzene); 766
(C–Cl stretch), 711 (aromatic C–H bending). HRMS (ESI)
calcd for C24H25ClN6S [M ? H]?: 464.1486; found:
464.1480; Anal. calculated for C24H25ClN6S: C 61.99, H
5.42, N 18.07, S 6.90; found: C 61.89, H 5.38, N 18.03, S
6.88.
(0.11 g); mp: 134–136 °C. H NMR (DMSO-d6) (d) ppm:
2.31 (s, 3H,CH3); 2.51 (s, 3H, NHCH3); 2.59-2.63 (t, 4H,
J = 4.9 Hz, N4(CH2)2); 2.65–2.69 (m, 4H, (CH2)2);
3.16–3.19 (t, 4H, J = 4.9 Hz, N1(CH2)2); 4.18 (s, 1H,
1
NHCH3); 7.18–7.97 (m, 8H, Ar–H). IR (KBr, m) cm-1
:
3410 (NH stretch); 3065, 3027 (aromatic C–H stretch);
2847, 2743 (aliphatic C–H stretch); 1644 (C–S stretch);
1608, 1596 (aromatic C=C stretch); 1263 (aliphatic C–N
stretch); 810 (para disubstituted benzene); 761 (C–Cl
stretch), 707 (aromatic C–H bending). HRMS (ESI) calcd
for C25H27ClN6S [M ? H]?: 478.1961; found: 478.1957;
Anal. calculated for C25H27ClN6S: C 62.65, H 5.68, N
17.54, S 6.69; found: C 62.56, H 5.59, N 17.45, S 6.54.
4-{4-[2-(4-(2-chloroquinoxalin-3-yl)piperazin-1-
yl)ethyl]phenyl}-thiazol-2-ol (10d)
2-{4-[4-(2-methylthiazol-4-yl)phenethyl]piperazin-1-yl}-3-
chloroquinoxaline (10g)
Recrystallisation Solvent: Ethanol.
%
Yield: 78 %
Recrystallisation Solvent: Ethanol- water. % Yield: 63 %
1
(0.175 g); mp: 192–194 °C. 1H NMR (DMSO-d6) (d) ppm:
2.49–2.58 (t, 4H, J = 4.7 Hz, N4(CH2)2); 2.62–2.67 (m,
4H, (CH2)2); 3.13–3.17 (t, 4H, J = 4.7 Hz, N1(CH2)2);
5.38 (br s, 1H, OH); 7.07 (s, 1H, thiazole); 7.14–8.01 (m,
8H, Ar–H). IR (KBr, m) cm-1: 3555 (OH stretch); 3071,
3045 (aromatic C–H stretch); 2829, 2749 (aliphatic C–H
stretch); 1637, 1606 (aromatic C=C stretch); 1582 (C=N
ring stretch); 1248 (aliphatic C–N stretch); 817 (para
disubstituted benzene); 762 (C–Cl stretch), 708 (aromatic
C–H bending). HRMS (ESI) calcd for C23H22ClN5OS
[M ? H]?: 451.1307; found: 451.1303; Anal. calculated
for C23H22ClN5OS: C 61.12, H 4.91, N 15.50, S 7.09;
found: C 61.09, H 4.86, N 15.43, S 7.05.
(0.142 g); mp: 86–88 °C. H NMR (DMSO-d6) (d) ppm:
2.49–2.55 (t, 4H, J = 4.7 Hz, N4(CH2)2); 2.64–2.71 (m,
4H, (CH2)2); 2.75 (s, 3H, CH3); 3.17–3.22 (t, 4H,
J = 4.7 Hz, N1(CH2)2); 7.15 (s, 1H, thiazole); 7.21–8.09
(m, 8H, Ar–H). IR (KBr, m) cm-1: 3045, 3032 (aromatic C–
H stretch); 2828, 2763 (aliphatic C–H stretch); 1639 (C–S
stretch); 1636, 1602 (aromatic C=C stretch); 1262 (ali-
phatic C–N stretch); 809 (para disubstituted benzene); 765
(C–Cl stretch), 709 (aromatic C–H bending). HRMS (ESI)
calcd for C24H24ClN5S [M ? H]?: 449.1342; found:
449.1337; Anal. calculated for C24H24ClN5S: C 64.06, H
5.38, N 15.56, S 7.13; found: C 63.99, H 5.29, N 15.45, S
7.04.
123

Med Chem Res (2013) 22:1660–1673
1669
4-{4-[2-(4-(2-methoxyquinoxalin-3-yl)piperazin-1-
yl)ethyl]phenyl}-thiazol-2-amine (11a)
for C25H28N6OS: C 65.19, H 6.13, N 18.25, S 6.96; found:
C 65.08, H 6.06, N 18.15, S 6.88.
Recrystallisation Solvent: Ethanol.
% Yield: 66 %
4-{4-[2-(4-(2-methoxyquinoxalin-3-yl)piperazin-1-
yl)ethyl]phenyl}thiazol-2-ol (11d)
1
(0.223 g); mp: 96–98 °C. H NMR (DMSO-d6) (d) ppm:
2.49–2.53 (t, 4H, J = 4.8 Hz, N4(CH2)2); 2.57–2.76 (m,
4H, (CH2)2); 3.27–3.32 (t, 4H, J = 4.8 Hz, N1(CH2)2);
3.72 (s, 3H, OCH3); 3.84 (s, 2H, NH2); 6.88 (s, 1H, thia-
zole); 7.23–8.00 (m, 8H, Ar–H). IR (KBr, m) cm-1: 3348,
3439 (NH stretch); 3065, 3027 (aromatic C–H stretch);
2828, 2763 (aliphatic C–H stretch); 1635, 1616 (aromatic
C=C stretch); 1556 (C=N ring stretch); 1255 (aliphatic
C–N stretch); 1118 (C–O stretch); 820 (para disubstituted
benzene); 709 (aromatic C–H bending). HRMS (ESI) calcd
for C24H26N6OS [M ? H]?: 446.2148; found: 446.2137;
Anal. calculated for C24H26N6OS: C 64.55, H 5.87, N
18.82, S 7.18; found: C 64.49, H 5.69, N 18.84, S 7.14.
Recrystallisation Solvent: Acetone.
% Yield: 78 %
(0.263 g); mp: 122–124 °C. 1H NMR (DMSO-d6) (d) ppm:
2.45-2.52 (t, 4H, J = 4.7 Hz, N4(CH2)2); 2.66–2.78 (m,
4H, (CH2)2); 3.21–3.29 (t, 4H, J = 4.7 Hz, N1(CH2)2);
3.73 (s, 3H, OCH3); 4.74 (s, 1H, thiazole); 5.42 (br s, 1H,
OH); 7.25–8.01 (m, 8H, Ar–H). IR (KBr, m) cm-1: 3558
(OH stretch); 3062, 3027 (aromatic C–H stretch); 2832,
2787 (aliphatic C–H stretch); 1647, 1615 (aromatic C=C
stretch); 1590 (C=N ring stretch); 1262 (aliphatic C–N
stretch); 1077 (C–O stretch); 819 (para disubstituted ben-
zene). 704 (aromatic C–H bending). HRMS (ESI) calcd for
C24H25N5O2S [M ? H]?: 447.1677; found: 447.1674;
Anal. calculated for C24H25N5O2S: C 64.41, H 5.63, N
15.65, S 7.16; found: C 64.26, H 5.60, N 15.51, S 7.08.
4-{4-[2-(4-(2-methoxyquinoxalin-3-yl)piperazin-1-
yl)ethyl]phenyl}-N-ethylthiazol-2-amine (11b)
4-{4-[2-(4-(2-methoxyquinoxalin-3-yl)piperazin-1-
yl)ethyl]phenyl}-5-methyl thiazol-2-amine (11e)
Recrystallisation Solvent: Ether. % Yield: 83 % (0.292 g);
mp: 114–116 °C. 1H NMR (DMSO-d6) (d) ppm: 2.46–2.51
(t, 4H, J = 4.7 Hz, N4(CH2)2); 2.57 (s, 3H, NHCH3);
2.65–2.72 (m, 4H, (CH2)2); 3.29-3.34 (t, 4H, J = 4.7 Hz,
N1(CH2)2); 3.68 (s, 3H, OCH3); 4.11 (s, 1H, NHCH3); 6.71
(s, 1H, thiazole); 7.35–8.04 (m, 8H, Ar–H). IR (KBr, m)
cm-1: 3350 (NH stretch); 3058, 3009 (aromatic C–H
stretch); 2817, 2760 (aliphatic C–H stretch); 1644, 1609
(aromatic C=C stretch); 1587 (C=N ring stretch); 1260
(aliphatic C–N stretch); 1079 (C–O stretch); 812 (para
disubstituted benzene); 712 (aromatic C–H bending).
HRMS (ESI) calcd for C25H28N6OS [M ? H]?: 460.1836;
found: 460.1827; Anal. calculated for C25H28N6OS: C
65.19, H 6.13, N 18.25, S 6.96; found: C 65.08, H 6.06, N
18.15, S 6.88.
% Yield: 42% (0.147 g, oil). 1H NMR (DMSO-d6) (d)
ppm: 2.35 (s, 3H, 5-CH3); 2.46–2.53 (t, 4H, J = 4.7 Hz,
N4(CH2)2); 2.58–2.72(m, 4H, (CH2)2); 2.76 (s, 3H, 2-CH3);
3.23-3.29 (t, 4H, J = 4.7 Hz, N1(CH2)2); 3.79 (s, 3H,
OCH3); 7.39-8.25 (m, 8H, Ar–H). IR (KBr, m) cm-1: 3044,
3026 (aromatic C–H stretch); 2832, 2758 (aliphatic C–H
stretch); 1640, 1604 (aromatic C=C stretch); 1580 (C=N
ring stretch); 1266 (aliphatic C–N stretch); 1112 (C–O
stretch); 809 (para disubstituted benzene), 708 (aromatic
C–H bending). HRMS (ESI) calcd for C26H29N5OS
[M ? H]?: 459.2126; found: 459.2118; Anal. calculated
for C26H29N5OS: C 67.94, H 6.36, N 15.24, S 6.98; found:
C 67.86, H 6.32, N 15.21, S 6.93.
4-{4-[2-(4-(2-methoxyquinoxalin-3-yl)piperazin-1-
yl)ethyl]phenyl}-5-methylthiazol-2-amine (11c)
4-{4-[2-(4-(2-methoxyquinoxalin-3-yl)piperazin-1-
ylethyl]phenyl}-N,5-dimethyl thiazol-2-amine (11f)
% Yield: 48% (0.173 g, oil). 1H NMR (DMSO-d6) (d)
ppm: 2.36 (s, 3H,CH3); 2.49–2.56 (t, 4H, J = 4.8 Hz,
N4(CH2)2); 2.60 (s, 3H, NHCH3); 2.63–2.79 (m, 4H,
(CH2)2); 3.26–3.36 (t, 4H, J = 4.8 Hz, N1(CH2)2); 3.68 (s,
3H, OCH3); 4.28 (s, 1H, NHCH3); 7.12–7.88 (m, 8H,
Ar–H). IR (KBr, m) cm-1: 3478 (NH stretch); 3047, 3115
(aromatic C–H stretch); 2832, 2758 (aliphatic C–H
stretch); 1646, 1613 (aromatic C=C stretch); 1587 (C=N
ring stretch); 1258 (aliphatic C–N stretch); 1115 (C–O
stretch); 818 (para disubstituted benzene), 703 (aromatic
C–H bending). HRMS (ESI) calcd for C26H30N6OS
[M ? H]?: 474.2335; found: 474.2328; Anal. calculated
Recrystallisation Solvent: Ether. % Yield: 70 % (0.244 g);
mp: 68–70 °C. 1H NMR (DMSO-d6) (d) ppm: 2.35 (s, 3H,
CH3); 2.51–2.56 (t, 4H, J = 4.9 Hz, N4(CH2)2); 2.59–2.76
(m, 4H, (CH2)2); 3.25–3.34 (t, 4H, J = 4.9 Hz, N1(CH2)2);
3.69 (s, 3H, OCH3); 3.89 (s, 2H, NH2); 7.18–7.95 (m, 8H,
Ar–H). IR (KBr, m) cm-1: 3440, 3428 (NH stretch); 3058,
3009 (aromatic C–H stretch); 2817, 2775 (aliphatic C–H
stretch); 1642, 1608 (aromatic C=C stretch); 1545 (C=N
ring stretch); 1261 (aliphatic C–N stretch), 1107 (C–O
stretch); 831 (para disubstituted benzene); 711 (aromatic
C–H bending). HRMS (ESI) calcd for C25H28N6OS
[M ? H]?: 460.1786; found: 460.1782; Anal. calculated
123

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Med Chem Res (2013) 22:1660–1673
for C26H30N6OS: C 65.80, H 6.37, N 17.71, S 6.76; found:
C 65.76, H 6.32, N 17.71, S 6.73.
[M ? H]?: 430.1920; found: 430.1915; Anal. calculated
for C24H26N6S: C 66.95, H 6.09, N 19.52, S 7.45; found: C
66.84, H 5.94, N 19.46, S 7.43.
2-{4-[4-(2-methylthiazol-4-yl)phenethyl]piperazin-1-yl}-3-
methoxyquinoxaline (11g)
5-methyl-4-{4-[2-(4-(quinoxalin-2-yl)piperazin-1-
yl)ethyl]phenyl}thiazol-2-amine (12c)
Recrystallisation Solvent: Acetone. % Yield: 47% (0.16 g);
mp: 88–90 °C. 1H NMR (DMSO-d6) (d) ppm: 2.47–2.54 (t,
4H, J = 4.9 Hz, N4(CH2)2); 2.57–2.67 (m, 4H, (CH2)2);
2.76 (s, 3H, CH3); 3.24–3.33 (t, 4H, J = 4.9 Hz,
N1(CH2)2); 3.75 (s, 3H, OCH3); 7.42 (s, 1H, thiazole);
7.54–8.31 (m, 8H, Ar–H). IR (KBr, m) cm-1: 3040, 3025
(aromatic C–H stretch); 2835, 2750 (aliphatic C–H
stretch); 1645, 1604 (aromatic C=C stretch); 1585 (C=N
ring stretch); 1269 (aliphatic C–N stretch); 1118 (C–O
stretch); 825 (para disubstituted benzene), 710 (aromatic
C–H bending). HRMS (ESI) calcd for C25H27N5OS
[M ? H]?: 445.1722; found: 445.1718; Anal. calculated
for C25H27N5OS: C 67.39, H 6.11, N 15.72, S 7.20; found:
C 67.31, H 6.07, N 15.66, S 7.13.
Recrystallisation Solvent: Methanol.
% Yield: 78%
(0.167 g); mp: 108–110 °C. 1H NMR (DMSO-d6) (d) ppm:
2.41 (s, 3H, CH3); 2.55–2.61 (t, 4H, J = 4.9 Hz,
N4(CH2)2); 2.68–2.77 (m, 4H, (CH2)2); 3.21–3.27 (t, 4H,
J = 4.9 Hz, N1(CH2)2); 3.92 (s, 2H, NH2); 7.14–8.16 (m,
9H, Ar–H). IR (KBr, m) cm-1: 3340, 3345 (NH stretch);
3056, 3035 (aromatic C–H stretch); 2845, 2750 (aliphatic
C–H stretch); 1646, 1606 (aromatic C=C stretch); 1590
(C=N ring stretch); 1256 (aliphatic C–N stretch); 821 (para
disubstituted benzene), 708 (aromatic C–H bending).
HRMS (ESI) calcd for C24H26N6S [M ? H]?: 430.1858;
found: 430.1851; Anal. calculated for C24H26N6S: C 66.95,
H 6.09, N 19.52, S 7.45; found: C 66.91, H 6.04, N 19.41, S
7.38.
4-{4-[2-(4-(quinoxalin-2-yl)piperazin-1-
yl)ethyl]phenyl}thiazol-2-amine (12a)
4-{4-[2-(4-(quinoxalin-2-yl)piperazin-1-
yl)ethyl]phenyl}thiazol-2-ol (12d)
Recrystallisation Solvent: n-Hexane.
% Yield: 68%
(0.142 g); mp: 110–112 °C. 1H NMR (DMSO-d6) (d) ppm:
2.55–2.62 (t, 4H, J = 4.8 Hz, N4(CH2)2); 2.75–2.88 (m,
4H, (CH2)2); 3.17–3.23 (t, 4H, J = 4.8 Hz, N1(CH2)2);
3.86 (s, 2H, NH2); 6.78 (s, 1H, thiazole); 7.28–8.25 (m, 9H,
Ar–H). IR (KBr, m) cm-1: 3445, 3423 (NH stretch); 3056,
3035 (aromatic C–H stretch); 2845, 2757 (aliphatic C–H
stretch); 1634, 1610 (aromatic C=C stretch); 1576 (C=N
ring stretch); 1260 (aliphatic C–N stretch); 829 (para
disubstituted benzene), 710 (aromatic C–H bending).
HRMS (ESI) calcd for C23H24N6S [M ? H]?: 416.1688;
found: 416.1681; Anal. calculated for C23H24N6S: C 66.32,
H 5.81, N 20.18, S 7.70; found: C 66.24, H 5.74, N 20.06, S
7.63.
Recrystallisation Solvent: Ethanol.
%
Yield: 71%
(0.147 g); mp: 142–144 °C. 1H NMR (DMSO-d6) (d) ppm:
2.59–2.63 (t, 4H, J = 4.8 Hz, N4(CH2)2); 2.70–2.88 (m,
4H, (CH2)2); 3.16–3.19 (t, 4H, J = 4.8 Hz, N1(CH2)2);
5.58 (br s, 1H, OH); 6.89 (s, 1H, thiazole); 7.10–7.97 (m,
9H, Ar–H). IR (KBr, m) cm-1: 3610 (OH stretch); 3049,
3015 (aromatic C–H stretch); 2862, 2798 (aliphatic C–H
stretch); 1638, 1614 (aromatic C=C stretch); 1578 (C=N
ring stretch); 1260 (aliphatic C–N stretch); 825 (para
disubstituted benzene), 702 (aromatic C–H bending).
HRMS (ESI) calcd for C23H23N5OS [M ? H]?: 417.1889;
found: 417.1887 Anal. calculated for C23H23N5OS: C
66.16, H 5.55, N 16.77, S 7.68; found: C 66.11, H 5.44, N
16.691, S 7.62.
N–methyl-4-{4-[2-(4-(quinoxalin-2-yl)piperazin-1-
yl)ethyl]phenyl}thiazol-2-amine (12b)
2-{4-[4-(2,5-dimethylthiazol-4-yl)phenethyl]piperazin-1-
yl}quinoxaline (12e)
Recrystallisation Solvent: Ethanol.
%
Yield: 56%
(0.121 g); mp: 152–154 °C. 1H NMR (DMSO-d6) (d) ppm:
2.34–2.49 (m, 4H, (CH2)2); 2.59–2.63 (t, 4H, J = 4.8 Hz,
N4(CH2)2); 2.93 (s, 3H, NHCH3); 4.12 (s, 1H, NHCH3);
3.11–3.18 (t, 4H, J = 4.8 Hz, N1(CH2)2); 6.92 (s, 1H,
% Yield: 70% (0.15 g, oil). 1H NMR (DMSO-d6) (d) ppm:
2.28 (s, 3H, 5-CH3); 2.54–2.59 (t, 4H, J = 4.9 Hz,
N4(CH2)2); 2.61–2.78 (m, 4H, (CH2)2); 2.76 (s, 3H,
2-CH3); 3.18–3.24 (t, 4H, J = 4.9 Hz, N1(CH2)2);
7.22–8.11 (m, 9H, Ar–H). IR (Neat) cm-1: 3060, 3039
(aromatic C–H stretch); 2845, 2757, 1369 (aliphatic C–H
stretch); 1632, 1616 (aromatic C=C stretch); 1577 (C=N
ring stretch); 1268 (aliphatic C–N stretch); 825 (para
disubstituted benzene), 706 (aromatic C–H bending).
HRMS (ESI) calcd for C25H27N5S [M ? H]?: 429.2127;
thiazole); 7.39–8.32 (m, 9H, Ar–H). IR (KBr, m) cm-1
:
3445 (NH stretch); 3056, 3035 (aromatic C–H stretch);
2845, 2757 (aliphatic C–H stretch); 1640, 1608 (aromatic
C=C stretch); 1588 (C=N ring stretch); 1262(aliphatic C–N
stretch); 826 (para disubstituted benzene), 712 (aromatic
C–H bending). HRMS (ESI) calcd for C24H26N6S
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Med Chem Res (2013) 22:1660–1673
1671
found: 429.2123. Anal. calculated for C25H27N5S: C 69.90,
H 6.34, N 16.30, S 7.46; found: C 69.82, H 6.28, N 16.22, S
7.42.
[3H]ketanserine, Perkin Elmer, Aspec: 67 Ci/mmol; D2:
[3H]spiperone, Amersham GE, Aspec: 101 Ci/mmol) and up
to six concentrations of the NCEs. Dilutions of the NCEs
were made with assay buffer. Nonspecific binding of the
radioligands was determined with 100 lM mianserin for
the 5-HT2A ligand [3H]ketanserine and 100 lM haloperidol
for D2 ligand [3H]spiperone. To block the 5-HT affinity of
the D2 radioligand [3H]spiperone, 10 lM ketanserin was
added to the respective assays. The assay samples were
incubated at ambient temperature for 60 min (D2) or
90 min (5-HT2A), rapidly filtered through Whatman GF/B
glass-fiber filters, and washed four times with ice-cold
assay buffer. Filter-bound radioactivity was determined by
liquid scintillation counting. All test compounds were
assayed in at least three independent experiments. The IC50
values were estimated using iterative nonlinear curve
fitting.
N,5-dimethyl-4-{4-[2-(4-(quinoxalin-2-yl)piperazin-1-
yl)ethyl]phenyl}thiazol–2-amine (12f)
% Yield: 69% (0.17 g, oil). 1H NMR (DMSO-d6) (d) ppm:
2.33 (s, 3H,CH3); 2.42–2.54 (m, 4H, (CH2)2); 2.59–2.67 (t,
4H, J = 4.8 Hz, N4(CH2)2); 2.77 (s, 3H, NHCH3);
3.14–3.17 (t, 4H, J = 4.8 Hz, N1(CH2)2); 4.42 (s, 1H,
NHCH3); 7.22–8.18 (m, 9H, Ar–H). IR (Neat) cm-1: 3445
(NH stretch); 3072, 3045 (aromatic C–H stretch); 2852,
2748 (aliphatic C–H stretch); 1644, 1612 (aromatic C=C
stretch); 1576 (C=N ring stretch); 1261 (aliphatic C–N
stretch); 824 (para disubstituted benzene), 710 (aromatic
C–H bending). HRMS (ESI) calcd for C25H28N6S
[M ? H]?: 444.2336; found: 444.2335. Anal. calculated
for C25H28N6S: C 67.54, H 6.35, N 18.90, S 7.21; found: C
67.42, H 6.28, N 18.82, S 7.19.
In vivo pharmacological studies
The Institutional Animal Ethics Committee of the Birla
Institute of Technology and Science, Pilani, Rajasthan,
India, approved experimentation on animals (Protocol No.
IAEC/RES/11/2). Swiss albino mice (25–30 g) of either
sex obtained from Hissar Agricultural University, Hissar,
Haryana, India were used for the pharmacological studies.
Pharmacokinetic studies carried out showed that the
exposure at 10 mg/kg dose was similar to the exposure of
several atypical antipsychotics at therapeutically relevant
doses, and hence this dose was chosen to carry out the in
vivo pharmacological tests. Statistical analysis was done
using GraphPad InStat software.
2-{4-[4-(2-methylthiazol-4-yl)phenethyl]piperazin-1-
yl}quinoxaline (12g)
Recrystallisation Solvent: Ether. % Yield: 69% (0.143 g);
mp: 128–130 °C. 1H NMR (DMSO-d6) (d) ppm: 2.42–2.55
(m, 4H, (CH2)2); 2.60–2.66 (t, 4H, J = 4.8 Hz, N4(CH2)2);
2.86 (s, 3H, CH3); 3.21–3.29 (t, 4H, J = 4.8 Hz,
N1(CH2)2); 7.14 (s, 1H, thiazole); 7.19–8.35 (m, 9H, Ar–
H). IR (KBr, m) cm-1: 3057, 3036 (aromatic C–H stretch);
2854, 2741 (aliphatic C–H stretch); 1648, 1629 (aromatic
C=C stretch); 1586 (C=N ring stretch); 1263 (aliphatic C–
N stretch); 822 (para disubstituted benzene), 711 (aromatic
C–H bending). HRMS (ESI) calcd for C24H25N5S
[M ? H]?: 415.1624; found: 415.1619. Anal. calculated
for C24H25N5S: C 69.37, H 6.06, N 16.85, S 7.72; found: C
69.29, H 6.01; N 16.82, S 7.59.
D2 receptor antagonism studies in nigrostriatal pathway
(climbing mouse assay)
Apomorphine hydrochloride (1 mg/kg) solution (as per the
base calculations) was prepared in triple-distilled water
containing 0.1 % w/v sodium metabisulphite and was
injected s.c. 1 h before testing.
Pharmacology
Risperidone (0.6 mg/kg) and NCEs (10 mg/kg) were
prepared as suspension in 0.25% w/v sodium carboxy-
methylcellulose in triple-distilled water and were injected
i.p. 30 min before testing.
In vitro radioligand displacement studies
The affinity and specificity of the NCEs were estimated in
radioligand displacement studies on rat 5-HT2A and D2
receptors obtained from rat cortical (5-HT receptors) and
striatal (D2 receptors) membrane preparations. Test com-
pounds were dissolved in DMSO (10 mM stock solution),
aliquoted, and stored at -25 °C. For competitive binding
experiments, the membrane preparations were thawed,
diluted with assay buffer, 50 mM TRIS–HCl, at pH 7.4,
and washed twice. The particular receptor preparation
Inhibition or reversal of Apomorphine-induced cage-
climbing behavior in mice by a test molecule is an indi-
cation of mesolimbic dopaminergic D2 receptor antago-
nism (Costall et al., 1978). During the experimentation,
mice were placed individually in separate aluminum cages,
measuring 20 9 15 9 15 cm3, with walls lined with 1 cm2
aluminum wire mesh (diameter 2 mm). They were placed
in the above cages for 30 min for adaptation before the
experiment. Groups of mice (eight per group) were
was incubated with the respective radioligand (5-HT2A
:
123

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Med Chem Res (2013) 22:1660–1673
administered with either the test molecule (10 mg/kg) or
vehicle or Risperidone i.p. 1 h prior to the apomorphine
challenge (1 mg/kg, s.c.). Mice were then observed for the
climbing behavior after 10, 20, and 30 min and the scoring
was done as below.
Induction of catalepsy by the test molecules is an indi-
cation of antagonism at nigrostriatal dopaminergic D2
receptors leading to EPS (Malick et al., 1977). During the
experimentation, mice were placed individually in separate
plastic translucent cages, measuring 20 9 15 9 15 cm3.
They were placed in the above cages for 30 min for
adaptation before the experiment. Groups of mice (eight
per group) were administered i.p. with either the test
molecule (10 mg/kg) or vehicle. The mice were then tested
for catalepsy by placing both the front paws on a 4 cm high
wooden block (6 9 4 9 4 cm3) and measuring the time
taken for it to come back to the normal posture. The
scoring was done in accordance with literature (Lumma Jr.
et al., 1981). If the animal maintained the imposed posture
for at least 20 s, then it was said to be cataleptic and given
one point. For every further 20 s it continued to maintain
the imposed posture, an extra point was given, thus the
animal was given a score of 2 points if it maintained the
posture for 40 s, 3 points for 60 s, and so on. The mice
were tested for cataleptic behavior 1.0, 2.0, 3.0, 4.0, and
5 h after treatment with the test molecule. Average cata-
leptic times and scores are calculated at each time of
measurement of cataleptic behavior per molecule. The
maximum of all average cataleptic scores/times are noted
per molecule and then conclusions are drawn with respect
to which test molecule is cataleptic and the degree of
catalepsy.
‘‘0,’’ when all the four feet were placed on the cage floor,
‘‘1,’’ when three feet were placed on the cage floor,
‘‘2,’’ when two feet were placed on the cage floor,
‘‘3,’’ when one foot was placed on the cage floor, and
‘‘4,’’ when all the four feet were off the cage floor.
The percentage inhibition or reversal of climbing
behavior of Apomorphine hydrochloride was calculated by
the difference from the score of treated subjects to the score
of control animals and referring it to score of control group
set to 100 %. Haloperidol (1.0 mg/kg, i.p.) was used as
control as it completely inhibited the climbing induced by
apomorphine.
5-HT2A receptor antagonism studies (quipazine-
induced head twitches)
Quipazine maleate (5 mg/kg) solution (as per the base
calculations) was prepared in triple-distilled water con-
taining 0.1 % w/v sodium metabisulphite and was injected
i.p. 30 min before testing. Risperidone (0.6 mg/kg) and
NCEs (10 mg/kg) were prepared as suspension in 0.25 %
w/v sodium carboxymethylcellulose in distilled water and
were also injected i.p. 30 min before testing.
Inhibition or reversal of quipazine-induced head twitches
in mice by the test molecule is an indication of central
serotonergic 5-HT2A receptor antagonism (Malick et al.,
1977). During the experimentation, mice were placed
individually in separate plastic translucent cages, measuring
20 9 15 9 15 cm3. They were placed in the above cages
for 30 min for adaptation before the experiment. Groups of
mice (eight per group) were administered i.p. with either the
test molecule (10 mg/kg) or vehicle or Risperidone 1 h
prior to the quipazine maleate challenge (5 mg/kg, i.p.).
Risperidone (0.6 mg/kg, i.p) was used as control as it
completely inhibits quipazine-induced head twitches in
mice. The head twitches were then counted between 30 and
40 min. The percentage inhibition or reversal of head
twitches was calculated by the difference from the count of
treated subjects to the count of control animals and referring
it to count of control group set to 100 %.
Conclusion
A series of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl) pip-
erazin-1-yl)ethyl]phenyl} thiazole derivatives were syn-
thesized and evaluated in vitro for their affinity for the
dopamine D2 and serotonin 5-HT2A receptors (Table 1).
All the final compounds were evaluated for the atypical
antipsychotic activity in animal models. The overall results
are summarized in Table 3. Compound 12d is the most
active among the synthesized compounds with 5-HT2A/D2
ratio of 1.23077 followed by 11f and 10a with 5-HT2A/D2
ratios of 1.14286 and 1.12857, respectively. All the above
three compounds are more active than the standard drug
risperidone (5-HT2A/D2 ratio of 1.0989) as they exhibited
higher 5-HT2A/D2 ratio than risperidone. None of the above
compounds exhibited catalepsy. Hence, these compounds
satisfy all the criteria required for a molecule to be an
atypical antipsychotic according to Meltzer’s classification
(Meltzer et al., 1989; Roth et al., 1998). Further studies in
transforming these agents into clinically useful agents are
in progress in our laboratory.
D2 receptor antagonism studies in nigrostriatal pathway
(catalepsy test)
NCEs (10 mg/kg) were prepared as suspension in 0.25 %
w/v sodium carboxymethylcellulose in triple-distilled
water and were injected i.p. 30 min before testing.
Acknowledgments Sincere thanks to UGC, New Delhi, India for
providing financial assistance. The authors are grateful to Head,
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Med Chem Res (2013) 22:1660–1673
1673
RSIC, CDRI, Lucknow for providing 1H NMR, elemental analysis,
and mass spectral data. The technical assistance of Tina Ludwig,
Leipzig, is highly appreciated.
Krishnan VSH, Srinivasulu KC (2000) Facile synthesis of mono and
dialkoxy quinoxalines. Het Commn 6:333–338
Lee T, Robichaud AJ, Boyle KE, Lu Y, Robertson DW, Miller KJ,
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Lowe JA III (1994) Atypical antipsychotics based on the D2/5-HT2
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Conflict of interest The authors declare no conflict of interest.
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