Synthesis and preliminary pharmacological evaluation of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides as novel atypical antipsychotic agents

Article abstract of DOI:10.1016/j.bmcl.2008.10.035

A series of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized by either microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, ¹H NMR, and MS) and the purity was ascertained by microanalysis. All the synthesized compounds 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. AG 3 was found to be the most active compound.

Full text of DOI:10.1016/j.bmcl.2008.10.035

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6054–6057
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and preliminary pharmacological evaluation of
N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides
as novel atypical antipsychotic agents
a
b
a
K. V. G. Chandra Sekhar a, , V. S. Rao , D. Ravi Kumar Vyas , M. Murali Krishna Kumar
*
a Chemistry Group, Birla Institute of Technology & Science, FDIII, Vidya Vihar, Pilani, Rajasthan 333 031, India
b Pharmacy Group, Birla Institute of Technology & Science, FDIII, Vidya Vihar, Pilani, Rajasthan 333 031, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides were synthe-
sized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized by
either microwave irradiation technique or by conventional synthesis and were characterized by spectral
data (IR, 1H NMR, and MS) and the purity was ascertained by microanalysis. All the synthesized com-
pounds were screened for their in vivo pharmacological activity in Swiss albino mice. D2 antagonism stud-
ies were performed using climbing mouse assay model and 5-HT2A antagonism studies were performed
using quipazine induced head twitches in mice. It was observed that none of the new chemical entities
exhibited catalepsy. AG 3 was found to be the most active compound.
Received 8 May 2008
Revised 9 August 2008
Accepted 8 October 2008
Available online 11 October 2008
Keywords:
Atypical antipsychotics
Glycine
Ó 2008 Elsevier Ltd. All rights reserved.
D2 Antagonists
5-HT2A Antagonists
Chloroethylphenylthiazoles
Conventional neuroleptics or typical antipsychotics such as
chlorpromazine, haloperidol, and fluphenazine are recognized as
effective agents in the treatment of positive symptoms of schizo-
phrenia, namely hallucinations and delusions. However, they show
poor or no efficacy against negative symptoms1 (apathy, social
withdrawal), and their use is frequently associated with serious
side effects, such as extrapyramidal syndrome2 (EPS), tardive dys-
kinesia3 (TD), and hyperprolactinemia.4 All these compounds were
found to be antagonists at dopamine D2 receptors.5
The introduction of clozapine for the pharmacotherapy of schizo-
phrenia represented a significant advance in the treatment of this
devastating mental illness. Clozapine is superior to typical neurolep-
tics in treating positive and negative symptoms, and is effective in
many patients who are refractory to typical antipsychotics.6,7 In
addition, clozapine does not induce the EPS commonly caused by
the typical agents. Because of these properties, clozapine was
termed ‘atypical’ and represents the prototype drug of this class.
Although clozapine is the most efficacious antipsychotic currently
available, serious side effects induced by the drug, including agran-
ulocytosis, impose substantial limitations on its use.
asidone, sertindole, iloperidone, aripiprazole, amisulpride, and zote-
pine.8 In fact, there is growing evidence that, most of the new
medications can offer some advantages over ‘typical’ or first gener-
ation antipsychotics (FGAs) such as greater improvement in nega-
tive symptoms, cognitive impairment, relapse prevention and
quality of life with fewer EPS and less TD.9 However, these advanta-
ges have been regarded as incremental and not substantial. In addi-
tion, concerns about side effects such as EPS have been replaced by
other distressing side effects, such as weight gain, hyperglycemia,
postural hypotention, seizures, cardiac ventricular arrhythmias,
and dyslipidemia.10,11
The rationale for development of the antipsychotic drugs
recently introduced, and currently under development is predomi-
nantly based on dopamine and serotonin hypotheses of schizophre-
nia. Since this strategy has apparently not yielded an antipsychotic
as efficacious as clozapine, it is absolutely necessary to consider
other hypotheses of schizophrenia to guide alternative strategies
for the discovery of novel antipsychotic agents. In this regard, the
NMDA receptor hypofunction hypothesis of schizophrenia provides
an alternative strategy for the drug development.
Over the past two decades, much attention regarding the treat-
ment for schizophrenia has focused on this new class of antipsy-
chotic medications and led to the proliferation of ‘atypical’
antipsychotics, including risperidone, olanzapine, quetiapine, zipr-
In the etiology of schizophrenia NMDA receptors hypofunction
is also reported.12 It is also reported that agonists at this site will
alleviate the negative and cognitive symptoms.13 Hence in this
work compounds are designed incorporating NMDA agonism and
D2 antagonism so that both negative symptoms (including cogni-
tive) and positive symptoms can be cured. This way of targeting/
designing we attempt for the first time.
* Corresponding author.
E-mail address: kvgcs@yahoo.com (K.V.G.C. Sekhar).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.035

K. V. G. C. Sekhar et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6054–6057
6055
The strategy of Ariens, which was promulgated few years ago,
has been employed for the design of potential atypical antipsy-
chotic agents.14 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, which binds to the
accessory binding site adjacent to the agonist binding site and
transforms the agonist into an antagonist. Using this strategy the
current marketed drug ziprasidone was developed.15 We adopted
this strategy and employed glycine, a co-agonist, at the NMDA
receptor16 as one portion of the molecule.
We synthesised compounds in which 2- and 5-substituted chlo-
roethylphenylthiazoles (CEP: 1–7) have been incorporated at the
piperazinyl nitrogen atom of acetamido glycine piperazine looking
for NMDA agonism and D2 antagonism. Seven new compounds have
been synthesized and the synthetic schemes are illustrated in
Schemes 1–3. Scheme 1 illustrates synthesis of 2- and 5-substituted
chloroethylphenylthiazoles (CEP:1–7) whereas Scheme 2 illustrates
synthesis of acetamido glycine piperazine (P1) while Scheme3 illus-
trates coupling of these two fragments to yield the title compounds.
Substituted chloroethylphenylthiazoles (fragment 1) were pre-
pared as per the literature protocol with modifications in some
steps.17 Acetyl glycine required as starting material for fragment
2 was prepared by acetylating glycine at room temperature using
the literature protocol.18 Microwave irradiation of acetyl glycine
with anhydrous piperazine in the presence of DCC in DMF for
about 5 min gave acetamido glycine piperazine19 (P1). Equimolar
amounts of acetamido glycine piperazine (P1) and 2- and 5-substi-
tuted chloroethylphenylthiazoles (CEP: 1–7) 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.20 All the synthesized compounds were characterized
by spectral (IR, 1H NMR, and mass) and elemental analysis data.
Infrared spectral analysis of the final compounds (AG: 1–7) showed
strong peaks at ꢀ3440 cmÀ1 (NH stretch); ꢀ3050 cmÀ1 (aromatic
C–H stretch); ꢀ2870 cmÀ1 (aliphatic C–H stretch); ꢀ1645 cmÀ1
(CO stretch); ꢀ700 cmÀ1 (C–S–C stretch); ꢀ1620 cmÀ1 (aromatic
C@C stretch); ꢀ1640 cmÀ1 (C@N ring stretch); ꢀ1255 cmÀ1 (ali-
phatic C–N stretch); ꢀ810 cmÀ1 (para disubstituted benzene). In
1H NMR spectra, methylene protons (cyclic) adjacent to N1 nitro-
gen of piperazine showed triplet in the range of d 3.11–3.36
whereas methylene protons (cyclic) adjacent to N4 nitrogen of
piperazine showed triplet in the range of d 2.46–2.69. Methyl pro-
tons of the amide functionality appeared as singlet at d 2.12. The
labile proton on amide functionality appeared as a singlet at d
8.10. Methylene protons of glycine were seen as singlet at d 4.20.
The final compounds showed signals corresponding to four protons
Scheme 1.
Scheme 2.
Scheme 3.

6056
K. V. G. C. Sekhar et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6054–6057
around d 7.10–7.49 for the aromatic protons as a multiplet. PMR
signal corresponding to four protons of the ethyl linker was ob-
served at d 2.60–2.70 as multiplet. Elemental (CHNS) analysis indi-
cated that the calculated and observed values were within the
acceptable limits ( 0.4%). Physical data of final compounds is rep-
resented in Table 1.
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, 17.09.07). Swiss albino
mice (25–30 g) of either sex obtained from Hissar Agricultural Uni-
versity, Hissar, Haryana, India were used for the pharmacological
studies. Inhibition or reversal of Apomorphine induced cage-climb-
ing behavior in mice by a test compound is an indication of meso-
limbic dopaminergic D2 receptor antagonism.21
The effect of pretreatment with 10 mg/kg dose of the test com-
pounds on apomorphine (0.5 mg/kg sc) induced cage climbing
behavior was studied by the literature method.21 Haloperidol
(1.0 mg/kg ip) was used as control as it completely inhibited the
climbing induced by apomorphine. Inhibition or reversal of quip-
azine 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 meth-
od.22 Risperidone (0.6 mg/kg ip) was used as control as it completely
inhibits quipazine induced head twitches in mice. Cataleptic effect
of new chemical entities (NCEs) was evaluated by the literature
method 23 and scoring was done as per literature.24
In this study, we have demonstrated the synthesis and pharma-
cological activity of novel N-2-(4-(4-(2-substitutedthiazol-4-yl)
Table 1
Physical constants of N-2-{4-[4-(2-substitutedthiazol-4-yl)piperazin-1-yl]-2-oxoethyl} acetamides (AG: 1–7)
Compound
R
Z
Mp (°C)
% Yield
Recryst. solvent
Mol. formulaa (Mol. weight)b
AG 1
AG 2
AG 3
AG 4
AG 5
AG 6
AG 7
NH2
NHCH3
NH2
OH
CH3
H
H
146–147
182–183
200–202
189–200
192–194
208–209
182–184
61
67
83
84
48
50
48
DMF–H2O
EtOH
Acetone
MeOH
MeOH
DMF–H2O
DMF–H2O
C19H25N5O2S (387)
C20H27N5O2S (401)
C20H27N5O2S (401)
C19H24N4O3S (388)
C21H28N4O2S (400)
C21H29N5O2S (415)
C20H26N4O2S (386)
CH3
H
CH3
CH3
H
NHCH3
CH3
a
Elemental (CHNS) analysis indicated that the calculated and observed values were within the acceptable limits ( 0.4%).
Molecular weight determination by mass spectral analysis.
b
Table 2
Results of D2, 5-HT2A antagonism, and catalepsy test of compounds AG 1–7
Compound
% D2 inhibition (Mean SEM)
% 5-HT2A inhibition (Mean SEM)
Max. avg. cataleptic time (s)
Max. avg. cataleptic score
10th min
20th min
30th min
AG 1
AG 2
AG 3
AG 4
AG 5
AG 6
AG 7
Risperidone
85 10
60 10
65 6.12
50 10
90 6.12
60 10
60 10
65 6.12
80 9.35
85 6.12
70 12.25
22 5.5
16.74
16.54
8.71
3.67
5.12
3.89
4.62
2.54
0
0
0
0
0
0
0
0
54 5.29
79 2.78
80 6.90
71 6.26
67 2.78
20 6.43
70 12.25
75 9.35
65 6.12
70 12.25
70 12.25
65 6.12
65 6.12
65 6.12
70 12.25
65 6.12
91
5
91
5
90
5
100
0
Table 3
Summary of results of in vivo pharmacological studies of AG 1–7
Compound
% 5-HT2A inhibition
% Max. D2 inhibition
5-HT2A/D2 ratio
Max. avg. cataleptic score
AG 1
AG 2
AG 3
AG 4
AG 5
AG 6
AG 7
Risperidone
22 5.55
54 5.29
79 2.78
80 6.90
71 6.26
67 2.78
20 6.43
90 6.12
60 10
0.24444
0.90000
1.12857
1.06667
0.8875
0.78883
0.28572
1.09890
0
0
0
0
0
0
0
0
70 12.25
75 9.35
80 9.35
85 11.12
70 12.25
100
0
91
5

K. V. G. C. Sekhar et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6054–6057
6057
7. Kane, J.; Honigfeld, G.; Singer, J.; Meltzer, H. Arch. Gen. Psychiatry 1988, 45, 789.
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A. C.; Kruse, C. G. J. Med. Chem. 2007, 50, 5103.
piperazin-1-yl)-2-oxoethyl)acetamides (AG 1–7) as atypical anti-
psychotic agents. The results (Table 2) clearly indicate that all
the NCEs have the capability of antagonizing mesolimbic dopami-
nergic D2 receptors with% inhibition varying between 50% and 90%
at the dose level studied (10 mg/kg). A maximum of 90% inhibition
was observed in AG 1, while a minimum of 50% inhibition was ob-
served in AG 2. The capability of antagonizing central serotonergic
5-HT2A receptors varied between 20% and 80% at the dose level
studied (10 mg/kg). A maximum of 80% inhibition was observed
in AG 4, while a minimum of 20% inhibition was observed in AG
7. The results tabulated in Table 2 clearly indicate that the maxi-
mum average cataleptic score observed is 0 for the NCEs at dose le-
vel studied (10 mg/kg) indicating that all compounds are
noncataleptic. The overall results of title compounds are summa-
rized in Table 3. Compound AG 3 is the most active one among
the synthesized compounds with 5-HT2A/D2 ratio of 1.1286 and
an average cataleptic score of zero (risperidone’s 5-HT2A/D2 ratio
is 1.0989). Hence this compound, better than risperidone, satisfies
all the criteria required for a molecule to be atypical antipsychotic
according to Meltzer’s classification.25 Further studies in trans-
forming these agents into clinically useful agents are in progress
in our laboratory.
11. Tamminga, C. A. Can. J. Psychiatry 1997, 42, 265.
12. Goff, D. C.; Coyle, J. T. Am. J. Psychiatry 2001, 158, 1367.
13. Duncan, G. E.; Zorn, S.; Lieberman, J. A. Mol. Psychiatry 1999, 4, 418.
14. Ariens, E. J.; Beld, A. J.; Rodrigues, J. M. F.; Simonis, A. M.. In The Receptors: A
Comprehensive Treatise; O’Brien, R. D., Ed.; Plenum: New York, 1979; Vol. 1, p
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R.; Ewing, F. E.; Newman, M. E.; Schmidt, A. W.; Furman, J. S.; Robinson, G. L.;
Jackson, E.; Johnson, C.; Morrone, J. J. Med. Chem. 1996, 39, 143.
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Ewing, F. E.; Newman, M. E.; Schmidt, A. W.; Furman, J. S.; Vincent, L. A.;
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1860.
18. Brain, S. F.; Antony, J. H.; Peter, W. G.; Austin, R. T. Vogels Text Book of Practical
Organic Chemistry, 5th ed., 1989, p 1155.
19. N-(2-oxo-2-piperazin-1-ylethyl)acetamide (P1): % Yield: 86% (1.35 g); melting
point: 192 °C. IR (KBr) cmÀ1: 3360 (N–H stretch); 2850, 2735 (aliphatic C–H
stretch); 1642 (C@O stretch); 1250 (aliphatic C–N stretch). 1H NMR (CDCl3) (d)
ppm: 2.12 (s, 3H, COCH3); 2.45–2.63 (t, 4H, N4(CH2)2); 3.10–3.21 (t, 4H,
N1(CH2)2); 4.62(s, 2H, COCH2NH); 5.35 (s, 1H, NH); 6.35 (s, 1H, COCH2NH).
Mass (FAB, M+): Calcd: 185.112. Found: 185.1. Anal. (C8H15N3O2): Calcd C,
51.88; H, 8.16; N, 22.69. Found C, 51.62; H, 8.04; N, 22.47.
20. N-{2-[4-(4-(2-aminothiazol-4-yl)phenethyl)
piperazin-1-yl]-2-oxoethyl}
acetamide (AG 1): % Yield: 61% (0.117 g); melting point: 146–147 °C. IR (KBr)
cmÀ1: 3428 & 3400 (NH2 stretch); 3330 (NH stretch); 3037, 3018 (aromatic C–
H stretch); 2980, 2955 (aliphatic C–H stretch); 1645 (C@O stretch); 1641 (C@N
ring stretch); 1620, 1592 (aromatic C@C stretch); 1257 (aliphatic C–N stretch);
808 (para disubstituted benzene); 700 (C–S–C stretch). 1H NMR (CDCl3) (d)
ppm: 2.12 (s, 3H, COCH3); 2.55–2.62 (t, 4H, N4(CH2)2); 2.67–2.72 (m, 4H,
(CH2)2); 3.16–3.19 (t, 4H, N1(CH2)2); 3.84 (s, 2H, NH2); 4.25 (s, 2H, COCH2NH);
8.11 (s, 1H, COCH2NH); 6.92 (s, 1H, thiazole); 7.15–7.49 (m, 4H, Ar-H). Mass
(FAB, M+): Calcd: 387.197. Found: 387.21. Anal. (C19H25N5O2S): Calcd C, 58.89;
H, 6.50; N, 18.07; S, 8.27. Found C, 58.62; H, 6.26; N, 17.97; S, 7.99.
21. Costall, B.; Naylor, R. J.; Nohria, V. Eur. J. Pharmacol. 1978, 50, 39.
22. Malick, J. B.; Doren, E.; Barnett, A. Pharmacol. Biochem. Behav. 1977, 6, 325.
23. Costall, B.; Naylor, R. J. Eur. J. Pharmacol. 1974, 27, 46.
Acknowledgment
Sincere thanks are due to UGC, New Delhi, India for providing
financial assistance.
References and notes
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