Benzo[d][1,3] oxathiols: Synthesis and biological evaluation as potential atypical antipsychotic agents

Article abstract of DOI:10.1007/s00044-009-9278-5

The present research paper reports the synthesis and biological evaluation of 6-(3-substitutedpropoxyl) benzo[d][1,3]oxathiol-2-ones as potential atypical antipsychotic agents. Accordingly, 10 derivatives with either amino or aryloxy substituents were synthesized. Potential antipsychotic activity of these compounds in terms of D₂ antagonism was evaluated by their ability to inhibit apomorphine-induced climbing behavior in mice and 5-HT₂ antagonistic activity of synthesized compounds was assessed by studying inhibition of 5-HTP-induced head twitches. Non-specific D₂ blockade was evaluated by studying propensity of these compounds to produce catalepsy in mice. All the synthesized compounds were found to exhibit D₂ and 5-HT₂ antagonist activity in behavioral models. However, they also induced mild to severe catalepsy. Among the 10 compounds tested, 5b and 5e exhibited maximum 'atypical antipsychotic activity like' profile. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-009-9278-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:29–35
DOI 10.1007/s00044-009-9278-5
ORIGINAL RESEARCH
Benzo[d][1,3] oxathiols: synthesis and biological evaluation
as potential atypical antipsychotic agents
•
Radha Charan Dash Mugdha R. Suryawanshi
•
•
Suhas M. Shelke Sharad H. Bhosale
•
Kakasaheb R. Mahadik
Received: 5 May 2009 / Accepted: 3 December 2009 / Published online: 24 December 2009
Ó Springer Science+Business Media, LLC 2010
Abstract The present research paper reports the syn-
thesis and biological evaluation of 6-(3-substitutedprop-
oxyl)benzo[d][1,3]oxathiol-2-ones as potential atypical
antipsychotic agents. Accordingly, 10 derivatives with
either amino or aryloxy substituents were synthesized.
Potential antipsychotic activity of these compounds in
terms of D2 antagonism was evaluated by their ability to
inhibit apomorphine-induced climbing behavior in mice
and 5-HT2 antagonistic activity of synthesized compounds
was assessed by studying inhibition of 5-HTP-induced
head twitches. Non-specific D2 blockade was evaluated by
studying propensity of these compounds to produce cata-
lepsy in mice. All the synthesized compounds were found
to exhibit D2 and 5-HT2 antagonist activity in behavioral
models. However, they also induced mild to severe
catalepsy. Among the 10 compounds tested, 5b and 5e
exhibited maximum ‘atypical antipsychotic activity like’
profile.
remains a top priority as it affects approximately 1% of the
world population (Taverne et al., 1998). Schizophrenia is a
chronic and severe disabling mental illness independent of
sex, location, social class, or color of the skin (Evans et al.,
2003). Active psychosis was ranked the third-most-dis-
abling condition, after quadriplegia and dementia and
before paraplegia and blindness (Aaron and David, 2004).
Although the pathophysiology of schizophrenia has not
been fully established, dysfunction of dopamine neurotrans-
mittersystem withinthebrainis believed to play a vital role in
symptoms expression and neuropsychological dysfunction of
the illness (Ross and Ramsay, 2002). Since 1950s classical
neuroleptic better known as typical antipsychotic such as
chlorpromazine and haloperidol, which are potent dopamine
D2 receptor antagonists have provide clear efficacy against
positive symptoms of schizophrenia (Navas et al., 1998).
However, these drugs are relatively ineffective in the treat-
ment of negative symptoms of the disease and also chronic
administration of these drugs is frequently associated with
serious extra pyramidal side effects (EPS) (Martin, 1997).
The discovery of newer atypical antipsychotic agents
such as clozapine and olanzapine are focused on mixed
dopamine D2 and serotonin 5-HT2 antagonist. Meltzer has
postulated that mixed D2/5-HT2 antagonist that exhibit
high affinity for 5-HT2 receptor and moderate affinity for
D2 receptor are more likely to have good antipsychotic
activity, treating positive as well as negative symptoms of
schizophrenia with lower potency to produce EPS (Meltzer
et al., 1989). Limitation of these atypical antipsychotics
include substantial weight gain, agranulocyctosis, blood
dyscrasias, and hyperglycemia on chronic medication
(Wirshing et al., 1999; Lieberman et al., 1988; Lowe et al.,
1991; Ravin and Masaguer, 2001). With a high refractive
treatment incidence and low compliance due to tolerability,
the search continues for novel atypical antipsychotics that
Keywords Antipsychotic ꢀ
6-(3-Substitutedpropoxyl)benzo[d][1,3]oxathiol-2-one ꢀ
Climbing behavior ꢀ Head twitches ꢀ Catalepsy
Introduction
The discovery of new effective drugs for the treatment of
the psychiatric disorders such as schizophrenia still
R. C. Dash ꢀ M. R. Suryawanshi ꢀ S. M. Shelke ꢀ
S. H. Bhosale (&) ꢀ K. R. Mahadik
Department of Pharmaceutical Chemistry, Poona College of
Pharmacy, Bharati Vidyapeeth University, Pune 411038, India
e-mail: dr_shbhosale@rediffmail.com
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Med Chem Res (2011) 20:29–35
have a better balance between efficacy and side effect
profile to treat this complex disease.
For last few years, our research group has been actively
working on exploring new lead molecules as potential
antipsychotics. Previously in our laboratory 7-[3-(substi-
tuted amino)propoxyll]-4-methylchromen-2-one a (Aparna
et al., 2005), coumarinoacetamide b (Bhosale et al., 2006),
and 7-[4-(substituted phenylpiperazin-1-yl)-alkoxyl]-4-
methylchromene-2-one c (Shelke et al., 2005) derivatives
were synthesized and reported as potential antipsychotic
agents (Fig. 1).
Fig. 2 6-Substituted-benzo[d][1,3]oxathiol-2one d as chemical bio-
isoter of 7-substituted-4-methyl chromen-2-one e
IR spectrum of synthesized compounds was recorded on
1
Jasco V-5300 FT-IR in potassium bromide disks. The H
As a continuation of our work on antipsychotic agents
that interact with D2 and 5HT2 receptors, we hereby report
synthesis and prepharmacological evaluation of 6-substi-
tuted-benzo[d][1,3]oxathiol-2-one as novel potential anti-
psychotic agents. As benzo[d] [1,3]oxathiol-2one d is the
chemical bio-isoster of 4-methylchromen-2-one e as shown
in Fig. 2, it was hypothesized that the present molecule
may exhibit potential antipsychotic profile.
NMR spectrum was recorded using NMR Varian Mercury
300 MHz using trimethyl silane (TMS) as internal
standard.
The title compound 6-(3-substituted propoxyl)-benzo
[d][1,3]oxathiol-2one was synthesized in four-step process
as per Scheme 1. The various derivatives synthesized are
illustrated in Table 1.
Methods and materials
Synthesis of 2-iminobenzo[d][1,3]oxathiol-6-ol 2
Chemistry
Solution of potassium thiocyanate (20 g, 0.41 mol) in
water (25 ml) was added while stirring at room tempera-
ture to a solution of resorcinol (5.5 g, 0.5 mol) and crys-
tallized copper sulfate (25 g, 0.15 mol) in water (125 ml).
The black precipitate initially formed during stirring
became colorless. The precipitate was then filtered and the
filtrate was mixed with 2-N sodium carbonate solution
(25 ml) to yield compound 2 as colorless crystals.
All the chemicals used in the synthesis were procured from
Qualigen and purified prior to use. The completion of
reaction was monitored by thin layer chromatography
performed on Merck precoated silica gel F254 plates. The
melting points were determined by open capillary method
on Campbel electronic apparatus and are uncorrected. The
Fig. 1 Previously synthesized
antipsychotic compounds by
a Aparna et al. (2005)
b Bhosale et al. (2006) c Shelke
et al. (2005)
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Med Chem Res (2011) 20:29–35
31
Scheme 1 Synthetic protocol
for title compound. a KSCN,
CuSO4, H2O; b 10% Hcl;
c Br–(CH2)3–Cl, K2CO3,
CH3CN; d sec amine/phenol,
K2CO3, CH3CN. For R: refer
Table 1
Table 1 Synthesized derivatives with biological evaluation results
Compound
R
Percentage inhibition
of climbing behaviora
Percentage inhibition
of head twitchesb
% Catalepsy
inductionb
5a
Piperidinyl
51.20
69.58
53.28
62.33
69.96
46.95
39.03
49.33
52.44
67.26
62.36
67.32
71.47
63.39
68.24
79.28
61.15
58.27
77.93
77.32
80.01
80.19
41.00
39.27
37.11
42.39
36.98
41.22
49.21
33.71
39.48
43.92
29.34
5b
Morpholinyl
5c
Diethylamino
Piperazinyl
5d
5e
1,2,4-Triazolyl
Naphthalen-2-yloxy
Naphthalen-1-yloxy
4-Chlorophenoxy
p-Tolyloxy
5f
5g
5h
5i
5j
4-Nitrophenoxy
Aripiprazoleb
P \ 0.05, number of animals, n = 6
a
60 mg/kg
b
25 mg/kg
Yield: 7.0 g (84%), mp: 149°C, molecular formula:
C7H5NO2S (167), elemental analysis: calcd. C 50.29, H
3.01, N 8.38, O 19.14, S 19.18; found C 50.15, H 2.96, N
8.24, O 19.44, S 19.21. IR mmax (cm-1) (KBr): 3411, 3384,
3022, 1706, 1654, 1226.
O 28.54, S 19.07; found C 49.78, H 2.36, O 28.59, S 19.27.
1
IR mmax (cm-1) (KBr): 3410, 3016, 1700, 1215, 1030. H
NMR (d ppm; CDCl3): 6.8 (s, 1H, C7–H), 6.73, and 6.71
(d, 2H, C4–H, and C5–H), 5.21 (s, 1H, OH).
Synthesis of 6-(3-chloropropoxyl)benzo[d][1,3]oxathiol-2-
one 4
Synthesis of 6-hydroxybenzo[d][1,3]oxathiol-2one 3
A solution of 2 (5.01 g, 0.03 mol) in 10% hydrochloric
acid (50 ml) was heated for 15 min on the steam bath.
Compound 3 separated on cooling in the form of fine
crystals (Werner, 1943).
A mixture of 3 (2.83 g, 0.017 mol), 1-bromo-3-chloro-
propane (2.5 ml, 0.025 mol) and anhydrous K2CO3 (3.5 g,
0.025 mol) in acetonitrile (30 ml) was refluxed for 24 h.
The solvent was removed under vacuum. The residue was
dissolved in methylene dichloride and washed with water
and latter with 5% NaOH solution. The organic layer was
Yield: 4.5 g (89%), mp: 158°C, molecular formula:
C7H4O3S (168), elemental analysis: calcd. C 49.99, H 2.40,
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Med Chem Res (2011) 20:29–35
6-[3-(Diethylamino)propoxyl]benzo[d][1,3]oxathiol-2-
one 5c
then washed with water and dried overnight on anhydrous
sodium sulfate. Methylene dichloride was removed under
vacuum to afford residue. The residue was recrystallized
from ethanol to furnish 4.
Yield: 2.92 g (52%), mp: 84°C, molecular formula:
C14H17NO4S (281), elemental analysis: calcd. C 59.76, H
6.81, N 4.98, O 17.06, S 11.40; found C 59.68, H 6.77, N
4.81, O 17.38, S 11.36. IR mmax (cm-1) (KBr): 3073, 2941,
Yield: 2.63 g (63%), mp: 74°C, molecular formula:
C10H9ClO3S (244), elemental analysis: calcd. C 49.08, H
3.71, Cl 14.49, O 19.62, S 13.10; found C 49.28, H 3.59, Cl
14.41, O 19.43, S 13.23. IR mmax (cm-1) (KBr): 3040,
1
1710, 1406. H NMR (d ppm, DMSO d6): 6.81(s, 1H, C7–
1
H), 6.71 (d, 2H, C4–H, and C5–H), 4.15 (t, 2H, –OCH2),
3.81 (t, 2H, –CH2CH2N–), 3.72 (q, 4H, NCH2–), 2.87 (m,
2H, –CH2–), 1.6(t, 6H –CH3).
2979, 1734, 1471, 1150, 1035. H NMR (d ppm; CDCl3):
6.8 (s, 1H, C7–H), 6.73 (d, 2H, C4–H, and C5–H), 4.15 (t,
2H, –OCH2), 3.80 (t, 2H, –CH2Cl), 2.24 (m, 2H, –CH2–).
General method of synthesis for compounds 5a–5e
6-[3-(Piperazin-1-yl)propoxyl]benzo[d][1,3]oxathiol-2-
one 5d
A mixture of 4 (4.88 g, 0.02 mol), appropriate sec amine
(0.02 mol) and anhydrous K2CO3 (3.50 g, 0.025 mol) was
added to the reaction flask and refluxed in acetonitrile for
18 h. The reaction mixture was filtered and the filtrate was
concentrated under vacuum. The residue was dissolved in
methylene dichloride. The solution was washed with water
and then with 10% HCl. The organic layer was then
washed again with water and dried overnight on anhydrous
sodium sulfate. Methylene dichloride was removed under
vacuum to afford residue. The residue was then recrystal-
lised from ethanol–water to yield the desired compound.
Yield: 3.82 g (65%), mp: 126°C, molecular formula:
C14H18N2O3S (294), elemental analysis: calcd. C 57.12, H
6.16, N 9.52, O 16.31, S 10.89; found C 57.08, H 6.12, N
9.47, O 16.47, S 10.86. IR mmax (cm-1) (KBr): 3290, 3018,
2964, 1720, 1587, 1410. H NMR (d, ppm, DMSO d6):
9.36 (s, 1H, NH), 6.81(s, 1H, C7–H), 6.71 (d, 2H, C4–H,
1
and C5–H), 4.15 (0t, 2H, –OCH2), 3.84 (t, 2H, –CH2CH2N–
0
0
), 3.75 (m, 4H C2 –H, and C6 –H), 3.73(m, 4H C3 –H, and
0
C5 –H), 2.87 (m, 2H, –CH2–).
6-[3-(4H-1,2,4-Triazol-4-yl)propoxyl]benzo[d][1,3]
oxathiol-2-one 5e
6-[3-(Piperidin-1-yl)propoxyl]benzo[d][1,3]oxathiol-2-
one 5a
Yield: 3.21 g (58%), mp: 133°C, molecular formula
C12H11N3O3S (277), elemental analysis: calcd. C 51.98, H
4.00, N 15.15, O 17.31, S 11.56; found C 51.91, H 3.86, N
15.11, O 17.63, S 11.49. IR mmax (cm-1) (KBr): 3080,
2964, 1728, 1427, 1392,1379, 1188. 1H NMR (d ppm,
DMSO d6): 6.80 (s, 1H, C7–H), 6.73 (d, 2H, C4–H, and
C5–H), 4.15 (t, 2H, –OCH2), 3.86 (t, 2H, –CH2N), 3.25 (s,
Yield: 3.28 g (56%), mp: 92°C, molecular formula:
C15H19NO3S (293), elemental analysis: calcd. C 61.41, H
6.53, N 4.77, O 16.36, S 10.93, found C 61.27, H 6.78, N
4.69, O 16.48, S 10.78. IR mmax (cm-1) (KBr): 3017, 2941,
1720, 1423, 1150, 1045. H NMR (d ppm; DMSO-d6):
6.81(s, 1H, C7–H), 6.73 (d, 2H, C4–H, and C5–H), 4.16 (t,
1
2H, –OCH2–), 3.89 (t, 2H, –CH2CH2N–), 1.63 (m, 6H,
0
0
0
0
0
0
0
2H, C3 –H, and C5 –H), 2.85 (m, 2H, –CH2–).
C3 –H, C4 –H, C5 –H), 2.65 (t, 4H, C2 –H, and C6 –H), 2.85
(m, 2H, –CH2–).
General method of synthesis of compounds 5f–5j
6-[3-(Morpholin-4-yl)propoxyl]benzo[d][1,3]oxathiol-2-
one 5b
A mixture of 4 (4.88 g, 0.02 mol), appropriate phenol
(0.02 mol), and anhydrous K2CO3 (3.50 g, 0.025 mol) was
refluxed in acetonitrile for 36 h. The reaction mixture was
filtered and concentrated under vacuum, residue dissolved
in methylene dichloride and washed with water and then
with 5% NaOH. Organic layer was again washed with
water and dried over anhydrous sodium sulfate. The filtrate
was concentrated under vacuum to provide crude solid. It
was than recrystallised from absolute ethanol to yield
desired compound.
Yield: 3.24 g (55%), mp: 98°C, molecular formula:
C14H17NO4S (295), elemental analysis: calcd. C 56.93, H
5.80, N 4.74, O 21.67, S 10.86; found. C 57.09, H 5.91, N
4.67, O 21.67, S 10.66. IR mmax (cm-1) (KBr): 3006, 2953,
1734, 1440, 1355, 1045. H NMR (d ppm; DMSO-d6):
6.81(s, 1H, C7–H), 6.73 (d, 2H, C4–H, and C5–H), 4.15 (t,
1
0
0
2H, –OCH2–), 4.02 (t, 4H, C2 –H, and C6 –H), 3.87 (t, 2H,
0
0
–CH2CH2N–), 3.81 (t, 4H, C3 –H, and C5 –H), 2.85 (m,
2H, –CH2–).
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33
6-[3-(Naphthalen-1-yloxy)propoxyl]benzo[d]
[1,3]oxathiol-2-one 5f
6-[3-(4-Nitrophenoxy)propoxyl]benzo[d][1,3]oxathiol-2-
one 5j
Yield: 2.81 g (40%), mp: 130°C, molecular formula:
C20H16O4S (352), elemental analysis: calcd. C 68.16, H
4.58, O 18.16, S 9.10; found C 68.09, H 4.51, O 18.34, S
9.06. IR mmax (cm-1) (KBr): 3107, 2943, 1709, 1402, 1070.
Yield: 2.91 g (42%), mp: 111°C, molecular formula:
C16H13NO6S (347), elemental analysis: calcd. C 55.33, H
3.77, N 4.03, O 27.64, S 9.23; found C 55.28, H 3.61, N
4.17, O 27.66, S 9.28. IR mmax (cm-1) (KBr): 3000, 2933,
1
1
0
H0 NMR (d ppm, CDCl3): 7.73 (s, 1H, C8 –H), 7.65 (d, 1H,
1751, 1505, 1539. H NMR (d, ppm, CDCl3): 8.11 (d, 2H,
0
0
0
0
0
0
C2 –H), 7.042 (t, 1H, C5 –H), 7.31 (t, 1H, C6 –H), 7.08–7.14
C3 –H, and C5 –H), 7.22 (d, 2H, C2 –H, and C6 –H), 6.87
(d, 1H, C4–H), 6.83 and 6.81 (d, 2H, C5–H, and C7–H),
4.15 (d, 2H, C1–H), 4.00 (t, 2H, –CH2O), 2.29 (m, 2H, m,
2H, –CH2–).
0
0
(d, 3H, C3 –H, C4 –H, and C7 –H), 6.84 (s, 1H, C7–H), 6.73
(d, 2H, C4–H, and C5–H), 4.15 (t, 2H, –OCH2), 4.02 (t, 2H,
–CH2O), 2.24 (m, 2H, –CH2–).
Biological activity
6-[3-(Naphthalen-2-yloxy)propoxyl]benzo[d]
[1,3]oxathiol-2-one 5g
Experimental groups
Yield: 3.02 g (43%), mp: 128°C, molecular formula:
C20H16O4S (352), elemental analysis: calcd. C 68.16, H
4.58, O 18.16, S 9.10; found C 68.21, H 4.55, O 18.23,
S 9.01. IR mmax (cm-1) (KBr): 2998, 2953, 1709,
Adult male albino mice (22 2 g) were used in this study.
They were housed in a quiet and temperature-controlled
room (25 3°C) with 12-h light/dark cycle. Food and
water were made freely available to the animals during the
study. Six animals were housed in each cage. Assays were
carried out at the same time of the day so as to avoid
variation due to circadian rhythms. For behavioral study
mice were divided into three groups—control, standard,
and test each with six animals. Methyl cellulose was used
for preparing suspension of drugs in water for injection
(WFI). Route of administration was i.p except wherever
mentioned. Aripiprazole was used as reference compound.
All the 10 compounds showed maximum inhibition of
climbing behavior at the dose 60 mg/kg. This dose was
selected for further study.
1
0
1425,1216. H NMR (d ppm, CDCl3): 08.15 (t, 1H, C3 –
0
H)0, 7.72 (t, 1H, C6 –H), 7.47 (t, 1H, C7 –H), 7.45 (d, 1H,
0
C1 –H), 7.39 (d, 1H, C8–H), 7.27 (d, 1H, C5 –H), 7.22 (d,
0
1H, C4 –H), 6.87 (d, 1H, C4–H), 6.81 (d, 2H, C5–H, and
C7–H), 4.15 (t, 2H, –OCH2), 4.01 (t, 2H, –CH2O), 2.29
(m, 2H, –CH2–).
6-[3-(4-Chlorophenoxy)propoxyl]benzo[d][1,3]oxathiol-2-
one 5h
Yield: 3.97 g (59%), mp: 112°C, molecular formula:
C16H13ClO4S (337), elemental analysis: calcd. C 57.06, H
3.89, Cl 10.53, O 19.00, S 9.52; found C 57.11, H 3.78, Cl
10.51, O 19.11, S 9.49. IR mmax (cm-1) (KBr): 3004, 2973,
Inhibition of climbing behavior
1
1700, 14508, 1367, 1201. H NMR (d, ppm, CDCl3):08.16
Ability of compound to inhibit apomorphine-induced
climbing behavior is an index of its D2-antagonism and
hence of potential antipsychotic activity.
0
0
(d, 2H, C3 –H, and C5 –H), 7.33 (d, 2H, C2 –H, and C6 –H),
6.87 (d, 1H, C4–H), 6.83 (d, 2H, C5–H, and C7–H), 4.15 (t,
2H, –OCH2), 3.98 (t, 2H, –CH2O), 2.31 (m, 2H, –CH2–).
Climbing behavior was assessed in the animals by
placing them individually in cylindrical wire mesh cage
(height 18 cm, diameter 14 cm). Animals given control
saline injections remained on the floor of cylinder,
exhibiting normal exploratory behavior, while animal
given apomorphine (1.0 mg/kg; s.c) climbed up the walls
of the cylinders holding onto the wire mesh with their
paws. Test or reference compound was given 30 min
before administration of apomorphine. Climbing behavior
was assessed at 5-min intervals for 30 min, starting from
5 min after apomorphine administration (Kesten et al.,
1999).
6-[3-(p-Tolyloxy)propoxyl]benzo[d][1,3]oxathiol-2-one 5i
Yield: 3.47 g (55%), mp: 105°C, molecular formula:
C17H16O4S (316), elemental analysis: calcd. C 64.54, H
5.10, O 20.23, S 10.13; found C 64.41, H 5.03, O 20.46, S
10.10. IR mmax (cm-1) (KBr): 3371, 3078, 2920, 1720,
1
0
1427, 1361. H NMR (d, ppm, CDCl3): 8.07 (d, 2H, C3 –H,
0
0
0
and C5 –H), 7.24 (d, 2H, C2 –H, and C6 –H), 6.87 (d, 1H
C4–H), 6.84 and 6.81 (d, 2H, C5–H, and C7–H), 4.18 (d,
2H, –OCH2), 3.99 (t, 2H, –CH2O), 2.27 (m, 2H, –CH2–),
2.38 (m, 3H, –CH3).
Data was expressed as percentage inhibition of climbing
behavior relative to control group (Table 1).
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Antagonism of head twitches
The important thing of interest in the preliminary
pharmacological screening was to determine the propensity
of the synthesized compounds to cause side effects in terms
of catalepsy. All the synthesized compounds displayed
dose-dependent cataleptic activity from mild to severe,
probably because of blockade of D2 receptors in the
nigrostriatal region. This could be considered as the
reflection of probable EPS they may induce in humans.
Effect of morpholine, diethylamine substitution on the
carbazole nucleus has been reported for D2 and 5HT2
antagonist activities (Masaguer et al., 2000). Effect of aryl
piperazine substitution on bezothiazolin-2-one has been
evaluated for D2 and 5HT2 antagonist activities (Taverne
et al., 1998). We have selected these substituents in the
amine series.
Antagonism of head twitches induced by L-5-hydroxytry-
ptophan (5-HTP) in mice indicates 5-HT2 antagonistic
activity. Carbidopa (25 mg/kg) was administered 20 min
after drug followed by administration of 5-HTP (100 mg/
kg) after 30 min. The numbers of head twitches were
counted for a period of 5 min after 20 min (Kim et al.,
1999). Data was expressed as percentage inhibition of head
twitches relative to control group (Table 1).
Catalepsy induction
Induction of catalepsy by compound is a reflection of its
ability to cause EPS in humans. 20 min after drug
administration, mouse was placed on a horizontal bar
(2 mm in diameter) kept at a height of 2.5 cm from the
platform, with its hind paws resting on the platform. The
time span for which the mouse retained its forepaws on
the horizontal bar during observation period of 5 min was
recorded (Khisti et al., 1998). Data was expressed as per-
centage induction with respect to control group.
Thus, we investigated the effects of the changes in the
secondary amine groups in the lead compound [5a–5e], the
alicyclic group, such as piperidine [5a], morpholine [5b],
piperazine [5d], diethyl amine [5c], and deactivated aro-
matic group 1,2,4-triazole [5e], on the inhibition of
climbing behavior [D2 antagonism]. Surprisingly the
triazolo-substituted derivate showed more effect than the
alicyclic groups piperidine, piperazine, and morpholine,
whereas the diethyl amine derivative showed the decreased
effect. Similar trend was observed on the inhibition to the
head twitches [5HT2 antagonism]. In catalepsy induction
model, the triazolo and diethyl amine derivatives displayed
least induction followed alicyclic amine derivatives. Thus,
all the derivatives in amine series exhibited significant D2
and 5-HT2 antagonistic activity, although, at higher dose
than the standard drug aripiprazole. However, all the
derivatives in amine series exhibited slightly increased
catalepsy induction as compared to aripiprazole.
Statistical analysis
All the biological data was analyzed using one-way
ANOVA. If the overall F ratio was significant, post hoc
comparison was carried out by Dunnett’s test. P value of
less than 0.05 was considered statistically significant.
Result and discussion
Next, keeping the 6-propyoxyl-benzo[d][1,3]oxathiol-2-
one moiety in the lead compound, changes in the aryl ether
were investigated. In this series, 4-substituted phenyl
derivatives were found to be more active than naphthyl
derivatives with respect to D2 and 5-HT2 antagonistic
activity. Interestingly again deactivated aromatic ring,
p-nitro derivative [5j] showed maximum D2 and 5-HT2
antagonism effect. In catalepsy induction test, p-chloro-
phenyl derivative displayed least catalepsy induction,
whereas all other derivatives in this series exhibited cata-
lepsy induction in the same range. Thus, it is evident that
derivatives in the ether series showed considerable D2 and
5-HT2 antagonistic activity, again at higher dose than ari-
piprazole. Derivatives in this series too displayed increased
catalepsy induction.
The aim of the undertaken research work is to make an
effort in the direction of synthesizing molecules with an
atypical antipsychotic like D2 and 5-HT2 antagonist
activity. Efforts were focused upon compounds possessing
a pharmacological profile suggestive of significant anti-
psychotic activity and minimal induction of extrapyramidal
side effects.
To evaluate the D2 antagonist activity, inhibition of
climbing behavior in mice induced by apomorphine was
used as a model. Since apomorphine being dopamine
agonist, inhibition of climbing induced by it could give
idea regarding the D2 antagonist activity of the test com-
pound which is supposed to be direct reflection of its
antipsychotic potential. 5-HT2 antagonistic activity is one
of the main features of atypical antipsychotics. As 5-HTP is
used as precursor of serotonin which acts as non-selective
agonist for serotonin receptor, inhibition of 5-HTP-induced
head twitches can be regarded as a hint for 5-HT2 antag-
onist activity.
In summary, from the combined results including inhi-
bition of climbing behavior [D2 antagonism], inhibition of
head twitches [5HT2] antagonism, and catalepsy induction,
compound 5e 6-[(1,2,4-triazololyl-propyloxyl)]benzo[d]
[1,3]oxathiol-2-one from secondary amine series and 5j
123

Med Chem Res (2011) 20:29–35
35
Kim SH, Rhee GS, Oh S, Park WK (1999) NMDA receptor
antagonists inhibit apomorphine-induced climbing behavior not
only in intact mice but also in reserpine-treated mice. Behav
Brain Res 100:135–142
6-[(4-nitrophenyl)-propyloxyl)]benzo[d][1,3]oxathiol-2-one
from the ether series can be considered as lead compounds
Lieberman JA, Johns CA, Kane JM, Rai K, Pisciotta AV, Saltz BL,
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Conclusion
Our studies suggest that all the 6-substituted-benzo[d]-
[1,3]oxathiol-2-one derivatives showed significant D2 and
5-HT2 antagonist activity in behavioral models, an activity
profile attributed to atypical antipsychotic agents. Thus,
this research work has furnished a novel molecule with
potential antipsychotic activity. However, the compounds
under investigation suffered from a drawback of catalepsy
induction in rodents, likely because of non-specific D2
blockade. All the synthesized compounds were found to be
less active than the reference drug aripiprazole. Neverthe-
less, taking into consideration ‘atypical antipsychotic like’
activity profile of the synthesized compounds, it will be
interesting to investigate this lead molecule further. Thus,
to improve the activity of this molecule, further research is
in progress at our laboratory.
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