Synthesis and antidepressant-like activity evaluation of sulphonamides and sulphonyl-hydrazones

Article abstract of DOI:10.1016/j.bmc.2011.05.056

In this study a series of sulphonamides and sulphonyl hydrazones of maleimide, naphthalimide and phthalimide derivatives was synthesized. The antidepressant effect of these compounds was evaluated by the forced-swimming test in mice. The behavioural parameter observed in this test is a reduction in the immobility time, which is indicative of antidepressant activity. All compounds, except 8, 11 and 24, were active as antidepressants. The most active compound was the sulphonyl-hydrazone 10 which showed an activity of around 72.02% at 60 mg/kg, it thus being more active than imipramine (10 mg/kg, ip), a commercial antidepressant. Other important results were obtained for the benzylnaphthalimide derivatives, the sulphonamides 21 and 22 showing activity of 64% at 10 mg/kg, also being more active than imipramine. These results indicate that the sulphonamides and sulphonyl-hydrazone cyclic imide derivatives are potential compounds for use in the designing of new candidates for the treatment of depression.

Full text of DOI:10.1016/j.bmc.2011.05.056

Bioorganic & Medicinal Chemistry 19 (2011) 4295–4306
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and antidepressant-like activity evaluation of sulphonamides
and sulphonyl-hydrazones
Kely Navakoski de Oliveira a, Philipe Costa b, José Roberto Santin b, Leonor Mazzambani b,
Cristiani Bürger b, Cristiano Mora a, Ricardo José Nunes a, Márcia Maria de Souza b,
⇑
a Departamento de Química, Universidade Federal de Santa Catarina, UFSC, Florianópolis, CCS/PMCF/UNIVALI, 88302-202, Itajaí, SC, Brazil
b Centro de Ciências da Saúde, CCS, Programa de Mestrado em Ciências Farmacêuticas/UNIVALI, Itajaí, SC, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study a series of sulphonamides and sulphonyl hydrazones of maleimide, naphthalimide and
phthalimide derivatives was synthesized. The antidepressant effect of these compounds was evaluated
by the forced-swimming test in mice. The behavioural parameter observed in this test is a reduction in
the immobility time, which is indicative of antidepressant activity. All compounds, except 8, 11 and
24, were active as antidepressants. The most active compound was the sulphonyl-hydrazone 10 which
showed an activity of around 72.02% at 60 mg/kg, it thus being more active than imipramine
(10 mg/kg, ip), a commercial antidepressant. Other important results were obtained for the benzylnaph-
thalimide derivatives, the sulphonamides 21 and 22 showing activity of 64% at 10 mg/kg, also being more
active than imipramine. These results indicate that the sulphonamides and sulphonyl-hydrazone cyclic
imide derivatives are potential compounds for use in the designing of new candidates for the treatment
of depression.
Received 3 March 2011
Revised 20 May 2011
Accepted 25 May 2011
Available online 31 May 2011
Keywords:
Antidepressant effect
Sulphonamides
Sulphonyl-hydrazones
Cyclic imides
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Depression is one of the most prevalent psychopathologies in
the Western world.1 It is characterized by anhedonia or the loss
of interest or pleasure in normal daily activities and feelings of sad-
ness.2 Additional symptoms may include feelings of guilt or low
self-worth, disturbed sleep or appetite, low energy, etc. In its worst
form it can lead to suicide.3 The high prevalence of suicide in de-
pressed patients (up to 15%) coupled with complications arising
from stress and its effect on the cardiovascular system have sug-
gested, that it will become the second leading cause of premature
death or disability worldwide by the year 2020.3
Its therapy relies on classical antidepressant drugs such as
monoamine oxidase inhibitors and drugs that inhibit the reuptake
of catecholamines.4 A common problem with the current antide-
pressant therapies is the several side effects (e.g., anti-cholinergic,
gastrointestinal distress, anxiety, insomnia and sexual dysfunc-
tion) produced by these drugs besides their slow onset of action
since there is a delay of about 4 weeks to alleviate the symptoms
of depression.5 In addition, a significant proportion of these pa-
tients will not respond to treatment, or will show only partial re-
sponse. Clinical limitations and adverse effects of currently used
antidepressants consequently, there is a need for faster, more
Figure 1. Cyclic imide derivatives active as antidepressants.
effective, therapeutic treatments with less side effects, in order
to limit the impact of depression on patients’ lives.6
In this regard, the cyclic imides and their derivatives have
played an important role in the treatment of psychopathologies
such as anxiety, schizophrenia, epilepsy and depression.7–12 The
tandospirone13 and NAN-190 (Fig. 1),14,15 for example, exert
⇑
Corresponding author. Tel.: +55 47 3341 7932x8066.
E-mail address: msouza@univali.br (M.M. de Souza).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.05.056

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antidepressant activity by inhibition of 5-HT1A receptors. More-
over, the promising antidepressant activity of sulphonamides16
and hydrazones17 has been reported in the literature, as well as
the sulphonylaziridines10 (Fig. 1). The presence of groups such as,
cyclic imides, sulphonyl and amines encouraged us to synthesize
and evaluated a series of sulphonamides and sulphonyl-hydra-
zones cyclic imide derivatives as part of our investigation work.
In this study, these compounds were tested in mice using the
forced-swimming test (FST) and tail suspension (TST) test two
experimental animal models has been extensively used as a
screening model for new antidepressant agents.
imides were added to 6 equiv of cold chlorosulphonic acid in the
second step, followed by heating at 60 °C for around 15 min. The
mixture was poured into water/ice and the sulphonyl chlorides
were obtained. In the next step, the sulphonyl chlorides (18–20
and 28) were condensed with different amines to prepare the
sulphonamides (21–24) and the sulphonyl hydrazides (when
hydrazine hydrate was used) (25 and 29). For the synthesis of
sulphonyl hydrazones (26, 30 and 31), the sulphonyl hydrazides
were condensed with benzaldehydes, as described for the
N-(p-chlorosulphonyl)phenylmalemide (1) derivatives.
The structures of the compounds were confirmed from chemi-
cal identification data obtained by 1H NMR, 13C NMR, IR and
elemental analysis.
2. Results
2.1. Chemistry
2.2. Evaluation of the antidepressant-like activity of the
compounds
The seven sulphonamides (2–4, 21–24) and nine sulphonyl-
hydrazones (7–12, 26, 30, 31) were synthesized as illustrated in
Schemes 1–3. In Scheme 1, the sulphonamides (2–4) and the sulpho-
nyl-hydrazones (7–12) were prepared starting from N-(p-chlorosul-
phonyl)phenylmalemide (1). The first step involved cycloaddition
between the sulphonyl chloride (1) and different dienes (furan or
2-methylfuran) in order to observe the influence of the different
substitutions on the maleimide. The reactions were carried out at
room temperature in diethyl ether, using furan or 2-methylfuran.
The sulphonamides (2–4) were obtained by condensation of the
Diels–Alder adducts with pyrrolidine or morpholine in methanol
at approximately 0 °C. The sulphonyl-hydrazones (7–12) were
obtained by reaction of the adducts with hydrazine hydrate and sub-
sequently with different benzaldehydes (Scheme 1).
A similar procedure was used to synthesize the compounds
21–24, 26, 30 and 31 (Schemes 2 and 3). In these cases, the sulpho-
nyl chlorides (18–20 and 28) were prepared in two steps. The prep-
aration of cyclic imides (15–17 and 27) occurred in the first step by
reaction between the appropriate cyclic anhydride and different
amines. The reaction was refluxed in ethanol for 1–6 h. The cyclic
When compared with their respective controls, the acute treat-
ment with all compounds of group I, comprising compounds 2 (30
and 60 mg/kg), 3 (10 mg/kg) and 4 (6 and 10 mg/kg), promoted a
decrease in the immobility time in the FST, as shown in Figure 2.
The values for the percentage reduction (IM) in the immobility
time with the highest dose used in this experiment for the three
compounds were, respectively, 28.80% [F(23,07) = 23.03, P <0.01],
85% [F(3,28) = 9.07, P <0.01], and 28.80% [F(3,28) = 35.73, P <0.01].
On analyzing the treatment with the compounds of group II
(Fig. 3) it was observed that the pre-treatment of animals with com-
pounds 8 and 11 did not produce a decrease in the immobility time
of the animals when compared with the control group. However,
this effect was observed in animals treated with compounds 7
(6 and 10 mg/kg), 9 (6 and 10 mg/kg) 10 (10–60 mg/kg) and 12
(6 and 10 mg/kg). The IM values for the immobility time calculated
in relation to these compounds (with the highest dose used) were,
respectively, 65.44% [F(3,28) = 35.73, P <0.001], 58.53% [F(3,28) = 7.56,
P <0.01], 62.83% [F(3,28) = 46.55, P <0.01], and 62.83% [F(3,27) = 41.97,
P <0.01]. In this group, compounds 10 and 12 had the same
Scheme 1. Synthesis of sulphonamides and sulphonyl-hydrazones N-(p-chlorosulphonyl)phenylmalemide derivatives. Reagents and conditions: (A) (i) furan or 2-
methylfuran, Et2O, rt; (ii) amine or N2H4, MeOH, ꢀ0 °C; (B) EtOH, rt, 1 h, benzaldehydes. ⁄Compounds not evaluated in biological test.

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4297
Scheme 2. Synthesis of naphthalimide derivatives. Reagents and conditions: (a) EtOH/AcOH, reflux, 1–6 h, appropriate amine; (b) HClSO3, 0–50 °C; (c) amine, MeOH, ca. 0 °C;
(d) EtOH, 2 or 3 drops concd HCl, rt, 1–3 h, benzaldehydes. ⁄Compound not evaluated in biological test.
Scheme 3. Synthesis of phthalimide derivatives. Reagents and conditions: (a) EtOH, reflux, 2 h, benzylamine; (b) HClSO3, 0–50 °C; (c) N2H4, MeOH, ca. 0 °C; (d) EtOH, 2 or 3
drops concd HCl, rt, 1–3 h, benzaldehydes.
pharmacological profile, differing only in the dose used to produce
the antidepressant-like effect in the animals.
Finally, the results obtained with the compounds of group V can
be seen in Figure 6. This group is represented by compounds 30
(6–30 mg/kg) and 31 (10–60 mg/kg), which were able to reduce
with statistical significance, the immobility time in the FST by
63.9% [F(3,28) = 43.08, P <0.01] and 68.64% [F(3,28) = 30.43, P <0.01],
respectively.
In a second experiment to confirm the antidepressant-like effect
of the compounds only those which showed activity in the FST
were tested again in the TST (Fig. 7). The results showed that all
tested compounds exhibited statistically anti-immobility effect
when compared with their respective controls, and the values for
the percentage reduction (IM) in the immobility time were: group
The compounds comprising group III are listed in Figure 4. Com-
pounds 21 (6 and 10 mg/kg), 22 (6 and 10 mg/kg) and 23 (6 and
10 mg/kg), respectively, promoted reductions in the immobility
time (with the highest dose used) of 52.26% [F(3,28) = 17.50, P
<0.01], 60.3% [F(3,27) = 24.64, P <0.01] and 52.63% [F(3,28) = 7.89, P
<0.01] compared with the control group. However, compound 24
(60 mg/kg) demonstrated no action, a result which was not of sta-
tistical significance due to the high degree of variation in the data.
The activity of compound 26 (10 mg/kg) (group IV) was 60.30%
[F(3,28) = 25.14], as observed in Figure 5.

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antidepressant-like activity but none of them showed a superior
effect to conventional antidepressants.
2.3. Evaluation of the locomotor effect of the compounds in the
open-field test
In this experiment it was observed that acute systemic treat-
ment with all compounds tested promoted no changes in the loco-
motor activity, as seen in Table 2. There was no statistical
significance for the behavioural parameters of rearing and crossing
observed in this test.
3. Discussion
Depression is a frequently seen psychiatric illness resulting
from the loss of psychosocial ability. It is a serious public health
problem with high morbidity and mortality and it also increases
the risk of comorbidity.
The average prevalence of depression among humans is 17–19%
and of suicide during depression is 15%.3,17 An important theory for
the formation of depression is the monoamine hypothesis, which
proposes that there is a decreasing effect of biological amines like
serotonin (5-HT), noradrenaline and dopamine during depression.18
It is well known that the serotonin system plays an important role in
the neural regulation of mood19 and enhancement of 5-HT neuro-
transmission is the basis of the therapeutic response to different
classes of antidepressant treatment.
In studies using drugs affecting the serotonergic system, the
inhibition of serotonin reuptake in the synaptic terminal or inhibi-
tion of its metabolism (monoaminooxidase inhibitors) has been
investigated. Also, antidepressants affecting 5-HT receptor sub-
types have been studied, since this class of antidepressants has
been frequently used in the therapy of depression20,21 and antide-
pressants used in clinical trials affect these mechanisms.
Given the number of drugs available on the market a question
arises: why study new compounds and assess their potential anti-
depressant activity? In fact, there are several reasons: (i) there is
still no drug on the market that offers a 100% cure rate for affective
disorders; (ii) the drugs available alter the behaviour of the users;
(iii) the drugs available exhibit various side-effects on adherence to
the treatment; (iv) there are few drugs available that affect the
causative agents of this disease and most are palliative; and (v)
some available medications are refractory.
For several years, natural or synthetic compounds with poten-
tial antidepressant action have been studied and the cyclic imides
are examples of these.7–12 Our research group was the first to dem-
onstrate that the structural analogues of cyclic imides have an anti-
depressant-like profile of action after acute treatment in the
classical model of Porsolt’s forced-swimming (behavioural despair)
test (FST), an assay generally used for the prediction of antidepres-
sant activity which does not involve pharmacological interaction.10
According to Porsolt et al. (1977),22–25 immobility seen in rodents
during swimming reflects behavioural despair, as seen in human
depression, and it is well known that the antidepressant drugs
cause a significant decrease in the immobility time in mice. In this
test, it has been shown that the majority of the extracts, com-
pounds or standard drugs studied significantly reduce the duration
of the immobility time in comparison to control animals.
Figure 2. Effect of compounds included in group I (A—Fu-pirrol, B—Fu-o-NO2, C—C-
fu-p-OH/3–10 mg/kg or 10–60 mg/kg, ip), with acute administration in mice, on
immobility time when evaluated in the forced swimming model. Data are reported
as means SEM. N = 8–10 mice. ⁄⁄P <0.01, compared to the control group (ANOVA
followed by Dunnett’s analysis).
I [2 (58.85%), 3 (31.17%), 4 (23.69%)]; group II [7 (57.50%), 9
(41.64%), 10 (62.87%), 12 (55.05%)]; group III [21 (45.57%), 22
(57.14%), 23 (30.61)]; group IV [26 (74.65%)], group
(69.21%), 31 (64.88%)].
V [30
In another experiment, the studied compounds were again
tested in the FST, and their activities were also compared with
classic agents antidepressives imipramine and fluoxetine (Table
1). The results show that for group I the order of effectiveness
was: fluoxetine > imipramine > 2 > 4 > 3. In group II, the antide-
pressant-like activity of 10 was superior to that of imipramine
but not to that of fluoxetine. In group III, 21 and 22 had effica-
cies similar to imipramine but lower than fluoxetine. In group
IV, 26 had an effect similar to imipramine but weaker than
fluoxetine. Finally, in group V, the order of efficacy observed in
the experiments was fluoxetine > imipramine > 31 > 30. In gen-
eral the results show that compounds in studies may show an
To confirm the results obtained in the FST, many researchers
have used in their experiments the tail suspension test (TST).26
The tail suspension test has become one of the most widely used
models for assessing antidepressant-like activity in mice. The same
way as observed in FST, the TST is based on the fact that animals
subjected to the short-term inescapable stress of being suspended
by their tail will develop an immobile posture.26–28

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4299
Figure 3. Effect of compounds included in group 2 (3–10 mg/kg or 10–60 mg/kg, ip), with acute administration in mice, on immobility time when evaluated in the forced
swimming model. Data are reported as means SEM. N = 8–10 mice. ⁄⁄⁄P <0.001 or ⁄⁄P <0.01, compared to the control group (ANOVA followed by Dunnett’s analysis).
Both tests has been validated as a suitable tool for predicting
the antidepressant properties of drugs.22–27 This inescapable
stressful situation can be evaluated by assessing different behav-
ioural strategies.22–28 The administration of compounds prior to
the test acutely reduced the total immobility time in these tests.
Several compounds may affect the normal pattern of behaviour
during the tests, suggesting antidepressant-like action as observed
through the behavioural response to an inescapable source of
stress. False-positive results can be obtained with certain drugs,
in particular psychomotor stimulants, which decrease immobility
time by stimulating locomotor activity.29 The anti-immobility ef-
fect of compounds in study seems not to be associated with any
motor effects, since mice treated with these compounds did not ex-
hibit increased of ambulation when tested in an open-field.
According to the results for the FST in mice, all compounds were
active, except 8, 11 and 24. In addition, the anti-immobility effect
of compounds in FST were also observed in TST. The most active
compound was the sulphonyl-hydrazone 10, which showed
72.02% of activity at a concentration of 60 mg/kg. This compound
was more active that imipramine (10 mg/kg), as shown in Table
1. However, this effect was only observed with a dose six times
higher than the reference drug.
On comparing the results, the sulphonamide oxabicyclo 2 was
more active than the other Diels–Alder adduct derivatives (group
I). The presence of a methyl group in the oxabicyclo in compounds
3 and 4 seems to increase the immobility time in the antidepres-
sant test. In group III, the best result was obtained with the 1,8-
benzylnaphthalimide derivatives 21 and 22. The substitution of

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Figure 4. Effect of compounds included in group 3 (3–10 mg/kg or 10–60 mg/kg, ip), with acute administration in mice, on immobility time when evaluated in the forced
swimming model. Data are reported as means SEM. N = 8–10 mice. ⁄⁄P <0.01, compared to the control group (ANOVA followed by Dunnett’s analysis).
benzylnaphthalimide, moiety increases the degree of mobility of
this molecule and may be responsible for the lack of activity.
In the results obtained for the sulphonyl-hydrazones (groups II,
IV and V), compound 10 of group II, with the oxobicyclo derivative
linked to a methyl group, was the most active compound. How-
ever, in the same group, 7, with a nitro group as a substituent,
was the least active compound, and 8 and 11 were inactive. It
can be assumed that the oxabicyclo derivatives (7 and 8) were less
active than the oxabicyclos linked to a methyl group (9–12). How-
ever, other oxabicyclo derivatives need to be synthesized in order
to confirm this assumption. In groups IV and V, the phthalimide
moiety seems to be important for the activity. In the FST, com-
pounds 30 and 31 led to reductions in the immobility time of
66.64% and 68.30%, respectively. The sulphonyl-hydrazone benzyl-
naphthalimide derivative 26 was less active than the correspond-
ing benzylphthalimide 30.
Figure 5. Effect of compounds included in group 4 (3–10 mg/kg, ip), with acute
It should be noted that the antidepressant-like activity of these
compounds detected in the forced swimming test is not due to CNS
stimulant properties, since they have no significant effects on the
motor activity in comparison to the control group at the doses as-
sayed in this test (Table 2). It is well known that psychostimulants,
such as caffeine, also decrease the immobility time in the FST but,
in contrast to antidepressants, cause marked motor stimulation,
indicating that the effects may be nonspecific.28–31
administration in mice, on immobility time when evaluated in the forced
swimming model. Data are reported as means SEM. N = 8–10 mice. ⁄⁄P <0.01, ⁄⁄⁄
P
<0.001 compared to the control group (ANOVA followed by Dunnett’s analysis).
the hydrogen with a chloro group in the fourth position on the
naphthalic ring is not so important in terms of the activity. In this
case, the sulphonamide 23, substituted with a chloro atom, was as
active as 22 (without the chloro). These compounds showed
around 50% of activity at a concentration of 10 mg/kg. According
to Table 1, compounds 21 and 22 were more active that imipra-
mine, a commercial drug, at a concentration of 10 mg/kg. However,
at a lower concentration (3 mg/kg), 21, 22 and 23 were not active.
Moreover, in this group, the derivative of phenylethylnaphthali-
mide 24 was totally inactive. The addition of a methyl group be-
tween the imide and the benzenesulphonamide, rather than the
4. Conclusions
As part of our ongoing investigations, seven sulphonamides and
nine sulphonyl-hydrazones of cyclic imides including maleimide,
benzylnaphthalimide, phenylethylnaphthalimide and benzylph-
thalimide, were synthesized. In the case of the maleimide

K. N. de Oliveira et al. / Bioorg. Med. Chem. 19 (2011) 4295–4306
4301
evaluate the antidepressant-like effect these compounds with
chronic treatment, as well as assess the toxicity of these.
5. Materials and methods
5.1. Drugs and solvents
The drugs and solvents used were: imipramine chlorhydrate
and fluoxetine purchased from Sigma–Aldrich Chemical Company
(St. Louis, USA) and the compounds synthesized. Due to the hydro-
phobic nature of these synthetic compounds, they were solubilised
in corn oil, while imipramine and fluoxetine were dissolved in sal-
ine solution (NaCl 0.9%) only. The volume administered to each
animal was 0.10 mL/10 g body weight.
5.2. Synthesis and features of compounds
All solvents and reagents were purchased from Merck and Sig-
ma–Aldrich. All the compounds were characterised by 1H NMR, 13
C
NMR, IR, and microanalysis. The purity of these compounds was
determined by TLC using several solvent systems of different polar-
ity. Infrared spectra were determined with a Perkin Elmer 16PC
spectrophotometer (Perkin Elmer, Wellesley, MA, USA). 1H NMR
and 13C NMR spectra were recorded with a Bruker AC-200F spec-
trometer (Rheinstetten, Germany) (400 MHz and 100 MHz, respec-
tively). CDCl3 and DMSO were used as solvents with
tetramethylsilane (TMS) as the internal standard; chemical shifts
(d) were determined in parts per million. For the CHN analysis, a Per-
kin Elmer 2400 CHN elemental analyser (Boston, MA, USA) was used.
In the thin layer chromatography, aluminium sheets with Silica Gel
60 F-254 and 0.2 mm thickness were employed.
The synthesis of compounds 2–12 is described in the litera-
ture.34 The synthesis and the physico-chemical data of the com-
pounds 21–24, 26, 30 and 31 are described below, along with the
data for the precursors (15–20, 25, 27–29). The compounds 21–
23, as well as, their precursors (15, 16, 18 and 19) were recently
published by our research group.36
Figure 6. Effect of compounds included in group 5 (6–30 mg/kg or 10–60 mg/kg,
ip), with acute administration in mice, on immobility time when evaluated in the
forced swimming model. Data are reported as means SEM. N = 8–10 mice. ⁄P
<0.05, ⁄⁄P <0.001, ⁄⁄⁄P <0.001 compared to the control group (ANOVA followed by
Dunnett’s analysis).
derivatives, the intermediates(sulphonyl chlorides) were submitted
to a Diels–Alder reaction with two different dienes, 2-methylfuran
and furan. These compounds were evaluated as antidepressant-like
agents. This behaviour was observed using the FST and TST in mice.
Almost all compounds exhibited an antidepressant-like effect. The
sulphonyl-hydrazone (10) was the most active in the antidepressant
test (FST) at a concentration of 60 mg/kg. Another important result
was obtained with the sulphonamides (21) and (22). They were
more active than imipramine, used at a concentration 10 mg/kg.
However, none of the compounds tested had superior efficacy com-
pared to fluoxetine. Moreover, analysis of the structure–activity
relationship suggested that benzylnaphthalimide is an important
group for the observed activity, being better than the phthalimide
derivatives.
5.2.1. 2-Benzyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (15)35
The 1,8-naphthalic anhydride (3.00 g, 15.00 mmol) was added in
a solution of benzylamine (1.65 mL, 15.00 mmol) in ethanol. The
mixture was refluxed for refluxed for 6 h. The crystal was formed
on cooling of the solution. The solid was filtered through a Büchner
funnel and washed twice with 20 mL of cold ethanol. Yield: 91%.
Mp: 197.9–198.6 °C (Lit 192 °C.36 1H NMR (CDCl3) d 5.37 (s, 2H,
CH2), 7.22–7.26 (t, 1H, ArH), 7.20–7.33 (t, 2H, ArH), 7.56–7.58 (dd,
2H, ArH, J = 7.03 Hz), 7.65–7.68 (t, 2H, ArH), 8.08–8.10 (dd, 2H,
ArH, J = 8.01 Hz), 8.52–8.54 (dd, 2H, ArH, J = 7.03 Hz). 13C NMR
(CDCl3) d 43.49 (CH2); 122.46, 126.83, 127.47, 127.98, 128.40,
129.03, 131.28, 131.42, 133.93, 137.29 (C Ar); 164.10 (C@O).
5.2.2. 2-Benzyl-6-chloro-1H-benzo[de]isoquinoline-1,3(2H)-
dione (16)35
The 4-chloro-1,8-naphthalic anhydride (3.00 g, 12.8 mmol) was
added in a solution of benzylamine (2.81 mL, 25.7 mmol) in etha-
nol. The reaction was carried out as described for the compound
(15). Yield: 85%. Mp: 176.0–176.2 °C (Lit. 168.5–170.5 °C).37 IR
The exact underlying molecular mechanism of action is presently
under investigation. According to current literature, the antidepres-
sant effects of sulphonyl-hydrazone not yet been investigated.
However, antidepressant effects of sulfonamides are well known.
N-[3,5-Dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazi-
nyl)benzenesulfonamide (SB-399885) a 5-HT6 receptor antagonist
exibe effect antidepressant like in FST test32 and, LY392098 a mem-
ber of a novel class of biarylpropylsulfonamides potentiates AMPA
receptor-mediated responses in FST and TST tests.33
The findings reported here are very significant because they re-
veal new potential tools for the treatment of depression, an impor-
tant psychopathology which is one of the most prevalent
throughout the world and is still in need of new and improved
therapeutic approaches. However, further studies are needed to
(KBr): 1689 and 1656 [
m N(C@O)2)], 1340 (m C–N), 741 (m Ar.)
cmꢁ1 1H NMR (CDCl3) d 5.40 (s, 2H, CH2), 7.04–7.06 (d, 2H, ArH,
.
J = 8.20 Hz), 7.14–7.16 (d, 2H, ArH, J = 8.20 Hz), 7.39–7.41 (d, 1H,
ArH, J = 7.42 Hz), 7.43 (t, 1H, ArH), 7.81–7.83 (d, 1H, ArH,
J = 7.42 Hz), 8.40–8.38 (d, 1H, ArH, J = 7.80 Hz), 9.43–9.41 (d, 1H,
ArH, J = 7.42 Hz). 13C NMR (CDCl3) d 43.60 (CH2); 121.41, 122.90,
127.29, 127.56, 127.76, 128.44, 128.91, 129.00, 129.13, 130.61,
131.22, 132.12, 137.01, 139.05 (C Ar); 163.37 (C@O), 163.62

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K. N. de Oliveira et al. / Bioorg. Med. Chem. 19 (2011) 4295–4306
Figure 7. Effect of compounds included all groups (A-group I, B-group II, C-group III, D-group IV and E-group V) with acute administration in mice, on immobility time when
evaluated in the TST. Data are reported as means SEM. N = 8–10 mice. ⁄⁄P <0.001, ⁄⁄⁄P <0.001 compared to the control group (ANOVA followed by Dunnett’s analysis).
(C@O). Anal. Calcd for C19H12ClNO2: C, 70.92; H, 3.76; N, 4.35.
128.82, 128.95, 129.10, 130.48, 130.96, 131.86, 138.59, 138.93 (C
Found: C, 70.51; H, 3.74; N, 4.37.
Ar), 163.13 (C@O), 163.40 (C@O).
5.2.3. 4-Chloro-1,8-N-phenylethylnaphthalimide (17)35
5.2.4. 4-[(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-
The 4-chloro-1,8-naphthalic anhydride 3.00 g (12.8 mmol) was
added in a solution of phenylethylamine (3.25 mL, 25.7 mmol) in
ethanol. The reaction was carried out as described for the com-
pound (15). Yield: 87%. Mp: 126.7–128.3 °C. IR (KBr): 1702 and
yl)methyl]benzenesulphonyl chloride (18)35
The cyclic imide (15) (2.00 g, 7.00 mmol) was slowly added in
chlorosulphonic acid cold (2.76 mL, 42.0 mmol). After addiction,
the mixture was stirred at 50 °C for around 10 min, until the evo-
lution of HCl ceased. The reaction mixture was poured onto ice
and extracted with chloroform. The organic phase was separated
and dried with anhydrous Na2SO4. The solvent was evaporated at
reduced pressure. Yield: 93%. Mp; 113.1–115.5 °C. IR (KBr) 1699
1656 [m N(C@O)2)], 1346 (m C–N), 738 (m Ar.). (Compound cited
by Mederski38 1H NMR (CDCl3) d 2.99–3.03 (t, 2H, CH2), 4.34–
4.38 (t, 2H, CH2), 7.20–7.24 (t, 1H, ArH), 7.28–7.32 (t, 2H, ArH),
7.35–7.36 (d, 2H, ArH, J = 7.02 Hz), 7.73–7.75 (d, 1H, ArH,
J = 7.81 Hz), 7.76–7.80 (t, 1H, ArH), 8.40–8.42 (d, 1H, ArH,
J = 7.81 Hz), 8.48–8.50 (d, 1H, ArH, J = 8.40 Hz), 8.57–8.59 (d, 1H,
and 1655 [
m N(C@O)2)], 1337 and 1172 (m –SO2), 1235 (m –CN),
776 (
m
Ar.). 1H NMR (CDCl3) d 5.24 (s, 2H, CH2), 7.30–7.32 (d, 2H,
ArH, J = 8.01 Hz).13
C
NMR (CDCl3)
d
34.19 (NCH2CH2); 41.86
ArH, J = 8.01 Hz), 7.51–7.54 (d, 2H, ArH, J = 8.20 Hz), 7.85–7.80 (t,
(NCH2CH2); 121.37, 122.85, 126.46, 127.27, 127.74, 128.48,
2H, ArH), 8.48–8.46 (d, 2H, ArH, J = 8.01 Hz), 8.51–8.49 (d, 2H,

K. N. de Oliveira et al. / Bioorg. Med. Chem. 19 (2011) 4295–4306
4303
Table 1
Effect of compounds imipramine (10 mg/kg, ip) and fluoxetine administered intraperitonealy in mice on immobility time when evaluated in the forced swimming model
Treatment
Dose (mg/kg)
Molecular weight (g/mol)
Dose (
lmol/kg)
Immobility time mean SEM (S)
Reduction of immobility time (%)
Group I
Vehicle
—
205.66 12.4⁄2⁄⁄
92.95 6.70⁄⁄
133.00 8.75
131.00 7.33⁄⁄
87.80 4.72⁄⁄⁄
54.26 4.72⁄⁄⁄
0
Compound 2
Compound 3
Compound 4
Imipramine
Fluoxetine
60
10
10
10
20
374.41
388.44
404.44
280.41
309.33
160
26
25
36
66
54.80
33.33
36.30
57.30
73.61
Group II
Vehicle
218.54 8.11
178.37 18.7⁄2⁄⁄⁄
90.37 6.50⁄⁄⁄
61.00 4.80
0
Compound 7
Compound 9
Compound 10
Compound 12
Imipramine
Fluoxetine
10
10
60
10
10
20
468.44
467.49
471.91
451.49
280.41
309.33
21
21
127
22
36
66
18.38
58.64
72.02
62.02
65.48
83.91
83.00 6.26⁄⁄⁄
75.44 8.25⁄⁄⁄
35.16 8.25⁄⁄⁄
Group III
Vehicle
188.50 7.18
67.37 6.14⁄⁄⁄
66.00 8.3⁄⁄⁄
82.00 7.9⁄⁄⁄
68.45 8.7⁄⁄⁄
44.65 6.14⁄⁄⁄
0
Compound 21
Compound 22
Compound 24
Imipramine
Fluoxetine
10
10
10
10
20
420.48
436.48
468.95
280.41
309.33
24
23
21
36
66
64.25
64.89
56.49
63.59
76.31
Group IV
Vehicle
178.25 7.23
70.75 6.15⁄⁄⁄
64.17 6.13⁄⁄⁄
37.89 7.9⁄⁄⁄
0
Compound 26
Imipramine
Fluoxetine
10
10
20
515.54
280.41
309.33
19
36
66
60.30
63.86
78.71
Group V
Vehicle
166 12.23
55.37 3.78⁄⁄⁄
52.25 6.32⁄⁄⁄
49.85 7.9⁄⁄⁄
33.18 3.94⁄⁄⁄
0
Compound 30
Compound 31
Imipramine
Fluoxetine
30
60
10
20
465.78
464.65
280.41
309.33
64
129
36
66.64
68.52
69.96
80.01
66
⁄P <0.05, ⁄⁄P <0.01 and ⁄⁄⁄P <0.001 as compared with vehicle. All comparations were made by ANOVA followed by Dunnett’s test.
Table 2
Effect of compounds administered intraperitonealy in mice evaluated in open field
test
7.57–7.55 (d, 2H, ArH, J = 8.20 Hz), 7.77–7.81 (m, 2H, ArH), 8.20–
8.22 (d, 1H, ArH, J = 7.81 Hz), 8.34–8.32 (d, 1H, ArH, J = 7.42 Hz),
8.37–8.39 (d, 1H, ArH, J = 7.42 Hz). 13C NMR (DMSO-d6) d 43.47
(CH2); 121.58, 122.87, 126.26, 127.86, 128.21, 128.83, 129.09,
130.72, 131.63, 132.35, 137.44, 138.30, 138.43, 147.14 (C Ar);
163.22 (C@O), 163.51 (C@O).
Treatment
Dose
(mg/kg)
Number of rearing
mean SEM (s)
Number of crossing
mean SEM
Vehicle
—
39.45 6.21
42.95 4.70
33.00 8.15
38.00 7.13
38.37 8.22
40.37 6.40
41.00 4.60
43.00 5.27
37.45 4.46
36.67 7.3
96.63 5.32
86.74 6.12
96.00 7.32
101.12 4.56
98.14 8.22
92.54 7.35
98.45 9.15
92.74 8.35
108.45 9.35
98.85 3.85
86.74 8.22
96.10 4.38
106.45 6.35
92.54 17.05
Compound 2
Compound 3
Compound 4
Compound 7
Compound 9
Compound 10
Compound 12
Compound 21
Compound 22
Compound 24
Compound 26
Compound 30
Compound 31
60
10
10
10
10
60
10
10
10
10
10
30
60
5.2.6. 4-Chloro-1,8-N-(p-
chlorosulfonyl)phenethylnaphthalimida (20)
The cyclic imide (17) 3.0 g (8.93 mmol) was slowly added in
chlorosulphonic acid cold 3.57 mL (53.60 mmol). The reaction
was carried out as described for the compound (18). Yield: 92%.
Mp: 200.2–200.9 °C. IR (KBr): 1702 and 1662 [
m N(C@O)2)], 1345
42.00 9.11
40.75 3.15
45.37 6.78
42.65 6.72
and 1171 ( –SO2), 1229 ( C–N), 780 (
m
m
m
Ar.). 1H NMR (DMSO-d6)
d 2.86–2.90 (t, 2H, CH2), 4.11–4.15 (t, 2H, CH2), 7.22–7.24 (d, 2H,
ArH, J = 8.00 Hz), 7.54–7.56 (d, 2H, ArH, J = 8.00 Hz), 7.84–7.86 (d,
1H, ArH, J = 7.80 Hz), 8.21–8.23 (d, 1H, ArH, J = 7.80 Hz), 8.36–
8.40 (m, 3H, ArH). 13C NMR (DMSO-d6) d 33.79 (CH2), 41.68
(CH2), 109.99, 121.69, 122.99, 126.46, 128.25, 128.74, 128.85,
129.13, 130.60, 131.41, 132.13, 138.13, 140.09, 146.43, 163.02
(C@O), 163.30 (C@O).
ArH, J = 8.01 Hz). 13C NMR (CDCl3) d 43.51 (CH2); 109.99, 122.60,
126.27, 127.53, 127.97, 131.71, 132.03, 135.27, 138.44 (C Ar);
164.18 (C@O).
5.2.5. 4-[(6-Chloro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)methyl]benzenesulphonyl chloride (19)35
5.2.7. 2-[4-(Pyrrolidin-1-ylsulphonyl)benzyl]-1H-
benzo[de]isoquinoline-1,3(2H)-dione (21)35
The cyclic imide (16) 2.0 g (6.21 mmol) was slowly added in
chlorosulphonic acid cold 2.55 mL (37.3 mmol). The reaction was
carried out as described for the compound (18). Yield: 67%. Mp:
In a solution of the sulphonyl chloride (18) (400 mg, 1.03 mmol)
in 30 mL of methanol were slowly added 2 equiv of pyrrolidine
(170 lL, 2.07 mmol) at approximately 0 °C. After addiction, the
136.0–138.2 °C. IR (KBr) 1702 and 1659 [
1173 ( –SO2), 1233 ( C–N), 780 (
Ar.) cmꢁ1
d6) d 5.16 (s, 2H, CH2), 7.32–7.34 (d, 2H, ArH, J = 8.20 Hz),
m
N(C@O)2)], 1343 and
mixture was stirred for 30 min at room temperature 0 °C. The
product was filtered and washed twice with 20 mL of cold metha-
nol. The product was recrystallized in chloroform. Yield: 61%. Mp
m
m
m
.
1H NMR (DMSO-

4304
K. N. de Oliveira et al. / Bioorg. Med. Chem. 19 (2011) 4295–4306
207.2–207.8 °C. IR (KBr): 1702 and 1658 [
m
–N(C@O)2)], 1331 and
5.2.11. 4-[(1,3-Dioxo-1H-benzo[de]isoquinoline-2(3H)-
yl)methyl]benzenesulphonyl hydrazide (25)
The hydrazine hydrate (252 g, 5.2 mmol) was slowly added in
1161 (m –SO2–), 770 (m .
arom.) cmꢁ1 1H NMR (DMSO-d6) d 1.54–
1.62 (m, 4H, –(CH2)2–), 3.06–3.10 (t, 4H, –CH2–N–CH2–), 5.32 (s,
2H, –CH2–), 7.57–7.59 (d, 2H, ArH, J = 8.20 Hz), 7.71–7.73 (d, 2H,
ArH, J = 8.20 Hz), 7.84–7.88 (t, 2H, ArH), 8.45–8.46 (d, 2H, ArH,
J = 7.22 Hz), 8.48–8.50 (d, 2H, ArH., J = 7.22 Hz). 13C NMR (DMSO-
d6) d 25.33 (–CH2–CH2–CH2–CH2–), 43.40 (CH2–N-ArH), 48.41
(CH2–N–CH2–); 122.55, 127.99, 128.20, 128.82, 131.76, 132.03,
132.83, 135.37, 135.61, 143.17 (C Ar.); 164.23 (C@O). Anal. Calcd
for C23H20N2O4S: C, 65.70; H, 4.79; N, 6.66; S, 7.63. Found: C,
65.44; H, 4.56; N, 6.63; S, 7.40.
l
a mixture of sulphonyl chloride (20) (1.00 g, 2.59 mmol) in ethanol.
The reaction was stirred and the temperature was kept at approx-
imately 0 °C during the addiction of the hydrazine. The product
was filtered and washed twice with 20 mL of cold methanol. Yield:
90%. Mp: 163.5–163.9 °C. 1H NMR (DMSO-d6) d: 3.38 (sbroad, 3H,
NH–NH2), 5.21 (s, 2H, CH2), 7.30–7.32 (d, 2H, ArH, J = 8.06 Hz),
7.54–7.56 (d, 2H, ArH, J = 8.06 Hz), 7.78–7.82 (t, 2H, ArH,
J = 7.33), 8.37–8.39 (d, 2H, ArH, J = 8.06 Hz), 8.41–8.43 (d, 2H,
ArH, J = 7.33 Hz). 13C NMR (DMSO-d6) d: 43.39 (CH2); 122.45,
126.29, 127.60, 127.90, 128.00, 131.62, 131.93, 135.20, 135.25,
138.42 (C Ar), 164.08 (C@O).
5.2.8. 2-[4-(Morpholin-1-ylsulphonyl)benzyl]-1H-
benzo[de]isoquinoline-1,3(2H)-dione (22)35
In a solution of the sulphonyl chloride (18) (400 mg, 1.03 mmol)
in 30 mL of methanol were slowly added 2 equiv of morpholine
5.2.12. 4-[2-(1,3-Dioxo-1H-benzo[de]isoquinoline-2(3H)-
yl)methyl]-N’-[(1E)-(3-methoxy-4-
(180
ried out as described for the compound (21). Yield: 62%. Mp:
221.7–223.3 °C. IR (KBr) 1703 and 1660 [ N(C@O)2)], 1336 and
1163 ( –SO2–), 1227 and 1104
–COC–) cmꢁ1 1H NMR
lL, 2.07 mmol) at approximately 0 °C. The reaction was car-
hydroxyphenyl)methylene]benzenesulphonyl hydrazone (26)
The sulphonyl hydrazide (25) (400 mg, 1.21 mmol) was added
in a solution of vanillin (184 mg, 1.21 mmol) in ethanol and two
drops of hydrochloric acid as catalyst. The mixture was stirred at
room temperature for 1 h. The reaction was checked by t.l.c. (ethyl
acetate/hexane 1:1). The mixture was poured out in water/ice. The
product was filtered and washed with cold water. Yield: 68%. Mp:
m
m
(
m
.
(DMSO-d6) d 2.79–2.82 (t, 4H, –CH2–N–CH2–), 3.57–3.59 (t, 2H, –
CH2–O–CH2–), 5.54 (s, 2H, –CH2–), 7.61–7.63 (d, 2H, ArH.,
J = 8.20 Hz), 7.65–7.67 (d, 2H, ArH., J = 8.20 Hz), 7.86–7.90 (t, 2H,
ArH), 8.47–8.49 (d, 2H, ArH., J = 8.20 Hz), 8.50–8.52 (d, 2H, ArH.,
J = 7.22 Hz). 13C NMR (DMSO-d6) d 43.72 (CH2–N-ArH), 46.58
(CH2–N–CH2–), 66.75 (CH2–O–CH2–); 123.05, 127.76, 128.77,
130.44, 132.39, 135.10, 143.39 (C Ar.); 164.89 (C@O). Anal. Calcd
for C23H20N2O5S: C, 63.29; H, 4.62; N, 6.42; S, 7.35. Found: C,
63.04; H, 4.68; N, 6.29; S, 7.37.
235.4–236.2 °C. 3484 (
N(C@O)2)], 1326 and 1198 (
m
OH), 3230 (
m
NH), 1696 and 1652 [
m
m
SO2), 1486 (
m
C–N). 1H NMR
(DMSO-d6) d: 3.83 (s, 3H, OCH3), 5.26 (s, 2H, CH2), 6.89–6.91 (d,
1H, ArH, J = 8.20 Hz), 6.89–6.91 (d, 1H, ArH, J = 8.20 Hz), 7.27–
7.29 (d, 1H, ArH, J = 8.20 Hz), 7.33–7.35 (d, 2H, ArH, J = 8.20 Hz),
7.48 (s, 1H, ArH), 7.55–7.57 (d, 2H, ArH, J = 8.00 Hz), 7.85–7.89 (t,
2H, ArH), 8.45–8.47 (d, 2H, ArH, J = 7.50 Hz), 8.50–8.52 (d, 2H,
ArH, J = 8.20 Hz), 8.62 (s, 1H, N@CH), 11.23 (s, 1H, NH). 13C NMR
(CDCl3) d: 56.23 (CH2), 109.99, 116.20, 122.56, 124.65, 125.69,
126.28, 127.55, 127.93, 128.11, 131.68, 132.00, 135.21, 138.38,
148.68, 150.94, 161.40, 164.13 (C@O). Anal. Calcd for C27H21N3O6S:
C, 62.90; H, 4.11; N, 8.15; S, 6.22. Found: C, 62.65, H, 4.45, N, 8.35,
S, 6.09.
5.2.9. 2-[4-(Morpholin-1-ylsulphonyl)benzyl]-1H-
benzo[de]isoquinoline-1,3(2H)-dione (23)35
In a solution of the sulphonyl chloride (19) (400 mg, 0.95 mmol)
in 30 mL of methanol were slowly added 2 equiv of morpholine
(165
ried out as described for the compound (21). Yield: 74%. Mp:
171.1–172.7 °C. IR (KBr) 1701 and 1663 [ –N(C@O)2)], 1341 and
1168 ( –SO2–), 1227 and 1105 (
-COC–) cmꢁ1 1H NMR (DMSO-
lL, 1.90 mmol) at approximately 0 °C. The reaction was car-
m
m
m
.
5.2.13. 2-Benzyl-1H-isoindol-1,3(2H)-dione (27)
d6) d: 2.81–2.78 (t, 4H –CH2–N–CH2–), 3.58–3.55 (t, 4H, –CH2–O–
CH2), 5.30 (s, 2H, –CH2–), 7.32–7.30 (d, 2H, ArH, J = 8.00 Hz),
7.54–7.52 (d, 2H, ArH, J = 8.00 Hz), 7.94–7.92 (m, 2H, ArH.), 8.85–
8.33 (d, 1H, ArH, J = 7.81 Hz), 8.51–8.48 (m, 2H, ArH.). 13C NMR
(DMSO-d6) d 43.57 (CH2–N-ArH), 46.50 (CH2–N–CH2–), 65.91
(CH2–O–CH2–); 121.88, 123.18, 126.25, 127.65, 128.36, 128.54,
129.07, 129.12, 130.93, 131.78, 132.51, 133.79, 138.44, 143.47 (C
Ar.); 163.48 (C@O), 163.76 (C@O). Anal. Calcd for C23H19ClN2O5S:
C, 58.66; H, 4.07; N, 5.95; S, 6.81. Found: C, 58.45; H, 4.05; N,
5.94; S, 7.03.
The phthalic anhydride (5.0 g, 34.0 mmol) and benzylamine
(4.0 mL, 34.0 mmol) were refluxed in acetic acid for 3 h. The reac-
tion was checked by t.l.c. (ethyl acetate/hexane 1:1). The product
was precipitate in cold water and filtered in Büchner funnel. The
product was recrystalized in ethanol. Yield: 96%. Mp: 116.1–
117.1 °C (Lit. 118 °C39 1H NMR (CDCl3) d: 4.84 (s,2H, CH2), 7.27–
)
7.33 (m, 3H, ArH), 7.43–7.44 (d, 2H, ArH, J = 7.03 Hz), 7.67–7.69
(m, 2H, ArH), 7.82–7.84 (m, 2H, ArH). 13C NMR (CDCl3) d: 41.60
(CH2); 123.30, 127.79, 128.57, 128.63, 132.07, 133.94, 136.33 (C
Ar); 167.99 (C@O).
5.2.10. 6-Chloro-2-[4-(pyrrolidin-1-ylsulphonyl)phenethyl]-1H-
benzo[de]isoquinoline-1,3(2H)-dione (24)
5.2.14. 4-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-
yl)methyl]benzenesulphonyl chloride (28)
In a solution of the sulphonyl chloride (20) (400 mg, 0.95 mmol)
in 30 mL of methanol were slowly added 2 equiv of pyrrolidine
The phthalimide (2.00 g, 8.43 mmol) was added in 6 equiv of
cold chlorosulphonic acid (3.90 mL, 59.0 mmol), followed by heat-
ing at around 60 °C until the evolution of HCl ceased. The mixture
was poured in a mixture of water and ice. The product was filtered
and washed with cold water. Yield: 84%. Mp: 120.3–123.6 °C.
(Lit.40 124–125 °C). 1H NMR (DMSO-d6) d: 4.75 (s, 2H, CH2), 7.25–
7.27 (d, 2H, ArH, J = 8.39 Hz), 7.55–7.57 (d, 2H, ArH, J = 8.21 Hz),
7.81–7.88 (m, 4H, ArH). 13C NMR (CDCl3) d: 41.27 (CH2), 123.92,
126.47, 127.50, 135.27, 137.85, 147.58 C Ar, 168.68 (C@O).
(167
ried out as described for the compound (21). Yield: 77%. Mp:
245.2–248.7 °C. IR (KBr): 1700 and 1662 [ N(C@O)2)], 1343 and
1158 ( SO2), 780 (
Ar.). 1H NMR (CDCl3) d: 1.94 (t, 4H, –CH2–
lL, 1.90 mmol) at approximately 0 °C. The reaction was car-
m
m
m
CH2–), 3.19 (m, 6H, –CH2–N–CH2– and –CH2-Ph), 4.42 (t, 2H, –
CH2–N–C@O), 7.51–7.28 (d, 2H, ArH., J = 8.5 Hz), 7.89–7.74 (m,
4H, ArH.), 8.64–8.44 (m, 3H, ArH.). 13C NMR (CDCl3) d: 25.44 (N–
CH2–CH2–CH2–), 34.23 (CH2-Ar), 41.41 (O@C–N–CH2), 48.16
(CH2–N–CH2); 121.49, 123.01, 128.01, 129.85, 131.15, 131.45,
131.91, 131.95, 132.34, 135.17, 139.60, 144.02 (C Ar); 163.53
(C@O), 163.79 (C@O). Anal. Calcd for C24H21ClN2O4S: C, 61.47; H,
4.51; N, 5.97; S, 6.84. Found: C, 61.27; H, 4.34; N, 5.98; S, 6.83.
5.2.15. 4-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-
yl)methyl]benzenesulphonyl hydrazide (29)
The hydrazine hydrate (103 mL, 3.0 mmol) was added in a solu-
tion of sulphonyl chloride (28) (550 mg, 1.60 mmol) in methanol at

K. N. de Oliveira et al. / Bioorg. Med. Chem. 19 (2011) 4295–4306
4305
around 0 °C. The reaction was checked by t.l.c. (ethyl acetate/hex-
onamides, derived from maleimides, using 2-methylfuran and fur-
an as dienes; group 2—sulphonyl-hydrazones derived from
maleimides, using 2-methylfuran and furan as dienes; group 3—
sulphonamides, derived from naphthalimides; group 4—sulpho-
nyl-hydrazone, derived from naphthalene; and group 5—sulpho-
nyl-hydrazone, derived from phthalimide. For each compound
experiments were performed with 3 doses, always starting with
10 mg/kg. The activity of each compound was compared with that
of drugs such as fluoxetine (20 mg/kg) and imipramine (10 mg/kg).
The doses used for the compounds were based on previous tests
with the same in models of antinociception (unpublished data).
The doses of fluoxetine and imipramine were used based on
literature.41,42
ane 1:1). The product was filtered and washed with cold methanol.
Yield: 85%. Mp: 160.2–161.4 °C. 1H NMR (DMSO-d6) d: 3.38 (slargo
,
2H, NH2), 4.87 (s, 2H, CH2), 7.53–7.55 (d, 2H, ArH, J = 8.20 Hz),
7.76–7.78 (d, 2H, ArH, J = 8.20 Hz), 7.86–7.93 (m, 4H, ArH), 8.40
(s, 1H, NH), 13C NMR (DMSO-d6) d: 41.17 (CH2); 124.01, 128.45,
128.66, 132.27, 135.33, 138.01, 142.04 (C Ar); 168.39 (C@O).
5.2.16. 4-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-N’-
[(1E)-(3-methoxy-4-
hydroxyphenyl)methylene]benzenesulphonyl hydrazone (30)
The sulphonyl hydrazide (29) (400 mg, 0.8 mmol) was added in
a solution of vanillin (131 mg, 0.8 mmol) in ethanol. The reaction
was carried out as described for the compound (26). Yield: 74%.
5.4.2. Forced-swimming test (FST)
Mp: 187.0–189.2 °C. IR (KBr): 3393 (
N(C@O)2)], 1600 ( Ph-OH), 1334 and 1168 (
1039 ( Ar-O–CH3), 701 (
ArH) cmꢁ1 1H NMR (CDCl3) d: 1.61 (s,
m
NH), 1765 and 1701 [
m
The FST is the most widely used pharmacological model for
assessing antidepressant activity.22–25 This method is based on
the observation of animals exposed to a situation of forced swim-
ming, in which they become passive and immobile after a period of
vigorous activity (struggling), producing only the movements re-
quired to keep their heads above the water. The FST was carried
out on mice according to the method of Porsolt et al. (1977).22
Swimming sessions were conducted by placing the animals in indi-
vidual Plexiglass cylinders (46 cm high ꢂ 20 cm diameter) contain-
ing 20 cm of water at 24 1 °C. All animals were forced to swim for
6 min, and the time spent in immobility during the last 4 min of a
6 min observation period was recorded manually by competent
observers. The animals were treated with the compounds (3, 10
and 30 mg/kg or 10, 30 and 60 mg/kg, ip), imipramine (10 mg/kg,
ip), Fluoxetine (20 mg/kg) or vehicle, 30 min before the test.
m
m
SO2), 1278 and
m
m
.
1H, OH); 3.93 (s, 3H, OCH3); 4.85 (s, 2H, CH2), 7.63–7.27 (m, 6H,
ArH and –N@CH–), 8.97–8.79 (m, 5H, ArH), 8.19 (s, 1H, NH). 13C
NMR (DMSO-d6) d: 41.18 (CH2); 56.37 (OCH3); 114.50, 123.80,
127.53, 128.42, 128.61, 129.41, 129.64, 132.11, 134.51 (Ar C);
141.16 (Ar C–SO2 and C@N); 142.01 (Ar C–OCH3); 161.21 (Ar C–
OH); 167.24 (C@O). Anal. Calcd for C23H19N3O6S: C, 59.35; H,
4.11; N, 9.03; S, 6.89. Found: C, 59.68; H, 3.93; N, 9.00; S, 6.57.
5.2.17. 4-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-N’-
[(1E)-(4-nitrophenyl)methylene]benzenesulphonyl hydrazone
(31)
The sulphonyl hydrazide (29) (400 mg, 0.8 mmol) was added in
a solution of p-nitrobenzaldehyde (121 mg, 0.8 mmol) in ethanol.
The reaction was carried out as described for the compound (26).
5.4.3. Tail suspension test (FST)
Yield: 70%. Mp: 221.7–223.6 °C. IR (KBr): 3148 (
m
NH), 1768 and
The total duration of immobility induced by tail suspension was
measured according to the method described by Steru et al.
(1985).26 Briefly, mice both acoustically and visually isolated were
suspended 50 cm above the floor by adhesive tape placed approx-
imately 1 cm from the tip of the tail. Immobility time was manu-
ally recorded during a 6 min period.27 Mice were considered
immobile only when they hung passively or stay completely
motionless. Conventional antidepressants decrease the immobility
time in this test.26
1700 [ N(C@O)2)], 1394 and 1116 ( SO2), 1594 (m
m
m
C–N). 1H
NMR (DMSO-d6) d: 4.85 (s, 2H, ArH), 7.54–7.57 (d, 2H, ArH,
J = 8.40 Hz), 7.90–7.81 (m, 8H, ArH), 8.02 (s, 1H, N@CH), 8.21–
8.23 (d, 2H, ArH, J = 8.40 Hz), 12.01 (s, 1H, NH). 13C NMR (DMSO-
d6) d: 40.79 (CH2); 123.97, 124.69, 128.42, 132.23, 135.28,
140.40, 142.79 (C Ar); 168.36 (C@O). Anal. Calcd for C22H16N4O6S:
C, 56.89; H, 3.47; N, 12.06; S, 6.90. Found: C, 56.68, H, 3.69, N,
11.84, S, 6.87.
Percentage decrease in immobility duration (%IM) for test and
standard drugs was calculated using following formula:
5.3. Animals
% IM ¼ ½ðA BÞ=Aꢃ ꢄ 100
where A is the duration of immobility (s) in control group and B is
the duration of immobility (s) in test group.
Male adult Swiss mice (25–35 g) were used in all experiments.
They were housed in groups of 20 animals per plastic cage under
controlled conditions of light (from 07:00 to 19:00 h) and temper-
ature (23 2 °C). The animals were allowed free access to standard
laboratory food and tap water, and to adapt to the laboratory envi-
ronment for at least one week before the behavioural assessment.
For each treatment, a different group of experimental and control
animals was used. All tests were carried out according to interna-
tional standards of animal welfare recommended by the Brazilian
Society of Neuroscience and Behaviour (Act 1992) and approved
by the local Committee for Animal Care in Research 311/2008/
CEP UNIVALI. The minimum number of animals and duration of
observation required to obtain consistent data were employed.
5.4.4. Evaluation of the spontaneous motor effect in the open-
field test
The open-field test was used to evaluate the exploratory
activity of the animals, as described in the literature.43 The
open-field arena was made of acrylic (transparent walls and
black floor). The arena measured 30 ꢂ 30 ꢂ 15 cm and was di-
vided into nine squares of equal area. The animals were placed
individually in the centre of the arena and allowed to explore
freely. The observed parameters were: ambulation or crossing
(the number of squares crossed with all four paws) and number
of rearings behaviour (exploratory behavior in which the animal
rises to support the body in the forelegs), both indicators being
recorded for the last 5 min of the 6 min testing period. The com-
pound or vehicle was administered 30 min before the open-field
test and evaluated for 6 min. Control animals received vehicle
(NaCl 0.9%) in the same proportion and at a constant volume
by the same route, under a similar schedule of administration.
5.4. Behavioural evaluation
5.4.1. Experimental design
The compounds were grouped according to the principal func-
tional group (sulphonamide or sulphonyl-hydrazone), to the origin
of the imides and, in the case of the maleimide derivatives, to the
dienes that were used in the synthesis, as follows: group 1—sulph-

4306
K. N. de Oliveira et al. / Bioorg. Med. Chem. 19 (2011) 4295–4306
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This research was supported by grants and fellowships from
CNPq (Conselho Nacional de Desenvolvimento Científico e Tec-
nológico), P. Costa and J. R. Santin are master’s degree students
in Pharmaceutical Sciences/UNIVALI., K. N. de Oliveira was the re-
cipient of a doctoral scholarship from CNPq. M. M. De-Souza is the
recipient of a research grant from CNPq. The authors wish to thank
Dr. Fiona Duarte for final English revision of the text.
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