Synthesis and antidepressant-like action of stereoisomers of imidobenzenesulfonylaziridines in mice evaluated in the forced swimming test

Article abstract of DOI:10.1016/j.bmc.2006.03.036

The present study describes the chemical synthesis and pharmacological evaluation of a new series of eleven compounds stereoisomers of imidobenzenesulfonylaziridines in the forced-swimming test (FST) in mice. The pharmacological results of these compounds

Full text of DOI:10.1016/j.bmc.2006.03.036

Bioorganic & Medicinal Chemistry 14 (2006) 5397–5401
Synthesis and antidepressant-like action of stereoisomers
of imidobenzenesulfonylaziridines in mice evaluated
in the forced swimming test
Filipe S. Duarte,a Evilazio da S. Andrade,b Ricardo A. Vieira,a,
Marina Uieara,b Ricardo J. Nunesb and Thereza C. M. de Limaa,*
aLaboratory of Neuropharmacology, Department of Pharmacology, CCB, Universidade Federal de Santa Catarina,
Floriano´polis, SC, 88049-900, Brazil
bDepartment of Chemistry, Universidade Federal de Santa Catarina, Floriano´polis, SC, 88040-900, Brazil
Received 11 August 2005; revised 18 March 2006; accepted 20 March 2006
Available online 15 May 2006
Abstract—The present study describes the chemical synthesis and pharmacological evaluation of a new series of eleven compounds
stereoisomers of imidobenzenesulfonylaziridines in the forced-swimming test (FST) in mice. The pharmacological results of these
compounds show that six of them, given intraperitoneally, reduced the immobility time of mice evaluated in the FST, an antidepres-
sant-like profile of action similar to imipramine, a well-known standard antidepressant drug used for comparison, without compro-
mising the animals’ motor performance. The putative antidepressant-like action demonstrated here indicates their viability for the
development of new therapeutic options for the treatment of depression.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
In the present work, a series of imidobenzenesulfonylaz-
iridine compounds was synthesized that brought togeth-
er in a single molecule the chemical functions of imide
and aziridine (3 and 4; Scheme 1), both known for their
pharmacological properties including antitumoral activ-
ity. Among the compounds possessing an aziridine ring,
mitomycin C has been used to treat stomach and lung
cancer.3–6 Moreover, the cyclic imide derivatives have
been known for several decades and have been widely
used in popular medicine in the treatment of several
Depression is one of the most prevalent psychopatholo-
gies in the Western world and its therapy relies on clas-
sical antidepressant drugs such as monoamine oxidase
inhibitors and drugs that inhibit the reuptake of
catecholamines.1 A common problem with the current
antidepressant therapies is the several side effects (e.g.,
anti-cholinergic, gastrointestinal distress, anxiety,
insomnia and sexual dysfunction) 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.2 Consequently, several research efforts are
pursuing the discovery of new antidepressants with less
side-effects, a faster onset of action and a better efficacy.
In order to accomplish these goals of obtaining new
compounds with antidepressant properties, we have
studied the chemical and biological aspects of cyclic imi-
des compounds.
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(3a-k)
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Keywords: Imidobenzenesulfonylaziridines; Antidepressant-like action;
Forced-swimming test.
X = H (a); 4-Cl (b); 3,4-Cl2 (c); 4-CH3 (d); 4-OCH3 (e); 4-Br (f); 4-NO2 (g); 3-ethyl (h);
3-NO2 (i); 4-F (j) and 4-OH (k).
*
Corresponding author. Tel.: 55 48 331 9491; fax: +55 48 337 5479;
e-mail addresses: thereza@farmaco.ufsc.br; t_de_lima@hotmail.com
Deceased author.
Scheme 1.
0968-0896/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2006.03.036

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F. S. Duarte et al. / Bioorg. Med. Chem. 14 (2006) 5397–5401
psychopathologies such as anxiety, schizophrenia, and
epilepsy.7–10
The pharmaceutical interest in these drugs was strength-
ened by the isolation of imides from natural sources7.
In this regard, in the present study several analogue
compounds of the cyclic imides were synthesized using
phyllantimide (an alkaloid extracted from Phyllantus
sellowianus) as the basic structure, and these compounds
were tested in mice evaluated in the forced-swimming
test, an animal model that has been extensively used as
a screening model for new antidepressant agents.
Figure 2. Effects of acute treatment with endo–endo stereoisomers of
imidobenzenesulfonylaziridines (4e, 4i, 4j, and 4k, 1 mg/kg, ip and the
standard antidepressant imipramine (IMI, 15 mg/kg, ip) on the
immobility time in a 5-min swimming test. Each column represents
means SEM. The dotted line represents the mean of the values of
control animals. *P < 0.05 as compared to control (all comparisons
were made by ANOVA followed by Dunnett’s test).
2. Results
2.1. Evaluation of the antidepressant-like effect of the
endo–endo stereoisomers of imidobenzenesulfonylaziridines
Acute treatment with the compounds 4a, 4b, 4c, 4f, 4g,
and 4h promoted a decrease in the immobility time in the
FST, as depicted in Figure 1 (control = 100.00 3.82 %;
(4a) = 76.62 3.62 %; (4b) = 76.84 7.82 %; (4c) =
73.33 7.06 %; (4f) = 73.77 8.22 %; (4g) = 75.64
activity registered on the open-field test, as depicted in
Figure 3 (A: number of crossings, control = 93.67 5.74
s; (4a) = 78.43 6.78 s; (4b) = 100.40 13.04 s; (4c) =
90.29 18.68 s; (4f) = 86.00 10.78 s; (4 g) = 77.86
10.57 s; (4h) = 80.29 4.84 s; F(6,36) = 0.55; P > 0.05;
B: rearing, control = 38.67 3.42 s; (4a) = 36.00 4.36
s; (4b) = 48.00 2.34 s; (4c) = 35.71 5.97 s; (4f) =
41.00 3.42 s; (4g) = 33.57 2.83 s; (4h) = 45.14 3.40
6.04 %; (4h) = 67.73 9.88 %; Imipramine(15 mg/kg)
=
44.52 7.75 %; (F(7, 53) = 5.46; P < 0.0001). The immobil-
ity time of animals treated with the other compounds 4d,
4e, 4i, 4j, and 4k did not statistically differ from control
values as shown in Figure 2 (control = 100.00 3.82 %;
(4d) = 74.09 17.29 %; (4e) = 89.91 9.13 %; (4i) =
86.20 5.81 %; (4f) = 111.06 1.70 %; (4k) = 90.65
6.64 %; Imipramine(15 mg/kg) = 44.52 7.75 %; F(6,46)
=
5.53; P > 0.05). However, compound 4d has a trend to
present an antidepressant-like profile of action which
did not reach statistical significance due to data variation.
2.2. Evaluation of the locomotor effect of the endo–endo
stereoisomers of imidobenzenesulfonylaziridines in the
open-field test
Acute systemic treatment with the compounds 4a, 4b,
4c, 4f, 4g, and 4h promoted no changes in the locomotor
Figure 1. Effects of acute treatment with different endo–endo stereo-
isomers of imidobenzenesulfonylaziridines (4a, 4b, 4c, 4f, 4g, and 4h,
1 mg/kg ip) and the standard antidepressant imipramine (IMI, 15 mg/
kg, ip) on the immobility time in a 5-min swimming test. Each column
represents means SEM. The dotted line represents the mean of the
values of control animals. *P < 0.05 as compared to control (all
comparisons were made by ANOVA followed by Dunnett’s test).
Figure 3. Effects of acute treatment with different endo–endo stereo-
isomers of imidobenzenesulfonylaziridines (4a, 4b, 4c, 4f, 4g, and 4h,
1 mg/kg ip) on the behavioral parameters (A, number of crossings and
B, rearing) evaluated in the open-field test. Each column represents
means SEM. *P < 0.05 as compared to control (all comparisons
were made by ANOVA followed by Dunnett’s test).

F. S. Duarte et al. / Bioorg. Med. Chem. 14 (2006) 5397–5401
5399
s; F(6,36) = 1.61; P > 0.05), as compared to the values
presented by control group.
evaluated in an open-field at the same dose which pre-
sented the antidepressant-like profile of action in the
FST. We observed that these compounds did not modify
the behavioral performance of mice evaluated in the
open-field test which essentially depends on their motor
function. This observation strongly indicates that the
reduction in the immobility time is due to a selective
antidepressant-like effect of these aziridine compounds
and not merely a result of a general stimulation of the
animal’s motor activity. Therefore, these compounds
deserve to be studied further because, as previously
mentioned, there is a need for new and improved antide-
pressant compounds.
3. Discussion
To the best of our knowledge, this is the first demonstra-
tion that the structural analogues of cyclic imides have
an antidepressant-like profile of action after acute treat-
ment in the classical Porsolt’s model of forced-swim-
ming test (FST).11,12 The FST was designed by Porsolt
as a primary screening test for antidepressants and it re-
mains one of the best models for this purpose for several
reasons. It is a low-cost, fast, and reliable model to test
potential antidepressant treatments with a strong predic-
tive validity. Porsolt et al. (1977) and Porsolt et al.
(1978), who proposed this behavioral model for the
screening of new antidepressant compounds, concluded
that the immobility time observed in the test reflected a
state of lowered mood or hopelessness in animals; thus,
this animal model is the most widely used tool for pre-
clinical screening of putative antidepressant agents.17–
We also intend to carry out biological assays with tumor
cell lines since the imidobenzenesulfonylaziridines pres-
ent potential anticancer activity due to the aziridine
ring.3–6 Nevertheless, as any other new compound, these
aziridines have to be tested in toxicological assays,
although in our preliminary test with Artemia salina
Leach they did not present any significant toxicity.24
20
The FST shows a strong sensitivity to monoamine
alterations and is a very specific cluster of stress-induced
behaviors that have no direct, empirical relation to
depression symptoms in humans, but which are none-
theless exquisitely sensitive to monoaminergic manipula-
tions.11,20 It also provides a useful model to study
neurobiological and genetic mechanisms underlying
stress and antidepressant responses.21–23
4. Conclusion
In conclusion, the present results showed a clear antide-
pressant-like effect for the endo–endo stereoisomers of
imidobenzenesulfonylaziridines after acute treatment.
The exact underlying molecular mechanism of action
is presently under investigation but the findings shown
here are very significant because they reveal new poten-
tial tools for the treatment of depression, an important
psychopathology which is one of the most prevalent
throughout the world and is still in need of new and
perhaps better therapeutic approaches.25
The present study describes the pharmacological
evaluation of a new series of eleven compound stereo-
isomers of imidobenzenesulfonylaziridines, six of which
showed a clear antidepressant activity in mice evaluat-
ed in the FST. On the other hand, our preliminary
studies showed that the compounds with exo–endo
configuration are inactive, probably due to severe steric
restrictions.15
5. Materials and methods
5.1. Drugs and solvents
Nevertheless, the compounds with endo–endo configu-
rations and four attached electron-withdrawing substit-
uents in the aromatic ring, except for compound 4j
(X = F), were active in the FST, whereas the
compounds with four attached electron-donating
substituents did not show any biological activity. In this
regard, studies involving cyclic imides have demonstrat-
ed that their biological activity is related to the opening
of the imidic ring due to a nucleophilic attack on one of
the carbonyls by a biomolecule.29 It has been previously
shown that succinimide derivatives possess an important
anticonvulsant activity, attributed to a –CO–NR–CO–
fragment also present in barbiturates and in other drugs
with well-known anticonvulsant activity.7
The drugs and solvents used were: imipramine chlorhy-
drate, from Sigma Chemical Company (St. Louis, USA)
and the endo–endo stereoisomers of imidobenzenesulf-
onylaziridines that were synthesized in-house.26 Due to
the hydrophobic characteristics of these synthetic com-
pounds, they were solubilized in corn oil, while imipra-
mine was dissolved in saline solution (NaCl 0.9%) only.
5.2. Compound synthesis and features
Analytical grade reagents were used and purified
according to methods cited in the literature.27 For the
´
determination of the melting point (mp), a Microquımi-
caTM device model MQRPF-301 was used. For the CHN
analysis, a CHN elemental analyzer PERKIN ELMER
On the other hand, many drugs are reported to affect
several aspects of motor function, resulting in false
assumptions about the drugs’ effects, which is specially
important in the forced-swimming test that is based on
a motor response of the animals. Thus, we cannot dis-
card the possibility that our results with the several com-
pounds are merely due to a general stimulation of the
animals’ motor activity. For this reason, animals were
1
2400 was used. H NMR and 13C NMR spectra were
recorded using a Brucker AC-200F (at 200 and
50 MHz, respectively). CDCl3 was used as the solvent
with TMS as the internal standard; chemical shifts (d)
were in parts per million. In the thin-layer chromatogra-
phy (TLC), aluminum sheets with silica gel 60 F-254 of
0.2 mm thickness were used. All imidobenzenesulfonylaz-

5400
F. S. Duarte et al. / Bioorg. Med. Chem. 14 (2006) 5397–5401
iridines were purified by column chromatography with
silica gel 60 (230–400 mesh) purchased from Merck.
17.0 cm; length, 30.0; width, 30.0 cm) with a black floor
marked with white lines in 10 cm2 areas. Thirty minutes
after administration of the compounds, each mouse was
placed in the center of the arena and their ambulation
was recorded for a 5-min period.13 The number of grid
lines crossed with both hind feet (number of crossings)
and the number of rearings were counted as an index
of spontaneous ambulation. After each trial, the open-
field apparatus was wiped and cleaned with ethanol
(10%) solution.
All compounds, except for compounds 4i, 4j, and 4k, were
obtained using previously described methodologies, with
minor modifications, which produced good yields
(approximate 65–90%) as recently reported by our
group.26 Compounds 4i, 4j, and 4k have not yet been
reported in the literature. The exo–endo (3) and endo–en-
do (4) imidobenzenesulfonylaziridines were synthesized
through a 1,3-dipolar-type reaction of p-toluenesulfony-
lazide (previously prepared) and different endo-norborn-
enesuccinimides (2). The endo-norbonenesuccinimides
were prepared through the Diels–Alder reaction between
substituted N-phenylmaleimides (1) and cyclopentadiene
according to the method described in the literature for
similar structures.28 The N-phenylmaleimides were pre-
pared through the reaction of a substituted aniline and
maleic anhydride in acetic anhydride.29
5.6. Experimental procedures
5.6.1. Compound synthesis. 9-(40-Methylphenylsulfonyl)-
4-(300-nitrophenyl)-(2R,6S,8R,10S)-4,9-diazatetracycle
[5.3.1.02,6.08,10]undecane-3,5-dione (4i). p-Toluenesulf-
onylazide (0.96 g, 0.0049 mol) was added to a mixture
of 4-(30-nitrophenyl)-4-aza-tricycle[5.2.1.02,6-endo]dec-8-
ene-3,5-dione (0.92 g, 0.0033 mol) in acetonitrile
(20 mL). The reaction was refluxed (26 h) and the sol-
vent was evaporated under vacuum. The solid residue
was triturated with methanol/chloroform (3:7) and fil-
tered off by suction to give the mixture of (3i) and (4i).
The endo–endo (4i) product was isolated by column
chromatography (silica gel, ethyl acetate/acetone/
hexane, 6:3:11). Yield: 88 %; mp (dec.) 280.0 °C Anal.
Calcd for C22H19N3 O6S: C, 58.27; H, 4.23; N, 9.27;
O, 21.16; S, 7.07. Found: C, 58.81; H, 4.58; N, 7.54.
1H NMR d ppm: CH2-11 (m: 1.90); CH2-11 and CH3–
Ph (br s: 2.32); CH-7 (s: 3.16); CH-8 (s: 3.30); CH-6
(s: 3.60); ArH (m: 7.06–8.32). 13C NMR d ppm: CH3–
Ph (21.56); CH2-11 (40.22); CH-7 (48.05); CH-8
(49.63); CH-6 (55.09); C Ar (123.87; 126.25; 128.12;
129.47; 132.34; 138.20; 145.24; 146.08); C@O (174.50).
All compounds were characterized by CHN analysis, 1H
NMR and 13C NMR.29 For exo–endo (4c) and endo–en-
do (4b) we also determined the molecular and crystal
structures by X-ray diffraction.30
5.3. Animals
Male adult Swiss mice (30–45 g) were used in all exper-
iments. They were housed in groups of 20 animals per
plastic cage under controlled conditions of light (from
07:00 to 19:00 h) and temperature (23 2 °C). The ani-
mals 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 behavioral
assessment. For each treatment, a different group of
experimental and control animals was used. All tests
were carried out according to international standards
of animal welfare recommended by the Brazilian Society
of Neuroscience and Behavior (Act 1992) and approved
by the local Committee for Animal Care in Research (#
081/CEUA and 23080.001156//2001-50/UFSC). The
minimum number of animals and duration of observa-
tion required to obtain consistent data were employed.
By this procedure the following imidobenzenesulfonyl-
aziridines were prepared:
9-(40-Methylphenylsulfonyl)-4-(400-fluorophenyl)-(2R, 6S,
8R,10S)-4,9-diazatetracycle[5.3.1.02,6.08,10]undecane-3,5-
dione (4j). Yield: 73%; mp 242.3–242.7 °C. Anal. Calcd
for C22H19FN2O4S: C, 60.39; H, 4.90; F, 3.18; N, 4.69;
O, 16.09; S, 10.75. Found: C, 60.45; H, 4.82; N, 5.02.
1H NMR d ppm: CH2-11 (d: 1.93, J = 10 Hz); CH2-11
and CH3–Ph (m: 2.34); CH-7 (s: 3.09); CH-8 (m: 3.23);
CH-6 (s: 3.56); ArH (m: 7.05 – 7.59). 13C NMR d
ppm: CH3–Ph (22.31); CH2-11 (40.75); CH-7 (48.73);
CH-8 (50.38); CH-6 (55.09); C Ar (115.99; 116.44;
128.54; 128.71; 129.05; 130.15; 133.29; 145.80; 164.73);
C@O (175.74).
5.4. Forced-swimming test
The forced-swimming procedure was a modification of
that described by Porsolt et al.11,12 Briefly, animals were
submitted to a swimming stress session for 15 min, 24 h
before being individually returned to the same plastic
cylinders (height 18.5 cm, diameter 12.5 cm) containing
13.5 cm of water at 25 °C, for 5 min. On the test day,
the behavioral observation was performed for up to
5 min by an experienced observer, who was blind to
the treatment condition. Animals were judged to be
immobile when they ceased struggling and remained
floating motionless in the water, making only those
movements necessary to keep the head above water.
9-(40-Methylphenylsulfonyl)-4-(400-hidroxyphenyl)-(2R,
6S,8R,10S)-4,9-diazatetracycle[5.3.1.02,6.08,10]undecane-
3,5-dione (4k). Yield: 81%; mp 128.8–129.4 °C. Anal.
Calcd for C22H20N2O5S: C, 62.25; H, 4.75; N, 6.60;
O, 18.85; S, 7.55. Found: C, 61.92; H, 4.84; N,
6.52. 1H NMR d ppm: CH2-11 (m: 1.97); CH2-11
and CH3–Ph (s: 2.33); CH-7 (s: 3.11); CH-8 (s:
3.23); CH-6 (s: 3.60); ArH (m: 7.58).13C NMR d
ppm: CH3–Ph (21.64); CH2-11 (40.09); CH-7
(47.99); CH-8 (49.64); CH-6 (55.25); C Ar (121.82;
126.90; 128.36; 129.51; 130.15; 132.61; 145.12;
149.57); C@O (174.96).
5.5. Open-field test
The spontaneous motor activity was measured in an
open-field made of transparent Plexiglas (height,

F. S. Duarte et al. / Bioorg. Med. Chem. 14 (2006) 5397–5401
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Duarte is a recipient of a Ph.D. scholarship and E. S.
Andrade was also a Ph.D. recipient from CNPq while
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authors wish to thank Dr. Gareth Cuttle for final
English revision of the text.
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