New thioureas based on thiazolidines with antioxidant potential

Article abstract of DOI:10.1016/j.tetlet.2015.10.037

Thiazolidine and pyrrolidine compounds containing a thiourea moiety were prepared using boric acid as a coupling agent in a multicomponent methodology. In addition, the antioxidant activity, as reflected by free radical scavenging, was evaluated. Some compounds were selected and tested in different antioxidant experiments and all of them were shown to be useful for the prevention of oxidative stress in biological systems and thus capable of reducing cellular injury.

Full text of DOI:10.1016/j.tetlet.2015.10.037

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New thioureas based on thiazolidines with antioxidant potential
Tiago Lima da Silva a, Laura Maria Forain Miolo a, Fernanda S. S. Sousa b, Lucimar M. P. Brod b,
Lucielli Savegnago b, Paulo Henrique Schneider a,
⇑
a Instituto de Química, Universidade Federal do Rio Grande do Sul (UFRGS), PO Box 15003, 91501-970 Porto Alegre, RS, Brazil
b Centro de Desenvolvimento Tecnológico—Unidade Biotecnologia, Grupo de Pesquisa de Neurobiotecnologia-UFPel, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Thiazolidine and pyrrolidine compounds containing a thiourea moiety were prepared using boric acid as
a coupling agent in a multicomponent methodology. In addition, the antioxidant activity, as reflected by
free radical scavenging, was evaluated. Some compounds were selected and tested in different antioxi-
dant experiments and all of them were shown to be useful for the prevention of oxidative stress in
biological systems and thus capable of reducing cellular injury.
Received 24 September 2015
Accepted 9 October 2015
Available online xxxx
Keywords:
Thiazolidine
Thiourea
Ó 2015 Elsevier Ltd. All rights reserved.
Thiosemicarbazide
Boric acid
Antioxidant
Introduction
its derivatives are important drug candidates, and they have
already been screened against several disorders. Anti-convulsant,
Recently, compounds containing
a
thiourea moiety have
sedative, antidepressant, anti-inflammatory, anti-hypertensive,
antihistaminic and anti-arthritic activities are a few among many
other biologically important properties shown by these
promising compounds.12a Recently, our group reported that
besides their antioxidant properties Se-phenyl thiazolidine
derivatives produced anti-nociceptive activity in experimental
models and did not modify any biochemical or locomotor
parameters or exploratory activities in mice.12b–d In addition,
they also have been used as important chiral pools for the
synthesis of several chiral ligands and organocatalysts.13
To the best of our knowledge, this is the first Letter in which a
thiourea containing a thiazolidine moiety has been described.
Therefore, it seems interesting to join together these two molecu-
lar fragments that have already proved separately to have impor-
tant biological activities. Herein we describe our efforts on the
development of a new methodology to synthesise new thioureas
based on thiazolidine and pyrrolidine heterocycles through a mul-
ticomponent reaction using boric and boronic acids as coupling
agents. An important feature of this new methodology is that it
avoids the use of high-cost coupling reagents, protection groups
or multiple steps to afford the final product.
received attention due their broad applications as organocatalysts1
in different asymmetric chemical reactions, such as Michael,2 Man-
nich,3 Diels–Alder,4 Friedel Craft5 and other reactions. Further-
more, thiourea has been applied as selective chemical sensor for
heavy metals6 as well as other environmentally toxic compounds.
Additionally this important class of compounds has shown impor-
tant biological properties such as anti-cancer,7 human anti-para-
sitic8 and other activities. Thiourea derivatives are also very
promising as building blocks for the synthesis of polymers9 or as
antioxidant9a components in polymer synthesis.
The classical methodologies for the synthesis of thioureas1e,10
are very efficient, leading to good or excellent product yields.
However, the classical methods involve the use of isothiocyanate,
thiophosgene and thiocyanate salts, which are very toxic and
harmful to the environment.10 Therefore new methodologies have
been developed to avoid using toxic starting materials while
retaining good yields. The use of carbonylimidazole (CDI)10d as a
substitute for thiophosgene, and the use of sunlight10a as the
reaction promoter are examples of safe, cheap and environmental
friendly methodologies.
In connection with this, thiazolidine derivatives have broad
applicability in medicinal chemistry having anti-cancer,11 anti-
HIV12e and other important biological activities. Thiazolidine and
Results and discussion
In 1996, Yamamoto described the synthesis of amides using
boronic acids as coupling reagents and organic acids and amines
as starting materials.14a An extension of this work was later
⇑
Corresponding author. Tel.: +55 51 3308 9636; fax: +55 51 3308 7304.
E-mail address: paulos@iq.ufrgs.br (P.H. Schneider).
http://dx.doi.org/10.1016/j.tetlet.2015.10.037
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
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2
T. L. da Silva et al. / Tetrahedron Letters xxx (2015) xxx–xxx
R2OH
3
R1
OH
OH
OR2
OR2
O
O
OR2
B
H+
B(OH)3
OH
R1
R1
+
O
O
O
5
4
1
2
Scheme 1. Proposed mechanism for the boric acid-catalysed esterification.13c
O
O
S
S
B(OH)3
2
S
S
N
H
N
HN
OH
N
H
H2N
toluene - 24h
HN
O
+
110°C
O
yield = 35%
7
6
8
Scheme 2. Coupling reaction between N-protected compound 6 and thiourea 7.
Table 2
Thioureas synthesised by reaction coupling using boric acida
Table 1
Catalytic activities of boronic and boric acida
O
HN
8
O
X
X
O
HN
8
O
OH
S
S
S
S
Catalyst
S
S
N
H
N
H
OH
N
H
7
Catalyst
N
H
N
H
HN
H2N
N
H
7
+
HN
H2N
9
+
9
X= C, S
Entry
1
Catalyst
Catalyst
load (mol %)
Solvent
Toluene
Time
(h)
Yieldb
(%)
Entry
Carboxylic acid
Load of catalyst
(mol %)
Solvent
Time
(h)
Yieldb
(%)
HO
OH
O
B
10
10
24
36
OH
1
2
3
30
30
30
30
Toluene
Toluene
Toluene
Toluene
12
47
51
—
N
H
OH
O
CF3
S
S
2
Toluene
24
33
12
12
12
HO
HO
HO
HO
HO
HO
HO
N
OH
B
OH
CF3
H
O
S
OH
B
OH
3
4
5
6
7
8
10
20
30
40
30
30
o-Xylene
Toluene
Toluene
Toluene
Toluene
Toluene
24
24
24
24
12
6
4
41
47
45
51
30
N
H
OH
OH
O
B
OH
4
—
N
OH
OH
B
OH
a
Experimental details: carboxylic acid (2.0 mmol), thiourea (2.2 mmol), toluene
in refluxing (10 mL) using Dean–Stark apparatus, 12 h.
OH
b
B
OH
Isolated yields.
OH
B
OH
Based on these previous results we envisioned the use of this
methodology for the coupling of thioureas and thiazolidine car-
boxylic acids. As the starting point, we chose the thiazolidine-N-
OH
B
Boc-protected 6 as an analogous a-hydroxy-acid, to react with N-
OH
phenyl thiourea 7 using 10 mol % of boric acid 2 as the coupling
reagent, in azeotropic reflux of toluene for 24 h. To our delight, we
obtained the unprotected compound 8 at 35% yield in one single step
(Scheme2). Thisresultsuggestsadualrolefortheboricacid, whereit
can act as a coupling reagent as well as a deprotecting agent. With
this result in hand, we performed another experiment, now using
the thiazolidine–4-carboxilic acid 9 without the amino group pro-
tection under the same conditions and as expected, after 24 h, we
obtained the compound 8 at 36% yield (entry 1—Table 1).
a
Experimental details: carboxylic acid (2.0 mmol), thiourea (2.2 mmol), solvent
(10 mL).
b
Isolated yields.
reported in which they used boronic acids for the coupling of
a-
hydroxy-acids and alcohols to afford esters in good to excellent
yields, keeping the stereoisomeric information from the
carboxylic acid.14a,b In both Letters the ordinary intermediate 4, a
To establish the best reaction conditions we investigated the
effect of catalyst loading, reaction time, solvent and temperature
bis-chelated compound from
a-hydroxy-acid -to boron catalyst,
was reported (Scheme 1).14a–f
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T. L. da Silva et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
O
X
O
HO
OH
B
O
N
H
-H2O
X
OH
S
O
2
OH
X
X
O
O
N
N
H2N
B
O
N
HO
N
H
HN
OH
B
OH
H2O
7
X
O
10
11
O
X= C, S
X
S
N
H
HN
O
HN
X
O
N
HO
B
OH
10
Scheme 3. Proposed reaction mechanism.
Table 3
increase in the amount of catalyst from 30 mol % to 40 mol % did
not improve the reaction yield (Table 1, entries 5 and 6). Having
established the optimum amount of catalyst we carried out two
more experiments with reduced reaction times, and found that
after 12 h the desired product was obtained with satisfactory
yields (Table 1, entry 7).
Multicomponent reaction to synthesise thiosemicarbazides based on pyrrolidine and
thiazolidinea
O
S
C
H
N
R2
AcOH ( Cat.)
MeOH
NH2
O
R1
O
H2N
13
Products
N
R2
N
H
N
H
+
+
R1
C
With the optimal condition in hand, we extended the protocol
S
12
14
15
to other thiazolidine derivatives as well as to
L
-proline. When -
L
proline was reacted with the respective thiourea 7, the desired pro-
duct was obtained at 46% yield (Table 2, entry 1). However the
reaction failed when substituted thiazolidine derivatives were
used (Table 2, entries 3 and 4). Probably the methyl group at the
nitrogen (entry 3), as well as, the bis-methyl group at position-2
of the heterocycle (entry 4) can negatively affect intermediate for-
mation through steric hindrance, as can be seen in Scheme 3.
Taking into account the results obtained from the carboxylic acid
variation we propose a reasonable mechanism for this coupling
reaction, also based on Yamamoto’s previous work.14f First the
complex 10 can be formed between the boric acid and carboxylic
Entry
1
Yieldb (%)
35
H
S
S
N
H
S
N
N
H
N
H
16
O
H
N
H
2
3
35
43
N
N
H
N
H
17
O
CF3
H
acid, as has been proposed for a-hydroxyl-acid derivatives. It was
N
S
H
also reported in previous work that this complex 10 can exist in
equilibrium with the dimeric form 11, which can explain the lack
of reactivity of substituted thiazolidines (Table 2, entries 3 and 4).
The subsequent nucleophilic attack of the amino moiety from the
thiourea derivative to the carbonyl moiety in complex 11 releases
the respective product and retrieves the boron catalyst back to the
reaction medium.
S
N
N
H
CF3
N
H
O
18
a
Experimental details: 12 (2.0 mmol), 13 (2.0 mmol), 14 (2.0 mmol), acetic acid
(droplet), refluxing methanol (10 mL), 12 h.
b
Isolated yields.
Keeping in mind the importance of this class of compounds and
combined with our long-term interest in the synthesis of thiazo-
lidine derivatives, we next turned our attention to the synthesis
of new thiazolidines containing a thiosemicarbazide moiety, in
order to evaluate the influence of their chemical structure on their
biological activities. According to the literature, thiosemicarbazide
derivatives have been described as potential anti-parasitic,15a,b,h
antibiotic,15i,e and antioxidant14c,d,f,g,j agents, among other
properties. This class of molecules also has a thiourea moiety
embedded in the molecular structure, which makes them
interesting for comparison with our previously synthesised
thiazolidines. Usually the synthesis of thiosemicarbazide
derivatives takes more than two steps and requires purification
by chromatographic techniques.15 This fact prompted us to explore
a new approach for the development of a more efficient and gen-
eral method to obtain thiosemicarbazides. For that purpose we
designed a one-pot multicomponent reaction between the methyl
on the reaction yield (Table 1). As can be seen from Table 1, boric
acid (entry 1—Table 1) and boronic acid (entry 2—Table 1) fur-
nished the desired product in similar yields. However due to the
nature of boric acid, which is cheap and easily available, we
decided to continue our studies by employing it as the catalyst.
In order to evaluate the effect of the reaction temperature, we
changed the solvent to xylene for the azeotropic reflux and
observed a dramatic decrease in the reaction yield. The poor yield
obtained for compound 8 in this case can be ascribed to the high
boiling point of the xylene, which can induce decomposition of
the starting material, as could be observed by TLC (Table 1, entry
3). The catalyst loading was shown to be crucial in order to obtain
of the desired product in satisfactory yields. Next, we observed that
the amount of the boric acid catalyst is an important feature, since
an improvement in yield from 36% to 47% was achieved when
30 mol % of boric acid was used (Table 1, entries 1 and 5). A further
Please cite this article in press as: da Silva, T. L.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.037

4
T. L. da Silva et al. / Tetrahedron Letters xxx (2015) xxx–xxx
S
R1
=
Pathway II
Pathway I
O
or
or
N
H
N
H
R1
12
CF3
NH2
NH2
+
R2
H2N
+
O
H2N
13
NCS
13
R2
=
14
CF3
O
O
R1
R2
NCS
O
S
S
R2
NH
H
N
R1
12
14
R1
R2
N
H
N
H
HN NH2
19
H2N NH
15
O
20
Scheme 4. Mechanism proposed for the multicomponent reaction to synthesise thiosemicarbazides based on pyrrolidine and thiazolidine.
Table 4
DPPH scavenging activity of thiourea
Compound
Concentration (lM)
IC50
10
50
100
500
H
S
S
N
N
H
N
S
S
S
21.83 4.04***
86.43 5.26***
92.25 3.60***
95.44 1.39***
27.66 2.51
N
H
N
H
16
O
CF3
H
36.01 5.69***
94.13 0.56***
94.90 0.92***
92.16 0.99***
20.33 2.31
23.00 2.64
H
N
N
H
CF3
N
H
O
O
18
S
37.69 3.99***
91.68 1.81***
93.11 1.63***
93.25 2.57***
N
H
N
H
N
19
H
Each value is expressed as mean SD (n = 3). Asterisks represent a significant effect compared with controls without thiourea assessed using Newman–Keuls multiple range
tests. IC50 is the concentration (lM) of thiourea required to reduce the initial concentration of DPPH radicals by 50%.
***
p <0.001.
Table 5
ABTS radical scavenging activity of thiourea
Compound
Concentration (lM)
IC50
1
5
10
50
—
100
—
H
S
S
N
N
H
N
S
S
S
10.41 4.37
58.03 13.94***
90.60 10.16***
2.83 0.7
N
H
N
H
16
O
CF3
H
5.38 2.35
8.78 3.89
55.02 10.94***
73.97 4.38***
93.79 7.33***
97.14 0.77***
4.54 0.5
5.15 1.5
H
N
N
H
CF3
N
H
O
O
18
S
48.54 8.56***
80.57 24.32***
98.81 1.61***
98.45 1.10***
N
H
N
H
N
19
H
Each value is expressed as mean SD (n = 3). Asterisks represent significant effects compared with controls without thiourea assessed using Newman–Keuls multiple range
tests. IC50 is the concentration (lM) of thiourea required to reduce the initial concentration of ABTS radicals by 50%.
***
p <0.001.
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T. L. da Silva et al. / Tetrahedron Letters xxx (2015) xxx–xxx
5
Table 6
Ferric reducing-antioxidant power (FRAP) assay
Compound
Concentration (lM)
1
5
10
50
—
H
S
S
N
N
H
N
S
S
S
0.223 0.02
0.428 0.04***
0.645 0.06***
N
H
N
H
16
O
CF3
H
0.190 0.07
0.150 0.01
0.201 0.09
0.387 0.07*
0.641 0.13**
1.515 0.29***
H
N
N
H
CF3
N
H
O
O
18
S
0.448 0.13**
1.638 0.18***
N
H
N
H
N
19
H
Each value is expressed as mean SD (n = 3). Asterisks represent significant effects compared with controls without thiourea assessed using Newman–Keuls multiple range
tests.
*
p <0.05.
p <0.01.
p <0.001.
**
***
ester from
L
-proline or thiazolidine derivatives, hydrazine hydrate
results demonstrate that thiourea 18 is more potent than thiourea
16 but is not different from thiourea 19 at scavenging the DPPH
radical.
and aryl isothiocyanate. In our first attempt, the reaction was car-
ried out using acetic acid as the catalyst in methanol, and after 12 h
the desired thiosemicarbazide was obtained in 35% yield, after only
one purification step. It is important to mention that this new pro-
cedure fulfils some important criteria consistent with green chem-
istry principles such as reducing synthesis steps, reducing
purification steps and atom economy, therefore adding an environ-
mental and financial value to this multicomponent strategy.
This new methodology was next applied and three new
thiosemicarbazides were synthesised, with the variation at the
heterocyclic ring or at the aromatic portion of the molecule
(Table 3).
For this reaction we proposed a reaction mechanism where the
pathways to reach the product are degenerate as described previ-
ouslyforthesynthesisofthiosemicarbazones.16 Thereactioncanfol-
low the pathway 1 (Scheme 4) where the first step is the reaction
between the methyl ester 12 and hydrazine 13 to afford, as interme-
diate, compound 19 which, at the end, reacts with aryl isothio-
cyanate resulting in thiosemicarbazide 15. On the other hand,
following pathway 2, the thiosemicarbazide 20 is produced first
and thereafter reacts with methyl ester 12 derivatives furnishing
the thiosemicarbazide 15. Thus, both pathwayslead to thesame pro-
duct, and therefore they are degenerate pathways (Scheme 4).
The main role of an antioxidant molecule is decreasing oxida-
tive stress during any cell injury.17 A large number of cellular pro-
cesses including those related to injuries generate reactive oxygen
species—ROS—which are quite harmful to cell integrity.17a,c,d
In the ABTS assay thioureas 16, 18 and 19 exhibited scavenging
activity of ABTS present at 5
lM, with IC50 values of 2.83 0.76,
4.54 0.5 and 5.15 1.5 M, respectively (Table 5). These results
l
demonstrate that thiourea 16 is more potent than thiourea 18
and 19 at scavenging the ABTS radical.
Based on these results, thioureas 16, 18 and 19 neutralised the
DPPH radical and quenched the ABTS free radicals. The DPPH and
ABTS radicals are stable free radicals commonly used as substrates
to evaluate in vitro antioxidant activity and to evaluate the ability
of antioxidants to scavenge free radicals, which are known to be a
major factor in the biological damage caused by oxidative stress.
Antioxidants can scavenge DPPH radicals by hydrogen donation,
which causes a decrease in DPPH absorbance19a,c,d and the ABTS
radical reacts quickly to electron donors. Thus, thioureas 16, 18
and 19 could prevent or decrease the damage to the human body
caused by free radicals, which attack biological macromolecules
such as lipids, proteins and DNA by hydrogen donation or by
acting as electron donors.
In addition to the antioxidant capacity of the thioureas in the
DPPH and ABTS assays, thioureas 16, 18 and 19 also showed reduc-
ing properties. The FRAP method is based on a redox reaction, in
which an easily reduced oxidant (Fe3+) is used in stoichiometric
excess and antioxidants act as reductants.19b Several previous
studies have shown that the electron donation capacity of
bioactive compounds, reflecting their reducing power, is
associated with their antioxidant activity.20 Thus, the reducing
capacity of a compound may serve as a significant indicator of its
potential antioxidant activity. In this study, thiourea 16 had a
Therefore, suitable antioxidant molecules must have
a high
capacity to trap ROS before they can cause injury to cells.17b,c
Furthermore, these compounds must present their antioxidant
activity at low concentration as well as with low toxicity.17e
From our set of synthesised molecules we chose those molecules
containing a thiazolidine heterocycle for the evaluation of their
antioxidant activity, because their biological activity as
antioxidants,18b–e,i antibiotics18a,f–h and anticancer agents11 has
previously been reported in the literature.
reducing capacity at concentrations ranging from 5 to 10
reaching the maximum absorbance at 50
reducing capacity at concentrations ranging from 10 to 50
reaching the maximum absorbance at 100
had a reducing capacity at concentrations ranging from 5 to
50 M reaching the maximum absorbance at 100 M (see Table 6).
l
M
lM. Thiourea 18 had a
lM
l
M and thiourea 19
l
l
Thioureas exhibited antioxidant activity in the DPPH and ABTS
radical scavenging assays at different concentrations. In the DPPH
assay thioureas 16, 18 and 19 exhibited scavenging activity for this
Conclusion
radical present at 10
20.33 2.31 and 23.00 2.64
l
M
with IC50 values of 27.66 2.51,
M, respectively (Table 4). These
We have developed two new methodologies to synthesise novel
compounds based on thiourea, thiazolidine and pyrrolidine. The
l
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6
T. L. da Silva et al. / Tetrahedron Letters xxx (2015) xxx–xxx
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Acknowledgments
We are grateful to CAPES, CNPq, INCT-CMN and FAPERGS for
financial support. We would especially like to thank the researcher
Lucielli Savegnago and her students who helped with the perfor-
mance of all of the antioxidant tests in this work.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
037.
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