Cobalt(III) complexes with thiosemicarbazones as potential anti-Mycobacterium tuberculosis agents

Article abstract of DOI:10.5935/0103-5053.20140149

Co^III complexes derived from 2-acetylpyridine N(4)-R thiosemicarbazone (Hatc-R, R = alkyl, aryl) have been characterized by elemental analysis, FTIR, UV-Visible and ¹H NMR spectroscopies, cyclic voltammetry (CV), conductimetry measur

Full text of DOI:10.5935/0103-5053.20140149

http://dx.doi.org/10.5935/0103-5053.20140149
J. Braz. Chem. Soc., Vol. 25, No. 10, 1848-1856, 2014.
Printed in Brazil - ©2014 Sociedade Brasileira de Química
0
103 - 5053 $6.00+0.00
Article
A
Cobalt(III) Complexes with Thiosemicarbazones as Potential
anti‑Mycobacterium tuberculosis Agents
a
b
c
c
Carolina G. Oliveira, Pedro Ivo da S. Maia, Marcelo Miyata, Fernando R. Pavan,
c
d
,a
Clarice Q. F. Leite, Eduardo Tonon de Almeida and Victor M. Deflon*
a
Instituto de Química de São Carlos, Universidade de São Paulo, 13566-590 São Carlos-SP, Brazil
Departamento de Química, Universidade Federal do Triângulo Mineiro, 38025-440 Uberaba-MG, Brazil
b
c
Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, 14801-902 Araraquara-SP, Brazil
d
Instituto de Química, Universidade Federal de Alfenas, 37130-000 Alfenas-MG, Brazil
III
Complexos de Co derivados da 2-acetilpiridina N(4)-R tiossemicarbazona (Hatc-R, R = alquil
ou aril) foram caracterizados por análise elementar, espectroscopia na região do infravermelho,
1
UV-Visível e H RMN, voltametria cíclica (VC), medidas de condutividade e difração de raios X
II
III
em monocristal. Os resultados obtidos são consistentes com a oxidação do centro de Co para Co
após a coordenação N,N,S-tridentada e monoaniônica dos ligantes tiossemicarbazonas, resultando
em complexos octaédricos iônicos do tipo [Co(atc-R) ]Cl. Os estudos de eletroquímica mostram
2
III
II
II
I
dois processos reversíveis, referentes aos pares redox Co /Co e Co /Co , que são afetados pelo
efeito indutivo dos grupos substituintes na posição N4 dos ligantes. Dois complexos de Co se
III
mostraram satisfatoriamente ativos, com valores de concentração inibitória mínima abaixo de
–
1
1
0 μmol L e um deles apresentou muito baixa citotoxicidade contra células VERO e J774A.1
(
IC ), conferindo-lhe altos índices de seletividade (SI > 10).
5
0
III
Co complexes derived from 2-acetylpyridine N(4)-R thiosemicarbazone (Hatc-R, R = alkyl,
1
aryl) have been characterized by elemental analysis, FTIR, UV-Visible and H NMR spectroscopies,
cyclic voltammetry (CV), conductimetry measurements and single crystal X-ray diffractometry. The
II
III
results obtained are consistent with the oxidation of the Co center to Co upon coordination of the
monoanionic N,N,S-tridentate thiosemicarbazone ligands, resulting in octahedral ionic complexes
of the type [Co(atc-R) ]Cl. Electrochemistry studies show two reversible processes referring to
2
III
II
II
I
the redox couples Co /Co and Co /Co which can be modified by the inductive effects of the
III
substituents groups at the N4 position of the ligands. Two Co complexes showed satisfactory
activity with minimal inhibitory concentration value under 10 μmol L and one presented quite low
cytotoxicity against VERO and J774A.1 cells (IC ), resulting in high selectivity index (SI > 10).
–1
50
Keywords: cobalt(III), thiosemicarbazones, anti-mycobacterium tuberculosis activity
3
Introduction
treatment, the TB problem is still expanding world-wide.
It’s estimated that one-third of the world’s population
is infected with dormant forms of MTB, 10% of which
will develop the disease among their lives. The actual
Tuberculosis (TB) still causes the death of millions
of people every year, more than any other disease around
4
the world, as described by the World Health Organization
research on TB has been focused on the increased number
of multidrug and extensively drug-resistant TB (MDR- and
1
(WHO). The pathogenicity of Mycobacterium tuberculosis
5
(
MTB), the human pathogen responsible for TB, is
XDR-TB), especially in HIV-positive patients, giving
6
based on the development of methods to survive inside
host cells, comprising the capacity to take possession
rise to very high mortality. The number of promising
anti-TB drugs following pre-clinical tests has increased
and although they involve diverse possible mechanisms, no
one targets dormant bacteria, which means that the latent
2
of macrophages. Despite a 95% efficacious 6-month
7
*
e-mail: deflon@iqsc.usp.br
infections cannot be eliminated by the moment. Therefore,

Vol. 25, No. 10, 2014
Oliveira et al.
1849
it is mandatory to develop new anti-MTB agents that can
solve the current therapy problems and inhibit the growth
of pathogenic microorganisms in their latent forms.
Biologically active transition metal complexes
containing the desired thiosemicarbazide (10 mmol)
and 2-acetylpyridine (10 mmol) for 1 h, as reported
elsewhere.
29,30
8-11
constitute an increasing research area. Metals like Mn,
Fe, Co, Ni, Cu and Zn, even in a very low concentration
in human body, are responsible for a series essential of
Instruments
FTIR spectra were measured as KBr pellets on a
1
0
biological functions being studied in the bioinorganic
Shimadzu IR Prestige-21 spectrophotometer between
1
2-14
−1
chemistry field.
Cobalt is an essential element for life
400 and 4000 cm . Elemental analyses were determined
being the main component of Vitamin B12, which is an
essential micronutrient that is required for human health
and, more importantly, is required in large quantities by
using a Leco Instrument, model Truspec CHNS-O.
The conductivities of the complexes were measured in
-3
–1
1 × 10 mol L MeOH or H O solutions using an Orion Star
2
1
5
cells that are replicating DNA prior to cell division.
Series conductometer. UV-visible (UV-Vis) spectra were
measured with a Shimadzu UV-1800 spectrophotometer
in MeOH solutions. The electrochemical experiments
were carried out at room temperature in acetonitrile
Moreover, a lot of new cobalt compounds have been
demonstrated to possess particular biological activities,
16-20
such as antitumor and antibacterial.
The interest on the thiosemicarbazones (TSCs) and their
–1
containing 0.1 mol L tetrabutylammonium perchlorate
(PTBA) (Fluka Purum) as supporting electrolyte, using an
electrochemical analyzer μAutolab III. Cyclic voltammetry
experiments were performed with a glassy carbon (CG)
working stationary electrode, a platinum auxiliary electrode
and an aqueous Ag/AgCl reference, carried out with a rate
21
metal complexes is due to their versatile chemistry and
2
2-26
pharmacological activities,
which also include anti-TB
1
1
properties. Frequently, the biological activity presented
by the free thiosemicarbazone ligands is enhanced upon
complexation. In an effort to select lead candidates for
treatment of TB, in the last few years we have studied
and reported complexes derived from thiosemicarbazones
2
7
–
1
–1
1
sweep of 100 mV s or 200 mV s . The H NMR spectra
were acquired using equipment Agilent 400/54 Premium
1
1
1
which presented a high anti-MTB activity. Precisely,
Shielded 9.4 T, working at 399.8 MHz for H. The NMR
IV
V 8
II 14
II
28
V
and V , Ni
and Mn complexes derived from
spectra were internally referenced to TMS.
Crystal structure determination
2-acetylpyridine thiosemicarbazones have shown excellent
activity against MTB. In this context, we focused our
interest in a continuation of the previous studies with some
of the first transition metal row by developing now new
Brown crystals of [Co(atc) ]Cl∙H O (1∙H O) were
2
2
2
III
Co compounds, cationic instead of neutral complexes
grown by slow evaporation of the ethanol mother solution
II
II
14,28
as the Ni and Mn compounds studied before.
Hence,
of 1. Crystals of [Co(atc-Ph) ]∙MeOH (5∙MeOH) were
2
believing in the high potential of such compounds as
anti-MTB agents and the biochemical features of cobalt,
here we describe the preparation of Co complexes derived
from 2-acetylpyridine-thiosemicarbazones, their full
characterization as well as the study of their anti-MTB
activity and cytotoxicity.
obtained by recrystallization of 5 in MeOH/CH Cl 1:2 at
2
2
room temperature. The data collections were performed
using Mo-Kα radiation (λ = 71.073 pm) on a BRUKER
APEX II Duo diffractometer. Standard procedures were
applied for data reduction and absorption correction.
The structures were solved with SHELXS97 using direct
III
31
methods, and all non-hydrogen atoms were refined with
3
2
Experimental
anisotropic displacement parameters with SHELXL97.
The hydrogen atoms were calculated at idealized positions
32
Materials
using the riding model option of SHELXL97. Table 1
presents more detailed information about the structures
determination.
2
-Acetylpyridine, thiosemicarbazide, 4-methyl-
3
4
-thiosemicarbazide, 4-ethyl-3-thiosemicarbazide,
-phenyl-3-thiosemicarbazide and analytical reagents
Determination of MICs
grade chemicals and solvents were obtained commercially
and used without further purification. 4-Cyclohexyl-3-
thiosemicarbazide was prepared as previously described.
The ligands Hatc, Hatc-Me, Hatc-Et, Hatc-Ch and Hatc-Ph
were prepared by refluxing equimolar ethanolic solutions
The anti-MTB activity of the compounds was
determined as MIC (minimal inhibitory concentration)
values by the REMA (Resazurin MicrotiterAssay) method
27
33
according to Palomino et al.

1
850
Cobalt(III) Complexes with Thiosemicarbazones as Potential anti-Mycobacterium tuberculosis Agents
J. Braz. Chem. Soc.
Table 1. Crystal data and structure refinement for [Co(atc) ]Cl∙H O (1∙H O) and [Co(atc-Ph) ]Cl∙MeOH (5∙MeOH)
2
2
2
2
1
∙H O
5∙MeOH
2
Empirical formula
Formula weight
Temperature / K
Wavelength / Å
Crystal system
C H ClCoN OS
C H ClCoN OS
2
1
6
20
8
2
29 30
8
498.90
665.11
296(2)
293(2)
0.71073
Monoclinic
0.71073
Monoclinic
Space group
P2 /n
P2 /c
1
1
Unit cell dimensions
a = 10.0774(4) / Å α = 90°
b = 17.4487(7) / Å β = 91.012(2)°
c = 11.6658(4) / Å γ = 90°
a = 9.9167(2) / Å α = 90°
b = 23.4163(5) / Å β = 121.17(10)°
c = 15.2784(3) / Å γ = 90°
3
Volume / Å
2050.97(14)
4
3035.55(11)
Z
4
–
3
Density (calculated) / (mg m )
1.616
1.455
–
1
Absorption coefficient / mm
F(000)
1.197
0.829
1024
1376
3
Crystal size / mm
0.19 × 0.17 × 0.06
2.10 to 25.35°
−12 ≤ h ≤ 11,
0.971 × 0.386 × 0.37
1.74 to 25.05°
Theta range for data collection
Index ranges
−11 ≤ h ≤ 11,
−27 ≤ k ≤ 24,
−16 ≤ l ≤ 18
−20 ≤ k ≤ 20,
14 ≤ l ≤ 14
−
Reflections collected
12598
18887
Independent reflections
Completeness to theta = 25.14° / %
Absorption correction
[R(int) = 0.0364]
99.3
[R(int) = 0.0181]
99.2
Semi-empirical from equivalents
0.7452 and 0.6388
Semi-empirical from equivalents
0.7452 and 0.6775
Max. and min. transmission
Refinement method
2
2
Full-matrix least-squares on F
Full-matrix least-squares on F
Data / restraints / parameters
3725 / 3 / 270
5327 / 0 / 382
2
Goodness-of-fit on F
1.037
1.068
Final R indices [I>2sigma(I)]
R indices (all data)
R = 0.0402, wR = 0.0981
R = 0.0316, wR = 0.0864
1
2
1
2
R = 0.0642, wR = 0.1112
R = 0.0367, wR = 0.0895
1 2
1
2
–
3
Largest diff. peak and hole / (e Å )
1.043 and −0.275
0.290 and −0.220
Cytotoxicity assay
Preparations
III
In vitro cytotoxicity assays (IC , half maximal
The Co complexes were synthesized by adding
0.25 mmol CoCl ∙6H O to solutions of 0.5 mmol of the
5
0
inhibitory concentration) were performed first on VERO
epithelial cells (ATCC CCL81). Following this approach,
the most selective compound (higher SI) was additionally
tested on the J774A.1 (ATCC TIB-67) murine macrophage
cell line. Both studies were recorded as reported before in
2
2
desired ligands in EtOH (15 mL). The resulting solutions
were stirred for 2 h under reflux. The solutions were kept
under slow evaporation at room temperature until brown
precipitates were formed. After 3 days the solids were
filtered off, washed with hexane and dried under vacuum.
2
8
a previously work.
Selectivity index
[Co(atc) ]Cl·H O (1·H O)
2
2
2
Yield 0.085 g (68%). Analysis: Calc. for
C H ClCoN OS : C, 38.52; H, 4.04; N, 22.46%. Found:
The selectivity index (SI) was calculated by dividing
IC50 for VERO cells by the MIC for the pathogen; if
SI ≥ 10, the compound is considered suitable for further
16
20
8
2
−1
C, 39.58; H, 4.19; N, 22.87%. IR (KBr) ν/cm 3259, 3101,
–5
–1
1620, 1598, 1035, 773; UV-Vis in 3.2 × 10 mol L MeOH
2
8
–1
–1
investigations.
solution [λ / nm (ε / L mol cm )]: 424 (4801), 365 (7289),

Vol. 25, No. 10, 2014
Oliveira et al.
1851
3
09 (14267), 233 (31028); Molar conductivity (Λ in H O):
(DMSO, 399.8 MHz): d 1.06-1.95 (m, 20H, Ch-H), 2.83
m
2
–
1
1
106.80 μS cm ; H NMR (DMSO, 399.8 MHz): d 2.80
(s, 6H, CH C=N), 3.84 (s, 2H, CH-Ch), 7.44-8.05 (m, 8H,
3
(
(
s, 6H, 2CH C=N), 7.45 (t, 2H, J 8.0 Hz, Py-H), 7.86-7.90
Py-H), 8.86 (s, 2H, NH-Ch).
3
m, 6H, 2Py-H and 2NH ), 8.02 (d, 2H, J 8.0 Hz, Py-H),
2
8.07 (t, 2H, J 8.0 Hz, Py-H).
[Co(atc-Ph) ]Cl (5)
2
Yield0.126g(80%).Analysis:Calc. forC H ClCoN S :
26
29
8 2
[
Co(atc-Me) ]Cl (2)
C, 53.12; H, 4.14; N, 17.70%. Found: C, 52.80; H, 4.73; N,
2
−
1
Yield0.085g(67%).Analysis:Calc. forC H ClCoN S :
17.25%. IR (KBr) ν/cm 3174, 1598, 1552 , 1074 , 752;
18
22
8 2
–5
–1
C, 42.48; H, 4.36; N, 22.02%. Found: C, 42.68; H, 4.55;
N, 21.61%. IR (KBr) ν/cm 3190, 1598, 1560, 1076,
7
[
UV-Vis in 2.21 × 10 mol L MeOH solution [λ / nm
−
1
–1
–1
(ε / L mol cm )]: 385 (20588), 315 (18190), 253 (37239);
–
5
–1
–1 1
73; UV-Vis in 1.96 × 10 mol L MeOH solution
Molar conductivity (Λ in MeOH): 88 μS cm ; H NMR
m
–1
–1
λ / nm (ε / L mol cm )]: 415 (10178), 367 (18214), 314
(DMSO, 399.8 MHz): d 2.99 (s, 6H, CH C=N), 7.08 (t,
3
(
1
24897), 260 (40102); Molar conductivity (Λ in H O):
60.00 μS cm ; H NMR (DMSO, 399.8 MHz): d 2.85
2H, J 6.0 Hz, Ph-H), 7.38 (t, 4H, J 8.0 Hz, Ph-H), 7.51 (t,
2H, J 6.0 Hz, Py-H), 7.69 (d, 4H, J 8.0 Hz, Ph-H), 8.02
(d, 2H, J 4.0 Hz, Py-H), 8.12-8.18 (m, 4H, Py-H), 10.37
(s, 2H, NH-Ph).
m
2
–
1
1
(s, 9H, 2CH C=N and 1CH NH), 2.97 (s, 3H, CH NH),
3
3
3
7
1
.45-8.09 (m, 8H, Py-H), 8.16 (s, 1H, NHCH ), 8.80 (s,
3
H, NHCH3).
Results and Discussion
[
Co(atc-Et) ]Cl·H O(3·H O)
2 2 2
Yield 0.086 g (61%). Analysis: Calc. for
C H ClCoN OS : C, 43.28; H, 5.09; N, 20.19%. Found:
Synthesis of the complexes
2
0
28
8
2
−1
C, 43.83; H, 5.17; N, 20.22%. IR (KBr) ν/cm 3197, 1598,
Reactions of CoCl ∙6H O with two equivalents
2
2
–
5
–1
1
556, 1078, 773; UV-Vis in 2.98 × 10 mol L MeOH
of Hatc-R in EtOH under reflux for 2 h results in
microcrystalline precipitates of the cobalt complexes 1-5 in
good yields (Scheme 1). Elemental analyses are consistent
–
1
–1
solution [λ / nm (ε / L mol cm )]: 413 (10302), 369
(
1
18993), 315 (25241); Molar conductivity (Λ in H O):
00 μS cm ; H NMR (DMSO, 399.8 MHz): d 1.00-1.20
m
2
–
1
1
+
with the formation of cationic complexes [Co(atc-R) ] , in
2
(
m, 6H, -CH CH ), 2.84 (s, 6H, CH C=N), 3.20-3.43 (m,
accordance with the observed molar conductivity values.
2
3
3
4
H, -CH CH ), 7.45-8.08 (m, 8H, Py-H), 8.16 (s, 1H,
All the compounds except [Co(atc-Ph) ]Cl are water
2
3
2
NHCH CH ), 8.86 (s, 1H, NHCH CH ).
soluble. They are very soluble in methanol and dimethyl
sulfoxide and sparingly soluble in dichloromethane and
chloroform, demonstrating a high hydrophilic character.
2
3
2
3
[
Co(atc-Ch) ]Cl (4)
2
Yield0.086g(53%).Analysis:Calc. forC H ClCoN S :
28
38
8 2
1
C, 52.13; H, 5.94; N, 17.37%. Found: C, 51.71; H, 6.70;
Infrared, UV-Vis and H NMR spectroscopies
−1
N, 16.81%. IR (KBr) ν/cm 3201, 1598, 1556, 1072, 775;
–5
–1
UV-Vis in 2.48 × 10 mol L MeOH solution [λ / nm
The IR spectra of the TSC ligands are characterized
by strong broad ν(NH) absorptions in the range
3365-3153 cm . One of them, around 3300 cm , is absent
–1
–1
(
ε / L mol cm )]: 428 (10967), 372 (21129), 316 (25564);
–1
1
−1
–1
Molar conductivity (Λ in MeOH): 100 μS cm ; H NMR
m
III
Scheme 1. Synthesis of the Co complexes.

1
852
Cobalt(III) Complexes with Thiosemicarbazones as Potential anti-Mycobacterium tuberculosis Agents
J. Braz. Chem. Soc.
III
1
in the spectra of the Co cationic complexes, according to
the monodeprotonation of these ligands.
The H chemical shift values of the free ligands were
8,30,35
III
previously reported.
H NMR behavior, with the hydrogen signals being found
as expected. The NH hydrogens of complex 1 are found
The Co complexes show similar
−
1
1
The ν(C=N) stretching band found around 1580 cm
–1
for the free Hatc-R is observed in the 1552-1620 cm range
for the complexes. The ν(N-N) band at higher frequencies
in the IR spectra of the complexes, between 1035 and
078 cm , comparing to those observed for the ligands,
in the 989-995 cm range, confirms coordination through
the azomethine nitrogen atom.
The ν(C=S) bands appear in two regions
1118-1074 cm and 800-846 cm ) for the free
2
at 7.90 ppm as a broad singlet, while the spectra of the
complexes 4 and 5 showed the NH signals at 8.86 and
10.37 ppm, respectively. For the complexes 2and 3, however,
two different signals relative to NH hydrogen atoms were
observed, at 8.81 and 8.16 ppm for 2 and at 8.86 and
8.17 ppm for 3. This is in accord with the non-equivalence
also observed for the methyl and ethyl groups, suggesting
that rotation around the C−NHR (R = ‑CH , −CH CH )
bond is not totally restricted. In fact, the methyl groups
attached to the NH fragments are also observed at different
chemical shifts for 2, one at 2.97 ppm and another one
around 2.85 ppm, overlapped with the signal for the methyl
–
1
1
–
1
13,34
–
1
–1
(
3
5
thiosemicarbazones, while for the complexes the C=S
3
2
3
–
1
42
only one band is observed (752-775 cm ), indicating
coordination through the sulfur atom and being consistent
with the deprotonation and consequent formation of a
C–S single bond in the thiosemicarbazone ligands. The
IR absorption bands assigned for the free ligands and
their cobalt complexes are consistent with the tridentate
coordination of the thiosemicarbazone derivatives in
a N,N,S-tridentate mode, through the sulfur atom, the
azomethine nitrogen and the pyridine nitrogen atoms,
forming octahedral complexes.
1
1
group of the CH −C=N moiety. The integration for this
3
broad peak (9 H) is consistent with this overlapping. In the
case of the complex 3, however, this observation is difficult
to confirm with certainty due to the overlapping of CH2
peakby residual water, while the methyl group appears as
a broad multiplet. For the complexes 1-5, the methyl group
The electronic spectra of the ligands show a band in
the 312-402 nm range, assignable to a combination of
internal n→π* and π→π*electronic transitions related to
(CH −C=N) is observed in the 2.80-2.99 ppm region. The
aromatic protons are observed between 7.08 and 8.18 ppm
for all the complexes.
3
3
0,36-39
III
the pyridine ring.
The spectra of the Co complexes
show the pyridine ring transitions, with the n→π* occurring
Crystal structures
at higher energies, below 300 nm, confirming the complexes
4
0
formation. Additional bands in the 360-400 nm range
ORTEP drawings of complexes1∙H O and 5∙MeOH with
2
are assignable as combinations of d→d transitions with
numbering scheme are represented in Figure 1. Crystal data
and structure refinement for both compounds are depicted in
Table 1. The cobalt complexes are monocationic, presenting
a chloride as counter ion. The thiosemicarbazone ligands
III
III
40
S→Co and Py→Co charge transfer transitions.
III 1
1
Therefore, it was not possible to see the Co T ← A
1g
1g
1
1
and T ← A allowed transitions usually observed in
2
g
1g
4
1
III
the visible region.
are coordinated to the Co center in N,N,S-tridentate mode
Figure 1. An ORTEP view of [Co(atc) ]Cl∙H O (1∙H O) (left) and [Co(atc-Ph) ]Cl∙MeOH (5∙MeOH) (right). Chloride and solvate molecules were omitted
2
2
2
2
for clarity.

Vol. 25, No. 10, 2014
Oliveira et al.
1853
and monoanionic form through the pyridine nitrogen atoms
N(1A) and N(1B), azomethine atoms N(2A) and N(2B) and
sulfur atoms S(1A) and S(1B).
Table 2. Selected bond lengths (Å) and angles (º) refined from X-ray
for 1∙H O and 5∙MeOH
2
1
∙H O
5∙MeOH
III
2
The Co complexes are clearly characterized by the
Bond Lengths
1.952(3)
II
smaller bond lengths compared to Mn [Mn(atc-Et) ]
2
Co(1)–N(1A)
Co(1)–N(2A)
Co(1)–N(1B)
Co(1)–N(2B)
Co(1)–S(1A)
Co(1)–S(1B)
S(1A)–C(8A)
S(1B)–C(8B)
N(3A)–C(8A)
1.9579(18)
1.8861(18)
1.9659(18)
1.8826(18)
2.2035(6)
2.2125(6)
1.745(2)
28
compound previously reported. This fact is assigned to
the change of the oxidation state +II to +III, resulting in a
larger attraction of the electrons from donor atoms of the
ligand. This fact is easily observed comparing the distances
of Co(1)–N(1) and Mn–N(1) 1.952(3) e 2.2806(15) Å,
respectively. The distance Co(1)–S(1A) = 2.2035(6) Å is
also shorter compared to Mn–S(1A) = 2.5216(5)Å distance.
Furthermore, the bond distances C(8A)–S(1A), 1.745(3) and
1.893(2)
1.959(3)
1.893(2)
2.2185(10)
2.2151(10)
1.745(3)
1.737(3)
1.741(2)
1
.745(2)Å for complexes 1∙H O and 5·MeOH, respectively,
1.321(4)
1.314(3)
2
are consistent with a single bond character. On the other
Bond Angles
82.82(11)
82.44(11)
95.85(11)
178.54(12)
98.15(11)
90.23(11)
95.43(9)
hand, the bond distance N(3A)–C(8A), 1.321(4)Å in 1∙H O
2
N(2A)–Co(1)–N(1A)
N(2B)–Co(1)–N(1B)
N(2B)–Co(1)–N(1A)
N(2B)–Co(1)–N(2A)
N(2A)–Co(1)–N(1B)
N(1A)–Co(1)–N(1B)
N(2B)–Co(1)–S(1A)
C(8A)–S(1A)–Co(1)
N(1A)–Co(1)–S(1A)
82.73(7)
82.55(7)
99.09(8)
177.90(7)
98.54(7)
90.41(7)
91.96(6)
94.47(7)
168.94(6)
and 1.314(3)Å in 5∙MeOH, shows a double bond character,
in accordance with the deprotonation of the TSCs ligands.
The coordination geometry around the metal
center is a distorted octahedron with the tridentate
thiosemicarbazone ligands perpendicular to each other
with N(1A)‑Co(1)‑N(2B) being close to 90º in both
complexes. A quite smaller distortion of the octahedral
94.58(12)
168.72(8)
III
angles is observed for the Co complexes when compared
II
28
with similar Mn compounds. This fact can be observed
through the bond angle N(2B)–M(1)–N(2A) that is around
III
1
59º in [Mn(atc-Et) ] and 178º in the Co complexes
2
studied here. The bond lengths are similar to those found for
III
43
other similar Co complexes. Selected data of interatomic
distances and main angles can be found in Table 2.
The crystal structure of 5∙MeOH is stabilized by
intermolecular hydrogen bonds, as shown in Figure 2. The
nitrogen atom N(4A) is H-bonded through H(4a) to the
oxygen atom O(1c) from a methanol molecule, while the
nitrogen atom N(4b) is H bonded with a chloride ion Cl(1),
which also interacts with a solvate molecule. The interactions
build a zigzag alignment of the species parallel to the c axis.
Figure 2. Crystalline and molecular structure of [Co(atc-Ph)2]
The crystal of 1∙H O is built up by intermolecular
2
Cl∙MeOH [N(4a)–H(4a)∙∙∙O(1c) = 158.3º, N(4b)–H(4)∙∙∙Cl(1) = 177.9º,
O(1)‑H(1)∙∙∙Cl(1) = 159.2º]. Symmetry operation used to generate O(1c),
H(1c) and Cl(1c): x, –y – 1/2, z – 1/2.
hydrogen bonds in diverse directions (see Supplementary
Information), which involve the NH groups, water solvate
2
molecules and chloride ions.
couples, while the two anodic processes correspond to the
I
II
II
III
Electrochemical studies
Co /Co and Co /Co couples. The complexes presented
here have an electrochemical behavior similar to that
III
44
All complexes presented a similar CV behavior,
observed for other Co complexes already reported.
showed exemplarily for 3 in Figure 3. One irreversible
Through the results depicted in Table 3, it is possible
to observe the inductive effects of the R group bonded
to the N(4) atom of the thiosemicarbazone ligand on
the redox potential values. The electron donating group
(R = Ch) tends to provide the more negative potential
(E1/2 = −1.10 V) while the electron withdrawing group
process and two well-defined quasi-reversible (i /i ≈1)
pa pc
waves are detected. The irreversible peak around 1.2 V is
assigned as an oxidation process involving the TSC ligand,
44
as previously reported for a similar compound. The two
III
II
II
I
cathode processes correspond to the Co /Co and Co /Co

1
854
Cobalt(III) Complexes with Thiosemicarbazones as Potential anti-Mycobacterium tuberculosis Agents
J. Braz. Chem. Soc.
Mycobacterium tuberculosis H RvATCC 27294. Synthetic
37
–1
compounds with MIC ≤ 12.5 μg mL are considered of
interest to be further evaluated in cytotoxicity tests, which
were primarily evaluated using normal epithelial cells
(
VERO). Complex 5, with SI ≥ 10 (SI = IC /MIC) for
50
VERO cells, was further analyzed against macrophages
cells J774A.1 (immunologic system cells).
The biological results (anti-MTB activity and cytotoxicity
against VERO cells) are shown in Table 4. Two cobalt
–1
complexes present MIC ≤ 12.50 μg mL , 4 and 5, with
–1
–1
values of 2.41 μmol L and 9.87 μmol L , respectively.
Complex 4 presented a similar activity as the free Hatc-Ch
–1 27
ligand (MIC = 2.82 μmol L ) while complex 5 was more
–1 27
+
–l
active than the free Hatc-Ph ligand (MIC = 57.75 μmol L ),
Figure 3. Cyclic voltammogram of [Co(atc-Et) ] (scan rate 100 mV s )
2
full amplitude and narrow amplitudes.
in this case improving the activity by complexation. In
the other cases the complexation to the Co didn’t lead
III
(
(
−
R = Ph) shifted the process to a less negative potential
E1/2 = −0.70 V), according to the order: −cyclohexyl <
to improvement on the activities in relation to the free
ligands. The cobalt salt CoCl ∙6H O was not effectively
2
2
–1
ethyl < −hydrogen < −methyl < −phenyl relative to
active (MIC > 105 μmol L ) showing that the activity of the
complexes cannot be merely associated to the presence of
the metal ion. Complex 5 presented quite low cytotoxicity
against VERO cells and therefore was also investigated on
III
II
Co /Co couple. In this context, the process relative to the
Co /Co couple presents the same trend, demonstrating
the same behavior to the first couple. In relation to the
second redox pair Co /Co the lower half-wave potential
is equal to −1.57 V (complex 4) and the higher potential
is E1/2 = −1.46 V (complex 5). Finally it is evidenced that
phenyl stabilizes better the oxidation state +II, while the
cyclohexyl group, with electron donating effect, reaches the
oxidation state +III easier than the other groups.
II
I
II
I
–1
macrophages cell line J774A.1 (IC = 988.79 μmol L )
50
resulting in high selectivity (SI = 100).
II
II
Ni and Mn structurally related compounds studied
1
4,28
before
showed to be more active in vitro than the
III
Co analogs studied here. This fact can be explained
by the increased polarity of the ionic Co compounds
III
II
II
II
We previously reported a similar trend with Mn
compared with the neutral Ni and Mn complexes, which
can influence the permeability through the lipid layer of
bacterial membrane resulting in a lower cellular inflow
of the active species. Otherwise, the cationic cobalt
complexes are very selective and also more water soluble
than the neutral nickel or manganese species, which could
enhance their absorption in vivo, compensating the eventual
lower cellular permeation.
II
III
complexes relative to oxidation of Mn /Mn and
Mn /Mn
influence of the groups bonded to N(4) atom observed
for Mn complexes is different for each redox pair. By
comparing the values found for manganese complexes,
it is possible to conclude that cobalt compounds oxidize
much more easily than the manganese ones, since cobalt
complexes are stabilized in oxidation state +III.
III
IV 28
with four of those ligands. However the
4
5
II
The high SI found for complex 5 shows its potential
for clinical use, with a wide difference between the
concentrations regarding the activity on the pathogen
and the cytotoxicity on normal epithelial VERO cells,
respectively. Furthermore, at the concentration the complex
is active on the pathogen it remains innocuous front the
Biological activity
The biological activity of the compounds was verified
by determining the values of MIC against strains of
III
II
II
I
Table 3. Cyclic voltammetry for the redox couples Co /Co and Co /Co for all four complexes, measured in acetonitrile with 0.1 M PTBA as the electrolyte
III II
/Co
II III
/Co
II
I
I
II
Complex
ECo
ECo
E1/2 / V
−0.80
−0.77
−0.80
−1.10
−0.70
ECo
E
E1/2 /V
−1.52
−1.50
−1.54
−1.57
−1.46
/Co
Co /Co
1
2
3
4
5
−0.86
−0.80
−0.86
−1.15
−0.73
−0.76
−0.73
−0.75
−1.02
−0.65
−1.54
−1.54
−1.60
−1.60
−1.52
−1.50
−1.47
−1.48
−1.54
−1.41

Vol. 25, No. 10, 2014
Oliveira et al.
1855
Table 4. Anti-MTB activity (MIC), cytotoxicity (IC ), and selectivity index (SI) of the complexes
5
0
MIC
IC50 (VERO cells)
a
Compound
SI
–
1
–1
–1
–1
/
μg mL
> 25
> 25
> 25
1.56
6.25
> 25
0.03
/ μmol L
> 50
/ μg mL
/ μmol L
872.05
950.69
178.89
18.31
[
[
[
[
[
Co(atc) ]Cl∙H O (1∙H O)
434.30
483.50
95.90
11.80
105.30
368.40
—
—
—
—
7.5
17
—
—
2
2
2
Co(atc-Me) ]Cl (2)
> 49
2
Co(atc-Et) ]Cl (3)
> 46
2
Co(atc-Ch) ]Cl (4)
2.41
2
Co(atc-Ph) ]Cl (5)
9.87
166.59
3409.2
—
2
CoCl ∙6H O
> 105
0.21
2
2
Isoniazid
a
VERO
–1
–1
–1
The selectivity index (SI) was calculated by the ratio IC
/MIC. MIC values for the ligands: Hatc = 31.3 μg mL (161.1 μmol L ); Hatc-Me = 7.8 μg mL
50
–1
–1
–1
–1
–1
–1
–1 27
(
37.4 μmol L ); Hatc-Et = 3.13 μg mL (14.08 μmol L ); Hatc-Ch = 0.78 μg mL (2.82 μmol L ); Hatc-Ph = 15.6 μg mL (57.75 μmol L ).
macrophage cells (J774A.1), which represent the first
immune response to the infection.
2. Li, R.; Sirawaraporn, R.; Chitnumsub, P.; Sirawaraporn, W.;
Wooden, J.; Athappilly, F.; Turley, S.; Hol, W. G. J.; J. Mol.
Biol. 2000, 295, 307.
Conclusions
3. Ananthan, S.; Faaleolea, E. R.; Goldman, R. C.; Hobrath,
J. V.; Kwong, C. D.; Laughon, B. E.; Maddry, J. A.; Mehta, A.;
Rasmussen, L.; Reynolds, R. C.; Secrist III, J. A.; Shindo, N.;
Showe, D. N.; Sosa, M. I.; Suling, W. J.; White, E. L.;
Tuberculosis 2009, 89, 334.
III
A series of Co compounds with thiosemicarbazones
ligands, changing the N(4) substituent group by H,
methyl, ethyl, cyclohexyl and phenyl could be synthesized
in satisfactory yields and fully characterized. The
4. Lin, P. L.; Dartois, V.; Johnston, P. J.; Janssen, C.; Via, L.;
Goodwin, M. B.; Klein, E.; Barry, C. E.; Flynn, J. L.; PNAS
2012, 109, 14188.
III
coordination of Hatc-Ph to the Co was able to enhance
the anti-M. tuberculosis activity when compared with the
free ligand. Moreover the results confirm that structural
changes in peripheral group of the ligands can affect
significantly the activity against M. tuberculosis as well
as the cytotoxicity. Complex 5 showed potential biological
results, not being the most active on the pathogen, but acting
more selectively and thus showing higher potentiality as
anti-M. tuberculosis agent.
5. Lun, S.; Guo, H.; Onajole, O. K.; Pieroni, M.; Gunosewoyo, H.;
Chen, G.; Tipparaju, S. K.;Ammerman, N. C.; Kozikowski,A. P.;
Bishai, W. R.; Nat. Commun. 2013, 4, 2907.
6. Hong, X.; Hopfinger, A. J.; Biomacromolecules 2004, 5,
1066.
7. Lång, H.; Quaglio, G.; Olesen, O. F.; Tuberculosis 2010,
90, 1.
8
. Maia, P. I. S.; Pavan, F. R.; Leite, C. Q. F.; Lemos, S. S.; de Sousa,
G. F.; Batista, A. A.; Nascimento, O. R.; Ellena, J.; Castellano,
E. E.; Niquet, E.; Deflon, V. M.; Polyhedron 2009, 28, 398.
Supplementary Information
Supplementary data are available free of charge at
http://jbcs.sbq.org.br as PDF file.
9. Tarallo, M. B.; Urquiola, C.; Monge, A.; Costa, B. P.; Ribeiro,
R. R.; Costa-Filho, A. J.; Mercader, R. C.; Pavan, F. R.; Leite,
C. Q. F.; Torre, M. H.; Gambino, D.; J. Inorg. Biochem. 2010,
104, 1164.
Acknowledgments
st
1
0. Alessio, E.; Bioinorganic Medicinal Chemistry, 1 ed.;
The authors thank FAPESP (Grants 2009/54011-8,
WILEY-VCH: Trieste, Italy, 2011.
2
011/16380-1 and 2013/14957-5), CNPq and CAPES for
11. Maia, P. I. S.; Graminha, A.; Pavan, F. R.; Leite, C. Q. F.;
Batista,A.A.; Back, D. F.; Lang, E. S.; Ellena, J.; Lemos, S. S.;
Salistre-de-Araujo, H. S.; Deflon, V. M.; J. Braz. Chem. Soc.
2010, 21, 1177.
supporting this work. This work is also a collaboration
research project of a member of the Rede Mineira de
Química (RQ-MG) supported by FAPEMIG (Project:
REDE-113/10).
12. Chen, C.; Zhu, X.; Li, M.; Guo, H.; Niu, J.; Russ. J. Coord.
Chem. 2011, 37, 435.
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FAPESP has sponsored the publication of this article.
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J. Braz. Chem. Soc., Vol. 25, No. 10, S1-S6, 2014.
Printed in Brazil - ©2014 Sociedade Brasileira de Química
0
103 - 5053 $6.00+0.00
Supplementary Information
SI
Cobalt(III) Complexes with Thiosemicarbazones as Potential
anti‑Mycobacterium tuberculosis Agents
a
b
c
c
Carolina G. Oliveira, Pedro Ivo da S. Maia, Marcelo Miyata, Fernando R. Pavan,
c
d
,a
Clarice Q. F. Leite, Eduardo Tonon de Almeida and Victor M. Deflon*
a
Instituto de Química de São Carlos, Universidade de São Paulo, 13566-590 São Carlos-SP, Brazil
Departamento de Química, Universidade Federal do Triângulo Mineiro, 38025-440 Uberaba-MG, Brazil
b
c
Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, 14801-902 Araraquara-SP, Brazil
d
Instituto de Química, Universidade Federal de Alfenas, 37130-000 Alfenas-MG, Brazil
Crystallographic data (excluding structure factors) for
the structures in this work were deposited in the Cambridge
Crystallographic Data Centre as supplementary publication
www.ccdc.cam.ac.uk/conts/retrieving.html or from the
Cambridge Crystallographic Data Centre, CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
E-mail: deposit@ccdc.cam.ac.uk.
numbers CCDC 988971 (1·H O) and 988972 (5·MeOH).
2
Copies of the data can be obtained, free of charge, via
IR spectra of compounds
Figure S1. IR spectrum (KBr) of complex 1.
*e-mail: deflon@iqsc.usp.br

S2
Cobalt(III) Complexes with Thiosemicarbazones as Potential anti-Mycobacterium tuberculosis Agents
J. Braz. Chem. Soc.
Figure S2. IR spectrum (KBr) of complex 2.
Figure S3. IR spectrum (KBr) of complex 3.
Figure S4. IR spectrum (KBr) of complex 4.

Vol. 25, No. 10, 2014
Oliveira et al.
S3
Figure S5. IR spectrum (KBr) of complex 5.
1
H NMR spectra of compounds
1
Figure S6. H NMR spectrum (DMSO, 399.8 MHz) of complex 1.

S4
Cobalt(III) Complexes with Thiosemicarbazones as Potential anti-Mycobacterium tuberculosis Agents
J. Braz. Chem. Soc.
1
Figure S7. H NMR spectrum (DMSO, 399.8 MHz) of complex 2.
1
Figure S8. H NMR spectrum (DMSO, 399.8 MHz) of complex 3.

Vol. 25, No. 10, 2014
Oliveira et al.
S5
1
Figure S9. H NMR spectrum (DMSO, 399.8 MHz) of complex 4.
1
Figure S10. H NMR spectrum (DMSO, 399.8 MHz) of complex 5.

S6
Cobalt(III) Complexes with Thiosemicarbazones as Potential anti-Mycobacterium tuberculosis Agents
J. Braz. Chem. Soc.
Figure S11. Crystalline and molecular structure of [Co(atc) ]Cl·H O [N(24)···O(1L) = 2.910(5) Å, N(24)-H(24A)···O(1L) = 146.5º], [N(24)···Cl(1J)
2
2
=
3.258(3) Å, N(24)-H(24B)···Cl(1J) = 157.6º], [N(14)···Cl(1G) = 3.223(3)Å, N(14)-H(14A)···Cl(1G) = 147.5º], [N(14)···Cl(1H) = 3.222(3)Å, N(14)-
F
L
H(14B)···Cl(1H) = 152.3º], [O(1)···Cl(1F) = 3.081(4) Å, O(1)-H(1w)···Cl(1F) = 174(4)º]. Symmetry operations used: 1−x,−y, 1−z; 1/2+x,1/2−y,1/2+z
J
G
H
;
1/2+x,1/2−y, −1/2+z; 1/2−x,1/2+y, 1/2−z; −1/2+x,1/2−y, −1/2+z.