A.M. Plutín et al. / Inorganic Chemistry Communications 63 (2016) 74–80
79
integrations and signal multiplicities are consistent with [Pt(dppf)2(L)]
PF6 structures for the complexes. All complexes are stable in dimethyl
sulfoxide solutions, for at least 48 h, according to their NMR spectra in
this solvent.
10-fold and 20-fold higher activities, than the respective free N,N-
disubstituted-N′-acyl thiourea.
The in vitro activity found for the complexes (1), (2), (5) and (7) is
comparable to those of some commonly used anti-M. tuberculosis
agents, like cycloserine (MIC = 122.4–489.7 μM), gentamicin (MIC =
4.19–8.38 μM), tobramycin (MIC = 8.56–17.11 μM), clarithromycin
(MIC = 10.70–21.40 μM) and ethambutol (MIC = 5.62 μM), which is
the clinically used as a first-line drug in several schemes of conventional
tuberculosis treatment [32].
The structural changes in the ligands and in the complexes probably
affect the interaction of the complexes with bacterial membrane. In our
previous work with some ruthenium complexes it was suggested that
the mechanism of their action against M. tuberculosis occurs in the cell
wall biosynthesis [33]. This could be also a suggestion for the mecha-
nism of the biological activity of the platinum complexes here studied,
where the interaction of them with the mycobacterium membrane is
modulated by the nature of the ligands present in the compounds.
The structures of complexes (4), (5) and (8) were determined by
X-ray diffraction analysis, and their ORTEP views are in Fig. 2 and select-
ed bond lengths (Å) and angles (°) for the complexes are listed in
Table 2. The thione C\\S bond in the coordinated anionic ligands
becomes formally a single bond making it longer (average = 1.707 Å)
than the C\\S bond of the neutral moieties [10], and the N(2)\C bond
(average 1.337 Å), which some double bond in the anionic moieties, is
typical for C\\N distances [31]. The N(1)\\C distance, 1.361 Ả (average),
is anionic and in the amine form. Thus the metal is coordinated to the
negatively charged organic molecules, which act as bidentate ligands,
through oxygen (average distance Pt–O = 2.058 Å) and through sulfur
(average distance Pt\\S = 2.304 Å) atoms. The Pt–S average distance
is close to the ones found for other copper(II)/thiosemicarbazones
complexes [23]. The remaining binding sites are occupied by dppf
diphosphane ligand (average distance Pt–P1 = 2.243 Å and Pt–
P(2) = 2.3229 Å). The distances for the C\S, C\N and C\O bonds in the
chelate rings, listed in Table 2, are the characteristic of single and double
bond lengths, respectively [31]. The CO bond distances are slightly sen-
sitive to the coordination of the ligand to the metal. In the case of the
bis-triphenylphosphine-N,N-diethyl-N′-furoilthioureato-k2O,S the CO
distance for the free ligand is 1.226(3) Å (average for two independent
molecules per asymmetric unit), and 1.271(9) and 1.281(8) Å respec-
tively, after its coordination to the metal [10].
4. Conclusions
A novel series of Pt(II) complexes with N,N-disubstituted-N′-acyl
thioureas as bidentate ligands was synthesized and thoroughly charac-
terized by several spectroscopic techniques and X-ray crystallography.
The X-ray crystallographic characterization shows that these ligands
coordinate with the metal through the oxygen and sulfur atoms. The
anti-M. tuberculosis activity assays of the new complexes provided
evidence that they show activity against M. tuberculosis H37Rv, in the
same order than the ethambutol, a first-line drug in several schemes
of conventional tuberculosis treatment. Thus, as can been seen from
Table 3, the MIC values are in order [Pt(dppf)(L5)]PF6 b [Pt(dppf)(L1)]
3.1. Anti-M. tuberculosis activity
PF6
[Pt(dppf)(L7)]PF6
[Pt(dppf)(L2)]PF6
[Pt(dppf)(L3)]PF6
b
b
b
b
The compounds (L1–L8) and complexes (1–8) were investigated for
their in vitro antimycobacterial activity against M. tuberculosis H37Rv
strains, by the REMA. The minimum inhibitory concentrations (MICs)
found for the platinum complexes, free ligands and ethambutol are
shown in Table 3.
As can be seen from Table 3 results some compounds exhibited anti-
M. tuberculosis activity, with reasonable low MIC values. Comparing the
MIC values of the free N,N-disubstituted-N′-acyl thiourea with the
values obtained for the complexes, it can be seen that the activity
of the complexes is much higher than those of the uncoordinated N,N-
disubstituted-N′-acyl thiourea, emphasizing the importance of the
presence of the metal for anti-M. tuberculosis activity presented by the
new complexes. Complexes (1), (2), (5) and (7) present approximately
[Pt(dppf)(L4)]PF6 ≈ [Pt(dppf)(L6)]PF6 ≈ [Pt(dppf)(L8)]PF6, showing
that the most active complexes are those containing small R2 groups,
like methyl or ethyl groups. Also, considering that the difference be-
tween complexes (1) and (7) is the R1 group and that their MIC values
are practically the same, it is possible to suggest that this group does not
influence substantially the activity of the complexes. The similar MIC
values of complexes (2) and (5) give support to this suggestion. Shortly,
the size of the R2 group influences the anti-M. tuberculosis activity of the
[Pt(dppf)(Ln)]PF6 complexes, which does not happen with the type of
R1 group, at least in the same extend. Taken altogether, the influence
of the R1 and R2 groups in the activity of the complexes can be due the
steric hindrance or polarity in their interaction with the Mycobacterium
membrane, affecting their cell wall biosynthesis. Thus, in this process the
size of the R2 group plays a crucial role. The low antimycobacterial activ-
ity of the free ligands probably is due to their no interactions with the
mycobacterium membrane.
Table 3
MIC values of antimycobacterial activity of Pt(II) complexes, free ligands and reference
drug.
Acknowledgments
Compounds
μg/mL
μmol/L
L1
L2
L3
L4
L5
L6
L7
L8
N25
N25
N25
N25
N25
N25
N25
N25
5.49 0.27
6.51 0.64
23.66 0.48
N25
4.62 0.06
N25
5.76 0.27
N25
N25
˃119.61
˃107.30
˃85.62
This work was supported by CAPES (Project Oficio/CSS/CGCI/
23038009487/2011-25/DRI/CAPES, AUX CAPES-MES-Cuba, 339/2011),
CNPq and FAPESP (Process 2013/14957-5 and 2014/13691-4) of Brazil.
˃75.30
˃110.62
˃75.30
˃116.82
˃73.96
Appendix A. Supplementary data
(1) [Pt(dppf)(L1)]PF6
(2) [Pt(dppf)(L2)]PF6
(3) [Pt(dppf)(L3)]PF6
(4) [Pt(dppf)(L4)]PF6
(5) [Pt(dppf)(L5)]PF6
(6) [Pt(dppf)(L6)]PF6
(7) [Pt(dppf)(L7)]PF6
(8) [Pt(dppf)(L8)]PF6
[Pt(dppf)Cl2]
Ethambutol
5.73 0.28
6.63 0.65
22.74 0.46
˃23.14
CCDC 1405958, 1405957 and 1405956 contain the supplementary
crystallographic data for Pt(dppf)(N,N-diphenyl-N′-benzoylthioureato-
k2O,S)]PF6 (4), Pt(dppf(N,N-diethyl-N′-furoylthioureato-k2O,S)]PF6 (5)
and Pt(dppf)(N,N-diphenyl-N′-thiophenylthioureato-k2O,S)]PF6 (8),
respectively. These data can be obtained free of charge via http://
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
4.74 0.06
˃23.14
5.99 0.28
˃23.01
˃30.47
5.00
5.62