Palladium(II)/N,N-disubstituted-N′-acylthioureas complexes as anti-Mycobacterium tuberculosis and anti-Trypanosoma cruzi agents

Article abstract of DOI:10.1016/j.poly.2017.05.003

The new complexes of Pd(II) with N,N-disubstituted-N′-acylthioureas:[(1) [Pd(dppf)(N,N-dimethyl-N′-benzoylthioureato-k²O,S)]PF₆, (2) [Pd(dppf)(N,N-diethyl-N′-benzoylthioureato-k²O,S)]PF₆, (3) [Pd(dppf)(N,N-dibut

Full text of DOI:10.1016/j.poly.2017.05.003

Accepted Manuscript
Palladium(II)/N,N-disubstituted-N ′-acylthioureas complexes as anti-Mycobac-
terium tuberculosis and anti-Trypanosoma cruziAgents
Ana M. Plutín, Anislay Alvarez, Raúl Mocelo, Raúl Ramos, Eduardo E.
Castellano, Monize M. da Silva, Wilmer Villarreal, Fernando R. Pavan, Cássio
Santana Meira, José Simão Rodrigues Filho, Diogo Rodrigo M. Moreira, Milena
Botelho P. Soares, Alzir A. Batista
PII:
S0277-5387(17)30325-X
http://dx.doi.org/10.1016/j.poly.2017.05.003
POLY 12616
DOI:
Reference:
To appear in:
Polyhedron
Received Date:
Revised Date:
Accepted Date:
30 January 2017
22 April 2017
1 May 2017
Please cite this article as: A.M. Plutín, A. Alvarez, R. Mocelo, R. Ramos, E.E. Castellano, M.M. da Silva, W.
Villarreal, F.R. Pavan, C.S. Meira, J.S.R. Filho, D.R.M. Moreira, M.B.P. Soares, A.A. Batista, Palladium(II)/N,N-
disubstituted-N ′-acylthioureas complexes as anti-Mycobacterium tuberculosis and anti-Trypanosoma cruziAgents,
Polyhedron (2017), doi: http://dx.doi.org/10.1016/j.poly.2017.05.003
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Palladium(II)/N,N-disubstituted-N′-acylthioureas complexes as anti-
Mycobacterium tuberculosis and anti-Trypanosoma cruzi Agents
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a*,
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Ana M. Plutín Anislay Alvarez , Raúl Mocelo , Raúl Ramos , Eduardo E. Castellano ,
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Monize M. da Silva , Wilmer Villarreal , Fernando R. Pavan , Cássio Santana Meira ,
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José Simão Rodrigues Filho , Diogo Rodrigo M. Moreira , Milena Botelho P. Soares
c*
Alzir A. Batista.
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Laboratorio de Síntesis Orgánica, Facultad de Química, Universidad de La Habana, La
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Habana, Cuba
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Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil
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Departamento de Química, Universidade Federal de São Carlos, CEP 13.565-905, São
Carlos, SP, Brazil
d
Faculdade de Ciências Farmacêuticas, UNESP, Araraquara, SP, Brazil
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eInstituto Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-750 Salvador, BA,
Brazil
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Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, CEP 41253-190,
Salvador, BA, Brazil.
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Corresponding Author
*E-mail: daab@ufscar.br (Alzir A. Batista) FAX number: 55-16-3351-8350
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Keywords: metal complexes, palladium, thioureas, tuberculosis, Trypanosoma cruzi.
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Abstract
The new complexes of Pd(II) with N,N-disubstituted-N′-acylthioureas:[(1)
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[Pd(dppf)(N,N-dimethyl-N′-benzoylthioureato-k O,S)]PF , (2) [Pd(dppf)(N,N-diethyl-
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N′-benzoylthioureato-k O,S)]PF , (3) [Pd(dppf)(N,N-dibuthyl-N′-benzoylthioureato-
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k O,S)]PF , (4) [Pd(dppf)(N,N-diphenyl-N′-benzoylthioureato-k O,S)]PF ,
(5)
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[Pd(dppf)(N,N-diethyl-N′-furoylthioureato-k O,S)]PF , (6) [Pd(dppf)(N,N-diphenyl-N′-
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furoylthioureato-k O,S)]PF , (7) [Pd(dppf)(N,N-dimethyl-N′- thiophenylthioureato-
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k O,S)]PF , and (8) [Pd(dppf)(N,N-diphenyl-N′-thiophenylthioureato-k O,S)]PF , were
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prepared and characterized by elemental analysis, and spectroscopic techniques. The
structures of complexes (2), (3), (5), (6) and (8) had their structures determined by X-
ray crystallography, confirming the coordination of the ligands with the metal through
sulfur and oxygen atoms, forming distorted square-planar geometries. These complexes
have shown antibacterial activity against Anti-M. tuberculosis H37Rv ATCC 27294.
The complexes exhibited antiparasitic activity against T. cruzi, while the metal-free
thioureas did not. The results demonstrated that the compounds described here can be
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considered as promising anti-M. tuberculosis and anti-T. cruzi agents, since in both
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cases their in vitro activity were better than reference drugs available for the treatment
of both diseases.
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1. Introduction
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The Mycobacterium tuberculosis (MTB), causative agent of tuberculosis, is
responsible for the death of around 2–3 million people, annually, and a global economic
toll of U$12 billion each year [1]. The rise of multidrug resistance (MDR) in MTB has
complicated and prolonged the treatment. Therefore, no new drugs have been developed
specifically against mycobacteria since the 1960s [2]. Thus, there is a great need to
develop new therapeutic agents to treat tuberculosis, so as to reduce the total duration of
treatment and to provide more effective drugs against MDR TB and latent tuberculosis
infection. This involves the development of new therapeutic strategies against bacterial
infection, which becomes more stringent, and one reason for this is mainly due the
bacterial drug resistance to currently administered treatments.
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Also, Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T.
cruzi), affects approximately 10 million people worldwide, with a high prevalence in
Latin America [3]. The few drugs available, benznidazole and nifurtimox, are only
effective in curing when administered during the acute phase, but not effective in
patients that have progressed to the chronic phase [4]. Furthermore, these drugs are not
considered ideal, due to their severe side effects [5]. Thus, the search for new anti-T.
cruzi compounds is also needed.
One strategy for the development of antimycobacterial and antiparasitic agents
from the inorganic point of view is to use an organic compound, which already exhibit
antibacterial property, as ligand, to form metal complexes. Thus, good candidates for
this purpose are thiourea and their derivatives, which are known for their antiviral,
antibacterial and cytotoxic properties [6]. There are several works in the literature
demonstrating the activity of this class of compounds, against parasites such as
Plasmodium falciparum, Trypanosoma brucei and T. cruzi [7]. In recent years, a
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number of urea, thiourea and acylthiourea derivatives containing (R)-2-amino-1-butanol
were evaluated against Mycobacterium tuberculosis strains H37Rv ATCC 27294,
showing good anti-tuberculosis effect, and the complexing capacity of thiourea
derivatives have been reported [8-9].
The biological activity of complexes containing thiourea derivatives has been
successfully screened for various biological processes and they exhibit a wide range of
biological activities, including antifungal, anticancer [9‐10] and insecticidal activities
[11]. Therefore, in order to extend the research on potential metallodrugs aiming the
M. Tuberculosis and Chagas desease we report here on some palladium complexes
containing the bis(diphenylphosphine)ferrocene and N,N-disubstituted-N′-acyl thioureas
as ligands. Detailed descriptions of synthesis and characterization of the ligands have
been reported elsewhere [12]. The Pd(II)/N,N-disubstituted-N′-acyl thioureas complexes
described in this work were synthesized, structurally characterized and were tested for
their anti-M. tuberculosis and anti-T. cruzi activity, showing good results.
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2. Experimental
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2.1. Materials and measurements
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The dichloro[bis(diphenylphosphino)ferrocene]palladium (II) was obtained from
Stream. All reagents were purchased with reagent grade and used without further
purification. Solvents were dried and used freshly distilled, unless otherwise specifically
indicated. Thin layer chromatography (TLC) was performed on 0.25 mmsilic gel pre-
coated plastic sheets (40/80mm) (Polygram_ SIL G/UV254, Macherey& Nagel, Düren,
Germany) using benzene/methanol (9/1) as eluent. The IR spectra were recorded on a
−
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FTIR Bomem-Michelson 102 spectrometer in the 4000–200 cm region using CsI
-1
pellets. Conductivity values were obtained using 1.0 mmol.L solutions of complexes
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in CH Cl , using a Meter Lab CDM2300 instrument. The molar conductance
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measurements (Λ ) were carried out in dichloromethane at 25 °C, using concentrations
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of 1.0 × 10 mol.L for the complexes. H, P{ H} and C NMR spectra were
recorded on a Bruker DRX 400 MHz, internally referenced to TMS for hydrogen
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chemical shift (δ). The P chemical shifts are reported in relation to H PO , 85%.
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CDCl was used as solvent, unless mentioned. Partial elemental analyses were carried
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out on the Department of Chemistry of the Federal University of São Carlos, in an
instrument of CHNS staff EA 1108 of the FISONS.
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2.2. Synthesis of N,N-dialkyl-N′-(acyl/aroyl)thioureas.
The N,N-disubstituted-N′-acylthioureas HL(1–8) used in this work were
synthesized by the procedure previously reported in the literature [12]. A solution of an
appropriate acyl chloride (30 mmol) in acetone (50 mL) was added dropwise to a
suspension of KSCN (0.01 mol) in acetone (30 mL). The mixture was stirred until a
precipitate appeared (ammonium chloride), indicating the formation of the respective
organic isothiocyanate. The corresponding amine (40 mmol), dissolved in acetone was
added slowly and with constant stirring to the resulting solution. The solution was
cooled in an ice-water bath and the stirring was continued at room temperature during
2–9 h, until the reaction was completed (the reaction progress was monitored by TLC).
The reaction mixture was then poured into 600 mL of cold water. The solid N,N-
disubstituted-N′-(acyl/aroyl)thioureas were collected by filtration and finally purified by
recrystallization from ethanol. The compounds were obtained as crystalline solids, in
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good yields. The identity of the products was confirmed by comparing their H and C
NMR data with those reported in the literature [12]. The structures of the N,N-
disubstituted-N′-acyl thioureas used as ligands in this work are shown in Figure 1.
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Figure1. Structures of the N,N-disubstituted-N′-acyl thioureas used as ligands in this
work.
2.3. Synthesis of the complexes
The complexes were prepared as yellow solid products by a similar method to
that used for [Pd(PPh ) Cl ] [9] from direct reactions with the precursor [Pd(dppf)Cl ],
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with the N,N-disubstituted-N′-acylthioureas, in methanol solutions. The complexes were
separated from the reaction mixtures as yellow crystalline solids. Filtration and further
washing with hot water and hot hexane were enough to afford pure and stable
compounds, in about 80% yields. Thus, the general procedure for the synthesis of the
complexes is described: A solution of [Pd(dppf)Cl ] (1.46 g; 2.00 mmol) in 5 mL of
2
methanol, was added dropwise to a solution of corresponding N,N-dialkyl-N′-
(acyl/aroyl)thiourea (2.00 mmol), dissolved in 30 mL of the same solvent, and 0.368 g
(2.00 mmol) of KPF . The reaction was heated under magnetic stirring at about 80 °C,
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for 2 h. The reaction mixture was left in the refrigerator overnight. The yellow solids
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obtained were filtered off and washed, successively, with hot water and hot hexane (3 ×
20 mL). The obtained compounds are stable in the air and in dimethylsuphoxide
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solutions, for at least 72 h, as showed P{ H} NMR experiments.
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The H, C and P{ H} NMR, IR and the elemental analyses, melting point
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temperature and molar conductivity (Λ , 1.0 × 10 mol L in CH Cl ) for the
m
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complexes (1-8) are listed below and the other data used for the characterization of the
complexes will be find in the text:
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(1) [Pd(dppf)(N,N-dimethyl-N′-benzoylthioureato-k O,S)]PF6
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H NMR, δ: 7.86–7.81 (m, 5H, Ph); 7.64–7.51 (m, 5H), 7.37–7.17 (m, 10H), 3.48 (3H,
13
s, CH ), and 3.18 (3H, s, CH ). NMR C, δ: 169.7 (C=S); 161.8 (C=O); 134.5, 134.4,
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134.4, 134.2, 134.1, 132.7–127.7 (C-Ph), 29.7 (CH ), 15.3 (CH ), P{ H} NMR, δ,
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41.12 (d); 28.06 (d); J = 19.43 Hz; IR, cm : ν(C=O) 1416, ν(C=S) 747; ν(C=N)
P-P
1502; Anal. (%): Found (Calc) for C H F FeN OP PdS: C, 52.26 (52.17); H, 3.90
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(3.88); N, 2.82 (2.77); S, 3.21 (3.17). Λ = 48.6 Ω cm mol .
m
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(2) [Pd(dppf)(N,N-diethyl-N′-benzoylthioureato-k O,S)]PF6
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H NMR, δ: 7.87–7.82 (m, 1H), 7.61–7.48 (m, 5H), 7.36–7.31 (m, 5H), 7.15–6.99 (m,
10H), 3.81 (d, J=7.07 Hz, 2H, CH ), 3.58 (d, J=7.07 Hz, 2H, CH ), 1.28 (t, J = 7.02,
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7.02 Hz, 3H, CH ), 1.31 (t, J = 7.02, 7.02 Hz, 3H, CH ); NMR C, δ: 170.0 (C=S);
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169.6 (C=O); 135.7, 135.6, 134.6, 134.5, 134.2–127.5 (C-Ph), 47.3 (CH ), 46.5 (CH ),
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13.1 (CH ), 12.1 (CH ); P{ H}, δ: 41.27 (d); 27. 41 (d); J = 21.86 Hz; IR, cm :
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P-P
ν(C=O) 1414, ν(C=S) 750; ν(C=N) 1501; Anal. (%): Found (Calc) for
C H F FeN OP PdS: C, 53.15 (53.07); H, 4.08 (4.16); N, 2.70 (2.69); S, 3.00 (3.08).
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MP: 270-272 C, Λ = 44.6 Ω cm mol .
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(3) [Pd(dppf)(N,N-dibutyl-N′-benzoylthioureato-k O,S)]PF6
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H NMR, δ: 8.04-7.99(m, 1H), 7.80-7.08 (m, 34H), 4.88 (d, J=7.08 Hz, 2H, CH ), 3.68
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(4H, q, CH ), 2.07-1.70 (2H, m, CH ), 0.93 (3H, t, CH , J = 7.01 Hz). NMR C, δ:
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170.6 (C=S), 168.5 (C=O), 135.6, 135.3, 135.2, 133.6–128.8 (C-Ph), 53.6 (CH ), 52.4
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(CH ), 20.9 (CH ), 14.2 (CH ); P{ H}, δ: 41.18 (d); 27. 63 (d); J = 20.26 Hz; IR,
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P-P
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cm : ν(C=O) 1495, ν(C=S) 747; ν(C=N) 1495; Anal. (%): Found (Calc) for
C H F FeN OP PdS: C, 54.54 (54.74); H, 4.65 (4.68); N, 2.53 (2.55); S, 2.85 (2.92),
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MP: 230-232 C, Λ = 47.6 Ω cm mol .
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(4) [Pd(dppf)(N,N-diphenyl-N′-benzoylthioureato-k O,S)]PF6
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H NMR, δ: 7.86–7.82 (m, 1H), 7.14 (s, 1H), 6.73 (d, J=1.60Hz, 1H), 6.86–6.83 (m,
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1H),NMR C, δ: 174.6 (C=S); 172.9 (C=O); 144.0, 143.1, 134.4, 134.3, 134.2, 134.1–
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127.3 (C\Ph). P{ H}, δ: 41.25 (d), 27.58 (d) J
= 20.26; IR, cm : ν(C=O) 1430,
P-P
ν(C=S) 752; ν(C=N) 1494; Anal. (%): Found (Calc) for C H F FeN OP PdS: C, 56.98
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(57.03); H, 3.90 (3.81); N, 2.37 (2.46); S, 2.78 (2.82). MP: 275-277 C, Λ = 48.6 Ω
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cm mol .
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(5) [Pd(dppf)(N,N-diethyl-N′-furoylthioureato-k O,S)]PF6
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H NMR, δ: 7.85–7.80 (m, 1H), 7.60–6.18 (3H, m, furoyl), 3.74 (2H, d, CH ), 3.34 (2H,
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d, CH ), 1.22 (3H, t, CH ), 0.95 (3H, t, CH ). NMR C, δ: 165.7 (C=S), 159.8 (C=O),
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145.9, 134.6, 134.5, 134.1–129.4 (C-Ph), 128.8–112.0 (C-Ph and furan ring), 47.2
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(CH ), 46.5 (CH ), 13.1 (CH ) 11.9 (CH ).
P{ H}, δ: 41.45 (d), 27.32 d); J
=
P-P
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19.43, IR, cm : ν(C=O) 1474., ν(C=S) 747; ν(C=N) 1504; Anal. (%): Found (Calc):
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Anal. (%): Found (Calc) for C H F FeN O P PdS: C, 51.15 (51.26); H, 3.97 (4.00);
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N, 2.68 (2.72); S, 3.09 (3.11). MP: 242-244 C, Λ = 48.6 Ω cm mol .
m
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(6) [Pd(dppf)(N,N-diphenyl-N′-furoylthioureato-k O,S)]PF6
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H NMR, δ: 7.91–7.80 (m, 1H), 7.63–7.43 (m, 1H), 7.20–6.99 (m, 1H), 6.53–6.16 (m,
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1H), 4.98 (s, 2H, CH ), 4.77 (s, 2H, CH ). NMR C, δ: 167.7 (C=S); 162.0 (C=O);
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149.5, 146.8, 146.1, 145.7, 145.2–112.3 (C-Ph), 53.5 (CH ), 52.8 (CH ). P { H}, δ:
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41, 30 (d), 27,54 (d), J = 19.43; IR, cm : ν(C=O) 1486, ν(C=S) 741; ν(C=N) 1573;
P-P
Anal. (%): Found (Calc) for C H F FeN O P PdS: C, 55.39 (55.41); H, 3.61 (3.66);
5
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N, 2.45 (2.49); S, 2.80 (2.84). MP: 264-266 C., Λ = 52.6 Ω cm mol .
m
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(7) [Pd(dppf)(N,N-dimethyl-N′- thiophenylthioureato-k O,S)]PF6
1
H NMR, δ: 8.02 (1H, dd, J1 = 7.2 Hz, J2 = 8.1 Hz, thiophene CH), 7.87 (1H, dd, J1 =
7.59 Hz, J2 = 8.2 Hz, thiophene CH), 6.70 (1H, dd, J1 = 6.7 Hz, J2 = 8.6 Hz, thiophene
1
3
CH), 7.59–7.27 (C-Ph) 0.97 (6H, t, CH , J = 7.1 Hz), NMR C, δ: 166.7 (C=S); 164.1
3
(C=O); 141.2, 134.6, 134.5, 134.5, 134.4, 132.4, 132.3, 132.2, 131.7, 128.9 - 125.6 ( C-
3
1
1
2
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Ph); 21.8 (2CH ). P{ H}, δ: 41.58 (d), 27.97 (d), J = 19.47; IR, cm : ν(C=O) 1418,
3
P-P
ν(C=S) 745; ν(C=N) 1494; : Anal. (%): Found (Calc) for C H F FeN OP PdS : C,
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49.35 (49.50); H, 3.60 (3.66); N, 2.71 (2.75); S, 6.20 (6.29). MP: 245-247 C., Λ =
M
−
1
2
-1
50.6 Ω cm mol .
2
(8) [Pd(dppf)(N,N-diphenyl-N′-thiophenylthioureato-k O,S)]PF6
1
H NMR, δ: 8.02 (1H, dd, J1 = 7.2 Hz, J2 = 8.1 Hz, thiophene CH), 7.90 (1H, dd, J1 =
7.5 Hz, J2 =8.2 Hz, thiophene CH), 7.89 (1H, dd, J1 = 6.7 Hz, J2 = 8.3 Hz, thiophene
1
3
CH), 7.82‐7.13 (m, 10H, arom‐H). NMR C, δ: 173.7 (C=S); 166.2 (C=O); 144.1,
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143.2, 140.8, 140.7, 134.7, 134.2, 134.1, 134.0, 133.9, 132.3, 128.5 - 127.8 (C-Ph);
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P{ H}, δ: 41.62 (d); 27. 63 (d); J = 19.43 Hz; IR, cm : ν(C=O) 1420, ν(C=S) 743;
P-P
ν(C=N) 1479; Anal. (%) Found (Calc) for C H F FeN OP PdS : C, 54.45 (54.63); H,
5
2
41
6
2
3
2
0
−1
2
-1
3.49 (3.61); N, 2.41 (2.45); S, 5.54 (5.61). MP: 256-258 C., Λ = 49.6 Ω cm mol .
M
2.4. Crystal structure determination.
Single crystals suitable for X-ray diffraction were obtained by slow evaporation
of CHCl :n-hexane (3:1) solutions of the complexes 2, 3, 5, 6 and 8. Diffraction data
3
were collected on an Enraf-Nonius Kappa-CCD diffractometer with graphite-
monochromated Mo Ka radiation (λ = 0.71073 Å). The final unit cell parameters were
based on all reflections. Data collections were performed using the COLLECT program
[13]; integration and scaling of the reflections were performed with the HKL Denzo–
Scalepack system of programs [14]. Absorption corrections were carried out using the
Gaussian method [15]. The structures were solved by direct methods with SHELXS-97
[16]. The models were refined by full-matrix least-squares on F2 by means of
SHELXL-97 [17]. The projection views of the structures were prepared using ORTEP-3
for Windows [18]. Hydrogen atoms were stereochemically positioned and refined with
the riding model. Data collections and experimental details are summarized in Table 1.
Relevant interatomic bond lengths and angles are listed in Table 2. Also included are
the CCDC deposit numbers for supplementary crystallographic data.
1
1
1
1
1
1
1
1
1
1
2
1
0

Table 1.Crystal data and refinement parameters for 2, 3, 5, 6, and 8 complexes.
Compound
2
3
5
6
8
Empirical formula
C H F FeN OP PdS.
C H F FeN OP
C H F FeN O P PdS C H F FeN O P PdS C H F FeN O P PdS
44 41 6 2 2 3 52 41 6 2 2 3 52 41 6 2 3 2
4
6
43
6
2
3
50 51
6
2
3
CH Cl
PdS
2
2
Formula weight
Crystal system
Space group
Temperature (K)
a (Å)
1125.97
Monoclinic
1097.15
Monoclinic
Pc
1031.01
Monoclinic
1127.09
Triclinic
P-1
1143.15
Triclinic
P-1
P2 /c
P2 /a
1
1
293
296
296
296
10.5650(2)
27.6270(8)
16.8200(4)
4861.2(2)
4
10.6147(5)
14.557 (1)
16.325(1)
2506.2(3)
2
10.8430(2)
28.8291(5)
14.1096(2)
4406.77(13)
4
12.5827(3)
13.8101(4)
14.9739(4)
2453.78(12)
2
12.5960(3)
13.8000(4)
15.0780(4)
2479.3 (1)
2
b (Å)
c (Å)
3
V (Å )
Z
3
D. calc (mg/m )
1.538
1.454
1.554
1.525
1.531
Absorption coefficient
−
1
0.981
2280
2.555 to 25.999
-11 ≤ h ≤ 13
0.846
0.958
2088
2.565 to 25.997
-12 ≤ h ≤ 13
-35 ≤ k ≤ 35
-16 ≤ l ≤ 17
38378
0.868
1140
2.972 to 25.999
-15 ≤ h ≤ 15
-17 ≤ k ≤ 16
-18 ≤ l ≤ 18
25632
0.899
1156
2.84 to 26.00
-15 ≤ h ≤ 15
-17 ≤ k ≤ 17
-18 ≤ l ≤ 18
28331
(
mm )
F(000)
1120
2.875 to 25.997
-12 ≤ h ≤ 13
-17 ≤ k ≤ 17
-20 ≤ l ≤ 16
12255
θ range for data collection (°)
Index ranges
-
-
32 ≤ k ≤ 34
20 ≤ l ≤ 12
25156
Reflections collected
Independent reflections
9351 [R(int) = 0.0386]
7966 [R(int) =
0.0592]
8639 [R(int) =
0.0926]
9547 [R(int) =
0.0481]
9719 [R(int) = 0.0387]
(
Rint)
Goodness-of-fit on F2
Final R índices
1.024
R1 = 0.0518
wR2 = 0.1345
1.044
R1 = 0.0603
wR2 = 0.1537
1.026
R1 = 0.0509
wR2 = 0.1275
1.019
R1 = 0.0479
wR2 = 0.1247
1.070
R1 = 0.0461
wR2 = 0.1314
[
I N 2σ (I)]
Largest diff. peak and hole
-3
0.848 and -0.631
1502550
0.779 and -0.487
1502551
0.888 and -0.810
1502552
0.623 and -0.794
1502553
1.160 and -0.794
1502554
(
eÅ)
CCDC deposit number
1
1

2.5. Antimycobacterial activity assay
Antimycobacterial activities of each tested compound and of the standard drug
ethambutol were determined in triplicate, in sterile 96-wel flat bottom microplates. The
tested compound concentrations ranged from 0.087-25 μg/mL, and the ethambutol from
0.015 to 1.0 μg/mL. The microplate Alamar Blue assay [19] was used to measure the
minimal inhibitory concentration (MIC) for the tested compounds (minimum concentration
necessary to inhibit 90 % growth of M. tuberculosis H Rv ATCC 27294). The development
3
7
of a pink color in the wells was taken as indicating bacterial growth and the maintenance of
a blue color as the contrary. The fluorescence of the dye was measured in a SPECTRAfluor
Plus microplate reader (Tecan*) in botton reading mode with excitation at 530 nm and
emission at 590 nm.
2.6 Antiparasitic activity
Y strain trypomastigotes of T. cruzi collected from the LLC-MK2 cell supernatant were
6
dispensed into 96-well plates at a cell density of 2.0 x10 cells/mL in 200 µL of RPMI
medium. Compounds were tested at eight concentrations from (10-0.01 µM), in triplicate.
o
The plate was incubated for 24 h at 37 C and 5 % CO . Aliquots from each well were
2
collected and the number of viable parasites, based on parasite viability, was assessed in a
Neubauer chamber and compared to untreated parasite culture. This experiment was
performed three times. Inhibitory concentration for 50 % (IC ) was calculated using data-
5
0
points gathered from three independent experiments. Benznidazole was used as a positive
control.
2.7 Cytotoxicity in murine cells
J774 cells (murine macrophages cell line, established from a tumor that arose in female
4
BALB/c mouse were placed on 96-well plates at a cell density of 5 x 10 cells/Ml in 200 µL
1
2

of RPMI-1640 medium (no phenol red) and supplemented with 10 % FBS and 50 µg/mL of
gentamycin and incubated for 24 h at 37°C and 5 % CO . Compounds were added in a series
2
of eight concentrations, in triplicate, and incubated for 72 h. Then, 20 µL/well of
AlamarBlue (Invitrogen, Carlsbad, USA) was added to all wells and incubated during 6 h.
Colorimetric readings were performed at 570 and 600 nm. Cytotoxic concentration for 50 %
(
CC ) was calculated using data-points gathered from three independent experiments.
50
Gentian violet was used as a positive control.
2.8 Propidium iodide (PI) and annexin V staining
7
T. cruzi trypomastigotes from Y strain (1x10 ) were incubated for 24 h at 37 °C in the
absence or presence of 1 (0.61 or 1.22 µM) or 4 (1.91 or 3.82 µM). After incubation, the
parasites were labeled for PI and FITC-annexin V using the annexin V-FITC apoptosis
detection kit (Sigma-Aldrich), according to the manufacturer’s instructions. Acquisition and
analyses was performed using a FACS Calibur flow cytometer (Becton Dickinson, San
Diego, CA), with FlowJo software (Tree Star, Ashland, OR). A total of 10.000 events were
acquired in the region previously established as that corresponding to trypomastigotes.
3. Results and discussion
The ligands were prepared following the procedures previously reported in the
literature [12] and were obtained in yields ranging from 79–91%. The complexes of the type
Pd(dppf)(L)] were obtained by the reactions between [Pd(dppf)Cl ] and the ligands (see
[
2
Scheme 1). The synthesized complexes were yellowish crystals and their elemental analyses,
melting point temperatures, and molar conductivities are listed in the experimental section.
Complexes 2, 3, 5, 6 and 8 were also characterized by single crystal X-ray diffraction.
1
3

Scheme I: Route for the syntheses of [Pd(dppf)( N,N-disubstituted-N′-acylthiourea)]PF6
complexes
The IR spectra of the complexes were compared with those of the free ligands. The
N-H stretching vibrations which exist in the ligands disappear. A broad peak ascribed to the
−
1
C-N bond appears around 1580–1600 cm , indicating deprotonation of the acylthioureido
group of the ligands during the complexes formation and therefore their coordination
−
1
through the oxygen and sulfur atoms [20-22]. The bands observed around 471–490 cm
were assigned to M–O [23, 24]. Assignment of the Pd-S stretching vibration bands at about
−
1
−1
3
60 cm are in accordance to the reported literature [25,26]. The bands in the 551–556 cm
range are assigned to M–N (imino nitrogen) [20]. Strong bands in the region of about 1500
-1
cm , are shown by the IR spectra of the complexes which may reasonably be assigned to
−
1
the coordinated C-O groups. The absorption bands at 815–878 cm in the spectra of free
N,N-disubstituted-N′-acylthioureas, attributed to the ν(C-S) stretching vibrations, shift to the
−
1
8
37–845 cm range in the complexes spectra, corresponding to the weakening of the C-S
double bond character [21].
1
In the H NMR spectra (CDCl ) of the ligands HL(1–8), the NH proton appears at
3
1
8
.79–8.45 ppm as broad singlets. This signal is absent in the H NMR spectra of the
corresponding palladium complexes, in the same solvent, as a consequence of the
deprotonation of the nitrogen atom. Similarly, the IR spectra of the ligands HL(1–8) show
-1
NH stretching vibrations in the range 3150–3260 cm , but these signals are absent in the
1
4

1
3
spectra of the corresponding metal complexes. In the C NMR spectra, the carbon atom of
the thiocarbonyl group appears at δ = 165.67–173.67 in the metal complexes, as mentioned
in the experimental section.
3
1
1
The P{ H} NMR spectra of the precursor [Pd(dppf)Cl ], in CH Cl solution,
2
2
2
shows a singlet peak for phosphorus atoms at δ = 35.12. For all complexes two doublets
arise, at about δ = 41.34 and 27.64, indicating the presence of two magnetically different
phosphorus atoms coordinated to the palladium(II) ion. Also in the region of δ = −138–158
−
a multiple signal of the PF , functioning as outer-sphere anions for the complexes is
6
observed, in accordance to the molar conductivity measurements for these complexes (see
experimental section). These data are consistent with those obtained for some
thiosemicarbazones and N,N-disubstituted-N′-acyl thioureas complexes [10, 21,27].
The molecular structures of 2, [Pd(dppf)(N,N-diethyl-N′-benzoylthioureato-
2
2
k O,S)]PF , 3, [Pd(dppf)(N,N-dibuthyl-N′-benzoylthioureato-k O,S)]PF , 5, [Pd(dppf)(N,N-
6
6
2
diethyl-N′-furoylthioureato-k O,S)]PF , 6, [Pd(dppf)(N,N-diphenyl-N′-furoylthioureato-
6
2
2
k O,S)]PF , and 8, [Pd(dppf)(N,N-diphenyl-N′-thiophenylthioureato-k O,S)]PF , are shown
6
6
in Fig. 2, and selected bond lengths and angles (°) for these structures are listed in Table 2.
1
5

Figure 2. ORTEP view of complexes 2, 3, 5, 6 and 8 showing 50% probability ellipsoids.
−
The (PF ) anion and some labels of the ligands are omitted for clarity. For complex 2 there
6
is a CH Cl solvated molecule, which was also omitted.
2
2
In all complexes the Pd(II) ion is nearly planar, in a fourfold environment. The
thione C-S bond in the coordinated anionic ligands becomes formally a single bond making
it longer (average = 1.734 Å) than the C=S bond of the neutral moieties [27, 28] (Fig. 2,
Table 2). Thus the metal is coordinated to the negatively charged organic molecules, which
act as bidentate ligands, through oxygen (average distance Pd-O = 2.0494 Å) and sulfur
(average distance Pd-S = 2.2964 Å) atoms. The Pd-S average distance is close to the ones
found for other palladium(II) thiosemicarbazones complexes [21]. The remaining binding
sites are occupied by biphosphines (dppf) (average distance Pd–P1 = 2.2604 Å and Pd–P2 =
1
6

2.3531 Å). The distances for the C-S and C-O bonds in the chelate rings, listed in Table 2,
are the characteristic of single and double bond lengths, respectively [9, 21, 27]. The N1-C1
and N2-N1 bond distances (average 1.3402 Å and 1.307 Å, respectively) present typical
bond lengths of double bond character, suggesting an electron delocalization in the acyl
thiourea moiety [21-27]. The C-O bond distances are slightly sensitive to the coordination of
the ligand to the metal. In previously work it was reported, on the bis-triphenylphosphine-
N,N-dietyl-N′-furoylthioureato-k2O,S, that the C-O distance for the free ligand is 1.226(3) Å
(average for two independent molecules per asymmetric unit), and 1.266(9) Å (average),
after its coordination to the metal [28].
Table 2. Selected bond lengths (Å) and angles (°) for 2, 3, 5, 6 and 8 complexes.
Bond lengths (Å)
Pd-O
Pd-P(1)
Pd-P(2)
Pd-S
S-C1
O-C2
C1-N1
C2-N1
2
3
5
6
8
2.046(3)
2.261 (1)
2.356 (1)
2.290 (1)
1.740(4)
1.274(5)
1.335(6)
1.297(6)
2.067(7)
2.266(2)
2.359(2)
2.295(2)
1.73 (1)
1.26 (1)
1.37(1)
1.29(1)
2.032(3)
2.255 (1)
2.35(1)
2.300 (1)
1.748(5)
1.259(5)
1.333(6)
1.309(6)
2.049(2)
2.2578(9)
2.3478(9)
2.2979(9)
1.721(4)
1.267(4)
1.334(5)
1.317(5)
2.053(2)
2.2620(8)
2.3527(8)
2.2991(9)
1.731(4)
1.270(4)
1.329(5)
1.322(4)
Angles (°)
O-Pd-S
91.88(9)
178.8 (1)
84.53(9)
175.94(4)
88.43(4)
95.12(4)
92.2(2)
178.8(2)
84.6(2)
176.8(1)
88.24(9)
94.99(8)
90.9 (1)
176.0 (1)
84.1(1)
174.41(4)
90.42(4)
94.74(4)
91.94(7)
179.41(8)
83.25(7)
174.64(3)
88.14(3)
96.70(3)
92.16(7)
178.67(9)
83.86(7)
174.29(3)
87.58(3)
96.49(3)
O-Pd-P(1)
O-Pd-P(2)
P(2)-Pd-S
P(1)-Pd-S
P(2)-Pd-P(1)
After structural characterization, the metal-free N,N-disubstituted-N′-acylthioureas
and metal complexes were investigated for their in vitro antimycobacterial activity against
M. tuberculosis H37Rv strain and antiparasitic activity against Y strain T. cruzi
trypomastigotes. The results are displayed in Table 3.
1
7

Table 3. Antimycobacterial, antiparasitic and cytotoxicity activity of ligands and complexes
-8.
1
(d)
Compound
M. tuberculosis H Rv T. cruzi IC
50
Cytotoxicity
SI
3
7
(a)
(b)
(c)
MIC (M)
˃119.6
˃100.3
˃85.6
±S.E.M.(M)
> 10
CC ±S.D.(M)
50
HL (1)
HL (2)
HL (3)
> 30
> 30
> 30
-
-
-
> 10
> 10
HL (4)
˃75.3
> 10
> 30
-
HL (5)
HL (6)
˃110.6
˃75.3
> 10
> 10
> 30
> 30
-
-
HL (7)
HL (8)
˃116.8
˃73.9
> 10
> 10
> 30
> 30
-
-
1
2
3
4
5
6
7
8
2.58 ± 0.38
2.82 ± 0.04
5.24 ± 0.33
17.32 ± 0.20
2.98 ± 0.02
6.36 ± 0.16
2.88 ± 0.07
9.71 ± 1.12
5.62
0.61 ± 0.27
0.53 ± 0.21
1.47 ± 0.47
1.91 ± 0.50
0.76 ± 0.20
1.91 ± 0.70
0.55 ± 0.07
1.59 ± 0.04
-
2.63 ± 1.25
1.53 ± 0.50
4.14 ± 1.35
8.83 ± 1.60
2.27 ± 0.64
3.86 ± 0.35
1.85 ± 0.48
5.83 ±0.72
-
4.3
2.9
2.8
4.6
3.0
2.0
3.3
3.7
-
Ethambutol
Benznidazole
Gentian Violet
-
-
10.61 ± 0.87
-
> 30
0.82 ± 0.12
>2.8
-
(
a)
(b)
Determined after 7 days incubation time with the drugs. Determined in trypomastigotes
(c)
after 24 h incubation.
selectivity index for antiparasitic activity, determined as CC (cytotoxicity)/IC
50
Determined in J774 macrophages after 72 h incubation. (d) SI =
50
(trypomastigotes).
None the metal-free ligands presented antimycobacterial activity in concentration
below 70 M, while the palladium complexes presented activity in the same micromolar
range as observed under Ethambutol treatment. Therefore, the presence of palladium is
essential to improve the antimycobacterial activity of the free ligands. Regarding structure-
activity relationships, the main difference between most and less active Pd(II) complexes is
the presence of a linear and alkyl side chain attached at R2 in the ligand structure. This may
be the reason for the decreased the antimycobacterial activity of complexes 4, 6 and 8 in
comparison to 1, 2, 3, 5 and 7.
1
8

Next, the antiparasitic activity was analyzed and the results were compared to the
reference drug benznidazole, which displayed an IC value of 10.61 ± 0.87 M. None the
5
0
metal-free ligands displayed antiparasitic activity, while the Pd(II) complexes exhibit
antiparasitic activity. In general, the metal complexes were more potent antiparasitic agents
than benznidazole, however, they presented lower selectivity indexes than benznidazole.
After observing that palladium complexes exhibit antiparasitic activity, it was investigated
how the complexes can cause parasite cell death. To this end, trypomastigotes were treated
with the IC or IC concentration of complexes 1 and 4 for 24 h and then stained with
5
0
99
PI/annexin (Figure 3).
Figure 3. Flow cytometry analysis of trypomastigotes (Ystrain) treated with 1 or 4 for 24 h
and stained with PI and annexin V. (A) Representative untreated trypomastigotes; (B)
1
9

-1
trypomastigotes treated with 1 (0.61 µmol L ); (C) trypomastigotes treated with 1 (1.22
µM); (D) trypomastigotes treated with 4 (1.91 µM). Three independent experiments were
performed, here on representative experiment is shown.
In comparison to untreated parasites, treatment with complex 1 at IC concentration
5
0
increased from 2.2 to 11.5 % cells positively stained for annexin. When the complex 1 was
added at IC99 concentration, the % of annexin-stained cells changed from 11.5 to 17.4,
indicating that complex acts in a concentration-dependent manner. It was also observed that
complex 1 treatment increased the double staining for PI/annexin. A similar cell death was
also observed when complex 4 was evaluated. The single and double staining observed here
for these complexes are indicative that parasite cell death occurs through an apoptosis
process. Antiparasitic properties of palladium complexes have been observed as causing
apoptotic cell death [29], while other metal transition complexes usually cause a necrotic
death [30].
4. Conclusions
A novel series of Pd(II)/N,N-disubstituted-N′-acyl thioureas is here reported. The IR
and NMR data suggest the coordination of the ligands to the metal center occurs bidentately,
through the oxygen and sulfur atoms, which was confirmed by X-ray crystallographic
characterization for complexes 2, 3, 5, 6 and 8. In vitro screening of complexes against M.
tuberculosis and T. cruzi revealed that metal-free ligands were inactive, while complexes
were activity. Structure-activity relationship indicated that their activity are dependent of the
R2 group present in the amine nitrogen, while the nature of R1, attached in the acyl group,
was less important for activity. The findings observed here reinforce that palladium are
valuable antiparasitic agents.
2
0

Acknowledgments
This work was supported by CAPES (Project Oficio/CSS/CGCI/ 23038009487/2011-
2
2
5/DRI/CAPES, AUX CAPES-MES-Cuba, 339/2011), CNPq, FAPESP (Processo
014/13691-4) and FAPESB.
Appendix A. Supplementary data Supplementary crystallographic data for complexes 2, 3,
, 6 and 8 (CCDC 1502550, 1502551, 1502552, 1502553 and 1502554, respectively) can be
5
obtained free of charge via http://www.ccdc.cam. ac.uk/conts/ retrieving.html, or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk.
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Synopsis
New complexes of Pd(II) with N,N-disubstituted-N′-acylthioureas, with general formula
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[
Pd(dppf)(N,N-disubstituted-N′-acylthioureato-k O,S)]PF , (dppf = 1,1-
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bis(diphenylphosphine) ferrocene) were prepared and characterized by elemental analysis,
spectroscopic techniques, and by X-ray crystallography. The structures of complexes show
that the ligands are coordinated to the metal through sulfur and oxygen atoms, forming
distorted square-planar geometries. The complexes have shown antibacterial activity
against Anti-M. tuberculosis H37Rv ATCC 27294. Also, the complexes exhibited good
antiparasitic activity against T. cruzi, while the metal-free thiourea did not.
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