Lipophilic gold(I) complexes with 1,3,4-oxadiazol-2-thione or 1,3-thiazolidine-2-thione moieties: synthesis and their cytotoxic and antimicrobial activities

Article abstract of DOI:10.1007/s10534-017-0046-6

Novel lipophilic gold(I) complexes containing 1,3,4-oxadiazol-2-thione or 1,3-thiazolidine-2-thione derivatives were synthesized and characterized by IR, high resolution mass spectrometry, and ¹H, ¹³C ³¹P NMR. The cytotoxicity of the compounds was evaluated considering cisplatin and/or auranofin as reference in different tumor cell lines: colon cancer (CT26WT), metastatic skin melanoma (B16F10), breast adenocarcinoma (MCF-7), cervical carcinoma (HeLa), glioblastoma (M059?J). Normal human lung fibroblasts (GM07492-A) and kidney normal cell (BHK-21) were also evaluated. The gold(I) complexes were more active than their respective free ligands and cisplatin. Furthermore, antibacterial activity was evaluated against Gram-positive bacteria Staphylococcus aureus ATCC 25213, Staphylococcus epidermidis ATCC 12228 and Gram-negative bacteria Escherichia coli ATCC 11229 and Pseudomonas aeruginosa ATCC 27853 and expressed as the minimum inhibitory concentration (MIC). The complexes exhibited lower MIC values when compared to the ligands and chloramphenicol against Gram-positive bacteria and Gram-negative bacteria. Escherichia coli was sensitive one to the action of gold(I) complexes.

Full text of DOI:10.1007/s10534-017-0046-6

Biometals
DOI 10.1007/s10534-017-0046-6
Lipophilic gold(I) complexes with 1,3,4-oxadiazol-2-thione
or 1,3-thiazolidine-2-thione moieties: synthesis and their
cytotoxic and antimicrobial activities
.
Angelina Maria de Almeida Bruno Assis de Oliveira Pedro Possa de Castro
.
.
ˆ
.
Camille Carvalho de Mendonc¸a Ricardo Andrade Furtado Heloiza Nicolella Diniz
.
.
.
Vania Lucia da Silva Claudio Galuppo Diniz Denise Crispim Tavares
.
.
ˆ
´
´
.
Heveline Silva Mauro Vieira de Almeida
Received: 20 June 2017 / Accepted: 18 August 2017
Ó Springer Science+Business Media, LLC 2017
Abstract Novel lipophilic gold(I) complexes con-
taining 1,3,4-oxadiazol-2-thione or 1,3-thiazolidine-2-
thione derivatives were synthesized and characterized
were more active than their respective free ligands and
cisplatin. Furthermore, antibacterial activity was
evaluated against Gram-positive bacteria Staphylo-
coccus aureus ATCC 25213, Staphylococcus epider-
midis ATCC 12228 and Gram-negative bacteria
Escherichia coli ATCC 11229 and Pseudomonas
aeruginosa ATCC 27853 and expressed as the min-
imum inhibitory concentration (MIC). The complexes
exhibited lower MIC values when compared to the
ligands and chloramphenicol against Gram-positive
bacteria and Gram-negative bacteria. Escherichia coli
was sensitive one to the action of gold(I) complexes.
by IR, high resolution mass spectrometry, and 1H, 13
C
31P NMR. The cytotoxicity of the compounds was
evaluated considering cisplatin and/or auranofin as
reference in different tumor cell lines: colon cancer
(CT26WT), metastatic skin melanoma (B16F10),
breast adenocarcinoma (MCF-7), cervical carcinoma
(HeLa), glioblastoma (M059 J). Normal human lung
fibroblasts (GM07492-A) and kidney normal cell
(BHK-21) were also evaluated. The gold(I) complexes
Keywords Azole Á Gold(I) complex Á Lipophilicity Á
Antitumor Á Antibacterial
A. M. de Almeida Á B. A. de Oliveira Á
P. P. de Castro Á C. C. de Mendonc¸a Á
M. V. de Almeida (&)
Department of Chemistry, Federal University of Juiz de
Fora, Campus Martelos, Juiz de Fora, MG 36036-900,
Brazil
Abbreviations
IR
Infrared
NMR
TMS
HEPES
Nuclear magnetic resonance
Tetramethylsilane
e-mail: mauro.almeida@ufjf.edu.br
R. A. Furtado Á H. N. Diniz Á D. C. Tavares
Department of Research on Natural Products, University
of Franca, Franca, SP 14406-600, Brazil
4-(2-Hydroxyethyl)piperazine-1-
ethanesulfonic acid,
N-(2-hydroxyethyl)piperazine-
N0-(2-ethanesulfonic acid)
High-resolution mass spectra
(eletrospray ionization)
Fetal bovine serum
V. L. da Silva Á C. G. Diniz
Department of Parasitology, Microbiology and
Immunology, Federal University of Juiz de Fora, Campus
Martelos, Juiz de Fora, MG 36036-900, Brazil
HMRS
(ESI)
FBS
MTT
Methylthiazolyldiphenyl-tetrazolium
bromide
H. Silva
Department of Chemistry, Federal University of Minas
Gerais, Campus Pampulha, Belo Horizonte,
MG 31270-901, Brazil
123

Biometals
cytotoxic then cisplatin. These structure–activity
relationship studies have shown the influence of a
tertiary phosphine group.
HAM-
F10
Nutrient mixture F-10
DMEM
XTT
Dulbecco’s Modified Eagle’s Medium
2,3-Bis(2-methoxy-4-nitro-5-
sulfophenyl)-2H-tetrazolium-5-
carboxanilide
Recently, we reported gold(I) and gold(III) com-
plexes containing derivatives of D-galactose, D-ribose
and D-glucono-1,5-lactone as ligand (Chaves et al.
2015). Their cytotoxicity and antitubercular activity
were evaluated and exhibited relevant results.
Another example of synthesis of gold complexes
containing thiazolidinic and oxadiazolic moieties was
revealed by Garcia et al. (2016). The gold(I) com-
plexes with ligands derived from adamantane and
tertiary phosphine were investigated towards their
interactions with the selenoenzyme thioredoxin reduc-
tase (TrxR), albumin interference, glutathione inter-
action and cytotoxicity. The mechanism of action of
gold(I) complexes is still not fully elucidated, but
these studies suggested the interaction between the
compounds and the TrxR enzyme, even in the
presence of albumin.
DMSO
PBS
Dimethylsulfoxide
Phosphate buffer saline
RPMI
1640
TTC
Roswell Park Memorial Institute 1640
medium
2,3,5-Triphenyltetrazolium chloride
Introduction
The discovery of antibacterial and antineoplastic
activities of cisplatin in the 1960s by Rosenberg was
a remarkable achievement in the history of medicinal
inorganic chemistry (Bakhtiar and Ochiai 1999;
Rosenberg et al. 1969). The antibacterial activity of
Au ions has been exploited since the discovery of
bacteriostatic effects of potassium dicyanidoaurate(I),
K[Au(CN)2], towards the tubercle bacillus by Robert
Koch (Benedek 2004). On the other hand, the wide use
of cisplatin in the treatment of human cancer is
restricted by the toxic side effects and the increasing of
drug resistance (Lucas et al. 2016). In order to solve
these issues, a larger number of gold based compounds
have been synthesized due their medicinal activities
(Medici et al. 2015).
In this work, we describe the synthesis, character-
ization, cytotoxic activity against tumor cell lines and
antibacterial activity of novel lipophilic gold(I) com-
plexes containing 1,3,4-oxadiazol-2-thione or 1,3-
thiazolidine-2-thione core and tertiary phosphines,
such as triphenylphosphine or triethylphosphine.
Materials and methods
All reagents and solvents were used without further
purification. [Au(PEt3)Cl] is commercially available
and [Au(PPh3)Cl] was synthesized from K[AuCl4]
according to the literature (Baenziger et al. 1976).
Infrared (IR) spectra were recorded on a Perkin-Elmer
1720 FTIR spectrometer in the region of
4000–350 cm-1 as a KBr pellet and average of 60
scans. 1H NMR (500 MHz), 13C NMR (125 MHz) and
31P NMR (202 MHz) spectra were recorded as
solutions in CDCl3 and CD3OD on a Avancer III HD
BRUKER 500 MHz spectrometer. The chemical
shifts were expressed as d (in ppm) with respect to a
standard internal TMS reference (1H NMR). The high-
resolution mass spectra were recorded on a LC–MS
TOF spectrometer, with electrospray ionization, at the
Interdisciplinary Nanoscience Center, Department of
Chemistry, Aarhus University, Denmark.
Auranofin (triethylphosphine-(2,3,4,6-tetra-O-acetyl-
b-1-D-thiopyranosato-S)gold(I)) is the first Au(I) thio-
late-triethylphosphine complex used in modern medicine
to the treatment of rheumatoid arthritis (Ott 2009).
Furthermore, auranofin is a potent inhibitor of multidrug-
resistant Gram-positive bacteria (Thangamani et al.
2016) and has also been found to be cytotoxic to
different tumor cells (Mirabelli et al. 1985; Shi et al.
1997).
Chaves et al. (2014) have synthetized gold(I) com-
plexes structurally related to auranofin containing the
P–Au–S unit. The ligands 3-benzyl-1,3-thiazolidine-
2-thione and 5-phenyl-1,3,4-oxadiazol-2-thione were
chosen due to their anti-inflammatory and analgesic
activities. The gold(I) complexes were evaluated
against two different tumor cells and were more
123

Biometals
Synthesis of ligands 11-15
5-Undecyl-1,3,4-oxadiazole-2(3H)-thione (13)
The ligands 11-15 were previously reported in the
literature and were prepared according to the
described methodology (Chaves et al. 2014; Manju-
natha et al. 2010). The fatty acids 1-5 were esterified
with methanol under acidic conditions for 24 h at
90 °C and the esters were reacted with hydrazine
(hydrate 64%) in ethanol at room temperature for
24 h, affording the hydrazides 6-10 that were then
treated with carbon disulfide under basic conditions
in ethanol at reflux, followed by subsequent acidifi-
cation with HCl (6 M). (Scheme 1). The final prod-
ucts 11-15 were purified by recrystallization using
ethanol.
Yield (94%) as a white solid, m.p. 62.9 °C. IR mmax
KBr (cm-1) 3149, 3111, 2917, 2842, 1623, 1511,
1302, 1176, 718; 1H NMR (500 MHz, CDCl3) d: 0.87
(t, J = 6.80 Hz, 3H), 1.25-1.39 (m, 16H), 1.73 (qui,
J = 7.45 Hz, 2H,), 2.69 (t, J = 7.60 Hz, 2H), 11.67
(br, 1H); 13C NMR (125 MHz, CDCl3) d: 14.3, 22.8,
25.7, 25.9, 28.9, 29.2, 29.4, 29.5, 29.7, 32.1, 165.1,
178.8.
5-Tridecyl-1,3,4-oxadiazole-2(3H)-thione (14)
Yield (88%) as a white solid, m.p. 71.7 °C. IR mmax
KBr (cm-1) 3172, 2925, 2852, 1619, 1489, 1385,
1
1165, 718; H NMR (500 MHz, CDCl3) d: 0.87 (t,
5-Heptyl-1,3,4-oxadiazole-2(3H)-thione (11)
J = 6.90 Hz, 3H), 1.25–1.38 (m, 20H), 1.73 (qui,
J = 7.45 Hz, 2H), 2.69 (t, J = 7.65 Hz, 2H), 11.67
(br, 1H); 13C NMR (125 MHz, CDCl3) d: 14.3, 22.9,
25.7, 25.8, 28.9, 29.2, 29.5, 29.7, 29.8, 32.1, 165.1,
178.8.
Yield (58%) as a white solid, m.p. 44.7 °C. IR mmax
KBr (cm-1) 3146, 3119, 2924, 2855, 1621, 1506,
1302, 1169, 717; 1H NMR (500 MHz, CDCl3) d: 0.88
(t, J = 6.75 Hz, 3H), 1.25–1.39 (m, 8H), 1.74 (qui,
J = 7.40 Hz, 2H), 2.69 (t, J = 7.50 Hz, 2H), 11.49
(br, 1H); 13C NMR (125 MHz, CDCl3) d: 14.2, 22.7,
25.8, 25.9, 28.8, 28.9, 31.7, 165.1, 178.9.
5-Pentadecyl-1,3,4-oxadiazole-2(3H)-thione (15)
Yield (86%) as a white solid, m.p. 75.8 °C. IR mmax
KBr (cm-1) 3193, 2923, 2845, 1614, 1483, 1382,
1
5-Nonyl-1,3,4-oxadiazole-2(3H)-thione (12)
1167, 720; H NMR (500 MHz, CDCl3) d: 0.86 (t,
J = 7.05 Hz, 3H), 1.24–1.36 (m, 24H), 1.73 (qui,
J = 7.45 Hz, 2H), 2.69 (t, J = 7.60 Hz, 2H), 11.94
(br, 1H); 13C NMR (125 MHz, CDCl3) d: 14.3, 22.8,
25.7, 25.9, 28.9, 29.2, 29.5, 29.7, 29.8, 32.1, 165.1,
178.8.
Yield (60%) as a white solid, m.p. 57.3 °C. IR mmax
KBr (cm-1) 3102, 2915, 2847, 1621, 1509, 1307,
1
1176, 721; H NMR (500 MHz, CDCl3) d: 0.90 (t,
J = 6.85 Hz, 3H), 1.25–1.43 (m, 12H), 1.76 (qui,
J = 7.55 Hz, 2H), 2.71 (t, J = 7.60 Hz, 2H), 11.04
(br, 1H); 13C NMR (125 MHz, CDCl3) d: 14.2,
22.9, 25.8, 25.9, 28.9, 29.2, 29.4, 29.5, 32.0, 165.1,
178.9.
Synthesis of ligands 26-30
The ligands 26-30 were previously reported and were
prepared according to the method described in the
Scheme 1 Synthesis of ligands 11-15
123

Biometals
3-Tetradecylthiazolidine-2-thione (29)
literature (Garcia et al. 2016). The alkyl halides 16-20
were treated with ethanolamine in ethanol for 48 h
under reflux (Coimbra et al. 2010; Reis et al. 2008).
The final step consisted of the cyclization of the amino
alcohol 21-25 with carbon disulfide under basic
conditions for 24 h at 70 °C (Scheme 2). The com-
pounds 26 and 27 were purified by column chro-
matography and the ligands 28-30 were purified by
recrystallization using ethanol.
Yield (73%) as a white solid, m.p. 47.3 °C. 1H NMR
(500 MHz, CDCl3) d: 0.88 (t, J = 7.10 Hz, 3H),
1.25–1.33 (m, 22H), 1.62–1.68 (m, 2H), 3.27
(t, J = 8.10 Hz, 2H), 3.73–3.76 (m, 2H), 4.06
(t, J = 8.10 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d: 14.3, 22.9, 26.9, 27.5, 29.5, 29.6, 29.7, 29.8, 32.1,
49.6, 56.8, 196.4.
3-Hexadecylthiazolidine-2-thione (30)
3-Octylthiazolidine-2-thione (26)
Yield (87%) as a white solid, m.p. 49.0 °C. 1H NMR
(500 MHz, CDCl3) d: 0.87 (t, J = 6.85 Hz, 3H),
1.23–1.28 (m, 26H), 1.65 (qui, J = 7.50 Hz, 2H), 3,26
(t, J = 8.05 Hz, 2H), 3.74 (t, J = 7.60 Hz, 2H), 4.06
(t, J = 7.75 Hz, 2H); 13C NMR (125 MHz, CDCl3) d:
14.3, 22.8, 27.0, 29.5, 29.7, 29.8, 29.9, 32.1, 49.5,
56.8, 196.3.
1
Yield (69%) as a yellow oil, H NMR (500 MHz,
CDCl3) d: 0.85-0.87 (m, 3H), 1.25–1.31 (m, 10H),
1.61–1.66 (m, 2H), 3.26 (t, J = 8.10 Hz, 2H), 3.73 (t,
J = 7.95 Hz, 2H), 4.06 (t, J = 7.85 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d: 14.2, 22.8, 26.8, 26.9,
27.4, 29.3, 29.4, 31.9, 49.5, 56.8, 196.2.
3-Decylthiazolidine-2-thione (27)
Synthesis of gold(I) complexes 31-50
1
Yield (55%) as a yellow oil, H NMR (500 MHz,
To a solution of [Au(PPh3)Cl] (0.3 mmol) or
[Au(PEt3)Cl] (0.3 mmol) in dichloromethane
(3.0 mL), the ligands 11-15 (0.3 mmol) was added
(Scheme 3). After stirring for 3 h at room temperature
K2CO3 (0.15 mmol) was added to adjust the pH to 6.
After 24 h at room temperature in the dark, the solvent
was removed under reduced pressure, furnishing a
white residue which was purified by preparative
chromatography (eluent: dichloromethane) to give
the desired compounds 31-40.
CDCl3) d: 0.87 (t, J = 7.10 Hz, 3H), 1.25–1.32 (m,
14H), 1.62–1.68 (m, 2H), 3.27 (t, J = 8.00 Hz, 2H),
3.73–3.76 (m, 2H), 4.06 (t, J = 7.75 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d: 14.3, 22.9, 26.9, 27.5,
29.4, 29.5, 29.6, 29.7, 32.0, 49.5, 56.8, 196.3.
3-Dodecylthiazolidine-2-thione (28)
Yield (42%) as a white solid, m.p. 40.0 °C. 1H NMR
(500 MHz, CDCl3) d: 0.88 (t, J = 7.10 Hz, 3H),
1.25–1.33 (m, 18H), 1.62–1.68 (m, 2H), 3.27 (t,
J = 8.10 Hz, 2H), 3.73–3.76 (m, 2H), 4.06 (t,
J = 8.10 Hz, 2H); 13C NMR (125 MHz, CDCl3) d:
14.3, 22.9, 26.9, 27.5, 29.5, 29.6, 29.7, 29.8, 32.1,
49.6, 56.8, 196.4.
Complexes 41-50 were obtained from treatment of
the ligands 26-30 (0.3 mmol) in dichloromethane
(3.0 mL) with a solution of [Au(PPh3)Cl] (0.3 mmol)
or [Au(PEt3)Cl] (0.3 mmol) in dichloromethane
(3.0 mL) (Scheme 4). After 24 h at room temperature
in the dark, the solvent was removed under reduced
Scheme 2 Synthesis of ligands 26-30
123

Biometals
Scheme 3 Synthesis of gold(I) complexes 31-40
Scheme 4 Synthesis of gold(I) complexes 41-50
pressure, furnishing a white residue which was
purified by preparative chromatography (eluent:
dichloromethane).
J = 7.10 Hz, 3H); 1.24–1.36 (m, 12H); 1.72 (qui,
J = 7.40 Hz, 2H); 2.74 (t, J = 7.60 Hz, 2H);
7.46–7.60 (m, 15H); 13C NMR (125 MHz, CDCl3)
d: 14.3, 22.9, 25.9, 26.8, 29.2, 29.4, 29.5, 29.6, 32.1,
129.2 (d, J = 57.5 Hz), 129,5 (d, J = 11.3 Hz), 132.1
(d, J = 2.5 Hz), 134.5 (d, J = 13.8 Hz); 167.3, 168.9;
31P NMR (202.4 MHz, CDCl3) d: 37.70; HRMS (ESI)
m/z calc. for C29H35AuN2OPS? [M ? H]? 687.1868,
found 687.1876.
[(5-Heptyl-1,3,4-oxadiazole-2(3H)-thione)
triphenylphosphine gold(I)] (31)
Yield (76%) as a white solid, m.p. 82.4 °C. IR mmax
KBr (cm-1) 3046, 2923, 2846, 1459, 1138, 1098, 752,
681, 534, 507; 1H NMR (500 MHz, CDCl3) d: 0.86 (t,
J = 7.10 Hz, 3H), 1.21–1.37 (m, 8H), 1.72 (qui,
J = 7.40 Hz, 2H), 2.74 (t, J = 7.40 Hz, 2H),
7.46–7.60 (m, 2H); 13C NMR (125 MHz, CDCl3) d:
14.3, 22.8, 25.9, 26.7, 29.0, 29.2, 31.8, 129.2 (d, JC-
[(5-Undecyl-1,3,4-oxadiazole-2(3H)-thione)
triphenylphosphine gold(I)] (33)
Yield (81%) as a white solid, m.p. 62.5 °C. IR mmax
KBr (cm-1) 3054, 2923, 2847, 1457, 1136, 1097, 750,
688, 536, 505; 1H NMR (500 MHz, CDCl3) d: 0.87 (t,
J = 6.85 Hz, 3H), 1.24–1.36 (m, 16), 1.71 (qui,
J = 7.50 Hz, 2H), 2.73 (t, J = 7.60 Hz, 2H);
7.45–7.59 (m, 15H); 13C NMR (125 MHz, CDCl3)
d: 14.3, 22.9, 25.8, 26.7, 29.2, 29.3, 29.5, 29.6, 29.8,
32.1, 129.1 (d, J = 58.8 Hz), 129.5 (d, J = 11.3 Hz),
132.1 (d, J = 2.5 Hz), 134.5 (d, J = 13.8 Hz), 167.1,
169.6; 31P NMR (202.4 MHz, CDCl3) d: 37.72;
HRMS (ESI) m/z calc. for C31H39AuN2OPS?
[M ? H]? 715.2181, found 715.2186.
= 58.8 Hz), 129.5 (d, JC-P = 11.3 Hz), 132.1, 134.5
P
(d, JC-P = 13.8 Hz), 167.2, 169.3; 31P NMR
(202.4 MHz, CDCl3) d: 37.71; HRMS (ESI) m/z calc.
for C27H31AuN2OPS? [M ? H]? 659.1555, found
659.1563.
[(5-Nonyl-1,3,4-oxadiazole-2(3H)-thione)
triphenylphosphine gold(I)] (32)
Yield (53%) as a white solid, m.p. 56.5 °C. IR mmax
KBr (cm-1) 3062, 2922, 2846, 1467, 1136, 1097, 751,
690, 543, 504; 1H NMR (500 MHz, CDCl3) d: 0.87 (t,
123

Biometals
[(5-Tridecyl-1,3,4-oxadiazole-2(3H)-thione)
triphenylphosphine gold(I)] (34)
(500 MHz, CDCl3) d: 0.87 (t, J = 7.15 Hz, 3H),
1.21–1.35 (m, 21H), 1.71 (qui, J = 7.55 Hz, 2H),
1.85–1.92 (m, 6H), 2.72 (t, J = 7.55 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d: 9.2, 14.2, 18.1 (d,
J = 33.8 Hz), 22.7, 25.7, 26.6, 29.1, 29.2, 29.3,
29.5, 31.9, 167.0, 168.8; 31P NMR (202.4 MHz,
CDCl3) d: 36.60; HRMS (ESI) m/z calc. for C17H35-
AuN2OPS? [M ? H]? 543.1868, found 543.1875.
Yield (56%) as a white solid, m.p. 60.0 °C. IR mmax
KBr (cm-1) 3059, 2922, 2852, 1461, 1137, 1093, 755,
693, 542, 497; 1H NMR (500 MHz, CDCl3) d: 0.87 (t,
J = 6.90 Hz, 3H), 1.24–1.37 (m, 20H), 1.72 (qui,
J = 7.55 Hz, 2H), 2.73 (t, J = 7.70 Hz, 2H),
7.45–7.60 (m, 15H); 13C NMR (125 MHz, CDCl3)
d: 14.3, 22.9, 25.9, 26.8, 29.2, 29.4, 29.5, 29.6, 29.7,
29.8, 32.1, 129.1 (d, J = 58.8 Hz); 129.5 (d,
J = 11.3 Hz); 132.1, 134.5 (d, J = 13.8 Hz); 167.3,
168.7; 31P NMR (202.4 MHz, CDCl3) d: 37.69;
HRMS (ESI) m/z calc. for C33H43AuN2OPS?
[M ? H]? 743.2494, found 743.2506.
[(5-Undecyl-1,3,4-oxadiazole-2(3H)-thione)
triethylphosphine gold(I)] (38)
Yield (82%) as a white solid, m.p. 44.3 °C. IR mmax
KBr (cm-1) 2955, 2920, 2849, 1448, 1129, 1040, 774;
1H NMR (500 MHz, CDCl3) d: 0.87 (t, J = 6.85 Hz,
3H), 1.20–1.36 (m, 25H), 1.71 (qui, J = 7.45 Hz, 2H),
1.85–1.91 (m, 6H), 2.71 (t, J = 7.60 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d: 9.3, 14.3, 18.2 (d,
J = 33.8 Hz), 22.9, 25.8, 26.7, 29.2, 29.4, 29.5,
29.6, 29.8, 32.1, 167.2, 168.9; 31P NMR
(202.4 MHz, CDCl3) d: 36.54; HRMS (ESI) m/z calc.
[(5-Pentadecyl-1,3,4-oxadiazole-2(3H)-thione)
triphenylphosphine gold(I)] (35)
Yield (86%) as a white solid, m.p. 62.0 °C. IR mmax KBr
(cm-1) 3060, 2929, 2846, 1467, 1132, 1095, 749, 695,
542, 506; 1H NMR (500 MHz, CDCl3) d: 0.87 (t,
J = 6.80 Hz, 3H), 1.20–1.37 (m, 24H), 1.72 (qui,
J = 7.50 Hz, 2H), 2.74 (t, J = 7.50 Hz, 2H), 7.46–7.60
(m, 15H); 13C NMR (125 MHz, CDCl3) d: 14.3, 22.9,
25.9, 26.8, 29.2, 29.4, 29.6, 29.7, 29.9, 32.1, 129.2 (d,
J = 58.8 Hz), 129.5 (d, J = 11.5 Hz), 132.1, 134.5 (d,
J = 13.8 Hz), 167.3, 168.7; 31P NMR (202.4 MHz,
CDCl3) d: 37.73; HRMS (ESI) m/z calc. for C35H47-
AuN2OPS? [M ? H]? 771.2807, found 771.2813.
?
for C19H38AuN2OPS [M ? H]? 571.2181, found
571.2179.
[(5-Tridecyl-1,3,4-oxadiazole-2(3H)-thione)
triethylphosphine gold(I)] (39)
Yield (94%) as a white solid, m.p. 52.8-53.4 °C. IR
m
max KBr (cm-1) 2960, 2923, 2853, 1451, 1128, 1044,
775; 1H NMR (500 MHz, CDCl3) d: 0.87 (t,
J = 6.85 Hz, 3H); 1.20–1.36 (m, 29H), 1.71 (qui,
J = 7.35 Hz, 2H); 1.85–1.92 (m, 6H), 2.72 (t,
J = 7.50 Hz, 2H); 13C NMR (125 MHz, CDCl3) d:
9.3, 14.3, 18.2 (d, J = 35.0 Hz), 22.9, 25.8, 26.7, 29.2,
[(5-Heptyl-1,3,4-oxadiazole-2(3H)-thione)
triethylphosphine gold(I)] (36)
Yield (84%) as a yellow oil. IR mmax KBr (cm-1) 2962,
2933, 2859, 1454, 1131, 1038, 775; 1H NMR
(500 MHz, CDCl3) d: 0.83-0.86 (m, 3H), 1.18–1.32
(m, 17H), 1.67–1.73 (m, 2H), 1.84-1.91 (m, 6H),
2.68–2.72 (m, 2H); 13C NMR (125 MHz, CDCl3) d:
9.2, 14.2, 18.1 (d, J = 33.8 Hz), 22.7, 25.7, 26.6, 28.9,
29.1, 31.7, 167.1, 168.7; 31P NMR (202.4 MHz,
CDCl3) d: 36.55; HRMS (ESI) m/z calc. for C15H31-
AuN2OPS? [M ? H]? 515.1555, found 515.1570.
29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 32.1167.2; 169.0; 31
P
NMR (202.4 MHz, CDCl3) d: 36.46; HRMS (ESI)
m/z calc. for C21H43AuN2OPS ? [M ? H]? 599.2494,
found 599.2591.
[(5-Pentadecyl-1,3,4-oxadiazole-2(3H)-thione)
triethylphosphine gold(I)] (40)
Yield (66%) as a white solid, m.p. 62.7 °C. IR mmax
KBr (cm-1) 2969, 2923, 2851, 1457, 1137, 1034, 776;
1H NMR (500 MHz, CDCl3) d: 0.87 (t, J = 6.85 Hz,
3H); 1.21–1.36 (m, 33H), 1.71 (qui, J = 7.55 Hz, 2H),
1.86–1.90 (m, 6H), 2.72 (t, J = 7.55 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d: 9.3, 14.3, 18.2 (d,
J = 35.00 Hz); 22.9, 25.3, 26.7, 29.2, 29.4, 29.5,
[(5-Nonyl-1,3,4-oxadiazole-2(3H)-thione)
triethylphosphine gold(I)] (37)
Yield (82%) as a yellow oil. IR mmax KBr (cm-1) 2955,
2920, 2849, 1448, 1129, 1040, 774; 1H NMR
123

Biometals
29.6, 29.8, 29.9, 32.1, 167.1, 169.1; 31P NMR
56.7, 128.7 (d, J = 61.3 Hz), 129.3 (d, J = 12.5 Hz),
132.0, 134.2 (d, J = 13.8 Hz), 196.2; 31P NMR
(202.4 MHz, CDCl3) d: 33.18; HRMS (ESI) m/z calc.
for C33H44AuNPS2? [M]? 746.2313, found 746.2331.
(202.4 MHz, CDCl3) d: 36.57; HRMS (ESI) m/z calc.
for C29H36AuNPS2 [M ? H]? 627.2807, found
?
627.2807.
[(3- (Octylthiazolidine-2-thione)triphenylphosphine
gold(I)] chloride (41)
[(3-Tetradecylthiazolidine-2-thione)
triphenylphosphine gold(I)] chloride (44)
Yield (40%) as a white solid, m.p. 237.6 °C. IR mmax
KBr (cm-1) 3052, 2925, 2850, 1293, 1228, 1098, 748,
691,544,503;1HNMR(500 MHz,CDCl3)d: 0.85-0.88
(m, 3H), 1.23–1.32 (m, 10H), 1.65 (qui, J = 7.45 Hz,
2H), 3.26 (t, J = 7.75 Hz, 2H), 3.74 (t, J = 7.60 Hz,
Yield (61%) as a white solid, m.p. 192.1 °C. IR mmax
KBr (cm-1) 3053, 2916, 2851, 1275, 1235, 1095, 747,
697, 540, 507; 1H NMR (500 MHz, CDCl3) d: 0.88 (t,
J = 7.10 Hz, 3H); 1.21–1.33 (m, 22H), 1.66 (qui,
J = 7.55 Hz, 2H), 3.27 (t, J = 8.05 Hz, 2H); 3.75 (t,
J = 7.55 Hz, 2H, H14), 4.06 (t, J = 7.80 Hz, 2H),
7.46–7.55 (m, 15H); 13C NMR (125 MHz, CDCl3) d:
14.4, 22.9, 29.5, 29.6, 29.7, 29.8, 29.9, 32.1, 49.6,
56.8, 128.9 (d, J = 61.25 Hz), 129.5 (d,
J = 12.50 Hz), 132.2, 134.4 (d, J = 13.75 Hz),
196.4; 31P NMR (202.4 MHz, CDCl3) d: 33.19;
2H), 4.07(t, J = 7.77 Hz, 2H), 7.44–7.55 (m, 15H);13
C
NMR (125 MHz, CDCl3) d: 14.3, 22.8, 26.9, 27.5, 29.3,
29.4, 31.9, 49.5, 56.9, 128.9 (d, J = 61.3 Hz), 129.4 (d,
J = 12.5 Hz), 132.2 (d, J = 2.5 Hz), 134.3 (d,
J = 13.8 Hz); 196,3; 31P NMR (202.4 MHz, CDCl3)
?
d: 33.17; HRMS (ESI) m/z calc. for C29H36AuNPS2
?
[M]? 690.1687, found 690.1692.
HRMS (ESI) m/z calc. for C35H48AuNPS2 [M]?
774.2626, found 774.2646.
[(3-Decylthiazolidine-2-thione)triphenylphosphine
gold(I)] chloride (42)
[(3-Hexadecylthiazolidine-2-thione)
triphenylphosphine gold(I)] chloride (45)
Yield (41%) as a white solid, m.p. 234.9 °C. IR mmax
KBr (cm-1) 3059; 2923; 2855; 1296; 1227; 1098; 748;
687; 543; 502; 1H NMR (500 MHz, CDCl3) d: 0.87 (t,
J = 7.05 Hz, 3H), 1.25–1.32 (m, 14H), 1.62–1.67 (m,
2H), 3.27 (t, J = 8.10 Hz, 2H), 3.75 (t, J = 7.65 Hz,
2H), 4.07 (t, J = 8.00 Hz, 2H), 7.44–7.55 (m, 15H);
13C NMR (125 MHz, CDCl3) d: 14.3, 22.9, 26.9, 27.5,
29.4, 29.5, 29.6, 29.7, 32.0, 49.6, 56.9, 128.9 (d,
J = 61.3 Hz), 129.4 (d, J = 12.5 Hz), 132.2 (d,
J = 2.5 Hz), 134.3 (d, J = 13.75 Hz), 196.3; 31P
NMR (202.4 MHz, CDCl3) d: 33.17; HRMS (ESI)
m/z calc. for C31H40AuNPS2? [M]? 718.2000, found
718.2016.
Yield (29%) as a white solid, m.p. 162.8 °C. IR mmax
KBr (cm-1) 3059, 2928, 2847, 1293, 1220, 1130, 747,
690, 551, 501; 1H NMR (500 MHz, CDCl3) d: 0.87 (t,
J = 6.85 Hz, 3H), 1.21–1.32 (m, 26H); 1.62–1.66 (m,
2H); 3.27 (t, J = 8.00 Hz, 2H), 3.73–3.76 (m, 2H),
4.06 (t, J = 7.75 Hz, 2H), 7.44–7.55 (m, 15H); 13C
NMR (125 MHz, CDCl3) d: 14.3, 22.9, 26.9, 27.5,
29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 32.1, 49.5, 56.8,
128.9 (d, J = 61.3 Hz), 129.4 (d, J = 12.5 Hz), 132.2
(d, J = 3.8 Hz), 134.3 (d, J = 13.8 Hz), 196.4; 31P
NMR (202.4 MHz, CDCl3) d: 33.17; HRMS (ESI)
m/z calc. for C37H52AuNPS2? [M]? 802.2939, found
802.2952.
[(3-Dodecylthiazolidine-2-thione)triphenylphosphine
gold(I)] chloride (43)
[(3-Octylthiazolidine-2-thione)triethylphosphine
gold(I)] chloride (46)
Yield (50%) as a white solid, m.p. 227.3 °C. IR mmax
KBr (cm-1) 3051, 2915, 2847, 1295, 1220, 1105, 748,
688, 550, 497; 1H NMR (500 MHz, CDCl3) d: 0.88 (t,
J = 7.10 Hz, 3H); 1.25–1.32 (m, 18H); 1.65 (qui,
J = 7.60 Hz, 2H), 3.27 (t, J = 8.00 Hz, 2H),
3.73–3.76 (m, 2H), 4.07 (t, J = 8.05 Hz, 2H),
7.45–7.55 (m, 15H); 13C NMR (125 MHz, CDCl3)
d: 14.1, 22.7, 26.8, 27.3, 29.4, 29.5, 29.6, 31.9, 49.4,
Yield (22%) as a yellow oil. IR mmax KBr (cm-1) 2963,
2925, 2851, 1219, 1047; 1H NMR (500 MHz, CDCl3)
d: 0.86 (t, J = 7.10 Hz, 3H), 1.15–1.22 (m, 9H),
1.23–1.32 (m, 10H), 1,64 (qui, J = 7.45 Hz, 2H),
1.80–1.87 (m, 6H), 3.27 (t, J = 8.05 Hz, 2H),
3.72–3.75 (m, 2H), 4.06 (t, J = 7.75 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d: 9.2, 14.2, 18.3 (d,
123

Biometals
[(3-Hexadecylthiazolidine-2-thione)
triethylphosphine gold(I)] chloride (50)
J = 36.3 Hz), 22.8, 26.9, 27.5, 29.3, 29.4, 31.9, 49.5,
56.8, 196.3; 31P NMR (202.4 MHz, CDCl3) d: 31.53;
HRMS (ESI) m/z calc. for C17H36AuNPS2 [M]?
?
Yield (31%) as a white solid, m.p. 54.9 °C. IR mmax
546.1687, found 546.1703.
1
KBr (cm-1) 2969, 2920, 2847, 1223, 1044; H NMR
(500 MHz, CDCl3) d: 0.85 (t, J = 6.85 Hz, 3H),
1.14–1.29 (m, 35H), 1.63 (qui, J = 7.55 Hz, 2H);
1.80–1.86 (m, 6H), 3.26 (t, J = 8.05 Hz, 2H), 3.72 (t,
J = 7.55 Hz, 2H), 4.06 (t, J = 8.05 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d: 9.2; 14.3, 18.2 (d,
J = 36,25 Hz), 22.8, 26.9, 27.4, 29.4, 29.5, 29.6,
29.7, 29.8, 32.1, 49.5, 56.8, 196.2; 31P NMR
(202.4 MHz, CDCl3) d: 31.57; HRMS (ESI) m/z calc.
for C25H52AuNPS2? [M]? 658.2939, found 658.2932.
[(3-Decylthiazolidine-2-thione)triethylphosphine
gold(I)] chloride (47)
Yield (78%) as a yellow oil. IR mmax KBr (cm-1) 2919,
1
2854, 1224, 1037; H NMR (500 MHz, CDCl3) d:
0.83 (t, J = 7.10 Hz, 3H), 1.12–1.28 (m, 23H), 1.61
(qui, J = 7.50 Hz, 2H), 1.79–1.85 (m, 6H), 3.25 (t,
J = 8.10 Hz, 2H), 3.70 (t, J = 7.60 Hz, 2H), 4.05 (t,
J = 7.75 Hz, 2H); 13C NMR (125 MHz, CDCl3) d:
9.1, 14.2, 18.2 (d, J = 36.3 Hz), 22.7, 26.8, 27.4, 29.3,
29.5, 29.6, 31.9, 49.4, 56.8, 196.1; 31P NMR
(202.4 MHz, CDCl3) d: 31.67; HRMS (ESI) m/z calc.
for C19H40AuNPS2? [M]? 574.2000, found 574.2019.
Citotoxicity assay
Method A: citotoxicity on rodent cell lines
[(3-Dodecylthiazolidine-2-thione)triethylphosphine
gold(I)] chloride (48)
Cytotoxicity activity was investigated using the MTT
assay against the normal cell Baby Hamster Kidney
(BHK-21) and the following cancer cell lines: murine
colon cancer cells (CT26.WT) and mouse metastatic
melanoma (B16-F10). Cells were harvested and
seeded in RPMI 1640 (Sigma-Aldrich) culture med-
ium, pH 7.4, supplemented with 10% fetal bovine
serum (FBS) antibiotics (0.01 mg/mL streptomycin
and 0.005 mg/mL penicillin; Sigma-Aldrich), and
2.38 mg/mL Hepes (Sigma-Aldrich) at cell densities
that varied depending on the cell line, 0.5 9 103–
2 9 103 cells/100 lL/well in a plate with 96 wells and
were then incubated at 37 °C in a humidified atmo-
sphere of 5% CO2 for 24 h for optimum adhesion.
Stock solutions of all compounds in DMSO were
serially diluted (100–0.1 lM) in cell culture medium
(\1% DMSO). After drug exposure for 72 h the cells
were incubated with MTT (5 lg/10 lL/well) for 4 h.
MTT is metabolized by viable cells resulting in a
violet complex product that, after being solubilized in
100 lL DMSO/well, can be quantified through col-
orimetric assay using a plate reader (absorbance at
570 nm). Auranofin were used as positive control
against these cell lines. The raw data were normalized
to cell viability of the negative control (culture
medium with no compounds) as 100%. The IC50
values were calculated by four parametric nonlinear
regressions using GraphPad Prism software.
Yield (36%) as a white solid, m.p. 34.0 °C. IR mmax
1
KBr (cm-1) 2962, 2917, 2850, 1226, 1131; H NMR
(500 MHz, CDCl3) d: 0.85 (t, J = 6.15 Hz, 3H),
1.16–1.23 (m, 27H), 1.62-1.65 (m, 2H), 1.80–1.87 (m,
6H), 3.27 (t, J = 8.65 Hz, 2H), 3.73 (t, J = 7.15 Hz,
2H), 4.06 (t, J = 7.30 Hz, 2H); 13C NMR (125 MHz,
CDCl3) d: 9.2, 14.3, 18.2 (d, J = 36.3 Hz), 22.8, 26.9,
27.5, 29.4, 29.5, 29.6, 29.7, 29.8, 32.1, 49.5, 56.8,
196.2; 31P NMR (202.4 MHz, CDCl3) d: 31.54;
?
HRMS (ESI) m/z calc. for C21H44AuNPS2 [M]?
602.2313, found 602.2327.
[(3-Tetradecylthiazolidine-2-thione)
triethylphosphine gold(I)] chloride (49)
Yield (32%) as a white solid, m.p. 43.5 °C. IR mmax
KBr (cm-1) 2921, 2851, 1230, 1047; 1H NMR
(500 MHz, CDCl3) d: 0.87 (t, J = 7.10 Hz, 3H);
1.16–1.32 (m, 31H), 1.63–1.68 (m, 2H), 1.80–1.87 (m,
6H), 3.27 (t, J = 8.05 Hz, 2H), 3.74 (t, J = 7.60 Hz,
2H), 4.06 (t, J = 7.70 Hz, 2H); 13C NMR (125 MHz,
CDCl3) d: 9.2, 14.3, 18.3 (d, J = 36.3 Hz), 22.9, 26.9,
27.5, 29.5, 29.7, 29.8, 29.9, 32.1, 49.6; 56.9, 196.3; 31
P
NMR (202.4 MHz, CDCl3) d: 31.48; HRMS (ESI)
m/z calc. for C23H48AuNPS2? [M]? 630.2626, found
630.2645.
123

Biometals
Method B: citotoxicity on human cell lines
ATCC 25213 (American Type Culture Collection,
Rockville, MD), Staphylococcus epidermidis ATCC
12228, Pseudomonas aeruginosa ATCC 27853
and Escherichia coli ATCC 11229 maintained in
BHI at 20 °C; 300 lL of each stock-culture was
added to 3 mL of BHI broth with glycerol, 20% v.v-1
(stock-culture) at -20 °C until the use. Prior to the
MIC determinations, 300 lL of each stock-culture
were added to 3 mL of BHI broth and incubated at
36 1 °C, overnight (16 h). As quality control,
purity of cultures was checked by Gram stain after
bacterial growth.
The cytotoxicity was measured using the in vitro
Toxicology Colorimetric Assay Kit (XTT; Roche
Diagnostics) according to manufacturer’s instructions.
For the evaluation of the cytotoxicity four cell lines
were used:
a normal human lung fibroblast
(GM07492-A), and three cancer cell lines, breast
adenocarcinoma (MCF-7), cervical carcinoma (HeLa)
and glioblastoma (M059 J). The cell lines were
cultured in HAM-F10 (Sigma-Aldrich) and DMEM
(Sigma-Aldrich) (1:1) culture medium supplemented
with 10% FBS (Nutricell), antibiotics (0.01 mg/mL
streptomycin and 0.005 mg/mL penicillin; Sigma-
Aldrich), and 2.38 mg/mL Hepes (Sigma-Aldrich) at
37 °C with 5% CO2. For these experiments, the cells
(104 cells/well) were plated onto 96-well microplates,
each well received 100 lL HAM F10/DMEN medium
containing the ligands or gold complexes, precursors
Au(PEt3)Cl, Au(PPh3), K[AuCl4] at concentrations
ranging from 12.5 to 1600 lM, and cisplatin at
concentrations ranging from 3.12 to 400 lM, dis-
solved in 0.4% DMSO. Negative (without treatment)
and solvent (0.4% DMSO) controls were included.
After incubation at 37 °C for 24 h, the medium was
removed; cells were washed twice with 100 lL PBS
(phosphate buffer saline) and exposed to 100 lL of
HAM-F10 medium without phenol red. Then, 25 lL
of XTT were added to each well. The microplates were
covered and incubated at 37 °C for 17 h. The
absorbance of sample was determined by a multiplate
reader (ELISA–Asys–UVM 340/Microwin 2000) at a
test wavelength of 450 nm and a reference wavelength
of 620 nm. Cell viability was expressed as a percent-
age of untreated cells, which served as the negative
control group and was designated as 100%. The
experiments were performed in triplicate.
Further, antimicrobial susceptibility tests were per-
formed by microdilution method, using Mueller–Hinton
broth, according to the CLSI guidelines (CLSI 2015),
considering the synthetized compounds and their chem-
ical solubility properties. The inoculum was prepared as
described previously. The compounds were dissolved in
DMSO (10% of the final volume) and diluted with
culture broth to a concentration of 256 lg/mL. Further
1:2 serial dilutions were performed in 96-well plates
followed by addition of culture broth to reach final
concentrations ranging from 256 to 0.0313 lg/mL;
270 lL of each dilution were distributed, as well as a
sterility control and a growth control (containing culture
broth and DMSO, without antimicrobial compound).
Each test and growth control well was inoculated with
30 lL of
a
bacterial suspension (108 CFU/
mL = McFarland barium sulfate standard 0.5). All
experiments were performed in triplicate and the
microdilution trays were incubated at 36 1 °C for
24 h. After drug exposure, bacterial growth was detected
after by incubation with TTC (2,3,5-triphenyltetra-
zolium chloride) solution (0.01 g/mL) at 36 °C,
30 min. As for MTT, TCC is metabolized (reduced) by
viable bacteria cells resulting in a red complex product
(changing from yellow to red) that is precipitated
allowing visual inspection or quantification through
colorimetric assay using a plate reader (absorbance at
340 nm). MIC values (expressed in micromolar) were
defined as the lowest concentration of each compound
which completely inhibited microbial growth (de
Almeida et al. 2013; de Souza et al. 2005; Ferreira 2014).
The IC50 values were calculated by parametric
nonlinear regressions using GraphPad Prism software
and the selectivity index was calculated by dividing the
IC50 value of the isolated compound obtained for non
tumoral cell by the IC50 value obtained for the cancer cell
line. Only values greater than 1 were considered selective.
Antibacterial assay: minimum inhibitory
concentration (MIC) determination
Results and discussion
The antibacterial potential of compounds was assessed
The ligands 11-15 were prepared by reaction of
hydrazides and carbon disulfide under basic conditions
against four bacteria species: Staphylococcus aureus
123

Biometals
in ethanol and were purified by recrystallization using
ethanol. The compounds 26-30 were synthesized by
reaction of the corresponding aminoalcohols and
excess of carbon disulfide under basic conditions,
and were isolated by column chromatography or by
recrystallization using ethanol. A series of novel
gold(I) triphenylphosphine and triethylphosphine
complexes 31-50 were obtained by reaction of the
corresponding ligands with [Au(PEt3)Cl] or
[Au(PPh3)Cl] in dichloromethane, at room tempera-
ture, and were isolated by preparative plate
chromatography.
The 1H NMR spectra of ligands 26-30 shows
signals corresponding to alkyl chain and three more
signals: a triplet at d 3.3 and two triplets at d 3.7 and
4.1 attributable to the CH2 outside and inside the
heterocyclic ring, respectively. For the complexes 41-
50 no changes were observed in the 1H NMR spectra.
At the same time, in the 1H NMR spectra of complexes
31-35 and 41-45, signals were observed in the d
7.5–7.6 region, corresponding to aromatic hydrogens
of the PPh3 group. For complexes 36-40 and 46-50 the
signal attributed to CH3 and CH2 of PEt3 group
appears in the d 1.2–2.0 region.
All the compounds were characterized by 1H NMR,
13C NMR, 31P NMR, infrared, high resolution mass
spectrometry and melting point. The complexes are
insoluble in water and soluble in dichloromethane,
DMSO and present a high chemical stability in organic
solvent mixtures.
Results of the high-resolution mass spectroscopy
and 1H NMR and 13C NMR suggested that the
obtained complexes were in the 1:1 metal/ligand ratio.
The 13C NMR spectra of the ligands 11-15 shows
the signals of lipophilic chain in the d 14.2–32.1
region. The signal at d 165.3 is attributed to the carbon
directly bounded to the N and O atoms in the
heterocyclic ring and at d 178.9 to the C(=S). For the
13C NMR of gold(I) complexes 31-40, an upfield shift
was observed for the signals corresponding to C(–S)
178.9/170 ppm.
In the 13C NMR spectra of the ligands 26-30 were
observed signals of alkyl chain in the d 14.2–32.0
region, signals in the d 49.0–57.0 region attributable to
the CH2 inside the heterocyclic ring and at d 196.2 to
the C(=S). Concerning complexes 41-50 the carbons
do not differ significantly those predicted for the free
ligands 26-30.
Our research group has recently investigated the
existence of two tautomeric forms of ligands 11-15:
thione or thiol (Chaves et al. 2017). The vibrational
spectra suggested that free ligands are present in
thione tautomer (NH), since we can identify an
absorption band corresponding to mNH at 3149, 3111
and 1511 cm-1 and the 2917 and 2842 cm-1 regions
show absorptions due to CH2 and CH groups. In the
IR spectra of complexes 31-40, in addition to the
absorptions observed for the ligands 11-15, we have
noticed the absence of mN–H and thioamide bands.
The ligands 26-30 also show absorptions in the
regions of 2900–2800 cm-1 assigned to CH2 and CH
and the thioamide bands were observed around
1219–1296 cm-1. It is also worth mention that no
significant changes were observed in the IR spectra
of complexes 41-50 in comparison to the spectra of
the ligands 26-30. Besides, in the infrared spectra of
all the gold(I) complexes 31-35 and 41-45, other
absorptions were observed in the regions of 3046,
1138, 1098, 752, 681, 534, 507 cm-1 attributable to
PPh3 group.
In the 13C NMR spectra of complexes 31-35 and
41-45, were observed signals due the phosphine
ligand that were observed as doublets between 128
and 135 ppm to PPh3 and, for the complexes 36-40
and 46-50, the phosphine signals appear in 9–18 ppm
to PEt3.
For the gold(I) complexes 31-35 and 41-45, the 31
P
NMR spectrum presents a single resonance at d 37.71
(31), 37.70 (32), 37.72 (33), 37.69 (34), 37.73 (35),
33.17 (41), 33.17 (42), 33.18 (43), 33.19 (44) and
33.17 (45) compared to PPh3AuCl (d 33.17) and, for
the gold(I) complexes 36-40 and 46-50, the 31P NMR
spectrum presents a single resonance at d 36.55 (36),
36.60 (37), 36.54 (38), 36.46 (39), 36.57 (40), 31.53
(46), 31.67 (47), 31.54 (48), 31.48 (49)and 31.57 (50)
comparatively to Et3PAuCl (d 33.45). In accordance to
the other analysis, the complexes with oxadiazole
derivative ligands 31-40 promote bigger interference
in NMR signals than complexes with thiazolidine
1
The H NMR and 13C NMR spectra of complexes
were analyzed and compared to the spectra of the free
ligands. In the 1H NMR spectra, the hydrogen signals
of the CH2 and CH3 of the longer alkyl chain ligand
appear in the d 0,8-3.0 region. For the ligands 11-15, a
signal at d 11.7 was also observed which was
attributed to NH and disappears in the spectra of
complexes 31-40, supporting the predominance of the
NH tautomer in solution.
123

Biometals
derivative ligands 41-50. The 31P NMR chemical shift
and assignments are summarized in Table 1.
phosphine gold(I) precursor complex and cisplatin,
justifying the designing of the new gold(I) complex.
The oxadiazole gold(I) complexes with tri-
ethylphosphine 36-40 were more promising and
selective than auranofin to murine colon carcinoma
(CT26.WT).
Biological evaluations
Antiproliferative activity
In Table 3, we observed an improvement in the
cytotoxic profile of thiazolidine gold(I) complexes
compared to their respective free ligands. In general,
gold(I) complexes were more active than their phos-
phine gold precursor complexes [Au(PPh3)Cl] and
[Au(PEt3)Cl], but a correlation between the molecular
structure of the complexes and the biological activity
could not be clearly observed.
The antiproliferative activity of the five oxadiazole
ligands 11-15 and a new series of oxadiazole
gold(I) complexes 31-40 was evaluated in comparison
with auranofin and cisplatin by method A in two tumor
cell lines (B16F10 and CT26.WT) and in a normal
kidney cell (BHK21) that was used to evaluate the
selectivity index. IC50 values, calculated from the cell
viability dose response curves obtained after 72 h drug
treatment in the MTT test are shown in Table 2. The
method A was also used to investigate the anticancer
activity of the thiazolidine ligands (26-30) and a new
thiazolidine gold(I) complexes series 41-50. IC50
values are shown in Table 3.
The cytotoxicity data of complexes 45 and 50
against murine melanoma cell line (B16F10) can be
highlighted since they were active as auranofin or
cisplatin. It is important to mention that the most
active thiazolidine complexes were those with higher
lipophilic chain for both B16F10 and CT26.WT cells.
The method B was used to assess the cytotoxicity of
the ligands 11-15 and 26-30 as well as the oxadiazole
and thiazolidine gold(I) complexes 31-50 on human
cell lines, such as GM07492-A, HeLa, MCF-7 and
M059 J cell line. The cultures received the [Au(PPh3)-
Cl], [Au(PEt3)Cl] precursors and cisplatin treatment
for 24 h. The viability of the cells was determined
establishing a relationship between the absorbance
obtained in the treated and negative control results.
IC50 values, calculated from the cell viability, are
shown in Tables 4 and 5.
Analyzing the results indicated in the Table 2, it is
noticed that the ligands showed improvement of the
antiproliferative activity with the increase of the
lipophilic chain present in their chemical structure.
All oxadiazole gold(I) complexes were more active
in the tested cell lines than their respective ligands.
Meanwhile, the presence of metal overcome the
lipophilic relationship to the activity. It was not
possible to identify biological activity-lipophilicity
correlation after gold complexation.
With respect to murine melanoma cell line
(B16F10), the oxadiazol gold(I) complexes with
triphenylphosphine 31-35 were up to 70 times more
active than the respective ligands and than their
As highlighted in Table 4, the oxadiazole ligands
showed low cytotoxic activity against the evaluated
cells ([100 lM). All oxadiazole gold(I) complexes
Table 1 31P NMR chemical shift for the gold(I) complexes 31-50 comparatively to [Au(PPh3)Cl] or [Au(PEt3)Cl]
R-AuPPh3
R-AuPEt3
oxadiazole derivative 31-35
(d)
Thiazolidine derivative 41-45
(d)
Oxadiazole derivative 36-40
(d)
Thiazolidine derivative 46-50
(d)
31
32
33
34
35
37.71
37.70
37.72
37.69
37.73
41
42
43
44
45
33.17
33.17
33.18
33.19
33.17
36
37
38
39
40
36.55
36.60
37.72
37.69
36.57
46
47
48
49
50
31.53
31.67
31.54
31.48
31.57
[Au(PPh3)Cl] = d 33.17
[Au(PEt3)Cl] = d 33.45
Bold value indicates the number of gold(I) complexes synthesized 31-50
123

Biometals
Table 2 Antiproliferative
activity of oxadiazole
compounds against tumor
(B16F10; CT26.WT) and
non tumor (BHK-21) cell
lines
Compound
IC50 (lM SD)
Tumor cells
B16F10
Non tumor cells
BHK-21
SI
CT26.WT
SI
11 (ligand)
12 (ligand)
13 (ligand)
14 (ligand)
15 (ligand)
31
66.9 1.8
[100
ND
ND
–
[100
ND
ND
0.7
0.7
2.0
1.9
1.9
1.3
1.4
1.5
7.1
7.4
7.2
3.3
2.9
1.9
2.5
3.2
3.6
[100
[100
[100
67.3 1.1
30.6 4.9
24.3 3.9
0.94 0,3
1.3 0.1
1.5 0.5
4.2 0.4
2.5 0.6
4.4 0.2
4.7 0.4
4.2 0.1
2.2 0.4
4.8 0.2
6.6 0.1
2.3 0.5
0.5 0.4
6.0 5.5
72.3 5.9
87.1 1.8
36.2 0.9
3.4 0.1
5.0 0.3
5.9 0.2
5.0 0.3
5.0 0.3
3.5 0.2
3.6 0.5
3.4 0.4
2.4 0.2
5.4 0.2
12.1 2.8
9.0 0.7
0.5 0.4
5.0 1.7
52.3 0.3
65.6 3.5
73.6 3.9
6.5 0.9
9.3 0.8
7.7 0.8
6.9 0.2
7.3 1.8
25.9 1.1
26.7 1.1
24.2 4.7
7.9 0.2
15.8 0.6
23.0 0.3
22.5 0.2
1.6 0.5
18.1 10.9
2.1
3.0
6.9
7.1
5.0
1.6
2.9
5.9
5.7
5.8
3.7
3.3
3.4
3.4
3.2
3.0
32
33
34
35
36
37
38
39
40
PPh3AuCl
PEt3AuCl
Auranofin
Cisplatin
SD standard deviation of
triplicate of two
independent experiments, SI
selectivity index
showed antitumor activity against HeLa, MCF-7 and
M059 J, except the complexes 35 and 40. These
results may suggest a decrease in the biological
response due to the increased lipophilicity (longer
alkyl chain).
7), 12.5 0.2 lM in cervical carcinoma (HeLa) and
22.3 0.1 lM in glioblastoma (M059 J).
Antibacterial activity
The oxadiazole gold(I) complexes with triph-
enylphosphine 31-34 were more active than phosphine
gold precursor complex [Au(PPh3)Cl], their respective
ligands and cisplatin (Chaves et al. 2015). The same
interpretation can be extended to gold(I) complexes
36-39 with triethylphosphine since they were more
active than their respective ligands and cisplatin.
The complexes 41-45 were more active than
phosphine gold precursor complex [Au(PPh3)Cl],
their respective ligands and cisplatin. The anticancer
activity of thiazolidine compounds against tumoral
strains (MCF-7; HeLa; M059 J) can be evidenced for
complex 42 in the thiazolidine gold(I) complexes with
triphenylphosphine (Table 5). In the thiazolidine
gold(I) complexes 45-50 with triethylphosphine, the
most active compound was the complex 49 with IC50
of 11.0 0.2 lM int breast adenocarcinoma (MCF-
The antibacterial activities of the ligands 11-15 and
26-30 and gold(I) complexes 31-50 are reported in
terms of the minimum inhibitory concentration (MIC)
values (lM), which are defined as the lowest concen-
tration of an antimicrobial compound that visibly
inhibits the growth of the bacteria. The antimicrobial
activities were evaluated against Staphylococcus
aureus, Staphylococcus epidermidis, Escherichia coli
and Pseudomonas aeruginosa and were compared
with chloramphenicol, [Au(PPh3)Cl] and [Au(PEt3)-
Cl] precursors. The results are summarized in Tables 6
and 7.
The oxadiazole gold(I) complexes (31-40) exhib-
ited marked antibacterial activity and were more
active than phosphine gold precursor complex
[AuPPh3Cl] or [AuPEt3Cl], their respective ligands
123

Biometals
Table 3 Antiproliferative
activity thiazolidine
compounds against tumor
(B16F10; CT26.WT) and
non tumor (BHK-21) cell
lines
Compound
IC50 (lM SD)
Tumor cells
B16F10
Non tumor cells
BHK-21
SI
CT26.WT
SI
26 (ligand)
[100
–
[100
–
[100
27 (ligand)
[100
–
[100
–
[100
28 (ligand)
[100
–
[100
–
[100
29 (ligand)
[100
–
[100
–
[100
30 (ligand)
6.6 0.1
5.2 0.1
5.9 0.6
1.7 0.3
1.8 0.1
1.0 0.6
1.3 0.1
12.3 0.8
1.5 0.3
2.5 0.1
0.5 0.0
6.6 0.1
2.3 0.5
0.5 0.4
6.0 5.5
1.9
4.3
4.4
2.6
2.2
1.3
2,5
1,1
1,5
5,4
2.4
3.4
3.4
3.2
3.0
13.3 0.7
5.8 0.7
6.2 1.1
3.3 0.2
2.5 0.3
1.4 0.1
3.5 0.2
3.6 0.5
3.4 0.4
2.4 0.2
1.4 0.0
12.1 2.8
9.0 0.7
0.5 0.4
5.0 1.7
–
13.1 1.1
22.4 2.9
25.5 0.6
4.4 0.1
3.9 1.5
1.3 0.1
3.2 0.7
13.2 1.1
2.2 0.1
13.4 0.3
1.2 0.2
23.0 0.3
22.5 0.2
1.6 0.5
18.1 10.9
41
3.9
4.1
1.3
1.6
–
42
43
44
45
46
0.9
3.7
0.6
5.6
–
47
48
49
50
[Au(PPh3)Cl]
[Au(PEt3)Cl]
Auranofin
Cisplatin
1.9
2.5
3.2
3.6
SD standard deviation of
triplicate of two
independent experiments, SI
selectivity index
and chloramphenicol. All the complexes were effec-
tive against the investigated Gram-positive bacteria
Staphylococcus aureus and Staphylococcus epider-
midis. Complex 38 turned out to be the most active one
against the growth of Gram-positive bacteria.
with MIC of 1.3, 0.2 and 0.2 lM, respectively against
Staphylococcus aureus.
Regarding Staphylococcus epidermidis, the com-
plex 46 was the most potent with MIC of 0.2 lM and
concerning Gram-negative bacteria, all the tri-
ethylphosphine thiazolidine gold(I) derivatives were
active against Escherichia coli, highlighting the
activity of complex 49 (MIC = 12.0 lM; see
Table 7).
With respect to Gram-negative bacteria, Escher-
ichia coli was the only one sensitive to the action of
oxadiazole gold(I) complexes with triethylphosphine
36-40. The complex 38 manifested more potent
antimicrobial activity (MIC = 14.0 lM; see Table 6).
The oxadiazole gold(I) complexes did not inhibit the
growth of Gram-negative Pseudomonas aeruginosa.
Comparing different phosphine ligands over the
Fig. 1, oxadiazole gold(I) complexes with tri-
ethylphosphine were more active than triphenylphos-
phine analogues against Gram-positive bacteria,
which is reflected in the same profile presented by
[Au(PPh3)Cl] and [Au(PEt3)Cl] precursors.
All the thiazolidine gold(I) complexes were more
active than phosphine gold precursor complex
[AuPPh3Cl] or [AuPEt3Cl], their respective ligands
and chloramphenicol. However, as can be seen in
Fig. 2, the antimicrobial result for complexes 45 and
50 bearing longer alkyl chains (16 carbon atoms)
suggest loss of activity against Staphylococcus aureus
and Staphylococcus epidermidis.
The thiazolidine gold(I) complexes 41-50 showed
promising antibacterial activity particularly against
the Gram-positive bacteria Staphylococcus aureus and
Staphylococcus epidermidis. The complexes 42, 46
and 48 displayed the best antiproliferative activity
Conclusions
This present work describes the synthesis of ten
oxadiazole and thiazolidinic ligands and twenty novel
123

Biometals
Table 4 Antiproliferative
activity of oxadiazole
compounds against tumoral
(MCF-7; HeLa; M059 J)
and non tumoral
Compound
IC50 (lM SD)
Tumor cells
Non tumor cells
GM04729-A
MCF-7
SI
HeLa
SI
M059 J
SI
(GM04729-A) cell lines
11 (ligand)
[100
–
–
–
–
–
–
–
[100
–
–
–
–
–
–
–
–
[100
–
–
–
–
–
–
–
[100
12 (ligand)
[100
[100
[100
[100
13 (ligand)
[100
[100
[100
[100
14 (ligand)
[100
[100
[100
[100
15 (ligand)
[100
[100
[100
[100
31
32
33
34
35
36
37
38
39
40
28.2 0.0
16.3 1.2
29.8 2.8
15.9 0.2
29.6 2.4
17.1 0.2
26.6 2.7
15.7 0.3
66.3 0.4 1.1 69.6 1.2
46.1 5.4 1.8 51.2 3.7
66.8 0.4 1,1 71.8 0.7
1.6 76.4 1.4 1.1 83.3 8.3
[100
19.5 3.2 1.5 32.9 3.2
15.0 2.2 15.4 1.7
–
[100
–
–
–
[100
–
–
–
[100
30.8 0.7
14.2 1.8
29.8 0.8
14.9 1.9
–
31.2 2.8 1.2 26.5 2.4
52.4 0.4 2.0 101.8 1.5
1.4 25.4 0.2 1.5 37.2 5.5
–
–
–
–
–
75.8 7.6 1,4 104.3 10.8
[100
–
–
–
–
[100
[100
13.0
[100
[100
\12.5
80.1
–
–
–
–
[100
[100
15.4
[Au(PPh3)Cl] [100
SD standard deviation of
triplicate of two
independent experiments, SI
selectivity index
[Au(PEt3)Cl]
Cisplatin
13.1
111.3
77.7
69.0
Table 5 Antiproliferative
activity thiazolidine
Compound
IC50 (lM SD)
Tumor cells
Non tumor cells
GM04729A
compounds against tumoral
(MCF-7; HeLa; M059 J)
and non tumoral
MCF-7
SI
HeLa
SI
M059 J
SI
(GM04729A) cell lines
26 (ligand)
[100
–
–
–
–
–
–
–
–
[100
[100
[100
[100
[100
–
–
–
–
–
[100
[100
[100
[100
[100
–
–
–
–
–
–
–
–
–
[100
27 (ligand)
[100
[100
28 (ligand)
[100
[100
29 (ligand)
[100
[100
30 (ligand)
[100
[100
41
42
43
44
45
46
47
48
49
50
45.9 4.8
27.4 3.3
28.1 1.4
59.0 2.2
40.8 0.1 1.1 49.9 8.5
43.3 2.4
28.1 0.2
28.4 0.5
87.4 4.7
27.9 0.5
29.0 1.4
–
–
29.6 1.5
36.7 3.0
1.5 74.9 2.2 1.2 92.7 5.8
45.6 10.6 1.1 29.9 0.6 1.7 32.1 0.7 1.6 50.6 5.5
38.0 0.9
35.2 1.0
14.9 1.8
11.0 0.2
13.3 0.7
–
–
36.3 0.2
28.2 1.9 1.2 35.2 1.2
22.5 0.2
–
36.4 0.3
–
–
–
–
–
–
–
–
37.3 0.3
34.5 0.1
16.9 0.8
14.5 2.7
23.0 1.5
[100
1.1 20.3 0.5
–
1.3 12.5 0.2 1.2 22.3 0.1
1.7 15.2 1.0 1.5 25.5 2.5
[Au(PPh3)Cl] [100
–
–
–
[100
13.0
–
–
–
[100
\12.5
80.1
SD standard deviation of
triplicate of two
independent experiments, SI
selectivity index
[Au(PEt3)Cl]
Cisplatin
13.1
15.4
111.3
77.7
69.0
123

Biometals
Table 6 Antibacterial
activity of oxadiazole
compounds against
Compound
MIC (lM)
S.aureus
S. epidermidis
E.coli
P. aeruginosa
reference strains
Staphylococcus aureus
ATCC 25213,
Staphylococcus epidermidis
ATCC 12228, Escherichia
coli ATCC 11229 and
Pseudomonas aeruginosa
ATCC 27853
11 (ligand)
[100
[100
[100
[100
[100
6.1
[100
[100
[100
[100
[100
3.0
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
7.8
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
99.0
12 (ligand)
13 (ligand)
14 (ligand)
15 (ligand)
31
32
2.9
2.9
33
2.8
2.8
34
2.7
2.7
35
2.6
2.6
36
0.2
0.2
37
0.2
0.1
14.8
38
0.1
0.1
14.0
39
0.4
0.4
26.8
40
0.4
0.4
25.6
[Au(PPh3)Cl]
[Au(PEt3)Cl]
Chloramphenicol
4.1
4.1
[100
11,4
0.4
0.7
49.5
99.0
49,5
Table 7 Antibacterial
activity of oxadiazole
compounds against
Compound
MIC (lM)
S.aureus
S. epidermidis
E.coli
P. aeruginosa
reference strains
Staphylococcus aureus
ATCC 25213,
Staphylococcus epidermidis
ATCC 12228, Escherichia
coli ATCC 11229 and
Pseudomonas aeruginosa
ATCC 27853
26 (ligand)
[100
[100
[100
[100
[100
2.8
[100
[100
[100
[100
[100
2.7
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
13.8
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
99.0
27 (ligand)
28 (ligand)
29 (ligand)
30 (ligand)
41
42
1.3
2.7
43
2.6
2.6
44
2.5
2.5
45
19.1
0.2
19.1
0.2
46
47
0.4
0.4
13.1
48
0.2
0.4
12.5
49
0.4
0.4
12.0
50
23.1
4.0
23.1
4.0
[100
[100
11.4
[Au(PPh3)Cl]
[Au(PEt3)Cl]
Chloramphenicol
0.4
0.7
49.5
99.0
49.5
123

Biometals
(B)
9
8
7
6
5
4
3
2
1
0
5,0
4,5
4,0
3,5
3,0
2,5
2,0
1,5
1,0
0,5
0,0
(A)
Ph
Et
Ph
Et
31
31
32
33
34
35
32
33
34
35
40
39
40
39
36
36
37
38
38
37
Staphylococcus aureus
Staphylococcus epidermidis
Fig. 1 Comparative antibacterial effect of gold(I) triph-
enylphosphine and triethylphosphine complexes containing
oxadiazole moieties. Compounds were assayed against A Sta-
phylococcus aureus (ATCC 2521) and B Staphylococcus
epidermidis. The average of MIC values from chloro(triph-
enylphosphine)gold(I) (grey columns) and chloro(triethylphos-
phine)gold(I)-derived complexes (black columns) were
obtained from Table 6
50
(A)
24
50
(B)
24
22
Ph
Et
22
Ph
Et
45
20
45
20
18
16
14
12
10
8
18
16
14
12
10
8
6
6
4
2
0
41
43
44
4
2
0
42
41
43
44
42
47
49
46
48
47
49
46
48
Staphylococcus aureus
Staphylococcus epidermidis
Fig. 2 Comparative antibacterial effect of gold(I) triph-
enylphosphine and triethylphosphine complexes containing
thiazolidine moieties. Compounds were assayed against A Sta-
phylococcus aureus (ATCC 2521) and B Staphylococcus
epidermidis. The average of MIC values from chloro(triph-
enylphosphine)gold(I) (grey columns) and chloro(triethylphos-
phine)gold(I)-derived complexes (black columns) were
obtained from Table 7
lipophilic gold(I) complexes bearing 1,3,4-oxadiazol-
2-thione or 1,3-thiazolidine-2-thione units and vari-
able long alkyl chain. The structural characterization
of the compounds was established on the basis of high-
resolution mass (HRMS) spectrometry, NMR, IR
spectra and melting point.
exposure time. All complexes were more active than
the respective ligands. The oxadiazol gold(I) com-
plexes with triphenylphosphine (31-35) was up to 70
times more active than the free ligand against murine
melanoma cell line (B16F10), and the phosphine
gold(I) precursor and cisplatin. Concerning thiazo-
lidine series, the cytotoxicity results of complexes 45
and 50 against B16F10 can be highlighted since they
The antiproliferative activity was evaluated against
different tumor cell lines by method A or B in different
123

Biometals
bacteria that grow aerobically (M07-A10), 10th edn. CLSI,
Wayne
Coimbra ES, de Almeida MV, Junior CO, Taveira AF, da Costa
CF, de Almeida AC, Reis EF, da Silva AD (2010) Syn-
thesis and antileishmanial activity of lipidic amino alco-
hols. Chem Biol Drug Des 75:233–235
de Almeida AM, Nascimento T, Ferreira BS, de Castro PP, Silva
VL, Diniz CG, Le Hyaric M (2013) Synthesis and
antimicrobial activity of novel amphiphilic aromatic amino
alcohols. Bioorg Med Chem Lett 23:2883–2887
de Souza SM, Delle Monache F, Smania A Jr (2005) Antibac-
terial activity of coumarins. Z Nat C 60:693–700
Ferreira BDS, de Almeida AM, Nascimento TC, de Castro PP,
Silva VL, Diniz CG, Le Hyaric M (2014) Synthesis and
biological evaluation of a new series of N-acyldiamines as
potential antibacterial and antifungal agents. Bioorg Med
Chem Lett 24:4626–4629
Garcia A, Machado RC, Grazul RM, Lopes MTP, Correa CC,
dos Santos HF, de Almeida MV, Silva H (2016) Novel
antitumor adamantane-azole gold(I) complexes as poten-
tial inhibitors of thioredoxin reductase. JBIC J Biol Inorg
Chem 21:275–292
Lucas SJ, Lord RM, Basri AM, Allison SJ, Phillips RM, Blacker
AJ, McGowan PC (2016) Increasing anti-cancer activity
with longer tether lengths of group 9 Cp* complexes.
Dalton Trans 45:6812–6815
were as active as auranofin or cisplatin and the
complex 49 was most active compound in human
cells, been up to 10 times more active than cisplatin.
In general, the free ligands were not effective in the
tested strains. All the complexes were effective against
the investigated Gram-positive bacteria Staphylococ-
cus aureus and Staphylococcus epidermidis with the
triethylphosphine derivatives up to 10 times more
active than triphenylphosphine compounds. Regard-
ing Gram-negative bacteria Escherichia coli was
sensitive to the action of gold(I) complexes containing
triethylphosphine. The oxadiazole and thiazolidine
gold(I) complexes did not inhibit the growth of Gram-
negative Pseudomonas aeruginosa.
Acknowledgements The authors wish to thank CAPES,
CNPq and FAPEMIG for financial supports and fellowships.
This work is a collaboration research project of members of the
´
Rede Mineira de Quımica (RQ-MG) supported by FAPEMIG
(Project: CEX- RED-0010/14).
Manjunatha K, Poojary B, Lobo PL, Fernandes J, Kumari NS
(2010) Synthesis and biological evaluation of some 1,3,4-
oxadiazole derivatives. Eur J Med Chem 45:5225–5233
Medici S, Peana M, Nurchi VM, Lachowicz JI, Crisponi G,
Zoroddu MA (2015) Noble metals in medicine: latest
advances. Coord Chem Rev 284:329–350
Mirabelli CK, Johnson RK, Sung CM, Faucette L, Muirhead K,
Crooke ST (1985) Evaluation of the in vivo antitumor
activity and in vitro cytotoxic properties of auranofin, a
coordinated gold compound, in murine tumor models.
Cancer Res 45:32–39
References
Baenziger NC, Bennett WE, Soborofe DM (1976)
Chloro(triphenylphosphine)gold(I). Acta Crystallogr Sect
B 32:962–963
Bakhtiar R, Ochiai E-I (1999) Pharmacological applications of
inorganic complexes. Gen Pharmacol 32:525–540
Benedek TG (2004) The history of gold therapy for tuberculosis.
J Hist Med Allied Sci 59:50–89
Chaves JDS, Neumann F, Francisco TM, Correa CC, Lopes
MTP, Silva H, Fontes APS, de Almeida MV (2014) Syn-
thesis and cytotoxic activity of gold(I) complexes con-
taining phosphines and 3-benzyl-1,3-thiazolidine-2-thione
or 5-phenyl-1,3,4-oxadiazole-2-thione as ligands. Inorg
Chim Acta 414:85–90
Chaves JDS, Damasceno JL, Paula MCF, de OliveiraPF Aze-
vedo GC, Matos RC, Lourenc¸o MCS, Tavares DC, Silva H,
Fontes APS, de Almeida MV (2015) Synthesis, charac-
terization, cytotoxic and antitubercular activities of new
gold(I) and gold(III) complexes containing ligands derived
from carbohydrates. Biometals 28:845–860
Ott I (2009) On the medicinal chemistry of gold complexes as
anticancer drugs. Coord Chem Rev 253:1670–1681
´
Reis EFC, Junior COR, Alves LL, Ferreira AP, De Almeida MV
(2008) Synthesis and immunosuppressive activity of lipo-
philic amino alcohols and diamines. Chem Biol Drug Des
72:596–598
Rosenberg B, Vancamp L, Trosko JE, Mansour VH (1969)
Platinum compounds: a new class of potent antitumour
agents. Nature 222:385–386
Shi J-C, Chen L-J, Huang X-Y, Wu D-X, Kang B-S (1997)
Chiral phosphine ligands derived from sugars 10. Synthe-
ses, structure, characterization, and antitumor activity of
the gold(I) complexes with sugar-substructure phosphine
ligands. J Organomet Chem 535:17–23
Thangamani S, Mohammad H, Abushahba MFN, Sobreira TJP,
Hedrick VE, Paul LN, Seleem MN (2016) Antibacterial
activity and mechanism of action of auranofin against
multi-drug resistant bacterial pathogens. Sci Rep 6:22571
Chaves JDS, Tunes LG, Franco CHJ, FranciscoTM Correa CC,
Murta SMF, Monte-Neto RL, Silva H, Fontes APS, de
Almeida MV (2017) Novel gold(I) complexes with
5-phenyl-1,3,4-oxadiazole-2-thione and phosphine as
potential anticancer and antileishmanial agents. Eur J Med
Chem 127:727–739
Clinical and Laboratory Standards Institute (CLSI) (2015)
Methods for dilution antimicrobial susceptibility tests for
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