Syntheses and biological activity of platinum(II) and palladium(II) complexes with phenyl-oxadiazole-ethylenediamine ligands

Article abstract of DOI:10.1080/00958972.2021.1871608

This work describes the synthesis, characterization, cytotoxicity and antibacterial activity of three ligands derived from phenyl-oxadiazole-ethylenediamine and their platinum(II) and palladium(II) complexes. These compounds were characterized by elemental analysis, and Raman, IR, and NMR spectroscopies. We have prepared complexes with different substituents on the aromatic ring to provide influence in the antibacterial activity and cytotoxicity. The 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). The cytotoxicity was evaluated in two different tumor cell lines: mouse metastatic mammary adenocarcinoma (4T1), and murine colon cancer cells (CT26WT), and a non-tumor cell Baby Hamster Kidney (BHK-21). Based on the results obtained for the antibacterial and the cytotoxic activity it is possible to conclude that the presence of metal and groups NO₂ and CF₃ contributed to antibacterial activity with low cytotoxicity.

Full text of DOI:10.1080/00958972.2021.1871608

Journal of Coordination Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gcoo20
Syntheses and biological activity of platinum(II)
and palladium(II) complexes with phenyl-
oxadiazole-ethylenediamine ligands
Caroline de Souza Pereira, Karine Braga Enes, Angelina Maria de Almeida,
Camille Carvalho de Mendonça, Vânia Lúcia da Silva, Cláudio Gallupo Diniz,
Mara Rubia Costa Couri & Heveline Silva
To cite this article: Caroline de Souza Pereira, Karine Braga Enes, Angelina Maria de Almeida,
Camille Carvalho de Mendonça, Vânia Lúcia da Silva, Cláudio Gallupo Diniz, Mara Rubia Costa
Couri & Heveline Silva (2021) Syntheses and biological activity of platinum(II) and palladium(II)
complexes with phenyl-oxadiazole-ethylenediamine ligands, Journal of Coordination Chemistry,
74:4-6, 823-837, DOI: 10.1080/00958972.2021.1871608
To link to this article: https://doi.org/10.1080/00958972.2021.1871608
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JOURNAL OF COORDINATION CHEMISTRY
2021, VOL. 74, NOS. 4–6, 823–837
https://doi.org/10.1080/00958972.2021.1871608
Syntheses and biological activity of platinum(II)
and palladium(II) complexes with phenyl-oxadiazole-
ethylenediamine ligands
Caroline de Souza Pereiraa, Karine Braga Enesa, Angelina Maria de Almeidaa,
a
b
b
^
ꢀ
ꢀ
Camille Carvalho de Mendonc¸a , Vania Lucia da Silva , Claudio Gallupo Diniz ,
Mara Rubia Costa Couria and Heveline Silvac
a
ꢀ
Departamento de Quımica, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil;
bDepartamento de Parasitologia, Microbiologia e Imunologia, Universidade Federal de Juiz de Fora,
Juiz de Fora, Minas Gerais, Brazil; Departamento de Quımica, Universidade Federal de Minas Gerais,
c
ꢀ
Belo Horizonte, Minas Gerais, Brazil
ABSTRACT
ARTICLE HISTORY
Received 30 July 2020
Accepted 11 December 2020
This work describes the synthesis, characterization, cytotoxicity and
antibacterial activity of three ligands derived from phenyl-oxadiazole-
ethylenediamine and their platinum(II) and palladium(II) complexes.
These compounds were characterized by elemental analysis, and
Raman, IR, and NMR spectroscopies. We have prepared complexes
with different substituents on the aromatic ring to provide influence
in the antibacterial activity and cytotoxicity. The 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 aer-
uginosa (ATCC 27853). The cytotoxicity was evaluated in two different
tumor cell lines: mouse metastatic mammary adenocarcinoma (4T1),
and murine colon cancer cells (CT26WT), and a non-tumor cell Baby
Hamster Kidney (BHK-21). Based on the results obtained for the anti-
bacterial and the cytotoxic activity it is possible to conclude that the
presence of metal and groups NO2 and CF3 contributed to antibacter-
ial activity with low cytotoxicity.
KEYWORDS
Metal complexes;
oxadiazole; antibacterial
activity; cytotoxic activity;
tumor cell
Abbreviations: br: broad signal; d: doublet; dd: doublet of dou-
blets; DMSO: dimethyl sulfoxide; MTT: (3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide; NMR: Nuclear Magnetic
Resonance; RPMI: Roswell Park Memorial Institute Medium
ꢀ
Departamento de Quımica, Universidade Federal de Minas
CONTACT Heveline Silva
hevelinequi@gmail.com
Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
Supplemental data for this article is available online at https://doi.org/10.1080/00958972.2021.1871608.
ß 2021 Informa UK Limited, trading as Taylor & Francis Group

824
C. DE SOUZA PEREIRA ET AL.
1. Introduction
Pseudomonas aeruginosa remains an important putative pathogen specially in nosoco-
mial infections related to high mortality rates in immunocompromised individual of
about 30% [1]. According to the World Health Organization these Gram-negative bac-
teria along the Gram-positive Staphylococcus aureus belong to a catalogue of twelve
concerned families of bacteria considered the greatest threat to human health [2].
Besides that, as antimicrobial chemotherapy is often necessary to overcome bacterial
infections, the emergence of antibiotic-resistant bacteria was considered a significant
health challenge worldwide [3]. Thus, these facts may provide a clear picture of the
magnitude of the antimicrobial resistance phenomenon and the necessity of new
compounds that can act against bacterial infection and overcome resistance.
In this context, an important class of compounds is oxadiazoles, which are five-
membered heterocycles and can be found in some different isomeric forms, being the
1,2,4- and 1,3,4- are the most used in medicinal chemistry [4]. The oxadiazole-derived
compounds have presented large biological properties such as antiviral, antibacterial,
antioxidant, anti-inflammatory, antifungal and anticancer activity [5–9]. The isomeric
form used in this work is 1,2,4-oxadiazole and the purpose of use is to favor the bio-
logical activity with the metal coordination.
The discovery of the antitumor properties of cisplatin (cis-diamminedichloridoplati-
num) by Rosenberg in the 1960s while researching the effect of electric field in the
bacteria growth boosted the research for drugs based on platinum for cancer treat-
ment [10–12]. Besides that, other metal compounds are used in medicine as the com-
R
V
pound of gold(I), Ridaura (auranofin) for rheumatoid arthritis and the complexes of
R
R
Sb(V) PentostamV (sodium stibogluconate) and GlucantimeV (N-methyl glucamine anti-
moniate) for leishmaniasis treatment [13]. Gold(I) and platinum(II) complexes with
ligands containing oxadiazole were reported and these compounds have presented
good activity against tumor cells, bacteria and Leishmania parasites [14–18]. In the
R
case of bacterial infections, the use of Ag(I) can be mentioned with SilvadeneV that is
a water-miscible cream containing silver sulfadiazine. This compound, when in contact
with a wound, releases silver ions that able to kill bacteria such as Pseudomonas aeru-
ginosa and methicillin-resistant Staphylococcus aureus (MRSA) [19]. Additionally, with
respect to the research of metal complexes, in a recent paper DuChane and collabora-
tors demonstrated the potent activity of a class of iridium piano-stool complexes with
diamine ligands against S. aureus and methicillin-resistant of S. aureus [20]. Another
work reported the analysis of the antibacterial and antifungal activity of about 1000
metal complexes, highlighted 30 compounds containing as metal Mn, Co, Zn, Ru, Ag,
Eu, Ir and Pt, that presented activity against Gram-positive and/or Gram negative bac-
teria, and activities down to nanomolar range in MRSA [21]. Thereby, we decided to
contribute with new platinum(II) complexes.
Based on the similarities between Pt(II) and Pd(II) we also decided to synthesize pal-
ladium complexes [22]. However, the palladium is much more labile than platinum
analogs and this fact limits the research of compounds based on this metal, whereas
the possibility of rapid hydrolysis in the organism can convert the palladium com-
plexes into inactive species unable to attain the biological targets [23]. The alternative
found to overcome this inconvenience is synthesis of chelates, which can make the

JOURNAL OF COORDINATION CHEMISTRY
825
Scheme 1. Synthesis of ligands.
complexes thermodynamically stable [24], which is the objective of this work. To pro-
mote a chelate coordination we have included the ethylenediamine moiety to the
phenyl-oxadiazole derivative.
Throughout this work we have reported the synthesis, characterization and evalu-
ation of cytotoxic and antibacterial activity of platinum(II) and palladium(II) complexes
compared to their ligands phenyl-oxadiazole-ethylenediamine containing different sub-
stituents on the aromatic ring to provide the influence in their biological activity.
2. Experimental
2.1. Materials and methods
All reagents were obtained from commercial sources and used without purification.
Brain Heart Infusion agar (BHIA), Mueller-Hinton broth (MHB) and Mueller Hinton agar
medium (AMH) were from Himedia Laboratories, Mumbai, India.
IR spectra were obtained with a Bruker Alfa FT-IR Spectrometer in KBr pellets.
1
Raman spectra were obtained on a Bruker RFS 100 FT-Raman. H NMR (500 MHz), 13C
NMR (125 MHz) and 195Pt (107.5 MHz) spectra were obtained in DMSO-d6 on a Bruker
Avance 500 MHz spectrometer. UV absorption spectra were obtained in aqueous solu-
tion (1% DMSO) on an UV-1800 Spectrophotometer Shimadzu. Finally, elemental analy-
~
ses were performed at the University of Sao Paulo (USP), Brazil.
2.2. Synthesis of ligands A–C (Scheme 1)
The synthesis of oxadiazoles was taken by the reaction of the corresponding benzoni-
trile (8 mmol) and sodium bicarbonate (12.8 mmol) with hydroxylamine hydrochloride
(12 mmol) in 15 mL of methanol. The reaction remained stirring for 6 h in reflux. After
cooling, the solvent was removed under reduced pressure and the mixture was puri-
fied by extraction with ethyl acetate and water, and then with brine solution, affording
the amidoxime.

826
C. DE SOUZA PEREIRA ET AL.
Scheme 2. Synthesis of complexes.
In the second stage, a solution of bromacetyl bromide (8.1 mmol) in 5 mL of
dichloromethane was slowly added to a solution of the respective amidoxime (6 mmol)
and potassium carbonate (6 mmol) in 15 mL of dichloromethane. The reaction was
stirred for 3 h at room temperature. The solvent was removed, and the mixture was
extracted with ethyl acetate/water and washed with brine solution. The solvent was
removed and it was added toluene, and the mixture remained heating at 100 ꢀC for
21 h. The reaction was cooled and the solvent removed affording the desired oxadia-
zole precursors.
A solution of the respective oxadiazole (3 mmol) in 5 mL of acetonitrile was slowly
added to a solution of ethylenediamine (8.1 mmol) and carbonate of potassium
(4.5 mmol) in 5 mL of acetonitrile. The reaction was allowed to stir for 1 h in reflux. The
reaction was cooled, and the solvent was removed under reduced pressure. The mix-
ture was extracted with dichloromethane and water, and brine solution. Then, the
crude mixture was purified by column chromatography employing dichloromethane
and methanol as eluent, affording the desired compounds. Yields: (A) 52%, (B) 49%,
(C) 53%.
1
A. IR (KBr), mmax (cmꢁ1): 3349, 3294, 3063, 2928, 2852, 1444, 1070; H NMR (500 MHz,
DMSO-d6), d (ppm): 2.61 (m, 4H, CH2-NH and CH2-NH2); 4.06 (s, 2H, CH2-oxadia-
zole); 7.56 (t, 3H, J ¼ 7.5 Hz, Ph), 8.02 (m, 2H, Ph); 13C NMR (125 MHz, DMSO-d6), d
(ppm): 41.2 (C-NH2); 44.2(C-NH); 51.7 (HN-C-oxadiazole); 126.3 (C-Ph); 127.0; 129.3;
131.5 (HC-Ph); 167.4 (N-C-N); 179.6 (N-C-O).
B. IR (KBr), mmax (cmꢁ1): 3362, 3304, 3090, 2939, 2861, 1516,1446, 1346, 1075; 1H
NMR (500 MHz, DMSO-d6), d (ppm): 2.61 (m, 4H, CH2-NH and CH2-NH2); 4.11 (s,
2H, CH2-oxadiazole); 7.86 (t, 1H, J ¼ 8 Hz, Ph), 8.43 (m, 3H, Ph), 8.70 (m, 1H, Ph);
13C NMR (125 MHz, DMSO-d6), d (ppm): 41.2 (C-NH2); 44.3 (C-NH); 51.8 (HN-C-oxa-
diazole); 121.5; 126.1 (HC-Ph); 127.7 (C-Ph); 131.3; 133.1 (HC-Ph), 148.3 (C-NO2);
166.1 (N-C-N); 180.4 (N-C-O).
C. IR (KBr), mmax (cmꢁ1): 3357, 2940, 2868,1418, 1326, 1066; 1H NMR (500 MHz,
DMSO-d6), d (ppm): 2.61 (m, 4H, CH2-NH and CH2-NH2); 4.09 (s, 2H, CH2-oxadia-
zole); 7.92 (d, 2H, J ¼ 8 Hz, Ph), 8.21 (d, 2H, J ¼ 8 Hz, Ph), 8.70 (m, 1H, Ph); 13C
NMR (125 MHz, DMSO-d6), d (ppm): 41.2 (C-NH2); 44.2 (C-NH); 51.8 (HN-C-oxadia-
1
2
zole); 120.6 (q, J ¼ 271.5 Hz, C-F3); 126.3; 127.9 (HC-Ph); 130.1 (C-Ph); 130.9 (q, J
¼ 31,5 Hz, C-CF3); 166.5 (N-C-N); 180.2 (N-C-O).

JOURNAL OF COORDINATION CHEMISTRY
827
2.3. Synthesis of complexes 1–6 (Scheme 2)
The complexes were obtained by slow addition of solution of the respective ligand
(0.3 mmol) in methanol (1 mL) to a 2.5 mL aqueous solution of K2PtCl4 (0.3 mmol) (for
1–3) or K2PdCl4 (0.3 mmol) (for 4–6). The reaction was kept protected from light under
stirring for 4 h at room temperature. The solid obtained was filtered off, washed with
water, methanol and dichloromethane. Yields: (1) 60%, (2) 76%, (3) 68%, (4) 73%, (5)
70%, (6) 56%.
1. IR (KBr), mmax (cmꢁ1): 3288, 3184, 3093, 2961, 2877, 1594, 1445, 1344, 1073; Raman
(cmꢁ1): 3074, 2966, 2893, 1608, 1527, 1475, 1446, 1159, 1005, 966, 577, 332, 160,
1
114; H NMR (500 MHz, DMSO-d6), d (ppm): 2.36 (m, 2H, CH2-NH2); 2.69 (m, 2H,
CH2-NH); 4.35 (dd, 1H, J ¼ 15.5 Hz, J ¼ 9 Hz CH2-oxadiazole); 4.75 (dd, 1H, CH2-
oxadiazole); 5.42 (m, 2H, NH2); 7.18 (br, 1H, NH); 7.59; 7.60; 7.61 (t, 3H, J ¼ 5 Hz,
Ph); 8.03; 8.05 (d, 2H, J ¼ 10 Hz, Ph); 13C NMR (125 MHz, DMSO-d6), d (ppm): 46.6
(C-NH2); 46.6 (C-NH); 56.5 (HN-C-oxadiazole); 125.9 (Ph-oxadiazole); 127.1; 129.37;
131.8 (C-Ph); 167.6 (N-C-N); 174.9 (N-C-O). 195Pt NMR (107.5 MHz, DMSO-d6), d
(ppm): -2354. Anal. Calc. for C11H14N4OPtCl2 (%): C, 27.27; H, 2.89; N, 11.57. Found:
C, 27.55; H, 2.82; N, 11.26.
2. IR (KBr), mmax (cmꢁ1): 3267, 3199, 3118, 2959, 2890, 1519, 1446, 1349, 1076; 1H
NMR (500 MHz, DMSO-d6), d (ppm): 2.36 (m, 2H, CH2-NH2); 2.68 (m, 2H, CH2-NH);
4.40 (dd, 1H, J ¼ 15.5 Hz, J ¼ 9 Hz CH2-oxadiazole); 4.79 (dd, 1H, CH2-oxadiazole);
5.44 (m, 2H, NH2); 7.25 (br, 1H, NH); 7.91 (m, 1H, Ph); 8.46 (m, 2H, Ph); 8.73 (m,
1H, Ph); 13C NMR (125 MHz, DMSO-d6), d (ppm): 46.6 (C-NH2); 46.8 (C-NH); 56.6
(HN-C-oxadiazole); 121.7; 126.4 (HC-Ph); 127.4 (C-Ph); 131.4; 133.2 (HC-Ph); 148.4
(C-NO2); 166.3 (N¼C-N); 175.7 (N-C-O). 195Pt NMR (107.5 MHz, DMSO-d6), d (ppm):
-2355. Anal. Calc. for C11H13N5O3PtCl2 (%): C, 24.95; H, 2.46; N, 13.23.Found: C,
24.54; H, 2.40; N, 12.41.
3. IR (KBr), mmax (cmꢁ1): 3303, 3182, 3091, 2957, 2884, 1418, 1065; Raman (cmꢁ1):
1
1624, 1542, 1488, 968, 778, 634, 569, 328; H NMR (500 MHz, DMSO-d6), d (ppm):
2.35 (m, 2H, CH2-NH2); 2.70 (m, 2H, CH2-NH); 4.38 (dd, J ¼ 15.6 Hz and J ¼ 9.6 Hz,
1H, CH2-oxadiazole); 4.78 (dd, 1H, J ¼ 2 Hz and J ¼ 15.6 Hz, CH2-oxadiazole); 5.44
(m, 2H, NH2); 7.23 (br, 1H, NH); 7.97 (d, J ¼ 8 Hz, 2H, Ph), 8.25 (d, J ¼ 8 Hz, 2H,
Ph); 195Pt NMR (107.5 MHz, DMSO-d6),
d (ppm): -2357. Anal. Calc. for
C12H13N4OF3PtCl2 (%): C, 26.09; H, 2.35; N, 10.14. Found: C, 26.01; H, 2.41; N, 9.76.
4. IR (KBr), mmax (cmꢁ1): 3183, 3101, 2968, 1445, 1070, 1028; Raman (cmꢁ1): 1607,
1
1527, 1000, 962, 550, 337, 303; H NMR (500 MHz, DMSO-d6), d (ppm): 2.46 (m, 2H,
CH2-NH2); 2.76 (m, 2H, CH2-NH); 4.38 (dd, J ¼ 9 Hz and J ¼ 16 Hz, 1H, CH2-oxadia-
zole); 4.57 (dd, J ¼ 2 Hz and J ¼ 9 Hz, 1H, CH2-oxadiazole); 4.97 (m, 2H, NH2); 6.78
(br, 1H, NH); 7.61 (m, 3H, Ph); 8.05 (m, 2H, Ph); 13C NMR (125 MHz, DMSO-d6), d
(ppm): 44.7 (C-NH2); 45.7(C-NH); 54.4 (HN-C-oxadiazole); 125.9 (C-Ph); 127.1; 129.3;
131.8 (HC-Ph); 167.5 (N-C-N); 175.0 (N-C-O). Anal. Calc. for C11H14N4OPtCl2 (%): C,
33.42; H, 3.54; N, 14.18. Found: C, 33.56; H, 3.58; N, 13.57.
5. IR (KBr), mmax (cmꢁ1): 3264, 3198, 3107, 2945, 2889, 1517, 1444, 1349, 1079, 1038;
1H NMR (500 MHz, DMSO-d6), d (ppm): 2.48 (m, 2H, CH2-NH2); 2.75 (m, 2H, CH2-
NH); 4.42 (dd, J ¼ 16 Hz and J ¼ 9 Hz, 1H, CH2-oxadiazole); 4.62 (dd, 1H, J ¼ 16 Hz

828
C. DE SOUZA PEREIRA ET AL.
and J ¼ 2 Hz, CH2-oxadiazole); 4.98 (m, 2H, NH2); 6.81 (br, 1H, NH); 7.91 (m, 1H,
Ph); 8.48 (m, 2H, Ph), 8.74 (m, 1H, Ph); 13C NMR (125 MHz, DMSO-d6), d (ppm): 44.7
(C-NH2); 45.8 (C-NH); 54.5 (HN-C-oxadiazole); 121.6; 126.4 (HC-Ph); 127.4 (C-Ph);
131.3; 133.2 (HC-Ph); 148.3 (C-NO2); 166.2 (N¼C-N); 175.8 (O-C¼N). Anal. Calc. for
C11H13N5O3PdCl2 (%): C, 30.00; H, 2.95; N, 15.91. Found: C, 30.59; H, 2.99; N, 15.41.
6. IR (KBr), mmax (cmꢁ1): 3311, 3186, 3103, 2955, 2890, 1418, 1324, 1065; Raman
1
(cmꢁ1): 3089, 2956, 2891, 1626, 1543, 1489, 1122, 968, 781, 550, 316, 285, 158; H
NMR (500 MHz, DMSO-d6), d (ppm): 2.47 (m, 2H, CH2-NH2); 2.77 (m, 2H, CH2-NH);
4.40 (dd, J ¼ 16 Hz and J ¼ 9 Hz, 1H, CH2-oxadiazole); 4.59 (dd, 1H, J ¼ 16 Hz and
J ¼ 2 Hz, CH2-oxadiazole); 4.97 (m, 2H, NH2); 6.80 (br, 1H, NH); 7.96 (d, J ¼ 8 Hz,
2H, Ph), 8.27 (d, J ¼ 8 Hz, 2H, Ph); 13C NMR (125 MHz, DMSO-d6), d (ppm): 44.8 (C-
1
NH2); 45.9 (C-NH); 54.5 (HN-C-oxadiazole); 120.6; 122.8; 124.9; 127.1 (C-F3, q, J ¼
2
270.9 Hz); 126.3; 126.4; 128.1 (HC-Ph); 129.8 (C-Ph); 131.2 (C-CF3, q, J ¼ 31,5 Hz);
166.7 (N-C-N); 175.6 (N-C-O). Anal. Calc. For C12H13N4OF3PdCl2 (%): C, 31.10; H,
2.81; N, 12.09. Found: C, 30.66; H, 2.80; N, 11.58.
2.4. Cytotoxicity assay
Cell viability was determined on the non-tumor cell BHK-21—Baby Hamster Kidney
and the tumor cell lines: CT26-WT–murine colon cancer cells and 4T1–mouse meta-
static mammary adenocarcinoma. The cells were harvested and seeded in RPMI 1640
culture medium, supplemented with fetal bovine serum (FBS) 10%, at densities rang-
ing as the cell line (0.5 ꢂ 103 and 2 ꢂ 103 cells/100 mL/well) of 96-well plates and were
appropriately incubated at 37 ꢀC in humidified atmosphere of 5% CO2 for 24 h to com-
plete adherence. In the wells were distributed 100 mL of decreasing concentrations
(100 to 0.1 mM) of compounds. The experiments were done in quadruplicate with cul-
ture medium as negative control and cisplatin as positive control against these
cell lines.
After exposure to the compounds for 72 h, the cells were incubated with MTT
(5 lg/10 lL/well) for 4 h. Next, all the supernatant liquid was removed, 100 lL of
DMSO/well was added, and cell viability determined by measuring absorbance at
492 nm in a microplate spectrophotometer. The IC50 was calculated using GraphPad
Prism 5.0 software.
2.5. Antimicrobial assay
Antibacterial activities of ligands and complexes were evaluated on strains of bacteria
Staphylococcus aureus ATCC 29213, Staphylococcus epidermidis ATCC 12228 (Gram-posi-
tive); Escherichia coli ATCC 11229, Pseudomonas aeruginosa ATCC 27853 (Gram-nega-
tive) employing Chloramphenicol as positive control and Mueller-Hinton Broth
(MHB–Himedia Laboratories, Mumbai, India) and bacterium as negative control.
For such an assessment it used the susceptibility test broth microdilution method-
ology according to CLSI guidelines [25]. Bacteria strains were routinely cultured at
37 ꢀC for 24 h on Brain Heart Infusion agar (BHIA—Himedia Laboratories, Mumbai,
India) and diluted in saline solution 0.9% (108 CFU/mL, according to McFarland

JOURNAL OF COORDINATION CHEMISTRY
829
Figure 1. Viability of cells (4T1, CT26WT and BHK21) exposed during 72 h to the highest concentra-
tion tested (100 mM) of the compounds. (A) Ligands A and B, (B) Pt complexes 1–3 and (C) Pd
complexes 4–6.
turbidity standards). From stock solution (in DMSO) serial dilutions were performed
from 2 mg/mL in Mueller-Hinton broth (MHB—Himedia Laboratories, Mumbai, India)
until reaching final concentrations between 256.0 and 2.0 mg/mL. The compounds with
inoculum were incubated at 37 ꢀC for 24 h and the minimum inhibitory concentration
(MIC) was calculated as the lowest concentration that prevented visible growth of the
strain. All tests were performed in duplicate.
2.6. Bactericidal and bacteriostatic activity
The minimal bactericidal concentrations (MBC) were determined by transferring culture
aliquots with sterile swabs to Petri dishes containing Mueller Hinton agar medium

830
C. DE SOUZA PEREIRA ET AL.
Table 1. Cytotoxicity, expressed as IC50 (lM), of complexes obtained by MTT assay against 4T1,
CT26WT and BHK21 cell lines. IC50 is defined as the drug required concentration to inhibit 50% of
cellular growth.
IC50 (lM)a
Compound
4T1
9.8
58.4
51.7
6.2
CT26-WT
BHK-21
2
3
6
2
7
5
1
>100
>100
>100
>100
>100
>100
Cisplatinb
6
1
8 2
aData are shown as the mean values of two independent experiments performed in triplicate with the corresponding
standard deviations.
bReference drug.
(AMH—Himedia Laboratories, Mumbai, India) and bacterial growth was evaluated after
incubation under aerobic conditions at 37 ꢀC for 24 h. The selected concentrations
were related to the MIC, considering two dilutions above and two dilutions below.
The MBC was determined as the lowest dilution that did not allow growth of the bac-
teria. To the compounds for which bacterial growth was observed for all dilutions
around MIC, the bacteriostatic effect was attributed.
3. Results and discussion
3.1. Structures and spectroscopic characterization
The ligands were obtained by a reaction in three steps (Scheme 1). Initially, it was
taken to obtain the amidoxime, in the second step the amidoxime reacts with bro-
moacetyl bromide getting the oxadiazole which finally reacts with ethylenediamine
obtaining the ligand. The ligand received proper purification in each step.
For these ligands, the experimental IR spectra showed broad absorptions assigned
to NH stretch in the 3400–3300 cmꢁ1 region. The 3090, 2920 and 2870 cmꢁ1 were
observed absorptions corresponding to CH of aromatic and symmetric and asymmetric
stretch of CH of aliphatic. Other bands were observed at 1444 cmꢁ1 m(CN) and
1070 cmꢁ1 m(CO) of oxadiazole. For ligand B in the 1516 and 1346 cmꢁ1 region show
stretch assigned to the NO2 group and for ligand C at 1326 cmꢁ1 it was observed one
band relative to the CF3 group. In the 1H NMR spectra, were observed a multiplet
around d ¼ 2.60 ppm with four hydrogens assigned to the CH2 group of ethylenedi-
amine, at d ¼ 4.09 ppm it was observed one singlet corresponding to the CH2 switched
on to the oxadiazole and in the region 7.56–8.70 ppm show signs it can be attributed
to aromatic hydrogens. In the 13C NMR spectra, signals were observed at 41.2 ppm
and 44.2 ppm and can be assigned the ethylenediamine carbons linked to NH2 and
NH, respectively, and at 51.7 ppm was observed the carbon that unity ethylenediamine
and the oxadiazole. For the aromatic carbons, were observed signals in the d region
120.6–133.1 ppm. Ultimately, at 166.1 ppm (N-C-N) and 180.4 ppm (N-C-O) were
observed other carbons of oxadiazole.
The complexes were obtained by reaction of the ligands with metal salt (K2PtCl4 or
K2PdCl4) in methanol/water under stirring for four hours when the solid complexes
(Scheme 2) could be filtered off.

JOURNAL OF COORDINATION CHEMISTRY
831
Table 2. MIC - Minimum inhibitory concentration of the compounds in bacteria strains.
MIC - Minimum inhibitory concentration—mg/mL (mM)
Gram-positive
S. epidermidis
Gram-negative
P. aeruginosa
Compound
S. aureus
E. coli
Ligand A
Ligand B
Ligand C
Complex 1
Complex 2
Complex 3
Complex 4
Complex 5
Complex 6
Chloramphenicol
256.0
256.0
64.0
256.0
32.0
32.0
256.0
32.0
16.0 (34.5)
16.0
256.0
256.0
256.0
256.0
256.0
128.0
256.0
256.0
256.0
256.0
256.0
256.0
16.0
256.0
256.0
256.0
256.0
256.0
256.0
256.0
256.0
128.0
32.0
256.0
16.0 (30.0)
8.0 (14.4)
256.0
8.0 (18.2)
64.0
32.0
Complexes were characterized using analytical and spectroscopic techniques. In the
IR spectra of the complexes (Figures S1–S6), in comparison with respective ligand, the
NH stretch was moved up to 200 cmꢁ1, and displayed around 3300–3200 cmꢁ1, indi-
cating N-coordinating proposal for the ligand to metal. The other bands were
observed without significant displacement. From the Raman spectra we notice the
emergence of two bands referring to stretching metal-Cl and metal-N at 330 (Pt-Cl)
and 570 (Pt-N) cmꢁ1 for platinum complexes that agree with the reported for cis-
[Pt(NH3)2Cl2] and trans-[Pt(NH3)2Cl2] complexes [26]. Similarly, at 316 (Pd-Cl) and 550
(Pd-N) cmꢁ1 for palladium complexes such as assigned for palladium(II) complex with
1
a ligand derived from EDTA [27]. In the H NMR spectra (Figures S7–S12) important
changes were observed which are strong indications of the coordination of the ligand
to the metal through the nitrogen of diamine, like the hydrogens of the ethylenedi-
amine that initially were together became separated and displaced at 2.4 ppm (CH2-
NH2) and 2.7 ppm (CH2-NH). The other CH2 appeared as two double doublets at
4.4 ppm and 4.7 ppm due to the formation of a chiral center after metal coordination.
1
Finally, the signals relative to NH2 (5.4 ppm) and NH (7.2 ppm) were observed. The H
NMR spectrum of 1 is assigned in the Supplementary Information (Figure S7), and it is
1
possible to observe the related modifications. All the signals observed in the H NMR
spectrum were assigned based on 2 D NMR experiment (1H-1H COSY—Figure S13).
Comparing the 13C NMR spectra for the complexes to the free ligands (Figures
S14–S19) we have observed the displacement of the assigned signals to carbons of
ethylenediamine, of the CH2 between ethylenediamine and oxadiazole ring, and the
quaternary carbons of oxadiazole, which indicates the proposed coordination.
Ultimately, for the 195Pt NMR spectra, the complexes show only one signal at
ꢁ2350 ppm which is expected for platinum coordinated to two nitrogen atoms and
two chlorides, since some works (theoretical and experimental) reported signals in this
region for complexes which presented the same coordination sphere [28–31]. Varying
the ligand substituents can result in variations about 100 ppm or more in the chemical
shifts [32], similar to that observed previously in the cited works. The values obtained
from elemental analysis agreed with the molecular formula proposed. The complexes
synthesized correspond to a 16-electron configuration with a square planar geometry.
Prior to biological studies, the compounds were submitted to UV-vis spectra deter-
mination at physiological conditions (buffer solution, 1% DMSO, pH 7.2 and 36 ꢀC)

832
C. DE SOUZA PEREIRA ET AL.
until 72 h to assess the stability. All compounds did not show any interference during
this time exposure. Representative spectrum of 1 is presented in the Supplementary
Material (Figure S20).
3.2. Cytotoxicity
The ligands were unable to inhibit cell viability at the concentrations used (up to
100 mM). Also, for complexes, the IC50 values (the concentration to inhibit 50% of cell
viability) were not determined since they were not able to inhibit the cell growth sat-
isfactorily, except for 2, 3 and 6 for 4T1 cells. Based on that, the results of cell viability
after 72 h of exposure to the compounds in their higher concentration (100 mM) are
shown in Figure 1. The IC50 calculated to these compounds and compared to cisplatin
are presented in Table 1. Only 2 shows IC50 9.8 2 lM closed to cisplatin (6.2 1 lM);
this result is very interesting since complex 2 (platinum complex) did not exhibit activ-
ity in non-tumor cell (BHK-21) been selective to mammary carcinoma cell (4T1).
Complexes 3 and 6 presented low cytotoxicity in 4T1 (IC50 around 50 mM) without
inhibition of cell viability of non-tumor cell line, which indicates some selectivity. In a
similar way, the literature shows a work that describes the cytotoxicity of metal com-
plexes with ligands derived of oxadiazole where it is possible to observe that coordin-
ation of the ligand to the metal improves the antitumor activity [16]. Other literature
of gold(I) complexes with oxadiazole derivatives as ligands showed better activity of
the complex when compared with the ligand (about eighty times) and were better
and more selective than cisplatin in B16-F10 tumor cell line (murine melanoma) [17].
In the case of platinum(II), one complex derived of oxadiazole showed good activity
(similar to cisplatin) and better cytotoxicity when compared with free ligands [14].
With respect to the ligands, it was reported that fifty-six synthetic compounds
derived of oxadiazole, being that 1,2,4-oxadiazole derived did not show significant
results for the cell lines tested [6]. The best results for these derivatives were for two
compounds with another diamine, the piperazine N-alkylated with a long carbon
chain. The 1,3,4-oxadiazoles showed better activity when compared with 1,2,4-oxadia-
zole, and some derived of 1,3,4- were capable to induce apoptosis in the tumor-cell
tested [6]. Thereby, how it was observed that the coordination improves the cytotoxic
activity, the ligands derived from oxadiazole are a promising class to study. In our
case, the compounds are not active enough to be promising as anticancer agents. On
the other way, the antibacterial activity evaluation is of special interest for compounds
that do not show cytotoxicity, facing the antimicrobial resistance issue.
3.3. Antibacterial activity
Based on related promising antimicrobial activity of the oxadiazoles we decided to
evaluate our compounds about it [33, 34]. The antibacterial activity of the compounds
was determined against four strains (Staphylococcus aureus, Staphylococcus epidermidis,
Escherichia coli and Pseudomonas aeruginosa). The susceptibility test broth microdilu-
tion methodology was used (Figure S21) and the MIC values obtained are given in
Table 2.

JOURNAL OF COORDINATION CHEMISTRY
833
Table 3. Evaluation of bactericidal (X) or bacteriostatic (S) activity of the synthesized molecules.
(lethal concentration in mg/mL).
Bacteria species
Gram-positive
S. epidermidis
Gram-negative
P. aeruginosa
Compound
S. aureus
E. coli
Ligand A
Ligand B
S
S
S
S
S
S
S
S
Ligand C
S
S
S
S
S
S
S
S
S
S
S
Complex 1
Complex 2
Complex 3
Complex 4
Complex 5
Complex 6
X(256)
X(256)
X(128)
X(256)
X(256)
X(256)
S
X(256)
S
X(256)
S
S
S
S
X(256)
X(256)
X(256)
Based on the MIC values, it is possible to observe that for Gram-positive strains, 2,
3, 5 and 6 were more active than the respective ligands. The positive control used
was chloramphenicol, widely used as reference drug in prospective assays with new
antimicrobial candidates. Chloramphenicol is an extended-spectrum agent with both
anti-Gram-positive and anti-Gram-negative bacteria, in different clinical protocols, but
with test limits well established by CLSI, which validates its uses as a quality control
drug to validate MIC assays [15, 25, 35–37]. It is important to state, however, that
chloramphenicol resistance has emerged, which is impacting its clinical efficacy [38].
According to our data, it was observed that 6 was as active as chloramphenicol
against S. aureus ATCC 29213, which was in turn within the MIC limits for the test
according to CLSI validating the observations. As an important bacterial group men-
tioned before these microorganisms figure as one of the twelve procaryotes of med-
ical importance considered the greatest threat to human health nowadays [2]. As
shown in Table 2, the relative MIC (34.5 mM) is lower than the IC50 (51.7 mM) for 6 in
the only cell line (4T1) it presents some activity (Table 1). With respect to S. epidermidis
strain, 2, 3 and 5 were more active than the control chloramphenicol. The coordin-
ation and the presence of groups NO2 and CF3 may favor activity in Gram-positive
bacteria. It was reported that compounds with NO2 and CF3 substituents in phenyl
ring present moderate or good activity against bacteria [39, 40]. The fact of the sub-
stituents has modified the activity in agreement with the literature, where it was
observed that the nature of the substituent groups and their position on aromatic
group affect the MIC values [41]. It is important to mention the difference between
the Gram-positive and Gram-negative strains, the former have a thick cell wall and the
latter have a relatively thin layer of peptidoglycan with an external phospholipidic
membrane [42]. In this way, the better activity of the tested compounds among Gram-
positive representative bacteria might be related to the structural differences between
Gram-negative and Gram-positive bacteria, especially considering the cell wall [43].
Similarly to what was observed in this work, Almeida and coworkers showed the syn-
thesis of gold(I) complexes with lipophilic ligands derived from oxadiazole and these
complexes exhibited excellent antibacterial activity in the same Gram-positive strains
tested in our paper, including being better than the ligands [15]. Besides the use of
the heterocyclic ring oxadiazole, in the structure of our compounds there are a
diamine and an aromatic ring, so, in this context, we can compare with compounds

834
C. DE SOUZA PEREIRA ET AL.
containing those unities. With respect to aromatic diamines, Vieira and coworkers
describe the synthesis and the antitubercular activity of platinum(II) and palladium(II)
with fluoroquinolones. In this work, the ligands bind to platinum(II) in the same way
of our complexes, forming a chelate with the diamine, and most complexes presented
better activity against Mycobacterium tuberculosis than Rifampicin [44]. The metals
employed in this work, platinum and palladium, were already assessed as antibacteri-
als and have shown similar or better activity than the standards used [45, 46]. Another
point reported in the literature that is in accordance to our results was the increased
activity after metal complexation [47, 48].
3.4. Bactericidal and bacteriostatic activity
The antibiotics are classified according to how they act on bacteria, being called bac-
tericidal the antibiotics that kill bacteria and bacteriostatic those that inhibit bacterial
growth [49]. Despite this, it is reported that bacteriostatic compounds can kill bacteria,
but in a higher concentration than bactericidal agents [50]. Thus, we have evaluated
this feature of the ligands and the complexes and classify them as bactericidal or bac-
teriostatic (Table 3).
There are antibiotics with bacteriostatic activity as chloramphenicol against
Staphylococcus aureus and Gram-negative bacilli of Enterobacteriaceae [51, 52], but in
several specific cases, in terms of chemotherapy it is needed potential antimicrobial
drugs with bactericidal action such as in endocarditis [53]. According to Table 3, all
ligands were bacteriostatic, in turn, considering the chemical complexes, bactericidal
activity was observed for some strains. Complex 6 (palladium(II) complex with the lig-
and containing CF3 as substituent) was the only compound which showed bactericidal
activity against all tested bacteria strains, but only in higher concentrations. For the S.
epidermidis strain, all the complexes were bactericidal, so the metal presence might be
associated to the observed activity.
4. Conclusion
This work describes the synthesis and characterization of three ligands derived from
phenyl-oxadiazole-ethylenediamine, whose difference lies in the substituent on the
aromatic ring, and their platinum(II) and palladium(II) complexes. We studied the anti-
bacterial and cytotoxicity activity for the compounds. It should be highlighted that 2
is the only compound presenting antitumor activity and selective to the carcinoma
mammalian cell (4T1). The fact that the compounds, in general, do not show cytotox-
icity in tumor cells or normal cells suggests that they could be used to treat bacterial
infections without causing toxicity to the host, an advance to be considered in poten-
tial biological application. Complexes 2, 3, 5 and 6 were more active when compared
with their ligands in Gram-positive strains. This fact highlights and reinforces evidence
that the coordination favored the activity and the presence of -NO2 and -CF3 in aro-
matic ring also contribute to the complex activity and selectivity. Thus, although fur-
ther prospective studies such as those with a broader panel of freshly isolated

JOURNAL OF COORDINATION CHEMISTRY
835
bacteria are needed, we may suggest that 3, 5 and 6 are potential candidates as anti-
microbial molecules without causing cytotoxicity.
Acknowledgements
The authors are grateful to CNPq, FAPEMIG, CAPES for the financial support and fellowships.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
~
ꢀ
This study was financed in part by the Coordenac¸ao de Aperfeic¸oamento de Pessoal de Nıvel
Superior - Brasil (CAPES) - Finance Code 001.
ORCID
Heveline Silva
https://orcid.org/0000-0003-3537-4961
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