Journal of Molecular Structure 1274 (2023) 134485

Contents lists available at ScienceDirect

Journal of Molecular Structure

journal homepage: www.elsevier.com/locate/molstr

Synthesis and characterization of thiosemicarbazone metal complexes:

Crystal structure, and antiproliferation activity against breast (MCF7)
and lung (A549) cancers
Mayada S. Ali a, Fathy A. El-Saied b, Mohamad ME. Shakdofa c, Sadashiva Karnik d,e,
Laila A. Jaragh-Alhadad a,d,∗
a
Chemistry Department, Faculty of Science, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait
b
Chemistry Department, Faculty of Science, El-Menoufia University, Shebin El-Kom, Egypt
c
Inorganic Chemistry Department, National Research Centre (ID 60014618), 33 El-Bohouth St., P.O. 12622, Dokki, Giza, Egypt
d
Cardiovascular and Metabolic Sciences Department, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, United States
e
Cleveland Clinic Learner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, United States

a r t i c l e i n f o a b s t r a c t

Article history: Thiosemicarbazone compound has pronounced anticancer activity, which increases by metal ions pres-
Received 28 August 2022 ence. New Ni(II), Cu(II), Pd(II), and Pt(II) complexes synthesized from 2-(2,3-dihydroxy benzylidene)-N-
Revised 31 October 2022
ethylhydrazine-1-carbothioamide ligand H3 L and had been characterized via NMR, GC–MS, FTIR, CHNS,
Accepted 2 November 2022
UV–vis, TGA, magnetic susceptibility measurements, and molar electric conductivity. X-ray crystallo-
Available online 3 November 2022
graphic data and the refinement structure of thiosemicarbazide ligand indicated a clear light colorless
Keywords: block with the formula C10 H13 N3 O2 S, which belongs to a monoclinic system with P1 21/ c1 space group
Thiosemicarbazone and adopts orthorhombic crystal with a = 5.1509(3) Å; b = 10.2856(6) Å; c = 11.3261(6) Å. The ligand
Metal complexes and the metal complexes were also tested for antiproliferation activity against the MCF7 breast and A549
Spectroscopic characterization lung cancer cell lines. The data showed that Ni(II), Cu(II), Pd(II), and Pt(II) complexes had potent an-
X-ray crystallography tiproliferation activity at the micromolar level. Pt(II) complex with square planar geometry exhibits the
MCF7
highest antiproliferation activity, while Ni(II) complex with distorted octahedral geometry showed the
A549
Antiproliferation assay
lowest antiproliferation activity in both cell lines.
© 2022 Elsevier B.V. All rights reserved.

1. Introduction
Recently, metal-based anticancer drugs played an essential role
in chemotherapy treatment because metal ions bind to specific co-
ordination to a nucleic acid which alters confirmations that has a
biological effect. Therefore, researchers focused on developing new
transition metal-based anticancer agents with low cytotoxicity for
cancer therapy. Thiosemicarbazone compounds and their deriva-
tives gained much attention from chemists and biologists because
of their highly stable-colored complexes with a wide variety of
stereochemistry for the spectrophotometric determination of metal
ions in different media [1–3]. In addition, to their antibacterial [4],
anticancer [5], and antiviral properties [6].
Thiosemicarbazone-derived nickel(II) complexes showed poten-
tial activities in cytotoxicity and apoptosis studies [7]. Harib-
abu et al. stated that nickel(II) bis (thiosemicarbazone) complexes
∗
Corresponding author at: Chemistry Department, Faculty of Science, Kuwait
University, P.O. Box 5969, Safat 13060, Kuwait.
E-mail address: laila.alhadad@ku.edu.kw (L.A. Jaragh-Alhadad).
showed significant activity against human breast (MCF7) and lung
(A549) cancer cell lines [8]. In 2018, a research study found that
nickel(II) bis (isatin thiosemicarbazone) complexes induced apop-
tosis through mitochondrial signaling pathways and G0/G1 cell cy-
cle arrest in IM-9 cells [9]. In addition, to its inhibitory activity
against the human adenocarcinoma cancer cell lines [10].
Additionally, thiosemicarbazone-derived copper(II) complexes
showed high anticancer activities [7]. Also, copper is considered as
an essential metal cofactor in all prokaryotes because it expresses
in the mitochondrial respiratory function, cytochrome c oxidase
(Cox), dehydrogenase 2, and tyrosinases reside in the cytoplas-
mic membrane [11]. Recently, in 2019 a study reported that Ni(II)
thiosemicarbazone complexes showed anticancer activity against
the malignant tumor cell lines; human alveolar adenocarcinoma
epithelial cell line (A549), human breast adenocarcinoma cell line
(MCF7), human prostate cancer cell line (DU145) and human lung
cell line (MRC-5) with IC50 value of 10.6 ± 0.14 μM [12].
Moreover, Pahontu et al. stated that palladium(II) complex
exhibited the best antiproliferation activities against NCI-H1573
lung adenocarcinoma, SKBR-3 human breast cancer, MCF-7 hu-

https://doi.org/10.1016/j.molstruc.2022.134485
0022-2860/© 2022 Elsevier B.V. All rights reserved.
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

man breast cancer, A375 human melanoma, and HL-60 human Table 1
The structural parameters of ligand H3 L.
promyelocytic leukemia cell lines [13]. Recently, in 2020, a com-
plex named triphenylphosphane-chlorido(pyrenecarboxaldehyde- Parameter Ligand H3 L
N(3)-cyclohexyl-thiosemicarbazonate) palladium(II) loaded into Formula weight 239.29
nanoparticles found a promising cytotoxic agent against resis- Chemical formula C10 H13 N3 O2 S
tant ovarian cancer cells OVCAR3 [14]. Furthermore, Hernández Temperature 296(2) K
et.al. tested palladium(II) thiosemicarbazone complexes encapsu- Wavelength Cu Kα (λ= 1.54178 Å)
Crystal system triclinic
lated into nanoparticles, the data demonstrated antiproliferative
Crystal size 0.100 × 0.150 × 0.300 mm
activity against DU-145 and HuTu80 cell lines [15]. Crystal habit clear colorless block
More recently, in 2021, platinum-based anticancer drugs such as Space group P −1
cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, and hep- Unit cell dimensions
taplatin play an essential role in the treatment of various solid tu- a (Å) 5.1509(3)
b (Å) 10.2856(6)
mors. They found Pt(II) binds to DNA and forms a stable complex
c (Å) 11.3261(6)
that stopped tumors in mouse models against Leukemia cells [16– α (°) 77.139(3)
17]. Cisplatin is one of the most effective chemotherapeutic drugs β (°) 84.185(3)
and has been used to treat a variety of human cancers: including γ (°) 88.810(4)
Density (g/cm3 ) 1.366
bladder [18], head and neck [19], lung [20], ovarian [21–22], and
F(000) 252
testicular cancers [23] because of its thermodynamic, and kinetic θ the range for data collection (°) 4.02 to 66.51
stability. In addition, its geometry, and the ability to crosslink to Volume (Å3 ) 581.99(6)
purine DNA base cause DNA damage and enhance cancer cell death Z 2
[24]. Absorption coefficient (mm−1 ) 2.407
Measured reflections 6799
Nowadays, there is great attention on synthesizing new efficient
Independent reflections 1997 [R(int) = 0.0544]
metal complexes targeting cancer because of patients’ drug resis- Observed reflections 1713
tance and toxicity. Based on the thiosemicarbazone activity and Refinement method Full-matrix least-squares on F2
NNS chelating system, new nickel(II), copper(II), palladium(II), and Final R indices (observed data) R1 = 0.0431, wR2 = 0.1170
platinum(II) complexes of thiosemicarbazone were designed, syn- R indices (all data) R1 = 0.0510, wR2 = 0.1265
Goodness-of-fit on F2 1.071
thesized, and characterized by spectroscopic studies. In addition,
Largest diff. peak and hole (eÅ−3 ) 0.274, −0.205
ligand structure is determined by x-ray crystallography. Moreover,
the parent ligand and its metal complexes were tested for their in-
vitro antiproliferative activity against MCF7 breast and A549 lung
using the Fourier techniques. Crystallographic data and details of
cancer cells.
structure refinements are reported in Table 1.

2. Materials and methods 2.2. Synthesis of the ligand H3 L

N-ethylhydrazinecarbothioamide, 2,3-dihydroxybenzaldehyde, (2,3-dihydroxybenzylidene)-N-ethylhydrazine-1-carbothioamide

metal salts: nickel(II) acetate Ni(OAc)2 ·4H2O, copper perchlorate
[Cu(ClO4 )2 ·6H2 O], potassium tetrachloropalladate (K2 PdCl4 ), potas-
sium tetra-chloroplatinate (K2 PtCl4 ), dimethyl sulfoxide (DMSO),
and ethanol (CH3 CH2 OH) were purchased from Merck and Aldrich
products with high analytical gradients and used directly without
further preparation.
CHNS values of ligand H3 L and its metal complexes were es-
tablished at the Microanalytical Unit (Varian Micro V1.5.8, CHNS
Mode, 15073036) at RSPU-Kuwait University. The metal content
was evaluated using ICP-OES GBC Quantum Sequential. The Fourier
transform infrared spectroscopy (FTIR) spectra were recorded
as potassium bromide (KBr) disc on FTIR-6300 type A (200–
40 0 0 cm−1 ). The UV–vis. spectra of the complexes were recorded
on Cary 5 UV–vis Spectrophotometer, Varian (20 0–90 0 nm). The
NMR (1 H, 13 C) spectra of the ligand H3 L and its diamagnetic com-
plexes were recorded in DMSO–d6 on a Bruker WP 200 SY spec-
trometer (300 MHz) at room temperature using tetramethylsilane
(TMS). The molar conductance values were measured using Orion
3 stars Conductivity Bridge. The magnetic measurements were car-
ried out on a Johnson-Matthey magnetic balance, UK. Thermogravi-
metric curves (TGA) were recorded (10–850 °C) on a Shimadzu
TGA-60; the nitrogen flow and heating rates were 50 ml/min and
10 °C min−1 , respectively. The differential scanning calorimetry
(DSC) curves were recorded on Netzsch DSC 204F1 Phoenix 240-
12-0274-L.
2.1. X-ray crystallography
The x-ray single-crystal diffraction data was collected on a
Rigaku R-AXIS RAPID diffractometer using filtered Mo-Kα radia-
tion. The structure was solved by the direct method and expanded
ligand H3 L was prepared by adding a 30 mL hot ethanolic solution
of N-ethyl hydrazine carbothioamide (11.9 g, 0.1 mmol) slowly
to 30 mL hot ethanolic solution of 2,3-dihydroxybenzaldehyde
(13.8 g, 0.1 mmol) (Scheme 1). The mixture was under heat, reflux,
and stirring for two hrs on the heating mantle. The precipitate was
filtered, and washed with ethanol and diethyl ether. The final was
product dried under vacuum over silica gel, and the percentage
yield was 91%. The final product was left for two days to obtain
the single crystal for refinement and crystalographic tests at room
temperature.
2.3. Synthesis of the metal complexes
All complexes were refluxing one mmol of the ligands un-
der investigation with one mmol of the metal salt Ni(OAc)2 ·4H2 O,
[Cu(ClO4 )2 ·6H2 O], K2 PdCl4 , and K2 PtCl4 in an ethanolic solution on
a water bath for three hrs. The obtained solid complexes were
filtered, washed several times with absolute ethanol, followed by
washing with diethyl ether, and then dried in a vacuum desiccator
over anhydrous calcium chloride overnight.
2.4. Cell culture and MTT assay
Roswell Park Memorial Institute (RPMI1640) cell culture me-
dia, fetal bovine serum (FBS), l-Glutathione, and penicillin-
streptomycin were obtained from media-core facility at Lerner
Research Institute in Cleveland Clinic and used directly with-
out preparation unless otherwise described. Cells were obtained
from the American Type Culture Collection (ATCC), maintained
in RPMI1640 media supplemented with 10% FBS, 1% peni-
cillin/streptomycin, and 1% Glutathione. Cells were incubated in

2
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

Scheme 1. Preparation of 2-(3,4-dihydroxybenzylidene)-N-ethylhydrazine-1-carbothioamide ligand H3 L, which is characterized by the NNS chelating system.

humidified air with 5% CO2 . FBS is inactivated at a 37 °C water Table 2

Bond lengths and angles for ligand H3 L.
bath for 30 min before use. Cell proliferation assay was carried
out based on the manufacturer’s protocol provided by WST-1 assay Ligand H3 L
Kit (ab65473 Abcam, USA). All experiments were done in triplicate, Bond lengths (Å) Bond angles (Å)
and the absorbance was recorded at 440 nm (SoftMax Pro 9.0 Flex
S1-C8 1.678(2) C8-N2-N1 121.04(18)
Station-Molecular devices).
O2-H2A 0.82 N1-N2-H2 119.5
Briefly, five to ten thousand cells in 100 μl growth media were O1-H1 0.82 C7-N1-N2 118.22(18)
seeded in the wells of 96 well plates. After 24 h. 100 μl of var- C1-C7 1.454(3) N1-C7-H2 119.5
ious concentrations of ligand and metal complexes were added O1-C2 1.361(3) N3-C8-S1 123.83(17)
O2-C3 1.356(3) N2-C8-S1 118.98(16)
to the cells and incubated for 24 h. in a CO2 incubator. Ten μl
N1-N2 1.369(3) N3-C8-N2 117.17(19)
WST-1 reagent was added followed by absorbance measurement N1-C7 1.280(3) C8-N3-H3 117.4
at 440 nm by plate reader. The data was analyzed in Graph Pad N2-C8 1.354(3) C8-N3-C9 125.1(2)
Prism software and normalized to controls by nonlinear regression N3-C8 1.329(3) N1-C7-C1 121.1(2)
analysis curve fit. N-H 0.86 C3-O2-H2A 109.5
C–C(Ar) 1.367–1.396 C2-O1-H1 109.5
C-H 0.93–0.97 C8-N2-H2 119.5
3. Results and discussion

3.1. Crystal structure of H3 L

X-ray crystallographic data and data collection of the re-
fined structure of 2-(2,3-dihydroxybenzylidene)-N-ethylhydrazine-
1-carbothioamide ligand H3 L are summarized in (Tables 1 & 2) and
(Fig. 1). X-ray crystal structure of the ligand H3 L showed a clear
light colorless block with the formula C10 H13 N3 O2 S and molecu-
lar weight of 239.29 that belongs to a monoclinic system with
P1 21/c1 space group. Data in Table 2 demonstrates that C(8)–
S(1) bond length of 1.678(2) Å is slightly longer than that reported
for C=S bond length (1.599 Å) and are typical of a delocalized π
electron system whereas [C=S] thiourea is (1.67–1.72 Å)][25]. The
C(7)–N(1) bond length of 1.280(3)Å is shorter than the value of
1.47 Å recorded for C–N bond length and within the values of C=N
double bond. N1-N2 1.369 Å showed N–N single bonds. The C2-
O1 bond length of 1.361 Å is in the range of a single C–O bond.
In addition, the sum of bond angles of C(8), N(2), and N(3) is
about 360°, is refers to sp2 hybridization. These observations con-
firmed that the ligand presented in the thione form S=C–NH and
the ligand’s crystal structure are in a solid state. N(1) and S(1)
atoms of the SNO chromophore are in anti-conformation concern-
ing C(7)–N(1) of the thione moiety. In such conformation, the lig-
and H3 L cannot behave as an NS tridentate ligand, but in solution

Fig. 1. Crystal structure of 2-(3,4-dihydroxybenzylidene)-N-ethylhydrazine-1-carbothioamide, ligand H3 L.

3
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

Table 3
Analytical and physical data for ligand H3 L and its metal complexes.

Calcd. (Found) (%)

Compounds Color M.Wt. M.P. (%) a
C H N S Cl M

H3 L (C10 H13 N3 O2 S) beige 239.29 207 50.40 (50.31) – 17.63 (17.30) 13.45 (13.55) – – –
[Ni(H2 L)(CH3 COO)(H2 O)]2 green 748.07 240 38.53 (38.97) 23.35 11.23 (13.53) 8.57 (9.93) – 15.69 (15.41) 23.35
(C24 H34 N6 O10 S2 Ni2 )
[Pd(HL)]2 (C20 H22 N6 O4 S2 Pd2 ) Pale brown 687.39 >330 34.95 (35.45) 5.85 12.23 (12.28) 9.33 (9.93) – 30.96 (30.34) 5.85
[Pt(HL)]2 Yellow 864.72 >330 27.78 (26.92) 5.46 9.72 (9.12) 7.42 (7.41) – 45.12 (44.71) 5.46
(C20 H22 N6 O4 S2 Pt2 )
[Cu2 (H2 L)2 (OH)(ClO4 )] Dark brown 720.12 >330 33.36 (33.76) 13.74 11.67 (11.34) 8.90 (8.15) 4.92 (4.64) 17.65 (17.15) 13.74
(C20 H25 N6 O9 S2 ClCu2 )

Fig. 2. Structural representation of thiosemicarbazone metal complexes chelation: Ni complex possesses distorted octahedral geometry, Pd and Pt metal complex pose square
planar geometry, and Cu complex has square pyramidal geometry.

and through the coordination, the molecule can rotate and bring
the S atom on the same side of N(1) and thereby facilitating coor-
dination to metal ions [25].
3.2. Characterization of thiosemicarbazones metal complexes
The obtained metal complexes are air-stable, possess as-
sorted colors. The solubility test showed that the complexes are
water-insoluble but soluble in a polar aprotic solvent such as
dimethyl sulfoxide (DMSO) and dimethylformamide (DMF). The
molar conductivity of metal complexes is 23.35, 5.85, 5.46, and
13.74 W-1 cm2 mol−1 , indicating their non-electrolytic nature [26].
Scientifically, the high value for Ni(I) complex could be due to
the partial solvolysis by DMSO [26–27]. The elemental, thermal,
and spectral analyses data were collected in (Table 3). The data
illustrated that metal complexes were composed in a molar ra-
tio (2L:2 M) with formulas of [Ni(H2 L)(CH3 COO)(H2 O)]2 , [Pd(HL)]2 ,
[Pt(HL)]2 , and [Cu2 (H2 L)2 (OH)(ClO4 )] as shown in (Fig. 2).
3.3. 1 H NMR spectrum analysis
NMR spectrum data of ligand H3 L in DMSO–d6 reported in
(Figs 3). Ligands’ data agreed with the proposed structure. The
two chemical shifts noted as a singlet at 9.514, 8.935 ppm (br, 1H,
OH11, and OH12) [15], 11.349 ppm (s, 1H, NH9), and 8.423 ppm (t,
1H, NH14) were assigned to the hydroxyl and thioamide protons
of (14HN-(S=C)NH9) moieties. The high δ values of these chem-
ical shifts may be related to their linking to highly electroneg-
ative atoms (oxygen and nitrogen). The conclusion demonstrated
that the intensity of the deuterated thiosemicarbazone spectrum
chemical shifts is low. The imine proton was observed as a sin-
gle peak at 8.376 ppm (s, 1H, H-7C=N) [16], while the doublet
chemical shifts noted at 7.377 (dd, 1H, 6CH) and 6.677 (d, 1H,
2CH), multiplet observed at 6.814 (m, 1H, 1CH) which attributed
to the protons of phenyl moiety. The spectrum also showed chem-
ical shifts at δ = 3.607 ppm (m, 2H, 15CH2 ) and 1.158 ppm (t, 3H,
16CH3 ) for ethyl group protons. The 1 H NMR spectrum showed
that thiosemicarbazone offered only a thio-keto form. This con-

4
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al.
1
Fig. 3.
1
Fig. 4. H NMR spectrum of Pd(II) complex.
clusion is confirmed by the existence of chemical shifts relevant
to (NH) but no one for (SH) of the thio-enol form [28]. The
1 H NMR spectra of the Pd(II) and Pt(II) complexes (Figs. 4 & 5)
showed the disappearance of the phenolic and thioamide protons
to clarify that Pd(II) and Pt(II) bonded to the thio-enol tautomer
via the deprotonated hydroxyl oxygen and thioamide sulfur atom
(Table 4).
3.4. 13 C NMR spectrum analysis
The 13 C NMR spectrum of ligand H3 L (Fig. 6) displayed a
chemical shift at 176.46 ppm for the thioketone carbon atom
Journal of Molecular Structure 1274 (2023) 134485
H NMR spectrum of ligand H3 L.
(10 C=S) [29–30]. The imine carbon (7 C=N) chemical shift ap-
peared at 139.76 ppm. [29–30]. Whereas the chemical shifts of
3 C–O (δ = 145.17 ppm) and 4 C–O (δ = 145.55 ppm) referred to
the attachment of hydroxyl groups to these carbons [31–32]. The
chemical shifts of other phenyl moiety carbons C1 , C2 , and C6
(δ = 118.98, 116.32, and 121.00 ppm) are typical values of aromatic
carbon [32–33]. Peaks at 38.27 and 14.64 ppm related to the ethyl
group carbon atoms (15 CH2 & 16 CH3 ). In Pd(II) and Pt(II) complexes
(Figs. 7 & 8), the thioamide δ (C = S) signal shifts to upfield by
about 5, 7 ppm in comparison with the parent thiosemicarbazone.
This upfield shift may be due to the movement of electron density
from the thioamide moiety to the Pd and Pt ions, and upon chela-
5
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

1
Fig. 5. H NMR spectrum of Pt(II) complex.

Table 4
Proton and carbon assignments of ligand H3 L and its Pd(II) and Pt(II) complexes.

Pd-complex Pt-complex
Position H3 L 1 H (ppm) H3 L 13
C (ppm) 1 13 1 13
H (ppm) C (ppm) H (ppm) C (ppm)

1 6.814(m) 118.98 6.856(m) 117.96 6.596(m) 117.97

2 6.677(d) 116.32 7.003(d) 114.99 6.966(m) 115.80
3 – 145.17 – 149.02 – 148.24
4 – 145.55 – 150.74 – 149.27
5 – 117.05 – 115.92 – 116.56
6 7.377(d) 121.00 7.269(d) 124.40 7.138(m) 124.21
7 8.376(s) 139.76 8.159(s) 146.77 8.415(s) 147.49
9 11.349(s) – – – –
10 – 176.46 – 171.18 – 169..30
11 9.514(br) – – – – –
12 8.935(br) – 8.025(br) – 8.707(s) –
14 8.423(t) 8.298(t)
15 3.607(m) 38.27 3.205(m) 41.33 3.304(m) 41.19
16 1.158(t) 14.64 1.229(t) 14.76 1.151(m) 14.68

tion that causes the thioamide, carbon nuclei de-shielded hence
the upfield shift [34].
3.5. Mass spectrum analysis (MS)
MS analysis of thiosemicarbazone ligand H3 L showed a molec-
ular peak at m/z = 239.1 (100%) and weak peaks surround it due
to 13 C and 15 N isotopes (Fig. 9). Other positive ions give peaks at
194.1 (7%), 151.1 (16%), 137.1 (31%), 71.0 (15%) and 60.0 (18%) mass
numbers. The intensities of these peaks indicate the stabilities of
these fragments. MS of [Ni(H2 L)(CH3 COO)(H2 O)]2 displayed multi
peaks representing sequential molecule degradation (Fig. 10). The
main peak appeared at m/e = 296.3 (Calcd. 296.78) representing
the stable species [Ni(H2 L)] with 100% abundance; this formula ex-
ists after removal of Ni+ H2 L+2OAc+2H2 O from the original com-
plex. The peak at 240.4 (51%) is corresponding to the ligand H3 L af-
ter the removal of the Ni atom. The spectrum of [Pd(H2 L)]2 showed
a molecular ion peak 345.6 with 21% intensity corresponding ex-
actly to [Pd(H2 L)] (Fig. 11). Also, multi peaks appeared at 279.6,
2459.5, 192.3, 129.1, 115.1, and 78.9 due to the degradation. The
MS of [Pt(H2 L)]2 showed a weak molecular ion peak 433.5 with 7%
intensity corresponding exactly to [Pt(H2 L)] (Fig. 12). On the other
hand, MS of [Cu2 (H2 L)2 (OH)(ClO4 )] showed a peak of intensity 17%
at m/e = 319 corresponding exactly [Cu(H2 L)OH] after the removal
of H3 L3 +Cu+ClO4 (Fig. 13).
3.6. FTIR spectrum analysis
FTIR spectrum bands of the ligand H3 L show peaks at 3452,
3409, and 3132 cm−1 , which referred to the hydroxyl ν (OH) and
imine ν (N–H) (Fig. 14) [33]. The weak bands which appeared
at 3062, 2978, 2877, and 2831 referred to the aromatic, azome-

6
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al.
13
Fig. 6. C NMR spectrum of the thiosemicarbazone ligand H3 L.
13
Fig. 7.
thine (H–C=N), and aliphatic protons [31,35-36]. The spectrum
also displayed bands at 1610, 1306, 1266, and 777 cm−1 , re-
lated to the imine ν (C=N) group, phenolic linkage ν (C–OH), and
thioamide ν (C=S) groups respectively (Table 5) [37–38]. These ob-
servations showed that thiosemicarbazone adopted only a thio-
keto form in the solid state. Concluded by the absence of the
band related to the ν (S–H) linkage (generally shown in the 2500–
Journal of Molecular Structure 1274 (2023) 134485
C NMR spectrum of Pd(II) complex.
2600 cm−1 ) [39]. This coordination is obvious when comparing the
ligand H3 L FTIR data with metal complexes’ FTIR data spectrum
(Figs. 15-16).
This matching clarifies that ligand H3 L worked either as diba-
sic tridentate thiosemicarbazone (H3 L) bonded with the Pd(II) and
Pt(II) ions via the imine nitrogen atom, thioamide group in its thio-
enol form, and the de-protonated hydroxyl group (OH11) of pheno-
7
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

13
Fig. 8. C NMR spectrum of Pt(II) complex.

Fig. 9. Mass spectrum of thiosemicarbazone ligand H3 L.

lic moieties as in Pd and Pt complexes. This way of chelation was
mended by four proofs as follow:
I. The disappearance of one hydroxyl band implies the deproto-
nation and participation of this phenolic hydroxyl group (OH11)
in the bonding, emphasizing the positive shift in the location of
the phenolic C–O band and the disappearance of the chemical
shift of the one hydroxyl proton in 1 H NMR spectra.
II. The negative shift in position (15–21 cm−1 ) and intensity of the
band of imine group (C=N) [29,38].
III. The misplaced of the imine group ν (N–H9) band upon chela-
tion system showed that the thiosemicarbazone in these
complexes interacted in the thio-enol form, which presents
in the region 1589–1595 cm−1 , assignable to ν (C=N–N=C)
[29].
IV. The negative shift in position (47–63 cm−1 ) and intensity of the
ν (C=S) group, which appear in the range 714–730 cm−1 [37,39].
V. The new bands at 600–601, 467–476 and 507–518 cm−1 could
be attributed to the ν (M-O), ν (M-S), ν (M←N) consecutively
[38,40].

8
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

Fig. 10. Mass spectrum of Ni(II) complex.

Fig. 11. Mass spectrum of Pd(II) complex.

On the other hand, this matching may inform that the ligand
H3 L worked as a monobasic tridentate thiosemicarbazone bonded
with the Ni(II) and Cu(II) ions via a covalent bond by the (O atom)
of a deprotonated hydroxyl group (OH11) of phenolic moieties and
coordinated via imine (N atom) and sulfur atom of ν (C=S) groups
as in Ni(II) and Cu(II) complexes (Fig. 17). This way of chelation
was mended by four pieces of evidence as follow:
I. The disappearance of the hydroxyl band implies the deproto-
nation and participation of the phenolic oxygen atom in the
bonding, emphasizing the positive shift in the location of the
phenolic C–O band, and the disappearance of the one hydroxyl
proton chemical shift in 1H–NMR spectra.
II. The negative shift in the location and intensity for the imine
(C=N) group by (3–20) cm−1 .

9
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

Fig. 12. Mass spectrum of Pt(II) complex.

Fig. 13. Mass spectrum of Cu(II) complex.

III. The negative shift location and intensity of the ν (C=S) group
and appearing at (735–740) cm−1 .
IV. The new bands at (594–654, 450-,470 and (518–576) cm−1
could be imputed to the ν (M-O), ν (M←S), and ν (M←N) suc-
cessively [38,40].
In Ni (II) complex, the existence of two bands at 1575 and
1340 cm−1 could be for the symmetric (ν s (CO2 − ) and asymmet-
ric ν as (CO2 − ) bands of the acetate ion. The difference () be-
tween ν as (CO2 − ) and ν s (CO2 − ) was 235 cm−1 signifying to uni-
chelated acetate anion [41–43]. Perchlorate in Cu(II) complex dis-
played bands at 1095 and 651 cm−1 featured for the uni-chelated
perchlorate group [41].
3.7. Magnetic moment (μeff )
The μeff data of ligand H3 L complexes at 300 °K is summarized
in Table 6. The μeff results demonstrated that Pd(II) and Pt(II) are
diamagnetic, which confirmed that these complexes have a square

10
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

Fig. 14. FTIR spectrum of the thiosemicarbazone ligand H3 L.

Table 5
FTIR spectral data for ligand H3 L and the assignments of its metal complexes.

H3 L/Ligand Pd(II) complex Pt(II) complex

Position 1 13 1 13 1 13
H (ppm) C (ppm) H (ppm) C (ppm) H (ppm) C (ppm)

1 6.814(m) 118.98 6.856(m) 117.96 6.596(m) 117.97

2 6.677(d) 116.32 7.003(d) 114.99 6.966(m) 115.80
3 – 145.17 – 149.02 – 148.24
4 – 145.55 – 150.74 – 149.27
5 – 117.05 – 115.92 – 116.56
6 7.377(d) 121.00 7.269(d) 124.40 7.138(m) 124.21
7 8.376(s) 139.76 8.159(s) 146.77 8.415(s) 147.49
9 11.349(s) – – – –
10 – 176.46 – 171.18 – 169..30
11 9.514(br) – – – – –
12 8.935(br) – 8.025(br) – 8.707(s) –
14 8.423(t) 8.298(t)
15 3.607(m) 38.27 3.205(m) 41.33 3.304(m) 41.19
16 1.158(t) 14.64 1.229(t) 14.76 1.151(m) 14.68

Table 6
The UV–vis spectra and magnetic moments data for ligand H3 L and its metal complexes.

Ligand/metal complexes bands d-d transitions Geometry μeff (BM)

H3 L (C10 H13 N3 O2 S) 253, 290, 355, 390 – – –
[Ni(H2 L)(CH3 COO)]2 .2·5H2 O 256, 300, 327, 352, 3
A2g (F)→3 T1g (F) distorted 1.36
(C24 H34 N6 O10 S2 Ni2 ) 420, 650 3
A2g (F)→3 T1g (P) octahedral
[Pd(HL)]2 256, 315, 332, 400, 1
A1g →1 A2g square planar Dia.
(C20 H22 N6 O4 S2 Pd2 ) 417, 650 1
A1g →1 B1g
1
A1g →1 E1g
[Pt(HL)]2 257, 337, 365, 420, 1
A1g →1 A2g Dia.
(C20 H22 N6 O4 S2 Pt2 ) 550 1
A1g →1 B1g
1
A1g →1 E1g
[Cu2 (H2 L)2 (OH)(ClO4 )] 253, 295, 357, 390, 2
B1g →2 A1g (dz2 ←dx2-y2 ), square 0.75
(C20 H25 N6 O9 S2 ClCu2 ) 600 2
B1g →2 B2g (dxy ←dx2-y2 ), pyramidal
2
B1g →2 E2g (dxz ,dyz ←dx2-y2 )

planar geometry. On the other hand, Ni(II) and Cu(II) complexes
were equal to 1.36 and 0.75 BM, respectively. These subnormal val-
ues of μeff for Ni(II) and Cu(II) complexes imputed to the presence
of antiferromagnetic interaction because of their bimetallic nature
for these complexes [44].
3.8. Electronic absorption spectrum (EA)
The EA spectra of the thiosemicarbazone ligand H3 L and its
metal complexes were measured at 300 °K in DMSO as shown
in (Table 6). The EA spectrum of the ligand has four bands at

11
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

Fig. 15. FTIR spectrum of Pd(II) complex.

Fig. 16. FTIR spectrum of the Pt(II) complex.

253, 290, 355, 390 nm (Fig. 18). The first two bands at 253 and
290 nm can be ascribed to the π →π ∗ in the benzenoid moiety
and intra-ligand transitions [45]are, which nearly unchanged on
chelation. Whereas the second bands at 355 and 390 nm could
be imputed to π →π ∗ transition relating to the (C=N) azome-
thine and (thioamide chromophore and its electronic system
charges to the phenolic moiety [38,46]. In some complexes, new
bands observed in the 400–420 nm ranges may be referred to
as LMCT transitions. The EA spectrum of Ni(II) complex in DMSO
showed broad- band at 650 nm, which is referred to as transi-
tions 3 A2g (F)→3 T1g (F) and 3 A2g (F)→3 T1g (P) suggesting distorted
octahedral around the Ni(II) centers [38].square-planar Pd(II)
complexes showed three spin-allowed transitions, 1 A1g →1 A2g ,
1 A →1 B 1 1
1g 1g and A1g → E1g as expected for D4h symmetry. The
d orbitals split into empty B1g (dx2-y2 ) orbital located at higher
energy level than the occupying orbitals A1g (dz2 ), B2g (dxy ), Eg

12
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

Fig. 17. FTIR spectrum of the Cu(II) complex.

Fig. 18. Electronic absorption spectrum of ligand H3 L and its Pd(II), Pt(II), and Cu(II) complexes.

(dxz , dyz ) [47]. The EA spectrum of the Pd(II) complex showed
two broad bands at 417 and 650 nm. The first could be attributed
to 1 A1g →1 Eg overlapped with LMCT. While the second could
be assigned to the superimposed 1 A1g →1 A2g , and 1 A1g →1 B1g
transitions. This data indicated that the Pd(II) complex has a
square-planar geometry, which agrees with the diamagnetic
nature of this complex [47–48]. The EA spectrum of Cu(II) com-
plex displayed a single wide-band at 600 nm, which referred
to as the super-imposed transitions 2 B1g →2 A1g (dz2 ←dx2-y2 ),
2 B →2 B (d ←d 2 B →2 E (d ,d ←d
1g 2g xy x2-y2 ), 1g 2g xz yz x2-y2 ) suggest-
ing a square pyramidal geometry around the Cu(II) centers
[49–50].
3.9. Thermogravimetric analysis (TGA)
To achieve further information about the stabilization and wa-
ter molecules nature of the complexes, the TGA analysis was mea-
sured in the 25 to 800 °C range (Figs. 19-22). The TGA data are
reported in (Table 7) and proved that there is an obvious matching
in losing weight between the suggested and calculated formula. All

13
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

Fig. 19. The TG thermogram of ligand H3 L.

Fig. 20. The TG thermogram of Ni(II) complex.

complexes displayed a steady part till the temperature reach 204
°C referring to the lack of any solvent abroad in the coordination
sphere. The TG thermograms of metal complexes showed decom-
position in two or three stages that can be comprehended as fol-
lows:
The first stage shows in Ni(II) complex occurs in the range 35–
86 °C with losing weight equal to 5.68(6.02%) for Ni(II), indicat-
ing the removal of 2.5 coordination water molecules and the ac-
etate removed in the 204 to 285 °C range with losing weight equal
to 16.39 (15.79%). While the complete dissociation of complexes
via the organic part oxidation occurs in the 270–554 °C range,
For Ni(II) complex 62.30 (62.50%) (Fig. 20), Pd(II) complex equal
to 67.29 (68.2%) (Fig. 21) and for Pt(II) the decomposition is 46.66
(46.51%) (Fig. 22) leaving 2Ni, 2Pd+C and 2Pt+C.
3.10. Biological activity assessment
Previously, studies showed that thiosemicarbazones complexes
have antimicrobial [29,31,47,51-53] and antiviral activities [54].
In addition, studies proved that metal complexes have potent

14
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

Fig. 21. The TG thermogram of Pd(II) complex.

Fig. 22. The TG thermogram of Pt(II) complex.

anticancer activity more than the metal-free ligand itself [13-
17,20,23,34,37,47]. In this study, the results proved that thiosemi-
carbazones metal complexes have anticancer activity with MCF7
breast cancer cell line.
Overall, it is worth noting that metal ion coordination, ori-
entation, aromatic moiety, and solubility increase their stability.
First, breast cancer MCF-7 cell growth was monitored for four
days (Fig. 23). Second, the MCF7 cells’ proliferation was tested
with one mM concentration of the ligand H3 L, and the result
was MCF-7 cell growth control with P˂ 0.0 0 01 (Fig. 24). The
data revealed that Pt(II) complex has the potent inhibitory effect
with IC50 value reaches 0.100 μM and then Pd(II) complex with
IC50 value reaches 11.18 μM followed by Cu(II) complex and IC50
value reaches 16.38 μM followed by Ni(II) complex and IC50 value
reaches 31.64 μM as shown in Table 8. Lung cancer cells A549
treated with the one mM concentration of the agents and the re-

15
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

Fig. 23. Monitoring MCF7 cell growth.

Fig. 24. Untreated and treating MCF7 cells with one mM concentration of ligand, the result revealed that ligand H3 L strongly controlled cancer cells’ growth.

Table 7
The TGA data of the ligand H3 L and its metal complexes.

Ligand/metal complexes Temp. ( °C) Weight loss% Found (calcd.) Assignment

H3 L (C10 H13 N3 O2 S) 180–320 36.67(37.24) Elimination of C3 H7 NS

320–591 63.33 (62.99) Elimination of C7 H8 N2 O2
[Ni(H2 L)(CH3 COO)]2 .2·5H2 O 35–86 5.68(6.02) Elimination of the water of hydration (2·5H2 O)
(C24 H34 N6 O10 S2 Ni2 ) 204–285 16.39(15.79) Elimination of the water of coordination and
acetate ion (2CH3 COOH)
300–554 62.30(62.50) Complete decomposition of the complex
554 15.57(15.69) 2Ni formed
[Pd(HL)]2 (C20 H22 N6 O4 S2 Pd2 ) 30–270 – Stable
270–387 67.29(68.2) Complete decomposition of the complex
387 32.71(32.55) 2Pd+C formed
[Pt(HL)]2 (C20 H22 N6 O4 S2 Pt2 ) 30–300 – Stable
300–387 53.33(53.49) Complete decomposition of the complex
387 46.66(46.51) 2Pt+C formed

sults were parallel with breast cancer cells data. The ligand control
cells growth with P˂ 0.0 0 01. Pt(II) complex is the potent agent in-
hibiting cell growth with IC50 value of 0.923 μM, followed by Pd(II)
complex with IC50 value reaches to 2.230 μM, then Cu(II) complex
and IC50 value reaches 5.300 μM, followed by Ni(II) complex with
IC50 value of 6.259 μM. Generally, the agents prevented cell growth
in lung cancer cells more than breast cancer cells. In-depth, the
IC50 data demonstrated that square planner geometry of Pt(II) and
Pd(II) reduce cancer cell growth more than square pyramidal Cu(II)
and then the distorted octahedral geometry Ni(II).

16
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al. Journal of Molecular Structure 1274 (2023) 134485

Table 8 compounds exhibited potent inhibitory effects at the micromolar

Cell growth inhibition of the parent ligand H3 L and its metal complexes treated
level. In sum, thiosemicarbazones metal complexes have proven to
with breast and lung cancer cells.
be anticancer agents.

Declaration of Competing Interest

The authors have no conflict to declare.

CRediT authorship contribution statement

Mayada S. Ali: Conceptualization, Data curation, Formal anal-

ysis, Writing – original draft. Fathy A. El-Saied: Supervision,
Methodology, Conceptualization. Mohamad ME. Shakdofa: Super-
vision. Sadashiva Karnik: Resources, Software, Supervision, Valida-
tion, Writing – review & editing. Laila A. Jaragh-Alhadad: Funding
acquisition, Methodology, Resources, Validation, Writing – review
& editing.

Ligand/complexes IC50 / 1μM Data Availability

H3 L (C10 H13 N3 O2 S) -a
[Ni(H2 L)(CH3 COO)]2 .2·5H2 O (C24 H34 N6 O10 S2 Ni2 ) 31.64 ± 0.230 b No data was used for the research described in the article.
[Pd(HL)]2 (C20 H22 N6 O4 S2 Pd2 ) 11.18 ± 0.341 c
[Pt(HL)]2 (C20 H22 N6 O4 S2 Pt2 ) 0.100 ± 0.109 d Acknowledgment
[Cu2 (H2 L)2 (OH)(ClO4 )] (C20 H25 N6 O9 S2 ClCu2 ) 16.38 ± 0.262 e

The authors would like to express their sincere gratitude to

RSPU- Kuwait University for providing the necessary facilities
projects: GS01/03, GS01/05, GS02/01, GS03/01, GS03/08. Further,
we acknowledge Lerner Research Institute at Cleveland Clinic for
providing all the facilities and materials for the biological tests.
References

Ligand/complexes
H3 L (C10 H13 N3 O2 S)
[Ni(H2 L)(CH3 COO)]2 .2·5H2 O (C24 H34 N6 O10 S2 Ni2 )
[Pd(HL)]2 (C20 H22 N6 O4 S2 Pd2 )
[Pt(HL)]2 (C20 H22 N6 O4 S2 Pt2 )
[Cu2 (H2 L)2 (OH)(ClO4 )] (C20 H25 N6 O9 S2 ClCu2 )
MCF7: breast cancer cell line, A549: lung cancer cell line. Data are presented as a
mean±SD of three independent experiments, MCF7 & A549 (P˂0.0 0 01), d > c > e
> b > a.
4. Conclusion
In the present study, a new thiosemicarbazone ligand was syn-
thesized, and its structure was proved by x-ray crystallography.
The ligand was introduced for ligation with Ni(II), Cu(II), Pd(II),
and Pt(II). The ligand acts as dibasic tridentate with the Pd(II),
and Pt(II) ions via the imine nitrogen atom, a thioamide group
in its thio-enol form, and the de-protonated hydroxyl group. On
the other hand, thiosemicarbazone Ni(II) and Cu(II) complexes are
a monobasic tridentate via a covalent bond by the (O atom) of
the deprotonated hydroxyl group of phenolic moieties and coordi-
nated via imine (N atom) and sulfur atom of ν (C=S) groups. Ni(II)
complex has distorted octahedral structure, Pd(II) and Pt(II) have
square-planar, and Cu(II) complex possess square pyramidal. Bio-
logically, the ligand act as a neutral anticancer agent while the
metal complexes showed potent MCF7 and A549 cell growth in-
hibition. The data demonstrated that Pt(II) followed by Pd(II) com-
plexes are the most cytotoxic agents with square planar geome-
try followed by square pyramidal geometry of Cu(II) complex and
then the distorted octahedral geometry Ni(II). In general, the tested
[1] E.M. Saad, M.S. El-Shahwai, H. Saleh, A.A. El-Asmy, Studies on bismuth (III)
complexes of ligands containing nitrogen/sulfur and extractive procedure for
determination of Bi (III), Transit. Met. Chem. 32 (2007) 155–162, doi:10.1007/
s11243- 006- 0138- 6.
[2] M.M. Hamada, O. El-Shafai, A.A. El-Asmy, Enhancement of the catalytic activ-
ity of [Cu2(TS)(OH)2(OAc)] using superconductor cuprate sample, Transit. Met.
Chem. 31 (2006) 714–719, doi:10.1007/s11243- 006- 0054- 9.
[3] N.S. Youssef, E.A. El-Zahany, A.M.A. El-Seidy, Synthesis and characterization
of new schiff base metal complexes and their use as catalysts for olefin cy-
IC50 / 1μM clopropanation, Phosp. Sulfur Silicon Relat. Elem. 185 (2010) 785–798, doi:10.
-a 1080/10426500902967904.
[4] H. Zhang, F. Xie, M. Cheng, F. Peng, Novel meta-iodobenzylguanidine-
6.259 ± 1.455 b
based copper thiosemicarbazide-1-guanidinomethylbenzyl anticancer com-
2.230 ± 1.322 c
pounds targeting norepinephrine transporter in neuroblastoma, J. Med. Chem.
0.923 ± 0.130 d 62 (2019) 6985–6991, doi:10.1021/acs.jmedchem.9b00386.
5.300 ± 1.371 e [5] B.N. Goswami, J.C.S. Kataky, J.N. Baruah, Synthesis and antibacterial activ-
ity of 1-(2,4-dichlorobenzoyl)-4-substituted thiosemicarbazides, 1,2,4-triazoles
and their methyl derivatives, J. Heterocycl. Chem. 21 (1984) 1225–1229, doi:10.
1002/jhet.5570210460.
[6] T. Bal-Demirci, G. Congur, A. Erdem, S. Erdem-Kuruca, N. Özdemir, K. Akgün-
Dar, B. Varol, B. Ülküseven, Iron (III) and nickel(II) complexes as potential
anticancer agents: synthesis, physicochemical and structural properties, cy-
totoxic activity and DNA interactions, New J. Chem. 39 (2015) 5643–5653,
doi:10.1039/C5NJ00594A.
[7] M. Sobiesiak, M. Cieślak, K. Królewska, J. Kaźmierczak-Barańska, B. Paster-
nak, E. Budziszm, Thiosemicarbazone-derived copper (ii), cobalt (ii) and nickel
(ii) complexes as potential anticancer agents: nuclease activity, cytotoxic-
ity, and apoptosis studies, New J. Chem. 11 (2011) 8973–9864, doi:10.1039/
C6NJ02899C.
[8] J. Haribabu, K. Jeyalakshmi, Y. Arun, N.S.P. Bhuvanesh, P.T. Perumal,
R. Karvembu, Synthesis, DNA/protein binding, molecular docking, DNA cleav-
age and in vitro anticancer activity of nickel (II) bis(thiosemicarbazone) com-
plexes, RSC Adv. 5 (2015) 46031–46049, doi:10.1039/C5RA04498G.
[9] C. Balachandran, J. Haribabu, K. Jeyalakshmi, N.S.P. Bhuvanesh, R. Karvembu,
N. Emi, S. Awale, Nickel(II) bis(isatin thiosemicarbazone) complexes induced
apoptosis through mitochondrial signaling pathway and G0/G1 cell cycle arrest
in IM-9 cells, J. Inorg. Biochem. 182 (2018) 208–221, doi:10.1016/j.jinorgbio.
2018.02.014.
[10] S.M. Kumar, J. Rajesh, K. Anitha, K. Dhahagani, M. Marappan, N.I. Gandhi,
G. Rajagopa, Synthesis, characterization, crystal structure and cytotoxic prop-
erties of thiosemicarbazide Ni(II) and Zn(II) complexes, Spectrochim. Acta Part
A: Mol. Biomol. Spectrosc. 142 (2015) 292–302, doi:10.1016/j.saa.2015.01.080.
[11] R.A. Festa, D.J. Thiele, Copper: an essential metal in biology, Curr. Biol. 21
(2013) R877–R883, doi:10.1016/j.cub.2011.09.040.
[12] J. Devi, M. Yadav, D.K. Jindal, D. Kumar, Y. Poornachandra, Synthesis, spec-
troscopic characterization, biological screening, and in vitro cytotoxic stud-
ies of 4-methyl-3-thiosemicarbazone derived Schiff bases and their Co (II), Ni

17
M.S. Ali, F.A. El-Saied, M.ME. Shakdofa et al.
(II), Cu (II) and Zn (II) complexes, Appl. Organomet. Chem. 33 (2018) e5154,
doi:10.1002/aoc.5154.
[13] E. Pahonțu, C. Paraschivescu, D.C. Ilieș, D. Poirier, C. Oprean, V. Păunescu,
A. Gulea, T. Roșu, O. Pratu, Synthesis and characterization of novel Cu(II),
Pd(II) and Pt(II) complexes with 8-Ethyl-2-hydroxytricyclo (7.3.1.02,7 ) tridecan-
13-one-thiosemicarbazone: antimicrobial and in vitro antiproliferative activity,
Molecules 21 (2016) 674, doi:10.3390/molecules21050674.
[14] C.G. Oliveira, L.F. Dalmolin, R.T.C. Silva, R.F.V. Lopez, P.I.S. Maia, J.A. Moreto,
PLGA-nanoparticles loaded with a thiosemicarbazone derived palladium (ii)
complex as a potential agent to new formulations for human ovarian
carcinoma treatment, New J. Chem. 35 (2020) 14759–15302, doi:10.1039/
D0NJ00580K.
[15] W. Hernández, A.J. Vaisberg, M. Tobar, M. Álvarez, J. Manzur, Y. Echevar-
ría, E. Spodine, In vitro antiproliferative activity of palladium (ii) thiosemi-
carbazone complexes and the corresponding functionalized chitosan coated
magnetite nanoparticles, New J. Chem. 40 (2016) 1853–1860, doi:10.1039/
C5NJ02429C.
[16] S. Jin, Y. Guo, Z. Guo, X. Wang, Monofunctional platinum (II) anticancer agents,
Pharmaceuticals 14 (2021) 133, doi:10.3390/ph14020133.
[17] B. Rosenberg, L. Vancamp, J.E. Trosko, V.H. Mansour, Platinum compounds: a
new class of potent antitumour agents, Nature 222 (1969) 385–386, doi:10.
1038/222385a0.
[18] V.G. Patel, W.K. Oh, M.D. Galsky, Treatment of muscle-invasive and advanced
bladder cancer in 2020, Acancer J. Clin. 71 (2020), doi:10.3322/caac.21631.
[19] W.M. Chang, Y.C. Chang, Y.C. Yang, S.K. Lin, P.M.H. Chang, M. Hsiao, AKR1C1
controls cisplatin-resistance in head and neck squamous cell carcinoma
through cross-talk with the STAT1/3 signaling pathway, J. Exp. Clin. Cancer Res.
38 (2019) 245, doi:10.1186/s13046- 019- 1256- 2.
[20] N. Zakaria, n.A. Satar, N.H. Abu Halim, S. Ngalim, N.M. Yusoff, J. Lin, B.H. Ya-
haya, Targeting lung cancer stem cells: research and clinical impacts, Front.
Oncol. 7 (2017) 80, doi:10.3389/fonc.2017.0 0 080.
[21] Z. Ai, Y. Lu, S. Qiu, Z. Fan, Overcoming cisplatin resistance of ovarian cancer
cells by targeting HIF-1-regulated cancer metabolism, Cancer Lett. 373 (2016)
36–44, doi:10.1016/j.canlet.2016.01.009.
[22] H. Peng, H. Jin, H. Zhuo, H. Huang, Enhanced antitumor efficacy of cisplatin for
treating ovarian cancer in vitro and in vivo via transferrin binding, Oncotarget
8 (2017) 45597–45611, doi:10.18632/oncotarget.17316.
[23] G. Vries, X. Rosas-Plaza, M.A.T.M. van Vugt, J.A. Gietema, S. Jong, Testicular can-
cer: determinants of cisplatin sensitivity and novel therapeutic opportunities,
Cancer Treat. Rev. 88 (2020) 102054, doi:10.1016/j.ctrv.2020.102054.
[24] S. Dasari, P.B. Tchounwou, Cisplatin in cancer therapy: molecular mechanisms
of action, Eur. J. Pharmacol. 740 (2014) 364–378, doi:10.1016/j.ejphar.2014.07.
025.
[25] E.-S.A. El-Samanody, Synthesis, spectroscopic characterization, x-ray crystal
structures, thermal behavior and antimicrobial activity of copper(II) complexes
with the novel (3,5-dimethyl-1H-pyrazol-1-yl)(morpholin-4-yl)methanethione,
Appl. Organomet. Chem. 32 (2018) e4586 10.1002/aoc.4586.
[26] W.J. Geary, The use of conductivity measurements in organic solvents for the
characterisation of coordination compounds, Coord. Chem. Rev. 7 (1971) 81–
122, doi:10.1016/S0010- 8545(00)80009- 0.
[27] N.N. Greenwood, B.P. Straughan, A.E. Wilson, Behaviour of tellurium(IV) chlo-
ride, bromide, and iodide in organic solvents and the structures of the species
present, J. Chem. Soc. A: Inorg. Phys. Theo. 7 (1968) 81–122, doi:10.1016/
S0 010-8545(0 0)80 0 09-0.
[28] M.M.E. Shakdofa, H.A. Mousa, A.M.A. Elseidy, A.A. Labib, M.M. Ali, A.S. Abd-El-
All, Anti-proliferative activity of newly synthesized Cd(II), Cu(II), Zn(II),Ni(II),
Co(II), VO(II), and Mn(II) complexes of 2-((4,9-dimethoxy-5-oxo-5H-furo[3,2-
g]chromen-6-yl)methylene) hydrazinecarbothioamide on three human cancer
cells, Appl. Organomet. Chem. 32 (2018) e3936, doi:10.1002/aoc.3936.
[29] D.C. Ilies, E. Pahontu, S. Shova, R. Georgescu, N. Stanica, R. Olar, A. Gulea,
T. Rosu, Synthesis, characterization, crystal structure and antimicrobial activ-
ity of copper(II) complexes with a thiosemicarbazone derived from 3-formyl-
6-methylchromone, Polyhedron 81 (2014) 123–131, doi:10.1016/j.poly.2014.05.
074.
[30] A. Sethukumar, C. Udhaya Kumar, R. Agilandeshwari, B. Arul Prakasam,
Synthesis, stereochemical, structural and biological studies of some 2,6-
diarylpiperidin-4-one N(40)-cyclohexyl thiosemicarbazones, J. Mol. Struct.
1047 (2013) 237–248, doi:10.1016/j.molstruc.2013.05.008.
[31] M.M.E. Shakdofa, A.S. El-tabl, A.S. Al-hakimi, M.A. Wahba, N. Morsy, Synthe-
sis, structural characterization and microbicide activities of mononuclear tran-
sition metal complexes of 2-(2-hydroxy-5-(p-tolyldiazenyl) benzylidene) hy-
drazinecarbothioamide, Ponte 73 (2017) 52–74, doi:10.21506/j.ponte.2017.6.4.
[32] H.R. Fatondji, S. Kpoviessi, F. Gbaguidi, J. Bero, V. Hannaert, J. Quetin-
Leclercq, J. Poupaert, M. Moudachirou, G.C. Accrombessi, Structure-activity
relationship study of thiosemicarbazones on an African trypanosome: try-
panosoma brucei brucei, Med. Chem. Res. 22 (2013) 2151–2162, doi:10.1007/
s0 0 044- 012- 0208- 6.
[33] E. Shahsavani, A.D. Khalaji, N. Feizi, M. Kučeráková, M. Dušek, Synthesis, char-
acterization, crystal structure and antibacterial activity of new sulfur-bridged
dinuclear silver(I) thiosemicarbazone complex [Ag2 (PPh3 )2 (μ-S-Brcatsc)2 (η1-
S-Brcatsc)2 ](NO3 )2 , Inorg. Chim. Acta 429 (2015) 61–66, doi:10.1016/j.ica.2015.
01.043.
[34] F.P. Andrew, P.A. Ajibade, Synthesis, characterization and anticancer studies
of bis(1-phenylpiperazine dithiocarbamato) Cu(II), Zn(II) and Pt(II) complexes:
crystal structures of 1-phenylpiperazine dithiocarbamato-S,S zinc(II) and Pt(II),
J. Mol. Struct. 1170 (2018) 24–29, doi:10.1016/j.molstruc.2018.05.068.
18
Journal of Molecular Structure 1274 (2023) 134485
[35] A. Sethukumar, C. Udhaya Kumar, R. Agilandeshwari, B. Arul Prakasam,
Synthesis, stereochemical, structural and biological studies of some 2,6-
diarylpiperidin-4-one N(4 )-cyclohexyl thiosemicarbazones, J. Mol. Struct. 1047
(2013) 237–248, doi:10.1016/j.molstruc.2013.05.008.
[36] L.A. Saghatforoush, S. Hosseinpour, M.W. Bezpalko, W.S. Kassel, X-ray crys-
tal structural and spectral studies of copper(II) and nickel(II) complexes of
functionalized bis(thiosemicarbazone) ligands and investigation of their elec-
trochemical behavior, Inorg. Chim. Acta 484 (2019) 527–534, doi:10.1016/j.ica.
2018.04.053.
[37] B. Şen, H.K. Kalhan, V. Demir, E.E. Güler, H.A. Kayalı, E. Subaş, Crystal struc-
tures, spectroscopic properties of new cobalt(II), nickel(II), zinc(II) and pal-
ladium(II) complexes derived from 2-acetyl-5-chloro thiophene thiosemicar-
bazone: anticancer evaluation, Mater. Sci. Eng. C Mater. Biol. Appl.: C 98 (2019)
550–559, doi:10.1016/j.msec.2018.12.080.
[38] A. Akbari, H. Ghateazadeh, R. Takjoo, B. Sadeghi-Nejad, M. Mehrvar, J.T. Mague,
Synthesis & crystal structures of four new biochemical active Ni(II) complexes
of thiosemicarbazone and isothiosemicarbazone-based ligands: in vitro antimi-
crobial study, J. Mol. Struct. 1181 (2019) 287–294, doi:10.1016/j.molstruc.2018.
12.109.
[39] Z. Piri, Z. Moradi–Shoeili, A. Assoud, Ultrasonic assisted synthesis, crystallo-
graphic, spectroscopic studies and biological activity of three new Zn(II), Co(II)
and Ni(II) thiosemicarbazone complexes as precursors for nano-metal oxides,
Inorg. Chim. Acta 484 (2019) 338–346, doi:10.1016/J.ICA.2018.09.054.
[40] Z.H.A. El-Wahab, M.M. Mashaly, A.A. Salman, B.A. El-Shetary, A.A. Faheim,
Co(II), Ce(III) and UO2 (VI) bis-salicylatothiosemicarbazide complexes: binary
and ternary complexes, thermal studies and antimicrobial activity, Spec-
trochim. Acta Part A Mol. Biomol. Spectrosc. 60 (2004) 2861–2873, doi:10.
1016/j.saa.2004.01.021.
[41] K. Nakamoto, in: Infrared and Raman Spectra of Inorganic and Coordina-
tion Compounds Part B: Applications in Coordination, Organometallic, and
Bioinorganic Chemistry, 6th ed., John Wiley & Sons INC, USA, 2009, p. 424,
doi:10.1002/aoc.1655.
[42] A.S. El-Tabl, M.M.E. Shakdofa, M.A. Whab, Synthesis, characterization and
fungicidal activity of binary and ternary metal(II) complexes derived from
4,4 -((4-nitro-1,2-phenylene) bis(azanylylidene))bis(3-(hydroxyimino)pentan-
2-one), Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 136 (2015) 1941–
1949, doi:10.1016/j.saa.2014.10.112.
[43] F.A. El-Saied, M.M.E. Shakdofa, A.S. El-Tabl, M.M.A. Abd-Elzaher, Coordina-
 
tion behaviour of N 1 ,N 4 -bis((1, 5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)methylene) succinohydrazide toward transition metal ions and
their antimicrobial activities, Main Group Chem. 13 (2014) 87–103, doi:10.
3233/MGC-140125.
[44] S.M. Emam, S.A. Abouel-Enein, E.M. Abdel-Satar, Structural characterization,
thermal investigation and biological activity of metal complexes containing
Schiff Base ligand (Z)-3-(1-((4,6-dimethyl-1H-pyrazolo[3,4-b] pyridin-3-
yl)imino)ethyl)-4-hydroxy-6-methyl-2H-pyran-2-one, Appl. Organometal.
Chem. 33 (2019) e4847, doi:10.1002/AOC.4847.
[45] M.R. Maurya, S. Agarwal, C. Bader, D. Rehder, Dioxovanadium(V) complexes
of ONO donor ligands derived from pyridoxal and hydrazides: models of
vanadate-dependent haloperoxidases, Eur. J. Inorg. Chem. 20 05 (20 05) 147–
157, doi:10.10 02/ejic.20 040 0211.
[46] N.M. Rageh, A.M.A. Mawgoud, H.M. Mostafa, Electronic spectra, solvatochromic
behaviour, and acidity constants of some new azocoumarin derivatives, Chem.
Pap. 53 (1999) 107–113 532a107.pdf.
[47] M. Gaber, H.A. El-Ghamry, M.A. Mansour, Pd(II) and Pt(II) chalcone complexes.
Synthesis, spectral characterization, molecular modeling, biomolecular dock-
ing, antimicrobial and antitumor activities, J. Photochem. Photobiol. A: Chem.
354 (2018) 163–174, doi:10.1016/j.jphotochem.2017.07.031.
[48] S. Aly, H.A. El-Boraey, Effect of gamma irradiation on spectral, XRD, SEM,
DNA binding, molecular modling and antibacterial property of some (Z)N-
(furan-2-yl)methylene)-2-(phenylamino)acetohydrazide metal(II) complexes, J.
Mol. Struct. 1185 (2019) 323–332, doi:10.1016/j.molstruc.2019.02.069.
[49] A.B.P. Lever, Inorganic Electronic Spectroscopy: Studies in Physical and The-
orytical Chemistry, 33, Elsevier science, Amsterdam, 1984, doi:10.1002/bbpc.
19850890122.
[50] M.T. Huseynova, M.N. Aliyeva, A.A. Medjidov, O. Şahin, B. Yalçın, Cu(II) complex
with thiosemicarbazone of glyoxylic acid as an anion ligand in a polymeric
structure, J. Mol. Struct. 1176 (2019) 895–900 10.1016/j.molstruc.2018.08.090.
[51] Z.A. Kaplancıklı, M.D. Altıntop, B. Sever, Z. Cantürk, A. Özdemir, Synthesis and
in vitro evaluation of new thiosemicarbazone derivatives as potential antimi-
crobial agents, J. Chem. 2016 (2016) 1–7, doi:10.1155/2016/1692540.
[52] I. Kizilcikli, Y.D. Kurt, B. Akkurt, A.Y. Genel, S. Birteksöz, G. Otük, B. Ulkü-
seven, Antimicrobial activity of a series of thiosemicarbazones and their Zn(II)
and Pd(II) complexes, Folia Microbiol (Praha) 52 (2007) 15–25, doi:10.1007/
BF02932132.
[53] E. Namiecińska, M. Sobiesiak, M. Małecka, P. Guga, B. Rozalska, E. Budzisz, An-
timicrobial and structural properties of metal ions complexes with thiosemi-
carbazide motif and related heterocyclic compounds, Curr. Med. Chem. 26
(2019) 664–693, doi:10.2174/0929867325666180228164656.
[54] J. Easmon, G. Heinisch, W. Holzer, B. Rosenwirth, Synthesis and antivi-
ral activity of thiosemicarbazone derivatives of pyridazinecarbaldehydes
and alkyl pyridazinyl ketones, Arzneimittelforschung 39 (1989) 1196–1201
PMID:2610710.