Inorganica Chimica Acta 523 (2021) 120407

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Inorganica Chimica Acta

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

Research paper

Structurally characterized zinc complexes of flavonoids chrysin and

quercetin with antioxidant potential
Eleftherios Halevas a, *, Barbara Mavroidi a, Maria Pelecanou a, Antonios G. Hatzidimitriou b, *
a
Institute of Biosciences & Applications, National Centre for Scientific Research “Demokritos”, 15310 Athens, Greece
b
Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece

A R T I C L E I N F O A B S T R A C T

Keywords: Chrysin and quercetin are two of the most prominent and bioactive flavonoids with a wide spectrum of beneficial
Zinc complexes properties, including antioxidant and radical scavenging activity. The complexation of these flavonoids with
Chrysin transition metal ions of biological interest can lead to the generation of novel metallodrugs with improved
Quercetin
pharmacological and biochemical properties. Within this framework, the synthesis and detailed structural and
Antioxidant activity
physico-chemical characterization of two novel heteroleptic complex assemblies of Zn(II) with chrysin and
Radical scavenging activity
quercetin and the ancillary aromatic chelator 2,2′ -bipyridine is presented. The two complexes represent the only
crystallographically characterized structures with Zn(II) as the central metal ion and chrysin or quercetin as the
ligands. The new complexes were biologically evaluated in vitro for their antioxidant potential, both exhibiting
strong radical scavenging activity in the 2,2-diphenyl-1-picrylhydrazyl assay, and merit further investigation of
their pharmacological profile.

1. Introduction
The tendency to benefit from the medicinal properties of natural
phytochemicals led scientists to consider flavonoids as viable options in
the therapy of several diseases. Flavonoids are ubiquitous plant sec­
ondary metabolites, that constitute important components of the human
diet. They have shown promising health promoting effects in human cell
cultures, experimental animal and clinical studies. Their abundance,
combined with their wide spectrum of pharmacological activity, which
includes anti-oxidative, anti-inflammatory, anti-mutagenic and anti-
carcinogenic properties, coupled with their capacity to modulate key
cellular enzyme function, have drawn considerable scientific and ther­
apeutic interest. The last two decades flavonoids have been the subject
of intense research to elucidate their molecular targets and mechanisms
of action, as well as to increase their metabolic stability and bioavail­
ability [1].
Many of the beneficial properties of flavonoids are highly related to
their antioxidant activity which depends mostly on the position and
number of hydroxyl moieties on their tricyclic core structure. As highly
reactive oxygen species (ROS) arise in the course of physiological pro­
cesses, while their over-production has been associated with several
degenerative pathologies [2], the capacity of flavonoids to directly
scavenge ROS is of prime interest. Further to their direct action on free
radicals, flavonoids exert antioxidant activity through chelation of metal
ions in the human body, like Fe(II), and Cu(II) that participate in re­
actions generating free radicals. Therefore, the capacity of flavonoids to
bind to metal ions, as well as the structure and stability of their com­
plexes is directly related with their physiological and/or pharmacolog­
ical activity [3].
In our on-going effort to develop new effective bioactive materials,
the properties of two of the most prominent flavonoids, chrysin and
quercetin (Fig. 1), were combined with those of the Zn(II) metal core.
Chrysin is found in the extract of blue passion flowers and is also found
in propolis, honey, and honeycombs while quercetin is widely present in
fruits and vegetables. Further to their antioxidant properties they have
both demonstrated beneficial effects against neurodegeneration,
inflammation, cancer and cardiovascular disease [1].
Zinc is one of the most abundant trace elements in the human body

Abbreviations: MeOH, methanol; Zn(CH3COO)2⋅2H2O, Zinc acetate dihydrate; ZnCl2, zinc chloride; DPPH, 2,2-diphenyl-1-picrylhydrazyl; FT-IR, Fourier
transform-infrared spectroscopy; GC, gas chromatography; HR-ESI-MS, high resolution-electrospray ionization mass spectra; NMR, nuclear magnetic resonance;
DMSO, dimethyl sulfoxide; TMS, tetramethylsilane; UV–Vis, UV–visible; TGA, thermogravimetric analysis; XRD, X-ray diffraction; SEM, standard error of mean;
ANOVA, analysis of variance; EtOH, ethanol; DMA, dimethylacetamide; DMF, dimethylformamide; TD-DFT, time-dependent density functional theory.
* Corresponding authors.
E-mail addresses: lefterishalevas@gmail.com (E. Halevas), hatzidim@chem.auth.gr (A.G. Hatzidimitriou).

https://doi.org/10.1016/j.ica.2021.120407
Received 11 January 2021; Received in revised form 18 March 2021; Accepted 10 April 2021
Available online 20 April 2021
0020-1693/© 2021 Elsevier B.V. All rights reserved.
E. Halevas et al.
and an important regulatory metal ion in cell metabolism, proliferation,
differentiation, and apoptosis [4,5]. Furthermore, it is one of the most
relevant metals to human health, partly due to its antioxidant properties
and its protective role against oxidative stress that is related to many
pathologies [6]. Several zinc complexes have shown beneficial proper­
ties in the fight against Alzheimer’s disease [7], microbial infections
[8,9], diabetes [10,11], inflammation [12], convulsions [13] and cancer
[14].
In this work, the synthesis, full structural and physico-chemical
characterization, as well as the initial investigation of the radical scav­
enging activity of two novel crystalline heteroleptic complex assemblies
of Zn(II) with chrysin (complex 1) and quercetin (complex 2) and the
ancillary aromatic chelator 2,2′ -bipyridine (Fig. 1) are presented. Even
though many analogous complexes exist in the literature [15-20], the
two complexes represent the only crystallographically characterized
structures with Zn(II) as the central metal ion and chrysin or quercetin as
the ligands.
2. Materials and methods
2.1. Materials
All experiments were carried out under aerobic conditions. The
following starting materials and solvents were purchased from com­
mercial sources (Sigma, Fluka) and were used without further purifi­
cation: chrysin, quercetin hydrate (C15H10O7⋅xH2O), 2,2′ -bipyridine,
triethylamine, zinc acetate dihydrate (Zn(CH3COO)2⋅2H2O), zinc chlo­
ride (ZnCl2), methanol (MeOH), and diethylether. For the biological
experiments, ascorbic acid and 2,2-diphenyl-1-picrylhydrazyl (DPPH)
were purchased from Sigma-Aldrich.
2.2. Characterization
Fourier Transform-Infrared (FT-IR) spectra were recorded on a Per­
kin Elmer 1760X spectrometer. A ThermoFinnigan Flash EA 1112 CHNS
elemental analyzer controlled by PC via the Eager 300 dedicated soft­
warewas used for the simultaneous determination of carbon, hydrogen,
and nitrogen (%).
High Resolution-Electrospray Ionization-Mass Spectra (HR-ESI-MS)
of 1 and 2 (Figs. S1A and S1B, Supplementary Information) were ob­
tained on an Agilent Technology LC/MSD trap SL instrument and
Thermo Scientific, LTQ Orbitrap XL™ high resolution system.
Solution nuclear magnetic resonance (NMR) spectra were obtained
in dimethyl sulfoxide-d6 (DMSO‑d6) at 25 ◦ C on a Bruker Avance DRX
Fig. 1. Schematic representation of complexes 1 and 2.
2
Inorganica Chimica Acta 523 (2021) 120407
500 MHz (1H at 500.13 MHz and 13C at 125.77 MHz). Tetramethylsilane
(TMS) was used as the internal standard. Assignment of 1H and 13C
chemical shifts was based on the combined analysis of a series of 1H–1H
and 1H–13C correlation experiments recorded using standard pulse se­
quences from the Bruker library.
UV–Visible (UV–Vis) measurements were carried out on a Hitachi
U2001 spectrophotometer in the range from 200 to 800 nm.
Steady state fluorescence emission and excitation spectra were
recorded on a Hitachi F-700 fluorescence spectrophotometer from
Hitachi High-Technologies Corporation. The employed slit widths (em,
ex) were 10 nm in the case of free chrysin and complex 1, and 5 nm for
plain quercetin hydrate and complex 2, respectively. The scan speed was
set at 60 nm⋅min− 1. All measurements were carried out at room tem­
perature. The system was supported by FL Solutions 2.1 computer
software, running on Windows XP.
A Perkin Elmer, Pyris 1, system was used to run the simultaneous
Thermogravimetric Analysis (TGA) experiments. The instrument mass
precision is 1 μg. About 10 mg of each complex was placed in an open
alumina sample pan for each experiment. High purity air was used at a
constant flow rate of 30 mL⋅min− 1, depending on the conditions
required for running the experiments. During the experiments, the
sample weight loss and rate of weight loss were recorded continuously
under dynamic conditions, as a function of time or temperature, in the
range 30–800 ◦ C. Prior to activating the heating routine program, the
entire system was purged with the appropriate gas for 10 min, at a rate
of 30 mL⋅min− 1, to ensure that the desired environment was established.
2.3. Synthesis
2.3.1. Preparation of [Zn(CH3COO)(C15H9O4)(C10H8N2)]9⋅CH3OH (1)
To a solution of Zn(CH3COO)2⋅2H2O (0.22 g, 1.0 mmol) in 10 mL
MeOH, chrysin (0.26 g, 1.0 mmol) was added under stirring. The
resulting homogeneous yellow solution was refluxed at 60 ◦ C for 2 h
under continuous stirring and then cooled to room temperature. Sub­
sequently, a solution of 2,2′ -bipyridine(0.16 g, 1.0 mmol) in MeOH (5
mL) was added to the reaction mixture under continuous stirring. The
resulting homogeneous yellow solution was refluxed at 60 ◦ C for an
additional 2 h and then cooled to room temperature. Triethylamine
(140 μL, 1.0 mmol) was subsequently added under continuous stirring
and the resulting clear homogeneous yellow solution was refluxed at
60 ◦ C for an additional 2 h and then cooled to room temperature. Sub­
sequently, the reaction flask was placed in a diethyl ether bath in a
closed vessel at room temperature. Four days later, yellow amorphous
material precipitated at the bottom of the flask. The resulting precipitate
E. Halevas et al. Inorganica Chimica Acta 523 (2021) 120407

was removed by filtration and the clear yellow filtrate was placed into Table 1
another reaction flask and left to evaporate slowly at 4 ◦ C. Two weeks Summary of crystal, intensity collection and refinement data for [Zn(CH3COO)
later, needle-like yellow crystalline material precipitated at the bottom (C15H9O4)(C10H8N2)]9⋅CH3OH (1), and [Zn(C15H9O7)(C10H8N2)Cl]⋅(CH3OH)⋅
of the flask. The product was isolated by filtration and dried in vacuo. 1.5(H2O) (2).
Yield: 0.12 g (23%). Anal. Calcd for 1, [Zn(CH3COO)(C15H9O4) 1 2
(C10H8N2)]9⋅CH3OH (1) (C244H184N18O55Zn9, Mr 4836.65): C, 60.59; Chemical formula C244H184N18O55Zn9 C26H24ClN2O9.50Zn
H, 3.83; N, 5.21%. Found: C, 60.61; H, 3.79; N, 5.18%. HR-ESI-MS Mr 9⋅(537.41) 617.32
(positive mode), calcd for [Zn(C15H9O4)(C10H8N2)]+ m/z = 473.0479, Crystal system Trigonal Triclinic
found m/z = 473.0479. Space group R3 P1
Temperature (K) 295 295
a (Å) 26.085 (9) 7.3099 (9)
2.3.2. Preparation of [Zn(C15H9O7)(C10H8N2)Cl]⋅(CH3OH)⋅1.5(H2O)
b (Å) 26.085 (9) 8.5487 (11)
(2) c (Å) 19.187 (7) 20.571 (3)
To a solution of ZnCl2 (0.14 g, 1.0 mmol) in 10 mL MeOH, quercetin α (◦ ) 90 86.506 (7)
hydrate (C15H10O7⋅1.5H2O) (0.34 g, 1.0 mmol) was added under stir­ β (◦ ) 90 84.779 (7)
ring. The resulting homogeneous orange solution was refluxed at 60 ◦ C γ (◦ ) 120 77.560 (6)
V (Å3) 11,306 (8) 1248.9 (3)
for 2 h under continuous stirring and then cooled to room temperature.
Z 2 2
Subsequently, a solution of 2,2′ -bipyridine (0.16 g, 1.0 mmol) in MeOH Dcalcd (Mg⋅m− 3) 1.420 1.504
(5 mL) was added to the reaction mixture under continuous stirring. The Radiation type MoKa MoKa
resulting homogeneous orange solution was refluxed at 60 ◦ C for an Wavelength, λ (Ǻ) 0.71073 0.71073
1
Abs. coeff. (µ), mm− 1.022 1.153
additional 2 h and then cooled to room temperature. To that, triethyl­
Range of h,k,l − 31 → 15, 0 → 31, 0 − 8 → 8, − 10 → 10, 0
amine (140 μL, 1.0 mmol) was added under continuous stirring. The → 23 → 25
resulting heterogeneous orange reaction mixture was refluxed at 60 ◦ C goodness-of-fit on F2 1.0000 1.0000
for an additional 2 h and then cooled to room temperature. The insoluble Measured, independent and 26955, 4785, 3424 25511, 4740, 3861
orange precipitate was removed by filtration. Subsequently, the reaction observed reflections (I > 2σ
(I))
flask with the clear orange filtrate was left to evaporate slowly at 4 ◦ C.
R 0.038 0.038
Ten days later, plate-like orange crystalline material precipitated at the Rw 0.080 0.075
bottom of the flask. The product was isolated by filtration and dried in
vacuo. Yield: 0.20 g (32%). Anal. Calcd for 2, [Zn(C15H9O7)(C10H8N2)
Cl]⋅(CH3OH)⋅1.5(H2O) (2) (C26H24ClN2O9.50Zn, Mr 617.32): C, 50.59; files.
H, 3.92; N, 4.54%. Found: C, 50.57; H, 3.88; N, 4.51%. HR-ESI-MS
(positive mode), calcd for [Zn(C15H9O7)(C10H8N2)]+ m/z = 521.0327, 2.5. Biological studies
found m/z = 521.0320.
2.5.1. DPPH radical scavenging activity
The stable free radical DPPH was used as a method for determining in
2.4. X-ray crystal structure determination vitro the antioxidant potential of complexes 1 and 2 as well as for all
starting materials chrysin, quercetin hydrate, 2,2′ -bipyridine, Zn
X-ray quality crystals of 1 and 2 were grown from a mixture of (CH3COO)2⋅2H2O, and ZnCl2, to allow for conclusions to be reached.
MeOH-diethyl ether and a MeOH solution, respectively. Crystals of 1 Methanolic solutions containing different concentrations of all tested
and 2 suitable for X-ray diffraction, with dimensions 0.22 × 0.03 × 0.03 compounds (10, 25, 50, 75, 100, 150, 200 × 10-6 mol⋅L-1) were added,
mm and 0.15 × 0.12 × 0.07 mm, respectively, were taken from the separately, to a DPPH solution (5⋅10-5 mol⋅L-1) in MeOH, at room tem­
mother liquor and mounted at room temperature on a Bruker Kappa perature. The reaction was kept in the dark for 40 min and the absor­
APEX 2 diffractometer, equipped with a triumph monochromator, using bance was measured using a Selecta UV-2005 UV–Vis
Mo Kα radiation. Cell dimensions and crystal system determination were spectrophotometer. An ascorbic acid solution (stock concentration 0.1
performed using 153 high θ reflections for 1, and 147 for 2, with 10◦ < θ mM) was used as reference antioxidant and blank solutions (respective
< 20◦ . Data collection (φ- and ω- scans) and processing (cell refinement, concentrations of the compounds added into MeOH) were also included.
data reduction and numerical absorption correction based on di­ The absorbance of the samples (A) at 517 nm [26] was recorded and
mensions) were performed using the SAINT and SADABS programs compared with that of control sample (Ao), which was prepared in an
[21,22]. The structures were solved by the SUPERFLIP package [23]. analogous method without the addition of any of the compounds. The
The CRYSTALS version 14.61 build 6236 program package was used for suppression ratio for DPPH was calculated from the following equation:

Absorbance of control (Ao ) − Absorbance of sample (A)

DPPH radical scavenging activity (%) =
Absorbance of control (Ao )

structure refinement (full-matrix least-squares methods on F2) and all

subsequently remaining calculations [24]. Molecular illustrations were
drawn with use of the Diamond 3.1 crystallographic package [25]. All
non-hydrogen non disordered atoms were anisotropically refined. All
hydrogen atoms were found at their expected positions and were refined
using proper riding constraints to the pivot atoms. Crystallographic
details for complexes 1 and 2 are summarized in Table 1. Further details
on the crystallographic studies as well as atomic displacement param­
eters are given as Supplementary Information as well as in the form of cif
Experiments were performed in duplicates in three independent
replications and the results were expressed as mean ± standard error of
mean (±SEM), depicted as error bars. The results were statistically
analyzed by two-way ANOVA (Analysis of variance) using GraphPad
Prism 8.0.1. Statistical significance was determined as non-significant
(ns) for p > 0.05, significant for p < 0.05(*) and p < 0.01(**) and
highly significant for p < 0.001(***).

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E. Halevas et al. Inorganica Chimica Acta 523 (2021) 120407

3. Results

3.1. Synthesis

The synthetic scheme of the heteroleptic Zn(II)-chrysin-2,2′ -bipyr­

idine and Zn(II)-quercetin-2,2′ -bipyridine complexes was the result of
thorough exploration of the experimental conditions regarding metal:
chelator and metal:ligand stoichiometry, solvent system, temperature,
pH, crystallization and isolation processes. To that end, complex 1 was
synthesized from simple reagents, from the reaction of Zn
(CH3COO)2⋅2H2O with chrysin and 2,2′ -bipyridine in MeOH, in the
presence of triethylamine. The overall stoichiometric reaction leading to
1 is shown schematically below:
In the case of complex 2, ZnCl2 reacted with quercetin and 2,2′ -
bipyridine in MeOH, in the presence of triethylamine. The stoichio­
metric reaction leading to the formation of 2 is shown schematically
below:
Diethylether was used as the precipitating solvent in the combination
of the vapor diffusion and slow evaporation techniques in the first re­
action described above. The second reaction mixture was left to evap­
orate slowly. Yellow and orange crystalline materials emerged in the
first and second reaction, respectively, the analytical composition of
which was consistent with the formulations in 1 and 2, as shown in the
equations above. Positive identification of the crystalline products was
achieved by elemental analysis, FT-IR and NMR spectroscopic methods,
and X-ray crystallographic determination for isolated single crystals of 1
and 2. Both complexes are stable in the crystalline form, in air, for fairly
long periods of time. They are also stable in DMSO solution as shown by
the NMR studies, even though slow replacement of the monodentate co-
ligand by the DMSO‑d6 solvent is presumed to take place with time. Both
species readily dissolve in MeOH, ethanol (EtOH), dimethylacetamide
(DMA), DMSO and dimethylformamide (DMF), are slightly soluble in Fig. 2. A. Diamond plot of complex assembly [Zn(CH3COO)(C15H9O4)
H2O and insoluble in acetone, acetonitrile, and dichloromethane at (C10H8N2)] in compound 1. B. Hydrogen bonding (red and blue dotted lines) in
compound 1.
room temperature.

considered to occupy the axial positions of the bipyramid while O1, O5

3.2. Description of X-ray crystallographic structures
The X-ray crystal structures of 1 and 2 reveal discrete solid-state
lattices. The molecular structures of 1 and 2 are given in Fig. 2A and
3A, respectively; selected bond distances and angles are listed in Table 2.
Complex 1 crystallizes in the trigonal space group R3, with eighteen
neutral complexes [Zn(CH3COO)(C15H9O4)(C10H8N2)] in the unit cell
and two badly disordered MeOH molecules. In the molecular structure
of 1 the Zn(II) cation is bound to the O,O-donor monoanionic chrysin, to
the chelating N,N-donor 2,2′ -bipyridine and to one of the carboxylate
oxygen atoms from the acetate ligand, thus giving rise to a ZnIIN2O3
coordination environment. The so formed coordination sphere could be
better described as presenting distorted trigonal bipyramidal geometry
(Fig. 2A) with a trigonality index, τ5, of 0.43 [27]. Atoms N1 and O2 are
and N2 form the equatorial plane. The Zn(II) is nearly placed on the
equatorial plane with a deviation of 0.153 Å towards the O2 oxygen
atom. The Zn-N (2,2′ -bipyridine) and Zn-O bond lengths are in the range
from 2.124(3)-2.179(3) Å and 1.963(2)-2.056(2), respectively. These
values are very similar to related literature reported bond distances
[11,28]. One intermolecular hydrogen bond is present in the lattice of 1
(Fig. 2B, Supplementary Information Table S1). The oxygen atom
from the free phenolic group of the chrysinato ligand binds the free
carboxylate oxygen atom of the acetato ligand from a neighboring
complex moiety. Because of these interactions, all the moieties are kept
close together forming infinite zig-zag chains parallel to the c crystal­
lographic axis. The so formed model results an 1D crystal lattice.
Complex 2 crystallizes in the triclinic space group P1, with two
molecules in the unit cell. The asymmetric unit contains one

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E. Halevas et al. Inorganica Chimica Acta 523 (2021) 120407

Table 2
Bond lengths [Å] and angles [deg] for [Zn(CH3COO)(C15H9O4)
(C10H8N2)]9⋅CH3OH (1), and [Zn(C15H9O7)(C10H8N2)Cl]⋅(CH3OH)⋅1.5(H2O)
(2).
Bond lengths (Å)

1 2

Zn(1)—O(1) 1.963 (2) Zn(1)—O(1) 2.045 (2)

Zn(1)—O(2) 2.056(2)
Zn(1)—O(5) 1.999 (2)
Zn(1)—N(1) 2.179 (3)
Zn(1)—N(2) 2.124 (3)
Angles (◦ )
1 2
O(1)—Zn(1)—O(2) 88.83 (8)
O(1)—Zn(1)—O(5) 102.91 (10)
O(2)—Zn(1)—O(5) 105.00 (9)
N(1)—Zn(1)—N(2) 75.76 (10)
N(1)—Zn(1)—O(1) 91.11 (10)
N(2)—Zn(1)—O(1) 118.93 (10)
N(1)—Zn(1)—O(2) 162.08 (9)
N(2)—Zn(1)—O(2) 88.61 (9)
N(1)—Zn(1)—O(5) 92.48 (10)
N(2)—Zn(1)—O(5) 136.34(10)
Zn(1)—O(2) 2.155 (2)
Zn(1)—Cl(1) 2.2352(9)
Zn(1)—N(1) 2.077 (3)
Zn(1)—N(2) 2.092 (3)
Cl(1)—Zn(1)—O(1) 100.90 (7)
Cl(1)—Zn(1)—O(2) 105.85 (7)
O(1)—Zn(1)—O(2) 79.20 (8)
N(1)—Zn(1)—N(2) 78.19 (10)
N(1)—Zn(1)—O(1) 153.56 (10)
N(2)—Zn(1)—O(1) 96.35 (10)
N(1)—Zn(1)—O(2) 88.47 (9)
N(2)—Zn(1)—O(2) 140.02 (11)
Cl(1)—Zn(1)—N(1) 104.96 (8)
Cl(1)—Zn(1)—N(2) 113.95 (9)

mononuclear [Zn(C15H9O7)(C10H8N2)Cl] neutral assembly, one lattice

MeOH molecule, and one and a half lattice H2O molecules. The Zn(II)
center is coordinated by one O,O-donor monoanionic quercetin in a
chelate bidentate mode, one chelating N,N-donor 2,2′ -bipyridine mole­
cule and a chloride anion, thereby giving rise to a ZnIIN2O2Cl environ­
ment and a coordination sphere reflecting a distorted square pyramidal
geometry (Fig. 3A) with a trigonality index, τ5, of 0.23 and Cl1 occu­
pying the axial position [27]. The Zn-N (2,2′ -bipyridine) and Zn-O bond
lengths are in the range from 2.077(3)-2.092(3) Å and 2.045(2)-2.155
(2) Å, respectively, whereas the Zn-Cl bond length is 2.2352(9) Å.
These values are very similar to related bond distances reported in the
literature [11,28,29]. A complex net from hydrogen bonding in­
teractions is formed as all three O5, O6 and O7 non coordinated phenolic
group oxygen atoms interact with oxygen and chlorine atoms from
neighboring complex, lattice water and MeOH molecules forming intra
hydrogen bonding interactions. The fourth non coordinated phenolic
oxygen O4 is interacting with the coordinated oxygen O2, while O1 is
interacting with the methanolic oxygen O8 forming inter hydrogen
bonding interactions. All these interactions form a rigid net keeping
complex and solvent moieties close and giving a final 2D crystal lattice
which expands along a and b crystallographic axes (Fig. 3B and 3C,
Supplementary Information Table S1).
Fig. 3. A. Diamond plot of complex assembly [Zn(C15H9O7)(C10H8N2)Cl] in
compound 2. B. Hydrogen bonding view along a (red and blue dotted lines) in
3.3. FT-IR spectroscopy compound 2. C. Hydrogen bonding view along b (red and blue dotted lines) in
compound 2.
The FT-IR spectra of 1 and 2 (Supplementary Information Figs. S2A
and S2B) indicate that complexation of Zn(II) ion by chrysin or quercetin confirming the existence of water molecules in the structure of complex
induces significant changes in their vibrational spectra. In the spectrum 2 [16]. All observations are in agreement with the structures of the
of complex 1 (Supplementary Information Fig. S2A), peaks from both complexes, as revealed by X-ray crystallography.
the chrysin and 2,2′ -bipyridine ligands are present, often coinciding or
producing joint broad clusters of peaks. However, the most character­
istic and clearly observed alteration is the sharp absorption band at 3.4. UV–Vis spectroscopy
1636 cm− 1 associated with the v(C– – O) stretching vibrations that is
shifted to lower frequencies compared to plain chrysin (1652 cm− 1), The UV–Vis spectra of chrysin, quercetin hydrate, and complexes 1
denoting the involvement of this group in the coordination of the Zn(II) and 2 were recorded in MeOH at a concentration of 10-5 M (Fig. 4A and
ion. 4B). The UV–Vis spectrum of pure chrysin (Fig. 4A) shows an absorption
In the FT-IR spectrum of complex 2 (Supplementary Information band at 312 nm, attributed to the B-ring cinnamoyl system (Band I) and
Fig. S2B) peaks from both the quercetin and 2,2′ -bipyridine ligands are related to the π → π* transitions, and one absorption band at 267 nm,
present. The sharp absorption band at 1653 cm− 1, attributed to the v assigned to the A-ring benzoyl system (Band II) and related to the π →
(C–– O) stretching vibrations, is slightly shifted to lower wavelengths π*, n → π*, and n → σ * transitions, respectively [30,31]. In the UV–Vis
compared to free quercetin (1665 cm− 1), indicating the participation of spectrum of complex 1 (Fig. 4A), the absorption Band I is observed as a
this group in the coordination of the Zn(II) ion. The v(O–H) stretching weak shoulder at 325 nm (ε ~ 21,400 М-1⋅cm− 1) and the absorption
vibrations appear as a broad band between 2931 and 3617 cm− 1, Band II appears at 271 nm (λmax, ε ~ 62,300 М-1⋅cm− 1). The observed

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E. Halevas et al. Inorganica Chimica Acta 523 (2021) 120407

A A
Chrysin
3000 Complex 1
1.00

Chrysin 2500
Complex 1

Intensity emission (a.u.)

0.75
2000
Absorbance

1500
0.50

1000

0.25
500

0
0.00 300 350 400 450 500 550 600
250 300 350 400 450 500 550 600 650 700 750 800
Wavelength (nm)
Wavelength (nm)

B
1.00 B Quercetin hydrate
Quercetin
6000 Complex 2
Complex 2

0.75 5000
Intensity emission (a.u.)
Absorbance

4000
0.50
3000

0.25 2000

0.00
250 300 350 400 450 500 550 600 650 700 750 800
Wavelength (nm)
Fig. 4. UV–Vis spectra of A) pure chrysin (solid line) and complex 1 (dashed
line) and B) pure quercetin (solid line) and complex 2 (dashed line) in MeOH at
a concentration of 10-5 M.
hyperchromic and short bathochromic shifts of the characteristic ab­
sorption bands compared to free chrysin, are indicative of the changes in
electronic distribution brought about by complexation and are in
agreement to literature reported metal complexes of chrysin [30-32].
Free quercetin (Fig. 4B) exhibits an absorption band at 372 nm
related to the π → π* transitions and assigned to the B-ring absorption of
the cinnamoyl system (Band I), and an absorption band at 255 nm
related to the π → π*, n → π*, and n → σ* transitions and attributed to the
A-ring absorption of the benzoyl system (Band II) [33-35]. The UV–Vis
spectrum of 2 (Fig. 4B) exhibits a B-ring absorption at 428 nm (ε ~
22,350 М-1⋅cm− 1) presenting a short hypochromic effect and a highly
bathochromic shift compared to free quercetin [36]. Moreover, the A-
ring absorption band is observed at 267 nm (λmax, ε ~ 33,370 М-1⋅cm− 1),
showing a short bathochromic and a highly hyperchromic shift
compared to plain quercetin. This hypochromic and highly bath­
ochromic shift to longer wavelength and lower absorbance values of
Band I compared to that of free quercetin can be assigned to the
increased conjugation of the Zn(II)-quercetin system induced by a new
ring formation involving the 3-OH and 4-oxo groups, as also observed in
related literature reports [16].
1000
0
420 440 460 480 500 520 540 560 580 600 620
Wavelength (nm)
Fig. 5. Fluorescence spectra of A) pure chrysin (solid line) and complex 1
(dashed line), and B) pure quercetin (solid line) and complex 2 (dashed line) in
MeOH at a concentration of 10-5 M.
3.5. Fluorescence studies
Steady state fluorescence measurements of complexes 1 and 2, as
well as chrysin and quercetin hydrate, were recorded in MeOH, at a
concentration of 10-5 M, and at room temperature (Fig. 5A and 5B).
Fig. 5A shows that free chrysin exhibits an emission with two specific
maxima at 352 nm and at around 432 nm when excited at 315 nm.
Complex 1 (Fig. 5A) exhibits a highly blue-shifted strong emission
maximum at 545 nm when excited at 271 nm, which could be assigned
to aromatic π → π * transitions and a contribution of a LMCT process in
the complexation site [33]. Free quercetin (Fig. 5B) exhibits two emis­
sion peaks when excited at 380 nm, one at around 465 nm and the
second at 515 nm, assigned to aromatic π → π* transitions [37,38]. The
emission spectrum of 2 (Fig. 5B), compared to that of plain quercetin,
shows a blue-shifted strong emission maximum at 545 nm, when excited
at 271 nm, which could also be assigned to aromatic π → π* transitions
and a contribution of a LMCT process in the complexation site [33]. The
observed differences in the emission spectra of complexes 1 and 2
compared to free chrysin and quercetin can be attributed to the rigid

6
E. Halevas et al. Inorganica Chimica Acta 523 (2021) 120407

Table 3 25 ◦ C are given in Table 3 together with the shifts of the flavonoids
1
H NMR chemical shifts for complexes 1 and 2 in DMSO‑d6 at 25 ◦ C. The chrysin and quercetin, as well as of the co-ligand 2,2′ -bipyridine, for
chemical shifts for the flavonoids chrysin and quercetin, as well as of the co- comparative purposes. The 1H–13C correlation spectrum for complex 1 is
ligand 2,2′ -bipyridine are included for comparative purposes. given in Fig. 6 and the corresponding one for complex 2 is given in Fig. 7.
Complex 1 Chrysin Complex Quercetin 2,2′ - For both complexes the peaks appear broad, indicating conformational
2 bipyridine mobility of the ligands, nevertheless, an assignment of all peaks was
H-3 6.82 6.94 possible. The appearance of the spectra is consistent with the assigned
H-6 5.89 6.22 6.16 6.18 structures with both flavonoid and 2,2′ -bipyridine present in solution. In
H-8 6.10 6.52 6.43 6.40 the 1H spectrum of complex 1, downfield shifts of H-3, H-6 and H-8 of
H-2′ 8.02 8.05 8.05 7.66
H-3′ 7.55 7.57
ring A are noted ranging from 0.42 − 0.12 ppm compared to free
H-4′ 7.57 7.59 chrysin, while the protons of the phenyl ring B remain essentially un­
H-5′ 7.55 7.57 6.87 6.88 affected by co-ordination. Downfield shifts are also noted in the 13C
H-6′ 8.02 8.05 7.97 7.53 spectrum for the carbons of ring A with more pronounced being those of
3-OH 9.36
C-5 (10.7 ppm) and C-7 (12.0 ppm). The NMR data, along with lack of
5-OH 12.81 11.57 12.48
7-OH 10.17 broad 10.98 10.75 10.77 the 5-OH peak in the spectrum of complex 1 suggest the coordination of
3′ -OH 9.13 9.58 Zn from the 5-OH and 4-oxo groups, in accordance to the crystallo­
4′ -OH 9.39 9.29 graphic findings. In the spectrum of complex 2, protons H-6 and H-8 of
H-1′ ’/H- 8.74 8.78 8.69 ring A remain unaffected by coordination compared to free quercetin.
10′ ’
On the contrary, downfield shifts are noted for proton H-2′ and H-6′ of
H-2′ ’/H- 7.55 7.66 7.45
9′ ’ the phenyl ring B. In the corresponding 13C spectrum, a notable down­
H-3′ ’/H- 7.98 8.17 7.95 field shift of 10.3 ppm is present for C-3 compared to free quercetin. All
8′ ’ the above NMR data (together with the lack of the 3-OH proton) are
H-4′ ’/H- 8.46 8.56 8.39
consistent with coordination of the Zn(II) ion through the 3-OH and the
7′ ’
Acetate 1.19 4-oxo groups of quercetin, as also proved in related literature reports via
FT-IR [16] and time-dependent density functional theory (TD-DFT)
calculations [43]. For the protons of the co-ligand 2,2′ -bipyridine,
complexation of the flavonoids to the Zn(II) ion, as also observed in downfield shifts are noted compared to free 2,2′ -bipyridine (0.04 ppm
other literature reports [32,33,39-42]. on average for complex 1 and 0.17 ppm on average for complex 2),
while in the 13C spectra the largest downfield shift is noted for C-2′ ’/C-
9′ ’, (2.5 ppm for complex 1 and 3.5 ppm for complex 2) (Table 4).
3.6. NMR studies Finally, it should be noted that in the solution of complex 1 the co­
ordinated acetate is present in a 1:1 ratio with the other ligands
The 1H and 13C chemical shifts for complexes 1 and 2 in DMSO-d6 at

Fig. 6. 1H–13C correlation spectrum of complex 1 in DMSO‑d6 at 25 ◦ C (1H range 8.96–5.69 ppm, 13
C range 152.16–85.96 ppm).

7
E. Halevas et al. Inorganica Chimica Acta 523 (2021) 120407

Fig. 7. 1H–13C correlation spectrum of complex 2 in DMSO‑d6 at 25 ◦ C (1H range 9.01–5.97 ppm, 13
C range 152.08–88.15 ppm).

change is noted in peaks H-3, H-8 and H-6, which may be reasonably
Table 4
13 attributed to slow replacement of the coordinated acetate or chloride, by
C NMR chemical shifts for complexes 1 and 2 in DMSO‑d6 at 25 ◦ C. The
DMSO‑d6 present in solution, the complexes remain intact, and free
chemical shifts for the flavonoids chrysin and quercetin, as well as of the co-
ligand 2,2′ -bipyridine are included for comparative purposes.
flavonoids or 2,2′ -bipyridine never appear in the NMR spectra, indi­
cating the strong affinity of both flavonoids and 2,2′ -bipyridine for the
Complex 1 Chrysin Complex 2 Quercetin 2,2′ -
Zn(II) ion and the overall stability of the generated complexes 1 and 2.
bipyridine

C-2 160.94 163.20 146.46 146.88

C-3 105.09 105.12 146.00 135.76 3.7. Thermal studies
C-4 180.92 181.84 177.54 175.88
C-5 172.21 161.42 159.09 160.76
C-6 102.43 99.00 98.01 98.25 The thermal decomposition of complexes 1 and 2 was studied by
C-7 176.43 164.39 163.37 163.93 TGA under an atmosphere of air (Fig. 8A and 8B). Complex 1 is ther­
C-8 89.16 94.11 93.37 93.43 mally stable up to 215 ◦ C. A significant weight loss is observed between
C-9 159.31 157.44 155.43 156.20
215 ◦ C and 473 ◦ C in line with the decomposition of the organic struc­
C-10 107.45 103.94 102.18 103.06
C-1′ 130.85 130.66 124.48 122.01
ture of the molecule. No clear plateaus are reached in this temperature
C-2′ 125.97 126.36 114.02 115.10 range, suggesting that the arising products are unstable and decompose
C-3′ 129.01 129.12 144.86 145.11 further. A plateau in the decomposition of 1 is reached at 473 ◦ C, with no
C-4′ 131.50 132.00 148.98 147.74 further loss up to 800 ◦ C, in line with the notion that the product at that
C-5′ 129.01 129.12 115.51 115.65
temperature and beyond (473 ◦ C) is ZnO. The total weight loss of ~
C-6′ 125.97 126.36 119.07 120.06
C-1′ ’/C- 149.02 148.98 149.31 84.77% is in good agreement with the theoretical value ~84.84%, ac­
10′ ’ cording to the following equation:
C-2′ ’/C- 124.71 125.69 122.24 Complex 2 is thermally stable up to 124 ◦ C. From that point on, a
9′ ’
narrow heat process points to the release of lattice MeOH and H2O
C-3′ ’/C- 137.52 139.66 137.37
8′ ’
molecules between 124 ◦ C and 194 ◦ C. Between 194 ◦ C and 247 ◦ C a
C-4′ ’/C- 120.63 121.47 120.47 plateau is reached. Further weight loss is observed between 247 ◦ C and
7′ ’ 597 ◦ C, in line with the decomposition of the organic structure of the
C-5′ ’/C- Not Not 155.25 molecule. No clear plateaus are reached in this temperature range,
6′ ’ detected detected
suggesting that the arising products are unstable and decompose further.
Acetate 22.16
A plateau in the decomposition of 2 is reached at 597 ◦ C, with no further
loss up to 800 ◦ C, in line with the notion that the product at that tem­
(Table 3), while in the spectrum of complex 2 signals of CH3OH, which perature and beyond (597 ◦ C) is ZnO. The total weight loss of ~ 87.01%
participates in the crystal lattice, are present at 4.10 ppm (hydroxyl, is in good agreement with the theoretical value ~ 86.82%, according to
broad) and 3.16 ppm (methyl) in the 1H spectrum, and at 48.57 ppm in the following equation:
the 13C spectrum. Even though with time in both complexes, a slow The observed results are consistent with previously reported results
of TGA on zinc-containing species [11,28,44,45].

8
E. Halevas et al. Inorganica Chimica Acta 523 (2021) 120407

activity. The Zn(II) complexation with the chrysin moiety affects the
A chemical properties of the flavonoid and leads to changes in the anti­
oxidant activity since complex 1 demonstrates a significantly higher
100
radical scavenging activity than chrysin in a dose-dependent manner (p
90 Complex 1 < 0.001 compared to chrysin and p < 0.001 compared to ZnCl2 and 2,2′ -
80 bipyridine). On the other hand, complex 2 scavenges DPPH radicals to
the same degree as plain quercetin, a fact that indicates that the for­
70 mation of the complex retains the antioxidant activity of free quercetin
Weight loss (%)

60 (p > 0.05 compared to quercetin and p < 0.001 compared to Zn

(CH3COO)2⋅2H2O and 2,2′ -bipyridine). Corresponding experiments of
50
plain precursors ZnCl2, Zn(CH3COO)2⋅2H2O and co-ligand 2,2′ -bipyr­
40 idine revealed no significant antioxidant activity (Supplementary In­
30 formation, Fig. S3).

20 4. Discussion
10
Metal-flavonoid complexes are currently actively investigated as a
0
new generation of nature-based metallodrugs for prevention and ther­
0 100 200 300 400 500 600 700 800
apy. Many studies in the literature report synthesis and characterization
Temperature ( C) of heteroleptic complexes of flavonoids [19]. However, in the majority
of these reports, the structure of the reported complexes is deduced
through the usual spectroscopic and analytical techniques (elemental
B analysis, FT-IR, NMR, HR-ESI-MS) and scarcely via X-ray crystallog­
raphy, mainly due to their low solubility in water and common organic
100 solvents that limits their crystallinity [19].
Complex 2 Our research group has a long-term expertise in the synthesis, crys­
90
tallization, isolation, structural and physico-chemical characterization
80 and biological evaluation of flavonoid metal complexes. To the best of
70 our knowledge, in the case of quercetin, there is only one crystallo­
graphically characterized metal complex reported in the literature, a
Weight loss (%)

60
heteroleptic Cu(II)-quercetin-2,2′ -bipyridine complex, produced by our
50 research group [33]. Moreover, in the case of chrysin, there are only four
40 crystallographically characterized metal complexes, a chrysin-organotin
compound [46] and three heteroleptic Ga(III)-chrysin complexes also
30 produced by our research group [32]. In this work, careful exploration
20 of the synthetic and crystallization conditions led to the isolation and
crystallization of complexes 1 and 2 which represent the only examples
10
of chrysin or quercetin bound to Zn(II) metal ion, in a coordination
0 environment confirmed via analytical, spectroscopic techniques and,
0 100 200 300 400 500 600 700 800 ultimately, X-ray crystallography.
Temperature ( C) Evaluation of scavenging activity by the DPPH method is considered
a fast and reliable assay to measure the in vitro antioxidant activity of a
Fig. 8. TGA diagrams of A) complex 1 and B) complex 2. compound [47]. The differences in antioxidant activity between chrysin
and quercetin is well documented in the literature [48,49] and is
3.8. DPPH radical scavenging activity attributed mainly to differences in structural characteristics, namely the
position and the number of hydroxyl moieties [50]. Flavonoids are ideal
Fig. 9 shows the dose–response curve of DPPH radical scavenging antioxidants not only due to their radical scavenging ability but also
activity of complexes 1 and 2, pure chrysin and plain quercetin hydrate their efficiency to chelate with metal ions [51]. In many cases, their
compared to ascorbic acid as positive control. Pure chrysin presents a metal complexes are found to be more active when compared to free
weak DPPH radical scavenging activity as witnessed by the low recorded ligands, while the increased antioxidant activity of the complexes is
values in contrast to plain quercetin which shows higher antioxidant attributed to the electron withdrawing effect of the metals ions that

9
E. Halevas et al. Inorganica Chimica Acta 523 (2021) 120407

crystallographically characterized material [16] and highlights the

A importance of the B-ring hydroxyl structure in scavenging free radicals
[55,56]. However, our results are significantly better compared to pre­
120 Chrysin vious findings on the antioxidant activity of quercetin complexes of Pb
Complex 1 (II) [57] and Tb(III) [58], of different structure, coordination mode, co-
DPPH radical-scavenging activity (%)

100 Ascorbic Acid ligands and solubility. Even though several reports exist in the literature
showing that the scavenging capacity of quercetin complexated with Cu
(II), Mg(II), Fe(II), Ru(II), Co(II), Cd(II), and rare earth elements is
80 stronger compared to pure quercetin [59], the lack of crystallographi­
cally defined structures makes quantitative comparisons difficult.
60
5. Conclusions

40 The two heteroleptic Zn(II)-chrysin-2,2′ -bipyridine and Zn(II)-quer­

cetin-2,2′ -bipyridine complexes presented herein, effectively incorpo­
rate two natural flavonoids, chrysin and quercetin, and bioactive Zn(II)
20
into stable structures. The detailed structural and physico-chemical
characterization of complexes 1 and 2, both in the solid state and in
0 solution, projected a well-defined coordination environment around Zn
0 50 100 150 200 (II) with stabilized chrysin and quercetin moieties and 2,2′ -bipyridine as
-1 an ancillary aromatic chelator. The two heteroleptic complexes repre­
Concentration g mL )
sent the only crystallographically characterized structures with Zn(II) as
the central metal ion and chrysin or quercetin as the ligands. Their
biological evaluation showed enhanced radical scavenging potential
compared to free chrysin and retainment of the strong antioxidant
B profile of quercetin. Additional studies by means of physico-chemical
and cellular assays are on the way to provide further insight into the
120 biological activity of these complexes.
Quercetin hydrate
Complex 2
DPPH radical-scavenging activity (%)

100 Ascorbic Acid Declaration of Competing Interest

The authors declare that they have no known competing financial

80 interests or personal relationships that could have appeared to influence
the work reported in this paper.
60
Acknowledgements

40 Dr. E. Halevas and Dr. B. Mavroidi gratefully acknowledge financial

20
0
0 50 100
-1
Concentration (mg mL )
Fig. 9. Effect of A) chrysin and complex 1, and B) quercetin hydrate and
complex 2 on DPPH radical scavenging activity. Ascorbic acid was used as
standard radical scavenger. Data were expressed as means ± SEM obtained in
three independent experiments.
facilitates the release of hydrogen to reduce the DPPH radical [52,53]. In
accordance to the above, in our study the complexation of chrysin with
Zn(II) enhanced the radical scavenging activity of the flavonoid. This
recorded enhancement is in agreement with previous reports on chrysin
complexes of Ge(IV), VO(II) and Ce(IV) that were found to be more
active DPPH scavengers compared to free chrysin [54]. However, in our
study the enhancement is much more pronounced, even compared to
ascorbic acid that is considered to be one of the most powerful antiox­
idants. To the authors’ knowledge, the present work represents the first
report on the promotion of the antioxidant activity of chrysin through Zn
(II) complexation.
In contrast, the formation of complex 2 did not alter or influence the
chemical properties and strong antioxidant profile of quercetin mole­
cule. This finding is in accordance to previous observations with non-
support by Stavros Niarchos Foundation (SNF) through implementation
of the program of Industrial Fellowships at NCSR “Demokritos”. Dr. E.
Halevas also acknowledges the Foundation for Education and European
Culture (IPEP) founded by Nicos & Lydia Tricha.
150 200
Appendix A. Supplementary data
Supplementary crystallographic data. CCDC 2015215 (1) and
CCDC 2015216 (2) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.cam.
ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: (+44) 1223-
336-033; or deposit@ccde.cam.ac.uk). Supplementary data to this
article can be found online at https://doi.org/10.1016/j.ica.2021.120
407.
Supplementary physicochemical and biological data. HR-ESI-MS
spectra of 1 (A) and 2 (B); Hydrogen bonds in 1 and 2; FT-IR spectra of
A) 2,2’-bipyridine, chrysin and complex 1, and B) 2,2’-bipyridine,
quercetin hydrate and complex 2; Effect of ZnCl2, Zn(CH3COO)2⋅2H2O
and 2,2’-bipyridine on DPPH radicalscavenging activity. Data were
expressed as means ± SEM obtained in three independent experiments.
References
[1] A.N. Panche, A.D. Diwan, S.R. Chandra, J. Nutr. Sci. 5 (2016), e47.
[2] B.H. Havsteen, Pharmacol. Ther. 96 (2002) 67–202.
[3] D. Malešev, V. Kuntić, J. Serbian Chem. Soc. 72 (2007) 921–939.
[4] H. Tapiero, K.D. Tew, Biomed. Pharmacother. 57 (2003) 399–411.

10
E. Halevas et al.
[5] G.K. Walkup, S.C. Burdette, S.J. Lippard, R.Y. Tsien, J. Am. Chem. Soc. 122 (2000)
5644–5645.
[6] M. Melnik, K. Györyová, J. Skoršepa, C.E. Holloway, J. Coord. Chem. 35 (1994)
179–279.
[7] M. Di Vaira, C. Bazzicalupi, P. Orioli, L. Messori, B. Bruni, P. Zatta, Inorg. Chem. 43
(2004) 3795–3797.
[8] Z. Li, F. Wu, Y. Gong, C. Hu, Y. Zhang, M. Gan, Chin. J. Chem. 25 (2007)
1809–1814.
[9] N.C. Kasuga, K. Sekino, M. Ishikawa, A. Honda, M. Yokoyama, S. Nakano,
N. Shimada, C. Koumo, K. Nomiya, J. Inorg. Biochem. 96 (2003) 298–310.
[10] D.do N. Marreiro, K.J.C. Cruz, J.B.S. Morais, J.B. Beserra, J.S. Severo, A.R.S. de
Oliveira, Antioxidants 6 (2017) 24.
[11] E. Halevas, O. Tsave, M. Yavropoulou, J.G. Yovos, A. Hatzidimitriou, V. Psycharis,
A. Salifoglou, J. Inorg. Biochem. 177 (2017) 228–246.
[12] C.T. Dillon, T.W. Hambley, B.J. Kennedy, P.A. Lay, J.E. Weder, Q. Zhou, Met. Ions
Biol. Syst. 41 (2004) 253–777.
[13] J. d’Angelo, G. Morgant, N.E. Ghermani, D. Desmaele, B. Fraisse, F. Bonhomme,
E. Dichi, M. Sghaier, Y. Li, Y. Journaux, J.R.J. Sorenson, Polyhedron 27 (2008)
537–546.
[14] M. Porchia, M. Pellei, F. Del Bello, C. Santini, Molecules 25 (2020) 5814.
[15] J. Tan, W. Bochu, Z. Liancai, Bioorg. Med. Chem. Lett. 17 (2007) 1197–1199.
[16] A.A. Andelescu, C. Cretu, V. Sasca, S. Marinescu, L. Cseh, O. Costisor, E.I. Szerb,
Polyhedron 147 (2018) 120–125.
[17] A. Primikyri, G. Mazzone, C. Lekka, A.G. Tzakos, N. Russo, I.P. Gerothanassis,
J. Phys. Chem. B. 119 (2015) 83–95.
[18] Y.H. Lee, P.T. Tuyet, Vitro Cell. Dev. Biol. -Animal 55 (2019) 395.
[19] M.M. Kasprzak, A. Erxleben, J. Ochocki, RSC Adv. 5 (2015) 45853–45877.
[20] R.F. de Souza, W.F. De Giovani, Spectrochim. Acta A Mol. Biomol. Spectrosc. 61
(2005) 1985–1990.
[21] Bruker Analytical X-ray Systems, Inc. Apex2, Version 2 User Manual, M86-E01078,
Madison, WI, 2006.
[22] Siemens Industrial Automation, Inc. SADABS: Area-Detector Absorption
Correction; Madison, WI, 1996.
[23] P.W. Betteridge, J.R. Carruthers, R.I. Cooper, K. Prout, D.J. Watkin, J. Appl. Cryst.
36 (2003) 1487.
[24] L. Palatinus, G. Chapuis, Appl. Cryst. 40 (2007) 786–790.
[25] DIAMOND – Crystal and Molecular Structure Visualization, Ver. 3.1c, Crystal
Impact, Bonn, Germany, 2006.
[26] S.B. Kedare, R.P. Singh, J. Food Sci. Technol. 48 (2011) 412–422.
[27] A.W. Addison, T.N. Rao, J. Reedijk, J. Van Rijn, G.C. Verschoor, J. Chem. Soc.,
Dalton Trans. 13 (1984) 1349.
[28] O. Tsave, E. Halevas, M.P. Yavropoulou, A. Kosmidis Papadimitriou, J.G. Yovos,
A. Hatzidimitriou, C. Gabriel, V. Psycharis, A. Salifoglou, J. Inorg. Biochem. 152
(2015) 123–137.
[29] M. Maeda, T. Ito, M. Hori, G. Johansson, Z. Naturforsch. 51a (1996) 63–70.
[30] E. Halevas, B. Mavroidi, O. Antonoglou, A. Hatzidimitriou, M. Sagnou,
N. Pantazaki, G. Litsardakis, M. Pelecanou, Dalton Trans. 49 (2020) 2734–2746.
11
Inorganica Chimica Acta 523 (2021) 120407
[31] J. Pusz, S. Wolowiec, J. Therm. Anal. Calorim. 110 (2012) 813–821.
[32] E. Halevas, A. Mitrakas, B. Mavroidi, D. Athanasiou, P. Gkika, K. Antoniou,
G. Samaras, E. Lialiaris, A. Hatzidimitriou, A. Pantazaki, M. Koukourakis,
M. Sagnou, M. Pelecanou, T. Lialiaris, Inorg. Chim. Acta 515 (2021), 120062.
[33] E. Halevas, A. Pekou, R. Papi, B. Mavroidi, A.G. Hatzidimitriou, G. Zahariou,
G. Litsardakis, M. Sagnou, M. Pelecanou, A.A. Pantazaki, J. Inorg. Biochem. 208
(2020), 111083.
[34] J. Joseph, K. Nagashri, Appl. Biochem. Biotechnol. 167 (2012) 1446–1458.
[35] A. Pekal, M. Biesaga, K. Pyrzynska, Biometals 24 (2011) 41–49.
[36] G. Accorsi, A. Listorti, K. Yoosaf, N. Armaroli, Chem. Soc. Rev. 38 (2009)
1690–1700.
[37] O.J. Rolinski, A. Martin, J.S. Birch, J. Biomed. Opt. 12 (2007), 034013.
[38] B. Sengupta, S.M. Reilly, D.E. Davis Jr., K. Harris, R.M. Wadkins, D. Ward,
D. Gholar, C. Hampton, J. Phys. Chem. B 119 (6) (2015) 2546–2556.
[39] J. Zhou, L. Wang, J. Wang, N. Tang, J. Inorg. Biochem. 83 (2001) 41–48.
[40] I.E. Serdiuk, A.S. Varenikov, A.D. Roshal, J. Phys. Chem. A 118 (2014) 3068–3080.
[41] M. Tan, J. Zhu, Y. Pan, Z. Chen, H. Liang, H. Liu, H. Wang, Bioinorg. Chem. Appl.
2009 (2009), 347872.
[42] H.R. Park, B.G. Kim, S.J. Kim, J.A. Yoon, K.M. Bark, B. Korean Chem. Soc. 39
(2018) 951–959.
[43] V.A. Muñoz, G.V. Ferrari, M.I. Sancho, M.P. Montaña, J. Chem. Eng. Data 61
(2016) 987–995.
[44] C. Duval, Inorganic Thermogravimetric Analysis, second and revised edition,
Elsevier Publishing Co., Amsterdam, 1963, pp. 416–420.
[45] A. Moezzi, M. Cortie, A. McDonagh, Dalton Trans. 45 (2016) 7385–7390.
[46] H. Xuana, J. Zhang, Y. Wang, C. Fu, W. Zhang, Bioorg. Med. Chem. Lett. 26 (2016)
570–574.
[47] P. Arulpriya, P. Lalitha, S. Hemalatha, Merr. Der Chem. Sin. 1 (2010) 73–79.
[48] G.M. Sulaiman, A.A. Al-Amiery, R. Bagnati, Int. J. Food Sci. Nutr. 65 (2014)
101–105.
[49] S.P. Deng, Y.L. Yang, X.X. Cheng, W.R. Li, J.Y. Cai, Int. J. Mol. Sci. 20 (2019) 975.
[50] L. De Martino, T. Mencherini, E. Mancini, R.P. Aquino, L.F.R. De Almeida, V. De
Feo, Int. J. Mol. Sci. 13 (2012) 5406–5419.
[51] M. Samsonowicz, E. Regulska, Spectrochim. Acta Part A Mol. Biomol. Spectrosc.
173 (2017) 757–771.
[52] L.Y. Tu, J. Pi, H. Jin, J.Y. Cai, S.P. Deng, Bioorg. Med. Chem. Lett. 26 (2016)
2730–2734.
[53] I.P. Ejidike, P.A. Ajibade, Molecules 20 (2015) 9788–9802.
[54] V. Uivarosi, A. C. Munteanu, Chapter 14 Flavonoid complexes as promising
anticancer metallodrugs, (2018).
[55] S.D. Banjarnahor, N. Artanti, Med. J. Indones. 23 (2014) 239–244.
[56] D. Procházková, I. Boušová, N. Wilhelmová, Fitoterapia 82 (2011) 513–523.
[57] R. Ravichandran, M. Rajendran, D. Devapiriam, J. Coord. Chem. 67 (2014)
1449–1462.
[58] J.E.N. Dolatabadi, A. Mokhtarzadeh, S.M. Ghareghoran, G. Dehghan, Adv. Pharm.
Bull. 4 (2014) 101–104.
[59] D. Xu, M.J. Hu, Y.Q. Wang, Y.L. Cui, Molecules 24 (2019) 1123.