Polyhedron 170 (2019) 312–324

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Polyhedron
journal homepage: www.elsevier.com/locate/poly

Effective anticancer activities of an acyclic symmetrical compartmental

Schiff base ligand and its Co(II), Cu(II) and Zn(II) complexes against the
human leukemia cell line K562
Lotfali Saghatforoush a,⇑, Keyvan Moeini a, Seyed Abolfazl Hosseini-Yazdi b, Zahra Mardani c,
Akbar Bakhtiari a, Alireza Hajabbas-Farshchi d, Soghra Honarvar a, Mohammed S.M. Abdelbaky e
a
Department of Chemistry, Payame Noor University, 19395-4697 Tehran, Islamic Republic of Iran
b
Department of Inorganic Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz 51666-14766, Islamic Republic of Iran
c
Inorganic Chemistry Department, Faculty of Chemistry, Urmia University, 57561-51818 Urmia, Islamic Republic of Iran
d
Department of Immunology, Faculty of Microbiology, Urmia University, 57561-51818 Urmia, Islamic Republic of Iran
e
Department of Physical and Analytical Chemistry, University of Oviedo-CINN, 33006 Oviedo, Spain

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

Article history: Syntheses of new N2O5 donor type compartmental Schiff base ligand, 2,20 -((((((2-hydroxypropane-1,3-
Received 6 March 2019 diyl)bis(oxy))bis(2,1-phenylene))bis(methylene))bis(azanylylidene))bis(methanylylidene))bis(4-nitro-
Accepted 29 May 2019 phenol) (H3L) and its cobalt(II), copper(II) and zinc(II) complexes, [Co(HL)] (1), [Cu2(L)(l-1,3-OAc)] (2)
Available online 13 June 2019
and [Zn(HL)] (3), are reported. The synthesized compounds were characterized by elemental analysis,
FT-IR, 1H and 13C NMR spectroscopies and X-ray single-crystal diffraction. In the structure of 1 and 3,
Keywords: the metal ion has a N2O2 coordination environment with tetrahedral geometry. Compound 2 is a binu-
Cobalt
clear complex, in which copper ions are bonded by NO4 donor atoms set in square planar coordination
Copper
Zinc
geometry. The ability of all compounds to interact with ten selected biomacromolecules (BRAF kinase,
K562 cell line CatB, DNA gyrase, HDAC7, rHA, RNR, TrxR, TS, Top II and B-DNA) are investigated by the docking calcu-
Docking study lations. In continue, the in vitro activities of all compounds against the human leukemia cell line K562
were investigated by evaluation of IC50 values and mode of cell death (apoptosis). The experiments
revealed that the cytotoxicity of the studied complexes is higher than or comparable with cisplatin.
Ó 2019 Elsevier Ltd. All rights reserved.

1. Introduction [20,21]. It is shown that such interactions have different effects

Metal complexes of Schiff base ligands occupy an important
role in the development of the chemistry of chelate systems. While
many polynuclear coordination complexes of these ligands with
interesting structural motifs have been studied in the literature,
especially, metal complexes of those Schiff base ligands with NO
donor atoms, closely resemble metallo-proteins [1–8]. In materials
chemistry, this class of compounds has widely been studied for
many potential applications such as chemosensors [9,10], catalysts
[11–13] and OLED materials [14]. On the other hand, Schiff base
ligands and their metal complexes show interesting pharmacolog-
ical effects such as anticancer [15], antibacterial [16,17] and urease
inhibitory [18,19] activities. Further, interaction of these com-
pounds with DNA molecule has been established previously
⇑ Corresponding author.
E-mail addresses: saghatforoush@gmail.com, l_saghatf@pnu.ac.ir
(L. Saghatforoush).
on DNA molecule, including DNA cleavage [22] and DNA duplex
cross-linking [23].
Compartmental Schiff bases, which are synthesized by the con-
densation reaction of diamines with salicylaldehyde or its deriva-
tives, have two cavities of different dimensions [24–29]. These
types of ligands can bind with one or two metal centers, enabling
the successful synthesis of homo- and/or heteronuclear metal com-
plexes with interesting stereochemistry [5,25,27,30]. The respec-
tive compounds have widely studied for their structural and
physical properties and are considered as promising catalysts
[31–33]. It is notable that, as an important issue in synthetic inor-
ganic chemistry, selective formation of mono- and dinuclear metal
complexes is of high interest in investigations ranging from the
chemistry of complexes with multiple metal–ligand bonds [34]
to simulating the active sites of enzymes with model compounds
[35].
In order to extend the chemistry of the compartmental Schiff
base compounds, in this work, synthesis of a new Schiff base

https://doi.org/10.1016/j.poly.2019.05.057
0277-5387/Ó 2019 Elsevier Ltd. All rights reserved.
 L. Saghatforoush et al. / Polyhedron 170 (2019) 312–324 313

proteins were selected either due to their reported roles in cancer

Scheme 1. Structure of the H3L ligand.
growth or as transport agents which affect drug pharmacokinetic
properties (e.g., rHA). The DNA gyrase was included to this list in
order to study the possible anticancer properties of the compounds
and their activity as antimalarial agents [55]. The knowledge
obtained from docking studies on the B-DNA could be useful in
developing potential probes for DNA structure and new therapeu-
tic reagents for tumors and other diseases [56]. In continuation,
experimental investigations on the anticancer potential of three
titled compounds, mode of cell death and apoptosis on the K562
cell lines were carried out. The K562 cell line is a pluripotent pre-
cursor cell that is positive for the Philadelphia (Ph) chromosome
and was originally derived from a patient with human chronic
myelogenous leukemia (CML) at the terminal stage of the last cri-
sis; this cell line is non-adherent and rounded, highly undifferenti-
ated with an active proliferative capacity and the inhibition of
apoptosis [57].

ligand, 2,20 -((((((2-hydroxypropane-1,3-diyl)bis(oxy))bis(2,1-phe-
nylene))bis(methylene))bis(azanylylidene))bis(methanylylidene))
bis(4-nitrophenol) (H3L, Scheme 1), is described. Also, cobalt(II),
copper(II) and zinc(II) complexes of H3L, [Co(HL)] (1), [Cu2(L)(l-
1,3-OAc)] (2) and [Zn(HL)] (3), were prepared and characterized.
The compounds were further studied by density functional theory
(DFT) methods. Moreover, biological and anticancer activities of
the compounds were investigated.
While Schiff base compounds are expected to exhibit biological
properties [15,36–41], coordination complexes of these ligands
with cobalt [15,42–45], copper [15,46–49] and zinc [15,49–52]
ions are promising biologically active compounds. To investigate
the biological activities of the new ligand (H3L) and its complexes,
their ability to interact with ten biomacromolecular targets were
evaluated by docking calculations [49,53,54]. BRAF kinase, Cathep-
sin B (CatB), DNA gyrase, Histone deacetylase (HDAC7), recombi-
nant Human albumin (rHA), Ribonucleotide reductases (RNR),
Thioredoxin reductase (TrxR), Thymidylate synthase (TS), Topoiso-
merase II (Top II) along with B-DNA were chosen for study. The
2. Experimental
2.1. Materials and instrumentation
All starting chemicals and solvents were reagent or analytical
grade and used as received. The infrared spectra were recorded
in the range between 4000 and 400 cm1 using KBr pellets by a
FT-IR Shimadzu- IRprestige-21 spectrometer. The 1H and 13C
NMR spectra were recorded on Bruker Avance 400 instrument;
chemical shifts d are given in parts per million, relative to TMS as
an internal standard. The carbon, hydrogen and nitrogen contents
were determined using a Perkin-Elmer 2400 elemental analyzer.
The melting points were determined with an electrically heated
Electrothermal 9100 apparatus.
2.1.1. Synthesis of 2,20 -((((((2-hydroxypropane-1,3-diyl)bis(oxy))bis
(2,1-phenylene))bis(methylene))bis(azanylylidene))bis
(methanylylidene))bis(4-nitrophenol) (H3L)
A solution of 0.33 g (2 mmol) of 2-hydroxy-5-nitrobenzalde-
hyde, dissolved in methanol (20 mL), was added to a stirring solu-

Table 1
Crystallographic data and structure refinement for complexes 1–3.

Complex 1 Complex 2 Complex 3

Empirical formula C31H26CoN4O9 C33H27Cu2N4O11 C31H26ZnN4O9
Formula weight (g mol1) 657.49 782.67 663.93
Crystal size (mm3) 0.12  0.09  0.06 0.45  0.25  0.24 0.43  0.23  0.21
T (K) 296 296 296
Crystal system triclinic monoclinic triclinic
 
Space group P1 P21/c P1
Unit cell dimensions (Å, °)
a 7.1649(14) 11.8822(6) 7.1653(6)
b 8.6078(17) 14.9653(9) 8.6223(7)
c 23.637(5) 18.8851(11) 23.618(2)
a 98.124(11) 90.000 97.917(3)
b 91.649(10) 107.613(3) 92.122(3)
c 104.841(10) 90.000 104.923(3)
V (Å3) 1391.8(5) 3200.7(3) 1392.5(2)
Z 2 4 2
q (g cm3) 1.569 1.624 1.583
l (mm1) 0.68 1.40 0.95
F(0 0 0), e 678 1596 684
h (°) 0.9–24.2 1.8–32.2 0.9–33.5
h, k, l ranges 8  h  8, 9  k  9, 17  h  16, 19  k  21, 10  h  10, 11  k  13,
27  l  27 26  l  28 33  l  34
Reflections collected/independent 30 466/4433/0.079 89 033/9665/0.038 25 686/9188/0.041
(Rint)
Data/ref. parameters 4433/412 9665/452 9188/412
Goodness-of-fit on F2 1.09 1.12 1.11
Final R indexes [I> = 2r (I)] R1 = 0.045, wR2 = 0.116 R1 = 0.032, wR2 = 0.101 R1 = 0.051, wR2 = 0.117
Final R indexes [all data] R1 = 0.074, wR2 = 0.139 R1 = 0.047, wR2 = 0.112 R1 = 0.076, wR2 = 0.131
Largest diff. peak/hole, (e Å3) 0.62/0.66 0.66/0.78 0.46/0.57
314 L. Saghatforoush et al. / Polyhedron 170 (2019) 312–324

Table 2
Selected bond lengths (Å) and angles (°) for complexes 1–3. The estimated standard deviations are given in parentheses.

Complex 1 Complex 2 Complex 3

Distances Co1AN10 1.987(3) Cu1AN2 1.946(2) Zn1AN10 1.990(2)
Co1AN18 1.985(3) Cu1AO1 2.043(1) Zn1AN18 1.995(2)
Co1AO14 1.933(2) Cu1AO8 1.926(1) Zn1AO14 1.945(2)
Co1AO19 1.913(3) Cu1AO9 2.237(1) Zn1AO19 1.926(2)
Cu1AO11 1.940(1)
Cu2AO2 1.954(1)
Cu2AO8 1.940(1)
Cu1ACu2 3.2193(4)
Angles N10ACo1AN18 119.4(1) O1ACu1AN2 92.55(6) N10AZn1AN18 119.59(8)
N10ACo1AN14 93.1(1) O1ACu1AO8 94.67(5) N10AZn1AO14 93.44(7)
N10ACo1AN19 118.2(1) O1ACu1AO9 98.75(5) N10AZn1AO19 118.61(7)
N18ACo1AN19 95.5(1) O1ACu1AO11 118.91(6) N18AZn1AO19 96.62(7)
O14ACo1AO19 111.3(1) Cu1AO8ACu2 112.78(6) O14AZn1AO19 110.49(7)
O1AC1AO2 126.4(2)

Table 3
Hydrogen bonds dimensions (Å and °) in the crystal structure of complexes 1–3.

DAH  A d(DAH) d(H  A) <(DHA) d(D  A) Symmetry code on A atom
1 O(5)AH(5)  O(14) 0.820 1.932 153.5 2.691(4) 1 + x, 1 + y, z
3 C(14)AH(14B)  O(19) 0.970 2.488 164.2 3.431(3) 1 + x, 1 + y, z
O(5)AH(5)  O(14) 0.820 1.885 164.7 2.685(3) 1 + x, 1 + y, z

tion of 0.302 g (1 mmol) of ((propane-1,3-diylbis(oxy))bis(2,1-phe-
nylene))dimethanamine (prepared according to the literature [1])
in the same solvent (20 mL). The reaction mixture was refluxed
for four hours and the product was filtered. Yield: 0.4 g, 67%; m.
p. 207 °C. Anal. Calc. for C31H28N4O9 (600.58): C, 62.00; H, 4.70;
N, 9.33. Found: C, 62.24; H, 4.76; N, 9.40%. IR (KBr, cm1): 3380
m (m OAH), 3060 m (mCAHar), 2927 m (mas CH2 and/or m CAH),
2871 m (ms CH2), 1651 m (mC@N), 1547 m (mas NO2), 1495 m (m
C@Car), 1450 m (das CH2), 1365 w (ds CH2), 1319 s (ms NO2), 1249
m (mas CAOACether), 1123 m (ms CAOACether), 1091 s (m CAN). 1H
NMR (400 MHz, DMSO-d6, ppm, Hz): d = 8.8 (s, 2H, OHphenol), 8.4)
s, 2H, CdH), 6.5–8.0)m, 14H, CHar), 4.9)s, 5H, CcH and OHalcohol),
4.4)m, 1H, CaH), 4.2)m, 4 H, CbH). 13C NMR (400 MHz, DMSO-d6,
ppm, Hz): d = 178.2 (C@N), 167.4 (CAOH), 157.1 (CANO2), 112.2–
134.3 (10 Car), 69.8 (Cb), 67.8 (Ca), 52.1 (Cc).
2.1.2. Synthesis of [Co(HL)] (1)
((Propane-1,3-diylbis(oxy))bis(2,1-phenylene))dimethanamine
(0.30 g, 1 mmol) was dissolved in methanol (10 mL) on heating
with successive addition of a methanolic solution (10 mL) of 2-
hydroxy-5-nitrobenzaldehyde (0.33 g, 2 mmol) and Co(OAc)24H2-
O (0.25 g, 1 mmol). The reaction mixtures were stirred for 4 h
under reflux and allowed to stand at room temperature. The
obtained solid was collected by filtration, washed with methanol,
and dried in air. The precipitate was recrystallized in mixture of
chloroform and methanol. After a few days, single crystals suitable
for X-ray data analysis were obtained from this solution. Yield:
0.28 g, 43%; decomposed at 280 °C. Anal. Calc. for C31H26CoN4O9
(657.49): C, 56.63; H, 3.99; N, 8.52. Found: C, 56.75; H, 4.06; N,
8.64%. IR (KBr, cm1): 3429 m (m OAH), 3016 w (m CAHar), 2924
w (mas CH2 and/or m CAH), 2848 w (ms CH2), 1604 s (m C@N), 1551
m (mas NO2), 1497 m (m C@Car), 1462 m (das CH2), 1398 w (ds
CH2), 1312 s (ms NO2), 1249 m (mas CAOACether), 1103 m (ms
CAOACether), 1038 m (m CAN).
2.1.3. Synthesis of [Cu2(L)(l-1,3-OAc)] (2)
The procedure for synthesis of 2 was similar to 1 except that Co
(OAc)24H2O was replaced by Cu(OAc)24H2O (0.25 g, 1 mmol).
Yield: 0.45 g, 58%; decomposed at 265 °C. Anal. Calc. for C33H27Cu2-
N4O11 (782.67): C, 50.64; H, 3.48; N, 7.16. Found: C, 50.68; H, 3.44;
N, 7.19%. IR (KBr, cm1): 3425 m (m OAH), 3016 m (m CAHar), 2924
w (mas CH2 and/or m CAH), 2870 w (ms CH2), 1647 m (mas COO), 1605
m (m C@N), 1550 m (mas NO2), 1475 m (m C@Car), 1448 m (das CH2),
1385 w (ds CH2), 1319 m (ms NO2 and/or ms COO), 1245 m (mas
CAOACether), 1099 m (ms CAOACether), 1033 w (m CAN), 650 m (d
OCO).
2.1.4. Synthesis of [Zn(HL)] (3)
The procedure for synthesis of 3 was similar to 1 except that Co
(OAc)24H2O was replaced by Zn(OAc)22H2O (0.22 g, 1 mmol).
Yield: 0.30 g, 46%; decomposed at 240 °C. Anal. Calc. for C31H26N4-
O9Zn (663.93): C, 56.08; H, 3.95; N, 8.44. Found: C, 56.15; H, 3.97;
N, 8.49%. IR (KBr, cm1): 3425 m (m OAH), 3062 w (m CAHar), 2916
w (mas CH2 and/or m CAH), 1631 s (m C@N), 1551 m (mas NO2), 1497
m (m C@Car), 1465 m (das CH2), 1316 s (ms NO2), 1250 m (mas
CAOACether), 1103 m (ms CAOACether), 1034 m (m CAN). 1H NMR
(400 MHz, DMSO-d6, ppm, Hz): d = 8.6)s, 2H, CdH), 6.5–8.3)m,
14H, CHar), 4.3–4.4)d, 5H, CcH and OHalcohol), 4.1)m, 5H, CaH and
CbH).
2.2. Crystal structure determination
For the synthesized complexes, data were collected on a Bruker
Kappa diffractometer with graphite monochromated Mo Ka
(k = 0.71073 Å). After data collection, in each case, an empirical
absorption correction was applied. The structures were then solved
by direct methods and refined on all F2. In all cases, non-hydrogen
atoms were refined with anisotropic thermal parameters. Hydro-
gen atoms were included in calculated positions and refined with
isotropic thermal parameters (ca. 1.2  (aromatic CH) or 1.5 
(Me, CH2, OH) the equivalent isotropic thermal parameters of their
parent carbon atoms). The data were corrected for Lorentz and
polarization effects. Bruker Saint Plus, including X-RED and X-
Shape (for data reduction and absorption correction) and the SHELX
and OLEX program suites [58] were used. Molecular structures and
unit cell diagrams were created using Ortep-III [59,60] and Dia-
mond [61] software. Details of crystal data, data collection, struc-
ture solutions and refinements are given in Table 1. Selected
bond lengths and angles of complexes are listed in Table 2. Hydro-
 L. Saghatforoush et al. / Polyhedron 170 (2019) 312–324 315

Fig. 1. ORTEP diagram of the molecular structure of 1. The ellipsoids are drawn at the 20% probability level. Hydrogen atoms are omitted for clarity.

gen bond geometries in the measured crystal structure of com-

pounds are given in Table 3.

2.3. Computational details

Geometry optimization and natural bond orbital (NBO) calcula-

tions were performed using Gaussian 09 software [62]. Density
functional theory (DFT) [63] calculations at B3LYP/LanL2DZ level
of theory were carried out without imposing molecular symmetry
constraints to obtain ground state structure of the isolated mole-
cules. Harmonic vibrational wavenumbers were calculated to con-
firm that no imaginary frequencies were predicted and the
calculated structures are converged to the minima on the potential
surface. NBO analyses were done at the same level of theory.
Molecular structures of the complexes, obtained by single crystal
X-ray diffraction analyses, were used as input file for calculations.
2.4. Docking details
The pdb files 4r5y, 3ai8, 5cdn, 3c0z, 2bx8, 1peo, 3qfa, 1njb, 4gfh,
1bna (respectively for the BRAF kinase, Cathepsin B (CatB), DNA
gyrase, Histone deacetylase (HDAC7), recombinant Human albu-
min (rHA), Ribonucleotide reductases (RNR), Thioredoxin reduc-
tase (TrxR), Thymidylate synthase (TS), Topoisomerase II (Top II),
B-DNA receptors used in this study) were obtained from the Pro-
tein Data Bank (pdb) [64]. The full version of Genetic Optimisation
(a)
Scheme 2. The average values of coordination bond lengths found in CSD for all
cobalt complexes with the presented coordination moiety.
for Ligand Docking (GOLD) 5.5 [65] was used for the docking. The
Hermes visualizer in the GOLD Suite was used to further prepare
the ligand, complexes and the receptors for docking. The cif files
of the complexes and the optimized structure of ligand were used
for docking studies. The region of interest used for Gold docking
was defined as all the protein residues within 6 Å of the reference
ligand ‘‘A” that accompanied the downloaded protein. For B-DNA,
the region of interest was defined on DNA backbone within 10 Å
of the O2, DT19 atoms for minor grave. All free water molecules
in the structure of the proteins were deleted before docking.
Default values of all other parameters were used and the com-
pounds were submitted to 10 genetic algorithm runs using the
GOLDScore fitness function.

Fig. 2. Hydrogen bonds in the crystal packing of 1. CoN2O2 units are shown as tetrahedrons. Only the hydrogen bonded H atoms are shown.
316 L. Saghatforoush et al. / Polyhedron 170 (2019) 312–324

2.5. Biological evaluation

2.5.1. Materials
Fetal bovine serum (FBS), propidium iodide (PI), acridine orange
(AO) and 3-(4,5-dinethylthiazol-2-yl)-2,5-diphenyl tetrazolium
bromide (MTT) were obtained from Sigma-Aldrich. RPMI-1640
medium was obtained from Gibco (UK). Dimethyl sulfoxide
(DMSO) was obtained from Merck. Fluorescent studies were done
by fluorescent microscope (OLYMPUS, USA).

2.5.2. Cell culture and treatments

Fig. 3. ORTEP diagram of the molecular structure of 2. The ellipsoids are drawn at
the 20% probability level.
Human leukemia cell line K562 and its adriamycin-selected
multidrug resistant subline K562/ADM were obtained from the
Pasteur Institute of Iran. All the cell lines were grown in RPMI
1640 medium containing 10% bovine serum (FBS), 100 U/mL peni-
cillin and 100 lg streptomycin (BIOCERA) at 37 °C in a humidified
5% CO2 incubator. Before being used, adriamycin (1 mg/L) was
added to K562/ADM cultures and kept in the drug-free medium
at least for two weeks to maintain MDR phenotype. The com-
pounds were dissolved in 180 lL of DMSO for in vitro assays.
2.5.3. The MTT assay
Cells were cultured at a density of 1  104/100 lL in a 96-well
plate and allowed to attach overnight. After incubated for 48 h

Fig. 4. Hydrogen bonds in the crystal packing of 2. CuNO4 units are shown as square-pyramids. Only the hydrogen bonded H atoms are shown.

Fig. 5. ORTEP diagram of the molecular structure of 3. The ellipsoids are drawn at the 20% probability level. Hydrogen atoms are omitted for clarity.
 L. Saghatforoush et al. / Polyhedron 170 (2019) 312–324 317

Fig. 6. p–p stacking (aqua color) and hydrogen bonds in the crystal packing of 3. ZnN2O2 units are shown as tetrahedrons. Only the hydrogen bonded H atoms are shown.
(Color online.)

(10 lL) and PI (10 lL) in the dark. After mixing the suspension with
a solution of AO/PI, analysis was performed under a fluorescence
microscope. While a green fluorescence shows apoptosis, a red col-
ored nucleus indicates necrotic cells.

3. Results and discussion

The Schiff base ligand H3L was prepared by condensation of 2-

Scheme 3. The average values of coordination bond lengths found in CSD for all
zinc complexes with the presented coordination moiety.
and 72 h with the titled chemicals, the cells were treated with the
MTT solution (5 mg/mL) at 37 °C for 4 h. The absorbance was mea-
sured at 498 nm using a microplate reader (Multiskan Spectrum,
Thermo Scientific). The inhibition rates were calculated on a
plate-by-plate basis for the test wells. The IC50 values were calcu-
lated using Bliss’ method based on the inhibitory rate curves.
2.5.4. AO/PI staining assay
Briefly, after treated with compounds for 24 h, K562 cells were
harvested, centrifuged at 400 rpm for 10 min and washed in PBS.
Then 1 mL of the suspension was incubated for 15 min with AO
hydroxy-5-nitrobenzaldehyde with diamine precursors in a 2:1
molar ratio. Three coordination complexes of this ligand were syn-
thesized by template condensation of the mentioned aldehyde and
diamine in the presence of the M(OAc)2 (M is Co (1), Cu (2) and Zn
(3)). The complexes are air-stable and soluble in DMSO.
3.1. Spectroscopic characterization
In the IR spectrum of the H3L, the broad absorption band at
3380 cm1 is due to the stretching vibration of the alcoholic func-
tional group, m (OAH), which is shifted to the higher frequencies
(45–49 cm1) after complexation. The weak bands observed at
above and below 3000 cm1 reveal, respectively, the aromatic
and aliphatic moieties in the molecular structure of all compounds.
Compared to that found for free ligand, the m (C@N) vibration band
is shifted to the lower frequencies (4–47 cm1) in the IR spectra of

Table 4
p–p stacking interactions dimensions (Å and °) in complexes 1–3.
Centroid–centroid distance Angle between the planes Perpendicular distance Slippage Type
1 3.749 6.37 – – Intramolecular
2 3.652 0.35 – – Intermolecular
3 3.743 6.14 – – Intramolecular
3.671 6.14 – – Intermolecular

Table 5
The NBO analysis results for the H3Lopt and complexes 2opt and 3opt. The values are the total of charge on the similar atoms. The values of parentheses show the variation of charge
on the atoms after coordination.

C COAc H HOAc N NNO2 O ONO2 OOAc Metal

H3Lopt –2.21 – 7.20 – 0.91 0.89 3.45 1.52 – –
2opt 1.88 0.18 5.69 0.72 1.10 0.87 3.26 1.59 1.45 1.82
(+0.33) (1.51) (0.19) (0.02) (+0.19) (0.07) (0.91 per each copper)
3opt 1.91 – 6.12 – 1.31 0.87 3.66 1.58 – 1.46
(+0.30) (1.08) (0.40) (0.02) (0.21) (0.06)
318 L. Saghatforoush et al. / Polyhedron 170 (2019) 312–324

Fig. 7. Optimized molecular structure of free gaseous H3L ligand.

complexes, confirming the coordination of imine nitrogen to the

metal centers. In the FT-IR spectra of the H3L and the complexes,
two bands were found at about 1550 and 1315 cm1 which can
be attributed, respectively, to the asymmetric and symmetric
stretching vibration of the nitro groups. The vibration bands mea-
sured at about 1250 and 1100 cm1, respectively, can be assigned
to the asymmetric and symmetric stretching vibrations of the ether
functional groups in these compounds.
In the FT-IR spectrum of 2, three bands at about 1640, 1320 and
650 cm1 (which are attributable to the mas (COO), ms (COO) and d
(OCO), respectively) confirm the presence of the acetato ligand in
the molecular structure of the compound. The difference (D value)
between the observed mas (COO) and ms (COO) wave numbers in the
IR spectrum of the corresponding metal complex reveals the coor-
dination mode of the acetate ligand. In coordination complexes
with monodentate acetato ligand, the D value is much greater than
that observed for acetate salt (164 cm1); however, when acetate
ion acts as a bidentate ligand in complexes, the measured D values
are significantly less than that for acetate salt [66,67]. The mea-
sured D value for 2 is 328 cm1 which is in consistent with a
pseudo-monodentate acetato ligand [68].
To interpret the NMR spectra, some of the carbon atoms in the
molecular structure of the ligand are marked in Scheme 1. In the
NMR spectrum of the free ligand, the proton signal attributable
to the phenolic hydrogen atoms is observed at the lowest magnetic
field. The signal is disappeared in the spectrum of the 3, confirming
the deprotonation of the phenolic groups during the complexation
process. Also, the signals which can be assigned to the aromatic
and imine protons are found in the downfield region of the mea-
sured spectra. The aliphatic protons are observed at the range of Fig. 8. Docking study results, showing the interaction between H3L and B-DNA
4–5 ppm. The 13C NMR spectrum, measured for free ligand, shows (minor grave).
sixteen distinct bands assigned to aromatic and aliphatic carbon
atoms in the molecular structure of the compound.

Table 6
The calculated fitness values for free H3L ligand and complexes 1–3.

B-DNAs/Min BRAF-Kinase CatB DNA-Gyrase HDAC7 rHA RNR TrxR TS Top II

H3L 93.05 68.99 50.14 54.82 70.64 70.40 68.56 83.28 76.29 71.07
Complex 1 44.37 38.50 32.94 39.59 39.59 23.14 51.17 0.47 53.65 54.88
Complex 2 68.49 51.19 37.72 39.42 31.29 26.62 42.51 34.68 51.73 18.90
Complex 3 44.91 31.17 26.46 40.15 39.38 22.70 50.19 43.41 58.55 51.66
 L. Saghatforoush et al. / Polyhedron 170 (2019) 312–324
3.2. Description of the crystal structures
3.2.1. Crystal structure of [Co(HL)] (1)
In the crystal structure of 1 (Fig. 1), the cobalt cation is tetraco-
ordinated by two nitrogen (N10 and N18) atoms of the imine moi-
eties and two phenolate oxygen atoms (O14 and O19) of the
deprotonated ligand (HL2). In tetracoordinated cobalt complexes,
donor atoms may arrange either in a tetrahedral or a square planar
configuration around the metal ion. To determine the coordination
geometry of the cobalt ion in this complex, the angular structural
parameter ssq was calculated using the formula introduced by
Hakimi et al. [69]. The index of tetragonality (ssq) is defined by
(hmaxhmin)/90, where hmax and hmin are the maximum and mini-
mum bond angles, respectively. For an ideal square plane,
hmax = 180° and hmin = 90° and ssq = 1; however, an ideal tetrahe-
dron will have hmax = 109.28°, hmin = 109.28° and therefore ssq = 0.
The calculated ssq value for complex 1 is 0.31, indicating a propen-
sity to a tetrahedral geometry (Figs. 1 and 2). The average values
found for CoAO and CoAN bond lengths in 1 (1.923 and 1.986 Å,
respectively) are slightly longer than the average bond distances
(1.877 and 1.940 Å for the CoAO and CoAN, respectively; see
Scheme 2) found in Cambridge structural database (CSD) [70].
In the molecular structure of this complex, the deprotonated
(HL)2 Schiff base acts as a tetradentate ligand and forms two
Fig. 9. Docking study results, showing the interaction between complex 1 and B-DNA (minor grave).
319
six-membered and one 14-membered chelate ring. When cobalt
complexes of macrocyclic ligands were excluded from the search
results, the formation of a 14-membered chelate ring around the
cobalt atom is very rare and only two examples were found in
CSD [15,71]. One of the six-membered chelate rings in the molec-
ular structure of 1 is planar (with the r.m.s. value of 0.028 Å calcu-
lated for the Co atom while another is the non-planar (with r.m.s.
value of 0.174 Å calculated for the Co1 atom). The difference in the
planarity of these chelate rings may be caused by dissimilarity in
the respective coordination bond angles. It is found that N(18)A
Co(1)AO(19) angle in the non-planar chelate ring is 2.42° smaller
than the N(10)ACo(1)AO(14) in planar ring.
3.2.2. Crystal structure of [Cu2(L)(l-1,3-OAc)] (2)
In the binuclear complex 2 (Fig. 3), all OAH groups in H3L are
deprotonated and L3 acts as a heptadentate ligand. The metal
centers in this complex are five-coordinated and bonded to
one nitrogen atom coming from the adjacent imine group and
four oxygen atoms. Each metal ion is coordinated by one pheno-
late and one ether oxygen atoms. The oxygen atom from the
deprotonated pendant alcoholic group (O8) bridges the Cu(II)
centers in the molecular structure of the 2. Also, each oxygen
atom from a bridging acetate ligand is coordinated to one metal
320 L. Saghatforoush et al. / Polyhedron 170 (2019) 312–324
Fig. 10. Docking study results, showing the interaction between complex 2 and B-DNA (minor grave).
ion in the complex. The pentacoordinated metal ions in 2, may
adopt either a square pyramidal or a trigonal bipyramidal
geometry which could be determined by applying the formula
presented by Addison et al. [69,72]. The angular structural
parameter, s (s = (b  a)/60, where a and b are the two largest
angles at the copper atom and b  a), was calculated to be
0.39 and 0.17, respectively for Cu1 and Cu2 atoms. Therefore,
both copper(II) centers are surrounded by donor atoms in a dis-
torted square pyramidal coordination geometry (Figs. 3 and 4).
Copper ions form the longest CuAO bond lengths with ether
oxygen atoms in complex 2. The L3 ligand forms four six-mem-
bered and two five-membered chelate rings in the molecular
structure of 2.
3.2.3. Crystal structure of [Zn(HL)] (3)
X-ray analysis of compound 3 revealed a zinc complex (Fig. 5)
with N2O2 coordination environment which is isostructural with
complex 1. The metal ion is coordinated by donor atoms in a dis-
torted tetrahedral geometry (the calculated ssq is 0.29) (Figs. 5
and 6). The average values of the measured ZnAN and ZnAO bond
lengths (1.993 and 1.936 Å, respectively) are comparable with the
respective CSD average values (Scheme 3).
Coordination of Zn(II) ions in complex 3 by the tetradentate
(HL)2 ligand, results in two six-membered and one rarely
observed 14-membered chelate ring. With the exception of zinc
complexes of macrocycles, only two examples were found in CSD
for zinc included 14-membered chelate rings [15,73]. The planarity
of the six-membered chelates in 3 are comparable with that found
for the cobalt(II) complex (1). While one of these rings is planner in
complex 3 (with r.m.s. value of 0.037 Å for the Zn atom), the other
ring very slightly deviates from planarity (calculated r.m.s. value of
0.178 Å for the Zn atom).
3.2.4. Crystal network interactions
In the crystal network of the compounds (Figs. 2, 4 and 6) inter-
molecular CAH  O (3) and OAH  O (1 and 3) hydrogen bonds
appear between adjacent complexes. In such weak interactions,
the oxygen atoms simultaneously participate as proton donors
and acceptors in hydrogen bonding; however, the carbon atoms
act as proton donors. In addition to the hydrogen bonds, the crystal
networks of the compounds are further stabilized by inter and
intra molecular p–p stacking interactions (Table 4) between aro-
matic rings [74,75] (Figs. 2 and 6). The H3L ligand may be consid-
ered to have two arms and each one possesses two aromatic
rings one in the middle and the other in the end of the arm. In 3,
ligand arms are twisted in a way that p–p stacking interactions
are formed between a terminal phenyl from one arm and the mid-
dle phenyl on the other one. Coordination behavior of the ligand
may be affected by such intra molecular p–p stacking interactions.
Also, in the crystal packing of 3, intermolecular p–p interactions
were found between the resting two phenyl rings. In the crystal
packing of compound 2, intermolecular p–p stacking interactions
were found between two middle aromatic rings from adjacent
complexes. As could be deduced from the geometrical parameters
 L. Saghatforoush et al. / Polyhedron 170 (2019) 312–324 321

Fig. 11. Docking study results, showing the interaction between complex 3 and B-DNA (minor grave).

Table 7 It was revealed that, for complexes, the calculated charge on the
Concentrations of H3L and its complexes in which a 50% decrease in K562 cell survival metal atoms (+0.91 and +1.46 for copper and zinc atoms, respec-
(expressed as IC50 (lg/ml)) is induced. The compounds were incubated with cells for
tively) is lower than the formal charge of the ion (+2) owing to
24, 48 and 72 h. mean ± SD IC50 values determined from three independent
experiments are presented. the electron donation of the ligand. Upon coordination, the calcu-
lated charge on the copper ion is remarkably decreased compared
Compounds 24 h 48 h 72 h
to that on the zinc center. It is notable that, the formal charges of
H3L 5.33 ± 0.32 5.34 ± 0.38 4.01 ± 0.52 two Cu(II) ions in complex 2 are compensated by one L3 Shiff base
Complex 1 1.85 ± 0.12 1.91 ± 0.10 1.80 ± 0.01
ligand and one acetate ligand, while in the molecular structure of 3
Complex 2 2.14 ± 0.52 2.50 ± 0.36 3.61 ± 0.37
Complex 3 4.25 ± 0.22 4.73 ± 0.19 2.55 ± 0.13 one Zn(II) ion is coordinated only by one HL2 ligand. On the other
hand, coordination geometry and the coordinated donor atoms
may affect the charge on metal ion in complex. It should be
of the p–p interactions in 2 (see Table 4), they are expected to be reminded that, the pentacoordinated Cu(II) ion in complexes 2
stronger than those observed for compounds 1 and 3. and the tetracoordinated Zn(II) in 3 are coordinated by different
donor atoms set. In complex 2, the calculated total charge on the
acetate ligand (0.55) is lower than its formal charge (1), indicat-
3.3. Theoretical studies
ing the electron flow from this ligand to the copper ion. The elec-
tron withdrawing nitro groups in metal coordinated ligands are
NBO analyses were done (Table 5) on free gaseous molecules of
calculated to be more negative than those in free ligand. Compared
H3L, 2 and 3 to study the atomic charge distribution before and
to the H3L, the calculated charges on ligand carbon atoms are more
after complexation of the ligand. All molecules were geometry
positive in complexes. The calculation results reveal that ligand
optimized before calculations. Fig. 7 presents the optimized molec-
carbon atoms play an important role in electron donation toward
ular structure of H3L. For the geometry optimized free gaseous
metal centers in complexes which decrease the positive charge
complex 2, s was calculated to be 0.03, indicating that metal ions
on the coordinated metal ions. Similar results have been reported
have perfect square-pyramidal coordination geometry. Similar to
previously [53,74].
the X-ray crystal structure analysis results, the calculated
CuAOEther bonds are the longest coordination bonds in the opti-
mized molecular structure. The calculated ssq value for the opti- 3.4. Docking studies
mized free gaseous 3, is 0.36. Therefore, similar to the observed
molecular structure of 3 in solid state, the coordination sphere For predicting the biological activities of free H3L ligand and its
around Zn(II) in gaseous phase inclines to a tetrahedral geometry. complexes, interactions of these compounds with ten macromolec-
322 L. Saghatforoush et al. / Polyhedron 170 (2019) 312–324

Table 8
Morphological changes of K562 cells after 48 h treatment with IC50 concentrations of H3L and complexes 1–3. The cells were stained with acridine orange and propidium iodide
and examined by a fluorescence microscope. The presence of early and late apoptosis along with the necrosis of K562 cells could be seen. (a): H3L, (b): complex 1, (c): complex 2,
(d): complex 3.

Cells after exposure to

Column graph Normal cells
compounds

(a)

(b)

(c)

(d)
 L. Saghatforoush et al. / Polyhedron 170 (2019) 312–324
ular receptors were studied using Gold [65] docking software. The
Gold docking results are reported in terms of the values of fitness,
where the higher fitness value means better docking interaction of
the compound [49,53,54]. Here, we report the best binding results
out of ten favorites predicted by Gold.
According to the Gold docking prediction results (Table 6), all
studied compounds can be considered as biologically active mate-
rials [49,53,54]. The best predicted target for H3L and the com-
plexes is TrxR and TS, respectively. Data listed in Table 6 reveal
that the compounds can place in the minor graves of the DNA
molecule and are good choices for DNA binding studies. Figs. 8–
11, respectively, represent the docking results for the interaction
between the synthesized compounds (free H3L and complexes 1–
3) and B-DNA (minor grave).
3.5. Biological screening
The in vitro cytotoxicity of H3L and its complexes on the human
cancer cell line K562 was evaluated. Results are expressed as the
IC50 values and are summarized in Table 7. The MTT assay indi-
cated that the compounds exerted significant cytotoxic effects
against K562 cell lines. By comparing the results with those
reported in the literature, it is found that the in vitro cytotoxicity
of the complexes are higher than (complex 1) or comparable with
(complex 2) the values reported for cisplatin (IC50 2.247 lg/ml for
72 h) [76]. The cytotoxic effects of the complexes 1–3 are higher
than that of free ligand. Therefore, the biological activities of the
ligand increases by binding to a metal center as observed previ-
ously [15,49]. The cytotoxic activity of the studied compounds
increases in the order of Co > Cu > Zn complexes.
Morphological characteristics of the K562 cells were analyzed
using fluorescence microscopy after double staining of the cells
with acridine orange (AO) and propidium iodide (PI) to determine
the type of cell death induced by the synthesized compounds. Mor-
phological features of apoptosis (such as chromatin condensation,
nuclear fragmentation and alterations in the size and the shape of
cells) were screened after 48 h treatment with IC50 concentrations
of the compounds. Also, the features of late apoptosis were clearly
expressed; the DNA was fragmented and stained orange and red.
As shown in Table 8, the percentage of early apoptotic cells after
treatment with complex 2 for 48 h is higher than the other com-
pounds (44%). Among the four tested compounds, H3L and complex
1 show significant ability to induce, respectively, secondary apop-
tosis (52%) and necrosis (58%) in K562 cells.
4. Conclusion
The compartmental Schiff base 2,20 -((((((2-hydroxypropane-
1,3-diyl)bis(oxy))bis(2,1-phenylene))bis(methylene))bis(azanylyli-
dene))bis(methanylylidene))bis(4-nitrophenol) (H3L) and the
respective coordination complexes [Co(HL)] (1), [Cu2(L)(l-1,3-
OAc)] (2) and [Zn(HL)] (3), were synthesized. The compounds were
characterized by IR, 1H and 13C NMR spectroscopic techniques and
single crystal X-ray diffraction analysis. As revealed by X-ray
diffraction studies, the metal ion in complexes 1 and 3 has tetrahe-
dral coordination geometry. The ligand molecule in these com-
pounds forms two six-membered and one 14-membered chelate
rings which is very rare in the CSD. Compound 2 is a binuclear cop-
per complex in which the metal ions have square pyramidal coor-
dination geometry.
In addition to the hydrogen bonds in the crystal packing of the
complexes, p–p stacking interactions were found between aro-
matic rings. Such weak intermolecular interactions are indicative
of high capability of these molecules to interact with neighboring
units, suggesting that they could be suitable candidates for docking
323
studies. It is found by docking calculations on three titled com-
pounds that they might be biologically active due to interacting
with the nine biomacromolecules (BRAF kinase, CatB, DNA gyrase,
HDAC7, rHA, RNR, TrxR, TS, Top II and B-DNA). According to our
predictions, TrxR and Ts is the best target, respectively, for free
ligand and complexes. The in vitro investigations revealed that all
compounds are biologically active; however, the synthesized com-
plexes are more cytotoxic than the free ligand. For the metal com-
plexes, the highest and lowest cytotoxic activity was observed for
cobalt and zinc compound, respectively. The experiments revealed
that the cytotoxicity of the nitro substituted complexes is higher
than (found for complex 1) or comparable with (observed for com-
plex 2) the cisplatin. According to the NBO analyses of the DFT opti-
mized free gaseous complexes, the carbon atoms in the molecular
structure of the compounds act as electron donors and decrease
the positive charge on the metal atom.
Acknowledgements
We acknowledge the financial support from the Council of the
Payame Noor University, Iran and Spanish Ministerio de Economía
y Competitividad (MAT2016-78155-C2-1-R and FPI grant BES-
2011-046948 to MSM.A.) and FEDER funding. The authors thank
Prof. Dr K. Adil from Universite du Maine, Institut des Molecules
et Materiaux du Mans, Le Mans Cedex, France for the X-ray crystal-
lography data collection.
Appendix A.
CCDC 1828805, 1828803 and 1828804 contains the supplemen-
tary crystallographic data for 1–3. These data can be obtained free
of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or
from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail:
deposit@ccdc.cam.ac.uk.
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