Synthesis, characterization, in vitro cytotoxicity activity, and molecular docking studies of mononuclear and binuclear Macroacyclic Schiff base complexes

Article abstract of DOI:10.1016/j.poly.2021.115380

A number of binuclear and mononuclear macroacyclic Schiff base complexes containing piperazine moieties were synthesized. The binuclear complexes (M₂L₁) characterized by elemental analysis, IR and, also Ni(II) complex by a X-ray single crystal structural analysis. In this case, X-ray showed that each nickel atom is in a mer-N₃O₃ octahedral coordination environment. Moreover, mononuclear macroacyclic Schiff base complexes (ML₂ and ML₃) were prepared based on the condensation reaction of an amine containing piperazine moiety and 2-hydroxy banzaldehyde or formyl pyridine in 1:2 mol ratio in the presence of Ni(II), Cu(II), and Co(II) ions. All of compounds were characterized by elemental analyses, FT-IR, mass spectrometry and ligands characterized by ¹H and ¹³C NMR spectroscopy. The cytotoxicity of the complexes was evaluated against two different cancer cell lines including MCF-7 (breast) and A549 (lung) adenocarcinoma cells. In general, binuclear complexes, possesses a higher cytotoxic effect against the tested cells than the other complexes. In addition, the biological assessment of complexes have been examined via molecular docking. As an interesting results, the binuclear complexes have the highest inhibition effect against cytotoxic receptors.

Full text of DOI:10.1016/j.poly.2021.115380

Polyhedron 207 (2021) 115380
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Synthesis, characterization, in vitro cytotoxicity activity, and molecular
docking studies of mononuclear and binuclear Macroacyclic Schiff
base complexes
a
,
*
a
a
a
Hassan Keypour , Fatemeh Forouzandeh , Saadat Hajari , Mahdi Jamshidi ,
b
c
Seyed Hamed Moazzami Farida , Robert William Gable
a
Faculty of Chemistry, Bu-Ali Sina University, Hamedan 65174, Iran
b
Department of Biology, Faculty of Science, Bu-Ali Sina University, Hamedan 65174, Iran
c
School of Chemistry, University of Melbourne, Victoria 3010, Australia
A R T I C L E I N F O
A B S T R A C T
Keywords:
A number of binuclear and mononuclear macroacyclic Schiff base complexes containing piperazine moieties
were synthesized. The binuclear complexes (M ) characterized by elemental analysis, IR and, also Ni(II)
complex by a X-ray single crystal structural analysis. In this case, X-ray showed that each nickel atom is in a mer-
octahedral coordination environment. Moreover, mononuclear macroacyclic Schiff base complexes (ML
and ML ) were prepared based on the condensation reaction of an amine containing piperazine moiety and 2-hy-
Piperazine
Macroacyclic
Mononuclear
Binuclear
2 1
L
N
3
O
3
2
3
Cytotoxic
droxy banzaldehyde or formyl pyridine in 1:2 mol ratio in the presence of Ni(II), Cu(II), and Co(II) ions. All of
compounds were characterized by elemental analyses, FT-IR, mass spectrometry and ligands characterized by 1H
and 13C NMR spectroscopy. The cytotoxicity of the complexes was evaluated against two different cancer cell
lines including MCF-7 (breast) and A549 (lung) adenocarcinoma cells. In general, binuclear complexes, possesses
a higher cytotoxic effect against the tested cells than the other complexes. In addition, the biological assessment
of complexes have been examined via molecular docking. As an interesting results, the binuclear complexes have
the highest inhibition effect against cytotoxic receptors.
1
. Introduction
2 2 2 3
ligands H L and H L bearing only one piperazine moiety and their Ni
(
II), Cu (II), and Co (II) complexes. These complexes were characterized
There have been two significant reasons behind extensive analyses
by several physicochemical techniques. Due to the rapid climate changes
and in our daily life habits, we witness a worldwide rise in the number of
cancer diseases as the main cause of death [17–18]. As a drug to destroy
the cancer cells, chemotherapy has been widely used to treat various
kinds of cancers [19–20]. It is worth mentioning that although, in
chemotherapy, we have the prescription of metal-based drugs, cancer
cells are still resistant to such drugs which can be regarded as its
fundamental drawback [21]. Accordingly, a wide variety of attempts has
been devoted to design metal complexes and discover novel metal drugs
[22]. Following the same line of thought, designing new complexes
which would be able to treat the infected cells and kill cancer tumors is
fundamentally significant. Consequently, the recent synthesis of the
above mentioned complexes would be greatly affective. Herein, the
cytotoxicity properties of the complexes in vitro Bioinformatics
approach has been applied to identify the pharmaceutical features of the
on the Schiff base complexes, i.e. selectivity and structural variety [1].
As chelating ligands, Schiff base complexes which can be applied in
coordination chemistry are derived from salicylaldehydes and poly-
amines [2]. It is worth mentioning that these complexes can be applied
in a wide variety of clinical [3], analytical [4], industrial [5] and bio-
logical [6] fields. Moreover, they can also be used in organic synthesis
and as catalysis [7]. Significantly, design of macroacyclic and macro-
cyclic novel bioactive agents, can greatly be affected by the presence of
Piperazine moieties [8]. During last decade, our attempt has been
focused on designing and development of novel Schiff base ligands
containing the piperazine moiety [9–15]. In this paper, we report a
number of novel bimetalic Schiff base complexes containing two
2
+
2+
piperazine moieties M2: L1 complexes) M = Cu and Ni ). Further-
more, in this work we also report the synthesis of two new Schiff base
*
Corresponding author.
E-mail address: haskey1@yahoo.com (H. Keypour).
https://doi.org/10.1016/j.poly.2021.115380
Received 30 March 2021; Accepted 16 July 2021
Available online 21 July 2021
0
277-5387/© 2021 Published by Elsevier Ltd.

H. Keypour et al.
Polyhedron 207 (2021) 115380
Table 1
2.3. X-ray crystallography
2 2 4 3 2 3
Crystal data and structure refinement for [Ni HL(H O) (CH CN) ]Cl .
2 2 4 3 2 3
Pale yellow single crystals of [Ni (HL)(H O) (CH CN) ]Cl were
Crystal data
crystallized by the slow vapour diffusion of diethyl ether into an
acetonitrile solution. Data were collected at 100 K at the MX beamline
Identification code
rwg2018_F29_252R
2 6
8.5Ni O
2
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
a/Å
C
33
H54.5Cl
3
N
at the Australian Synchrotron, fitted with a silicon double crystal
monochromator and Dectris Eiger 16 M detector, the wavelength being
890.12
100.0019(2)
Monoclinic
tuned to approximate Mo-K
reduction was performed with XDS [29] using medium multi-scan ab-
sorption correction in SADABS [30]. Using Olex [31], the structure was
α radiation (λ = 0.71091 Å) [28]. Data
1
P2 /c
7.5190(15)
25.634(5)
23.866(5)
90
2
b/Å
solved with the ShelXT [32] structure solution program using Intrinsic
Phasing and refined with the ShelXL [33] refinement package using
c/Å
◦
◦
◦
α
/
2
β/
92.29(3)
90
Least Squares minimization on F , using all data. All non-hydrogen
γ/
atoms were refined with anisotropic displacement parameters, while all
hydrogen atoms were placed at geometrical estimates and refined using
the riding model. Charge balance indicates that the ligand is protonated,
with bond lengths indicating that the hydrogen atom is localized on one
3
Volume/Å
4596.3(16)
4
Z
3
ρ
calcg/cm
1.286
ꢀ
1
μ/mm
1.040
F(000)
1868.0
4
of the non-coordinating piperazine nitrogen atoms, N . The difference
3
Crystal size/mm
Radiation
0.02 × 0.01 × 0.01
MoK
(λ = 0.71091)
5.066 to 56.58
electron density map showed a number of peaks due to disordered/
diffuse solvent which was modelled using the solvent mask routine in
α
2
Θ range for data collection/◦
2
OLEX ; the volume was consistent with four molecules of acetonitrile,
Index ranges
ꢀ 10 ≤ h ≤ 9, ꢀ 28 ≤ k ≤ 31, ꢀ 31 ≤ l ≤ 18
Reflections collected
Independent reflections
Data/restraints/parameters
24,696
however the electron density indicated that only one molecule remained
in the crystal. The refinement also showed that the crystal also had
minor twinning (about 2%) however, as it was not possible to carry out a
refinement using solvent mask on a twinned crystal the final refinements
were carried out using the Solvent Mask routine without accounting for
10,316 [Rint = 0.0663, Rsigma = 0.0829]
10316/16/488
1.186
2
Goodness-of-fit on F
Final R indexes [I>=2
σ
(I)]
R
R
1
1
= 0.1181, wR
= 0.1728, wR
2
= 0.3490
= 0.3862
Final R indexes [all data]
2
ꢀ
3
Largest diff. peak/hole / e Å
1.03/-0.71
twinning. Crystallographic data for the complex [Ni
2
(HL)
(
H
2
O) (CH CN) ].3Cl is listed in Table 1.
4
3
2
these drugs, revealing that the method is an effective one [23–25]. Thus,
we applied AutoDock Vina, AutoDock 4.2, PyRx, and Molegro Virtual
Docker (MVD) with the aim of calculating and predicting the in-
teractions and the binding affinity between the ligands and the macro-
molecules [26–27]. Moreover when the cytotoxic properties were
implemented, we aimed at estimating the interactions between (Mutant
2
.4. Molecular docking
The anti-cancer activity of synthesized complexes have been per-
formed via molecular docking of two anti-cancer receptors (Mutant
Y1248L) MET receptor tyrosine kinase (PDB ID: 3DKG), ERK2 (PDB ID:
ZXT) with relevant complexes. Molecular Virtual Docker (MVD), high
accuracy and precision software, is chosen to calculate binding affinity
kJ/mol) of complexes binding modes in cavities receptors. At first,
(
4
(
Y1248L) MET receptor tyrosine kinase (PDB ID: 3DKG), ERK2 (PDB ID:
ZXT) with the complexes. As a result, one can reach this conclusion that
4
(
by synthesizing the complexes, we will have an effective potential in-
hibition against receptors’activities. When the results from the analysis
of the cytotoxicity properties in vitro were compared to those of the
molecular docking, it was revealed that they were in good agreement.
synthesized complexes’ structure was drawn via chem draw software
and optimized via Gaussian 09. The parameter setting of MVD was as
following: MolDock Score as the score function; ligand evaluation: in-
ternal ES, Algorithm: MolDock SE; internal HBond; max. population
2
2
size: 50 sp –sp torsions, all checked; several runs: 20 runs; neighbor
distance factor: 1.00: maximum interactions: 1500; max. steps: 300.
2
. Experimental
.1. Materials
-Nirto benzyl chloride ,1,2-Dibromoethane, 1-(2-aminoethyl)
2
2
.5. Cytotoxicity in vitro
2
We purchased the human breast (MCF-7; IBRC C10082) and lung
piperazine, phthalic anhydride, 2-hydroxybenzaldehyde, 2- formyl
pyridine and Ni (II), Cu (II), and Co (II) perchlorates were commercial
products (from Merck, Aldrich and Fluka), and were used without
further purification. Solvents were of reagent grade and were purified by
the usual methods.
(
(
A549; IBRC C10080) from the Iranian Biological Resource Center
IBRC; Tehran, Iran). DMEM: Ham’s F12, applied in culturing the Lung
cell lines, were supplemented with L-glutamine, 10% Fetal Bovine Serum
ꢀ 1
ꢀ 1
(
FBS), 100 units mL
penicillin and 100
μg mL
streptomycin.
Moreover, we also applied the supplemented Ham’s F12 medium to
culture A549 cell line. In a humidified atmosphere, we kept the cells at
Caution! Perchlorate salts are potentially explosive. Only a small
amount of material should be prepared and handled with great care.
◦
3
7 C, with 5% CO
2
. It was in DMSO that the compounds were dissolved
-
1
at 20 mM L concentration. Afterwards, they were diluted in the culture
medium at the following concentrations: 1.56, 3.13, 6.25, 12.50, 25, and
2
.2. Physical measurements
Infrared spectra have been measured from 400 to 4000 cm as KBr
-
1
5
0 mM L . To prevent the DMSO toxicity, less than 0.5% (v/v) con-
ꢀ 1
centration was chosen for the DMSO. The assessment was performed
using the modified cell viability (MTT) method in which MTT (3-[4, 5-
dimethylthiazolyl]-2,5-diphenyltetrazolium bromide) reduction was
detected. Clearly, the allocation of the cells (5 × 104) was performed in
1
pellets on a Perkin Elmer Spectrum RXI FT-IR spectrophotometer.
H
1
3
and C NMR spectra have been recorded on a Bruker Avance DPX-400
spectrometer at 400 MHz and deuteriated dimethyl sulfoxide
(
6 3
DMSO‑d ) and CDCl has been used as solvent. Mass spectra were
each well with 100 L RPMI medium supplemented with 10% FBS in a
μ
recorded on an Agilent Technologies (HP) 5973 mass spectrometer
operating at an ionization potential of 70 eV. Elemental analyses were
carried out by Elementar Analysen systeme GmbH.
9
6-well plate25. After performing the adhesion for 24 h, in order to
triplicate the wells (0 to 50 M), dilution of the compounds (doubling)
was added. In addition, in order to prevent the toxicity of the solvent,
.5% (v/v) was chosen to be the final DMSO concentration. Accordingly,
μ
0
2

H. Keypour et al.
Polyhedron 207 (2021) 115380
2 1
Scheme 1. The processes of synthesis of M L .
Scheme 2. The processes of synthesis of polyamine.
the addition of 10
μ
L MTT after 12 h. was followed by incubating the
2 3
2.6.2. Synthesis of Schiff base complexes (ML and ML )
◦
plates at 37 C for an additional 4 h. Subsequently, it was in DMSO (100
a) Synthesis of polyamine
μ
L) that the formazan blue was dissolved. It is worth mentioning that, at
90 nm, we used ELISA plate reader to analyze the optical density (OD)
A beaker was used to melt the phthalic anhydride (1.48 g, 10 mmol)
◦
4
at180 C and, then, we added 1-(2-aminoethyl) piperazine (1.29 g, 10
of each well. The determination of the cell survival curves was carried
out by the incubated cells in 0.5% DMSO presence The compound’s
concentration - inhibiting the growth of the cell by 50% (IC50) – in-
dicates the cytotoxicity. The three-times performance of the tests was
followed by recording the mean values.
mmol) to the beaker. In addition, it was stirred for 15 min and, then,
allowed to cool. Afterwards, we aimed at washing the solid product with
hot ethanol and, then, dissolving it in hot acetonitrile which was also
2 3
followed by the addition of K CO (2.76 g, 20 mmol). Subsequently, to
the refluxed mixture, we aimed at adding a solution of 2-nitrobenzyl
chloride (1.37 g, 8 mmol) in acetonitrile (40 ml) and, then, the
mixture was refluxed for another 48 h and, then, filtered. Finally, we
attempted to cool the solution at room temperature. When the solvent
was dried, we added water which resulted in extracting the product with
chloroform (3*25 ml), as an orange oil. There were some insoluble
materials which were filtered off and heated under reflux with HCl (200
cm3, 25%w/w) for 12 h. The pulverized solid was stirred in the
boiling1:3 ethanol–water (20 min). The resulted phthalic acid was
removed by filtration and, then, the filtrate was evaporated and poured
into absolute EtOH. The washed residue with absolute EtOH and was
dried in vacuo and, then, a suspension of amine salt (1 mmol) in ethanol
(10 ml) was added to a solution of NaOH (21 mmol) in ethanol (10 ml).
After the 30 min. stirring of the mixture at room temperature, we aimed
at filtering the precipitate and evaporating the filtrate to dryness. The
resulting yellow powder was characterized as the pure compound. The
addition of the nitro intermediate (7 mmol, 1.94 g) suspension to an
aqueous ethanol solution (water: 20 ml, ethanol: 300 ml) was followed
by heating the mixture to boil until we had the materials dissolved.
Besides, the addition of the ammonium chloride (1.49 g) was also fol-
lowed by heating until we had the materials dissolved It was to our hot
solution that we slowly added zinc powder (5.9 g), over a period of 1.5 h
and, then, the solution was refluxed for 12 h. The resulting solution was
cooled to room temperature and filtered under vacuum. When the sol-
vent was dried, we added water (50 ml) and, then, the product was
2
2
.6. Synthesis
.6.1. Synthesis of Schiff base complexes–H
The Schiff base ligand H L was synthesized as described previously
2 1
2 1
L
[
16]. The Schiff base complexes were prepared by direct condensation of
the Schiff base ligand H (1 mmol), dissolved in 25 ml ethanol, with
the metal salts CuCl O or NiCl ⋅6H O (2 mmol), dissolved in 25 ml
⋅6H
of ethanol, following by the addition of NEt (2 mmol), to deprotonate
2 1
L
2
2
2
2
3
the hydroxyl groups of the salicylaldehyde. The resulting mixture was
refluxed with stirring for 12 h, then the formed complexes were filtered
off and washed with cold ethanol. The complexes were dried in a vac-
uum desiccator over anhydrous calcium chloride. Crystals of the nickel
complex were obtained by slow diffusion of Et
solution. (Scheme 1).
2
O vapour into a CH
3
CN
[
Ni-L
1 28 6 8
]: Pale yellow crystals. Yield: (65%). C25H Cl2NiN O
(MW:
6
70.12) C, 44.2; H,6.1; N, 12.8. Found: C, 44.1; H, 6.2 N, 12.7 IR(KBr,
ꢀ
1
–
–
–
–
N)py] 1092, 625 t
cm )1625 t (C
–
N), 1592, 1566 t [(C
). ESI-MS (m/z): 472.25.
Cu-L ]: Green powder. Yield: (73%). C25
74.98) C, 42.2; H, 5.9; N, 10.5. Found: C, 42.5; H, 6.1; N, 10.6 IR(KBr,
–
C), (C
(
ClO-
4
[
1
28 6 8
H Cl2CuN O (MW:
6
ꢀ
1
–
–
–
–
cm )1619 t (C
N), 1599, 1574 t [(C
–
C), (C N)py] 1096, 621 t
–
(
ClO-
4
) ESI-MS (m/z): 476.65.
3

H. Keypour et al.
Polyhedron 207 (2021) 115380
Scheme 3. The processes of synthesis of H
2
L
2
and H
L
2 3
.
Scheme 4. The processes of synthesis of metal complexes ML
2
and ML
3
.
extracted with chloroform (3 × 50 ml). Finally, we aimed at drying the
combined extracts and , then, filtering and drying them by rotary
evaporation in order to afford a beige powder diamine compound
ppm) dH = 2.51–2.85 (H py), 2.65–3.81 (H aliphatic), 6.35–7.80 (m, H
aromatic), 8.15, 8.36 (s, Himin), 13.45 (2H(OH)).
13C NMR (DMSO‑d
115.75–162.10 (Caromatic), 161.63, 163.29 (Cimin).
: Yield: 0.18 g (87 %). Anal. Calc. for C25
C, 76.20; H, 6.60; N, 17.25. Found: C, 76.32; H, 6.45; N, 17.33%. IR
6
,
ppm) dc
=
53.66–61.54(C aliphatic),
ꢀ 1
(
scheme 2). Yield: 1.45 g (77%). EI-MS (m/z): 234.18 IR (KBr, cm ):
1
3
300–3253, 1615 m(NH
aliphatic), 2.5–2.63 (m, 8Hpy),2.3,5.39(4H, NH
NMR(DMSO‑d
, ppm) dC = 38.-58.93 (C aliphatic), 51.80 –54.01 (Cpy,),
13.59–146.90 (CAr).
b) synthesis of the Schiff base ligands (H
A solution of the prepared polyamine (0.5 mmol) in absolute ethanol
10 ml) was added drop wise to a solution of either 2-hydroxybenzalde-
2
). H NMR (DMSO‑d
6
, ppm) dH 2.35–3.35 (H
2
H
2
L
3
28 6
H N (MW: 412.53):
1
3
) 6.43–6.96(4HAr).
C
ꢀ
1
–
–
–
1
6
(KBr, cm ): 1625 (C
NMR (DMSO‑d
, ppm) dH = 2.2–3.85(Haliphatic), 2.68–3.62 (HPy),
, ppm)
–
N), 1610, 1586 [m (C
–
C) and m(C
–
N)Py]. H
1
6
1
3
2
L
2
and H
2
L
3
)
6.840–7.85 (m, HAro), 8.32, 8.45(s, 2Himin). C NMR (DMSO‑d
6
dc = 46.13–58.69(Caliphatic), 55.3–59.63 (Cpy), 118.53–159.8 (CAro),
(
161.9–163.5 (Cimin).
hyde or pyridine-2-carbaldehyde in absolute ethanol (20 ml). After
refluxing the solution for 12 h the resultant yellow powder was filtered
off, washed with diethylether and dried under vacuum (Scheme 3).
2 3
c) synthesis of the metal complexes (ML and ML )
General procedure. The metal complexes were prepared by adding
the ligands (H
2
L
2
or H
2
L
3
) (1 mmol) dissolved in 25 ml of methanol to a
O (1 mmol) (M: Co2 , Ni ,Cu ) dissolved in
a few drop of triethylamine was also
added. The clear solution was refluxed for 24 h and reaction mixture
+
2+
2+
H
2
L
2
: Yield: 0.16 g (72%). Anal. Calc. for C27
H
30
4
N O
2
(MW:442.55):
solution of M(ClO )
4 2
⋅6H
2
C,73.28;H, 6.83; N, 12.66 Found: C, 73.18; H, 6.77; N, 12.75%., IR (KBr,
2 2
20 ml methanol. In the case of H L
ꢀ
1
–
–
6
C), 1618 m(C N). H NMR (DMSO‑d ,
1
cm ): 3430 m(OH), 1594 m(C
–
–
4

H. Keypour et al.
Polyhedron 207 (2021) 115380
64.16; H, 4.11; N, 7.86%. IR (KBr, cm 1): 1623 m(C
ꢀ
–
–
N), 1596, 1577,
).EI-MS (m/z): 702.86
]: Brown powder. Yield: 0.32 g (53 %). Anal. Calc. for
CoN 10 (MW: 698.37): C, 46.44; H, 4.04; N, 8.02. Found: C,
6.34; H, 4.12; N, 7.98%. IR (KBr, cm ): 1610 m(C
Table 2
–
–
N)]Py, 1098, 620 m(ClO-
The elemental analysis data of the ligands and complexes.
[m(C
Co-L
28Cl
–
C) and m(C
–
4
[
2
Compound
Yield
%)
%Found(Calc)
C
(
C
27
H
2
4
O
H
N
ꢀ 1
–
–
4
N), 1594, 1535,
). ESI-MS (m/z): 698.20.
]: Red-brown powder. Yield: 0.3 g (50 %). Anal. Calc. for
NiO10 (MW: 698.13): C, 46.45; H, 4.04; N, 8.41. Found: C,
[
[
Cu
Ni
Cl
2
HL
1
(H
2
O)
4
]Cl
3
73%
65%
42.5(42.2)
44.1(44.2)
6.1(5.9)
6.2(6.1)
10.6(10.5)
12.7(12.8)
–
–
N)]Py, 1091, 626 m(ClO-
[
m(C
Ni-L
28Cl
–
C) and m(C
–
4
2
HL(H
2
O) (CH CN) ]
4
3 2
[
2
3
C
27
H
2
N
4
H
2
L
2
72%
58%
53%
50%
87%
71%
67%
59%
73.18
6.77
12.75
ꢀ 1
–
–
(
73.28)
64.16
64.13)
46.34
46.44)
46.38
46.45)
76.15
76.20)
44.72
44.79)
44.78
44.81)
44.39
44.49)
(6.83)
4.11
(12.66)
7.86(7.97)
46.38; H, 4.1; N, 8.32%. IR (KBr, cm ): 1612 m (C N), 1597, 1538 [m
(
ClO
CoL
NiL
4
)
2
[CuL
](ClO
](ClO
2
]
–
[
–
–
N)]Py. ESI-MS (m/z): 698.06
(
C
–
C) and m(C
Co-L ]: Orange powder: Yield 0.48 g(71%) Anal. Calc. for
28Cl CoN (MW: 670.36): C, 44.79; H, 4.21; N, 12.54. Found: C,
44.72; H, 4.32; N, 12.43 IR(KBr,cm )1614 t (C
(
(4.01)
4.12
3
[
2
4
)
2
7.98 (8.02)
8.32(8.41)
C
25
H
2
6 8
O
(
(4.04)
4.1(4.04)
ꢀ 1
–
–
[
2
4
)
2
N), 1594, 1565 t
4
). ESI-MS (m/z): 670.28
N)py] 1092, 623 t (ClO-
(
[
(C
–
–
C), (C
–
–
H
2
L
3
6.55(6.6)
17.33
(
(17.25)
12.43
[
[
[
CoL
3
](ClO
](ClO
](ClO
4
)
2
4.32
Table 4
Bond lengths and bond angles for [Ni
(
(4.21)
4.30
(12.54)
12.49
2
1 2 4 3 2 3
HL (H O) (CH CN) ]Cl .
NiL
3
4 2
)
(
(4.21)
4.25
(12.54)
12.56
[
Ni HL(H O) (CH CN) ]Cl
3
2
2
4
3
2
CuL
3
4 2
)
Bond
Angle ˚( )
Bond
Length(Å)
(
(4.18)
(12.45)
O1-Ni1-O3
O1-Ni1-O4
O1-Ni1-N2
O1-Ni1-N7
O3-Ni1-O4
O3-Ni1-N2
O3-Ni1-N7
O4-Ni1-N2
N1-Ni1-O1
N1-Ni1-O3
N1-Ni1-O4
N1-Ni1-N2
87.8(2)
91.3(2)
174.4(3)
90.9(3)
177.8(2)
93.1(2)
89.8(3)
88.0(2)
92.0(3)
92.7(3)
89.3(2)
82.5(3)
Ni1-O1
Ni1-O3
Ni1-O4
Ni1-N1
Ni1-N2
Ni1-N7
Ni2-O2
Ni2-O5
Ni2-O6
Ni2-N5
Ni2-N6
Ni2-N8
2.032(6)
2.037(5)
2.062(4)
2.008(8)
2.231(7)
2.061(9)
2.037(6)
2.050(4)
2.047(5)
2.322(7)
2.018(7)
2.116(8)
Table 3
Important infrared bands of synthesized compounds.
ꢀ
1
Ѵ(cm
)
Ѵ(O
–
H)
Ѵ(C
–
N)
Ѵ(Mꢀ O)
Ѵ(Mꢀ N)
H
2
L
1
–
–
1637
1619
1625
1618
1614
1610
1612
1625
1614
1615
1629
–
–
[
[
Cu
Ni
2
HL
HL
1
(H
(H
2
O)
O)
4
]Cl
(CH
3
465
447
–
601
542
–
2
1
2
4
3
CN)
2
]Cl
3
3430
H
2
L
2
–
–
–
–
–
–
–
[
[
[
CuL
CoL
NiL
2
](ClO
](ClO
](ClO
4
)
2
428
467
456
–
526
524
536
–
515
535
542
2
4
)
2
2
4
)
2
Table 5
2 3
H L
Docking results (kJ/mol) of synthesized complexes with enzymes in the active
sites.
[
[
[
CoL
3
](ClO
](ClO
](ClO
4
)
2
–
NiL
3
4
)
2
–
CuL
3
4
)
2
Ѵ(O
–
H)
–
Synthesized complexes/Receptors
3DKG
4ZXT
Cu-L
1
ꢀ 130.494
ꢀ 105.74
ꢀ 86.62
ꢀ 82.33
ꢀ 80.94
ꢀ 79.99
ꢀ 73.13
ꢀ 71.13
ꢀ 179.6
ꢀ 114.46
ꢀ 99.02
ꢀ 85.25
ꢀ 81.61
ꢀ 80.13
ꢀ 76.21
ꢀ 72.22
Ni-L
Cu-L
1
allowed to cool at room temperature. The resulting complexes were
filtered off, washed with excess of ethanol to remove traces of any
unreacted metal salts, and dried in vacuum; the resulting products were
characterized as the pure compounds (scheme 4).
2
Ni-L
Co-L2
2
Cu-L
3
Ni-L
Co-L
3
[
Cu-L
28Cl
2
]: Green powder. Yield: 0.29 g (58%). Anal. Calc. for
3
C
27
H
2
CuN
4
O10 (MW: 702.98): C, 64.13; H, 4.01; N, 7.97. Found: C,
2 2 4 3 2 3
Fig. 1. ORTEP representation of [Ni HL(H O) (CH CN) ]Cl .
5

H. Keypour et al.
Polyhedron 207 (2021) 115380
Fig. 2. Binding residues and interactions of (I) MET receptor tyrosine kinase (PDB ID: 3DKG) and (II) ERK2 (PDB ID: 4ZXT) with Cu-L2.
Fig. 3. Binding residues and interactions of (I) MET receptor tyrosine kinase (PDB ID: 3DKG) and (II) ERK2 (PDB ID: 4ZXT) with Co-L3 complex.
[
Ni-L
3
]: Green powder. Yield: 0.45 g (67%). C25
H
28Cl
N
2 6
NiO
8
(MW:
[Cu-L
3 2 6 8
]: Green powder. Yield: 0.4 g (59%) C25H28Cl CuN O (MW:
6
70.12) C, 44.81; H, 4.21; N, 12.54. Found: C, 44.78; H, 4.30; N, 12.49
674.98) C, 44.49; H, 4.18; N, 12.45. Found: C, 44.39; H, 4.25; N, 12.56
ꢀ 1
–
–
–
–
–
ꢀ 1
–
–
–
–
C), (C N)py] 1098, 621
IR(KBr,cm )1615 t (C
t (ClO-
–
N), 1595, 1566 t [(C
C), (C
N)py] 1092, 625
IR(KBr,cm )1629 t (C
t (ClO-
–
N), 1598, 1572 t [(C
–
4
). ESI-MS (m/z): 670.05.
4
) ESI-MS (m/z): 674.88.
6

H. Keypour et al.
Polyhedron 207 (2021) 115380
1
Fig. 4. Binding residues and interactions of MET receptor tyrosine kinase (PDB ID: 3DKG) with Cu-L .
3
. Result and discussion
coordinated to metal ion [36]. The ligand and complexes are soluble in
most organic solvents. According to the results of the elemental analysis
The synthesis of the binuclear macroacyclic Schiff base complexes
2 3
as well as previous similar works, the structure of complexes-L and L
was carried out using the direct reaction of H
2
L
1
and Cu (II) and Ni (II)
should be described as octahedral geometries [15]. All of the compounds
are air stable The elemental analysis data of the complexes are given in
Table 2.
metal ions in 2:1 M:H L ratio in refluxing ethanol. Elemental analysis, IR
2
and X-ray structural analysis were used to characterize the mentioned
complexes; as Table 1 illustrates the X-ray crystallographic data. Ac-
cording to the resulted data, 2:1 M:HL complex was successfully formed.
3
.1. IR spectral data
Herein, hexadentate N
and H , respectively) is proposed; as derived from 2-hydroxy-banzal-
dehyde or 2-formylpyridine condensation. Ligands (H and H
synthesis was confirmed by the mass spectra, illustrating the peaks at
42.55 and 488.64 m/z, The preparation of Cu (II), Ni (II), Co (II) and
4 2 6 2 2
O and N Schiff-base ligands synthesis (H L
2
L
3
ꢀ 1
A band at 3428 cm is illustrated by the IR spectrum of the Schiff
base ligand (H ), as being absent in the complexes, showing the co-
2
L
2
2 3
L )
2 1
L
ordination through the deprotonated phenolic OH groups. An absorp-
4
ꢀ 1
tion band at 1637 cm is also revealed by the IR spectrum of the Schiff
perchlorate was performed using direct reaction of the ligands and metal
salts in a mixed methanolic and ethanolic solution in equimolar ratio
–
base ligand (H
2
L
1
), as being connected to the C
–
N stretching mode.
ꢀ 1
This band is shifted towards lower frequencies by 12–18 cm , clarifying
the fact the coordination of the imine nitrogen atom to the metal. In this
(
1:1). Mass spectrometry, IR spectroscopy and elemental analysis were
used to characterize the complexes. In this sense, we have a very similar
ꢀ 1
sense, weak bands at 542–601 and 447–465 cm can be assigned to the
ѵ(Mꢀ N) and ѵ(Mꢀ O) vibrations; supporting the participation of the
nitrogen atom of the azomethine group and phenolate oxygen of the
ligand. It is in the free ligand spectrum that one can observe these bands.
ꢀ 1
infrared spectra, recorded in the region 4000–500 cm . Accordingly,
ꢀ
1
1
610–1623 cm can be regarded as a sharp band illustrated by the
spectra. Besides, it possesses the following characteristics: attributed to
–
N), shifted to the lower frequency on going from the free ligand
m (C
at 1618 cm for H
and being consistent with the coordination of the imine nitrogen to the
–
The spectra (for –H
–
–
) with the following characteristics: being attributed to m (C N),
2
L
2
and H
2
L
3
) illustrate a sharp band (1610–1629 cm-
ꢀ 1
ꢀ 1
(
2
L
2
and 1628 cm for H
2
L
3
) to the metal complexes,
1
ꢀ 1
ꢀ 1
2
and 1625 cm for
shifted to lower frequency (at 1618 cm for H2L
–
metal ions. In addition C
clarifies the occurrence of Schiff base condensation. We witnessed no
–
O and NH stretching vibrations’ absence
2 3
H L
), and being consistent with the imine nitrogen coordination to the
–
–
metal ions. Moreover, when C O and NH stretching vibrations are not
ꢀ 1
O
–
H stretching bands in the IR region 3400–3300 cm for [H
complexes [34,35], confirming the phenolic functions’ deprotonation.
The phenolic C O stretching vibrations can ascribe to the band at 1186
] which, because of the O–metal coordination, can be
shifted to lower frequencies. It is worth mentioning that absorptions at
2 2
L ]
present in the spectra, it can be related to the aldehyde and diamine;
clarifying the Schiff base condensation occurrence. Phenolic functions’
deprotonation was established when O H stretching bands were not
–
–
ꢀ
1
2 2
cm for [H L
present in the IR region 3400–3300 cm-1 for [H
2 2
L ] complexes. It is
worth mentioning that we found out specific adsorptions at 1100 and
ꢀ
1
1
100 and 620 cm were for the perchlorate anions. Moreover, the not-
ꢀ 1
6
20 cm . Moreover, we also witnessed that the perchlorate bands did
splited perchlorate bands indicated that perchlorate ions were not
not split, clarifying the fact that perchlorate ions were not coordinated to
7

H. Keypour et al.
Polyhedron 207 (2021) 115380
A549
Cu-L1
Ni-L1
Cu-L2
Ni-L2
Co-L2
Cu-L3
Ni-L3
Co-L3
1
00.00
9
8
7
6
5
4
3
2
1
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0
.00
1
.56
3.13
6.25
12.50
25.00 50.00
Concentraꢀon (μM)
MCF-7
9
8
7
6
5
4
3
2
1
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
Cu-L1
Ni-L1
Cu-L2
Ni-L2
Co-L2
Cu-L3
Ni-L3
Co-L3
0
.00
1
.56
3.13
6.25
12.50
25.00
50.00
Concentraꢀon (μM)
Fig. 5. Graphical representation of the anticancer activity of the synthesized complexes in the human different.
Ni is co-planar with all atoms of the coordinating 2-iminomethyl phenol
group and coordinating nitrogen atoms of the piperazine and acetoni-
Table 6
Comparison of cytotoxicity (IC50 values based on
compounds.
μ
M) of the synthesized
A549
trile molecules. The two NiN
3
O planes are nearly coplanar, with the
◦
dihedral angle being 4.20(4) , while the distance between the two nickel
atoms is 12.270 (3) Å. There are three chloride counter anions in the
structure, indicating that the ligand is protonated, localized on one of
the non-coordinating piperazine nitrogen atoms, N4; the N4-C distances
are slightly longer than the N3-C distances. The Ni-O and Ni-N bond
lengths are similar, in the range 2.008(8)-2.116(8) Å, except for those
involving the piperazine moiety which are significantly longer (Ni-N2:
2.231(7) Å, Ni-N5: 2.322(7) Å); the angles around the metal show little
deviation from those expected for a regular octahedron. On complexa-
tion there are significant changes in the conformation of the ligand. The
distance between the imino nitrogen atoms is 14.850 (13) Å, compared
to 16.8230 (17) Å for the free ligand [16], while the piperazine rings are
now almost perpendicular to the imino methyl phenol group, with the
dihedral angles between the carbon atoms of the piperazine rings and
Structure
MCF-7
Cu-L
Ni- L
Cu-L
1
9.48 ± 0.24
12.16 ± 0.79
16.37 ± 1.09
18.49 ± 1.4
20.11 ± 2.16
24.56 ± 3.09
29.56 ± 3.09
33.46 ± 3.09
10.15 ± 0.6
13.63 ± 0.91
17.07 ± 1.02
18.33 ± 1.85
21.82 ± 2.3
26.67 ± 3.57
28.56 ± 3.09
34.51 ± 3.19
1
2
Ni-L
Co-L
2
2
Cu-L
3
Ni-L
Co-L
3
3
metal ion [36] Selected peaks in the IR spectra are given in Table 3.
3
.2. Description of the X-ray structure of binuclear complex
◦
◦
the imino methyl phenol group being 73(3) and 88.2(3) , compared to
The ligand adopts an extended arrangement, coordinating to two
◦
2
4.94(5) for the free ligand. While in the free ligand the phenol oxygen
nickel atoms, with each nickel atom being in an octahedral environment
coordinated by one oxygen atom and one nitrogen atom from the 2-imi-
nomethyl phenol group, one nitrogen from a piperazine group, one
molecule of acetonitrile and two molecules of water in a trans
atoms are in a trans arrangement, due to the ligand lying on a centre of
symmetry, here the phenol oxygen atoms, and both metal atoms, now lie
on the same side of the ligand. These differences indicate that the ligand
has a significant degree of flexibility. Hydrogen bonds link the ions into
3 3
arrangement, to give a mer-N O octahedral environment (Fig. 1). Each
8

H. Keypour et al.
Polyhedron 207 (2021) 115380
a 3D network, with channels lying along the a-axis, in which the solvent
reaction with metal salts in a solution (a methanolic/ethanolic one) in
equimolar ratio (1:1). Mass spectrometry, IR spectroscopy and
elemental analysis were applied to characterize the complexes. Besides,
molecular docking and in vitro were used to analyse the cytotoxic
characteristics of the synthesized complexes. Both methods resulted in
molecules reside. The important bond lengths and angles for [Ni-L
reported in Table 4.
1
] are
3
.3. Molecular docking studies
Molecular modeling of synthesized complexes has been carried out
1 1
similar conclusions. It was found out that vitro, Cu-L and Ni-L com-
plexes were mostly against the two synthesized cell lines. Molegro Vir-
tual Docker software was applied to predict and calculate the binding
affinity and the interactions of synthesized compounds in the receptors’
for biological evaluation (anti-cancer activity) via the MVD program.
The water molecules and unique ligands were eliminated from the re-
ceptor structure and ready for docking studies. The anti-cancer feature
of complexes is based on Mol Dock Score, which is remarkable with
negative value of Mol Dock Score (kJ/mol). As shown in Table 5, the Cu-
1 1
cavities Finally, it is worth mentioning that Cu-L and Ni-L complexes
possess the greatest MolDock Score of all of the complexes. The highlight
of biological results is good conformity of molecular docking and MTT
results. Cu-L1 and Ni-L1 complexes have the highest inhibitory effect
against receptors or MCF-7 and A549 cell lines. All in all, the theoretical
and experimental data indicated that the relevant complexes have
remarkable anti-cancer effect
L
1
complex has the highest inhibitory effect against 3DKG (-130.494 kJ/
mol) and 4ZXT (-179.6 kJ/mol) receptors compared to other complexes.
3
In contrast, Co-L complex has the least biological evaluation than other
complexes.
Also, Binding residues and interactions of MET receptor tyrosine
kinase (PDB ID: 3DKG) and ERK (PDB ID: 4ZXT) with Cu-L , Cu-L and
Co-L complexes (Figs. 2, 3 and 4). There are a variety of interactions
2
1
2
Declaration of Competing Interest
3
such as van der walls, alkyl, Pi-sigma, Pi-sulfur, Pi-alkyl, carbon
hydrogen bond, Pi-donor hydrogen bond, and Pi-anion are detected
from docking results (Fig S1-S12) [37–40].
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
3
.4. Cytotoxicity in vitro
Acknowledgements
MTT assay was applied to analyze the cytotoxicity profiling of the
synthesized compounds, applying lung (A549) and breast (MCF-7) cell
lines. The reduction of the yellow MTT by the dehydrogenase’s enzy-
matic activity was followed by analyzing the cell viability. Fig. 5 illus-
trates the percentage of the cell viability of the comparative cytotoxicity
patterns Destroying 50% of the cells requires IC50 values of the com-
plexes, as measured by the dose-survival curves for the growth inhibi-
tion of the tow cell lines (Table 6). We found out high efficiency in the
We are grateful to the Faculty of Chemistry of Bu Ali Sina University,
for financial supports. This research was undertaken in part using the
2
MX beamline at the Australian Synchrotron, part of ANSTO, Victoria,
Australia, and made use of the Australian Cancer Research Foundation
(ACRF) detector.
Appendix A. Supplementary data
Cu-L
IC50 values helps us to find out that MCF-7 cells (average IC50 value;
0.52 M) are more chemosensitive than A549 cell. Finally, extreme
cytotoxicity in the Cu-L (average IC50 values less than 10
M) –was
1
and Ni-L
1
, stopping the cell lines’ growth. In addition, comparing
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.poly.2021.115380.
2
μ
1
μ
greater than other complexes. As a worldwide malignancy in females,
breast cancer is able to greatly affect the population, creating important
public health problems. Accordingly, our sole concern in this study was
to analyze the compounds’ cytotoxic potency on the breast (MCF-7) cell
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