Synthesis, structural characterization, DFT and molecular simulation study of new zinc-Schiff base complex and its application as a precursor for preparation of ZnO nanoparticle

Article abstract of DOI:10.1016/j.molstruc.2020.127715

In this study, the metal complex [ZnL(2-aminopyridine)Br] (I) was synthesized from a metal salt with Schiff base ligand (HL). The synthesized complex (I) was elucidated by using FT-IR, UV–Vis spectroscopy, ¹H NMR, and. Moreover, the crystal str

Full text of DOI:10.1016/j.molstruc.2020.127715

Journal Pre-proof
Synthesis, structural characterization, DFT and molecular simulation study of new
zinc-Schiff base complex and its application as a precursor for preparation of ZnO
nanoparticle
Masumeh Galini, Mehdi Salehi, Maciej Kubicki, Mehdi Bayat, Rahime Eshaghi
Malekshah
PII:
S0022-2860(20)30039-9
DOI:
https://doi.org/10.1016/j.molstruc.2020.127715
MOLSTR 127715
Reference:
To appear in: Journal of Molecular Structure
Received Date: 14 July 2019
Revised Date: 8 January 2020
Accepted Date: 8 January 2020
Please cite this article as: M. Galini, M. Salehi, M. Kubicki, M. Bayat, R.E. Malekshah, Synthesis,
structural characterization, DFT and molecular simulation study of new zinc-Schiff base complex and its
application as a precursor for preparation of ZnO nanoparticle, Journal of Molecular Structure (2020),
doi: https://doi.org/10.1016/j.molstruc.2020.127715.
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Graphical abstract
The complex [ZnL(2-ampy)Br] was synthesized and structurally characterized. The crystal of
complex was determined by single X-ray diffraction study. Docking calculations of these
complex were performed to explore the exact binding sites. The nature of the Zn→L bonds in
the compound was analyzed with NBO, EDA analyses and molecular docking. The ZnO
nanoparticles were prepared via combustion method of the complex at 700℃ for 8 h. Finally,
crystallinity, purity, and morphology of the ZnO nanoparticles were characterized by FT-IR,
XRD, FESEM, and TEM.

Synthesis, structural characterization, DFT and molecular
simulation study of new zinc-Schiff base complex and its
application as a precursor for preparation of ZnO
nanoparticle
a
a
,
b
c
Masumeh Galini , Mehdi Salehi *, Maciej Kubicki , Mehdi Bayat , Rahime Eshaghi
a
Malekshah
a
Department of chemistry, Semnan University, Semnan 35351-19111, Iran
b
Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland
c
Department of Inorganic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 65167, Iran
Abstract:
In this study, the metal complex [ZnL(2-aminopyridine)Br] (I) was synthesized from a metal salt
with Schiff base ligand (HL). The synthesized complex (I) was elucidated by using FT-IR, UV-
1
Vis spectroscopy, H-NMR, and. Moreover, the crystal structure of the complex was determined
by X-ray analysis and revealed the complex has a distorted tetrahedral coordination structure.
The stimulation revealed the binding pattern of this compound with BNA that the free energy
(
ꢀG) of interaction is −7.73 kcal/mol. Also, free energy (ꢀG) of complex (I) with EGFR-TKD,
ABL/dasatinib complex and the ABL/imatinib complex was by -6.47, - 5.20 and - 6.60 kcal/mol.
Then, the nature of the Zn→L bonds in the complex (I) was analyzed with NBO and EDA
analyses. In the next step, ZnO nanoparticles were prepared via combustion synthesis method of
the complex (I) at 700℃ for 8 h. Finally, crystallinity, purity, and morphology of the ZnO
nanoparticles were characterized by FT-IR, XRD, FESEM, and TEM.
1

Keywords: Crystal structure, ZnO nanoparticles, Hydrolytic cleavage, Molecular docking, Non-
receptor tyrosine kinases, Receptor tyrosine kinases.
1
. Introduction
The discovery of new transition metal complexes with Salicylaldehyde Schiff base played a
significant role in the growth and development of coordination chemistry for their applications,
properties and interesting structures [1-3]. The discovery of new transition metal complexes with
Salicylaldehyde Schiff base explicate the mechanism of transamination reactions in biological
system [4-6]. Among these complexes, Schiff base zinc complexes, especially chiral Zn(II)
complexes
have been
attracted much attention because
of their
physiological
and
pharmacological activities[7]. Also, the synthesis of several salicylaldehydes and 2-
Aminopyridine derivatives−Schiff base from the simple condensation and their complex was
reported [8-11]. The theoretical studies of the ground state intramolecular proton transfer (IPT)
and solvation effect have also been reported from 2-aminopyridine with 2-hydroxy-1-
naphthaldehyde and 2-hydroxy salicylaldehyde [12]. Zhu et al. studied synthesis and crystal
structure of polynuclear tridentate with cobalt(II) sulfate and cobalt(II) perchlorate [13]. In the
other article, the biological properties of binuclear Ru(II) complexes with Schiff bases derived
from 5-chlorosalicyladehyde and 2-aminopyridine and its 5-substituted salicylideneimine
homologues were reported [14]. Giri et al. synthesized a tetranuclear Cu(II) complex
[Cu L (H O) ](ClO ) using the terdentate Schiff base 2-(pyridine-2-yliminomethyl)-phenol
4 4 2 4 4 4
(HL) [15]. In addition to, antimicrobial activity of copper(II) complex of Schiff base derived
from 2-(salicylidene) aminopyridine was tested in comparison with the activity of the
corresponding Schiff base [16]. Tyagi et. al. reported Ni(II) and Zn(II) metal complexes of Schiff
base and tested cytotoxic activity of against human breast cancer cell line (MCF-7) and human
2

hepatocellular liver carcinoma cell line (HepG2). Also, The DFT studies of Schiff bases and
metal complexes has been assigned for Co(II), Ni(II) Cu(II) and Zn(II) complexes using the 6-
3
1+g(d,p) basis set. The theoretical results certainly supported experimental data confirms the
suggested structure [17]. In another study, Zn(II) complex was analysed using molecular
dynamics simulation and molecular docking studies. Molecular docking studies shown Zn(II)
complex located to the major groove [18]. So far, the Schiff base zinc complexes containing the
bromide ligands and salicylaldehyde have rarely been reported. Furthermore, among transition
metal oxides, zinc oxide have attracted increasing attention for its unique physical and chemical
properties such as gaseous sensors [19], photocatalysts [20], and additives in many industrial
products [21]. There are several methods to prepare nanostructured ZnO such as solvothermal
and hydrothermal [22-24], sol-gel [25], polymerization [26], and mechanochemical methods
[27]. This work, FT-IR, ultraviolet-visible spectra (UV-Vis), and X-ray were used to describe the
structure of new complex (I). In addition, the nature of the Zn→L bonds in the complex was
analyzed with NBO (The Natural Bond Orbital) and EDA (energy and decomposition analysis)
techniques. Furthermore, ZnO nanoparticles were successfully prepared via combustion
synthesis method of the complex (I) (Scheme 1). The morphology and structure of the as-
prepared ZnO were investigated by FESEM, TEM, XRD, and FT-IR spectra. Eventually, the
docking study of selected compound with (PDB ID: 1BNA), the epidermal growth factor
receptor (EGFR-TKD) (PDB ID: 1M17), the ABL/dasatinib complex (PDB ID: 2GQG) and the
ABL/imatinib complex (PDB ID: 2HYY) were accomplished in order to predict the chosen
binding site.
3

Scheme 1. Synthetic procedure for the preparation of Schiff base ligand and complex (2:1) and
protocol of ZnO nanoparticles.
2
2
. Experimental
.1. Materials and methods
All the materials in the experiment were purchased from Aldrich and Merck and used without
further purification. FT-IR spectra in KBr plates were performed on FT-IR SHIMADZU
-1
spectrophotometer in 4000-400 cm . UV-Vis spectra were recorded on a UV-1650 PC
1
SHIMADZU spectrophotometer in methanol (MeOH) solution. H-NMR measurements were
recorded with the NMR BRUKER 300MHz spectrometer, using deuterated methanol (CD OD)
3
as the solvent. Also, the crystallographic information and phase purity of the nanostructure were
acquired with the X-ray powder diffraction (XRD) using Bruker D8000 Germany in a scanning
o
range of 2θ = 10–90 and CuK
α
radiation. The morphological and structural characteristics, as
4

well as particle size distribution of the nanostructures of ZnO, were investigated using the field
emission scanning electron microscope (FESEM, Hitachi model S-4160) and a transmission
electron microscopy (TEM, Philips-CM300).
2
.2. Synthesis of the Schiff-base ligand HL
The Schiff-base ligand HL was performed according to the literature procedure [28]. The ligand
was prepared by condensing salicylaldehyde with 2-aminopyridine in 1:1 molar ratio in 20 mL
EtOH. The reaction solution was refluxed at room temperature for 3 h. The orange crystalline
powder separated by a Buchner funnel, washed with absolute ethanol, and dried under vacuum.
-1
Mol. Wt.: 198.22 g/moL. mp. 70 ℃. FT-IR: νmax cm (KBr): 1608 (s, C=N), 1556, 1573 (s,
−
1
−1
C=Carom), 1278 (s, C-O). UV–Vis: λmax (nm) (ε, M cm ) (MeOH): 347(25300), 295(29900),
1
2
1
2
68(29800), 221(38600). HNMR (CDCl , 400 MHz): 6.91-8.57(m, 8H), 9.52(s, 1H), 13.05(s,
3
H).
.3. Synthesis of the Complex [ZnL(2-aminopyridine)Br] (I)
2
An ethanol solution (5 mL) of ZnBr (0.225 g, 1 mmol) was added dropwise into the ethanol
solution (15 mL) of Schiff base ligand HL (0.396 g, 2 mmol). The resulting yellow mixture was
refluxed for 3 h, then allowed to cool down at room temperature. The single yellow crystals
suitable for X-ray data collection were obtained by slow evaporation after 2 days. The crystals
were separated, washed with a small amount of cold pure ethanol, and dried under vacuum. Mol.
-1
Wt.: 436.62 g/moL. mp. 220 ℃ FT-IR: ν cm (KBr): 1614 (s, C=N), 1496, 1529 (s, C=Carom),
,
max
−
1
−1
1
2
2
263 (s, C-O). UV–Vis: λmax (nm) (ε, M cm ) (MeOH): 405(12300), 300(29200),
1
32(39400). H-NMR (CD
3
OD, 300 MHz): 6.6(m, 12H), 4.8(s, DOH), 9.2(s, 1H).
.4. Preparation of ZnO nanostructure of the complex (I)
5

An appropriate amount of complex (I) powder (1g) as the precursor for ZnO was weighed and
transferred into a crucible. The crucible containing complex was heated at 700℃ for 8 h. Then,
the white powder obtained from the calcination complex was collected for characterization.
2
.5. X-ray crystallography
Diffraction data were collected by the ω-scan technique at room temperature on Rigaku Xcalibur
four-circle diffractometer with Eos CCD detector and graphite-monochromated MoK radiation
α
(λ=0.71069 Å). The data were corrected for Lorentz-polarization as well as for absorption effects
[29]. Precise unit-cell parameters were determined by a least-squares fit of 4109 reflections of
the highest intensity chosen from the whole experiment. The structure was solved with SIR92
2
[
30] and refined with the full-matrix least-squares procedure on F by SHELXL-2013 [31]. All
non-hydrogen atoms were refined anisotropically, hydrogen atoms from NH group were found
2
in difference Fourier maps and isotropically refined, all other hydrogen atoms were placed in
idealized positions and refined as ‘riding model’ with isotropic displacement parameters set at
1
.2. The crystallographic and refinement data are summarized in Table 1.
Table 1.
Crystallographic data for the structural analysis has been deposited with the Cambridge
Crystallographic Data Centre, Nos. CCDC-1534258. Copies of this information may be obtained
free of charge from: The Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK. Fax:
+
44(1223)336-033, e-mail:deposit@ccdc.cam.ac.uk, or www: www.ccdc.cam.ac.uk.
2
.6. Computational methods
The geometries of the compound investigated here were optimized without symmetry constraints
at the BP86 [32-33]/def2-SVP [34] level of theory using the Gaussian03 software [35]. It has
been shown that BP86 is a suitable level for calculation of bonding situation M←L among these
6

complexes [36-40]. Vibrational frequency analyses, calculated at the same level of theory,
indicate that the optimized structures are at the stationary points corresponding to local minima
without any imaginary frequency. The geometry of the metal complex (I) was determined by the
X-ray crystal structure analysis (Fig. 3) and was fully optimized at the above-mentioned level of
theory. NBO analyses were also carried out with the internal model GAUSSIAN 03. The
bonding analysis in terms of energy-decomposition analysis was carried out at
1
BP86/TZ2P(ZORA)//BP86/def2-SVP with C symmetry. The basis sets for all elements have
triple-f quality augmented by one set of polarization functions (ADF basis set TZ2P(ZORA))
with the program package ADF 2009.01. EDA calculations were carried out to analyze the
+
-
nature of bonds between the [ZnPy(R)] and [L] (Schiff base ligand) fragments in the complex
I).
.7. Docking Studies
(
2
To investigate antitumor activity, the possible basis in target sites, best orientation of the
molecule, and targeted therapeutic strategies of compounds, we used computational approaches.
The metal complex was used from their crystal structure as a CIF file and converted to the PDB
format using Mercury software 1.4.2. The crystal structure of the B-DNA dodecamer
d(CGCGATATCGCG)2 (PDB ID: 1BNA) [41], crystal structure of the epidermal growth factor
receptor (EGFR-TKD) (PDB ID: 1M17), the ABL/dasatinib complex (PDB ID: 2GQG) and the
ABL/imatinib complex (PDB ID: 2HYY) were retrieved from the protein data bank
(http://www.rcsb.org./pdb). Molecular docking study of complex Zn(II) with protein tyrosine
kinase, drugs of anticancer (Afatinib, Erlotinib, Gefitinib) with the epidermal growth factor
receptor was implemented using AutoDock 4.2 calculations (The Scripps Research Institute, La
Jolla, CA, USA). All water molecules of receptor were removed. The Zn(II) complex was
7

enclosed in a box with number of grid points in x×y×z directions (74×64×117 Å) with a grid-
point spacing of 0.991 Å for 1BNA, A grid box of the size 126 × 126 × 126 Å with a grid-point
spacing of 0.502 Å for the epidermal growth factor receptor (EGFR) and a grid box of the size
1
1
26 × 126× 126 Å with a grid-point spacing of 0.991 Å for GQG and a grid box of the size 126 ×
26× 126 Å with a grid-point spacing of 0.825 Å for 2HYY were selected for docking purpose.
The best optimized model having lowest energy was picked up from the one minimum energy
(
root mean square deviation, RMSD = 0.0) from the 100 runs to compare the structural similarity
42]. Then, the interactions of protein tyrosine kinase and non-receptor tyrosine kinases with
[
complex (I) were analyzed Discovery Studio 3.0 Accelrys and DS Visualizer.
3
3
. Results and discussions
.1. Synthesis
1
The new complex (I) was synthesized and characterized by FT-IR, H-NMR, UV-Vis, and X-ray
analysis. It is worth mentioning that this complex is completely soluble in common organic
solvents such as methanol, ethanol, and chloroform. Some spectroscopic data for ligand and
metal complex in Table S1 are in good agreement with the expected values.
3
3
.2. Spectroscopic characterization of the complex (I)
.2.1. FT-IR spectra
The FT-IR spectra of HL and the complex I provide useful information about the metal-ligand
bonding, with results summarized in Table S1. The absorption peaks in the area around 3334
−
1
and 3415 cm indicate the existence of NH group in the complex [43], emphasizing that the
2
amino N-atom is not participating in bonding [44]. Therefore, this observation is appropriate
with the X-ray crystal structure of the complex that shows coordination of the 2-aminopyridine
ligand only through the pyridine N-atom. The FT-IR spectra of the free ligand reveal that a band
8

-1
at 3051 cm may be assigned to ʋ(OH), which is absent in the spectrum of complex, indicating
coordination through the deprotonated phenolic OH group [45, 46]. The absorption band in the
ligand attributed to the phenolic oxygen (C-O) group that was shifted to a lower frequency in the
-1
complex. The infrared spectra of the ligand showed a band at 1608 cm assigned to the
azomethine group ʋ(C=N) while this band in the spectrum of the complex was shifted to the
-1
higher frequency 1614 cm , due to participation the nitrogen of azomethine group in
coordination [46-48].
3
.2.2. Electronic spectra
The electronic spectra of the free Schiff base ligand and its complex in methanol solution are
shown in Fig S1. The electronic spectrum of free ligand shows four bands in the regions 221,
2
68, 295, and 347 nm, with the three first band indexed to the π→π
⃰
transition of the aromatic
*
ring and the azomethine chromophore and the last band corresponding to n→π . In complex (I),
the band at 405 nm can be assigned to the charge-transfer (CT) transition by metal-to-ligand
(MLCT) π-back bonding, which is absent for the HL ligand.
1
3
.2.3. H-NMR spectra of Schiff base ligand and complex (I)
1
The H-NMR spectra of the Schiff base ligand and its complex (I) were recorded in CD
3
OD
solution (Fig.s S2 and S3). The position of the imine proton (CH=N) signal and O-H signal of
Schiff base ligand observed at 9.52 and 13.05 ppm, respectively [49, 50]. While, the multiplets
of aromatic protons are in the region between 6.91-8.57 ppm [51, 52]. The signal of the imine
proton and the phenolic OH disappeared in the spectrum of the complex. Disappearing Phenolic-
OH signal (hydroxyl protons) corresponded to deprotonation of phenolic proton and confirmed
coordination through phenolic oxygen to the metal ions. Also, due to the a peak at 4.84 ppm
region, corresponded to DOH proton
9

3
.3.3. Description of the crystal structures
The perspective view of the complex (I) is shown in Fig. 1, some geometrical data are listed in
Table 2. Zn cation is 4-coordinated, by two atoms (N and O) of ligand molecule, a nitrogen from
coordinated 2-aminopyridine molecule and a bromine atom, in a distorted tetrahedral fashion
(bond angles are in the range 93.48(10)º-123.16(11)º). The ligand molecule is only slightly
folded and the dihedral angle between the terminal ring planes is 11.76(17) º. The intramolecular
N-H···N hydrogen bond, with the ring nitrogen of the L molecule (not involved in coordination)
is possible because the coordinated pyridine ring is twisted by ca. 60º with respect to the L
molecule.
In the crystal structure (Fig. 2) the N-H···Br hydrogen bonds connect molecules into infinite
chains along x-direction. Both intra- and intermolecular interactions are enforced by secondary
C-H···O, weak hydrogen bonds. Table 3 lists the hydrogen bond data.
Fig.s 1-2
Tables 2-3
3
.3.4. Theoretical studies
The molecular structure of the complex (I) which determined by the X-ray crystal structure
see Fig. 1), and fully optimized at BP86/def2-SVP level of theory. Data show that in above
(
complex similar to that obtained by X-ray crystal structures, one nitrogen and one oxygen atoms
from the Schiff base ligand, one nitrogen from pyridine group and also one bromine atom are
arranged around the Zn(II) within a distorted tetrahedral geometry (Fig. 3). Selected calculated
bond lengths and bond angles of complex (I) are given in Table 4. As it can be seen, the
calculated bond length of Zn←N
and Zn←N
which obtained from σ-donation of N atom of
3
2
Schiff base and pyridine ligands to metal ion are about 0.05 and 0.06 Å larger than experimental
1
0

1
data (See Table 4). Also the Zn–O bond length in the complex which obtained from σ-donation
of O atom of phenoxide group to metal ion is about 0.06 larger than experimental data. Some
selected optimized and X-ray experimental values of bond lengths and bond angles around the
metal ion are respectively shown in Table 2 for complex (I). The optimized values are similar to
+
that obtained with experimental data. In continuation, two interacting fragments, [ZnPy(R)] and
-
[
L] (Schiff base ligand) in the complex (I) are considered and nature of bonds between
mentioned fragments are studied with the help of NBO analysis. The values of natural charges on
-
Zn metal ion and N, O and Br atoms as well as total charge of [L] ligand(Schiff base ligand) in
the complex are also studied (Table S2).
The observed data confirms that the Zn(II) metal ion is carried the positive and N, O Br and
Schiff base ligand are carried negative natural charges respectively. Also the values of charge
+
transfer from L ligand (Schiff base ligand) to [ZnPy(R)] fragment in the complex is about -
0
.42e. The Wiberg bond indices (WBIs) for Zn→L bonds are calculate and corresponding
values are included in Table 4. The values of WBIs for Zn→N and Zn→O bonds in the
2
1
complex are about 0.30 and 0.32 respectively. Also in the complex the value of M→N bonds
obtained from Schiff base ligand is similar to that obtained from pyridine group (Table 4).
In recent years, Morokuma [53] and Ziegler et al [54] presented the "energy decomposition
analysis" (EDA) method. With the help of this technique, we could explain the strength of M←L
σ donation and M→L back bonding in the complexes [53-57].
+
-
To better relalized the nature of the bond between two interacting fragments, [ZnPy(R)] and [L]
ligand(Schiff base ligand) in complex (I), the energy-decomposition analysis (EDA) is carried
out at BP86/TZ2P(ZORA)//BP86/def2-SVP with C symmetry. The results indicated that the
int for complex (I) is about 197.3 kcal mol (Table S3). The dissociation of the ꢀEint values
1
-1
∆E
1
1

into the Pauli repulsion ꢀEPauli and the three attractive components shows that roughly 64.5%
comes from the electrostatic attraction (ꢀEelstat) while ~32.4% from the orbital term ꢀEorb and
3.1% from ∆Edisp in complex (I). In addition, the values of ∆Eelstat show that the nature of L→Zn
bonds in the complex is more electrostatic. The covalent bonding between two interacting
+
-
fragments [ZnPy(R)] and [L] (Schiff base ligand) in the complex becomes dominant by the
calculated deformation densities ꢀρ, which are associated with the important orbital interactions
between the corresponding fragments. The EDA-NOCV (energy decomposition analysis- the
natural orbital for chemical valence) method makes it possible to calculate the individual
contributions of pairwise interactions. Usually, there are only a small number of pairwise
interactions that make a significant contribution to ꢀEorb (Table S3). Fig. 4 shows the important
deformation densities (ꢀρ) and the associated energy values which provide about 74.6% of the
overall orbital interactions for [LZnPy(R)] complex. Visual inspection of Fig. 4 indicates that
ꢀρ1, ꢀρ2, ꢀρ3, and ꢀρ5 comes from the Zn←L σ donation from lone pair of N and O atoms of
L ligand (Schiff base ligand) to Zn metal ion in complex (I). Also in last figure, it seems that the
deformation densities ꢀρ3, represent the Zn←L π-donation (Fig. 4). Note that the colour in Fig.
4
denotes the charge flow, which is from the red to the blue region.
Fig.s 3-4.
Table 4.
5
. Molecular docking of DNA, receptor tyrosine kinases (RTKs), nonreceptor tyrosine
kinases (ABL and ARG) and EGFR-TKD
Deoxyribonucleic acid (DNA) is a nucleic acid that be one of the main biological targets for the
cancer therapy, and many compounds as DNA replication inhibitors exert their anticancer effects
through binding to DNA and damage in cancer cells. Also, overexpression or mutational
1
2

activation of some members of receptor tyrosine kinases (RTKs) such as epidermal growth factor
receptor participate in the development and progression of numerous human malignancies such
as gastric cancer, acute myelocytic leukemia and lymphoblastic leukemia (ALL) [58]. Also, the
nonreceptor tyrosine kinases (ABL and ARG) express and regulate diverse cellular functions
including cell proliferation, growth and survival, invasion, morphogenesis, apoptosis and
migration which can lead to cancer. ABL kinase is an important drug target in the treatment and
management of various cancers [59]. Computational docking is extremely potential tool design
of such metal– based compounds and the development of drugs as new therapeutic targets.
Binding affinity between DNA and on co-protein-targeted new drugs is very important in
predicting the binding and in-depth knowledge of cancer molecular mechanisms [59, 60]. The
lowest-energy values of the binding suggest that they reasonably binds to macromolecules. The
docking results are shown as binding free energy in Fig.5a, listed in Table 5, the calculated
minimum relative binding energy (ꢀG) for complex (I) was -7.73 kcal/mol, which determine the
stable binding as between DNA receptor and complex. Moreover, Zn (II) complex could bind to
the minor groove of DNA by intercalating (Fig 5b.) which would affect the stability of DNA,
thus exhibiting the anticancer activities [61-63]. Also, the compound I can interact with DNA
through H-binding bonds of the NH with the backbone phosphate (2.18 and 2.49 Ȧ). The
2
calculated binding free energies complex (I), Afatinib, Erlotinib and Gefitinib with receptor
EGFR-TKD are dominated by the vdW_hb_desolv: -6.47, -7.52, -6.58 and -7.18 kcal/mol,
respectively (Table 5). The crystal structure of the complex (I) with the EGFR-targeted reveals
that complex (I) binds to EGFR in the activation P-loop (Fig 6a) [64]. Also, drugs of anticancer
such as Afatinib, Gefitinib and Erlotinib are docked in the activation P-loop (Fig 6b). In addition
to, compound (I) exhibite hydrogen interactions with SYS A773 and PRO A770 the key
1
3

residues, while Afatinib and Erlotinib interact to MET A769 and SYS A773 the amino acid
residues by hydrogen bonds. Results suggest that compound (I) can be a therapeutic role in
treatment and management of cancer like Afatinib and Gefitinib. The binding free energy
(
ꢀGbinding) of the compound (I) to ABL/dasatinib complex and the ABL/imatinib complex was
obtained as -5.20 and -6.60 kcal/mol, respectively. While the binding free energy of Nilotinib
anticancer drug) for ABL/dasatinib complex and the ABL/imatinib complex is -6.83 and -8.41
(
kcal/mol and the binding free energy of Imatinib (anticancer drug) for ABL/dasatinib complex
and the ABL/imatinib complex is -8.42 and -10.03 kcal/mol, respectively. The hydrogen binding
of compound (I) interact the amino acid residues of ABL/dasatinib complex (TYR A435) and the
ABL/imatinib complex (ALA A395). Our computational studies represented that complex (I)
will use as tyrosine kinase inhibitor in treatment cancer by inhibition of the epidermal growth
factor receptor (EGFR).
Fig.s 5a-b and 6a-b.
Table 5
6
6
. Spectroscopic characterization of the nanoparticle complex (I)
. 1. FT-IR ZnO nanoparticles
The FT-IR spectrum was used to characterize and also confirm the formation of zinc oxide
–
1
nanoparticles of the complex (I) as a precursor (Fig. S4). The absorption band at about 430 cm
corresponds to the vibrational Zn-O band [65, 66]. Characteristic bands of the complex are not
detected, suggesting that they decomposed completely into zinc oxide phase without impurities.
6
.2. X-ray diffraction studies
Fig. S5 shows the XRD pattern of the ZnO nanoparticles obtained via combustion method from
the complex (I). Eight characteristic diffraction peaks at 2θ = 31.72°, 34.39°, 36.22°, 47.50°,
1
4

5
6.55°, 62.84°, 67.91°, and 69.03° corresponding to (100), (002), (101), (102), (110), (103),
(112), and (201) crystal planes can be indexed to Hexagonal ZnO phase with lattice parameters
of a = b = 3.250 A° and c = 5.206 A° according to the standard JCPDS card No. 36–1451[67].
The crystallite size of ZnO was calculated using the Scherrer’s equation (ꢀꢁꢂꢃ = 0.9ꢄλ /β (cosθ))
[68], where D, λ, θ, and β are the average crystalline size, the X-ray wavelength of Cu Kα, the
Bragg’s diffraction angle, and the full width at half maximum (FWHM) of the diffraction peak,
respectively. In this pattern, average particle size at main reflection (2θ = 36.22°) was obtained
as 36.73 nm. As presented in Table S4, a larger 2θ is caused by the larger crystal size. Also, high
purity hexagonal ZnO nanostructure could be obtained via this synthesis method.
6
.3. TEM images
The morphology of the ZnO nanoparticles investigated by TEM is presented in Fig S6. Typical
TEM image clearly shows that the particles of zinc oxide have a homogeneous and uniform
distribution in the rode shape with 5-20 nm width and 20-50 nm length.
7
. Conclusion
In this study, the synthesis and characterization of a new complex of Zn(II) was derived from
Schiff base ligand and a metal with molar ratio 1:2. The structure of the synthesized complex
1
was determined through their FT-IR, H-NMR and UV-Vis data. Moreover, the crystal structure
of complex (I) was characterized by X-ray. Based on all these data, distorted tetrahedral
molecular geometries are suggested for the metal complex. The bonding situation between two
+
-
interacting fragments, [ZnPy(R)] and [L] ligand (Schiff base ligand) in zinc complex, was
characterized by NBO and energy-decomposition analysis (EDA), as well as its natural orbitals
for chemical valence variation (EDA-NOCV). The ETS-NOCV schemes demonstrated that the
1
5

ꢀEorb term mainly arises from Zn←L σ donation, while a smaller contribution comes from
Zn←L σ-donation. Then, it can be claimed that ZnO nanoparticles were successfully fabricated
via combustion synthesis method from complex (I). The morphology and crystalline structure of
the synthesized zinc oxide nanoparticles were studied by FESEM, TEM, FT-IR, and XRD. As a
result, the multifaceted and homogeneous ZnO nanoparticles with appropriate size distribution
and hexagonal crystal phase structures were obtained by this approach. Besides, molecular
docking techniques were exhibited remarkably that the Zn(II) complex bind to the minor groove
of the DNA helix. Also, complex (I) will use as tyrosine kinase inhibitor in treatment cancer by
inhibition of the epidermal growth factor receptor (EGFR).
Acknowledgements
We thank Semnan University for supporting this study.
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3

Table 1. Crystal data, data collection and structure refinement for complex (I).
Parameter
Value
Formula weight
Color and habit
Crystal system
Crystal size, mm
Space group
a, Å
b, Å
c, Å
α, deg
436.61
Colorless, prism
Monoclinic
0.10 × 0.15 × 0.25
P2 /c
1
7.9510(3)
21.2732(9)
10.2429(4)
90
Β, deg
101.557(4)
90
1697.39(12)
4
γ, deg
3
V, Å
Z
-3
ρ calcd, g cm
F(000)
µ, mm )
1.709
872
3.812
−1
Number of unique
data
3287
Number of
restraints
0
Number of
parameters
Goodness of fit on
F2
2
25
1.054
R , wR (I > 2σ(I))
0.0495, 0.0834
0.0364, 0.0777
1
2
R , wR (all data)
1
2

i
Table 2. Selected bond lengths (Å) and bond angles (º) for the complex (I). Symmetry code: 3/2-x,1/2-y,z.
Complex
Bond lengths (Å)
Bond angles (º)
Selected bond
X-ray
Optimized
2.08 (2.02)
2.01 (1.96)
2.06 (2.00)
2.39 (2.38)
Selected angle
X-ray
Optimized
Zn1-O10A(Zn–O1)
Zn1-N7A(Zn-N2)
Zn1-N1B(Zn-N3)
Zn1-Br1
1.959(2)
2.003(3)
2.022(3)
2.3824(5)
N7A-Zn1-O10A(O -Zn-N )
93.48(10)
115.85(7)
108.83(8)
102.58(10)
89.57 (93.49)
118.30 (115.86)
117.03 (108.84)
98.09 (102.54)
1
2
N7A-Zn1-Br1(N -Zn-Br )
2
1
O10A-Zn1-Br1(O -Zn-Br )
1
1
O10A-Zn1-N1B(O -Zn-N )
1
3
N7A-Zn1-N1B(N -Zn-N )
123.16(11)
109.61(8)
118.31 (123.14)
111.80 (109.62)
2
3
N1B-Zn1-Br1(N -Zn-Br )
3
1
Table 3. Hydrogen bond data (Å, º) for complex (I).
D
H
A
D-H
0.92 (6)
0.86(5)
0.95
H···A
2.23(6)
2.87(5)
2.43
D···A
D-H···A
142(4)
151(4)
164
N2B
N2B
C3B
C6B
H2B1
H2B2
H3B
H6B
N1A
Br1
O10A
O10A
3.015(5)
3.649(4)
3.356(5)
3.137(4)
i
i
0.95
2.52
123

Table 4. Wiberg bond indices (WBI) of complex (I) at BP86/def2-SVP level of theory.
WBI
0.30
0.30
0.32
0.60
Zn-N (Zn1-N7A)
2
Zn-N (Zn1-N1B)
3
Zn–O (Zn1-O10A)
1
Zn–Br1
Table 5. The epidermal growth factor receptor (1M17), the Abelson leukemia virus protein kinase (2GQG) and (2HYY) docking results with the
complex Zn (Unit:kcal/mol)
DNA
-7.73
-8.55
-8.44
-0.12
-1.51
0.82
EGFR-TKD
2GQG
-5.20
-6.09
-6.05
-0.04
-1.68
-0.89
-1.68
2HYY
-6.60
-7.50
-7.51
-0.01
-1.68
-0.89
-1.68
*
Estimated Free Energy of Binding (kcal/mol )
-6.47
Final Intermolecular Energy (kcal/mol )
vdW + Hbond + desolv Energy (kcal/mol )
Electrostatic Energy (kcal/mol )
-7.36
-7.19
-0.17
-1.7
Final Total Internal Energy (kcal/mol )
Torsional Free Energy (kcal/mol)
-0.89
-1.7
Unbound System's Energy (kcal/mol )
-1.51

Fig. 1. A perspective view of the complex (I); ellipsoids are drawn at the 50% probability
level, hydrogen atoms are shown as spheres of arbitrary radii. Intramolecular hydrogen bond
is shown as dashed blue line.
Fig. 2. Crystal structure of complex (1), as seen along z-direction; hydrogen bonds are shown
as thin lines.

Fig. 3. Optimized geometries of complex (I) at BP86/def2-SVP level of theory.
Fig. 4. Deformation densities ∆ρ associated with the most important orbital interactions in
complex (I).
.