Synthesis, theoretical investigations, biocidal screening, DNA binding, in vitro cytotoxicity and molecular docking of novel Cu (II), Pd (II) and Ag (I) complexes of chlorobenzylidene Schiff base: Promising antibiotic and anticancer agents

Article abstract of DOI:10.1002/aoc.4527

Three new Cu (II), Pd (II) and Ag (I) complexes of bidentate Schiff base ligand 2-[(4-chlorobenzylidene)amino] phenol (HL) were synthesized. The stoichiometric ratios and physicochemical properties of these complexes were determined using elemental analys

Full text of DOI:10.1002/aoc.4527

Received: 26 April 2018
DOI: 10.1002/aoc.4527
Revised: 27 June 2018
Accepted: 3 July 2018
F U L L P A P E R
Synthesis, theoretical investigations, biocidal screening,
DNA binding, in vitro cytotoxicity and molecular docking of
novel Cu (II), Pd (II) and Ag (I) complexes of
chlorobenzylidene Schiff base: Promising antibiotic and
anticancer agents
1
1,2
1
Laila H. Abdel‐Rahman
| Mohamed Shaker S. Adam
| Ahmed M. Abu‐Dief
|
3
4
5
6
H. Moustafa | Maram T. Basha | Ahmed S. Aboraia | Badriah Saad Al‐Farhan |
1
Hanan El‐Sayed Ahmed
1
Chemistry Department, Faculty of
Three new Cu (II), Pd (II) and Ag (I) complexes of bidentate Schiff base ligand
2‐[(4‐chlorobenzylidene)amino] phenol (HL) were synthesized. The stoichio-
metric ratios and physicochemical properties of these complexes were deter-
mined using elemental analyses, magnetic measurements, infrared and UV–
visible spectra, molar conductivity measurements and thermal analyses. The
results revealed that the metal ions coordinated with through azomethine
nitrogen and phenolic oxygen atoms. AgL and PdL complexes are present in
a 1:1 molar ratio with square planar and tetrahedral geometry, respectively,
Science, Sohag University, Sohag, Egypt
2
Department of Chemistry, College of
Science, King Faisal University, Al Hufuf,
Al Hassa, Saudi Arabia
3
Chemistry Department, Faculty of
Science, Cairo University, Giza, Egypt
4
Department of Chemistry, Faculty of
Science, University of Jeddah, Jeddah,
Saudi Arabia
5
Medicinal Chemistry Department,
while CuL complex is present in a 1:2 molar ratio with octahedral geometry.
2
Faculty of Pharmacy, Assiut University,
Assiut, Egypt
The electronic structure and nonlinear optical parameters of HL and the stud-
6
Department of Chemistry, Faculty of
ied 1:1 and 1:2 complexes were investigated theoretically at the DFT‐B3LYP/6‐
Girls for Science, King Khalid University,
Abha, Saudi Arabia
311G** level of theory. The compounds were screened against various strains
of bacteria and fungi. They displayed good results for inhibition against the
studied pathogenic microorganisms. Absorption spectroscopic, viscosity and
gel electrophoresis measurements were used for studying the interaction of
the prepared complexes with calf thymus DNA (CT‐DNA). The studied com-
plexes showed a good interaction with CT‐DNA via intercalation and groove
modes. Moreover, molecular docking of these complexes was studied to under-
stand the drug–DNA interactions and calculate the potential binding mode and
energy. The anticancer effects of HL and its complexes, on selected human car-
cinoma cell lines, were determined. The cytotoxicity results showed that the
prepared complexes are more potent than the Schiff base ligand.
Correspondence
Laila H. Abdel‐Rahman and Ahmed M.
Abu‐Dief, Chemistry Department, Faculty
of Science, Sohag University, Sohag 82534,
Egypt.
Email: lailakenawy@hotmail.com, laila.
abdelrahman@science.sohag.edu.eg;
ahmed_benzoic@yahoo.com
KEYWORDS
chlorobenzilidine, CT‐DNA, cytotoxicity, docking, NLO properties
Appl Organometal Chem. 2018;e4527.
wileyonlinelibrary.com/journal/aoc
© 2018 John Wiley & Sons, Ltd.
1 of 21
https://doi.org/10.1002/aoc.4527

2
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ABDEL‐RAHMAN ET AL.
1
| INTRODUCTION
2 | EXPERIMENTAL
Schiff base ligands have received much attention in
recent years due to their ability to coordinate with var-
ious metal ions and their potent applications in medi-
The materials and instrumentation used in this study are
given in the supporting information (S1).
[
1]
cine and pharmacy because of their antibacterial,
[
2]
[3]
[4]
2.1 | Synthesis of Ligand
anticancer,
antifungal,
anti‐tubercular
and anti‐
[5]
inflammatory activities. Bidentate Schiff base ligand
The ligand 2‐[(4‐chlorobenzylidene)amino] phenol (HL)
was synthesized by adding an ethanolic solution (20 ml)
of 4‐chlorobenzaldehyde (10 mmol, 1.40 g) to an
ethanolic solution (20 ml) of 2‐aminophenol (10 mmol,
of 2‐aminophenol and 4‐chlorobenzaldhyde has various
[6,7]
clinical and biological applications.
In fact, Pd (II)
complexes have a significant anti‐tumour activity with
minimum side effects compared to cisplatin which
has some drawbacks such as nephrotoxicity, drug resis-
1.09 g). This mixture was stirred under reflux at 70°C
for 2 h using triethylamine as a catalyst and then allowed
to cool to room temperature to afford a yellow solid pre-
cipitate. The obtained precipitate was then filtered and
washed with ethanol.
[8–10]
tance and cervical renal problems.
Palladium (II)
complexes show structural properties similar to those
of Pt (II) and promising cytotoxicity, so they are suit-
able for metallodrugs. Silver (I) complexes have great
Yield 78%; yellow colour; m.p. >115°C. FT‐IR (KBr, cm
[11]
biological therapeutic activities.
Furthermore, Cu
−1
1
)
: 1624 (C¼N), 3302 (―OH). H NMR (DMSO‐d , δ,
6
(II) complexes are used as anticancer agents due to
ppm): 8.98 (s, 1H, OH), 8.73 (s, 1H, N¼CH), 7.24–7.22 (d,
their selective permeability of cancer cell membranes.
However, there is no systematic study of the electronic
structures and nonlinear properties of the studied com-
plexes. Therefore, such study is important for under-
standing the activity and nonlinear optical (NLO)
properties of these complexes. Nonlinear optics explains
the response of nonlinear properties such as polariza-
2
2
H, 2CH ), 7.10–7.08 (d, 2H, 2CH ), 6.92–6.90 (d, 2H,
ar
ar
13
CH ), 6.85–6.83 (d, 2H, 2CH ). C NMR (DMSO‐d , δ,
ar
ar
6
ppm): 114.83 (CH), 115.16 (CH), 116.42 (CH), 117.32
(
(
CH), 119.58 (CH), 120.14 (CH), 128.19 (CH), 129.25
CH), 129.8 (CH), 130.88 (C , CH―Cl), 131.64 (C ,
q
q
CH―CH¼N), 158.50 (C , CH―OH), 192.75 (CH¼N).
q
Anal. Calcd for C H NClO (%): C, 67.39; H, 4.32; N,
13
10
[
12]
tion, frequency, path or phase of incident light.
6.05. Found (%): C, 67.30; H, 3.8; N, 6.13.
One of the NLO phenomena is second harmonic gener-
ation where intense light of longer wavelength is con-
verted to light of wavelength of half of the incident
value, upon absorption by a NLO material.
2.2 | Synthesis of Metal Complexes
.2.1 | Synthesis of CuL complex
2
2
From this point of view, the aim of the investigation
reported here was to synthesize a Schiff base ligand from
the condensation of 2‐aminophenol and 4‐chloro-
benzaldehyde and its Pd (II), Ag (I) and Cu (II) complexes
and to characterize them via various analytical and phys-
ical tools. The geometrical parameters, electrostatic
potential and natural bond order (NBO; natural charges,
natural population and natural configuration) of the
investigated ligand and its complexes were calculated,
using B3LYP/6‐311G**. The electronic dipole moment
CuCl
⋅2H O (5 mmol, 0.85 g) was dissolved in 20 ml of
2
2
commercial ethanol and added to HL (10 mmol, 2.31 g)
dissolved in acetone (20 ml). Then, the obtained mixture
was stirred for 1 h and evaporated overnight to afford a
black complex precipitate. The obtained precipitate was
filtered, washed with ethanol and finally kept in a
desiccator.
2.2.2 | Synthesis of PdL complex
(
μ) and first‐order hyperpolarizability (β) values of the
studied complexes were computed to study the NLO
properties. Global reactivity descriptors, namely electro-
negativity (χ), hardness (η) and softness (S), of the stud-
ied complexes were calculated and analysed. Moreover,
antibacterial and antifungal bioassays were conducted
and the interaction with calf thymus DNA (CT‐DNA)
of these complexes was evaluated. In addition to that,
we investigated their anticancer activity towards various
cancer cell lines. Biological applications of the prepared
compounds were confirmed via performing molecular
docking study.
The PdL complex was synthesized by mixing 5 mmol of
Pd (OAc) (1.12 g) dissolved in acetone (20 ml) with 5
2
mmol of HL (1.15 g) dissolved in acetone (20 ml). The
solution was stirred under reflux at 50°C for 2 h to afford
a dark brown precipitate. Then, the obtained precipitate
was filtered, washed with ethanol and dried over anhy-
drous CaCl .
2
1
H NMR (DMSO‐d , δ, ppm): 8.29 (s, 1H, N¼CH),
6
7.43–7.42 (d, 2H, 2CH ), 7.26–7.21 (d, 2H, 2CH ), 7.08–
ar
ar
7.06 (d, 2H, 2CH ), 6.36–6.32 (d, 2H, 2CH ), 2.49 (s,
ar
ar
3H, OCOCH3).

ABDEL‐RAHMAN ET AL.
3 of 21
2
.2.3 | Synthesis of AgL complex
2.5 | Kinetic Studies of Schiff Base Metal
Complexes
The AgL complex was prepared by mixing AgNO (5
3
mmol, 0.849 g) dissolved in commercial ethanol (20 ml)
with HL (5 mmol, 1.15 g) dissolved in acetone (20 ml)
and was stirred for 1 h, whereupon a black complex pre-
cipitated. This precipitate was collected by filtration, puri-
fied by washing several times with diethyl ether and dried
The integral method of the Coats–Redfern equation was
used for determining the kinetic parameters of the
decompositions process for the metal complexes accord-
[
17,18]:
ing to the following equation
ꢀ
ꢁ
ꢀ
ꢂ
ꢃꢁ
log½w∞=ðw∞ − wÞꢀ
AR
ϕE*
2RT
E≠
over anhydrous CaCl .
2
log
¼ log
1 −
(4)
2
1
T
H NMR (DMSO‐d , δ, ppm): 8.23 (s, 1H, N¼CH),
6
7
7
.48–7.45 (d, 2H, 2CH ), 7.27–7.25 (d, 2H, 2CH ), 7.19–
ar
ar
E≠
1
.08 (d, 2H, 2CH ), 6.80–6.47 (d, 2H, 2CH ).
−
ar
ar
2
:303RT
where w∞ is the mass loss at the accomplishment of the
decomposition reaction, w is the mass loss at temperature
T, ϕis the rate of heating and R is the universal gas con-
stant. The left‐hand side of equation (4) is plotted against
2
.3 | Estimation of Stoichiometry of
Complexes
Estimation of stoichiometry for the prepared complexes
was done from the molar ratio and the continuous varia-
tion methods.
combined, stirred and allowed to equilibrate. The absor-
bance was measured at λmax for each solution and plotted
against the mole fraction of metal ion or the mole fraction
of ligand.
*
≠
1/T since 1 – 2RT/E ≈1. E and A were estimated from
[13–15]
Metal salt and ligand solutions were
the slope and the intercept of this plot, respectively. The
≠
enthalpy of activation (ΔH ), the entropy of activation
≠
≠
(ΔS ) and the activation free energy change (ΔG ) were
[
16–18]:
determined from the following relations
≠
≠
ΔH ¼ E − RT
(5)
(6)
(7)
2
.4 | Estimation of Apparent Formation
ꢂ
ꢃ
Ah
Constants of Complexes
≠
ΔS ¼ 2:303R log
kbT
From the results of the continuous variation method, the
PdL and AgL complexes are present in a 1:1 molar ratio
while the CuL complex is present in a 1:2 molar ratio.
≠
≠
ΔG ¼ ΔH − TΔS
2
Thus the formation constants (K ) of these complexes
f
where h and k are the Planck and Boltzmann constants,
respectively.
b
were obtained from spectrophotometry measurements
[16,17]:
according to the following relations
2
.6 | Computational Methods
A=Am
Kf ¼
in the case of
(1)
(2)
2
ð1−A=A Þ C
All computations were carried out using the Gaussian
m
[
19]
1
:1 molar ration
in the case of
2
09W software package.
Molecular geometries of all
the studied complexes were fully optimized using the
B3LYP/GENECP level of theory. For H, C, N, Cl and O
atoms, the 6‐311G** basis set was used and Los Alamos
National Laboratory Double Zeta (LANL2DZ) basis set
for Ag, Cu and Pd atoms.
mization, no symmetry constraints were applied.
HOMO and LUMO energy values of complexes were uti-
lized to calculate the electronegativity and chemical hard-
ness as follows: χ = (I + A)/2 (electronegativity), η= (I −
A)/2 (chemical hardness), S = 1/2η(chemical softness),
where I and A are ionization potential and electron affin-
A=Am
Kf ¼
3
4
ð1−A=A Þ C
m
1
:2molar ration
[
20–23]
During the geometry opti-
[
24]
where A is arbitrarily selected from the values of absor-
bance on either side of the absorbance peak, Am is maxi-
mum absorbance for the prepared complexes and C is the
primary molar metal concentration. Also, ΔG (the free
energy change of the complexes) was determined at
≠
[16,17]:
2
5°C using the following relation
[
25,26]
ity, respectively, and I = −EHOMO and A = −ELUMO
.
≠
NBO calculations were carried out at the B3LYP/6‐31G**
level to qualitatively calculate the intermolecular charge
delocalization in the complexes. Throughout this work,
molecular orbitals were constructed using the GaussView
ΔG ¼ −RT lnKf
(3)
where K is the formation constant, R is the gas constant
and T is the temperature in kelvin.
f

4
of 21
ABDEL‐RAHMAN ET AL.
[
27]
5
.08 visualization program.
The total static dipole
were separated from the infected parts of the host plant.
The fungal strains were directly mixed with potato dex-
trose agar and dispersed into Petri dishes. Filter paper
discs were saturated with DMSO solutions of the studied
moment (μ), the mean polarizability <α>, the anisotropy
of the polarizability Δαand the mean first hyper-
polarizability <β> using the x, y, z components were cal-
[28,29]:
−1
culated using the following equations
compounds with concentrations of 10 and 20 mg ml .
ꢄ
ꢅ
These plates were placed in an incubator at 35°C for 72
h. The results were recorded as zones of inhibition and
were compared with fluconazole as standard drug.
1=2
2
x
2
y
2
z
u ¼ u þ u þ u
(8)
À
Á
α þ α þ α
xx
yy
zz
α ¼
(9)
(10)
(11)
2
.9 | Binding of Schiff Base Metal
3
Complexes with CT‐DNA
ꢄ
ꢅ
À
Á
À
ꢄ
Á
1=2
2
2
2
CT‐DNA was dissolved in Tris–HCl buffer (60 mM, pH
=
protein contamination such that CT‐DNA solution gave
a ratio of UV absorption at 260/280 nm equal to 1.92.
The stock solution of CT‐DNA was stored at 4°C.
Δα ¼ αxx−αyy þ α −α
þ ðα −α Þ
yy
zz
zz
xx
7.2) by sonication. CT‐DNA was sufficiently free from
ꢅ
1
=2
2
x
2
2
z
β ¼ β þ β þ β
y
βx ¼ βxxx þ βxyy þ βxzz
βy ¼ βyyy þ βxxy þ βyzz
βz ¼ βzzz þ βxxz þ βyyz
(12)
(13)
(14)
2
.9.1 | Electronic spectroscopy for inter-
action of complexes with CT‐DNA
The complexes were dissolved in dimethylformamide
(
DMF) solvent. Electronic spectra were obtained by keep-
ing the complex concentrations constant while changing
the CT‐DNA concentration in the interaction medium.
The absorption due to free CT‐DNA was eliminated by
adding an appropriate amount of CT‐DNA to both com-
plex solution and reference solution and the spectral data
obtained were considered to result from the DNA–metal
complex aggregation. From the electronic spectral data,
Kb (the intrinsic binding constant) was estimated from
plotting [DNA]/(ε − ε ) versus [DNA] according to the
2
.7 | Antibacterial Bioassay
The antibacterial activities of the synthesized compounds
were screened against three bacterial strains, Escherichia
coli (−ve), Bacillus subtilis (+ve) and Staphylococcus
aureus (+ve), using the agar well dilution method.
The compounds were dissolved in dimethylsulfoxide
[
30–35]
a
b
[
30–35]:
following relation
−
1
(
DMSO) with concentrations of 10 and 20 mg ml .
½
DNAꢀ
1
1
1
Nutrient agar was prepared, then sterilized in an auto-
clave and poured in sterile Petri plates. After cooling of
nutrient agar in the Petri plates, the studied organisms
were grown on the agar. After that, sterile paper discs
¼
½DNAꢀ
þ
Kb εb − εf
(15)
εa − εf
εb − εf
where [DNA] is the molar concentration of CT‐DNA in
base pairs, ε , ε and ε are the extinction coefficients of
free, apparent and fully bound complex, respectively.
Parameters ε and ε were estimated from the isolated
metal complex calibration curve Aabs/[complex] and
DNA calibration curve Aabs/[DNA], respectively. K was
calculated from the ratio of slope to intercept of this plot.
ΔG (standard Gibbs free energy) for DNA binding was
calculated from the following equation
f
a
b
(
Whatman) each saturated with a solution of the pre-
pared compounds were placed in the agar by working
holes using a sterile cork borer. The Petri dishes were
f
a
[30–36]
incubated for 24 h at 37°C.
The standard drug
b
gentamycin was screened under similar conditions for
comparison. DMSO has no activity against the microbial
strains and was used as a negative control.
≠
b
[
30–35]:
≠
b
2.8 | Antifungal Bioassay
ΔG ¼ −RT lnKb
(16)
The antifungal activities of the synthesized ligand and its
complexes were studied against three fungal strains, Can-
dida albicans, Aspergillus flavus and Trichophyton
rubrum, using the well diffusion method with potato dex-
2
.9.2 | Viscosity measurements for inter-
action of complexes with CT‐DNA
An Oswald micro‐viscometer was used for measuring the
viscosity of the synthesized complexes with CT‐DNA at a
[30–36]
trose agar as the environment.
These fungal species

ABDEL‐RAHMAN ET AL.
5 of 21
constant temperature of 25°C. With maintaining the con-
centration of CT‐DNA constant (420 μM), the fluidity
times were registered for various concentrations of the
complexes (0–250 μM). Bubbling nitrogen gas was used
to mix the solution through the viscometer. The viscosity
of the complexes with CT‐DNA was measured from the
mean value of three readings. The relative viscosity for
the complexes with CT‐DNA (η°) was estimated from
molecular docking through the following steps: hydrogen
atoms were added, conformational search was applied to
all the compounds and the best conformers underwent
[
38]
energy decrease using the MMFF94 force field.
Energy
decrease with the steepest algorithm was applied, after
which conjugate gradient method was run until it reached
−
1
−1
an RMS gradient of 0.00001 kcal mol Å . A database of
HL and its complexes was generated for further docking
studies. The standard protocol of the docking was used in
MOE 2016.08. The Alpha Triangle placement that derives
poses by random superposition of the ligand HL atom trip-
lets alpha sphere dummies in the target site was used to
detect the poses. The London dG scoring function esti-
mated the free binding energy of the ligand from a given
pose. A number of 50 cycles of calculation was used to esti-
mate the best poses of the docked molecules. The produced
dock file was created with different poses for the investi-
gated ligand and arranged according to the final score
function (S). S is the score of the last stage that was not
set to None. The database browser was used for examining
the different poses that were selected for the best ones.
[30–35]:
the following relation
t − t°
t°
η ¼
(17)
where t is the time for fluidity observed in seconds, t° is
the time for fluidity of buffer in seconds and η/η° (the rel-
ative viscosity) was plotted against 1/R, where
½
DNAꢀ
R ¼
(18)
½
complexꢀ
2.9.3 | Gel electrophoresis for interaction
of complexes with CT‐DNA
2.11 | Anticancer Activity
Gel electrophoresis is used as a method for studying the
[30–35,37]
binding of complexes with DNA.
The complexes
The studied compounds were examined against Hep‐G2
cell line (hepatocellular carcinoma), MCF‐7 cell line
(breast carcinoma) and HCT‐116 cell line (colon carci-
noma) at Cairo University, Pharmacology Department,
Cancer Biology Department and the National Cancer
Institute. The absorbance for each well was determined
with an ELISA microplate reader (Σ960, Meter Tech,
USA) at 564 nm. Firstly, in a 96‐multiwell plate, cells
were placed (104 cells per well) for 24 h at 37°C. Sec-
ondly, various concentrations in DMSO of the com-
pounds (0, 1, 2.5, 5 and 10 μM) were added to this
plate. Thirdly, the plate was incubated for 48 h at 37°C
were added to CT‐DNA in equal volume and incubated
at 37°C for 1 h. After that, the mixtures were mixed with
DNA Loading Dye at a 1:1 molar ratio and then loaded
onto the gel (1%) in TAE buffer. A constant voltage (100
V) was applied for 60 min. Finally, the gel was imagined
under UV light using a transilluminator. Panasonic
DMC‐LZ5 Lumix DNA gel documentation system (In
genius3) was used for photographing the illuminated gel.
2.10 | Molecular Docking
A Dell Precision™T3600 Workstation (Intel Xeon E5‐1660
.3 GHz, ECC RDIMM 1 TB (7200 RPM), 1 GB NVIDIA
and in an atmosphere of 5% CO . After that, the plate
2
3
was fixed, rinsed and stained with sulforhodamine B
stain. Acetic acid was used to remove excess stain and
then the plate was treated with Tris–EDTA buffer. An
ELISA reader was used to measure the intensity of col-
our. The inhibitory concentration (IC ) was estimated
Quadro 2000, 16 GB 1600 MHz DDR3, Windows 7 Profes-
sional (64 bit)) was used to study the molecular docking of
the complexes. Molecular Operating Environment MOE
package version 2016.08 was used for the docking studies.
X‐ray crystal structure of a B‐DNA dodecameric d (CGCG
5
0
[
30–32,37]:
according to the following equation
AATTCGCG) running 3′‐5′direction (PDB ID: 1BNA)
2
ControlOD − compoundOD
was used to study the docking at 1.9 Å resolution. The
structure of DNA was imported into MOE and hydrogen
atoms were added and then subjected to the optimization
of energy. The resulting model was subjected the search
of systematic conformation with a gradient of RMS of
IC50 ð%Þ ¼
× 100
(19)
ControlOD
3
| RESULTS AND DISCUSSION
.1 | Infrared (IR) Spectroscopy
−
1
0
.01 kcal mol using default parameters in the Site Finder
3
tool embedded in MOE. HL and its complexes were visual-
ized by ChemBioDraw Ultra 12.0 for further preparation in
the MOE. HL and its complexes were prepared for
The nature of functional groups bonded to the metal ions
was identified using IR spectroscopy. The IR characteristic

6
of 21
ABDEL‐RAHMAN ET AL.
42]
[
frequencies for HL and its complexes along with their
assignments (Figures S1 and S2) are recorded in Table 1.
Bands due to ―OH and ―CH¼N groups are distinctive
and offer proof regarding the structure of HL and its bond-
ing with metals. A band at 1624 cm in the ligand spec-
trum is due to ―C¼N bond stretching vibration. On
complexation, this band is shifted to 1586, 1590 and 1630
cm in the spectra of CuL , PdL and AgL, respectively.
The change of this band is a distinct indication of the
involvement of the azomethine nitrogen atoms in complex
ions indicating its involvement in coordination.
The
1
H NMR spectrum of the PdL complex shows a singlet
signal at 2.45 ppm which is assigned to (OCOCH ) pro-
3
tons, indicating that this group binds to the metal ions
−
1
1
in the complex. The H NMR spectrum of CuL cannot
2
be measured due to the interference of its paramagnetic
[
30]
properties.
−
1
13
The C NMR spectrum of HL (Figure S5) exhibits a
signal at 192.75 ppm that may be assigned to azomethine
carbon. The signals appearing in the region 114.83–158.50
ppm are assigned to phenyl carbons.
2
[30,39]
formation.
This is supported by the appearance of
−
1
bands at 543, 501 and 515 cm corresponding to the
stretching vibration of M―O bond for CuL , PdL and
AgL, respectively. Bands at 483, 435 and 475 cm corre-
2
−
1
3.3 | Electronic Spectroscopy
spond to the stretching vibration of M―N bond in CuL ,
2
−1
The electronic spectral data coupled with magnetic
[33–35]
PdL and AgL, respectively.
The band at 3302 cm
moment values suggest a structural geometry for the pre-
observed in the ligand spectrum is due to stretching vibra-
[43]
pared complexes.
Electronic spectroscopy was used for
tions of free ―OH. This band is shifted to 3316, 3424 and
confirming the stereochemistry of metal ions in the com-
−
1
3
424 cm in the spectra of CuL , PdL and AgL, respec-
2
plexes depending on the positions and number of d–d
−
1
tively. The band at 828–834 cm (OH rocking) suggests
[30–32,37]
transition peaks.
The values of the maximum
the presence of coordinated water in all the prepared com-
absorption wavelength (λmax) and the molar absorptivity
εmax) are listed in Table 2 and the spectra are presented
[40]
plexes. In the low‐frequency region, th ligand spectrum
(
−
1
shows an absorption band at 1198 cm which can result
in Figure 1. The electronic absorption spectra of HL and
its complexes were recorded in the wavelength range
from the stretching vibration for the phenolic group
(CO). The shifting of that band to lower wavenumber on
200–800 nm and at 298 K. The n → π* transition of HL
coordination shows that the oxygen atoms of the phenolic
appeared around λmax = 288 nm in the UV–visible region.
The ligand‐to‐metal charge transfer (LMCT) band
appears around λmax = 483, 489 and 468 nm in the
[30]
groups are coordinated to the metal centre.
1
13
absorption spectra of CuL , PdL and AgL, respectively.
2
3
.2 | H NMR and C NMR Spectra
The d → d transition band for the CuL , PdL and AgL
2
NMR spectroscopy was used to confirm the identity of the
complexes appears in the region 501–557 nm.
1
compounds. The H NMR spectrum of HL (Figure S3)
shows two singlet signals at 8.73 and 8.98 ppm assigned
to azomethine (CH¼N) proton and one phenolic ―OH.
Moreover, it shows multiple signals at 6.83–7.24 ppm
for eight aromatic protons. The higher values of δ for
the ―OH group can be assigned to the presence of inter-
3.4 | Spectrophotometric Determination
of Stoichiometry of Complexes
3.4.1 | Continuous variation and molar
ratio methods
[41]
molecular hydrogen bonding.
For the PdL and AgL
1
complexes (Fig. S4), their H NMR spectra show singlet
signals at 8.23 and 8.29 ppm which are assigned to
azomethine (CH¼N) proton, respectively, so the change
of the position of HC¼N group signal indicates that it
participates in bonding with the metal ions. The hydroxyl
group signal disappeared on complexation with metal
Continuous variation and molar ratio methods were used
for determining the stoichiometry of the prepared com-
[
44–48]
plexes.
The continuous variation curve displays
absorbance maximum at a mole fraction of ligand of
0.5–0.7 showing the complexation of Cu (II) ion to the
ligand in a molar ratio of 1:2 and of Pd (II) and Ag (I) ions
−
1
TABLE 1 Characteristic IR bands (cm ) of HL and its metal complexes
Compound
ν(OH)/H
2
O
ν(CH)ar
ν(C¼N)
ν(C―O)
ν(M―O)
ν(M―N)
HL
3302
3316
3424
3423
3044
3051
3054
3071
1624
1586
1590
1630
1198
1087
1150
1114
—
543
501
515
—
483
435
475
CuL
PdL
AgL
2

ABDEL‐RAHMAN ET AL.
7 of 21
TABLE 2 Electronic spectral measurements of HL and its metal complexes
3
−1
−1
Compound
λmax (nm)
ε (dm mol mm
)
Assignment
HL
239
536.87
539.82
539.82
395.28
π→π*
π→π*
n→π*
Intra‐ligand band
251
288
354
CuL
PdL
AgL
2
239
5375.37
5795.80
5915.91
5135.13
5675.68
3423.42
π→π*
π→π*
n→π*
Intra‐ligand band
LMCT band
d–d band
251
288
360
483
557
239
5075.08
5195.20
5375.37
4504.50
5075.38
5165.17
π→π*
π→π*
n→π*
Intra‐ligand band
LMCT band
d–d band
251
288
355
489
525
239
1990.00
1960.00
465.00
370.00
340.00
π→π*
π→π*
Intra‐ligand band
LMCT band
d–d band
246
409
468
501
FIGURE 2 Curves of Job's method of the metal complexes in
aqueous ethanol medium at [HL] = [M] = 10 M at 298 K
FIGURE 1 Electronic spectra of HL and its metal complexes in
DMF at 298 K
−
3
to the ligand in a molar ratio of 1:1 (Figure 2). The molar
ratio curve confirmed the same molar ratio of metal ions
to ligand (Figure S6).
The obtained K values show the high stability of the pre-
f
pared complexes. The K values increase in the following
f
order: AgL <PdL <CuL . Moreover, the stability constant
2
≠
(
pK) and Gibbs free energy (ΔG ) values of the complexes
were estimated. The negative values of Gibbs free energy
[13–17]
3.4.2 | Determination of apparent forma-
show that the reaction is spontaneous and favoured.
tion constants for complexes
3.5 | Elemental Analyses
The formation constants (K ) of the prepared complexes
f
were calculated from spectrophotometry measurements
by utilizing the continuous variation method (Table 3).
The elemental analyses results for HL and its complexes are
listed in Table 4. These suggest that HL forms complexes

8
of 21
ABDEL‐RAHMAN ET AL.
≠
TABLE 3 Values of formation constant (K
f
), stability constant (pK) and Gibbs free energy (ΔG ) for Schiff base metal complexes
≠
−1
Complex Type of complex
K
f
pK
ΔG (kJ mol
)
9
5
5
CuL
PdL
AgL
2
1:2
1:1
1:1
10.88 × 10
14.38 × 10
1.90 × 10
10.04
6.16
5.28
−57.26
−35.13
−30.11
TABLE 4 Physical and analytical data of HL and its metal complexes
−
1
Analysis: found (calcd)
C (%) H (%) N (%)
Compound
Molecular formula
Molecular
weight
M.p. and dec.
temp. (°C)
Λ
m
(Ω
2
−1
Colour
cm mol
)
μ
eff (BM)
HL C13
CuL
PdL C15
AgL C13
H
10NClO
Cl
14NClO
13NClO
231.5
Yellow
Black
115
—
—
67.30 (67.39) 4.38 (4.32) 6.13 (6.05)
54.03 (53.93) 4.07 (4.15) 4.90 (4.84)
2
C
26
H
24
N
2
2
O
5
Cu 578.5
(<300)
20.80
4.00
7.70
1.47
H
4
Pd
Ag
413.9
374.3
Dark brown (<300)
Black (<300)
Diamagnetic 43.59 (43.49) 3.50 (3.38) 3.46 (3.38)
Diamagnetic 41.80 (41.68) 3.40 (3.47) 3.86 (3.74)
H
3
with Cu (II) ion in a molar ratio of 1:2 and with Pd (II)
and Ag (I) ions in a molar ratio of 1:1.
and have tetrahedral and square planar geometries,
respectively.
[39,42]
[42]
3.6 | Electrical Conductivity
3.8 | Mass Spectra
Measurements
Mass spectra were obtained at 250°C and 70 eV in elec-
tron ionization mode. The observed molecular ions peaks
are in good agreement with results from elemental analy-
ses (Figure 3, and Figures S7 and S8). The mass spectra of
All prepared complexes are non‐electrolytes due to the
absence of any counter ions in their structures. The
values of molar conductance are 20.80, 4.00 and 7.70
−
1
2
−1
[39]
Ω
cm mol for CuL , PdL and AgL, respectively, in
complexes confirm their stoichiometry.
2
[30–35]
DMF at room temperature (Table 4).
3
.9 | Thermogravimetric Analysis
3
.7 | Magnetic Measurements
Thermal analysis was used to evaluate the stability of the
metal complexes and the existence of water molecules
inside or outside the central metal ion coordination
The geometric structure of the prepared complexes was
confirmed using magnetic measurements. The observed
magnetic moments for the prepared complexes are listed
[
30]
sphere.
The thermograms of the studied complexes
in Table 4. The CuL complex is paramagnetic and has
indicate the presence of one hydrated and two coordi-
2
an octahedral geometry corresponding to one electron
nated water molecules in the CuL complex, one mole-
cule of coordinated water in the PdL complex and two
2
[44]
pair.
The PdL and AgL complexes are diamagnetic
2
FIGURE 3 Mass spectrum of the CuL complex

ABDEL‐RAHMAN ET AL.
9 of 21
molecules of coordinated water in the AgL complex. The
thermal behaviour of the studied complexes shows loss of
hydrated or/and coordinated water molecules in the first
step; then degradation of the HL molecule in the next
step (Table 5).
coordinated water molecules with mass loss of 9.69%
(calcd 9.60%). The second stage at 220–420°C corresponds
to the removal of part of the ligand (C H Cl) with mass
loss of 33.20% (calcd 33.30%). The third step within the
range 420–630°C involves removal of organic ligand moi-
7
5
The thermogram of CuL shows five degradation steps
ety to finally give ½Ag O as a residue with a net weight
2
2
within the range 37–608°C. The first stage at 37–196°C
corresponds to the elimination of one hydrated and two
coordinated water molecules with mass loss of 9.25%
loss of 30.79% (calcd 30.90%).
3
.9.1 | Kinetic parameters for thermal
(calcd 9.32%). The second stage at 200–300°C corresponds
degradation of complexes
to the removal of part of the ligand (C H Cl) with mass
6
4
≠
loss of 19.35% (calcd 19.28%). The third stage at 300–
33°C corresponds to the removal of part of HL
C H NCl) with mass loss of 23.85% (calcd 23.94%).The
The energy of activation (E ), Arrhenius constant (A),
≠
≠
4
entropy of activation (ΔS ), enthalpy of activation (H )
≠
(
and free energy change (ΔG ) were determined by the
7
5
fourth stage at 435–540°C corresponds to the removal of
Coats–Redfern relation. The obtained data are given in
Table 5. In most thermal steps, S≠ values are negative
suggesting degradation through an abnormal pathway
for those steps and the degradation processes are
part of HL (C H O) with mass loss of 15.99% (calcd
6
4
1
5.91%). The fifth stage at 540–608°C corresponds to the
removal of other parts of the ligand with mass loss of
≠
1
7.72% (calcd 17.81%) to give CuO as a residue.
unfavourable. The H values are positive indicating that
[
30–33,37]
The thermal analysis curve of the PdL complex shows
degradation processes are endothermic.
It is evi-
≠
four degradation steps within the range 37–614°C. The
first stage at 37–160°C corresponds to the elimination of
one coordinated water molecule with mass loss of 4.47%
dent that the G values increase with increasing tempera-
ture. The negative values of activation entropy show a
great activated state. This can occur through oxygen
chemisorption and other decomposition products. The
activated state can be indicated by the polarization bonds
which occur through electronic transitions.
(
calcd 4.35%). The second stage at 165–280°C corresponds
−
to the removal of (CH COO ) group with mass loss of
3
1
4.36% (calcd 14.25%). The third stage at 285–440°C cor-
responds to the removal of part of the ligand (C H NCl)
7
5
with mass loss of 33.38% (calcd 33.47%). The fourth step
at 444–614°C includes the loss of the other parts of the
ligand to finally give PdO as a residue.
The thermal behaviour of the AgL complex shows
three degradation steps in the range 37–630°C. The first
stage at 37–218°C corresponds to the elimination of two
3
.10 | Stability Range of Complexes
The pH profile (absorbance versus pH) shows typical dis-
sociation curves and a high stability range of pH (5–10)
for the synthesized complexes (Figure 4). The results indi-
cate that the synthesized complexes are more stable
TABLE 5 Thermogravimetric analysis and parameters of thermokinetic activation of each decomposition step for the complexes
Weight loss (%)
E≠
ΔS≠
(J mol
ΔH≠
(k J mol
ΔG≠
(kJ mol
Dec.
Dec.
assignment (kJ mol
A
−1
4
−1
−1
−1
−1 −1
Complex temp. (°C) Calcd
Found
)
(× 10 s
)
)
)
K )
CuL
2
35–196
9.32
19.28
23.94
15.91
17.81
9.25
19.35
23.85
15.99
17.72
3H
2
O
Cl
12
7.2
−17.86
−18.28
−18.65
−18.87
−18.99
10.37
9.50
8.40
7.51
6.94
13.87
14.98
16.47
17.94
18.48
2
00–300
00–433
35–540
40–608
C
6
H
4
3
4
5
C
7 5
H
NCl
C
6
H
H
4
O
N
C
7
5
Residue
PdL
>608
13.74
13.84
CuO
—
—
—
37–160
4.35
14.25
33.47
18.37
4.47
14.36
33.38
18.29
H
2
O
18
25
2.7
3.0
−18.63
−19.19
−19.64
−19.98
16.67
15.67
14.34
12.89
19.65
21.04
22.98
25.16
−
1
2
4
65–280
85–440
44–614
CH
3
COO
NCl
C
7
H
5
6 4
C H
Residue
AgL
<614
29.56
29.50
PdO
2H
—
—
—
37–218
20–420
20–630
9.60
33.20
24.30
9.69
33.10
24.40
2
O
−18.84
−19.49
−19.90
23.23
21.51
19.76
27.34
29.70
32.30
2
4
C
7
H
5
Cl
6 4
C H
NO
Residue
<630
30.90
30.79
½Ag
2
O
—
—
—

10 of 21
ABDEL‐RAHMAN ET AL.
magnetic measurements, the suggested structures for
the synthesized complexes were identified (Scheme 1).
3.11 | Molecular Orbital Calculations
The optimized geometrical parameters, natural charges
on active centres, natural configuration of the metal ions
and energetics of the ground state for the studied 1:1 and
1:2 complexes were calculated and discussed using
B3LYP/GENECP. From the elemental analysis and spec-
troscopic data, metal ions are coordinated to the ligand
via N7 and O12 atoms, two water molecules in the case
of AgL and one water and one acetate anion in the case
of PdL, forming diamagnetic 1:1 square planar and tetra-
hedral complexes, respectively. In the case of the 1:2
copper complex, the metal ion coordinated to the ligand
via N7, O16, N21 and O18 atoms and two water mole-
cules forming a paramagnetic distorted octahedral
complex.
FIGURE 4 pH profiles of the metal complexes in DMF
3.11.1 | Geometry of ligand
The ligand studied in this work and its anion were opti-
mized using the B3LYP/6‐311G** level of theory. Energy
gap (E ), and natural charge on active centres are pre-
g
sented in Figure 5. For the computed energy gap, as
the energy gap decreases, the reactivity of the compound
increases. In our case, E of the anion is less than that of
g
−
1
the neutral ligand by 2.65 eV (ca 61 kcal mol ), i.e. the
anionic form of the ligand is more chemically reactive
than the neutral form in the reaction medium and hence
interacts with the metal ion to form the studied com-
plexes. The natural charges computed from the NBO
analysis show that the most negative centres for chela-
tion in the ligand and its anion are N7 and O9 atoms.
In the case of the anion, the natural charge on N7 and
O9 atoms increased by 0.028e and 0.03e, respectively.
SCHEME 1 Suggested structures of new metal complexes
[41,43,44]
compared to the ligand.
Consequently, the desired
pH range for various applications of the synthesized com-
plexes is pH = 5–10.
Based on the obtained results of elemental analyses,
IR and electronic spectra, and molar conductance and
FIGURE 5 Optimized structure, vector of the dipole moment, numbering system, energy gap and natural charge on active centres of the
ligand and its anion using B3LYP/6‐311G**

ABDEL‐RAHMAN ET AL.
11 of 21
These results confirm that these two centres coordinated
with the central positive metal ion to form 1:1 and 1:2
complexes.
member ring, CuO18C19C20N21, and with two water
molecules via O48 and O49 atoms to form a paramagnetic
distorted octahedral structure. There is a good agreement
[49–51]
between the experimental X‐ray bond lengths
obtained for some related complexes (Ag―N, Cu―N
and Pd―N are 2.230, 1.960 and 1.730 Å, respectively,
and Ag―O, Cu―O and Pd―O are 2.320, 1.956 and
1.904 Å, respectively) and the computed bond lengths at
the B3LYP/6‐311G** level of theory (Table S1). In our
studied complexes, most of the M―N and M―O bonds
show elongation upon complexation. The elongation of
the M―O bond is greater in AgL and the M―N bonds
in 1:2 Cu complex. The length of the coordinate covalent
bonds between metal and ligand site, i.e. M―N and
M―O, is too long compared to the typical MX (X = O
3
.11.2 | Geometry of complexes
The optimized geometry, numbering system, vector of the
dipole moment, bond lengths, bond angles and dihedral
angles of all 1:1 and 1:2 metal complexes studied in this
work are presented in Table S1 and Figure 6. In the
AgL complex, the metal ion coordinates with O12 and
N7 atoms of the ligand to form a five‐member ring,
namely AgN7C6C5O12, and with two water molecules,
via O27 and O28 atoms, to form a diamagnetic square
planar structure (Figure 6). In the case of the PdL com-
plex, the metal ion coordinates with N7 and O12 atoms
to form a five‐member ring, namely PdN7C6C5O12, and
with one water molecule via O26 atom and one acetate
group O29 to form a diamagnetic tetrahedral structure.
[
52]
or N) bond length.
The too long M―O and M―N bonds in the complexes
mean that the ionic character of these bonds is small. The
bond angles computed theoretically at the B3LYP/6‐
311G** level in our studied complexes are listed in
On the other hand, the CuL complex coordinates with
2
N7 and O16 atoms to form a five‐member ring, namely
CuN7C1C2O16, with N21 and O18 atoms to form a five‐
Table S1. The bond angles in CuL
and 97° which compare nicely with the experimental data
vary between 84°
2
FIGURE 6 Optimized structure, vector of the dipole moment and numbering system for the complexes using B3LYP/GENECP

12 of 21
ABDEL‐RAHMAN ET AL.
[
53]
as obtained from X‐ray analysis for O complexes.
The
sub‐shells and natural electronic configuration of the
metal ions in the coordination sphere of 1:1 and 1:2 com-
plexes are presented in Tables 6 and 7. The most electro-
negative charges are accumulated on O12 and N7 atoms
of the ligand in the 1:1 complexes and on O16, O18, N7
and N21 atoms in the 1:2 complex. These electronegative
atoms in the coordination sphere have a tendency to
donate electrons to the central metal ions. It is observed
from the data in Tables 6 and 7 that the negative charges
of the coordinated atoms increase after complexation.
This may be referred to the back‐donation of the charge
from the metal ion to the coordinated atoms of the ligand
h
obtained values of the bond angles show a distorted octa-
hedral geometry. Whereas, the bond angles in AgL vary
between 108° and 124° and in the case of PdL between
1
07° and 119°. The values of the dihedral angles around
metal ion in the coordination sphere in the studied com-
plexes (Table S1) are far from 0° or 180° which indicate
that the metal ion is not in the same plane as the donat-
ing sites, i.e. the studied complexes are non‐planar.
3.11.3 | Natural charges and natural
of CuL and AgL. The amounts of the increases in the
2
population
natural charge on each atom of the coordination sphere
and the metal‐to‐ligand back‐donation are listed in
Table 6. The total amount of the charges transferred from
Ag to L is 0.175e and from Cu to L is 0.262e. Whereas, the
most electropositive atoms, Ag, Pd and Cu, have a ten-
dency to accept electrons from the coordinated atoms of
the ligand. In the 1:1 PdL and AgL complexes, the Ag
The natural charge on the coordinated centres before and
after complexation and the natural population of the elec-
trons of each metal ion in the core, valence and Rydberg
TABLE 6 Natural charge on coordinated centres of the
complexes
9.91
ion received 0.3594e (3d ) and Pd ion received 0.3568e
8.75
Centre
HL
CuL
2
PdL
AgL
(3d ). Whereas, for 1:2 CuL complex, the Cu ion
2
9.29
received 1.0628e (3d ) from the active sites of the
O12
−0.703
−0.541
−0.787
0.084
ligands (Table 7).
M → L
N7
−0.447
−0.396
−0.539
0.092
3.11.4 | Global reactivity descriptors
M → L
O27
−0.961
−0.968
The frontier molecular orbital energies of the studied 1:1
and 1:2 complexes were calculated using B3LYP/
GENECP and are presented in Table S2 and Figure 7.
EHOMO of the studied complexes which measures the
donating property follows the order Ag > Cu > Pd. The
accepting property of the studied complexes which is
represented by ELUMO follows the order Ag >Cu >Pd.
O28
O16
−0.703
−0.447
−0.447
−0.703
−0.719
0.016
M → L
N7
−0.520
0.073
M → L
N21
The energy gap (E ) between HOMO and LUMO of the
g
−0.564
0.117
studied complexes characterizes the molecular chemical
stability (reactivity). The results in Figure 7 and Table
S2 indicate that the smaller the energy gap of the com-
plexes, the easier the charge transfer and the polarization
within the molecule. The order of decreasing reactivity in
the studied complexes is PdL >>CuL2 >AgL. Using
HOMO and LUMO energies, ionization potential and
electron affinity can be expressed as I ~ −EHOMO and A
M → L
O18
−0.759
0.056
M → L
O48
−0.940
−0.958
O49
O26
−0.935
−0.676
O29
~
−ELUMO (Table S2). The variation of electronegativity
TABLE 7 Natural charge, natural population and natural electronic configuration of the metal ions for the complexes
Natural population
Natural
charge
Natural electronic
configuration
Complex
Core
Valence
Rydberg
Total
0
.26 9.29 0.51 0.01
CuL
PdL
AgL
2
0.9372
0.6432
0.6405
17.99
35.97
35.99
10.057
9.364
0.0124
0.0128
0.0089
28.063
45.356
46.359
Core 4s 3d 4p 5p
0
.21 8.75 0.01 0.41
Core 5s 4d 5d 6p
0
.21 9.91 0.01 0.24
10.356
Core 5s 4d 5p 6p

ABDEL‐RAHMAN ET AL.
13 of 21
FIGURE 7 HOMO and LUMO charge
density maps of the complexes using
B3LYP/GENEC
(
χ) values is supported by electrostatic potential, the
chemical softness S in the studied complexes is CuL >AgL
2
results in Table S2 showing that the order of decreasing
>>PdL.
χ (increasing charge transfer within the studied com-
plexes) is CuL > AgL >> PdL. The chemical hardness
2
3
.11.5 | NLO properties
(
η) = (I − A)/2, electronegativity (χ) = (I + A)/2, chemi-
cal potential (V) = −(I + E)/2 and chemical softness (S)
1/2η were calculated and are presented in Table S2.
No experimental or theoretical investigations were found
addressing NLO properties for the ligand and the studied
complexes; therefore, this triggered our interest to under-
take this study. In order to study the relationship between
molecular structure and NLO properties, the polarizabil-
ities α, Δα and hyperpolarizabilities (β) of the ligand
=
The small η values for the studied complexes reflect the
ability of charge transfer inside the studied complexes.
The order of decreasing charge transfer within the studied
complexes is CuL > AgL >>PdL. The order of decreasing
2

14 of 21
ABDEL‐RAHMAN ET AL.
and the studied complexes were calculated using B3LYP/
GENECP and the results are listed in Table 8. The polar-
izabilities and first‐order hyperpolarizabilities are
reported in atomic units (au), the calculated values have
been converted into electrostatic units (esu) using a con-
upon complexation. The value for the AgL complex is
440 times greater than that for PNA, and the value for
the CuL complex is 7653 times greater and for the PdL
2
complex is 774 times greater than that for PNA
(Table 8). Therefore, the studied complexes are promising
candidates for NLO materials.
−
24
version factor of 0.1482 × 10
esu for αand 8.6393 ×
−
33
1
0
esu for β. p‐Nitroaniline (PNA) is a standard proto-
[54,55]
type used in NLO studies.
In this study, PNA was
3.12 | Antimicrobial Bioassay for
chosen as a reference as there were no experimental
values of NLO properties of the studied ligand and com-
plexes. The magnitude of βis one of the key factors in
an NLO system. The analysis of βcomputed theoretically
for the ligand and the studied complexes indicated that
the value for the ligand is 92 times greater than that of
the reference PNA indicating that the HL has promising
NLO properties. The value of βfor the ligand increases
Complexes
The ligand and its complexes were examined against
three strains of bacteria and against three strains of
[
31,32]
fungi.
The results are reported in Tables 9 and 10
and shown in Figures 8, 9, S9 and S10. All examined
compounds show good antimicrobial activity against
the microorganisms. It is observed that the complexes
TABLE 8 Total static dipole moment (μ), mean polarizability (α),anisotropy of polarizability (Δα) and first‐order hyperpolarizability (β) for
the studied complexes
Property
PNA
HL
CuL
2
PdL
AgL
μ
μ
μ
μ
x
−4.351
0.652
−3.855
1.554
0.920
6.604
4.835
8.238
6.934
y
−0.246
0.808
z
−2.088
4.871
−4.716
6.286
1D
2.44
6.968
∝
xx
∝
xy
∝
yy
∝
zz
∝
xz
∝
yz
−147.3
−5.6
−219.9
3.08
−138.3
−1.29
−149.7
−11.13
15.19
−107.8
−111.2
−3.7
−235.2
12.6
−132.4
−12.1
6.59
−0.64
−9.3
−1.28
3.5
13.9
−20.1
4.08
(
(
∝)
∝)
1
1
au
−122.1
−153.5
2.274 × 10
240.515
−94.266
−1.397 × 10
123.355
−42.64
−6.319 × 10
160.762
−
24
−23
−23
−23
−23
−24
esu
22 × 10
1.809 × 10
37.914
5.6189 × 10
−34.5
Δ∝au
−
24
−23
−23
Δ∝esu
3.5644 × 10
100.5
1.828 × 10
135.01
24.8
2.3825 × 10
−53.58
−23.43
41.37
β
β
β
β
β
β
β
β
β
β
xxx
xxy
xyy
yyy
xxz
xyz
yyz
xzz
yzz
zzz
23.6
−93.4
−23.7
−41.7
3.4
−10.6
−171.6
42.6
−8.2
−97.26
−3.29
8.8
16.6
−4.02
4.12
19.6
6.27
4.3
−20.8
−25.1
5.6
−30.27
23.58
−13.9
−42.9
2.3
−33.5
37.8
−75.07
29.52
−1.3
−67.8
33.9
β au
165.5182
1.4299 × 10
13731
1389.24
790.952
6.8330 × 10
−
30
−27
−25
−26
−27
β esu
15.5 × 10
1.1862 × 10
1.2 × 10

ABDEL‐RAHMAN ET AL.
15 of 21
TABLE 9 Results of antibacterial bioassay of HL and its metal complexes
Inhibition zone (mm)
Compound
E. coli (−ve)
B. subtilis (+ve)
S. aureus (+ve)
−
1
Conc. (mg ml
)
10
20
10
20
10
20
HL
4 ± 0.23
14 ± 0.53
13 ± 0.22
17 ± 0.29
20 ± 0.71
8 ± 0.05
29 ± 0.66
28 ± 0.76
33 ± 0.11
40 ± 0.33
5 ± 0.17
17 ± 0.09
16 ± 0.91
20 ± 0.19
26 ± 0.15
13 ± 0.27
39 ± 0.13
36 ± 0.32
45 ± 0.87
51 ± 0.72
4 ± 0.63
15 ± 0.07
14 ± 0.61
13 ± 0.33
25 ± 0.93
11 ± 0.88
35 ± 0.39
33 ± 0.08
38 ± 0.41
45 ± 0.11
CuL
PdL
AgL
2
Gentamycin
TABLE 10 Results of antifungal bioassay of HL and its metal complexes
Inhibition zone (mm)
Compound
T. rubrum
A. flavus
10
4 ± 0.11
C. albicans
−
1
Conc. (mg ml
)
10
20
8 ± 0.55
20
10
20
HL
5 ± 0.05
16 ± 0.22
14 ± 0.33
19 ± 0.25
24 ± 0.55
7 ± 0.82
25 ± 0.14
23 ± 0.9
29 ± 0.19
31 ± 0.88
3 ± 0.10
11 ± 0.10
9 ± 0.10
14 ± 0.12
15 ± 0.71
5 ± 0.04
21 ± 0.19
18 ± 0.59
23 ± 0.80
25 ± 0.90
CuL
PdL
AgL
2
28 ± 0.10
25 ± 0.14
32 ± 0.41
37 ± 0.62
15 ± 0.22
12 ± 0.55
17 ± 0.29
16 ± 0.49
Fluconazole
[
58,59]
are more active than the free ligand and this activity is
explained in terms of chelation theory.
It is
[56,57]
promoted on coordination with metal ions.
How-
observed that in the complexes, the metal has a positive
charge, so it is moderately mutual with the donor atoms
present in the Schiff base ligand and there may be π‐
electron delocalization over the whole chelate. This che-
lation gives rise to a lipophilic property for the metal
complexes and assists their permeation through the
ever, the complexes have moderate activity as compared
with standards drugs. This promotion in the activity
may be dependent on the basis that the ligand has a
carbon–nitrogen double bond. The activity of the com-
plexes is greater than that of the ligand and can be
FIGURE 8 Histogram showing the comparative antibacterial
activities of HL and its complexes at a concentration of 20 mg ml
FIGURE 9 Histogram showing the comparative antifungal
activities of HL and its complexes at a concentration of 20 mg ml
−1
−1

16 of 21
ABDEL‐RAHMAN ET AL.
TABLE 11 MIC of HL and its complexes against bacterial and fungal strains
−
1
MIC of bacteria and fungi (mg ml
)
Compound
E. coli (−ve)
B. subtilis (+ve)
6.25
C. albicans
A. flavus
T. rubrum
HL
7.75
3.50
3.50
2.50
6.50
2.75
3.00
1.50
3.00
3.25
2.00
6.25
6.00
2.50
2.75
1.25
6.25
2.75
3.00
1.75
7.50
3.25
3.25
2.25
CuL
PdL
AgL
2
TABLE 12 Activity index of HL and its complexes against bacterial and fungal strains
Activity index (%)
Compound
S. aureus (+ve)
B. subtilis (+ve)
E. coli (−ve)
C. albicans
A. flavus
T. rubrum
HL
20.00
72.50
70.00
82.50
25.49
76.47
70.58
88.23
24.44
77.77
73.33
84.44
21.62
75.67
67.56
86.48
21.87
78.12
71.87
90.62
19.23
80.70
69.23
88.46
CuL
PdL
AgL
2
Activity index ð%Þ
Inhibition zone of compound ðmmÞ
¼
× 100
20)
Inhibition zone of standard ðmmÞ
(
3
3
.13 | Binding of Complexes with CT‐DNA
.13.1 | Electronic spectroscopy for inter-
action of complexes with CT‐DNA
Electronic absorption spectroscopy is an important
method for studying DNA binding with metal complexes.
DNA binding is in three types: (i) binding interaction
between two grooves of the DNA double helix; (ii) interca-
lation between the stacked base pairs of native DNA; and
(iii) electrostatic interaction with the negatively charged
nucleic sugar–phosphate structure, which is along the
external DNA double helix and does not have selectiv-
FIGURE 10 Electronic absorption scans for binding of DNA
with PdL complex (10 M) in 0.01 M Tris buffer (pH = 7.2, 298
−
3
K) with CT‐DNA (0–100 μM, from bottom to top)
[
32–35,38,39,60]
lipid layer of the membranes of bacteria. Also, other fac-
tors should be considered such as solubility, activity,
conductivity and bond length between the metal and
ligand. Minimum inhibitory concentration (MIC) pro-
files of the studied compounds against selected strains
of bacteria and fungi are summarized in Table 11. The
MIC values of HL and its complexes against the selected
strains of bacterial and fungi indicated that HL has
lower antimicrobial activity than its complexes. The
activities for the compounds were confirmed by calcu-
lating the potency index (Table 12) according to the fol-
ity.
The absorption spectral data for the inter-
action DNA with the complexes through intercalation
shows significant hypochromicity and a red‐shift due to
the strong π → π* transition due to interaction between
the base pairs of DNA and the aromatic chromophore
ligand of metal complexes (Figure 10, and Figures S11
[
61]
and S12).
The spectra were obtained as a function of
the addition of buffer solutions of pure CT‐DNA to buffer
solutions of the studied complexes. The π–π* transition
energy is lowered when the orbital of the inserted ligand
couples with the orbital of the base pairs and this leads
bathochromicity, so the interaction is via intercalation
[30–35]:
lowing relation

ABDEL‐RAHMAN ET AL.
17 of 21
TABLE 13 Spectroscopic parameters and K
b
results for DNA interaction with the complexes
λ
max
λ
max
Type of
chromism
Binding
constant (× 10 )
a
5
−1
Complex
free (nm)
bound (nm)
Δn
Chromism (%)
ΔG (kJ mol )
CuL
PdL
AgL
2
239
242
255
364
486
3
2
3
3
5.29
5.69
5.88
5.29
252
361
483
Hypo
3.10
−31.33
239
242
254
492
527
3
2
3
2
2.12
2.08
1.52
1.05
252
489
525
Hypo
Hypo
1.27
1.16
−29.12
−28.89
239
01
242
503
3
2
2.00
11.76
5
aChromism (%) = (Absfree – Absbound)/Absfree.[30–35]
mode. When the conjugation orbital is partially filled by
electrons, this leads to a reduction in the transition
probabilities and so leading to hypochromicity. The spec-
troscopic parameters and K for the DNA interaction with
b
the synthesized complexes are listed in Table 13. K was
b
calculated from the ratio of slope to intercept (Figures
S13–S15). The synthesized metal complexes could bind to
DNA mainly through the intercalative mode through the
series CuL >PdL >AgL.
2
3
.13.2 | Viscosity measurements for inter-
action of complexes with CT‐DNA
Dynamic viscosity measurements are used to study the
binding mode of metal complexes with DNA.
FIGURE 11 Dynamic viscosity measurements of the complexes
at [DNA] = 0.5 mM ([complex] and [ethidium bromide] = 25–250
μM at 298 K)
[30–35,37,60]
Under suitable conditions, the intercalation of com-
pounds such as ethidium bromide leads to a significant
increase in the DNA viscosity because of an increase in
the isolation of base pairs at the intercalation sites and
[62]
hence an increase in the overall DNA length.
With
an increasing amount of complexes, the relative viscosity
of CT‐DNA increases indicating that these complexes can
bond with CT‐DNA via intercalation mode as shown in
[
42]
Figure 11.
These viscosity measurements show that
all the synthesized complexes can intercalate among adja-
cent CT‐DNA base pairs causing an extension in the DNA
helix and thus increasing the viscosity with increasing
complex concentration.
TABLE 14 Details of docked Schiff base metal complexes
Code
CuL
k
b
S
E
conf
FIGURE 12 Gel electrophoresis results for DNA in the presence
of the metal complexes. Lane 1: DNA ladder; lane 2: PdL complex +
2
3.10
1.27
1.16
−6.0040
−5.2442
−4.8835
−955.3530
−191.6363
−101.1103
PdL
AgL
CT‐DNA; lane 3: AgL complex + CT‐DNA; lane 4: CuL
2
complex +
CT‐DNA; lane 5: PdL complex

18 of 21
ABDEL‐RAHMAN ET AL.
FIGURE 13 Three‐dimensional plots and corresponding two‐dimensional plots of interaction of the complexes with DNA
growth of a pathogenic organism by interaction with
the genome.
3.14 | Molecular Docking
Molecular docking is a great approach for understanding
the interaction between investigated complexes and a bio-
logical target which is important in medical treatment. In
our investigation, the synthesized complexes were studied
by molecular docking using MOE version 2016.08 to
understand the drug–DNA interactions to explore the
potential binding mode and energy. Docked ligand con-
formation was evaluated according to hydrogen bonding,
binding energy and hydrophobic interaction between the
synthesized complexes and B‐DNA (PDB ID: 1BNA).
From the docking scores, the details of the docked com-
plexes were obtained (Table 14).
FIGURE 14 IC50 values for HL, its metal complexes and
vinblastine drug against Hep‐G2, MCF‐7 and HCT‐116 cell lines
The docking studies showed that the prepared docked
complexes fit mainly in the DNA minor groove and
involve hydrophobic as well as hydrogen bonding interac-
tions with DNA bases. Most of the optimal results of
docking were in the GC region. Binding interactions of
the prepared complexes are displayed in Figure 13.
3
.13.3 | Gel electrophoresis for interaction
of complexes with CT‐DNA
Gel electrophoresis is a method used to study the interac-
tion DNA with complexes.
phoresis showed that the intensity of the DNA treated
[31–35,60]
The gel after electro-
with the complexes has partially decreased in CuL and
The CuL complex showed the best binding score and
2
2
AgL, and, in contrast, disappears in PdL, possibly
energy conformation of −6.0040 and −955.3530 kcal mol
, respectively, with one π–H interaction and three
[63]
−1
because of the complete cleavage of DNA
(Figure 12).
From DNA binding with the investigated complexes, it
can be derived that the studied complexes lower the
hydrogen bonds with the DNA. In the CuL complex,
the copper metal forms hydrogen‐donor bond with
2

ABDEL‐RAHMAN ET AL.
19 of 21
guanine base through one of the complex water molecules
while the two para chloro groups form hydrogen‐donor
bonds with cytosine and thymine bases. The distance of
the hydrogen bonds was 3.01–4.06 Å.
the control. Moreover, the interaction of CT‐DNA with
the studied complexes has been effectively estimated
using electronic absorption, viscosity measurements and
gel electrophoresis. The DNA interaction studies suggest
that the interaction of these complexes with CT‐DNA
occurs via intercalative and groove modes. The docking
studies showed that the prepared docked complexes fit
mainly in the DNA minor groove and involve hydropho-
bic as well as hydrogen bonding interactions with DNA
bases. Most of the optimal results of docking were in
the GC region. Furthermore, the growth inhibition effect
of the studied compounds was examined against HCT‐
3.15 | Anticancer Activity of Complexes
The prepared compounds were examined against Hep‐G2
cell line (hepatocellular carcinoma), MCF‐7 cell line
(breast carcinoma) and HCT‐116 cell line (colon carci-
noma) within the concentration range 0–10 μM. The
values for IC50 were estimated for HL and its complexes
116, HepG‐2 and MCF‐7 cell lines. Among these com-
(Figure 14 and Table S3). Cytotoxicity results show that
pounds, the CuL complex significantly decreases cell
2
CuL , PdL and AgL have an anticancer activity where
2
viability in time‐ and dose‐dependent manners. These
biological results from our investigation would be benefi-
cial in investigating DNA interaction when exposed to
metal complexes and may lead to an improvement in
metal‐based therapeutic drugs.
the IC50 values for HCT‐116 cell line are in the range
−
1
3
2
1
3.4–72.4 μg μl , for Hep‐G2 cell line are in the range
−
1
0.5–59.9 μg μl and for MCF‐7 cell line are in the range
−
1
2.8–51 μg μl . It is observed from these results that the
prepared complexes are more potent than the ligand and
showed manifest anticancer activity compared to vinblas-
tine drug because their biological properties are affected
via the complexation locations and the nature of the
metal ion which was considered in Tweed's chelation the-
ORCID
Laila H. Abdel‐Rahman
2885
Mohamed Shaker S. Adam
http://orcid.org/0000-0001-7375-
http://orcid.org/0000-0001-
[30–32,64]
ory.
The positive charge on metal ions increases
the acidity of the coordinated ligand and makes stronger
hydrogen bonds enhancing the biological activity. The
biological activity is also affected by the coordination
locations and the nature of the metal modifying the bind-
8826-3558
Ahmed M. Abu‐Dief http://orcid.org/0000-0003-3771-9011
[
30–32]
ing ability to DNA.
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