Spectroscopic, density functional theory, nonlinear optical properties and in vitro biological studies of Co(II), Ni(II), and Cu(II) complexes of hydrazide Schiff base derivatives

Article abstract of DOI:10.1002/aoc.6246

Complexes of three molecularly designed phenylacetohydrazide Schiff base derivatives—N′-(2-hydroxybenzylidene)-2-phenylacetohydrazid (HL¹), N-(1-(2-hydroxyphenyl)ethylidene)-2-phenylacetohydrazide (HL²), and N′-((1-hydroxynaphthalen-2-yl)methylene)-2-phenylacetohydrazide (HL³)—with some bivalent metal ions were synthesized and investigated by several spectroscopic and analytical techniques. The crystal structure of HL¹ ligand has been solved by conventional X-ray diffraction technique. Molecular geometries of HL¹ and the studied complexes were investigated using the DFT-B3LYP/GENECP level of theory. Quantum and non-quantum global reactivity descriptors as well as the nonlinear optical properties were calculated. Biological parameters such as antimicrobial and antioxidant activities, fluorescence quenching studies, and viscosity measurements of the complexes were carried out. Molecular docking studies of HL¹ and complexes using Molecular Operating Environment (MOE) software are reported. The different biological studies and the molecular docking were correlated to each other. The biological studies supported that the complexes can bind to DNA via intercalative mode and showed a various DNA binding potency.

Full text of DOI:10.1002/aoc.6246

Received: 26 January 2021
DOI: 10.1002/aoc.6246
Revised: 7 March 2021
Accepted: 12 March 2021
F U L L P A P E R
Spectroscopic, density functional theory, nonlinear optical
properties and in vitro biological studies of Co(II), Ni(II),
and Cu(II) complexes of hydrazide Schiff base derivatives
Ramadan M. Ramadan1
Hussein Moustafa3
Ayman Abdel Aziz1
| Samir M. El-Medani2
| Abdelmoneim Makhlouf2
|
|
| Manal A. Afifi2
| Matti Haukka4
1Chemistry Department, Faculty of
Science, Ain Shams University, Cairo,
Egypt
2Department of Chemistry, Faculty of
Science, Fayoum University, Fayoum,
Egypt
3Department of Chemistry, Faculty of
Science, Cairo University, Giza, Egypt
4Department of Chemistry, University of
Jyvaskyla, PO Box 35, Jyvaskyla, Finland
Complexes of three molecularly designed phenylacetohydrazide Schiff
base derivatives—N0-(2-hydroxybenzylidene)-2-phenylacetohydrazid (HL1),
N-(1-(2-hydroxyphenyl)ethylidene)-2-phenylacetohydrazide (HL2), and N0-
((1-hydroxynaphthalen-2-yl)methylene)-2-phenylacetohydrazide (HL3)—with
some bivalent metal ions were synthesized and investigated by several spectro-
scopic and analytical techniques. The crystal structure of HL1 ligand has been
solved by conventional X-ray diffraction technique. Molecular geometries of
HL1 and the studied complexes were investigated using the DFT-B3LYP/
GENECP level of theory. Quantum and non-quantum global reactivity descrip-
tors as well as the nonlinear optical properties were calculated. Biological
parameters such as antimicrobial and antioxidant activities, fluorescence
quenching studies, and viscosity measurements of the complexes were carried
out. Molecular docking studies of HL1 and complexes using Molecular Operat-
ing Environment (MOE) software are reported. The different biological studies
and the molecular docking were correlated to each other. The biological stud-
ies supported that the complexes can bind to DNA via intercalative mode and
showed a various DNA binding potency.
Correspondence
Ramadan M. Ramadan, Chemistry
Department, Faculty of Science, Ain
Shams University, Cairo, Egypt.
Email: rmramadan@sci.asu.edu.eg
K E Y W O R D S
biological activity, CT-DNA binding, DFT studies, molecular docking, nonlinear optical
properties, X-ray analysis
1 | INTRODUCTION
widely used in different applications such as anticancer,
anti-HIV, antiradical, antibacterial, antifungal, and DNA
In the last two decades, the necessity to prepare and
develop novel antibacterial drugs with better mechanism
of action and structure–activity relationship becomes vital
biomedical need.[1] Schiff base ligands, especially those
having hydrazide–hydrazone moiety [−(C=O)NHN=CH],
were found to be excellent pharmacophores for designing
and developing various biologically active materials.[2–4]
These bases as well as their metal complexes are
cleavage.[5–7] In addition, hydrazide derivatives were found
to possess a broad spectrum of antibacterial activities.
Also, they can act as a good potential for oral drugs used,
for example, in the treatment of genetic disorders like
thalassemia.[8,9] Interest in binding of metal complexes to
nucleic acids (DNA and RNA) was motivated to under-
stand the basics of these interaction modes as well as
the development of metal complexes to use them as
Appl Organomet Chem. 2021;e6246.
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© 2021 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.6246

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RAMADAN ET AL.
anti-inflammatory or anticancer drugs.[10] Several series of
important hydrazide–hydrazone derivatives were found to
have promising anticancer activities.[11–13] Also, some
transition metal hydrazone complexes such as zinc(II)
and nickel(II) complexes were found to have anti-
inflammatory, antibacterial, anticancer, antihypertensive,
and DNA-binding activities.[14,15] Furthermore, complexes
of some transition metals such as cobalt(II), nickel(II), and
copper(II) presented various biochemical actions either as
essential trace metals or as a constituent of different exoge-
nously administered compounds in humans. These com-
plexes were also found to be serious in vitro and in vivo
bioactive species. Importance of these derivatives appeared
from their increasing interest as potential drugs for thera-
peutic intervention in various diseases.[16–19] Recently, we
reported the synthesis and spectroscopic, structural, and
theoretical studies along with the biological properties of
two molecularly designed hydrazone ligands derived from
phenylacetohydrazide as well as their Cu(II) complexes.[2]
In order to continue our investigations of these Schiff base
derivatives, here we report the synthesis and the X-ray
analysis of another new hydrazone ligand, HL1
(Scheme 1). Also, the synthesis and spectroscopic and
theoretical studies as well as the biological properties of
cobalt(II), nickel(II), and copper(II) complexes of that
ligand and its related ligands (HL2 and HL3; Scheme 1)
are reported.
from Fluka. Co (NO3)2ꢀ6H2O, Ni (CH3COO)2ꢀ4H2O, and
Cu (CH3COO)2ꢀH2O were provided from Sigma-Aldrich.
All other chemicals used in this study were purchased
from Fluka.
2.2 | Instrumentation
Infrared measurements were carried out using a Unicam
Mattson 1000 FTIR spectrometer using KBr discs.
Electronic absorption spectra were recorded on a Unicam
UV2-300 UV–VIS spectrophotometer. Fluorescence mea-
surements were done on a Jenway 6270 fluorimeter. The
excitation source was a pulsed xenon lamp. Nuclear
magnetic resonance (NMR) measurements were carried
out on a Bruker BioSpin 300-MHz spectrometer using
DMSO-d6 solvent. Magnetic susceptibilities of the com-
plexes (Gouy's method) were measured using a Sherwood
Scientific magnetic balance. Elemental analyses were
carried out using a PerkinElmer 2400 CHN elemental
analyzer. Mass spectra of solid complexes (70 eV, EI) were
performed on a Finnigan MAT SSQ 7000 spectrometer.
Thermogravimetric (TG) analysis were done under stream
of nitrogen gas (heating rate = 10ꢁC/min) using a
Shimadzu DT-50 thermal analyzer. Conductivity measure-
ments were carried out in dimethyl sulfoxide (DMSO)
(1 × 10−3 M, 25ꢁC) using Jenway 4010 conductivity meter.
2 | EXPERIMENTAL
2.1 | Reagents
2.3 | Preparations of ligands
2.3.1 | Preparation of (E)-N0-
(2-hydroxybenzylidene)-
The reported chemicals and reagents (analytical reagent
grade) in this study were used without further
purification. 2-Phenylacetohydrazide, salicylaldehyde
(d = 1.146, 98%), and organic solvents were provided
2-phenylacetohydrazid, HL1
A mixture of 2-phenylacetohydrazide (0.01 mol, 1.5 g)
and salicylaldehyde (0.01 mol, 1.06 g = 0.95 mL) was
SCHEME 1 Structure of the ligands

RAMADAN ET AL.
3 of 24
refluxed in absolute ethanol for 3 h at which a brown
product was separated. The residue was filtered off and
then washed several times with cold ethanol. The
product was recrystallized from hot ethanol to yield a
crystalline brown product.
(1.9 mmol, 0.37 g). The crude complex was rec-
rystallized from hot ethanol to give faint green crystals
for nickel complex and green crystals for copper
derivative.
2.4.3 | Synthesis [Ni(L2)2], [Co(L3)2]ꢀ2H2O,
and [(NiL3)2] complexes
2.3.2 | Preparation of N-
(1-(2-hydroxyphenyl)ethylidene)-
2-phenylacetohydrazide, HL2
Similar procedure as that used for the preparation of
complexes of HL1 was performed with the use of the
other two ligands (HL2 and HL3).
Color, yield, elemental analysis, and mass spectral
and effective magnetic moment data for the reported
derivatives are given in Table 1.
The HL2 ligand was prepared as described before[2]: A
mixture of 2-phenylacetohydrazide (0.01 mol, 1.5 g) and
20-hydroxyacetophenone (0.01 mol, 1.2 mL) was refluxed
in absolute ethanol for 3 h at which a yellow product was
separated. The residue was filtered off, washed with cold
ethanol for several times, and then recrystallized
from hot ethanol to give a crystalline yellow product
(yield = 80%).
2.5 | X-ray structure analysis
Suitable single crystals of the ligand HL1 for X-ray
diffraction measurements were obtained by slow
evaporation of dilute alcoholic solution at room
temperature. The X-ray diffraction data was collected on
a Bruker KAPPA APEX II CCD diffractometer using Mo
Kα radiation (λ = 0.71073 Å). Detailed procedures for cell
refinement, data collection, and structural refinement
were performed as described before.[2,20–25] The structure
was solved by direct methods (SHELXS-97) and refined
by full-matrix least-squares method based on F2
(SHELXL-97). The graphics interface program X-Seed
was used for data presentation.[22] The crystallographic
data of HL1 are presented in Table 2.
2.3.3 | Preparation of N0-
((1-hydroxynaphthalen-2-yl)methylene)-
2-phenylacetohydrazide, HL3
Similar procedure as that used for the preparation of HL2
was performed with the use of
2-phenylacetohydrazide (0.01 mol, 1.5 g) and 1-hydroxy-
2-naphthaldehyde (0.01 mol, 1.72 mL). Yellow crystalline
product was separated after recrystallization from ethyl
acetate (yield = 75%).
a
mixture of
2.4 | Synthesis of complexes
2.6 | Computational studies
2.4.1 | Synthesis [Co(L1)2] complex
All calculations were performed using Gaussian 09W
software package. B3LYP/GENECP method using
double-zeta plus polarization basis set 6-31G (d,p) for C,
H, N, and O atoms and LANL2DZ basis set for the metal
atoms was used to compute the geometries of the ligand
and complexes. Quantum parameters such as electroneg-
ativity (χ), chemical hardness (η), electrophilicity, global
softness, ionization potential, and electron affinity were
estimated by using the HOMO and LUMO energies.
Non-quantum parameters like the surface area grid
(SAG), molar volume (MV), hydration energy (HE),
polarizability (Pol), and molar refractivity (MR) were
carried out using HyperChem 8.0.7. Natural bond
orbital has been performed to measure the qualitative
intermolecular delocalization in compounds. Total static
dipole moment, (μ), mean polarizability (α), anisotropy
of the polarizability (Δα), and the mean first-order
To an ethanolic solution of HL1 (1.9 mmol, 0.50 g) was
added to an aqueous solution of Co (NO3)2 (1.9 mmol,
0.55 g) drop by drop. The mixture was refluxed for 3 h.
The reaction mixture was left to stand at room tempera-
ture for few hours. The separated orange residue was fil-
tered off and washed several times with cold ethanol and
ether. The crude was then recrystallized from hot ethanol
to give fine crystalline product.
2.4.2 | Synthesis [Ni(L1)2] and [Cu(L1)2]ꢀ
2H2O complexes
Similar procedure was employed as that used for the
synthesis of [Co(L1)2] complex with the use of either
Ni (CH3COO)2 (1.9 mmol, 0.47 g) or Cu (CH3COO)2

4 of 24
RAMADAN ET AL.
TABLE 1 Color, yield, elemental analysis, mass spectrometry, and effective magnetic moment data for the reported compounds
Elemental analysis, found (calc.) Mass spectrometry
Mol.
wt.
Fragments
(m/z)
μeff
Compound
Color
%Yield
% C
% H
% N
BM
HL1
C15H14N2O2
[Co(L1)2]
CoC30H26N4O4
[Ni(L1)2]
NiC30H26N4O4
Brown
80
70.47 (70.85)
5.80 (5.55)
10.66 (11.02)
254.29
565.49
565.26
606.14
286.33
593.31
304.35
701.64
724.08
250, 254, 255
561, 562
560, 562
578, 593, 607
269
-
Orange
64
70
68
80
62
75
73
68
63.82 (63.72)
63.56 (63.75)
60.10 (59.45)
67.04 (67.12)
64.73 (64.78)
74.77 (74.98)
65.33 (65.05)
62.89 (63.03)
4.41 (4.63)
4.81 (4.64)
4.69 (4.99)
6.38 (6.34)
5.10 (5.10)
5.42 (5.30)
4.52 (4.88)
3.88 (4.18)
10.20 (9.91)
9.73 (9.91)
9.01 (9.24)
9.66 (9.78)
9.17 (9.44)
9.12 (9.21)
8.13 (7.99)
7.57 (7.74)
3.45
2.83
1.59
-
Faint green
Green
[Cu(L1)2]ꢀ2H2O
CuC30H30N4O6
HL2
C16H18N2O3
[Ni(L2)2]
NiC32H30N4O4
HL3
C19H16N2O2
Yellow
Faint green
Yellow
591
2.62
-
305
[Co(L3)2]ꢀ2H2O
Reddish brown
Faint green
694, 697, 698
675,720
3.27
2.45
CoC38H34N4O6
[(NiL3)2]
Ni2C38H30N4O4
hyperpolarizability (β) using the x, y, z components were
radical when deactivated by antioxidants. Ascorbic acid
was used as a standard compound. Stock solutions of the
reported complexes were dissolved in methanol/DMSO
(5:1) and then diluted to different concentrations.
Detailed procedure for the DPPH free radical scavenging
activity studies is previously given.[27]
calculated as reported in literature.[26]
2.7 | Biological activity studies
2.7.1 | Antibacterial activity
The HL1 ligand and its reported complexes were
screened in vitro for their antibacterial activities using
agar well diffusion method. Experimental details of the
investigations are as described previously.[27] The
antibacterial activities were scanned against two bacterial
species: Staphylococcus aureus (gram positive) and
Escherichia coli (gram negative). Ampicillin was used as a
standard. Measurements were carried out in triplicate for
each compound, and their average values are reported.
2.7.3 | DNA-binding studies
The DNA-binding experiments of the complexes using
calf thymus (CT-DNA) were carried out at room tempera-
ture. Detailed steps of the experiments are as described
before.[27,29]
2.7.4 | Fluorescence quenching
measurements
2.7.2 | Antioxidant assay (2,2-diphenyl-
1-picrylhydrazyl free radical scavenging
activity)
Studies of the competitive binding of DNA with
ethidium bromide (EB) solution were carried out at
different concentrations (1.0–8.0
concentrations of EB and CT-DNA were kept constant
(1.0 × 10−5 M for each). Before measurements, the
resulting solutions were shaken up and incubated for
30 min. Details for the procedure and measurements are
described previously.[27,30]
×
10−5 M). The
In vitro antioxidant activities of the reported complexes
were evaluated using scavenging the stable 2,2-diphenyl-
1-picrylhydrazyl (DPPH) radical method.[28] The radical
scavenging test depends on the absorbance change of the

RAMADAN ET AL.
5 of 24
TABLE 2 Crystal structure data of the Schiff base ligand (HL1)
2.8 | Molecular docking studies
Empirical formula
Formula weight
Temperature
C15 H14 N2 O2
254.28
Molecular docking studies were performed using Molecular
Operating Environment (MOE) software package version
2016.08. X-ray crystal structure of a B-DNA (dodecamer d
[CGCGAATTCGCG]2 running 30–50 direction, PDB ID:
1BNA) was used as a macromolecule target. Structure of
the DNA was energetically optimized after inserting
hydrogen atoms. The resulting model afforded to
systematic conformational research with RMS gradient of
0.01 kcal mol−1.
120(2) K
Wavelength
1.54184 Å
Crystal system
Space group
Monoclinic
P21/c
Unit cell dimensions
a = 10.7596(3) Å
b = 13.5263(4) Å
c = 8.9645(3) Å
α = 90ꢁ
β = 100.047(3)ꢁ
γ = 90ꢁ
1284.66(7) Å3
3 | RESULTS AND DISCUSSION
3.1 | Spectroscopic studies
Volume
Z
4
The Schiff base ligand HL1 and the previously reported
HL2 and HL3[[2]] were synthesized by condensation of the
appropriate amine and aldehyde derivatives (Scheme 1).
Interaction of the Schiff bases HL1 and HL2 with M(II),
M = Co(II), Ni(II), or Cu(II) ions gave coordination
complexes with a general formula [M(L)2], except for [Cu
(L1)2]ꢀ2H2O, which was crystallized with two water mole-
cules. On the other hand, cobalt(II) and nickel(II) deriva-
tives of HL3 ligand have different structural arrangements
([Co(L3)2]ꢀ2H2O and [(NiL3)2]). The structure of HL1
and the complexes was investigated by using different
Density (calculated)
Absorption coefficient
F(000)
1.315 mg/m3
0.720 mm−1
536
0.326 × 0.281 × 0.131 mm3
4.173–76.854ꢁ
Crystal size
Theta range for data collection
Index ranges
−11 < =h < =13
−17 < =k < =16
−11 < =l < =10
Reflections collected
8239
Independent reflections
2696 [R(int) = 0.0237]
1
spectroscopic tools, such as FTIR, H NMR, and mass,
Completeness to
theta = 67.684ꢁ
99.8%
along with elemental analyses, magnetic measurements,
molar conductivity, and thermal analysis. In addition, the
structure of HL1 was elucidated by single-crystal X-ray dif-
fraction technique. Elemental analyses and mass spectral
data of the reported compounds were in accordance with
the proposed molecular formulas. The molar conductivi-
ties of 1 × 10−3 M solutions of all complexes at 25ꢁC were
found to be in the range of 10–13 Ω−1 mol−1 cm2, indicat-
ing that nonelectrolyte characteristics of these derivatives
and the ligand anions are directly bonded to the M(II) cen-
ters neutralizing their charges. The effective magnetic
moment (μeff) values calculated from the magnetic suscep-
tibility measurements at 298 K are given in Table 1. Except
for [Ni(L3)]2, the reported μeff values of the other com-
plexes confirmed that they were mononuclear derivatives.
The little deviation of the magnetic moment values from
the spin-only values could be due to spin–orbit coupling.
On the other hand, the binuclear nickel(II) derivative
of HL3 gave an effective magnetic moment (μeff)
value = 4.90 BM, that is, 2.45 BM for each Ni species. This
value represents the spin-only value of two unpaired
electrons for every nickel ion.
Absorption correction
Max. and min. transmission
Refinement method
Analytical
0.978 and 0.955
Full-matrix least squares on
F2
Data/restraints/parameters
Goodness of fit on F2
2696/0/180
1.046
Final R indices [I > 2sigma(I)]
R indices (all data)
R1 = 0.0508, wR2 = 0.1423
R1 = 0.0527, wR2 = 0.1438
n/a
Extinction coefficient
Largest diff. peak and hole
0.278 and −0.232 e.Å−3
2.7.5 | Viscosity measurements
Viscosity experiments were performed using Ostwald vis-
cometer immersed in a water bath at a constant tempera-
ture. Samples of CT-DNA were prepared by sonication in
order to reduce complexity arising from the CT-DNA
flexibility. Flow time was measured three times for each
sample, and the average was then calculated. Data were
presented and estimated as described before.[2]
The infrared spectra (KBr pellets) of the ligand and
complexes were performed in the wavenumber range of

6 of 24
RAMADAN ET AL.
1
4000–400 cm−1. Important FTIR data for HL1 and the
reported complexes are given in Table 3. The FTIR spec-
trum of the HL1 displayed stretching frequency bands at
3330, 3278, 3198, 1637, 1588, 1244, and 1075 cm−1, which
are assigned to υ(OH), υ(NH), υ(C O), υ(C N), υ(C–O),
and υ(N–N), respectively.[2,27,31] Thus, the FTIR spectrum
of the HL1 ligand in the solid state indicated that they
existed in a keto form structure (Scheme 1). The 1H NMR
studies of HL1 in DMSO displayed a set of four slightly
broad singlets at 9.04, 9.16, 10.04, and 11.18 ppm due to
the protons of OH and NH groups. These signals were
disappeared on the addition of D2O (Figure 1). The line
broadening of the four signals with comparable rates con-
firmed that the protons of the OH and NH groups are
exchangeable, that is, the compound is fluxional at the
NMR time scale. Therefore, HL1 existed in solution in
two tautomeric (keto and enol) forms (Scheme 1).[32] The
fact that HL1 exists in two isomers with a ratio of about
4:1 is also confirmed from the appearance of two
signals for two CH=N (8.30 and 8.42 ppm) and two CH2
(3.86 and 3.96 ppm). In addition, the H NMR spectrum
of HL1 exhibited multiplet signals corresponded to the
aromatic protons (6.90–7.34 ppm). Interestingly, HL2
(a similar derivative to HL1 with substitution of the
azomethine proton by a methyl group; Scheme 1) was
not fluxional at the NMR time scale, whereas HL3 was
fluxional.[2]
The FTIR spectra of the reported complexes exhibited
the ligand bands with the appropriate shifts because
of complex formation. The OH vibrational bands of
the ligands disappeared from the FTIR spectra of the
cobalt(II) and nickel(II) complexes. In the case of [Cu
(L1)2]ꢀ2H2O and [Co(L3)2]ꢀ2H2O complexes, new OH
bands (3428 and 3443 cm−1) appeared due to the water
molecules. The shifts in the bands of the other functional
groups, such as C=N, C=O, and C–O, toward low fre-
quencies indicated that the ligands coordinated to metal
ion from their O and N donor atoms.[2,27] All the reported
complexes displayed new non-ligand bands for stretching
frequencies of the M–O and M–N moieties due to
TABLE 3 Important FTIR data for the reported compounds
FTIR data, cm−1
Compound
HL1
ν(OH)
ν(NH)
ν(C=O)
ν(C=N)
ν(C–O)
ν(M–O)
ν(M–N)
3330(m)
3278(m)
3198(s)
1637(s)
1588(vs)
1244(m)
---
---
[Co(L1)2]
[Ni(L1)2]
---
---
3198(s)
3199(s)
3198(s)
3200(m)
3194(m)
---
1589
1500
1187(m)
1195(m)
1200(m)
1240(m)
1188 (m)
1188 (m)
531(w)
532(w)
532(w)
528(w)
524(w)
500(w)
492(w)
478(w)
478(w)
511(w)
480(w)
483(w)
1593(m)
1592(m)
1629(s)
1615(s)
---
1524(vs)
1511(m)
1587(s)
[Cu(L1)2]ꢀ2H2O
3428(m)
---
[Ni(L2)2]
[Co(L3)2]ꢀ2H2O
[Ni(L3)]2
3443(m)
---
1600(s)
1616(s) 1600(s)
FIGURE 1 The 1H NMR spectra of the Schiff base (HL1): (a) in DMSO; (b) in DMSO + D2O

RAMADAN ET AL.
7 of 24
complex formation[33] (Table 3). Figure 2 illustrates the
proposed structures of the reported complexes. As can be
noted, the ligands coordinated to the metal ions with the
keto form, except for [(NiL3)2] complex, where the HL3
ligand bound to the metal with the enol form. Such
behavior was previously observed in the copper dimer
[(CuL3)2].[2]
refinements. Ranges of h, k, and l for the ligand were
−11 ≤ h ≤ 13, −17 ≤ k ≤ 16, −11 ≤ l ≤ 10. The crystallo-
graphic data for the ligand derivative are summarized in
Table 2, and selected bond lengths and bond angles are
given in Table 4. The crystallographic analysis showed
that HL1 crystallized in monoclinic P21/c space group
with a Z value of 4. The ORTEP representation of HL1
ligand is given in Figure 3. The structure is nonplanar,
and the molecule is completely unsymmetrical with a C1
point group. The phenolic azomethine N–N and C=O
moieties are almost in the same plane, although the
benzyl part of the molecule is bent on the plane. The
dihedral angles of C(1)–C(6)–C(7)–N(1) and N(1)–N(2)–C
(8)–C(9) are 170.20ꢁ and 179.30ꢁ. On the other hand, the
torsion angles of C(8)–C(9)–C(10)–C(15) and C(8)–C(9)–
C(10)–C(11) are 79.73ꢁ and 76.53ꢁ. Also, the angles C
(8)–N(2)–N(1), N(1)–C(7)–C(6), O(2)–C(8)–N(2), and O
(2)–C(8)–C(9) have values around 120ꢁ. These values are
corresponding to sp2 hybridization and indicating that
this part of molecule is nearly planar. The bond lengths
of C(7)–N(1) in the imine group and N(1)–N(2) are 1.289
and 1.384 Å, respectively. These values are in the normal
range of double and single bond separation.[34,35] These
3.2 | X-ray crystallographic studies
The crystal structure of HL1 was determined by X-ray dif-
fraction analysis. The data for the crystal structure of
HL1 are deposited in Cambridge Crystallographic Data
Center (see Supporting information). Accurate lattice
parameters were determined from least-squares refine-
ments of well-centered reflections in the range of
4.173ꢁ ≤ θ ≤ 76.854ꢁ. During data collection, three stan-
dard collections were periodically observed without sig-
nificant intensity variations. The collected reflections
were found to be 8239, whereas the independent reflec-
tions were 2696 with I > 2:00σ(I). The observed reflec-
tions were used for structure determination and
FIGURE 2 The proposed
structures of the reported
complexes

8 of 24
RAMADAN ET AL.
TABLE 4 Important bond lengths and angles for the Schiff base (HL1) ligand
Bond lengths (Å)
O(1)–C(1)
1.356(2)
1.289(2)
1.340(2)
1.456(2)
O(2)–C(8)
N(1)–N(2)
O(1)–H(1)
C(8)–C(9)
1.227(2)
1.3840(18)
0.87(3)
N(1)–C(7)
N(2)–C(8)
C(6)–C(7)
1.519(2)
Bond angles (ꢁ)
C(1)–O(1)–H(1)
C(8)–N(2)–N(1)
O(1)–C(1)–C(6)
O(2)-C(8)-C(9)
107.5(18)
120.08(13)
122.10(14)
121.35(15)
C(7)–N(1)–N(2)
O(1)–C(1)–C(2)
O(2)–C(8)–N(2)
C(10)–C(9)–C(8)
115.80(13)
117.80(14)
123.78(14)
110.38(13)
FIGURE 3 ORTEP diagram of the Schiff base (HL1) ligand with 30% thermal ellipsoid
values are comparable with the values found for the
ligand HL2 (1.2944 and 1.3723 Å), where the hydrogen of
azomethine was substituted with a methyl group.[2] Fur-
thermore, the C(8)–O(2) and C(1)–O(1) bond lengths are
found to be 1.227 and 1.356 Å, which confirmed the pres-
ence of a double and a single bond characteristics for the
two groups. All other bond lengths and bond angles are
found in the normal ranges observed for similar
compounds. Content of the unit cell of HL1 crystal
showed that the molecules are connected to a net of
hydrogen bonds (Figure 4). It showed the presence of
intramolecular hydrogen bonding (O(1)–H(1)ꢀꢀꢀN(1)) and
intermolecular hydrogen bonding (N(2)–H(2)ꢀꢀꢀO(2) and
aromatic hydrogen atoms with oxygen of adjacent mole-
cules). Table 5 illustrates the van der Waals displacement
between H, the donor (D), and the acceptor (A) as well as
the DHA angle.
analysis studies of the complexes of HL1 ligand gave
more information about the thermal stability of the
metal complexes, the presence of hydrated water mole-
cules, and the sequence of thermal decomposition. The
TG plot of [Co(L1)2] displayed two overlapped decom-
position steps and a well-defined and resolved step. The
overlapped two decomposition steps occurred in the
temperature range of 200–345ꢁC with a net weight loss
of 84.7% corresponding to elimination of most of organic
moieties (C28H22N4O4). The second decomposition step
occurred in the temperature range of 380–650ꢁC with a
weight loss of 5.2% and corresponded to the elimination
of C2H4 moiety to give finally a metallic residue (10.1%).
The thermal plot of [Ni(L1)2] exhibited four decomposi-
tion steps. The second and the third steps were over-
lapped. The first decomposition step occurred in the
temperature range of 170–318ꢁC with a net weight loss
of 36.6% corresponding to elimination of C10H13N3O2
moieties. The second and third overlapped decomposi-
tion peak occurred in the temperature range of
320–380ꢁC with a weight loss of 19.2% and corresponded
to the material decomposition of C6H6NO species. The
third resolved decomposition step existed in the
3.3 | Thermal analysis
TG technique is very useful in confirming the composi-
tion and structure of the complexes. The thermal

RAMADAN ET AL.
9 of 24
FIGURE 4 Unit cell packing diagram for the Schiff base (HL1) ligand
TABLE 5 Hydrogen bonds for the
D–HꢀꢀꢀA
d(D–H) Å
d(HꢀꢀꢀA) Å
1.85(3)
d(DꢀꢀꢀA) Å
2.6279(17)
2.7304(17)
<(DHA)ꢁ
Schiff base (HL1) ligand
O(1)–H(1)ꢀꢀꢀN(1)
N(2)–H(2)ꢀꢀꢀO(2)
0.87(3)
0.90(2)
148(3)
166(2)
1.85(2)
temperature range of 380–825ꢁC with a weight loss of
26.5% corresponding to the elimination of C12H7 species
to afford the residue NiC2 + O (17.7%). The TG plot of
[Cu(L1)2]ꢀ2H2O displayed two overlapped and two well-
resolved decomposition steps. The overlapped first and
second decomposition steps occurred in the temperature
range of 100–295ꢁC with a net weight loss of 27.1%
corresponding to elimination of 2H2O + C8H6N2 species.
The second decomposition peak occurred in the temper-
ature range of 295–518ꢁC with a weight loss of 44.9%
and corresponded to the material decomposition of
C17H10N2O2 moieties. The third decomposition step
occurred in the temperature range of 518–1000ꢁC with a
weight loss of 13.9% corresponding to the elimination of
C5H10O species and yielded a copper oxide residue.
From the thermal data, it was confirmed that
the copper complex crystallized with two water
molecules. In addition, it can indicate that the thermal
stability of the complexes has the order [Cu(L1)2]ꢀ
2H2O > [Co(L1)2] > [Ni(L1)2].
3.4 | Molecular orbital computation of
HL1 and its complexes
3.4.1 | Geometrical optimization of HL1
and its complexes
Optimized geometrical parameters, natural charges on
the active centers, natural configuration of the metal
ions, and energetics of the ground state for the studied
compounds were computed using density functional the-
ory (DFT) method at the B3LYP/GENECP level of theory.
The ligand HL1 was found to exist in solution in two
geometrical structures, namely, the keto and enol forms
(see above, Scheme 1). Therefore, both the two structures

10 of 24
RAMADAN ET AL.
FIGURE 5 The optimized geometry of the Schiff base (HL1) ligand in its two tautomeric forms
TABLE 6 The energetics and partial charge of active centers of
The optimized structures, numbering system, the vec-
tors of dipole moment, bond lengths, and bond angles of
the three complexes of HL1 ([Cu(L1)2], [Co(L1)2], and
[Ni(L1)2]) are presented in Figure 6. In these complexes,
the metal ions are in octahedral environment and coordi-
nated to two ligands, each with a five-membered ring and
a six-membered ring. The computed M–N and M-–O bond
lengths showed elongation upon complexation. The bonds
between M and ligand sites in [Cu(L1)2]ꢀ2H2O—for
example, Cu44–N2 = 2.029 Å, Cu44–O9 = 2.103 Å,
Cu44–O43 = 2.299 Å, Cu44–N23 = 2.012 Å, Cu44–
O30 = 2.014 Å, and Cu44–O62 = 2.429 Å—and the bond
angles between the metal species and the binding sites in
the coordination sphere vary between 76.16ꢁ and 103.35ꢁ.
The bonds between M and ligand sites in the case of [Ni
(L1)2] are Ni44–N2 = 1.912 Å, Ni44–O9 = 1.935 Å, Ni44–
the tautomers of HL1 and its anion
HL1 (keto)
HL1 (enol)
−840.176
−0.00716
0.00123
L1
−839.652
−0.05378
−
ET, au
EHOMO, au
ELUMO, au
Eg (eV)
O9
−840.181
−0.00187
0.00622
0.220
0.05921
3.073
0.228
−0.60694
−0.67532
−0.43341
−0.25259
5.7148
−0.67835
−0.69195
−0.46906
−0.36564
2.899
−0.65785
−0.80907
−0.39155
−0.33074
9.9646
O18
N10
N11
μ, D
(keto/enol) were considered for optimization. The opti-
mized geometry of HL1 in the two tautomeric forms is
shown in Figure 5. The energetics of the ligand and natu-
ral charges are listed in Table 6.
O43 =
2.459 Å,
Ni44–N23 =
1.945 Å,
Ni44–
O30 = 2.250 Å, and Ni44–O62 = 2.094 Å. The bond angles
between the metal species and the binding sites in the
coordination sphere varied between 80.51ꢁ and 98.77ꢁ. On
the other hand, the bonds between M and ligand sites in
[Co(L1)2] are Co44–N2 = 2.019 Å, Co44–O9 = 2.008 Å,
Co44–O43 = 2.141 Å, Co44–N23 = 2.037 Å, Co44–
O30 = 2.056 Å, and Co44–O62 = 2.098 Å, and the bond
angles between the metal ion and binding sites in the coor-
dination sphere vary between 79.11ꢁ and 104.64ꢁ. The cal-
culated dihedral angles around the metal in the
coordination sphere for the three complexes were far from
0ꢁ or 180ꢁ. This revealed that the metal species is not in
the same plane of the donating sites and the rest of the
ligand, that is, the complexes, are not planar.
The observed data indicated that the keto form is
more stable than the enol form by ꢂ12 kcal mol−1 as
reflected from the calculated total energy. These data are
confirmed by the experimental finding. It is clear that the
natural charges calculated from the NBO analysis
showed that the most negative centers for chelation are
the two oxygen and adjacent nitrogen atoms (O9, O18,
and N11). In addition, the anion form of the ligand was
considered for optimization using the same level of the-
ory. It was found that the natural charges on (O9, O18,
and N11) in L1− are greater than that in HL1. By compar-
ing the data of the anion and the keto form of the ligand,
it can be concluded that the anion is the favorite moiety
for the complexation process. This could be due to the
higher dipole moment for L1−, which is higher than the
dipole moment of HL1 itself. The higher dipole moment
usually indicates higher polarity and higher tendency to
react with other charged species.
3.4.2 | Natural charge and natural
population of HL1 and its complexes
The accumulation of charges on the individual atoms
coordinated with the metal ion before and after

RAMADAN ET AL.
11 of 24
FIGURE 6 Optimized structures of the Schiff base (HL1) complexes
TABLE 7 Natural charge and natural population of complexes of HL1
Natural population
Complex
[Co(L1)2]
[Ni(L1)2]
[Cu(L1)2]
Natural charge
−0.08492
Core
Valence
4.57907
9.30110
10.58103
Rydberg
0.00839
0.01476
0.01099
Total
Natural electronic configuration
8.99746
17.99440
17.99665
13.58492
27.31026
28.58866
[core]4s(0.13), 3d(4.22), 4p(0.08), 5p(0.15)
[core]4s(0.27), 3d(8.59), 4p(0.44), 5p(0.01)
[core]4s(0.26), 3d(9.90), 4p(0.42), 5p(0.01)
0.68974
0.41134
complexation, natural population of electrons of each
metal ion in the core, valence and Rydberg subshells, and
natural electronic configuration of metal ions in the coor-
dination globe of the complexes of HL1 ligand are given
in Tables 7 and 8. The most electronegative charges
existed on O9, O18, and N11 atoms of the ligand and
complexes. Thus, these electronegative atoms in the
most electropositive charges are centered on the Cu(II),
Ni(II), and Co(II) ions. Such atoms are more able to
receive electrons from the ligands. In [Cu(L1)2] complex,
the Cu central ion receives 1.5886e from the ligand with
3d9.90 configuration. In the case of [Ni(L1)2] complex,
the Ni ion receives 1.3102e from the ligand with 3d8.59
configurations. In the case of [Co(L1)2] complex, the Co
ion receives 1.9150e from the ligand with 3d4.22
configurations.
coordination sphere have
a tendency to provide
electrons to the central metal. On the other hand, the

12 of 24
RAMADAN ET AL.
3.4.3 | Quantum global reactivity
descriptors of HL1 and its complexes
(L1)2] < [Cu(L1)2] < [Ni(L1)2]. Smaller η values for the
complexes imitated the ability of charge transfer inside the
molecules. The order of increasing charge transfer within
the complexes is [Ni(L1)2] > [Co(L1)2] > [Cu(L1)2].
The global reactivity descriptors of HL1 anion and its
complexes—HOMO and LUMO, energy gap (Eg), electro-
negativity(χ), chemical potential (V), electron affinity (A),
ionization potential (I), chemical hardness (η), and chem-
ical softness (S)—are presented in Table 9. The Eg separa-
tion between the HOMO and LUMO of the complexes
characterizes the molecular chemical reactivity. The
smaller energy gap reflects the ease of the charge transfer
and polarization within the compound. The donating
properties, EHOMO, of the complexes follow the order [Ni
(L1)2] > [Co(L1)2] > [Cu(L1)2], whereas the accepting
properties, ELUMO, follow the order [Cu(L1)2] > [Co
(L1)2] > [Ni(L1)2]. Thus, the order of increasing chemi-
3.4.4 | Non-quantum global reactivity
descriptors for HL1 anion and its complexes
The calculated values of the physicochemical properties
of HL1 anion and its complexes are given in Table 10.
The considered computed parameters are MV, HE, Pol,
SAG, and MR. Calculations were carried out using Hyp-
erChem 8.0.7. Molecular polarizability (Pol) characteris-
tics is defined by the capacity of the electronic system of
a molecule to modulate itself upon application of external
electric field of light. The meaning of molecular polariz-
ability stems from its important role in the modeling of
many biological activities and properties of molecules.
Molecular polarizability depends on the molecular
volume that determines the transport characteristics of
molecules. In biological environment, for example, it
cal reactivity follows the order [Ni(L1)2]
> [Co
(L1)2] > [Cu(L1)2]. FromtheHOMOandLUMOenergies,
ionization potential and electron affinity are expressed as
Iꢂ −EHOMOandAꢂ −ELUMO.Thevariationsinelectronega-
tivity(χ)valuesissustainedbytheelectrostaticpotential.The
resultsshowedthattheorderofdecreasingelectronegativity,
thatis,increasingchargetransferwithinthecomplexes,is[Co
TABLE 1 0 Non-quantum global parameters of HL1 anion and
its complexes
TABLE 8 Natural charge on the coordinated centers of
complexes of HL1
Parameter
SAG, Å2
MV, Å3
L1−
[Co(L1)2] [Ni(L1)2] [Cu(L1)2]
451.08
762.54
761.57
1407.63
1.91
761.57
1407.63
1.91
Center
O9
L1−
[Co(L1)2]
−0.31398
−0.35196
−0.14734
−0.33557
−0.29596
−0.13884
[Ni(L1)2]
−0.61766
−0.65704
−0.31553
−0.57997
−0.60224
−0.31105
[Cu(L1)2]
−0.64282
−0.70447
−0.28104
−0.52073
−0.58300
−0.28896
724.06 1409.22
−0.64616
−0.80601
−0.31956
−0.64616
−0.80601
−0.31956
Log P
1.84
1.91
O18
N11
O9
HE, kcal
mol−1
Pol, Å3
MR, Å3
−6.28
−14.64
−14.48
−14.41
81.09
81.09
55.45
160.40
565.49
55.46
160.40
565.27
55.47
160.40
570.11
O18
N11
MW, amu
253.28
TABLE 9 Quantum global
properties of HL1 anion and its
complexes
Parameter
ET, au
L1−
−839.652
−0.05378
[Co(L1)2]
−1823.863
−0.15788
−0.05171
2.8878
[Ni(L1)2]
−1848.078
−0.15617
[Cu(L1)2]
−1874.710
−0.17609
EHOMO, au
ELUMO, au
Eg, eV
−0.05921
3.073
−0.07707
2.1515
4.2478
2.0963
3.1720
1.0757
0.4648
−3.1996
−0.04979
3.4353
4.7896
1.3542
3.0719
1.7177
0.2910
−3.5910
I, eV
1.4628
4.2943
A, eV
−1.6105
−0.0738
1.5366
1.4065
χ, eV
2.8504
η, eV
1.4439
S, eV
0.3253
0.3462
V, eV
−2.2679
−4.1124

RAMADAN ET AL.
13 of 24
includes blood–brain barrier penetration and intestinal
absorption.[36] Thus, the modeling of molecular proper-
ties and biological properties need the use of molecular
volume in the quantitative structure–activity relation-
ships. Molar refractivity is a steric parameter, and it
depends on the spatial array of the aromatic rings in mol-
ecules. The significance of the spatial arrangement is
essential to study the interaction of drug molecules with
the receptors.[37] It also depends on the London
dispersive forces, which play a strong role in drug
molecule–receptor interactions. Table 10 illustrates that
the polarizability data, MR, and SAG are mostly propor-
tional to the size and molecular weight of the reported
complexes. The data also show that the hydration energy
increases because of increasing the hydrophobic values.
The number of hydrogen bonds between acceptor and
donor affects the change in the values of the hydration
energy.[38]
3.4.5 | Nonlinear optical properties of
HL1 anion and its complexes
In order to determine the relationship between molecular
structure and nonlinear optical (NLO) properties, the
polarizabilities and hyperpolarizabilities of the reported
complexes of HL1 were calculated. Total static dipole
moment (μ), mean polarizability (α), anisotropy of
polarizability (Δα), and the mean of first-order
hyperpolarizability (β) of the ligand and its complexes are
listed in Table 11. The polarizabilities and first-order
hyperpolarizabilities are given in atomic units (au). The
calculated values for α and β have been converted into
electrostatic units (esu) using conversion factors
(0.1482 × 10−24 esu for α and 8.6393 × 10−33 esu for β).
Urea was used as a standard prototype in the NLO stud-
ies.[39] The magnitude of β is one of the key factors in a
NLO system. The theoretical analysis of β for HL1 and its
complexes showed that both the L1 and [Co(L1)2] are
−
TABLE 11 Nonlinear optical properties of HL1 anion and its complexes
Parameter
μx
L1−
−4.8227
[Cu(L1)2]
−3.4470
[Ni(L1)2]
0.3091
[Co(L1)2]
−1.7541
−1.4928
8.5677
μy
3.3344
0.3517
0.3430
0.8638
μz
2.8755
5.6883
μ, D
5.8736
4.50199
5.76177
8.87191
αxx
−155.4734
−156.5369
−117.1237
16.5974
−199.1806
−183.5469
−228.1542
−13.6887
7.2178
−194.9582
−210.3597
−223.9595
−16.5676
−24.5580
10.4222
−198.7639
−199.8309
−242.5692
−25.6764
6.4472
αyy
αzz
αxy
αxz
3.1031
αyz
−0.3168
−143.044
−2.119 × 10–23
21.1386
−3.9854
−0.1726
−213.721
−3.167 × 10−23
43.28166
14.1877
α, au
α, esu
Δα, au
βxxx, au
βyyy
−203.627
−3.017 × 10–23
39.2026
−209.759
−3.108 × 10−23
25.13201
−32.9232
62.2989
−28.6122
−21.8399
0.9351
−9.4458
38.4135
7.2048
βzzz
−20.0290
−1.8560
42.6708
46.1826
βxyy
−32.8975
76.3865
−0.5201
−18.8236
44.1482
−12.2676
13.7234
βxxy
64.3180
βxzz
−13.6388
−12.2361
7.7621
−58.8046
−23.5458
−31.8397
−29.7298
−10.1743
123.750
−39.8389
30.7659
βxxz
5.9723
βyzz
11.4005
−12.1919
7.6161
βyyz
0.3675
−4.4493
−27.0125
69.446
βxyz
−5.6705
98.230
8.486 × 10−31
19.0636
β, au
β, esu
93.060
8.039 × 10−31
1.069 × 10−30
5.999 × 10−31

14 of 24
RAMADAN ET AL.
fourfold greater than urea. However, the [Ni(L1)2] and
[Cu(L1)2] complexes are threefold and fivefold greater
than urea. These findings confirmed that the reported
complexes are effective NLO candidates.
cobalt(II) and nickel(II) ions in the two complexes con-
firmed the nonplanarity conformation of their structure.
3.5.2 | Natural charge and natural
population for the complexes of HL2
and HL3
3.5 | Molecular orbital computations of
the complexes of HL2 and HL3
The accretion of charges on the individual atoms coordi-
nated with the metal ion before and after complexation,
valence and Rydberg subshells, natural population of the
electrons of each metal ion in the core, and natural elec-
tronic configuration of the metal ions in the coordination
sphere of the HL2 and HL3 complexes are tabulated in
Tables 12 and 13. The most electronegative charges are
cumulated on N11, O9, and O18 atoms of the ligands and
the complexes. These electronegative atoms in the coordi-
nation globe have, thus, a tendency to give electrons to the
central metal ions. The most electropositive charges
accrued on the Co(II) and Ni(II) species. Such atoms are
more likely to receive electrons from the ligands. In the
case of [Ni(L2)2], the nickel(II) central metal ion receives
1.2881e from the ligand with 3d8.56 configuration
(Table 12). Again, the most electropositive charges accrued
on the Co(II) and Ni(II) ions. Such atoms are more likely
to receive electrons from the ligands. In the case of [Co
(L3)2] complex, the Co central metal ion receives 1.4175e
from the ligand with 3d7.65 configurations. For the
[(NiL3)2] complex, the two Ni central metal ions receive
1.24916e and 1.31859e from the ligand with 3d8.65 and
3d8.71configurations. In addition, there is an electron back-
donation in the case of [(NiL3)2] from Ni to N11 and N11
of the other ligand by 0.00754 and 0.0163, respectively.
3.5.1 | Geometrical optimization of the
complexes
The geometrical optimizations of the two ligands HL2 and
HL3 were previously reported.[2] The optimized structural
geometry, numbering, dipole moment, bond lengths, and
bond angles of the complexes of HL2 and HL3 are shown
in Figure 7. In [Ni(L2)2] complex, the metal ion coordi-
nated to two ligands, each forming a five- membered ring,
namely, Ni21–O9-C8–N10–N11, and a six-membered ring,
Ni21–N11–C12-C14–C19–O20, forming a distorted octahe-
dral structure. The computed M–N and M–O bond lengths
showed elongation upon complexation.[2] These bond
lengths are much longer compared with the typical MX
bond lengths (X = O or N).[40] The bonds between M
and ligand sites in [Ni(L2)2] are Ni21–N22 = 2.076 Å,
Ni21–O33 = 2.647 Å, Ni21–O20 = 1.867 Å, Ni21–
N11 = 1.979 Å, Ni21–O41 = 2.010 Å, and Ni21–
O9 = 1.971 Å. On the other hand, the bond angles
between the nickel(II) ion and binding sites in the coordi-
nation sphere vary between 68.98ꢁ and 126.68ꢁ. The calcu-
lated dihedral angles around the metal species in the
coordination sphere were far from 0ꢁ or 180ꢁ and revealed
that the complexes is nonplanar.
The optimized structure of [Co(L3)2] complex
exhibited a distorted octahedral structure similar to that
of [Co(L1)2] and [Ni(L2)2] complexes (Figures 6 and 7).
The bonds between Co and ligand sites are
Co24–N11 = 1.965 Å, Co24–O9 = 2.064 Å, Co24–
3.5.3 | Quantum global reactivity
descriptors for the complexes of HL2 and
HL3
O25 =
1.834 Å,
Co24–N37 =
1.928 Å,
Co24–
O40 = 1.848 Å, and Co24–O23 = 1.874 Å. In addition,
the bond angles between cobalt ion and binding sites in
the coordination sphere vary between 79.04ꢁ and 93.17ꢁ.
In the case of [(NiL3)2] complex, the spectroscopic and
analytical studies showed that it has a dinuclear structure
similar to that observed for [(CuL3)2] complex.[2] The
bonds between Ni and ligand coordination sites were
found to have the following values: Ni24–N11 = 1.871 Å,
The global properties of the complexes of HL2 and
HL3 are presented in Table 14. The donating
properties, EHOMO, of the complexes follow the order [Co
(L3)2] > [Ni(L2)2] > [(NiL3)2], whereas the accepting
properties,
ELUMO
,
are
[Ni(L2)2]
>
[Co
(L3)2] > [(NiL3)2]. From the energy gap (Eg), the order
of increasing reactivity follows the order [Co(L3)2] > [Ni
(L2)2] > [(NiL3)2]. The variation of electronegativity (χ)
values is sustained by electrostatic potential. Table 14
shows that the order of decreasing χ (increasing charge
transfer within the complexes) is [Co(L3)2] < [Ni
(L2)2] < [(NiL3)2]. The ability of charge transfer inside
the complexes (η) follows the order [Co(L3)2] > [Ni
(L2)2] > [(NiL3)2].
Ni24–O9 =
1.878 Å,
Ni24–O39 =
1.884 Å,
Ni24–O23 = 2.075 Å, Ni40–N44 = 1.847 Å, Ni24–
O47 = 1.854 Å, Ni24–O39 = 1.945 Å, and Ni24–
O23 = 1.927 Å. The bond angles between Ni ion and the
binding sites in the coordination sphere varied between
77.51ꢁ and 108.01ꢁ. The dihedral angles around the

RAMADAN ET AL.
15 of 24
FIGURE 7 Optimized geometries, numbering system, vectors of dipole moment, bond lengths, and bond angles of the complexes of
HL2 and HL3
3.5.4 | Non-quantum global reactivity
descriptors for the complexes of HL2 and
HL3
complexes (Table 15). In addition, the data showed that
an increase in the hydrophobic values would result in an
increase in the hydration energy. It is well known that
the number of hydrogen bonds between acceptor and
donor within the molecule affects the change in the
values of hydration energy.[38]
The polarizability data, MR, and SAG are found to be
proportional to the size and the molecular weight of the

16 of 24
RAMADAN ET AL.
TABLE 12 Natural charge and natural population of complexes of HL2 and HL3
Natural population
Complex
Natural charge
0.71190
Core
Valence
9.27887
8.40450
9.25293
9.32175
Rydberg
0.01440
0.02297
0.00870
0.00920
Total
Natural electronic configuration
[Ni(L2)2]
[Co(L3)2]
[(Ni(24)L3)2]
[(Ni(40)L3)2]
17.99483
17.99009
17.98753
17.98763
27.28810
26.41755
27.24916
27.31859
[core]4s(0.26)3d(8.56) 4p(0.01) 5p(0.46)
[core]4s(0.26) 3d(7.65) 4p(0.50) 4d(0.01) 5p(0.01)
[core]4s(0.28) 3d(8.65) 4p(0.21) 5p(0.11)
[core]4s(0.28) 3d(8.71) 4p(0.09) 5p(0.24)
0.58245
0.75084
0.68141
TABLE 13 Natural charge on coordinated centers of complexes of HL2 and HL3
Center
O9
L2−
[Ni(L2)2]
−0.56094
−0.62359
−0.29566
--
[Co(L3)2]
−0.59271
−0.63307
−0.25903
--
[(NiL3)2]
−0.64240
−0.71358
−0.32710
0.00754
−0.64846
−0.80606
−0.36071
--
O18
N11
M ! L
O9
−0.64846
−0.80606
−0.36071
--
−0.64558
−0.68267
−0.32052
--
−0.59885
−0.63523
−0.24866
--
−0.64240
−0.69748
−0.33586
0.0163
O18
N11
M ! L
TABLE 14 Quantum global
Parameter
ET, au
L2−
[Ni(L2)2]
L3−
[Co(L3)2]
[(NiL3)2]
properties of HL2 and HL3 anions and
−878.978
−1926.703
−993.331
−2130.834
−2323.201
their complexes
EHOMO, au
ELUMO, au
Eg, eV
−0.05072
−0.15135
−0.06098
−0.12427
−0.21217
0.05822
2.963
−0.07093
2.1874
−0.05980
0.2850
−0.07813
1.2550
3.3801
2.1251
2.7526
0.6275
0.7968
−2.3175
−0.11718
2.5837
I, eV
1.3795
4.11672
1.92929
3.023005
1.093715
0.45715
−3.023005
1.6586
5.7710
A, eV
−1.5835
−0.102
1.4815
−1.6265
0.0160
3.1872
χ, eV
4.4791
η, eV
1.6425
1.2919
S, eV
0.3374
0.3044
0.38702
−4.1773
V, eV
−2.1712
−0.9718
3.5.5 | NLO properties for the complexes
of HL2 and HL3
3.6 | Biological activity studies
3.6.1 | Antibacterial activity
Analysis of the computed values of β for the ligands and
complexes showed that L2 anion is six times greater
Antibacterial activities of the HL1 ligand and its complexes
were screened in vitro against two bacteria, E. coli
(gram negative) and S. aureus (gram positive), and
compared with the known antibiotic: ampicillin as an
antibacterial drug. The results indicated that all the com-
plexes, except for the copper(II) derivative, have medium
antibacterial activities with respect to that of standard
(Table 17). The copper(II) complex has almost equal
−
−
than urea, whereas that of L3 anion is four times
greater. On the other hand, the β values for [Ni(L1)2],
[Co(L3)2], and [(NiL3)2] are nine, six, and five times
greater than urea, respectively. These values confirmed
the effectiveness of the complexes as NLO candidates.
The result also showed that the NLO properties increased
after complexation (Table 16).

RAMADAN ET AL.
17 of 24
TABLE 15 Non-quantum global
properties of the complexes of HL2 and
HL3
Parameter
SAG, Å2
MV, Å3
L2−
[Ni(L2)2]
810.30
1480.94
3.82
L3−
[Co(L3)2]
886.17
1649.65
2.06
[(NiL3)2]
464.24
767.63
2.80
545.20
902.32
1.91
892.29
1660.84
2.56
Log P
HE, kcal mol−1
Pol, Å3
MR, Å3
−5.03
29.99
85.56
267.31
−12.31
59.13
−7.22
34.33
99.28
303.34
−14.06
67.82
−13.86
67.22
169.35
593.32
196.79
665.61
192.89
722.08
MW, amu
TABLE 16 Nonlinear optical properties of the complexes of HL2 and HL3
Parameter
μx
L2−
−6.2423
[Ni(L1)2]
−4.9746
L3−
−3.9297
[Co(L3)2]
−1.2278
[(NiL3)2]
−0.2220
0.9511
μy
0.6129
−1.5332
−6.3278
−4.4312
−2.0088
−5.4425
μz
−3.7867
−0.5475
−0.0163
μ, D
6.4569
8.89532
6.25406
5.60607
0.976801
−251.4181
−273.3155
−281.4643
21.7355
αxx
−165.8107
−157.5241
−129.1993
16.4126
−191.0098
−245.5255
−232.1840
5.5998
−168.3159
−170.4271
−144.2745
−4.9223
−226.8709
−268.1970
−260.2305
12.8561
αyy
αzz
αxy
αxz
−4.3566
−8.4255
5.5405
−26.8051
−3.5975
−7.3279
αyz
0.7243
−11.7620
−222.906
−3.303 × 10−23
341.2284
−122.5740
−28.0939
−18.7025
−45.6772
−62.2953
18.5961
7.3209
−1.7683
α, au
α, esu
Δα, au
βxxx, au
βyyy
−150.844
−2.235 × 10–23
33.2517
−161.005
−2.386 × 10–23
25.1635
−251.766
−3.731 × 10–23
−268.732
−3.982 × 10–23
26.9135
37.9748
−104.0948
−59.7630
19.8294
−58.8850
−71.5709
−12.0768
−25.5541
34.3919
−15.7478
−95.5321
2.6856
−27.5311
90.6218
βzzz
44.9645
βxyy
−17.0150
67.7049
−53.1361
−27.5208
35.3874
2.8666
βxxy
−31.2332
25.3993
βxzz
−7.5757
−19.1640
37.0768
βxxz
−18.9820
7.2446
−11.6121
−38.9327
−1.1085
9.6918
82.2592
βyzz
21.5118
−8.1829
−1.1774
βyyz
−29.6504
11.6346
−22.3486
−0.8195
−22.6376
67.6481
−34.4865
−45.7672
109.495
βxyz
−24.7459
200.270
1.730 × 10−30
β, au
β, esu
132.740
1.146 × 10−30
104.814
9.055 × 10−31
135.831
1.173 × 10−30
9.459 × 10−31
activity similar to that of ampicillin. Therefore, coordina-
tion of Cu(II) ion to the ligand greatly enhanced the
antibacterial activity. The activity of the ligand and
complexes can be demonstrated by the cell permeability
concept and/or Tweedy's chelation theory.[41–43] Due to
the high polarity of metal ions, the cell permeability
concept declared that these ions can hardly pass through
the membrane, which surrounds the cell. On chelation,
the polarity of the metal ions is significantly reduced as a
result of the overlap of ligand and metal orbitals. Such
overlap will lead to a partial contribution of the positive
charge of metal ion with the donor groups. Furthermore,
the lipophilicity of copper(II) complex is improved as the
π-electron delocalization over the whole chelating
ring increases. Subsequently, the penetration of the
complex into lipid membranes will be enhanced and then
blocking the Cu(II) binding sites in the enzymes of
microorganisms.

18 of 24
RAMADAN ET AL.
3.6.2 | Antioxidant activities by DPPH
radical scavenging activity
was used as a standard. The % DPPH˙ scavenging values at
30-min incubation time are shown in Figure 8. It was
observed that the antioxidant activities increased with
increasing concentration of the complexes. It is worth to
mention that at low concentration up to 100 μM,
the percentage scavenging activities of the two complexes,
[Cu(L1)2] and [Co(L3)2], are higher than the standard.
After that concentration (100 μM), all the scavenging
activities of the complexes are smaller relative to the stan-
dard. In terms of IC50 (concentration of the sample
required to inhibit 50% of radical), the data showed that
[Cu(L1)2] complex has a potent antioxidant activity with
the lowest IC50 value relative to other complexes
(Figure 9). The IC50 order of the complexes is as follows:
[Cu(L1)2] (52.3 μg/mL) < [Co(L3)2] (79.1 μg/mL) < [Co
(L1)2] (101.3 μg/mL) < [Ni(L2)2] (107.5 μg/mL) <
[(NiL3)2] (120.2 μg/mL) < [Ni(L1)2] (166.4 μg/mL).
The free radical oxidative process plays a significant patho-
logical role in causing many human diseases together with
aging.[44] Thus, the antioxidant drugs are capable to pro-
tect the cells and organisms from damage caused by oxida-
tive stress during metabolism. For this reason, there are
extensive studies in literature to check the antioxidant
activities of various synthetic compounds. There are many
different methodologies used to study the antioxidant
activities. The free radical DPPH˙ is commonly used for
free radical scavenging determination due to its ease
and convenience. In vitro antioxidant activity of the inves-
tigated complexes was evaluated by DPPH˙ free radical
scavenging method. Antioxidant properties of the samples
were measured using different concentrations (25, 50,
100, 150, and 200 μg/mL). For comparison, ascorbic acid
3.6.3 | Fluorescence quenching studies
TABLE 17 Antimicrobial activities of HL1 and its complexes
Fluorescence spectroscopy is an excellent and useful
technique used to study the interactions between small
molecules and macromolecules such as DNA.[45] This
technique illustrates information about the binding prop-
erties (such as the binding mechanism, binding mode,
binding constant, binding sites, and intermolecular
distances) of the small molecules to protein/DNA.[46]
Fluorescence quenching refers to any process that
decreases the fluorescence intensity from a fluorophore
induced by a variety of molecular interactions including
Inhibition zone diameter (mg/mm)
Escherichia coli
Staphylococcus aureus
Compound
HL1
[Co(L1)2]
[Ni(L1)2]
[Cu(L1)2]
Ampicillin
(gram negative)
(gram positive)
13
0.0
11
23
25
12
12
10
20
21
FIGURE 8 The percent DPPH˙ radical
scavenging activities of the reported complexes
compared with the standard ascorbic acid

RAMADAN ET AL.
19 of 24
FIGURE 9 Trends in the inhibition of
DPPH˙ radical by the investigated complexes
FIGURE 10 Fluorescence emission spectra of the EB–DNA system in the absence (dashed line) and presence (solid line) of reported
complexes. Arrows indicate the intensity changes upon increasing the concentration of the complexes
excited-state reactions, molecular rearrangements, energy
transfer, ground-state complex formation, and collisional
quenching.[47] EB reagent is used to study the potential
DNA-binding mode of the complexes. EB emits intense
fluorescence band at 608 nm in the presence of CT-DNA
due to the strong intercalation between it and the adja-
cent DNA base pairs. Addition of a second molecule that
binds to DNA more strongly than EB will quench the
DNA-induced EB emission.[44] Extent of quenching of
the fluorescence of EB bound to DNA reflects the extent
of the DNA binding to the added second molecule. The
emission spectra of DNA bound to EB in the absence and
presence of different concentrations of the investigated
complexes are shown in Figure 10.

20 of 24
RAMADAN ET AL.
From figures, it can be noticed that addition of the
complexes and CT-DNA were further investigated by vis-
cosity measurements to identify the effect of interaction
on the length of CT-DNA (Figure 12). The hydrodynamic
methods, which are sensitive to the change in DNA
length, are regarded as the least obvious and most critical
tests of binding in solutions. Intercalating agents increase
the relative specific viscosity, (η/ηo)1/3, of CT-DNA due to
the elongation of the double helix to accommodate the
compounds in between the base pairs. In contrast, a par-
tial and/or nonclassical intercalation may bend or kink
the DNA helix. Under the same conditions, typical results
in less pronounced effect on its effective length and
concomitantly its viscosity.[50] On increasing concentra-
tion of complexes, plots of relative viscosity versus
[complex]/[DNA] exhibited significant increase in the
viscosity of DNA solution. This indicates that complexes
bind to CT-DNA through an intercalation binding
mode.[51] The classical intercalators, such as EB, are
known to increase the base pair separation, resulting in
an increase in the relative viscosity of the CT-DNA. How-
ever, the effect of the transition metal complexes is less
than that observed for EB intercalator, which indicated a
weak intercalative interaction between the complexes
and CT-DNA. The presence of transition metal com-
plexes is accounting for the higher binding extent of the
complexes with CT-DNA. The increased degree of viscos-
ity, which may depend on its affinity to DNA, follows the
order of [Cu(L1)2] > [Ni(L1)2] > [Co(L1)2] > [Co(L3)2]
complexes to CT-DNA pretreated with EB caused high
reduction in emission intensity along with the increase in
concentration of the reported derivatives. This indicates
that the complexes strongly compete with EB and bind to
DNA at the same sites occupied by EB. Fluorescence
quenching occurs by dynamic and static quenching
mechanisms. The dynamic mechanism results from colli-
sion between the quencher and the fluorophore, whereas
the static mechanism can be due to the formation of a
complex between the fluorophore and quencher.[48] The
quenching constant, Ksv, is obtained from the slope of the
linear plot {Io/I versus [Q]}. The plots (Figure 11) illus-
trate that the quenching of EB bound to CT-DNA by the
complexes is in good agreement with the linear
Stern–Volmer equation. The KSV values were found to
be [Co(L1)2] (0.93 × 104), [Ni(L1)2] (0.75 × 10−4), [Cu
(L1)2] (1.19 × 104), [Ni(L2)2] (0.78 × 104), [Co(L3)2]
(0.97 × 104), and [(NiL3)2] (1.68 × 104), respectively.
3.6.4 | Viscosity measurements
Although the fluorescence quenching studies mentioned
above offer essential information about the binding
modes of complexes to DNA, they are lacking certain evi-
dences to support an intercalative binding model.[49]
Therefore, the interaction modes between the reported
FIGURE 11 The profile of fluorescence variation of the studied complexes versus molar concentrations

RAMADAN ET AL.
21 of 24
FIGURE 12 Effects of increasing the
concentrations of the studied complexes on the
relative viscosity of CT-DNA
FIGURE 13 Molecular docking interactions (2D and 3D) of HL1 and its complexes with DNA
> [(NiL3)2] > [Ni(L2)2], which is consistent with the
suggested hypothesis from fluorescence quenching data.
The increased degree of viscosity showed that changing
the metal environment could modulate the binding prop-
erty of the complex with DNA.[52] Results of DNA binding
studies confirmed the suggested intercalative mode mecha-
nism for interaction between the compounds and DNA.
3.7 | Molecular docking studies
Molecular docking is a good theoretical process to declare
the type of interaction between synthetic drugs and bio-
logical macromolecular target such as protein or DNA.
The analysis is used to predict conformational changes
associated with the amino acid moieties at the binding

22 of 24
RAMADAN ET AL.
position to accommodate the docked inhibitors. HL1
ligand and the reported complexes were subjected to
molecular docking studies using the MOE version
2016.08 to identify the compound-DNA interactions
(Figures 13 and 14). The docked ligand and complexes
conformations were compared according to the binding
energy, hydrophobic interactions, and hydrogen bonding
between the compound and the B-DNA (PDB ID: 1BNA).
The docking analysis determined the way by which the
docked derivatives fundamentally fit with the DNA
minor groove. It also demonstrated the hydrophobic,
ionic, and hydrogen bonding interactions with the DNA
base parts. It was found that most optimal docking fitted
in the DG, DC, and DA regions. All the compounds dis-
played very good binding scores with high negative
values (Table 18). This represents high binding affinity
between the DNA receptor and indicates higher effi-
ciency of the bioactive reagents. In the case of free HL1,
the binding interaction came from hydrogen bonds
formed between DG16 and the OH group of ligand, as
well as the interaction of DA18 with the phenyl moiety
and hydrogen bonds formed between water molecules
and the NH moiety of ligand (Figure 13). For [Co(L1)2]
complex, the binding interaction came from hydrophobic
interaction between amino acid moieties such as DA
17, DC 11, DC 15, and DG 16 with the aromatic moiety
of the ligand as well as the interaction and hydrogen
bonds of DG3 12 with the phenyl moiety. In the case of
the three complexes, [Ni(L1)2], [Cu(L1)2], and [Ni
(L2)2], they showed similar interaction with the DNA
(hydrogen bonding interactions with DA 18, DC 11, and
DG3 12 regions as well as hydrophobic interactions with
DA 17, DG 10, DC 15, and DG 16) (Figures 13 and 14).
This could be due to their identical structures and simi-
larity between the two ligands (Figure 2). The two com-
plexes [Co(L3)2] and [(NiL3)2] interacted only through
hydrophobic binding with DNA through the amino acid
residues such as DG 10, DG 16, DA 17, DC 15, and DG3
TABLE 1 8 The values of final score functions of the
interaction of DNA with HL1 and the reported complexes
Compound
HL1
S
−5.1557
−5.4508
−5.3070
−5.2215
−5.4531
−5.0700
−6.2719
[Co(L1)2]
[Ni(L1)2]
[Cu(L1)2]
[Ni(L2)2]
[Co(L3)2]
[(NiL3)2]
FIGURE 14 Molecular docking interactions (2D and 3D) of the complexes of HL2 and HL3 with DNA

RAMADAN ET AL.
23 of 24
12 and the aromatic moieties of the ligand (Figure 14).
Interestingly, the dimer nickel(II) complex, [(NiL3)2],
exhibited the best binding score with a value of
−6.2719 kcal mol−1. This could be due to the presence of
two metal species and the expanding structure, which
gave more chance of binding (Figure 14). Therefore, it is
obvious that these bioactive derivatives are effectively
able to interact with the available binding sites of the
macromolecule target. In addition, the theoretical studies
supported the experimental findings of the fluorescence
quenching and viscosity measurements, which indicated
the intercalative mode for DNA interaction. The order
of decreasing of binding interaction of the complexes
is as follows: [(NiL3)2] > [Ni(L2)2] > [Co(L1)2] > [Ni
(L1)2] > [Cu(L1)2] > [Co(L3)2].
ORCID
Ramadan M. Ramadan https://orcid.org/0000-0002-
9755-5410
Samir M. El-Medani https://orcid.org/0000-0002-7519-
2241
Abdelmoneim Makhlouf https://orcid.org/0000-0001-
7485-1834
Hussein Moustafa https://orcid.org/0000-0001-5707-
4244
Manal A. Afifi https://orcid.org/0000-0002-5643-2991
Matti Haukka https://orcid.org/0000-0002-6744-7208
Ayman Abdel Aziz https://orcid.org/0000-0003-0041-
6607
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Ramadan
Ramadan:
Project
administration;
[14] R. P. Bakale, G. N. Naik, C. V. Mangannavar, I. S.
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supervision. Samir El-Medani: Investigation; project
administration; supervision. Abdelmoneim Makhlouf:
Investigation; methodology; supervision. Hussein
Moustafa: Data curation; formal analysis; software;
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analysis; investigation; methodology. Matti Haukka:
Formal analysis; methodology; software; validation.
Ayman Abdel Aziz: Data curation; formal analysis;
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