Novel azomethine Pd (II)- and VO (II)-based metallo-pharmaceuticals as anticancer, antimicrobial, and antioxidant agents: Design, structural inspection, DFT investigation, and DNA interaction

Article abstract of DOI:10.1002/poc.4009

The new NO bidentate imine ligand, namely, (2-[(3-nitro-benzylidene)-amino]-benzoic acid) (NBA) imine ligand (L), and its Pd (II) and VO (II) complexes have been synthesized and characterized by utilizing different physiochemical methods including elemental analyses, Fourier transform infrared (FT-IR), nuclear magnetic resonance (NMR), molar conductance, and magnetic susceptibility measurements. The stability constant of these complexes has also been determined. In studies of these complexes, they were found to have [M(L)] composition where the ligand acts as a bidentate and coordinates with the various metal ions through azomethine and one oxygen atom. Moreover, the suggested geometrical structure of Pd (II) and VO (II) complexes is square planar and a distorted square pyramid, respectively. Density functional theory (DFT) calculations for the different metal complexes were studied and show a good agreement with the experiment data. The minimum inhibitory concentration method has been applied to evaluate the in vitro antimicrobial activity. Furthermore, the interaction of calf thymus DNA with the metal-imine chelates has been assessed, and Pd (II) complex showed the strongest interaction with DNA for a binding constant value of (9.72 × 10⁴ kcal mol^?1). The cytotoxic activity of the new metal chelates has been evaluated against three human cancer cell lines (hepatic carcinoma HepG2 cells, breast carcinoma cells MCF-7, and colon carcinoma cells HCT-116). It has found that NBAPd complex exhibited a significant decrease in the time and dose of the cell viability than did the reference drug vinblastine. The antioxidant activity of the tested compounds was determined and compared with that of vitamin C as a standard drug. It has been found that the metal complexes exhibit higher activity than the free ligand. The finding from this investigation revealed that the new compounds are considered to be prospective antibiotic and anticancer agents.

Full text of DOI:10.1002/poc.4009

Received: 1 June 2019
DOI: 10.1002/poc.4009
Revised: 22 July 2019
Accepted: 2 August 2019
R E S E A R C H A R T I C L E
Novel azomethine Pd (II)‐ and VO (II)‐based metallo‐
pharmaceuticals as anticancer, antimicrobial, and
antioxidant agents: Design, structural inspection, DFT
investigation, and DNA interaction
Ahmed M. Abu‐Dief1
| Laila H. Abdel‐Rahman1 | Mohamed R. Shehata2 |
Azza A. Hassan Abdel‐Mawgoud1
1 Chemistry Department, Faculty of
Abstract
Science, Sohag University, Sohag, Egypt
The new NO bidentate imine ligand, namely, (2‐[(3‐nitro‐benzylidene)‐amino]‐
benzoic acid) (NBA) imine ligand (L), and its Pd (II) and VO (II) complexes
have been synthesized and characterized by utilizing different physiochemical
methods including elemental analyses, Fourier transform infrared (FT‐IR),
nuclear magnetic resonance (NMR), molar conductance, and magnetic suscep-
tibility measurements. The stability constant of these complexes has also been
determined. In studies of these complexes, they were found to have [M(L)]
composition where the ligand acts as a bidentate and coordinates with the var-
ious metal ions through azomethine and one oxygen atom. Moreover, the sug-
gested geometrical structure of Pd (II) and VO (II) complexes is square planar
and a distorted square pyramid, respectively. Density functional theory (DFT)
calculations for the different metal complexes were studied and show a good
agreement with the experiment data. The minimum inhibitory concentration
method has been applied to evaluate the in vitro antimicrobial activity. Fur-
thermore, the interaction of calf thymus DNA with the metal‐imine chelates
has been assessed, and Pd (II) complex showed the strongest interaction with
DNA for a binding constant value of (9.72 × 104 kcal mol−1). The cytotoxic
activity of the new metal chelates has been evaluated against three human can-
cer cell lines (hepatic carcinoma HepG2 cells, breast carcinoma cells MCF‐7,
and colon carcinoma cells HCT‐116). It has found that NBAPd complex exhib-
ited a significant decrease in the time and dose of the cell viability than did the
reference drug vinblastine. The antioxidant activity of the tested compounds
was determined and compared with that of vitamin C as a standard drug. It
has been found that the metal complexes exhibit higher activity than the free
ligand. The finding from this investigation revealed that the new compounds
are considered to be prospective antibiotic and anticancer agents.
2 Chemistry Department, Faculty of
Science, Cairo University, Giza, Egypt
Correspondence
Ahmed M. Abu‐Dief, Chemistry
Department, Faculty of Science, Sohag
University, Sohag 82524, Egypt.
Email: ahmed_benzoic@yahoo.com
KEYWORDS
anticancer activity, antimicrobial activity, DFT calculations, DNA interaction, imine complexes
J Phys Org Chem. 2019;e4009.
wileyonlinelibrary.com/journal/poc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/poc.4009

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ABU‐DIEF ET AL.
1 | INTRODUCTION
The preparation of novel drugs with a broad spectrum of
activities such as antimicrobial and anticancer activities
has gained attention in recent years.[1–3] There is much
interest in NO bidentate imine ligands, which have wide
implementations in several domains,[4–7] depending on
their molecular structure.[8,9] Therefore, understanding the
structure of these types of chelators is essential. Moreover,
polydentate imine chelators have been found to have plenty
of advantages inside their capacity of coordination[10] and
biological activity[11] and in the extracting of metals in
analytical chemistry.[12] It was reported that minor modifi-
cations in the ligand structure having hard/soft atoms such
as oxygen, sulfur, and nitrogen have affected the activity of
compounds.[13–15] Cancer is the third leading cause of
human mortality worldwide. Thus, many investigations on
coordination of imine ligands with transition metal ion have
been reported and showed that these complexes possess
anticancer activity.[4–7,16] Pd (II) chelates with various appli-
cations are used in chemistry, medicine, and biologyfieldsas
antimicrobial, anti‐inflammatory, and antitumor drugs. In
biology, vanadium ions also play a substantial part as coun-
terions for protein (DNA and RNA). The oxyvanadyl Schiff
base chelates are of interest as an inhibitor of protein‐
tyrosine phosphatase 1B and DNA interacting reagents, as
previously reported.[17] Although a large amount of infor-
mation is reported on the coordination chemistry of Schiff
bases with a variety of metal ions and their biological activ-
ities, little is known about bidentate NO imine ligand and
their complexes. Considering this reason and also as a con-
tinuation of our previous research works,[18–33] the present
study describes the synthesis and characterizations of the
new bidentate imine chelator and its VO (II) and Pd (II)
complexes. The characterizations of spectroscopic and the
thermal for these new metal chelates have been reported.
In addition to their structure, elucidation will be confirmed
on the basis of different physicochemical tools and density
functional theory (DFT) calculations. Moreover, the biolog-
ical activities of these compounds versus selected types of
bacteria and fungi have been evaluated. Moreover, the
Calf thymus DNA (CT‐DND) binding ability of studied
metal complexes has been estimated. The antiproliferative
activity toward various cancer cell lines has been deter-
mined. The synthetic pathway of imine chelator and its
metal complexes is shown in Scheme 1.
SCHEME 1 Synthetic strategy for the preparation of the
investigated NBA ligand and its Pd (II) and VO (II) complexes
anthranilic acid, vanadyl acetylacetonate (VO(CHO),
98%), and palladium acetate (Pd (OAc)2, 98%) have been
acquired from Sigma‐Aldrich. Spectroscopic grade
dimethylformamide (DMF, 99%), ethanol (99%), and
HCl (36%) products had been utilized. CT‐DNA,
bromophenol blue dye, ethidium bromide, and tris
(hydroxymethyl)‐aminomethane (Tris) had been acquired
from Sigma‐Aldrich Chemie (Germany).
2.2 | NBA imine ligand preparation
(2‐[(3‐Nitro‐benzylidene)‐amino]‐benzoic acid) (NBA)
imine ligand was synthesized via the condensation reac-
tion of 2‐aminobenzoic acid (5 mmol, 0.69 g) dissolved
in warm ethanol (65°C) and 3‐nitrobenzaldehyde
(5 mmol, 0.756 g) dissolved in warm ethanol in a 1:1
molar ratio. The resulting mixture was heated at reflux
for 3 hours. The resulting yellow solid was filtered,
washed three times with ethanol, and dried under vac-
uum in the presence of dehydrated CaCl2.
2 | EXPERIMENTAL
2.1 | Reagents
All chemicals were used as received from the manufac-
turer. Starting materials such as 3‐nitrobenzaldehyde,

ABU‐DIEF ET AL.
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[NBA]; yield 92%; color pale yellow; melting point 215
°C; solubility, ethanol; mol wt 270.20. Anal. calculated for
[C14H10N2O4]: C 62.18%, H 3.70%, N 10.36%. Found: C
62.13%, H 3.68%, N 10.37%. Selected Fourier transform
infrared (FT‐IR) (KBr disc cm−1): 3473 ν(H2O), 1626
ν(C═N), 3071 ν (CH)ar.
2.5 | Computational routes for
substantiation the proposed structures of
the suggested compounds
The lowest energy geometries had been calculated, apply-
ing DFT and utilizing the Gaussian09 program. The
DFT/B3LYP/LANL2DZ level of theory had been utilized
for the geometry optimization to get the lowest energy
structures for ligands and their complexes.
1H NMR (δ, ppm), in DMSO‐d6: 10.16 (s, 1H, COOH),
8.69 (s, 1H, CH═N), 6.51 to 8.48 (m, 8H, aromatic).
13C NMR (δ, ppm), in DMSO‐d6: 192, 170, 139, 138,
137, 136, 133, 132, 131, 130, 121, 120, 115, and 114.
2.6 | Biological inspection
2.3 | Preparation of NBAPd and NBAVO
complexes
We tested the biocidal screening of the new NBA imine
ligand and its metal chelates versus different strains of
bacteria (Serratia marcescens (−ve), Escherichia coli
(−ve), and Micrococcus luteus (+ve)) through using nutri-
ent agar as a good diffusion method.[26–28,33–35] The anti-
fungal activity of the compounds was also checked using
the diffusion method against certain strains of fungi
(Aspergillus flavus, Geotrichum candidum, and Fusarium
oxysporum) with potato dextrose agar (PDA) as circum-
ference as mentioned in detail in our previous
work.[27,28,30–33,37]
The metal‐imine complexes were synthesized upon
heating an aqueous ethanolic solution of VO(CHO) or
Pd (OAc)2, (10 mmol, 2.65 g and 2.24 g, respectively) with
the NBA ligand (5 mmol, 1.35 g; or 10 mmol, 2.70 g) in
the case of VO (II) under reflux with stirring for 2 to 3
hours. The resulting mixture was allowed to cool to ambi-
ent temperature, and the resulting solids were filtered,
washed with an excess of ethanol, and dried under vac-
uum to give the metal complexes in 68% to 79% yield.
Scheme 1 shows the synthesis of the NBA ligand and its
corresponding metal complexes.
2.7 | DNA binding study
1H NMR of NBAPd (δ, ppm), in DMSO‐d6: 8.70 (s, 1H,
CH═N), 8.53 to 7.02 (m, 8H, aromatic).
Stock solution of CT‐DNA was prepared according the
method that is described in detail at the Supporting
Information.
[NBAPd]; yield 90%; color dark yellow; Dec. temp
270°C; solubility, DMF; mol wt 452.40; Anal. calculated
for [C16H14N2O7Pd]: C 42.44%, H 3.09%, N 6.19%. Found:
C 41.85%, H 3.23%, N 6.27%; Λm (Ω−1 mol−1 cm−2) 23.51;
μeff diamagnetic; selected FT‐IR (KBr disc cm−1): 3423
ν(H2O), 1620 ν(C═N), 3069 ν (CH)ar, 819 ν(H2O) coordi-
nated, 537 (M–O), 449 (M–N).
[NBAVO]; yield 84%; color black; Dec. temp > 240°C;
solubility, DMF; mol wt 613.94. Anal. calculated for
[C28H19N4O9.5V]: C 54.73%, H 3.09%, N 9.12%. Found: C
53.79%, H 3.11%, N 8.98%; Λm (Ω−1 mol−1 cm−2) 14.80;
μeff 1.73 BM; selected FT‐IR (KBr disc cm−1): 3447
ν(H2O), 1599 ν(C═N), 3096 ν (CH)ar, 990 ν(V=O), 838
ν(H2O) coordinated, 557 (M–O), 468 (M–N).
2.7.1 | UV‐visible absorption titration
In this study, we have investigated the metal complexes'
interaction with CT‐DNA using UV‐vis absorption titra-
tion experiments,[28,33,37] which were discussed in the
Supporting Information.
2.7.2 | Hydrodynamic estimations
Hydrodynamic estimations were executed by using
Oswald miniaturized scale viscometer and were set aside
at a consistent temperature of 25°C, which is discussed in
more detail in our previous work.[30–34,36]
2.4 | Physical characterization
Melting point, element microanalysis (CHN), magnetic
susceptibility, molar conductance, thermogravimetric
analysis (TGA), and IR, 1H NMR, and 13C NMR spectros-
copies were all performed as described in literature
work.[17–38] Details of these studies are given in the
Supporting Information.
2.7.3 | Agarose gel electrophoresis
We have used agarose gel electrophoresis route[34] to
examine the DNA binding products as thoroughly
discussed in our previous work.[30–36]

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ABU‐DIEF ET AL.
3.1.1 | 1H NMR and 13C NMR spectra of
the suggested NBA imine ligand
2.8 | Cytotoxic studies
For this study, three human cancer cell lines were uti-
lized in our in vitro screening experiments. These
included breast cancer (MCF‐7), colon carcinoma (HCT‐
116), and human liver carcinoma (HepG2) cell
lines,[28,30–32,38,39] as thoroughly discussed in the
Supporting Information.
1
The H NMR spectrum of NBA (Figure 1) imine ligand
emitted two singlet signals at δ = 10.16 ppm for the car-
boxylic group; it offers singlet signal at δ = 8.69 for
azomethine group. Also, it displays multiplet signals at
8.48 to 6.51 ppm for aromatic of 8‐CH protons. 13C
NMR presents the peaks at different values of δ, as fol-
lows: azomethine group (CH═N) at δ 170.00 ppm, the
carboxylic group at 192 ppm, and aromatic carbon atoms
in the area 114.00 to 139.00 ppm (cf. Figure S1).
2.9 | Antioxidant assay (DPPH free radical
scavenging activity)
1
The H NMR spectrum of NBAPd complex confirmed
In vitro antioxidant activity of the newly synthesized
NBA azomethine ligand and its metal chelates was evalu-
ated using scavenging of the stable DPPH radical modi-
fied method. Details of this study are given in the
Supporting Information.
the framework protons of the NBA. The peak due to car-
boxylic group disappeared, which suggests that de‐
protonation occurred and confirmed its chelation to Pd
(II) ion. The singlet signal at δ = 8.70 ppm for (CH═N)
has also been shown. In addition, it shows aromatic pro-
tons at 8.53 to 7.02 ppm. It also shows two singlet signals
at 3.28 and 1.91, which are assigned to coordinated water
molecule and (CH3COO−) protons, respectively, as
shown in Figure S2. We cannot perform NMR spectra
for NBAVO complex owing to its paramagnetic behavior
that will cause a noise in the spectrum of the complex;
and thus, no data can be obtained from it.
3 | RESULTS AND DISCUSSION
3.1 | Physicochemical properties of the
NBA imine ligand and their new complexes
All attempts to obtain X‐ray quality crystals for the pre-
pared compounds have been unsuccessful to date. We
tried to obtain a single crystal for the prepared com-
pounds using different methods such as evaporation and
layering using two different miscible solvents, but we fail
owing to the powder nature of the prepared compounds.
3.1.2 | Infrared spectra
Infrared spectrum (in Section 2) of the imine (NBA) (cf.
Figure S3) presented distinguishing bands at 1626 cm−1
FIGURE 1 1H NMR spectrum of NBA
azomethine ligand

ABU‐DIEF ET AL.
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for CH═N group (cf. Section 2). Evidence for imine
ligand formation was the absence of carbonyl and amino
peaks of the starting materials. Also, the band at 1626
cm−1 is referred to the CH═N group of the imine, which
was moved downfield (1599‐1620 cm−1) upon complexa-
tion, hence elucidating the coordination of N atom of
the CH═N group to the central metal ions (cf. Figures S3
and S4).[26,30–32,40] Furthermore, the appearance of bands
in area 537 to 557 cm−1 is referred to metal‐oxygen bond
and in the area 468 to 449 cm−1 to metal‐nitrogen bond
confirm formation of the desired complexes. Importantly,
appearance of wide bands at 3423 to 3447 cm−1 in the
spectra of metal‐imine complexes refers to molecules of
water, which were hydrated. In addition, the existence
of bands at 819 to 838 cm−1 referred to the molecules of
water, which were coordinated in all metal‐imine com-
plexes.[30,32] The IR spectra of the prepared VO (II) com-
plex shows a band at 990 cm−1, which is assigned to
vibration of VO (II) in monomeric complexes.[30–32]
For NBAPd complex, two essential strong‐to‐medium
bands were found at 1566 and 1350 cm−1, which could be
assigned to (ʋasy COO−) and (ʋsy COO−) vibrations of car-
boxylate ion of acetate group.[40] The difference between
the asymmetric and symmetric stretching vibration
motions ʋ[(ʋasy COO) − (ʋsy COO)] was found to be 215
cm−1, which was matched with monodentate ligation.[40]
FIGURE 2 Molecular electronic spectra of 10−3M of NBA imine
ligand and its complexes in DMF at 298 K
metal ions in the as‐prepared complexes (cf. Figure 2 and
Table S1).
The Nujol mull spectrum of NBAVO complex showed
two bands at 11 230, 15 390, and 21 685 cm−1 can be
assigned to 2B2 → E2, 2B2 → B1, and 2B2 → 2A2 transitions,
respectively; these bands are similar to those of distorted
square pyramidal oxovanadium (II) complexes.[43]
The bands at 28 695 cm−1 in the spectra of NBAPPd com-
plex are assignable to a combination of eg, (dyz, dzx)–b1g
1
1
(dx2–y2), ie, A1g → Eg and MLCT, indicating a square
planar geometry.[43,44]
3.1.3 | Electronic spectra
Two methods were employed for the identification of the
electronic transitions in the investigated compounds. One
of them depends on the solution of the prepared com-
pounds in specific solvents, and we applied the Beer law
to calculate molar absorptivity of each compound. The
second method is Nujol mull method is performed in
near‐infrared absorption spectra over the wavelength
region from 200 to 1700 μm for the compounds in the
solid state to confirm the geometry of the complexes.
3.1.4 | Magnetic predisposition
estimations
As illustrated in Section 2, the magnetic moment (μeff) is
measured at 298 K for the as‐prepared metal‐imine com-
plexes, which shows that μeff value of 1.73 for VO (II). This
value indicates that NBAVO complex was paramagnetic
with a distorted square pyramidal geometry,[30,32,45] unlike
the μeff of the Pd (II) complex, which was unmeasurable,
thereby confirming its diamagnetic properties.[46,47]
Thus, the absorbance is determined in cm−1
.
The UV‐vis absorption spectra (cf. Figure 2) of the
NBA imine ligand give rise to an absorption band at
approximately 400 nm, which is ascribed to the n → π*
transition of the nitrogen atom in the chromophoric
azomethine group. DMSO solutions of the as‐prepared
imine complexes show a large absorption band at 335 to
415 nm, which is due to the coordination of the nitrogen
atom in the NBA ligand with the metal ions, which
causes electrons to transfer from the ligand to the metal.
Moreover, a new absorption band was observed at 413
to 415 nm, which was assigned to the d‐d transition for
all the metal complexes.[30–32,40–42] These results lend fur-
ther support that the NBA ligand is coordinated to the
3.1.5 | Thermal analysis
The first stage in the decomposition process of NBAPd
complex is related to elimination of coordinated water
molecule and acetate group at 33 to 328°C with mass loss
(found 17.02%, calc. 17.02%). The second step corresponds
to the elimination of the part of ligand “C7H4O” with mass
loss (22.96%, calc. 22.99%). The third step is the removal of
another part of ligand “C7H5N2O2” with mass losses
(found 32.93%, calc. 32.94%). Finally, metal oxide residue
is the final product of thermal decomposition.[48] NBAVO

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ABU‐DIEF ET AL.
TABLE 1 Thermo‐kinetic activation parameters of each decom-
position step for the prepared complexes
complex shows a loss in weight that takes place from 35 to
110°C, which can be ascribed to the removal of half‐lattice
water molecule with weight loss (found 1.41%, calc.
1.465%). The second and third steps correspond to mass
losses of the same formula of C14H9N2O4 from the ligand
within the temperature ranges of 112 to 332°C and 334 to
527°C with weight losses at 43.75% (calc. 43.82%), 43.83%
(calc. 43.82%), respectively, leaving VO as a residue, as
shown in Scheme 2. The thermal analysis information con-
curs well with the proposed stoichiometry obtained from
the consequences of elemental analysis findings.[30,32]
E*, KJ
mol−1
A,
S−1
H,* KJ
mol−1
G*, KJ
mol−1
S*, J
mol−1 K−1
Complex
NBAPd
28.60
0.017
27.10
25.50
24.60
76.80
129.40
159.20
−274.78
−280.73
−282.82
NBAV
43.92
0.17
43.30
42.10
40.30
61.10
99.20
153.30
−247.87
−257.23
−262.73
Kinetic aspects
between imine ligand (NBA) and the metal salts (Pd (II)
and VO (II)) was determined by the continuous variation
and molar ratio routes, as shown in Figures 3 and S5. The
The thermo‐kinetic parameters of the new metal chelates
degradation steps are listed in Table 1. From the acquired
information, the next views could be concluded.
maximum absorption in the curve observed at Xligand
0.50 shows a 1:1 metal:ligand molar ratio, while Xligand
=
=
The entropy change (S*) values for the new metal che-
lates were negative. This implies that the activated metal
chelate is more regular than the parent reactants. The
positive values of H* mean that the degradation processes
were endothermic. The high positive values of the free
energy of activation (G*) for most steps in the degradation
reactions of the new metal chelates indicate that the deg-
radation reaction is slower than the formation reaction.
This means that the free energy of the last product (resi-
due) is higher than that of the underlying compound.
There is an obvious relation between (E*) and (A) for
the acquired metal chelates. The comparatively low
values of (A) revealed the slow nature of pyrolysis reac-
tion of the chelates. The greater positive amount of (E*)
demonstrates that the procedures involved translational,
rotational, and vibrational states besides changes in
mechanical potential energy for metal chelates.[49]
0.7 for the VO (II) complex, where the results were consis-
tent with those of a 1:2 stoichiometric ratio.[27,28,30–33,37]
Formation constants of the as‐synthesized complexes
The degree of interaction between the reagents that form
the metal complex was measured using the stability con-
stant. The apparent formation constants (Kf) of the metal‐
imine complexes were estimated from the data obtained
via a continuous variation approach. Table 2 shows very
high Kf values estimated for all the metal complexes,
which reflect their high stability. In addition, the Kf
values obtained for the desired complexes were in the
order of NBAVO > NBAPd complex. The negative values
obtained for the associated Gibbs free energy reveal that
the reaction between the metal and imine ligand was
spontaneous and favorable.
A great stability pH range (4‐9) for the new metal‐
imine chelates and typical dissociation curves was
displayed by pH profile (absorbance versus pH) as dem-
onstrated in Figure 4. This explained that the consistency
of the metal chelate can greatly stabilize imine ligands.
Consequently, proper pH extent for different applications
3.1.6 | Stoichiometry of the as‐prepared
metal‐imine complexes
The stoichiometry of the as‐prepared metal‐imine com-
plexes during their formation in solution via the reaction
SCHEME 2 Thermogravimetric
degradation steps for the prepared imine
complexes

ABU‐DIEF ET AL.
7 of 18
3.1.7 | Molecular orbital calculations
Molecular DFT calculation of NBA azomethine ligand
and its NBAPd chelate
The optimized structures of the ligand NBA and the com-
plex NBAPd as the lowest energy configurations are
shown in Figure 5. The palladium atom is four‐
coordinate in a distorted square planar geometry the
atoms O2, N1, O6, and O5, which are almost in one plane
deviated by −0.593°. The bond angles in the square are
between 83.95° and 103.5° (Table 3).
The distance between N1···O1 in ligand (2.655 Å) is
shorter than that in the complex (2.798 Å) owing to the
hydrogen bond between N1 and O1–H in the ligand.
The bonds N1–C7 and N1–C10 (1.309 and 1.446 Å) in
complex are longer than those in the ligand (1.278 and
1.411 Å); the elongation is due to complex formation.
Figure 6 shows the normal charges on the atoms of
NBA imine ligand and NBAPd complex, which indicates
large electron density (more negative) of the coordinated
atoms N1, O1, O6, and O5.
FIGURE
3
Continuous variation plots for the prepared
complexes in aqueous‐ethanolic medium at (NBAPd) = (NBAVO)
= 10−3M and 298 K
TABLE 2 The formation constant (Kf), stability constant (pK),
and Gibbs free energy (G*) values of the synthesized complexes at
298 K
Molecular DFT calculation of ligand NBA and NBAVO
complex
Type of
Complex
Log
Kf
G*, KJ
mol−1
The optimized structures of NBA and its complex
NBAVO as the lowest energy configurations are exhibited
in Figure 7. The vanadium atom is five‐coordinate in a
square pyramidal geometry with O2 in the axial position
and vanadium atoms are in the body center of the struc-
ture of pyramidal. The atoms N1, O1, N2, and O3 are
nearly in one plane, which deviated by 19.90°. The bond
angles combining V and the atoms found in the plane
are range from 83.93° to 88.59°. The bond angles involv-
ing the axial atom O2═V and atoms in plane range from
98.18° to 115.2° (Table 3).
Complex
Kf
2.91 × 104
183.03 × 104
NBAPd
NBAV
1:1
1:2
4.46
8.26
−25.47
−47.14
for the new metal‐imine chelates is derived from pH =
3.5 to pH = 11. The proposed formula for the metal che-
lates is identified by correlation among the existence of
magnetic measurements, molar conductance, elemental
analysis, electronic spectra, and infrared spectra.
The distance between N1···O1 in ligand (2.655 Å) is
shorter than that in the complex (N1–O1 = 2.736 Å or N2–
O3 = 2.704 Å) due the hydrogen bond between N1 and
O1–H in the ligand. The bonds N1–C7 and N1–C10 (1.278
and 1.411 Å) in the free ligand are shorter than the corre-
sponding bonds in complex (1.312 and 1.451 Å) or (1.307
and 1.442 Å); the elongation is due to complex formation.
Figure 7 shows the normal charges on the atoms of
ligand and NBAVO complex, which indicate large elec-
tron density (more negative) of the coordinated atoms
N1, O1, N2, and O3.
Figure 5 shows the natural charges (obtained using NBO
calculation) on the atoms of ligand, which indicates large
electron density (more negative) of the coordinated atoms
N1 and O1. Figure 8 shows the molecular electrostatic
potential (MEP) surface is located at the positively (blue
color) and negatively (red color; it is bound loosely or excess
electrons) charged electrostatic potential in the molecule.
FIGURE 4 Dissociation curve of the prepared imine complexes
at different pH values

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ABU‐DIEF ET AL.
FIGURE 5 The optimized structure of
NBA, the vector of the dipole moment,
and the natural charges on active centers
of NBA by density function B3LYP/
LANL2DZ
TABLE 3 Important optimized bond lengths (Å) and bond angles
(°) of NBAPd and NBAVO complexes
indicate that the selected complexes are more stable than
the free NBA ligand, and the total energy for NBAVO
complex is much more negative, which is related to the
formation of 1:2 (V:L). Also, the energy gab (Eg) = ELUMO
− EHOMO is smaller in case of complexes than that of
NBA ligand owing to chelation of ligand to metal ions
(Table 4). The lowering of Eg in complexes compared
with that of ligand explains the charge transfer interac-
tions upon complex formation. Figure 9 shows that the
molecular orbitals of HOMO are located on the active
sites around metal and that those of LUMO are away
from metal.
Bond
Type of Length, Type of
Bond Angle
Type of
Angle, ° Angle
Angle, °
Å
Pd–N1 2.020
Pd–O1 2.015
Pd–O6 2.040
Pd–O5 2.088
N1–Pd–O1 87.85
N1–Pd–O6 103.5
O5–Pd–O6 83.95
O1–Pd–O5 84.60
N1–Pd–O5 172.3
O1–Pd–O6 168.6
O1–N1–
O6–O5
−0.593
V–N1
V–N2
V–O1
V–O3
V═O2
2.145
2.131
1.894
1.904
1.596
N1–V–O1
N1–V–O3
N2–V–O3
N2–V–O1
85.03
88.59
83.93
86.62
O2–V–N1 100.5
O2–V–N2
98.18
O2–V–O1 115.2
O2–V–O3 115.2
3.2 | Pharmacology
N1–V–N2 161.3
O1–V–O3 129.6
Antimicrobial (bacteria and fungi) activity tests were per-
formed at least three times under identical conditions.
These activities were estimated by measuring the inhibi-
tion zone (cf. Table 5 and Figure 10) and minimum inhib-
itory concentration (MIC) (cf. Table 6 and Figure 11). In
these experiments, both ofloxacin and fluconazol were
employed as references for the antibacterial and antifun-
gal tests, respectively. In general, as can be clearly seen
from the obtained results, the antimicrobial potency of
N1–O1–
N2–O3
19.90
The calculated total energy, HOMO energies, LUMO
energies, and the dipole moment for the titled NBA
ligand and its Pd (II) and VO (II) complexes are presented
in Table 4. The more negative values of the total energy of
the titled metal chelates than those of free NBA ligand
FIGURE 6 The optimized structure, the vector of the dipole moment, and the natural charges on active centers of [Pd (NBA)H2O] using
B3LYP/LANL2DZ

ABU‐DIEF ET AL.
9 of 18
FIGURE 7 The optimized structure, the vector of the dipole moment, and the natural charges on active centers of [VO (NBA)2] using
B3LYP/LANL2DZ
FIGURE 8 Molecular electrostatic
potential (MEP) surface of ligand (NBA)
and complexes ([Pd (NBA)H2O] and [VO
(NBA)2]) using B3LYP/LANL2DZ
the imine (NBA) ligand was relatively low when com-
pared with its metal complexes.
TABLE 4 Calculated energies of imines and their complexes at
B3LYP/LANL2DZ
Overall, we also noted that the antimicrobial activity of
the investigated compounds was in the order of BNAPd >
BNAVO > Pd (II) > VO (II) > NBA ligand. However, for
Gram‐negative bacteria, it was established that the
NBAPd complex was the most effective and displayed
the highest inhibition zone (26 0.17), which was very
near to that of the reference antibiotic, ofloxacin (29
0.25). This behavior was demonstrated in terms of the
Overtone concept and chelation theory,[28] where in a
complex, which is chelated, the positive charge of the
Dipole
E
HOMO LUMO
E
Momenta
NBA
−950.078 −0.2639 −0.1269 0.1370 4.558
NBAPd −1380.75
NBAVO −2044.90
−0.2480 −0.1373 0.1107 4.178
−0.2284 −0.1015 0.1269 7.394
Abbreviations: E, ELUMO − EHOMO (eV); E, the total energy (a.u.); HOMO,
highest occupied molecular orbital (eV); LUMO, lowest unoccupied molecu-
lar orbital (eV).
aDipole moment (Debye).

10 of 18
ABU‐DIEF ET AL.
bacteria and various fungi in terms of the MIC. From
the data, it can be concluded that the NBAPd complex
exhibits the most powerful inhibition activity for the cho-
sen microorganisms. The order of increasing antimicro-
bial activity for the remaining compounds against
bacteria and fungi (E. coli, M. luteus, and A. flavus) is as
follows: NBAPd > NBAVO complex.
The activities of the tested complexes were confirmed
by calculating the potency index (Table S2) according to
the following relation.[27,28,30–32,37]
Compared with those of old researches, the activities of
the tested palladium complex are higher than others.[52–54]
Inhibition zone of complex ðmmÞ
Activity index ðAÞ ¼
× 100:
Inhibition zone of standard drug ðmmÞ
(1)
On comparing the antibacterial activity of our investi-
gated compounds with that in literature as shown in
Table 5, we found that our compounds show potent activ-
ity than other compounds in literature against S.
marcescens bacteria.[50] On the other hand, by comparing
the antifungal activity of our investigated compounds
with that in literature as shown in Table 5, we found that
our compounds show potent activity than do other com-
pounds in literature against A. flavus [17; 55].
3.3 | DNA binding potency
3.3.1 | Electronic spectra of the
metal‐imine complexes with DNA
Electronic absorption spectroscopy was employed to
investigate the binding mode of the metal‐imine com-
plexes to calf thymus (deoxyribonucleic acid sodium salt,
CT‐DNA). Depending on the strong stacking interactions
of the aromatic chromophore with the base pairs of DNA,
the intercalative mode of binding generally gives rise to
hypochromism along with a red shift.[28,37] Figure 12
shows the representative absorption spectra of the
NBAPd complex in the absence and presence of CT‐
DNA. The spectra display hypochromism upon increas-
ing the DNA concentration, indicating the weak interac-
tion between the metal‐imine complex and the DNA
base pairs. The intrinsic binding constants (Kb) for the
NBAPd and NBAVO complexes were estimated to be
9.72 × 104 and 1.74 × 104 mol−1 dm−3, respectively.
Importantly, the Kb value of the NBAPd complex was
similar to the value reported for the intercalator ethidium
bromide with CT‐DNA (18.81 × 104 mol−1 dm−3). This
means that the NBAPd complex binds strongly to CT‐
DNA, whereas the rest of the complexes moderately
interact with CT‐DNA in the following order: NBAPd >
FIGURE 9 HOMO and LUMO charge density maps of ligand
(NBA) and complexes ([Pd (NBA)H2O] and [VO (NBA)2]) using
B3LYP/LANL2DZ
metal ion is partly shared to the donor atoms that exist in
the ligand, thereby causing electron delocalization over
the whole chelated ring. This, in turn, increases the lipoid
layers of the bacterial membrane. Moreover, other factors,
such as solubility, conductivity, and dipole moment, can
also be considered as potential causes for the enhanced
biological potency of these metal‐imine complexes.
The data listed in Tables 5 and 6 show the efficacy of
the NBA ligand and the as‐prepared metal complexes
toward various Gram‐positive and Gram‐negative

ABU‐DIEF ET AL.
11 of 18

12 of 18
ABU‐DIEF ET AL.
intercalation mode of CT‐DNA with the as‐prepared
metal‐imine complexes.[28,37,53–56]
3.3.3 | Gel electrophoresis
The DNA binding activity of the new compounds has
been studied by agarose gel electrophoresis method (cf.
Figure 14). The gel after electrophoresis significantly
explained that the intensity of all the treated DNA sam-
ples has been partially detracted, possibly because of the
interaction with DNA. In contrast to the added DNA,
there is a variation in the bands of metal‐imine chelates.
This indicates that the controlling DNA alone does not
show any visible cleavage, whereas the metal chelates
showed cleavage. However, the nature of reactive inter-
mediates involved in the DNA binding with the metal
chelates was not be clear. These results displayed that
the metal ions play a significant part in the interaction
with separated DNA, so we could conclude that the com-
pound minimizes the growth of the pathogenic organism
through interaction with genome. Our results revealed
that partial binding to DNA was observed by VO (II)
and Pd (II) imine metal chelates.[30,32,37,55,56]
FIGURE 10 Histogram showing the comparative antibacterial
activities of the prepared compounds (NBA, NBAPd, and NBAVO)
against Micrococcus luteus (+ve) bacteria
NBAVO complex. The intrinsic binding constants (Kb) of
the metal‐imine complexes with CT‐DNA were evaluated
using
the
Wolfe‐Shimmer
relationship.
The
spontaneity/nonspontaneity of the interaction between
the metal complexes and CT‐DNA was used to estimate
the free energy (ΔG) from the binding constant (Kb)
values, as summarized in Table 7.
3.3.4 | The suggested mechanism for
interaction of the studied imine complexes
with DNA
ΔG ¼ −RTlnKb:
(2)
In our investigation, correlation between spectroscopic
and hydrodynamic measurements between the new com-
plexes and DNA can mean several binding modes. The
metal chelate interacts with DNA, likely in a mode that
includes hydrophobic interaction or electrostatic. As
expressed previously, NBAPd, metal chelate, has a
replaceable water ligand in solution, which might be
substituted with DNA molecules in the solution.[32–37]
Likewise, because of the expulsion of water ligand from
the metal chelate in solution, the explored metal chelates
would have a flat part in the middle. Accordingly, con-
ceivable interaction of the NBAPd, metal chelate, with
DNA could be as follow (cf. Schemes 3 and 4): first, the
interaction of Pd (II) metal chelate with base backbone
3.3.2 | Viscosity measurements
Dynamic viscosity measurements are the most important
way of investigating the binding mode of the interactions
between CT‐DNA and the metal‐imine complexes.[52] The
viscosity measurements show that all the as‐prepared
metal complexes intercalate between adjacent CT‐DNA
base pairs, giving rise to lengthening of the DNA double
helix and an increase in viscosity, as shown in Figure 13
. The results suggest that all the metal‐imine complexes
intercalate with the adjacent base pairs, thereby causing
lengthening of the DNA helix, which facilitates the
TABLE 6 Minimum inhibitory concentration (MIC) for antimicrobial assay of the prepared imine and its complexes
Bacteria
Fungi
Escherichia
coli
Micrococcus
luteus
Serratia
marcescens
Aspergillus
flavus
Geotrichum
candidum
Fusarium
oxysporum
Compounds
NBA
3.75
1.75
2.25
4.50
2.25
3.00
5.50
2.75
3.50
5.50
3.25
4.25
5.00
2.75
3.50
5.25
3.00
4.00
NBAPd
NBAV

ABU‐DIEF ET AL.
13 of 18
FIGURE 11 Histogram showing MIC
values for antimicrobial activity of the
prepared compounds
FIGURE 12 Spectral scans of the interaction of NBAPd complex
(10−3 mol−1 dm−3) in 0.01 mol−1 dm−3 Tris buffer (pH 7.2, 298 K)
with CT‐DNA (0‐30) μM DNA, from top to bottom
FIGURE 13 The effect of increasing concentration of the
prepared complexes on the relative viscosities of DNA at (DNA) =
0.5 mM, (complex) and (EB) = 25‐250 μM and 298 K
of DNA, and second, insertion of the flat part of the metal
chelate among the base pairs and thus coordination of Pd
(II) with base pairs of DNA.
and HepG2 tumor cell lines was evaluated in terms of their
IC50 (minimum concentration required to inhibit 50%
of cell growth) values, as shown in Table S4 and Figure 15
3.4 | Cytotoxicity of the as‐prepared
metal‐imine complexes
[45]
.
From the results, both the NBA ligand and its com-
plexes inhibit the growth of the HCT‐116, MCF‐7, and
HepG2 cells in a dose‐dependent manner, but their poten-
cies were quite different (cf. Figure 15). The calculated
The in vitro cytotoxicity of the NBA ligand and its Pd (II)
and VO (II) metal complexes against HCT‐116, MCF‐7,
TABLE 7 Spectral parameters for the interaction of the prepared imine complexes
Type of
Chromism
Binding Constant
Complex
λmax Free, nm
λmax Bound, nm
n
Chromism, %a
104 (Kb)b
G*, KJ mol−1
−28.45
NBAPd
331
257
324
239
7
18
13.79
13.14
Hypo
Hyper
9.72
NBAV
351
288
343
290
8
2
7.47
3.32
Hypo
Hypo
1.74
−24.19
[22–28]
aChromism (%) = (Absfree − Absbound)/Absfree
bBinding constant Kb = mol−1 dm−3
.
.

14 of 18
ABU‐DIEF ET AL.
HepG2 and MCF‐7 cells with IC50 values of 10.10 and 12.10
μg/μL when compared with the standard drug, vinblastine
(4.80 and 8.60 μg/μL, respectively). From these data, it can
be concluded that the NBAPd complex may be considered
as a promising pharmaceutical drug for liver tumors. More-
over, [NBAVO] displays a very good inhibition ability
toward HepG2 cell lines, and its IC50 value was 14.80
μg/μL, which is comparable with that of vinblastine (4.80
μg/μL). The cytotoxic potencies of the new metal com-
plexes toward various carcinoma cell lines can be ordered
according to their IC50 values, as follows: liver carcinoma
cell line HepG2, colon cancer HCT‐116 cell line, and breast
cancer MCF‐7 cell line, NBAPd > NBAVO > NBA ligand.
The overall findings of this section indicate that an
improvement in the anticancer potency occurred upon
coordination of the NBA ligand with the designated
metal ions. The increased cytotoxicity observed for the
metal complexes is most likely due to the positive charge
of the metal ions, which increased the acidity of the
coordinated NBA ligand that bears protons, thereby giv-
ing rise to more potent hydrogen bonds with a negative
charge in the DNA of the cancer cells.[37,57–64] The
results obtained for the in vitro cytotoxic activities of
the as‐prepared complexes are in agreement with their
DNA and protein binding capacities.
FIGURE 14 DNA binding results of the prepared imine
complexes based on gel electrophoresis Lane 1: DNA ladder: lane
2, NBAPd + DNA; lane 3, NBAVO + DNA; and lane 4, NBAPd
complex
IC50 values (cf. Table S3) reveal that all the metal complexes
are more potent than the free ligand NBA, and the NBAPd
complex has the highest ability to inhibit the growth of both
SCHEME 3 Suggested mechanism for
the interaction of NBAPd complex with
DNA: A, replacement; B, intercalation
binding

ABU‐DIEF ET AL.
15 of 18
SCHEME 4 Suggested mechanism for the interaction of HNAPPd complex with DNA via electrostatic and grove binding
FIGURE 15 IC50 values of the NBA
ligand and its complexes against human
colon carcinoma cells (HCT‐116 cell line),
hepatic cellular carcinoma cells (HepG2),
and breast carcinoma cells (MCF‐7) cell
line
On comparing the anticancer activity of our investi-
gated compounds with that in literature as shown in
3.4.1 | Determination of antioxidant
activity for the selected metal NBA chelates
Table S3, we found that our compounds show potent
activity than do other compounds in literature against
hepatic cellular carcinoma cells (HepG2 cell line) and
breast carcinoma cells (MCF‐7 cell line).[65]
Most of the investigations take the simple procedure
reliability of DPPH assay to evaluate the antioxidant
activity of their targets.[66] Because of the ease and

16 of 18
ABU‐DIEF ET AL.
FIGURE 16 Trends in the inhibition of
DPPH˙ radical by the NAB imine ligand
and its complexes
convenience of DPPH˙ radical, it has been widely used for
free radical scavenging assessments. Thus, DPPH free
radical scavenging method was employed to evaluate
the antioxidant activity of the newly selected NBA imine
ligand and its metal chelates. Different concentrations
(10, 25, 50, 100, and 150 μg/mL) of the tested samples
were used, and ascorbic acid was used as a standard for
the comparison of the activity. From the obtained results,
NBA ligand exhibits moderate antioxidant activity,
whereas its selected Pd (II) and VO (II) chelates exhibit
enhancement in antioxidant activity than do the ligand
and standard ascorbic acid. The presence of azomethine
and –OH groups has a direct effect on the DPPH free rad-
ical scavenging activity. So when a test sample has added
solution, the free radical is neutralized by the test sample,
which donate either a hydrogen or an electron that
results in the neutralization of free radical. Less free rad-
ical will be available when the free radical is neutralized
by a test sample.[67] It was observed that antioxidant
activity of the investigated compounds increased with
increasing concentrations. In terms of IC50, the data have
shown that NBAPd complex showed potent antioxidant
activity with the lowest IC50 value of 44 μg/mL, as shown
in Figure 16.
metal chelates adopted square planer geometry in case
of Pd (II) ion and distorted square pyramidal geometry
in VO (II) ion. The antipathogenic screening studies indi-
cate that the investigated metal chelates are good antimi-
crobial agents toward various organisms compared with
its corresponding ligand, with following the order:
NBAPd > NBAVO > NBA ligand. Additionally, the inter-
action of the metal chelates with CT‐DNA has been suc-
cessfully checked and explored by electronic absorption,
gel electrophoresis, and viscosity measurements. The
DNA interaction studies suggest the intercalative and
replacement modes of interaction with binding constants
according to the following sequence: NBAPd > NBAVO
complex. Furthermore, the growth inhibitory impact of
the suggested compounds had been checked on HepG2,
HCT‐116, and MCF‐7 cancer cells, and NBAPd complex
significantly decreases the cell viability time and dose
dependently.
ORCID
Ahmed M. Abu‐Dief
https://orcid.org/0000-0003-3771-
9011
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