Studies on some metal complexes of a quinoxaline?based unsymmetrical ONNO donor ligand: Synthesis, spectral characterization, thermal, in vitro biological and DFT studies

Article abstract of DOI:10.1007/s10973-016-5953-1

Abstract: Co(II), Ni(II), Cu(II) and Zn(II) complexes of an unsymmetrical tetradentate ONNO donor ligand, 3-(-(3-(-1-(2-hydroxyphenyl)ethylideneamino)propylimino)methyl)quinoxalin-2(1H)-one (L) have been synthesized and characterized by elemental analysis, molar conductance, magnetic susceptibility measurements, FTIR, UV–Vis., mass and ¹H NMR spectral studies. ESR spectra of the Cu(II) complex under room (300?K) and liquid nitrogen temperature (77?K) were also recorded. Thermal behavior of the newly synthesized ligand and its metal complexes was assessed by TG–DTG analysis. All the complexes are found to be mononuclear. Crystallinity, average grain size and unit cell parameters were determined from powder X-ray diffraction study. Electrochemical behavior of the compounds was examined by cyclic voltammetry technique. The in vitro antimicrobial screening of the unsymmetrical ligand and corresponding metal chelates was tested against some bacterial strains (E. coli, K. pneumoniae, S. pneumoniae and S. aureus) and fungal strains (A. niger, A. flavus, P. chrysogenum and R. stolonifer). The in vitro antioxidant and anticancer activities of the compounds were also evaluated. DFT studies were done to optimize the structure of the compounds and to calculate nonlinear optical properties of the compounds. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10973-016-5953-1

J Therm Anal Calorim
DOI 10.1007/s10973-016-5953-1
Studies on some metal complexes of a quinoxaline based
unsymmetrical ONNO donor ligand
Synthesis, spectral characterization, thermal, in vitro biological and DFT studies
C. Justin Dhanaraj1 Jijo Johnson1
•
Received: 4 March 2016 / Accepted: 8 November 2016
´
´
Ó Akademiai Kiado, Budapest, Hungary 2016
Abstract Co(II), Ni(II), Cu(II) and Zn(II) complexes of an
unsymmetrical tetradentate ONNO donor ligand, 3-(-(3-(-
1-(2-hydroxyphenyl)ethylideneamino)propylimino)methyl)
quinoxalin-2(1H)-one (L) have been synthesized and
characterized by elemental analysis, molar conductance,
magnetic susceptibility measurements, FTIR, UV–Vis.,
X-ray diffraction study. Electrochemical behavior of the
compounds was examined by cyclic voltammetry tech-
nique. The in vitro antimicrobial screening of the unsym-
metrical ligand and corresponding metal chelates was
tested against some bacterial strains (E. coli, K. pneumo-
niae, S. pneumoniae and S. aureus) and fungal strains (A.
niger, A. flavus, P. chrysogenum and R. stolonifer). The
in vitro antioxidant and anticancer activities of the com-
pounds were also evaluated. DFT studies were done to
optimize the structure of the compounds and to calculate
nonlinear optical properties of the compounds.
1
mass and H NMR spectral studies. ESR spectra of the
Cu(II) complex under room (300 K) and liquid nitrogen
temperature (77 K) were also recorded. Thermal behavior
of the newly synthesized ligand and its metal complexes
was assessed by TG–DTG analysis. All the complexes are
found to be mononuclear. Crystallinity, average grain size
and unit cell parameters were determined from powder
Electronic supplementary material The online version of this
article (doi:10.1007/s10973-016-5953-1) contains supplementary
material, which is available to authorized users.
& C. Justin Dhanaraj
c.justindhanaraj@gmail.com
1
Department of Chemistry, University College of Engineering,
Nagercoil (Anna University Constituent College),
Konam, Nagercoil, Tamil Nadu 629 004, India
123

C. J. Dhanaraj, J. Johnson
Graphical Abstract
Thermal studies
Anticancer studies
Electrochemical studies
Antioxidant studies
Antimicrobial studies
DNA intraction studies
Keywords TG–DTG Á Antimicrobial Á Antioxidant Á MTT
assay Á Nonlinear optical properties
cisplatin is limited due to acquired and intrinsic resistance
of cancer cells to the drug and its high toxicity to some
normal cells. Therefore, there exists an enormous interest
to improve the design of metallodrugs having reduced
toxicity and a high spectrum of activity, especially drugs
that would show activity against cell lines resistant to
cisplatin [5].
Introduction
Schiff bases have a double bond (R–C=N) and synthe-
sized by the condensation of primary amines and active
carbonyl groups (aldehydes/ketones). Schiff bases display
fascinating properties. They act as metal complexing
agents in biological systems, catalyst carriers, corrosion
inhibitors, thermostable materials and coloring agents.
They are also widely used as preparatory materials in the
synthesis of important antifungals, antibiotics, antitumors
and antiallergics due to their biological activities [1]. It
has been suggested that the azomethine linkage is
responsible for the biological activities of Schiff bases
[2]. Metal complexes of Schiff base ligand have shown
desirable enhancement in their biological activities after
chelation as compared to un-coordinated Schiff base
ligand [3].
Quinoxaline derivatives and their metal chelates show
some remarkable biological activities [6–10]. Literature
survey [11] reveals that no reports are available on
unsymmetrical Schiff base ligands incorporating quinoxa-
line derivatives. It is also noticed that the biological
(especially anticancer activities) and molecular modeling
studies of quinoxaline-based Schiff base transition metal
complexes are not much explored.
By considering the above facts, an attempt has been
made to develop some novel bioactive metal complexes
of an ONNO donor unsymmetrical Schiff ligand
including quinoxaline, o-hydroxyacetophenone and 1,3-
diaminopropane. Herein we report the synthesis, spec-
tral characterization, thermal, electrochemical, powder
XRD, in vitro antimicrobial, DNA cleavage, antioxidant
and anticancer activities and DFT studies of Co(II),
Ni(II), Cu(II) and Zn(II) complexes of a Schiff base
ligand having azomethine (HC=N) and imine (C=N)
donor sites.
The modern era of metal-based anticancer drugs began
with the innovation of the antitumor properties of cisplatin.
Presently, cisplatin, oxaliplatin and carboplatin are among
the most important chemotherapeutics used against a
variety of cancers [4]. Despite its success, clinical use of
123

Studies on some metal complexes of a quinoxaline based unsymmetrical ONNO donor ligand
Synthesis of ligand
Experimental
Materials
The unsymmetrical Schiff base ligand L was synthesized
by the following procedure. The Schiff base half unit 2-(1-
(3-aminopropylimino)ethyl)phenol was prepared by fol-
lowing the method reported earlier [12, 13] with slight
modification. To the methanolic solution of o-hydroxy-
acetophenone (5.0 mmol), a methanolic solution of 1,3-
diaminopropane (7.5 mmol) was added drop by drop from
a dropping funnel. To the above mixture, few drops of Con.
H2SO4 (as dehydrating agent) was added and stirred with
heating for *2 h. The resultant solution was cooled to
room temperature, and the fluorescent green-colored pro-
duct 2-(1-(3-aminopropylimino)ethyl)phenol formed was
washed with ether and cold water. The product was then
filtered and dried over anhydrous calcium chloride. The
product obtained was recrystallized from hot methanol.
In the second step, to the solution of 3-hydrox-
yquinoxaline-2-carboxaldehyde (5.0 g, 28.7 mmol, in
500 mL distilled water), 3–4 drops of conc. HCl was added
to acidify the aqueous solution. An alcoholic solution of
The chemicals used were of AnalaR grade except o-
phenylenediamine and used as received without further
purification. O-phenylenediamine (LR grade, Loba Che-
mie, India) was purified through recrystallization from hot
methanol. Hydrazine hydrate, bromine, calcium carbonate,
o-hydroxyacetophenone, 1,3-diaminopropane, metal(II)
acetates and solvents were bought from Merck. Sodium
pyruvate and glacial acetic acid were bought from SRL
PVT. Ltd., India.
Instrumental
Elemental analyses of ligand and its metal complexes
were carried out using Perkin Elmer elemental analyzer.
The metal contents in the metal complexes were deter-
mined by standard EDTA titration. Molar conductance of
the complexes was measured using Systronic, MK-509
digital conductivity meter. FTIR spectra were recorded
using Brucker ALPHA-D spectrophotometer by KBr
2-(1-(3-aminopropylimino)ethyl)phenol
(7.09 g,
28.7 mmol, in 50 mL methanol) was added to the above
solution dropwise with constant stirring. The dark red-
colored Schiff base precipitated was filtered, washed with
petroleum ether and dried over anhydrous calcium chlo-
ride. The ligand was recrystallized from hot methanol.
pellet method from 4000–400 cm-1 1H NMR and 13C
.
NMR spectra of ligand and its Zn(II) complex were
recorded with Brucker 700 MHz spectrometer using
CDCl3 solvent with TMS as internal standard. DART-MS
spectra were recorded on a JEOL-Accu TOF JMS mass
spectrometer. Magnetic moments were measured by Guoy
method and corrected for diamagnetism of the component
using Pascal’s constants. Electronic absorption spectra
were recorded on Lasany UV–visible double-beam spec-
trophotometer (Model No. I-2902) at the wavelength
range 190–1100 nm. ESR spectra of the [Cu(L)] complex
were recorded at 300 and 77 K in DMSO solution using
Varian, USA E-112 ESR spectrometer using tetracya-
noethylene (TCNE) as g-marker. Thermal analysis was
carried out under nitrogen and air atmospheres at a
heating rate of 10 8C per minute using PerkinElmer
Diamond TG/DTA analyzer. Alumina crucibles were
used for recording thermogravimetric curves. The metal
content present in the final residues obtained from the
thermal analysis in air atmosphere was also determined
using a Shimadzu AA 7000 Atomic Absorption Spec-
trometer. Cyclic voltammetry measurements were done
using electrochemical analyzer CH instrument electro-
chemical workstation (Model 650 C) using a glassy car-
bon working electrode (GCE) and Ag/AgCl reference
electrode and platinum counter electrode. Powder XRD
studies were carried out using XPERT-PRO, X-ray
diffractometer system.
Synthesis of metal complexes
The Co(II), Ni(II), Cu(II) and Zn(II) complexes of L was
prepared by the following procedure. L (2 mmol) dissolved
in 50 mL of methanol was mixed with solution of metal
acetates (2 mmol) in 50 mL methanol and was stirred for
*6–8 h at 60–80 °C. The precipitate formed was filtered
off, washed with cold methanol and dried in vacuum over
anhydrous calcium chloride.
Biological studies
In vitro antimicrobial activity
In vitro antibacterial activities of L and its complexes were
tested against two gram-negative (E. coli and K. pneumo-
niae) and two gram-positive (S. pneumoniae and S. aureus)
bacterial strains by disk diffusion method [14]. The fungal
species used for antifungal activity screening are A. niger,
A. flavus, P. chrysogenum and R. stolonifer. Amikacin was
used as standard antibacterial agent, and fluconazole was
used as standard antifungal agent. The test organisms were
grown on nutrient agar (Muller Hinton agar for bacteria
and antimitotic agar for fungi) medium in petri plates. The
123

C. J. Dhanaraj, J. Johnson
compounds were prepared in DMF and soaked in filter
paper disks of 5 mm diameter and 1 mm thickness. The
disks were placed on the previously seeded plates and
incubated at 37 °C. The diameter of inhibition zone around
each disk was measured after 24 h for bacterial and 72 h
for fungal species. The antimicrobial activities of the
compounds were established by calculating their activity
index by using the following expression [15].
Hydrogen peroxide scavenging activity
The ability of the compounds to scavenge hydrogen per-
oxide was assessed by this method. A solution of H2O2
(40 mM) was prepared in phosphate buffer (0.1 M, pH
7.4). The compounds in DMF solution at the concentration
of 10 mg/10 lL were added to H2O2 solution (0.6 mL),
and the total volume was made up to 3 mL. The absor-
bance of the reaction mixture was recorded at 230 nm in a
spectrophotometer. A blank solution containing phosphate
buffer without H2O2 was prepared and used as control. The
extent of H2O2 scavenging of the extracts was calculated
using the following expression [17].
Inhibition zone of compound ðmmÞ
Activity index ðAÞ ¼
Inhibition zone of standard drug ðmmÞ
 100
ð1Þ
À
Á
Acontrol À Asample
% of H2O2 scavenging activity ¼
 100
ð3Þ
DNA cleavage
Acontrol
The cleavage of supercoiled pUC18 DNA to its nicked
circular and linear forms was studied by using agarose gel
electrophoresis. pUC18 DNA (0.3 lg) was dissolved in
5 mmol L-1 Tris–HCl/50 mmol L-1 NaCl buffer (pH 7.2)
and was treated with the complexes. The mixture was
incubated at 37 °C for 1 h and then mixed with the loading
buffer containing 25% bromophenol blue, 0.25% xylene
cyanol and 30% glycerol. Each sample (10-3 M, 0.5 lL)
was loaded into 1% (w/v) agarose gel. Electrophoresis was
done for 2 h at 100 V in Tris–acetate–EDTA (TAE) buffer
(pH 8.0). The gel was stained with ethidium bromide for
5 min after electrophoresis and then photographed under a
UV transilluminator. In DNA cleavage experiment, H2O2
and DMSO were used as oxidizing and reactive oxygen
species (ROS) scavenger, respectively. The DNA cleavage
efficiency of the complexes was measured by determining
the ability of the complexes to convert the supercoiled
DNA to nicked circular form and linear form.
In vitro anticancer study
The human breast adenocarcinoma cell line (MCF7) was
obtained from National Centre for Cell Science (NCCS),
Pune, and grown in Eagle’s minimum essential medium
(EMEM) containing 10% fetal bovine serum (FBS). All the
cells were maintained at 37 °C, 5% CO2, 95% air and
100% relative humidity. The monolayer cells were
detached with trypsin–ethylenediaminetetraacetic acid
(EDTA) to make single-cell suspensions, and viable cells
were counted using a hemocytometer and diluted with a
medium containing 5% FBS to give final density of
1 9 105 cells/mL. Hundred microliters per well of cell
suspension was seeded into 96-well plates at plating den-
sity of 10,000 cells per well and incubated at 37 °C, 5%
CO2, 95% air and 100% relative humidity. After 24 h, the
cells were treated with serial concentrations of the test
samples. They were initially dissolved in neat dimethyl-
sulfoxide (DMSO) and diluted to twice the desired final
maximum test concentration with serum-free medium.
Additional fourfold and twofold serial dilutions were made
to provide a total of five sample concentrations. Aliquots of
100 lL of these different sample dilutions were added to
the appropriate wells already containing 100 lL of med-
ium, giving the required final sample concentrations. Fol-
lowing drug addition, the plates were incubated for an
additional 48 h at 37 °C, 5% CO2, 95% air and 100%
relative humidity. The medium without samples served as
control, and triplicate was maintained for all concentra-
tions. Tamoxifen was used as standard drug.
Superoxide anion scavenging activity
The scavenging effect of the compounds on superoxide
anion radicals was estimated as follows: the reaction
mixture contained 1 mL of riboflavin (3.3 3 10 mol L-1),
methionine (0.01 mol L-1), 1 mL of nitro blue tetrazolium
chloride (NBT, 4.6 3 10 mol L-1) and phosphate buffer
solution as solvent (0.05 mol L-1, pH 7.8). After adding
1 mL of sample (mg/mL), the reaction mixture was illu-
minated at 4000 lx and 25 °C for 30 min. The absorbance
of the reaction mixture was measured at 560 nm with a
spectrophotometer, and the percentage of superoxide rad-
ical scavenging activity was calculated according to the
following formula [16].
3-[4,5-Dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide
(MTT) assay 3-[4,5-dimethylthiazol-2-yl]2,5-diphenylte-
trazolium bromide (MTT) is a yellow water-soluble
% of super oxide anion scavenging activity
À
Á
Acontrol À Asample
¼
 100
ð2Þ
Acontrol
123

Studies on some metal complexes of a quinoxaline based unsymmetrical ONNO donor ligand
tetrazolium salt. A mitochondrial enzyme in living cells,
succinate dehydrogenase, cleaves the tetrazolium ring,
converting the MTT to an insoluble purple formazan.
Therefore, the amount of formazan produced is directly
proportional to the number of viable cells. After 48 h of
incubation, 15 lL of MTT (5 mg/mL) in phosphate-buf-
fered saline (PBS) was added to each well and incubated at
37 °C for 4 h. The medium with MTT was then flicked off,
and the formazan crystals formed were dissolved in 100 lL
of DMSO, and absorbance at 570 nm was measured using
a microplate reader. The percentage of cell inhibition was
determined using the following formula [18, 19].
The absolute electronegativity (vabs) and absolute
hardness (g) are related to IA and EA [27] and is given
below (Eqs. 7 and 8).
vabs ¼ ðIE þ EAÞ=2 ¼ ðEHOMO þ ELUMOÞ=2
g ¼ ðIE À EAÞ=2 ¼ ðEHOMO À ELUMOÞ=2
ð7Þ
ð8Þ
Another two important properties related to chemical
potential (l) [28] and hardness (g) are electrophilicity
index (x) and global softness (S). These values were cal-
culated using Eqs. (9)–(11) [29].
l ¼ ÀðEHOMO þ ELUMOÞ=2
x ¼ l2=2g
S ¼ 1=g
ð9Þ
ð10Þ
ð11Þ
% of cell inhibition ¼ 100 À Abs ðsampleÞ=Abs ðcontrolÞ
 100
ð4Þ
Nonlinear optical effects Nonlinear optical (NLO)
parameters such as static dipole moment (lo), mean
polarizability (|ao|), anisotropy of polarizability (Da) and
first hyperpolarizability (bo) of the compounds were cal-
culated using the following Eqs. 12–15 [28]. The first
hyperpolarizability (bo) is a third rank tensor that can be
described by a 3 9 3 9 3 matrix. The 27 components of
the 3D matrix can be reduced to 10 components due to the
Kleinman symmetry [30].
Using GraphPad Prism software, nonlinear regression
graph was plotted between % cell inhibition and log con-
centration and IC50 values were determined.
DFT studies
The geometry optimization of the ligand and its metal
complexes was carried out theoretically using Gaussian
09W program package [20] by DFT/B3LYP method.
6-31G(d,p) and LANL2DZ are the basis sets chosen. All
computational process of ligand and metal complexes were
made by using GaussView 5.0.8 software [21]. Here the
B3LYP stands for Becke’s three parameters exchange
functional (B3) [22] in combination with the Lee–Yang–
Parr correlation functional (LYP) [23]. 6-31G(d,p) is a
popular polarized basis set which adds ‘p’ function to
hydrogen atoms in addition to the ‘d’ functions on heavy
atoms, while LANL2DZ is a basis set for post-third row
atoms. This basis set uses effective core potential (ECP) in
calculations [24]. The geometries of the metal complexes
were fully optimized at B3LYP/GENECP level by using
6-31G(d,p) basis sets for C, H, N and O atoms and
LANL2DZ basis sets for Co, Ni, Cu and Zn atoms in gas
phase. GENECP is a keyword with the combination of
6-31G(d,p) and LANL2DZ standard basis sets. The atomic
charge distributions of atoms in the compounds were
determined by natural population analysis (NPA). The NPA
calculations were made at B3LYP/LANL2DZ level [25].
According to Koopmans’ theorem [26],
ꢀ
ꢁ
lo ¼ l2x þ l2y þ l2z
ð12Þ
ð13Þ
À
Á
ao ¼ ð1=3Þ axx þ ayy þ azz
nh
i
o
Á
1=2
À
Á
À
Á
2
2
2
Da ¼
axxÀayy þ ayyÀazz þðazzÀaxxÞ =2
ð14Þ
ð15Þ
h
À
Á
À
2
2
bo ¼ bxxx þ bxyy þ bxzz þ byyy þ byzz þ byxx
i
1=2
À
Á
2
þ bzzz þ bzxx þ bzyy
Results and discussion
The unsymmetrical ligand L and its metal complexes are
stable at room temperature in the solid state. L is dark red
in color and is soluble in organic solvents, such as
methanol, ethanol, chloroform, acetonitrile, DMF and
DMSO. The metal complexes are obtained as colored
crystalline solids. The metal complexes of L are soluble
in acetonitrile, DMF, DMSO, chloroform and THF. All
the metal complexes are sparingly soluble in methanol
and ethanol. The analytical data of L and its [Co(L)],
[Ni(L)], [Cu(L)] and [Zn(L)] complexes are given in
Table 1.
ÀEHOMO ¼ IE
ÀELUMO ¼ EA
ð5Þ
ð6Þ
where IE and EA stands for ionization energy and electron
affinity, respectively.
123

C. J. Dhanaraj, J. Johnson
Table 1 Analytical and physical data of L and its metal(II) complexes
Compound
Yield/%
M. Wt
Color
Elemental analysis/%
Found/Calcd.
Molar conductance
/X-1 cm2 mol-1
C
H
N
M
–
L
71
46
53
66
62
348
405
405
409
411
Dark red
68.91/68.95
59.29/59.27
59.33/59.30
58.52/58.60
58.80/58.33
5.82/5.79
4.41/4.48
4.51/4.48
4.47/4.43
4.50/4.41
16.12/16.08
13.78/13.82
13.88/13.83
13.69/13.67
13.68/13.61
–
[Co(L)]
[Ni(L)]
[Cu(L)]
[Zn(L)]
Brownish red
Brownish yellow
Brownish green
Reddish yellow
14.59/14.54
14.48/14.49
15.48/15.50
15.80/15.88
8.6
5.5
5.2
2.1
Molar conductance
stretching frequency. In the IR spectra of the metal com-
plexes, this band shows some shift towards low wave
number region for about 10–4 cm-1. This confirms the
coordination imino group nitrogen atom with the central
metal ion in the metal chelates. In the IR spectrum of L,
another strong band seen at 1566 cm-1 is ascribed to
azomethine (–HC=N) stretching frequency. This band is
shifted to lower wave umber, 1560 cm-1, in the IR spectra
of [Ni(L)] complex. On the other hand, the azomethine
band is shifted to higher wave numbers, 1577, 1573 and
1572 cm-1, in [Co(L)], [Cu(L)]and [Zn(L)] complexes,
respectively. This indicates the coordination of azomethine
nitrogen atom to metal ion in metal complexes. The
absence of bands in *3500 and 1676 cm-1 regions indi-
cate that the ligand exists in iminol form in the metal
chelates [32]. Furthermore, this confirms the coordination
of phenolic oxygen atom of o-acetophenone and quinoxa-
line moieties through deprotonation. The presence a new
set of bands in the metal chelates in the region
1347–1340 cm-1 corresponds to the [C–O stretching fre-
quencies. This also confirms the coordination of L via two
phenolic oxygen atoms through deprotonation. In the IR
spectra of metal complexes, appearance of new bands in
the region 476–462 and 412–403 cm-1 are attributed to
M–O and M–N bond stretching frequencies, respectively
[33]. Based on the above observations, it is concluded that
L behaves as a tetradentate ONNO donor ligand in the
metal chelates, coordinating through the azomethine and
imino group nitrogen and through the deprotonation of
Molar conductance measurement of the metal complexes
was taken in DMF (10-3 mol dm-3) solutions at room
temperature. The molar conductance values of the [Co(L)],
[Ni(L)], [Cu(L)] and [Zn(L)] complexes are found to be in
the range 2.1–8.6 X-1 cm2 mol-1; this low molar con-
ductance values (Table 1) propose that the metal com-
plexes are non-electrolytes [31]. Thus, all the metal
complexes of L are found to be neutral.
Characterization of the ligand and its metal
complexes
IR spectra
The IR spectra of L and its metal complexes were recorded
in the wave number region 4000–400 cm-1 (Figure S1),
and the important IR spectral data are given in Table 2.
The IR spectrum of L shows a broad band centered at
3454 cm-1, which is assigned to the combination of –NH
vibration of the quinoxaline ring and –OH stretching
vibrations of phenolic –OH group in the o-acetophenone
moiety. The band at 1676 cm-1 in the IR spectrum of L is
assigned to the [C=O stretching frequency of the
quinoxaline ring carbonyl group. These two bands suggest
the existence of L in keto form. This is further supported
by NMR spectral studies. The strong band observed at
1650 cm-1 is assigned to the benzophenone imino [C=N
Table 2 FTIR spectral data of L and its metal(II) complexes (cm-1
)
Compound
m(OH?NH)
m(HC=N)
m(C=N)
m(C=O)
m(C–O)
m(M–O)
m(M–N)
L
3454
1566
1577
1560
1570
1572
1650
1640
1644
1643
1640
1676
–
–
–
[Co(L)]
[Ni(L)]
[Cu(L)]
[Zn(L)]
–
–
–
–
–
–
–
–
1344
1347
1335
1347
462
470
476
467
406
412
409
403
123

Studies on some metal complexes of a quinoxaline based unsymmetrical ONNO donor ligand
Magnetic susceptibility measurements
phenolic oxygen atoms in the o-hydroxyacetophenone and
quinoxaline moieties.
The leff of the metal ions in the metal chelates of L was
calculated after making proper diamagnetic corrections.
The [Co(L)] complex has a magnetic moment value 4.25
BM, which is found to be in agreement with the reported
values for tetrahedral Co(II) complexes [36]. The [Ni(L)]
complex has magnetic moment value of 3.23 BM, sug-
gesting a tetrahedral environment around the Ni(II) ion
[37]. The [Cu(L)] complex possesses magnetic moment
value 1.88 BM, which is consistent with the square planar
geometry around the Cu(II) ion [38].
Electronic absorption spectra
The electronic absorption spectra of L and its metal(II)
complexes (Figure S2) were recorded in DMF solution at
room temperature. The absorption region, assignment of
the absorption bands and proposed geometry of the com-
plexes are given in Table 3. The electronic spectrum of
ligand exhibits three bands. The band observed at
35,461 cm-1 is due to the p–p* transition of aromatic rings
of ligand. The absorption band at 31,348 cm-1 is assigned
to the n–p* of azomethine chromophore. The other low-
energy broad band observed at 23,529 cm-1 is presumably
due to the intraligand charge transfer transition.
1H NMR
1
The H NMR spectrum of L is given in Figure S3a. The
signal for azomethine proton in L appears as a singlet at
7.9 ppm. The other two singlets seen in the 1H NMR
spectrum of L at 16.4 and 12.2 ppm are assigned to the
quinoxaline ring –NH [36] and o-hydroxy acetophenone –
OH proton [39] resonance, respectively. The multiplet seen
in 6.7–7.7 ppm range is due to the aromatic protons of L as
expected. The o-hydroxyacetophenone methyl group pro-
ton resonance was observed at 2.6 ppm. The other peaks
observed at 3.4, 3.7 and 2.2 ppm are ascribed to the 1,3-
diaminopropane group aliphatic proton resonance.
The spectrum of [Co(L)] complex exhibits transitions at
35,971, 26,316 and 12,771 cm-1. The bands at 35,971 and
26,316 cm-1 are attributed to the p–p* and n–p* transi-
tions, respectively. The d–d transition observed at
12,771 cm-1
is
assignable
to
the
4A2(F) ?
4T1(P) transition corresponding to tetrahedral geometry.
The electronic absorption spectrum of [Ni(L)] complex
exhibits two intraligand charge transfer and one d–d tran-
sition band. The p–p* transition band is observed at
36,101 cm-1. The absorption band due to n–p* transition
is seen at 23,923 cm-1. The d–d transition band corre-
1
The H NMR spectrum of the [Zn(L)] complex (Fig-
1
ure S3b) was compared with that of L. In the H NMR
3
sponding to 3T1(F) ? T1(P) transition is seen at
*18,182 cm-1. This suggests that the Ni(II) complex
possesses tetrahedral geometry [34]. The [Cu(L)] complex
also exhibits three absorption bands. The bands found at
37,037 and 27,855 cm-1 are assignable to the p–p* and n–
p* transitions, respectively. The broad absorption band
observed in the 20,000–16,667 cm-1 region centered at
spectrum of [Zn(L)] complex, the signals due to quinoxa-
line ring –NH and o-hydroxy acetophenone –OH proton
resonance are not observed. This reveals the presence of
L in its enol form and coordination of two phenolic oxygen
atoms through deprotonation. The downfield shift of
azomethine proton signal further tells the coordination of
azomethine nitrogen atom. The signals due to aromatic and
aliphatic protons of 1,3-diaminopropane also show some
2
*18,108 cm-1 is assignable to the 2B1g ? A1g transition,
corresponding to square planar geometry of the Cu(II)
complex [35]. The [Zn(L)] complex exhibits only the
intraligand charge transfer bands at 32,258 and
23,641 cm-1 in its electronic absorption spectrum.
1
shift in the H NMR spectrum of [Zn(L)] complex, due to
the change in the electronic environment around these
groups on chelation.
13C NMR
In the 13C NMR spectrum of L (Figure S4), the signals
seen at 164.3 and 172.6 ppm are ascribed to the carbonyl
carbon and phenolic[C–O carbon resonance, respectively.
The imino group carbon and azomethine carbon resonance
are observed at 136.6 and 132.8 ppm, respectively. The
signal observed at 130.92 ppm is assigned to the quinox-
aline ring [C=N carbon resonance. The aromatic carbon
signals are seen at 117.2–128.2 ppm region. The o-hy-
droxyacetophenone group methyl carbon peak is observed
at 46.5 ppm. Three different kinds of carbon atoms present
Table 3 Electronic absorption bands and magnetic moments of
L and its metal(II) complexes
Compound
m/cm-1
l
eff/BM
Geometry
L
35,461/31,348/23,529
35,971/26,316/12,771
36,101/23,923/18,182
37,037/27,855/18,018
32,258/23,641
–
–
[Co(L)]
[Ni(L)]
[Cu(L)]
[Zn(L)]
4.25
3.23
1.88
–
Tetrahedral
Tetrahedral
Square planar
Tetrahedral
123

C. J. Dhanaraj, J. Johnson
in the 1,3-diaminopropane moiety resonates at 30.9, 26.8
and 14.74 ppm. In the 13C NMR spectrum of [Zn(L)]
complex, the aliphatic carbon resonance remains almost
unchanged. The carbonyl carbon signal is not found in the
spectrum of [Zn(L)] complex, and a new signal is observed
at 170.4 ppm, which indicates the existence of enol form of
L in the metal chelates. The phenolic [C–O signal shows
small shift due to its coordination of the metal ion through
deprotonation.
(2.04) [ 2.0027 indicate that the unpaired electron is
localized in d2x - dy2 orbital of the Cu(II) ion [40]. The
calculated G value (4.21) states the absence of magnetic
interaction between Cu(II) ions in its solid state. The
absence of any half-field signal at 1600 G corresponds to
DMs = 2 transition, ruling out any magnetic exchange
between Cu(II) centers [41].
The calculated a2 (0.43), b2 (0.98) and c2 (0.93) values
are found to be less than unity. In the present investigation,
K\(0.42) [ K (0.40) values found for the [Cu(L)] complex
k
Mass spectrometry
indicate the presence of substantial in-plane p-bonding
[42]. The results of EPR, electronic absorption spectral and
magnetic moment measurements suggest that the [Cu(L)]
complex has square planar geometry. The calculated
empirical factor value (f = (g /A ) = 137.57) further
The DART mass spectrum L is given in Figure S5. In the
mass spectrum of L, the molecular ion peak seen at m/
z = 349.3 with relative intensity 23% matches with the
molecular mass [M ? 1] of L. The base peak observed at
m/z = 175.09 matches the molecular mass of (M ? 1) of
3-hydroxyquinoxaline-2-carboxaldehyde. In addition to
these peaks, L shows a series of molecular ion peaks at
391.36 (12%), 326.18 (10%), 311.17 (28%), 309.15 (23%),
255.02 (35%), 212.20 (9%), 177.10 (70%) and 114.11
(13%) corresponding to various fragments. In the mass
spectra of [Co(L)], [Ni(L)], [Cu(L)] and [Zn(L)] com-
plexes, the molecular ion peaks are appeared at 407.21
(M ? 2, 16%), 406.36 (M ? 1, 8%), 409.91 (M, 12%) and
at 413.73 (M ? 2, 11%), respectively. The representative
mass spectrum of metal complexes is provided in the
supplementary file (Figure S6). Similar to L, the metal
complexes also show several molecular ion peaks corre-
sponding to various fragmentation processes. The observed
molecular ion peaks in the mass spectra of the compounds
are in good agreement with their proposed structures
arrived on the basis of elemental analysis and other spectral
techniques.
k
k
confirms square planar geometry of the [Cu(L)] complex.
Thermal analysis
Thermal analyses of L and its metal(II) complexes were
done in the temperature range 40–725 °C in nitrogen and
air atmosphere. Alumina was used as the reference com-
pound. All the compounds display multistage thermal
decomposition pattern in their thermogravimetric curves.
L shows two stages of thermal decompositions (Fig. 1)
in the temperature ranges 95–168 and 168–370 °C with
DTG peaks at 148 and 255 °C, respectively. The first-stage
decomposition (mass loss (%): obs./calcd.: 16.15/15.51)
corresponds to the loss of acetophenone moiety from
L. The final-stage decomposition (mass loss: obs./calcd.:
83.35/83.11) is due to the removal of remaining organic
moieties from the ligand. The thermogravimetric curve of
[Co(L)] complex shows three stages of decomposition. The
thermal decomposition of [Co(L)] complex occurs (Fig. 2)
in the temperature ranges 100–215, 215–495 and
495–675 °C. The corresponding DTG peaks were observed
at 162, 274 and 559 °C, respectively. The first-stage mass
loss 10.93% (calcd. 12.59%) is due to the loss of o-hy-
droxyacetophenone part from L. The second (mass loss:
obs./calcd.: 37.55/35.62) and third (mass loss: obs./calcd.:
24.93/25.93) stages of thermal decompositions correspond
to the loss of remaining organic moiety from the metal
chelate.
EPR spectroscopy
The X-band EPR spectra of the [Cu(L)] complex recorded
in DMSO at liquid nitrogen temperature (77 K) and in the
solid state at room temperature (300 K) are given in Fig-
ure S7. The calculated ESR parameters of the [Cu(L)]
complex are given in Table 4. The EPR spectrum of the
[Cu(L)] complex at 77 K shows four well-resolved
hyperfine peaks. The observed values g (2.16) [ g\
k
Table 4 ESR parameters of [Cu(L)] complex
Complex
g tensors
Hyperfine constant 9 10-4
Bonding parameters
[Cu(L)]
g
g\
giso
A
A\
G
a2
b2
c2
K
K\
k
k
k
At 77 K
2.16
–
2.04
–
–
157
–
65
–
4.21
–
0.43
–
0.98
–
0.93
–
0.42
–
0.40
–
At 300 K
2.02
123

Studies on some metal complexes of a quinoxaline based unsymmetrical ONNO donor ligand
from L. The second (mass loss (%): obs./calcd.: 15.15/
100
80
60
40
20
0
15.19)- and third (mass loss (%): obs./calcd.: 37.55/38.13)-
stage decompositions were assigned to the loss of
diaminopropane and quinoxaline moieties from the metal
chelate.
0.0
–0.2
–0.4
–0.6
The [Cu(L)] complex shows two stages of thermal
decomposition. In the thermogravimetric curve of [Cu(L)]
complex (Fig. 4), these decompositions were seen at the
temperature ranges 110–210 and 210–490 °C. The first-
stage decomposition with an endothermic DTG peak at
153 °C (mass loss (%): obs./calcd.: 16.05/16.40) and the
second-stage decomposition with an endothermic DTG
peak at 238 °C (mass loss (%): obs./calcd.: 55.34/56.64)
are because of the loss of organic moieties from the metal
complex. The [Zn(L)] complex displays two stages of
thermal decomposition (Fig. 5) at 110–490 and
490–720 °C range with resultant DTG peaks at 380 and
714 °C, respectively. The first-stage thermal decomposi-
tion (mass loss (%): obs./calcd.: 16.05/16.40) corresponds
to loss of acetophenone and diaminopropane parts from the
metal chelate. The second-stage decomposition (mass loss
(%): obs./calcd.: 35.38/37.39) is due the removal of
quinoxaline moiety of the [Zn(L)] complex.
373
473
573
673
773
873
973
Temperature/K
Fig. 1 TG–DTG curves of L (m: 9.57 mg)
0.10
100
80
60
40
20
0
0.05
0.00
–0.05
–0.10
–0.15
–0.20
The thermal analysis of the metal complexes in air
atmosphere was also conducted to analyze the metal con-
tent. The metal content in the final residues was analyzed
by atomic absorption spectroscopy [43]. The final product
of [Co(L)] complex is observed as CoO residue
(obs./calcd.: 18.20/18.49%). The CoO residue is formed
after the elimination of organic moieties from the complex
at the temperature range 495–675 °C with DTA peak at
about 560 °C. The DTA curves of [Ni(L)] complex display
(Fig. 6) an endothermic peak at 430 °C, due to the loss of
organic part and the formation of stable NiO as final pro-
duct (obs./calcd.: 18.35/18.42%). Likely for the [Cu(L)]
and [Zn(L)] complexes, the final products are found as
373
473
573
673
773
873
973
Temperature/K
Fig. 2 TG–DTG curves of [Co(L)] complex (m: 9.71 mg)
The [Ni(L)] complex displays three stages of thermal
decomposition (Fig. 3). The decompositions of [Ni(L)]
complex occurs at the temperature ranges 105–268,
268–380 and 380–550 °C with endothermic DTG peaks at
146, 338 and 404 °C, respectively. This first stage of
decomposition (mass loss (%): obs./calcd.: 35.76/36.56)
corresponds to the removal of o-hydroxyacetophenone part
100
80
60
40
20
0
0.0
100
0.00
–0.1
–0.2
–0.3
–0.4
–0.5
80
–0.05
60
–0.10
40
20
0
–0.15
–0.20
373
473
573
673
773
873
973
373
473
573
673
773
873
973
Temperature/K
Temperature/K
Fig. 3 TG–DTG curves of [Ni(L)] complex (m: 11.37 mg)
Fig. 4 TG–DTG curves of [Cu(L)] complex (m: 11.37 mg)
123

C. J. Dhanaraj, J. Johnson
0.00
100
80
–0.02
–0.04
N
60
40
20
0
N
–0.06
–0.08
–0.10
–0.12
O
N
M
O
N
373
473
573
673
773
873
973
Temperature/K
Fig. 5 TG–DTG curves of [Zn(L)] complex (m: 5.38 mg)
200
Exo
(M = Co(II), Ni(II) and Zn(II))
Endo
100
0
N
N
N
N
473
673
873
Temperature/K
u
C
Fig. 6 DTA curve of [Ni(L)] complex
O
O
stable CuO (obs./calcd.: 19.10/19.40%) and ZnO
(obs./calcd.: 19.65/19.76%), respectively.
The proposed structure of metal complexes is given in
Scheme 1.
Scheme 1 Proposed structure of metal complexes
Electrochemical analysis
The cyclic voltammograms of the compounds were recor-
ded at 300 K in DMSO solution with scan rate 0.05 V s-1
Powder XRD
.
The potential range was -0.8 to 2.0 V for L. For [Co(L)],
[Ni(L)] and [Cu(L)] complexes, the potential range was
-0.8 to 1.4 V. The potential ranges for [Zn(L)] complex
was -0.6 to 1.4 V. The cyclic voltammograms of the
compounds are given in the supplementary data
(Figure S9).
The powder XRD patterns of L and its metal complexes
˚
were recorded over the 2h = 0–80 A range and are dis-
played in Figure S8. L and its [Cu(L)] complex display
some crystalline peaks in their XRD diffractogram, while
the other metal complexes did not show any peaks. From
the powder XRD patterns, we have calculated the average
crystallite size and also refined the unit cell parameters.
The average crystallite sizes of the compounds are calcu-
lated using Scherrer’s formula [44]. The calculated average
crystallite size of L and its [Cu(L)] complex is 51.20 and
33.74 nm, respectively. This states that L and [Cu(L)]
complexes are in nanocrystalline phase, while the [Co(L)],
[Ni(L)] and [Zn(L)] complexes are amorphous in nature.
The refined unit cell parameters of L and its [Cu(L)]
complex are determined using trial and error method and
are given in Table S1. L and [Cu(L)] complex are included
in the triclinic crystal system.
L shows one irreversible cathodic peaks at Epc
=
-0.42 V versus Ag/AgCl. The [Co(L)] complex shows
only one irreversible anodic peak at 0.08 V versus Ag/
AgCl. This irreversible anodic peak is assignable to the
Co(II)/Co(III) oxidation process. The [Ni(L)] complex
displayed two irreversible peaks versus Ag/AgCl. The first
cathodic peak at Epc = -0.68 V corresponds to the Ni(II)/
Ni(I) reduction, and the corresponding anodic peak at
Epa = 1.18 V corresponds to the Ni(I)/Ni(II) oxidation
process [45]. The [Cu(L)] complex also shows (Fig. 7) two
peaks, the cathodic peak at Epc = 0.04 V versus Ag/AgCl
corresponding to the formation of Cu(II)/I couple. The
123

Studies on some metal complexes of a quinoxaline based unsymmetrical ONNO donor ligand
associated anodic peak was observed at Epa = 1.00 V,
equivalent to Cu(I)/Cu(II) couple. The peak-to-peak sepa-
ration DEp is 0.96 V which confirms that the process is
irreversible. The [Zn(L)] complex shows only one irre-
versible cathodic peak at Epc = 0.12 V versus Ag/AgCl.
lipopolysaccharide components; this makes the cell wall
impermeable to antimicrobial substances. Gram-positive
bacteria, on the other hand, are more susceptible because
they only have an outer peptidoglycan layer which is per-
meable [46].
The antifungal activity screening result is displayed in
Fig. 9. From the figure, it is obvious that L is active against
all the fungal strains under screening. The [Co(L)] complex
is active against A. flavus and P. chrysogenum. The [Ni(L)]
and [Cu(L)] complexes are inactive only against the fungal
strain R. stolonifer; whereas the [Zn(L)] complex shows
inhibition efficiency only against the fungal strain A. flavus.
Among the newly synthesized compounds, [Cu(L)] com-
plex (47.36%) exhibits higher antifungal activity against A.
niger. The Co(II) complex shows higher inhibition effi-
ciencies against the fungal strains A. flavus (52.17%) and P.
chrysogenum (80.00%), while L shows highest antifungal
activity against the fungal strain R. stolonifer (50.00%).
The order of antifungal activity is as follows:
[Co(L)] [ L [ [Cu(L)] [ [Ni(L)] [ [Zn(L)].
Biological studies
Antimicrobial activity
The inhibition efficiencies of L and its [Co(L)], [Ni(L)],
[Cu(L)] and [Zn(L)] complexes were tested against some
gram-positive and gram-negative bacterial strains by agar
diffusion method. The results obtained in terms of activity
index are displayed in Fig. 8. From the figure, it is clear
that the [Ni(L)] and [Zn(L)] complexes do not show any
inhibition efficiency against the gram-positive bacterial
strains. L (46.66%), [Co(L)] complex (29.16%) and
[Cu(L)] complex (33.33%) are active against the gram-
positive bacterial strain S. aureus. The bacterial strain S.
Pneumoniae is resistant toward L and its metal complexes.
The [Co(L)] complex does not show any antibacterial
activities against the gram-negative bacterial strain E. coli.
The Cu(II) complex shows highest inhibition efficiency
against the gram-negative bacterial strains E. coli (36.00%)
and K. Pneumoniae (39.13%). L and its [Co(L)] and
[Ni(L)] complexes are inactive against the gram-negative
bacterial strain K. Pneumoniae. The compounds follow the
order of antibacterial activity as: [Cu(L)] [ L [
[Zn(L)] [ [Cu(L)] [ [Ni(L)].
Moreover, the antimicrobial activity index of L and its
metal complexes points out that S. aureus is the most
susceptible bacterium of all tested strains and that the
activity is more noticeable on gram-positive bacterial
strains. This distinction in sensitivity between gram-posi-
tive and gram-negative bacteria might be associated with
the dissimilarities in the morphological compositions
among these microbes. Gram-negative bacteria have an
outer phospholipid membrane carrying the structural
The antimicrobial screening of the compounds reveals
that the [Cu(L)] and [Co(L)] complexes have highest
antibacterial and antifungal potentials, respectively.
DNA cleavage
The interaction of plasmid pUC18 DNA with L and its
metal(II) complexes was studied using agarose gel elec-
trophoresis method in the presence of an oxidizing agent
(H2O2) and in the presence of reactive oxygen species
scavenger (DMSO). When a supercoiled circular plasmid
DNA is subjected to DNA cleavage study, if scission
occurs on one strand (single-stranded nicking), the super-
coiled Form I will be relaxed to generate a slow-moving
open circular form (Form II). If both strands are cleaved
(double-stranded nicking), a linear form (Form III) that
migrates between Form I and Form II will be generated
[47].
The DNA cleavage studies of the compounds in the
presence of H2O2 (Fig. 10a) show that except L, the metal
chelates completely degrade all the three forms of pUC18
DNA. L cleaves pUC18 DNA into its open circular form
(Form II). This proposes that DNA cleavage process occurs
through oxidative cleavage mechanism. In oxidative
cleavage mechanism, when redox-active metal complexes
interact with DNA in the presence of an oxidizing agent, it
is supposed to produce different reactive oxygen species
(ROS), depending on specific complex and conditions. A
non-diffusible metal-peroxo intermediate has been invoked
in some cleavage reactions though in others cases, Fenton-
like chemistry, which invokes release of freely diffusible
hydroxyl (OHÁ) or hydroperoxyl (HO2Á) radical, has been
assumed. The metal complexes in the presence of H2O2
3.2
2.8
2.4
2.0
1.6
1.2
0.8
0.4
0
–0.4
–0.8
–1.2
–1.6
–0.8 –0.6 –0.4 –0.2
0
0.2 0.4 0.6 0.8 1.0 1.2 1.4
Potential/V
Fig. 7 Cyclic voltammogram of [Cu(L)] complex
123

C. J. Dhanaraj, J. Johnson
Fig. 8 Antibacterial activity of
L and its metal(II) complexes
100
90
80
70
60
E. Coli
K. Pneumoniae
S. Aureus
50
40
S. Pneumoniae
30
20
10
0
L
[Co(L)]
[Ni(L)]
[Cu(L)]
[Zn(L)]
Amikacin
Fig. 9 Antifungal activity of
L and its metal(II) complexes
100
90
80
70
60
50
40
30
20
10
0
A. Niger
A. Flavus
P. Chrysogenum
R. Stolonifer
L
[Co(L)]
[Ni(L)]
[Cu(L)]
[Zn(L)]
Fluconazole
may generate reactive hydroxyl/hydroperoxyl radical that
can destruct the deoxyribose ring or otherwise a metal-
peroxo species may take part directly in the oxidation of
deoxyribose ring [48].
1
2
3
4
5
(a)
(b)
To recognize the contribution of ROS, electrophoresis
experiment was carried out in the presence DMSO as a
standard scavenger for reactive oxygen intermediates under
the same experimental conditions. Addition of DMSO
results in complete inhibition of the cleavage activity of all
the present compounds (Fig. 10b), proposing the possibil-
ity of formation of diffusible hydroxyl radical as the
reactive species leading to strand scission [49].
C
C1 C2
1
2
3
4
5
Antioxidant activity
Superoxide anion scavenging activity The in vitro
superoxide anion scavenging activities of L and its meta-
l(II) complexes were evaluated by spectroscopic method
using NBT as indicator. The percentage of superoxide
anion elimination capabilities of the compounds are dis-
played in Fig. 11. The results show that the compounds
possess moderate superoxide anion scavenging abilities.
The inhibition efficiencies of the compounds are in the
range 43.36–84.54%. Among the compounds, [Zn(L)] and
[Cu(L)] complexes show highest and lowest superoxide
Fig. 10 a DNA cleavage activity of L and its metal complexes
(where Lanes 1, 2, 3, 4 and 5 are DNA-treated with L, [Co(L)],
[Ni(L)], [Cu(L)] and [Zn(L)] complexes (50 lM) along with 100 lM
H2O2). b DNA cleavage activity of L and its metal(II) complexes
(where Lane C: control DNA (untreated sample), Lane C1: DNA with
0.5 lL DMSO, Lane C2: DNA with 100 lM H2O2, Lane 1:
L?H2O2?DMSO, Lane 2: [Co(L)] complex ? H2O2 ? DMSO,
Lane 3: [Ni(L)] complex?H2O2?DMSO, Lane 4: [Cu(L)] com-
plex ? H2O2 ? DMSO and Lane 5: [Zn(L)] complex ?
H2O2 ? DMSO
123

Studies on some metal complexes of a quinoxaline based unsymmetrical ONNO donor ligand
anion scavenging activities, respectively. L shows 63.48%
elimination activity of superoxide anions from the reaction
mixture. On chelation, L with Co(II), Ni(II) and Cu(II) ions
slightly lowered its activity, while chelation of L with
Zn(II) ion enhanced its antioxidant activity. The order of
superoxide anion scavenging activity is as follows:
[Zn(L)] [ L [ [Co(L)] [ [Ni(L)] [ [Cu(L)].
and S11, respectively. The figures pointed out that the
anticancer activity of the compounds depends on concen-
tration. As the concentration of compounds increases, the
activity also increased. The anticancer activity results of
the compounds in terms of IC50 values are provided in
Table 5. Among the synthesized compounds, the Cu(II)
complex has low IC50 value and is highly active. L and its
[Co(L)] complex are ineffective, and their IC50 values are
greater than 100 lM. On comparing the IC50 values of the
compounds with standard drug (tamoxifen), the com-
pounds are not much effective against the human breast
adenocarcinoma cell line.
Hydrogen peroxide scavenging activity The in vitro
hydrogen peroxide scavenging activity results (Fig. 12)
reveal that the [Co(L)] and [Ni(L)] complexes have mod-
erate hydrogen peroxide scavenging power. The percentage
of hydrogen peroxide elimination activity of L and its
metal complexes ranges 25.55–62.70%. Among the present
compounds, the [Ni(L)] complex shows highest and
[Cu(L)] complex shows lowest hydrogen peroxide scav-
enging activity. The order of activity is as follows:
[Ni(L)] [ [Co(L)] [ L [ [Zn(L)] [ [Cu(L)].
The enhanced anticancer activity of [Ni(L)], [Cu(L)]
and [Zn(L)] complexes compared with the uncoordinated
L may be ascribed to the increase in conjugation with –
R=N–R0 moiety in L on chelation. The variation in the
cytotoxicity of the metal complexes with the same ligand at
a given concentration describes a synergistic effect upon
coordination of metal ions. Additionally, improved activity
of metal chelates may also be attributed due to higher
lipophilic nature of the complexes which increased due to
chelation. It is most likely due to fast diffusion of the
chelates through the cell membrane or due to the chelation
effect [3].
Anticancer activity
The in vitro anticancer activity of the compounds against
the human breast adenocarcinoma (MCF7) cell lines was
evaluated by MTT assay. The cell viability and the effect
of increasing concentration (0.25–100 lM) of the com-
pounds against MCF7 cell line are given in Figures S10
DFT studies
100
Geometry optimization The structure of L and its meta-
l(II) chelates was optimized using Gaussian 09 program.
B3LYP/6-31G(d,p) and B3LYP/LANL2DZ basis sets were
used for the geometry optimization of L and its metal(II)
complexes, respectively. The selected bond lengths and
bond angles for the compounds are provided in Table 6.
The optimized structure of the compounds is depicted in
Fig. 13. The optimum energies of L and its [Co(L)],
[Ni(L)], [Cu(L)] and [Zn(L)] complexes are -1143.63,
1287.54, -1311.81, -1338.64 and -1208.11 a.u, respec-
tively. Theses energy values indicate that on chelation,
metal chelates become more stable than the L. Among the
metal complexes, [Ni(L)] complex is found to be more
stable. From the optimized structures, it is obvious that
100
84.54
90
80
70
63.48
56.69
50.69
60
50
40
30
20
10
0
43.36
Control
L
[Co(L)] [Ni(L)] [Cu(L)] [Zn(L)]
Fig. 11 Superoxide anion scavenging activity of L and its metal(II)
complexes
100
100
90
Table 5 IC50 values of L and its metal(II) complexes
80
70
62.7
Compound
IC50/lM
60
50
42.02
L
[100
[100
97.03
40.39
76.53
11.20
36.92
40
30
20
10
0
27.26
[Co(L)]
[Ni(L)]
[Cu(L)]
[Zn(L)]
Tamoxifena
21.55
Control
L
[Co(L)] [Ni(L)] [Cu(L)] [Zn(L)]
Fig. 12 Hydrogen peroxide scavenging activity of L and its metal(II)
complexes
a
Standard drug
123

C. J. Dhanaraj, J. Johnson
Table 6 Selected geometrical parameters of L and its metal(II)
complexes
Table 6 continued
Bond
connectivity
Bond
length/A
Bond
connectivity
Bond
angle/8
˚
Bond
connectivity
Bond
length/A
Bond
connectivity
Bond
angle/8
˚
16C–18N
18N–45Zn
28N–29C
28N–45Zn
44O–45Zn
36C–44O
1C–14N
1.2931
2.1176
1.3075
2.0850
1.9400
1.3088
1.3320
1.3377
16C–18N–19C
19C–22C–25C
25C–28N–29C
30C–29C–34C
15O–45Zn–44O
15O–45Zn–18N
44O–45Zn–28N
44O–45Zn–18N
117.018
115.648
122.251
118.071
115.967
92.990
L
1C–15N
1.3013
1.2238
1.3891
1.0136
1.2707
1.0944
1.4562
1.4534
1.2768
1.3627
3C–14N–4C
124.954
121.238
130.841
109.622
112.321
121.250
125.693
116.701
122.291
108.522
4C–16O
14N–4C–16O
1C–17C–19N
19N–20C–23C
20C–23C–26C
26C–29N–30C
25N–30C–31C
31C–30C–35C
30C–35C–37C
37C–45O–46 H
4C–14N
14N–8H
17C–19N
17C–18H
19N–20C
26C–29N
29N–30C
37C–45O
[Co(L)]
91.133
4C–13N
133.593
L acts as a tetradentate ligand and coordinates with the
metal ions through two nitrogen atoms: one from azome-
thine and another from imine groups, through phenolic
oxygen atom of quinoxaline ring through deprotonation
and through phenolic oxygen atom of acetophenone moiety
through deprotonation. The ligand-to-metal ratio is found
to be 1:1. The [Co(L)], [Ni(L)] and [Zn(L)] metal com-
plexes possess tetrahedral geometry, while the [Cu(L)]
complex possesses square planar geometry.
4C–15O
1.2936
1.8953
1.2918
2.0883
1.3044
1.9933
1.8654
1.3041
1.3828
1.3331
13N–4C–15O
119.836
113.312
120.316
109.233
127.657
119.981
107.032
90.259
15O–45Co
16C–18N
18N–45Co
28N–29C
28N–45Co
44O–45Co
36C–44O
1C–14N
14N–1C–16C
16C–18N–19C
19C–22C–25C
25C–28N–29C
30C–29C–34C
15O–45Co–44O
15O–45Co–18N
44O–45Co–28N
44O–45Co–18N
Frontier molecular orbitals The highest occupied
molecular orbital (HOMO) and the lowest unoccupied
molecular orbital (LUMO) energy portrays the capability
of electron-donating and electron-accepting properties of a
compound. These orbitals are a pair of orbitals in the
compound, which allows them to interact more strongly.
HOMOs and LUMOs are sometimes titled as frontier
molecular orbitals (FMOs), for the reason that they lie at
the outmost boundaries of the electrons of compounds. The
frontier molecular orbitals play a vital role in the optical
and electrical properties. The frontier orbital energy gaps
also help to illustrate the kinetic stability and the chemical
reactivity of a compound. A molecule with a small frontier
orbital gap is generally associated with high chemical
reactivity and low kinetic stability and is also termed as
soft molecule [50].
87.245
4C–13N
128.018
[Ni(L)]
4C–15O
1.2870
1.8856
1.2985
1.9696
1.3239
1.9565
1.8272
1.2926
1.3314
1.3410
13N–4C–15O
14N–1C–16C
16C–18N–19C
19C–22C–25C
25C–28N–29C
30C–29C–34C
15O–45Ni–44O
15O–45Ni–18N
44O–45Ni–28N
44O–45Ni–18N
119.484
115.208
114.215
112.169
118.274
116.644
107.490
91.133
15O–45Ni
16C–18N
18N–45Ni
28N–29C
28N–45Ni
44O–45Ni
36C–44O
1C–14N
90.631
4C–13N
119.775
[Cu(L)]
The energies for second highest occupied molecular
orbital (HOMO-1), the highest occupied molecular orbital
(HOMO), the lowest unoccupied molecular orbital
(LUMO) and the second lowest unoccupied molecular
orbital (LUMO?1) were calculated for L and its [Co(L)],
[Ni(L)], [Cu(L)] and [Zn(L)] complexes, and the values are
given in Table 7. The energy gap between [HOMO–
LUMO] for L and its [Co(L)], [Ni(L)], [Cu(L)] and
[Zn(L)] complexes is -0.23555, -0.11204, -0.10927,
-0.12788 and -0.00574 a.u, respectively. From the FMO
values, some global reactivity parameters such as absolute
electronegativity (vabs), absolute hardness (g), elec-
trophilicity index (x) and global softness (S) were calcu-
lated using the equations given in the experimental section
4C–15O
1.2826
1.9407
1.2924
2.0194
1.3143
2.0627
1.8990
1.2826
1.3316
1.3425
13N–4C–15O
119.019
113.557
118.236
115.454
117.783
116.998
91.424
15O–45Cu
16C–18N
18N–45Cu
28N–29C
28N–45Cu
44O–45Cu
36C–44O
1C–14N
14N–1C–16C
16C–18N–19C
19C–22C–25C
25C–28N–29C
30C–29C–34C
15O–45Cu–44O
15O–45Cu–18N
44O–45Cu–28N
44O–45Cu–18N
92.122
90.031
4C–13N
90.132
[Zn(L)]
4C–15O
1.2887
1.9466
13N–4C–15O
14N–1C–16C
118.906
112.327
15O–45Zn
123

Studies on some metal complexes of a quinoxaline based unsymmetrical ONNO donor ligand
Fig. 13 Optimized structure of a L, b [Co(L)], c [Ni(L)], d [Cu(L)] and e [Zn(L)] complexes
Table 7 Frontier molecular orbital parameters, absolute electronegativity (vabs), absolute hardness (g), chemical potential (l), electrophilicity
index (x), global and softness (S) values of L and its metal(II) complexes
Parameters/eV
L
[Co(L)]
[Ni(L)]
[Cu(L)]
[Zn(L)]
[HOMO - 1]
-0.23527
-0.23364
0.00191
0.00622
-0.23555
-0.24149
0.1158
-0.19511
-0.19568
-0.08364
-0.08184
-0.11204
-0.11327
0.1396
-0.20503
-0.19386
-0.08459
-0.06679
-0.10927
-0.13824
0.1392
-0.09255
-0.22229
-0.09441
-0.09206
-0.12788
-0.00049
0.1583
-0.22465
-0.10600
-0.10026
-0.01207
-0.00574
-0.21258
0.1031
HOMO
LUMO
[LUMO ? 1]
[HOMO–LUMO]
{[HOMO - 1] - [LUMO ? 1]}
vabs
l
-0.1158
0.1177
-0.1396
0.0560
-0.1392
0.0546
-0.1583
0.0639
-0.1031
0.0028
g
x
S
0.0569
0.1740
0.1773
0.1960
1.8529
4.2453
8.9253
9.1516
7.8198
174.2160
and are given in Table 7. The molecules having a large
energy gap are known as hard molecules, and molecules
having a small energy gap are known as soft molecules.
The soft molecules are more polarizable than the hard ones
because they need small energy for excitation [51]. The
calculated absolute hardness values suggest that L and its
metal complexes are moderately hard materials. The higher
biological activities of the metal compounds are ascribed to
their low hardness values.
charges. The carbon atoms C(6), C(7), C(8), C(9), C(10),
C(20), C(23), C(26), C(31), C(36), C(38), C(40) and C(41)
hold negative Mulliken and atomic charges. The carbon
atom C(35) display positive Mulliken and negative natural
atomic charges. The atomic charge analysis results of
L and its complexes are given in Table S2-S6. Atomic
charge analyses of metal complexes reveal that all the
metal complexes show more or less comparable charge
distributions. Mulliken and negative natural atomic charge
analyses show that all the metal ions and hydrogen atoms
have positive and all oxygen and nitrogen atoms have
negative charges. In [Co(L)], [Ni(L)], [Cu(L)] and [Zn(L)]
complexes, the carbon atoms C(6), C(7), C(8), C(9), C(19),
C(22), C(25), C(30), C(35), C(37), C(39) and C(40) display
negative Mulliken and natural atomic charges. In the
Co(II), Ni(II) and Cu(II) complexes, the C(34) atom bears
positive Mulliken and negative natural atomic charges. In
Atomic charge analysis The Mulliken and natural atomic
charge distributions in L and its [Co(L)], [Ni(L)], [Cu(L)]
and [Zn(L)] complexes were analyzed by B3LYP/6-
31G(d,p) and B3LYP/LANL2DZ basis sets, respectively.
All the nitrogen and oxygen atoms in L have negative
atomic charges in both Mulliken and natural atomic charge
analyses, while all hydrogen atoms possess positive
123

C. J. Dhanaraj, J. Johnson
Table 8 Calculated dipole moment (lo), polarizability (|ao|), anisotropy of polarizability (Dao), first hyperpolarizability (bo) and its components
using B3LYP/6-31G(d,p) basis set for L and B3LYP/LANL2DZ basis set for the metal(II) complexes of L
Parameter
L
[Co(L)]
[Ni(L)]
[Cu(L)]
[Zn(L)]
Dipole moment
lx
-2.6827
3.7182
2.8288
5.3874
-4.0641
-4.1075
-3.6155
1.8039
ly
-5.5994
0.6463
6.9490
-5.1994
0.2980
6.6328
6.3138
-1.1121
7.3602
6.5642
1.1632
6.9062
lz
lo
Polarizability
axx
-99.0691
-148.4995
-147.9733
19.5397
-130.7546
-138.2736
-167.3948
21.5592
-128.8761
-137.4350
-167.3509
21.4229
-134.4598
-142.5087
-164.0784
21.7877
-140.0679
-145.3055
-159.9372
21.9983
ayy
azz
|ao|
Dao
49.1694
33.5192
34.9894
26.5263
17.8369
Hyperpolarizability
bxxx
bxxy
bxyy
byyy
bxxz
bxyz
byyz
bxzz
byzz
bzzz
bo
-5.8808
21.7011
35.6816
2.7223
-19.4816
17.6789
-37.6196
-54.8577
32.4690
15.5444
-6.7373
-24.2611
-13.2677
5.1598
-26.4275
17.7719
-39.1918
-54.1846
29.2586
14.7717
-4.9757
-22.7992
-14.5057
4.0714
-25.0613
-2.5880
-42.6021
43.9378
-32.4610
2.3287
-31.3048
-14.4548
37.8918
47.5285
41.8182
14.1279
-15.2494
27.9643
13.9403
-14.0661
0.5151
41.3789
-14.5658
-4.8107
-41.7371
5.9442
8.7606
-22.3641
17.0256
13.5104
0.9311
31.3456
0.6508
0.8690
0.9148
lo in Debye; |ao| and Dao in 10-24 esu; bo in 10-30 esu
[Zn(L)] complex, the C(34) atom possesses negative
charge in both Mulliken and natural atomic charges.
compared with that of urea (bo = 0.37 9 10-30 esu) [52].
This value is compared with that of L and its metal com-
plexes; they show a number of times greater hyperpolar-
izability values than that of urea. From this, we can
conclude that the compounds are better NLO candidates.
Nonlinear optical effects To understand the NLO effects
of L and its metal complexes, the NLO parameters such as
static dipole moment (lo), mean polarizability (|ao|), ani-
sotropy of polarizability (Da) and first hyperpolarizability
(bo) were calculated using the equations given in the
experimental section.
Conclusions
The values calculated using DFT are given in Table 8.
The general ranking of NLO properties of the compounds
is as follows:
The
unsymmetrical
ligand
3-(-(3-(-1-(2-hydrox-
yphenyl)ethylideneamino)propylimino)methyl)quinoxalin-
2(1H)-one (L) and its Co(II), Ni(II), Cu(II) and Zn(II)
complexes have been synthesized and characterized by
spectral and analytical methods. From the studies, follow-
ing conclusions are drawn. The molar conductance values
of the metal complexes are found to be in the range 2.1–8.6
X-1 cm2 mol-1. This shows that the metal complexes of
L are non-electrolytes. FTIR spectral study gave vital
information about the coordination behavior of L. L coor-
dinates with the metal ions through the azomethine and
imine group nitrogen atoms and through the deprotonation
of phenolic oxygen atoms in the o-hydroxyacetophenone
[Zn(L)] [ [Cu(L)] [ [Co(L)] [ [Ni(L)] [ L (based on
|ao| value)
L [ [Ni(L)] [ [Co(L)] [ [Cu(L)] [ [Zn(L)] (based on
Da value)
[Cu(L)] [ [Ni(L)] [ [Co(L)] [ L [ [Zn(L)]) (based on
bo value)
In the meantime, there is no experimental hyperpolar-
izability (bo) values available for the present compounds;
hence, the calculated values of the compounds were
123

Studies on some metal complexes of a quinoxaline based unsymmetrical ONNO donor ligand
4. Parrilha GL, Ferraz KSO, Lessa JA, Oliveira KN, Rodrigues BL,
and quinoxaline moieties. Tetrahedral geometry is pro-
posed for the [Co(L)], [Ni(L)] and [Zn(L)] complexes,
whereas square planar geometry has been assigned for the
[Cu(L)] complex. Thermal analysis reveals that the metal
complexes are thermally more stable than L. The order of
thermal stability is as follows: [Cu(L)] = [Zn(L)] [
[Ni(L)] [ [Co(L)] [ L. From the analytical, spectral and
thermal studies, the following general formula is assigned
to the metal complexes [M(L)].
Ramos JP, Souza-Fagundes EM, Ott I, Beraldo H. Metal com-
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thioredoxin reductase and glutathione reductase. Eur J Med
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5. Sanghamitra NJ, Phatak P, Das S, Samuelson AG, Somasun-
daram K. Mechanism of cytotoxicity of copper(I) complexes of
1,2-bis(diphenylphosphino)ethane.
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6. Budagumpi S, Kulkarni NV, Kurdekar GS, Sathisha MP,
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pyrazole derivative: a special emphasis on DNA binding and
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Electrochemical studies using cyclic voltammetry show
that the metal(II) complexes are electrochemically active.
From powder XRD analysis, it is concluded that L and its
[Cu(L)] complex are in nanocrystalline phase, while
Co(L), Ni(L) and Zn(L) complexes are amorphous in
nature. Average crystallite size calculated for L and its
Cu(II) complex is 51.20 and 33.74 nm, respectively. The
in vitro biological assays show that the [Cu(L)] complex
has highest antibacterial activity. The order of antibacterial
activity of L and its metal complexes is as follows:
8. Galal SA, Abdelsamie AS, Soliman SM, Mortier J, Wolber G, Ali
MM, Tokuda H, Suzuki N, Lida A, Ramadan RA, El Diwani HI.
Design, synthesis and structure-activity relationship of novel
quinoxaline derivatives as cancer chemopreventive agent by
[Cu(L)] [ L [ [Zn(L)] [ [Co(L)] [ [Ni(L)].
The
inhibition of tyrosine kinase receptor. Eur
2013;69:115–24.
J Med Chem.
[Co(L)] complex exhibits highest antifungal activity. The
DNA binding affinity of L and its metal(II) complexes
follows the order [Zn(L)] [ L [ [Cu(L)] [ [Ni(L)] [ [-
Co(L)]. DNA cleavage study suggests that the DNA
cleavage process occurs through oxidative cleavage
mechanism. The in vitro antioxidant studies reveal that the
[Zn(L)] and [Ni(L)] complexes possess highest superoxide
anion and hydrogen peroxide scavenging activities,
respectively. In anticancer study, the [Cu(L)] complex has
lowest IC50 value (40.39 lM) and is highly active.
Molecular docking studies are in accordance with the DNA
binding and MTT assay results. DFT studies indicate that
L and its metal(II) complexes are good NLO material
candidates.
9. Galal SA, Khairat SHM, Ragab FAF, Abdelsamie AS, Ali MM,
Soliman SM, Mortier J, Wolber G, El Diwani HI. Design, syn-
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ones as anti-tumor active agents with inhibition of tyrosine kinase
receptor and studying their cyclooxygenase-2 activity. Eur J Med
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Abbs Fen Reji, Asst. Professor, Department of Chemistry, NMCC,
Marthandam, for DFT studies.
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