DNA/BSA binding interactions and VHPO mimicking potential of vanadium(IV) complexes: Synthesis, structural characterization and DFT studies

Article abstract of DOI:10.1002/aoc.4125

Vanadium(IV) Schiff base complexes (VOL¹-VOL³) were synthesized and characterized by elemental analysis, various spectral methods and single crystal XRD studies. Structural analysis of VOL² reveals that the central vanadium ion in the complex is six coordinate with distorted octahedral geometry. Density functional theory (DFT) and time dependent (TD-DFT) studies were used to understand the electronic transitions observed in the complexes in UV–Vis spectra. The electrochemical behavior of the complexes was investigated in acetonitrile medium exhibit quasi-reversible one electron transfer. The DNA and BSA protein binding interaction of vanadium complexes has been explored by UV–Vis and fluorescence spectral methods and viscosity measurements reveal that the complexes interact with CT-DNA through intercalation mode and follows the order VOL¹?3?2. The complexes exhibit binding interactions with BSA protein. The complexes act as chemical nuclease and cleave DNA in the presence of H₂O₂. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to evaluate the radical scavenging activity demonstrate the antioxidant property of the complexes. The antimicrobial activity was screened for several microorganisms, Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli. The mimicking of vanadium haloperoxidase was investigated by the bromination of the organic substrate phenol red by vanadium complexes in the presence of bromide and H₂O₂.

Full text of DOI:10.1002/aoc.4125

Received: 28 July 2017
DOI: 10.1002/aoc.4125
Revised: 4 September 2017
Accepted: 7 September 2017
F U L L P A P E R
DNA/BSA binding interactions and VHPO mimicking
potential of vanadium(IV) complexes: Synthesis, structural
characterization and DFT studies
M.A. Neelakantan
| Chithiraivel Balakrishnan | V. Selvarani | M. Theetharappan
Chemistry Research Centre, National
Engineering College, K.R. Nagar,
Kovilpatti, 628 503 Thoothukudi District,
Tamil Nadu, India
Vanadium(IV) Schiff base complexes (VOL1‐VOL3) were synthesized and
characterized by elemental analysis, various spectral methods and single crystal
XRD studies. Structural analysis of VOL2 reveals that the central vanadium ion
in the complex is six coordinate with distorted octahedral geometry. Density
functional theory (DFT) and time dependent (TD‐DFT) studies were used to
understand the electronic transitions observed in the complexes in UV–Vis
spectra. The electrochemical behavior of the complexes was investigated in
acetonitrile medium exhibit quasi‐reversible one electron transfer. The DNA
and BSA protein binding interaction of vanadium complexes has been
explored by UV–Vis and fluorescence spectral methods and viscosity mea-
surements reveal that the complexes interact with CT‐DNA through interca-
lation mode and follows the order VOL1 < VOL3 < VOL2. The complexes
exhibit binding interactions with BSA protein. The complexes act as chemical
nuclease and cleave DNA in the presence of H2O2. The 2,2‐diphenyl‐1‐
picrylhydrazyl (DPPH) assay was used to evaluate the radical scavenging
activity demonstrate the antioxidant property of the complexes. The antimi-
crobial activity was screened for several microorganisms, Staphylococcus
aureus, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli. The mim-
icking of vanadium haloperoxidase was investigated by the bromination of
the organic substrate phenol red by vanadium complexes in the presence of
bromide and H2O2.
Correspondence
Neelakantan Mallanpillai
Ananthakrishnan Nair, Chemistry
Research Centre, National Engineering
College, K.R. Nagar, Kovilpatti 628 503,
Thoothukudi District, Tamil Nadu, India.
Email: drmaneelakantan@gmail.com;
maneels@rediffmail.com
Funding information
Science and Engineering Research Board
(SERB), Department of Science and Tech-
nology, India, Grant/Award Number:
EMR‐II/2014/000081
KEYWORDS
vanadium(IV) complexes, DNA binding and cleavage, oxidative bromination of phenol red, Schiff bases
1 | INTRODUCTION
electrostatic.[2] Schiff base metal complexes containing
planar aromatic groups exhibit DNA interactions via
Metal complexes due to their tunable geometry, intense
metal to ligand charge transfer bands, versatile redox
and propensity for binding to biomolecules are useful
probes for studying the drug‐DNA interactions.[1] Metal
complexes interact with DNA through non‐covalent
interactions (intercalation and groove‐binding) or/and
intercalative mode and have potential antiproliferative
abilities.[3] The primary intracellular target for drugs is
DNA base pairs, which can damage the cells and prevent
the replication, resulting in cell death.[4] Thus, the DNA‐
metal complex interaction studies are important for the
design and development of novel drugs in medicine
Appl Organometal Chem. 2017;e4125.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
1 of 16
https://doi.org/10.1002/aoc.4125

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NEELAKANTAN ET AL.
without any side effects.[5] Metal complexes are capable of
acting as artificial nucleases and cleave DNA, thus leads
to develop new chemotherapeutic agents.
III CHNOS elemental analyzer. Conductance measure-
ments were performed using
a
Metrohm 712
conductometer. Magnetic measurements were made
on powdered samples at 25 °C using Guoy balance.
FT‐IR spectra were recorded on Shimadzu 8400 IR
Spectrophotometer using KBr pellets. UV–Visible spec-
tra of the compounds were recorded on Shimadzu
2450 UV–Vis spectrophotometer. Fluorescence spectra
were performed on Jasco FP‐8300 fluorescence Spectro-
Vanadium in the form of Na+H2VO4 is the second‐
−
most abundant transition metal in seawater.[6] It is an
essential trace element for some living organisms and
possibly essential for normal human health. In vivo, vana-
dium acts as metal cation or as phosphate analogue
depending upon the oxidation state of the metal.[7] In pro-
tein, DNA and RNA vanadium ions play a role as counter
ions.[2,8] Vanadium dependent haloperoxidase enzymes
have been identified in marine algae,[9] lichens[10] and
fungi.[11] In algal bromoperoxidase and in certain pro-
karyotic nitrogenases, vanadium acts as a cofactor. Vana-
dium haloperoxidase catalyzes many organic compounds
by oxidative halogenation in the presence of halide ions
and hydrogen peroxide.[12] Biosynthesis of many natural
products is catalyzed by vanadium bromoperoxidase.[13]
The presence of vanadium in vanadium haloperoxidase,
and the insulin‐mimic activity,[14] and potential antican-
cer activity[14] of some vanadium complexes created inter-
est towards the studies on coordination chemistry of
vanadium. In vanadium haloperoxidase enzyme the histi-
dine component is covalently bonded to a vanadate moi-
ety.[15] Thus the development of vanadium complexes
containing oxygen and nitrogen ligation sites is
important.[16]
fluorometer.
Cyclic
voltammetry
studies
were
performing using CHI620E spectroelectrochemical
workstation. The working electrode was glassy carbon;
platinum wire was used as the auxiliary electrode,
Ag/AgCl as reference electrode. Electrochemical experi-
ments were done at room temperature using buffer
solution of vanadium complexes with 5% DMSO con-
taining tetrabutylammonium perchlorate (TBAP) as
the supporting electrolyte.
2.2 | Synthesis of vanadium Schiff base
complexes
Synthesis of Schiff bases (L1‐L3) are reported in our pre-
vious paper.[3] The Schiff base vanadium complexes
(VOL1‐VOL3) were synthesized by addition of methano-
lic solution of respective Schiff bases (L1‐L3) (10 mmol)
with aqueous solution of vanadium sulfate (10 mmol)
followed by Et3N (20 mmol) solution. The reaction mix-
ture was refluxed for 5 h and the obtained green precip-
itate was filtered and washed with ethanol (Scheme 1).
After that this dried compound was dissolved in DMSO
and layered by methanol for crystallization. Dark green
color block shaped crystal of VOL2 was obtained after
one week time.
The hydroxyl‐substituted Schiff bases have drawn
considerable attention owing to their effective coordi-
nation with metal ions and their pharmacological
properties.[17–20] The propargyl group containing com-
pounds play a significant role in neuroprotection and
having exclusive inhibitory properties towards the fla-
vin‐linked oxidases.[21] In view of all these facts, we
synthesized
three
vanadium(IV)
Schiff
base
complexesand characterized by various spectral methods
and single crystal XRD analysis. The DNA binding and
cleavage activities of the complexes were studied by dif-
ferent spectral techniques. The antioxidant and antimi-
crobial activities of metal complexes were also
investigated. The catalytic potential of these complexes
were evaluated by the oxidative bromination of phenol
red to bromophenol blue.
VOL1: Yield: 82%. M.p.: 240 °C. Anal. Calc. for
C23H20N2O5V: C, 60.67; H, 4.43; N, 6.15; Found: C,
60.35; H, 4.85; N, 6.35 (%). FT‐IR (KBr disk, cm−1
)
(Selected bands): 2108 terminal υ(C ≡ CH), 1596
υ(C = N), 879 υ(V = O). UV–Vis (λmax/nm): 459, 575. μeff:
−1
1.73 B.M. Λm (Ω
mol−1 cm2): 8.9
VOL2: Yield: 85%. M.p.: 271 °C. Anal. Calc. for
C23H20N2O5V: C, 60.67; H, 4.43; N, 6.15; Found: C,
60.42; H, 4.67; N, 6.13.26 (%). FT‐IR (KBr disk, cm−1
)
(Selected bands): 2103 terminal υ(C ≡ CH), 1599
2 | EXPERIMENTAL
υ(CH = N), 904 υ(V = O). UV–Vis (λmax/nm): 454,
−1
570.μeff: 1.78 B.M. Λm (Ω
mol−1 cm2): 10.7
2.1 | Materials and methods
VOL3: Yield: 84%. M.p.: 269 °C. Anal. Calc. for
C22H18N2O5V: C, 59.87; H, 4.11; N, 6.35; Found: C,
2,4‐dihydroxybenzaldehyde,
3‐bromopropyne,
1,2‐
diaminopropane, 1,3‐diaminopropane, ethylenediamine,
vanadyl sulphate, potassium iodide, potassium bicar-
bonate and triethylamine were procured from Aldrich.
Microanalyses were done with an Elemental Vario EL
59.86; H, 4.10; N, 6.33 (%). FT‐IR (KBr disk, cm−1
)
(Selected bands): 2106 terminal υ(C ≡ CH), 1601
υ(CH = N), 896 υ(V = O). UV–Vis (λmax/nm): 416,
−1
583.μeff: 1.75 B.M. Λm (Ω
mol−1 cm2): 7.1

NEELAKANTAN ET AL.
3 of 16
CH3
N
NH2
CH3
N
NH2
N
N
O
VOSO4
Et3N
Propane-1,2-diamine
Methanol
V
OH HO
O
O
Methanol
O
O
O
O
O
O
L1
VOL1
H
N
N
H2N
NH2
N
O
N
V
VOSO4
Et3N
Propane-1,3-diamine
O
OH HO
O
O
Methanol
Methanol
O
OH
O
O
O
L2
VOL2
A
H2N
NH2
N
N
N
O
N
V
VOSO4
Et3N
Ethane-1,2-diamine
OH HO
O
O
Methanol
Methanol
O
O
O
L3
VOL3
SCHEME 1 Synthesis of Schiff bases (L1‐L3) and vanadium complexes (VOL1‐VOL3)
2.3 | Single crystal XRD analysis
2.5 | Biological studies
X‐ray diffraction details of vanadium complex (VOL2)
were collected on a Bruker SMART APEX II diffractome-
ter equipped with graphite monochromated (MoKα radia-
tion (λ = 0.71073 Å) at 293(2) K.[22] The structure was
solved by conventional direct methods, as implemented
in SHELXS‐97 program. E‐Map calculated for the best
phase generated by the SHELXS program revealed the
positions of all the non‐hydrogen atoms and these were
refined by a full‐matrix least squares refinement proce-
dure using SHELXL‐97.[23] The positions of all the hydro-
gen atoms were fixed geometrically. The hydrogen atoms
were included in the refinement by allowing them to ride
on the corresponding carrier atoms. The refinement con-
verged to a final R factor of 0.0542.
2.5.1 | Absorption method
DNA binding studies were done in Tris–HCl/NaCl buffer
(5 mMTris–HCl, 50 mM NaCl, pH 7.2) containing 5% ace-
tonitrile. DNA gave the ratio of absorbance at 260 and
280 nm, (260/280 = 1.86), demonstrating that the DNA
was adequately free of protein.[27] The DNA concentra-
tion of per nucleotide was calculated from the absorption
intensity at 260 nm (ε = 6600 M−1 cm−1).[28] The UV–Vis-
ible spectral titrations were performed in buffer using a
fixed concentration of the vanadium complexes (40 μM)
in the range of 200–400 nm to increments of DNA. Vana-
dium complex‐DNA solutions were allowed to incubate
for 1 h before the spectra were recorded. The intrinsic
association constant, Kb was determined by the following
equation,
2.4 | DFT studies
½DNAꢀ
½DNAꢀ
1
À
Á
À
Á
À
Á
¼
þ
The DFT calculations were performed using Gaussian 09
package[24] at B3LYP level.[25] All the elements except
vanadium were assigned the 6‐311G(d,p) basis set.
Lanl2dz basis set with effective core potential was used
for the vanadium atoms.[26] The vibrational frequency cal-
culations were carried out to ensure that the optimized
geometries correspond to the local minima and there are
only positive Eigen values.
εa−εf
εb−εf
Kb εb−εf
where, εa, εf and εb are the extinction coefficient of the
apparent, free and bound metal complex, respectively.
The association constant (Kb) determined from the ratio
of slope to intercept from the plot of [DNA]/(εa – εf) vs.
[DNA].

4 of 16
NEELAKANTAN ET AL.
plot of relative absorbance (A/A30°) vs. temperature,
where A is the observed absorbance and A30 is the absor-
bance at 30 °C.
2.5.2 | Emission method
The binding interaction of metal complex with CT‐DNA
was further evaluated using emission spectral techniques.
The emission intensities of ethidium bromide (EB) bound
DNA was measured at 602 nm with an excitation wave-
length of 580 nm in the absence and presence of vana-
dium complex (0.0–100 μM) in Tris–HCl buffer
(5mMTris–HCl, pH 7.2). The emission intensity of EB
bound DNA was measured, which is used to find out
the binding ability of metal complexes. Using classical
Stern‐Volmer equation,
2.5.5 | Viscosity experiments
Viscosity experiments were carried out using Ostwald
type viscometer at 30.0 0.1 °C in a thermostatic water
bath. DNA (100 μM) were titrated with vanadium com-
plex (0.0‐100 μM), examined the difference in the viscosity
and the flow time was measured with a digital stopwatch.
The specific viscosity values were calculated using the
equation, η = (t–to)/to, where to and t is the total flow time
for the buffer and for DNA in the presence and absence of
the metal complex, respectively. The data are obtainable
as (η – ηο)1/3 vs. binding ratio, where η is viscosity of
DNA in the presence of metal complexes and ηο is viscos-
ity of DNA alone.
F0= F ¼ 1 þ Ksv½Qꢀ ¼ 1 þ Kqτ½Qꢀ
where F0 and F is the emission intensity in the absence
presence of quencher, Ksv is the Stern‐Volmer quenching
constant, Kq is DNA quenching rate constant and τ is
DNA average lifetime without quencher, which is equal
to 10−8 s for bio‐macromolecules,[29] the quenching con-
stant (Ksv) value is obtained as a slope from the plot of
F0/F vs. [Q]. The Kb and n can be calculated from the
equation,[30]
2.6 | Protein binding studies
The protein binding studies of vanadium complexes were
performed by using fluorescence spectral method. The
protein stock solution was prepared in 50 mM phosphate
buffer (pH 7.2) and stored in the dark at 4 °C for further
use. A solution of BSA (1.0 × 10−6 M) was titrated with
different concentrations of vanadium complex (0.0–
50 μM). Fluorescence spectra of the samples were
recorded in the wavelength range of 290–450 nm upon
excitation at 280 nm. Synchronous fluorescence spectra
were also recorded with the same concentration of BSA
and the complex corresponding to the Δλ values (differ-
ence between the excitation and emission wavelengths
of BSA), 15 and 60 nm.
logðF0– FÞ= F ¼ logKb þ nlog½Qꢀ
where Kb is the binding constant and n is the number of
binding sites in DNA base pairs. The plots of
log[(F0 − F)/F] vs. log[Q].
2.5.3 | DNA cleavage experiment
DNA cleavage ability of vanadium complexes (VOL1‐
VOL3) was done using supercoiled (SC) pUC19 DNA in
50 mM Tris–HCl/10 mM NaCl buffer. Stock solutions of
metal complexes were prepared in acetonitrile and the
pH was adjusted to 7–8 by addition of base. The reactions
were carried out incubating DNA (20 μM) at 36 0.1 °C
in the presence/absence of metal complexes (40 μM) for
1 h. After incubation, the reaction mixture was loaded
on 0.8% agarose gel for electrophoresis in TBE buffer
(50 mM Tris base, 25 mM boric acid, 2 mM EDTA) at
100 V for 1 h. Finally the gel was photographed under
UV light by LARK gel documentation system.
2.7 | Antioxidant activity
DPPH assay is used for the measurement of antioxidant
activity of the vanadium complexes. 0.001 M concentra-
tion of the Schiff base (L1‐L3) or VOL1‐VOL3 solution is
added to 0.001 M DPPH. The reaction mixture kept at
room temperature for 30 minutes in dark. The spectro-
photometric measurements were done at 517 nm. For
positive control, ascorbic acid is used. These measure-
ments are run in triplicate. The % of scavenging activity
inhibition is calculated,
2.5.4 | Thermal denaturation study
DNA helix melting studies were employed by using
Shimadzu‐2450 spectrophotometer equipped with digital
temperature controller. The temperature was gradually
increased at a rate of 5 °C min−1 and the absorbance of
CT‐DNA (100 μM) was measured at 260 nm in the
absence/presence of metal complexes (20 μM). The melt-
ing temperature (Tm) values were determined from the
Scavenging activity ð%Þ ¼ ½ðA0–AÞ=A0ꢀ×100
Where A0 is the absorbance of DPPH• without the
vanadium complex and A is the absorbance of DPPH in
the presence of complex. The IC50 value is the concentra-
tion of the antioxidant required to scavenge 50% DPPH•
and is calculated from the inhibition curve.

NEELAKANTAN ET AL.
5 of 16
solution of vanadium sulfate (10 mmol) followed by
Et3N (20 mmol) solution. The reaction mixture was
refluxed for 5 h and the obtained green precipitate was fil-
tered and washed with ethanol (Scheme 1). Crystal of
VOL2 suitable for X‐ray analysis was obtained by dissolv-
ing the complex in DMSO and layered by methanol. Dark
green color block shaped crystal of VOL2 was obtained
after one week time.
2.8 | Antibacterial assay
The microbial activity of the synthesized compounds
against bacterial strains Staphylococcus aureus, Bacillus
subtilis, Pseudomonas aeruginosa, Escherichia coli was
determined by disc diffusion method in Mueller‐Hinton
Agar.[31] The in vitro antibacterial activity was carried out
against 24 h cultures of bacterial strains. Stock solutions
of test compounds (0.001 M) were prepared in 95% aqueous
medium containing 5% DMSO. Sterilized agar media
(20 ml) was poured into each pre‐sterilized Petri dish.
Solidification is allowed by placing the plates in an incuba-
tor at 37 °C for 1 h. 24 h culture suspension was poured and
neatly swabbed with the pre‐sterilized cotton swabs. 5 mm
diameter of paper disk soaked in 20 μL of 0.001 M com-
pounds was placed on the inoculated plates and allowed
to dry for 15 min. These dishes were transferred to an incu-
bator maintained at 37°C for 24 h. The microbial activity
was measured from the diameter of the clear zone
appeared around the papers in each plate. Experiments
were triplicates and standard deviation was calculated.
3.2 | Crystal structure description
The asymmetric unit of brown VOL2 complex consists of
one independent molecule (Figure 1). The compound
crystallizes in monoclinic system with space group P21/
c. The V(IV) center of VOL2 complex is hexacoordinated
and is present in a distorted octahedral VO4N2 coordina-
tion with the basal plane by the Schiff base molecule
through O1, O3, N1, N3 atoms and O6 of the solvent
DMSO molecule. Vanadyl oxygen O5 occupies the axial
position, which forms angle between 94.84(17)° to
105.19(17)° range with the basal plane defined previously.
The crystallographic data and observed intra and intermo-
lecular interactions are given in Table 1 and S1. From the
crystal packing of VOL2, it is clear that C–H…O intermo-
lecular interactions stabilize the metal complex (Figure
S1). Atom C24 acts as a donor to O1i and atom C25 acts
3 | RESULT AND DISCUSSION
3.1 | Synthesis of vanadium Schiff base
complexes
The synthesis of Schiff bases (L1‐L3) were reported in our
earlier work.[3] All the vanadium complexes (VOL1‐VOL3)
were synthesized by adding methanolic solution of
respective Schiff bases (L1‐L3) (10 mmol) to aqueous
as a donor to O3i, generating R2 (8) graph set motif. Both
2
the aromatic rings are planar, with a maximum deviation
of 0.016(3) Å in the ring (C15‐C20). The dihedral angle
between the aromatic rings is 53.46(2)°. The sum of bond
FIGURE 1 ORTEP view of VOL2 (50% probability level)

6 of 16
NEELAKANTAN ET AL.
angles around atoms C7 (360.0(3)°) and C15 (359.0(3)°) of
aromatic ring in the molecule is in accordance with sp2
hybridization. The bond lengths of N(1)‐V(1), N(2)‐V(1),
phenoxy O(1)–V(1), and O(3)–V(1) are 2.093(3) Å,
2.098(3) Å, 1.951(2) Å and 1.963(2) Å, respectively. The
bond angles O(1)–V(1)–O(3), O(1)–V(1)–N(1) and N(1)–
V(1)–N(2) are 86.51(9), 88.19(10) and 92.62(11), respec-
tively. The apical position is occupied by the oxo ligand.
The terminal V–Ooxo bond distance of 1.605(2) Å and
the vanadium displaced from mean plane of the four
N2O2 is approximately 0.22 Å, which is a value character-
istic of six‐rather than five‐coordination. The solvent
dimethyl sulfoxide group shows an extended conforma-
tion values of [V1–O6–S1–C24] is +125.7(2)° and [V1–
O6–S1–C25] is −130.6(2)°] positive anti‐clinal and nega-
tive anti‐clinal conformation. The bond length and bond
angle distances well harmonize with the corresponding
values reported for the related systems (Table S2).[32] In
addition, the bond valence sum (BVS) calculated for the
V center in VOL1 (3.66), VOL2 (3.74) and VOL3 (3.68)
clearly suggest an oxidation state of +4 for vanadium in
these compounds (Table S3).
3.3 | FT‐IR spectra
The free Schiff bases exhibit a broad band between 3450
and 3200 cm−1 with a maximum at 3406 and 3385 cm−1
is attributed to the phenolic hydroxyl ν(O–H) frequency
with O–H···N intramolecular hydrogen bonding. This
bond is absent in the vanadium complexes indicating that
the hydroxyl oxygen atom is coordinated to vanadium
with deprotonation (Figure S2). On the other hand, the
phenolic oxygen ν(C‐O), which occurs in the region
1301–1307 cm−1 for the Schiff bases, moved to higher fre-
quencies after complexation (Table S4). The azomethine
stretching frequency of the free ligands appeared in the
range of 1625–1631 cm−1 has been shifted to lower fre-
quencies in metal complexes suggest that azomethine
nitrogen is coordinated to the vanadium ions. The high
intensity sharp band observed in the region of 879–
TABLE 1 Crystallographic parameters for VOL2 complex
Parameters
VOL2
Empirical formula
C25 H26N2O6 SV
Formula weight
533.48
Temperature (K)
293 (2)
Wavelength (Å)
0.71073
Crystal system, Space group
Unit cell dimensions
Monoclinic, P21/c
a = 16.0613(9) Å
b = 7.6951(3) Å
c = 22.1374(11) Å
α = 90°
β = 112.226(2)°
γ = 90°
Volume (Å3)
2532.7(2)
4, 1.399
Z, Dcal (Mgm−3
)
Absorption coefficient (mm−1
)
0.516
F(000)
1108
Crystal size (mm)
0.25 × 0.23 × 0.20
1.94 to 28.32
Theta range for data collection (°)
Limiting indices
18 < =h < =21, −10 < =k < =10, −29 < =l < =27
Reflections collected / unique
R (int)
24510 / 6284
0.0782
Completeness θ = 25°
Refinement method
99.9%
Full‐matrix least‐squares on F2
Data / restraints / parameters
Goodness‐of‐fit on F2
6284 / 0 / 316
1.015
Final R indices [I > 2σ(I)]
R1 = 0.0542, wR2 = 0.1338
R1 = 0.1079, wR2 = 0.1600
0.416 and −0.479
R indices (all data)
Largest diff. peak and hole (e.Å‐3)

NEELAKANTAN ET AL.
7 of 16
904 cm−1 is attributed to the V = O vibrations indicating
the monomeric nature of the vanadium complex with no
intermolecular interaction with participation of the
V = O moiety in the solid state. The single crystal XRD
studies also confirm this nature of binding.
carried out. All the vanadium complexes show a high
energy absorption band in the range 285–403 nm can be
attributed to the LMCT or MLCT charge transfer transi-
tions. The spectra show one lowest energy absorption
band in the range 542–579 nm can be attributed to the
d‐d transitions,[33] (Table S5). The calculated values agree
well with the experimental values. The FMO diagram and
calculated absorption spectra of all the vanadium com-
plexes were given in Figures S4 and S5.
3.4 | Electronic absorption spectra and
magnetic moment
The absorption spectra of VOL1‐VOL3 were recorded in
acetonitrile at room temperature (Figure S3) and the band
assignments are given in Table 2. The Schiff bases show
two strong bands appear in the region 275–304 nm for
para substituted benzene compound and third band in
the region 385–387 nm for π‐π* transition of azomethine
group. The complexes show a strong band observed
around 454–459 nm is due to the enolate oxygen to
vanadium(IV) transition. The low intensity d‐d band
around 570–583 nm is due to the ligand field transition
dxz, dyz, to dxy of the VO2+ center. The calculated mag-
netic moment values of vanadium complexes are in the
range of 1.73–1.78BM at room temperature are consistent
with the spin only value corresponds to the paramagnetic
nature of mononuclear complexes in d1 system.[33]
3.5 | EPR spectra
The VOL1‐VOL3 exhibit well resolved axial anisotropy
with eight line hyperfine splitting pattern in acetonitrile
medium at 77 K (Figures 2 and S6). This is due to the
unpaired electron of the 51V nucleus (I = 7/2) and indi-
cates the presence of mononuclear oxovanadium(IV) spe-
cies. The spin Hamiltonian parameters and the hyperfine
coupling constants calculated, g║ < g┴ and A║ > A┴[g║
(1.96–1.97) and g┴ 2.03] suggest that the metal complex
has an axially compressed octahedral geometry around
the V(IV) center with an unpaired electron in the dxy
orbital. The calculated G values are in the range of 4.1–
6.8 demonstrates that the exchange interaction between
the vanadium ions is negligible. The molecular orbital
coefficients σ bonding (α2) and π bonding (β2) were
In order to get more information on the nature of tran-
sitions in electronic absorption spectra of VOL1‐VOL3,
TD‐DFT calculations using B3LYP/6‐311G(d,p) level were
TABLE 2 Electronic absorption spectral data of vanadium complexes in acetonitrile
Complex
VOL1
λmax (nm)
Assignments
Geometry
μeff (BM)
2
459
575
2B2 → B1
Distorted octahedral
1.73
2
2B2 → E
2
VOL2
VOL3
454
570
2B2 → B1
Distorted octahedral
Distorted octahedral
1.78
1.73
2
2B2 → E
2
416
583
2B2 → B1
2
2B2 → E
FIGURE 2 EPR spectrum of VOL1 at
77 K in acetonitrile

8 of 16
NEELAKANTAN ET AL.
calculated. The calculated values suggest that in‐plane
bonding (σ) is more covalent than out of plane bonding
(π) (Table 3).
All the three complexes exhibit similar voltammograms
in the negative region (0.0 to −1.0 V) containing an oxida-
tion and corresponding reduction process with one elec-
tron transfer (Figure S7). The VOL1‐VOL3 shows a
quasi‐reversible single electron wave at the potential
range of ~ − 0.621 V, which is assigned to the reduction
of V(IV) to V(III). The corresponding oxidation process
occurs in the potential of ~ − 0.48 V.[34]
3.6 | Electrochemistry
The electrochemical property of VOL1‐VOL3 in acetoni-
trile was studied by recording the cyclic voltammograms.
TABLE 3 Spin Hamiltonian parameters of vanadium complexes in acetonitrile
All
A┴
Aav
g∐
A∐
Complex
VOL1
×10−4
gII
g⊥
gav
G
KII
K⊥
α2
β2
γ2
165
77
81
79
106
108
112
1.92
2.02
1.98
4.6
116
120
109
0.31
0.38
0.53
0.58
0.72
VOL2
VOL3
161
178
1.93
1.95
2.02
2.01
1.99
1.99
4.1
6.8
0.40
0.44
0.47
0.47
0.61
0.64
0.65
0.68
0.75
0.73
(a)
(b)
(c)
(d)
FIGURE 3 Absorption spectra of (a) VOL1; (b) VOL2 and (c) VOL3 (40 μM) with increasing amount of CT‐DNA; (d) plot of [DNA]/(εa – εf)
vs [DNA] for VOL1‐VOL3 with CT‐DNA

NEELAKANTAN ET AL.
9 of 16
and bathochromic shift in wavelength. The electronic
absorption study was carried out by maintaining the con-
centration of vanadium complex constant (40 μM) and
varying the concentration of CT‐DNA (0.0‐100 μM). Upon
the incremental addition of CT‐DNA with VOL1‐VOL3,
the absorption intensity was gradually decreased
(hypochromism) in the region of 260–305 nm by 25%,
22% and 16% respectively along with a bathochromic shift
of 2–5 nm (Figure 3). This may be due to the interaction
between aromatic chromophore in the vanadium complex
and base pairs of DNA.[35] The observed results suggest
that all the VOL1‐VOL3 were bound to CT‐DNA through
intercalative mode[36] and follows the order
VOL1 < VOL3 < VOL2. In general, the flat‐electron rich
aromatic compounds strongly interact with DNA base
pairs. The complex, VOL1 and VOL3 are formed with
3.7 | DNA binding study
3.7.1 | Absorption spectral study
Electronic absorption spectral titration method was
employed to find out the binding interaction of VOL1‐
VOL3 with DNA. Metal complexes bind to DNA by inter-
calation are distinguished by the change in absorbance
TABLE 4 DNA association constant (Kb), Stern‐Volmer constant
(Kq) and apparent binding constant (Kapp) for VOL1‐VOL3
Kb
Kq
Kapp
Complexes
(M−1)× 105 (M−1) × 105
n
(M−1) × 106
VOL1
3.66
5.19
4.01
2.24
3.21
2.58
3.4
4.96
4.42
4.71
VOL2
VOL3
4.9
4.1
(a)
(b)
(c)
(d)
FIGURE 4 Emission quenching curves of EB bound to CT‐DNA in the presence of, (a) VOL1; (b) VOL2 and (c) VOL3 (0.0–100 μM) in Tris–
HCl buffer. (d) Stern‐Volmer plot of VOL1‐VOL3 with CT‐DNA

10 of 16
NEELAKANTAN ET AL.
five‐membered chelate rings, but the complex VOL2 has
six‐membered chelate rings. The complex VOL2 with six‐
membered chelate rings easily and strongly interact with
DNA base pairs and has higher DNA binding affinity
value than the VOL1 and VOL3. The presence of methyl
group in L1 may be the reason for the difference in bind-
ing ability of VOL1 and VOL3 with DNA. The intrinsic
binding constants (Kb) values are listed in Table 4 and
are compared with similar type of compounds (Table
S6). From the results, it is clear that the complexes inter-
act with DNA through intercalation and show similar
binding affinity towards DNA.
metal complex and DNA, whereas the low melting tem-
perature value (1–3 °C) point out a non‐intercalative bind-
ing mode.[40] The helix melting curves of DNA (200 μM)
in the absence and presence of complexes (VOL1‐VOL3)
(20 μM) are depicted in Figure 5a. The observed ΔTm
values demonstrate that all the vanadium complexes bind
to DNA via intercalation mode.
3.7.4 | Viscosity studies
To understand the binding interaction between the vana-
dium complex and DNA, viscosity studies were done on
CT‐DNA by the addition of different concentration of
VOL1‐VOL3. Generally, optical and photophysical studies
givethe clues about the binding, that are essential, but
not enough to predict the binding mode between DNA
3.7.2 | Fluorescence quenching study
The binding affinity of VOL1‐VOL3 with DNA was further
examined using fluorescence quenching experiments,
based on the dislocation of ethidium bromide (EB) from
CT‐DNA base pairs. The groove binders and intercalators
can decrease the fluorescence intensity of EB‐DNA adduct
by replacing the EB and/or by tolerant the excited state elec-
tron of EB via photo‐electron transfer mechanism.[37] The
EB molecule has very weak emission intensity in Tris‐HCl
buffer. But the emission intensity of EB is significantly
increased due to the intercalation into the double helical
structure of DNA base pairs. After the additions of VOL1‐
VOL3 to EB‐DNA, the emission intensity of EB‐DNA
adduct was significantly decreased of ca. 36%, 43% and
40%, respectively. The observed results suggest that all the
vanadium complexes competitively bind to DNA
(Figure 4). The calculated quenching constant values and
number of binding sites (Kq = 3.21 × 105; n = 4.9) suggest
that the quenching efficiency of VOL2 complex is higher
than the VOL1 (Kq = 2.24 × 105; n = 3.4) and VOL3 (Kq = 2
.58 × 105; n = 4.1) complexes, which is agreement with the
electronicabsorptiontitrationsdata.Inaddition,theapprent
binding constant (Kapp) value of complexes were calculated
using the equation, KEB[EB] = Kapp[compound], where
[EB], KEB = 1.0 × 107 M−1 is the complex concentration
has the value at 50% reduction ofthe emission intensity
and [EB] = 2.5 μM (Table 4). The quenching and bind-
ing constant values indicate that all the VOL1‐VOL3
interact with CT‐DNA via intercalation mode.[38]
(a)
3.7.3 | DNA melting study
DNA helix melting studies were carried out to predict the
binding character of complexes to DNA and their relative
binding strength.[39] The melting temperature represents
the breaking of hydrogen bonds between the double
stranded DNA base pairs to form the single stranded
DNA. The high melting temperature (ΔTm) value is sug-
gestive of an intercalative binding mode between the
(b)
FIGURE 5 (a) Thermal melting profiles of CT‐DNA with VOL1‐
VOL3 and (b) effects of increasing concentrations of VOL1‐VOL3
on the relative viscosities of CT‐DNA

NEELAKANTAN ET AL.
11 of 16
and metal complexes. The viscosity measurements are
used to predict the binding model in solution. When a
metal complex interacts with DNA through classical
intercalation binding mode results lengthening of DNA
helix and break the hydrogen bond between the base
pairs, which leads to an increase in DNA viscosity. The
partial and/or non‐classical intercalation of complex
results bend or kink the DNA helix leads to decrease of
the viscosity of DNA.[41] Upon the incrimental addtition
of VOL1‐VOL3, the relative viscosity of CT‐DNA was sig-
nificantly increased and the obtained results suggest that
the complexes are inserted between the DNA bases
FIGURE 6 (a) Electronic absorption spectra of BSA protein with VOL1‐VOL3; (b‐d) emission quenching spectra of BSA in the presence of
increasing amounts of (b) VOL1; (c) VOL2 and (d) VOL3. [BSA] = 1 μM and [complex] = 0–50 μM; (e) stern‐Volmer plot for VOL1‐VOL3 with
BSA protein; (f) Scatchard plot for VOL1‐VOL3 with BSA protein

12 of 16
NEELAKANTAN ET AL.
(Figure 5b) through intercalation and the binding
between the vanadium complex and CT‐DNA follows
the order VOL1 < VOL3 < VOL2.
with protein and n is the number of binding sites. The
binding constant (Kb) values and the number of binding
sites (n) were calculated from the plot of log[(F0 − F)/F]
versus log[Q] (Figure 6f). The observed results clearly
indicate that the vanadium complexes have only one
binding site is existing to interact with protein molecules
(Table 5).
3.8 | Protein binding studies
The absorption spectra of protein (BSA) with VOL1‐VOL3
were carried out to predict the type of quenching process.
Addition of vanadium complexes to BSA protein, the
absorption band at 281 nm is increased without any shift
(Figure 6a). The observed results suggest that the binding
of vanadium complexes with BSA protein through static
quenching process.[36] The structural changes of BSA pro-
tein upon the addition of vanadium complexes were stud-
ied by fluorescence spectral method (excitation at 281 nm)
3.9 | Synchronous emission spectra
To get information about the molecular microenviron-
ment of the protein, synchronous emission spectra of pro-
tein in the absence and presence of vanadium complexes
were studied. The protein containing amino acids (tyro-
sine, tryptophan and phenylalanine) is responsible for
the fluorescence property of BSA protein. The excitation
and emission wavelengths (Δλ = λem − λex) reflect the
nature of the chromophore.[44,45] The small Δλ value
(15 nm) is due to the tyrosine residue, whereas a large
Δλ value (60 nm) is characteristic of tryptophan resi-
due.[46] Upon the addition of vanadium complexes, the
emission intensity of tryptophan and tyrosine residue
was decreased at 302 nm and 342 nm, respectively (Fig-
ures S8 and S9). The observed results indicate that the
interaction of vanadium complexes with BSA protein pro-
voked micro‐environmental and conformational changes
in the BSA protein.[47]
in the wavelength range of 290–450 nm. A 1.0 × 10−6
M
solution of protein was titrated with different concentra-
tions of vanadium complexes (0.0–50 μM). Upon the addi-
tion of vanadium complex, the emission intensity at
340 nm is gradually decreased due to the interaction of
the complex hydrophobically with the BSA protein
(Figure 6b‐d).[42] The fluorescence quenching was
explained by Stern‐Volmer relation,
F0= F ¼ 1 þ Ksv½Qꢀ
Where F0 and F are the emission intensities of absence
and presence of vanadium complexes. Ksv is linear Stern‐
Volmer quenching constant and [Q] is the concentration
of complexes. The Ksv can be calculated using the plot of
(F0/F) versus log [Q] (Figure 6e). The small molecules
bind in parallel to a set of equivalent site on a macromol-
ecule and the equilibrium between free and bound mole-
cules is established by Scatchard equation,[43]
3.10 | Chemical nuclease activity
DNA cleavage ability of VOL1‐VOL3 was evaluated
with pUC19DNA. In general, metal complexes cleave
pUC19DNA with or without any external agents, and
as a result supercoiled form (Form I) of DNA relaxed
to open circular nicked form (Form II). Usually, Form
I migrates faster than the Form II on electrophoresis
and further cleaved to generate a linear form (Form
III), which migrates between the Form I and Form
II.[48] In the absence of vanadium complexes, no dis-
tinct cleavage pattern was observed in the DNA (lane
1). In the absence of external agents such as H2O2,
the vanadium complexes were not able to cleave the
DNA (Lane: 2–4). But in the presence of H2O2, all
the complexes cleave the DNA and transform the
supercoiled form of DNA (Form I) into open circular
log½ðF0− FÞ=Iꢀ ¼ log Kb þ n log½Qꢀ
where Kb is the binding constant of vanadium complexes
TABLE 5 BSA protein binding constant (Kb), quenching constant
(Kq) and number of binding sites (n) for VOL1‐VOL3
Complex
Kb (M−1) × 106
Ksv (M−1) × 105
n
VOL1
3.95
3.54
1.08
VOL2
VOL3
4.22
4.03
3.78
3.66
1.02
0.98
(II)
(I)
1
2
3
4
5
6
7
FIGURE 7 DNA cleavage activity of VOL1‐VOL3, lane 1: Control; lane 2: DNA + VOL1; lane 3: DNA + VOL2; lane 4: DNA + VOL3; lane 5;
DNA + VOL1 + H2O2; lane 6: DNA + VOL2 + H2O2; lane 7: DNA + VOL3+ H2O2

NEELAKANTAN ET AL.
13 of 16
nicked form (Form II, Lane: 5–7) (Figure 7). The
observed results suggest that all the vanadium com-
plexes can efficiently cleave the plasmid DNA in the
presence of H2O2. This suggests that the DNA cleavage
intervened by vanadium complexes should adopt an
oxidative mechanism.
In oxidative DNA cleavage, the transition‐metal‐
mediated hydroxyl radical production occurs through
two well‐known pathways such as Fenton and Haber‐
Weiss mechanism. The Haber‐Weiss reaction is the
most feasible mechanism for the DNA cleavage induced
by the metal complexes. Haber‐Weiss reaction involves
the reaction of superoxide with H2O2 to produce O2,
hydroxide and OH•. The probable mechanism of DNA
damage induced by metal complexes is follows,
3.12 | Antibacterial activity
The Schiff bases and their vanadium(IV) complexes
(VOL1‐VOL3) were screened for their in vitro antimicro-
bial activities against gram positive Staphylococcus aureus
and Bacillus subtilis bacteria and gram negative
Pseudomonas aeruginosa and Escherichia coli bacteria to
assess their potential antimicrobial activity. The zone of
inhibition of the vanadium complexes were compared
with the Schiff bases (L1‐L3) and the control, ampicillin
(Figure S11). Comparative antibacterial studies show that
the inhibition order follows: Ampicillin > vanadium
complex > Schiff bases (Table S8). The antibacterial activ-
ity increases with increasing the concentrations of the
compounds, but they are still lower than that of the con-
trol. The antibacterial activity of vanadium complexes
may be due to the contact antibacterial mechanism or
the stripping antibacterial mechanism or the both. In
the contact antibacterial mechanism, the vanadium metal
quickly attaches with the –SH of pheron in the bacterial
body terminates the metabolism process due to the loss
of action of enzyme of the organism and killed the bacte-
ria. In the stripping antibacterial mechanism, the antibac-
terial ions stripping from the antibacterial material react
with the protein deactivates the enzymes of the organism,
which results in termination of metabolism process and
death of the bacteria.
VO2þ þ e–→VO2
þ
VO2þ þ O2→VO2þ þ O2 •
–
O2 • þ H2O2→O2 þ OH• þ OH–
–
The generation of OH• radical, superoxide anion and
hydrogen peroxide are responsible for the cleavage of
DNA by complexes. The abstraction of H atom by the
reactive OH• radical from deoxyribose sugar may be the
reason for the cleavage of pUC19 DNA. The results sug-
gest that the oxidative process is involved in the DNA
cleavage reaction.[49]
3.13 | Bio‐mimicking catalytic
Bromination reaction (phenol red to
bromophenol blue)
Vanadium dependent haloperoxidase catalyzes many
organic compounds by oxidative halogenation in the pres-
ence of halide ions and hydrogen peroxide. Several
oxovanadium complexes catalyze the bromination of
organic substrates in the presence of bromide ions and
H2O2 and mimic the vanadium haloperoxidases. The
bromoperoxidase activity of the enzymes and their model
complexes is determined by the kinetic study of the oxida-
tive bromination of phenol red to bromophenol blue.[50]
The catalytic activity of VOL1‐VOL3 was evaluated using
phenol red as model substrate and the reaction was
monitored by UV–Vis spectrophotometric method
(Scheme S1). The absorption band of phenol red was grad-
ually decreased at 441 nm with VOL1, 439 nm with VOL2
and 440 nm with VOL3 and a new peak appeared at
586 nm (VOL1), 588 nm (VOL2) and 591 nm (VOL3) is
due to formation of bromophenol as product (Figure 8a‐
c). The isosbestic points at 494 nm (VOL1), 494 nm
(VOL2) and 495 nm (VOL3) shows the conversion of phe-
nol red to bromophenol blue and the reaction was com-
pleted after ∼2 h under ambient conditions. The kinetic
3.11 | Antioxidant property
DPPH assay has been widely used to investigate the
scavenging activities of several compounds. DPPH radi-
cal was scavenged by antioxidants through the donation
of hydrogen or electron, forming the reduced DPPH‐H•.
The stable DPPH radical has absorption maximum cen-
tered at about 517 nm. When an electron or a free radi-
cal species is absorbed results in discoloration from
purple to yellow and the absorption band disappears.
Addition of the compounds reduces the intensity of
absorption of DPPH radical. The radical‐scavenging
activity of the Schiff bases (L1‐L3) and their vanadium
complexes (VOL1‐VOL3) in methanol are given in Figure
S10. The 50% inhibitory concentration (IC50) values
imply that the scavenging effect of the compounds fol-
lows the order VOL1‐VOL3 > L2 > L3 > L1 (Table S7).
The IC50 values of vanadium complexes are close to
the value of the control, ascorbic acid (11.55 μM). The
results obtained clearly indicate that the vanadium com-
plexes are good antioxidants.

14 of 16
NEELAKANTAN ET AL.
FIGURE 8 (a‐c) Oxidative bromination of phenol red catalyzed by VOL1‐VOL3 in aqueous phosphate buffer at pH = 7.2; (d‐f) initial rates
versus substrate concentrations for bromination reaction catalyzed by VOL1‐VOL3
studies of the plots for the above conversion are given in
Figure 8d‐f and the reaction exhibits saturation kinetics
based on the Michaelis–Menten model. Michaelis binding
constant (Km), maximum velocity (Vmax) and rate con-
stant for dissociation of substrates (kcat) were calculated
from the Lineweaver‐Burk graph of 1/rate versus 1/[S]
(Figure S12), using the equation 1/V = (KM/Vmax)(1/
[S]) + 1/Vmax (Table 6). A control reaction was carried
out without the vanadium complex shows no appreciable
change in the absorbance (Figure S13).

NEELAKANTAN ET AL.
15 of 16
TABLE 6 Kinetic parameters for bromination of phenol red by
VOL1‐VOL3
ORCID
M.A. Neelakantan http://orcid.org/0000-0002-6321-0668
Complex
Vmax (M min−1
)
KM (M)
kcat (h−1
)
VOL1
VOL2
VOL3
6.60 × 10−3
7.24 × 10−3
6.86 × 10−3
2.93 × 10−3
3.11 × 10−3
2.82 × 10−3
396.0
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Financial supports received from the Science and Engi-
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