Spectroscopic studies, structural characterization and electrochemical studies of two cobalt (III) complexes with tridentate hydrazone Schiff base ligands: Evaluation of antibacterial activities, DNA-binding, BSA interaction and molecular docking

Article abstract of DOI:10.1002/aoc.4019

Co(III) complexes of tridentate Schiff base ligands derived from N-(2-hydroxybenzylideneamino)benzamide (H₂L¹) and 2-(2-hydroxybenzylidene)hydrazine-1-carboxamide (H₂L²) were synthesized and characterized using

Full text of DOI:10.1002/aoc.4019

Received: 22 April 2017
DOI: 10.1002/aoc.4019
Revised: 5 July 2017
Accepted: 6 July 2017
F U L L P A P E R
Spectroscopic studies, structural characterization and
electrochemical studies of two cobalt (III) complexes with
tridentate hydrazone Schiff base ligands: Evaluation of
antibacterial activities, DNA‐binding, BSA interaction and
molecular docking
Roghayeh Fekri1 | Mehdi Salehi1
| Asadollah Asadi2 | Maciej Kubicki3
1 Department of Chemistry, College of
Co(III) complexes of tridentate Schiff base ligands derived from N‐(2‐
hydroxybenzylideneamino)benzamide (H2L1) and 2‐(2‐hydroxybenzylidene)
hydrazine‐1‐carboxamide (H2L2) were synthesized and characterized using
IR, Raman, 1H–NMR and UV–Vis spectroscopies. X‐ray single crystal structures
of complexes 1 and 2 have also been determined, and it was indicated that these
Co(III) complexes are in a distorted octahedral geometry. The cyclic voltamm-
etry (CV) of the complexes indicates an irreversible redox behavior for both
complexes 1 and 2. The antibacterial effects of the synthesized compounds have
been tested by minimum inhibitory concentration and minimum bactericidal
concentration methods, which suggested that the metal complexes exhibit bet-
ter antibacterial effects than the ligands against Gram‐positive bacteria. The
effects of the drug (drug = ligands and complexes) on bovine serum albumin
(BSA) were examined using circular dichroism (CD) spectropolarimetry, and
it was revealed that the BSA (BSA, as a carrier protein) secondary structure
changed in the presence of the drug. Interaction of the drug with calf‐thymus
DNA (CT‐DNA) was investigated by UV–Vis absorption, fluorescence emission,
CV and CD spectroscopy. Binding constants were determined using UV–Vis
absorption. The results indicated that the studied Schiff bases bind to DNA,
with the hyperchromic effect and non‐intercalative mode in which the metal
complexes are more effective than ligands. Furthermore, molecular docking
simulation was used to obtain the energetic and binding sites for the interaction
of the complexes with Mycobacterium tuberculosis enoyl‐acyl carrier protein
reductase (InhA), and results showed that complex 1 has more binding energy.
Science, Semnan University, Semnan, Iran
2 Department of Biology, Faculty of
Science, University of Mohaghegh
Ardabili, Ardabil, Iran
3 Faculty of Chemistry, Adam Mickiewicz
University, Umultowska 89b, 61‐614
Poznan, Poland
Correspondence
Mehdi Salehi, Department of Chemistry,
College of Science, Semnan University,
Semnan, Iran.
Email: msalehi@semnan.ac.ir
KEYWORDS
antibacterial activities, cobalt (III), crystal structures, DNA‐ and BSA‐binding, molecular docking
simulation, spectroscopic studies
Appl Organometal Chem. 2017;e4019.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4019

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FEKRI ET AL.
two complexes of Co(III) with tridentate Schiff base
ligands have been prepared (Scheme 1), and investigated
using X‐ray crystallography, FT‐IR, Raman, UV–Vis,
1H–NMR spectral studies and cyclic voltammetry (CV).
The compounds were screened for anti‐bacterial activity
against Gram‐positive and Gram‐negative bacteria. The
details of DNA‐binding and BSA‐binding of these
compounds have also been reported. In addition, silico
anti‐tuberculosis properties were investigated via
computational methods, such as molecular docking
simulation.
1 | INTRODUCTION
Metal complexes of multi‐dentate Schiff base ligands have
been studied[1] due to their various potential applications
in many fields.[2] The stability of pharmaceutical drugs,
including physicochemical stability, is significant. There-
fore, it is important to find an alternative approach that
can enhance the stability of drugs by changing the
structural properties of these compounds.[3] Hydrazones
have attracted considerable attention not only because of
their variety of structure, but also for their various
biological and chemical applications,[4] including antican-
cer,[5] anti‐tubercular,[6] antioxidant,[7] antibacterial,[8]
antifungal,[9]
anti‐inflammatory[10]
and
cytotoxic
2 | EXPERIMENTAL
activities.[11] The bioinorganic chemistry of nickel and
cobalt has been rapidly expanded, and nickel and cobalt
complexes showed important biological activity, such as
DNA‐binding and protein‐binding.[12–14] Bovine serum
albumin (BSA) has been studied extensively in drug tests
as a replacement for human serum albumin (HSA)
because it has been proven to have a high homology and
a similarity to HSA. These proteins act as drug carriers
in the body, and it is interesting to study the interactive
behaviors of the metal complexes with protein and
determine their binding constants. The binding of
metallodrugs with serum albumin is important for their
distribution and metabolism in vivo.[15–17] In addition,
studying interactions between metal complexes and
DNA is beneficial for the design of new drugs and has
long been the subject of intense investigation in relation
to the development of new reagents for medicine and
genetic research; thus, it has a key role in pharmacol-
ogy.[18–20] Small molecules are capable of binding to
DNA via various types of bonds, including electrostatic‐
binding, groove‐binding, intercalative‐binding and
hydrogen bonds.[21] Tuberculosis is a lung infection
caused mainly by Mycobacterium tuberculosis (Mtb), and
it is the leading bacterial infectious agent.[22] InhA, the
enoyl‐acyl carrier protein, is an essential enzyme of M.
tuberculosis and thus it is a good target; additionally,
FAS II system (fatty acid synthase) is present in bacteria
but absent in humans.[23] Molecular docking is a key tool
in structural molecular biology and computer‐assisted
drug design, and it is applied to understand the structural
interaction between drug and receptor.[24] In this study,
2.1 | Materials and methods
All chemicals and solvents were of the highest purity and
used as received. IR spectra were recorded as KBr discs
with a Bruker FT‐IR spectrophotometer. UV–Vis spectra
of solutions were recorded on a Shimadzu UV‐1650PC
spectrophotometer. The Raman spectra were obtained
with a Bruker (SENTERRA) spectrometer, according to
the standard EN 60825–1/10.2003. 1H–NMR spectra were
obtained on a BRUKER AVANCE DR X400 (400 MHz)
spectrometer, using dimethylsulfoxide (DMSO) as solvent.
Calf‐thymus
DNA
(CT‐DNA),
BSA,
Tris–HCl
(trishydroxymethylaminomethan‐hydrochloride), methy-
lene blue (MB), DMSO, dimethylformamide (DMF) and
other chemicals were purchased from Sigma‐Aldrich.
2.2 | Procedure for synthesis of the Schiff
bases
2.2.1 | Synthesis of N‐(2‐
hydroxybenzylidene) benzohydrazide
(H2L1)
The Schiff base used was prepared by mixing an ethanolic
solution (20 ml) of 10 mmol of benzohydrazide with 10
mmol of salicylaldehyde in the same volume of ethanol,
and the mixture was refluxed for 4 h. When a light yellow
precipitate was formed, the solid formed was filtered and
washed with 4 ml of cooled ethanol. Yield: 80%; m.p.
178 °C. FT‐IR:
cm−1 (KBr): 1674 (C = O), 1622
max
SCHEME 1 Synthesis of complexes
(1–2)

FEKRI ET AL.
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(C = N). UV–Vis: λmax (nm) (ε, M−1 cm−1) (DMSO): 398
(850), 304 (720).
diffractometer with Eos CCD detector and graphite‐
monochromated MoKα radiation (λ = 0.71069 Å). The
data were corrected for Lorentz‐polarization as well as
for absorption effects.[25] Precise unit‐cell parameters were
determined by the least‐squares fit of reflections of the
highest intensity (5208 for 1, 3369 for 2), chosen from the
whole experiment. The structures were solved with
SIR92,[26] and refined with the full‐matrix least‐squares
procedure on F2 by SHELXL‐2013.[27] All non‐hydrogen
atoms were refined anisotropically, hydrogen atoms from
NH2 group in 2 were found in difference Fourier maps
and isotropically refined, all other hydrogen atoms were
placed in idealized positions and refined as ‘riding model’
with isotropic displacement parameters set at 1.2 times Ueq
of appropriate carrier atoms. The positions of hydrogen
atoms from water molecules in 1 were calculated on the
basis of potential (or certain) hydrogen bonding interac-
tions. Table 1 lists the relevant crystallographic and refine-
ment data. Crystallographic data for the structural analysis
have been deposited with the Cambridge Crystallographic
Data Centre, Nos. CCDC‐1512977 (1) and CCDC‐1512978
(2). Copies of this information may be obtained free of
charge from: The Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44(1223)336–033; e‐mail:
deposit@ccdc.cam.ac.uk, or www: www.ccdc.cam.ac.uk).
2.2.2 | Synthesis of 2‐(2‐
hydroxybenzylidene) hydrazine‐1‐
carboxamide (H2L2)
The synthesis of H2L2 was performed using the same
procedure for H2L1, while using hydrazinecarboxamide
instead of benzohydrazide. The light yellow precipitate
was obtained. Yield: 75%; m.p. 161 °C. FT‐IR:
cm−1
max
(KBr): 1681 (C = O), 1612 (C = N). UV–Vis: λmax (nm)
(ε, M−1 cm−1) (DMSO): 400 (890), 338 (1290).
2.3 | Procedure for the synthesis of
complexes (1) and (2)
2.3.1 | Synthesis of [CoIII(L1)(py)3]ClO4 (1)
Cobalt (III) hydrazone complex was obtained by the
direct reaction of the ligand (0.5 mmol) with cobalt (II)
salt [CoII(CH3COO)24H2O] in the mixture of methanol
in a molar ratio (1:1) under reflux conditions, and air
was bubbled through the reaction mixture. The red
solution turned brown upon the formation of [CoIII(L1)]
complex. To this solution, 0.5 ml pyridine was added and
the reaction mixture was further refluxed for 1 h. Then,
to the resulting dark brown solution, 0.5 mmol of
NaClO4 was added and the mixture was stirred for 5
min. Dark brown crystals of 1 that are suitable for
X‐ray crystallography were obtained after 4 days by slow
evaporation of the solvent. Yield: 56%; m.p. 370 °C.
2.5 | Cyclic voltammetry
Cyclic voltammograms were recorded by using
a
metrohm 757 VA computerace at 25 °C under a nitrogen
atmosphere using lithium perchlorate as supporting
electrolyte (complex concentration of about 1 × 10−3
M
FT‐IR:
cm−1 (KBr): 1604 (C = N), 1618 (C = O).
max
in DMF solution) and were performed using glassy carbon
as working electrode, a platinum wire as an auxiliary
electrode and Ag/AgCl as a reference electrode.
UV–Vis: λmax (nm) (ε, M−1 cm−1) (DMSO): 636 (1150),
386 (1140). H–NMR (DMSO‐d6, 400 MHz): 8.3 (s, 1H,
1
CH = N).
2.6 | In vitro antibacterial efficiency
2.3.2 | Synthesis of [CoIII(L2)(py)3]ClO4 (2)
The test compounds were screened in vitro for their
antibacterial activities against two Gram‐positive species
[Staphylococcus aureus (PTCC‐1112), Bacillus subtilis
This complex was prepared by the same method as for
complex 1, except that H2L2 was used instead of H2L1.
Yield: 45%; m.p. 325 °C. FT‐IR:
cm−1 (KBr): 1595
max
(PTCC‐1254)]
and
two
Gram‐negative
species
(C = N), 1645 (C = O). UV–Vis: λmax (nm) (ε, M−1 cm−1
)
[Escherichia coli (PTCC‐1270), Klebsiella pneumoniae
(PTCC‐1053)]. The minimum inhibitory concentration
(MIC) was determined according to the microdilution
method, which applied LB broth; and for measuring
the minimum bactericidal concentration (MBC), 100 μl
liquid collected from the MIC was added to Mueller
Hinton agar plates. The plates were then coated and
incubated at 37 °C.[28,29] The activities of the
compounds against bacteria were measured after 24 h,
and DMSO was used as the solvent of choice. The
MBC is the lowest concentration at which an
(DMSO): 644 (830), 398 (1230). 1H–NMR (DMSO‐d6,
400 MHz): 8.2 (s, 1H, CH = N).
2.4 | X‐ray crystallography
Diffraction data were collected by the ω‐scan technique,
for 1 at 130(1) on Rigaku SuperNova four‐circle
diffractometer with Atlas CCD detector and mirror‐
monochromated CuKα radiation (λ = 1.54178 Å), and
for 2 at 100(1) K on Rigaku Xcalibur four‐circle

4 of 17
FEKRI ET AL.
TABLE 1 Crystal data, data collection and structure refinement
Compound
1
2
−
Formula
2(C29H25CoN5O2+)2(ClO4−)3H2O
C23H22CoN6O2+C5H5N ClO4
Formula weight
Crystal system
Space group
a (Å)
1321.88
Orthorhombic
P212121
12.2804(3)
13.9299(4)
35.490(2)
90
651.94
Monoclinic
P21/n
14.5594(4)
12.1452(3)
16.3488(4)
104.177(3)
2802.86(13)
4
b (Å)
c (Å)
β (°)
V (Å3)
6071.1(4)
4
Z
Dx (g cm−3
)
1.45
1.55
F (000)
2728
1244
μ (mm−1
)
5.72
0.77
Θ range (°)
Reflections:
Collected
2.49–67.49
3.31–28.34
21 042
1937 (0.079)
8153
13 160
5900 (0.044)
4157
Unique (Rint
)
With I > 2σ(I)
R(F) [I > 2σ(I)]
wR(F2) [I > 2σ(I)]
R(F) (all data)
0.095
0.043
0.242
0.082
0.110
0.077
wR(F2) (all data)
0.253
0.094
Goodness of fit
1.40
1.03
Max/min Δρ (e Å−3
)
1.16/−0.62
0.37/−0.56
antimicrobial agent will kill a particular microorganism,
and the MIC is the lowest concentration of antimicro-
bial that produced inhibition of bacterial growth. Also,
kanamycin and co‐trimoxazole were the standard anti-
bacterial agents included in the test.[30]
2.8 | DNA‐binding experiments
2.8.1 | Preparation of the stock solution
The DNA‐binding experiments of the synthesized com-
pounds with CT‐DNA were performed in 0.01 M Tris–HCl
(trishydroxymethylaminomethan‐hydrochloride) buffer
(pH 7.4) using DMSO solution of the synthesized
compounds at room temperature. MB is a fluorescent
probe for DNA structure, which has been employed in
the examination of the synthesized compounds binding
mode to DNA. The stock solution of MB was prepared by
dissolving it in deionized double‐distilled water. All the
spectroscopic experiments were performed at room
temperature.
2.7 | Protein‐binding studies
Circular dichroism (CD) spectra of the reactions of
ligands and metal complexes with BSA were recorded
on Jasco J‐810 spectropolarimeter using a 1‐mm cell in a
constant concentration of BSA (BSA = 0.5 × 10−4
moldm−3) and varying concentrations of synthesized
compounds (0.5 and 1 × 10−4 moldm−3) in the far‐UV
range (200–260 nm), at room temperature. The stock
solution of BSA was prepared in 0.01 M phosphate buffer
(pH 7.4), and solutions of the synthesized compounds
were prepared by dissolving them in methanol. Secondary
structural elements were calculated by using the CDNN
program.[31]
2.8.2 | Absorbance spectroscopy
The UV–Vis spectra of CT‐DNA were recorded on a
UV–Vis spectrophotometer (T‐60, PG Instrument UK).
The absorption spectra of ligands and complexes (1) and

FEKRI ET AL.
5 of 17
(2) in the absence and presence of DNA solution were
recorded for a constant DNA concentration (5 × 10−5 M),
and the wavelengths of different concentrations of the
synthesized compounds ranged from 240 to 300 nm.
crystals suitable for X‐ray crystallography were obtained
by slow evaporation of methanol solution of complexes 1
and 2 at room temperature.
3.2 | IR and Raman spectra
2.8.3 | Emission spectroscopy
The IR spectra provide valuable information regarding
the coordinating behavior of the ligand to the metal
ion. The ʋ(C = N) bands appearing at 1622 cm−1 (H2L1)
and 1612 cm−1 (H2L2) are shifted to lower energies
(1618 cm−1 for 1 and 1595 cm−1 for 2) in the spectra of
the complexes, indicating that the ligands are coordi-
nated to the metal ions through the nitrogen atoms of
the azomethine groups. Furthermore, deprotonation of
phenolic functions is confirmed by the lack of O‐H
stretching bands in the IR region 3179–3270 cm−1 for
complexes. Also, the stretching of metal‐oxygen and
metal‐nitrogen bands of the complexes appeared in the
lower wavelength region in the range of 662–691 and
548–623 cm−1, respectively. In the free ligands, the
C = O stretching vibrational bands appeared at 1674
and 1681 cm−1, which assigned for H2L1 and H2L2,
respectively, and disappeared in the spectra of its com-
plexes. The Raman spectra of complexes are helpful to
identify the vibrational and rotational modes in a system.
The C‐H bending of aromatic ring occurs in the region
1200–1300 cm−1. The C‐C and C‐O stretching vibrations
are in the region 1000–1200 cm−1. Also, the 1618 cm−1
band of 1 and the 1606 cm−1 band of 2 are assigned to
C = N stretching vibration.[35]
The emission spectra of MB as fluorescence probe, in the
presence of CT‐DNA alone or with ligands and com-
plexes, were achieved using a JASCO FP‐750 spectrofluo-
rimeter (Tokyo, Japan) equipped with a 150 W Xenon
lamp, using 1.0‐cm quartz cuvette, that a fixed amount
of DNA and MB ([CT‐DNA] = [MB] = 5 × 10−5 M)
was titrated with increasing the amounts of the synthe-
sized compounds. Samples were excited at 630 nm, and
emission spectra were recorded from 660 to 750 nm.
2.8.4 | Electrochemical studies
Cyclic voltammograms were recorded by using
a
Potentiostat/Galvanostat (Model 263A, EG&G, USA)
under a nitrogen atmosphere, [CT‐DNA] = [complexes]
= 5 × 10−5 M in DMSO solution. The electrodes used
have been previously mentioned in ‘Cyclic voltammetry’.
2.8.5 | CD spectropolarimetry
The CD spectra were performed with a fixed concentra-
tion of DNA (5 × 10−5 M) with varying concentrations
of ligands and metal complexes (1) and (2), 7 and
9 × 10−6 M in the far UV range (230–290 nm), by spec-
tropolarimeter mentioned in ‘Protein‐binding studies’.
3.3 | 1H–NMR spectra
1
The H–NMR spectra of cobalt complexes 1 and 2 were
2.9 | Molecular docking simulation
studies
recorded in DMSO at room temperature using TMS as
an internal standard. The NH2 protons for 2 appeared
between 8.65 and 8.68 ppm. The aromatic protons of the
phenyl ring and protons of pyridine were located between
6.75 and 8.97 ppm for 1, and 6.63 and 8.02 ppm for 2.
The target protein enoyl‐acyl carrier protein reductase
(InhA) from M. tuberculosis (PDB code: 2NSD) was
downloaded from Protein Data Bank (www.rcsb.org).[32]
Hex docking software was applied to calculate docking
energies and to find the most probable binding sites.[33]
Argus Lab is the electronic structure program that was
used for optimizing the structures after deleting the
ClO4 from crystallographic data.[34]
1
Also, the H–NMR spectrum of the complexes 1 and 2
shown at δ ≈ 8.30 and δ ≈ 8.22 have been assigned to
the azomethine protons (s, 1H, CH = N), respectively
(Figure 1a and b).
3.4 | Electronic spectra
3 | RESULTS AND DISCUSSION
3.1 | Synthesis and characterization
The electronic absorption spectra of ligands and their
transition metal complexes in methanol (1 × 10−4 M)
were recorded at the wavelength range 205–700 nm at
room temperature. In the UV region, the bands appeared
at 232 nm (H2L1) and 227 nm (H2L2) due to π→π* transi-
tion of the benzene ring, also the bands at 325 nm and
329 nm are attributable to n→π* for H2L1 and H2L2,
The reported Co(III) complexes have been prepared by
refluxing methanolic solution of the tridentate Schiff base
ligand and cobalt (II) acetate in the presence of pyridine
and NaClO4 in aerobic conditions (Scheme 1). The brown

6 of 17
FEKRI ET AL.
FIGURE 1 1H–NMR spectrum of (a) 1 and (b) 2 in DMSO at 298 K
respectively, which disappeared upon complexation. In
addition, the electronic spectra of ligands show bands at
296 nm for H2L1 and 303 nm for H2L2, corresponding to
the π→π* type electronic transition of the C = N. On com-
plexation these bands were shifted and appeared at 400
nm and 377 nm, indicating coordination of azomethine
nitrogen to the central metal ion for 1 and 2, respectively.
Also, for both complexes, d‐d transitions probably
appeared in the area under the charge transfer.
Table 2. The two Co complexes are six‐coordinated
(O2N from almost planar L molecules, three N atoms
from three pyridine fragments) in quite regular octahe-
dral geometry (Table 2). In the symmetry‐independent
part of the unit cell of 1 there are two cationic complex
molecules, two perchlorate anions and three water
molecules which – together with one of the perchlorate
anions – make the infinite (anionic) layers of hydrogen‐
bonded fragments (Figure 4). In the crystal structure of 2
there are dimeric, hydrogen‐bonded structures, involving
two complex molecules connected by N‐H···N hydrogen
bonds and two perchlorate anions connected to the
cationic complex by N‐H···O hydrogen bond (Figure 5).
Table 3 lists the details of hydrogen bonds.
3.5 | X‐ray studies
The perspective views of the complexes are shown in
Figures 2 and 3, and some geometrical data are listed in
The smallest and largest angles are shown.

FEKRI ET AL.
7 of 17
TABLE 2 Selected geometrical parameters (Å, °) with s.U. Values
in parentheses
1A
1B
2
Co1‐O1
1.860(9)
1.871(8)
1.8662(17)
Co1‐N8
1.858(11)
1.873(9)
1.834(10)
1.874(8)
1.862(2)
Co1‐O10
Co1‐N(py)
1.8802(17)
1.958(12)
1.962(11)
1.978(12)
1.956(10)
1.966(10)
1.978(11)
1.963(2)
1.967(2)
1.977(2)
C1‐O1
1.353(16)
1.307(18)
1.370(15)
1.370(17)
1.271(16)
1.350(14)
1.348(15)
1.384(14)
1.333(15)
1.311(14)
1.325(3)
1.292(3)
1.388(3)
1.330(3)
1.300(3)
C7‐N8
N8‐N9
N9‐C10
C10‐O10
178.5(4)
175.7(5)
178.9(5)
178.0(3)
177.3(4)
172.9(5)
177.02(7)
178.16(8)
174.10(9)
FIGURE 2 A perspective view of the cationic co complex 1;
ellipsoids are drawn at the 50% probability level, hydrogen atoms
are shown as spheres of arbitrary radii
carbon as the working electrode and Ag/AgCl as the refer-
ence electrode, and lithium perchlorate is used as the
supporting electrolyte (2 M) in the process. In order to
compare the CVs of 1 and 2, they have been presented in
Figure 6. Voltammogram (1) display a reduction peak at
−0.47 V and an oxidation peak at 0.56 V. Also, the electro-
chemical behavior of complex 2 showed an oxidative
response at 0.66 V and during the cathodic scan it showed
a reductive response at −0.34 V, where oxidative and
reductive responses are assigned to Co(II) → Co(III)
and Co(III) → Co(II), respectively.
3.7 | Antibacterial activity
Over recent years, hydrazone derivatives have received
more attention in bioinorganic chemistry, for example
antibacterial activity against Gram‐positive and Gram‐
negative bacteria, and antibacterial activity dependent
on their structural properties. Some transition metal com-
plexes of related compounds showed good antibacterial
activity against Gram‐positive bacteria.[36–38] The
antibacterial activity of ligands and complexes (1) and
(2) were assessed against E. coli and K. pneumoniae
(Gram‐negative), and S. aureus and B. subtilis
(Gram‐positive) strains. The MIC and MBC values of the
compounds are summarized in Table 4. The results show
that the synthesized compounds exhibit good biotical
behavior towards the Gram‐positive bacterial streams.
The external membrane of Gram‐positive bacteria may
have a significant effect on antibacterial activity of
FIGURE 3 Perspective views of complex 2; ellipsoids are drawn
at the 50% probability level, hydrogen atoms are shown as spheres
of arbitrary radii
3.6 | Electrochemical studies
The CV experiments for 1 and 2 were performed in DMF
solution using platinum as the auxiliary electrode, glass

8 of 17
FEKRI ET AL.
FIGURE 4 (top) hydrogen‐bonded
water‐perchlorate system in 1; (bottom)
crystal packing of 1 as seen along the
hydrogen‐bonded water chain (shown in
van der Waals radii representation)
TABLE 3 Hydrogen bond and weak interactions data (Å, °); only
the strongest interactions are shown
D
1
H
A
D‐H
H···A
D···A
D‐H···A
O1W
O1W
O2W
O2W
O3W
O3W
2
H1W1 O3Ca 0.88
H1W2 O2W 0.87
2.12
1.99
2.42
2.01
2.17
2.03
3.00(2)
2.74(3)
3.25(4)
2.75(4)
3.01(3)
2.82(3)
178
144
168
148
170
156
H2W1 O1Cb 0.84
H2W2 O3Wc 0.84
H3W1 O4Cd 0.85
H3W2 O1W
0.84
N11A H11A N9Ae 0.81(3) 2.15(3) 2.952(3) 172(3)
N11A H11B
O1C
0.85(3) 2.21(3) 3.046(3) 168(2)
Symmetry codes:
a1/2 − x, 1 − y, −1/2 + z;
b1 − x, −1/2 + y, ½ − z;
c1/2 + x, ½ − y, −z;
d−x, −1/2 + y, ½ − z;
e1 − x, 2 − y, 1 − z.
compared with the free ligands (H2L1 and H2L2). This
may be explained by chelation theory,[39,40] according to
which complexation reduces the polarity of the central
metal atom because of partial sharing of its positive
charge with the donor group within the whole chelate,
thus chelation or complexation increases the lipophilic
nature of the central atom, which favors permeation of
the complexes through the lipid layer of the cell
membrane and resulted in enhancement of activity. For
FIGURE 5 (top) hydrogen‐bonded dimeric building block of 2
(hydrogen bonds are shown as thin blue lines); (bottom) the
placements of the neutral pyridine molecules (blue) in the crystal
structure of 2
compounds. It has been observed that the metal
complexes (1) and (2) show higher antibacterial activities

FEKRI ET AL.
9 of 17
of the synthesized compounds to BSA varied as 1:0, 1:1 and
1:2. The CD spectra of BSA exhibited two negative bands at
209 and 220 nm, which contribute to the π–π* and n–π*
transitions for the peptide bond of the α‐helix,[45] respec-
tively (Figure 7, curve a).
The assignments of the secondary structure elements
(fα, f, fturn and frandom) with and without H2L1, H2L2, 1
and 2 were obtained using a software program shown in
Table 5. The binding of the synthesized compounds to
BSA induced a conformational change of BSA, which
decreased band intensity without any significant shift
of the peaks, indicating that the drug induced a slight
decrease in the α‐helical structure content of the protein
(fα) and the content of turn (fturn). In addition, f‐sheet
(f) and random coli (frandom) increased due to the
binding of the synthesized compounds. The marked
decrease in the α‐helical structure content of protein
(fα) probably occurred because of the interaction
between drug and BSA, which can be confirmed by
the value of the binding constant (K) using Equations
(1) and (2), based on the method of Kim and
Baldwin.[46–49] Thus, the aim of this study was to
examine the interaction of BSA with drug, and to
investigate possible structural changes on the
secondary structure of BSA after the addition of drug.
FIGURE 6 CVs of complexes 1 and 2 in DMF and in lithium
perchlorate as a supporting electrolyte, GC working; ag/AgCl
reference; Pt auxiliary electrodes, [complexes] = 1 × 10−3
[lithium perchlorate] = 2 M
,
compounds H2L1 and H2L2, and also for 1 and 2, the
results suggest that replacement of the amino group with
the phenyl ring led to better activity against
Gram‐positive bacteria and thus, according to Table 4, in
general, antibacterial activity in Gram‐positive bacteria
of H2L1, H2L2, 1 and 2 followed the sequence below:
1>2>H2L1>H2L2
ƒU ¼ ðУF–УÞ=ðУF–УUÞ
(1)
(2)
3.8 | CD spectropolarimetry
Recently, many techniques have been used to investigate
the interaction of proteins with drugs.[41,42] BSA, as carrier
and the most abundant plasma protein in the blood circu-
latory system, is one of the most extensively studied pro-
teins due to its structural similarity to HSA. It has a high
percentage of the α‐helical structure, which shows a spe-
cific CD signal in the far‐UV region. CD spectroscopy is a
sensitive method to monitor the conformational changes
of proteins, and is very sensitive to changes in the second-
ary structure.[43,44] The far‐UV CD spectra for BSA (0.5 ×
10−4 moldm−3) were measured in the absence and pres-
ence of the synthesized compounds. Figure 7 shows the
CD spectra of a fixed concentration of BSA; the molar ratio
K ¼ ƒU=ð1−ƒUÞ ¼ ƒU=ƒF ¼ ðУF–УÞ=ðУ–УUÞ
where ƒF and ƒU are the fractions of BSA present in the
folded and unfolded conformations, respectively, and УF
and УU are the values of ellipticity of the folded and
unfolded states, respectively. The binding constant values
of the synthesized compounds are calculated to be 3.0 ×
102, 2.8 × 102, 1.9 × 103 and 1.1 × 103 M for H2L1,
−1
H2L2, 1 and 2, respectively. These data indicate that the
binding of complexes is stronger than that of the ligands.
Under the same conditions, complex 1 affects BSA
conformation more strongly than complex 2 (substitution
of a phenyl ring instead of amino group). The obtained
TABLE 4 Antibacterial activity, MIC and MBC, of ligands and their complexes (× 10−6 M)
Gram‐positive bacteria
Gram‐negative bacteria
B. subtilis
S. aureus
K. pneumoniae
E. coli
Compound
H2L1
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
416
104
416
208
416
104
416
416
H2L2
558
52
279
6.5
558
26
279
3.2
558
208
558
558
104
279
558
208
279
558
208
279
1
2
139.6
34.9
139.6
17.4

10 of 17
FEKRI ET AL.
FIGURE 7 CD spectra of BSA in the presence of increasing amounts of drug at pH 7.4. BSA = 0.5 × 10−4 moldm−3 (a); BSA = 0.5 ×
10−4 moldm−3 + drug = 0.5 × 10−4 moldm−3 (b); and BSA = 0.5 × 10−4 moldm−3 + drug = 1 × 10−4 moldm−3 (c); drug = H2L1,
H2L2 and complexes (1) and (2)
TABLE 5 Fractional contents of the secondary structure of BSA (0.5 × 10−4 moldm−3) in the absence and presence of H2L1, H2L2 and
complexes (1) and (2)
Concentration ratios
of BSA to H2L, H2L2
Compound
H2L1
and complexes (1) and (2)
fα
f
fturn
frandom
1:0
0.416
0.152
0.169
0.260
1:1
1:2
0.133
0.129
0.324
0.327
0.164
0.164
0.377
0.377
H2L2
1:0
1:1
1:2
0.416
0.134
0.131
0.152
0.323
0.326
0.169
0.164
0.164
0.260
0.377
0.378
1
2
1:0
1:1
1:2
0.416
0.205
0.175
0.152
0.261
0.286
0.169
0.169
0.169
0.260
0.363
0.369
1:0
1:1
1:2
0.416
0.181
0.165
0.152
0.280
0.294
0.169
0.169
0.168
0.260
0.368
0.371
K‐values were compared with previously known hydrazide
derivatives,[50,51] which were dependent on the stability
and structure of related compounds.
interactions with small molecules. The UV–Vis absorp-
tion measurements were carried out by keeping the con-
centration of DNA fixed and varying the concentration
of the ligands and complexes, which may lead to forma-
tion of a DNA…drug ground state complex. The UV–Vis
absorption spectrum of DNA shows a broad band (240–
300 nm) in the UV region with a maximum absorption
at 258 nm. This maximum arises due to the π→π* transi-
tions of DNA bases.[52] Absorption spectra of DNA
increased upon increasing the concentration of the syn-
3.9 | DNA‐binding studies
3.9.1 | Electronic absorption studies
UV–Vis absorption spectroscopy is perhaps the simplest
and most commonly employed instrumental technique
for studying both the stability of DNA and their
thesized
compounds
(hyperchromism).
The

FEKRI ET AL.
11 of 17
hyperchromic effect is a feature of the spectra of DNA due
to its double‐helix structure, and changes in its conforma-
tion and structure after the drug bound to DNA (damage
to the DNA double‐helix structure after the drug bound
to DNA). On the other hand, hyperchromism can be
attributed to external contact (surface binding) with
where Aobs is the observed absorbance of the solution that
contained various concentrations of drug at 258 nm, α is
the degree of association between DNA and drug,
DNA
and are the molar extinction coefficients at the defined
c
wavelength (λ = 258 nm) for DNA and the formed
compound, respectively, ‘l’ is the optical path length,
and C0 is the primal concentration of DNA. Equation (5)
can be expressed as Equation (6), where A0 and Ac are
the absorbances of the ligands and their complexes with
DNA at 258 nm, respectively, with a concentration of C0.
Also, α can be equated to (Kapp[drug])/(1 + Kapp[drug]),
so that Equation (6) can be changed to Equation 7:
the
duplex.[53,54]
Furthermore,
the
observed
hyperchromism and no shift in the location of the peak
(258 nm) is indicative of partial or non‐intercalative‐
binding modes (Figure 8), such as dative bonds, electro-
static forces, hydrogen bonds, van der Waals forces and
hydrophobic interactions.[55–57] These hyperchromic
shifts indicate that all the synthesized compounds inter-
act with CT‐DNA with non‐intercalative‐binding
modes. Based upon the variation in absorbance, the
apparent association constant (Kapp) of the drug with
DNA can be determined according to the Benesi–
Hildebrand equation,[58] and the equilibrium for the
formation of the compound between DNA and drug
was determined by Equation (4):
1
1
1
1
¼
þ
:
(7)
A
obs−A0 Ac−A0
K
app−ðAc−A0Þ ½drugꢀ
According to Equation (5), a linear relationship can be
obtained between 1/(Aobs – A0) and the reciprocal concen-
tration of drug, with a slope equal to 1/Kapp(Ac – A0) and
an intercept of 1/(Ac − A0) (Figure 9).[59] The apparent
binding association constants (Kapp) for ligands and
complexes have been calculated and were listed in
Table 6. By comparing the previously reported
compounds, including hydrazide derivatives, it was
observed that the binding apparent association constants
were dependent on the structural properties,[60,61] also
the addition of metal ions solutions to ligand solution
Drug: ligand or complex.
DNA þ drug⇌DNA…drug
½DNA…drugꢀ
(3)
Kapp
¼
(4)
(5)
½DNAꢀ: ½drugꢀ
Aobs ¼ ð1 − αÞC0ɛDNAɭ þ αC0ɛcɭ
Aobs ¼ ð1–αÞA0 þ αAc
influenced it. The apparent association constant (Kapp
)
increased toward the metal centers. For compounds
H2L1, H2L2, 1 and 2, the substitution of an amino group
(6)
FIGURE 8 Absorption spectra of DNA in Tris–HCl buffer (DNA = 5 × 10−5 M) upon addition of H2L1, H2L2 and complexes (1) and (2)
(0, 7, 8, 9 and 10) × 10−6 M, for curves a–e, respectively

12 of 17
FEKRI ET AL.
FIGURE 9 Linear relationship between 1/(Aobs – A0) and the reciprocal concentration of drug, with a slope equal to 1/Kapp(Ac – A0) and an
intercept equal to 1/(Ac − A0)
TABLE 6 Binding constants of DNA with synthesized
compounds
quenched. This reflects the strong interaction between the
electronic states of MB and that of adjacent nucleic acid
bases. But, if a significant increase occurs in MB emission
it means that interaction between synthesized compounds
and DNA causes the separation of MB from DNA.[65,66]
There is no remarkable increase in the fluorescence
intensity of the probe molecule in the presence of increas-
ing amounts of the synthesized compounds; that suggests
non‐weaving interaction of ligands and complexes with
DNA. Thus, these results imply that the synthesized
compounds interact with DNA via non‐intercalating,
and interaction between MB and DNA is intercalating as
the interaction between synthesized compounds with
DNA‐MB does not cause a significant change in the
emission, and this is evidence for non‐intercalative mode of
binding. In other words, MB molecules are not released from
the DNA helix after the addition of H2L1, H2L2, 1 and 2.[57]
−1
Compound
H2L1
Binding constant (M
1.6 × 102
)
R2
0.99
H2L2
1 × 102
16.6 × 102
11.1 × 102
0.97
0.99
0.96
1
2
instead of phenyl ring weakened the DNA‐binding, thus
on the basis of the results (Table 6), the apparent associa-
tion constant (Kapp) of H2L1, H2L2, 1 and 2 followed the
sequence below:
1 > 2 > H2L1 > H2L2:
3.9.2 | Fluorescence studies
3.9.3 | Electrochemical studies
Fluorescence spectroscopy is probably one of the
techniques that is most commonly used for studying
interactions between metal complexes and DNA. The
interaction of ligands and complexes (1) and (2) with
DNA has been recorded by the use of MB. MB is a
well‐known intercalator and tricyclic[62–64] that is often
used as a spectral probe to establish the mode of binding
of small molecules to double‐helical DNA. The emission
spectra of the MB‐DNA solution are shown in Figure 10
by the addition of various amounts of ligands and
complexes (1) and (2). As is shown in Figure 10, by adding
DNA to MB, the fluorescent intensity of MB is remarkably
It is a useful technique to study the interaction of
electro‐active complexes with DNA.[67] CVs of 1 and 2 in
the absence and presence of DNA are depicted in
Figures 11 and 12. The CV for complexes 1 and 2
evidenced anodic responses at 0.60 V and 0.71 V, respec-
tively, which are believed to be due to Co(II) → Co(III)
oxidation. The corresponding cathodic responses at
−0.36 V for 1 and −0.26 V for 2 are attributable to Co(III)
→ Co(II) reduction. Addition of DNA to the complex
solution causes an increase in peak current for 1 and 2.
The observed increase in the peak currents is related to

FEKRI ET AL.
13 of 17
FIGURE 10 Fluorescence spectra of MB‐DNA system, in the presence of H2L1, H2L2 and complexes (1) and (2), [CT‐DNA] = [MB] =
5 × 10−5 M, (0, 7, 8, 9 and 10) × 10−6 M and λex = 630 nm
FIGURE 11 CVs of complex 1 in Tris–HCl buffer in (a) the
FIGURE 12 CVs of complex 2 in Tris–HCl buffer in (a) the
absence and (b) the presence of CT‐DNA, [DNA] =
absence and (b) the presence of CT‐DNA, [DNA] =
[complex] = 5 × 10−5
M
[complex] = 5 × 10−5
M
the interaction between the complexes and DNA.
Furthermore, the peak potential shifted to a more
negative value in the presence of DNA for both complexes
that is typical of the non‐intercalation of synthesized
complexes into DNA. On the other hand, if the interaction
mode is non‐intercalative, the peak potential shifts to a
more negative value, while intercalation‐binding results
in the shifts to a more positive value.[68–70]
compounds and CT‐DNA. CD spectra of DNA were
performed in the presence of increasing amounts of drug
(the DNA concentration was fixed at 5 × 10−5 M). A
solution of CT‐DNA exhibits a positive band (276 nm)
from base stacking interactions, and a negative band
(244 nm) from the right‐handed helicity of DNA.[71,72]
After adding drug to CT‐DNA, a decrease in both positive
and negative bands was observed without any significant
shift in the band maxima (shifting to zero levels).
Incubating DNA with drug results in a conformational
3.9.4 | CD spectra
Circular dichroism spectroscopy is also
a useful
technique to analyze interactions between synthesized

14 of 17
FEKRI ET AL.
FIGURE 13 The changes of CD spectra of DNA in the presence of addition of drug, DNA = 5 × 10−5 M (−), DNA = 5 × 10−5 M +
drug = 7 × 10−6 M (−), DNA = 5 × 10−5 M + drug = 9 × 10−6 M (−)
FIGURE 14 Docking conformation of
complexes 1 and 2 with 2nsd (a and b),
respectively
change in the DNA, as the conversion from a more B‐like
to a more C‐like state. The incubation of DNA with drug
shows less perturbations at the bands, attributed to a
typical non‐intercalative mode for all synthesized
compounds, as shown in Figure 13.[57,68,73,74]
3.10 | Molecular docking simulation
studies
Molecular docking plays an important role in binding
affinity and orienting different drugs to their bio‐targets

FEKRI ET AL.
15 of 17
TABLE 7 Hex results for the docking of enoyl‐acyl carrier protein
(2nsd) with (1) and (2)
Also, the binding of the synthesized compounds to BSA
was investigated by CD spectropolarimetry, and results
showed that the secondary structure of BSA changed after
synthesized compounds bound to BSA. In addition, the
molecular docking simulation technique has been used
to dock the complex with InhA target in M. tuberculosis.
Thus, the binding of drugs to proteins and DNA is of great
importance in pharmacy and biochemistry.
Distancebetween Fast Fourier
Total energy complex and
transform
(FFT, N)
Compound (kcal mol−1
)
receptor (R, Å)
1
2
−343.26
−317.78
16.2
25
25
16
ACKNOWLEDGEMENTS
such as proteins. Docking of the target compounds into
the enoyl‐acyl carrier protein reductase, which is one of
the M. tuberculosis enzymes, InhA, shows structural
information on the binding interactions.[75–78] Docking
was conducted with a procedure involving multiple
conformer shape‐matching alignment of a molecule to a
cavity followed by energy minimization on both
complexes (1) and (2) and a pair of InhA structures in
PDB format (http://www.pdb.org) at the binding region.
Energy minimization is an important step in molecular
docking. Hex (v8.0.0) docking program was used to obtain
the energetic and binding site for the interaction of
complexes (1) and (2) with 2nsd. Another docking
program, Argus lab program, was used to optimize the
structures after deleting the ClO4 from crystallographic
data that builds a molecule with on‐screen building
facilities provided by Argus lab program. Figure 14 and
Table 7 show the results of docking of 2nsd with
complexes (1) and (2), and indicate that complex (1) has
more binding energy to 2nsd.
The authors gratefully acknowledge the Faculty of
Chemistry at Semnan University, and the University of
Maraghegh Ardabil for supporting this work.
ORCID
Mehdi Salehi http://orcid.org/0000-0002-1335-1032
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