Co and Cu complexes with 2-acetylpyridine-4-hydroxy phenylacetyl acylhydrazone: Synthesis, crystal structures, CT-DNA/BSA binding behaviors, antibacterial activities and molecular docking studies

Article abstract of DOI:10.1016/j.poly.2020.114619

Two mononuclear complexes [Co(HL)L]NO₃ (1) and [Cu(HL)₂](NO₃)₂ (2)were synthesized from the reaction of 2-acetylpyridine-4-hydroxy phenylacetyl acylhydrazone (HL) with copper/cobalt nitrate hydrate. The single-c

Full text of DOI:10.1016/j.poly.2020.114619

Polyhedron 187 (2020) 114619
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Polyhedron
journal homepage: www.elsevier.com/locate/poly
Co and Cu complexes with 2-acetylpyridine-4-hydroxy phenylacetyl
acylhydrazone: Synthesis, crystal structures, CT-DNA/BSA binding
behaviors, antibacterial activities and molecular docking studies
⇑
Jie Yang, Xiang-rong Liu , Ming-kun Yu, Wen-bo Yang, Zai-wen Yang, Shun-sheng Zhao
College of Chemistry and Chemical Engineering, Xi’an University of Science and Technology, Xi’an 710054, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two mononuclear complexes [Co(HL)L]NO3 (1) and [Cu(HL)2](NO3)2 (2)were synthesized from the reac-
tion of 2-acetylpyridine-4-hydroxy phenylacetyl acylhydrazone (HL) with copper/cobalt nitrate hydrate.
The single-crystal XRD results revealed the central Co and Cu ions in two complexes are both six-coordi-
nated showing a distorted octahedral geometry. Thermal stabilities of 1, 2 and HL were explored by ther-
mogravimetry (TG) and the apparent activation energy (Ea) followed the order 2 > 1 > HL. The interactions
of 1, 2, HL with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) were investigated through
UV–Vis absorption spectroscopy, fluorescence spectroscopy, microcalorimetry and molecular docking
approach. From UV–Vis absorption spectroscopy and fluorescence spectroscopy results, it is shown that
1, 2 and HL can bind with CT-DNA by intercalation mode and quench the fluorescence of BSA through
static process. The binding constants Kib of three compounds toward CT-DNA/BSA followed the order:
1 > 2 > HL. Thermogenic curves of three compounds interacting with CT-DNA and BSA were measured
Received 22 January 2020
Accepted 25 May 2020
Available online 1 June 2020
Keywords:
Complex
Acylhydrazone
Crystal structure
DNA/BSA binding
Antibacterial activities
by microcalorimetry. The calculated enthalpies, entropies and Gibbs’ free energy change (
DH > 0,
D
S > 0, G < 0) indicated that all the interaction processes were endothermic and spontaneous.
D
Molecular docking results further validated the intercalation binding mode of 1, 2 and HL with CT-
DNA and the fluorescence quenching of tryptophan in BSA in presence of three compounds. It also
demonstrated that hydroxyl, benzene ring, pyridine ring, and carbonyl group of 1, 2, HL are the most
favorable binding site in DNA/BSA interaction. The antimicrobial activities of HL, 1 and 2 against
Staphylococcus aureus (S. aureus) and Bacillus subtilis (B. subtilis) were determined presenting that 1 and
HL can inhibit the growth of S. aureus and B. subtilis, separately. Cellular uptakes of 1 and 2 into S. aureus
and B. subtilis showed the amount of Co accumulation in S. aureus is bigger than that of Cu.
Ó 2020 Elsevier Ltd. All rights reserved.
1. Introduction
are easier to coordinate because of the additional N donor atom.
Many acylhydrazone complexes were synthesized and among
Acylhydrazones as a special kind of Schiff base have been
widely investigated because their structures are similar to that of
natural biological substances [1]. The C@N and NAN linkages in
the acylhydrazone molecules play an essential role in the design
and construction of promising bioactive agents [2–4]. As reported
in many literature, acylhydrazones display various biological activ-
ities such as antithrombotic [5], antimicrobial [6], antitubercular
[7], antimalarial [8], anticancer [9] and antioxidant [10] activities.
Moreover, acylhydrazones exhibit strong coordination abilities
and flexible coordination modes due to the N, O donor atoms. It
has also been found that acylhydrazones containing pyridine ring
which, much attention has been paid to Co and Cu complexes
[11–15]. Cobalt and copper are indispensable trace elements in
the human body. Co2+ could involve in the synthesis of vitamin
B12 in vivo, which indirectly regulates the synthesis of DNA [16]
while Cu2+ plays a vital role in enzymatic reactions [17–20]. When
Co2+ or Cu2+ ion coordinates with organic ligand, the polarity of Co
or Cu complex would be deduced because
p-electron is delocal-
izated over the chelate ring and the donor groups also partially
share positive charge of the metal ion. And the reduction in polar-
ity enhances the lipophilicity of the complex which consequently
makes the permeation of complex through the lipid layer of organ-
ism more efficient [21,22].
Besides, DNA is the primary target for many kinds of drugs
[23–28] and it plays an important role in gene regulation during
⇑
Corresponding author.
E-mail address: liuxiangrongxk@163.com (X.-r. Liu).
https://doi.org/10.1016/j.poly.2020.114619
0277-5387/Ó 2020 Elsevier Ltd. All rights reserved.

2
J. Yang et al. / Polyhedron 187 (2020) 114619
the life process. Metal complexes could bind to DNA through
electrostatic effect, groove binding or intercalation [29]. Serum
albumins are significant biological macromolecules which can
reversibly bind to drug molecules and transport them to target
tissues and organs [30]. Compared with normal cells, tumor tissue
cells have high vascular densities, large gaps between endothelial
cells and abnormal lymphatic drainage. These abnormal features
lead to the enhanced permeability and retention (EPR) effect of
tumor tissue cells. Because of the EPR effect, complex-albumin
adduct can easily accumulate in tumor tissue cells to meet their
high energy needs for proliferation rather than normal cells
[31,32]. Thus, serum albumins greatly influence the distribution
and absorption of drugs [33]. Therefore, investigation on the inter-
actions between the compound and DNA/serum albumins could
ascertain the mechanism of drug effect and be beneficial in the
design of new chemotherapy metal-based drugs [34].
In this work, a new acylhydrazone ligand containing pyridine
ring (HL) and its Co(Ⅱ) (1), Cu(Ⅱ) (2) complexes were synthesized
and their single crystals were obtained as well. The ligand and
the complexes were characterized by elemental analyses, single-
crystal X-ray diffraction, FT-IR and TG-DTG. The binding abilities
of HL, 1 and 2 with calf thymus DNA (CT-DNA) were studied by
UV–Vis spectroscopy. And the interactions of HL, 1 and 2 with
bovine serum albumin (BSA) were explored by fluorescence spec-
troscopy. The interaction enthalpies and interaction time of HL, 1
and 2 with CT-DNA/BSA were determined by microcalorimetry.
Moreover, in order to identify binding locations and mechanisms,
the molecular docking of the three compounds with DNA/BSA were
performed on Autodock 4.0 software. Staphylococcus aureus and
Bacillus subtilis were used to evaluate the antibacterial activities
of all compounds.
2.2.2. Synthesis of HL (2-acetylpyridine-4-hydroxy phenylacetyl
acylhydrazone)
2-acetylpyridine-4-hydroxy phenylacetyl acylhydrazone was
synthesized by the reaction of 4-hydroxy phenylacetyl hydrazine
(0.0498 g, 0.3 mmol) and 2-acetylpyridine (33.6 mL, 0.3 mmol) in
methanol (15 mL). And 2–3 drops acetic acid were added into
the mixture as the catalyst. The mixture solution was refluxed
and stirred for 3 h under 65 °C. Then the resultant solution was fil-
tered and stood for 3 d at room temperature. The colorless single
crystals were obtained. Yield: 72.46%. M.p.: 181–182 °C. Anal. Calc.
for C15H15N3O2 (%) HL: C, 66.90; H, 5.61; N, 15.60. found: C, 67.15;
H, 5.41; N, 15.13. IR (KBr, cmꢀ1): (
1596.
mN-H) 3256, (mC=O) 1625, (mC=N)
2.2.3. Synthesis of 1 ([Co(HL)L]NO3)
1 was prepared by stirring a mixture solution of HL (0.0538 g,
0.4 mmol), 5–10 drops pyridine and cobaltous nitrate hexahydrate
(0.0290 g, 0.2 mmol) in ethanol (15 mL) for 4 h under 80 °C. The
resultant solution was filtered and stood for 3 d at room tempera-
ture. The dull-red single crystals were obtained. Yield: 68.36%. M.
p.: 242–244 °C. Anal. Calc. for C30H31CoN7O7 (%) 1: C, 54.67; H,
4.43; N, 14.88. found: C, 54.28; H, 4.72; N, 14.26. IR (KBr, cmꢀ1):
(mN-O) 1376, (mN-H) 3240, (mC=O) 1608, (mC=N) 1502, (mCo-O) 538,
(mCo-N) 774 [35].
2.2.4. Synthesis of 2 ([Cu(HL)2]NO3)2)
2 was prepared by stirring a mixture solution of HL (0.0538 g,
0.4 mmol) and cupric nitrate trihydrate (0.0242 g, 0.2 mmol) in
methanol (15 mL) for 4 h under 65 °C. The resultant solution was
filtered and stood for 3 d at room temperature. The green single
crystals were obtained. Yield: 69.28%. M.p.: 204–205 °C. Anal. Calc.
for C30H30CuN8O10 (%) 2: C, 49.58; H, 4.16; N, 15.43. Found: C,
50.22; H, 3.72; N, 15.11. IR (KBr, cmꢀ1): (
C=O) 1605, ( C=N) 1585, ( Cu-O) 535, ( Cu-N) 634. The synthetic
mN-O) 1380, (mN-H) 3247,
2. Experimental
(m
m
m
m
routes of HL, 1 and 2 are shown in Scheme 1.
2.1. Chemicals and methods
All chemicals are commercially available for analytical grade
and used without further purification. Elemental analyses (C, H
and N) for the compounds were carried out on a P.E. 2400-II instru-
ment. Infrared spectra were obtained on a Bruker Tensor-Ⅱ Fourier
infrared spectrometer. The crystal structures of compounds were
2.3. Thermogravimetric experiments of HL, 1 and 2
The TG curves of test compounds were obtained in N2 atmo-
sphere within the temperature range of room temperature to
800 °C. And the heating rates were set as 5, 10 and 15 °Cꢁminꢀ1
.
performed with graphite monochromator Mo-K
(k = 0.71073 Å) on a Bruker Smart Apex II CCD diffractometer
and the data were collected by the /2h scan technique at 296(2)
a radiation
2.4. CT-DNA-binding studied by UV–vis spectroscopy
x
The CT-DNA solution (2.88 ꢂ 10-4 M) was prepared by dissolv-
ing CT-DNA in Tris-HCl buffer solution (0.01 M, pH = 7.9). And the
UV–Vis spectra of CT-DNA solution showed bands at 260 nm and
280 nm with a 1.8:1 ratio suggesting that the CT-DNA is free from
protein. Test compounds were dissolved in mixed solution of
DMSO and Tris-HCl (5:95, V/V) with concentration of 1 ꢂ 10-4 M.
K. The crystal structures were solved by direct methods and fined
by full-matrix least-squares on F2 with the SHELXL program. Ther-
mogravimetric analysis was carried out by the Mettler Toledo TGA
analyzer. UV–Vis spectra were used to study the interaction
between compounds and CT-DNA on TU-1900 spectrophotometer.
BSA binding abilities of compounds were monitored by P. E. Fluo-
rescence spectrometer LS55 (kex = 280 nm). Interaction enthalpies
of compounds with CT-DNA/BSA were measured by C80
microcalorimeter. Antibacterial evaluations of compounds were
determined by Mueller-Hilton agar media. The cellular uptake
amounts of cobalt/copper complexes were measured by using Nex-
ION 350D ICP-MS.
CT-DNA solution (50 lL for each time) was dropped into the solu-
tions of test compounds (3 mL) and reference solution (Tris-HCl-
DMSO buffer solution). After each addition of CT-DNA, the UV–Vis
spectra were recorded in the range of 250–500 nm under 28 °C.
2.5. BSA-binding studied by fluorescence spectroscopy
2.2. Synthesis of compounds
BSA solution (1 ꢂ 10ꢀ7 M) was prepared by dissolving BSA in
Tris-HCl-NaCl buffer solution (0.01 M, pH = 7.2). The solutions of
test compounds (1 ꢂ 10ꢀ4 M) were prepared by dissolving them
in a mixture of DMSO and Tris-HCl-NaCl buffer (5:95, V/V). Then
2.2.1. Synthesis of 4-hydroxy phenylacetyl hydrazide
An alcoholic solution (5 mL) of methyl 4-hydroxyphenylacetate
(1.6617 g, 10 mmol) was added to 80% hydrazine hydrate (8 mL)
under continuous stirring. The mixture was heated at 80 °C and
refluxed for 2–3 h. Then resultant solutions were filtered and stood
for 3 d at room temperature to give the colorless crystals.
the solutions of test compounds (30
lL for each time) were
dropped into the BSA solution (3 mL) and reference solution. The
mixed solution was monitored by fluorescence spectrometer in
the wavelength range of 300–540 nm under 28 °C. The excitation

J. Yang et al. / Polyhedron 187 (2020) 114619
3
Scheme 1. Synthetic routes of HL, 1 and 2.
wavelength was 280 nm and the excitation/emission slit widths
were all 5 nm.
studies of three compounds interacting with DNA/BSA were done
on Autodock 4.0 software. Genetic Algorithm was selected as 100
runs to search best conformer. For each of the docking case, the
lowest energy conformation was selected as the binding mode.
The visualization of the docked pose was performed using Pymol
and Discovery Studio 4.5.
2.6. Microcalorimetry experiments of HL, 1 and 2 with CT-DNA/BSA
The solutions of test compounds (1 mL, 1 ꢂ 10-4 M) and Tris-
HCl/Tris-HCl-NaCl buffer solution (1 mL) were added in the bottom
of the sample cell and reference cell respectively. Then 2 mL of CT-
DNA (2.88 ꢂ 10-4 M) or BSA solutions (1 ꢂ 10-7 M) were added in
both up of sample cell and reference cell. The sample cell and ref-
erence cell were put into microcalorimeter. After the baseline of
heat flow was stable, the solutions in upper and bottom cells were
mixed. And the heat flows of the reaction were recorded at 28 °C.
2.8. Antibacterial tests
Antibacterial activities of the ligand and its Co and Cu com-
plexes were tested by the agar well diffusion method using nutri-
ent agar media. Each test compound was dissolved in an aqueous
solution of DMSO as the co-solvent with a concentration of
D
H was obtained by integrating exothermic peak.
200
l
gꢁmLꢀ1. Two species of pathogenic bacteria, Staphylococcus
2.7. Molecular docking studies of HL, 1 and 2 with DNA/BSA
aureus (S. aureus) and Bacillus subtilis (B. subtilis) were used to
screen the antibacterial activities of compounds. Pathogenic bacte-
rial strains were incubated in sterile nutrient broth at 37 °C for
24 h. Per dish contains 10 mL nutrient agar and 2 mL inoculums
of bacterial strain (106 cfuꢁmLꢀ1). The Oxford cups were placed in
The crystal structures of DNA (PDB ID: 1XRW) and BSA (PDB ID:
3 V03) were chosen from RCSB Protein Data Bank (http://www.
rcsb.org/pdb). The ligands were removed from 1XRW.pdb and
3 V03.pdb by using Discovery Studio 4.5. The crystal structures
of three compounds were obtained from X-ray single crystal data,
and CIF files were converted into PDB format using Mercury soft-
ware. 1, 2 and HL were added Gasteiger charges and merged
non-polar hydrogen atoms by Autodock tools. Molecular docking
a solidified medium. 250
lL of each test compound solution was
poured in the respective cups and the plates including control
group were incubated 16–18 h at 37 °C. The experiment was per-
formed in triplicate under strict aseptic conditions and the antibac-
terial activity of each compound was expressed in terms of the

4
J. Yang et al. / Polyhedron 187 (2020) 114619
mean diameter of zone of inhibition (mm) produced by the respec-
tive compound.
try. In complex 1, the bond length of C8-O2 (1.303(5) Å) is closed to
that of C8-N1 (1.314(6) Å), it could be deduced that there exists an
electron conjugated effect among C8-O2-N1 which causes the loss
of a proton. Fig. S2 and Table S1 show 1 has four hydrogen bonds
between ligand and NOꢀ3 to form a scissors configuration. As shown
in Fig. S3 and Table S1, 2 has seven hydrogen bonds between ligand
and NOꢀ3 forming a 2D structure. As far as the bond lengths of Cu
complex are concerned, it is worth highlighting that the Cu1-O2
(2.183(2)Å) and Cu1-O4 (2.360(2)Å) are longer than Co1-O2
(1.904(3)Å) and Co1-O4 (1.911(3)Å) (Table 2), as a result of tetrag-
onal elongation. Similar variation has already been observed in
other literature [40,41]. The presence of tetragonal distortion leads
to the conformation change of the octahedral geometry of the com-
plexes. And the difference in the configuration moves the bonding
sites of the complex away or towards the DNA. Therefore, the
tetragonal distortion could influence the interactions of complex
with DNA [42].
2.9. Cellular uptake studies using ICP-MS
Overnight cultured S. aureus and Bacillus subtilis (106 cfuꢁmLꢀ1
)
were incubated with either 1 or 2 (150
l
gꢁmLꢀ1) for 16 h at 37 °C.
After incubation, the culture tubes were centrifuged for 20 min and
the resulting supernatant was removed. Then the cell pellets were
washed three times with PBS buffer solution (5 mL) and re-cen-
trifuged every time. Cellular pellets were digested with 200 uL of
70% HNO3 and then diluted to 5 mL with 3% HNO3. The obtained
samples were measured by ICP-MS to determine the cobalt/copper
content.
3. Results and discussion
3.1. Structure descriptions
3.2. Thermal stabilities
The molecular structures and the illustrations of bond distance
of HL, 1 and 2 are presented in Figs. 1–3. View of hydrogen bonds
of HL, 1 and 2 are illustrated in Figs. S1–S3. The crystallographic
data for HL, 1 and 2 are given in Table 1. The selected bond lengths
(Å) and angles (°) are displayed in Table 2. Hydrogen bond lengths
(Å) and angles (°) are shown in Table S1.
HL crystallized in the monoclinic system, space group P21/c
with bond distances and angles in the expected ranges. As shown
in Table 2, C8-O2 (1.223(6) Å) is a typical C@O double bond [36].
And the N2-C9 (1.275(6) Å) is shorter than the CAN single bond
(1.47 Å) [37], which could be classified as a C@N double bond
[38,39]. These data show that HL includes a keto group. The dihe-
dral angle of the pyridine ring and benzene ring in HL is 72.14°
which indicates that they are not in the same plane. The torsion
angles of N2-N1-C8-C7 (-178.8(4)°) and N1-N2-C9-C10 (179.5
(4)°) show that the N1 and N2 atoms are not in exact parallel
planes. Fig. S1 is the view of hydrogen bonds in HL and there are
two kinds of hydrogen bonds N1-H1. . .O2 and O1-H1A. . .N2
between the adjacent molecule which forms the 2D structure in
HL.
Complex 1 and 2 crystallized in the orthorhombic system, space
group Pbca and monoclinic system, space group P21/n, respectively.
As seen from Fig. 2, within the cationic unit, Co2+ ion was coordi-
nated by an anionic ligand L-, a neutral ligand HL and NOꢀ3 anion
presenting in the complex to neutralize the charge of cation.
Fig. 3 shows 2 consists of a Cu2+ ion, two neutral ligands and the
other two NOꢀ3 anions in the complex which is different from 1.
For complexes 1 and 2, the coordination environments of Co2+
and Cu2+ ions both contain nitrile nitrogen (N2, N5), pyridyl nitro-
gen (N3, N6), keto oxygen (O2, O4) atoms, which occupy the apical
positions of the polyhedron to form a distorted octahedral geome-
The thermal stabilities of HL, 1 and 2 were studied at heating
rates of 5, 10 and 15 °Cꢁminꢀ1 in the temperature range from room
temperature to 800 °C. The TG curves of HL, 1 and 2 at the heating
rate of 5 °Cꢁminꢀ1 are plotted in Fig. 4 and DTG curves at three
heating rates are shown in Figs. S4-S6, separately. According to
Fig. 4 and Fig. S4, the thermal decomposition of HL characterized
by one stage. HL loses 73.62% of its mass at 199.73–420.17 °C,
which is assigned to the bond breaking of C9-C10 (calcd. 71.00%).
The loss group for HL in thermal decomposition processes are illus-
trated in Fig. S7. As seen from Fig. 4 and Fig. S5, complex 1 under-
goes three stage of decomposition. The first decomposition stage of
1 at 221.46–285.07 °C with the weight loss of 11.37% resulting
from the loss of NOꢀ3 (calcd. 10.16%). In the second stage, the
weight loss is 22.61% at 285.07–463.69 °C. TG curve shows a
weight loss of 56.74% in the temperature range of 463.69–800 °C
at third stage. For complex 2, one significant weight loss peak is
observed from Fig. 4 and Fig. S6. It occurs with the weight loss of
19.83% at 181.61–252.90 °C corresponding to the loss of two
NOꢀ3 (calcd. 17.09%). Further, 2 undergoes few hardly distinguish-
able stages and did not completely decomposed until 800 °C.
The kinetic parameters of main decomposition process, such as
pre-exponential factor (A) and apparent activation energy (Ea) of
three compounds were calculated by Kissinger (1) and Ozawa (2)
equations [43]:
!
ꢀ
ꢁ
b
Tp2
AR
Ea
Ea
RTp
ln
¼ ln
ꢀ
ðKissingerÞ
ð1Þ
ð2Þ
ꢂ
ꢃ
AEa
RGð
Ea
RTp
lgb ¼ lg
ꢀ 2:315 ꢀ 0:4567
ðOzawaÞ
a
Þ
Fig. 1. Molecular structure of HL with 30% probability and the illustration of bond distance.

J. Yang et al. / Polyhedron 187 (2020) 114619
5
Fig. 2. Molecular structure of 1 with 30% probability and the illustration of bond distance.
Fig. 3. Molecular structure of 2 with 30% probability and the illustration of bond distance.
Table 1
are listed in Table 3. It can be seen that the results calculated from
the two methods are consistent and the Ea values follow the order:
2 > 1 > HL. Therefore, the decomposition of complex 2 requires
more energy. And 2 displays the most excellent thermal stability
among three compounds which may be related to its maximum
number of hydrogen bonds [44].
Crystallographic data for HL, 1 and 2.
HL
1
2
CCDC number
formula
1474071
15H15N3O2
1524772
[Co(HL)L]NO3 [Cu(HL)2]
(NO3)2
1475317
C
formula weight
crystal system
space group
a (Å)
b (Å)
c (Å)
269.30
monoclinic
P21/c
9.468(5)
16.836(9)
8.776(5)
90.00
99.669(10)
90.00
1379.1(13)
4
1.297
568
2.18–25.100
296(2)
658.53
726.16
orthorhombic monoclinic
Pbca
13.077(2)
18.739(3)
23.709(4)
90.00
90.00
90.00
5809.7(17)
8
1.510
3.3. Interaction of the compounds with CT-DNA
P21/n
1.3813(2)
1.2432(2)
1.9122(3)
90.00
102.779(3)
90.00
3202.4(9)
4
1.506
The binding behavior of the small molecule with CT-DNA was
often investigated by UV–Vis absorption spectra. Generally, the
changes in absorption spectra are closely related to DNA-binding
mode. The absorption spectra of HL, 1 and 2 interacting with CT-
DNA are given in Fig. S8, Fig. 5 and Fig. 6, respectively. The intrinsic
binding constants Kib of HL, 1 and 2 were calculated under the fol-
lowing equation (3) [45]:
a
(°)
b (°)
c
(°)
V (Å3)
Z
Dc(gꢁcmꢀ3
F (0 0 0)
h Range
T (K)
)
2744
2.08–25.10
296(2)
1500
1.66–25.10
296(2)
½DNAꢃ
½DNAꢃ
1
¼
þ
ð3Þ
ea
ꢀ
ef eb
ꢀ
ef Kibðeb
ꢀ
ef
Þ
final R indices (I > 2sigma
(I))
R1 = 0.1124
wR2 = 0.3914 wR2 = 0.1296 wR2 = 0.1201
R1 = 0.11455
R1 = 0.0445
where [DNA] represents the concentration of CT-DNA,
e
a the appar-
ent extinction coefficient of the compound in the presence of CT-
DNA, eb the molar extinction coefficient for the free compound
and ef the molar extinction coefficient for compound fully binding
with CT-DNA. The insets in Fig. S8, Fig. 5 and Fig. 6 show the plots
where Tp is the maximum temperature of endothermic peak in the
fastest decomposition stage, R the gas constant, b the heating rate,
and G(a) the integral mechanism function. The calculated results

6
J. Yang et al. / Polyhedron 187 (2020) 114619
Table 2
Selected bond lengths (Å) and angles (°) for HL, 1 and 2.
compound
bond length
bond angle
torsion angle
HL
O1-C3 1.362(6)
O2-C8 1.223(6)
N1-C8 1.355(6)
N1-N2 1.398(5)
N2-C9 1.275(6)
Co1-N2 1.854(4)
Co1-N3 1.923(4)
Co1-N6 1.947(4)
Co1-N5 1.853(3)
Co1-O2 1.904(3)
Co1-O4 1.911(3)
C8-O2 1.306(5)
C8-N1 1.314(6)
C9-N2 1.295(6)
Cu1-N2 1.937(3)
Cu1-N3 2.047(3)
Cu1-O2 2.183(2)
Cu1-N5 1.962(3)
Cu1-N6 2.168(3)
Cu1-O4 2.360(2)
C8-O2 1.234(4)
C8-N1 1.347(4)
C9-N2 1.285(4)
O1-C3-C4 123.2(4)
O2-C8-N1 124.2(4)
C8-N1-N2 118.5(4)
N2-N1-C8-O2 2.8(7)
N2-N1-C8-C7 ꢀ178.8(4)
N2-C9-C10-N3 173.0(5)
N1-N2-C9-C10 179.5(4)
C8-N1-N2-C9 ꢀ158.0(4)
Co1-N2-N1-C8 0.6(5)
O2-Co1-N2-N1 ꢀ0.1(3)
N5-Co1-O4-C23 ꢀ2.0(3)
Co1-N5-N4-C23 2.4(4)
N2-Co1-O2-C8 ꢀ0.5(3)
N2-N1-C8-C7 175.7(4)
N3-Co1-N2-N1 ꢀ179.9(3)
N5-Co1-N6-C25 ꢀ1.0(3)
O4-Co1-N5-C24 ꢀ179.5(4)
N2-Cu1-O2-C8 13.4(2)
N5-Cu1-O4-C23 22.5(2)
N3-Cu1-N2-C9 0.0(3)
N2-C9-C15 126.8(4)
C14-N3-C10 117.5(5)
N2-Co1-O2 82.17(16)
N2-Co1-N3 82.69(18)
N5-Co1-O4 82.17(14)
N5-Co1-N6 81.98(15)
N5-Co1-N2 179.23(18)
O2-Co1-N3 164.85(15)
O2-Co1-O4 88.65(13)
N5-Co1-N3 97.96(16)
O4-Co1-N6 164.08(14)
N2-Cu1-O2 76.75(10)
N3-Cu1-N2 79.50(11)
N5-Cu1-O4 72.97(10)
N5-Cu1-N6 77.08(11)
N2-Cu1-N5 176.46(11)
O2-Cu1-N3 152.39(10)
O2-Cu1-O4 87.11(8)
N5-Cu1-N3 103.87(11)
N6-Cu1-O4 146.10(10)
1
2
N6-Cu1-N5-C24 ꢀ8.0(2)
C8-N1-N2-Cu1 12.6(3)
C23-N4-N5-Cu1 18.2(3)
N5-Cu1-N3-C14 0.0(3)
N5-Cu1-N3-C10 ꢀ176.9(2)
N2-Cu1-N6-C29 ꢀ3.5(3)
of [DNA]/(ea
– ef)] versus [DNA]. The binding constants Kib, calcu-
obtained for 1 and 2 suggested that complexes 1 and 2 are strongly
lated by the ratio of slop to the intercept are listed in Table 4.
As observed in Fig. S8, the absorption spectra band at 283 nm
showed hypochromism and a slight red shift from 283 to 285 nm
with the addition of CT-DNA into HL. It indicated that the empty
bound to CT-DNA by intercalation mode [49].
3.4. Interaction of the compounds with BSA
p
p
* orbital of HL couples with a
* transition energies were decreased [46]. For 1, the band
* tran-
p orbital of CT-DNA and the
Serum albumins (BSA) has been used in this experiment due to
its low cost, wide availability and structural similarity to human
serum albumins. Small molecules binding to BSA can be measured
by fluorescence spectra. Fig. S9, Fig. 7 and Fig. 8 show the effects of
test compounds on the fluorescence intensities of BSA. It can be
seen that BSA emits a strong fluorescence peak at 340 nm when
the exciting wavelength is 280 nm. And continuous addition of
compounds into BSA solution quenched the endogenous fluores-
cence of BSA which indicates that HL, 1, 2 could bind to the BSA
and result in microenvironment change around the tryptophan of
the BSA [50,51].
?
p
at 263 nm (Fig. 5) is probably due to the intra-ligand
p ? p
sitions of HL and the band at 358 nm is attributable to the ligand-
to-metal charge transfer (LMCT) transitions [47]. With the addition
of CT-DNA into 1, the absorption spectra band at 263 and 358 nm
show hypochromism and a slight red shift of 1 nm. Fig. 6 is similar
with Fig. 5, the band at 276 nm is assigned to
p ? p* transitions of
HL and 343 nm is representing the LMCT. Obvious hypochromism
were also observed at 276 and 343 nm and a slight red shift was
also observed from 276 nm to 284 nm. The intrinsic binding con-
stants Kib of HL, 1 and 2 are 2.56 ꢂ 105, 1.71 ꢂ 108 and
1.76 ꢂ 106 Mꢀ1 and the values of two complexes are all higher than
that of classical intercalator like EB (Kib = 3.3 ꢂ 105 Mꢀ1) [48]. The
spectral characteristic of hypochromism and and Kib values
To further clarify the quenching process, fluorescence quench-
ing data were analysis by Stern-Volmer equation (4) with the
hypothesis that dynamic process occurred [52,53]:
F0=F ¼ 1 þ Kqs0½Qꢃ ¼ 1 þ Ksv½Qꢃ
ð4Þ
where F0, F represent the fluorescence intensities in the absence and
presence of quencher, respectively, Ksv the Stern-Volmer quenching
constant, [Q] the quencher concentration, Kq the bimolecular
quenching constant, s0 the average lifetime of protein in the
absence of quencher, and its value is 10-8 s [54]. Ksv and Kq values
were obtained from the plots of F0/F versus [Q] (as insets in
Fig. S9, Fig. 7 and Fig. 8) and shown in Table S2.
The Kq values corresponding to HL, 1 and 2 go beyond the limit
of dynamic quenching rate constant 2 ꢂ 1010 Mꢀ1ꢁsꢀ1 [55]. Thus,
the preceding assumption is invalid and the quenching processes
of three compounds interacting with BSA are static quenching. It
can be described by Scatchard equation (5) [56]:
lg½ðF0 ꢀ FÞ=Fꢃ ¼ lgKA þ nlg½Qꢃ
ð5Þ
where KA and n are binding constant and the number of binding
sites, respectively. Binding constants obtained from the plots of lg
[(F0-F)/F] versus log[Q] (Fig. S10) and listed in Table 5.
In Table 5, the values of KA follow sequence 1>2>HL suggesting
that complexes have stronger protein-binding abilities than HL.
Fig. 4. TG curves of HL, 1 and 2 (b = 5 °Cꢁminꢀ1).

J. Yang et al. / Polyhedron 187 (2020) 114619
7
Table 3
Kinetic parameters of thermal decomposition processes of HL, 1 and 2.
compound
b (°C∙minꢀ1
)
Tp (°C)
Kissinger
Ea (kJ∙molꢀ1
155.7
Ozawa
)
lgA
r
Ea (kJ∙molꢀ1
157.2
)
r
HL
1
5
300.21
312.47
318.82
249.81
254.57
259.38
206.35
207.83
210.70
11.85
ꢀ0.9991
ꢀ0.9992
10
15
5
10
15
5
257.1
450.5
23.68
47.43
ꢀ0.9883
ꢀ0.9442
252.8
636.0
ꢀ0.9891
ꢀ0.9460
2
10
15
Table 4
Parameters for the interactions of HL, 1 and 2 with CT-DNA.
compound Kib (Mꢀ1
linear fitting equation
)
R2
HL
1
2.56 ꢂ 105 CDNA/(ea
-
e
f) = 1.202 ꢂ 10ꢀ4 CDNA
–
0.9911
4.69 ꢂ 10ꢀ10
1.71 ꢂ 108 CDNA/(ea
-
e
f) = 8.245 ꢂ 10ꢀ5
1
CDNA + 4.81 ꢂ 10ꢀ14
2
1.76 ꢂ 106 CDNA/(ea
-
e
f) = 7.933 ꢂ 10ꢀ5
0.9999
CDNA + 4.49 ꢂ 10ꢀ12
Fig. 5. UV–Vis absorption spectra of CT-DNA interacting with 1 (Inset: plot of
[DNA]/(ea f) versus [DNA]).
-
e
Fig. 7. Fluorescence emission spectrum of 1 interacting with BSA (Inset: plot of F0/F
versus [Q]).
Fig. 6. UV–Vis absorption spectra of CT-DNA interacting with 2 (Inset: plot of
[DNA]/(ea f) versus [DNA]).
-
e
Moreover, the values of binding site are close to 1, showing that
there exists a single binding site in BSA for HL, 1 and 2. Thus, the
tryptophan residues involved in the interactions might be Trp213
or Trp134 [57]. Overall, BSA can be considered as an excellent car-
rier to transport the entire three compounds in vivo.
Fig. 8. Fluorescence emission spectrum of 2 interacting with BSA (Inset: plot of F0/F
versus [Q]).

8
J. Yang et al. / Polyhedron 187 (2020) 114619
Table 5
Parameters for the interactions of HL, 1 and 2 with BSA calculated by Scatchard equation.
compound
KA (Mꢀ1
)
n
linear fitting equation
R2
HL
1
2
1.03 ꢂ 104
4.20 ꢂ 104
1.24 ꢂ 104
0.89
0.93
0.90
lg[(F0-F)/F] = 0.89lg[Q] + 4.01
lg[(F0-F)/F] = 0.93lg[Q] + 4.62
lg[(F0-F)/F] = 0.90lg[Q] + 4.09
0.9921
0.9735
0.9840
values of
CT-DNA/BSA are all endothermic. All the
indicating that interaction processes are spontaneous reaction and
driven by entropy. Moreover, H > 0, S > 0 mean that hydrophobic
D
H suggest that the interaction between HL, 1, 2 and
DG values are negative,
D
D
forces play a major role in the binding between HL, 1, 2 and CT-
DNA/BSA [60,61].
3.6. Molecular docking studies of compounds with DNA/BSA
The molecular docking technique was used to identify binding
locations and mechanisms of three compounds interacting with
DNA/BSA. Docking studies have been performed on DNA with the
sequence of d(CCTCGTCC)2 in the presence of HL, 1 and 2. The best
docking perspectives of three compounds with DNA are shown in
Fig. S11, Fig. 11 and Fig. 12. These docked poses show the interca-
lation mode of DNA with HL, 1 and 2 which is agreement with the
spectroscopy experiment results. O2 atom and O1-H1A group of HL
formed two hydrogen bonds with DG5 in DNA double strand. There
are several hydrophobic contacts between HL and DG4, DG5 in
DNA double strand. In the case of complex 1, hydrogen bonding
interaction was observed between N1-H4 group and phosphate
oxygen atom of DC7. O1-H1A group exhibited hydrogen bonding
interactions with oxygen atom of DG5. The NAH group of DG5 in
another DNA strand formed hydrogen bond with O2 atom in 1.
Additionally, 1 has hydrophobic contacts with bases of DNA at
DG 4, DG 5 and DT6. The O3-H3 group in complex 2 interacted with
deoxyribose oxygen atoms of DG2 to form hydrogen bond. Also,
NAH groups in DC4 residue displayed hydrogen bonding with O2
and O5 atoms of complex 2. In addition, there also exist hydropho-
bic interactions between 2 and DA3, DC4, DG5, DC4 nucleobases.
The best docking poses of three compounds with BSA are shown
in Fig. S12, Fig. 13 and Fig. 14. As can be seen, HL docked around
Trp134 in subdomain IB, whereas complex 1 and 2 docked around
Trp213 in subdomain IIA [59]. It also supports the fluorescence
quenching of tryptophan in BSA in presence of HL, 1 and 2 which
is obtained from fluorescence spectroscopy experimental results
(Section 3.4). In ligand HL, OAHꢁ ꢁ ꢁO hydrogen bond formed
between the compound and the ASP108 residue. It also involved
in hydrophobic interactions with ARG196, HIS145, ARG144 and
PRD110. Similarly, The O1-H1A group in complex 1 interacted with
oxygen atom of GLU339 residue to form hydrogen bond. There also
exists electrostatic interaction between 1 and protein residue
GLU443. Several categories of hydrophobic interactions were
Fig. 9. Thermogenic curves of HL, 1 and 2 with CT-DNA.
Fig. 10. Thermogenic curves of HL, 1 and 2 with BSA.
3.5. Microcalorimetry studies of compounds with DNA/BSA
Figs. 9 and 10 are the thermogenic curves of HL, 1 and 2 inter-
acting with CT-DNA and BSA, respectively. Gibbs’ free energy
detected between
1 and GLU293, LYS294, ARD217, VAL342,
change (
D
G) and entropy change (
D
S) are calculated by the equa-
PRO446 and CYS447. The OAH group in complex 2 also interacted
with oxygen atoms of GLN220 and TYR156 to form two hydrogen
bonds. And the NAH group of ARG194 formed hydrogen bond with
O4 atom in 2. In addition, complex 2 exhibited electrostatic inter-
action with GLU291 and hydrophobic interactions with ARG217,
LYS221 and LYS187.
tions (6) and (7) [58,59]:
D
S ¼ ðD
H ꢀ
D
GÞ=T
ð6Þ
ð7Þ
D
G ¼ ꢀRTlnK
where
D
H is enthalpy change obtained by integrating the peak area,
According to the molecular docking studies results, hydroxyl
group of benzene ring, benzene ring, pyridine ring, and carbonyl
group of test compound are the most favorable binding site in
DNA/BSA interaction. Hydrophobic force is the main force in the
binding of HL, 1 and 2 to DNA/BSA which is consistent with the
microcalorimetry experimental results.
R the gas constant, T the experimental temperature, K the binding
constant has been calculated by equation (3) and (5) as above men-
tioned. The corresponding parameters are listed in Table S3. As
shown in Figs. 9, 10 and Table S3, the duration time of DNA/BSA
interaction is within 40 min for each compound and the positive

J. Yang et al. / Polyhedron 187 (2020) 114619
9
Fig. 11. Molecular docking perspective of the 1 with DNA and three-dimensional interactions generated by Discovery Studio 4.5 (right).
Fig. 12. Molecular docking perspective of the 2 with DNA and three-dimensional interactions generated by Discovery Studio 4.5 (right).
3.7. Antibacterial activities studies
that both Co and Cu were accumulated in S. aureus and B. subtilis.
The amount of Co accumulation in S. aureus is bigger than that of
Cu. And the cellular uptake amounts of Co and Cu in B. subtilis
are basically the same and all lower.
S. aureus and B. subtilis are used to evaluate the antibacterial
activities of HL, 1 and 2. From the data presented in Table S4, it
can be seen that 1 exhibits best antibacterial activity against S. au-
reus with a MIC value of 150
against S. aureus (if antimicrobial zone less than 8 mm, the com-
l
gꢁmLꢀ1 while HL and 2 are inactive
4. Conclusion
pound can be judged inactive for bacteria). Also, HL can inhibit
A new ligand 2-acetylpyridine-4-hydroxy phenylacetyl acylhy-
drazone (HL) and its two complexes [Co(HL)L]NO3 (1) and [Cu
(HL)2](NO3)2 (2) were synthesized. The results of single-crystal
XRD showed 1 and 2 are mononuclear and belong to orthorhombic,
space group Pbca and monoclinic, space group P21/n, respectively.
Thermal stability of three compounds follow the sequence:
2>1>HL. The interactions of 1, 2 and HL with CT-DNA/BSA were
studied by UV–Vis spectroscopy and fluorescence spectroscopy
separately, revealing intercalation mode between compounds
and CT-DNA and static quenching smechanism in BSA fluorescence
quenching. The binding constants of three compounds interacting
with CT-DNA/BSA both follow the order: 1>2>HL. Microcalorime-
the growth of B. subtilis with a MIC value of 200
l
gꢁmLꢀ1. This
may be due to 1 possesses excellent binding ability with CT-
DNA/BSA, which is playing an essential role in the antibacterial
activity. Besides, the antibacterial ability of metal complexes could
also be related to the nature of ion, geometry of complexes, steric,
pharmacokinetic, hydrophilicity and lipophilicity [62].
3.8. Cellular uptake of complexes into bacterial cells
The cellular uptakes results of the complexes 1 and 2 into S. aur-
eus and B. subtilis are displayed in Table 6. These results showed

10
J. Yang et al. / Polyhedron 187 (2020) 114619
Fig. 13. Molecular docking perspective of the 1 with BSA (left) and three-dimensional interactions generated by Discovery Studio 4.5 (right).
Fig. 14. Molecular docking perspective of the 2 with BSA and three-dimensional interactions generated by Discovery Studio 4.5 (right).
2.59 l
g/106 cells which is bigger than that of Cu, the accumulations
of Co and Cu in B. subtilis are all lower.
Table 6
Cellular uptakes of complexes 1 and 2 into S. aureus and B. subtilis.
bacteria
complex 1
Co (
g/106 cells)
complex 2
Cu (
g/106 cells)
l
l
CRediT authorship contribution statement
S. aureus
B. subtilis
2.59
1.41
1.19
1.44
Jie Yang: Investigation, Writing - original draft. Xiang-rong Liu:
Investigation, Writing - review & editing, Funding acquisition.
Ming-kun Yu: Investigation. Wen-bo Yang: Validation. Zai-wen
Yang: Data curation. Shun-sheng Zhao: Formal analysis.
try results showed the interactions of three compounds with CT-
DNA/BSA are endothermic processes and hydrophobic force mainly
contributes in the interaction between 1, 2, HL and CT-DNA/BSA.
Molecular docking results confirmed the intercalation mode
between compounds and CT-DNA. And HL docked around Trp134
in subdomain IB, whereas complex 1 and 2 docked around
Trp213 in sub-domain IIA. Hydroxyl group of benzene ring, ben-
zene ring, pyridine ring, and carbonyl group of three compounds
were main binding sites in DNA/BSA interaction. Antibacterial
studies showed that 1 and HL can inhibit the growth of B. subtilis
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
and S. aureus with MIC values of 150
l
gꢁmLꢀ1 and 200
l
gꢁmLꢀ1
,
This work was supported by the National Natural Science Foun-
dation of China (Nos. 21073139, 21373158, U1903133), Science
respectively. The amount of Co accumulation in S. aureus is

J. Yang et al. / Polyhedron 187 (2020) 114619
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