Urease inhibition studies of six Ni(II), Co(II) and Cu(II) complexes with two sexidentate N2O4-donor bis-Schiff base ligands: An experimental and DFT computational study

Article abstract of DOI:10.1016/j.jinorgbio.2019.110959

Six novel complexes, [Ni(C₃₆H₃₄N₂O₁₀)]·2.25CH₃OH·0.5C₄H₁₀O (1), [Co(C₃₆H₃₄N₂O₁₀)] (2), [Cu(C₃₆H₃₄N₂O<

Full text of DOI:10.1016/j.jinorgbio.2019.110959

JournalofInorganicBiochemistry204(2020)110959
Contents lists available at ScienceDirect
Journal of Inorganic Biochemistry
journal homepage: www.elsevier.com/locate/jinorgbio
Urease inhibition studies of six Ni(II), Co(II) and Cu(II) complexes with two
sexidentate N2O4-donor bis-Schiff base ligands: An experimental and DFT
computational study
⁎
⁎
Hu Wanga, Cungang Xua, Xia Zhanga, Dongmei Zhanga, Fan Jinb, , Yuhua Fana,
a Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, Qingdao,
China
b HITS-Heidelberg Institute for Theoretical Studies, Schloß Wolfsbrunnenweg 35, 69118 Heidelberg, Germany
A R T I C L E I N F O
A B S T R A C T
Keywords:
Six novel complexes, [Ni(C36H34N2O10)]·2.25CH3OH·0.5C4H10
O
(1), [Co(C36H34N2O10)] (2), [Cu
Metal complex
X-ray structure
Theoretical calculation
Urease inhibitor
Molecular docking
(C36H34N2O10)]·2CH3OH (3), [Ni(C36H32N2O8Cl2)]·2CH3OH (4), [Co(C36H32N2O8Cl2)]·4CH3OH (5) and [Cu
(C36H32N2O8Cl2)]·2CH3OH (6) with two sexidentate N2O4-donor bis-Schiff base ligands (C36H34N2O10 = 1,2-bis
(2-methoxy-6-formylphenoxy)ethane-L-tyrosine; C36H32N2O8Cl2 = 1,2-bis(2-methoxy-6-formylphenoxy)ethane-
L-4-chlorophenylalanine) have been synthesized and structurally characterized. Theoretical calculation of the six
complexes was carried out by density functional theory (DFT) Becke's three-parameter hybrid (B3LYP) method
employing the 6-3lG basis set, indicating that the calculation results are in accordance with experimental results.
Moreover, the inhibitory activities of complexes 1–6 were tested in vitro against jack bean urease. At the same
time, molecular docking was investigated to determine the probable binding mode. The experimental values and
docking simulation exhibited that complexes 3 and 6 showed strong inhibitory activity (IC50 = 10.36
1.13,
15.63
3.04 μM) compared with the positive reference acetohydroxamic acid (IC50 = 26.99
1.43 μM).
Their structure-inhibitory activity relationship was further discussed from the perspective of molecular docking
and theoretical calculation.
1. Introduction
Urease is implicated in the pathogenesis of a number of human
pathogens, including bacteria Yersinia enterocolitica, Proteus mirabilis
In the past few decades, the research of pharmaceutical inorganic
chemistry has developed rapidly. Metal complexes have various im-
portant therapeutic applications in different areas, such as cancer
treatment [1–5], antibacterial therapy [6–8], and anti-inflammatory
agents [9–11]. The metallodrugs play an important role in the process
of enzyme inhibition due to their unique mode of interaction compared
with common organic inhibitor. The metal ion is the key of the good
inhibitory activities of metal complexes and the activities are mainly
influenced by coordination environment of the metal ion and its oxi-
dation state as well as of the structure of the ligand [12–19]. It's worth
noting that Schiff base complexes have gained considerable attention
due to their remarkable biological activities (such as, antibacterial,
anti-inflammatory and antiviral activities) [20,21,22,23], catalytic ac-
tivities [24–26], electroluminescent properties [27,28], fluorescence
properties [29], nonlinear optical (NLO) properties [30], and applica-
tions in sensors [31] and organic photovoltaic materials [32].
and Mycobacterium tuberculosis [33–35]. Another major ureolytic pa-
thogen is Helicobacter pylori, the originator of several severe disease
conditions, such as gastritis, gastric ulcers or even gastric cancer
[36–38]. Urease inhibitors have long been considered as targets for new
antiulcer drugs, as the ureolytic activity of the bacterial pathogens re-
sults in damage to gastric epithelium, leading to inflammation [34].
Recently, urease inhibition study has attracted increasing attention
[39–42] and numerous of Schiff base complexes' inhibitory activities
have been detected due to their good inhibitory performance [43–46].
To the best of our knowledge, there is rare report on the synthesis of
two different series of Ni(II), Co(II) and Cu(II) complexes with
sexidentate N2O4-donor bis-Schiff base ligand and the study of
structure-urease inhibitory activity relationship discussed from
the perspective of molecular docking and theoretical calculation. In
view of these observations, in this work, six novel complexes, [Ni
(C36H34N2O10)]·2.25CH3OH·0.5C4H10
O (1), [Co(C36H34N2O10)] (2),
⁎ Corresponding authors.
E-mail addresses: pkujinfan@gmail.com (F. Jin), haidafyh301@163.com (Y. Fan).
https://doi.org/10.1016/j.jinorgbio.2019.110959
Received 27 October 2019; Received in revised form 3 December 2019; Accepted 9 December 2019
Availableonline16December2019
0162-0134/©2019PublishedbyElsevierInc.

H. Wang, et al.
JournalofInorganicBiochemistry204(2020)110959
[Cu(C36H34N2O10)]·2CH3OH (3), [Ni(C36H32N2O8Cl2)]·2CH3OH (4),
[Co(C36H32N2O8Cl2)]·4CH3OH (5) and [Cu(C36H32N2O8Cl2)]·2CH3OH
(6) with two sexidentate N2O4-donor bis-Schiff base ligands
Elemental Anal Calc (%) for [Cu(C36H34N2O10)]·2CH3OH: C 58.34, H
5.41, N 3.58; found: C 58.15, H 5.69, N 3.64.
[Ni(C36H32N2O8Cl2)]·2CH3OH (4): The complex was synthesized by
a procedure similar to that for the complex 1, but using L-4-chlor-
ophenylalanine (0.100 g, 0.5 mmol) instead of L-tyrosine. The dark
green block-shaped crystals were formed after about 3 days by slow
diffusion of ether into a concentrated methanol solution of the complex
at room temperature. Yield: 62% based on L-4-chlorophenylalanine. IR
(KBr, cm−1): 1654, 1575, 1356, 1206, 550, 456. Elemental Anal Calc
(%) for [Ni(C36H32N2O8Cl2)]·2CH3OH: C 56.05, H 4.95, N 3.44; found:
C 55.91, H 5.08, N 3.50.
(C36H34N2O10
=
1,2-bis(2-methoxy-6-formylphenoxy)ethane-L-tyr-
osine; C36H32N2O8Cl2 = 1,2-bis(2-methoxy-6-formylphenoxy)ethane-L-
4-chlorophenylalanine) have been synthesized, characterized and
evaluated in the urease inhibitory activity. Additionally, based on
crystal data, density functional theory (DFT) calculation of six com-
plexes was performed using the Gaussian 03 program suite.
Nevertheless, due to the interest of understanding their role in urease
inhibition, docking simulation was carried out using the AutoDock Vina
program to position the complex into the active site of urease to de-
termine the probable binding mode. The docking result show good
correlation with experimental data. At last, the structure-inhibitory
activity relationship was further discussed from the perspective of
molecular docking and theoretical calculation.
[Co(C36H32N2O8Cl2)]·4CH3OH (5): The complex was synthesized by
a
procedure similar to that for the complex 4, but using Co
(CH3COO)2·4H2O (0.125 g, 0.5 mmol) instead of Ni(CH3COO)2·4H2O.
The red block-shaped crystals were formed after about 3 days by slow
diffusion of ether into a concentrated methanol solution of the complex
at room temperature. Yield: 63% based on L-4-chlorophenylalanine. IR
(KBr, cm−1): 1648, 1577, 1363, 1210, 546, 459. Elemental Anal Calc
(%) for [Co(C36H32N2O8Cl2)]·4CH3OH: C 54.68, H 5.51, N 3.19; found:
C 54.57, H 5.61, N 3.25.
2. Experimental
2.1. Chemicals and physical measurements
[Cu(C36H32N2O8Cl2)]·2CH3OH (6): The complex was synthesized by
All chemical reagents were of analytical grade and were used
without further purification. L-tyrosine and L-4-chlorophenylalanine
were purchased from Aladdin. Urease (from jack beans, type III, activity
31,660 units/mg solid), N-[2-hydroxyethyl]piperazine-N′-[2-ethane-
sulfonic acid] (HEPES) buffer and urea (Molecular Biology Reagent)
were purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). IR
spectra were recorded as KBr pellets on a Nicolet 170SX spectro-
photometer in the 4000–400 cm−1 region. Elemental analyses (C, H
and N) were obtained with a model 2400 Perkin-Elmer analyzer. X-ray
diffraction data were collected on an Enraf-nonius CAD-4 dif-
fractometer. Enzyme inhibitory activity was measured with a BioTek
Synergy HT microplate reader.
a procedure similar to that for the complex 4, but using Cu
(CH3COO)2·H2O (0.125 g, 0.5 mmol) instead of Ni(CH3COO)2·4H2O.
The blue block-shaped crystals were formed after about 4 days by slow
diffusion of ether into a concentrated methanol solution of the complex
at room temperature. Yield: 65% based on L-4-chlorophenylalanine. IR
(KBr, cm−1): 1653, 1580, 1379, 1209, 561, 457. Elemental Anal Calc
(%) for [Cu(C36H32N2O8Cl2)]·2CH3OH: C 55.71, H 4.92, N 3.42; found:
C 55.59, H 5.12, N 3.53.
2.3. Crystallographic data collection and structure determination
Single crystals with dimensions of 0.3
0.28 × 0.15 × 0.12 (2), 0.28 × 0.15 × 0.12 (3), 0.28 × 0.15 × 0.12
(4), 0.19 0.15 0.12 (5), 0.19 0.15 0.12 mm (6)
× 0.22 × 0.15 (1),
2.2. Synthesis of the complexes
×
×
×
×
were mounted on a Bruker APEX-II CCD X-ray single-crystal dif-
fractometer at 173 K with graphite-monochromatized Mo-Kɑ radiation
(λ = 0.71073 Å) by using the φ and ω scan mode at room temperature.
SADABS2008/1 is applied to absorption correction. The structures were
solved and refined by using SHELXT and SHELX [48] programs. Choose
the highest symmetry in all cases. Derivation of non‑hydrogen atoms by
Fourier synthesis. The positional and thermal parameters were refined
by full matrix least-squares (on F2) to convergence [49]. The hydrogen
atom of the organic ligand is theoretically determined and improved by
a fixed thermal factor.
[Ni(C36H34N2O10)]·2.25CH3OH·0.5C4H10O (1): L-tyrosine (0.181 g,
1.0 mmol) and potassium hydroxide (0.056 g, 1.0 mmol) were dis-
solved in methanol (40 mL) and then 1,2-bis(2-methoxy-6-for-
mylphenoxy)ethane (0.165 g, 0.5 mmol) [47] was added to the solu-
tion. The mixture was heated to 50 °C with stirring and then refluxed
for 5 h to give a bright yellow solution. After that, a methanol solution
(15 mL) of Ni(CH3COO)2·4H2O (0.124 g, 0.5 mmol) was added to the
above solution. The resulting mixture was stirred and refluxed at 50 °C
for 5 h. The resulting solution was cooled at room temperature and then
filtered. The dark green block-shaped crystals were formed after about
4 days by slow diffusion of ether into a concentrated methanol solution
of the complex at room temperature. Yield: 63% based on L-tyrosine. IR
(KBr, cm−1): 1647, 1578, 1364, 1197, 551, 448. Elemental Anal Calc
(%) for [Ni(C36H34N2O10)]·2.25CH3OH·0.5C4H10O: C 58.77, H 5.88, N
3.41; found: C 58.65, H 6.02, N 3.52.
2.4. Computational procedure
Becke's three-parameter hybrid (B3LYP) level was selected for DFT
calculation by the basis set of 6-31G for the C, H, O, N and Cl atoms
[50–52], while LANL2DZ basis set was used for Ni, Co and Cu atoms
[53]. Atom coordinates used in the calculations were from crystal-
lographic data, and a molecule in the unit cells was selected as the
initial model. All calculations were conducted on a Pentium IV com-
puter using Gaussian 03 program [54].
[Co(C36H34N2O10)] (2): The complex was synthesized by a proce-
dure similar to that for the complex 1, but using Co(CH3COO)2·4H2O
(0.125 g, 0.5 mmol) instead of Ni(CH3COO)2·4H2O. The red block-
shaped crystals were formed after about 3 days by slow diffusion of
ether into a concentrated methanol solution of the complex at room
temperature. Yield: 66% based on L-tyrosine. IR (KBr, cm−1): 1644,
1579, 1362, 1202, 557, 452. Elemental Anal Calc (%) for [Co
(C36H34N2O10)]: C 60.59, H 4.80, N 3.93; found: C 60.46, H 4.92, N
4.03.
2.5. Measurement of jack bean urease inhibitory activity
The measurement of urease activity was carried out according to the
literature reported by Tanaka [55]. Generally, the assay mixture, con-
taining 25 μL of jack bean urease (40 kU/L) (dissolved in distilled
water) and 25 μL of the tested complexes with different concentrations
(dissolved in DMSO/H2O mixture (1:1 v/v)), was preincubated for 1 h
at 37 °C in a 96-well assay plate. After preincubation, 200 μL of
100 mmol HEPES (N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic
acid]) buffer pH = 6.8 containing 500 mmol urea and 0.002% phenol
[Cu(C36H34N2O10)]·2CH3OH (3): The complex was synthesized by a
procedure similar to that for the complex 1, but using Cu
(CH3COO)2·H2O (0.125 g, 0.5 mmol) instead of Ni(CH3COO)2·4H2O.
The filtrate was left for slow evaporation at room temperature. The blue
block-shaped crystals were formed after about 1 week. Yield: 65%
based on L-tyrosine. IR (KBr, cm−1): 1649, 1581, 1379, 1215, 554, 459.
2

H. Wang, et al.
JournalofInorganicBiochemistry204(2020)110959
red were added and incubated at 37 °C [56]. The reaction was measured
by micro plate reader (570 nm), which was required to produce enough
ammonium carbonate to raise the pH of a HEPES buffer from 6.8 to 7.7,
the endpoint being determined by the colour of phenol red indicator
[57].
3.2.1. Crystal structure of [Ni(C36H34N2O10)]·2.25CH3OH·0.5C4H10O (1)
Complex 1 crystallizes in the orthorhombic crystal system and space
group P212121 (Table 1). As shown in Fig. 1a, the central Ni(II) adopts a
distorted octahedral geometry that is defined by two nitrogen donors
from C]N groups occupying the axial positions, two oxygen donors
from ether groups and two oxygen donors from carboxyl groups in the
equatorial plane, forming a type of sexidentate N2O4-donor bis-Schiff
base complex.
2.6. Docking simulations
The corresponding bond angles of O(3)eNi(1)eO(6) [166.22 (14)°]
and O(4)eNi(1)eO(7) [164.79 (14)°] are both less than 180° appar-
ently, while, the bond angle of N(1)eNi(1)eN(2) [174.48 (18)°] is very
close to 180°. At the same time, the bond angles of N(1)eNi(1)eO(3)
[83.11 (16)°], N(1)eNi(1)eO(4) [94.68 (15)°], N(1)eNi(1)eO(6)
[78.01 (14)°] and N(1)eNi(1)eO(7) [97.88 (16)°] indicate that the
central Ni(II) adopts a distorted octahedral geometry. Atoms O(3), O
(4), O(6) and O(7) occupy each vertex of the basal site, while N(1) and
N(2) locate in the apical positions of the octahedral structure. The bond
lengths of N(1)eC(10) and N(2)eC(26) are 1.267 (7) and 1.262 (7) Å
respectively, which are consistent with our previous reported values
[46,59,60]. It indicates that there are two double bonds in this complex:
the first between C(10) and N(1), and the other between C(26) and N
(2). The bond lengths of Ni(1)eO(3) and Ni(1)eO(4) are 1.993 (4) Å
and 2.012 (4) Å respectively, which are shorter than those of Ni(1)eO
(6) 2.104 (4) Å and Ni(1)eO(7) 2.097 (3) Å, suggesting that the co-
ordination abilities of the carboxyl O(3) and O(4) are stronger than
those of the ether O(6) and O(7) atoms (Table S1). Furthermore, each
ligand serves as a bridging ligand to connect two Ni(II) centers into
supramolecular by OeH⋯O hydrogen bonds (yellow dash bonds: O(1)
eH(1)⋯O(4), symmetry code: x − 1/2, −y + 3/2, −z + 1) and
CeH⋯O interactions (red dash bonds), forming a two dimensional
supramolecular layer structure (Fig. 1b, Table S3).
Molecular docking of the inhibitor with the three-dimensional
structure of jack bean urease was carried out using the AutoDock Vina
program suite [58]. The ligand structure in docking protocol was used
as a crystal structure. The crystal structure of jack bean urease was
obtained from Protein Data Bank (http://www.pdb.org/pdb/home/
home.do) with the PDB ID of 3LA4 at a resolution of 2.05 Å. The gra-
phical user interface AutoDockTools (ADT 1.5.4) was performed to
setup every inhibitor enzyme interaction where all hydrogen atoms
were added, Gasteiger charges were calculated and nonpolar hydrogen
atoms were merged to carbon atoms. In all docking, a grid box with a
size of 60 Å pointing in x, y and z directions was centered on the cat-
alytic site of the protein. The docking parameters were set to default.
The flexible ligand mode was used for docking. The docking procedure
of the complexes 1–6 with the active site of jack bean urease was
performed as described.
3. Results and discussion
3.1. Synthesis
The general synthesis of the complexes 1–6 is shown in Scheme 1. In
the first step, 1,2-bis(2-methoxy-6-formylphenoxy)ethane was synthe-
sized by the reaction between o-vanillin and 1,2-dibromoethane with
the ratio of 2:1. Then, 1,2-bis(2-methoxy-6-formylphenoxy)ethane re-
acted with L-tyrosine and L-4-chlorophenylalanine respectively to form
the corresponding N2O4-donor bis-Schiff base. Finally, two types of bis-
Schiff bases reacted with Ni(CH3COO)2·4H2O, Co(CH3COO)2·4H2O and
Cu(CH3COO)2·H2O respectively with the ratio of 1:1 to afford the
complexes 1–6. Crystals of complexes 1–6 suitable for X-ray diffraction
can be obtained through slow evaporation method and liquid-liquid
diffusion method. The summary of the key crystallographic information
are given in Table 1 and Table 2.
3.2.2. Crystal structure of [Co(C36H34N2O10)] (2)
Complex 2 crystallizes in the orthorhombic crystal system and space
group P212121. The complex also has a distorted octahedral geometry in
which the carboxyl O atoms are also more tightly coordinated than the
ether O atoms (Fig. 2a, Table S1). The 2-D structure of complex 2 is
formed by two types of OeH⋯O hydrogen bonds (yellow dash bonds: O
(8)eH(8)⋯O(2), symmetry code: 1/2+x, 1/2-y, 1-z; O(10)eH(10)⋯O
(3), symmetry code: 1 − x, 1/2 + y, 1/2 − z) and CeH⋯O interactions
(red dash bonds) (Fig. 2b, Table S3).
3.2. Crystal structure description
3.2.3. Crystal structure of [Cu(C36H34N2O10)]·2CH3OH (3)
Complex 3 crystallizes in the orthorhombic crystal system and space
group P212121. The complex also has a distorted octahedral geometry in
which the carboxyl O atoms are also more tightly coordinated than the
ether O atoms (Fig. 3a, Table S1). In addition, there is two free solvent
methanol molecules in the crystalline lattice. The 2-D structure of
The molecular structures of complexes 1–6 were determined by
single crystal X-ray analysis as shown in Figs. 1-6, and the comparison
of the selected bond lengths and angles of the complexes can be found
in Table S1 and Table S2.
Scheme 1. The general synthesis routes of six complexes 1–6.
3

H. Wang, et al.
JournalofInorganicBiochemistry204(2020)110959
Table 1
Crystal data and structure refinement parameters for complexes 1–3.
Parameter
1
2
3
Empirical formula
C
40.25H48N2O12.75Ni
C36H34N2O10Co
713.58
173
C38H42N2O12Cu
782.27
205
Formula weight
822.51
Temperature (K)
170
Wavelength (Å)
0.71073
0.71073
Orthorhombic
P212121
11.145 (4)
11.625 (5)
38.061 (15)
90
0.71073
Orthorhombic
P212121
12.647 (3)
16.476 (3)
8.8918 (18)
90
Crystal system
Orthorhombic
P212121
Space group
a (Å)
11.236 (4)
11.621 (5)
37.220 (17)
90
b (Å)
c (Å)
α (°)
β (°)
90
90
90
γ (°)
90
90
90
Volume (Å3)
4860 (4)
4931 (3)
4
1852.7 (6)
2
Z
4
Calculated density (g/cm3)
Absorption coefficient (mm−1
F(000)
1.124
0.961
1.402
)
0.454
0.390
0.656
1734
1484
818
Crystal size (mm)
θ range for data collection (°)
Limiting indices
0.3 × 0.22 × 0.15
1.836 to 27.817
−12 ≤ h ≤ 14
-15 ≤ k ≤ 15
−46 ≤ l ≤ 48
25,108/11,376
[Rint = 0.0547]
0.990
0.28 × 0.15 × 0.12
1.070 to 25.007
−11 ≤ h ≤ 13
−13 ≤ k ≤ 13
−45 ≤ l ≤ 43
31,961/8678
0.28 × 0.15 × 0.12
2.030 to 27.586
−16 ≤ h ≤ 16
−19 ≤ k ≤ 21
−11 ≤ l ≤ 11
15,413/4263
[Rint = 0.064]
0.994
Reflections collected/unique
[Rint = 0.1263]
0.998
Completeness to θ = 25.02
Max. and min. Transmission
Data/restraints/parameters
Goodness of fit on F2
0.7456 and 0.5786
11,376/532/558
1.094
0.7452 and 0.5671
8678/480/411
0.975
0.7456 and 0.6184
4263/0/244
1.019
b
R1a, wR2 [I > 2σ(I)]
R1 = 0.0798
wR2 = 0.2080
R1 = 0.1003
wR2 = 0.2201
0.757 and −0.629
R1 = 0.0955
R1 = 0.0477
wR2 = 0.1026
R1 = 0.0671
wR2 = 0.1120
0.566 and −0.530
wR2 = 0.2437
R1 = 0.1398
b
R1a, wR2 (all data)
wR2 = 0.2630
0.806 and −0.512
Largest diff. peak and hole (e. Å3)
a
b
R = Σ(|F0|-|FC|)/Σ|F0|.
wR = [Σw(|F0|2-|FC|2)2/Σw(F02)]1/2
.
complex 3 is formed by two types of OeH⋯O hydrogen bonds (yellow
dash bonds: O(5)eH [5]⋯O [6], symmetry code: x − 1, y, z; O(6)eH
(6A)⋯O [3], symmetry code: -) and CeH⋯O interactions (red dash
bonds) (Fig. 3b, Table S3).
dash bonds: O(3)eH(3)⋯O(2), symmetry code: -), CeH⋯O interactions
(red dash bonds) and CeH⋯Cl interactions (dark-red dash bonds)
(Fig. 6b, Table S3).
3.3. DFT calculations
3.2.4. Crystal structure of [Ni(C36H32N2O8Cl2)]·2CH3OH (4)
Complex 4 crystallizes in the orthorhombic crystal system and space
group P212121. The complex also has a distorted octahedral geometry in
which the carboxyl O atoms are also more tightly coordinated than the
ether O atoms (Fig. 4a, Table S2). In addition, there is two free solvent
methanol molecules in the crystalline lattice. The 2-D structure of
complex 4 is constructed by CeH⋯O interactions (red dash bonds).
(Fig. 4b).
In the present study, the superposition of optimized (fuchsia) and
crystal structures (turquoise) of complexes 1–6 are depicted in Fig. S1
and Fig. S2. It is clear that the coordination environment part of each
complex is well superimposed together. This proves that the selected
basis sets are suitable for the calculation of complexes 1–6.
As we know, molecular electrostatic potential (MEP) is related to
the electronic density and is a very useful descriptor in understanding
sites for electrophilic attack and nucleophilic reactions [61]. The elec-
trostatic potential V(r) is also well suited for analyzing processes based
on the ‘recognition' of one molecule by another, as in drug-receptor and
enzyme-substrate interactions, in which two species first ‘see’ each
other through their potentials [62]. To predict the electrophilic or nu-
cleophilic attack sites, molecule ‘recognition' sites and hydrogen
bonding or weak interactions for the investigated molecules, MEP
surfaces were obtained based on the optimized geometry.
3.2.5. Crystal structure of [Co(C36H32N2O8Cl2)]·4CH3OH (5)
Complex 5 crystallizes in the monoclinic crystal system and space
group C2/c. The complex also has a distorted octahedral geometry in
which the carboxyl O atoms are also more tightly coordinated than the
ether O atoms (Fig. 5a, Table S2). In addition, there is four free solvent
methanol molecules in the crystalline lattice. The 2-D structure of
complex 5 is constructed by one type of OeH⋯O hydrogen bonds
(yellow dash bonds: O(6)eH [6]eO [1], symmetry code: -) and
CeH⋯O interactions (red dash bonds) (Fig. 5b, Table S3).
Herein, only the MEP maps of optimized structures of complexes 3
and 6 (Fig. 7) were discussed as an example because the MEP maps of
other complexes are very similar by judging from the Figs. S9–S12, and
the MEP interval distributions [63,64] of complexes 3 and 6 were de-
picted in Fig. 8. The surface area distribution in different electrostatic
potential intervals of the two complexes is relatively even. For complex
3, the percentage of positive and negative electrostatic potential areas
are 47.64% and 52.36% respectively. For complex 6, the percentage of
positive and negative electrostatic potential areas are 44.88% and
55.12% respectively. It is clear that the most positive regions are
3.2.6. Crystal structure of [Cu(C36H32N2O8Cl2)]·2CH3OH (6)
Complex 6 crystallizes in the orthorhombic crystal system and space
group P21212. The complex also has a distorted octahedral geometry in
which the carboxyl O atoms are also more tightly coordinated than the
ether O atoms (Fig. 6a, Table S2). In addition, there is two free solvent
methanol molecules in the crystalline lattice. The 2-D structure of
complex 6 is formed by one type of OeH⋯O hydrogen bonds (yellow
4

H. Wang, et al.
JournalofInorganicBiochemistry204(2020)110959
Table 2
Crystal data and structure refinement parameters for complexes 4–6.
Parameter
4
5
6
Empirical formula
C
38H40N2O10Cl2Ni
C40H48N2O12Cl2Co
878.63
C38H40N2O10Cl2Cu
819.16
173
Formula weight
814.33
Temperature (K)
173
173
Wavelength (Å)
0.71073
0.71073
Monoclinic
C2/c
0.71073
Orthorhombic
P21212
13.437 (2)
15.501 (3)
9.0373 (14)
90
Crystal system
Orthorhombic
P212121
Space group
a (Å)
14.347 (5)
16.728 (5)
16.853 (6)
90
19.967 (4)
10.5685 (18)
20.021 (4)
90
b (Å)
c (Å)
α (°)
β (°)
90
101.294 (6)
90
90
γ (°)
90
90
Volume (Å3)
4045 (2)
4143.1 (13)
4
1882.4 (5)
2
Z
4
Calculated density (g/cm3)
Absorption coefficient (mm−1
F(000)
1.337
1.409
1.445
)
0.668
0.607
0.782
1696
1836
850
Crystal size (mm)
θ range for data collection (°)
Limiting indices
0.28 × 0.15 × 0.12
1.715 to 26.407
−14 ≤ h ≤ 17
−20 ≤ k ≤ 20
−21 ≤ l ≤ 21
33,211/8284
[Rint = 0.0874]
0.998
0.19 × 0.15 × 0.12
2.075 to 25.008
−23 ≤ h ≤ 23
−12 ≤ k ≤ 12
−23 ≤ l ≤ 22
15,267/3667
[Rint = 0.1070]
0.999
0.19 × 0.15 × 0.12
2.006 to 26.363
−15 ≤ h ≤ 16
−19 ≤ k ≤ 19
−10 ≤ l ≤ 11
8026/3657
Reflections collected/unique
[Rint = 0.0897]
0.965
Completeness to θ = 25.02
Max. and min. transmission
Data/restraints/parameters
Goodness of fit on F2
0.7454 and 0.6602
8284/0/485
0.988
0.7455 and 0.6174
3667/0/263
0.7140 and 0.4699
3657/0/243
0.982
0.988
b
R1a, wR2 [I > 2σ(I)]
R1 = 0.0466
wR2 = 0.0931
R1 = 0.0752
wR2 = 0.1047
0.437 and −0.424
R1 = 0.0571
R1 = 0.0627
wR2 = 0.1093
R1 = 0.1083
wR2 = 0.1319
0.427 and −0.314
wR2 = 0.1213
R1 = 0.1005
b
R1a, wR2 (all data)
wR2 = 0.1387
0.689 and −0.439
Largest diff. peak and hole (e. Å3)
a
b
R = Σ(|F0|-|FC|)/Σ|F0|.
wR = [Σw(|F0|2-|FC|2)2/Σw(F02)]1/2
.
located around hydroxyl oxygens (yellow ball, V(r): 0.079 a.u.,
0.079 a.u.) of the complexes 3, indicating that these atoms are possible
sites for nucleophilic attack. In contrast, the most negative regions are
located around carboxyl oxygens (magenta ball, V(r): −0.097 a.u.,
−0.097 a.u.; −0.093 a.u., −0.094 a.u.) of the complexes 3 and 6.
Thus, these atoms are preferred possible sites for electrophilic attack. At
the same time, these hydroxyl oxygens and carboxyl oxygens may form
hydrogen bond or weak interaction. It is consistent with the experi-
mental results that hydroxyl oxygens and carboxyl oxygens are proton
donors and receptors of hydrogen bonds respectively, through which
the supermolecular structure is assembled (Figs. 1b-6b; Table S3). The
hydroxyl oxygens and the carboxyl oxygens with the extreme values of
the electrostatic potential may be the first to be seen in the molecular
recognition process or enzyme-substrate interaction process.
At the same time, the discussion of the natural atomic charges and
frontier molecular orbitals can be found in Supplementary Information
(SI) file (Tables S4–S7, Figs. S3–S8).
3.4. Inhibitory activity against jack bean urease
Two Schiff base ligands and the corresponding Ni(II), Co(II) and Cu
(II) complexes 1–6 were screened for inhibitory activity against jack
bean urease (Table 3). It was found that the synthesized ligands H2L1–2
exhibited no inhibitory ability to inhibit the jack bean urease.
Fig. 1. The molecular structure (a) and the 2-D layer structure (b) of [Ni(C36H34N2O10)]·2.25CH3OH·0.5C4H10O (1), which constructed by OeH⋯O hydrogen bonds
(yellow dash bonds) and CeH⋯O interactions (red dash bonds).
5

H. Wang, et al.
JournalofInorganicBiochemistry204(2020)110959
Fig. 2. The molecular structure (a) and the 2-D layer structure (b) of [Co(C36H34N2O10)] (2), which constructed by OeH⋯O hydrogen bonds (yellow dash bonds) and
CeH···O interactions (red dash bonds).
Compared with the standard inhibitor acetohydroxamic acid (AHA,
IC50 = 26.99 1.43 μM), the Schiff base complexes 3 and 6 displayed
potent inhibitory activity (IC50 = 10.36 1.13; 15.63 3.04 μM).
amino acid residues with the corresponding M(II) complexes 1, 3, 4 and
6 showed −37.24, −41.42, −36.00 and −39.33 kJ/mol respectively.
The docking results further verify the difference of their urease in-
hibitory activities obtained from the urease-inhibitory measurement.
The binding models of complexes 1, 3, 4 and 6 with urease (3LA4)
were shown in Fig. 9, Fig. 10, Fig. S14 and Fig. S15, with all the amino
acid residues that interact with urease indicated. In the binding model,
the carboxyl O atom of complex 1 forms one hydrogen bond with the
side chain NeH of MET746 with the distance and angle of the Ne-
H⋯Ocomplex-1 being 2.085 Å and 139.5° respectively. The phenolic H
atom of complex 1 forms one hydrogen bond with the O atom of GLY12.
The hydrogen-bonding distance and angle of OeHcomplex-1⋯OGLY12 are
1.911 Å and 155.4°. At the same time, complex 1 formed cation-π in-
teraction with said chain N cation of amino-acid residue LYS716, with
the distance of the interaction being 6.214 Å (Fig. S14a). Notably, in the
best docking conformation (Fig. 9a), as expected, complex 3 formed
three types of hydrogen bonds with amino-acid residues MET746,
LEU839 and SER421. The hydrogen-bonding distances and angles of
MET746 NeH⋯Ocomplex-3, LEU839 NeH⋯Ocomplex-3 and complex-3
OeH⋯OSER421 are 2.451, 2.322, 2.347 Å and 107.2, 172.5, 106.5° re-
spectively. The carboxyl O atom of complex 4 forms one hydrogen bond
with the side chain OeH of SER834 with the distance and angle of the
interaction being 2.269 Å and 124.6° respectively. The methoxy O atom
complex 4 forms one hydrogen bond with the side chain OeH of
THR578 with the distance and angle of the interaction being 2.309 Å
and 162.2° respectively (Fig. S15a). The two carboxyl O atoms of
complex 6 forms one hydrogen bond with the side chain NeH of
MET746 and NeH of LEU839 respectively. The hydrogen-bonding
distance and angle of MET746 NeH⋯Ocomplex-6 are 2.240 Å and 110.4°,
Thus it can be seen that coordination to Cu(II) ion resulted in the im-
proved inhibitory activity [65–67]. It should be noted that in terms of
the inhibitory strength towards jack bean urease the complexes studied
form the order: 3 > 6 > 1 > 2 > 4 > 5. Interestingly, complex 3
is potent than complex 6 as a result of the difference between electron-
giving substituent (hydroxy) and electron-withdrawing substituent
(chlorine) on the aromatic ring. At the same time, the spatial steric
hindrance of the 4-chlorophenyl pendant group in complex 6 is higher
than that of the 4-hydroxyphenyl pendant group in complex 3. When
compared with Cu(II) complexes 3 and 6, the Ni(II) and Co(II) com-
plexes (1, 2, 4 and 5) exhibit weaker urease inhibitory activity under
the same condition. The results indicate that inhibitory activities of
metal complexes as the urease inhibitor depend on not only the organic
ligands but also the central ions [66].
3.5. Molecular docking study
The binding models of complexes 1, 3, 4 and 6 with jack bean ur-
ease (3LA4) were simulated using the AutoDock Vina program [58] to
validate their structure-activity relationships. The results revealed that
the four target molecules fitted well in the active pocket of jack bean
urease (Fig. S13). Additional interactions were established in a variety
of conformations because of the flexibility of the complexes and the
amino acid residues of the urease. The optimized cluster (10 occur-
rences) was ranked by energy level in the best conformation of the
inhibitor-urease modeled structures, and the affinity energy of the
Fig. 3. The molecular structure (a) and the 2-D layer structure (b) of [Cu(C36H34N2O10)]·2CH3OH (3), which constructed by OeH···O hydrogen bonds (yellow dash
bonds) and CeH···O interactions (red dash bonds).
6

H. Wang, et al.
JournalofInorganicBiochemistry204(2020)110959
Fig. 4. The molecular structure (a) and the 2-D layer structure (b) of [Ni(C36H32N2O8Cl2)]·2CH3OH (4), which constructed by CeH⋯O interactions (red dash bonds).
Fig. 5. The molecular structure (a) and the 2-D layer structure (b) of [Co(C36H32N2O8Cl2)]·4CH3OH (5), which constructed by OeH⋯O hydrogen bonds (yellow dash
bonds) and CeH⋯O interactions (red dash bonds).
Fig. 6. The molecular structure (a) and the 2-D layer structure (b) of [Cu(C36H32N2O8Cl2)]·2CH3OH (6), which constructed by OeH⋯O hydrogen bonds (yellow dash
bonds), CeH⋯O interactions (red bonds) and CeH⋯Cl interactions (dark-red dash bonds).
while that of LEU839 N-H⋯Ocomplex-6 are 2.224 Å and 164.1°. At the
same time, complex 6 formed π-π stacking interaction with the said
chain benzene ring of amino-acid residue PHE712, σ-π interaction with
the C atom of amino-acid residue PHE838, with the distances of the
interactions being 5.245 and 3.757 Å respectively (Fig. 10a).
occupied molecular orbital (HOMO) of carboxyl O atoms in the opti-
mized structures of Cu(II) complexes 3 (21.72%, 27.27%) and 6
(30.32%, 22.53%) are obviously much higher than the corresponding
values observed in the Ni(II) and Co(II) complexes 1 (2.70%, 0.31%), 2
(8.96%, 8.18%), 4 (5.91%, 7.42%) and 5 (9.61%, 9.64%) (Fig. S16).
Therefore, these O atoms in complexes 3 and 6 are much more easier to
give electrons and are much more easier to be recognized by amino-acid
residue of urease. This result can reasonably explain the difference in
urease inhibitory activity between the Cu(II) complex and the same
series of Ni(II), Co(II) complexes with the same ligand from the per-
spective of theoretical calculation. And after docking, the values of
EHOMO of complexes 3 and 6 increased (−5.687 eV to −5.442 eV;
In the inhibitor-urease complex conformation, the Cu(II) complexes
3 and 6 showed a more stabilized structure than the corresponding Ni
(II) complexes 1 and 4. The docking structures of complexes 3 and 6 are
overlayed with the geometrically optimized structures, and it is found
that the superposition is good, except for a certain degree of spatial
change of the side groups (Fig. 11). This result satisfies the principle of
spatial geometric complementarity. The percentages of highest
7

H. Wang, et al.
JournalofInorganicBiochemistry204(2020)110959
Fig. 7. The total electron density mapped with electrostatic surface of complexes 3 and 6 (mapped into the electron density isosurface of 0.001 electrons/au3). The
yellow ball corresponds to the maximum point of the electrostatic potential, and the magenta ball corresponds to the minimum electrostatic potential.
Fig. 8. The MEP interval distributions of complexes 3 and 6.
Table 3
amino-acid residue SER421. In contrast, no hydrogen bond was found
between 4-chlorophenyl pendant group in complex 6 and the amino
acid residues of the urease active site. At the same time, the spatial
steric hindrance of the 4-chlorophenyl pendant group is relatively
higher than that of the 4-hydroxyphenyl pendant group in complex 3.
This probably causes the activity difference of complexes 3 and 6 as
urease inhibitors. In addition, the affinity energy (−41.42 kJ/mol) in
the modeled structure of 3-urease complex is slightly lower than the
corresponding value (−39.33 kJ/mol) observed in the 6-urease com-
plex. The results further demonstrate the certain degree of difference of
urease inhibitory activity of these two Cu(II) complexes.
Inhibition of jack bean urease by Schiff base ligands and com-
plexes 1–6.
Tested materials
IC50 (μM)
H2L1–2
> 100
20.43
26.01
10.36
30.52
36.41
15.63
26.99
Complex 1
Complex 2
Complex 3
Complex 4
Complex 5
Complex 6
Acetohydroxamic acida
1.26
2.35
1.13
3.12
1.56
3.04
1.43
a
Used as a positive control.
4. Conclusion
−5.903 eV to −5.692 eV) (Fig. S17, Fig. S18), and the percentages of
HOMO of the carboxyl O atoms further increased slightly (Fig. S16).
Compared binding modes of all four complexes, complex 3, as a
guest molecule, is well embedded into the active pocket of jack bean
urease through three types of hydrogen bonds interactions mentioned
above, including the OeH⋯OSER421 hydrogen bond interaction formed
between the 4-hydroxyphenyl pendant group in complex 3 and the
In summary, the present paper has reported the synthesis, crystal
structures, DFT calculations and urease inhibition properties of two
different series of Ni(II), Co(II) and Cu(II) complexes with sexidentate
N2O4-donor bis-Schiff base ligand. It was found that complexes 3
(IC50 = 10.36
1.13 μM) and 6 (IC50 = 15.63
3.04 μM) possess
the good inhibitory activities again jack bean urease. Moreover, the
structure-inhibitory activity relationship of complex 1–6 was further
8

H. Wang, et al.
JournalofInorganicBiochemistry204(2020)110959
Fig. 9. The modeled structure (a) of
urease-inhibitor complex 3, NeH⋯O
hydrogen bond
interaction
and
OeH⋯O hydrogen bond interaction
are presented as red dash lines. Binding
mode (b) of complex 3 with jack bean
urease. The enzyme is shown as surface
and the complex is shown as sticks.
Fig. 10. The modeled structure (a) of
urease-inhibitor complex 6, NeH···O
hydrogen bond interaction, π-π
stacking interaction and σ-π interaction
are presented as red dash lines and
yellow lines. Binding mode (b) of
complex 6 with jack bean urease. The
enzyme is shown as surface and the
complex is shown as sticks.
Fig. 11. The superposition of optimized (fuchsia) and docking structures (red) of complexes 3 (a) and 6 (b).
discussed from the perspective of molecular docking and theoretical
calculation, suggesting that the Cu(II) complexes 3 and 6 have good
potential as the urease inhibitor in the future. Theoretical calculation
results showed a good accordance between experimental and calculated
results. Detailed investigations are continuing to study the mechanisms
of urease inhibitory activity reported here.
Acknowledgments
This research was supported by the National Natural Science
Foundation of China to C.F. Bi (No. 21371161), the Specialized
Research Fund for the Doctoral Program of Higher Education of China
to Y.H. Fan (No. 20120132110015)
9

H. Wang, et al.
JournalofInorganicBiochemistry204(2020)110959
Appendix A. Supplementary data
[27] A.N. Gusev, M.A. Kiskin, E.V. Braga, M. Chapran, G. Wiosna-Salyga,
G.V. Baryshnikov, V.A. Minaeva, B.F. Minaev, K. Ivaniuk, P. Stakhira, H. Ågren,
W. Linert, J. Phys. Chem. C 123 (2019) 11850–11859.
Crystallographic information of three complexes have been de-
posited with the Cambridge Crystallographic Data Center as supple-
mentary publication CCDC No. 1525034 (for 1), No. 1848911 (for 2),
No. 1559238 (for 3), No. 1841584 (for 4), No. 1842892 (for 5), No.
1844678 (for 6). Copies of the data may be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EB, UK (Fax:
+44-1223-336-033; E-mail: deposit@ccdc.cam.ac.uk or http://www.
ccdc.cam.ac.uk). Supplementary data to this article can be found online
at https://doi.org/10.1016/j.jinorgbio.2019.110959.
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