Synthesis, crystal structure and urease inhibition of a trinuclear copper(II) complex with reduced Schiff base ligand

Article abstract of DOI:10.1016/j.inoche.2018.12.009

A trinuclear copper(II) complex, [Cu₃L₂]·2ClO₄·2CH₃CN, with the reduced Schiff base ligand 2,2′-((propane-1,3-diylbis(azanediyl))bis(methylene))diphenol (H₂L) was prepared. The complex was characterized by elemental analysis, IR and UV–Vis spectra, and single crystal X-ray diffraction. The ligand coordinates to the Cu atoms through the amino nitrogen and phenolate oxygen, giving square planar geometry. The ligand and the complex were tested for their Jack bean urease inhibitory activities. The IC₅₀ value of the complex on the urease inhibition is 1.6 ± 1.2 μmol·L^?1. Molecular docking study of the complex was performed to study the inhibition.

Full text of DOI:10.1016/j.inoche.2018.12.009

Accepted Manuscript
Synthesis, crystal structure and urease inhibition of a trinuclear
copper(II) complex with reduced Schiff base ligand
Mengmeng Duan, Yanmin Li, Luyao Xu, Huailan Yang, Fuwen
Luo, Yixing Guan, Bitong Zhang, Changling Jing, Zhonglu You
PII:
S1387-7003(18)31008-6
DOI:
Reference:
https://doi.org/10.1016/j.inoche.2018.12.009
INOCHE 7197
To appear in:
Inorganic Chemistry Communications
Received date:
Revised date:
Accepted date:
17 November 2018
12 December 2018
17 December 2018
Please cite this article as: Mengmeng Duan, Yanmin Li, Luyao Xu, Huailan Yang, Fuwen
Luo, Yixing Guan, Bitong Zhang, Changling Jing, Zhonglu You , Synthesis, crystal
structure and urease inhibition of a trinuclear copper(II) complex with reduced Schiff base
ligand. Inoche (2018), https://doi.org/10.1016/j.inoche.2018.12.009
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ACCEPTED MANUSCRIPT
Synthesis, crystal structure and urease inhibition of a trinuclear copper(II) complex
with reduced Schiff base ligand
Mengmeng Duan, Yanmin Li, Luyao Xu, Huailan Yang, Fuwen Luo, Yixing Guan,
Bitong Zhang, Changling Jing, Zhonglu You
Department of Chemistry and Chemical Engineering, Liaoning Normal University,
Dalian 116029, PR China
ABSTRACT
A trinuclear copper(II) complex, [Cu3L2]·2ClO4·2CH3CN, with the reduced Schiff
base ligand 2,2'-((propane-1,3-diylbis(azanediyl))bis(methylene))diphenol (H2L) was
prepared. The complex was characterized by elemental analysis, IR and UV-Vis
spectra, and single crystal X-ray diffraction. The ligand coordinates to the Cu atoms
through the amino nitrogen and phenolate oxygen, giving square planar geometry. The
ligand and the complex were tested for their Jack bean urease inhibitory activities.
The IC50 value of the complex on the urease inhibition is 1.6 ± 1.2 μmol·L-1.
Molecular docking study of the complex was performed to study the inhibition.
Keywords: Reduced Schiff base; Copper(II) complex; Crystal structure; Urease
inhibitor
Urease is a nickel-containing hydrolase enzyme, which exists in various organisms,
such as plants, bacteria, algae, fungi, and invertebrates, and occurs in animal and soil

Corresponding author at: Department of Chemistry and Chemical Engineering, Liaoning Normal University,
Dalian 116029, PR China.
E-mail address: youzhonglu@126.com
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[1,2]. Urease can catalyze the decomposition of urea into ammonia in high efficiency
[3,4]. The enzyme possesses harmful effects on both human health and fertile soil
[5,6]. High urease activity in soil leads to increase ammonia toxicity in air and
economic problems [7,8]. The negative effects oblige us to explore novel urease
inhibitors. Our research group has pioneered the study of Schiff base and their
complexes as urease inhibitors [9-14]. Schiff bases have been reported as effective
antibacterial agents [15,16], and show interesting urease inhibitory activity [17].
Copper complexes also show various biological properties [18,19]. Reduced Schiff
bases are in general more stable than Schiff bases. Metal complexes have been proved
to possess significant inhibitory activities on various enzymes [20,21]. As a part of
our ongoing research on urease inhibition with metal complexes, a copper(II) complex
with reduced Schiff base ligand (H2L) was prepared and tested for its urease
inhibitory activity. The mechanism of urease inhibition was studied by using docking
techniques.
H2L
To a dry methanol solution (100 mL) of salicylaldehyde (2.42 g, 0.02 mol) was
added dropwise a dry methanol solution (50 mL) of 1,3-diaminopropane (0.74 g, 0.01
mol) over 1 h. Then the reaction mixture was refluxed for 2 h. After the solution was
cooled, NaBH4 (1.9 g, 0.05 mol) was carefully added. The reaction solution was
refluxed for a further 30 min, filtered, and the solvent removed under reduced
pressure by using a rotary evaporator. The residue was treated with 1 mol·L-1 NaOH
(100 mL). Then extracted into chloroform (4 × 50 mL). The resulting chloroform
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solution was extracted by shaking with 3 mol·L-1 HCl (4 × 50 mL). The acid phase
was made basic (pH > 12) by the addition of 1 mol·L-1 NaOH and the crude product
was then back extracted into chloroform. The chloroform extracts were combined and
dried over anhydrous Na2SO4, filtered, and the solvent removed under vacuum by
using a rotary evaporator to yield the product as oil. Yield 2.3 g (80%). Anal. Calc. for
C17H22N2O2: C, 71.3; H, 7.7; N, 9.8. Found: C, 71.1; H, 7.8; N, 9.6%. IR data (cm–1):
ν(OH) 3450, ν(NH) 3289, ν(CHaromatic) 3070, νas(CH2) 2931, νs(CH2) 2875,
ν(C=Caromatic) 1602, 1456, ν(C-N) 1035. UV–Vis data (methanol, λ/nm): 260, 293. 1H
NMR (500 MHz, CDCl3, ppm) δ 7.18 (td, 2H, ArH), 7.00 (d, 2H, ArH), 6.84 (dd, 2H,
ArH), 6.80 (td, 2H, ArH), 4.01 (s, 4H, ArCH2), 2.76 (t, 4H, CH2), 1.80 (m, 2H, CH2).
A methanolic solution (30 mL) of copper perchlorate hexahydrate (0.74 g, 2.0
mmol) was added to an acetonitrile solution (30 mL) of H2L(0.29 g, 1.0 mmol) with
stirring. The mixture was stirred at room temperature for 30 min to give a blue
solution. The resulting solution was allowed to stand in air for a few days until three
quarter of the solvent was evaporated. Blue block-shaped crystals of the complex,
suitable for X-ray single crystal diffraction were formed at the bottom of the vessel.
The crystals were isolated by filtration and dried in air. Yield 29%. Anal. Calc. for
C38H46Cl2Cu3N6O12: C, 43.9; H, 4.5; N, 8.1. Found: C, 43.7; H, 4.4; N, 7.9%. IR data
(cm–1): ν (NH) 3240, ν(CHaromatic) 3070, νas(CH2) 2935, νs(CH2) 2873, ν(C=Caromatic
1607, 1456, 1482, ν(Cl-O) 1093, δ(O-Cl-O) 631, ν(C≡N) 761. UV–Vis data
(methanol, λ/nm): 273, 390. ΛM (10–3 M in methanol): 212 Ω–1 cm2 mol–1.
)
Diffraction intensities for the complex were collected at 298(2) K using a Bruker
SMART 1000 CCD area-detector diffractometer with MoKα radiation (λ = 0.071073
nm). The collected data were reduced with SAINT [22], and multi-scan absorption
correction was performed using SADABS [23]. Structure of the complex was solved
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by direct methods and refined against F2 by full-matrix least-squares method using
SHELXTL [24]. All of the non-hydrogen atoms were refined anisotropically. The
hydrogen atoms attached to the amino N atoms were located from a difference Fourier
map and refined isotropically, with N–H distances restrained to 0.90(1) Å. The
remaining hydrogen atoms were placed in calculated positions and constrained to ride
on their parent atoms. The crystal data and structure refinement for the complex are
listed in Table 1.
The measurement of urease inhibitory activity was carried out according to the
literature method [25]. The assay mixture containing 75 μL of Jack bean urease and
75 μL of tested compounds with various concentrations (dissolved in DMSO) was
pre-incubated for 15 min on a 96-well assay plate. Acetohydroxamic acid was used as
a reference. Then 75 μL of phosphate buffer at pH 6.8 containing phenol red (0.18
mmol·L-1) and urea (400 mmol·L-1) were added and incubated at room temperature.
The reaction time required for enough ammonium carbonate to form to raise the pH
phosphate buffer from 6.8 to 7.7 was measured by micro-plate reader (560 nm) with
end-point being determined by the color change of phenol-red indicator.
Molecular docking study of the complex into the 3D X-ray structure of the Jack
bean urease (entry 4UBP in the Protein Data Bank) was carried out by using the
AutoDock 4.0 software as implemented through the graphical user interface
AutoDockTools (ADT 1.5.2). The graphical user interface AutoDockTools was
employed to setup the enzymes: all hydrogens were added, Gasteiger charges were
calculated and nonpolar hydrogens were merged to carbon atoms. The Ni initial
parameters are set as r = 1.170 Å, q = +2.0, and van der Waals well depth of 0.419
kJ·mol–1 [26]. The 3D structure of the ligand molecule was saved in pdb format with
the aid of the program Mercury. The resulting files were saved as pdbqt format.
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The AutoDockTools was used to generate the docking input files. In the docking,
grid box size of 66 × 54 × 66 for the complex points in x, y, and z directions was built,
the maps were centered on the original ligand molecule (HAE) in the catalytic site of
the protein. A grid spacing of 0.375 Å and a distances-dependent function of the
dielectric constant were used for the calculation of the energetic map. 100 runs were
generated by using Lamarckian genetic algorithm searches. Default settings were used
with an initial population of 50 randomly placed individuals, a maximum number of
2.5 × 106 energy evaluations, and a maximum number of 2.7 × 104 generations. A
mutation rate of 0.02 and a crossover rate of 0.8 were chosen. The results of the most
favorable free energy of binding were selected as the resultant complex structures.
The ligand H2L was readily prepared by the condensation reaction of
salicylaldehyde with propane-1,3-diamine, followed by reduction with NaBH4. The
complex was prepared by reaction of H2L with copper perchlorate in the mixture
solution of methanol and acetonitrile. The conductance value of 212 Ω–1 cm2 mol–1 in
methanol for the complex indicates that it behaves as 1:2 electrolyte in this solvent
[27].
Molecular structure of the complex is shown in Figure 1. X-ray crystallography
reveals that the complex possesses a crystallographic inversion symmetry. The
asymmetric unit of the complex contains a mononuclear [Cu3L2]2+ cation, two
perchlorate anions, and two acetonitrile molecules of crystallization. The Cu···Cu
distance is 2.985(2) Å. The central Cu atom, located at the inversion center, is
coordinated by four phenolate O atoms from two ligands, forming square planar
geometry. The terminal Cu atoms are coordinated by two amino N and two phenolate
O atoms of the ligand, also forming square planar geometry. The coordinate bond
lengths in the complex are comparable to those observed in copper(II) complexes with
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similar ligands [28,29]. The displacement of the terminal Cu atom from the equatorial
plane is 0.0012(3) Å. The CuL unit in the complex is butterfly-shaped, with the
dihedral angle formed by the two benzene rings of 129.8(7)°. The four-membered
chelate ring Cu1-O1-Cu2-O2 is not planar but is slightly roof-shaped. The chelate
ring formed by the atoms Cu1, N1, C8, C9, C10 and N2 is in a chair conformation.
The diagonally positioned atoms, Cu1 and C9, are shifted from the least-squares plane
defined by the atoms N1, N2, C8 and C10 by -0.687(3) and 0.727(5) Å, respectively.
In the crystal structure of the complex, the [Cu3L2]2+ cations are linked together by
perchlorate anions and acetonitrile molecules through hydrogen bonds (Figure 2).
The weak and broad absorption centered at 3450 cm–1 in the spectrum of H2L
substantiates the presence of O–H groups, which are absent in the complex. The weak
and sharp bands indicative of the N–H groups of H2L and the complex are located at
3289 and 3240 cm–1, respectively. The strong absorption band at 1093 cm–1 for the
complex is assigned to the stretching vibrations of the perchlorate anions. The weak
band at 631 cm–1 is assigned to the asymmetric O-Cl-O bending mode of the
perchlorate anions.
The UV-Vis spectra of H2L and the complex were recorded in methanol with
concentration of 10-5 mol·L-1. The free ligand H2L and the complex displayed strong
bands centered at 260 and 273 nm, respectively, which can be assigned to the
intra-ligand π–π* transition of the aromatic rings. The charge transfer LMCT band is
located at 390 nm. The spectrum of the complex showed weak and broad d-d
2
electronic transition in the range 630-670 nm, which is assigned to Eg(D)→2T2g(D)
[30].
The percentage inhibition values at concentration of 12.5 μmol·L-1 for H2L and the
complex are 5.5 ± 1.8 and 99.7 ± 2.5, respectively. Acetohydroxamic acid and copper
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perchlorate were used as references, with IC50 values of 36.3 ± 2.5 and 8.5 ± 1.7
μmol·L-1, respectively. The free Schiff base showed poor inhibition, while the
complex showed excellent inhibition, with IC50 value of 1.6 ± 1.2 μmol·L-1. As
comparison, the urease inhibition of the copper perchlorate is weaker than the copper
complex. The urease inhibitory activity of the present copper complex is in general
comparable to the copper complexes with Schiff bases [10,12,13].
Molecular docking study was performed to investigate the binding effect between
the molecule of the complex and the active site of the Jack bean urease. The binding
models of the complex with the urease were depicted in Figures 3-5. The results
revealed that the molecule of the complex fits well with the active pocket of the
urease (Figures 3 and 4). The size of the molecule might be the basal principle of the
inhibition. Additional interactions have been established in a variety of conformations
because of the flexibility of the complex molecules and the amino acid residues of the
enzyme. The optimized clusters (100 occurrences each) were ranked by energy level
in the best conformation of inhibitor–urease modeled structures, where the docking
score is –10.04. As comparison, the docking score for the AHA inhibited model is
–5.01. The negative value indicates that the complex molecule binds well with the
urease.
The mechanism of urease inhibition by the complex was considered to be
embedded in the active pocket of the urease and interact with the residues ASP165
and ASN168 (Figure 5). In addition, there are some hydrophobic interactions between
the complex and the residues of the urease. The mechanism of urease inhibition by the
complex was considered to be well block the entrance of the urease active pocket, and
hindered the urea to access to the urease active center. The results endorse that the
complex may serve as a structural template for the design and development of novel
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urease inhibitors.
Conclusion
The present study reports the synthesis, characterization and crystal structure of a
trinuclear copper(II) complex with reduced Schiff base ligand. The ligand coordinates
to the Cu atoms through the phenolate oxygen and amino nitrogen. The complex has
excellent inhibitory activity against Jack bean urease, which may be used as a
precursor for the design of novel urease inhibitors.
Acknowledgment
This work was financially supported by the Education Office of Liaoning Province
(Project No. LF201783611), and the Undergraduate Innovation and Entrepreneurship
training program of Liaoning Province (Project No. cx201802017).
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Table 1 Crystal data and refinement parameters for the complex
Formula
C38H46Cl2Cu3N6O12
1040.33
FW
Crystal shape/colour
Crystal size /mm
block/blue
0.270.230.23
Monoclinic
P21/n
Crystal system
Space group
a (Å)
11.6098(7)
13.6343(10)
13.8590(8)
102.220(2)
b (Å)
c (Å)
 (º)
V (Å3)
2144.1(2)
2
Z
0.71073
 (MoK) (Å)
T (K)
298(2)
1.667
 (MoK) (cm–1)
Tmin
0.6617
0.7004
18404/284
3980
Tmax
Reflections/parameters
Unique reflections
Observed reflections [I  2(I)]
Restraints
2197
2
Goodness of fit on F2
1.013
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0.0727, 0.1489
0.1424, 0.1840
R1, wR2 [I  2(I)]
R1, wR2 (all data)
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Figure 1. A perspective view of the molecular structure of the complex with the atom
labeling scheme. Thermal ellipsoids are drawn at 30% probability level. Selected
bond lengths (Å) and bond angles (°): Cu1-O1 1.959(4), Cu1-O2 1.952(4), Cu1-N1
2.012(6), Cu1-N2 2.001(6), Cu2-O2 1.917(4), Cu2-O1 1.918(4); O2-Cu1-O1
77.42(18), O2-Cu1-N2 93.7(2), O1-Cu1-N2 171.1(2), O2-Cu1-N1 169.4(2),
O1-Cu1-N1 92.0(2), N2-Cu1-N1 96.9(3), O2-Cu2-O2A 180, O2-Cu2-O1A
100.75(19), O2-Cu2-O1 79.25(19), O1-Cu2-O1A 180.
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Figure 2. Molecular packing diagram of the complex. Hydrogen bonds are shown as
dashed lines. N1–H1 = 0.90(1) Å, H1∙∙∙N3 = 2.67(14) Å, N1∙∙∙N3 = 3.20(1) Å,
N1–H1∙∙∙N3 = 119(12)º; N2–H2 = 0.90(1) Å, H2∙∙∙N3 = 2.64(15) Å, N2∙∙∙N3 = 3.12(1)
Å, N2–H2∙∙∙N3 = 114(12)º; N2–H2 = 0.90(1) Å, H2∙∙∙O6i = 2.19(8) Å, N2∙∙∙O6i =
3.01(1) Å, N2–H2∙∙∙O6i = 151(14)º; C5–H5 = 0.93(1) Å, H5∙∙∙O5ii = 2.49(7) Å,
C5∙∙∙O5ii = 3.41(1) Å, C5–H5∙∙∙O5ii = 169(12)º; C19–H19C = 0.96(1) Å, H19C∙∙∙O5iii
= 2.58(7) Å, C19∙∙∙O5iii = 3.32(1) Å, C19–H19C∙∙∙O5iii = 135(12)º; symmetry codes: i)
3/2 – x, 1/2 + y, 1/2 – z; ii) 1/2 – x, 1/2 + y, 1/2 – z; iii) 1 – x, 1 – y, 1 – z.
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Figure 3. Binding mode of the complex with the urease. The enzyme is shown as grey
surface. The complex is shown as sticks.
Figure 4. Binding mode of the complex with the urease. The enzyme is shown as grey
surface, and the complex is shown as blue surface.
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Figure 5. Binding mode of the complex with the urease. Only the interacting residues
are displayed. The interactions are shown as dashed spheres.
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Graphical Abstract
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Highlights
► A novel trinuclear copper(II) complex was prepared. ► The complex has been characterized by
single crystal X-ray diffraction. ► The complex show strong urease inhibitory activity. ► This is
the first example of urease inhibition with reduced Schiff base complex.
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