Preparation and structural characterization of hetero-dinuclear Schiff base copper(II)-zinc(II) complexes and their inhibition studies on Helicobacter pylori urease

Article abstract of DOI:10.1016/j.poly.2011.05.048

A series of hetero-dinuclear Cu^II-Zn^II complexes, [CuZnCl₂L¹] (1), [CuZnCl₂L²] (2), [CuZnBr₂L³] (3), [CuZnBr₂L⁴(DMF)] (4), [CuZnCl₂L⁴] (5), [CuZnCl₂L⁵] (6), [CuZnCl₂L³] (7) and [CuZnBr₂L¹] (8), where L¹, L², L³, L⁴ and L⁵ are the deprotonated forms of N,N′-bis(3-ethoxysalicylidene) -1,3-propanediamine (H₂L¹), N,N′-bis(2- hydroxynaphthylmethylidene)-1,3-propanediamine (H₂L²), N,N′-bis(3-methoxysalicylidene)-1,3-propanediamine (H₂L ³), N,N′-bis(salicylidene)-1,3-propanediamine (H ₂L⁴) and N,N′-bis(salicylidene)-1,4-butanediamine (H₂L⁵), respectively, have been synthesized and characterized by physico-chemical methods and single-crystal X-ray diffraction. The complexes were tested for their urease inhibitory activity. Complexes 1 and 8 show effective urease inhibitory activity with IC₅₀ values of 2.2 and 10.7 μM. The molecular docking study of the complexes with the Helicobacter pylori urease was performed.

Full text of DOI:10.1016/j.poly.2011.05.048

Polyhedron 30 (2011) 2186–2194
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Preparation and structural characterization of hetero-dinuclear Schiff base
copper(II)–zinc(II) complexes and their inhibition studies on Helicobacter pylori
urease
⇑
Zhong-Lu You , Yao Lu, Na Zhang, Bo-Wen Ding, Hui Sun, Peng Hou, Che Wang
Department of Chemistry and Chemical Engineering, Liaoning Normal University, 116029 Dalian, PR China
a r t i c l e i n f o
a b s t r a c t
A series of hetero-dinuclear CuII–ZnII complexes, [CuZnCl2L1] (1), [CuZnCl2L2] (2), [CuZnBr2L3] (3),
[CuZnBr2L4(DMF)] (4), [CuZnCl2L4] (5), [CuZnCl2L5] (6), [CuZnCl2L3] (7) and [CuZnBr2L1] (8), where L1, L2,
L3, L4 and L5 are the deprotonated forms of N,N0-bis(3-ethoxysalicylidene)-1,3-propanediamine (H2L1),
N,N0-bis(2-hydroxynaphthylmethylidene)-1,3-propanediamine (H2L2), N,N0-bis(3-methoxysalicylidene)-
1,3-propanediamine (H2L3), N,N0-bis(salicylidene)-1,3-propanediamine (H2L4) and N,N0-bis(salicylidene)-
1,4-butanediamine (H2L5), respectively, have been synthesized and characterized by physico-chemical
methods and single-crystal X-ray diffraction. The complexes were tested for their urease inhibitory activity.
Article history:
Received 23 February 2011
Accepted 13 May 2011
Available online 23 June 2011
Keywords:
Schiff base
Cu–Zn complex
Crystal structure
Urease inhibition
Complexes 1 and 8 show effective urease inhibitory activity with IC50 values of 2.2 and 10.7
ular docking study of the complexes with the Helicobacter pylori urease was performed.
lM. The molec-
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
1,3-propanediamine (H2L2), N,N0-bis(3-methoxysalicylidene)-1,
3-propanediamine (H2L3), N,N0-bis(salicylidene)-1,3-propanedi-
amine (H2L4) and N,N0-bis(salicylidene)-1,4-butanediamine (H2L5),
respectively, were prepared and structurallycharacterized(Chart 1).
The urease inhibitory activity of the complexes and the molecular
docking analysis of the complexes with Helicobacter pylori urease
were investigated.
Urease (urea amidohydrolase; E.C.3.5.1.5) is a nickel-containing
metalloenzyme that catalyzes the hydrolysis of urea to form ammo-
nia and carbamate [1,2]. The resulting carbamate spontaneously
decomposes to yield a second molecule of ammonia and carbon
dioxide. High concentrations of ammonia arising from these reac-
tions, as well as the accompanying pH elevation, have important
negative implications in medicine and agriculture [3–6]. Control of
the activity of urease through the use of inhibitors could counteract
these negative effects. In recent years, urease inhibitors play an
important role in the treatment of infections caused by urease pro-
ducing bacteria [7]. Inhibitors of urease can be broadly classified into
two fields: (1) organic compounds, such as acetohydroxamic acid,
humic acid and 1,4-benzoquinone [8–10]; (2) heavy metal ions, such
as Cu2+, Zn2+, Pd2+ and Cd2+ [11,12]. Complexes containing metal
atoms as urease inhibitors have seldom been reported, though there
are reports of organotin(IV), vanadium(IV), bismuth(III), copper(II),
and cadmium(II) complexes bearing interesting urease inhibitory
activities [13–20]. In this paper, a series of hetero-dinuclear cop-
per(II)–zinc(II) complexes, [CuZnCl2L1] (1), [CuZnCl2L2] (2),
[CuZnBr2L3] (3), [CuZnBr2L4(DMF)] (4), [CuZnCl2L4] (5), [CuZnCl2L5]
(6), [CuZnCl2L3] (7) and [CuZnBr2L1] (8), where L1, L2, L3, L4 and L5 are
the deprotonated forms of N,N0-bis(3-ethoxysalicylidene)-1,3-pro-
panediamine (H2L1), N,N0-bis(2-hydroxynaphthylmethylidene)-
2. Experimental
2.1. General methods and materials
Starting materials, reagents and solvents were purchased from
commercial suppliers and were purified before use. Elemental anal-
yses were performed on a Perkin–Elmer 240C elemental analyzer.
The IR spectra were recorded on a Jasco FT/IR-4000 spectrometer
as KBr pellets in the 4000–200 cmꢀ1 region. The 1H NMR spectra
were recorded on a Bruker Avance 400 MHz spectrometer with tet-
ramethylsilane as the internal reference. Molar conductance was
measured with a Shanghai DDS-11A conductometer. X-ray diffrac-
tion was carried out on a Bruker Smart 1000 CCD diffractometer.
Caution: Copper perchlorate is potentially explosive, only a small
quantity should be used and it should be handled with great care.
2.2. Synthesis of the Schiff bases
⇑
The synthesis and crystal structures of the Schiff bases H2L3,
H2L4 and H2L5 have been reported [21–23]. The Schiff bases were
Corresponding author. Tel.: +86 411 84216387.
E-mail address: youzhonglu@yahoo.com.cn (Z.-L. You).
0277-5387/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2011.05.048

Z.-L. You et al. / Polyhedron 30 (2011) 2186–2194
2187
N
N
N
N
HO
OH
OEt
OH
OEt
HO
H2L1
H2L2
N
N
N
N
HO
OH
HO
OH
OMe
OMe
H2L3
H2L4
HO
N
N
OH
H2L5
Chart 1. The Schiff bases.
synthesized by the same methods as described in the literature. To
a methanolic solution (50 mL) of the corresponding aldehydes
(2.0 mmol each) was added a methanolic solution (50 mL) of pro-
pane-1,3-diamine (1.0 mmol, 0.075 g) with stirring. The mixture
was stirred for 30 min at room temperature to give a yellow pre-
cipitate. Three quarters of the solvent was evaporated to give a
great deal of the yellow precipitate, which was isolated by filtra-
tion and washed with a little cold MeOH and then dried in air.
For H2L1: Yield 97%. Characteristic IR data (cmꢀ1): 3435 (m),
1635 (s), 1231 (m). Anal. Calc. for C21H26N2O4: C, 68.1; H, 7.1; N,
7.6. Found: C, 68.3; H, 7.2; N, 7.5%. 1H NMR data (CDCl3, ppm) d:
1.35 (t, 6H, CH3), 2.03 (m, 2H, CH2), 3.69 (t, 4H, CH2), 4.07 (t, 4H,
OCH2), 6.85–7.23 (m, 6H, C6H3), 8.51 (s, 2H, CH@N), 12.5 (s, 2H,
OH). For H2L2: Yield 96%. Characteristic IR data (cmꢀ1): 3427 (m),
1631 (s), 1227 (m). Anal. Calc. for C25H22N2O2: C, 78.5; H, 5.8; N,
7.3. Found: C, 78.3; H, 5.8; N, 7.4%. 1H NMR data (CDCl3, ppm) d:
2.03 (m, 2H, CH2), 3.69 (t, 4H, CH2), 7.20–8.07 (m, 12H, C10H6),
12.2 (s, 2H, OH). For H2L3: Yield 93%. Characteristic IR data
(cmꢀ1): 3433 (m), 1636 (s), 1232 (m). Anal. Calc. for C19H22N2O4:
C, 66.6; H, 6.5; N, 8.2. Found: C, 66.7; H, 6.5; N, 8.3%. 1H NMR data
(CDCl3, ppm) d: 2.03 (m, 2H, CH2), 3.69 (t, 4H, CH2), 3.81 (s, 6H,
CH3), 7.02–7.23 (m, 6H, C6H3), 8.51 (s, 2H, CH@N), 12.5 (s, 2H,
OH). For H2L4: Yield 97%. Characteristic IR data (cmꢀ1): 3327 (w),
1637 (s), 1278 (m). Anal. Calc. for C17H18N2O2: C, 72.3; H, 6.4; N,
9.9. Found: C, 72.1; H, 6.5; N, 9.9%. 1H NMR data (CDCl3, ppm) d:
2.03 (m, 2H, CH2), 3.68 (t, 4H, CH2), 6.83–7.37 (m, 8H, C6H4), 8.33
(s, 2H, CH@N), 12.3 (s, 2H, OH). For H2L5: Yield 93%. Characteristic
IR data (cmꢀ1): 3341 (w), 1636 (s), 1278 (m). Anal. Calc. for
times with cold MeOH and dried in air. Yield 83%. Characteristic
IR data (cmꢀ1): 1618 (s), 1181 (m). Anal. Calc. for C21H24Cl2Cu-
N2O4Zn: C, 44.4; H, 4.3; N, 4.9. Found: C, 43.7; H, 4.5; N, 5.1%.
2.3.2. [CuZnCl2L2] (2)
To a methanolic solution (50 mL) of H2L2 (0.19 g, 0.5 mmol) a
mixture of Cu(ClO4)2ꢁ6H2O (0.19 g, 0.5 mmol) and ZnCl2 (0.07 g,
0.5 mmol) dissolved in MeOH (20 mL) was added with stirring.
The mixture was stirred for 30 min at room temperature to give
a blue precipitate. Blue block-shaped single crystals suitable for
X-ray diffraction were obtained by slow diffusion of diethyl ether
into a N,N-dimethylformamide solution of the precipitate. The
crystals were isolated, washed three times with cold MeOH and
dried in air. Yield 67%. Characteristic IR data (cmꢀ1): 1619 (s),
1195 (m). Anal. Calc. for C25H20Cl2CuN2O2Zn: C, 51.7; H, 3.5; N,
4.8. Found: C, 51.0; H, 3.4; N, 5.1%.
2.3.3. [CuZnBr2L3] (3)
Complex 3 was synthesized by a similar method as that
described for 2, with H2L2 being replaced by H2L3 (0.17 g,
0.5 mmol), and ZnCl2 being replaced by ZnBr2 (0.12 g, 0.5 mmol).
Blue block-shaped single crystals of 3 were isolated, washed three
times with cold MeOH and dried in air. Yield 68%. Characteristic IR
data (cmꢀ1): 1618 (s), 1182 (m). Anal. Calc. for C19H20Br2CuN2O4Zn:
C, 36.3; H, 3.2; N, 4.5. Found: C, 36.7; H, 3.3; N, 4.6%.
2.3.4. [CuZnBr2L4(DMF)] (4)
Complex 4 was synthesized by a similar method as that
described for 2, with H2L2 being replaced by H2L4 (0.14 g,
0.5 mmol), and ZnCl2 being replaced by ZnBr2 (0.12 g, 0.5 mmol).
Blue block-shaped single crystals of 4 were isolated, washed three
times with cold MeOH and dried in air. Yield 73%. Characteristic IR
data (cmꢀ1): 1663 (s), 1616 (s), 1180 (m). Anal. Calc. for
C
18H20N2O2: C, 73.0; H, 6.8; N, 9.4. Found: C, 72.8; H, 6.8; N,
9.5%. 1H NMR data (CDCl3, ppm) d: 1.63 (m, 4H, CH2), 3.70 (t, 6H,
CH2), 7.00–7.72 (m, 8H, C6H4), 8.51 (s, 2H, CH@N), 12.1 (s, 2H, OH).
2.3. Synthesis of the complexes
2.3.1. [CuZnCl2L1] (1)
C
20H23Br2CuN3O3Zn: C, 37.4; H, 3.6; N, 6.5. Found: C, 37.2; H,
To a methanolic solution (50 mL) of H2L1 (0.18 g, 0.5 mmol), a
mixture of Cu(ClO4)2ꢁ6H2O (0.19 g, 0.5 mmol) and ZnCl2 (0.07 g,
0.5 mmol) dissolved in MeOH (20 mL) was added with stirring.
The mixture was stirred for 30 min at room temperature to give
a blue solution. Upon standing at room temperature, blue block-
shaped crystals of 1, suitable for X-ray crystal structural determi-
nation, were formed. The crystals were isolated, washed three
3.6; N, 6.6%.
2.3.5. [CuZnCl2L4] (5)
Complex 5 was synthesized by a similar method as that de-
scribed for 1, with H2L1 being replaced by H2L4 (0.14 g, 0.5 mmol).
Blue block-shaped single crystals of 5 were isolated, washed three
times with cold MeOH and dried in air. Yield 45%. Characteristic IR

2188
Z.-L. You et al. / Polyhedron 30 (2011) 2186–2194
data (cmꢀ1): 1617 (s), 1178 (m). Anal. Calc. for C17H16Cl2CuN2O2Zn:
experiment. A mixture containing 25
lL (4U) of H. pylori urease
C, 42.5; H, 3.4; N, 5.8. Found: C, 42.7; H, 3.5; N, 5.9%.
and 25 L of the test compound was pre-incubated for 3 h at room
l
temperature in a 96-well assay plate. The urease activity was
determined by measuring ammonia production using the indophe-
nol method as described by Weatherburn [28].
2.3.6. [CuZnCl2L5] (6)
Complex 6 was synthesized by a similar method as that de-
scribed for 1, with H2L1 being replaced by H2L5 (0.15 g, 0.5 mmol).
Blue block-shaped single crystals of 6 were isolated, washed three
times with cold MeOH and dried in air. Yield 72%. Characteristic IR
data (cmꢀ1): 1616 (s), 1180 (m). Anal. Calc. for C18H18Cl2CuN2O2Zn:
C, 43.7; H, 3.7; N, 5.7. Found: C, 43.9; H, 3.6; N, 5.8%.
2.6. Molecular docking study
Molecular docking of the complexes into the 3D X-ray struc-
tures of H. pylori urease structure (entry 1E9Y in the Protein Data
Bank) was carried out by using the AUTODOCK 4.2 software as imple-
mented through the graphical user interface AutoDockTools (ADT
1.5.4). The graphical user interface AutoDockTools was employed
to setup the enzymes: all hydrogens were added, Gasteiger charges
were calculated and non-polar hydrogens were merged to carbon
atoms. The Ni initial parameters were set as r = 1.170 Å, q = +2.0
and van der Waals well depth = 0.100 kcal/mol [29]. The cif files
of the complexes were transferred to pdb files with the program
CHEMBIO3D. The pdb files were further transferred to pdbqt files with
AutoDockTools.
2.3.7. [CuZnCl2L3] (7)
Complex 7 was synthesized by a similar method as that de-
scribed for 2, with H2L1 being replaced by H2L3 (0.17 g, 0.5 mmol).
Blue block-shaped single crystals of 7 were isolated, washed three
times with cold MeOH and dried in air. Yield 51%. Characteristic IR
data (cmꢀ1): 1618 (s), 1181 (m). Anal. Calc. for C19H20Cl2CuN2O4Zn:
C, 42.2; H, 3.7; N, 5.2. Found: C, 42.5; H, 3.7; N, 5.1%.
2.3.8. [CuZnBr2L1] (8)
Complex 8 was synthesized by a similar method as that de-
scribed for 1, with ZnCl2 being replaced by ZnBr2 (0.12 g,
0.5 mmol). Blue block-shaped single crystals of 8 were isolated,
washed three times with cold MeOH and dried in air. Yield 78%.
Characteristic IR data (cmꢀ1): 1618 (s), 1182 (m). Anal. Calc. for
AutoDockTools was used to generate the docking input files. In
all dockings, a grid box size of 90 ꢂ 90 ꢂ 90 points in the x, y and z
directions was built, the maps were centered on the original ligand
molecule in the catalytic site of the protein. A grid spacing of
0.375 Å and a distances-dependent function of the dielectric con-
stant were used for the calculation of the energetic map. Hundred
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 ꢂ 106
energy evaluations and a maximum number of 2.7 ꢂ 104 genera-
tions. A mutation rate of 0.02 and a crossover rate of 0.8 were cho-
sen. The results of the most favorable free energy of binding were
selected as the resultant complex structures.
C21H24Br2CuN2O4Zn: C, 38.4; H, 3.7; N, 4.3. Found: C, 38.5; H,
3.6; N, 4.5%.
2.4. X-ray crystallography
Diffraction intensities for the complexes were collected at
298(2) K using a Bruker Smart 1000 CCD area-detector diffractom-
eter with Mo Ka radiation (k = 0.71073 Å). The collected data were
reduced with the SAINT program [24], and multi-scan absorption
correction was performed using the SADABS program [25]. The struc-
tures were solved by direct methods. The complexes were refined
against F2 by full-matrix least-squares method using the SHELXTL
package [26]. All of the non-hydrogen atoms were refined aniso-
tropically. Hydrogen atoms were placed in calculated positions
and constrained to ride on their parent atoms. The propyl groups
in 1, 3 and 7 were disordered over two distinct sites, with occupan-
cies of 0.494(3) (C10–C11–C12) and 0.506(3) (C100–C110–C120) for
one molecule and of 0.473(3) (C31–C32–C33) and 0.527(3) (C310
–C320–C330) for the other molecule in 1, of 0.641(3) (C8–C9–C10)
and 0.359(3) (C80–C90–C100) in 3, and of 0.344(3) (C8–C9–C10)
and 0.656(3) (C80–C90–C100) in 7. The crystallographic data for
the complexes are summarized in Tables 1a and 1b. Selected bond
lengths and angles are given in Table 2.
3. Results and discussion
3.1. Chemistry
The Schiff bases H2L1–H2L5 were synthesized by the reaction of
propane-1,3-diamine or butane-1,4-diamine with similar substi-
tuted salicylaldehydes in absolute MeOH, with high yields and
purity. The air-stable yellow crystallites of the Schiff bases are solu-
ble in DMSO and DMF, partially soluble in MeOH, EtOH, CH3CN and
CHCl3, and are insoluble in water. The elemental analyses are in good
agreement with the chemical formulae proposed for the com-
pounds. The complexes were synthesized by the reaction of the
Schiff bases with copper(II) and zinc(II) salts in a ratio of 1:1:1 in
MeOH. The single crystals of 1, 5, 6 and 8 were obtained by slow
evaporation of a methanolic solution of the complexes, while those
of 2, 3, 4 and 7 were obtained by slow diffusion of diethyl ether into
N,N-dimethylformamide solutions of the complexes. All of the com-
plexes are stable in air at room temperature. The molar conductivity
of the complexes measured in MeOH at a concentration of approxi-
2.5. Urease inhibitory activity assay
H. pylori (ATCC 43504; American Type Culture Collection,
Manassas, VA) was grown in brucella broth supplemented with
10% heat-inactivated horse serum for 24 h at 37 °C under microaer-
obic conditions (5% O2, 10% CO2 and 85% N2). The method of prep-
aration of H. pylori urease by Mao [27] was followed. Briefly, broth
cultures (50 mL, 2.0 ꢂ 108 CFU mLꢀ1) were centrifuged (5000g,
4 °C) to collect the bacteria, and after washing twice with phos-
phate-buffered saline (pH 7.4), the H. pylori precipitation was
stored at ꢀ80 °C. The H. pylori was returned to room temperature
and mixed with 3 mL of distilled water and protease inhibitors,
then sonication was performed for 60 s. Following centrifugation
(15 000g, 4 °C), the supernatant was desalted through Sepha-
dexG-25 column (PD-10 columns, Amersham-Pharmacia Biotech,
Uppsala, Sweden). The resultant crude urease solution was added
to an equal volume of glycerol and stored at 4 °C until use in the
mately 10ꢀ3 M are 15.3
for 2, 9.0
ꢀ1 cm2 molꢀ1 for 3, 8.5
ꢀ1 cm2 molꢀ1 for 5, 15.5 ꢀ1 cm2 molꢀ1 for 6, 11.2
for 7, and 9.0
ꢀ1 cm2 molꢀ1 for 8, indicating the non-electrolytic
X
ꢀ1 cm2 molꢀ1 for 1, 17.2
ꢀ1 cm2 molꢀ1 for 4, 18.0
ꢀ1 cm2 molꢀ1
X
ꢀ1 cm2 molꢀ1
X
X
X
X
X
X
nature of the complexes in solution [30].
3.2. Structure description of the complexes
Single-crystal X-ray diffraction shows that the complexes are
structurally similar dinuclear copper(II)–zinc(II) compounds (Figs.
1–8 for 1–8, respectively). Complexes 1–8 crystallize in the triclinic
ꢀ
space group P1, monoclinic space group P21/n, orthorhombic space

Z.-L. You et al. / Polyhedron 30 (2011) 2186–2194
2189
Table 1a
Crystallographic and experimental data for the complexes 1–4.
Complex
1
2
3
4
Formula
Molecular weight
T (K)
C
21H24Cl2CuN2O4Zn
C25H20Cl2CuN2O2Zn
580.2
298(2)
C19H20Br2CuN2O4Zn
629.1
298(2)
C20H23Br2CuN3O3Zn
642.1
298(2)
568.2
298(2)
Crystal shape/color
Crystal size (mm3)
Crystal system
Space group
a (Å)
block/blue
0.23 ꢂ 0.20 ꢂ 0.20
triclinic
block/blue
0.30 ꢂ 0.30 ꢂ 0.28
monoclinic
P21/n
10.494(2)
18.720(4)
11.797(2)
90
103.07(3)
90
2257.4(8)
4
block/blue
0.20 ꢂ 0.20 ꢂ 0.18
orthorhombic
Pca21
13.242(2)
11.004(2)
14.701(2)
90
90
90
2142.3(5)
4
1.951
block/blue
0.30 ꢂ 0.28 ꢂ 0.27
orthorhombic
P212121
10.337(2)
14.533(3)
15.848(4)
90
90
90
2380.8(9)
4
1.792
ꢀ
P1
11.433(2)
12.899(2)
16.349(3)
95.420(2)
102.814(2)
95.474(2)
2323.6(7)
4
b (Å)
c (Å)
a
(°)
b (°)
c
(°)
V (Å3)
Z
Dcalc (g cmꢀ3
)
1.624
2.207
1.707
2.268
l
(Mo K
a
) (mmꢀ1
)
5.870
5.282
F(0 0 0)
1156
1172
1236
1268
Independent reflections
10210
4932
4408
5161
Observed reflections (I ꢃ 2
r
(I))
6247
0.631 and 0.667
583
3672
0.549 and 0.580
298
3191
0.386 and 0.418
274
3608
0.300 and 0.330
273
Minimum and maximum transmission
Parameters
Restraints
7
0
7
0
Goodness-of-fit on F2
1.026
0.0473, 0.1075
0.0902, 0.1272
1.024
0.0454, 0.1052
0.0678, 0.1155
0.993
0.0380, 0.0763
0.0646, 0.0843
1.005
0.0465, 0.0850
0.0817, 0.0953
R1, wR2 [I ꢃ 2
r
(I)]a
R1, wR2 (all data)a
w(Fo ꢀ Fc2)/
R .
w(Fo2)2]1/2
a
2
R1 = Fo ꢀ Fc/Fo, wR2 = [
R
Table 1b
Crystallographic and experimental data for the complexes 5–8.
Complex
5
6
7
8
Formula
Molecular weight
T (K)
C
17H16Cl2CuN2O2Zn
C18H18Cl2CuN2O2Zn
494.2
298(2)
C19H20Cl2CuN2O4Zn
540.2
298(2)
C21H24Br2CuN2O4Zn
657.2
298(2)
480.1
298(2)
Crystal shape/color
Crystal size (mm3)
Crystal system
Space group
a (Å)
block/blue
0.18 ꢂ 0.17 ꢂ 0.15
monoclinic
P21/c
11.610(2)
8.258(2)
18.275(3)
90
98.780(2)
90
1731.7(5)
4
block/blue
0.12 ꢂ 0.10 ꢂ 0.10
triclinic
block/blue
0.32 ꢂ 0.30 ꢂ 0.27
orthorhombic
Pca21
13.017(2)
10.848(2)
14.814(2)
90
90
90
2091.9(5)
4
1.715
block/blue
0.32 ꢂ 0.30 ꢂ 0.27
monoclinic
P21/n
11.032(3)
13.108(3)
16.803(4)
90
101.976(3)
90
2376.9(10)
4
ꢀ
P1
7.856(2)
9.988(2)
13.313(1)
93.579(3)
101.966(2)
111.625(2)
938.9(3)
2
b (Å)
c (Å)
a
(°)
b (°)
c
(°)
V (Å3)
Z
Dcalc (g cmꢀ3
)
1.842
2.935
1.748
2.709
1.836
5.295
l
(Mo K
a
) (mmꢀ1
)
2.447
F(0 0 0)
964
498
1092
1300
Independent reflections
3939
3949
4057
4989
Observed reflections (I ꢃ 2
r
(I))
2653
0.620 and 0.667
226
2606
0.737 and 0.773
235
3064
0.508 and 0.558
274
2921
0.282 and 0.329
282
Minimum and maximum transmission
Parameters
Restraints
0
0
7
0
Goodness-of-fit on F2
1.026
0.0471, 0.0934
0.0805, 0.1048
0.994
0.0545, 0.1121
0.0902, 0.1271
1.007
0.0332, 0.0602
0.0544, 0.0674
1.025
0.0507, 0.1058
0.1021, 0.1244
R1, wR2 [I ꢃ 2
r
(I)]a
R1, wR2 (all data)a
w(Fo ꢀ Fc2)/
R .
w(Fo2)2]1/2
a
2
R1 = Fo ꢀ Fc/Fo, wR2 = [
R
group Pca21, orthorhombic space group P212121, monoclinic space
group P21/c, triclinic space group P1, orthorhombic space group
In complex 1, there are two independent molecules in the
asymmetric unit. Each Cu atom in the complexes, except for 4, is
four-coordinated by two imino N and two phenolic O atoms of
the corresponding Schiff base ligand, forming a slightly distorted
square-planar coordination. The Cu atom in 4 is five-coordinated
by two imino N and two phenolic O atoms of L4 in the basal plane,
and by one N atom of a DMF molecule at the apical position, form-
ing a square pyramidal coordination. The average trans angles are
165.8(2)° in 1, 169.8(1)° in 2, 165.6(2)° in 3, 169.9(2)° in 4,
ꢀ
Pca21 and monoclinic space group P21/n, respectively. The Cuꢁ ꢁ ꢁZn
distances are 3.193(2) and 3.186(2) Å for 1, 3.065(2) Å for 2,
3.185(2) Å for 3, 3.084(2) Å for 4, 3.075(2) Å for 5, 3.053(2) Å for
6, 3.196(2) Å for 7 and 3.175(2) Å for 8. The dihedral angles be-
tween the corresponding two aromatic rings are 30.6(3)° and
30.7(3)° in 1, 7.6(3)° in 2, 25.9(3)° in 3, 9.1(3)° in 4, 7.9(3)° in 5,
41.8(3)° in 6, 27.7(3)° in 7 and 34.5(3)° in 8.

2190
Z.-L. You et al. / Polyhedron 30 (2011) 2186–2194
Table 2
Table 2 (continued)
Selected bond lengths (Å) and angles (°) for the complexes.
Zn1–O1
Zn1–Cl1
2.022(3)
2.204(2)
157.7(2)
92.4(2)
102.4(2)
76.0(1)
Zn1–O2
Zn1–Cl2
2.015(3)
2.188(2)
79.8(1)
1
Cu1–O1
Cu1–N1
Cu2–O5
Cu2–N3
Zn1–O1
Zn1–Cl1
Zn2–O5
Zn2–Cl3
O3–Cu1–O1
O1–Cu1–N1
O1–Cu1–N2
O5–Cu2–N4
N4–Cu2–O7
N4–Cu2–N3
O1–Zn1–O3
O3–Zn1–Cl1
O3–Zn1–Cl2
O5–Zn2–O7
O7–Zn2–Cl3
O7–Zn2–Cl4
1.947(3)
1.956(4)
1.918(3)
1.963(4)
2.098(3)
2.222(1)
2.081(3)
2.220(1)
79.1(1)
Cu1–O3
Cu1–N2
Cu2–O7
Cu2–N4
Zn1–O3
Zn1–Cl2
Zn2–O7
Zn2–Cl4
O3–Cu1–N1
O3–Cu1–N2
N1–Cu1–N2
O5–Cu2–O7
O5–Cu2–N3
O7–Cu2–N3
O1–Zn1–Cl1
O1–Zn1–Cl2
Cl1–Zn1–Cl2
O5–Zn2–Cl3
O5–Zn2–Cl4
Cl3–Zn2–Cl4
1.925(3)
1.959(4)
1.954(3)
1.953(4)
2.102(3)
2.233(1)
2.116(3)
2.231(1)
165.7(1)
92.4(1)
97.5(2)
79.3(1)
92.7(1)
166.2(1)
113.2(1)
109.9(1)
125.8(1)
106.5(1)
117.7(1)
127.5(1)
O2–Cu1–N1
N1–Cu1–O1
N1–Cu1–N2
O2–Zn1–O1
O1–Zn1–Cl2
O1–Zn1–Cl1
O2–Cu1–O1
O2–Cu1–N2
O1–Cu1–N2
O2–Zn1–Cl2
O2–Zn1–Cl1
Cl2–Zn1–Cl1
92.6(2)
155.6(2)
109.9(1)
116.9(1)
118.8(1)
113.4(1)
114.3(1)
7
Cu1–O1
Cu1–N1
Zn1–O1
Zn1–Cl1
O1–Cu1–O2
O2–Cu1–N1
O2–Cu1–N2
O1–Zn1–O2
O2–Zn1–Cl1
O2–Zn1–Cl2
1.929(2)
1.947(3)
2.083(3)
2.224(1)
78.7(1)
164.3(1)
92.8(1)
71.4(1)
Cu1–O2
Cu1–N2
Zn1–O2
Zn1–Cl2
O1–Cu1–N1
O1–Cu1–N2
N1–Cu1–N2
O1–Zn1–Cl1
O1–Zn1–Cl2
Cl1–Zn1–Cl2
1.932(3)
1.953(4)
2.112(3)
2.234(1)
92.9(1)
165.4(1)
97.9(2)
109.8(1)
117.1(1)
122.4(1)
93.1(1)
165.6(2)
166.0(2)
93.0(1)
97.0(2)
71.9(1)
108.3(1)
115.3(1)
72.2(1)
112.5(1)
107.0(1)
116.2(1)
109.1(1)
8
Cu1–O1
1.922(4)
1.975(5)
2.087(4)
2.357(1)
164.6(2)
93.1(2)
97.2(2)
72.4(1)
109.9(1)
114.9(1)
Cu1–O3
Cu1–N2
Zn1–O3
Zn1–Br2
O1–Cu1–O3
O1–Cu1–N1
O3–Cu1–N1
O1–Zn1–Br1
O1–Zn1–Br2
Br1–Zn1–Br2
1.945(4)
1.937(5)
2.106(4)
2.360(1)
79.7(2)
Cu1–N1
Zn1–O1
Zn1–Br1
O1–Cu1–N2
N2–Cu1–O3
N2–Cu1–N1
O1–Zn1–O3
O3–Zn1–Br1
O3–Zn1–Br2
2
Cu1–O1
Cu1–N1
Zn1–O1
Zn1–Cl1
1.927(2)
1.958(3)
2.015(2)
2.190(1)
79.6(1)
90.6(1)
169.8(1)
40.0(1)
130.0(1)
75.7(1)
113.0(1)
111.0(1)
38.0(1)
Cu1–O2
Cu1–N2
Zn1–O2
Zn1–Cl2
1.931(2)
1.932(3)
2.008(2)
2.190(1)
169.9(1)
90.3(1)
92.9(2)
164.3(2)
122.3(1)
105.7(1)
121.8(1)
O1–Cu1–O2
O2–Cu1–N2
O2–Cu1–N1
O1–Cu1–Zn1
N2–Cu1–Zn1
O2–Zn1–O1
O1–Zn1–Cl2
O1–Zn1–Cl1
O2–Zn1–Cu1
Cl2–Zn1–Cu1
O1–Cu1–N2
O1–Cu1–N1
N2–Cu1–N1
O2–Cu1–Zn1
N1–Cu1–Zn1
O2–Zn1–Cl2
O2–Zn1–Cl1
Cl2–Zn1–Cl1
O1–Zn1–Cu1
Cl1–Zn1–Cu1
99.5(1)
39.8(1)
129.9(1)
109.8(1)
117.8(1)
121.0(1)
37.9(1)
114.1(1)
124.8(1)
3
Cu1–O1
Cu1–N1
Zn1–O1
Zn1–Br1
O2–Cu1–O1
O1–Cu1–N2
O1–Cu1–N1
O1–Zn1–O2
O2–Zn1–Br2
O2–Zn1–Br1
1.933(3)
1.956(5)
2.082(4)
2.388(1)
79.0(1)
166.1(2)
92.2(2)
71.8(1)
Cu1–O2
Cu1–N2
Zn1–O2
Zn1–Br2
O2–Cu1–N2
O2–Cu1–N1
N2–Cu1–N1
O1–Zn1–Br2
O1–Zn1–Br1
Br2–Zn1–Br1
1.925(4)
1.944(5)
2.106(4)
2.368(1)
92.6(2)
165.2(2)
98.1(2)
109.7(1)
116.5(1)
122.6(1)
115.5(1)
110.0(1)
4
Cu1–O1
Cu1–O3
Cu1–N2
Zn1–O2
1.965(4)
2.307(4)
1.979(5)
2.006(4)
2.337(1)
78.3(1)
91.5(2)
166.9(2)
93.9(2)
96.3(2)
76.4(1)
116.0(1)
111.6(1)
Cu1–O2
Cu1–N1
Zn1–O1
Zn1–Br1
1.961(4)
1.971(5)
2.001(4)
2.338(1)
Fig. 1. A perspective view of the two independent molecules in the asymmetric
unit of 1 with the atom labelling scheme. The thermal ellipsoids are drawn at the
30% probability level. Only the major components of the disordered groups are
shown for clarity.
Zn1–Br2
O2–Cu1–O1
O1–Cu1–N1
O1–Cu1–N2
O2–Cu1–O3
N1–Cu1–O3
O1–Zn1–O2
O2–Zn1–Br2
O2–Zn1–Br1
O2–Cu1–N1
O2–Cu1–N2
N1–Cu1–N2
O1–Cu1–O3
N2–Cu1–O3
O1–Zn1–Br2
O1–Zn1–Br1
Br2–Zn1–Br1
166.0(2)
91.1(2)
97.6(2)
93.4(2)
95.1(2)
115.4(1)
110.9(1)
119.0(1)
169.1(2)° in 5, 156.6(2)° in 6, 164.8(2)° in 7 and 164.4(2)° in 8. The
Cu atoms slightly deviate from the least-squares planes defined by
the four donor atoms of the Schiff base ligands by 0.003(2) Å in 1,
0.033(2) Å in 2, 0.007(2) Å in 3, 0.163(2) Å in 4, 0.022(2) Å in 5,
0.024(2) Å in 6, 0.013(2) Å in 7 and 0.004(2) Å in 8. The coordinate
bond lengths related to the Cu atoms are comparable to each other
and also comparable to the corresponding values observed in other
similar copper(II) complexes with Schiff bases [31,32].
The Zn atom in each complex is four-coordinated by two pheno-
lic O atoms of the corresponding Schiff base ligand, and by two X
atoms (X = Cl for 1, 2, 5, 6, 7; X = Br for 3, 4, 8) forming a slightly
distorted tetrahedral coordination. The X–Zn–X planes in the com-
plexes are nearly perpendicular to the CuL units, which can de-
crease the steric effects between them. The Zn–O bond lengths in
the complexes are comparable to each other, and the Zn–Br bonds
5
Cu1–O1
Cu1–N1
Zn1–O1
Zn1–Cl1
O1–Cu1–O2
O2–Cu1–N2
O2–Cu1–N1
O1–Zn1–O2
O2–Zn1–Cl1
O2–Zn1–Cl2
1.940(3)
1.961(3)
2.003(3)
2.206(1)
78.0(1)
92.3(1)
168.2(1)
75.2(1)
Cu1–O2
Cu1–N2
Zn1–O2
Zn1–Cl2
O1–Cu1–N2
O1–Cu1–N1
N2–Cu1–N1
O1–Zn1–Cl1
O1–Zn1–Cl2
Cl1–Zn1–Cl2
1.944(3)
1.960(4)
2.007(3)
2.210(1)
170.0(1)
91.2(1)
98.6(1)
119.7(1)
108.5(1)
116.4(1)
117.8(1)
112.5(1)
6
Cu1–O1
Cu1–N1
1.945(3)
1.934(4)
Cu1–O2
Cu1–N2
1.928(3)
1.985(4)

Z.-L. You et al. / Polyhedron 30 (2011) 2186–2194
2191
Fig. 2. A perspective view of the molecular structure of 2 with the atom labelling
scheme. The thermal ellipsoids are drawn at the 30% probability level.
Fig. 5. A perspective view of the molecular structure of 5 with the atom labelling
scheme. The thermal ellipsoids are drawn at the 30% probability level.
Fig. 3. A perspective view of the molecular structure of 3 with the atom labelling
scheme. The thermal ellipsoids are drawn at the 30% probability level. Only the
major components of the disordered groups are shown for clarity.
Fig. 6. A perspective view of the molecular structure of 6 with the atom labelling
scheme. The thermal ellipsoids are drawn at the 30% probability level.
Fig. 7. A perspective view of the molecular structure of 7 with the atom labelling
scheme. The thermal ellipsoids are drawn at the 30% probability level. Only the
major components of the disordered groups are shown for clarity.
Fig. 4. A perspective view of the molecular structure of 4 with the atom labelling
scheme. The thermal ellipsoids are drawn at the 30% probability level.

2192
Z.-L. You et al. / Polyhedron 30 (2011) 2186–2194
Table 3
Inhibition of urease by the tested materials.
Tested materials
Inhibition ratea, %
IC50 (lM)
1
2
3
4
5
6
7
95.3 3.3
35.2 2.2
6.9 1.4
4.4 0.7
17.2 1.3
21.5 2.7
20.2 2.3
72.7 4.1
3.1 0.6
1.3 0.4
2.4 1.0
0.7 0.2
2.7 0.5
87.5 2.1
2.2 0.1
31.2 1.2
–
–
–
–
–
10.7 0.8
–
–
–
–
–
8
HL1
HL2
HL3
HL4
HL5
Acetohydroxamic acid
35.3 0.4
a
The concentration of the tested material is 10
l
g mLꢀ1
.
acetohydroxamic acid (IC50 = 35.3 0.4
lM). Based on the above
study, we can preliminarily conclude that the ethoxy-substituted
groups in the phenyl rings, as well as the chloride ligands, may play
an important role in the inhibition.
Fig. 8. A perspective view of the molecular structure of 8 with the atom labelling
scheme. The thermal ellipsoids are drawn at the 30% probability level.
The inhibitory activity of hetero-dinuclear complexes against
urease is reported for the first time in this study. Many pure cop-
per(II), nickel(II), cobalt(II/III), cadmium(II) and silver(I) complexes
have shown inhibitory activities against urease [37,38,20,39,40].
The zinc(II) complexes have shown weak activities [41]. It is inter-
esting that the activities of 1 and 8 in this work are stronger than
the nickel(II) and zinc complexes [37,41], and are superior or com-
parable to the copper(II) complexes [38,20]. These results reveal
that complexes 1 and 8 may serve as important and selective can-
didates for further investigations and structural modifications.
in 3, 4 and 8 are much longer than the Zn–Cl bonds in 1, 2, 5, 6 and
7. All the coordinate bond lengths in the complexes related to the
Zn atoms are comparable to the corresponding values observed in
similar zinc(II) complexes with Schiff bases [33,34].
3.3. IR spectra
The IR spectra of the Schiff bases and the complexes provide
information about the metal–ligand bonding. Assignments are
based on typical group frequencies. Weak and broad absorptions
centered at about 3430 cmꢀ1 substantiate the presence of phenol
groups in the Schiff bases, which are absent in the complexes.
The strong absorption bands in the region 1631–1637 cmꢀ1 in
the spectra of the Schiff bases assigned to the azomethine
3.5. Molecular docking study
Since the complexes 1 and 8 show effective urease inhibitory
activity, the molecular docking study was performed to investigate
the binding effects between the complexes and the active sites of
the H. pylori urease. The binding models of complexes 1 and 8 in
the enzyme active site of urease are depicted in Figs. 9 and 16. In
both cases, there is one kind of interaction between the ethoxy
group and the Asn168 residue. Both complexes form hydrophobic
interactions with Ala169 and Ala365 residues of the urease. The
binding energy of the complexes with the urease are ꢀ5.57 eV
for 1 and ꢀ4.26 eV for 8. The results of the molecular docking study
could explain the effective inhibitory activity of 1 and 8 against H.
m(C@N) [35] shift to lower wave numbers in the complexes,
1616–1619 cmꢀ1, attributed to the coordination of the imine nitro-
gen to the metal atoms. The strong absorption bands of Ar–O in the
Schiff bases at 1227–1278 cmꢀ1 [36] are located at lower frequen-
cies for the complexes, viz. 1181 cmꢀ1 for 1 and 7, 1195 cmꢀ1 for 2,
1182 cmꢀ1 for 3 and 8, 1180 cmꢀ1 for 4 and 6, and 1178 cmꢀ1 for 5.
The strong absorption band at 1663 cmꢀ1 in the spectrum of 4 is
assigned to the stretching vibration of the C@O group in the coor-
dinated DMF molecule. The close resemblance of the shape and the
positions of the bands suggest similar coordination modes for the
complexes, in accordance with the structural features.
3.4. Pharmacology
The results of the urease inhibition are summarized in Table 3.
Compared with the reference inhibitor acetohydroxamic acid, the
Schiff bases have no or very weak interactions on urease. The com-
plexes exhibited from weak to moderate and excellent inhibition.
The chlorido-coordinated complexes 1, 2, 5, 6 and 7 show inhibi-
tion rates in the range 17–98%, and the bromido-coordinated com-
plexes 3, 4 and 8 show inhibition rates in the range 4–73%. On a
detailed comparison of 1 and 8, 3 and 7, as well as 4 and 5, we
can find that the inhibitory activity of the chlorido-coordinated
complexes is more effective than that of the bromido-coordinated
ones. When compared to other complexes, 1 and 8 show very
strong urease inhibitory activities, with IC50 values of 2.2 and
Fig. 9. Binding mode of 1 with H. pylori urease. The enzyme is shown as surface. The
10.7
l
M, respectively, which is even lower than that of
complex is shown as sticks.

Z.-L. You et al. / Polyhedron 30 (2011) 2186–2194
2193
Fig. 13. Binding mode of 5 with H. pylori urease. The enzyme is shown as surface.
Fig. 10. Binding mode of 2 with H. pylori urease. The enzyme is shown as surface.
The complex is shown as sticks.
The complex is shown as sticks.
Fig. 14. Binding mode of 6 with H. pylori urease. The enzyme is shown as surface.
The complex is shown as sticks.
Fig. 11. Binding mode of 3 with H. pylori urease. The enzyme is shown as surface.
The complex is shown as sticks.
Fig. 15. Binding mode of 7 with H. pylori urease. The enzyme is shown as surface.
The complex is shown as sticks.
Fig. 12. Binding mode of 4 with H. pylori urease. The enzyme is shown as surface.
The complex is shown as sticks.
pylori urease. As a comparison, a molecular docking study on the
other complexes was also carried out, as shown in Figs. 10–15.
The binding energies are ꢀ2.12 eV for 2, ꢀ1.07 eV for 3, +3.35 eV
for 4, ꢀ3.40 eV for 5, ꢀ3.13 eV for 6 and ꢀ3.53 eV for 7. It can be
seen that the binding energies for these complexes are somewhat
higher than those of 1 and 8. The positive value of the binding en-
ergy for 4 indicates the model is unconvincing, and the molecule
cannot effectively combine with the active center of urease.
4. Conclusion
The present study reports the synthesis, structures and urease
inhibitory activities of eight hetero-dinuclear copper(II)–zinc(II)
complexes with Schiff bases. The urease inhibitory activities of
the complexes 1 and 8 are much stronger than that of acetohydrox-
amic acid and the other complexes in this paper. Considering that
copper(II) and zinc(II) complexes have interesting biological

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Z.-L. You et al. / Polyhedron 30 (2011) 2186–2194
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Fig. 16. Binding mode of 8 with H. pylori urease. The enzyme is shown as surface.
The complex is shown as sticks.
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This work was financially supported by the National Science
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Appendix A. Supplementary data
CCDC 720671 (1), 720673 (2), 720672 (3), 720674 (4), 822721
(5), 822722 (6), 719722 (7) and 822758 (8) contains the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge via http://www.ccdc.cam.ac.uk/conts/
retrieving.html, or from the Cambridge Crystallographic Data Cen-
tre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-
033; or e-mail: deposit@ccdc.cam.ac.uk.
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