Synthesis, structures, and urease inhibition of nickel(II), zinc(II), and cobalt(II) complexes with similar hydroxy-rich Schiff bases

Article abstract of DOI:10.1080/00958972.2011.653785

Four new nickel(II), zinc(II), and cobalt(II) complexes, [Zn(L ¹)₂]·H₂O (1), [Ni(L¹) ₂]·H₂O (2), [Ni(L²)₂] (3), and [Co(L³)₂]·H₂O (4),

Full text of DOI:10.1080/00958972.2011.653785

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Synthesis, structures, and urease
inhibition of nickel(II), zinc(II), and
cobalt(II) complexes with similar
hydroxy-rich Schiff bases
Yao Lu a , Da-Hua Shi b , Zhong-Lu You a , Xiao-Shuang Zhou a &
Kun Li a
a Department of Chemistry and Chemical Engineering , Liaoning
Normal University , Huanghe Road 850#, Dalian 116029 , P.R.
China
b School of Chemical Engineering , Huaihai Institute of
Technology , Lianyungang 222005 , P.R. China
Published online: 20 Jan 2012.
To cite this article: Yao Lu , Da-Hua Shi , Zhong-Lu You , Xiao-Shuang Zhou & Kun Li (2012)
Synthesis, structures, and urease inhibition of nickel(II), zinc(II), and cobalt(II) complexes
with similar hydroxy-rich Schiff bases, Journal of Coordination Chemistry, 65:2, 339-352, DOI:
10.1080/00958972.2011.653785
To link to this article: http://dx.doi.org/10.1080/00958972.2011.653785
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Journal of Coordination Chemistry
Vol. 65, No. 2, 20 January 2012, 339–352
Synthesis, structures, and urease inhibition of nickel(II),
zinc(II), and cobalt(II) complexes with similar
hydroxy-rich Schiff bases
YAO LUy, DA-HUA SHIz, ZHONG-LU YOU*y,
XIAO-SHUANG ZHOUy and KUN LIy
yDepartment of Chemistry and Chemical Engineering, Liaoning Normal University,
Huanghe Road 850#, Dalian 116029, P.R. China
zSchool of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005,
P.R. China
(Received 8 August 2011; in final form 6 December 2011)
Four new nickel(II), zinc(II), and cobalt(II) complexes, [Zn(L1)2] ꢀ H2O (1), [Ni(L1)2] ꢀ H2O (2),
[Ni(L2)2] (3), and [Co(L3)2] ꢀ H2O (4), derived from hydroxy-rich Schiff bases 2-{[1-(5-chloro-2-
hydroxyphenyl)methylidene]amino}-2-methylpropane-1,3-diol (HL1), 2-{[1-(2-hydroxy-3-
methoxyphenyl)methylidene]amino}-2-ethylpropane-1,3-diol (HL2), and 2-{[1-(5-bromo-2-
hydroxyphenyl)methylidene]amino}-2-methylpropane-1,3-diol (HL3) have been synthesized
and characterized by elemental analyses, infrared spectroscopy, and single-crystal X-ray
determination. Each metal in the complexes is six-coordinate in a distorted octahedral
coordination. The Schiff bases coordinate to the metal atoms through the imino N, phenolate
O, and one hydroxyl O. In the crystal structures of HL1 and the complexes, molecules are linked
through intermolecular O–Hꢀ ꢀ ꢀO hydrogen bonds, forming 1-D chains. The urease inhibitory
activities of the compounds were evaluated and molecular docking study of the compounds with
the Helicobacter pylori urease was performed.
Keywords: Schiff base; Zinc; Nickel; Cobalt; Crystal structure; Urease inhibition
1. Introduction
Considerable attention has been focused on transition metal complexes containing Schiff
bases [1–4]. These complexes play an important role in coordination chemistry related to
catalysis and enzymatic reactions [5, 6], magnetism and molecular architectures [7, 8].
Schiff-base complexes are of particular interest to inorganic chemists since their
structural, spectral, and chemical properties often strongly depend on the detailed ligand
structures. The Schiff bases 2-{[1-(5-chloro-2-hydroxyphenyl)methylidene]amino}-2-
methylpropane-1,3-diol
(HL1),
2-{[1-(2-hydroxy-3-methoxyphenyl)methylidene]
amino}-2-ethylpropane-1,3-diol (HL2), and 2-{[1-(5-bromo-2-hydroxyphenyl)methyli-
dene]amino}-2-methylpropane-1,3-diol (HL3) (scheme 1) are similar multidentate
*Corresponding author. Email: youzhonglu@yahoo.com.cn
Journal of Coordination Chemistry
ISSN 0095-8972 print/ISSN 1029-0389 online ß 2012 Taylor & Francis
http://dx.doi.org/10.1080/00958972.2011.653785

340
Y. Lu et al.
z
OH
Y
N
OH
OH
X
Scheme 1. The Schiff bases (for HL1: X ¼ H, Y ¼ Cl, Z ¼ Me; for HL2: X ¼ OMe, Y ¼ H, Z ¼ Et; for HL3:
X ¼ H, Y ¼ Br, Z ¼ Et).
ligands, however, the complexes derived from them have seldom been reported [9–11].
Recently, we reported the urease inhibitory activity of some Schiff-base complexes
[12–14]. As a detailed study on the structures and coordination behavior of the Schiff
bases, and as an extension of the work on the exploration of new urease inhibitors, in this
study the crystal structures and urease inhibitory activity of HL1 and four new
complexes, [Zn(L1)2] ꢀ H2O (1), [Ni(L1)2] ꢀ H2O (2), [Ni(L2)2] (3), and [Co(L3)2] ꢀ H2O (4),
are investigated.
2. Experimental
2.1. Materials and methods
Solvents and reagents were purchased from Aldrich and used without purification.
Elemental analyses for C, H, and N were performed on a Perkin-Elmer 240C elemental
analyser. Infrared (IR) spectra were recorded on a Nicolet AVATAR 360 spectrometer
1
as KBr pellets from 4000 to 400 cmꢁ1. H NMR spectra were recorded on a Bruker
AVANCE 500 MHz spectrometer with tetramethylsilane as internal reference.
Electronic spectra were recorded on a Perkin Elmer Lambda 40 UV/Vis spectrometer
using HPLC grade acetonitrile as solvent.
2.2. Synthesis of HL1
To methanolic solution (20 cm3) of 5-chlorosalicylaldehyde (0.156 g, 1.0 mmol) was
added a methanolic solution (20 cm3) of 2-amino-2-methyl-1,3-propanediol (0.105 g,
1.0 mmol) with stirring. The mixture was stirred for 20 min at room temperature to give
a clear yellow solution. After keeping the solution in air for a week, yellow block-
shaped crystals of HL1, suitable for X-ray crystal structural determination, formed at
the bottom of the vessel on slow evaporation of about 80% of the solvent. The crystals
were isolated by filtration, washed three times with cold methanol, and dried in a
vacuum desiccator using anhydrous CaCl2. Yield, 0.173 g, 71%. Anal. Calcd for
C11H14ClNO3 (%): C, 54.2; H, 5.8; N, 5.8. Found: C, 54.0; H, 5.9; N, 5.7. IR data (KBr,
1
cmꢁ1): 3316 (br, w, ꢀArOH), 1640 (s, ꢀCH¼N). H NMR data (d-DMSO, ppm): ꢁ ¼ 1.41
(s, 3H, CH3), 3.61 (br, 2H, CH2OH), 3.81 (s, 4H, CH2OH), 6.90–7.62 (m, 3H,
aromatic), 8.51 (s, 1H, CH¼N), 13.1 (s, 1H, ArOH). UV-Vis (ꢂ, nm): 261, 392.

Hydroxy-rich Schiff bases
341
2.3. Synthesis of HL2 and HL3
The yellow microcrystalline products of HL2 and HL3 were prepared by the same
method as described for HL1, with similar starting materials. Yields: 93% for HL2 and
87% for HL3. For HL2: Anal. Calcd for C13H19NO4 (%): C, 61.6; H, 7.6; N, 5.5.
Found: C, 61.3; H, 7.6; N, 5.6. IR data (KBr, cmꢁ1): 3327 (br, w, ꢀArOH), 1637 (s,
ꢀ
CH¼N). 1H NMR data (d-DMSO, ppm): ꢁ ¼ 0.89 (t, 3H, CH2CH3), 1.60 (q, 2H,
CH2CH3), 3.62 (br, 2H, CH2OH), 3.81 (s, 4H, CH2OH), 3.85 (s, 3H, OCH3), 6.83–7.26
(m, 3H, aromatic), 8.51 (s, 1H, CH¼N), 12.8 (s, 1H, ArOH). UV-Vis (ꢂ, nm): 263, 396.
For HL3: Anal. Calcd for C11H14BrNO3 (%): C, 45.8; H, 4.9; N, 4.9. Found: C, 45.6; H,
5.0; N, 4.7. IR data (KBr, cmꢁ1): 3313 (br, w, ꢀArOH), 1641 (s, ꢀCH¼N). H NMR data
1
(d-DMSO, ppm): ꢁ ¼ 1.41 (s, 3H, CH3), 3.61 (br, 2H, CH2OH), 3.81 (s, 4H, CH2OH),
6.80–7.81 (m, 3H, aromatic), 8.51 (s, 1H, CH¼N), 12.7 (s, 1H, ArOH). UV-Vis (ꢂ, nm):
262, 395.
1
2.4. Synthesis of [Zn(L )2] H2O (1)
.
To methanolic solution (10 cm3) of HL1 (48.6 mg, 0.2 mmol) was added an aqueous
solution (3 cm3) of Zn(ClO4)2 ꢀ 6H2O (37.2 mg, 0.1 mmol) with stirring. The mixture was
stirred for 30 min at room temperature to give a clear colorless solution. After keeping
the solution in air for a few days, small colorless block-shaped crystals of the complex,
suitable for X-ray crystal structural determination, formed at the bottom of the vessel
on slow evaporation of the solvent. The crystals were isolated, washed three times with
cold water/methanol (V : V ¼ 1 : 1), and dried in a vacuum desiccator containing
anhydrous CaCl2. Yield: 27 mg, 47% (based on HL1). Anal. Calcd for
C22H28Cl2N2O7Zn (%): C, 46.5; H, 5.0; N, 4.9. Found: C, 46.3; H, 5.0; N, 4.9. IR
data (KBr, cmꢁ1): 3403 (br, w, ꢀwater), 3272 (w, ꢀOH), 1631 (s, ꢀCH¼N). UV-Vis (ꢂ, nm):
246, 373, 580.
1
2
3
2.5. Synthesis of [Ni(L )2] H2O (2), [Ni(L )2] (3), and [Co(L )2] H2O (4)
.
.
Complexes 2, 3, and 4 were prepared by the same method as that described for 1, with
similar starting materials. Yields: 55% for 2, 63% for 3, and 46% for 4. For 2: Anal.
Calcd for C22H28Cl2N2NiO7 (%): C, 47.0; H, 5.0; N, 5.0. Found: C, 46.7; H, 5.1; N, 5.0.
IR data (KBr, cmꢁ1): 3391 (br, w, ꢀwater), 3273 (w, ꢀOH), 1631 (s, ꢀCH¼N). UV-Vis (ꢂ,
nm): 245, 377, 615, 963. For 3: Anal. Calcd for C26H36N2NiO8 (%): C, 55.4; H, 6.4; N,
5.0. Found: C, 55.6; H, 6.6; N, 4.8. IR data (KBr, cmꢁ1): 3275 (w, ꢀOH), 1628 (s,
ꢀ
CH¼N). UV-Vis (ꢂ, nm): 243, 380, 610, 965. For 4: Anal. Calcd for C22H28Br2CoN2O7
(%): C, 40.6; H, 4.3; N, 4.3. Found: C, 40.3; H, 4.5; N, 4.2. IR data (KBr, cmꢁ1): 3397
(br, w, ꢀwater), 3272 (w, ꢀOH), 1633 (s, ꢀCH¼N). UV-Vis (ꢂ, nm): 247, 380, 515.
2.6. X-ray structural determination
Diffraction intensities for HL1 and the complexes were collected at 298(2) K using a
˚
Bruker SMART CCD area detector with Mo-Kꢃ radiation (ꢂ ¼ 0.71073 A). The
collected data were reduced using SAINT [15] and multi-scan absorption corrections
were performed using SADABS [16]. The structures were solved by direct methods and

342
Y. Lu et al.
refined against F2 by full-matrix least-squares using the SHELXTL package [17]. All
non-hydrogen atoms were refined anisotropically. The imino H in 1 and the hydroxyl
and water hydrogen atoms in the complexes were located in difference Fourier maps
and refined isotropically with N–H, O–H, and H ꢀ ꢀ ꢀ H distances restrained to 0.90(1),
˚
0.85(1), and 1.37(2) A, respectively. All other hydrogen atoms were placed in
geometrically ideal positions and constrained to ride on their parent atoms. The
crystallographic data for the compounds are summarized in table 1. Selected bond
lengths and angles are given in table 2.
2.7. Urease inhibitory activity assay
Helicobacter 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 37ꢂC under microaerobic conditions (5% O2, 10% CO2, and 85% N2). The
method of preparation of the urease by Mao et al. [18] was followed. Briefly, broth
cultures (50 mL, 2.0 ꢃ 108 CFU mLꢁ1) were centrifuged (5000 g, 4ꢂC) to collect the
bacteria, and after washing twice with phosphate-buffered saline (pH ¼ 7.4), the
H. pylori precipitate was stored at ꢁ80ꢂC. While the H. pylori was returned to room
temperature, and mixed with 3 mL of distilled water and protease inhibitors, sonication
was performed for 60 s. Following centrifugation (15,000 g, 4ꢂC), the supernatant was
desalted through SephadexG–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 4ꢂC until use in the experiment. The mixture,
containing 25 mL (4U) of the urease and 25 mL of the test compound, was pre-incubated
for 3 h at room temperature in a 96-well assay plate. Urease activity was determined for
three parallel times by measuring ammonia production using the indophenol method as
described by Weatherburn [19].
2.8. Molecular docking study
Molecular docking of the complexes into the 3-D X-ray structure of the H. pylori urease
(entry 1E9Y in the Protein Data Bank) was carried out by using AutoDock 4.2 software
as implemented through the graphical user interface AutoDockTools (ADT 1.5.4). The
graphical user interface AutoDockTools was employed to setup the enzymes: all
hydrogen atoms were added, Gasteiger charges were calculated and non-polar
hydrogen atoms were merged to carbons. The Ni initial parameters are set as
ꢁ1
˚
r ¼ 1.170 A, q ¼ þ2.0, and van der Waals well depth of 0.100 kcalmol [20]. The
molecules of the compounds were transferred to pdb files with the program
ChemBio3D. The pdb files were further transferred to pdbqt files with the
AutoDockTools.
AutoDockTools was used to generate the docking input files. In the docking grid box
sizes of 40 ꢃ 50 ꢃ 40 for HL1 and 70 ꢃ 60 ꢃ 60 for the complexes points in x, y, and
z directions were built, the maps were centered on the original ligand molecule in the
˚
active site of the protein. A grid spacing of 0.375 A and a distances-dependent function
of the dielectric constant were used for the calculation of the energy 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

Hydroxy-rich Schiff bases
343

344
Y. Lu et al.
1
Table 2. Selected bond lengths (A) for HL and 1–4.
˚
HL1
N1–C7
O1–C2
O3–C10
1.296(3)
1.292(2)
1.413(3)
N1–C8
O2–C9
1.485(3)
1.416(2)
1
Zn1–O1
Zn1–O4
Zn1–N1
2.056(2)
2.017(2)
2.082(3)
Zn1–O2
Zn1–O5
Zn1–N2
2.251(3)
2.280(3)
2.075(3)
2
Ni1–O1
Ni1–O4
Ni1–N1
2.019(4)
2.038(4)
2.028(5)
Ni1–O2
Ni1–O6
Ni1–N2
2.129(5)
2.158(5)
2.042(5)
3
Ni1–O1
Ni1–O5
Ni1–N1
1.986(1)
1.991(1)
2.010(2)
Ni1–O3
Ni1–O7
Ni1–N2
2.097(1)
2.099(1)
2.009(2)
4
Co1–O1
Co1–O4
Co1–N1
2.045(3)
2.017(4)
2.081(4)
Co1–O3
Co1–O6
Co1–N2
2.175(4)
2.160(4)
2.089(4)
2.5 ꢃ 106 energy evaluations, and a maximum number of 2.7 ꢃ 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.
3. Results and discussion
3.1. Chemistry
The Schiff bases HL1, HL2, and HL3 were obtained as yellow solid products, stable in
air at room temperature, and soluble in common polar organic solvents such as DMSO,
DMF, methanol, ethanol, and acetonitrile. Single-crystals suitable for X-ray diffraction
for HL1 were obtained; however, for HL2 and HL3 it is hard to obtain well-shaped
single-crystals from common organic solvents, including methanol, ethanol, dichlor-
omethane, and acetonitrile. The complexes derived from the Schiff bases were all
crystallized as mononuclear compounds. They are also stable in air at room
temperature, soluble in DMF, DMSO, and acetonitrile, but slightly soluble in methanol
and ethanol, and insoluble in water. The molar conductivities of the complexes
measured in acetonitrile at 10ꢁ3 mol Lꢁ1 are 10–25 ꢀꢁ1 cm2 molꢁ1, indicating the non-
electrolytic nature of the complexes in solution [21].
3.2. IR spectra
IR spectra of the Schiff bases and their complexes provide information about the metal–
ligand bonding. Assignments are based on typical group frequencies. Weak and broad
absorptions centered at 3313–3327 cmꢁ1 in spectra of the Schiff bases and at 3273 cmꢁ1
in the complexes are attributed to hydroxyl groups. The weak and broad absorption

Hydroxy-rich Schiff bases
345
Figure 1. The structure of HL1 showing the atom-numbering scheme. Displacement ellipsoids are drawn at
the 30% probability level and hydrogen atoms are shown as small spheres of arbitrary radii. Intramolecular
hydrogen bond is shown as a dashed line.
centered at 3400 cmꢁ1 in spectra of 1, 2, and 4 are attributed to lattice water molecules.
Several weak peaks observed for HL1 and the complexes from 3180 to 2860 cmꢁ1 are
due to the aromatic and aliphatic C–H stretches. Strong absorptions at 1640 cmꢁ1 in
spectra of the Schiff bases are assigned to azomethine, ꢀ(C¼N) [22]. These bands shift
to lower wavenumbers in the complexes (1628–1633 cmꢁ1), attributed to coordination
of nitrogen of the azomethine to metal. The phenolic ꢀ(Ar–O) in the Schiff bases
exhibit strong bands at 1230 cmꢁ1 [23]. However, in the complexes the bands appear at
1165–1183 cmꢁ1, which may be assigned to skeletal vibration related to phenolic
oxygen, shifted to lower frequencies when the phenolic oxygen atoms coordinate
[24, 25]. The weak bands at 410–550 cmꢁ1 for the complexes can be assigned to the M–
O and M–N vibrations [26].
The close resemblance of the shape and the positions of the absorption bands suggest
similar coordination modes for the complexes. IR spectra of HL1 and the complexes are
consistent with the X-ray structural results.
3.3. Structures of HL1 and the complexes
Figures 1–5 give perspective views of HL1 and 1–4 with atomic labeling systems. In the
molecular structure of HL1, hydrogen of hydroxyl is transferred to the imino nitrogen,
generating an intramolecular N1–H1 ꢀ ꢀ ꢀ O1 hydrogen bond. The formation of the N–H
bond made the C7–N1 bond slightly longer than typical C¼N bonds. Complexes 1, 2, 3,
and 4 are structurally similar mononuclear zinc(II), nickel(II), nickel(II), and cobalt(II)
compounds, respectively. Complexes 1, 2, and 4 contain a water of crystallization. Zn,
Ni, and Co in the complexes are six-coordinate by two imino nitrogen atoms, two
phenolate oxygen atoms, and two hydroxyl oxygen atoms from two deprotonated
Schiff-base ligands, forming distorted octahedral geometry. The distortion of the

346
Y. Lu et al.
Figure 2. The structure of 1 showing the atom-numbering scheme. Displacement ellipsoids are drawn at the
30% probability level.
octahedral coordination can be observed from the bond angles subtended at the metal,
ranging from 76.3(1) to 103.2(1)ꢂ for 1, 78.2(2) to 98.8(2)ꢂ for 2, 81.8(1) to 95.2(1)ꢂ for 3,
and 76.8(2) to 100.5(2)ꢂ for 4 for the perpendicular angles, and from 163.8(1) to
166.1(1)ꢂ for 1, 168.0(2) to 170.7(2)ꢂ for 2, 171.1(1) to 175.8(1)ꢂ for 3, and 165.4(1) to
168.0(2)ꢂ for 4 for the longitudinal angles. The two Schiff-base ligands in the complexes
are almost perpendicular to each other, decreasing the steric effects between the
molecules. The dihedral angles between the two benzene rings are 69.5(2)ꢂ for 1,
66.1(2)ꢂ for 2, 84.2(2)ꢂ for 3, and 71.8(3)ꢂ for 4.
The Schiff-base ligands coordinate to metal as the deprotonated form. The bond
lengths of C7–N1 and C18–N2 in 1 and 2 are shorter than that of C7–N1 in HL1,
together with the bond lengths of C2–O1 and C13–O4 in 1 and 2 being longer than that
of C2–O1 in HL1, indicating the coordination of the imino N and the phenolate O. For
the C–O bonds of the propane-1,3-diol moiety, there are no obvious changes during
coordination.

Hydroxy-rich Schiff bases
347
Figure 3. The structure of 2 showing the atom-numbering scheme. Displacement ellipsoids are drawn at the
30% probability level.
Figure 4. The structure of 3 showing the atom-numbering scheme. Displacement ellipsoids are drawn at the
30% probability level.

348
Y. Lu et al.
Figure 5. The structure of 4 showing the atom-numbering scheme. Displacement ellipsoids are drawn at the
30% probability level.
Table 3. Geometrical parameters for hydrogen bonds.
D–H ꢀ ꢀ ꢀ A (ꢂ)
˚
D–H (A)
˚
˚
Hydrogen bonds
H ꢀ ꢀ ꢀ A (A)
D ꢀ ꢀ ꢀ A (A)
HL1
N1–H1 ꢀ ꢀ ꢀ O1
O3–H3 ꢀ ꢀ ꢀ O2#1
O2–H2 ꢀ ꢀ ꢀ O1#2
0.91(1)
0.82
0.82
1.82(2)
1.91
1.83
2.602(2)
2.677(2)
2.645(2)
142(3)
156
174
1
O3–H3 ꢀ ꢀ ꢀ O6#3
O6–H6 ꢀ ꢀ ꢀ O4#4
O2–H2 ꢀ ꢀ ꢀ O1#4
O5–H5 ꢀ ꢀ ꢀ O7#5
0.82
0.82
0.85(1)
0.84(1)
1.96
1.91
1.79(1)
1.96(2)
2.749(4)
2.697(3)
2.628(3)
2.769(5)
160
160
168(5)
162(5)
2
O3–H3 ꢀ ꢀ ꢀ O1#4
O6–H6 ꢀ ꢀ ꢀ O4#4
O5–H5 ꢀ ꢀ ꢀ O3#3
O2–H2 ꢀ ꢀ ꢀ O7
0.82
1.90
2.671(6)
2.628(6)
2.745(7)
2.724(8)
157
165(8)
163
0.85(1)
0.82
0.85(1)
1.80(3)
1.95
1.88(2)
172(8)
3
O4–H4 ꢀ ꢀ ꢀ O5
O8–H8 ꢀ ꢀ ꢀ O1
O7–H7 ꢀ ꢀ ꢀ O8#6
O3–H3 ꢀ ꢀ ꢀ O4#7
0.82
0.82
0.84(1)
0.84(1)
1.84
1.86
1.85(1)
1.86(1)
2.651(2)
2.657(2)
2.679(2)
2.667(2)
169
163
168(3)
161(3)
4
O2–H2 ꢀ ꢀ ꢀ O5#3
O5–H5 ꢀ ꢀ ꢀ O4#4
O3–H3 ꢀ ꢀ ꢀ O1#4
O6–H6 ꢀ ꢀ ꢀ O7
O7–H7A ꢀ ꢀ ꢀ O2#8
0.82
0.82
0.85(1)
0.85(1)
0.85(1)
1.92
1.97
1.80(1)
1.86(1)
1.94(2)
2.720(5)
2.699(5)
2.647(5)
2.712(7)
2.760(6)
163
148
175(6)
174(7)
162(7)
Symmetry codes: #1 1 þ x, y, z; #2 1 ꢁ x, ꢁ1/2 þ y, 3/2 ꢁ z; #3 1/2 ꢁ x, ꢁ1/2 þ y, 1/2 ꢁ z; #4 1/2 ꢁ x, 1/2 þ y, 1/2 ꢁ z; #5 x, 1 þ y,
#6
#7
#8
z; 1 ꢁ x, 1 ꢁ y, 2 ꢁ z; ꢁx, ꢁy, 1 ꢁ z; x, 2 ꢁ y, 1/2 þ z.

Hydroxy-rich Schiff bases
349
Table 4. Inhibition of urease by the tested materials.
Tested materials
Inhibition rate* (%)
HL1
1
2
3
83 ꢅ 3
40 ꢅ 2
43 ꢅ 3
38 ꢅ 2
33 ꢅ 2
90 ꢅ 4
4
Acetohydroxamic acid
*The concentration of the tested material is 100 mmol Lꢁ1
.
Figure 6. Binding mode of HL1 with H. pylori urease. Left: the enzyme is shown as surface and HL1 is
shown as sticks. Right: hydrogen bonds are shown as dashed lines.
In the crystal structures of HL1 and the complexes, molecules are linked through
intermolecular O–H ꢀ ꢀ ꢀ O hydrogen bonds (table 3), forming 1-D chains.
3.4. Pharmacology
The results of the urease inhibition are given table 4. The acetohydroxamic acid (AHA)
was used as a reference. HL1 exhibits effective activity and the complexes show
relatively weak activities. Considering that the structures of the complexes are very
similar to each other, the central metals play no role during the inhibition.
3.5. Molecular docking study
The molecular docking study was performed to investigate the binding interactions
between the compounds and the active site of the H. pylori urease. In the X-ray
structure available for native urease, two nickels were coordinated by His136, His138,
Kcx219, His248, His274, Asp362, and water, while in the AHA-inhibited urease, the
water molecules were replaced by AHA [27]. In order to give an explanation on
the inhibitory activity of the compounds, molecular docking of the compounds into the

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Y. Lu et al.
Figure 7. Binding mode of 1 with H. pylori urease. Left: the enzyme is shown as surface and 1 is shown as
sticks. Right: hydrogen bonds are shown as dashed lines.
Figure 8. Binding mode of 2 with H. pylori urease. Left: the enzyme is shown as surface and 2 is shown as
sticks. Right: hydrogen bonds are shown as dashed lines.
AHA binding site of the urease was performed on the binding model based on the
urease complex structure (1E9Y.pdb). The binding models of the compounds and the
urease are depicted in figures 6–10. HL1 is well filled in the active pocket of the urease,
with docking score of ꢁ7.31. Four hydrogen bonds form between HL1 and the urease.
In addition, two hydroxyl groups of HL1 are very close to the two Ni’s of the active site
of urease. For 1, 2, 3, and 4 the docking scores are ꢁ6.36, ꢁ6.37, ꢁ5.43, and ꢁ6.61,
respectively. Even though they are lower than the docking score of AHA (ꢁ5.01), they
show only weak inhibitory activities. This might be caused by the large bulk of the
complex molecules, which made them difficult to approach the active site of the urease.
The complex molecules are located at the entry of the pocket, leading to urea molecules
difficulty binding with the active site of the urease. This might explain why the

Hydroxy-rich Schiff bases
351
Figure 9. Binding mode of 3 with H. pylori urease. Left: the enzyme is shown as surface and 3 is shown as
sticks. Right: hydrogen bonds are shown as dashed lines.
Figure 10. Binding mode of 4 with H. pylori urease. Left: the enzyme is shown as surface and 4 is shown as
sticks. Right: hydrogen bonds are shown as dashed lines.
complexes show weak inhibitory activities. The results of the molecular docking study
explain well the activities of the compounds against H. pylori urease.
4. Conclusion
In this work, three hydroxy-rich Schiff bases were used to prepare four new zinc(II),
nickel(II), and cobalt(II) complexes. The crystal structures of the Schiff base HL1 and
the complexes were characterized by X-ray diffraction. All the reactions resulted in the
formation of mononuclear complexes where the metal is bound to two mono-anionic
Schiff-base ligands. The Schiff bases coordinate tridentate to the metal through
phenolato O, imino N, and one hydroxyl O. The Schiff base HL1 exhibits activity
against H. pylori urease, while the complexes show relatively weak activities.

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Y. Lu et al.
Supplementary material
Crystallographic data for HL1 and the complexes have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC
832398 (HL1), 832399 (1), 838254 (2), 838255 (3), 838256 (4). Copies of these data can
be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB21EZ, UK; Fax: þ44 1223 336033.
Acknowledgments
This work was financially supported by the National Science Foundation of China
(Project No. 20901036).
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