Synthesis and crystal structures of cobalt(III), copper(II), nickel(II) and zinc(II) complexes derived from 4-methoxy-N′-(pyridin-2-ylmethylene)benzohydrazide with urease inhibitory activity

Article abstract of DOI:10.1080/00958972.2018.1533959

Urease catalyzes the decomposition of urea into ammonia, which has harmful effects on both human health and fertile soil. Aiming at exploring novel urease inhibitors, a series of hydrazone compounds and their Co^III, Cu^II, Ni^II

Full text of DOI:10.1080/00958972.2018.1533959

Journal of Coordination Chemistry
ISSN: 0095-8972 (Print) 1029-0389 (Online) Journal homepage: http://www.tandfonline.com/loi/gcoo20
Synthesis and crystal structures of
cobalt(III), copper(II), nickel(II) and zinc(II)
complexes derived from 4-methoxy-N'-
(pyridin-2ylmethylene)benzohydrazide with urease
inhibitory activity
Guifa Jiang, Huiyuan Yu, Jun-Yan Cheng, Sihan Guo, Wenqi Zhai, Yumin Jiang,
Ang Li, Zhiwen Li & Zhonglu You
To cite this article: Guifa Jiang, Huiyuan Yu, Jun-Yan Cheng, Sihan Guo, Wenqi Zhai,
Yumin Jiang, Ang Li, Zhiwen Li & Zhonglu You (2018): Synthesis and crystal structures
of cobalt(III), copper(II), nickel(II) and zinc(II) complexes derived from 4-methoxy-N'-
(pyridin-2ylmethylene)benzohydrazide with urease inhibitory activity, Journal of Coordination
Chemistry, DOI: 10.1080/00958972.2018.1533959
To link to this article: https://doi.org/10.1080/00958972.2018.1533959
Accepted author version posted online: 08
Oct 2018.
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Synthesis and crystal structures of cobalt(III), copper(II), nickel(II) and
zinc(II) complexes derived from 4-methoxy-N'-(pyridin-2-
ylmethylene)benzohydrazide with urease inhibitory activity
GUIFA JIANG†, HUIYUAN YU†, JUN-YAN CHENG‡, SIHAN GUO†, WENQI ZHAI†, YUMIN JIANG†,
ANG LI†, ZHIWEN LI† and ZHONGLU YOU*†
†Department of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, P. R. China
‡College of Chemistry, Chemical Engineering and Material Science, Shandong Normal University,
Jinan 250014, P.R. China
Urease catalyzes the decomposition of urea into ammonia, which has harmful effects on both
human health and fertile soil. Aiming at exploring novel urease inhibitors, a series of hydrazone
compounds and their CoIII, CuII, NiII and ZnII complexes were prepared from
4-methoxy-N'-(pyridin-2-ylmethylene)benzohydrazide (HL). They are [CoClL(NCS)] (1),
[CoL2]·Cl·CH3OH·H2O (2), [CuL(NCNCN)]n·nCH3OH (3), [NiL(HL)]·ClO4·CH3OH (4) and
[ZnClL(OH2)]·CH3OH (5). The compounds were characterized by physico-chemical methods.
Structures of the complexes were further confirmed by single crystal X-ray diffraction. The
metal ions in 1, 3 and 5 display square pyramidal coordination and 2 and 4 display octahedral
coordination. The inhibitory effects of the compounds on Jack bean urease were evaluated. The
results showed that 3 has effective urease inhibitory activity, with IC50 value of (7.3 ± 1.0)
μmol∙L–1.
Keywords: Hydrazone; Metal complexes; Crystal structure; Urease inhibition
1. Introduction
Urease (EC 3.5.1.5; urea amidohydrolase) is a binuclear nickel-dependent hydrolase enzyme,
which occurs widely in animals and soil [1-3]. Urease enzyme catalyzes the decomposition of
urea into ammonia and carbon dioxide in high efficiency [4], with the rate of catalyzed reaction
1014 times higher than the non-catalyzed reaction [5]. The enzyme possesses harmful effects on
both human health and fertile soil. Bacterial urease is a virulent factor including the formation of
infection stones, pyelonephritis, peptic ulceration, hepatic encephalopathy, and other diseases
[6-8]. High urease activity in soil leads to increased ammonia toxicity in the air and economic
*Corresponding author. Email: youzhonglu@126.com

problems [9-11]. All these negative effects oblige us to explore effective urease inhibitors. Our
research group has pioneered the study of Schiff base and their complexes as urease inhibitors
[12-16]. In our previous report, we have identified some copper(II) complexes with Schiff bases
or hydrazones as a promising type of lead structures as urease inhibitors [17-20]. Hydrazones
have been reported as effective antibacterial agents [21-23] and show interesting urease
inhibitory activity [24, 25]. Metal complexes have proved to possess significant inhibitory
activities on various enzymes [26, 27]. As part of our ongoing research on urease inhibition with
metal complexes, some hydrazones and their CoIII, CuII, NiII and ZnII complexes are presented
here.
2. Experimental
2.1. Materials and measurements
2-Pyridinecarboxaldehyde and 4-methoxybenzohydrazide were purchased from Sigma-Aldrich.
All other reagents and solvents were purchased from China Chemical Reagent Co. Ltd. Jack
bean urease was purchased from Sigma-Aldrich. Elemental analyses were performed on a
Perkin-Elmer 240C elemental analyzer. IR spectra were recorded on a Jasco FT/IR-4000
spectrometer as KBr pellets from 4000–400 cm–1. UV-Vis spectra were recorded on a
13
Perkin-Elmer Lambda 900 spectrometer. 1H and C NMR spectra were recorded on a 500 MHz
Bruker Avance instrument. The urease inhibitory activity was measured on a Bio-Tek Synergy
HT microplate reader. Single crystal structures were determined using a Bruker D8 Venture
single crystal diffractometer.
2.2. Synthesis of 4-methoxy-N'-(pyridin-2-ylmethylene)benzohydrazide (HL)
2-Pyridinecarboxaldehyde (0.1 mol, 10.7 g) and 4-methoxybenzohydrazide (0.1 mol, 16.6 g)
were mixed in methanol (100 mL). The mixture was stirred for 30 min at room temperature to
give a colorless solution. The solution was allowed to stand in air to slowly evaporate to give
well-shaped single crystals. The crystals were isolated by filtration, washed three times with cold
methanol and dried in air. Yield: 23.2 g (91%). Characteristic IR data (KBr, cm-1): 3189 (NH),
1646 (C=O), 1605 (C=N). UV–Vis data (methanol, λ/nm): 215, 305. Anal. Calcd for C14H13N3O2:
C, 65.9; H, 5.1; N, 16.5. Found: C, 66.1; H, 5.2; N, 16.3%. 1H NMR (500 MHz, DMSO) δ 11.90
(s, 1H, NH), 8.62 (d, 1H, ArH), 8.48 (s, 1H, ArH), 7.97-7.86 (m, 4H, ArH), 7.41 (s, 1H, CH=N),

13
7.07 (d, 2H, ArH), 3.84 (s, 3H, CH3). C NMR (126 MHz, DMSO) δ 162.74, 162.14, 153.41,
149.45, 147.38, 136.78, 129.66, 125.21, 124.20, 119.77, 113.74, 55.42.
2.3. Synthesis of 1-5
2.3.1.Chloro-[N-(2-pyridylmethylene)-4-methoxybenzenecarbohydrazonato]-isothiocyanato
cobalt(III), [CoClL(NCS)] (1). The Schiff base HL (1.0 mmol, 0.26 g) was dissolved in
methanol (20 mL), to which was added dropwise CoCl2·6H2O (1.0 mmol, 0.24 g) and NH4NCS
(1.0 mmol, 0.076 g) dissolved in methanol (10 mL). The mixture was stirred for 10 min at room
temperature and filtered. The filtrate was kept in air for a few days to form crystals suitable for
single crystal X-ray diffraction. The crystals were isolated by filtration. Yield: 0.15 g (37%).
Characteristic IR data (KBr, cm-1): 2079 (NCS), 1603 (CH=N). UV–Vis data (methanol, λ/nm):
253, 295, 390. Anal. Calcd for C15H12ClCoN4O2S: C, 44.3; H, 3.0; N, 13.8. Found: C, 44.5; H,
2.9; N, 13.6%. ΛM (10–3 M in acetonitrile): 19 Ω–1 cm2 mol–1.
2.3.2.Bis[N-(2-pyridylmethylene)-4-methoxybenzenecarbohydrazonato]cobalt(III) chloride
methanol monohydrate, [CoL2]·Cl·CH3OH·H2O (2). The Schiff base HL (1.0 mmol, 0.26 g)
was dissolved in methanol (20 mL), to which was added dropwise CoCl2·6H2O (1.0 mmol,
0.24 g) dissolved in methanol (10 mL). The mixture was stirred for 10 min at room temperature
and filtered. The filtrate was kept in air for a few days to form crystals suitable for single crystal
X-ray diffraction. The crystals were isolated by filtration. Yield: 0.17 g (52%). Characteristic IR
data (KBr, cm-1): 3345 (OH), 1600 (CH=N). UV–Vis data (methanol, λ/nm): 270, 385. Anal.
Calcd for C29H30ClCoN6O6: C, 53.3; H, 4.6; N, 12.9. Found: C, 53.5; H, 4.6; N, 12.7%. ΛM (10–
3 M in acetonitrile): 115 Ω–1 cm2 mol–1.
2.3.3.catena-Poly{[N-(2-pyridylmethylene)-4-methoxybenzenecarbohydrazonato]copper(II)
-μ1,5-dicyanoamido} methanol, [CuL(NCNCN)]n·nCH3OH (3). The Schiff base HL (1.0 mmol,
0.26 g) was dissolved in methanol (20 mL), to which was added dropwise CuCl2·2H2O
(1.0 mmol, 0.17 g) and NaN(CN)2 (1.0 mmol, 0.089 g) dissolved in methanol (10 mL). The
mixture was stirred for 10 min at room temperature and filtered. The filtrate was kept in air for a
few days to form crystals suitable for single crystal X-ray diffraction. The crystals were isolated
by filtration. Yield: 0.26 g (62%). Characteristic IR data (KBr, cm-1): 3478 (OH), 2309, 2251,

2176 (N(CN)2), 1606 (CH=N). UV–Vis data (methanol, λ/nm): 245, 293, 385. Anal. Calcd for
C17H16CuN6O3: C, 49.1; H, 3.9; N, 20.2. Found: C, 49.1; H, 3.7; N, 20.3%. ΛM (10–3 M in
acetonitrile): 16 Ω–1 cm2 mol–1.
2.3.4.[N-(2-pyridylmethylene)-4-methoxybenzenecarbohydrazonato][4-methoxy-N'-(pyridi
n-2-ylmethylene)benzohydrazido]nickel(II) perchlorate methanol, [NiL(HL)]·ClO4·CH3OH
(4). The Schiff base HL (1.0 mmol, 0.26 g) was dissolved in methanol (20 mL), to which was
added dropwise Ni(ClO4)2·6H2O (1.0 mmol, 0.37 g) dissolved in methanol (10 mL). The mixture
was stirred for 10 min at room temperature and filtered. The filtrate was kept in air for a few
days to form crystals suitable for single crystal X-ray diffraction. The crystals were isolated by
filtration. Yield: 0.21 g (60%). Characteristic IR data (KBr, cm-1): 3441 (OH), 3263 (NH), 1606
(CH=N), 1101 and 1080 (ClO4). UV–Vis data (methanol, λ/nm): 310, 350, 375. Anal. Calcd for
C29H29ClN6NiO9: C, 49.8; H, 4.2; N, 12.0. Found: C, 49.7; H, 4.3; N, 11.8%. ΛM (10–3 M in
acetonitrile): 130 Ω–1 cm2 mol–1.
2.3.5. Aqua-chlorido-[N-(2-pyridylmethylene)-4-methoxybenzenecarbohydrazonato]zinc(II)
methanol, [ZnClL(OH2)]·CH3OH (5). The Schiff base HL (1.0 mmol, 0.26 g) was dissolved in
methanol (20 mL), to which was added dropwise ZnCl2 (1.0 mmol, 0.136 g) dissolved in
methanol (10 mL). The mixture was stirred for 10 min at room temperature and filtered. The
filtrate was kept in air for a few days to form crystals suitable for single crystal X-ray diffraction.
The crystals were isolated by filtration. Yield: 0.27 g (67%). Characteristic IR data (KBr, cm-1):
3432 (OH), 1605 (CH=N). UV–Vis data (methanol, λ/nm): 278, 320, 373. Anal. Calcd for
C15H18ClN3O4Zn: C, 44.5; H, 4.5; N, 10.4. Found: C, 44.4; H, 4.3; N, 10.3%. ΛM (10–3 M in
acetonitrile): 22 Ω–1 cm2 mol–1.
2.4. X-ray crystallography
Diffraction intensities for the hydrazones and the complexes were collected at 298(2) K using a
Bruker D8 Venture diffractometer with MoKα radiation (λ = 0.71073 Å). The collected data
were reduced with SAINT [28], and multi-scan absorption correction was performed using
SADABS [29]. Structures of the hydrazones and complexes were solved by direct methods and
refined against F2 by full-matrix least-squares method using SHELXTL [30]. All of the

non-hydrogen atoms were refined anisotropically. The amino and water H atoms in the
compounds were located from 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) Å, respectively. The remaining
hydrogen atoms were placed in calculated positions and constrained to ride on their parent atoms.
The thermal parameters for the Cl ion in 1 are larger than other atoms. We have attempted to
refine with a disorder model concluding OH, but have not succeeded. The water H atoms of 2
cannot be added accurately because of the disorder of the water molecule. The methanol
molecule in 4 is to some extent disordered. Crystallographic data for the hydrazones and the
complexes are summarized in table 1. Selected bond lengths and angles are given in table 2.
2.5. Urease inhibitory activity assay
The measurement of urease inhibitory activity was carried out according to the literature method
[31]. 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 a micro-plate reader
(560 nm) with end-point being determined by the color change of phenol-red indicator.
3. Results and discussion
3.1. Chemistry
The hydrazone compound was readily prepared by the condensation reaction of equimolar
quantities of 2-pyridinecarboxaldehyde and 4-methoxybenzohydrazide in methanol (scheme 1).
The complexes were prepared by reaction of equimolar quantities of the hydrazone, metal salts,
and secondary ligands (NCS for 1, N(CN)2 for 3) in methanol. Single crystals of the complexes
were obtained by slow evaporation of the methanolic solution of the complexes. Molar
conductivities of 1, 3 and 5 measured in methanol at concentration of 10–3 mol∙L–1 are in the
range of 15-50 Ω–1 cm2 mol–1, indicating the non-electrolytic nature of them in such solution [32].
Molar conductivities of 2 and 4 measured in methanol at a concentration of 10–3 mol∙L–1 are in

the range of 100-140 Ω–1 cm2 mol–1, indicating the 1:1 electrolytic nature of them in such
solution [32].
O M e
O M e
H
N
C H O
H
N
N
+
H2
N
N
O
N
O
Scheme 1. The synthetic procedure for HL.
3.2. Structure description of the complexes
3.2.1. Structure description of 1. The molecular structure of 1 is shown in figure 1. The Co ion
is in a square pyramidal geometry, with the pyridine N, imino N, and carbonyl O atoms of the
hydrazone ligand, and one thiocyanate N atom located at the basal plane, and with the Cl ligand
located at the apical position. The Co ion deviates from the least-squares plane defined by the
four basal donor atoms by 0.248(1) Å. The dihedral angle between the pyridine and benzene
rings of the hydrazone ligand is 4.6(5). The Co-O and Co-N bond lengths are in the range
1.92-2.03 Å, which are comparable to those observed in cobalt(III) complexes with hydrazone
ligands [33, 34]. A longer distance is observed for Co-Cl bond length (2.651(5) Å), yet, it is
similar to those in other chlorido-coordinated cobalt complexes [35, 36]. In the crystal structure
of the complex, the molecules are linked through intermolecular C3–H3···S1 hydrogen bonds
[C3–H3 = 0.93 Å, H3···S1i = 2.86 Å, C3···S1i = 3.706(3) Å, C3–H3···S1i = 152(5); symmetry
code for i: – x, 1–y, –z], to form chains along the c axis. The chains are further linked via weak
Cl···N interactions (3.096(3) Å) from the a axis to form a two-dimensional network (figure 2). It
is not uncommon for the Cl···N interactions. Bathori and coworkers reported a compound
bis-2,4-(biphenyl-4-yloxy)-6-chloro-[1,3,5]triazine, in which the Cl···N interactions are 3.05 Å
[37].
3.2.2. Structure description of 2. The molecular structure of 2 is shown in figure 3. The
compound contains a mononuclear cobalt(III) complex cation, a Cl anion, a methanol and a
water molecule of crystallization. The Co ion in the complex is coordinated by two pyridine N,
two imino N, and two carbonyl O atoms from two hydrazone ligands, forming an octahedral

geometry. The dihedral angles between the pyridine and benzene rings of the hydrazone ligands
are 9.4(4) and 7.2(4). The Co-O and Co-N bond lengths are in the range 1.85-1.93 Å, which
are comparable to those observed in cobalt(III) complexes with hydrazone ligands [33, 34]. The
Co1-N1 bond in this complex is shorter than that of 1, which might be caused by the electronic
withdrawing effects of the Cl and NCS ligands in 1. In the crystal structure of the complex, the
molecules are linked through O5–H5···Cl1, C15–H15···Cl1ii and C16–H16···Cl1iii hydrogen
bonds [O5–H5 = 0.82 Å, H5···Cl1 = 2.37 Å, O5···Cl1 = 3.066(5) Å, O5–H5···Cl1 = 143(5);
C15–H15 = 0.93 Å, H15···Cl1ii = 2.81 Å, C15···Cl1ii = 3.596(6) Å, C15–H15···Cl1ii = 143(6);
C16–H16 = 0.93 Å, H16···Cl1iii = 2.74 Å, C16···Cl1iii = 3.619(6) Å, C16–H16···Cl1iii = 157(6);
symmetry codes for ii: 1/2–x, 1/2+y, z; iii: 1/2+x, 1/2–y, 1–z] to form dimeric structures
(figure 4).
3.2.3. Structure description of 3. Molecular structure of 3 is shown in figure 5. The complex is
a dicyanoamide bridged polynuclear copper(II) compound. The smallest repeat unit contains a
[Cu(NCNCN)L] moiety and a methanol molecule of crystallization. The Cu ion is in a square
pyramidal geometry, with the pyridine N, imino N, an enolate O atom of the hydrazone ligand,
and one dicyanoamide N atom located at the basal plane, and with another dicyanoamide N atom
located at the apical position. The Cu ion deviates from the least-squares plane defined by the
four basal donor atoms by 0.300(1) Å. The dihedral angle between the pyridine and benzene
rings of the hydrazone ligand is 2.0(5). The Cu-O and Cu-N bond lengths in the basal plane are
in the range 1.93-2.07 Å, which are comparable to those observed in copper(II) complexes with
hydrazone ligands [38, 39]. The Cu1-N6A bond in the apical position of the square pyramid is
2.214(4) Å, indicating it is loosely coordinated to the Cu ion. In the crystal structure of the
complex, the methanol molecules are linked to the complex molecules through O3–H3···O1
hydrogen bonds [O3–H3 = 0.82 Å, H3···O1 = 2.26 Å, O3···O1 = 3.034(6) Å, O3–H3···O1 =
159(5)]. The [CuL] units are linked through dicyanoamide groups to form chains along the
a-axis (figure 6).
3.2.4. Structure description of 4. The molecular structure of 4 is shown in figure 7. The
complex contains a [NiL(HL)]+ cation, a perchlorate anion and a methanol molecule of
crystallization. The Ni ion is coordinated by two pyridine N, two imino N, one carbonyl O, and

one enolate O atoms, forming an octahedral geometry. The bond Ni1-N2 is longer than that of
Ni1-N5, and the bond Ni1-O1 is longer than that of Ni1-O2, which indicates the different types
of the hydrazone ligands, one is neutral, and the other one has a negative charge. The dihedral
angles between the pyridine and benzene rings of the hydrazone ligands are 7.0(5) and 19.9(6).
The Ni-O and Ni-N bond lengths, except Ni1-O1, are in the range 1.96-2.10 Å, which are
comparable to those observed in nickel(II) complexes with hydrazone ligands [40, 41]. In the
crystal structure of the complex, the perchlorate anions are linked to the complex molecules
through C16–H16···O7iv and C18–H18···O6v hydrogen bonds [C16–H16 = 0.93 Å, H16···O7iv
= 2.27 Å, C16···O7iv = 3.142(5) Å, C16–H16···O7iv = 155(6); C18–H18 = 0.93 Å, H18···O6v =
2.57 Å, C18···O6v = 3.246(6) Å, C18–H18···O6v = 130(6); symmetry codes: iv: –x, 1–y, 1–z; v:
iv: x, –1+y, 1+z]. The methanol molecules are linked to the complex molecules through O9–
H9A···N6vi and C27–H27···O9vii hydrogen bonds [O9–H9A = 0.82 Å, H9A···N6vi = 2.06 Å,
O9···N6vi = 2.855(5) Å, O9–H9A···N6vi = 164(5); C27–H27 = 0.93 Å, H27···O9vii = 2.56 Å,
C27···O9vii = 3.474(6) Å, C27–H27···O9vii = 168(7); symmetry codes: vi: 1+x, y, z; vii: –1+x,
y, z]. Adjacent complex molecules are linked through N3–H3···O2viii hydrogen bonds [N3–H3 =
0.90 Å, H3···O2viii = 1.87 Å, N3···O2viii = 2.729(5) Å, N3–H3···O2viii = 159(6); symmetry code
for viii: 1–x, 1–y, 1–z] to form dimers. The dimers are further linked through C12–H12···O4ix
hydrogen bonds [C12–H12 = 0.93 Å, H12···O9ix = 2.57 Å, C12···O9ix = 3.474(6) Å, C12–
H12···O9ix = 165(7); symmetry code for ix: x, y, 1+z] to form chains along the c-axis (figure 8).
3.2.5. Structure description of 5. The molecular structure of 5 is shown in figure 9. The
complex contains a [ZnClL(OH2)] complex molecule and a methanol molecule of crystallization.
The Zn ion is in a square pyramidal geometry, with the pyridine N, imino N, and enolate O atom
of the hydrazone ligand, and one Cl ligand located in the basal plane, and with one water O atom
located at the apical position. The Zn ion deviates from the least-squares plane defined by the
four basal donor atoms by 0.432(1) Å. The dihedral angle between the pyridine and benzene
rings of the hydrazone ligand is 10.5(3). The Zn-O and Zn-N bond lengths are in the range
2.01-2.09 Å, which are comparable to those observed in zinc(II) complexes with hydrazone
ligands [42]. A longer distance is observed for Zn-Cl bond length (2.2559(9) Å), yet, it is similar
to those in chlorido-coordinated zinc complexes [43, 44]. In the crystal structure of the complex,
adjacent complex molecules are linked through O3–H3A···N3viii hydrogen bonds [O3–H3A =

0.84 Å, H3A···N3viii = 1.91 Å, O3···N3viii = 2.756(5) Å, O3–H3A···N3viii = 175(5)] to form
dimers. The dimers are further linked by methanol and water molecules through O4–H4···Cl1vii
and O3–H3B···O4 hydrogen bonds [O4–H4 = 0.82 Å, H4···Cl1vii = 2.39 Å, O4···Cl1vii
=
3.208(5) Å, O4–H4···Cl1vii = 173(6); O3–H3B = 0.84 Å, H3B···O4 = 1.87 Å, O3···O4 =
2.709(5) Å, O3–H3B···O4 = 178(6)] to form chains along the a-axis (figure 10).
3.3. IR and UV-Vis spectra
The medium and broad absorptions in the region 3300–3500 cm–1 in the spectra of 2-5
substantiate the presence of O–H groups. The sharp bands indicative of the N–H vibrations of
HL and 4 are located at 3189 and 3263 cm–1, respectively. The intense band indicative of the
C=O vibration of HL is observed at 1646 cm–1, however, it is absent in the spectra of the
complexes, indicating the enolisation of the amide functionality and subsequent proton
replacement by the metal ions. The strong absorption bands in the region 1600–1610 cm–1 for
HL and the complexes are assigned to the azomethine ν(C=N) [45]. The typical absorptions at
2079 cm–1 for 1 is assigned to the vibration of the NCS ligand, at 2176 cm–1 for 3 is assigned to
the vibration of the N(CN)2 ligand, and at 1080 cm–1 for 4 is assigned to the vibration of the
perchlorate anion.
Electronic spectra of the complexes were recorded at 10-5 M in methanol. The complexes
displayed strong bands centered at 290-320 nm, which can be assigned to the n–π* transition of
the chromophore (-C=N-NH-CO). The charge transfer LMCT bands are located in the range
370–400 nm.
3.4. Pharmacology study
The inhibition curves of the complexes are shown in scheme 2. The percent inhibition of the
complexes on Jack bean urease are summarized in table 3. Complex 3 shows effective urease
inhibitory activity, with IC50 value of (7.3 ± 1.0) μmol∙L–1. The remaining complexes have no or
weak activity. As a comparison, acetohydroxamic acid (AHA) was used as a reference drug with
the percent inhibition of (84.3 ± 3.9)% and with IC50 value of (37.2 ± 4.0) μmol∙L–1. Copper
perchlorate can inhibit urease activity, with IC50 value of (8.8 ± 1.4) μmol∙L–1. Cobalt perchlorate,
nickel perchlorate and zinc perchlorate have weak or no activity against the urease. The copper
complex 3 has stronger activities than the copper(II) complex with N-hydroxyethyl-N-

benzimidazolylmethylethylenediaminediacetic acid (IC50 = 35 μM) [46], and also better than the
copper(II) complexes with Schiff base ligands (IC50 = 19 and 39 μM) [47], and comparable to
those with hydrazone ligands (IC50 = 1.5-18.3 μmol·L-1) [48].
The coordination geometries of the metals and the secondary ligands may influence the
inhibition potential of the complexes. For 1 and 5, there are Cl ligands, which are difficult to
substitute by the thiol group of the active center of the urease. For 2 and 4, the metals are in
octahedral coordination, which are in a sealed cavity, and difficult to interact with the enzyme.
For 3, the dicyanoamide ligand is loosely coordinated in the apical position of the square
pyramidal geometry, which can be readily substituted by the thiol group of the enzyme, and
block the entrance of the active pocket.
1
2
3
4
5
100
80
60
40
20
0
0.01
0.1
1
10
100
-1
Concetration (molL )
Scheme 2. Inhibition curves of the complexes.
4. Conclusion
The present study reports the syntheses, characterization and crystal structures of new complexes
of CoIII, CuII, NiII and ZnII. The copper complex has effective urease inhibitory activity, which
can be further optimized and developed as prospective lead urease inhibitor.

Supplementary data
CCDC 1812960 (1), 1812961 (2), 1813292 (3), 1812962 (4) and 1812963 (5) contain the
supplementary crystallographic data for this paper. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (+44) 1223-336-033; or E-mail:
deposit@ccdc.cam.ac.uk.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was financially supported by the Natural Science Foundation of China (Project
No. 21641012), the Innovative Entrepreneurial Training Program of Liaoning Normal University
(Project No. cx201802017), and the Education Office of Liaoning Province (Project No.
LF201783611).
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Figure 1. Molecular structure of 1 showing the atom-numbering scheme. Displacement ellipsoids
are drawn at 30% probability level.
Figure 2. Molecular packing structure of 1 viewed along the b axis. Hydrogen bonds shown as
dashed lines.

Figure 3. Molecular structure of 2 showing the atom-numbering scheme. Displacement ellipsoids
are drawn at 30% probability level.

Figure 4. Molecular packing structure of 2 viewed along the b axis. Hydrogen bonds shown as
dashed lines.

Figure 5. Molecular structure of 3 showing the atom-numbering scheme. Displacement ellipsoids
are drawn at 30% probability level.

Figure 6. Molecular packing structure of 3 viewed along the c axis. Hydrogen bonds shown as
dashed lines.

Figure 7. Molecular structure of 4 showing the atom-numbering scheme. Displacement ellipsoids
are drawn at 30% probability level.

Figure 8. Molecular packing structure of 4 viewed along the b axis. Hydrogen bonds shown as
dashed lines.
Figure 9. Molecular structure of 5 showing the atom-numbering scheme. Displacement ellipsoids
are drawn at 30% probability level.

Figure 10. Molecular packing structure of 5 viewed along the b axis. Hydrogen bonds shown as
dashed lines.

Table 1. Crystal data for 1-5.
1
2
3
4
5
Formula
C15H12ClCoN4O2S
406.73
C29H30ClCoN6O6
652.97
C17H16CuN6O3
415.90
C29H29ClN6NiO9
699.74
C15H18ClN3O4Zn
405.14
FW
Crystal shape / color
Block / brown
0.19×0.18×0.15
Monoclinic
P21/n
Block / brown
0.30×0.27×0.26
Orthorhombic
Pbcn
Block / blue
Block / brown
Block / colorless
0.35×0.32×0.30
Monoclinic
P21/c
Crystal size/mm
Crystal system
Space group
a (Å)
0.25×0.23×0.22 0.21×0.18×0.17
Triclinic
P-1
Triclinic
P–1
7.384(2)
17.681(2)
13.715(2)
90
25.314(2)
12.187(2)
19.422(2)
90
7.543(2)
9.857(2)
13.840(1)
108.260(2)
91.090(2)
109.648(2)
911.5(3)
2
10.885(2)
11.718(1)
13.196(2)
72.325(2)
79.037(2)
79.733(2)
1561.3(4)
2
7.546(1)
17.454(2)
13.076(2)
90
b (Å)
c (Å)
α ()
99.941(2)
90
90
95.197(2)
90
β ()
90
γ ()
V (Å3)
1763.7(5)
4
5991.9(12)
8
1715.2(4)
4
Z
λ (MoKα) (Å)
T (K)
0.71073
298(2)
0.71073
298(2)
0.71073
298(2)
0.71073
298(2)
0.71073
298(2)
μ (MoKα) (cm–1)
1.257
0.715
1.229
0.770
1.612
Tmin
0.7961
0.8142
0.7487
0.7738
4752 / 247
3328
0.8550
0.6024
Tmax
0.8338
0.8360
0.8803
0.6435
Reflections / parameters 9433 / 218
33859 / 398
5590
8323 / 459
5690
9818 / 226
3176
Unique reflections
3209
2068
Observed reflections
4397
2280
2966
2523
[I > 2σ(I)]
Restraints
0
3
0
120
3
Goodness of fit on F2
R1, wR2 [I > 2σ(I)]
R1, wR2 (all data)
1.072
1.081
1.042
0.989
1.052
0.0726, 0.1424
0.1225, 0.1661
0.0668, 0.2244
0.0834, 0.2465
0.0573, 0.1353
0.0935, 0.1586
0.0760, 0.1749
0.1546, 0.2239
0.0404, 0.0805
0.0570, 0.0887

Table 2. Selected bond lengths (Å) and angles () for 1-5.
1
2
3
4
5
M = Co
2.030(6)
1.926(5)
1.990(4)
1.962(7)
2.637(4)
M = Co
1.928(4)
1.853(4)
1.911(3)
1.928(4)
M = Cu
2.068(4)
1.934(4)
2.011(3)
M = Ni
2.093(6)
2.001(5)
2.182(5)
M = Zn
2.185(2)
2.070(2)
2.090(2)
M1–N1
M1–N2
M1–O1
Co1–N4
Co1–Cl1
Co1–N5
1.858(4)
1.910(3)
Co1–O3
Cu1–N4
1.970(4)
2.214(4)
Cu1–N6A
Ni1–N5
1.967(5)
2.089(5)
2.094(5)
Ni1–O2
Ni1–N4
Zn1–O3
2.010(2)
2.2559(9)
75.75(9)
149.20(9)
74.37(9)
Zn1–Cl1
N2–M1–N1
O1–M1–N1
N2–M1–O1
N2–Co1–N4
N4–Co1–O1
N4–Co1–N1
N2–Co1–Cl1
N4–Co1–Cl1
O1–Co1–Cl1
N1–Co1–Cl1
N2–Co1–N5
N5–Co1–O3
N2–Co1–O3
N5–Co1–O1
O3–Co1–O1
N5–Co1–N1
O3–Co1–N1
N5–Co1–N4
O3–Co1–N4
N2–Cu1–N4
N4–Cu1–O1
N4–Cu1–N1
N2–Cu1–N6A
O1–Cu1–N6A
N4–Cu1–N6A
N1–Cu1–N6A
N5–Ni1–N2
80.0(2)
83.23(16)
164.67(15)
81.55(14)
96.38(15)
91.15(15)
92.29(16)
80.28(16)
157.84(15)
78.85(15)
78.0(2)
158.7(2)
79.0(2)
152.36(19)
74.32(19)
158.8(2)
100.1(2)
98.0(3)
104.15(17)
97.1(2)
93.44(16)
95.37(17)
178.56(16)
81.32(14)
98.66(14)
97.01(14)
90.91(13)
98.21(15)
89.63(15)
83.65(15)
164.96(14)
158.80(17)
99.87(16)
96.87(17)
101.57(16)
96.02(15)
99.61(17)
95.38(16)
177.6(2)

N5–Ni1–O2
N2–Ni1–O2
N5–Ni1–N1
O2–Ni1–N1
N5–Ni1–N4
N2–Ni1–N4
O2–Ni1–N4
N1–Ni1–N4
N5–Ni1–O1
O2–Ni1–O1
N4–Ni1–O1
O3–Zn1–N2
O3–Zn1–O1
O3–Zn1–N1
O3–Zn1–Cl1
O1–Zn1–Cl1
N2–Zn1–Cl1
N1–Zn1–Cl1
75.87(19)
103.99(18)
99.6(2)
92.13(19)
79.2(2)
101.1(2)
154.67(19)
96.4(2)
108.08(19)
94.18(18)
89.20(19)
104.38(10)
93.31(10)
101.15(10)
106.33(7)
101.69(7)
149.21(8)
100.10(7)

Table 3. Inhibition of urease by the tested materials.
Tested materials
Percentage inhibition rate#
IC50 (μmol∙L–1)
46.0 ± 2.7
27.8 ± 4.0
89.5 ± 3.8
39.5 ± 1.9
25.0 ± 2.6
–
> 100
1
> 100
2
7.3 ± 1.0
> 100
3
4
> 100
5
HL
> 100
Copper perchlorate
Cobalt perchlorate
Nickel perchlorate
Zinc perchlorate
87.5 ± 2.6
35.5 ± 2.1
22.9 ± 3.3
–
8.8 ± 1.4
> 100
> 100
> 100
Acetohydroxamic acid
84.3 ± 3.9
37.2 ± 4.0
#
The concentration of the tested material is 100 μmol∙L–1. – indicates no
activity.
Graphical abstract