Synthesis and structural characterization of Schiff base copper(II) complexes with Helicobacter pylori urease inhibitory activities

Article abstract of DOI:10.1016/j.ica.2015.07.014

Three new mononuclear copper(II) complexes, [CuL¹(N₃)] (1), [CuL¹(NCS)] (2), and [CuL²(NCS)] (3), where L¹ is the monoanionic form of 5-diethylamino-2-[(pyridin-2-ylmethylimino)methyl]phenol (HL¹

Full text of DOI:10.1016/j.ica.2015.07.014

Inorganica Chimica Acta 435 (2015) 299–304
Contents lists available at ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Synthesis and structural characterization of Schiff base copper(II)
complexes with Helicobacter pylori urease inhibitory activities
a
b
a
a
a
a,
⇑
Fang Niu , Ke-Xiang Yan , Linhan Pang , Dan Qu , Xinlu Zhao , Zhonglu You
a
Department of Chemistry and Chemical Engineering, Liaoning Normal University, 116029 Dalian, PR China
Department of Dermatology, Huashan Hospital, Shanghai 200040, PR China
b
a r t i c l e i n f o
a b s t r a c t
1
1
2
Article history:
Received 19 May 2015
Received in revised form 28 June 2015
Accepted 7 July 2015
Available online 22 July 2015
Three new mononuclear copper(II) complexes, [CuL (N )] (1), [CuL (NCS)] (2), and [CuL (NCS)] (3), where
3
1
1
2
L
is the monoanionic form of 5-diethylamino-2-[(pyridin-2-ylmethylimino)methyl]phenol (HL ), and L
2
is the monoanionic form of 2-[1-(2-piperidin-1-ylethylimino)ethyl]phenol (HL ), have been synthesized
and characterized by physico-chemical methods, as well as single crystal X-ray determination. The Cu
atoms in the complexes are coordinated by the donor atoms of the Schiff base ligands and nitrogen atom
of the pseudohalide ligands, forming square planar geometry. The complexes showed effective urease
inhibitory activities. Complex 1 showed the most urease inhibitory activity, with IC50 value of
Keywords:
Schiff base
Copper complex
Crystal structure
Urease inhibition
Molecular docking study
1
.5 ± 1.1 lM. Molecular docking study of the complexes with Helicobacter pylori urease was performed.
As a result, complex 1 matches well with the cavity of the active center of the urease, and forms weak
interaction with residues ASP316, LEU318, MET317, CYS321, HIS322 and ARG328.
Ó 2015 Elsevier B.V. All rights reserved.
1
. Introduction
Urease is a nickel-containing metalloenzyme that catalyzes the
donor atoms serve as well-known chelating agents for transition
metal complexes, which show interesting biological activities
[15–17]. Schiff bases also possess urease inhibitory activities
[18,19]. In recent years, copper(II) complexes with a variety of
Schiff bases and other medicinally attractive functionalities were
intensively studied for their excellent urease inhibitory activity
[20–22]. However, study on the urease inhibition of Schiff base
copper complexes is still rare, and no accurate structure–activity
relationship was concluded. As an extension of this work, three
hydrolysis of urea to form ammonia and carbamate [1,2]. The
resulting carbamate spontaneously decomposes to yield ammonia
and carbon dioxide. High concentration of ammonia arising from
the reaction, as well as the accompanying pH elevation, has impor-
tant negative implication in medicine and agriculture [3–6].
Control the activity of urease through inhibitors could counteract
these negative effects [7]. Inorganic copper salts have been
reported to possess potential urease inhibitory activity [8,9].
Heavy metal ions inhibit both plant and bacterial ureases at the
1
1
new copper(II) complexes, [CuL (N
3
)] (1), [CuL (NCS)] (2), and
2
1
[CuL (NCS)] (3), where L is the monoanionic form of 5-diethy-
lamino-2-[(pyridin-2-ylmethylimino)methyl]phenol (HL ), and L
1
2
2+
+
2+
following approximate order of effectiveness: Hg ꢀ Ag > Cu
>
is the monoanionic form of 2-[1-(2-piperidin-1-ylethylimino)
2
+
2+
2+
2+
3+
2+
2+
2
Ni > Cd > Zn > Co > Fe > Pb > Mn [9,10]. But the appli-
cation of inorganic copper salts, as well as some organic urease
inhibitors, have been limited either by unsatisfied bioavailability,
or by toxicity in biological system or in nature [10–12].
Consequently, it is worthy to discover and comprehensively study
alternative urease inhibitors. It is proved that the cytotoxicity of
inorganic metal ions can be severely decreased when they form
metal complexes with organic ligands [13,14]. It can be stated that
urease inhibition of transition metal complexes is influenced both
by the types of ligand and metal ions. Schiff bases bearing N and O
ethyl]phenol (HL ), have been prepared and structurally character-
ized. Urease inhibitory activity and molecular docking analysis of
the complexes with Helicobacter pylori urease were studied.
2
. Experimental
2.1. General methods and materials
Starting material, reagents and solvents were purchased from
commercial suppliers and used as received. H. pylori urease,
HEPES (Ultra) buffer and urea (Molecular Biology Reagent) were
purchased from Sigma–Aldrich. Elemental analyses were per-
formed on a Perkin–Elmer 240C elemental analyzer. IR spectra
⇑
Corresponding author.
E-mail address: youzhonglu@126.com (Z. You).
http://dx.doi.org/10.1016/j.ica.2015.07.014
020-1693/Ó 2015 Elsevier B.V. All rights reserved.
0

3
00
F. Niu et al. / Inorganica Chimica Acta 435 (2015) 299–304
2
were recorded on a Jasco FT/IR-4000 spectrometer as KBr pellets in
the 4000–400 cm region. UV–Vis spectra were recorded on a
[CuL (NCS)] (3): 2-Acetylphenol (0.14 g, 1.0 mmol) and 2-piper-
idin-1-ylethylamine (0.13 g, 1.0 mmol) were mixed and stirred in
methanol (30 mL) at room temperature for 30 min. Then, ammo-
À1
Lambda 900 spectrometer. Molar conductance was measured with
a Shanghai DDS-11A conductometer. X-ray diffraction was carried
out on a Bruker SMART 1000 CCD diffractometer.
Caution: Copper perchlorate is potentially explosive, only small
quantity should be used and handled with great care.
nium thiocyanate (0.076 g, 1.0 mmol) and Cu(ClO
4
2 2
) Á6H O (0.39 g,
1.0 mmol) dissolved in methanol (20 mL) were added to the solu-
tion. The final mixture was stirred for 30 min at room temperature
to give blue solution. Upon standing at room temperature, blue
block-shaped single crystals of 3 were formed. The crystals were
isolated, washed three times with cold methanol and dried in air.
2.2. Synthesis of the complexes
À1
Yield: 71%. Characteristic IR data (cm ): 2093 (s), 1600 (s), 1584
1
[
CuL (N
3
)]
(1):
4-Diethylaminosalicylaldehyde
(0.19 g,
(s), 1529 (m), 1438 (m), 1352 (w), 1337 (m), 1233 (m), 1135 (w),
1037 (w), 950 (w), 862 (m), 757 (m), 635 (w), 558 (w), 527 (w),
474 (w), 448 (w), 407 (w). UV–Vis data in acetonitrile [kmax (nm),
1
.0 mmol) and 2-aminomethylpyridine (0.11 g, 1.0 mmol) were
mixed and stirred in methanol (30 mL) at room temperature for
0 min. Then, sodium azide (0.065 g, 1.0 mmol) and
Cu(ClO O (0.39 g, 1.0 mmol) dissolved in methanol (20 mL)
Á6H
were added to the solution. The final mixture was stirred for
0 min at room temperature to give blue solution. Upon standing
À1
À1
3
e
(L mol cm )]: 225, 15,600; 270, 4550; 300, 3680; 370, 2537.
4
)
2
2
Anal. Calc. for C16 21CuN OS: C, 52.4; H, 5.8; N, 11.5. Found: C,
52.2; H, 5.8; N, 11.6%.
H
3
3
at room temperature, blue block-shaped single crystals of 1 were
formed. The crystals were isolated by filtration, washed three
times with cold methanol and dried in air. Yield: 56%.
2.3. X-ray crystallography
Diffraction intensities for the complexes were collected at
298(2) K using a Bruker SMART 1000 CCD area-detector diffrac-
À1
Characteristic IR data (cm ): 2046 (s), 1595 (s), 1515 (m), 1496
(
(
(
(
m), 1413 (w), 1387 (m), 1357 (w), 1247 (m), 1140 (m), 1071
w), 826 (w), 758 (m), 706 (m), 661 (w), 608 (w), 570 (w), 460
tometer with Mo Ka radiation (k = 0.71073 Å). The collected data
were reduced with SAINT [23], and multi-scan absorption correction
w), 416 (w). UV–Vis data in acetonitrile [kmax (nm),
e
was performed using SADABS [24]. Structures of the complexes were
À1
À1
2
L mol cm )]: 269, 20,800; 283, 18,210; 373, 17,950; 440,
8,100. Anal. Calc. for C17 20CuN O: C, 52.6; H, 5.2; N, 21.7.
Found: C, 52.8; H, 5.3; N, 21.5%.
solved by direct methods, and refined against F by full-matrix
1
H
6
least-squares methods using SHELXTL [25]. All non-hydrogen atoms
were refined anisotropically. Hydrogen atoms were placed in cal-
culated positions and constrained to ride on their parent atoms.
Crystallographic data for the complexes are summarized in
Table 1. Selected bond lengths and angles are given in Table 2.
1
[
CuL (NCS)] (2): Complex 2 was synthesized by the same
method as that described for 1, with sodium azide replaced by
ammonium thiocyanate (0.076 g, 1.0 mmol). Blue block-shaped
single crystals of 2 were obtained. Yield: 45%. Characteristic IR data
À1
(
cm ): 2091 (s), 1598 (s), 1519 (m), 1496 (m), 1387 (w), 1345 (m),
2.4. Urease inhibitory activity assay
1
6
248 (m), 1138 (m), 1074 (w), 822 (w), 762 (m), 706 (w), 660 (w),
08 (w), 570 (w), 529 (w), 473 (w), 412 (w). UV–Vis data in ace-
H. pylori (ATCC 43,504; 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-
À1
À1
tonitrile [kmax (nm),
e
(L mol cm )]: 234, 22,400; 290, 8326;
20CuN OS: C, 53.5; H, 5.0; N, 13.9.
3
70, 28,250. Anal. Calc. for C18
H
4
Found: C, 53.4; H, 4.9; N, 13.8%.
obic condition (5% O
2
, 10% CO
2
, and 85% N
2
). For urease inhibition
Table 1
Crystallographic and experimental data for the complexes.
Complex
1
2
3
Formula
C
17
H
20CuN
6
O
C
18
H
20CuN
4
OS
16 3
C H21CuN OS
Mr
387.9
404.0
367.0
T (K)
298(2)
298(2)
298(2)
Crystal shape/color
Crystal size (mm )
Crystal system
Space group
a (Å)
block/blue
block/blue
block/blue
3
0.17 Â 0.15 Â 0.15
0.20 Â 0.20 Â 0.17
0.15 Â 0.13 Â 0.12
monoclinic
P21/n
11.232(6)
13.139(7)
11.750(6)
90
111.31(3)
90
1615.5(15)
4
triclinic
monoclinic
P2/c
P1ꢀ
10.8608(6)
12.4681(7)
13.5926(8)
79.385(1)
74.191(1)
83.213(1)
1736.2(2)
4
11.821(2)
7.420(2)
21.118(3)
90
102.543(2)
90
1808.2(7)
4
1.484
b (Å)
c (Å)
a
(°)
b (°)
(°)
c
3
V (Å )
Z
D
l
À3
c
(g cm
(Mo K
)
1.484
1.276
1.509
1.486
À1
a
) (mm
)
1.337
F(000)
804
836
764
Measured reflections
Independent reflections
Observed reflections (I P 2
Parameters
9164
6390
5156
455
8332
3339
2550
228
7615
2756
1734
200
r
(I))
Restraints
0
0
0
Min. and max. transmission
0.8123 and 0.8317
1.027
0.0284, 0.0804
0.0394, 0.0875
0.7759 and 0.8046
1.051
0.0357, 0.0809
0.0530, 0.0888
0.8079 and 0.8419
0.972
0.0678, 0.1542
0.1103, 0.1772
2
Goodness-of-fit (GOF) on F
a
R
R
1
, wR
, wR
2
[I P 2
(all data)
r
(I)]
a
1
2
= [P
w(F
À Fc )/
Pw(F
2)2]1/2.
o
a
2
2
R
1
= F
o
À F
c
/F
o
, wR
2
o

F. Niu et al. / Inorganica Chimica Acta 435 (2015) 299–304
301
Table 2
carried out by using AutoDock 4.0. First, AutoGrid component of
the program pre-calculates a 3D grid of interaction energies based
on the macromolecular target using the AMBER force field. The
Selected bond lengths (Å) and angles (°) for the complexes.
1
3
Cu1–O1
Cu1–N2
Cu2–O2
Cu2–N8
O1–Cu1–N1
N1–Cu1–N4
N1–Cu1–N2
O2–Cu2––N7
N7–Cu2–N10
N7–Cu2–N8
1.8972(14)
2.0107(17)
1.8943(14)
1.9957(18)
94.09(7)
173.86(8)
82.31(7)
93.90(7)
Cu1–N1
Cu1–N4
Cu2–N7
Cu2–N10
O1–Cu1–N4
O1–Cu1–N2
N4–Cu1–N2
O2–Cu2–N10
O2–Cu2–N8
N10–Cu2–N8
1.9309(16)
1.9527(19)
1.9362(17)
1.9631(19)
91.55(7)
176.10(6)
91.99(8)
90.42(7)
cubic grid box of 70 Â 70 Â 90 Å size (x, y, z) with a spacing of
0
.375 Å and grid maps were created representing the catalytic
active target site region where the native ligand was embedded.
Then automated docking studies were carried out to evaluate the
binding free energy of the inhibitor within the macromolecule.
The GALS search algorithm (genetic algorithm with local search)
was chosen to search for the best conformer. The parameters were
set using the software ADT (AutoDockTools package, version 1.5.4)
on PC which is associated with AutoDock 4.0. Default settings were
used with an initial population of 50 randomly placed individuals,
175.61(8)
82.46(7)
176.35(6)
93.22(8)
2
Cu1–O1
Cu1–N2
O1–Cu1–N1
N1–Cu1–N4
N1–Cu1–N2
1.8839(19)
1.999(2)
93.47(9)
176.46(10)
82.88(10)
Cu1–N1
Cu1–N4
O1–Cu1–N4
O1–Cu1–N2
N4–Cu1–N2
1.917(2)
1.939(3)
89.55(9)
176.06(9)
94.15(10)
6
a maximum number of 2.5 Â 10 energy evaluations, and a maxi-
4
mum number of 2.7 Â 10 generations. A mutation rate of 0.02
and a crossover rate of 0.8 were chosen. Results differing by less
than 0.5 Å in positional root-mean-square deviation (RMSD) were
clustered together and the results of the most favorable free energy
of binding were selected as the resultant complex structure.
3
Cu1–O1
Cu1–N2
O1–Cu1–N3
N3–Cu1–N1
N3–Cu1–N2
1.860(5)
2.054(5)
88.8(2)
177.9(2)
92.0(2)
Cu1–N1
Cu1–N3
O1–Cu1–N1
O1–Cu1–N2
N1–Cu1–N2
1.961(5)
1.945(6)
92.8(2)
171.0(2)
86.2(2)
3
. Results and discussion
3
.1. Chemistry
8
À1
assay, 50 mL broth cultures (2.0 Â 10 CFU mL ) were centrifuged
5000 g, 4 °C) to collect the bacteria. After washing twice with
The complexes were synthesized by reaction of the Schiff bases
(
with copper(II) chlorate and pseudohalide salts in a molar ratio of
:1:1 in methanol. Single crystals of the complexes were obtained
phosphate-buffered saline (pH = 7.4), the H. pylori precipitation
was stored at –80 °C. When H. pylori was returned to room temper-
ature, and mixed with 3 mL of distilled water and protease inhibi-
tors, sonication was performed for 60 s. Following centrifugation
1
by slow evaporation of their methanol solutions. The complexes
are stable in air at room temperature. Molar conductivity
values of the complexes measured in methanol at concentration
of approximately 10
1
(
15,000g, 4 °C), the supernatant was desalted through Sephadex
À3
À1
2
2
À1
M
are 23.3
X
cm mol
for 1,
G-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
À1
2
À1
À1
À1
8.7
X
cm mol for 2, and 27.7
X
cm mol for 3. The low
molar conductivity values indicate non-electrolytic nature of the
complexes in solution [27].
experiment. The assay mixture, containing 25
l
L (10 U) of H. pylori
of cell suspension
4.0 Â 10 CFU mL ) for the urease assay of intact cells and
L of the test compound, was pre-incubated for 3 h at room
urease which was replaced by 25
lL
7
À1
(
3.2. Structure description of the complexes
25 l
temperature in a 96-well assay plate. Urease activity was deter-
mined by measuring ammonia production using the indophenol
method as described by Weatherburn [26].
Single-crystal X-ray diffraction showed that the complexes are
structurally similar mononuclear copper(II) species (Fig. 1 for 1,
Fig. 2 for 2, Fig. 3 for 3). In the asymmetric unit of 1, there are
two independent molecules. Each Cu atom in the complexes is
coordinated by the NNO donor set of the Schiff base ligand, and
one N atom of azide or thiocyanate ligand, forming slightly dis-
torted square-planar geometry. The Cu atoms deviate from the
least-squares planes defined by the corresponding four donor
2.5. Molecular docking study
Molecular docking study of the complexes into 3D X-ray struc-
ture of H. pylori urease (entry 1E9Y in the Protein Data Bank) was
Fig. 1. A perspective view of the two independent molecules in the asymmetric unit of 1 with the atom labeling scheme. Thermal ellipsoids are drawn at the 30% probability
level.

3
02
F. Niu et al. / Inorganica Chimica Acta 435 (2015) 299–304
Fig. 2. A perspective view of the molecular structure of 2 with the atom labeling scheme. Thermal ellipsoids are drawn at the 30% probability level.
Fig. 3. A perspective view of the molecular structure of 3 with the atom labeling scheme. Thermal ellipsoids are drawn at the 30% probability level.
atoms by 0.033(2) Å for 1, 0.004(2) Å for 2, and 0.086(2) Å for 3.
The coordinate bond lengths related to the Cu atoms in the three
complexes are similar to each other, and also comparable to those
observed in copper(II) complexes with Schiff bases [28,29]. The
coordinate bond angles in the complexes slightly deviate from
ideal values, which is caused by the strain created by the five-
membered chelate rings Cu–N–C–C–N.
The dihedral angles between benzene and pyridine rings of the
Schiff base ligands are 6.9(3)° for 1, and 3.5(3)° for 2. As expected,
the piperidine ring of 3 is in chair conformation.
Table 3
Inhibition of urease by the tested materials.
Tested materials
Percentage Inhibition ratea
IC50 (lM)
1
2
3
HL
HL
93.0 ± 4.5
74.1 ± 3.6
69.2 ± 5.1
5.5 ± 2.0
3.8 ± 1.7
87.5 ± 2.6
84.3 ± 3.9
1.5 ± 1.1
16.7 ± 3.2
18.3 ± 2.7
–
1
2
–
Copper perchlorate
Acetohydroxamic acid
8.8 ± 1.4
37.2 ± 4.0
a
The concentration of the tested material is 100 lM.
3.3. IR and UV–Vis spectra
In the infrared spectrum of 1, strong absorption band at
046 cm can be assigned to the vibration of the azide ligand. In
3. The medium absorption bands due to the vibration of Ar–O are
À1
À1
À1
À1
2
located at 1247 cm for 1, 1248 cm for 2, and 1233 cm for 3.
The close resemblance of shape and positions of the infrared
absorptions suggests similar coordination mode of the complexes,
which agrees well with the structural features determined by
single crystal X-ray diffraction.
the infrared spectra of 2 and 3, strong absorption bands at about
À1
2
092 cm can be assigned to the vibrations of the thiocyanate
ligands. The typical absorption for azomethine groups,
observed at 1595 cm for 1, 1598 cm for 2, and 1600 cm for
m
(C@N), are
À1
À1
À1

F. Niu et al. / Inorganica Chimica Acta 435 (2015) 299–304
303
Fig. 4. Binding mode of 1 with Helicobacter pylori urease. Left: The enzyme is shown as surface, and the complex is shown as sticks. Hydrogen bonds are shown as wireframe.
Right: The enzyme is shown as ribbons, and the complex is shown as sticks.
The electronic spectra of the complexes showed similar UV
bands. The bands centered at about 370 nm originate from the
phenolate to copper ion charge-transfer [30]. The intense UV bands
4. Conclusion
The present study reports the synthesis, structures and urease
inhibitory activity of three new mononuclear copper(II) complexes
with tridentate Schiff bases. All complexes showed effective urease
in the range of 230–270 nm are attributed to the intra-ligand
⁄
charge transfer (
p
?
p
). However, in the electronic spectra of
the complexes, the bands associated with d ? d transitions are
not observed, which may due to the intensity of the charge transfer
and intra-ligand transitions [31].
inhibitory activities. Complex
inhibitory activity, with IC50 value of 1.5 ± 1.1
copper(II) complexes have interesting biological activities and
have been widely used in medicine, complex 1 in this paper may
be used in the treatment of infections caused by urease producing
bacteria.
1
showed prominent urease
M. Considering
l
3.4. Pharmacology
The results of urease inhibition are summarized in Table 3.
Acknowledgment
In comparison with the reference inhibitor acetohydroxamic
acid, Schiff bases HL1 and HL2 have no or very weak interac-
tions on the urease. Complexes 1, 2, and 3 showed effective
urease inhibitory activities, with IC50 values of 1.5 ± 1.1,
This work was financially supported by Program for Liaoning
Excellent Talents in University (Project No. LR2014032).
1
6.7 ± 3.2, and 18.3 ± 2.7
l
M, respectively, which are even lower
M).
than that of acetohydroxamic acid (IC50 = 37.2 ± 4.0
l
Appendix A. Supplementary material
Complex 1 showed prominent stronger activity than 2 and 3.
The structural difference between 1 and 2 is just the secondary
ligands, viz. N for 1 and NCS for 2. As for 2 and 3, the activities
3
CCDC 940553 (1), 940555 (2), and 892372 (3) contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via http://www.ccdc.cam.ac.uk/data_request/
cif. Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.ica.2015.07.
are equal within the deviations. The activity of 1 is similar to
one copper complex reported by Li and co-workers, with
Schiff base 2,4-dibromo-6-{[2-(4-hydroxyphenyl)ethylimino]
methyl}phenol as ligand [21], and superior to the copper com-
plexes derived from 4-nitro-2-{[2-(2-hydroxyethylamino)
ethylimino]methyl}phenol [22].
0
14.
References
3.5. Molecular docking study
[
[
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[3] S. Bai, P. Bharti, L. Seasotiya, A. Malik, S. Dalal, Pharm. Biol. 53 (2015) 326.
[
[
4] D. Mora, S. Arioli, PLoS Pathog. 10 (2014) e1004472.
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Macedo, L.V. Modolo, RSC Adv. 5 (2015) 44507.
binding effects between the complexes and the active sites of
H. pylori urease. In the X-ray structure available for the native
H. pylori urease, two Ni atoms are coordinated by HIS136,
HIS138, KCX219, KCX219, HIS248, HIS274, ASP362 and water mole-
cules, while in the acetohydroxamic acid inhibited urease, the
water molecules are replaced by acetohydroxamic acid. The bind-
ing model of 1 in the enzyme active site of urease is depicted in
Fig. 4. The molecule of the complex matches well with the cavity
of the active center of the urease, while molecules of 2 and 3
located at the outside of the cavity. The molecule of 1 forms weak
interactions with residues ASP316, LEU318, MET317, CYS321,
HIS322 and ARG328. The binding energy of 1 with the urease is
À5.61 kcal/mol, which is lower than the acetohydroxamic acid
inhibited model of À5.01 kcal/mol. The results of molecular dock-
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