Synthesis, structures, and urease inhibitory activities of oxovanadium(V) complexes with Schiff bases

Article abstract of DOI:10.1016/j.ica.2011.11.039

A series of oxovanadium(V) complexes, [VO₂L¹] ₂ (1), [VO₂L²]₂ (2), [VO ₂L³]₂ (3), [VO₂L⁴] ₂ (4), [VO(OCH₃)L

Full text of DOI:10.1016/j.ica.2011.11.039

Inorganica Chimica Acta 384 (2012) 54–61
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Inorganica Chimica Acta
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Synthesis, structures, and urease inhibitory activities of oxovanadium(V)
complexes with Schiff bases
b
a
a
a
a
Zhong-Lu You a, , Da-Hua Shi , Ji-Cai Zhang , Yu-Ping Ma , Che Wang , Kun Li
⇑
a Department of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, PR China
b School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, PR China
a r t i c l e i n f o
a b s t r a c t
A series of oxovanadium(V) complexes, [VO2L1]2 (1), [VO2L2]2 (2), [VO2L3]2 (3), [VO2L4]2 (4), [VO(OCH3)L5]
(5), and [VO(OCH3)(HOCH3)L6] (6) (HL1 = 2-ethoxy-6-{[2-(2-hydroxyethylamino)ethylimino]methyl}phe-
nol, HL2 = 4-chloro-2-{[2-(2-hydroxyethylamino)ethylimino]methyl}phenol, HL3 = 2-methoxy-6-[(2-
methylaminoethylimino)methyl]phenol, HL4 = 4-chloro-2-[(2-methylaminoethylimino)methyl]phenol,
HL5 = N0-(2-hydroxy-3-ethoxybenzylidene)-3-hydroxy-2-naphthohydrazide, and HL6 = N0-(2-hydroxy-5-
chlorobenzylidene)-3-hydroxy-2-naphthohydrazide), have been prepared and structurally characterized
by physico-chemical methods and X-ray diffraction. The inhibition rates (%) with the concentration of
Article history:
Received 30 May 2011
Received in revised form 9 November 2011
Accepted 12 November 2011
Available online 6 December 2011
Keywords:
Schiff base
Oxovanadium complex
Crystal structure
Urease inhibition
100 lM for the complexes on Helicobacter pylori urease are 18.96 0.44 (1), 33.01 1.80 (2), 35.83 0.78
(3), 48.09 1.23 (4), 45.91 2.09 (5), and 90.72 1.91 (6). The relationship between the structures and ure-
ase inhibitory activities indicates that the chloro-substituted complexes have stronger activity than the alk-
oxy-substituted complexes. It is notable that one of the chloro-substituted complexes has very strong
urease inhibitory activity, with IC50 value of 17.35 1.01 lM, which is much lower than that of the aceto-
hydroxamic acid coassayed as a standard urease inhibitor. The kinetic studies reveal that the complex is a
mixed-competitive inhibitor of urease. The molecular docking study of the complexes with the Helicobacter
pylori urease was performed.
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
for their insulin-enhancing activities [17–19]. After searching the
literature, we find that the vanadium(IV) complexes also possess
Urease is a nickel-containing metalloenzyme that catalyzes the
hydrolysis of urea to form ammonia and carbamate [1,2]. The
resulting carbamate spontaneously decomposes to yield a second
molecule of ammonia and carbon dioxide. High concentration of
ammonia arising from these reactions, as well as the accompanying
pH elevation, have important negative implication 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 have played an important role in the treat-
ment of the infections caused by urease producing bacteria [7].
Inhibitors of urease can be broadly classified into two fields: (1) or-
ganic compounds, such as acetohydroxamic acid, humic acid, and
interesting urease inhibitory activity [20]. As an extensive study
on the oxovanadium complexes and their urease inhibitory activity,
in this paper, a series of new oxovanadium(V) complexes, [VO2L1]2
(1), [VO2L2]2 (2), [VO2L3]2 (3), [VO2L4]2 (4), [VO(OCH3)L5] (5), and
[VO(OCH3)(HOCH3)L6] (6) (HL1 = 2-ethoxy-6-{[2-(2-hydroxyeth
ylamino)ethylimino]methyl}phenol, HL2 = 4-chloro-2-{[2-(2-hydr
oxyethylamino)ethylimino]methyl}phenol, H2L3 = 2-methoxy-6-
[(2-methylaminoethylimino)methyl]phenol, H2L4 = 4-chloro-2-
[(2-methylaminoethylimino)methyl]phenol, HL5 = N0-(2-hydroxy-
3-ethoxybenzylidene)-3-hydroxy-2-naphthohydrazide, HL6 = N0-
(2-hydroxy-5-chlorobenzylidene)-3-hydroxy-2-naphthohydrazide;
Scheme 1) were synthesized and structurally characterized. The
urease inhibitory activity of the complexes was investigated both
from the experimental and from the docking analysis using the
AutoDock 4.0 program [21].
1,4-benzoquinone [8–10]; (2) heavy metal ions, such as Cu2+
,
Zn2+, Pd2+, and Cd2+ [11,12]. Considering the metal complexes are
a kind of versatile enzyme inhibitors [13], we have recently re-
ported the properties of a number of complexes with Schiff bases
[14–16]. The results show that the Schiff base copper(II) complexes
have potential urease inhibitory activities. Vanadium complexes
have been widely investigated in biological chemistry, especially
2. Experimental
2.1. General remarks and physical measurements
⇑
Reagents and solvents were purchased from commercial suppli-
ers and were used without further purification. Protease inhibitor
Corresponding author. Tel.: +86 411 84216387.
E-mail address: youzhonglu@yahoo.com.cn (Z.-L. You).
0020-1693/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2011.11.039

Z.-L. You et al. / Inorganica Chimica Acta 384 (2012) 54–61
55
H
N
H
Cl
N
OH
N
OH
N
OH
OH
OEt
HL1
HL2
H
N
H
N
Cl
N
N
OH
OH
OMe
H2L4
H2L3
OH
OH
H
N
H
N
Cl
N
N
O
O
OH
OH
OEt
HL5
HL6
Scheme 1. The Schiff bases.
(Complete mini EDTA-free) was purchased from Roche Diagnostics
GmbH (Mannhein, Germany) and Brucella broth was from
[Becton–Dickinson] (Cockeysville, MD). Horse serum was obtained
from Hyclone (Utah, America). Elemental analyses were performed
on a Perkin-Elmer 240C elemental analyzer. The IR spectra were re-
corded on a Jasco FT/IR-4000 spectrometer as KBr pellets in the
4000–200 cmꢀ1 region. Molar conductance was measured with a
Shanghai DDS-11A conductometer. X-ray diffraction was carried
out on a Bruker SMART 1000 CCD area diffractometer. UV–vis spec-
tra were recorded on a Perkin-Elmer Lambda 9 instrument. The
EPR spectra of the complexes were measured using a Bruker
EMX Micro Premium X spectrometer.
ture for 30 min to give solutions with color from yellow to deep
brown. X-ray quality single crystals were formed by slow evapora-
tion of the solutions in air after a few days.
2.3.1. Bis(l2-oxo)bis(2-ethoxy-6-{[2-(2-hydroxyethylamino)ethylimi
no]methyl}phenolato)dioxodivanadium(V) (1)
Yellow single crystals. Yield: 62%. Anal. Calc. for C26H38N4O10V2:
C, 46.7; H, 5.7; N, 8.4. Found: C, 46.4; H, 5.9; N, 8.2%. IR data: 3371
(m), 3202 (w), 1640 (s), 1598 (m), 1557 (w), 1468 (s), 1448 (s),
1418 (w), 1392 (m), 1292 (s), 1253 (s), 1223 (m), 1174 (w), 1112
(w), 1079 (m), 1044 (m), 996 (w), 914 (s), 856 (s), 785 (w), 748
(m), 636 (w), 614 (w), 477 (w), 441 (w), 373 (w), 349 (w), 326
(w). UV–vis spectra data in DMSO [nm (e
, Mꢀ1 cmꢀ1)]: 256
(1.4 ꢁ 104), 370 (3.4 ꢁ 103), 563 (172).
2.2. Synthesis of the Schiff bases
To a methanolic solution (50 mL) of substituted salicylalde-
hyde (2.0 mmol) a methanolic solution (30 mL) of primary amine
(2.0 mmol) was added with continuous stirring. The mixture was
stirred for 30 min at room temperature to give yellow solution.
The solvent was evaporated to give yellow gummy product of
the Schiff base, which was washed with methanol and dried in
air. Yields: 83–87%. Anal. Calc. for C13H20N2O3 (HL1): C, 61.9; H,
8.0; N, 11.1. Found: C, 61.7; H, 8.1; N, 11.3%. Anal. Calc. for
2.3.2. Bis(l2-oxo)bis(4-chloro-2-{[2-(2-hydroxyethylamino)
ethylimino]methyl}phenolato)dioxodivanadium(V) (2)
Yellow single crystals. Yield: 67%. Anal. Calc. for
C22H28
Cl2N4O8V2: C, 40.7; H, 4.3; N, 8.6. Found: C, 41.0; H, 4.5; N, 8.5%.
IR data: 3464 (m), 3211 (w), 1638 (s), 1593 (w), 1539 (m), 1465
(s), 1383 (s), 1335 (w), 1292 (s), 1201 (w), 1182 (m), 1133 (w),
1093 (w), 1061 (m), 1020 (m), 970 (w), 921 (m), 886 (m), 841
(s), 707 (m), 660 (w), 549 (w), 526 (w), 454 (w), 426 (w), 339
C
11H15ClN2O2 (HL2): C, 54.4; H, 6.2; N, 11.5. Found: C, 54.7; H,
(w), 326 (w). UV–vis spectra data in DMSO [nm (e
, Mꢀ1 cmꢀ1)]:
6.3; N, 11.5%. Anal. Calc. for C11H16N2O2 (HL3): C, 63.4; H, 7.7;
N, 13.4. Found: C, 63.6; H, 7.7; N, 13.2%. Anal. Calc. for
253 (1.4 ꢁ 104), 372 (3.2 ꢁ 103), 558 (183).
C
10H13ClN2O (HL4): C, 56.5; H, 6.2; N, 13.2. Found: C, 56.1; H,
6.3; N, 13.3%. Anal. Calc. for C21H20N2O4 (HL5): C, 69.2; H, 5.5;
N, 7.7. Found: C, 69.5; H, 5.5; N, 7.6%. Anal. Calc. for
2.3.3. Bis(
l2-oxo)bis(2-methoxy-6-[(2-methylaminoethylimino)
methyl]phenolato)dioxodivanadium(V) (3)
C
19H15ClN2O3 (HL6): C, 64.3; H, 4.3; N, 7.9. Found: C, 64.6; H,
Orange single crystals. Yield: 72%. Anal. Calc. for C22H30N4O8V2:
C, 45.5; H, 5.2; N, 9.7. Found: C, 45.3; H, 5.4; N, 9.6%. IR data: 3235
(w), 1635 (s), 1598 (m), 1557 (w), 1471 (s), 1456 (s), 1397 (m),
1312 (s), 1251 (s), 1226 (s), 1173 (w), 1157 (w), 1085 (m), 1047
(w), 1024 (w), 969 (w), 929 (s), 837 (s), 783 (w), 744 (m), 635
(w), 610 (w), 573 (w), 472 (w), 437 (w), 401 (w), 353 (w). UV–vis
4.4; N, 7.6%.
2.3. Synthesis of the complexes
A methanolic solution (20 mL) of the Schiff base (0.5 mmol) was
added with stirring to a methanolic solution (20 mL) of VO(acac)2
(0.5 mmol, 0.133 g). The mixtures were stirred at room tempera-
spectra data in DMSO [nm (
e
, Mꢀ1 cmꢀ1)]: 251 (1.3 ꢁ 104), 367
(3.2 ꢁ 103), 561 (167).

56
Z.-L. You et al. / Inorganica Chimica Acta 384 (2012) 54–61
2.3.4. Bis(
l2-oxo)bis(4-chloro-2-[(2-methylaminoethylimino)methyl]
squares method using the SHELXTL package [24]. All non-hydrogen
phenolato)dioxodivanadium(V) (4)
atoms were refined anisotropically. The amino H atoms in the com-
plexes 1–4, and the methanol H atom in the complex 6 were lo-
cated from difference Fourier maps and refined isotropically,
with NꢀH and OꢀH distances restrained to 0.90(1) and 0.85(1) Å,
and with Uiso(H) set to 0.08 Å2. The remaining H atoms in the com-
plexes were placed in calculated positions and constrained to ride
on their parent atoms. The O3 atom in complex 1 is disordered over
two sites, with occupancies of 0.778(2) and 0.222(2). The crystallo-
graphic data for the complexes are summarized in Tables 1 and 2.
Selected bond lengths and angles are listed in Table 3.
Orange single crystals. Yield: 54%. Anal. Calc. for C20H24Cl2N4
O6V2: C, 40.8; H, 4.1; N, 9.5. Found: C, 40.5; H, 4.2; N, 9.5%. IR data:
3247 (w), 1649 (s), 1594 (w), 1538 (m), 1463 (s), 1421 (w), 1376
(m), 1302 (s), 1185 (m), 1090 (m), 1058 (w), 1012 (w), 933 (s),
854 (s), 806 (m), 708 (m), 660 (w), 545 (m), 466 (w), 453 (w),
402 (w), 364 (w), 318 (w). UV–vis spectra data in DMSO [nm (e,
Mꢀ1 cmꢀ1)]: 258 (1.4 ꢁ 104), 389 (3.5 ꢁ 103), 572 (186).
2.3.5. Methoxy(N0-(2-hydroxy-3-ethoxybenzylidene)-3-hydroxy-2-
naphthohydrazonato)oxovanadium(V) (5)
Brown single crystals. Yield: 65%. Anal. Calc. for C21H19N2O6V: C,
56.5; H, 4.3; N, 6.3. Found: C, 56.2; H, 4.5; N, 6.2%. IR data: 1638 (s),
1600 (s), 1575 (w), 1557 (m), 1525 (m), 1470 (m), 1445 (m), 1342
(w), 1305 (w), 1273 (m), 1251 (s), 1183 (w), 1145 (w), 1111 (m),
1072 (s), 990 (s), 891 (w), 861 (w), 763 (m), 738 (m), 633 (m), 536
(w), 478 (w), 361 (w), 337 (w). UV–vis spectra data in DMSO [nm
2.5. Measurement of urease inhibitory activity
Helicobacter pylori (ATCC 43504; American Type Culture Collec-
tion, Manassas, VA) was grown in Brucella broth supplemented
with 10% heat-inactivated horse serum for 24 h at 37 °C under
microaerobic condition (5% O2, 10% CO2, and 85% N2). The method
of the preparation of H. pylori urease by Mao [25] was followed.
Briefly, broth cultures (50 mL, 2.0 ꢁ 108 CFU mLꢀ1) were centri-
fuged (5000g, 4 °C) to collect the bacteria, and after washing twice
with phosphate-buffered saline (pH 7.4), the H. pylori precipitation
was stored at ꢀ80 °C. 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 centrifu-
gation (15000g, 4 °C), the supernatant was desalted through
SephadexG-25 column (PD-10 columns, Amersham Pharmacia Bio-
tech, Uppsala, Sweden). The resultant crude urease solution was
added to an equal volume of glycerol and stored at 4 °C until use
(e
, Mꢀ1 cmꢀ1)]: 235 (3.5 ꢁ 104), 260 (2.3 ꢁ 104), 335 (1.9 ꢁ 104).
2.3.6. Methanolmethoxy(N0-(2-hydroxy-5-chlorobenzylidene)-3-
hydroxy-2-naphthohydrazonato)oxovanadium(V) (6)
Brown single crystals. Yield: 77%. Anal. Calc. for C20H18ClN2O6V:
C, 51.2; H, 3.9; N, 6.0. Found: C, 51.4; H, 3.8; N, 6.1%. IR data: 3429
(m), 1641 (s), 1605 (m), 1577 (w), 1541 (s), 1521 (s), 1466 (m),
1386 (w), 1364 (m), 1341 (m), 1309 (m), 1279 (m), 1243 (w),
1220 (m), 1195 (w), 1148 (w), 1060 (s), 1027 (w), 985 (m), 873
(w), 823 (m), 747 (s), 716 (w), 669 (w), 632 (m), 572 (w), 507
(w), 482 (w), 343 (w). UV–vis spectra data in DMSO [nm (e,
Mꢀ1 cmꢀ1)]: 230 (1.9 ꢁ 104), 267 (2.1 ꢁ 104), 327 (2.2 ꢁ 104).
in the experiment. The mixture, containing 25
lL of the H. pylori
urease and 25 L of the test compound, was pre-incubated for
l
3 h at room temperature in a 96-well assay plate. Urease activity
was determined by measuring ammonia production using the
indophenol method as described by Weatherburn [26].
2.4. X-ray crystallography
Diffraction intensities for the complexes were collected at
298(2) K using a Bruker SMART 1000 CCD area diffractometer with
MoKa
radiation (k = 0.71073 Å). The collected data were reduced
2.6. Kinetic studies
using the SAINT program [22], and multi-scan absorption correction
was performed using the SADABS program [23]. The structures were
solved by direct method and refined against F2 by full-matrix least-
Enzyme activities were determined at room temperature using
four concentrations of substrate (50, 100, 200, and 300 lM) in the
Table 1
Crystallographic and experimental data for the complexes 1, 2, and 3.
Complex
1
2
3
Formula
Formula weight
T (K)
C
26H38N4O10V2
C22H28Cl2N4O8V2
649.3
298(2)
C22H30N4O8V2
580.4
298(2)
668.5
298(2)
Crystal shape/color
Crystal size (mm3)
Crystal system
Space group
a (Å)
block/orange
0.23 ꢁ 0.21 ꢁ 0.20
monoclinic
P21/n
9.840(2)
6.751(1)
22.081(3)
94.790(2)
1461.7(4)
2
block/orange
0.27 ꢁ 0.23 ꢁ 0.22
monoclinic
P21/c
7.239(2)
15.415(4)
11.744(3)
99.532(2)
1292.4(6)
2
block/yellow
0.30 ꢁ 0.30 ꢁ 0.23
monoclinic
P21/c
7.634(2)
20.341(3)
8.566(2)
109.958(2)
1250.2(5)
2
b (Å)
c (Å)
b (°)
V (Å3)
Z
Dcalc (g cmꢀ3
)
1.519
0.701
696
3167
1.668
0.985
664
2805
1.542
0.801
600
1879
l
(MoK
F(000)
Data collected
Unique data (I P 2
a
) (mmꢀ1
)
r
(I))
1876
2421
1382
Minimum and maximum transmission
Parameters
0.855 and 0.873
206
0.777 and 0.812
176
0.795 and 0.837
169
Restraints
9
1
1
Goodness-of-fit on F2
0.997
1.052
1.036
R1, wR2 [I P 2
r
(I)]a
0.0584, 0.1021
0.1157, 0.1221
0.300 and ꢀ0.460
0.0302, 0.0763
0.0361, 0.0792
0.333 and ꢀ0.333
0.0398, 0.0878
0.0602, 0.0996
0.309 and ꢀ0.265
R1, wR2 (all data)a
Large difference on peak and hole (e Åꢀ3
)
P
P
2
1=2
R1 ¼ Fo ꢀ Fc=Fo; wR2 ¼ ½ wðF2o ꢀ Fc2Þ= wðFo2Þ ꢂ
.
a

Z.-L. You et al. / Inorganica Chimica Acta 384 (2012) 54–61
57
Table 2
Crystallographic and experimental data for the complexes 4, 5, and 6.
Complex
4
5
6
Formula
Formula weight
T (K)
C
20H24Cl2N4O6V2
C21H19N2O6V
446.3
298(2)
C20H18ClN2O6V
468.7
298(2)
589.2
298(2)
Crystal shape/color
Crystal size (mm3)
Crystal system
Space group
a (Å)
block/yellow
0.18 ꢁ 0.17 ꢁ 0.16
monoclinic
P21/c
6.803(1)
11.515(2)
15.137(3)
97.144(2)
1176.6(3)
2
block/brown
0.30 ꢁ 0.27 ꢁ 0.27
monoclinic
P21/c
16.438(2)
6.325(1)
18.971(3)
96.492(2)
1960.0(6)
4
block/brown
0.17 ꢁ 0.13 ꢁ 0.12
monoclinic
P21/n
13.445(2)
6.802(2)
22.505(3)
102.216(3)
2011.5(7)
4
b (Å)
c (Å)
b (°)
V (Å3)
Z
Dcalc (g cmꢀ3
)
1.663
1.066
600
2545
1.513
0.548
920
4166
1.548
0.667
960
4389
l
(MoK
F(000)
Data collected
Unique data (I P 2
a
) (mmꢀ1
)
r
(I))
2316
3134
2116
Minimum and maximum transmission
Parameters
0.831 and 0.848
158
0.853 and 0.866
274
0.895 and 0.924
277
Restraints
1
0
1
Goodness-of-fit on F2
1.051
1.047
0.990
R1, wR2 [I P 2
r
(I)]a
0.0269, 0.0732
0.0301, 0.0753
0.255 and ꢀ0.300
0.0426, 0.1041
0.0619, 0.1145
0.398 and ꢀ0.438
0.0660, 0.1149
0.1611, 0.1454
0.304 and ꢀ0.370
R1, wR2 (all data)a
Large difference on peak and hole (e Åꢀ3
)
P
P
2
1=2
R1 ¼ Fo ꢀ Fc=Fo; wR2 ¼ ½ wðF2o ꢀ Fc2Þ= wðFo2Þ ꢂ
.
a
presence or absence of three concentrations of 6 (10, 20, and
40 M). Then data were plotted by the method of Lineweaver–Burk
3. Results and discussion
l
to reveal the mechanism of inhibition. Replots of the slopes versus
the inhibitor concentrations gave estimates of Ki, the dissociation
constant for 6 binding to urease.
The Schiff bases were synthesized by the reaction of equimolar
quantities of chloro- or alkoxy-substituted salicylaldehydes with
primary amines or hydrazones in methanol. All the complexes were
synthesized by the reaction of the methanol solution of the Schiff
bases with VO(acac)2. The compounds have been characterized by
elemental analysis and IR spectra. Structures of the complexes were
further confirmed by X-ray crystallography. The molar conductance
values of the complexes measured in methanol at the concentration
2.7. Docking study
Molecular docking study of the complexes into the 3D X-ray
structure of the H. pylori urease (entry 1E9Y in the Protein Data
Bank) was carried out by using the AutoDock 4.0 software as
implemented through the graphical user interface AutoDockTools
(ADT 1.5.2).
of 10ꢀ3 M are in the range 4–30
X
ꢀ1 cm2 molꢀ1, indicating the non-
electrolytic nature of the complexes [28]. The vanadium in the com-
plexes is +5 oxidation state and therefore EPR silent.
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 are set as r = 1.170 Å, q = +2.0,
and van der Waals well depth of 0.100 kcal/mol [27]. The 3D struc-
tures of the ligand molecules were saved in Mol2 format with the
aid of the program Mercury. The partial charges of Mol2 file were
further modified by using the ADT package so that the charges of
the non-polar hydrogen atoms assigned to the atoms to which
the hydrogen is attached. The resulting files were saved as pdbqt
format.
The AutoDockTools was used to generate the docking input
files. In all docking a grid box size of 90 ꢁ 90 ꢁ 90 points in x,
y, and z directions was built, the maps were centered on the ori-
ginal ligand molecule in the catalytic site of the protein. A grid
spacing of 0.375 Å and a distances-dependent function of the
dielectric constant were used for the calculation of the energetic
map. One hundred runs were generated by using Lamarckian ge-
netic algorithm searches. Default settings were used with an ini-
tial population of 50 randomly placed individuals, a maximum
number of 2.5 ꢁ 106 energy evaluations, and a maximum num-
ber of 2.7 ꢁ 104 generations. A mutation rate of 0.02 and a cross-
over rate of 0.8 were chosen. The results of the most favorable
free energy of binding were selected as the resultant complex
structures.
3.1. Structure description of the complexes
The molecular structures of the complexes 1–4 are shown in
Figs. 1–4, respectively. X-ray crystallography reveals that the four
complexes are similar centrosymmetric dimeric oxovanadium(V)
compounds. The difference among the complexes is the variety of
the Schiff base ligands. The Vꢃ ꢃ ꢃV distances are 3.124(1) Å for 1,
3.112(1) Å for 2, 3.155(1) Å for 3, and 3.170(1) Å for 4. Each V atom
in the complex is six-coordinated through three bonds to oxo
groups and through three bonds to the tridentate Schiff base ligand,
forming an octahedral geometry. The distances between atoms V1
and O4 in 1 and 3, V1 and O3 in 2, and V1 and O2 in 4 are in the
range 1.608(2)–1.617(2) Å, indicating they are typical V@O bonds.
The atoms O5 in 1, O4 in 2, O3 in 3 and 4 are bridging groups.
The coordinate bond lengths in the complexes are comparable to
each other, and also comparable to those observed in other similar
oxovanadium complexes [29,30]. The distortion of the octahedral
coordination can be observed by the coordinate bond angles, rang-
ing from 76.3(1)° to 107.9(2)° (1), 76.0(1)° to 106.4(1)° (2), 77.0(1)°
to 107.1(2)° (3), and 74.6(1)° to 107.0(1)° (4), for the perpendicular
angles, and from 154.6(1)° to 170.4(1)° (1), 155.9(1)° to 173.3(1)°
(2), 154.6(1)° to 171.0(1)° (3), 152.5(1)° to 170.3(1)° (4), for the
diagonal angles. In each complex, there form two intramolecular
NꢀHꢃ ꢃ ꢃO hydrogen bonds in the dimeric molecule.

58
Z.-L. You et al. / Inorganica Chimica Acta 384 (2012) 54–61
Table 3
Selected bond lengths (Å) and angles (°) for the complexes.
1
V1–O1
V1–O5
V1–N2
1.894(2)
1.658(2)
2.167(3)
107.9(2)
98.7(1)
154.6(1)
93.0(2)
157.5(1)
170.4(1)
84.2(1)
V1–O4
V1–N1
V1–O5A
O4–V1–O1
O4–V1–N1
O1–V1–N1
O5–V1–N2
N1–V1–N2
O5–V1–O5A
N1–V1–O5A
1.617(3)
2.134(3)
2.346(3)
101.2(1)
96.2(1)
83.9(1)
93.3(1)
77.3(1)
78.8(1)
76.4(1)
O4–V1–O5
O5–V1–O1
O5–V1–N1
O4–V1–N2
O1–V1–N2
O4–V1–O5A
O1–V1–O5A
N2–V1–O5A
79.6(2)
2
V1–O1
V1–O4
V1–N2
1.918(2)
2.314(2)
2.171(2)
106.4(1)
99.8(1)
155.9(1)
94.4(1)
156.8(1)
173.4(1)
82.8(2)
V1–O3
V1–N1
V1–O4A
O3–V1–O1
O3–V1–N1
O1–V1–N1
O4A–V1–N2
N1–V1–N2
O4–V1–O4A
N1–V1–O4
1.617(2)
2.164(2)
1.668(2)
100.7(1)
95.7(1)
84.9(1)
92.6(1)
76.0(1)
78.4(1)
78.8(1)
O3–V1–O4A
O4A–V1–O1
O4A–V1–N1
O3–V1–N2
O1–V1–N2
O3–V1–O4
O1–V1–O4
N2–V1–O4
Fig. 1. A perspective view of the molecular structure of 1 with the atom labeling
scheme. The thermal ellipsoids are drawn at the 30% probability level. Unlabeled
atoms are related to the symmetry position 1 ꢀ x, ꢀy, 1 ꢀ z.
80.6(1)
3
V1–O1
V1–O4
V1–N1
1.905(2)
1.608(2)
2.176(3)
107.1(1)
98.6(1)
92.7(1)
96.5(1)
84.9(1)
171.0(1)
84.1(1)
77.5(1)
V1–O3
V1–O3A
V1–N2
O4–V1–O1
O4–V1–N2
O1–V1–N2
O3A–V1–N1
N2–V1–N1
O3–V1–O3A
N2–V1–O3
2.349(2)
1.672(2)
2.135(3)
102.2(1)
92.2(1)
158.2(1)
154.6(1)
77.04(1)
77.94(1)
80.0(1)
O4–V1–O3A
O3A–V1–O1
O3A–V1–N2
O4–V1–N1
O1–V1–N1
O4–V1–O3
O1–V1–O3
N1–V1–O3
4
V1–O1
V1–O3
V1–N1
1.920(1)
1.671(1)
2.168(2)
107.0(1)
97.9(1)
93.4(1)
99.2(1)
84.8(1)
170.3(1)
85.8(1)
74.6(1)
V1–O2
V1–O3A
V1–N2
O2–V1–O1
O2–V1–N2
O1–V1–N2
O3–V1–N1
N2–V1–N1
O3–V1–O3A
N2–V1–O3A
1.611(2)
2.377(1)
2.151(2)
101.2(1)
93.0(1)
158.3(1)
152.5(1)
76.8(1)
O2–V1–O3
O3–V1–O1
O3–V1–N2
O2–V1–N1
O1–V1–N1
O2–V1–O3A
O1–V1–O3A
N1–V1–O3A
Fig. 2. A perspective view of the molecular structure of 2 with the atom labeling
scheme. The thermal ellipsoids are drawn at the 30% probability level. Unlabeled
atoms are related to the symmetry position ꢀx, 1 ꢀ y, 2 ꢀ z.
78.3(1)
78.5(1)
5
V1–O1
V1–O5
V1–N1
O5–V1–O6
O6–V1–O1
O6–V1–O3
O5–V1–N1
O1–V1–N1
1.827(2)
1.578(2)
2.094(2)
109.2(1)
99.7(1)
88.0(1)
99.9(1)
83.0(1)
V1–O3
V1–O6
1.945(2)
1.744(2)
O5–V1–O1
O5–V1–O3
O1–V1–O3
O6–V1–N1
O3–V1–N1
105.4(1)
102.5(1)
146.6(1)
148.7(1)
74.4(1)
6
V1–O1
V1–O4
V1–O5
1.840(3)
1.578(3)
2.374(3)
103.7(2)
101.6(2)
94.5(2)
96.9(2)
82.9(2)
176.0(2)
81.0(2)
79.2(1)
V1–O2
V1–O6
V1–N1
O4–V1–O1
O4–V1–O2
O1–V1–O2
O6–V1–N1
O2–V1–N1
O6–V1–O5
O2–V1–O5
1.959(3)
1.753(3)
2.129(3)
99.4(2)
97.9(2)
152.7(2)
157.7(2)
74.2(2)
80.0(2)
80.3(2)
O4–V1–O6
O6–V1–O1
O6–V1–O2
O4–V1–N1
O1–V1–N1
O4–V1–O5
O1–V1–O5
N1–V1–O5
Fig. 3. A perspective view of the molecular structure of 3 with the atom labeling
scheme. The thermal ellipsoids are drawn at the 30% probability level. Unlabeled
atoms are related to the symmetry position 1 ꢀ x, 1 ꢀ y, 1 ꢀ z.
and the methoxide O atom constitute the basal plane, and the
oxo O atom occupies the apical position. The displacement of the
V atom from the basal plane toward the apical oxo group is
0.476(1) Å. The extent of distortion of a square-pyramidal geome-
try toward a trigonal-bipyramidal geometry can be measured by
The molecular structure of the complex 5 is shown in Fig. 5. The
V atom is in a distorted square-pyramidal coordination. The phe-
nolate O, imine N, and enolic O atoms of the hydrazone ligand,

Z.-L. You et al. / Inorganica Chimica Acta 384 (2012) 54–61
59
is 0.323(1) Å. The coordinate bond lengths in the complex are com-
parable to those observed in the complexes 1–5 and those ob-
served in other similar complexes [33,34]. The distortion of the
octahedral coordination can be observed by the coordinate bond
angles, ranging from 74.2(2)° to 103.7(2)° for the perpendicular an-
gles, and from 152.7(2)° to 176.0(2)° for the diagonal angles.
3.2. IR spectra
The IR spectra of the ligands exhibit sharp bands in the region
3200–3250 cmꢀ1, which are assigned to the
m
(N–H) vibrations. The
middle absorption bands in the range 3350–3470 cmꢀ1 in the com-
plexes 1, 2, 5, and 6, are assigned to the (O–H) vibrations. The
(C@O) stretches in HL5 and HL6 and at 1653 and 1655 cmꢀ1, respec-
m
Fig. 4. A perspective view of the molecular structure of 4 with the atom labeling
scheme. The thermal ellipsoids are drawn at the 30% probability level. Unlabeled
atoms are related to the symmetry position 2 ꢀ x, ꢀy, ꢀz.
v
tively, which are absent in the complexes 5 and 6, consistent with
the enolisation of the amide functionalities and subsequent proton
replacement by the vanadium atoms. The bands appearing at 1273
and 1278 cmꢀ1 for 5 and 6, respectively, are assigned to the
m(C–
O)(enolic) vibrations. The strong absorption bands at 1640 cmꢀ1 in
1, 1638 cmꢀ1 in 2, 1635 cmꢀ1 in 3, 1649 cmꢀ1 in 4, 1638 cmꢀ1 in 5,
and 1641 cmꢀ1 in 6, respectively, are attributed to the
m(C@N) vibra-
tion [35]. The bands observed at 996 cmꢀ1 in 1, 970 cmꢀ1 in 2,
969 cmꢀ1 in 3, 956 cmꢀ1 in 4, 990 cmꢀ1 in 5, and 984 cmꢀ1 in 6,
respectively, are assigned to the m(V@O) stretches [34].
3.3. Pharmacology
The measurement of H. pylori urease inhibitory activity was car-
ried out for three parallel times. The inhibition rates (%) with the
Fig. 5. A perspective view of the molecular structure of 5 with the atom labeling
scheme. The thermal ellipsoids are drawn at the 30% probability level.
250
A
200
150
100
50
the value of
two larger coordinate bond angles [31]. For an ideal square-pyra-
midal geometry is 0 and for an ideal trigonal-bipyramidal geom-
etry is 1. The value of is 0.035. Thus, the coordination can be
defined as a slightly distorted octahedral geometry. The coordinate
bond lengths in the complex are comparable to those observed in
other similar oxovanadium complexes [32,33].
The molecular structure of complex 6 is shown in Fig. 6. The V
atom in the complex is in a distorted octahedral coordination. The
dianioinic tridentate ligand coordinates to the V atom through the
phenolate O, imine N, and enolic O atoms, forming a six- and a five-
membered chelate rings. The methoxide O atom is trans to the
imine N atom in the molecule. The O,N,O donor atoms of the
hydrazone ligand and the methoxide O atom define the equatorial
plane of the octahedron. The two axial positions are occupied by
one oxo O atom and one methanol O atom. The displacement of
the V atom towards the O4 donor atom from the equatorial plane
s
which is defined as (b ꢀ
a)/60°, where a and b are the
s
s
s
0
-0.025
-0.015
-0.005
0.005
0.015
0.025
-50
1/S (mM-1)
8000
B
7000
6000
5000
4000
3000
2000
1000
0
-100
-50
0
50
M
Fig. 7. Steady-state inhibiotion of urease by compound 6. (A) Lineweaver–Burk plot
of reciprocal of initial velocities vs. reciprocal of four urea concentrations in the
absence (h) and presence of 10 lM (j), 20 lM (N), and 40 lM (d) of the
compound. (B) Secondary plots of the Lineweaver–Burk plot, slope vs. various
concentrations of the compound.
Fig. 6. A perspective view of the molecular structure of 6 with the atom labeling
scheme. The thermal ellipsoids are drawn at the 30% probability level.

60
Z.-L. You et al. / Inorganica Chimica Acta 384 (2012) 54–61
concentration of 100
l
M for the complexes are 18.96 0.44 (1),
complexes 1, 2, and 3 form hydrophobic interactions with Ala169
and Ala365 of the urease; the complex 4 forms hydrophobic inter-
actions with Leu252 of the urease; the complexes 5 and 6 form
hydrophobic interactions with Ala365 of the urease. It is notable
that the docking score of 6 (ꢀ7.98) is lower than those of 1
(ꢀ2.79), 2 (ꢀ0.87), 3 (ꢀ0.66), 4 (ꢀ7.00), and 5 (ꢀ5.89). The result
of molecular docking study could explain the strong inhibitory
activity of 6 against urease.
33.01 1.80 (2), 35.83 0.78 (3), 48.09 1.23 (4), 45.91 2.09
(5), and 90.72 1.91 (6). The acetohydroxamic acid was used as a
reference [7] with the inhibition rate (%) of 87.30 3.35. It can be
seen that the chloro-substituted complexes have stronger activi-
ties against urease than the methoxy- or ethoxy-substituted com-
plexes. The trend is accord with those reported by Smee and co-
workers [36]. The IC50 value (17.35 1.01
lM) for 6 was deter-
mined since it has strong urease inhibitory activity, which is much
lower than the acetohydroxamic acid (46.27 0.73
much lower than the vanadyl sulfate (207.13 3.10
l
l
M), and also
M).
4. Conclusion
The Lineweaver–Burk plot (Fig. 7A) revealed that 6 is a mixed-
competitive inhibitor of urease. Double plot of the Lineweaver–
Burk plot (Fig. 7B) showed that the Ki value of the compound
This paper reports the synthesis, structures, and urease inhibi-
tory activities of a series of oxovanadium(V) complexes with Schiff
bases. The urease inhibitory activity of the complex 6 is superior to
those of the acetohydroxamic acid and the other complexes. The
kinetic studies reveal that the complex is a mixed-competitive
inhibitor of urease. Considering the oxovanadium complexes have
interesting biological activities and have been widely used in med-
icine [18–20,37,38], the complex 6 may be used in the treatment of
infection caused by the urease producing bacteria.
against urease was 99.99 lM.
3.4. Molecular docking study
Fig. 8 (complex 6) is a representative of the binding model of
the complexes in the enzyme active site of urease. The hydrogen
bonds among the complexes and the active sites of the urease were
listed in Table 4. For 1, there is one kind of hydrogen bond formed
by the hydroxy group with the O atom of Gln364. For 2, there are
two kinds of hydrogen bonds formed by the amino group with
the O atom of Asn168, and by the hydroxy group with the O atom
of Asp223. For 3 and 4, there are no hydrogen bonds. For 5, there is
one kind of hydrogen bond formed by the hydroxyl O atom of the
complex with the amino group of Agr338. For 6, there are three
kinds of hydrogen bonds formed by the hydroxyl O atom of the
complex with the amino group of Arg338, by the oxo O atom of
the complex with the amino group of His221, and by the hydroxy
group of the complex with the O atom of Asn168. In addition, the
Acknowledgements
This work was financially supported by the Natural Science
Foundation of China (Project No. 20901036), and by the Distin-
guished Young Scholars Program of Higher Education of Liaoning
Province (Grant No. LJQ2011114).
Appendix A. Supplementary material
CCDC 802003, 802004, 802007, 802008, 802005, and 802006
for compounds 1–6, respectively, contains the supplementary crys-
tallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ica.2011.11.039.
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