Syntheses, crystal structures, and Urease inhibitory activity of two zinc complexes with 2-[(3-Cyclohexylaminopropylimino)methyl]-6-alkoxyphenol

Article abstract of DOI:10.1080/15533174.2010.522645

Two new Schiff base zinc(II) complexes, [ZnL1IN₃] (1) and [ZnL2(N₃)₃] (2) (L1 = 2-[(3-cyclohexylaminopropylimino) methyl]-6-ethoxyphenol, L2 = 2-[(3-cyclohexylaminopropylimino)methyl]-6- methoxyphenol), were prepared and structural characterized by elemental analyses, infrared spectroscopy, and single-crystal X-ray diffraction. Both complexes are mononuclear zinc(II) compounds. The Zn atom in each complex is four-coordinated in a tetrahedral geometry. Both complexes show urease inhibitory activities. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15533174.2010.522645

Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 40:831–835, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2010.522645
Syntheses, Crystal Structures, and Urease
Inhibitory Activity of Two Zinc Complexes with
2-[(3-Cyclohexylaminopropylimino)methyl]-6-alkoxyphenol
Chen-Yi Wang, Zhi-Ping Han, Jin-Yun Ye, and Xiang Wu
Department of Chemistry, Huzhou University, Huzhou, P. R. China
6-methoxyphenol, respectively, were prepared and structural
characterized. The urease inhibitory activities of the complexes
were determined.
Two new Schiff base zinc(II) complexes, [ZnL1IN3] (1) and
[ZnL2(N3)2] (2) (L1 = 2-[(3-cyclohexylaminopropylimino)methyl]-
6-ethoxyphenol, L2 = 2-[(3-cyclohexylaminopropylimino)methyl]-
6-methoxyphenol), were prepared and structural characterized by
elemental analyses, infrared spectroscopy, and single-crystal X-ray
diffraction. Both complexes are mononuclear zinc(II) compounds.
The Zn atom in each complex is four-coordinated in a tetrahedral
geometry. Both complexes show urease inhibitory activities.
EXPERIMENTAL
Materials and Methods
All chemicals and reagents used for the preparation of the lig-
ands and the complexes were commercial products (Lancaster)
and were used without further purification. Jack bean urease was
obtained from Sigma-Aldrich Co. (St. Louis, MO, USA). C, H
and N analyses were performed with a Perkin-Elmer 2400 se-
ries II analyzer. The infrared spectra (KBr pellet) were recorded
Keywords crystal structure, urease inhibition, Schiff base, synthesis,
zinc
INTRODUCTION
Ureases are an important class of enzymes involved in the
degradative processing of urea.[1–3] They are ubiquitous in na-
ture and are directly associated with the formation of infec-
tion stones and contribute to the pathogenesis of pyelonephri-
tis, urolithiasis, ammonia encephalopathy, hepatic coma and
urinary catheter encrustation. High concentration of ammo-
nia arising from these reactions, as well as the accompany-
ing pH elevation, have important implications in medicine and
agriculture.[4,5] Therefore, urease inhibitors have recently at-
tracted much attention as potential new anti-ulcer drugs. A
recent research indicated that the Schiff base complexes had
potent urease inhibitory activity.[6] Zinc complexes with Schiff
bases have attracted much attention in coordination chemistry
and bioinorganic chemistry due to their versatile structures and
interesting biological properties.[7–12] In this paper, two new
zinc(II) complexes, [ZnL1IN3] (1) and [ZnL2(N3)2] (2), where
L1 and L2 are 2-[(3-cyclohexylaminopropylimino)methyl]-6-
ethoxyphenol and 2-[(3-cyclohexylaminopropylimino)methyl]-
using a FTS165 Bio-Rad FTIR spectrophotometer in the range
–1
4000–400 cm
.
Synthesis of L1 and L2
The Schiff bases L1 and L2 were prepared according to the
literature method.[13] Anal. calcd for C18H28N2O2 (L1, %): C,
71.0; H, 9.3; N, 9.2. Found: C, 70.7; H, 9.3; N, 9.3. Anal. Calcd
for C17H26N2O2 (L2, %): C, 70.3; H, 9.0; N, 9.6. Found: C,
70.5; H, 9.2; N, 9.5.
Synthesis of (1)
To a methanol solution (10 ml) of L1 (0.1 mmol, 30.4 mg)
and sodium azide (0.1 mmol, 6.5 mg) was added with stirring
a methanol solution (5 ml) of ZnI2 (0.1 mmol, 31.9 mg). The
mixture was stirred for 30 min at room temperature and filtered.
Upon keeping the filtrate in air for a few days, colorless block-
shaped crystals of (1), suitable for X-ray single-crystal diffrac-
tion, were formed at the bottom of the vessel. The crystals were
collected by filtration, washed three times with cold methanol
and dried in air. Yield: 45%. Anal. calcd for C17H26N8O2Zn
(%): C, 46.4; H, 6.0; N, 25.5. Found: C, 46.0; H, 6.2; N, 25.2.
Received 15 July 2009; accepted 4 August 2010.
This work was financially supported by the Natural Science Foun-
dation of China (No. 31071856), the Natural Science Foundation of
Zhejiang Province (No. Y407318), and the Applied Research Project
on Nonprofit Technology of Zhejiang Province (No. 2010C32060).
Address correspondence to Chen-Yi Wang, Department of Chem-
istry, Huzhou University, Huzhou 313000, P. R. China. E-mail:
chenyi wang@163.com
Synthesis of (2)
To a methanol solution (10 ml) of L2 (0.1 mmol, 29.0 mg)
and sodium azide (0.1 mmol, 6.5 mg) was added with stirring
831

832
C.-Y. WANG ET AL.
TABLE 1
Crystal data for (1) and (2)
TABLE 2
◦
˚
Selected bond lengths (A) and bond angles ( ) for (1) and (2)
Complex
(1)
(2)
(1)
Formula
Fw
Crystal shape/colour
Crystal size (mm3)
Crystal system
C17H26N8O2Zn
439.8
block/colorless
C18H28IN5O2Zn
538.7
block/colorless
Bond lengths
Zn1–O1
Zn1–N3
1.927(3)
1.983(5)
Zn1–N1
Zn1–N6
1.982(4)
1.967(4)
0.28 × 0.27 × 0.27 0.32 × 0.30 × 0.27 Bond angles
Monoclinic
P21/c
Monoclinic
P 21/n
O1–Zn1–N6
N6–Zn1–N1
N6–Zn1–N3
110.0(2)
119.3(2)
107.3(2)
O1–Zn1–N1
O1–Zn1–N3
N1–Zn1–N3
97.1(2)
114.7(2)
108.5(2)
Space group
˚
a (A)
11.045(2)
13.129(2)
16.644(2)
120.94(1)
2070.2(5)
4
0.71073
298(2)
1.216
12.434(3)
12.755(3)
14.464(3)
103.49(3)
2230.6(8)
4
0.71073
298(2)
2.506
˚
(2)
b (A)
˚
Bond lengths
Zn1–O1
Zn1–N3
Bond angles
O1–Zn1–N3
N3–Zn1–N1
N3–Zn1–I1
c (A)
β (◦)
V (A )
1.948(4)
1.975(5)
Zn1–N1
Zn1–I1
1.998(4)
2.5734(9)
3
˚
Z
111.3(2)
112.5(2)
108.3(2)
O1–Zn1–N1
O1–Zn1–I1
N1–Zn1–I1
96.3(2)
116.5(2)
111.6(2)
˚
λ (Mo-Kα) (A)
T (K)
µ (Mo-Kα) (mm
Tmin
–1
)
0.727
0.501
Tmax
0.735
0.551
Reflections collected
Data/restraint
/parameters
12302
4489/0/254
13402
5004/0/245
connecting atoms. The crystallographic data for the complexes
are summarized in Table 1. Selected bond lengths and angles
are listed in Table 2. Hydrogen bonds are listed in Table 3.
Rint
Goodness of fit on F2
0.0425
1.058
0.0488
1.028
0.0563, 0.1351
0.0992, 0.1549
ꢀ
R1, wR2 [I ≥ 2σ(I)]a 0.0554, 0.1503
R1, wR2 (all data)a
0.0930, 0.1716
Measurement of Urease
The assay mixture, containing 25 µL (4U) of jack bean urease
and 25 µL (100 µg) of the test compound, was preincubated
for 0.5 or 3 h at room temperature in a 96-well assay plate.
After preincubation, 0.2 mL of 100 mM phosphate buffer pH 6.8
containing 500 mM urea and 0.002% phenol red were added and
incubated at room temperature. The reaction time was measured
by micro plate reader (570 nm), which was required for enough
ammonium carbonate to form to raise the pH of a phosphate
buffer from 6.8 to 7.7.[17] The results are listed in Table 4.
ꢀ
ꢀ
aR1
w(Fo2)2]1/2
=
||Fo| – |Fc|| /
|Fo|, wR2 = [ w(Fo2– Fc2)2/
ꢀ
a methanol solution (5 ml) of Zn(CH3OO)2·2H2O (0.1 mmol,
22.0 mg). The mixture was stirred for 30 min at room tem-
perature and filtered. Upon keeping the filtrate in air for a few
days, colorless block-shaped crystals of (2), suitable for X-ray
single-crystal diffraction, were formed at the bottom of the ves-
sel. The crystals were collected by filtration, washed three times
with cold methanol and dried in air. Yield: 37%. Anal. calcd for
C18H28IN5O2Zn (%): C, 40.1; H, 5.2; N, 13.0. Found: C, 40.5;
H, 5.3; N, 12.8.
TABLE 3
◦
˚
Distances (A) and angles ( ) involving hydrogen bonding of
the complexes
X-ray Crystallography
. . .
D–H
. . .
. . .
. . .
A
d(D–H) d(H A) d(D A) Angle(D–H A)
Suitable single crystals were mounted on glass-fibers. The
diffraction experiments were carried out on a Bruker AXS
SMART CCD diffractometer. The program SMART[14] was
used for collecting frames of data, indexing reflections and de-
termination of lattice parameters, SAINT[14] for integration of
the intensity of reflections and scaling, SADABS[15] for absorp-
tion correction, and SHELXTL[16] for space group and structure
determination and least-squares refinements on F2. All non-
hydrogen atoms were refined anisotropically. Hydrogen atoms
were placed at idealized positions and allowed to ride on the
(1)
. . .
. . .
. . .
N2–H2A O1 0.90
N2–H2A O2 0.90
N2–H2B N8 0.90
1.91
2.34
2.04
2.762(4)
2.978(4)
2.921(6)
157(5)
128(5)
167(5)
(2)
. . .
. . .
N2–H2A N5 0.90
2.18
2.02
2.25
2.990(7)
2.801(6)
3.003(6)
149(5)
145(5)
140(5)
N2–H2B O1 0.90
. . .
N2–H2B O2 0.90

SYNTHESES AND UREASE INHIBITORY ACTIVITY
833
TABLE 4
Inhibitory activities against urease
Tested materials
IC50 (µM)
(1)
(2)
L1
72.31 0.31
56.05 0.82
>100
L2
>100
ZnI2
>100
Acetohydroxamic acid
45.37 0.31
RESULTS AND DISCUSSION
Synthesis and Characterization
FIG. 1. The structure of (1), showing the atom-numbering scheme. Displace-
ment ellipsoids are drawn at the 30% probability level.
The two Schiff base ligands were readily synthesized via
Schiff base condensation using equimolar quantities of N-
cyclohexylpropane-1,3-diamine with 3-ethoxysalicylaldehyde
and 3-methoxysalicylaldehyde, respectively. The complex (1)
was synthesized by mixing equimolar quantities of L1, NaN3
and ZnI2 in methanol, yielding an iodide and azide-coordinated
tetrahedral zinc(II) complex. The complex (2) was synthesized
by a similar procedure as that described for (1), but with L1 re-
placed by L2, and with ZnI2 replaced by Zn(CH3COO)2·2H2O,
yielding an azide-coordinated tetrahedral zinc(II) complex. It
can be seen that the coordinate ability of the iodide anion is
superior to that of the acetate anion.
In the crystal structure of (1), molecules are linked through
intermolecular N–H· · ·N and N–H· · ·O hydrogen bonds, form-
ing a network (Figure 3). In the crystal structure of (2),
molecules are linked through intermolecular N–H· · ·N and N–
H· · ·O hydrogen bonds, forming layers along the bc direction
(Figure 4).
Urease Inhibitory Activities
From Table 4, it can be seen that both complexes showed
weak urease inhibitory activities with the IC50 values of 72.31
µM for (1) and 56.05 µM for (2), respectively, which are
larger than that of the acetohydroxamic acid coassayed as
a standard reference against the urease. It is notable that
both complexes possess stronger urease inhibitory properties
than the corresponding Schiff bases and the zinc iodide, but
weaker than those of the copper(II) complexes we reported
previously.[6,22]
In the infrared spectra of the Schiff bases L1 and L2, the weak
–1
and broad absorption bands in the region 3280–3400 cm are
assigned to the stretching vibration of the O–H bonds, which
absent in the complexes. The strong absorption bands at 1637
–1
cm for L1 and L2 are assigned to the azomethine groups,
ν(C=N),[18] which are shifted to lower frequencies in the com-
–1
–1
plexes (1623 cm for (1) and 1621 cm for (2)). The strong
absorption of the azide groups in both complexes is at about
–1
2035 cm
.
Structure Description of (1) and (2)
Figures 1 and 2 give perspective views of the complexes
(1) and (2), respectively. In both complexes, the Zn atom is
four-coordinated and is best described as having a tetrahedral
geometry. Both Schiff bases chelate to the Zn atoms in biden-
tate fashion employing the phenolate O and imine N atoms.
The other two positions are occupied by coordinated I atom and
N atoms from the azide groups. The coordinate bond angles,
ranging from 97.1(2) to 119.3(2)◦ for (1) and from 96.3(2) to
116.5(2)◦ for (2), support the slightly distorted tetrahedral ge-
ometries. The coordinate bond lengths of (1) and (2) are similar
to each other (Table 2), and comparable with the values observed
in other similar zinc(II) complexes with Schiff bases.[13,19–21]
As expected, the cyclohexyl rings in the complexes adopt chair
conformations.
FIG. 2. The structure of (2), showing the atom-numbering scheme. Displace-
ment ellipsoids are drawn at the 30% probability level.

834
C.-Y. WANG ET AL.
CONCLUSION
Two Schiff base zinc(II) complexes with azide and iodide
co-ligands have been synthesized according to the standard pro-
cedure, and their structures were characterized by X-ray crystal-
lography. Both complexes showed moderate urease inhibitory
activities.
SUPPLEMENTARY MATERIALS
CCDC–739929 and 739930 contain the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge at www.ccdc.cam.ac.uk/conts/retrieving.html, or from
the Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: +44-1223-336-033; E-mail:
deposit@ccdc.cam.ac.uk.
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