Synthesis, structures, and urease inhibitory activities of three copper(II) and zinc(II) complexes with 2-{[2-(2-hydroxyethylamino)ethylimino] methyl}-4-nitrophenol

Article abstract of DOI:10.1016/j.ejmech.2010.03.012

In order to explore novel urease inhibitors, three new mononuclear complexes of Cu(II) and Zn(II) with Schiff base 2-{[2-(2-hydroxyethylamino) ethylimino]methyl}-4-nitrophenol have been prepared and structurally characterized by X-ray crystallography. Amo

Full text of DOI:10.1016/j.ejmech.2010.03.012

European Journal of Medicinal Chemistry 45 (2010) 3196e3199
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, structures, and urease inhibitory activities of three copper(II)
and zinc(II) complexes with 2-{[2-(2-hydroxyethylamino)ethylimino]
methyl}-4-nitrophenol
,
a
b
b
Zhong-Lu You a , Li-Li Ni , Da-Hua Shi , Shun Bai
*
a Department of Chemistry and Chemical Engineering, Liaoning Normal University, Huanghe Road 850, 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
Article history:
In order to explore novel urease inhibitors, three new mononuclear complexes of Cu(II) and Zn(II) with
Schiff base 2-{[2-(2-hydroxyethylamino)ethylimino]methyl}-4-nitrophenol have been prepared and
structurally characterized by X-ray crystallography. Among the three complexes, two Cu(II) complexes
show strong urease inhibitory activities with the IC50 values being much lower than that of the aceto-
Received 8 May 2009
Received in revised form
4 March 2010
Accepted 10 March 2010
Available online 16 March 2010
hydroxamic acid, while the Zn(II) complex shows no activity at the concentration of 100 mM.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
Schiff base
Complex
Crystal structure
Urease inhibition
1. Introduction
methyl}-4-nitrophenol) were synthesized and structurally charac-
terized. The urease inhibitory activities of the complexes were
investigated.
Urease (urea amidohydrolase; E.C.3.5.1.5) is a nickel-containing
metalloenzyme that catalyzes the hydrolysis of urea to form
ammonia and carbamate [1,2]. The resulting carbamate spontane-
ously decomposes to yield a second molecule of ammonia and
carbon dioxide. High concentrations of ammonia arising from these
reactions, as well as the accompanying pH elevation, have impor-
tant negative implications in medicine and agriculture [3e6].
Control of the activity of urease through the use of inhibitors could
counteract these negative effects. In recent years, urease inhibitors
play an important role in the treatment of the infections caused by
urease producing bacteria [7]. Inhibitors of urease can be broadly
classified into two fields: (1) organic compounds, such as aceto-
hydroxamic acid, humic acid, and 1,4-benzoquinone [8e10];
(2) heavy metal ions, such as Cu2þ, Zn2þ, Pd2þ, and Cd2þ [11,12]. The
metal complexes as urease inhibitors have seldom been reported,
which indicates that the metal complexes of organotin(IV), vana-
dium(IV), bismuth(III), copper(II), and cadmium(II) bearing inter-
esting urease inhibitory activities [13e17]. In this paper, three
copper(II) and zinc(II) complexes, [CuLNO3] (1), [CuClL] (2), and [Zn
(CH3COO)L] (3) (HL ¼ 2-{[2-(2-hydroxyethylamino)ethylimino]
2. Results and discussion
2.1. Chemistry
HL was synthesized by the reaction of equimolar quantities of
5-nitrosalicylaldehyde with N-(2-hydroxyethyl)ethylenediamine in
a methanol solution (Scheme 1). All the complexes were synthe-
sized by the reaction of the methanol solutions of HL with the
corresponding metal salts (copper nitrate for 1, copper chloride for
2, and zinc acetate for 3; Scheme 2). The compounds have been
characterized by elemental analysis and IR spectra. Structures of
the complexes were further confirmed by X-ray crystallography
(CCDC e 730 768 for 1, 730 769 for 2, and 730 770 for 3).
2.2. Structure description of the complexes
X-ray crystallography reveals that the structures of the three
complexes are similar mononuclear compounds. In each complex,
the metal atom is in a square-pyramidal geometry, coordinated by
the four donor atoms of L at the basal plane, and with the apical
position occupied by the anion comes from the corresponding
* Corresponding author. Tel.: þ86 411 84216387.
E-mail address: youzhonglu@yahoo.com.cn (Z.-L. You).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.03.012

Z.-L. You et al. / European Journal of Medicinal Chemistry 45 (2010) 3196e3199
3197
H
N
O2N
CHO
O2N
H
N
N
OH
+
H2N
OH
OH
OH
HL
Scheme 1. Synthesis of HL.
metal salts, viz. nitrate for 1 (Fig. 1), chloride for 2 (Fig. 2), and
ꢀ
acetate for 3 (Fig. 3). The metal atoms deviate by 0.160(2) A in 1,
ꢀ
ꢀ
0.296(2) A in 2, and 0.642(2) A in 3, respectively, from the least-
squares plane defined by the four basal donor atoms. Close exam-
ination of the structures reveal that the CueO and CueN bond
lengths in 1 and 2 are comparable to each other, while the ZneO
and ZneN bond lengths in 3 are a little longer than the corre-
sponding values in 1 and 2. All the coordinate bond lengths can be
considered as normal by comparison with those reported in the
literatures. The crystals of the complexes are stabilized by hydrogen
bonds (Table 1).
2.3. Pharmacology
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.
The measurement of jack bean urease inhibitory activity was
carried out for three parallel times according to the literature
phenol-red method [18]. The results are summarized in Table 2.
Complexes 1 and 2 show strong urease inhibitory activity with the
IC50 values being much lower than that of the acetohydroxamic
acid coassayed as a standard urease inhibitor [7], while complex 3
shows no activity. The results in this paper are accordance with
those reported previously, that the zinc(II) complexes have much
weak urease inhibitory activities [19].
acetohydroxamic acid. Considering the copper(II) complexes have
interesting biological activities and have been widely used in
medicine [20e22], the two copper(II) complexes in this paper may
be used in the treatment of infections caused by urease producing
bacteria.
4. Experimental protocols
3. Conclusion
Starting materials, reagents and solvents were purchased from
commercial suppliers and purified before use. Elemental analyses
were performed on a PerkineElmer 240C elemental analyzer. The
IR spectra were recorded on a Jasco FT/IR-4000 spectrometer as KBr
pellets in the 4000e200 cme1 region. X-ray diffraction was carried
out at a Bruker SMART 1000 CCD area diffractometer equipped with
The present study reports the synthesis, structures and urease
inhibitory activities of three mononuclear copper(II) and zinc(II)
complexes with Schiff base HL. The urease inhibitory activities of
the copper(II) complexes are superior than that of the
MoKa radiation, and the structures were solved by direct methods
O2N
N
using SHELXTL 97 software [23]. The crystallographic data for the
complexes are summarized in Table 3. Selected bond lengths and
angles are given in Table 4.
Cu(NO3)2
NH
O
1
Cu
4.1. Synthesis of HL
O
OH
O2N
To the methanol solution (50 mL) of 5-nitrosalicylaldehyde
(1.0 mmol, 0.167 g) was added a methanol solution (30 mL) of
O2N
N
CuCl2
NH
O
2
HL
+
Cu
Zn
Cl
OH
O2N
N
Zn(CH3COO)2
NH
OH
O
3
O
MeOC
Fig. 2. A perspective view of the molecular structure of 2 with the atom labeling
Scheme 2. Synthesis of the complexes.
scheme. The thermal ellipsoids are drawn at the 30% probability level.

3198
Z.-L. You et al. / European Journal of Medicinal Chemistry 45 (2010) 3196e3199
Table 3
Crystallographic and experimental data for the complexes.
Complex
1
2
3
Formula
Mr
C11H14CuN4O7 C11H14ClCuN3O4
C13H17N3O6Zn
376.7
377.8
351.2
T (K)
298(2)
block/blue
0.27 ꢃ 0.25
ꢃ 0.25
Monoclinic
P21/c
8.256(1)
13.040(1)
13.409(1)
99.267(3)
1424.7(2)
4
298(2)
block/blue
0.34 ꢃ 0.32 ꢃ 0.32 0.32 ꢃ 0.32 ꢃ 0.27
298(2)
block/colorless
Crystal shape/color
Crystal size (mm3)
Crystal system
Space group
Monoclinic
P21/c
Monoclinic
P21/c
ꢀ
a (A)
11.834(2)
10.779(2)
11.011(2)
96.75(1)
1394.7(3)
4
11.875(3)
9.900(2)
14.309(5)
114.397(12)
1532.0(8)
4
ꢀ
b (A)
ꢀ
c (A)
b
(ꢀ)
3
ꢀ
V (A )
Z
D
c (g cme3
)
1.761
1.578
1.673
1.773
1.633
1.638
m
(Mo-K
a
) (mmꢁ1
)
F(000)
772
716
776
Data collected
Unique data
3073
2215
3017
2517
3441
2741
(I ꢄ 2
s(I))
Min. and max.
transmission
Parameters
Restraints
0.675 and
0.694
214
0.584 and 0.601
0.622 and 0.666
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.
187
2
1.025
215
2
1.046
0.0359, 0.0913
0.0478, 0.0977
2
Goodness-of-fit on F2 1.030
R1, wR2 [I ꢄ 2
s
(I)]a
0.0368, 0.0941 0.0302, 0.0816
0.0584, 0.1090 0.0380, 0.0871
Table 1
R1, wR2 (all data)a
ꢀ
ꢀ
Hydrogen bond distances (A) and bond angles ( ) for the complexes.
Large diff. peak
and hole (e A
0.603 and
ꢁ0.304
P
0.642 and ꢁ0.537 0.516 and ꢁ0.376
e3
ꢀ
)
DeH/A
d(DeH)
d(H/A)
d(D/A)
Angle (DeH/A)
P
a
1/2
R1 ¼ Fo ꢁ Fc/Fo, wR2
¼
[
w(Fo2 ꢁ Fc2)/ w(Fo2)2
]
1
N3eH3A/Oi7
N3eH3A/Oi6
O4eH4A/Ni4i
O4eH4A/Oi7i
2
0.90(2)
0.90(2)
0.85(2)
0.85(2)
2.64(4)
2.61(2)
2.65(2)
1.82(2)
3.118(4)
3.393(4)
3.442(4)
2.632(3)
114(3)
146(3)
156(4)
158(4)
for 30 min to give clear solutions. X-ray quality single crystals were
formed by slow evaporation of the solutions in air for a few days.
N3eH3A/Cl1iii
O4eH4A/Cl1iv
3
0.90(2)
0.85(2)
2.68(2)
2.22(2)
3.365(2)
3.061(2)
134(2)
173(3)
4.2.1. 2-{[2-(2-Hydroxyethylamino)ethylimino]methyl}-4-
nitrophenolatonitratocopper(II) (1)
N3eH3A/O6v
O4eH4A/O5vi
0.90(2)
0.85(2)
2.54(3)
1.783(5)
3.237(3)
2.595(3)
136(3)
159(4)
Blue single crystals. Yield: 73%. Characteristic IR data (cme1):
3434 (w), 3231 (w), 1653 (s), 1605 (s), 1550 (s), 1376 (s), 1308 (s),
Symmetry codes: (i) 1 e x, 2 e y, e z; (ii) x, 3/2 e y, 1/2 þ z; (iii) 1 e x, e y, 1 e z; (iv) 1 x,
1/2 e y, ꢁ1/2 þ z; (v) 2 e x, ꢁ1/2 þ y, 1/2 e z; (vi) 2 e x, 1/2 þ y, 1/2 e z.
Table 4
N-(2-hydroxyethyl)ethylenediamine (1.0 mmol, 0.104 g) with stir-
ring. The mixture was stirred for 30 min at room temperature to give
a yellow solution. The solvent was evaporated to give yellow powder,
which was washed with cold methanol and dried in air. Yield: 91%.
Characteristic IR data (cme1): 3351 (m), 3233 (w), 1635 (s), 1356 (s),
1513 (s). Anal. calcd. for C11H15N3O4: C, 52.2; H, 6.0; N, 16.6; Found C,
51.8; H 6.1; N 16.8%.
ꢀ
ꢀ
Selected bond lengths (A) and angles ( ) for the complexes.
1
Cu1eO3
Cu1eO5
Cu1eN3
O3eCu1eN2
N2eCu1eN3
N2eCu1eO4
O3eCu1eO5
N3eCu1eO5
2
1.888(2)
2.424(2)
1.986(2)
94.09(9)
85.1(1)
165.2(1)
90.9(1)
97.6(1)
Cu1eO4
Cu1eN2
2.005(2)
1.929(2)
O3eCu1eN3
O3eCu1eO4
N3eCu1eO4
N2eCu1eO5
O4eCu1eO5
171.5(1)
95.7(1)
83.6(1)
93.3(1)
97.6(1)
4.2. Synthesis of the complexes
Cu1eO3
Cu1eN2
Cu1eCl1
O3eCu1eN2
N2eCu1eN3
N2eCu1eO4
O3eCu1eCl1
N3eCu1eCl1
3
1.913(2)
1.935(2)
2.574(1)
93.8(1)
Cu1eO4
Cu1eN3
2.014(2)
2.013(2)
A methanol solution (10 mL) of HL (0.1 mmol, 25.3 mg) was added
with stirring to a methanol solution (10 mL) of the corresponding
metal salt (0.1 mmol), viz. copper nitrate for 1, copper chloride for 2,
and zinc acetate for 3. The mixtures were stirred at room temperature
O3eCu1eN3
O3eCu1eO4
N3eCu1eO4
N2eCu1eCl1
O4eCu1eCl1
167.3(1)
94.7(1)
82.0(1)
98.4(1)
102.2(1)
84.8(1)
155.4(1)
102.6(1)
90.1(1)
Table 2
Inhibition of urease by the tested materials.
Zn1eO3
Zn1eO6
Zn1eN3
O6eZn1eO3
O3eZn1eN2
O3eZn1eO4
O6eZn1eN3
N2eZn1eN3
2.003(2)
1.950(2)
2.161(2)
98.0(1)
88.3(1)
90.6(1)
110.7(1)
81.4(1)
Zn1eO4
Zn1eN2
2.082(2)
2.051(2)
Tested materials
IC50(mM)
1
2
3
HL
22.40 ꢂ 0.08
24.25 ꢂ 0.05
O6eZn1eN2
O6eZn1eO4
N2eZn1eO4
O3eZn1eN3
O4eZn1eN3
122.8(1)
101.3(1)
135.6(1)
150.7(1)
78.4(1)
>100
>100
45.32 ꢂ 0.27
Acetohydroxamic acid

Z.-L. You et al. / European Journal of Medicinal Chemistry 45 (2010) 3196e3199
3199
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Blue single crystals. Yield: 71%. Characteristic IR data (cme1):
3446 (w), 3220 (w), 1660 (s), 1601 (s), 1551 (m), 1397 (m), 1312 (vs),
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Colorless single crystals. Yield: 90%. Characteristic IR data
(cme1): 3436 (w), 3316 (w), 1653 (s), 1604 (s), 1550 (m), 1492 (m),
1390 (m), 1313 (vs), 1103 (m). Anal. calcd. for C13H17N3O6Zn: C, 41.5;
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This work was financially supported by the National Science
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