Synthesis, structures and urease inhibition studies of Schiff base metal complexes derived from 3,5-dibromosalicylaldehyde

Article abstract of DOI:10.1016/j.ejmech.2012.09.037

Eleven mononuclear copper(II), nickel(II), zinc(II) and cobalt(II) complexes of Schiff base ligands derived from 3,5-dibromosalicylaldehyde/3,5- dichlorosalicylaldehyde were synthesized and determined by single crystal X-ray analysis. The crystal structures of complexes 1, 2, 4, 5, 6, 8 and 11 present the square-planar coordination geometry at the metal center and complexes 7, 9 and 10 show the distorted tetrahedral geometry. While one copper center in 3 has a square-planar geometry, the other copper is slightly distorted square-planar. The inhibitory activities of all the obtained complexes were tested in vitro against jack bean urease. It was found that Schiff base copper(II) complexes 1, 3, 5, 8 and 11 showed strong urease inhibitory activities (IC₅₀ = 1.51-3.52 μM) compared with acetohydroxamic acid (IC₅₀ = 62.52 μM), which was a positive reference. Their structure-activity relationships were further discussed.

Full text of DOI:10.1016/j.ejmech.2012.09.037

European Journal of Medicinal Chemistry 58 (2012) 323e331
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, structures and urease inhibition studies of Schiff base metal complexes
derived from 3,5-dibromosalicylaldehyde
*
*
Yongming Cui, Xiongwei Dong, Yuguang Li , Zuowen Li, Wu Chen
Engineering Research Center for Clean Production of Textile Printing, Ministry of Education, Wuhan Textile University, Wuhan 430073, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Eleven mononuclear copper(II), nickel(II), zinc(II) and cobalt(II) complexes of Schiff base ligands derived
from 3,5-dibromosalicylaldehyde/3,5-dichlorosalicylaldehyde were synthesized and determined by
single crystal X-ray analysis. The crystal structures of complexes 1, 2, 4, 5, 6, 8 and 11 present the square-
planar coordination geometry at the metal center and complexes 7, 9 and 10 show the distorted tetra-
hedral geometry. While one copper center in 3 has a square-planar geometry, the other copper is slightly
distorted square-planar. The inhibitory activities of all the obtained complexes were tested in vitro
against jack bean urease. It was found that Schiff base copper(II) complexes 1, 3, 5, 8 and 11 showed
Received 13 May 2012
Received in revised form
22 August 2012
Accepted 10 September 2012
Available online 3 October 2012
Keywords:
strong urease inhibitory activities (IC50
¼
1.51e3.52 mM) compared with acetohydroxamic acid
Transition metal complexes
Schiff base ligands
X-ray structure
(IC50 ¼ 62.52
m
M), which was a positive reference. Their structureeactivity relationships were further
discussed.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Urease inhibitors
Molecular docking
1. Introduction
copper(II) complexes with tetradentate thiolate Schiff base ligands
(N2S2) has been reported to depend on the backbone flexibility and as
Transition metal complexes of Schiff-bases derived from salicy-
laldehyde and its derivatives have become the hot topics of contem-
porary research because of their promising use foreground [1]. For
example, acting as single-molecule magnets (SMMs) [2], as lumi-
nescent probes [3], as catalysts for specific DNA [4] and RNA [5]
cleavage reactions. Salen-type Schiff-base may act as a bidentate
N,O- [6] and a tridentate N,O,O-donor ligand [7], and so on, to yield
mono-, bi-, dimer, 1D, 2D, 3D complexes [8] together with other
coordinating moieties such as azide ion, thiocyanate and carboxylic
group. Among them, bis-bidentate Schiff base copper(II) complexes
derived from the condensation of salicyladehyde and its derivatives
with various primary amines have attracted considerable interest
because in the solid state they display a wide range of stereo-
chemistries going from square planar to pseudo-tetrahedral [9]. It
hasbeenproposedthattheextentofdistortionfromthesquareplanar
geometry in those molecules results from the volume of the substit-
uent at the coordinating nitrogen [10], sometimes electronic effects
[11], and crystal packing forces in some cases [12]. For example,
pseudo-tetrahedral distortion in the solid state structures of some
the backbone becomes more flexible, distortion grows [13].
Urease (urea amidohydrolase; EC 3.5.1.5) is a nickel-dependent
metalloenzyme that rapidly catalyses the hydrolysis of urea to
form ammonia and carbamate [14]. Many microorganisms utilize
urea as a source of nitrogen for augmentation. Urease plays an
important role in nitrogen metabolism of plant during the germi-
nation process [15]. The reaction catalyzed by urease may cause
a pH increase and an accumulation of ammonia, which has
important implications in medicine and agriculture. In the past
decades some urease inhibitors have been reported such as
hydroxamic acid derivatives, phosphorodiamidates, and imidazoles
[16]. Some of urease inhibitors cannot be used in vivo because of
their toxicity or instability. Thus, it is interesting to seek novel
urease inhibitors with good bioavailability and low toxicity.
Recently, some d-transition metal complexes (M ¼ Cu, Co, Ni,
etc.) of such Schiff-bases with the potent inhibitory activities
against urease were also reported by us [17]. In this paper, we
synthesized some new Schiff base metal complexes with a mono-
nuclear metal center, and investigated their inhibitory activities
against jack bean urease. Docking simulation using AUTODOCK was
performed to position these complexes into the active site of jack
bean urease to determine the probable binding conformation [18].
* Corresponding authors. Tel./fax: þ86 27 8761 1776.
E-mail addresses: liyg2010@wtu.edu.cn (Y. Li), cym981248@163.com (W. Chen).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.09.037

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Y. Cui et al. / European Journal of Medicinal Chemistry 58 (2012) 323e331
2. Results and discussion
2.1. Synthesis
All the complexes were prepared from reactions of 3,5-
dibromosalicylaldehyde or 3,5-dichlorosalicylaldehyde with primary
amines and the corresponding metal salts (Scheme 1). The obtained
complexes were microcrystalline solids which were stable in air and
had melting points above 200 ꢀC. They were soluble in organic
solvents such as methanol, DMF and DMSO. All the central metal
atoms in the complexes 1e11 were four-coordinated by the oxygen
and nitrogen donor atoms of two Schiff base ligands. The elemental
analysis was in good agreement with the chemical formula proposed
for complexes 1e11.
2.2. IR analysis
Fig. 1. Ball-and-stick representation of the crystal structure of 1, atoms are shown as
sphere of arbitrary diameter.
The Schiff base metal complexes 1e11 were characterized by
single crystal X-ray diffraction, FTIR spectroscopy and elemental
analysis. The IR spectra of these complexes exhibit strong absorption
at 1626e1603 cmꢁ1, assignable to the v(C]N) absorption [19]. The
C]N groups in the complexes 1e11 show strong absorption at 1620,
reveals that these complexes are the mononuclear metal struc-
tures. Complexes 1, 6, 7 and 11 crystallize in the monoclinic space
group C2/c and P21/c, while the other complexes crystallize in the
triclinic space group P-1. The metal coordination environments of
these complexes are similar, where the metal ion is four-
coordinated by two imine N atoms and two phenolic O atoms
from two Schiff base ligands (L) in a trans position. Here, the Schiff
base ligands HL1e6 derived from 3,5-dibromosalicylaldehyde and
3,5-dichlorosalicylaldehyde act as the bidentate N,O-donor ligands
(Scheme 1). Crystal structures of complexes 2, 3, 4, 9 and 10
contain two independent mononuclear metal molecules in the
asymmetric unit. There is a small but definite distortion of the
N2O2 coordination sphere around the metal center from square-
planar to tetrahedral.
All bond lengths and angles in the structure are similar to those
observed in bis(salicylaldiminato) copper(II) and nickel(II)
complexes (Table 1). An unusual feature of the structure is the
distortion of the cobalt(II) and zinc(II) coordination sphere. As
shown in Figs. 7, 9 and 10, the cobalt(II) and zinc(II) atoms are in
a distorted tetrahedral geometry and each one is four-coordinated
by two N atoms and two O atoms from two Schiff base ligands.
1616, 1621, 1615, 1619, 1614, 1626, 1618, 1616, 1603, 1625 cmꢁ1
,
respectively. Duetotheimpactofmetalatoms, theamino-absorption
peaksoftheSchiffbase ligandsshifttolowerwavenumber. However,
the C]N stretching band is significantly lower in comparison to that
of the corresponding vibration in cobalt complex 10 at 1603 cmꢁ1. In
addition, the appearances of the broad strong absorption between
1516 and 1505 cmꢁ1 couldbereasonablyattributedtothepresenceof
the benzene ring C]C backbone stretching vibration absorption
peak. Several weak bands observed in the range 3000e2800 cmꢁ1
are most likely due to the aromatic CeH groups. These Schiff base
metal complexes were confirmed by the additional weak bands in
the regions 484e430 cmꢁ1 and 542e513 cmꢁ1 which were attrib-
uted to n(MeO) and n(MeN), respectively [20].
2.3. Crystal structure description
Molecular structures of Schiff base metal complexes 1e11 are
shown in Fig. 1e11, respectively. Single crystal X-ray diffraction
R2
X
R1
H
CH R1
X
X
CH
X
R1
O
N
O
N
R2
.
Methanol
r.t.
M(NO3)2 xH2O
M
R2
H2N CH
+
N
OH
OH
O
X
R1
CH
Complexes 1-11
X
X
HL1-5 (X = Br); HL6 (X = Cl)
X
R2
HL1
HL2
H
HL3
HL4
H
HL5
CH3
HL6
CH3
CH3
R1 =
H
H
R2 =
M =
CH2CH2CH3
CH(CH3)2
CH2CH3
CH2CH2Br CH3
Cu (1); Ni (2)
Cu (3); Ni (4) Cu (5); Ni(6); Cu (8)
Zn (7)
Zn (9);
Co (10)
Cu (11)
Scheme 1. General structure of the Schiff base ligands HL1e6 and complexes 1e11.

Y. Cui et al. / European Journal of Medicinal Chemistry 58 (2012) 323e331
325
Fig. 2. Ball-and-stick representation of the crystal structure of 2 (symmetry codes:
a: ꢁx, 1 ꢁ y, 1 ꢁ z; b: 1 ꢁ x, 2 ꢁ y, 1 ꢁ z), atoms are shown as sphere of arbitrary
diameter.
Fig. 4. Ball-and-stick representation of the crystal structure of 4 (symmetry codes:
a: ꢁx, ꢁy, ꢁz; b: ꢁ1 þ x, ꢁ1 þ y, z), atoms are shown as sphere of arbitrary diameter.
tetrahedral than planar. The bite angles O1eZn1eO1# (123.4(3)ꢀ),
N1eZn1eO1 (114.2(3)ꢀ), N1eZn1eO1# (95.1(3)ꢀ) and N1eZn1e
N1# (116.6(3)ꢀ) in 7 and the bite angles O1eZn1eO2 (114.5(3)ꢀ),
N1eZn1eO1 (96.8(3)ꢀ), N1eZn1eO2 (110.3(3)ꢀ), N2eZn1eO1
(108.9(3)ꢀ), N2eZn1eO2 (95.3(3)ꢀ) and N1eZn1eN2 (131.8(3)ꢀ)
(the bite angles of NeZn2eO are similar) in 9 also support the
distortion from the tetrahedral geometry.
In each copper(II) and nickel(II) complex molecule, the metal ion
occupies the center site of the basal plane by two bidentate
chelating ligands. Both nitrogen atom and oxygen atom are at
special positions on the perpendicular axes, and the point of
intersection of coordinate axes is a metal ion. The trans-[OeMeO#]
and trans-[NeMeN#] (M ¼ Cu, Ni) angles are within 177.3(3)e
ꢀ
ꢀ
180(3) . The CueN(imine) (1.973(4)e2.027(3) A) and the Cue
As shown in Fig. 10, the cobalt(II) atom in complex 10 is in
a distorted tetrahedral geometry and is four-coordinated by two N
atoms and two O atoms from two Schiff base ligands. The average
ꢀ
O(phenolic) (1.892(3)e1.915(4) A) bond lengths are comparable
with the bond lengths observed for copper(II) compound [21]. The
bond distances of NieN(imine) and NieO(phenolic) and the
chelating bite angles are slightly different with that of copper(II)
complexes, which are comparable with the corresponding values
reported for analogous square planar Ni(II) species [22]. In all of the
copper(II) and nickel(II) complex structures, the MN2O2 basal plane
is exactly planar. The dihedral angle between the planes defined by
M/N1/O1 and M/N1#/O1# is nearly 0ꢀ. These values indicate
a coplanar quadrilateral geometry of the N2O2 basal plane around
the metal center.
ꢀ
bond distances of Co1eO and Co1eN are 1.900(4) and 1.988(4) A,
ꢀ
while that of Co2eO and Co2eN are 1.912(4) and 1.993(4) A,
respectively. The angles subtended at the Co(II) ion of the distorted-
tetrahedral geometry (CoN2O2) is in the range 95.0(2)e129.4(2)ꢀ.
The angle between two six-membered chelating planes was
79.7(2)ꢀ.
2.4. Inhibitory activity against jack bean urease
The molecular structures of Schiff base zinc(II) complexes 7 and
9 are depicted in Figs. 7 and 9, and representative bond length and
angle values are collected in Table 1. The zinc atom is coordinated to
two imine nitrogen and two phenolic oxygen atoms of the Schiff
The abilities of complexes 1e11 to inhibit urease were deter-
mined by obtaining their IC50 values against jack bean urease (see
Table 2). Generally, heavy metal ions are believed to inhibit the
urease by binding to the sulfhydryl groups of cysteines, and
possibly nitrogen e (histidine) and oxygen e (aspartic and gluta-
mic acids) in the urease active site [23]. Metal ions as enzyme
base ligands. The dihedral angle
N1 and Zn1/O1#/C2#/C1#/C6#/N1# planes in 7 is 87.7(3)ꢀ, whereas
the dihedral angles between the Zn1/O1/C2/C1/C7/N1 and Zn1/
q between the Zn1/O1/C2/C1/C6/
q
O2/C12/C11/C17/N2 planes, the Zn2/O3/C22/C21/C27/N3 and Zn2/
O4/C32/C31/C37/N4 planes in 9 are 80.4(3)ꢀ and 83.9(3)ꢀ, respec-
tively. For a planar (local D2h) geometry
pseudo-tetrahedral (local D2d) geometry
q
would be 0ꢀ, and for
q
would be 90ꢀ; the metal
ion is therefore in a geometry that is much closer to pseudo-
Fig. 3. Ball-and-stick representation of the crystal structure of 3 (symmetry codes:
a: ꢁx, 1 ꢁ y, 1 ꢁ z), atoms are shown as sphere of arbitrary diameter.
Fig. 5. Ball-and-stick representation of the crystal structure of 5 (symmetry codes: a:
1 ꢁ x, 2 ꢁ y, 1 ꢁ z), atoms are shown as sphere of arbitrary diameter.

326
Y. Cui et al. / European Journal of Medicinal Chemistry 58 (2012) 323e331
Fig. 6. Ball-and-stick representation of the crystal structure of 6 (symmetry codes:
a: ꢁx, 1 ꢁ y, 1 ꢁ z), atoms are shown as sphere of arbitrary diameter.
Fig. 8. Ball-and-stick representation of the crystal structure of 8 (symmetry codes:
a: ꢁx, ꢁy, ꢁz), atoms are shown as sphere of arbitrary diameter.
inhibitors exhibit different ability to inhibit urease. Inhibitory
efficiency of metal ions toward urease follows the order:
Cu2þ > Ni2þ > Zn2þ > Co2þ, which has been reported in the
literature [24].
compared with 1, the Schiff base nickel(II) complex 2 exhibits the
weak urease inhibitory activity under the same condition. This
shows that inhibitory efficiency of the complexes toward urease
may be influenced not only by ligands but also by the transition
metal ion.
Compared with the standard inhibitor acetohydroxamic acid
(AHA, IC50 ¼ 62.52
m
M), the Schiff base copper(II) complexes 1, 3, 5,
8 and 11 display potent inhibitory activities (IC50 ¼ 1.51e3.52
mM)
against jack bean urease. It should be noted that in terms of the
inhibitory strength toward jack bean urease, the five Schiff base
copper(II) complexes form the order: 8 > 3 > 11 > 5 > 1. For these
transition metal complexes used as urease inhibitors, copper(II)
complexes exhibit stronger ability to inhibit urease due to the
strong Lewis acid properties of copper metal ion. Among the five
Schiff base copper(II) complexes tested, 8 exhibits strongest ability
to inhibit urease probably due to its shortest primary amine chain
and the Br substitution on the primary amine. Interestingly, 3
derived from 3,5-dibromosalicylaldehyde is much more potent
than 11 derived from 3,5-dichlorosalicylaldehyde. This defines the
Br substitution patterns in the aromatic ring for obtaining the
potent activity. 1 exhibits weakest ability to inhibit urease among
the five copper(II) complexes probably resulting from its longest
primary amine chain.
2.5. Molecular docking study
In the X-ray structure available for the native jack bean urease
(entry 3LA4 in the Protein Data Bank), the two nickels were coor-
dinated by His407, His409, Asp633, Lys490, His519, His545 and
water molecules [25]. Molecular docking of the copper(II)
complexes 1, 3, 5, 8 and 11 into the active site of jack bean urease was
performed on the binding model based on the jack bean urease
structure (3LA4.pdb). This provides an understanding of the present
inhibitory activity of these Schiff base copper(II) complexes against
jack bean urease. As shown in Fig. 12, the lowest binding energy of
the copper(II) complexes 1, 3, 5, 8 and 11 presents ꢁ5.10 kcal/
mol, ꢁ5.98 kcal/mol, ꢁ5.34 kcal/mol, ꢁ7.18 kcal/mol and ꢁ5.45 kcal/
mol, respectively. According to the minimum energy principle, the
lowest energy leads to highest stability of complex formed by ligand
and receptor. The docking results of the binding energy consistent
with the inhibitory activities of the five complexes against jack bean
urease.
The ability of 5 to inhibit the urease exhibits stronger than that
of 6, at the same time, the inhibitory ability of 6 shows stronger
than that of 7, although their crystal structures are very similar. This
also shows that inhibitory efficiency of the complexes toward
urease: copper complex > nickel complex > zinc complex. When
The binding models of the Schiff base copper(II) complexes 8
and 3 at the active site of jack bean urease are depicted in Fig. 13. In
8eurease model, it should be noted that the complex formed
hydrophobic interactions with five amino acid residues Val 591,
Fig. 7. Ball-and-stick representation of the crystal structure of 7 (symmetry codes:
a: ꢁx, y, 1/2 ꢁ z), atoms are shown as sphere of arbitrary diameter.
Fig. 9. Ball-and-stick representation of the crystal structure of 9, atoms are shown as
sphere of arbitrary diameter.

Y. Cui et al. / European Journal of Medicinal Chemistry 58 (2012) 323e331
327
Table 1
ꢀ
ꢀ
Selected bond lengths (A) and angles ( ) for complexes 1e11.
1
Cu(1)eO(1)
1.894(4)
Cu(1)eN(1)
2.015(4)
Cu(1)eO(2)
1.915(4)
Cu(1)eN(2)
2.013(4)
88.36(17)
90.64(18)
177.28(18)
O(1)eCu(1)eO(2)
O(2)eCu(1)eN(1)
O(2)eCu(1)eN(2)
178.29(17)
91.22(17)
89.85(17)
O(1)eCu(1)eN(1)
O(1)eCu(1)eN(2)
N(1)eCu(1)eN(2)
2 (a: ꢁx, 1 ꢁ y, 1 ꢁ z; b: 1 ꢁ x, 2 ꢁ y, 1 ꢁ z)
Ni(1)eO(1)
1.833(3)
Ni (1)eN(1)
1.923(3)
1.923(3)
Ni (1)eO(1)a
1.833(3)
Ni (1)eN(1)a
Ni(2)eO(2)
1.844(3)
1.844(3)
Ni (2)eN(2)
1.912(3)
1.912(3)
Ni (2)eO(2)b
Ni (2)eN(2)b
O(1)eNi (1)eO(1)a
O(1)aeNi (1)eN(1)
O(1)aeNi (1)eN(1)a
O(2)eNi (2)eO(2)b
O(2)beNi (2)eN(2)
O(2)beNi (2)eN(2)b
180.00(14)
92.48(14)
87.52(14)
180.00(16)
88.02(14)
91.98(14)
O(1)eNi (1)eN(1)
O(1)eNi (1)eN(1)a
N(1)eNi (1)eN(1)a
O(2)eNi (2)eN(2)
O(2)eNi (2)eN(2)b
N(2)eNi (2)eN(2)b
87.52(14)
92.48(14)
179.998(1)
91.98(14)
88.02(14)
180.00(16)
Fig. 10. Ball-and-stick representation of the crystal structure of 10, atoms are shown as
sphere of arbitrary diameter.
Ala440, Ala436, Ala636 and Leu589, respectively. Compared with
8eurease model, 3 formed hydrophobic interactions with only
three amino acid residues Val 591, Ala440 and Ala636. The docking
results may explain the inhibitory activity of 8 against jack bean
urease better than that of 3. The binding models of 11, 5 and 1 at the
active site of jack bean urease are depicted in Fig. 14. In the
complex-urease models, only one amino acid residue Ala636
formed hydrophobic interactions with 11, 5 and 1, respectively. In
contrast to the complex-urease complex our previous reported
[26], there was no hydrogen bond formed in the binding models.
Their urease inhibitory property may be attributed to the above
hydrophobic interactions formed between these copper complexes
and jack bean urease.
3 (a: ꢁx, 1 ꢁ y, 1 ꢁ z)
Cu(1)eO(1)
1.901(3)
1.901(3)
1.891(3)
1.884(3)
180.0 2
90.62(15)
89.38(15)
154.09(16)
92.26(15)
94.14(15)
Cu(1)eN(1)
1.994(4)
1.994(4)
1.975(4)
Cu(1)eO(1)a
Cu(1)eN(1)a
Cu(2)eO(2)
Cu(2)eO(3)
Cu(2)eN(2)
Cu(2)eN(3)
1.973(4)
O(1)eCu(1)eO(1)a
O(1)aeCu(1)eN(1)
O(1)aeCu(1)eN(1)a
O(2)eCu(2)eO(3)
O(2)eCu(2)eN(3)
O(3)eCu(2)eN(3)
O(1)eCu(1)eN(1)
O(1)eCu(1)eN(1)a
N(1)eCu(1)eN(1)a
O(2)eCu(2)eN(2)
O(3)eCu(2)eN(2)
N(2)eCu(2)eN(3)
89.38(15)
90.62(15)
180.0(2)
93.35(15)
93.26(15)
150.66(17)
4 (a: ꢁx, ꢁy, ꢁz; b: ꢁ1 þ x, ꢁ1 þ y, z)
The best docking model of enzyme surface structure of 8e
urease complex is showed in Fig. 15, from the figure, we can see
that 8 was well filled in the active pocket of the urease. The results
of molecular docking study could explain the difference of inhibi-
tory activity of the complexes against jack bean urease.
Ni(1)eO(1)
1.850(3)
1.850(3)
1.844(3)
1.844(3)
180.0
91.89(15)
88.11(15)
180.0
Ni (1)eN(1)
1.899(4)
1.899(4)
1.924(4)
1.924(4)
88.11(15)
91.89(15)
180.0
92.02(15)
87.98(15)
180.00(15)
Ni (1)eO(1)a
Ni (1)eN(1)a
Ni(2)eO(2)
Ni (2)eN(2)
Ni (2)eO(2)b
Ni (2)eN(2)b
O(1)eNi(1)eO(1)a
O(1)aeNi(1)eN(1)
O(1)aeNi(1)eN(1)a
O(2)eNi(2)eO(2)b
O(2)beNi(2)eN(2)
O(2)beNi(2)eN(2)b
O(1)eNi(1)eN(1)
O(1)eNi(1)eN(1)a
N(1)eNi(1)eN(1)a
O(2)eNi(2)eN(2)
O(2)eNi(2)eN(2)b
N(2)eNi(2)eN(2)b
3. Conclusion
87.98(15)
92.02(15)
This paper describes the synthesis, crystal structures and urease
inhibitory activities of eleven new copper(II), nickel(II), zinc(II) and
cobalt(II) complexes with the bidentate N,O-donor Schiff base
ligands. It was found that the copper(II) complexes exhibited good
inhibitory activity against jack bean urease. The docking calcula-
tions described here suggested that in the future, the Schiff base
copper(II) species have good potential as the urease inhibitor. The
trend in this work is in accord with the studies reported earlier.
Detailed investigations are continuing to study the mechanisms of
the inhibitory activity reported here.
5 (a: 1 ꢁ x, 2 ꢁ y, 1 ꢁ z)
Cu(1)eO(1)
1.901(3)
1.901(3)
179.999(2)
91.18(12)
88.82(12)
Cu(1)eN(1)
2.014(3)
2.014(3)
88.82(12)
91.18(12)
180.00(18)
Cu(1)eO(1)a
Cu(1)eN(1)a
O(1)eCu(1)eO(1)a
O(1)aeCu(1)eN(1)
O(1)aeCu(1)eN(1)a
O(1)eCu(1)eN(1)
O(1)eCu(1)eN(1)a
N(1)eCu(1)eN(1)a
6 (a: ꢁx, 1 ꢁ y, 1 ꢁ z)
Ni(1)eO(1)
1.849(2)
1.849(2)
180.000(1)
92.69(11)
87.31(11)
Ni (1)eN(1)
1.927(3)
1.927(3)
87.31(11)
92.69(11)
180.000(2)
Ni (1)eO(1)a
Ni (1)eN(1)a
O(1)eNi (1)eO(1)a
O(1)aeNi (1)eN(1)
O(1)aeNi (1)eN(1)a
O(1)eNi (1)eN(1)
O(1)eNi (1)eN(1)a
N(1)eNi (1)eN(1)a
7 (a: ꢁx, y, 1/2 ꢁ z)
Zn(1)eO(1)
1.921(2)
1.921(2)
123.36(14)
95.13(10)
114.15(10)
Zn(1)eN(1)
2.006(3)
2.006(3)
114.15(10)
95.13(10)
116.60(16)
Zn(1)eO(1)a
Zn(1)eN(1)a
O(1)eZn(1)eO(1)a
O(1)aeZn(1)eN(1)
O(1)aeZn(1)eN(1)a
O(1)eZn(1)eN(1)
O(1)eZn(1)eN(1)a
N(1)eZn(1)eN(1)a
8 (a: ꢁx, ꢁy, ꢁz)
Cu(1)eO(1)
1.899(4)
1.899(4)
180.0
88.88(19)
91.12(19)
Cu(1)eN(1)
2.021(5)
2.021(5)
91.12(19)
88.88(19)
180.0
Cu(1)eO(1)a
Cu(1)eN(1)a
O(1)eCu(1)eO(1)a
O(1)aeCu(1)eN(1)
O(1)aeCu(1)eN(1)a
O(1)eCu(1)eN(1)
O(1)eCu(1)eN(1)a
N(1)eCu(1)eN(1)a
9
Zn(1)eO(1)
Zn(1)eO(2)
1.913(4)
1.930(4)
Zn(1)eN(1)
Zn(1)eN(2)
1.994(5)
1.998(5)
Fig. 11. Ball-and-stick representation of the crystal structure of 11 (symmetry codes:
a: ꢁx, 1 ꢁ y, 1 ꢁ z), atoms are shown as sphere of arbitrary diameter.
(continued on next page)

328
Y. Cui et al. / European Journal of Medicinal Chemistry 58 (2012) 323e331
Table 1 (continued )
Zn(2)eO(3)
Zn(2)eO(4)
1.940(4)
1.908(4)
Zn(2)eN(3)
Zn(2)eN(4)
1.990(5)
1.977(5)
O(1)eZn(1)eO(2)
O(2)eZn(1)eN(1)
O(2)eZn(1)eN(2)
O(4)eZn(2)eO(3)
O(3)eZn(2)eN(4)
O(4)eZn(2)eN(4)
114.47(17)
110.28(18)
95.32(19)
110.65(16)
108.31(17)
96.82(18)
O(1)eZn(1)eN(1)
O(1)eZn(1)eN(2)
N(1)eZn(1)eN(2)
O(3)eZn(2)eN(3)
O(4)eZn(2)eN(3)
N(3)eZn(2)eN(2)
96.87(19)
108.99(19)
131.8(2)
95.16(18)
115.74(18)
129.8(2)
10
Co(1)eO(1)
Co(1)eO(2)
Co(2)eO(3)
Co(2)eO(4)
O(1)eCo(1)eO(2)
O(2)eCo(1)eN(1)
O(2)eCo(1)eN(2)
O(4)eCo(2)eO(3)
O(3)eCo(2)eN(4)
O(4)eCo(2)eN(4)
1.898(4)
1.902(4)
1.923(4)
1.900(4)
113.08(19)
110.1(2)
95.4(2)
117.90(19)
111.5(2)
95.7(2)
Co(1)eN(1)
Co(1)eN(2)
Co(2)eN(3)
Co(2)eN(4)
O(1)eCo(1)eN(1)
O(1)eCo(1)eN(2)
N(1)eCo(1)eN(2)
O(3)eCo(2)eN(3)
O(4)eCo(2)eN(3)
N(3)eCo(2)eN(2)
1.982(5)
1.994(6)
1.985(6)
2.001(6)
96.4(2)
115.4(2)
127.2(2)
95.0(2)
Fig. 12. . The binding energy between eleven complexes and jack bean urease (entry
3LA4 in the Protein Data Bank).
109.3(2)
129.4(2)
dichlorosalicylaldehyde (76.5 mg, 0.4 mmol)] in an aqueous aceto-
nitrile solution (5 mL). The mixture was stirred for 15 min at room
temperature to give an orange solution, which was added to
a methanol solution (5 mL) of M(NO3)2$xH2O (0.2 mmol) (M ¼ Cu,
x ¼ 3; M ¼ Co, Zn, Ni, x ¼ 6). The mixture was stirred for another
15 min at room temperaturetogive a clear solution and then filtered.
The filtrate was kept in air for about a week, forming block crystals.
The crystals were isolated, washed three times with distilled water
and dried in a vacuum desiccator containing anhydrous CaCl2.
11 (a: ꢁx, 1 ꢁ y, 1 ꢁ z)
Cu(1)eO(1)
1.892(3)
1.892(3)
180.0
91.03(12)
88.97(12)
Cu(1)eN(1)
2.027(3)
2.027(3)
88.97(12)
91.03(12)
180.000(1)
Cu(1)eO(1)a
Cu(1)eN(1)a
O(1)eCu(1)eO(1)a
O(1)aeCu(1)eN(1)
O(1)aeCu(1)eN(1)a
O(1)eCu(1)eN(1)
O(1)eCu(1)eN(1)a
N(1)eCu(1)eN(1)a
4. Experimental section
4.1. Materials and physical measurements
4.2.1. [Cu$(C11H12Br2NO)2] (1)
Brown solid, X-ray quality single crystals were obtained, yield:
200.6 mg (73%). IR (KBr, cmꢁ1): 3425, 2950, 2865, 2364, 1620, 1580,
1514, 1448, 1322, 1216,1163, 1021, 857, 750, 707, 625, 525, 483. Anal.
Calcd. for C22H24CuBr4N2O2: C, 36.12; H, 3.31; N, 3.83. Found: C,
36.25; H, 3.41; N, 3.67%.
Urease (from jack beans, type III, activity 22 units/mg solid),
HEPES (Ultra) buffer and urea (Molecular Biology Reagent)
were from Sigma. 3,5-Dibromosalicylaldehyde and 3,5-
dichlorosalicylaldehyde were purchased from Aldrich and used
without further purification. Distilled water was used for all
procedures. All experiments were performed at ambient
temperature. Elemental analyses (C, H and N) were performed on
a PE-2400(II) analyzer. Infrared spectra of solid samples were
recorded using KBr pellets on a Nexus 870 FT-IR spectropho-
tometer between 4000 and 400 cmꢁ1. The crystallographic data
for complexes were collected on a Bruker Smart 1000 CCD area
detector diffractometer. The enzyme inhibitory activity was
measured on a Bio-Tek SynergyÔ HT microplate reader.
4.2.2. [Ni$(C11H12Br2NO)2] (2)
Dark-green solid, yield: 191.3 mg (76%). IR (KBr, cmꢁ1): 3446,
3067, 2953, 2867, 2363,1742,1616,1581,1514,1443,1320,1217,1171,
1111, 966, 863, 747, 717, 513, 455. Anal. Calcd. for C22H24NiBr4N2O2: C,
36.36; H, 3.33; N, 3.85. Found: C, 36.44; H, 3.47; N, 3.72%.
4.2.3. 3/2[Cu$(C11H12Br2NO)2]$H2O (3)
Dark-green solid, yield: 323.3 mg (69%). IR (KBr, cmꢁ1): 3447,
3063, 2955, 2865, 2365, 1750, 1621, 1581, 1511, 1444, 1387, 1319,
1214, 1162, 1037, 864, 751, 710, 624, 534, 484. Anal. Calcd. for
4.2. Synthesis of the complexes
C
33H38Cu1.5Br6N3O4: C, 35.54; H, 3.43; N, 3.77. Found: C, 35.40; H,
General procedure for the synthesis of Schiff base ligands and
complexes 1e11: primary amine (0.4 mmol) was added to the
solution of 3,5-dibromosalicylaldehyde (112 mg, 0.4 mmol) [3,5-
3.47; N, 3.65%.
4.2.4. [Ni$(C11H12Br2NO)2] (4)
Brown solid, yield: 111.7 mg (78%). IR (KBr, cmꢁ1): 3425, 3070,
2956, 2865, 1746,1615,1582, 1514,1439, 1382, 1317, 1218,1171, 1030,
951, 862, 747, 719, 665, 522, 441. Anal. Calcd. for C22H24NiBr4N2O2:
C, 36.36; H, 3.33; N, 3.65. Found: C, 36.01; H, 3.65; N, 3.23%.
Table 2
Inhibition of jack bean urease by complex 1e11, Cu(II) ion, Ni(II) ion,
Zn(II) ion and Co(II) ion.
Tested materials
IC50 (mM)
4.2.5. [Cu$(C10H10Br2NO)2] (5)
Complex 1
Complex 2
Complex 3
Complex 4
Complex 5
Complex 6
Complex 7
3.52 ꢂ 0.21
88.00 ꢂ 1.28
2.14 ꢂ 0.12
76.00 ꢂ 1.59
2.55 ꢂ 0.13
82.00 ꢂ 2.12
>100
Black solid, yield: 193.1 mg (73%). IR (KBr, cmꢁ1): 3422, 2963,
2928, 2863, 2368,1619,1514,1447,1322,1216,1165,1103,1041,1011,
858, 751, 707, 625, 524, 479, 410. Anal. Calcd. for C20H20CuBr4N2O2:
C, 34.15; H, 2.87; N, 3.98. Found: C, 34.31; H, 2.66; N, 3.83%.
4.2.6. [Ni$(C10H10Br2NO)2] (6)
Complex 8
Complex 9
Complex 10
Complex 11
Acetohydroxamic acid
1.51 ꢂ 0.22
Dark-green solid, yield: 181.5 mg (77%). IR (KBr, cmꢁ1): 3422,
2957, 2867, 1741, 1614, 1516, 1446, 1384, 1321, 1217, 1172, 1087, 955,
863, 786, 718, 661, 542, 510, 430. Anal. Calcd. for C20H20NiBr4N2O2:
C, 34.38; H, 2.88; N, 4.01. Found: C, 34.44; H, 2.96; N, 4.03%.
>100
>100
2.45 ꢂ 0.19
62.52 ꢂ 0.16

Y. Cui et al. / European Journal of Medicinal Chemistry 58 (2012) 323e331
329
Fig. 13. Binding modes of 8 (a) and 3 (b) with jack bean urease (entry 3LA4 in the Protein Data Bank).
Fig. 14. Binding modes of 11 (a), 5 (b) and 1 (c) with jack bean urease (entry 3LA4 in the Protein Data Bank).
4.2.7. [Zn$(C10H10Br2NO)2] (7)
751, 709, 624, 531, 479. Anal. Calcd. for C20H18CuBr6N2O2: C, 27.89;
H, 2.11; N, 3.25. Found: C, 27.36; H, 2.37; N, 3.31%.
Yellow solid, yield: 172.1 mg (82%). IR (KBr, cmꢁ1): 3422, 3067,
2958, 2926, 2870, 2616, 2466, 2364, 1737, 1626, 1580, 1510, 1442,
1344, 1308, 1248, 1211, 1153, 1093, 1060, 980, 864, 840, 752, 706,
601, 534, 472. Anal. Calcd. for C20H20ZnBr4N2O2: C, 34.05; H, 2.86;
N, 3.97. Found: C, 34.11; H, 2.98; N, 3.31%.
4.2.9. [Zn$(C10H10Br2NO)2] (9)
Yellow solid, yield: 180.9 mg (78%). IR (KBr, cmꢁ1): 3447, 3066,
2968, 2894, 2366, 1750, 1616, 1508, 1447, 1343, 1311, 1215,1145, 868,
834, 755, 708, 672, 610, 529, 442. Anal. Calcd. for C20H20ZnBr4N2O2:
C, 34.05; H, 2.86; N, 3.97. Found: C, 33.89; H, 2.97; N, 4.06%.
4.2.8. [Cu$(C10H9Br3NO)2] (8)
Black solid, yield: 253.6 mg (68%). IR (KBr, cmꢁ1): 3421, 2930,
2362, 1618, 1582, 1515, 1446, 1320, 1253, 1201, 1160, 1042, 864, 771,
4.2.10. [Co$(C10H10Br2NO)2] (10)
Black solid, yield: 181.6 mg (77%). IR (KBr, cmꢁ1): 3427, 3065,
2968, 2891, 2363, 1751, 1603, 1505, 1436, 1310, 1213, 1147, 977, 866,
837, 752, 712, 612, 530, 472. Anal. Calcd. for C20H20CoBr4N2O2: C,
34.37; H, 2.88; N, 4.01. Found: C, 34.26; H, 2.76; N, 4.18%.
4.2.11. [Cu$(C10H10Cl2NO)2] (11)
Dark-green solid, yield: 146.2 mg (72%). IR (KBr, cmꢁ1): 3447,
2958, 1625, 1516, 1459, 1344, 1211, 1174, 1111, 977, 865, 760, 684,
542, 457. Anal. Calcd. for C20H20CuCl4N2O2: C, 45.69; H, 3.84; N,
5.33. Found: C, 45.33; H, 3.66; N, 5.28%.
4.3. Crystal structure determinations
X-ray crystallographic data [27] were collected on a Bruker
SMART Apex II CCD diffractometer using graphite-monochromated
ꢀ
Mo K
a
(l
¼ 0.71073 A) radiation. The collected data were reduced
usingthe SAINT program, and empirical absorption corrections were
performed using the SADABS program. The structures were solved
bydirectmethods and refined against F2 byfull-matrix least-squares
methods using the SHELXTL version 5.1. All of the non-hydrogen
Fig. 15. The enzyme surface model of structure of 8ejack bean urease complex.

330
Y. Cui et al. / European Journal of Medicinal Chemistry 58 (2012) 323e331
Table 3
Crystal data for 1e5.
Complex
1
2
3$2H2O
4
5
Empirical formula
Molecular weight
Crystal system
Space group
C
22H24Br4CuN2O2
C22H24Br4NiN2O2
726.78
Triclinic
P-1
11.4302(11)
11.5394(11)
11.7855(12)
67.435(2)
63.037(2)
71.027(2)
291(2)
1257.7(2)
2
1.919
708
7.147
C33H38Br6Cu1.5N3O4
635.99
Triclinic
C22H24Br4N4NiO2
726.78
Triclinic
P-1
11.3730(11)
11.6486(11)
12.4117(12)
99.003(2)
109.180(2)
117.971(2)
298(2)
1273.0(2)
2
1.896
708
7.061
C20H20Br4CuN2O2
703.56
Triclinic
P-1
8.3204(13)
8.3222(12)
8.7868(13)
107.548(3)
100.686(2)
94.835(2)
291(2)
563.64(15)
1
2.073
339
8.077
731.61
Monoclinic
C2/c
28.5396(19)
9.7215(6)
22.4937(15)
90.00
126.919(2)
90.00
273(2)
4989.4(6)
8
1.948
2840
P-1
ꢀ
a (A)
12.6437(15)
12.8608(16)
14.3346(17)
63.500(2)
74.452(2)
80.832(2)
291(2)
2007.6(4)
2
1.845
ꢀ
b (A)
ꢀ
c (A)
a
b
g
(ꢀ)
(ꢀ)
(ꢀ)
T (K)
3
ꢀ
V (A )
Z
rcalcd. (g cmꢁ3
F(000)
)
1085
6.810
m(Mo K
a
) (mmꢁ1
)
7.304
Data/restraint/parameters
4893/0/282
1.016
5133/0/285
1.018
7783/7/436
1.026
5191/0/287
1.016
2181/0/134
1.006
Goodness-of-fit on F2
Final R1, wR2 [I > 2
s(I)]
0.0555, 0.1052
0.0471, 0.0776
0.0479, 0.1118
0.0528, 0.1092
0.0350, 0.0810
atoms were refined anisotropically. All other hydrogen atoms were
placed in geometrically ideal positions and constrained to ride on
their parent atoms. The crystallographic data for the Schiff base
metal complexes are summarized in Tables 3 and 4.
Bank) was carried out using the DOCK 4.2 program suite [31e34].
The graphical user interface AutoDockTools (ADT 1.4.5) was per-
formed to setup every inhibitoreenzyme interaction, where all
hydrogen atoms were added, Gasteiger charges were calculated
and nonpolar hydrogen atoms were merged to carbon atoms. The
ꢀ
Ni initial parameters are set as r ¼ 1.170 A, q ¼ þ2.0, and van der
4.4. Measurement of jack bean urease inhibitory activity
Waals well depth of 0.100 kcal/mol [35]. As performed by the
graphical user interface AutoDockTools, the catalytic center and the
peripheral anionic site of the target protein were scanned to eval-
uate the modeled binding mode of the inhibitoreurease complex.
The flexible docking of the ligand structures was done by the
Lamarckian genetic algorithm (LGA), searching for favorable
bonding conformations of the ligands at the sites of the target
protein. The docking procedure of Schiff base copper(II) complexes
with the enzyme active site of jack bean urease was performed as
described previously by our group [26].
The measurement of urease activity was carried out according to
the literature reported by Tanaka [28]. Generally, the assay mixture,
containing 25
mL (12 kU/L) of jack bean urease (100 mM HEPES, pH
6.8) and 25 L of the tested complexes of different concentrations
m
(dissolved in the solution of DMSO:H2O ¼ 1:1 (v/v)), was pre-
incubated for 1 h at 37 ꢀC in a 96-well assay plate. After pre-
incubation, 200 mL of 100 mM HEPES (pH 6.8) buffer [29] containing
500 mM urea and 0.002% phenol red were added and incubated at
37 ꢀC. The reaction was measured by microplate reader (570 nm),
which was required to produce enough ammonium carbonate to
raise the pH of a HEPES buffer from 6.8 to 7.7, the end-point being
determined by the color of phenol red indicator [30].
Supplementary data
CCDC numbers 829314e829324 contain the supplementary
crystallographic data (CIF) for this article. These data can be ob-
tained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.
html, or from the Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: þ44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk).
4.5. Docking simulations
Molecular docking of the inhibitor with the three-dimensional
structure of jack bean urease (entry 3LA4 in the Protein Data
Table 4
Crystal data for 6e11.
Complex
6
7
8
9
10
11
Empirical formula
Molecular weight
Crystal system
Space group
C
20H20Br4NiN2O2
C20H20Br4ZnN2O2
705.39
Monoclinic
C2/c
24.2589(10)
4.8716(2)
21.8687(9)
90.00
115.583(4)
90.00
296(2)
2331.06(17)
4
2.010
1360
C20H18Br6CuN2O2
861.36
Triclinic
P-1
8.0174(17)
8.8097(19)
8.987(2)
97.260(4)
99.397(4)
94.340(4)
291(2)
618.2(2)
1
2.314
407
10.599
C20H20Br4ZnN2O2
705.39
Triclinic
P-1
9.911(4)
13.316(5)
19.908(8)
73.054(7)
76.083(7)
81.981(7)
291(2)
2432.7(16)
4
1.926
1360
7.598
C20H20Br4CoN2O2
698.95
Triclinic
C20H20Cl4CuN2O2
525.72
Monoclinic
P21/c
8.2010(9)
16.9612(19)
8.2010(9)
90.00
103.54
90.00
291(2)
1109.1(2)
2
698.73
Monoclinic
P21/c
13.2223(4)
4.65950(10)
20.8412(5)
90.00
119.109(2)
90.00
291(2)
1121.84(5)
2
2.069
676
P-1
ꢀ
a (A)
9.9465(6)
13.3142(8)
19.9025(12)
73.0350(10)
76.0200(10)
81.7250(10)
298(2)
2438.6(3)
4
1.904
ꢀ
b (A)
ꢀ
c (A)
a
b
g
(ꢀ)
(ꢀ)
(ꢀ)
T (K)
3
ꢀ
V (A )
Z
rcalcd. (g cmꢁ3
F(000)
)
1.574
534
1.574
1348
7.276
m
(Mo Ka) (mmꢁ1
)
8.008
7.929
Data/restraint/parameters
2568/0/134
1.016
2268/0/133
1.006
2384/0/142
1.003
10020/18/531
1.009
9442/12/531
1.019
2167/12/135
1.006
Goodness-of-fit on F2
Final R1, wR2 [I > 2
s(I)]
0.0337, 0.0730
0.0292, 0.0615
0.0518, 0.1363
0.0560, 0.0793
0.0629, 0.0962
0.0509, 0.1296

Y. Cui et al. / European Journal of Medicinal Chemistry 58 (2012) 323e331
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This work was financially supported by Natural Science Foun-
dation of Nation (21101122), Natural Science Foundation of Hubei
Province (2009CDA022), and the National Technology Support
Project (2010BAD02B03, 2010BAD02B04, 2010BAD02B06).
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