Synthesis, characterization and distinct butyrylcholinesterase activities of transition metal complexes of 2-[(E)-(quinolin-3-ylimino)methyl]phenol

Article abstract of DOI:10.1016/j.ica.2012.04.036

2-[(E)-(Quinolin-3-ylimino)methyl]phenol (H-QMP) was synthesized by condensing salicylaldehyde with 2-aminoquinoline and fully characterized by mass spectrometry, ¹H and ¹³C{¹H}NMR, and IR spectroscopies. The metal complex

Full text of DOI:10.1016/j.ica.2012.04.036

Inorganica Chimica Acta 390 (2012) 210–216
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Synthesis, characterization and distinct butyrylcholinesterase activities of
transition metal complexes of 2-[(E)-(quinolin-3-ylimino)methyl]phenol
a
b
b
Muhammad Ikram a,b, Saeed-Ur-Rehman a, , Sadia Rehman , Robert J. Baker , Carola Schulzke
⇑
a Institute of Chemical Sciences, University of Peshawar, Pakistan
b School of Chemistry, University of Dublin, Trinity College Dublin 2, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
2-[(E)-(Quinolin-3-ylimino)methyl]phenol (H-QMP) was synthesized by condensing salicylaldehyde with
2-aminoquinoline and fully characterized by mass spectrometry, 1H and 13C{1H}NMR, and IR spectrosco-
pies. The metal complexes [M(QMP)(OAc)]H2O where M = Cu(II) and Zn(II) and [M(QMP)2] where M = Ni
and Co(II) were prepared from the metal acetates. All transition metal complexes were assigned geome-
tries based on the UV–Vis spectra, conductivity and magnetic susceptibilities. [M(QMP)2], {where M = Ni
and Co(II)}, were further characterized by single crystal X-ray diffraction and were found to be pseudo-
octahedral with interquinoline interaction to the metal center. The complexes were screened for acetyl-
cholinesterase (AChE) and butyrylcholinesterase (BChE). Only cobalt and copper containing complexes
Received 10 February 2012
Received in revised form 15 April 2012
Accepted 23 April 2012
Available online 3 May 2012
Keywords:
Transition metal complexes
X-ray single crystal diffraction
Acetylcholinesterase and
butyrylcholinesterase inhibition activities
were found to be active against BChE with IC50 = 69 0.0112 and 5 0.0004
l
M
SEM, respectively. Sur-
prisingly no activity was observed for AChE, therefore selective BChE inhibition was observed for copper
and cobalt complexes only.
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
associated with their poor selectivity towards AChE [8]. To over-
come AD, drugs have been developed which prevent the hydrolysis
Alzheimer’s disease (AD) is a degenerative brain disease, which
destroys the neurons and the connections to the cerebral cortex
and causes dementia which progresses from short term memory
loss to complete immobility [1]. Dementous neurofibrillary tangles
are probably caused by the oxidative effects of lipids [2–4]. Amy-
loid beta (Ab or Abeta) is a peptide linkage of 36–43 amino acids
and appears to be the main constituent of amyloid plaques found
in the brains of patients with Alzheimer’s disease. Ab is involved
in oxidative stress of the lipids found in the cell membranes of
the tissues which ultimately lead to dementia. The hydrolysis reac-
tion as shown in Scheme 1 below takes place at the catalytic site, of
which the residue serine 200 (Ser-200) is an integral part.
Inhibition of acetylcholinesterase is considered as a promising
approach for the treatment of Alzheimer’s disease (AD) and for
possible therapeutic applications in the treatment of Parkinson’s
disease, ageing, and myasthenia gravis [5,6]. Meanwhile, butyr-
ylcholinesterase (BChE) has been considered to be directly associ-
ated with the side effects of the acetylcholinesterase (AChE)
inhibitors and the existing drugs for Alzheimer Disease (AD) [7].
More recent studies have shown that BChE is found in significantly
higher quantities in AD plaques than in the plaques of age related
non-demented brains. Other relevant studies have also reported
that the unfavorable side effect profile of AChE inhibitors are not
of the acetylcholine by blocking the acetylcholinesterase (AChE).
Acetylcholinesterase inhibitors (AChEIs) prevent the acylation of
the hydroxyl group of Ser200. Reported AChEIs are (ꢀ)-Huprine,
Tacrine, and Hup A Dimers (Fig. 1) [9–21].
Furthermore, it was found that the brain requires high metal ion
[Cu(II), Zn(II) and Fe(III)] concentrations for numerous essential
functions. In Alzheimer’s patients the metal ion homeostasis is se-
verely deregulated. The metals are not aggregates but only part of
these i.e. they accumulate in the form of Ab aggregates in dementia
and hence stressful oxidative processes are triggered. Therapies,
which are currently used for overcoming the oxidative stress, in-
clude (i) ameliorating or inhibiting Ab aggregation and induced
Reactive Oxygen Species (ROS) generation, (ii) use of antioxidants
and (iii) use of metal chelators. Clioquinol metal complexes are
found to be the most promising drugs in AD treatment. Despite
the human trials for clioquinol drugs already taking place, the
mode of action is still not clear [22]. Our interest in investigating
AChE and BChE inhibition came from the study carried out by Budi-
mir et al. of the metal based drugs of this important class of li-
gands. According to them, ligands of such class can take part in
metal exchange reactions which will ultimately lead to decrease
in Ab plaques [22]. It was also found that metal chelators of the
N, O-type with an aromatic environment can easily cross the blood
brain barrier and can cause the formation of metalated rings
including aromatic properties with Ab plaques. The ab initio DFT
of various aromatic ligands toward copper complexation studies
⇑
Corresponding author. Tel.: +92 321 90 20756.
E-mail address: srachem@yahoo.com ( Saeed-Ur-Rehman).
0020-1693/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ica.2012.04.036

M. Ikram et al. / Inorganica Chimica Acta 390 (2012) 210–216
211
O
linesterase, horse serum butyrylcholinesterase, acetylthiocholine
iodide, butyrylthiocholine chloride, 5,50-thiobis-2-nitrobenzoic
acid (DTNB) and eserine were purchased from Sigma. Unless other-
wise stated, all reactions were carried out under a dinitrogen
atmosphere.
O
O
+
AChE, H O
OH
+
2
N
N
+
OH
Scheme 1. Hydrolysis of ACh by AChE.
2.2. Instrumentation
carried out by Sodupe et al. show that increasing the sigma donat-
ing property of the ligand might affect the therapeutic activity of
the complexes [22]. In the H-QMP ligand the quinoline nitrogen
is increasing the electron density of the ring and hence the cova-
lency toward transition metal ions. It was also found to offer
opportunities for inducing substrate chirality and reorientations
in geometry around the metal center, thereby tuning the metal’s
electronic structure. Metal complexes of Ni(II), Co(II), Cu(II) and
Zn(II) were synthesized by condensing with H-QMP as ligand pre-
cursor. The metals are not aggregates but only part of these i.e.
they accumulate in the form of Ab aggregates in dementia, there-
fore these metal complexes are supposed to be active in overcom-
ing the oxidative stress of metal ion accumulation in Ab
aggregation. The brain of Alzheimer patients show that metal ions
present inside the body accumulate in plaques which consequently
produce hydrogen peroxide causing damage to the brain. Previ-
ously it was reported that metal complexes containing copper
aggregate the senile plaque more efficiently than any other metal
complex [23]. Here, we extended the research in this field to cer-
tain other metal ions such as cobalt(II) and nickel(II).
Elemental analyses were carried out on Varian Elementar II. The
metal ion content in all samples was carried out by atomic absorp-
tion spectrophotometer (Vario 6, Analytic Jena). The instrument
was operated on single beam mode. The concentration of each me-
tal was determined against standard calibration curve with regres-
sion value (R2) of 0.9997 obtained with commercial standards
(CPA Chem. Ltd., Bulgaria). Melting points were recorded on a Gal-
lenkamp apparatus. IR spectra were recorded using Shimadzo FTIR
Spectrophotometer Prestige-21. 1H NMR were measured with Bru-
ker DPX 400 MHz (400.23 MHz) whereas, 13C{1H} NMR were re-
corded on Bruker AV 400 MHz (150.9 MHz) spectrometers in
CDCl3 at room temperature. Chemical shifts are reported in ppm
and standardized by observing signals for residual protons. UV–
Vis spectra were recorded on a BMS UV-1602. Molar conductance
of the solutions of the metal complexes was determined with a
conductivity meter type HI-8333. All measurements were carried
out at room temperature with freshly prepared solutions. Magnetic
susceptibilities were measured on a Sherwood Gouy Balance at
room temperature calibrated with Hg[Co(SCN)4]. Mass spectra
were recorded on a LCT Orthogonal Acceleration TOF Electrospray
mass spectrometer. Single crystal analyses were carried out using
Rigaku Saturn-724 diffractometer (graphite-monochromated Mo
These metal complexes will potentially lead to increased metal
ion concentration through exchange processes and decreased se-
nile plaques. This study should be of great importance in the explo-
ration of metal based drugs for neurological disorders.
Ka radiation, k = 0.71073 Å) at 108(2) K.
2. Experimental
2.3. Synthesis of 2-[(E)-(quinolin-3-ylimino)methyl]phenol (H-QMP)
2.1. Materials and methods
Salicylaldehyde (1.2 cm3, 0.011 mol) was added to a solution of
3-aminoquinoline (1.6 g, 0.011 mol) in ethanol which was stirred
for 3 h. An orange solution was obtained and concentrated using
rotary evaporator. The product was purified by washing with 10%
copious n-hexane and methanol solution. (Yield: 1.5 g, 55%). M.p.
190–191 °C. IR: 3200(bd), 1591(s), 1554(s), 1492(s), 1381w,
1361(s), 1338(s), 1319(w), 1280(s), 1224(s), 1203(s), 1165(s),
1109(s), 927(s), 900(s), 848(s), 798(s), 780(s), 750(s), 736(s),
All chemicals, buffers and solvents used were of analytical
grade. Metal(II) acetates (where metal(II) = Co, Ni, Cu and Zn) were
obtained from Riedel-de-Haen, and were partially dehydrated by
drying the hydrated salts in a vacuum oven for several hours at
80–100 °C. 3-aminoquinoline was obtained from Sigma Aldrich
whereas salicylaldehyde was obtained from Acros Organics. Sol-
vents were distilled at least twice before use. Electric eel acetylcho-
638(s), 610(w) cmꢀ1 1H NMR (400.23 MHz, CD3OD, 303 k):
.
H
N
O
HN
(CH )n
2
HN
H
N
2
N
Cl
N
NH
O
NH
Cl
(-)-Huprine
2
Tacrine
Hup A Dimers where n = 10 & 12
N
OH
Cliquinol
Fig. 1. Drugs used for treating Alzheimer Disease.

212
M. Ikram et al. / Inorganica Chimica Acta 390 (2012) 210–216
d = 11.0 (s, 1H, Ar-OH), 9.0 (s, 1H, –HC@N), 8.8 (s, 1H, H2), 8.10 (d,
l
eff: 4.5 B.M. Anal. Calc. for C18H16N2O4Cu: C, 55.74; H, 4.16; N,
3
3JHH = 8.35 Hz, 1H, H9), 8.0 (s,1H, H4), 7.8 (d, JHH = 7.72 Hz, 1H,
7.22; Cu, 16.38. Exp.: C, 55.44; H, 4.10; N, 8.22; Cu, 15.88%. MS-
3
3
H6), 7.73 (d, JHH = 7.9 Hz, 1H, H8), 7.70 (t, JHH = 7.55 Hz, 1H,
ES:
m/z
(%) = 387.8771
(10%)
[C18H16N2O4Cu+],
(90%)
3
H16), 7.4 (m, 1H, H17), 7.3 (d, JHH = 7.6, 1H, H18), 7.1 (d,
[C16H12N2O+], ꢁm = 0.01 S cmꢀ1
.
3
3JHH = 8.03 Hz, 1H, H15), 7.0 (d, JHH = 7.48 Hz, 1H, H7) ppm,
13C{1H} NMR (150.9 MHz, CD3OD, 303k), 165(HC@N–, C12), 162
(aromatic C–OH, C14), 147 (C, C10), 146 (CH, C2), 142 (C, C5),
134 (CH, C15), 133 (CH, C18), 129.4 (CH, C17), 129.2 (CH, C16),
128 (C, C3), 127.8 (CH, C6), 127.4 (CH, C7), 124.7 (CH, C8), 116
(CH, C9) ppm. Anal. Calc. for C16H12N2O: C, 77.40; H, 4.87; N,
11.28. Exp.: C, 76.80; H, 5.10; N, 10.89%. EI-MS: m/z (%) 249.1017
(100%) [C16H12N2O+].
2.9. 2-[(E)-(Quinolin-3-ylimino)methyl]phenolatoacetatoaquozinc(II)
(4)
IR analysis: 3000–3400(bd), 1734(w), 1606(s), 1568(s),
1492(w), 1361(s), 1338(s), 1280(s), 1203(s), 1165(s), 977(s),
848(s), 750(s), 638(s) cmꢀ1. Anal. Calc. for C18H16N2O4Zn: C,
55.47; H, 4.14; N, 7.19; Zn, 16.78. Exp.: C, 55.74; H, 4.10; N, 7.22;
Zn, 16.38%. MS-ES: m/z (%) = 389.7396 (5%) [C18H16N2O4Zn+],
249.110 (100%) [C16H12N2O+], 145.1200 (2%) [C9H8N2+],
2.4. Synthesis of [M(QMP)2] where M = Ni and Co(II) acetates
ꢁ
m = 0.01 S cmꢀ1
.
0.011 mol of metal(II) acetates were stirred in a minimum vol-
ume of dried methanol and 0.024 mol of H-QMP in a minimum vol-
ume of dried methanol was added to the metal solution. The
mixture was stirred for 2–3 h at room temperature. The metal
complex was collected after filtration and copiously washed sev-
eral times with 5% n-hexane containing methanol.
2.10. AChE and BChE inhibition assay
AChE Inhibition was determined spectrophotometrically, with
acetylthiocholine as substrate, by modifying the method reported
by Ellman [24]. The reaction was carried out in 100
phosphate buffer (pH 8.0) at 25 °C. In a typical assay, 140
fer, 20 l of enzyme preparation (final concentration 0.037 U/ml in
0.1 M phosphate buffer solution), and 20 l (0.05 mM) of metal
l
M sodium
ll of buf-
2.5. Bis(2-[(E)-(quinolin-3-ylimino)methyl]phenolato)nickel(II) (1)
l
l
X-ray quality crystals were formed by slow diffusion of dichlo-
romethane and diethyl ether. After three days dark green diamond
shaped single crystals appeared. IR: 1612(s), 1558(s), 1537(s),
1496(s), 1471(s), 1444(s), 1388(w), 1369(s), 1321(s), 1220(w),
1155(s), 1136(w), 1124(s), 1035(s), 999(w), 898(s), 819(s), 810(s),
compound solution were mixed and incubated for 30 min. Ten
microliters (0.15 mM) of 5,50-dithio-bis-nitrobenzoic acid (DTNB)
was added, and the reaction was initiated by adding 10 ll of acet-
ylthiocholine. Butyrylthiocholine chloride was used as a substrate
to assay BChE under similar conditions as above. The rates of
hydrolysis of acetylthiocholine and butyrylthiocholine were deter-
mined by monitoring the formation of the yellow 2-nitro-5-sul-
fanylbenzoate anion (as a result of the reaction of DTNB with the
thiocholine released by the enzymatic hydrolysis) at a wavelength
of 412 nm. Methanol was used as negative control. Galanthamine
750(s),
= 27.7 Mꢀ1 cmꢀ1
32H22N4O2Ni: C, 69.47; H, 4.01; N, 10.13; Ni, 10.61. Exp.: C,
732(s),
636(s),
596(w)
cmꢀ1
.
kmax = 720 nm
(e
,
1A1g ? 1A2g).
leff: 2.7 B.M. Anal. Calc. for
C
70.43; H, 3.88; N, 11.56; Ni, 10.50%. EI-MS: m/z (%) 554.2787
(15%) [C32H22N4O2Ni+ + 2H+], 249.5734 (100%) [C16H12N2O+],
145.3759 (5%) [C9H8N2+], ꢁm = 0.01 S cmꢀ1
.
dissolved in methanol was used as standard drug at 10 lg/ml con-
centrations. All the reactions were performed in triplicate in 96-
well microplates in Spectrmax 340 (Molecular Devices, USA).
2.6. Bis(2-[(E)-(quinolin-3-ylimino)methyl]phenolato)cobalt(II) (2)
IR analysis: 2800–3300(bd), 1656(w), 1604(s), 1533(s), 1500(s),
1419(w), 1338(s), 1236(s), 1192(s), 1120(s), 1029(s), 980(s),
2.11. Determination of IC50 values
894(s), 800(w), 752(s), 667(s), 650(s) cmꢀ1
.
kmax = 640 nm
The concentrations of test compounds that inhibited the hydro-
lysis of substrates (acetylthiocholine and butyrylthiocholine) by
50% (IC50) were determined by monitoring the effect of increasing
concentrations of these compounds on the inhibition values. The
IC50 values were then calculated using the EZ-Fit Enzyme Kinetics
program (Perrella Scientific Inc., Amherst, USA).
(e , leff: 4.4 B.M. Anal. Calc. for
= 16.6 Mꢀ1 cmꢀ1 2A2g ? 2B1g),
C32H22N4O2Co: C, 69.44; H, 4.01; N, 10.12; Co, 10.65. Exp.: C,
68.66; H, 4.23; N, 9.68; Co, 11.12%. MS-ES+: m/z (%) 553.1060
(48%) [C32H22N4O2Co+], 249.1078 (100%) [C16H12N2O+], 145.1128
(10%) [C9H8N2+], ꢁm = 0.03 S cmꢀ1
.
2.7. Synthesis of [M(QMP)(CH3COO)]H2O where M = Cu and Zn(II)
acetates
2.12. Crystal structure determination
Suitable single crystals for X-ray structural analyses of 1 and 2
were mounted on a glass fiber, and the respective data were col-
lected on a Rigaku Saturn-724 diffractometer (graphite-monochro-
0.011 mol of metal(II) acetates was stirred in a minimum vol-
ume of dried methanol to which 0.011 mol of H-QMP in a mini-
mum volume of dried methanol was added. The mixture was
stirred for 2–3 h at room temperature. In metal salts containing
water of crystallization excess dimethoxy propane was added for
dehydrating and the solution was stirred for 3 h at room tempera-
ture under nitrogen before adding the ligand. The metal complex
was collected after filtration and washed many times with n-hex-
ane containing methanol.
mated Mo K
were solved by direct methods (SHELXS-97) and refined against all
data by full-matrix least-squares methods on F2
SHELXL-97) [25].
a radiation, k = 0.71073 Å) at 108(2) K. The structures
(
All non-hydrogen-atoms were refined with anisotropic displace-
ment parameters. The hydrogen atoms were refined isotropically
on calculated positions using a riding model with their Uiso values
constrained to 1.5 Ueq of their pivot atoms for terminal sp3 carbon
atoms and 1.2 times for all other carbon atoms.
2.8. 2-[(E)-(Quinolin-3-ylimino)methyl]phenolatoacetatoaquocopper
(II) (3)
3. Results and discussion
IR analysis: 3290(bd), 1729(w), 1604(s), 1555(s), 1480(s),
1360(s), 1338(s),1280(w), 1200(s), 1160(w), 980(s), 848(s),
The ligand H-QMP was synthesized by condensing salicylalde-
hyde with 3-aminquinoline to yield the phenolic Schiff base ligand.
750(s), 650(s) cmꢀ1. kmax = 850 nm ( = 19.3 Mꢀ1 cmꢀ1 2E ? 2T2).
e ,

M. Ikram et al. / Inorganica Chimica Acta 390 (2012) 210–216
213
N
N
M
O
O
OH
2
O
N
M = Cu(OAc) and Zn(OAc)
2
2
N
N
OH
N
O
M
O
N
N
M = Co(OAc) and Ni(OAc)
2
2
Scheme 2. Metal complexation by H-QMP.
The UV–Vis spectra of compounds 1, 2, and 3 were measured in
the region of 200–1000 nm. These spectra show only one absorp-
tion band each for all of the compounds viz.; for 1 the major
absorption at 720 nm was assigned to a transition 1A1g ? 1A2g
since the other charge transfer bands caused by 1A1g ? 1B1g and
1A1g ? Eg transitions are expected to be observed in the lower
absorption region. However, no significant absorption of this kind
was observed in rigorously purified samples, possibly because
these transitions are buried beneath the absorption region for
1A1g ? 1A2g. The 2.7 B.M. leffective value and the absorption band
in the visible region confirm that the crystal field splitting between
sets of dyz, dzx and dz2 orbitals and dxy and dx2 ꢀ y2 orbitals is
large. Furthermore, the energies of the dxy and dx2 ꢀ y2 orbitals
9
8
6
7
N
1
10
2
5
12
3
4
N
18
11
13 14
17
OH
19
16 15
Scheme 3. Atoms numbering used for NMR signals.
This was characterized by 1H and 13C{1H} NMR spectroscopy which
shows the expected resonances. The 1H and 13C{1H} NMR peaks
were assigned on the basis of Scheme 3. Two singlets observed up-
field at dH = 11.0 ppm dH = 9.0 ppm are assigned to the –HC@N–
and phenolic protons, respectively. The remaining NMR spectrum
shows the region for aromatic protons. The 13C{1H} spectrum also
shows the azomethine peak at 165 ppm and the Ar–C–OH peak at
162 ppm, respectively. The aromatic resonances were explicitly as-
signed in the 1H and 13C{1H} spectra. The ligand H-QMP was re-
acted with the divalent metal ions of Ni, Co, Cu and Zn as shown
in Scheme 2. The elemental composition of the ligand and metal
complexes were unambiguously determined and reported which
suggest the proposed composition for all compounds. This is fur-
ther supported by ESI(+) mass spectrometry. Due to paramagnetic
nature of the metal complexes of H-QMP ligand, the NMR recorded
for all the complexes show broad unidentifiable peaks, therefore
results were not presented. All the complexes were found to be
non-electrolyte in nature confirming coordination of the OAcꢀ li-
gands in 3 and 4.
Since the IR spectra of all metal complexes are quite similar, the
discussion is confined to the most important vibrations in the re-
gion of 4000–600 cmꢀ1 in relation to the structure. The free ligand
IR spectrum shows a broad peak around 3400 cmꢀ1, which is as-
signed to the –OH stretch. This absorption region either decreases
in size or broadens to a large extent upon complexation with metal
ions. Coordinated water in case of 3 and 4 shows a similar absorp-
tion band. The sharp band in the H-QMP spectrum at 1624 cmꢀ1 is
(D
E = 1.73 ꢂ 10ꢀ3 eV) are similar enough to allow for their occupa-
tion with one single electron each. The splitting of orbitals is
shown in Fig. 2.
It was concluded by Gray and Ballhausen that for ligand-to-me-
tal transitions (exhibited unambiguously by complexes without an
intraligand
by nearly 10000 cmꢀl, whereas for metal-to-ligand transitions
(shown by complexes with an intraligand system), the three
p system) the two charge-transfer bands are separated
p
charge-transfer bands shown by nickel square planar complexes
are more closely spaced (approximately 2000–3000 cmꢀ1 apart)
[25,26]. The metal complexes formed with the aromatic monoan-
ionic ligand H-QMP are therefore expected to yield transitions
which will overlap in a narrow range.
For 2 the absorption occurs at 640 nm which was tentatively as-
signed to the 2A2g ? 2B1g transition on the basis of the
16.6 Mꢀ1 cmꢀ1 molar extinction coefficient value. It was presumed
that for the C2v symmetry of the cobalt complex the 2A2g ? 2B1g
transition is allowed whereas 2A2 ? 2A1 is forbidden. The 4.4
B.M. leffective value and the visible absorption band for 2 show that
the dyz and dzx set of orbitals and the dz2, dxy, dx2 ꢀ y2 set of orbi-
tals are spaced closely. The crystal filed splitting
(
D
E = 1.93 ꢂ 10ꢀ3 eV) between dz2 and the dxy, dx2 ꢀ y2 set of orbi-
tals is not very high as compared to complex 1 (see Fig. 2). There-
fore each of dz2 and dxy orbitals are occupied by a single electron
resulting in a high spin cobalt complex. For 3 the visible band ob-
served at 850 nm is assigned to the 2E ? 2T2 tetrahedral transition.
assigned to the
m
(C@N) vibration mode which was found to be shift-
ing by the difference of
D
m
(C@N) = 10–30 cmꢀ1 in metal complexes.
All transitions are assigned to the excitation from p
from the phenolate ion to dp⁄ orbitals of the metal ion. The
imine-nitrogen also donates p
electrons to the dp⁄ orbital of the
p electrons
In 3 and 4 the C@O stretchꢀf1or the coordinated acetate ion is ob-
served at 1729 and 1734 cm , respectively. The C-O stretch of ace-
tate is observed at 1280 cmꢀ1 for both complexes 3 and 4.
Except for the zinc complex all complexes show magnetic mo-
ments for spin only values. For 1, 2, and 3 the magnetic moment
values suggest that the complexes are high spin.
p
metal ion leading to transitions, which were presumed to be
occurring in the region of 500–700 nm. However, these bands are
obscured by the more intense phenolate to metal ion transitions
[25].

214
M. Ikram et al. / Inorganica Chimica Acta 390 (2012) 210–216
3.1. Structural analyses
the metal is not symmetrical. This is further evidenced by the dihe-
dral angle of 28.48° between the planes N(1)–C(7)–C(6)–C(1)–O(1)
(the chelate ring) and N(2)–C(16)–C(10)–C(15)–C(8) (the pendent
quinoline group). The dihedral angle between planes O(1)–
O(1A)–Ni(1)–N(1)–N(1A) and C(16)–N(2)–C(15)–C(10)–C(9)–
C(8)–N(1) is 48.87° showing significant non coplanarity of the
NiO2N2 plane and the six membered chelate ring formed with
the QMP anion and the metal. Aside from the planar complex core
the ligands exhibit two further planar parts; i.e. the quinoline moi-
ety and the phenyl moiety, which are both tilted slightly away
from the central plane in opposite direction. For the two ligands
the quinoline planes are (necessarily) coplanar as are the two phe-
nyl moieties. In the crystal packing each quinoline nitrogen atom,
which is not involved in direct bonding is pointing directly to
one nickel or cobalt atom of a neighboring molecule creating a
pseudo octahedral environment around the metal center, which
is exposed to two such functional groups from different neighbors
(Fig. 6). The distance between these nitrogen atoms and the nickel
centers is 2.973 Å (almost 1 Å longer than the direct Ni–N bond)
emphasizing that this is a rather week interaction. By comparing
the Ni–O [1.901 Å], Ni–N [2.032 Å] bond distances as well as the
Co–O [1.905 Å], Co–N [2.037 Å] bond distances with those in re-
lated complexes that do not bear any N-heterocyclic rings, i.e.
[1.833 and 1.902 Å] in (C26H24O6N2Ni) [28] and with [1.913 and
2.007 Å] in (C26H20CoN2O2) it becomes apparent that the metal
chelate core MO2N2 is less tightly bound due to the quinoline–me-
tal interactions forming the pseudo-octahedral geometry as shown
in Fig. 5 [27,28].
Both 1 and 2 crystallize from dichloromethane/ether solutions
at room temperature in the monoclinic space group P21/c, with
one half of the symmetric monomer in the asymmetric unit (Figs. 3
and 4). The structures of both complexes are, except for the central
metal, identical. Therefore we are refraining from an in-depth
study of the individual structures except where the difference is
apparent enough to warrant discussion and instead focus predom-
inantly on the structural evaluation of 1. The ORTEP plots for 1 and
2 show that both central metals are coordinated by two ligands in
trans fashion generating an almost perfect square planar coordina-
tion geometry (nickel and cobalt lie directly in the N2O2 plane with
no deviation from it). The O(1)–M–O(1A) and N(1)–M–N(1A)
[where M = Ni(II), and Co(II)] bond angles are (due to the space
group symmetry) exactly 180° and emphasize coplanarity
(Fig. 3). The O(1)–Ni(1)–N(1) is only slightly deviated from a per-
fect right angle with 90.37°. The small difference of the bond an-
gles C(1)–O(1)–Ni(1) (125.19°) and N(1)–C(7)–Ni(1) (120.87°)
shows that the chelate ring formed by the anionic ligands and
In complex 2 the C(1)–O(1)–Co(1) bond angle is 125.13°, and
the C(7)–N(1)–Co(1) bond angle is 120.84° showing little differ-
ence to 1. Similarly the dihedral angle between the planes pro-
duced by N(1)–C(7)–C(6)–C(1)–O(1) (the chelate ring) and N(2)–
C(16)–C(10)–C(15)–C(8) (the pendent quinoline group) is equal
to 28.83° showing the same trend of non coplanarity of the chelate
atoms and with the rest of the molecule.
Fig. 2. Crystal field splitting for 1 and 2 on the basis of UV–Vis and leffective
.
3.2. AChE and BChE inhibition
New cholinesterase inhibitors, in addition to their potential
clinical importance if followed by proper pharmacological-investi-
gations, would help in defining the role of BChE in brain develop-
ment, health and ageing and reveal the value of BChE inhibition
as a novel strategy for the treatment of AD [7]. Here, we report
the AChE and BChE inhibition capabilities of the four synthesized
metal complexes and their mutual relationships (Table 1). All com-
pounds were found inactive against acetylcholinesterase. The co-
balt and copper QMP complexes were shown to be selectively
inhibiting BChE, whereas the remaining compounds are inactive.
It was previously reported that during the development of AD
the activity of BChE increases by 40–90%. Examination of the amy-
loid plaque also show the increased concentration of BChE [35,36].
Therefore the selective BChE inhibitors like copper and cobalt QMP
complexes may be good therapeutic agents. It has been shown that
the amyloid protein precursor (APP) possesses specific selective
Zn2+ and Cu2+ binding sites which mediate its physicochemical
behavior and if occupied, may cause inhibition of AChE and BChE
[29]. BChE inhibitors have been used to delay symptoms of AD pa-
tients by virtue of their ability to enhance acetylcholine availabil-
Fig. 3. Molecular structure of 1. Thermal ellipsoids are shown at 50% probability. H
atoms are omitted for clarity reasons. Selected bond lengths [Å] and angles [°]: Ni–O
1.9011(11); Ni–N 2.0323(13); O–Ni–O 180; N–Ni–N 180; O–Ni–N (intra) 90.37(5);
O–Ni–N (inter) 89.63(5).
ity. Their involvement in
a cholinergic anti-inflammatory
pathway connect BChE and AChE with a possible marker of low-
grade systemic inflammation observed in Type-2 diabetes, obesity,
hypertension, coronary heart disease, and AD [30,31]. Thus, new
metal based inhibitors for BChE are among the most sought after
targets for therapeutic use in AD treatment [32,33]. Our results,
as summarized in Table 1 clearly show that the copper complex
is much more active than the cobalt complex, which is in accor-
Fig. 4. Molecular structure of 2. Thermal ellipsoids are shown at 50% probability. H
atoms are omitted for clarity reasons. Selected bond lengths [Å] and angles [°]: Ni–O
1.905(11); Ni–N 2.037(13); O–Co–O 180; N–Co–N 180; O–Co–N (intra) 89.55(5); O–
Co–N (inter) 90.45(5).

M. Ikram et al. / Inorganica Chimica Acta 390 (2012) 210–216
215
Fig. 5. Intermolecular interactions between quinoline nitrogens and nickel in the crystal structure of 1 leading to the pseudo-octahedral coordination environment of nickel.
Fig. 6. Crystal packing diagrams for 1 and 2.
dance with senile plaque naturally containing copper. Due to the
abundance of copper in particular in the brain, complexes are ex-
pected to be actively involved in decreasing the amyloid plaques
in AD patients as well as eliminating oxidative stress from proac-
tive metal ions, provided the metal binds at the targeted binding
sites of APP [8]. It has been shown with potentiometric and spec-
troscopic studies that copper coordinates at the N-terminus of
the Ab-peptides, but in equilibrium with the internal histidyl
(His13 and His14) sites. The binding based in both cases on the
deprotonation of amide groups present on the surface of plaques,
but the latter binding mode strongly favors copper over other me-
tal ions [34].

216
M. Ikram et al. / Inorganica Chimica Acta 390 (2012) 210–216
Table 1
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Acknowledgment
The authors Muhammad Ikram and Sadia Rehman gratefully
acknowledge the Higher Education Commission (HEC) Pakistan
for providing the indigenous and IRSIP scholarships for this work.
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}
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