Mixed-ligand metal complexes containing an ONS Schiff base and imidazole/benzimidazole ligands: Synthesis, characterization, crystallography and biological activity

Article abstract of DOI:10.1007/s11243-014-9842-9

Salicylaldehyde-4-methylthiosemicarbazone (H₂MTSali) has been prepared via the condensation reaction of 4-methyl-3-thiosemicarbazide and salicylaldehyde. Four new mixed-ligand copper(II) and nickel(II) complexes with a general formula [M(MTSali)L] (M = Cu²⁺ or Ni²⁺; L = co-ligand) were synthesized, where L is either imidazole (im) or benzimidazole (bzim). The Schiff base and its mixed-ligand complexes were characterized by IR and UV/Vis spectroscopy, and the complexes by molar conductivity and magnetic susceptibility measurements. The spectroscopic data indicated that the Schiff base behaves as a tridentate ONS donor ligand coordinating via the phenoxide-oxygen, azomethine-nitrogen, and thiolate-sulphur atoms. Magnetic data indicate a square planar environment for the nickel(II) complexes while molar conductance values indicate that the metal complexes are essentially non-electrolytes in DMSO solution. X-ray crystallography shows Cu(MTSali)bzim (1) and Ni(MTSali)bzim (3) to be isostructural, with the metal(II) ions being coordinated by a N₂OS donor set that defines an approximate square planar geometry; in both cases, the benzimidazole is splayed with respect to the coordination plane. The copper(II) complexes were active against MDA-MB-231 and MCF-7 breast cancer cell lines, more so than H₂MTSali, whereas the nickel(II) complexes were inactive.

Full text of DOI:10.1007/s11243-014-9842-9

Transition Met Chem
DOI 10.1007/s11243-014-9842-9
Mixed-ligand metal complexes containing an ONS Schiff base
and imidazole/benzimidazole ligands: synthesis, characterization,
crystallography and biological activity
•
Nurul Ain Mazlan Thahira Begum S. A. Ravoof Edward R. T. Tiekink
•
•
•
Mohamed Ibrahim Mohamed Tahir Abhi Veerakumarasivam Karen A. Crouse
•
Received: 4 May 2014 / Accepted: 27 May 2014
Ó Springer International Publishing Switzerland 2014
Abstract Salicylaldehyde-4-methylthiosemicarbazone
(H2MTSali) has been prepared via the condensation reac-
tion of 4-methyl-3-thiosemicarbazide and salicylaldehyde.
Four new mixed-ligand copper(II) and nickel(II) com-
plexes with a general formula [M(MTSali)L] (M = Cu2?
or Ni2?; L = co-ligand) were synthesized, where L is
either imidazole (im) or benzimidazole (bzim). The Schiff
base and its mixed-ligand complexes were characterized by
IR and UV/Vis spectroscopy, and the complexes by molar
conductivity and magnetic susceptibility measurements.
The spectroscopic data indicated that the Schiff base
behaves as a tridentate ONS donor ligand coordinating via
the phenoxide-oxygen, azomethine-nitrogen, and thiolate-
sulphur atoms. Magnetic data indicate a square planar
environment for the nickel(II) complexes while molar
conductance values indicate that the metal complexes are
essentially non-electrolytes in DMSO solution. X-ray
crystallography shows Cu(MTSali)bzim (1) and
Ni(MTSali)bzim (3) to be isostructural, with the metal(II)
ions being coordinated by a N2OS donor set that defines an
approximate square planar geometry; in both cases, the
benzimidazole is splayed with respect to the coordination
plane. The copper(II) complexes were active against MDA-
MB-231 and MCF-7 breast cancer cell lines, more so than
H2MTSali, whereas the nickel(II) complexes were inactive.
Introduction
Thiosemicarbazones have received considerable attention
since the 1950s owing to their ability to coordinate metal
centres [1] and due to the fact that these molecules and their
complexes have applications as therapeutics and imaging
agents [2]. For example, metal complexes of various
substituted thiosemicarbazones such as those derived from
9-anthraldehydethiosemicarbazone have been reported to
possess cytotoxic properties against several human cancer
cell lines such as MDA-MB-231 and MCF-7 breast cancers
[3]. In another study, 2-benzoylpyridine-derived N(4)-
substituted thiosemicarbazones were shown to have anti-
fungal activity against Candida albicans and were reported
to be more potent than an analogous unsubstituted com-
pound, 2-benzoylpyridine thiosemicarbazone [4]. It has also
been reported that the thiosemicarbazone Schiff base of
2-hydroxyacetophenone inhibited the growth of Paecilo-
myces variotii, and its activity was higher than the copper(II)
complex containing the same Schiff base, suggesting that
biological activity depended on the size of the complex [5].
Salicylaldehyde thiosemicarbazone Schiff bases and their
metal complexes have also been well studied, again due to
N. A. Mazlan Á T. B. S. A. Ravoof (&) Á
M. I. M. Tahir Á K. A. Crouse
Department of Chemistry, Faculty of Science, Universiti Putra
Malaysia, 43400 Serdang, Selangor, Malaysia
e-mail: thahira@upm.edu.my
E. R. T. Tiekink
Department of Chemistry, University of Malaya,
50603 Kuala Lumpur, Malaysia
A. Veerakumarasivam
Genetic Medicine Research Center, Faculty of Medicine and
Health Sciences, Universiti Putra Malaysia, 43400 Serdang,
Selangor, Malaysia
A. Veerakumarasivam
Perdana University Graduate School of Medicine, Perdana
University, 43400 Serdang, Selangor, Malaysia
K. A. Crouse
Department of Chemistry, School of Science and Technology,
Cape Breton University, Sydney, NS B1P 6L2, Canada
123

Transition Met Chem
OH
Experimental
H
H
N
N
All chemicals were of analytical grade and were used as
supplied. Reagents: 4-phenyl-3-thiosemicarbazide (Sigma
Aldrich), salicylaldehyde (Fluka), imidazole (Acros
organic), benzimidazole (Acros organic), copper(II) acetate
monohydrate (Ajax Chemical), nickel(II) acetate tetrahy-
drate (Fluka) and nitric acid (65 %, R & M).
N
S
Fig. 1 Chemical structure of salicylaldehyde-4-methyl-3-thiosemi-
carbazone (H2MTSali)
Solvents: Absolute ethanol (99.8 %, Systerm), dichlo-
romethane (Systerm) and dimethyl sulfoxide (DMSO;
Systerm).
their various biological applications [6–8]. While there are a
number of metal complexes derived from salicylaldehyde-4-
methyl-3-thiosemicarbazone (H2MTSali; Fig. 1) reported in
the literature [9–11], to date there are no complementary
cytotoxicity data. The Schiff bases synthesized in the present
study, by the reaction of thiosemicarbazide with salicylal-
dehyde derivatives, have a backbone similar to that in the
ligand derived from o-vanillin with N(4)-phenylsemicar-
bazide in a series of ruthenium(II) carbonyl complexes
which exhibited antibacterial activity against Bacillus sp.
and Pseuodomonas sp. [6]. Some copper(II), nickel(II) and
cobalt(II) complexes have been synthesized with methyl-
thiosemicarbazide and 5-formyl-6-hydroxy coumarin/8-
formyl-7-hydroxy-4-methylcoumarin and shown to have
remarkable activity against various bacterial strains [7].
Furthermore, nickel(II) complexes of salicylaldehyde-4-
substituted thiosemicarbazone were also reported to be good
antimicrobial agents against Escherichia coli and Bacillus
subtilis [8].
The CHNM elemental analyses were performed on a
LECO CHNS-932 elemental analyzer. IR spectra were
recorded on PerkinElmer 100 spectrophotometer
(4,000–280 cm-1). Molar conductance of 10-3 M solutions
of the metal complexes in DMSO were measured using a
Jenway 4310 conductivity meter and a dip-type cell with a
platinised electrode. Magnetic susceptibilities were mea-
sured with a Sherwood Scientific MSB-AUTO magnetic
susceptibility balance at 298 K. The UV–Vis spectra were
recorded in the range of 1,000–200 nm on a Shimadzu UV-
2501 PC recording spectrophotometer.
Preparation of salicylaldehyde-4-methyl-3-
thiosemicarbazone (H2MTSali)
A solution of salicylaldehyde (0.1 mol) in absolute ethanol
(10 ml) was added to a solution of 4-methyl-3-thiosemi-
carbazide (0.1 mol) in 40 ml of the same solvent. The
mixture was heated and stirred until a white precipitate
formed which was filtered off, washed with cold ethanol
and dried over silica gel. Yield: 81 %, m.p: 213–214 °C.
(lit. m.p: 207 °C [17] ).
In the present study, in order to prepare a new series of
mixed-ligand metal complexes, the single atom donor
ligands, imidazole and benzimidazole, were reacted
simultaneously with H2MTSali and copper(II) or nickel(II)
acetate. The imidazole ring is biologically relevant as it is a
mimic of the histidine moiety and hence is able to act as a
co-ligand in metal complexes, potentially enabling them to
bind with biomolecules [12]. Benzimidazole is a bicyclic
derivative of imidazole. There are several benzimidazole-
based drugs such as the proton pump inhibitor lansopraz-
oleÒ used to treat gastroesophageal reflux disease, and
gastric and duodenal ulceration [13], the antihelmenthic
drug mebendazoleÒ [14] and the anti-fungal agent thia-
bendazoleÒ [15]. Bearing hydrogen atom donors and
acceptors, imidazole and benzimidazole may contribute to
interesting supramolecular architectures [16].
General method for the synthesis of the mixed-ligand
metal complexes
The required metal salt (Cu(CH3COO)2Á4H2O or Ni(CH3-
COO)2ÁH2O, 1 mmol) was dissolved in 10 ml of absolute
ethanol. An equimolar amount of imidazole or benzimid-
azole in 15 ml of dichloromethane was added to this
solution, and the mixture was heated with stirring for about
15 min. A solution of the Schiff base, H2MTSali (0.2093 g,
1 mmol), dissolved in hot ethanol (30 ml) was then added
to the metal-imidazole solution. The resulting mixture was
heated and stirred until the final volume was reduced by
half. The solid formed upon cooling the mixture to room
temperature was filtered off. The synthesis of the com-
plexes generally required a large excess of imidazole/
benzimidazole to ensure that they remained as co-ligands
[18].
This new series of complexes were investigated as a part
of our ongoing research into mixed-ligand complexes and
the evaluation of their biological properties. It is hoped that
this work will provide some insight into the potential
biological properties of mixed-ligand metal complexes
containing tridentate ONS Schiff bases and imidazole
derivatives.
Physiochemical and spectroscopic data for H2MTSali
and 1–4 are given in Tables 1 and 2, respectively.
123

Transition Met Chem
Table 1 Physical properties and elemental analysis
Compounda
Colour
m.p (°C)
Kb
lc (BM)
Elemental Analysisd (%)
C
H
N
M
H2MTSali
White
213–214
196–197
207–208
286–288
236–237
–
–
50.78(51.65)
49.53(49.41)
42.76(42.66)
50.00(50.03)
43.33(43.28)
5.39(5.30)
4.58(4.14)
3.96(3.58)
4.25(3.94)
4.12(3.63)
19.92(20.08)
18.86(18.01)
21.13(20.73)
19.14(18.23)
22.13(21.03)
–
Cu(MTSali)bzim (1)
Cu(MTSali)im (2)
Ni(MTSali)bzim (3)
Ni(MTSali)im (4)
a
Dark brown
Green–brown
Brown
0.39
0.34
0.75
0.57
1.96
1.88
Dia
Dia
16.34(16.38)
18.97(18.81)
15.41(15.28)
18.26(17.62)
Brown
H2MTSali salicylaldehyde-4-methyl-3-thiosemicarbazone, bz benzimidazole, im imidazole
Molar conductance (X-1 cm2 mol-1) of 10-3 M solutions in DMSO
Magnetic moments at 298 K
b
c
d
Calculated values are given in parentheses
Table 2 Selected IR and electronic absorptions
Compound
IR bands (cm-1
)
Electronic spectra (in DMSO) kmax(log e)c
v (O–H) v (N–H) v (C=N)a,b
v (N–N) v (C=S) v (C–S)
H2MTSali
3,256 m 3,358 m –, 1,604 s
1,027 m 872 m
–
256(4.06); 335(3.49)
Cu(MTSali)bzim (1)
Cu(MTSali)im (2)
Ni(MTSali)bzim (3)
Ni(MTSali)im (4)
a
–
–
–
–
3,230 m 1,741 w, 1,594 s
3,443 w 1,651 m, 1,596 s
3,248 m 1,724 w, 1,592 s
1,023 m
1,023 m
1,022 s
–
–
–
–
812 s
836 s
829 m
825 m
255(4.88); 324(4.34); 394(4.20); 572(2.28)
263(4.29); 325(4.32); 394(4.21); 527(2.39)
255(5.01); 308(4.26); 365(4.27); 733(0.61)
258(4.43); 307(4.05); 368(4.18); 731(0.66)
3,449 w 1,653 w, 1,595 m 1,021 w
C=N band from imidazole/benzimidazole
b
c
C=N band from the H2MTSali
Units of kmax is in nm and units of log e is in L mol-1 cm-1
X-ray crystal structure analyses of Cu(MTSali)bzim (1)
and Ni(MTSali)bzim (3)
refinement details are given in Table 3. The molecular
structure diagrams were drawn with ORTEP for Windows
[21], and the crystal packing diagram was drawn with
DIAMOND [22]. Crystallographic data for the structures
reported herein have been deposited with the Cambridge
Crystallographic Data Centre. CCDC deposition numbers
997831 and 997832 contain the supplementary crystallo-
graphic data for Cu(MTSali)bz (1) and Ni(MTSali)bz (3),
respectively. The data can be obtained free of charge from
the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CG2IEZ, UK: Fax: (?44) 1223-336-033;
or email: deposit@ccdc.cam.ac.uk or at http://www.ccdc.
cam.ac.uk/conts/retrieving.html.
Prismatic pale yellow crystals of 1 were obtained after
leaving the mother liquor at room temperature for 3 days,
while dark brown plates of 3 were collected after a slow
evaporation from its methanol/acetonitrile (1:1) solution.
The selected crystals were mounted on a fibre loop using
perfluoropolyether oil which was placed on an Oxford Dif-
fraction Gemini CCD diffractometer and rapidly cooled in a
stream of cold N2 to 100 K using an Oxford Cryosystems
Cobra unit. Diffraction data were measured with graphite-
˚
monochromated Mo Ka radiation, k = 0.71073 A, and were
processed with the CrysAlis Pro software suite [19]. The
structures were solved by direct methods (SHELXS97 [20]
through the WinGX Interface [21] ) and refined (anisotropic
displacement parameters, C-bound hydrogen atoms in the
riding model approximation and a weighting scheme of the
formw = 1/[r2(F20) ? aP2 ? bP] where P = (F02 ? 2F2c)/3)
with SHELXL97 on F2 [20]. The N-bound hydrogen
atoms were located from difference maps and refined
Cytotoxicity assays
The MCF-7 (oestrogen receptor-positive human breast
cancer cells) and MDA-MB-231 (oestrogen receptor-neg-
ative human breast cancer cells) cell lines were obtained
from the National Cancer Institute, USA. The cells were
cultured in 25 cm 9 25 cm 9 25 cm tissue culture flasks
˚
with N–H = 0.88 0.01 A. Crystallographic data and
123

Transition Met Chem
Results and discussion
Table 3 Crystallographic data and refinement details for 1 and 3
Compound
1
3
Syntheses and characterization
Empirical
formula
C
16H15CuN5OS
C16H15N5NiOS
The physical properties and analytical data of the Schiff
base, H2MTSali, and its mixed-ligand metal complexes are
given in Table 1. Elemental analysis indicates good
agreement with the proposed formulae. The Schiff base is
soluble in most organic solvents, while the metal com-
plexes are soluble in tetrahydrofuran, methanol and
DMSO. The Schiff base and its metal complexes were
stable in a desiccator for months.
Formula
weight
388.93
384.10
Crystal system Monoclinic
Monoclinic
Space group
P21/c
P21/c
˚
a = 12.2188(5) A
˚
a = 12.3406(3) A
Unit cell
dimensions
˚
b = 6.6262(3) A
˚
b = 6.7682(2) A
˚
c = 19.9168(14) A
˚
c = 19.2353(4) A
b = 94.238(5)°
˚
1,608.14(15) A
b = 95.465(2)°
˚
1,599.30(7) A
3
3
The magnetic moments of the copper(II) complexes
1 and 2 are 1.88 and 1.96 BM, respectively (Table 1),
as expected for d9 complexes [24]. Nickel(II) com-
plexes 3 and 4 exhibit diamagnetic properties which
indicate distorted square planar geometry. The com-
plexes are non-electrolytes in DMSO solution [25],
indicating that both the Schiff base and imidazole (or
benzimidazole) are coordinated and do not exist as free
ions/species.
Volume
Z
4
4
Dx
1.606 g cm-3
1.501 mm-1
1.595 g cm-3
1.357 mm-1
Absorption
coefficient
(l)
F(000)
796
792
Crystal size
0.09 9 0.15 9 0.22 mm 0.10 9 0.22 9 0.25 mm
Theta range
for data
collection
2.6–27.5°
2.6–27.5°
In the infrared spectrum of H2MTSali, a strong azo-
methine band, v(C=N), was observed at 1,604 cm-1 as was
a medium intensity v(N–N) band at 1,027 cm-1 [26].
Complexation shifted these bands to lower frequencies
(Table 2) indicating coordination through the azomethine
nitrogen [22]. A weak v(C=N) band from the imidazole
moieties appears in the region 1,651–1,741 cm-1, which is
lower than for the respective free ligand, indicating their
presence in 1–4 as a co-ligand. Upon complexation, the
v(O–H) band of H2MTSali was no longer present in the IR
spectra of 1–4 further supporting the coordination of the
phenoxide-oxygen of MTSali to the copper(II) and nick-
el(II) ions. The medium v(C=S) band at 872 cm-1 of the
H2MTSali Schiff base was not observable in the spectra of
the metal complexes because of the formation of a C–S
bond upon complexation of the H2MTSali with the central
metal ion. The presence of v(C–S) bands around
812–836 cm-1 [27] indicates the H2MTSali coordinates to
the copper(II) and nickel(II) ion in its thiolate form as a
binegatively charged tridentate ligand.
Meas. data/
unique data/
Rint
14,323/3,635/0.059
2,923/2/224
1.02
26,129/3,646/0.056
3,282/2/224
1.03
Obs. data/
restraints/
parameters
Goodness of
fit on F2
Final R indices R = 0.041, Rw = 0.096 R = 0.028, Rw = 0.071
[I [ 2r(I)]
a and b in
weighting
scheme
0.054, 1.058
0.040, 0.972
Final R indices R = 0.059, Rw = 0.111 R = 0.033, Rw = 0.076
(all data)
-3
-3
˚
0.66 and -0.79 e A
˚
0.40 and -0.34 e A
Largest
residual
electron
density peak
and hole
The UV/Vis spectra of the complexes in DMSO solution
are given in Table 2. The bands (255–263 and 307–325 nm)
are attributed to intra-ligand n–p* and p–p* transitions,
respectively. A single weak d–d transition (572 nm for 1
and 527 nm for 2) indicates that the copper(II) d9 metal ion
is in a square planar environment [28]. The diamagnetic
nickel(II) complexes displayed a weak d–d transition as
expected for square planar nickel(II) (733 nm for 3 and
731 nm for 4) [29]. The appearance of S ? M charge
transfer transitions at 365–394 nm supports ligation to the
metal ion through sulphur [30].
containing RPMI 1640 culture medium supplemented with
10 % foetal bovine serum (FBS) and 1 % penicillin. The
cytotoxicity was determined using the 3-(4,5-dimethylthi-
azol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay
(Sigma, USA) as described by Mosmann [23]. Controls
that contained untreated cells were included for each
sample. Cytotoxicity was expressed as IC50, i.e. the con-
centration of drug that inhibits the growth of cancer cells
by 50 % as compared to the control. Tamoxifen was used
as the standard cytotoxin.
123

Transition Met Chem
˚
Table 4 Selected bond lengths (A) and angles (8)
Parameter
1 (M=Cu)
3 (M=Ni)
M–S1
2.2466(8)
1.933(2)
1.945(2)
1.987(2)
1.743(3)
1.390(3)
1.293(4)
1.327(4)
167.90(7)
85.84(8)
93.57(9)
173.41(10)
2.1422(5)
1.8712(12)
1.8555(14)
1.9105(15)
1.7361(18)
1.4014(19)
1.306(2)
M–O1
M–N1
M–N4
S1–C8
N1–N2
N1–C1
N2–C8
1.314(2)
S1–M–O1
S1–M–N1
O1–M–N1
N1–M–N4
173.84(4)
87.43(5)
95.61(6)
174.44(6)
The structure determination of 1 shows that the cop-
per(II) atom adopts a four-coordinate geometry in which
the dinegative, tridentate MTSali anion is attached to it via
its phenoxide-oxygen, azomethine-nitrogen and thiolate-
sulphur donor atoms, and the fourth site is occupied by a
benzimidazole nitrogen atom. The deviations of the S1, O1,
N1 and N4 donor atoms from their least-squares plane are
Fig. 2 Molecular structure of Cu(MTSali)bzim (1) with displacement
ellipsoids drawn at the 70 % probability level and showing atom-
numbering scheme
˚
0.1527(10), 0.1768(11), -0.1686(11) and -0.1610(10) A,
respectively, with the root mean square (rms) deviation
˚
˚
being 0.1650 A. The Cu atom lies 0.0520(11) A above the
least-squares plane. The major deviation of an angle sub-
tended at the Cu centre by the donor atoms from 90/180° is
approximately 12°, for S1–Cu–O1, so that to a first
approximation, the coordination geometry is based on a
square planar arrangement. The deviation from an ideal
square planar geometry is likely to be partly steric in ori-
gin. The dihedral angle between the N2OS donor set and
the least-squares plane through the benzimidazole mole-
˚
cule (rms deviation = 0.0169 A) is 44.80(6)° indicating a
splayed disposition with the five-membered ring oriented
towards the sulphur atom. The avoidance of a steric clash
might explain why the five-membered chelate ring is best
described as having an envelope conformation with the Cu
˚
atom being the flap atom, lying 0.304(4) A above the plane
Fig. 3 Molecular structure of Ni(MTSali)bzim (3) with displacement
ellipsoids drawn at the 70 % probability level and showing atom-
numbering scheme
of the four remaining atoms of the chelate ring (rms
˚
deviation = 0.0086 A). By contrast, the rms deviation for
˚
the six-membered chelate ring is 0.0055 A.
The crystal structure of H2MTSali is available [10], and
compared to the coordinated MTSali dianion in 1, the
thione-sulphur and hydroxyl-oxygen atoms are anti. The
availability of the non-coordinated structure enables a
discussion of the systematic changes in key bond lengths
upon coordination. The major difference between the
neutral and anionic forms is found in the S1–C8 and
N2=C8 bond lengths of 1 which are significantly elongated
and contracted compared to the values in H2MTSali of
X-ray crystallographic analysis of Cu(MTSali)bzim (1)
and Ni(MTSali)bzim (3)
Cu(MTSali)bzim (1) and Ni(MTSali)bzim (3) are isostruc-
tural, each crystallising in the monoclinic space group
P21/c. Crystallographic data and refinement details are col-
lated in Table 3, ORTEP diagrams are given in Figs. 2 and 3,
and selected geometric parameters appear in Table 4.
123

Transition Met Chem
Fig. 4 Supramolecular chain in
Cu(MTSali)bzim (1) mediated
by N–HÁÁÁO and N–HÁÁÁN
hydrogen bonding, shown as
orange and blue dashed lines,
respectively. (Color figure
online)
Table 5 Cytotoxicity scores (IC50 value, lM) for H2MTSali and 1–4
˚
1.6833(13) and 1.3501(16) A, respectively [10], confirming
the formation of a thiolate-S1 atom and an azo N2=C8
bond.
Compound
MCF-7a
MDA-MB-231b
H2MTSali
2.60
0.22
[5.0
0.40
The essential features of the molecular structure of
Ni(MTSali)bzim (3) match those just described for 1. The
expected systematic contraction in the Ni-donor atom bond
lengths is apparent from Table 4. The distortions from the
ideal square planar geometry are markedly less as seen, for
Cu(MTSali)bzim (1)
Cu(MTSali)im (2)
Ni(MTSali)bzim (3)
Ni(MTSali)im (4)
Tamoxifen (Standard drug)
0.20
0.39
[5.0
[5.0
4.04
[5.0
[5.0
13.46
˚
example, in the reduced rms deviation of 0.0904 A for the
N2OS donor set; the dihedral angle between the donor set and
˚
the benzimidazole molecule (rms deviation = 0.0123 A) is
IC50 is the inhibitory concentration at 50 %, i.e. the concentration of
drug that inhibits the growth of cancer cells by 50 %. IC50 values
\0.5 lM indicate that the complex is potent, whereas IC50 scores of
0.5–5.0 and[5.0 lM indicate that the compound is moderately active
and inactive, respectively
49.23(4)°. The six-membered chelate ring is planar (rms
˚
deviation = 0.0079 A), but the five-membered is still an
˚
envelope with Ni being the flap atom, lying 0.134(2) A above
a
MCF-7 (oestrogen receptor-positive human breast carcinoma)
b
the least-squares plane of the remaining atoms (rms devia-
˚
tion = 0.0011 A). Given the close similarity in the molec-
MDA-MB-231 (oestrogen receptor-negative- human breast
carcinoma)
ular structures of 1 and 3, the greater distortions from the
ideal geometry in 1 are ascribed to the presence of unpaired
electrons about the copper(II) ion.
via benzimidazole-N–HÁÁÁO(phenoxide) hydrogen bonds to
generate a supramolecular helical chain as illustrated for 1
in Fig. 4.
The molecular structures of 1 and 3 have precedents in
the literature whereby the benzimidazole ligand is replaced
by a pyridine molecule which adopts a similar splayed
relationship to the square plane [31]; as an aside, these
structures are also isostructural.
Cytotoxicity
The most notable feature of the crystal packing for 1
(and 3) is the formation of N–HÁÁÁO and N–HÁÁÁN hydrogen
bonds; geometric details characterising these are given.1
The amide-N–HÁÁÁN(azomethine) hydrogen bonds occur
between centrosymmetrically related molecules leading to
eight-membered {ÁÁÁHNCN}2 supramolecular synthons.
The dimeric units thus formed assemble along the b-axis
The cytotoxic scores are given in Table 5. The copper(II)
complexes are potent against both MCF-7 (oestrogen
receptor-positive human breast cancer) and MDA-MB-231
(oestrogen receptor-negative human breast cancer) cell
lines. The Schiff base, H2MTSali, shows moderate activity
towards the MCF-7 cells, while it was inactive towards
MDA-MB-231. The simple metal(II) acetate salts used in
the complex preparation were inactive against both cell
lines. Complexation of H2MTSali to copper(II) resulted in
a more cytotoxic compound. Complex 2, which had an
imidazole co-ligand, was slightly more cytotoxic than
complex 1, with benzimidazole. Generally, low water
solubility of benzimidazoles is thought to be a limiting
factor for their bioavailability [32]. Both nickel(II) com-
plexes, 3 and 4, were inactive against both breast cancer
1
i
˚
Intermolecular hydrogen bonds in 1: N3–H1nÁÁÁN2 = 2.179(14) A,
i
˚
N3ÁÁÁN2 = 3.043(3) A with angle at H1n = 168(3)°. N5–
H1nÁÁÁO1ii = 1.863(19) A, N5–H2nÁÁÁO1 = 2.726(3) A with angle
at H2n = 166(3)°. Symmetry operations i: -x, 2 - y, 1 - z; ii: 1 -
x, ‘ ? y, 1‘ - z. Intermolecular hydrogen bonds in 3: N3–
ii
˚
˚
i
i
˚
˚
H1nÁÁÁN2 = 2.201(12) A, N3ÁÁÁN2 = 3.061(2) A with angle at
˚
H1n = 167.5(18)°.
N5–H1nÁÁÁO1ii = 1.870(14) A,
N5–
H2nÁÁÁO1ii = 2.7329(19) A with angle at H2n = 167.9(18)°. Sym-
˚
metry operations i: 1 - x, 1 - y, 1 - z; ii: 2 - x, ‘ ? y, 1‘ - z.
123

Transition Met Chem
5. West DX, Yang Y, Klein TL, Goldberg KI, Leberta AE, Valdes-
Martinez J, Toscano RA (1995) Polyhedron 14:1681
6. Jayabalakrishnan C, Natarajan K (2001) Synth React Inorg Metal
Org Chem 31:983
cell lines. The IC50 values for 1 and 2 indicate that they
deserve further study.
7. Patil SA, Naik VH, Kulkarni AD, Badami PS (2010) Spectrochim
Acta A 75:347
Conclusion
8. Saswati, Dinda R, Schmiesing CS, Sinn E, Patil YP, Nethaji M,
Stoeckli-Evans H, Acharyya R (2013) Polyhedron 50:354
9. Lobana TS, Kumari P, Butcher RJ, Jasinski JP, Golen JA (2012)
Z Anorg Allg Chem 638:1861
The reaction of Cu(II) and Ni(II) acetate with salicylalde-
hyde-4-methyl-3-thiosemicarbazone (H2MTSali) in the
presence of imidazole or benzimidazole yielded a new series
of mixed-ligand transition metal complexes. The dinegative
MTSali anion coordinates to the central metal ion as a tri-
dentate ONS donor ligand, yielding distorted square planar
complexes, as supported by spectroscopic analysis and
confirmed by X-ray crystallography. H2MTSali is moder-
ately active against MCF-7 but inactive towards MDA-MB-
231. Activity against both the MCF-7 and MDA-MB-231
cell lines was markedly enhanced by copper(II) complexa-
tion with imidazole and benzimidazole as an additional
ligand, whereas nickel(II) had the opposite effect.
ˇ
´
´
´
´
10. Vrdoljak V, Cindric M, Milic D, Matkovic-Calogovic D, Novak
P, Kamenar B (2005) Polyhedron 24:1717
11. Carballo R, Castineiras A, Covelo B, Garcia-Matinez E, Niclos J,
Vazquez-Lopez EM (2004) Polyhedron 23:1505
12. Heijden M, Vliet PMV, Haasnoot JG, Reedijk J (1993) Dalton
Trans 24:3675
13. Miner P, Katz PO, Chen Y, Sostek M (2003) Am J Gastroenterol
98:2616
14. Borgers M, de Nollin S, De Brabander M, Thienpot D (1975) Am
J Vet Res 36:1153
15. Gann PH, Neva FA, Gam AA (1994) J Infect Dis 169:1076
16. Goodgame DML, Goodgame M, Rayner-Canham GW (1969)
Inorg Chim Acta 3:406
17. Taniyama H, Miyoshi F, Sakakibara E, Uchida H (1957) Yak-
ugaku Zasshi 77:191
Acknowledgments We thank the Department of Chemistry and the
Molecular Genetics Laboratory, Universiti Putra Malaysia, for pro-
viding the laboratory facilities and the Chemical Crystallography
Laboratories (UPM) for provision of X-ray crystallographic services.
The research was funded by Universiti Putra Malaysia (UPM) under
the Research University Grant Schemes (RUGS No. 9419400) and the
Malaysian Fundamental Research Grant Scheme (FRGS No. 01–02–
13–1344FR). N.A.M wishes to thank the UPM for the award of a
Graduate Research Fellowship. This research is also supported by
High Impact Research MoE Grant UM.C/625/1/HIR/MoE/SC/03
from the Ministry of Higher Education, Malaysia, and the University
of Malaya.
18. Ravoof TBSA, Crouse KA, Tahir MIM, How FNF, Rosli R,
Watkins DJ (2010) Transit Metal Chem 35:871
19. Agilent (2011) CrysAlis PRO. Agilent Technologies, Yarnton
20. Sheldrick GM (2008) Acta Cryst A64:112
21. Farrugia LJ (2012) J Appl Cryst 45:849
22. Brandenburg K (2006) DIAMOND. Crystal Impact GbR, Bonn
23. Mosmann T (1983) J Immunol Methods 65:5
24. Tarafder MTH, Ali MA, Wee DJ, Azahari K, Silong S, Crouse
KA (2000) Transit Metal Chem 25:456
25. Ravoof TBSA, Crouse KA, Tahir MIM, Cowley AR, Ali MA
(2004) Polyhedron 26:1159
26. Hossain ME, Begum J, Alam MN, Nazimuddin M, Ali MA
(1993) Transit Metal Chem 18:497
27. West DX, Nassar AA, El-Saied FA, Ayad MI (1999) Transit
Metal Chem 24:617
28. Bolos CA, Papazisis KT, Kortsaris AH, Voyatzi S, Zambouli D,
Kyriakidis DA (2002) J Inorg Biochem 88:25
29. Ravoof TBSA, Crouse KA, Tahir MIM, Cowley AR, Ali MA
(2004) Polyhedron 23:2491
30. Ali MA, Mirza AH, Bujang FH, Hamid MHSA, Bernhardt PV
(2006) Polyhedron 25:3245
31. Lobana TS, Kumari P, Hundal G, Butcher RJ (2010) Polyhedron
29:1130
References
1. Lobana TS, Sharma R, Bawa G, Khanna S (2009) Coord Chem
Rev 253:977
2. Dilworth JR, Hueting R (2012) Inorg Chim Acta 389:3
3. Beckford FA, Shaloski M Jr, Leblanc G, Thessing J, Lewis-Al-
leyne LC, Holder AA, Li L, Seeram NP (2009) Dalton Trans
48:10757
4. Costa RFF, Rebolledo AP, Matencio T, Calado HDR, Ardisson
JD, Cortes ME, Rodrigues BL, Beraldo H (2005) J Coord Chem
58:1300
32. Capece BPS, Castells G, Perez F, Arboix M, Cristofol C (2000)
Vet Res Commun 24:339
123