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Polyhedron 27 (2008) 1141–1149

www.elsevier.com/locate/poly

Synthesis and characterization of cobalt(II), nickel(II),

copper(II), zinc(II) and cadmium(II) complexes of benzyl
N-[1-(thiophen-2-yl)ethylidene] hydrazine carbodithioate and benzyl
N-[1-(thiophen-3-yl)ethylidene] hydrazine carbodithioate
and the X-ray crystal structure of bis{benzyl
N-[1-(thiophen-2-yl)ethylidene] hydrazine carbodithioate}nickel(II)
Mun-Hoe Eddy Chan a, Karen A. Crouse a,*, M. Ibrahim M. Tahir a, Rozita Rosli b,
Nasir Umar-Tsafe b, Andrew R. Cowley c
a
Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
b
Clinical Genetics Unit, Department of Human Growth and Development, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia,
43400 Serdang, Selangor, Malaysia
c
Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK

Received 11 July 2007; accepted 22 November 2007

Available online 15 February 2008

Abstract

Two bidentate Schiff bases have been synthesized by reaction of S-benzyldithiocarbazate with 2-acetylthiophene and 3-acetylthio-
phene to give benzyl N-[1-(thiophen-2-yl)ethylidene] hydrazine carbodithioate (SB2ATP) and benzyl N-[1-(thiophen-3-yl)ethylidene]
hydrazine carbodithioate (SB3ATP). The SB2ATP and SB3ATP were then reacted with five metal ions, cobalt(II), nickel(II), copper(II),
zinc(II) and cadmium (II) to form 10 metal complexes, all of general formula ML2. The compounds synthesized were assayed for their
bioactivities against selected pathogens and cancer cells. X-ray crystal structure analysis of Ni(SB2ATP)2 showed it to be a distorted
square planar complex. All the compounds are non-electrolytes in DMSO. Cu(SB2ATP)2 showed strong activity towards Candida lypoly-
tica. SB2ATP, SB3ATP, Co(SB2ATP)2, Cd(SB2ATP)2 and Cu(SB3ATP)2 showed weak activity against several microbes and fungi while
the others showed no activity toward these targets. SB2ATP and Cd(SB3ATP)2 showed significant bioactivity towards human myeloid
leukemia (HL-60) while Co(SB3ATP)2 showed slight cytotoxic activity towards this cell line. SB2ATP, SB3ATP, Co(SB2ATP)2,
Cu(SB2ATP)2, Cu(SB3ATP)2, Zn(SB2ATP)2 and Cd(SB2ATP)2 showed significant chemotherapeutic activity against human breast car-
cinoma with positive estrogen receptor (MCF-7) while the remainder of the compounds showed significant bioactivity. The Schiff bases
displayed higher cytotoxic activity compared to their metal complexes except for Cu(SB3ATP)2. None of the compounds showed any
cytotoxic activity towards human cervical cancer (HeLa) or towards human breast carcinoma with negative estrogen receptors
(MDA-MB-231).
Ó 2007 Elsevier Ltd. All rights reserved.

Keywords: S-Benzyldithiocarbazate; Dithiocarbazate derivatives; 2-Acetylthiophene; 3-Acetylthiophene; Schiff base

1. Introduction

The synthesis and complexation of substituted dithioc-

*
Corresponding author. Tel.: +60 3 89466788; fax: +60 3 89435380. arbazate esters has continued to garner interest [1–12] since
E-mail address: crouse@pc.jaring.my (K.A. Crouse). many are biologically active. It has been proposed that the

0277-5387/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2007.11.035
1142 M.-H. E. Chan et al. / Polyhedron 27 (2008) 1141–1149

biological activity of these Schiff bases and their metal 2.3. The preparation of benzyl N-[1-(thiophen-2-
complexes may come from their interaction with potential yl)ethylidene] hydrazine carbodithioate and benzyl N-[1-
donors of biological heterocycles in vivo [13,14]. The effi- (thiophen-3-yl)ethylidene] hydrazine carbodithioate
ciency of the Schiff bases as therapeutic agents has often (SB2ATP)
been enhanced upon coordination with a metal [15,16]. In
many cases, the pharmacological activity has been found The Schiff base, benzyl N-[1-(thiophen-2-yl)ethylidene]
to be highly dependent on the identity of the metal and hydrazine carbodithioate, SB2ATP, was synthesized as
the donor sequence of the ligands with different ligands reported previously [17]. S-Benzyldithiocarbazate, SBDTC
showing widely different biological activities although they (9.9 g, 0.05 mol) was dissolved in absolute ethanol (35 ml).
may vary only slightly in their molecular structure To this solution was added 2-acetylthiophene (6.3 g,
[7,15,16]; however, the mechanism has yet to be deter- 0.05 mol) also in absolute ethanol (30 ml). The mixture
mined. To date, no pattern has emerged to enable the activ- was heated while being stirred for 15 min and later allowed
ity to be predicted on the basis of the structure of the to stand for 20 min whereupon a precipitate formed. This
dithiocarbazate derivatives. Thus, it is worthwhile to carry precipitate was filtered and dried over silica gel. Crude
out the study of additional isomeric dithiocarbazates and products were recrystallized from absolute ethanol.
their metal complexes to supplement available information The Schiff base, benzyl N-[1-(thiophen-3-yl)ethylidene]
with a view of towards elucidation of the selectivity pattern hydrazine carbodithioate, SB3ATP, was synthesized by
of this class of compounds. We have previously reported substituting the 2-acetylthiophene with 3-acetylthiophene.
the structure of benzyl N-[1-(thiophen-2-yl)ethylidene]
hydrazine carbodithioate, SB2ATP [17]. Herein, we exam- 2.4. General method for preparation of the metal complexes
ine SB2ATP and benzyl N-[1-(thiophen-3-yl)ethylidene]
hydrazine carbodithioate (SB3ATP) and their metal com- To 0.005 mol of metal salt dissolved in absolute ethanol
plexes of cobalt(II), nickel(II), copper(II), zinc(II)and (20 ml) was added Schiff base (0.01 mol) in 20 ml of abso-
cadmium(II). Since some of the related heterocyclic thio- lute ethanol. The mixture was heated while being stirred.
semicarbazones and their Schiff bases also possess bio- The precipitate was filtered, washed with ice-cold ethanol
chemical and pharmacological properties which may and dried over silica gel. The yield and melting point were
afford potential therapeutic applications [18,19] it is antic- recorded for each product. Metal ions used were cobalt,
ipated that continuance of this work may provide some nickel, copper, zinc and cadmium.
basis for comparison and an understanding of structure–
reactivity relationships. 2.5. Physical measurements

2. Experimental IR spectra were recorded on a Perkin–Elmer 1650X

FTIR spectrometer using KBr pellets, in the 4000–
2.1. Materials 400 cm1 region. Elemental analyses were carried out using
a LECO CHNS-932 and a Perkin–Elmer Plasma 1000
All chemicals were analytical grade and, unless other- Emission Spectrometer. 1H NMR spectra were obtained
wise specified, were used as received. The solvents were on a JOEL JNM 400 MHz spectrometer. The molar con-
purified by conventional methods. ductance of 103 M solutions of the metal complexes in
DMSO were measured at 30 °C using a Jenway 4310 con-
2.2. Preparation of S-benzyldithiocarbazate ductivity meter and a dip-cell with platinized electrode.
Electronic absorption spectra were obtained on a Shima-
This compound was synthesized as reported previously dzu UV-2501 PC spectrophotometer using DMSO solu-
[3]. Potassium hydroxide (11.4 g, 0.2 mol) was dissolved tions in the 200–900 nm region. An Electrothermal digital
completely in 90% ethanol (70 ml) and the mixture was melting point apparatus was used to determine the melting
cooled in an ice bath. To the mixture, hydrazine hydrate points. Room temperature magnetic susceptibility data
(10 g, 0.2 mol) was added slowly with stirring. Carbon disul- were collected with a Sherwood Scientific MSB-AUTO
phide (15.2 g, 0.2 mol) was then added drop-wise with vigor- magnetic susceptibility balance at 300 K.
ous stirring. The temperature of the reaction mixture was
not allowed to rise above 5 °C during the period of addition 2.6. X-ray structure determination
of carbon disulfide. The resulting brown oil was separated
by means of a separating funnel and dissolved in 40% etha- Dark brown crystals of the Ni(II) complex, Ni(S-
nol (60 ml) and the solution was cooled in ice. Benzyl chlo- B2ATP)2, were formed when an acetonitrile solution was
ride (25.3 g, 0.2 mol) was added slowly with vigorous allowed to slowly evaporate for a couple of weeks. The
stirring. The white product was separated by filtration, selected crystal of the Ni(II) complex was mounted on a
washed with water and dried in air. The crude product glass fiber using perfluropolyether oil and cooled rapidly
was recrystallized from absolute ethanol; yield, 24.5 g to 150 K in a stream of cold N2 using an Oxford Cryosys-
(61.9%); the melting point was 124 °C (Lit. 123–125 °C) [1]. tems CRYOSTREAM unit. Diffraction data were mea-
 M.-H. E. Chan et al. / Polyhedron 27 (2008) 1141–1149 1143

sured using an Enraf-Nonius Kappa CCD diffractometer biostatic (inhibitory) activity as described by Hufford and
(graphite-monochromatic Mo Ka radiation, k = Clark [24]. The lowest concentration that completely inhib-
0.71073 Å). Intensity data were processed using the ited visible microbial growth was recorded as the minimum
DENZO-SMN package [20]. The crystal was found to be inhibitory concentration (MIC, lg/ml). Streptomycin and
monoclinic with a = 10.5360(3) Å, b = 8.5915(2) Å, c = nystatin (Sigma, USA) were used as positive controls for
17.0856(5) Å and b = 103.6699(11)°. The structure was bacteria and fungi, respectively.
solved in the space group P2/c using the direct-methods
program SIR92 [21] which located all non-hydrogen atoms. 2.7.3. Cytotoxic assay
Subsequent full-matrix least-squares refinement of F was 2.7.3.1. Cell culture. Five cell lines were used: human mye-
carried out using CRYSTALS program suite [22]. Coordinates loid leukemia (HL-60), human ovarian cancer (Caov-3),
and anisotropic thermal parameters of all non-hydrogen human cervical cancer (HeLa), human breast carcinoma
atoms were refined. Hydrogen atoms were positioned geo- with positive estrogen receptor (MCF-7) and human breast
metrically after each cycle of refinement. A five-term carcinoma with negative estrogen receptor (MDA-MB-
Chebychev polynomial weighting scheme was applied. 231). All the cell lines were obtained from the National
Refinement converged satisfactorily to give R = 6.01 and Cancer Institute, USA. HL-60, Caov-3, HeLa and MDA-
Rw = 6.13 with minimum and maximum residual electron MB-231 were grown in RPMI-1640 adjusted to contain
density of 0.74 and 1.07 e Å3. 0.024 M sodium bicarbonate and 10% fetal calf serum.
While MCF-7 was grown in RPMI-1640 containing
2.7. Bioactivity 0.018 M sodium bicarbonate supplemented with 0.001 M
sodium pyruvate, 1 ml of 10 mg/ml bovine insulin and
Antimicrobial assays were carried out at the Laboratory 10% fetal calf serum. All the cells were incubated in an
of Molecular and Cell Biology, Institute of Biosciences, atmosphere of 5% CO2, 100% relative humidity at 37 °C.
Universiti Putra Malaysia while cytotoxic assays were done
at the Clinical Genetics Unit, Department of Human 2.7.3.2. Treatments and sample dilutions. Cells from all cell
Growth and Development, Faculty of Medicine and lines were counted, diluted and inoculated on to sterile 96-
Health Sciences, Universiti Putra Malaysia. well microtiter plates. Cells were inoculated in a volume of
100 ll per well at densities between 5000 and 20 000 cells
2.7.1. Qualitative antimicrobial assay per well (Table 1). The microtiter plates containing the cells
Eight pathogenic microbial strains were used to test the were preincubated overnight at 37 °C in an atmosphere of
biological potential of the compounds: (i) Methicillin resis- 5% CO2 and 100% relative humidity to allow stabilization
tant staphylococcus (MRSA), (ii) Bacillus subtilis wild type prior to addition of compounds.
(B29), (iii) Bacillus subtilis mutant defective DNA repair Stock solutions of the compounds (10 mg/ml) were pre-
(B28), (iv) Pseudomonas aeruginosa (60690), (v) Candida pared using DMSO. The compounds were then diluted
albicans (CA), (vi) Aspergillus ochraceous (398), (vii) Sac- with complete medium to concentrations ranging from
charomyces cereviceae (20341) and (viii) Candida lypolytica 100 lg/ml to 0.3 lg/ml. Immediately after preparation of
(2075). The antimicrobial activity of each compound was these intermediate dilutions, 100 ll aliquots of each dilu-
determined qualitatively through the modified disc diffu- tion were added to the appropriate microtiter plate wells.
sion method [23]. A lawn of microorganisms was prepared The treated cultures were incubated for 4 days in an atmo-
by pipetting and evenly spreading 10 ll of inocula sphere of 5% CO2 and 100% relative humidity at 37 °C and
(adjusted turbid metrically to 105–106 CFU/cm3 the end-point was measured using MTT assay as described
[CFU = colony forming units]) onto agar set in petri below.
dishes. Nutrient agar (NA) was used for bacteria while
potato dextrose agar (PDA) was used for fungi. Filter 2.7.3.3. MTT assay. Cytotoxicity was evaluated using MTT
paper discs (Whatman no. 1) measuring 6 mm in diameter (3-[4,5-dimethylthiazo-2-yl]-2,5-diphenyltetrazolium bro-
were impregnated with dimethylsulphoxide (DMSO) stock mide) (Sigma, USA) assay following Mosmann [25] and
solution of the compounds (100 mg/cm3) and dried under Monks [26]. The MTT assay was based on metabolic
sterile conditions. The dried discs were then placed on reduction of (3-[4,5-dimethylthiazo-2-yl]-2,5-diphenyltet-
the previously inoculated agar surface. The plates were
inverted and incubated for 24 h at 37 °C for the bacteria
and 30 °C for the fungi. Antimicrobial activity was indi- Table 1
cated by the presence of clear inhibition zones around the Cancer cell lines and inoculation densities used in compound screening
discs. Cell lines Cells/well
HL-60 20 000
2.7.2. Quantitative antimicrobial assay Caov-3 5000
Compounds that showed positive antimicrobial activity HeLa 5000
with the disc diffusion assay were subjected to the broth MCF-7 5000
MDA-MB-231 7500
dilution method for the qualitative measurement of micro
1144 M.-H. E. Chan et al. / Polyhedron 27 (2008) 1141–1149

razolium bromide) (MTT). A 40 ll aliquot of MTT solu- 12.43 ppm (SB3ATP) due to N–H protons, indicating that
tion (2.5 mg MTT in 1 ml of PBS solution) was added even in solution they exist predominantly as the thione tau-
directly to all the appropriate microtiter plate wells con- tomers. In the presence of metal salts, they can quickly con-
taining cells, complete growth media and test agents as pre- vert to the thiol form and coordinate to the metal ion in its
pared above. The culture was then incubated for 4 h to deprotonated thiolate form.
allow for MTT metabolism to formazan. After this, the Both SB2ATP and SB3ATP display a broad and weak
supernatant was pipetted out and 200 ll of DMSO was band (3184 cm1 and 3188 cm1, respectively) attributable
added to dissolve the formazan. The plates were agitated to m(N–H). In the spectra of the complexes, this band was
on a plate shaker to ensure a homogeneous solution and not present. This indicates that the ligands were coordi-
the optical densities were read on an automated spectro- nated in their deprotonated form. In the IR spectra of
photometric plate reader (model MRX II microplate Elisa the complexes, the m(C@N) band is not shifted but the
reader) at a test wavelength of 570 nm and a reference m(N–N) band of the free ligands shifted to considerably
wavelength of 630 nm. Cytotoxicity is shown as the mini- higher wave numbers suggesting coordination via the azo-
mum concentration required to reduce the absorbance of methine nitrogen atom. The shift of the m(C@S) at
treated cells by 50% with reference to the untreated cells 914 cm1 (SB2ATP) and 968 cm1 (SB3ATP) to the higher
(CD50). Tamoxifen and etoposide were used as cytotoxic wave numbers for the metal complexes imply coordination
standards. through the thiol sulfur. All the significant IR bands of
the Schiff bases and their metal complexes are tabulated
3. Results and discussion (Table 3).

3.1. IR spectroscopy and elemental characterization 3.2. Molar conductivity and magnetic susceptibility

Table 2 shows the yield, colour, melting points and ele- Molar conductivity data are presented in Table 4. All
mental analysis of the synthesized compounds. All the compounds are non-electrolytes in DMSO indicating
compounds were synthesized in reasonable yield. The covalent bonding in each case. Although some dissociation
CHNS values of the compounds were determined to be of the complexes seems to occur, the conductance values
in agreement with the empirical formulae. These dithiocar- are much lower than that expected for 1:1 electrolytes in
bazate substituted esters, SB2ATP and SB3ATP, are capa- this solvent. All metal complexes were diamagnetic with
ble of exhibiting thione–thiol tautomerism existing in either the exception of CoSB2ATP with leff = 2.589  106 BM
form or as an equilibrium mixture (Fig. 1). (unfortunately, data are unavailable for the CoSB3ATP
The IR spectra of the free ligands, SB2ATP and complex).
SB3ATP, in KBr do not exhibit a m(S–H) band at around
2700 cm1, but show a broad and weak band at 3.3. Electronic spectra
3184 cm1 for SB2ATP and 3188 cm1 for SB3ATP attrib-
utable to m(N–H). This indicates that in the solid state, the Electronic spectral data of the synthesized compounds
ligand remains in the thione form. Although an equilibrium are shown in Table 5. The Schiff bases, SB2ATP and
mixture of the thione and thiol tautomeric forms may be SB3ATP, exhibit (n ? p*)thiophene bands at 357 nm and
expected to exist in solution, the 1H NMR spectra of 337 nm, respectively [18]. The (n ? p*)dithiocarbazate band
SB2ATP and SB3ATP in DMSO do not exhibit any signal was observed at 392 nm for SB2ATP and 337 nm for
at approximately 4 ppm due to the S–H proton, however, SB3ATP. Upon coordination with metal complexes, the
they display signals at 12.51 ppm (SB2ATP) and (n ? p*)thiophene and (n ? p*)dithiocarbazate band shifted.

Table 2
Yield, colour, melting point and elemental analysis of synthesized compounds
Compound Yield (%) Colour MP (°C) Found (calculated) (%)
C H N S
SB2ATP 72.6 yellow 131 54.55 (54.87) 4.54 (4.60) 9.38 (9.14) 31.38 (31.28)
Co(SB2ATP)2 51.3 green 181 50.02 (50.21) 3.86 (3.91) 8.77 (8.36) 29.06 (28.71)
Ni(SB2ATP)2 66.3 dark brown 177 49.08 (50.23) 4.03 (3.91) 8.09 (8.37) 32.22 (28.73)
Cu(SB2ATP)2 71.1 dark brown 138 49.88 (49.86) 4.05 (3.89) 8.04 (8.31) 29.43 (28.52)
Zn(SB2ATP)2 59.5 yellow 184 49.51 (49.73) 4.09 (3.88) 8.22 (8.28) 29.82 (28.44)
Cd(SB2ATP)2 70.1 yellow 171 46.32 (46.50) 3.05 (3.62) 7.91 (7.75) 27.61 (26.59)
SB3ATP 80.3 yellow 130 54.01 (54.87) 4.30 (4.60) 9.33 (9.14) 29.23 (31.28)
Co(SB3ATP)2 49.6 dark brown 195 51.03 (50.21) 3.13 (3.91) 7.66 (8.36) 28.45 (28.71)
Ni(SB3ATP)2 62.3 green 217 49.57 (50.23) 3.92 (3.91) 8.91 (8.37) 29.68 (28.73)
Cu(SB3ATP)2 74.3 dark green 169 49.86 (49.86) 3.83 (3.89) 8.56 (8.28) 28.41 (28.44)
Zn(SB3ATP)2 67.3 light yellow 179 49.21 (49.73) 4.01 (3.88) 7.89 (8.28) 28.89 (28.44)
Cd(SB3ATP)2 63.1 light yellow 178 46.41 (46.50) 3.54 (3.62) 8.08 (7.75) 26.77 (26.59)
 M.-H. E. Chan et al. / Polyhedron 27 (2008) 1141–1149 1145

S S

S S

CH3 CH3 CH3 CH3

N N N N

HN N HN N

S SH S SH

S S S S

a b c d
Fig. 1. The thione and thiol form of SB2ATP (a,b) and SB3ATP (c,d).

Table 3 observed at 856 nm [27]. Ni(SB3ATP)2 did not exhibit a

Significant IR bands of the Schiff bases and their metal complexes band in this region. The 4T1 (P) ? 4A2 transition can be
Compound m(N–H) m(C@N) m(N–N) m(CSS) seen at 416 nm for both of the Ni(II) complexes [27]. The
(cm1) (cm1) (cm1) (cm1) LMCT S ? d absorption for Ni(SB3ATP)2 is at 281 nm
SB2ATP 3184 1530 1034 914 but for Ni(SB2ATP)2 this band was hidden by a strong
Co(SB2ATP)2 1552 1030 934 CT transition.
Ni(SB2ATP)2 1552 1070 990 Cu(II) complexes are usually highly distorted [27]. The
Cu(SB2ATP)2 1556 1072 1026 1
Zn(SB2ATP)2 1562 1076 1018
A1 ? 1A2 and 1A1 ? 1B1 transitions can be assigned in
Cd(SB2ATP)2 1560 1074 1018 the 500 nm and 400 nm region, respectively [3]. The
SB3ATP 3188 1526 1056 968 absorption at 262 nm in the Cu(SB3ATP)2 spectrum is
Co(SB3ATP)2 1568 1078 1004 expected to be the LMCT S ? d and the 570 nm can be
Ni(SB3ATP)2 1572 1076 994 assigned to the 1A1 ?1E transition (see Fig. 1).
Cu(SB3ATP)2 1574 1080 948
Zn(SB3ATP)2 1572 1072 1006
Cd(SB3ATP)2 1578 1080 1002
3.4. The structure of [Ni(SB2ATP)2]

The molecular structure of Ni(SB2ATP)2 is a distorted

Table 4 square planar monomeric entity with twofold axis running
Molar conductance of the metal complexes
through to the metal ion. A perspective view with the
Compound (X1 cm2 mol1) atomic numbering scheme of the complex and its packing
Co(SB2ATP)2 25.9 arrangement are shown in Figs. 2 and 3, respectively.
Ni(SB2ATP)2 10.5 Selected crystallographic data and refinement data are
Cu(SB2ATP)2 9.7
given in Tables 6 and 7. The nickel(II) ion is coordinated
Zn(SB2ATP)2 11.6
Cd(SB2ATP)2 10.3 through the azomethine nitrogen atom N(2) and the mer-
Co(SB3ATP)2 20.9 capto-sulfur atom S(12) of the Schiff base ligands at
Ni(SB3ATP)2 6.1 1.949(2) and 2.148(1) Å, respectively. The nickel atom
Cu(SB3ATP)2 2.7 adopts a distorted square planar geometry with N(2)–
Zn(SB3ATP)2 12.3
N(1)–N(20 ), N(2)–Ni(1)–S(12) and S(12)–Ni(1)–S(120 )
Cd(SB3ATP)2 16.7
angles of 104.05°, 86.07° and 87.86°. A weak interaction
between thiophenyl sulfur to the nickel ion is reflected by
The UV–vis spectra of Co(II), d7, complexes indicate the Ni(1)–S(5) distance of 3.22 Å which could be the cause
that they are distorted tetrahedral structure. The 4T1 for the distortion from a perfect square planar geometry.
(F) ? 4A2 bands can be seen at 716 nm and 705 nm for The N(10)–C(11) distance in the complex is 1.292(4) Å,
SB2ATP and SB3ATP complexes, respectively [27]. The while for the free ligand it is 1.342(2) Å [17]. The decrease
band at 416 nm for both Co(II) complexes can be assigned in length of this bond upon complexation through the adja-
to the 4T1 (P) ? 4A2 transition [27]. The bands at 286 nm cent N(2) atom. The C(11)–S(12) and N(2)–C(3) bond
(SB2ATP) and 262 nm (SB3ATP) are assigned to the lengths in the complex are 1.737(3) Å and 1.303(3) Å,
LMCT S ? d. The Ni(SB2ATP)2 complex adopts a dis- respectively. These distances are longer than those
torted square planar structure with the 4T1 (F) ? 4A2 band observed for the free ligand 1.650(2) Å and 1.276(2) Å
1146 M.-H. E. Chan et al. / Polyhedron 27 (2008) 1141–1149

Table 5
Electronic spectral data for synthesized compounds
Compound (n ? p*)thiophene (n ? p*)dithiocarbazate kmax (nm)
CT and d–d transitions
SB2ATP 357 (4.3) 392 (3.5)
Co(SB2ATP)2 338 (4.1) 384 (3.5) 286 (4.0) 416 (3.6) 716 (1.5)
Ni(SB2ATP)2 335 (3.5) 383 (3.5) 416 (3.6) 856 (2.3)
Cu(SB2ATP)2 332 (3.6) 377 (3.4) 405 (3.6) 562 (3.0)
Zn(SB2ATP)2 363 (3.9) 388 (3.5) 294 (3.6) 411 (3.5)
Cd(SB2ATP)2 360 (4.2) 389 (3.2) 283 (4.0) 259 (4.0) 470 (3.5)
SB3ATP 337 (4.1) 364 (3.6)
Co(SB3ATP)2 344 (4.0) 375 (3.5) 262 (4.2) 416 (3.6) 705 (1.0)
Ni(SB3ATP)2 340 (3.9) 387 (3.3) 281 (3.8) 416 (3.6)
Cu(SB3ATP)2 333 (3.5) 376 (3.4) 298 (3.6) 416 (3.6) 563 (3.2) 572 (2.3)
Zn(SB3ATP)2 338 (4.3) 386 (3.5) 260 (4.1) 296 (4.3)
Cd(SB3ATP)2 332 (4.2) 382 (3.5) 260 (4.1) 294 (4.2)
Log e (mol1 cm1) are in parentheses.

C7 C8

C6 C9
C4

C3

S5 N10
N2 C14

Ni1 C15
C11 C16
C17
S13 C20
S12 C18
C19

Fig. 2. ORTEP diagram of Ni(SB2ATP)2 with 50% probability displacement ellipsoids showing the distorted square planar arrangement around the metal
centre.

[17], as expected and as corroborated by the shifts observed 2-furylaldehyde (NS) and 2-furylmethylketone (NS0 ) did
in the infrared spectrum. The C–N bond distances of the not show not much inhibitory activity against targeted
complex of the bi-chelated ligands are typical for double microbes, Methicillin resistant staphylococcus (MRSA),
bond Schiff base compounds [11]. The C–S bond distances Bacillus subtilis-wild type (B29), Bacillus subtilis-mutant
of 1.737(3) Å indicate single bond character which supports defective DNA repair (B28) and Pseudomonas aeruginosa
the suggestion that the complex formation involves the (60690) [10]. However, all the compounds showed clear
ligand in its thiol form. The C(3)–N(2)–N(10)–C(11) has inhibition zones of 10 mm and above against Aspergillus
a s-trans disposition with the benzyl and 1-(thiophene-2- ochraceous (398) except the cadmium complex of the 2-
yl)ethylideamine groups nearly orthogonal to each other furylmethylketone Schiff base [10].
(79.76°). The complexes of the Schiff bases prepared using the
same ketone, 2-furylmethylketone, and aldehyde, 5-
3.5. Biological activities methyl-2-furylaldehyde, but with different dithiocarbazate
moiety, S-methyldithiocarbazate, Cd(NS)2, Sn(NS0 )2 and
3.5.1. Antimicrobial activity Co(NS0 )2 showed clear inhibition of MRSA, B29, B28,
All compounds were assayed for microbial activity. The 60690, Candida albicans (CA), Aspergillus ochraceous
disc diffusion technique was employed [23]. The Cu(S- (398), Saccharomyces cerevisiae (20341) and Candida
B2ATP)2 showed strong activity towards Candida lypolyti- lypolytica (2075) with the exceptions that Cd(NS)2 and
ca. SB2ATP, SB3ATP, Co(SB2ATP)2, Cd(SB2ATP)2 and Sn(NS0 )2 were inactive towards MRSA and CA, respec-
Cu(SB3ATP)2 showed weak microbial activity towards tively. However, Cd(NS0 )2, Fe(NS0 )Cl2 and Pb(NS0 )2 were
several microbes and fungi while the others showed no inactive towards all target bacteria. Cd(NS0 )2 was active
activity toward the target microbes and fungi. Quantitative against CA and 20341, while Fe(NS0 )Cl2 and Pb(NS0 )2
assays were not carried out for these compounds since they showed clear inhibition of 2075 and 398, respectively.
showed low activity. Sn(NS)2 showed activity against 60690, MRSA, B29,
Lead, tin, iron, cobalt and cadmium complexes of S- 2075 and 398. While Fe(NS)Cl2, Pb(NS)2 and Co(NS)2
benzyldithiocarbazate Schiff bases formed using 5-methyl- were inactive towards all target bacteria and fungi [28].
 M.-H. E. Chan et al. / Polyhedron 27 (2008) 1141–1149 1147

Table 7
Selected bond lengths (Å) and bond angles (°) for Ni(SB2ATP)2
Bond lengths
Ni(1)–N(2) 1.949(2) S(5)–C(6) 1.683(3)
Ni(1)–N(2) 1.949(2) N(10)–C(11) 1.292(4)
Ni(1)–S(12) 2.1489(7) C(11)–S(12) 1.737(3)
Ni(1)–S(12) 2.1489(7) C(11)–S(13) 1.741(3)
N(2)–C(3) 1.303(3) S(13)–C(14) 1.822(3)
c N(2)–N(10) 1.423(3) C(14)–C(15) 1.501(4)
C(3)–C(4) 1.452(3) C(15)–C(16) 1.378(4)
C(3)–C(9) 1.506(4) C(15)–C(20) 1.397(4)
C(4)–S(5) 1.713(3)
Bond angles
N(2)–Ni(1)–N0 (2) 104.05(12) C(3)–C(4)–C(8) 126.1(2)
N(2)–Ni(1)–S(12) 86.07(6) S(5)–C(4)–C(8) 110.91(19)
N(2)–Ni(1)–S0 (12) 162.71(6) C(4)–S(5)–C(6) 92.87(14)
N0 (2)–Ni(1)–S(12) 162.71(6) S(5)–C(6)–C(7) 112.8(2)
N0 (2)–Ni(1)–S0 (12) 86.07(6) N(2)–N(10)–C(11) 111.0(2)
S(12)–Ni(1)–S0 (12) 87.87(4) N(10)–C(11)–S(12) 124.97(19)
Ni(1)–N(2)–C(3) 130.16(17) N(10)–C(11)–S(13) 121.38(19)
Ni(1)–N(2)–N(10) 118.10(16) S(12)–C(11)–S(13) 113.63(15)
C(3)–N(2)–N(10) 111.7(2) NI(1)–S(12)–C(11) 95.50(9)
b N(2)–C(3)–C(4) 119.6(2) C(11)–S(13)–C(14) 103.65(13)
a N(2)–C(3)–C(9) 122.1(2) S(13)–C(14)–C(15) 105.7(2)
C(4)–C(3)–C(9) 118.3(2) C(14)–C(15)–C(16) 120.2(3)
C(3)–C(4)–S(5) 122.9(2) C(14)–C(15)–C(20) 121.3(3)

Substitution of the N with S in the five-membered ring

has considerably altered the activity of the compounds
Fig. 3. Packing arrangement of Ni(SB2ATP)2 viewed along the b axis. towards target microbes and fungi as has substitution of
the benzene ring with a methyl group.
Table 6
Summary of crystal data and structure refinement parameters for 3.5.2. Cytotoxic activity
Ni(SB2ATP)2 The results of the cytotoxic assays are shown in Table 8.
Chemical formula C28H26N4Ni1S6 SB2ATP and Cd(SB3ATP)2 showed significant bioactivity
Formula weight 669.65 towards human myeloid leukemia (HL-60) while Co-
Crystal class monoclinic (SB3ATP)2 showed slight cytotoxic activity towards this
Space group P2/c cell line. SB2ATP, SB3ATP, Co(SB2ATP)2, Cu(SB2ATP)2,
a (Å) 10.5360(3)
Cu(SB3ATP)2, Zn(SB2ATP)2 and Cd(SB2ATP)2 showed
b (Å) 8.5915(2)
c (Å) 17.0856(5) significant chemotherapeutic activity against human breast
a (°) 90 carcinoma with positive estrogen receptor (MCF-7) while
b (°) 103.6699(11) the remainder of the compounds showed significant bioac-
c (°) 90 tivity towards this cell line. The Schiff bases show higher
V (Å3) 1502.78(7)
cytotoxic activity compared to their metal complexes
Z 2
Mo Ka (Å) 0.7107 except for Cu(SB3ATP)2. It can be deduced that metal che-
T (K) 150 lation may slightly inhibit cytotoxic activity. The SB2ATP
qcalc (Mg m3) 1.480 Schiff bases showed a slightly lower cytotoxic dose concen-
l (mm1) 1.088 tration than SB3ATP. None of the compounds showed any
Sample dimension (mm) 0.10  0.22  0.32
cytotoxic activity towards human cervical cancer (HeLa) or
F (0 0 0) 692
h Range for data collection (°) 5–27 towards human breast carcinoma with negative estrogen
Limiting indices 13 6 h 6 13, receptors (MDA-MB-231).
11 6 k 6 11, Previous studies have shown that bidentate S-ben-
22 6 l 6 22 zyldithiocarbazate Schiff bases formed using 5-methyl-2-
Reflections collected/unique [Rint] 6786/3439 [0.02]
furylaldehyde (NSa) and 2-furylmethylketone (NSb) and
Maximum and minimum transmission 0.79 and 0.90
Data/restrains/parameters 2583/0/177 the Pb(NSa)2 complex exhibited high cytotoxicity against
Goodness-of-fit on F2 1.0294 the Human T-lympho-blastic leukemia (CEM-SS) cell line.
Minimum and maximum residual 0.74 and 1.07 The Cd(NSb)2 complex was inactive towards the CEM-SS
electron density (e Å3) cell line in contrast to results reported on other Cd com-
R, Rw 6.01, 6.13
plexes containing similar bidentate ligands [10,11]. S-meth-
1148 M.-H. E. Chan et al. / Polyhedron 27 (2008) 1141–1149

Table 8 for the NiSB2ATP complex. The diamagnetic Zn(II) and

Cytotoxic activity Cd(II) ions are expected to be tetrahedral complexes since
Compound IC50 (lg/ml) they are unlikely to form bridged dimeric square planar
HL-60 Caov-3 HeLa MCF-7 MDA-MB-231 structures. The results of magnetic measurements for the
SB2ATP 13 1.4 Cu complexes may possibly be understood in terms of
Co(SB2ATP)2 1.8 spin-spin interaction. The thiophenyl substituents dis-
Ni(SB2ATP)2 played lower activity towards target microbes and fungi
Cu(SB2ATP)2 4.2 than the furanyl groups in comparable complexes and also
Zn(SB2ATP)2 3.9
Cd(SB2ATP)2 4
appeared to inhibit the cytotoxicity.
SB3ATP 2.8
Co(SB3ATP)2 Acknowledgements
Ni(SB3ATP)2
Cu(SB3ATP)2 1.6 We would like to thank the Department of Chemistry,
Zn(SB3ATP)2
Cd(SB3ATP)2 9 11.7
Faculty of Science, Clinical Genetics Unit, Department
Tamoxifen 3.0 2.7 1.5 5.0 of Human Growth and Development, Faculty of Medicine
Etoposide 0.5 and Health Sciences and the Laboratory of Molecular and
Human myeloid leukemia (HL-60); Human ovarian cancer (Caov-3.); Cell Biology, Institute of Biosciences, Universiti Putra
Human cervical cancer (HeLa); Human breast carcinoma with positive Malaysia for the provision of laboratory facilities. This re-
estrogen receptor (MCF-7); Human breast carcinoma with negative search was funded by grants from the Ministry of Science,
estrogen receptor (MDA-MB-231). Technology and Innovation Malaysia, under the Intensifi-
IC50 (lg/ml) = inhibition dose at 50%, i.e., the concentration to inhibit
growth of cancer cells by 50%.
cation of Research in Priority Areas Scheme (IRPA Grant
na, not available. nos. 09-02-040755 and 09-02-04-0296).
64 lg/ml = chemotherapeutic significant; 4–30 lg/ml = bioactive
significant. Appendix A. Supplementary material
Empty columns indicates P30 lg/ml, i.e. not significant.
CCDC 245093 contain the supplementary crystallo-
yldithiocarbazate Schiff bases prepared using 2-furylmeth- graphic data for complex Ni(SB2ATP)2. These data can
ylketone (NSc) and 5-methyl-2-furylaldehyde (NSd), gave be obtained free of charge via http://www.ccdc.cam.
complexes, Cd(NSc)2, Cd(NSd)2 and Co(NSc)2, which were ac.uk/conts/retrieving.html, or from the Cambridge Crys-
very active against CEM-SS and cervical cancer cell (HeLa) tallographic Data Centre, 12 Union Road, Cambridge
lines [28]. The compounds synthesized in this work were CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: deposit@
not assayed against CEM-SS due to the unavailability of ccdc.cam.ac.uk. Supplementary data associated with this
the cell line. article can be found, in the online version, at doi:10.1016/
As a general observation, it appears that the complexes j.poly.2007.11.035.
of the S-benzyldithiocarbazate Schiff base containing the
acetylthiophene moiety are not as toxic as the related References
2-furylmethylketone and 5-methyl-2-furylaldehyde com-
plexes. It would, therefore, seem that substitution of [1] M.A. Ali, S.E. Livingstone, Coord. Chem. Rev. 13 (1974) 101.
[2] M.A. Ali, R. Bose, J. Inorg. Nucl. Chem. 39 (1977) 265.
oxygen by sulfur in the substituent five-membered rings
[3] M.A. Ali, M.T.H. Tarafder, J. Inorg. Nucl. Chem. 39 (1977) 1785.
reduces cytotoxicity. [4] M.T.H. Tarafder, M.A. Jalil Miah, R.N. Bose, M.A. Ali, J. Inorg.
Nucl. Chem. 43 (1981) 3151.
4. Conclusion [5] M.A. Ali, R.N. Bose, Polyhedron 3 (1984) 517.
[6] Z. Xu, E.C. Alyea, G. Ferguson, M.C. Jennings, Polyhedron 10
The SB2ATP and SB3ATP behave as uninegatively (1991) 1625.
[7] M.E. Hossain, M.N. Alam, J. Begum, M. Akbar Ali, M. Nazimud-
charged bidentate ligands with Co(II), Ni(II), Cu(II), din, F.E. Smith, R.C. Hynes, Inorg. Chim. Acta 249 (1996) 207.
Zn(II) and Cd(II) complexes. The IR spectra of the free [8] M. Akbar Ali, A.H. Mirza, R.J. Butcher, M.T.H. Tarafder, M.A. Ali,
ligands indicate that in solid state the ligand remains in Inorg. Chim. Acta 320 (2001) 1.
the thione form. The thione and thiol tautomeric forms [9] M.T.H. Tarafder, A. Kasbollah, K.A. Crouse, A.M. Ali, B.M.
may be expected to exist in solution but the 1H NMR spec- Yamin, H.-K. Fun, Polyhedron 20 (2001) 2363.
[10] M.T.H. Tarafder, T.-J. Khoo, K.A. Crouse, A.M. Ali, B.M. Yamin,
tra of SB2ATP and SB3ATP indicates that the ligands, H.-K. Fun, Polyhedron 21 (2002) 2691.
even in solution, exist predominantly as the thione tautom- [11] M.T.H. Tarafder, T.-J. Khoo, K.A. Crouse, A.M. Ali, B.M. Yamin,
ers. All complexes are non-electrolytes in DMSO signifying H.-K. Fun, Polyhedron 21 (2002) 2547.
covalent bonding in each case. The CoSB2ATP complex is [12] Y.-C. Shi, H.-M. Yang, H.-B. Song, C.-G. Yan, X.-Y. Hu, Polyhe-
dron 23 (2004) 567.
paramagnetic with its magnetic moment indicating that it is
[13] S.C. Chan, L.L. Koh, P.-H. Leung, J.D. Ranford, K.Y. Sim, Inorg.
a square planar structure, the diamagnetic Ni(II) com- Chim. Acta 236 (1995) 101.
plexes are expected to be in a square planar environment. [14] X.-H. Zhu, X.-F. Chen, X.-M. Ren, X.-Z. You, S.S.S. Raj, H.-K.
This has been verified by crystallographic measurements Fun, Polyhedron 18 (1999) 3683.
 M.-H. E. Chan et al. / Polyhedron 27 (2008) 1141–1149 1149

[15] M.A. Ali, C.M. Haroon, M. Nazimuddin, S.M.M.-u.-H. Majumder, [21] A. Altomare, G. Cascarano, G. Giacovazzo, A. Guagliardi, M.C.
Trans. Met. Chem. 17 (1992) 133. Burla, G. Polidori, M. Camalli, J. Appl. Cryst. 27 (1994) 435.
[16] M.E. Hossain, M.N. Alam, M.A. Ali, M. Nazimuddin, F.E. Smith, [22] D.J. Watkin, C.K. Prout, J.R. Carruthers, P.W. Betteridge, Crystals,
R.C. Hynes, Polyhedron 15 (1996) 973. 10 ed., Chemical Crystallography Laboratory, University of Oxford,
[17] M.-H.E. Chan, K.A. Crouse, M.T.H. Tarafder, B.M. Yamin, Acta 1996.
Crystallogr., Sect. E 59 (2003) 628. [23] A.W. Bauer, M.D.K. Kirny, J.C. Sherries, M. Turck, Am. J. Clin.
[18] J. Garcia-Tojal, A. Garcia-Orad, J.L. Serra, J.L. Pizarro, L. Lezama, Pathol. 45 (1966) 493.
M.I. Arriortua, T. Rojo, J. Inorg. Biochem. 75 (1999) 45. [24] C.D. Hufford, A.M. Clark, Elsevier 2 (1988) 421.
[19] J. Garcia-Tojal, J.L. Pizarro, A. Garcia-Orad, A.R. Perez-Sanz, M. [25] T. Mosmann, J. Immunol. Methods 65 (1983) 55.
Ugalde, A. Alvarez Diaz, J.L. Serra, M.I. Arriortua, T. Rojo, J. [26] A. Monks, K. Paull, D. Vistica, C. Hose, J. Langley, P. Cronise, A.
Inorg. Biochem. 86 (2001) 627. Vaigro-Wolff, M. Gray-Goodrich, H. Campbell, J. Mayo, M. Boyd,
[20] Z. Otwinowski, D. Minor, Processing of X-ray diffraction data J. Nat. Cancer Inst. 83 (1991) 757.
collected in oscillation mode in methods in enzymology, in: [27] A.B.P. Lever, Inorganic Electronic Spectroscopy, 2nd ed., vol. 33,
C.W. Carterjr., R.M. Sweet (Eds.), Macromolecular Crystallog- Elsevier Science Publishers, 1984.
raphy, Part A, vol. 276, Academic Press, New York, 1997, [28] K.-B. Chew, M.T.H. Tarafder, K.A. Crouse, A.M. Ali, B.M. Yamin,
p. 307. H.-K. Fun, Polyhedron 23 (2004) 1385.