Synthesis, characterization and bioactivity of mixed-ligand Cu(II) complexes containing Schiff bases derived from S-benzyldithiocarbazate and saccharinate ligand and the X-ray crystal structure of the copper-saccharinate complex containing S-benzyl-β-N-(acetylpyrid-2-yl)methylenedithiocarbazate

Article abstract of DOI:10.1016/j.poly.2006.03.007

Mixed-ligand complexes of general formula, [Cu(NNS)(sac)] (NNS′ = S-benzyl-β-N-(2-acetylpyrid-2-yl)methylenedithiocarbazate, NNS″ = S-benzyl-β-N-(2-benzoylpyrid-2-yl)methylenedithiocarbazate and NNS? = S-benzyl-β-N-(6-methylpyrid-2-yl)methylenedithio-carbazate, sac = the saccharinate anion) have been synthesized by reacting [Cu(sac)₂(H₂O)₄] · 2H₂O with the appropriate ligands in ethanol and characterized by various physico-chemical techniques. Magnetic and spectral evidence indicate that the complexes are four-coordinate in which the Schiff bases coordinate as NNS ligands and the sac- anion coordinates as a unidentate N-donor ligand. An X-ray crystallographic structural analysis of [Cu(NNS′)(sac)] shows that the complex has a distorted square-planar geometry with the Schiff base coordinated to the copper (II) ion as a uninegatively charged tridentate chelating agent via the pyridine nitrogen atom, the azomethine nitrogen atom and the thiolate sulphur atom while the fourth coordination position is occupied by the N-bonded saccharinate anion. The complexes have been evaluated for their biological activities against selected pathogens and cancer cell lines. They display weak activity against the pathogenic bacteria and fungi. The complexes were highly active against the leukemic cell line (HL-60) but only [Cu(NNS′)(sac)] was found to exhibit strong cytotoxicity against the ovarian cancer cell line (Caov-3). All complexes were inactive against the breast cancer cell line (MCF-7).

Full text of DOI:10.1016/j.poly.2006.03.007

Polyhedron 26 (2007) 1159–1165
www.elsevier.com/locate/poly
Synthesis, characterization and bioactivity of mixed-ligand
Cu(II) complexes containing Schiff bases derived from
S-benzyldithiocarbazate and saccharinate ligand and the X-ray
crystal structure of the copper-saccharinate complex containing
S-benzyl-b-N-(acetylpyrid-2-yl)methylenedithiocarbazate
a
a,
a
Thahira B.S.A. Ravoof , Karen A. Crouse *, M. Ibrahim M. Tahir ,
b
c
Andrew R. Cowley , M. Akbar Ali
a
Department of Chemistry, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Department of Chemistry, Universiti Brunei Daussalam, Jalan Tungku Link, BE1410, Brunei Darussalam
b
c
Received 30 June 2005; accepted 13 March 2006
Available online 30 March 2006
Abstract
Mixed-ligand complexes of general formula, [Cu(NNS)(sac)] (NNS0 = S-benzyl-b-N-(2-acetylpyrid-2-yl)methylenedithiocarbazate,
NNS00 = S-benzyl-b-N-(2-benzoylpyrid-2-yl)methylenedithiocarbazate and NNS000 = S-benzyl-b-N-(6-methylpyrid-2-yl)methylenedithio-
carbazate, sac = the saccharinate anion) have been synthesized by reacting [Cu(sac)2(H2O)4] Æ 2H2O with the appropriate ligands in
ethanol and characterized by various physico-chemical techniques. Magnetic and spectral evidence indicate that the complexes are
four-coordinate in which the Schiff bases coordinate as NNS ligands and the sac- anion coordinates as a unidentate N-donor ligand.
An X-ray crystallographic structural analysis of [Cu(NNS0)(sac)] shows that the complex has a distorted square-planar geometry with
the Schiff base coordinated to the copper (II) ion as a uninegatively charged tridentate chelating agent via the pyridine nitrogen atom, the
azomethine nitrogen atom and the thiolate sulphur atom while the fourth coordination position is occupied by the N-bonded sacchari-
nate anion. The complexes have been evaluated for their biological activities against selected pathogens and cancer cell lines. They dis-
play weak activity against the pathogenic bacteria and fungi. The complexes were highly active against the leukemic cell line (HL-60) but
only [Cu(NNS0)(sac)] was found to exhibit strong cytotoxicity against the ovarian cancer cell line (Caov-3). All complexes were inactive
against the breast cancer cell line (MCF-7).
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: Copper (II) complexes; Dithiocarbazate Schiff base; Saccharin complexes; S-benzyldithiocarbazate; Tridentate NNS Schiff bases
1. Introduction
preliminary studies indicated that high doses caused uri-
nary bladder carcinoma [1] in mice. The ban was, however,
lifted by the US FDA in 1991 when further studies dis-
proved the earlier findings [2].
Because of the commercial importance of the sacchari-
nate anion (Fig. 1) as a non-caloric sweetener and its ability
to act as a polyfunctional ligand, many studies on its metal
complexes, especially that of first row transition metals,
have been carried out [3–12].
Saccharin (1,2-benzisothiazoline-3-(2H)one 1,1-dioxide)
was widely used as an artificial sweetener, especially in
the 1970s’ but was later banned as a food additive when
*
Corresponding author. Tel.: +603 89466788; fax: +603 89435380.
E-mail address: crouse@pc.jaring.my (K.A. Crouse).
0277-5387/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2006.03.007

1160
T.B.S.A. Ravoof et al. / Polyhedron 26 (2007) 1159–1165
with ethanol and dried in a desiccator over silica gel for
O
O
24 h. Yield: (ca. 75%). Crystals of [Cu(NNS0)(sac)] (where
NNS0 = S-benzyl-b-N-(2-acetylpyrid-2-yl)methylenedithio-
carbazate) suitable for X-ray diffraction analysis were
obtained from an acetonitrile solution.
S
-N
2.2. Physical measurements
O
Microanalyses for carbon, hydrogen, nitrogen and sul-
phur were carried out using a LECO CHNS-932 instru-
ment. The IR spectra as KBr pellets were recorded using
a Perkin–Elmer FT IR 1750X spectrophotometer (4000–
400 cmꢀ1). The molar conductance of 10ꢀ3 M solutions
of the metal complexes in DMSO were measured at
29 ꢁC using a Jenway 4310 conductivity meter and a dip-
type cell with a platinized electrode. Magnetic susceptibili-
ties at room temperature were measured using a Sherwood
Scientific MSB-AUTO magnetic susceptibility balance.
The UV–Vis spectra were run on a Shimadzu UV-2501
PC Recording Spectrophotometer (900–200 nm).
Fig. 1. The structure of the saccharinate anion.
A suggestion has been made that the importance of sac-
charin complexes lies in the potential use of saccharin as an
antidote for metal poisoning [11,13]. Metal complexes of
saccharin could also play a role in understanding human
metabolic processes [6].
Since very little information has been reported on
mixed-ligand complexes containing saccharin and triden-
tate sulfur–nitrogen chelating agents as co-ligands, we
report herein the synthesis, characterization and bioactivity
of mixed-ligand copper (II) complexes of three HNNS
ligands formed between S-benzyldithiocarbazate with 2-
acetylpyridine, 2-benzoylpyridine and 6-methyl pyridine-
2-aldehyde (Fig. 2) with saccharinate anion as a co-ligand.
2.3. X-ray structure determination of [Cu(S-benzyl-b-N-(2-
acetylpyrid-2-yl)methylenedithiocarbazate)(sac)]
Beautiful green-brown crystals of the metal complex
were formed after the acetonitrile solution was allowed to
slowly evaporate for a few weeks. A selected crystal was
mounted on a glass fibre using perfluoropolyether oil and
cooled rapidly to 150 K in a stream of cold N2 using an
Oxford Cyrosystems CYROSTREAM unit. Diffraction
data were measured using an Enraf-Nonius Kappa CCD
diffractometer (graphite-monochromated Mo Ka radia-
2. Experimental
All chemicals and solvents were of analytical grade and
were used as received. The S-benzyldithiocarbazate
(SBDTC), its Schiff bases (HNNS0, HNNS00 and HNNS000
and [Cu(sac)2(H2O)4] Æ 2H2O were prepared by the follow-
ing literature methods [6,14–16].
˚
tion, k = 0.71073 A). Intensity data were processed using
2.1. General method of synthesis of the complexes
the DENZO-SMN package [17]. The structures were solved
using the direct-methods program [18] to locate all non-
hydrogen atoms. Subsequent full-matrix least-squares
refinement on F was carried out using CRYSTALS Program
Suite [19]. Coordinates and anisotropic thermal parameters
of all non-hydrogen atoms were refined. Hydrogen atoms
were positioned geometrically after each cycle of refine-
ment. A five-term Chebychev polynomial weighting scheme
[Cu(sac)2(H2O)4] Æ 2H2O [6] (0.536 g, 0.001 mol) dis-
solved in boiling water (25 ml) was mixed with a solution
of the appropriate Schiff base (0.001 mol) in ethanol
(40 ml), and the resulting mixture was heated on a water
bath for 30 min. On standing overnight, the mixture
yielded crystalline complexes which were filtered, washed
N
N
N
N
N
N
NH
NH
S
NH
S
S
S
S
S
Fig. 2. Structure of HNNS0, HNNS00 and HNNS000 ligands, respectively (in thione form).

T.B.S.A. Ravoof et al. / Polyhedron 26 (2007) 1159–1165
1161
was applied. Refinement converged satisfactorily to give
Hufford and Clark [23]. The lowest concentration that
completely inhibited visible microbial growth was recorded
as the minimum inhibitory concentration (MIC, lg cmꢀ3).
Streptomycin and nystatin were used as positive controls
for bacteria and fungi, respectively.
R = 0.0301 and Rw = 0.0360 with residual electron den-
ꢀ3
˚
sity minimum and maximum of ꢀ0.49 and 0.44 e A
.
Further crystallographic and refinement details are shown
in Table 3.
2.4. Bioactivity
2.4.4. Cytotoxic assay
The HL-60 (Human T-lymphoblastic leukemia) and
MCF-7 cell lines were obtained from the National Cancer
Institute, USA. The cells were cultured in RPMI-1640
(Sigma) medium supplemented with 10% fetal calf serum.
Cytotoxicity was determined using the microtitration of
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-
mide (MTT) assay (Sigma, USA) as reported by Mosmann
[20]. Controls that contained only cells were included for
each sample. Cytotoxicity was expressed as CD50, i.e. the
concentration that reduced the absorbance of treated cells
by 50% with reference to the control (untreated cells).
Doxorubicin, Tamoxifen and Cisplatin were used as stan-
dard cytotoxins.
2.4.1. Target microorganisms
Eight pathogenic microbials were used to test the bio-
logical potential of the complexes. They were Methicillin
resistant staphylococcus (MRSA), Bacillus subtilis wild type
(B29), Subtilis mutant (mutant defective DNA repair-B28),
Pseudomonas aeruginosa (60690), Candida albicans (CA),
Aspergillus ochraceous (398), Saccaromyces ceciricaee
(20341) and Candida lypolytica (2075). The source of
microbes and culture maintenance were as previously
described [20].
2.4.2. Qualitative antimicrobial assay
Antimicrobial activity of each sample was qualitatively
determined by a modified disc diffusion method [21] as pre-
viously detailed [22]. A lawn of microorganisms was pre-
pared by pipetting and evenly spreading inoculum
(10ꢀ4 cm3, adjusted turbidometrically to 105–106 cfu cmꢀ3
(cfu: colony forming units) on to agar set in Petri dishes,
using Nutrient agar (NA) for the bacteria and potato dex-
trose agar (PDA) for fungi. Whatman No. 1 filter paper
discs of 6 mm diameter were impregnated with stock solu-
tion of the compound (100 mg cmꢀ3) and dried under ster-
ile conditions. The dried discs were then placed on the
previously inoculated agar surface. The plates were
inverted and incubated for 24 h at 30 ꢁC for bacteria and
37 ꢁC for fungi. Antimicrobial activity was indicated by
the presence of clear inhibition zones around the discs.
Commercially available streptomycin (Sigma, USA) was
used for the antibacterial control while nystatin (Sigma,
USA) was used as the antifungal control.
3. Results and discussion
The reaction of [Cu(sac)2(H2O)4] with the Schiff bases in
boiling ethanol afforded crystalline complexes containing
one Schiff base and one saccharinate ligand. The physico-
chemical properties of the complexes together with their
analytical data are shown in Table 1. The analytical data
support the proposed formulations for the complexes.
The complexes are sparingly soluble in most organic sol-
vents but dissolve readily in donor solvents such as DMSO
and DMF. They appear to be stable in air.
3.1. Magnetic and conductivity data
The complexes exhibit room temperature magnetic
moments in the 1.8–1.87 BM range (Table 1), which is nor-
mal for a 3d9 metal ion in a magnetically dilute environment
[8]. Their molar conductance values in DMSO (Table 1) fall
in the range of 9.31–27.4 ohmꢀ1 cm2 molꢀ1 indicating that,
although some dissociation of these complexes seems to
occur in this solvent, the conductance values are much
lower than that expected for a 1:1 electrolyte [24]. The con-
2.4.3. Quantitative antimicrobial assay
Compounds that showed positive (>15 mm) anti-micro-
bial inhibition with the disc diffusion assay were subjected
to the broth dilution method for the quantitative measure-
ment of microbiostatic (inhibitory) activity as described by
Table 1
Analytical data and physical properties of the Cu(II) complexes
Compounda
Colour
M.p. (ꢁC)
Kb
lc
Analytical datad (%)
C
H
N
S
Cu
[Cu(NNS0)(sac)]
[Cu(NNS00)(sac)]
[Cu(NNS000)(sac)]
a
brown-green
dark green
green
212
230
146
27.41
9.31
13.41
1.87
1.80
1.84
48.11 (48.29)
52.42 (53.32)
47.64 (48.30)
3.30 (3.50)
3.31 (3.31)
3.75 (3.50)
10.37 (10.24)
10.22 (9.21)
10.61 (10.24)
17.41 (17.58)
14.94 (15.82)
17.27 (17.58)
11.35 (11.61)
10.41 (10.45)
11.77 (11.61)
NNS0 = S-benzyl-b-N-(2-acetylpyrid-2-yl)methylenedithiocarbazate,
NNS00 = S-benzyl-b-N-(2-benzoylpyrid-2-yl)methylenedithiocarbazate
and
NNS000 = S-benzyl-b-N-(6-methylpyrid-2-yl)methylenedithiocarbazate.
b
Molar conductance (ohmꢀ1 cm2 molꢀ1) of ca. 10ꢀ3 M solutions in DMSO.
Magnetic moments at 298 K.
c
d
Calculated values are given in parentheses.

1162
T.B.S.A. Ravoof et al. / Polyhedron 26 (2007) 1159–1165
Table 3
ductivity data, therefore, support that both the saccharinate
anion and the Schiff base are coordinated to the central cop-
per (II) ion as uninegatively charged ligands [25].
Crystallographic data and structure refinement details for [Cu(NNS0)(sac)]
Empirical formula
Formula weight
Temperature (K)
C22H18CuN4O3S3
546.15
150
0.71073
3.2. Electronic and infrared spectra
˚
Wavelength (A)
Crystal system
Space group
Unit cell dimensions
triclinic
ꢀ
The IR spectra of the ligands exhibit the m(C@N),
m(NAN) and m(CSS) bands at ca. 1580, 1050–1100 and
800–900 cmꢀ1 (Table 2), respectively, which are shifted in
the spectra of the metal complexes indicating coordination
of the ligands to the copper (II) ions via the pyridyl nitro-
gen, the azomethine nitrogen and the thiolate sulphur
atom. The coordination of the azomethine nitrogen to
the metal is indicated by the shift of the m(C@N) band
and the m(N@N) band to higher frequencies (Table 2). Gen-
erally, evidence of coordination of thiosemicarbazone and
dithiocarbazate ligands to metal ions via the azomethine
nitrogen has been based on the shifting of the azomethine
C@N band of the free ligand from higher to lower wave-
numbers in the spectra of the metal complexes [26]. How-
ever, shifting of this band to both higher and lower
frequencies has been reported [27]. The m(N@N) bands of
all the free ligands were shifted to higher wavenumbers
on complexation as a result of a reduction in the repulsion
between the lone pairs of electrons on the nitrogen atoms
due to coordination via the azomethine nitrogen atom
[28]. The lowering of the m(CSS) band in the spectra of
the copper (II) complexes as compared to the frequencies
for the free ligands indicates coordination through one of
the sulphur atoms. The pyridine ring deformation mode
at ca. 600 cmꢀ1 in the spectra of the free ligands is shifted
to higher wavenumbers in the spectra of the complexes
indicating coordination of the pyridine ring nitrogen atom
to the copper (II) ion. The spectra of the complexes do not
exhibit the m(NH) bands of the free ligands supporting the
fact that deprotonation of the ligands occurs during their
coordination to the copper (II) ion. In addition to showing
P1
˚
a (A)
8.4795(2)
9.5364(2)
15.5272(4)
97.56(9)
92.93(1)
115.373(1)
1116.50(5)
2
1.293
558.00
0.08 · 0.12 · 0.18
9001/5068 [0.0002]
0.90, 0.86
4070/0/298
1.063
R = 0.0301, Rw = 0.0360
0.44 and ꢀ0.49
˚
b (A)
˚
c (A)
a (ꢁ)
b (ꢁ)
c (ꢁ)
Volume (A3)
Z
Absorption coefficient (mmꢀ1
F(000)
)
Crystal size (mm)
Reflections collected/unique [Rint
Maximum and minimum transmission
Data/restraints/parameters
Goodness-of-fit on F2
]
Final R indices [I > 3Di]
Largest differential peak and hole (e A
ꢀ3
˚
)
the characteristic bands due to the Schiff bases, the IR spec-
tra of the present copper (II) complexes also show the
m(SO2)sym, m(SO2)assym and m(C@O) bands for the sacchari-
nate ion at ca. 1150, 1290 and 1640 cmꢀ1, respectively
[11,29–31]. An X-ray crystallographic structural analysis
of [Cu(S-benzyl-b-N-(2-acetylpyrid-2-yl)methylenedithio-
carbazate)(sac)] agrees with the interpretation of the above
IR spectral data.
The electronic spectra of the copper (II) complexes
(Table 2) exhibit intra-ligand bands attributable to
n ! p* transition in the range 328–354 nm, S ! Cu(II)
charge transfer band in the 422–400 nm and a d–d band
in the 700–640 nm range. The presence of the S ! Cu(II)
Table 2
Selected IR bands and electronic spectral data for the ligands and their copper (II)-saccharinate complexes
Compounda
IR bands
mNH
Electronic spectrab
max(loge) nm(L molꢀ1 cmꢀ1
mCN
mNN
1063s
1040s
mCSS
890w
848m
msSO2
masSO2
mCO
m(py)
622m
600m
k
)
HNNS0
HNNS00
3175w
1579m
1582m
339(4.4)
354(4.5)
3024w
2916w
HNNS000
3080w
2910w
1584m
1592m
1592m
1592m
1052s
838w
816w
816m
789m
608m
630m
607m
612m
342(4.6)
[Cu(NNS0)(sac)(H2O)]
[Cu(NNS00)(sac)(H2O)]
1074m
1090m
1057w
1154s
1156s
1146s
1294s
1306s
1288vs
1674s
1648s
1641s
640(2.7), 398(4.1)
328(4.6)
651(2.4), 422(3.9)
340(4.2)
[Cu(NNS000)(sac)(H2O)]
700(2.5)
342(4.2)
a
NNS0 = S-benzyl-b-N-(2-acetylpyrid-2-yl)methylenedithiocarbazate,
NNS00 = S-benzyl-b-N-(2-benzoylpyrid-2-yl)methylenedithiocarbazate
and
NNS000 = S-benzyl-b-N-(6-methylpyrid-2-yl)methylenedithiocarbazate.
b
loge (L molꢀ1 cmꢀ1) are given in parentheses.

T.B.S.A. Ravoof et al. / Polyhedron 26 (2007) 1159–1165
1163
LMCT band at ca. 420 nm in all these spectra is indicative
of the coordination of the Schiff base to the copper (II) ion
via the thiolate sulphur atom [32]. Such LMCT bands are
common in the electronic spectra of copper (II) complexes
of related tridentate NNS thiosemicarbazone ligands [33].
The presence of a d–d band in the 690–640 nm range agrees
well with the position of the d–d band in the electronic
spectra of other square-planar copper (II) complexes
that contain the CuN3S chromophore, some structures of
which have been established by X-ray diffraction
[2,10,22,34,35].
4. The structure of the [Cu(S-benzyl-b-N-(2-acetylpyrid-2-
yl)methylenedithiocarbazate)(sac)] complex
The thermal ellipsoid drawing of the [Cu(NNS0)(sac)]
molecule with the atom numbering scheme is shown in
Fig. 3. The bond lengths and bond angles are given in
Table 4. The complex crystallizes as a monomeric species.
As implied by the physicochemical results, the copper (II)
ion is of distorted four-coordinate geometry with the donor
atoms of the Schiff base being the pyridine nitrogen atom,
the azomethine nitrogen atom and the mercapto-sulphur
atom. The nitrogen of the saccharinate anion occupies
the fourth coordination position. The Schiff base is coordi-
nated to the copper (II) ion in its iminothiolate form. Tau-
tomerism of the dithiocarbazate ligand to its iminothiolate
form is expected to convert the C@S bond to a single C–S
bond, but the length of the C–S bond in the present com-
plex falls between a C–S single bond and C@S double
bond, indicating extensive delocalization over the C–N–
N–C–S chain. This is also evident in the interatomic bond
Fig. 3. ORTEP diagram of C22H18CuN4O3S3 (with 50% probability
displacement ellipsoids) with atomic numbering scheme.
Table 4
0
˚
Selected bond lengths (A) and bond angles for [Cu(NNS )(sac)]
Bond lengths
Bond angles
Cu(1)–N(1)
Cu(1)–N(8)
Cu(1)–S(11)
Cu(1)–N(21)
C(7)–N(8)
N(8)–N(9)
C(10)–N(9)
C(10)–S(11)
2.016(16)
1.958(16)
2.243(5)
1.966(16)
1.295(2)
1.389(2)
1.301(3)
1.739(19)
N(1)–Cu(1)–N(1)
N(21)–Cu(1)–S(11)
N(8)–Cu(1)–S(11)
N(21)–Cu(1)–N(1)
N(8)–Cu(I)–N(1)
N(8)–Cu(1)–N(21)
165.22(5)
97.51(5)
85.02(5)
96.99(7)
80.68(7)
175.76(7)
˚
˚
distances, C(7)–N(8) [1.295(2) A], N(8)–N(9)[1.389(2) A],
˚
and C(10)–N(9) [1.301(3) A]. The C(10)–S(11) bond
˚
[1.739(19) A] retains its partial double bond character with
˚
the length between that of a C–S single bond [1.82 A] and a
˚
C@S double bond [1.62 A]. It is longer than that found in
Table 5
Comparison of bond lengths in some copper (II)-saccharinate complexes
Compounda
Cu–Nsac
Cu–S
Cu–Npy
Cu–Nazo
Cu–Osac
2.113(8)
Ref.
[Cu(pytsc)(sac)(H2O)] Æ 0.5H2O
[Cu(pysme)(sac)(MeOH)]
[Cu(6mpsme)(sac)(H2O)]
[Cu(sac)(NH3)4]
1.974(8)
1.967(2)
2.004(2)
2.264(3)
2.295(9)
2.304(8)
2.020(8)
2.062(2)
2.113(2)
1.956(8)
1.958(2)
1.973(2)
[10]
[35]
[34]
[37]
[Cu(sac)(NH3)4] Æ sac Æ H2O
2.328(2)
2.309(2)
2.715(2)
2.705(3)
[37]
[37]
[Cu(sac)2(mpy)2]
2.335(15)
1.966(16)
1.933(2)
1.965(5)
1.9667(13)
2.016(16)
[8]
this work
[37]
[Cu(NNS0)(sac)]
2.243(5)
1.958(16)
[Cu(sac)(PPh3)2] Æ CH2Cl2
½CuðsacÞðPPh3Þ2ꢁ ꢂ 3CHCl3
2.130(2)
[37]
4
trans-[Cu(sac)2(NH3)4]
2.508(12)
2.07(12)
[37]
2.042(12)
[Cu(sac)2(H2O)4] Æ 2H2O
2.061(2)
[2]
a
pytsc = pyridine-2-aldehydethiosemicarbazone, pysme = pyridine-2-aldehyde SMDTC, 6mpsme = 6-methylpyridine-2-aldehyde SMDTC, mpy = 2-
pyridylmethanol.

1164
T.B.S.A. Ravoof et al. / Polyhedron 26 (2007) 1159–1165
˚
Table 7
the free methylpyruvate Schiff base of SMDTC [1.652(6) A]
[25] and pyridine-2-carboxaldehydethiosemicarbazone
[1.698(3) A] [28]. The Cu–S [2.243(5) A], Cu–Nazomethine
Cytotoxic activities of the copper (II)-saccharinate complexes
Compounda
HL-60
MCF-7
Caov-3
˚
˚
˚
˚
[Cu(NNS000)(sac)]
[Cu(NNS000)(sac)]
Doxorubicin (standard)
Tamoxifen (standard)
Cisplatin (standard)
–
–
–
–
0.40
40.0
13.5
[1.958(16) A} and Cu–Npy [2.016(16) A] bond lengths com-
pare well with other copper (II)-saccharinate complexes
regardless of the geometry around the central Cu(II) ion,
as shown in Table 5.
[Cu(NNS )(sac)]
0.25
0.50
0.80
1.80
An examination of the bond angle data in Table 4 shows
that the [Cu(NNS0)(sac)] complex does not have ideal
square-planar geometry. The angles N(21)–Cu(1)–S(11),
N(8)–Cu(1)–S(11), N(21)–Cu(1)–N(1) and N(8)–Cu(1)–
N(1) deviate substantially from that expected for an ideal
square-planar structure. This distortion could be due to
the restricted bite size of the deprotonated tridentate Schiff
base ligand.
1.00
HL-60 = Human Myeloid Leukemic Cells, MCF-7 = Human Breast
Carcinoma Cells with Positive Estrogen Receptor, Caov-3 = Human
Ovarian Papillary Adenocarcinoma Cancer Cells, – ,inactive.
a
CD50 < 5.0 lg cmꢀ3 – strongly active, CD50 5.0 < 10.0 lg cmꢀ3
–
>
moderately active, CD50 10.0 < 25.0 lg cmꢀ3 – weakly active, CD50
25.0 lg cmꢀ3 – not active. CD50 (lg cmꢀ3) = Cytotoxic dose at 50%, i.e.
the concentration to reduce growth of cancer cells by 50%.
is strongly active; CD50 values of 5.0–10.0 lg cmꢀ3 indicate
that the complex is moderately active, values of 10.0–
25.0 lg cmꢀ3 indicate that the complex is weakly active
and values above 25 lg cmꢀ3 indicate that the complex
is inactive. The complexes, [Cu(NNS00)(sac)] and
[Cu(NNS000)(sac)] exhibit marked activity against the HL-
60 cell line (Human Myeloid leukemic cells) with
CD50(lg cmꢀ3) values of 0.25 and 0.5, respectively,
whereas the complex [Cu(NNS0)(sac)] is inactive. S-ben-
zyldithiocarbazate from which the Schiff bases are derived
[34] and the simple CuCl2 Æ 2H2O salt are both inactive.
Since complexes with bulkier ligands are expected to be
thermodynamically less stable, it is possible that the
5. Biological activities
5.1. Antimicrobial activities
These copper (II) complexes have been assayed against
several selected pathogens to evaluate their antibacterial
and antifungal properties. The results collected in Table 6
indicate that the complexes are weakly active against all
the bacteria and fungi chosen (inhibitory zones < 15 mm).
The values are lower than those found for both SBDTC
and SMDTC [28,36]. The [Cu(NNS000)(sac)(H2O)] complex
is completely inactive against the bacteria and fungi
assayed whereas the [Cu(NNS00)(sac)] complex is com-
pletely inactive towards the bacterial strains and weakly
active against the fungal strains. This is in contrast with
the antimicrobial activities of the complexes of SMDTC
that have been shown to exhibit moderate to strong activ-
ities against the bacteria and fungi assayed [34]. It appears
that the coordination of the saccharinate anion to the cop-
per (II) in the complexes of the present tridentate Schiff
base ligands diminishes the antibacterial and antifungal
activities of the Schiff bases which were previously found
to be active against several bacteria and fungi [34].
saccharinate
ligand
from
[Cu(NNS00)(sac)]
and
[Cu(NNS000)(sac)] are more easily displaced in solution
making available a site through which coordination can
occur with a suitable donor atom in the cancer cells. All
of the Cu(II) complexes reported herein are inactive against
the MCF-7 cell line (human breast carcinoma with positive
estrogen receptor). The values for the standards, Doxoru-
bicin, Tamoxifen and cisplatin are 0.8, 1.8 and
1.00 lg cmꢀ3, respectively (see Table 7).
6. Conclusion
5.2. Cytotoxic activities
The reaction of [Cu(sac)2(H2O)4] Æ 2H2O with the triden-
tate Schiff bases derived from S-benzyldithiocarbazate and
heterocyclic ketones in a methanol–water mixture produces
crystalline green complexes in high yields which are mixed-
The measure of cytoxicity used in this work, CD50, is the
concentration required to reduce growth of cancer cells by
50%. CD50 values <5.0 lg cmꢀ3 indicate that the complex
Table 6
Qualitative antimicrobial assay resultsa (diameter in mm)
Compound
MRSA
B29
60690
S-T
C.A
398
20341
[Cu(NNS000)(sac)]
[Cu(NNS000)(sac)]
12
–
–
13
–
–
14
–
–
12
–
–
12
8
–
11
7
–
12
7
–
[Cu(NNS )(sac)]
Streptomycin (antibacterial control)
Nystatin (antifungal control)
31
30
30
30
21
25
24
Methicillin resistant staphylococcus (MRSA); Bacillus subtilis wild type (B29), P. aeruginosa (60690); S. typhimurium (S-T), C. albicans (C.A), A. ochraceous
(398), S. ceciricaee (20341).
a
Diameter of 15 mm and above is considered active; –, inactive.

T.B.S.A. Ravoof et al. / Polyhedron 26 (2007) 1159–1165
1165
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Acknowledgements
We thank the Department of Chemistry and Laboratory
of Molecular and Cell Biology, Institute of Biosciences,
Universiti Putra Malaysia, for the provision of laboratory
facilities and the University of Oxford for providing X-ray
crystallographic services. We also thank Md. Uwaisulqarni
Osman for technical assistance. The research was funded
by a grant from the Ministry of Science and Environment,
Malaysia, under the Intensification of Research in Priority
Areas Scheme (IRPA Grant Nos. 09-02-04-0296 and 09-02-
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