Synthesis, characterisation and biological activities of S-2- or S-4-methylbenzyl-β-N-(di-2-pyridyl)methylenedithiocarbazate and Cu(II), Ni(II), Zn(II) and Cd(II) complexes

Article abstract of DOI:10.1016/j.poly.2017.05.053

Metal complexes of general formula, [M(NNS)₂] (M?=?Cu(II), Ni(II), Zn(II) and Cd(II); NNS′?=?S-2-methylbenzyl-β-N-(di-2-pyridyl)methylenedithiocarbazate (1), NNS″?=?S-3-methylbenzyl-β-N-(di-2-pyridyl)methylenedithiocarbazate (2) and NNS??=?S-4-

Full text of DOI:10.1016/j.poly.2017.05.053

Accepted Manuscript
Synthesis, characterization and biological activities of S-2- or S-4-methylben-
zyl-β-N-(di-2-pyridyl)methylenedithiocarbazate and Cu(II), Ni(II), Zn(II) and
Cd(II) complexes
T.B.S.A. Ravoof, K.A. Crouse, E.R.T. Tiekink, M.I.M. Tahir, E.N.Md. Yusof,
R. Rosli
PII:
S0277-5387(17)30409-6
DOI:
http://dx.doi.org/10.1016/j.poly.2017.05.053
POLY 12672
Reference:
Polyhedron
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 April 2017
26 May 2017
30 May 2017
Please cite this article as: T.B.S.A. Ravoof, K.A. Crouse, E.R.T. Tiekink, M.I.M. Tahir, E.N.Md. Yusof, R. Rosli,
Synthesis, characterization and biological activities of S-2- or S-4-methylbenzyl-β-N-(di-2-
pyridyl)methylenedithiocarbazate and Cu(II), Ni(II), Zn(II) and Cd(II) complexes, Polyhedron (2017), doi: http://
dx.doi.org/10.1016/j.poly.2017.05.053
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Synthesis, characterization and biological activities of S-2- or S-4-
methylbenzyl-β-N-(di-2-pyridyl)methylenedithiocarbazate and Cu(II),
Ni(II), Zn(II) and Cd(II) complexes
T. B. S. A. Ravoofa*, K. A. Crousea, E. R. T. Tiekinkb, M. I. M. Tahira, E. N. Md. Yusofa, R.
Roslic
a Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400
Serdang, Selangor, Malaysia.
b Research Centre for Crystalline Materials, School of Science and Technology, Sunway
University, Bandar Sunway, 47500 Selangor, Malaysia
c Department of Biomedical Sciences, Faculty of Medicine and Health Sciences,
Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
*corresponding author: thahira@upm.edu.my
Metal complexes of general formula, [M(NNS)2] (M = Cu(II), Ni(II), Zn(II) and Cd(II); NNS’
=
S-2-methylbenzyl--N-(di-2-pyridyl)methylenedithiocarbazate (1), NNS’’= S-3-
methylbenzyl--N-(di-2-pyridyl)methylenedithiocarbazate (2) and NNS’’’= S-4-
methylbenzyl--N-(di-2-pyridyl)methylenedithiocarbazate (3) have been synthesized by
reacting the respective metal acetates with the Schiff bases in an ethanol/acetonitrile mixture.
They have been characterized by various physico-chemical techniques. Magnetic and spectral
evidence indicate the formation of six-coordinate complexes in which the Schiff base
coordinates as a uninegatively charged tridentate NNS ligand. The crystal structures of
[Ni(NNS’)2] (5), [Ni(NNS’’’)2] (13) and [Cd(NNS’)2] (7) were solved via single-crystal X-ray
crystallographic analysis. All three complexes possess a distorted octahedral geometry where
two Schiff bases are coordinated to the central metal ion via the pyridine nitrogen-atom, the
azomethine-nitrogen atom and the thiolate-sulphur atom; like donor atoms in the N4S2 donor
set are mutually trans. The complexes have been assayed against selected pathogens and
cancer cell lines. The complexes were inactive against all the fungal strains tested, but were
mildly active against the bacterial strains tested, especially against Bacillus subtilis. Anti-
microbial activity generally improved upon complexation with the transition metal ions. The
Schiff bases and their transition metal complexes were mostly inactive against the examined

2
cancer cell lines. The Schiff bases 1-3 were inactive against the MCF-7 (Human Breast cancer
cells with positive estrogen receptor) and the MDA-MB-231 (Human Breast cancer cells with
negative estrogen receptor) cell lines. Only 9 was active against MCF-7 whereas 10 and 13
were active against the MDA-MB-231 cell line. Cytotoxic activity was observed to be
enhanced upon complexation particularly for the Ni(II) complexes.
Keywords: biological activities, S-R-methylbenzyldithiocarbazate, di-2-pyridylketone, Schiff
bases
1.
Introduction
Dithiocarbazate Schiff bases and their transition metal complexes [1-10] have been of
considerable interest to scientists for many years as they show a wide range of therapeutic
properties against various diseases, with different anti-bacterial, anti-malarial, anti-viral and
anti-tumour properties [1-10]. In recent years, heterocyclic thiosemicarbazones and Schiff
bases derived from S-alkyl dithiocarbazates have been considered as useful model compounds
for sulphur-containing analogues of purine and pyrimidine bases [11-13]. The π-
delocalisation of charge and the configurational flexibility of their molecular chain give rise
to a great variety of coordination modes [14-18]. Their chemistry and pharmacological
applications have been widely investigated as well [1-6, 15-18].
Coordination compounds, especially those that contain nitrogen-sulphur ligands are
synthesized via relatively simple, cost-effective procedures and it has been observed that
small changes in their structure, such as change of substituents and their chelation to different
metal ions cause great changes in their bioactivities. The coordination of these compounds
often lead to enhanced biological activity in several pathogenic fungi [3, 19-21]. Some of
these metal complexes have been known to accelerate drug action and the efficacy of a
therapeutic agent [1-6, 19-21].
The Schiff bases synthesized in this study are the di-2-pyridylketone Schiff bases of
isomeric
dithiocarbazates,
S-2-methylbenzyldithiocarbazate,
S-3-methylbenzyl
dithiocarbazate and S-4-methylbenzyldithiocarbazate (Fig. 1).

3
S
N
S
S
N
S
S
N
S
NH
NH
NH
N
N
N
N
N
N
(1)
(2)
(3)
Fig. 1. Thione forms of the isomeric di-2-pyridylketone Schiff bases
Investigations have shown that di-2-pyridylketone thiosemicarbazone and an
analogue, 2-benzoylpyridine thiosemicarbazone, demonstrated marked and selective anti-
tumour activity in vitro and also in vivo against many tumours. Di-2-pyridylketone
thiosemicarbazone has also been found to possess several structural characteristics important
for iron chelating efficacy and potent anti-proliferative activity, and can be further modified
as anti-neoplastic agents. Iron has a crucial role in the active site of ribonuclease reductase
which is the rate-limiting step of DNA synthesis. This Schiff base and other similar
compounds have been found to be well-tolerated by experimental animals in vivo and lead to
low toxicity to normal tissues [22-24].
Recently, studies on analogous Schiff bases, di(2-pyridyl)ketone 4,4-dimethyl-3-
thiosemicarbazone
(Dp44mT)
and
di(2-pyridyl)ketone
4-cyclohexyl-4-methyl-3-
thiosemicarbazone (DpC) showed them to be highly potent and selective anti-tumour and
anti-metastatic compounds [25]. Both of these agents had different efficacies and toxicity in
vivo. Another study reported that Dp44mT had potential to overcome multi-drug resistance
issues in cancer treatment. The drugs had greater activity in drug-resistant tumour cells than
their drug-sensitive counterparts [26].
We report herein the synthesis, characterization and biological activities of three novel
isomeric dithiocarbazate Schiff bases of di-2-pyridylketone and their Cu(II), Ni(II), Zn(II) and
Cd(II) complexes, their bioactivities against selected microbes and breast cancer cells, as well
as the X-ray crystallographic analyses of three complexes, i.e. Ni(II) (5 and 7) and Cd(II)
(13).

4
2.
Experimental
2.1. Instrumentation
The analyses for carbon, hydrogen, nitrogen and sulphur were carried out using a LECO
CHNS-932 instrument. The IR spectra, as KBr pellets, were recorded on a Perkin-Elmer FT
IR 1750X spectrophotometer (4000-400 cm-1). Metal determinations were carried out using a
Perkin-Elmer Plasma 1000 Emission Spectrometer. The molar conductance of 10-3
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 susceptibilities 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 (1000-200 nm).
2.2. Preparation of S-n-methylbenzyldithiocarbazate (n = 2, 3 and 4)
Following a procedure adapted from Ravoof et al. [27] and Omar et al. [28], potassium
hydroxide (11.4 g, 0.2 mol) was dissolved in absolute ethanol (70 ml). To this solution,
hydrazine hydrate (10 g, 0.2 mol) was added and the mixture was cooled in an ice-salt bath to
0 °C. Carbon disulphide (15.2 g, 0.2 mol) was added dropwise with constant stirring over a
period of 1 h. The two layers that subsequently formed were separated using a separating
funnel. The light-brown lower layer was dissolved in 40% ethanol (60 ml) below 5 °C. The
mixture was kept in an ice-bath and to it, n-methylbenzyl chloride (n = 2, 3 or 4) (26.5 ml, 0.2
mol) was added dropwise with vigorous stirring of the mixture. The sticky white product
which formed was filtered and left to dry overnight in a dessicator over anhydrous silica gel.
(Yields: ca 85% for each compound, m.p. n = 2: 171.2 °C, n = 3: 132.3 °C and n = 4: 160.0
°C).
2.3. Preparation of S-n--N-(di-2-pyridyl)methylenedithiocarbazate [n = 2-methylbenzyl
or 3-methylbenzyl or 4-methylbenzyl] (1, 2, and 3)
S-n-dithiocarbazate (0.01 mol, 2.12 g) was dissolved in hot acetonitrile (150 ml). This was
added to an equimolar amount of di-2-pyridylketone (0.01 mol, 1.84 g) in ethanol (10 ml).
The mixture was heated for 30 mins and then allowed to stand for a few hours or placed in a
refrigerator. The bright-yellow crystals that formed were filtered, washed with cold ethanol
and recrystallized from acetonitrile. Yields were high, ca 85%.

5
1H-NMR (1): (DMSO-d6, ppm, 14.94 (s, 1H, NH), 7.13 – 7.32 (multiplet, 16H, Ar-H), 4.46
(d, 4H, -SCH2), 2.35 (s, 3H, -CH3); 13C-NMR: (DMSO-d6, ppm,), 198.98 (C=S), 164.71
1
(C=N), 126.15-154.49 (Ar-C), 36.25 (S-CH2), 18.79 (CH3). H-NMR (2): (DMSO-d6, ppm,
14.94 (s, 1H, NH), 7.22 – 8.85 (multiplet, 13H, Ar-H), 4.48 (s, 2H, -SCH2), 2.28 (s, 3H, -
CH3); 13C-NMR: (DMSO-d6, ppm,), 199.08 (C=S), 148.70 (C=N), 123.61-148.70 (Ar-C),
1
38.25 (S-CH2), 20.94 (CH3). H-NMR (3): (DMSO-d6, ppm, 15.25 (s, 1H, NH), 7.10 – 7.95
(multiplet, 13H, Ar-H), 4.44 (s, 2H, -SCH2), 2.26 (s, 3H, -CH3); 13C-NMR: (DMSO-d6,
ppm,), 199.33 (C=S), 154.50 (C=N), 123.55-150.47 (Ar-C), 36.75 (S-CH2), 20.69 (CH3).
Mass data m/z(%) (1/2/3): [M]+ 378(0.40/0.06/0.03), [C12H10N4S]+ 240(-/24.25/23.57),
[C12H12N4]+
211(0.40/10.54/12.09),
[C11H8N3]+
183(0.03/5.71/3.27),
[C8H10S]+
138(0.22/41.19/21.97), [C6H5N2]+ 105(100.0/100.0/100.0), [C7H8]+ 91(2.65/6.05/5.02),
[C5H5N]+ 78(4.79/55.52/55.77).
O
S
N
N
NH2
S
N
H
R3
R1
dissolved in hot CH3CN/Ethanol
& heated (30 minutes)
R2
S
N
N
N
S
N
H
R3
R1
R2
Where;
R1
R2 R3
1 = CH3
2 = H
3 = H
H
CH3
H
H
H
CH3
Scheme 1. General synthesis of the isomeric Schiff bases

6
2.4. General method of synthesis of the transition-metal complexes (4-15)
The transition metal salts used were the acetate salts of Cu(II), Ni(II), Cd(II) and Zn(II)
(0.001 mol) which was dissolved in hot ethanol (10 ml) and mixed with a solution of the
Schiff base (0.002 mol, 0.76 g) in acetonitrile (100 ml) The resulting mixture was heated for
30 mins. On standing overnight, the mixture yielded crystalline complexes which were
filtered off and dried overnight in a desiccator over anhydrous silica gel. Yields: ca 70%.
Crystals of 5, 7 and 13 suitable for X-ray diffraction analysis were obtained from acetonitrile
solution over one week. Analytical, physical and spectral data on the complexes are displayed
in Tables 2 and 3.
S
N
N
N
S
N
H
M(II) acetate
(Dissolved in hot
ethanol)
R3
R1
R2
(Dissolved in hot CH3CN)
Heated (30 minutes)
R2
N
N
R1
R3
N
S
N
S
N
M
S
N
N
S
N
R3
R1
R2
Scheme 2. General synthesis of the metal complexes

7
2.5. X-ray crystallography analysis
Intensity data for 5, 7 and 13 were measured at 150 K on a Nonius Kappa CCD
diffractometer using MoKα radiation, λ = 0.71073 Å [29]. The structures were solved by
direct methods (SHELXS97 [30] through the WinGX Interface [31]) and refined (anisotropic
displacement parameters, C-bound H atoms in the riding model approximation and a
2
2
weighting scheme of the form w = 1/[σ2(Fo ) + aP2 + bP] where P = (Fo + 2Fc2)/3) with
SHELXL2014/7 on F2 [32]. The molecular structure diagrams shown in Figs 2-4 were drawn
with 70% displacement ellipsoids for 5 and 50% for each of 13 and 7 [31]. Crystallographic
data are collated in Table 1. The crystal packing diagrams were generated with DIAMOND
[33] with additional crystallographic analysis employing PLATON [34].
Table 1
Summary of the crystallographic data for 5, 7, and 13.
5
13
7
Formula
C40H34N8NiS4
813.70
C40H34N8NiS4
813.70
C40H34CdN8S4
867.39
Formula weight
Crystal size (mm)
0.06 x 0.10 x0.46 0.10 x 0.20 x 0.30 0.24 x 0.30 x 0.32
Crystal system
monoclinic
C2/c
monoclinic
P21/n
monoclinic
C2/c
Space group
a/Å
22.7123(6)
13.0429(4)
14.7375(4)
90
15.5569(4)
16.0046(5)
16.7904(4)
90
22.8859(3)
13.0785(2)
15.1730(2)
90
b/Å
c/Å
/°
/°
120.8310(10)
90
112.023(2)
90
121.3720(10)
90
/°
V/Å3
3748.79(19)
4/0.5
3875.47(19)
4/1
3877.54(10)
4/0.5
Z/Zꞌ
Dc/g cm–3
1.442
1.395
1.486
/mm–1
0.783
0.757
0.820
range/°
5.2–27.5
8048
5.1–27.9
8246
5.1–27.5
8027
Reflections measured
Independent reflections; Rint
Reflections with I > 2(I)
Number of parameters
R, obs. data; all data
4251, 0.034
3236
6420, 0.038
6240
4417, 0.014
4002
241
480
241
0.036, 0.058
0.040, 0.066
0.026, 0.030

8
a; b in wght scheme
Rw, obs. data; all data
GoF (F2)
0.052; 0
0.084, 0.093
1.01
0.033; 2.727
0.087, 0.097
1.04
0.043; 2.072
0.069, 0.072
1.04
max, min (e Å–3)
CCDC Nos
0.49, -0.46
1492224
0.33, -0.62
1492225
0.74, -0.56
1492226
2.6. Bioactivity
2.6.1. Target microorganisms
Seven pathogenic microbials were used to test the biological potential of the complexes. They
were Methicillin resistant staphylococcus (MRSA), Bacillus subtilis wild type (B. Sub),
Pseudomonas aeruginosa (P. aer), Salmonella Choleraesuis (S. cho) Candida albicans (C.
A.), Aspergillus ochraceous (A. Och) and Saccaromyces cerevisiae (S.Cere). The source of
the microbes and culture maintenance were as previously described [35].
2.6.2. Qualitative anti-microbial assay
Anti-microbial activity of each sample was qualitatively determined by a modified disc
diffusion method [36] as previously detailed [37]. A lawn of microorganisms was prepared by
pipetting and evenly spreading inoculum (10-4 cm3, adjusted turbidometrically to 105 – 106 cfu
cm3 (cfu: colony forming units) on to agar set in Petri dishes, using Nutrient agar (NA) for the
bacteria and potato dextrose agar (PDA) for fungi. Whatman No. 1 filter paper discs of 6 mm
diameter were impregnated with a stock solution of the trial compound (100 mg cm-3) and
dried under sterile conditions. The dried discs were then placed on the previously inoculated
agar surface. The plates were inverted and incubated for 24h at 30 °C for bacteria and 37 °C
for fungi. Anti-microbial activity was indicated by the presence of clear inhibition zones
around the discs. Commercially available streptomycin (Sigma, USA) was used for the anti-
bacterial control while nystatin (Sigma, USA) was used as the anti-fungal control.
2.6.3. Quantitative anti-microbial assay.
Compounds that showed positive (diameter >15 mm) anti-microbial inhibition with the disc
diffusion assay were subjected to the broth dilution method for the quantitative measurement
of microbiostatic (inhibitory) activity as described by Hufford and Clark [38]. The lowest
concentration that completely inhibited visible microbial growth was recorded as the

9
minimum inhibitory concentration (MIC, µg/ml). Streptomycin and nystatin were used as
controls for bacteria and fungi, respectively.
2.6.4. Cytotoxic assay
The MCF-7 (Human breast cancer cells with positive estrogen receptor) and MDA-MB-231
(Human breast cancer cells with negative estrogen receptor) cell lines were obtained from the
National Cancer Institute, U.S.A. The cells were cultured in RPMI-1640 / DMEM (High
glucose) (Sigma) medium supplemented with 10% fetal calf serum. Cytotoxicity was
determined using the microtitration of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
bromide (MTT) assay (Sigma, USA) as reported by Mosmann [35]. Controls that contained
only cells were included for each sample. Cytotoxicity was expressed as IC50, i.e. the
concentration that reduced the absorbance of treated cells by 50% with reference to the
control (untreated cells). Tamoxifen was used as the standard cytotoxin.
3.
3.1. Synthesis
The physicochemical properties of the Schiff bases (1-3) and their metal complexes
Results and discussion
(4-15) together with their analytical data are shown in Table 2. The three isomeric Schiff
bases only differ from each other in the position of a methyl group (CH3) attached to the
benzene ring. The analytical data (Table 2) indicated good agreement with the proposed
formulations for the compounds. The complexes were soluble in most organic solvents and
appeared to be stable in air. The complexes adopted a six-coordinate geometry containing two
tridentate NNS Schiff bases.
Table 2
Analytical data and physical properties of the HNNS Schiff bases (1-3) and their metal
complexes (4-15)
μ b
Analytical data (%) c
 a
M.p
(°C)
Compound
Colour
C
H
N
S
M
-
Light-
yellow
-
-
-
-
62.97
4.68
14.57
17.96
HNNS’ (1)
87
(63.46) (4.79) (14.80) (16.94)
63.35 4.71 14.24 16.87
(63.46) (4.79) (14.80) (16.94)
62.85 4.74 14.15 17.24
(63.46) (4.79) (14.80) (16.94)
58.67 4.22 13.65 15.42
-
HNNS’’ (2)
Yellow
147
127
166
-
Light-
yellow
Dark-
green
-
HNNS’’’ (3)
[Cu(NNS’)2 ] (4)
-
9.63
1.98
7.65
(58.69) (4.19) (13.69) (15.67) (7.76)

10
7.20
3.02
59.60
(59.0)
4.17
(4.21) (13.77) (15.76) (7.21)
4.25 13.28 15.26 7.65
(58.56) (4.18) (13.66) (15.63) (7.97)
diam. 55.02 3.89 13.25 15.02 12.78
(55.39) (3.95) (12.92) (14.79) (12.96)
58.34 4.49 13.04 15.21 7.69
(58.69) (4.19) (13.69) (15.67) (7.76)
58.93 4.12 13.24 15.12 7.14
(59.04) (4.21) (13.77) (15.76) (7.21)
diam. 57.88 4.09 13.24 15.64 7.91
(58.56) (4.18) (13.66) (15.63) (7.97)
diam. 55.15 3.86 13.06 15.14 12.65
(55.39) (3.95) (12.92) (14.79) (12.96)
58.19 4.02 13.77 16.04 8.02
(58.69) (4.19) (13.69) (15.67) (7.76)
59.25 4.15 13.25 14.98 6.96
(59.04) (4.21) (13.77) (15.76) (7.21)
diam. 57.96 4.25 13.96 15.02 7.06
(58.56) (4.18) (13.66) (15.63) (7.97)
10.98 diam. 54.96 4.02 13.41 14.22 12.68
(55.39) (3.95) (12.92) (14.79) (12.96)
13.54
15.47
7.04
[Ni(NNS’)2] (5)
Brown
Yellow
Yellow
244
247
199
168
280
234
238
134
221
227
177
8.73
diam. 58.15
[Zn(NNS’)2] (6)
[Cd(NNS’)2] (7)
[Cu(NNS’’)2] (8)
[Ni(NNS’’)2] (9)
[Zn(NNS’’)2] (10)
[Cd(NNS’’)2] (11)
[Cu(NNS’’’)2] (12)
[Ni(NNS’’’)2] (13)
[Zn(NNS’’’)2] (14)
[Cd(NNS’’’)2] (15)
4.54
Dark-
green
Dark-
brown
12.12 1.74
11.39 2.87
9.04
Yellow
Orange
Green
8.94
12.18 1.65
Golden-
green
8.84
6.49
2.82
Yellow
Yellow
a Molar conductance (-1 cm2 mol-1) of ca 10-3 M solutions in DMSO;
b Magnetic moments at 298 K in B.M.; c Calculated values are given in parentheses
3.2. Magnetic and conductivity data
The magnetic moments of the copper(II) complexes at room temperature were in the
range of 1.65-1.98 B.M, as expected for a 3d9 metal ion in a magnetically dilute environment
[1-6]; Table 2. The nickel(II) complexes exhibited magnetic moments ranging from 2.82 to
3.02 B.M. According to previous studies [3, 39], octahedral nickel(II) complexes with two
unpaired electrons will have magnetic moments between 2.9 and 3.4 B.M which indicates a
small but definite orbital contribution to the magnetic moment. The magnetic moments of the
zinc(II) and cadmium(II) complexes were found to be diamagnetic, which indicated distorted
octahedral structures [40]. All the complexes were non-electrolytes in DMSO, evidence that
the two ligands moieties did not dissociate in solution [41]. The conductivity data supported
the coordination of the two Schiff bases to the metal ion and the absence of free ions in
solution [42].
3.3. Infrared and electronic spectra
Important and characteristic IR absorptions are given in Table 3. The IR spectra of the
ligands exhibited v(C=N), v(N-N) and v(CSS) bands at ca 1584-1632, 964-1082 and 944-966
cm-1, respectively. These bands shifted in the spectra of the metal complexes indicating the
coordination of the ligands to the metal ions via the pyridine-nitrogen, azomethine-nitrogen
and thiolate-sulphur atoms. The coordination of the azomethine-nitrogen to metal ions was

11
indicated by the shifting of the v(C=N) band to lower frequencies and the shift of the v(N-N)
band to higher frequencies [42]. The lowering of the v(C=N) band was due to the M-N
formation, which lowered the C=N bond order [1-6, 40-43]. However, in the spectrum of the
[Cu(NNS’)2] complex, the v(C=N) band shifted from lower to higher frequency as has been
observed in other reports [1-6, 40-44]. The v(N-N) bands of the Schiff bases shifted from
lower to higher wavenumbers upon complexation due to the reduction in the repulsion
between the lone pairs of electrons on the nitrogen atoms as a result of the coordination
through the azomethine-nitrogen atom [1-6, 43]. The shift of v(CSS) bands to higher
frequencies in the complexes indicated the coordination via one of the sulphur atoms. The
absence of the v(NH) band in the spectra of the metal complexes suggested that the ligand lost
one proton on complexation, thus acting as a uninegatively charged ligand [40].
The electronic spectral data for all compounds are tabulated in Table 3. The electronic
spectra of the complexes in DMSO exhibited intra-ligand bands which was attributed to the
nπ* transition in the 360-275 nm range and SM(II) charge transfer bands in the 440-400
nm range. The presence of the SM(II) LMCT band confirmed the coordination of the Schiff
base to the metal ion via its thiolate-sulphur atom [1-6, 45]. Nickel(II) and copper(II)
complexes exhibited low intensity bands in the 704-600 nm range, which was attributed to
weak d-d transition bands, consistent with complexes that have six-coordinate geometry [46].
Meanwhile, the zinc(II) and cadmium(II) complexes did not exhibit any d-d transitions as
they have d10 configurations [47] and normally only exhibit intra-ligand and charge-transfer
transitions [40].
Table 3
Selected IR bands and electronic spectral data of the HNNS Schiff bases (1-3) and their metal
complexes (4-15)
IR bands (cm-1)
Electronic spectra (In DMSO)
λ max (log ε)
Compound
ν(C=N) ν(N-N) ν(CSS) ν(NH)
1584 s 964 s
958 m
3052 w 280 (3.20)
1
2
3
1608 m 1058 s 944 m
1632 m 1082 s 966 w
3036 w 320 (3.19), 360 (3.48)
3030 w 275 (3.08), 300 (2.88), 400 (3.08)
275 (3.00), 330 (2.85), 430 (2.90),
-
1594 s 1074 s 985 m
1584 m 1088 s 996 s
4
5
675 (1.40)
292 (2.38), 350 (2.19), 437 (1.99),
-
704 (0.30)

12
1582 s 1090 s 982 m
1562 s 1080 s 985 m
1590 m 1092 s 994 m
1588 m 1092 s 980 m
1588 m 1086 s 976 m
1596 m 1090 s 976 m
-
-
-
-
-
-
300 (3.10), 330 (2.95), 410 (2.88)
300 (2.90), 330 (2.85), 400 (2.85)
360 (3.11), 440 (2.90)
6
7
8
320 (3.20), 360 (3.26), 440 (3.18)
330 (2.95), 360 (3.11), 400 (3.13)
320 (3.00), 360 (3.18), 400 (3.20)
9
10
11
280 (3.00), 330 (2.84), 420 (2.54),
685 (1.40)
280 (3.10), 340 (3.08), 425 (2.95),
600 (1.30)
1590 m 1090 s 979 s
1596 m 1088 s 981 s
-
-
12
13
1582 m 1090 s 988 s
1560 m 1092 s 994 s
-
-
275 (2.88), 350 (3.00), 400 (3.00)
14
15
300 (3.20), 390 (1.93)
3.4. Structural commentary
The molecular structure of 5 is shown in Fig. 2 and selected geometric parameters are
listed in Table 4. The nickel(II) atom is located on a crystallographic twofold axis of
symmetry and is chelated by two deprotonated 1 ligands resulting in a neutral complex
formulated as 5.
Fig. 2 Molecular structure and atom labelling scheme for 5. The Ni atom lies on a
crystallographic twofold axis. Unlabelled atoms are related by the symmetry operation 1-x, y,
½-z.

13
The anion derived from 1 is tridentate, coordinating the nickel(II) centre via the
thiolate-sulphur, the azomethine-nitrogen and one of the pyridyl-nitrogen atoms; the second
pyridyl-nitrogen atom is non-coordinating. The Ni–N(azomethine) bond length is shorter than
the Ni–N(pyridyl) bond, Table 4. The tridentate ligand spans meridional positions in a
distorted octahedron and defines two five-membered chelate rings hinged at the Ni–N2 bond.
The Ni,S1,C1,N1,N2 chelate ring is non-planar (r.m.s. deviation = 0.144 Å), having an
envelope conformation with the nickel(II) atom being the flap atom. Similarly, the
Ni,N2,C2,C3,N3 ring is twisted about the C2–C3 bond (r.m.s. deviation = 0.095 Å); the
dihedral angle between the best planes through the rings is 4.85(7)°. The arrangement of the
ligand donors is such that like-atoms occupy mutually trans positions, Table 4.
The molecular structure of the isomeric analogue 13, is shown in Fig. 3 and geometric
data given in Table 4. Complex 13 lacks the molecular symmetry of 5 but, the overall
structure is in essential agreement with that just described. There some experimentally
distinct differences in chemically equivalent bond lengths, most notably in the Ni–S1, S3
separations of 2.3952(6) and 2.4257(6) Å, respectively, which are shorter and longer,
respectively, than the equivalent bonds in 5, i.e. 2.4159(5) Å. There is a close concordance in
the key bond angles in 5 and 13 with the exceptions being in the N2–M–N6 and N3–M–N7
angles which are wider and narrower, each by about 5°, in 5 cf. 13, Table 4.
Fig. 3 Molecular structure and atom labelling scheme for 13.
Crystals were also obtained for 7 which proved to be isostructural with 5, thereby also
having crystallographic twofold symmetry, the molecular structure and data of which are
represented in Fig. 4 and Table 4, respectively.

14
Table 4
Summary of the key geometric (Å, °) data for 5, 7 and 13.
5; M = Ni
13; M = Ni
7; M = Cd
M–S1
M–N2
M–N3
M–S3
M–N6
M–N7
N1–N2
N5–N6
2.4159(5)
2.0241(15)
2.1310(16)
2.4159(5)a
2.0241(15)a
2.1310(16)a
1.394(2)
2.3952(6)
2.0000(18)
2.0986(19)
2.4257(6)
1.9961(18)
2.1236(18)
1.376(3)
376(3)
1.708(2)
1.757(2)
1.703(2)
1.762(2)
1.316(3)
1.314(3)
1.296(3)
1.302(3)
82.07(5)
160.51(5)
82.05(5)
159.89(5)
78.54(7)
78.12(7)
92.82(2)
171.31(7)
89.73(7)
2.5635(4)
2.3328(12)
2.4334(13)
2.5635(4) b
2.3328(12) b
2.4334(13) b
1.3871(19)
1.3871(19) b
1.7304(15)
1.7561(16)
1.7304(15)
1.7561(16) b
1.304(2)
1.394(2)a
1.7160(19)
1.7572(19)
1.7160(19)
1.7572(19)a
1.307(2)
C1–S1
C1–S2
C21–S3
C21–S4
C1–N1
C21–N5
C2–N2
C22–N6
S1–M–N2
S1–M–N3
S3–M–N6
S3–M–N7
N2–M–N3
N6–M–N7
S1–M–S3
N2–M–N6
N3–M–N7
1.307(2)a
1.298(2)
1.304(2) b
1.286(2)
1.298(2)a
81.57(4)
1.286(2) b
76.19(3)
159.11(4)
81.57(4)a
159.11(4)a
77.81(6)
144.89(3)
76.19(3) b
144.89(3) b
68.72(4)
77.81(6)a
94.87(3)a
166.18(9)a
95.81(8)a
68.72(4) b
107.39(2) b
151.12(7) b
91.02(7) b
a Symmetry-related atoms are generated by the symmetry operation: 1-x, y, ½-z.
b Symmetry-related atoms are generated by the symmetry operation: 1-x, y, 1½-z.

15
Fig. 4 Molecular structure and atom labelling scheme for 7. The Cd atom lies on a
crystallographic twofold axis. Unlabelled atoms are related by the symmetry operation 1-x, y,
1½-z.
The major difference between the molecular structure of 7 and the nickel(II)
analogues, 5 and 13, rests with the distortions from octahedral geometry, in particular as
manifested in the S1–M–N3 and N2–M–N6 bond angles which are narrower in 7 by about
15° cf. 5.
The molecular packing of 5 is dominated by C–H…S and C–H…π interactions.
Supramolecular zigzag chains along the c-axis are sustained by pendent-pyridyl-C–
H…S(thioether) and methylene-C–H…S(thiolate) interactions as shown in Fig. 5; geometric
parameters associated with these interactions are collated in Table 5. The chains are linked
into a three-dimensional architecture by pyridyl-C–H…π(tolyl) and tolyl-C–H…π(pendent
pyridyl) interactions, Fig. SI 42.
Fig. 5. A supramolecular zigzag chain in the crystal of 5, aligned along the c-axis sustained
by C–H…S interactions (non-participating hydrogen atoms have been removed).
A wider range of intermolecular interactions contribute to the molecular packing of
13. The presence of pyridyl-C–H…S(thioether) and tolyl-C–H…N(pyridyl) interactions
combine to generate jagged supramolecular layers parallel to the ab-plane, Fig. 6. These are
connected via methylene-, methyl-C–H…π(pyridyl) and pyridyl-C–H…π(tolyl) interactions
as well as π…π interactions between pyridyl rings (Table 5) to consolidate the three-
dimensional packing, Fig. SI 43.

Table 5
Summary of the key geometric (Å, °) parameters characterising the identified intermolecular contacts in the crystals of 5, 7 and 13.
5:
A
H
B
H…B
2.85
A…B
A–H…B
Symmetry operation for B
1-x, 1-y, 1-z
C12
H12
S2
3.729(2)
154
C13
H13b
H11
S1
2.57
2.93
2.91
3.448(2)
3.622(3)
3.774(3)
147
131
147
x, 1-y, ½+z
C11
Cg(C14-C19)a
Cg(N4, C8-C12)
1-x, y, 1½-z
C20
H20a
½+x, 1½-y, ½+z.
13:
C11
H11
H36
H13b
H30
S4
2.87
2.60
2.76
2.93
3.785(3)
3.421(3)
3.688(3)
3.738(4)
3.826(3)
3.6562(13)
161
-x, 1-y, 1-z
C36
N4
145
-1+x, 1½-y, -½+z
x, 1½-y, -½+z
x, 1½-y, ½+z
C13
Cg(N3, C3-C7)
Cg(C34-C39)
Cg(N4,C8-C12)
Cg(N7,C23-C27)
156
C30
143
C40
H40a
2.86
168
-1+x, 1½-y, -½+z
-x, -½+y, 1½-z.
_
_
Cg(N3,C3-C7)
8.79(11)b
7:

17
C12
C13
C11
C20
H12
S1
2.86
2.76
2.93
2.99
3.7348(19)
3.6908(18)
3.634(2)
154
157
132
149
1-x, 1-y, 1-z
x, 1-y, -½+z
1-x, y, ½-z
H13b
H11
S1
Cg(C14-C19)
Cg(N4, C8-C12)
H20a
3.858(3)
-½+x, 1½-y, -½+z
a: Cg is the centre of gravity of the specified ring; b: is the angle of inclination between rings

Fig. 6. A supramolecular layer parallel to the ab-plane in the crystal of 13, sustained by C–
H…S and C–H…N interactions (non-participating hydrogen atoms have been removed).
Finally, despite being isostructural with 5, the molecular packing in 7 presents distinct
features. In 7, supramolecular chains with a zigzag topology are found and these mediated by
C–H…S interactions with pyridyl- and methylene-hydrogen atom donors as in 5 but in 7,
these involve the thiolate-S1 atoms only, Fig. SI 44, Table 5. The chains are connected into a
three-dimensional architecture by pyridyl-C–H…π(tolyl) and methyl-C–H…π(pyridyl)
interactions, Fig. 7, which closely resembles the molecular packing in 5 (see Fig. SI 42).

19
Fig. 7. A view in projection down the c-axis of the unit cell contents for 7. The C–H…S and
C–H…π interactions are shown as orange and purple dashed lines, respectively.
3.5. Biological activities
3.5.1. Anti-microbial activities
All of the complexes have been assayed against several selected bacteria and fungi to evaluate
their anti-bacterial and anti-fungal potential. The data tabulated in Table 6 indicate that most
of the complexes were inactive against all chosen pathogens (inhibitory zones <15 mm). All
the three Schiff bases were inactive against the microbes assayed. The compounds in this
study were also inactive towards all the fungal strains tested [Candida albicans (C.A.),
Aspergillus ochraceous (A.Och) and Saccaromyces cerevisiae (S.Cere)]
Complex 8 was slightly active against the bacterial strains, while 4 and 12 were only active
against Bacillus subtilis (B. Sub). Complex 15 was also strongly active against the bacterial
strains tested while 5 was active against only MRSA. Many of the complexes were found to
be active against Bacillus subtilis (B. Sub). Only 5, 8, 13 and 15 were selected for quantitative
anti-bacterial analysis. The data obtained indicated that the complexes that were anti-bacterial
had MIC values (minimum inhibitory concentration, µg/mL) that were much higher than

20
streptomycin indicating that they were not as effective, as a higher concentration was needed
in order to be lethal against the bacterial strains tested. The MIC values are tabulated in Table
7. However, all the inhibition zones obtained were lower than those observed in the anti-
bacterial activities of other related S-methyldithiocarbazate (SMDTC) and S-
benzyldithiocarbazate (SBDTC) complexes [48].
Table 6
Qualitative anti-bacterial assay dataa (inhibition diameter in mm)
Compound
MRSA
P. aer
S. cho
B. sub
12
12
-
-
-
-
3
-
-
-
4
22
-
-
-
5
-
-
12
12
18
10
10
16
12
23
23
-
6
-
-
-
7
10
-
6
-
6
-
8
10
-
-
-
12
-
-
-
13
14
-
-
-
-
20
20
-
23
24
-
15
Streptomycin
Nystatin
20
-
Bacteria: MRSA – Methicillin-resistant Staphylococcus aureus, P. aer – Pseudomonas
aeruginosa, S. cho – Salmonella cholerasuis, B. sub – Bacillus subtilis - wild type
a Inhibition diameter > 15 mm is strongly active; - indicates ‘not active’
Table 7
Quantitative anti-bacterial assay dataa
MIC values (µg/mL)
Compound
MRSA
3125
-
P. aer
S. cho
B. sub
-
-
-
-
-
5
8
1562

21
-
-
-
781
781
48.8
-
13
15
-
391
12.2
-
391
17.0
-
Streptomycin
Nystatin
12.2
-
a
MIC (µg/mL) = minimum inhibitory concentration, i.e. the lowest concentration to
completely inhibit microbial growth.
3.5.2. Cytotoxic activities
The cytotoxicity data of the Schiff bases and their metal complexes are given in Table 8. All
complexes have been examined for their cytotoxicity against two human breast cancer cell
lines, MCF-7 and MDA-MB-231 where MCF-7 is a estrogen, progesterone receptor-positive,
HER2 negative cell line while MDA-MB-231 is a triple negative (ER, PR and HER2) breast
cancer cell line. MCF-7 is a perfect model for hormone therapy while MDA-MB-231 is a
perfect model for chemotherapy. Because of their properties, only certain drugs can be
effective to treat the particular cancer cells and often, the mechanism of action of these
synthesised drugs occur through different pathways in both the cell lines.
Most of the compounds including the Schiff bases were found to be inactive against both
cancer cells with IC50 values >25 µg/ml. Complex 4 had moderate activity towards MDA-
MB-231 and weak activity against MCF-7, with IC50 values of 9.5 and 12.0 µg/ml,
respectively. It was interesting to note that 9 was strongly active (0.4 µg/ml) against MCF-7
but showed no activity towards MDA-MB-231. Meanwhile, the closely-related 13 was
moderately active against MDA-MB-231 but inactive against MCF-7. The latter pattern was
also observed for 10. Thus, only a small change in the backbone of the structure of a complex
can change the ability of the complex to act as an anti-cancer agent to different cell lines, in
this case, the positioning of the methyl group and the nature of the metal ion [42]. Complexes
7, 11 and 15 were notably inactive when assayed against both cancer cells. The findings in
this work mimic earlier reports of bioactivities of first row transition metal complexes where
cytotoxic activity of the complexes is affected by the nature of the constituent metal ion and
ligand [49, 50]. The IC50 values of the standard, Tamoxifen, were between 5.0 and 5.5 µm/ml.
Table 8
Cytotoxic assay data (IC50 values in µg/ml)

22
IC50 (µg/ml) a
MDA-MB-231c
MCF-7b
12.0
15.0
0.4
Complex
9.5
4
>5.0
>5.0
0.4
6
9
>5.0
>5.0
5.0
10
4.0
13
Tamoxifen
5.5
aIC50 is the cytotoxic dose at 50%, i.e. the concentration required to reduce growth of cancer
cells by 50%. IC50 values < 5.0 g/ml indicate that the complex is strongly active whereas
IC50 values of 5.0-10.0, 10.0-25.0 and > 25.0 g/ml indicate that the complex is moderately
active, weakly active and inactive, respectively.
bMCF-7 (Human Breast carcinoma with positive estrogen receptor)
cMDA-MB-231 (Human Breast carcinoma with negative estrogen receptor)
4.
Conclusions
The reaction of isomeric tridentate Schiff bases derived from isomericdithiocarbazates and a
heterocyclic ketone with metal acetates in an ethanol/acetonitrile mixture produced
beautifully crystalline coloured nickel(II), copper(II), zinc(II) and cadmium(II) complexes in
high yields. These complexes had six-coordinate geometries in which the Schiff bases acted
as uninegatively charged tridentate ligands, and with like-atoms being mutually trans. The X-
ray crystal structure determination of 5, 7 and 13 showed that the complexes had slightly
distorted octahedral geometry where the metal ion was coordinated to two tridentate NNS
ligands. Most of the complexes in this study had weak potential as anti-microbial agents and
showed selective and specific activities as anti-cancer agents when examined against human
breast cancer cell lines. As the biological properties of structurally similar dithiocarbazate
complexes are of much interest, it would be worthwhile to study the structure-bioactivity
relationship of these complexes in-silico, to elucidate potential mechanisms of action.
4.
Supplementary material
Crystallographic data for the structural analysis have been deposited with the Cambridge
Crystallographic Data Centre, CCDC No. 1492224 (5), 1492225 (13) and 1492226 (7).
Copies of this information may be obtained free of charge from The Director, CCDC, 12

23
Union Road, Cambridge, CB2 1EZ, UK (fax: +44-1223-336033; e-mail: deposit@ccdc.cam.
ac.uk or www: http://www.ccdc.cam.ac.uk).
Acknowledgements
We thank the Department of Chemistry, the Molecular Genetics Laboratory and Chemical
Crystallography Laboratory of Universiti Putra Malaysia (UPM) for providing the laboratory
facilities and X-ray crystallographic services. This research was funded by Universiti Putra
Malaysia (UPM) and the Malaysian Government under the Intensification of Research in
Priority Areas Scheme (IRPA grant No. 09-02-04-0296) and the Malaysian Fundamental
Research Grant Scheme (FRGS No. 01–01-16-1833FR).
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S
N
S
S
N
S
S
N
S
NH
NH
NH
N
N
N
N
N
N
Fig 1: Isomeric di-2-pyridylketone Schiff bases (HNNS)
Fig 2: ORTEP diagram of [Ni(NNS’)2] (5)

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The article describes the synthesis and characterisation of isomeric Schiff bases derived from
S-R-methylbenzyldithiocarbazate (R=2,3,4) and di-2-pyridyl ketone (referred to as NNS’,
NNS’’, NNS’’’); and their metal complexes of general formula, [M(NNS)2] (M = Cu(II),
Ni(II), Zn(II) and Cd(II). They have been characterized by various spectro-analytical
techniques. The crystal structures of [Ni(NNS’)2], [Ni(NNS’’’)2] and [Cd(NNS’)2] were
solved via single-crystal X-ray crystallographic analysis where all three complexes possessed
a distorted octahedral geometry. The complexes have been assayed against selected pathogens
where they were inactive against all the fungal strains tested, but were mildly active against
Bacillus subtilis. The Schiff bases and their transition metal complexes were also mostly
inactive against the examined cancer cell lines MCF-7 and the MDA-MB-231. Cytotoxic
activity was observed to be enhanced upon complexation, particularly for the Ni(II)
complexes.