Synthesis, crystal structure, characterisation, and antifungal activity of 3-thiophene aldehyde semicarbazone (3STCH), 2,3-thiophene dicarboxaldehyde bis(semicarbazone) (2,3BSTCH2) and their nickel (II) complexes

Article abstract of DOI:10.1016/j.jinorgbio.2012.04.022

The reaction of nickel (II) chloride and bromide with 3-thiophene aldehyde semicarbazone (3STCH) and 2,3-thiophene dicarboxaldehyde bis(semicarbazone) (2,3BSTCH₂) leads to the formation of a series of new complexes: [NiCl₂(3STCH)₂], [NiBr₂(3STCH)₂], [NiCl(2,3BSTCH₂)(H₂O)]Cl, and [NiBr(2,3BSTCH ₂)(H₂O)]Br respectively. The crystal structures of the two ligands 3STCH, 2,3BSTCH₂ and of the complex [NiBr(2,3BSTCH ₂)(H₂O)]Br have been determined by X-ray diffraction methods. For all these complexes, the central ion is coordinated through the oxygen atom of the carbonyle and the azomethine nitrogen atom of the semicarbazone. The antifungal activity of the complexes and their corresponding ligands was evaluated against some strains of respectively, Candida albicans, Candida glabrata and Aspergillus fumigatus. The complexes with 3STCH and 2,3BSTCH₂ revealed interesting CMI₈₀ values specifically against C. glabrata. Cytotoxicity assay was also carried out in vitro on MRC5 cells.

Full text of DOI:10.1016/j.jinorgbio.2012.04.022

Journal of Inorganic Biochemistry 115 (2012) 36–43
Contents lists available at SciVerse ScienceDirect
Journal of Inorganic Biochemistry
journal homepage: www.elsevier.com/locate/jinorgbio
Synthesis, crystal structure, characterisation, and antifungal activity of 3-thiophene
aldehyde semicarbazone (3STCH), 2,3-thiophene dicarboxaldehyde
bis(semicarbazone) (2,3BSTCH2) and their nickel (II) complexes
a
Kusaï Alomar a, Vincent Gaumet b, Magali Allain c, Gilles Bouet a, , Anne Landreau
⁎
a
Laboratoire SONAS, EA 921, Université d'Angers, IFR QUASAV 149, UFR Sciences Pharmaceutiques et Ingénierie de la Santé, 16 Boulevard Daviers, F-49045 Angers cedex 01, France
UMR 990 Inserm, Imagerie Moléculaire et Thérapie Vectorisée, Université d'Auvergne, Faculté de Pharmacie, 28 place Henri Dunant, 63001 Clermont-Ferrand cedex 1, France
Institut des Sciences et Technologies Moléculaires d'Angers (MOLTECH-Anjou), UMR CNRS 6200, Université d'Angers, 2 Boulevard Lavoisier, 49045 Angers cedex 01, France
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of nickel (II) chloride and bromide with 3-thiophene aldehyde semicarbazone (3STCH) and 2,3-
thiophene dicarboxaldehyde bis(semicarbazone) (2,3BSTCH2) leads to the formation of a series of new com-
plexes: [NiCl2(3STCH)2], [NiBr2(3STCH)2], [NiCl(2,3BSTCH2)(H2O)]Cl, and [NiBr(2,3BSTCH2)(H2O)]Br respectively.
The crystal structures of the two ligands 3STCH, 2,3BSTCH2 and of the complex [NiBr(2,3BSTCH2)(H2O)]Br have
been determined by X-ray diffraction methods. For all these complexes, the central ion is coordinated through
the oxygen atom of the carbonyle and the azomethine nitrogen atom of the semicarbazone. The antifungal activity
of the complexes and their corresponding ligands was evaluated against some strains of respectively, Candida
albicans, Candida glabrata and Aspergillus fumigatus. The complexes with 3STCH and 2,3BSTCH2 revealed interest-
ing CMI80 values specifically against C. glabrata. Cytotoxicity assay was also carried out in vitro on MRC5 cells.
© 2012 Elsevier Inc. All rights reserved.
Received 1 February 2012
Received in revised form 23 April 2012
Accepted 24 April 2012
Available online 24 May 2012
Keywords:
Thiophene
Semicarbazone
Crystal structure
Nickel complexes
Antifungal activity
Cytotoxicity
1. Introduction
(II) complexes showed an octahedral geometry, coordinating through
the oxygen atom of the furan ring and the imino nitrogen atom. Many
Thiosemicarbazones, semicarbazones and their metal complexes have
been extensively studied in recent years [1,2], mainly because of their
various biological and antimicrobial properties [3–5]. Semicarbazones
usually act as chelating ligands with transition metal ions, bonding
through the carbonyle oxygen and the hydrazine nitrogen atoms [6].
However, semicarbazonescharacha have received much less atten-
tion than their sulphur-containing analogues. As a contribution to a
better understanding of this versatile class of compounds [7], the het-
erocyclic semicarbazones (e.g.: furans) which functional group attached
at 2-position, have been the subjects of extensive investigation for their
structural studies as well as their potent biological properties [7,8].
Chemically speaking, the heterocyclic semicarbazones are of high inter-
est because of their versatility as ligands. This is due to the presence
of several potential donor atoms, their flexibility, and their ability to
coordinate either in neutral or deprotonated forms because of their
tautomerism equilibrium leading to keto and enol forms [9]. So they
are compounds with versatile structural features and they can coordi-
nate to the metal either as a neutral ligand or as a deprotonated anion.
We have previously described the furanic semicarbazones:
2-furaldehyde semicarbazone, 5-methyl 2-furfural semicarbazone and
3-(2-furyl)prop-2-enal semicarbazone [10,11]. In this series, the nickel
examples of pharmacological applications with this class of compounds
have been evaluated for their antitumor [12], antibacterial [13,14]
and antifungal [15,16] activities. In many cases, upon coordination to
metal ions, the bioactivity of these organic compounds increases
[17,18] and sometimes with a decreased toxicity [19]. As a part of
our continuous research work pertaining to the synthesis, the char-
acterisation and the biological activity of metal complexes from
semicarbazones and thiosemicarbazones with five-membered hetero-
cycles [19,20], we describe here some new transition metal complexes
obtained from 3-thiophenaldehyde semicarbazone (3STCH) and 2,3-
thiophene dialdehyde bis(semicarbazone) (2,3BSTCH2) (Fig. 1) as li-
gands and nickel (II) chlorides and bromides. In addition, the crystal
structures of the ligands and of the complex [NiBr(2,3BSTCH2)(H2O)]Br
are described. The antifungal activities of the two ligands and their
complexes were evaluated against Candida albicans, Candida glabrata
and Aspergillus fumigatus. Moreover, the evaluation in vitro of their
cytotoxicity towards MRC5 cells was performed.
2. Experimental
2.1. Reactants
All reactants and solvents were of analytical grade. Semicarbazide
hydrochloride and thiophene-3-carboxaldehyde were purchased from
⁎
Corresponding author. Tel.: +33 2 41 22 66 00; fax: +33 2 41 22 66 34.
E-mail address: gilles.bouet@univ-angers.fr (G. Bouet).
0162-0134/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.jinorgbio.2012.04.022

K. Alomar et al. / Journal of Inorganic Biochemistry 115 (2012) 36–43
37
NH2
Table 1
Crystallographic data.
(a)
(b)
Name
3STCH
2,3BSTCH2
[NiBr(2,3BSTCH2)
O
(H2O)]Br
N
NH
Formula
Formula weight
Crystal system
Space group
a (Å)
b (Å)
c (Å)
α (°)
β (°)
C6H7N3OS
169.21
C8H10N6O2S
254.28
C8H12NiBr2N6O3S
490.80
S
Monoclinic
P21/c
Monoclinic
Monoclinic
P21/c
P21/
c
11.523 (2)
5.4289 (5)
12.524 (2)
90
10.2925 (9)
15.5806 (6)
13.908 (1)
90
6.8882 (4)
7.2754 (4)
29.9878 (19)
90
S
102.09 (2)
90
97.615 (9)
90
95.491 (3)
90
N
N
γ (°)
V (Å3)
766.1 (2)
4
Yellow
2210.7 (3)
8
Yellow
1495.93 (15)
4
Green dark
2.179
Z
NH
NH2
NH
H2N
Colour
Dcalc (g.cm−3
)
1.454
1.528
Crystal size (mm)
0.54×0.23×0.08
0.364
0.3×0.13×0.08
0.294
0.51×0.23×0.07
6.796
O
O
μ (mm−1
)
hkl limits
−14≤h≤14
−6≤k≤6
−15≤l≤15
1.81, 26.07
0.0466
−13≤h≤13
−20≤k≤20
−18≤l≤18
2.94, 27.51
0.0699
−9≤h≤9
−9≤k≤9
−40≤l≤37
2.7, 28.8
0.035
Fig. 1. Chemical structure of the ligands: (a) 3-thiophene carboxaldehyde semicarbazone
(3STCH), (b) 2,3-thiophene dicarboxaldehyde bis(semicarbazone) (2,3BSTCH2).
θ
min, θmax (°)
R1 for I>2 σ(I)
wR2 for I>2 σ(I)
Alfa Aesar, thiophene-2,3-dicarboxaldehyde from Aldrich (France).
Nickel hydrated salts (Prolabo) were used as received.
0.1099
0.1144
0.11
2.2. Measurements
time of 10 s per frame using the APEX2 software [22]. Unit cell refine-
ment on all observed reflections and data reduction were performed
using SAINT [23]. Scaling and a numerical absorption correction, based
upon crystal size and faces indexing, were done using SADABS [23].
The minimum and maximum transmission factors were 0.167 and
0.621, respectively. Systematic absences and intensity statistics were
consistent with the compound having crystallised in the centrosymmetric
monoclinic space group P21/c. A total of 12,282 reflections were collected,
merged based upon identical indices yielding 3877 data (Rint =0.031)
which 3123 had I>2σ (I).
The structure was determined by direct methods with the suc-
cessful location of all non-hydrogen atoms of the unique molecule
within the asymmetric unit using the programme SHELXS [24]. The
structure was refined with SHELXL [21]. All non-hydrogen atoms
were refined anisotropically. Rotation of the thienyl ring by 180° cau-
ses the sulphur atom and the C(2)\H group to change places, the
C(3) converting to C(4) and vice versa. Bearing in mind that the van
der Waals volume of C\H group is close to the volume of a sulphur
atom both conformations can be realised in the same crystallographic
position [25]. This leads to a static disordering in the crystal structure.
The values of the free factors which identify the population densities
of the atoms are 0.840(6) for the first thienyl description (atoms A)
and 0.160(6) for the second thienyl description (atoms B). Best results
have been obtained when couples C1A/C1B, C3A/C4B, and C4A/C3B are
constrained to same positions. The hydrogen atoms were included in cal-
culated positions according to their geometry and refined riding on car-
bon atoms. Hydrogen atoms linked to oxygen of water molecule were
located in subsequent difference Fourier maps, refined and geometrical-
ly restrained to the same distance (DFIX command of SHELXL97). The
final structure was refined to convergence with R(F)=3.52% and
GOOF=1.091 for those 3123 data with Fo>4σ(Fo) [R(F)=5.05% and
GOOF=1.108 for all 3877 data]. An empirical correction for extinction
was also attempted but found to be equal to zero within the error and
therefore not applied.
Elemental analyses were carried out by the service central of analy-
ses (C.N.R.S. Vernaison, France) or by Plateforme Intégrée d'Analyse
Moléculaire (PIAM), Faculté des Sciences, Université d'Angers (France).
DSC diagrams were recorded in the 25–400 °C range with a Mettler
DSC 822e unit, with the help of Mettler Toledo STARe SW 8.10 System
software (Laboratoire de Physique, Faculté de Pharmacie, Angers);
the heating rate was 10 °C per min. All measurements were made in
40 mm3 closed Al crucibles. The IR spectra were recorded with a Bruker
FTIR Vector 22 spectrometer between 4400 and 400 cm−1 (KBr discs).
The far IR spectra were recorded with a Bruker Vertex FTIR spectropho-
tometer in the 650 to 50 cm−1 range using polyethylene discs (Institut
des Matériaux Jean Rouxel, université de Nantes (France)).
2.3. Crystal data collection and processing
Crystals of the ligands 3STCH, and 2,3BSTCH2 are monoclinic with
space group P21/c. The crystal and instrumental parameters used in the
unit-cell determination and data collection are summarised in Table 1.
X-ray single-crystal diffraction data were collected at 293 K on a STOE-
IPDS diffractometer for 3STCH and on a BRUKER-NONIUS KappaCCD
diffractometer for 2,3BSTCH2, both equipped with a graphite monochro-
mator using MoKα radiation (λ=0.71073 Å) (MOLTECH-Anjou, UMR
CNRS 6200, Université d'Angers). The structures were solved by direct
methods and refined on F2 by full-matrix least-squares method with
anisotropic approximation for all non-hydrogen atoms, using SHELX97
package [21]. For 3STCH, absorption was corrected by Gaussian tech-
nique and the H atoms were found by Fourier difference synthesis. For
2,3BSTCH2, absorption was corrected by SADABS programme (Sheldrick,
Bruker, 2000) and the H atoms were included in the calculation without
refinement.
The complex [NiBr(2,3BSTCH2)(H2O)]Br was crystallised from a
water–ethanol mixture at room temperature as pale yellow plates.
A crystal 0.07×0.23×0.51 mm3 in size was placed and optically centred
on a Bruker KAPPA APEX II diffractometer equipped with a Mo Kα radi-
ation (λ=0.71073 Å) at 293 (2)K. The initial unit cell was indexed
using the difference vectors method of a random set of reflections col-
lected from three series of 0.5° wide omega-scans, 20 s per frame, and
12 frames per series that were well distributed in reciprocal space.
The crystal to detector distance was 50 mm. A total of 1064 frames
were collected to θmax=28.8° with 0.5° wide scans and an exposure
2.4. Biological activities
2.4.1. Microorganisms
Antifungal activity was assayed on human pathogenic fungi, including
yeasts of the Candida genus: C. albicans (ATCC 66396), C. glabrata (LMA
90-1085), and one opportunistic mould A. fumigatus (CBS 11326). All

38
K. Alomar et al. / Journal of Inorganic Biochemistry 115 (2012) 36–43
fungi were obtained from the parasitology and mycology laboratory
of the CHU of Angers. Moulds were cultivated at 37 °C on yeast extract–
peptone–dextrose agar (YPDA) containing 0.5 g.L−1 chloramphenicol
for 2 days for yeasts and 3 days for A. fumigatus.
prepared from 2.5 mmol (0.64 g) of 2,3BSTCH2 according to the indi-
vidual procedure described below.
2.6.1. Dichloro bis(3-thiophenaldehyde semicarbazone) nickel (II)
[NiCl2(3STCH)2]
2.4.2. Determination of antifungal activity
NiCl2·6H2O (0.64 g; 2.5 mmol; 10 mL) was added to the 3STCH
ethanolic solution (20 mL) was maintained at room temperature for
4 h [3].
Tests were performed by following the guidelines of the approved
reference method for yeasts (NCCLS document M27A) [26] and
according to the NCCLS guidelines for filamentous fungi (M38-P)
[27]. Briefly, the yeast suspensions were prepared in RPMI-1640 cul-
ture medium and adjusted spectrophotometrically at 630 nm to
reach a final concentration of ca. 0.5×103 to 2.5×103 cells per mL.
The tests were performed using sterile 96 flat shaped well microtitre
plates. Serial two-fold drug dilutions were made in DMSO. Drugs
were dispensed at a volume of 5 μL in triplicate into the wells to ob-
tain final concentrations from 250 to 1.95 μg.mL−1. After 48 h at
37 °C for the yeasts, and 72 h for A. fumigatus, the spectrophotometric
MIC endpoint was calculated from the turbidimetric data as the lowest
drug concentration giving rise to an inhibition of growth equal to or
greater than 80% of that the drug-free control (MIC80). Amphotericine
B was used as a positive control.
2.6.2. Dibromo bis(3-thiophenaldehyde semicarbazone) nickel (II)
[NiBr2(3STCH)2]
NiBr2·x H2O (0.59 g; 2.5 mmol; 10 mL) was added to the ethanolic
solution of 3STCH (20 mL) under refluxing conditions. The reflux was
maintained for 6 h.
2.6.3. {Aquo chloro [2,3-thiophenaldehyde bis(semicarbazone)] nickel
(II)} chloride [NiCl(2,3BSTCH2)(H2O)]Cl
NiCl2·6 H2O (0.64 g; 2.5 mmol; H2O; 10 mL) was added to
2,3BSTCH2 (0.64 g; 2.5 mmol; EtOH; 10 mL) in a sealed flask and
heated up to reflux under pressure for 24 h. After cooling, the solution
is concentrated under reduced pressure until the complex precipitated.
DMSO activity was evaluated from 10 to 0.075% final concentra-
tions, according in the same way. The tests were performed using
sterile 96 flat shaped well microtitre plates. For each dilution, 20 μL
of DMSO was added to 180 μL of RPMI medium previously inoculated
with yeasts or A. fumigatus. After an incubation of 48 h at 37 °C for the
yeasts and 72 h for A. fumigatus, the spectrophotometric MIC end-
point were calculated from the turbidimetric data compared to that
of the DMSO-free control. The chosen threshold was 2.5% final con-
centration in DMSO because growth was still significant with respec-
tively 71% for A. fumigatus and 86% for yeasts.
2.6.4. {Aquo bromo [2,3-thiophenaldehyde bis(semicarbazone)] nickel
(II)} bromide [NiBr(2,3BSTCH2)(H2O)]Br
This complex was obtained in the same way than the corresponding
chloro compound, starting from NiBr2 (0.59 g; 2.5 mmol; H2O; 10 mL)
and 2,3BSTCH2 (0.64 g; 2.5 mmol; EtOH; 10 mL).
3. Results and discussion
3.1. Crystal structure of 3STCH
2.4.3. Cytotoxicity
The main crystal parameters are reported in Table 1. The mono-
clinic unit cell (space group P21/c) contains four molecules. The mol-
ecule of 3STCH with numbering scheme is given in Fig. 2. The
molecule 3STCH is quite planar with a feeble mean deviation to the
plane. The most important deviation is observed for C3: 0.063 Å.
The oxygen atom O1 and the hydrazone nitrogen N3 are in E position
with respect to the C1\N2 bond. This configuration is often observed
in semicarbazones and its stability is due to the presence of an intra-
molecular hydrogen bond between N3-imino atom and H1B from
Cytotoxicity was evaluated at Institut de Chimie des Substances
Naturelles, CNRS UPR 2301 (Gif sur Yvette, France) on MRC5 cells in
DMSO at 10−5 and 10−6 M according to the procedure described by
Moret et al. [28]. Taxotere was used as the reference substance.
2.5. Synthesis of the ligands
2.5.1. Synthesis of 3STCH
This ligand was obtained from thiophene-3-carboxaldehyde and
semicarbazide hydrochloride (1:1 M ratio). To a solution (MeOH) of
semicarbazide hydrochloride (1 g; 9 mmol; 15 mL), potassium hydrox-
ide (0.5 g; 15 mL; MeOH) was added, after 10 min KCl precipitated. The
solution was filtered and a solution of thiophene-3-carboxaldehyde
(1 g; 9 mmol; 15 mL; EtOH) was added. The mixture was refluxed
for 1 h and then cooled. The ligand was removed by filtration and
recrystallised from ethanol. Yellow single crystals suitable for X-ray
analysis were grown [29].
NH2, this interaction is weak but sufficient to stabilise the
configuration.
E
Representative bond distances and angles for 3STCH are shown in
Table 2. The C1\O1 bond length (1.239 Å) is typical of a double bond.
The length of the C2\N3 bond is 1.275 Å while the length of N2\N3
is 1.375 Å. These distances are typical of a C_N double bond and an
N\N single bond respectively [6].
The packing arrangement in the unit cell is given in Fig. 3a. The
packing of a group of independent molecules is governed by N\H…
O hydrogen bonds (Table 4, Fig. 3b). They are consistent with those
2.5.2. Synthesis of 2,3BSTCH2
This ligand was prepared from thiophene-2,3-dicarboxaldehyde
and semicarbazide (1:2 M ratio) obtained as described above. The
mixture was refluxed for 3 h and then cooled. The solid was filtered
and recrystallised from ethanol [30]. Yellow single crystals suitable
for X-ray analysis were grown at room temperature by slow evapora-
tion of a mixture of ethanol (50%) and water (50%).
2.6. Preparation of the complexes
All the complexes with 3STCH were prepared starting from
5 mmol (0.85 g) of 3STCH dissolved in EtOH. The ethanolic solution
of the metal halide was added slowly while stirring. The complexes
were removed by filtration, washed with MeOH and finally dried in
vacuum over silica gel. All the complexes with 2,3BSTCH2 were
Fig. 2. Crystal structure and atoms numbering for 3STCH.

K. Alomar et al. / Journal of Inorganic Biochemistry 115 (2012) 36–43
39
observed in the case of the P-dimethylaminobenzaldehyde semi-
carbazone where similar intermolecular N\H…O hydrogen bonds
occurred [31].
3.1.1. Crystal structure of 2,3BSTCH2
The main crystal parameters are reported in Table 1. Some repre-
sentative bond lengths and angles are reported in Table 3. The mono-
clinic unit cell (space group P21/c) contains eight molecules in four
groups of tow independent molecules. The tow independent mole-
cules with numbering scheme are given in Fig. 4. The first and the
second molecules lie in quite parallel planes with a 9.595° deviation.
Each of the tow independent molecules is quite planar with a fee-
ble mean deviation to the plane. The most important deviations ob-
served are as follows: N6: 0.195 Å, N8: 0.247 Å, N9: 0.478 Å, N11:
0.212 Å, N12: 0.341 Å and C9: 0.392 Å. The oxygen atom O1 and the
hydrazone nitrogen N1 are in E position with respect to the C6\N2
bond, the same configuration is observed for O2 and N4 referring to
C8\N5 bond. Its stability is due to the presence of an intramolecular
hydrogen bond between N-imino atom and H from NH2. The dis-
tances N1\H3B, N4\H6B, N7\H9B, N10\H12B are 2.326, 2.299,
2.296 and 2.288 Å respectively and consequently these interactions
are weak, but sufficient to stabilise the E configuration [32].
Some very slight differences appear in the bond distances and
angles in the semicarbazone moiety between the two molecules. Rep-
resentative bond distances and angles for the two independent mole-
cules are shown in Table 3. The C\O bond lengths (1.240, 1.246 Å)
are typical of a C_O double bond. The bond lengths of the C5\N1
and C7\N4 bonds are 1.271 and 1.283 Å respectively, these distances
are typical of a C_N. That the bond length of N1\N2, N4\N5 is
1.378, 1.369 Å respectively, these distances correspond to an N\N
single bond and similar values are observed for the second indepen-
dent molecule. Similar values were observed in the cases of diaqua[2,6-
diacetylpyridine bis(semicarbazone)]chromium (III) hydroxide dinitrate
hydrate and dichloro[2,6-diacetylpyridine bis(semicarbazone)]iron (III)
chloride dihydrate complexes [33] and manganese (II) complex with
2,6-diacetylpyridine bis(2-aminobenzoylhydrazone) as well [34].
The packing arrangement in the unit cell is given in Fig. 5 and it is
governed by intermolecular hydrogen bonds. The molecules are sta-
cked in parallel planes along b axis and the intermolecular hydrogen
bonding (Table 5) occurred through carbonyl oxygen atoms. The
first independent molecule gives 5 hydrogen bonds: O1 with H11
and H9B; O2 linked with H2A, H9A and H12A. Four hydrogen bonds
are observed in the second independent molecule: O3 with H5A and
H3B and O4 with H3A and H6A. All these intermolecular hydrogen
bonds are located between neighbour sets of two independent mole-
cules and, inside a set, there is no hydrogen bond between the two
molecules.
Fig. 3. Cell packing (a) and hydrogen bonding (b) for 3STCH.
molecule, acting as a tetradentate ligand, and the apical positions are
occupied by a bromide ion and the oxygen atom of the water molecule.
The four basal atoms are coplanar with O2\Ni1\N1 and N4\Ni1\O1
angles of 173.58° and 176.14° respectively. The corresponding bond
pairs have nearly the same length. The basal bond distances Ni1\N1,
Ni1\N4, Ni1\O1 and Ni1\O2 are 2.013 Å, 2.018 Å, 2.021 Å and
2.011 Å respectively (Table 4). The elongated axial bond length Ni1\O3
(water) is 2.143 Å and angle between O3\Ni1\Br1 is 178.38° [35].
Table 3
Selected bond lengths (Å) and angles (°) of 2,3BSTCH2.
Bond lengths
Bond angles
3.2. Crystal structure of the nickel complex [NiBr(2,3BSTCH2)(H2O)]Br
C5\N1
C6\O1
C6\N3
C6\N2
C7\N4
C8\O2
C8\N6
C8\N5
C13\N7
C14\O3
C14\N9
C14\N8
C15\N10
C16\O4
C16\N12
C16\N11
N1\N2
N4\N5
N7\N8
N10\N11
1.271
1.240
1.332
1.353
1.283
1.246
1.341
1.357
1.277
1.236
1.333
1.368
1.286
1.233
1.330
1.347
1.378
1.369
1.371
1.373
N1\C5\C3
124.5 (3)
124.0 (3)
118.9 (3)
117.1 (3)
120.0 (3)
123.4 (3)
119.4 (3)
117.1 (3)
123.4 (3)
124.0 (3)
119.4 (3)
122.8 (3)
120.2 (3)
116.6 (3)
117.0 (3)
115.1 (2)
121.2 (2)
116.3 (2)
120.0 (2)
115.5 (2)
O1\C6\N3
O1\C6\N2
N3\C6\N2
N4\C7\C4
Relevant crystal data for [NiBr(2,3BSTCH2)(H2O)]Br is given in
Table 1. A perspective view of [NiBr(2,3BSTCH2)(H2O)]Br compound
with the atom numbering scheme is shown in Fig. 6.
The complex molecule is quite planar and its E, E′ configuration al-
lows Ni2+ to adopt a (4+2) surrounding. The equatorial positions are
occupied by two nitrogen and the two oxygen atoms of the 2,3BSTCH2
O2\C8\N6
O2\C8\N5
N6\C8\N5
N7\C13\C11
O3\C14\N9
O3\C14\N8
O4\C16\N12
O4\C16\N11
N9\C14\N8
N12\C16\N11
C5\N1\N2
C6\N2\N1
C13\N7\N8
C14\N8\N7
C15\N10\N11
Table 2
Selected bond lengths (Å) and angles (°) of 3STCH.
Bond lengths
Bond angles
C1\N1
C1\N2
C1\O1
C2\N3
N2\N3
1.330
1.363
1.239
1.275
1.375
N1\C1\N2
N1\C1\O1
N2\C1\O1
C1\N2\N3
C2\N3\N2
116.74
124.35
118.90
119.76
115.35

40
K. Alomar et al. / Journal of Inorganic Biochemistry 115 (2012) 36–43
Fig. 6. Crystal structure and atoms numbering for [NiBr(2,3BSTCH2)(H2O)]Br.
This bromide ion is also linked, via a second hydrogen bond, to a
water molecule.
3.3. Structures of complexes
3.3.1. Analytical data
Fig. 4. Crystal structure and atoms numbering for 2,3BSTCH2.
The elemental analysis of the ligands and their complexes is
summarised in Table 6. A good harmony between the experimental
and calculated values is observed and the formulae of the complexes
are: [NiCl2(3STCH)2], [NiBr2(3STCH)2], [NiCl(2,3BSTCH2)(H2O)]Cl and
[NiBr(2,3BSTCH2)(H2O)]Br respectively.
The melting points were determined using Differential Scanning
Calorimetry (DSC). In all complexes, the decomposition follows the
beginning of the melting process.
The crystal structure displays many hydrogen bonds (Table 5) be-
tween bis(semicarbazone), water molecule and bromide ions forming
a three-dimensional network. The molecular packing diagram is show
in Fig. 7, hydrogen bondings have been omitted for clarity (Fig. 7).
These bonds appeared between a hydrogen atom from a NH group
in a complex molecule and a bromide ion in a neighbour unit cell.
a
3.3.2. Infrared spectra
b
The main infrared vibration bands are reported in Table 7. In princi-
ple, since the ligands contain a carbonyl functional group, it can exhibit
the ketone–enol tautomerism. The ν(OH) band around 3350 cm−1 is
absent from the IR spectra of the ligands but the ν(N\H) band at
3163 (3STCH) and 3146 cm−1 (2,3BSTCH2) is present, indicating that,
in the solid state, the ligands stand as the ketone tautomer. The spec-
trum of the ligands exhibits a strong band at 1685 cm−1, due to the
C_O stretching vibration [5].
c
(a)
In the case of the nickel complexes of 3STCH, [NiCl2(3STCH)2] and
[NiBr2(3STCH)2], the ν(NH2) vibration band is slightly shifted to lower
wavenumbers whereas ν(N\H) is shifted to higher values (Table 7).
The ring breathing remains quite unchanged when passing from ligands
to complexes at ca. 832 cm−1. In the mean time, the band corresponding
to ν(C_N) is not significantly modified. The ν(C_O) vibration band is
Table 4
(b)
Bond lengths (Å) and angles (°) for the complex [NiBr(2,3BSTCH2)(H2O)]Br.
Bond lengths
Bond angles
Ni1\Br1
Ni1\O1
Ni1\O2
Ni1\O3
Ni1\N1
Ni1\N4
O1\C6
O2\C8
N1\C5
N1\N2
N2\C6
N3\C6
N4\C7
N4\N5
N5\C8
N6\C8
2.620
2.022
2.011
2.143
2.013
2.018
1.244
1.253
1.277
1.381
1.366
1.316
1.282
1.376
1.359
1.328
Br1\Ni1\O1
Br1\Ni1\O2
Br1\Ni1\O3
Br1\Ni1\N1
Br1\Ni1\N4
O1\Ni1\O2
O1\Ni1\O3
O1\Ni1\N1
O1\Ni1\N4
O2\Ni1\O3
O2\Ni1\N1
O2\Ni1\N4
O3\Ni1\N1
O3\Ni1\N4
N1\Ni1\N4
Ni1\N1\N2
90.46
92.10
178.38
92.64
88.97
94.61
89.96
81.02
176.14
86.31
173.58
81.59
88.97
90.51
102.82
109.35
Fig. 5. Cell packing (a) and hydrogen bonding (b) for 2,3BSTCH2.

K. Alomar et al. / Journal of Inorganic Biochemistry 115 (2012) 36–43
41
Table 5
Table 6
Bond lengths (Å), angles (°) of intermolecular hydrogen bonds for ligands and Ni (II)
complex.
Analytical data.
Elemental analysis found
(Calc.)
Compound
D\H…A
d(H…A)
d(D…A)
Angle
(°)
(Å)
(Å)
Compound
Colour
Yield MP
C (%)
H (%)
N (%)
3STCH
N1\H1A…O1
N2\H2A…O1
N11\H11…O1
N9\H9B…O1
N2\H2A…O2
N9\H9A…O2
N12\H12A…O2
N5\H5A…O3
N3\H3B…O3
N3\H3A…O4
N6\H6A…O4
N2\H2n…Br1
N2\H2n…Br2
N3\H31n…Br1
N3\H32n…Br1
N5\H5n…Br2
N6\H61n…O2
N6\H62n…O3
N6\H61n…O1
O3\H31o…Br1
O3\H32…Br2o
1.94
2.16
2.07
2.78
2.39
2.16
2.25
1.99
2.49
2.05
2.25
3.05
2.95
2.67
2.76
2.45
2.37
2.35
2.62
2.66
2.47
2.89
2.92
2.92
3.28
3.05
2.98
2.98
2.85
3.13
2.89
2.96
3.79
3.38
3.53
3.55
3.24
3.06
3.16
3.21
3.35
3.20
169.30
174.02
170.45
118.98
134.40
157.40
141.67
176.09
131.64
166.11
140.67
146.00
113.00
172.00
154.00
152.00
138.00
157.00
128.00
153.00
168.00
(%)
(°C)
3STCH
Yellow 90
Yellow 88
231
42.37
3.96
24.57
2,3BSTCH2
(42.59) (4.17) (24.83)
36.83 4.06 32.82
(37.79) (3.96) (33.05)
29.78 3.22 17.23
(30.80) (3.02) (17.96)
26.72 2.35 15.21
(25.88) (2.53) (15.09)
23.87 2.97 20.69
(23.91) (3.01) (20.91)
19.66 2.50 17.30
(19.58) (2.46) (17.12)
2,3BSTCH2
224
213
231
209
269
[NiCl2(3STCH)2]
[NiBr2(3STCH)2]
[NiCl(2,3BSTCH2)(H2O)]Cl
Green
Green
67
60
70
73
Dark
green
[NiBr(2,3BSTCH2)(H2O)]Br
[NiBr(2,3BSTCH2)(H2O)]Br Dark
green
geometry, the nickel (II) ion is linked to the two ligands with the O
and N atoms in the same plane, while the two halogenides are located
on the orthogonal axis to this plane. This structure was already ob-
served for similar compounds with semicarbazone functional group
[5].
The structure of [NiCl(2,3BSTCH2)(H2O)]Cl was determined on the
basis of the crystal structure of the [NiBr(2,3BSTCH2)(H2O)]Br. As
their spectroscopic data are similar, the chloro compound is identical
to the bromo one (Fig. 8).
significantly shifted to lower wavenumbers. In addition, the spectra
of these nickel complexes show the three vibration bands ν(M\O),
ν(M\N) and ν (M\X) at 350, 527 and 227 cm−1 respectively, indicat-
ing that the coordinating atoms are O atom (keto) and N atom (imino)
for each ligand.
3.4. Biological activities
In the spectra of the complexes of 2,3BSTCH2, [NiCl(2,3BSTCH2)(H2O)]
Cl and [NiBr(2,3BSTCH2)(H2O)]Br, we find the same shifts for ν(NH2),
ν(N\H) and ν(C_O) bands than in the case of the nickel complex
of 3STCH. In addition, the band ν(OH) is located at 3355 and
3358 cm−1 for these two compounds. These results show that the co-
ordination and the structures of the choro of the bromo complexes are
very similar.
Antifungal assays (Table 8) showed that both, 3STCH and
2,3BSTCH2 are inactive against all strains, although the corresponding
complexes exhibited a moderate activity (31 to 5 μg.mL−1) specifical-
ly on C. glabrata. In Fig. 9, the shortest bars corresponding to higher
activity are observed for [NiCl2(3STCH)2] (2), [NiBr2(3STCH)2] (3),
[NiCl(2,3BSTCH2)(H2O)]Cl (5) and [NiBr(2,3BSTCH2)(H2O)]Br (6)
against C. glabrata. As the MIC80 values for Amphotericin are very
low, they are not visible on this chart.
3.3.3. Structures of the complexes
The determined MIC80 values revealed that complexes deriving
from 2,3BSTCH2 are slightly more active than the corresponding 3STCH
ones. Basis on molar concentrations, [NiBr(2,3BSTCH2)(H2O)]Br is 3.5
times more active (31 μg.mL−1 or 6.31×10−5 M) than [NiBr2(3STCH)2]
(125 μg.mL−1 or 2.25×10−4 M). On the opposite side, the chloro-
complexes exhibit some similar activity the MIC80 is 62 μg.mL−1
The proposed structures of the complexes [NiCl2(3STCH)2],
[NiBr2(3STCH)2] are given in Fig. 8. They were determined from
their spectroscopic data and their DSC diagrams revealing a similar
behaviour for the two complexes. In these compounds, the coordinat-
ing atoms are O (keto) and N (imino) for each ligand. In an octahedral
Fig. 7. Cell packing and hydrogen bonding for [NiBr(2,3BSTCH2)(H2O)]Br.

42
K. Alomar et al. / Journal of Inorganic Biochemistry 115 (2012) 36–43
Table 7
Infrared data for the ligands and the complexes (cm−1).
Compound
ν(NH2)
ν(OH)
ν(NH)
ν(C_N)
ν(C_O)
Resp. cycle
ν(N\N)
ν(M\N)
ν(M\O)
ν(M\X)
3STCH
2,3BSTCH2
[NiCl2(3STCH)2]
[NiBr2(3STCH)2]
[NiCl(2,3BSTCH2)(H2O)]Cl
[NiBr(2,3BSTCH2)(H2O)]Br
3450
3464
3449
3434
3480
3482
–
3163
3109
3291
3168
3151
3147
1648
1594
1639
1605
1600
1601
1685
1684
1673
1668
1674
1670
820
758
832
832
777
811
942
931
942
942
952
930
–
–
–
–
–
–
–
–
527
532
440
503
350
348
335
322
227
224
227
223
–
3355
3358
NH2
X
(a)
NH
C. albicans (left)
C. glabrata (middle)
A. fumigatus (right)
N
O
S
X
Ni
S
300
O
250
200
150
100
50
N
NH
NH2
X = Cl or Br
(b)
NH2
+
NH
N
O
H2O
NH2
Ni
Cl
Cl-
O
0
S
N
1
6
2
3
4
5
NH
Fig. 9. Compared MIC80 for the ligands 1 and 4 and the complexes 2–3 and 5–6 (numbers
refer to Table 8).
Fig. 8. Structures of the complexes [NiCl2(3STCH)2], [NiBr2(3STCH)2] (a) and [NiCl
(2,3BSTCH2)(H2O)]Cl (b).
reported for manganese complexes [15]. It is also asses the impor-
tance of antifungal testing on liquid medium.
(1.54×10−4 M) for [NiCl(2,3BSTCH2)(H2O)]Cl and 62 μg.mL−1 (1.32×
10−4 M) for [NiCl2(3STCH)2].
A weak or no activity was found for all the compounds at 10−5
M
against MRC5 cells lines, suggesting the absence of cytotoxicity as
well as their potential interest on human pathogenic yeasts. These
results differ from those previously described in our laboratory with
2-furfural semicarbazone and 5-methyl 2-furfural semicarbazone
for which the copper (II) complexes exhibited a cytotoxic activity
[36,37]. So these new complexes with thiophen semicarbazones
could be eventually used against C. glabrata after testing a large num-
ber of strains to confirm this activity.
In addition, no activity was found for all the compounds on solid
media (data not shown). Nevertheless, as it was already reported
[38], these results could indicate that increasing steric hindrance
and molar molecular weight lead to restricted diffusion on solid
media because of their increasing lipophilic character as previously
4. Conclusion
We have synthesised and characterised two new ligands bearing re-
spectively one and two semicarbazone moieties: 3STCH and 2,3BSTCH2.
These molecules lead to four new complexes with Ni (II). The com-
plexes obtained with 3STCH are similar to those described with various
monosemicarbazones. The bis(semicarbazone) 2,3BSTCH2 allows us to
obtain the complexes [NiX(2,3BSTCH2)(H2O)]X (X=Cl or Br) which
have not been described for semicarbazones nickel complexes. Finally
the determination of MIC80 values against C. albicans, C. glabrata and
A. fumigatus revealed that the ligands are quite inactive against all
strains, while complexes deriving from 2,3BSTCH2 are more active
than the corresponding 3STCH ones against C. glabrata.
Table 8
Antifungal activity of the ligands and the complexes (minimal concentration inhibiting 80% of fungal growth or MIC80) expressed in μg.mL−1
.
Fungi
Compound (number)
Candida albicans
Candida glabrata
Aspergillus fumigatus
ATTC 66396
LMA 1085
CBS 11326
3STCH (1)
>250
250
>250
>250
250
>250
62
125
>250
62
>250
>250
>250
>250
>250
>250
6
[NiCl2(3STCH)2] (2)
[NiBr2(3STCH)2] (3)
2,3BSTCH2 (4)
[NiCl(2,3BSTCH2)(H2O)]Cl (5)
[NiBr(2,3BSTCH2)(H2O)]Br (6)
Amphotericine B
>250
0.062
31
0.125

K. Alomar et al. / Journal of Inorganic Biochemistry 115 (2012) 36–43
43
[17] I.C. Mendes, M.A. Soares, R.G. Dos Santos, C. Pinheiro, H. Beraldo, Eur. J. Med.
Chem. 44 (2009) 1870–1877.
Appendix A. Supplementary data
[18] J.G. Da Silva, L.S. Azzolini, S.M.S.V. Wardell, J.L. Wardell, H. Beraldo, Polyhedron 28
(2009) 2301–2305.
[19] K. Alomar, A. Landreau, M. Kempf, M.A. Khan, M. Allain, G. Bouet, J. Inorg. Biochem.
104 (2010) 397–404.
CCDC 855944 (3STCH), 855943 (2,3BSTCH2) and 855897
([NiBr(2,3BSTCH2)(H2O)]Br) contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre CCDC (12
Union Road. Cambridge, CB2 IEZ, UK; fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk) or via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data to this article can be found online at http://dx.doi.
org/10.1016/j.jinorgbio.2012.04.022.
[20] K. Alomar, M.A. Khan, M. Allain, G. Bouet, Polyhedron 28 (2009) 1273–1281.
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— Program for Crystal Structure Analysis (Release
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[24] G.M. Sheldrick, SHELXS97 and SHELXL97, Universität Göttingen, Göttingen, Germany,
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