Synthesis, characterization and biocidal activity of new organotin complexes of 2-(3-oxocyclohex-1-enyl)benzoic acid

Article abstract of DOI:10.1016/j.ejmech.2009.11.026

The reaction of 1,3-cyclohexadione with 2-aminobenzoic acid has produced the 2-(3-oxocyclohex-1-enyl)benzoic acid (HOBz). Subsequent reactions of the ligand with organotin chlorides led to [Me₂Sn(OBz)O]₂ (1), [Bu₂Sn(OBz)O]

Full text of DOI:10.1016/j.ejmech.2009.11.026

European Journal of Medicinal Chemistry 45 (2010) 883–889
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, characterization and biocidal activity of new organotin complexes
of 2-(3-oxocyclohex-1-enyl)benzoic acid
a
a
,
b
c
d
*
Flaviana T. Vieira , Geraldo M. de Lima , Jos e´ R. da S. Maia , Nivaldo L. Speziali , Jos e´ D. Ardisson ,
e
e
e
Leonardo Rodrigues , Ary Correa Junior , Oscar B. Romero
a
Departamento de Qu ´ı mica, Universidade Federal de Minas Gerais, UFMG, Avenida Ant oˆ nio Carlos 6627, Belo Horizonte MG, CEP 31270-901, Brazil
Departamento de Qu ´ı mica, Universidade Federal de Viçosa, UFV, Avenida P. H. Rolfs, s/n, Viçosa-MG, CEP 36571-000, Brazil
Departamento de F ´ı sica, Universidade Federal de Minas Gerais, UFMG, Avenida Ant oˆ nio Carlos 6627, Belo Horizonte MG, CEP 31270-901, Brazil
Centro de Desenvolvimento em Tecnologia Nuclear, CDTN/CNEN, Avenida Ant oˆ nio Carlos 6627, Belo Horizonte MG, CEP 31270-901, Brazil
Departamento de Microbiologia, Instituto de Ci eˆ ncias Biol o´ gicas, Universidade Federal de Minas Gerais, UFMG, Avenida Ant oˆ nio Carlos, 6627, Belo Horizonte MG, CEP 31270-901,
b
c
d
e
Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 March 2009
Received in revised form
The reaction of 1,3-cyclohexadione with 2-aminobenzoic acid has produced the 2-(3-oxocyclohex-1-
enyl)benzoic acid (HOBz). Subsequent reactions of the ligand with organotin chlorides led to [Me
n(OBz)O] (1), [Bu Sn(OBz)O] (2), [Ph Sn(OBz)O] (3), [Me Sn(OBz)] (4), [Bu Sn(OBz)] (5) and
Ph Sn(OBz)] (6). All complexes have been fully characterized. In addition the structure of complexes (2)
2
S-
2
2
2
2
2
3
3
3
November 2009
[
3
Accepted 12 November 2009
Available online 18 November 2009
and (4) have been authenticated by X-ray crystallography. The biological activity of all derivatives has
been screened against Cryptococcus neoformans and Candida albicans. In addition we have performed
toxicological testes employing human kidney cell. The complexes (3), (5) and (6) displayed the best
values of inhibition of the fungus growing, superior to ketoconazole. Compound (5) presented promising
results in view of the antifungal and cytotoxicity assays.
Keywords:
Antifungal activity
C. Albicans
C. Neoformans
Organotin carboxylates
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
of interesting biologic applications have been found for organotin
2 2 3
complexes. For example, Bu SnCl or Ph SnCl can inhibit oedemas
Tributyltin oxide (TBTO) was one of the first organotin
compound to be used as biocide agent [1] in anti-fouling paints for
ships [2,3]. However, important environmental problems have
forced some nations to prohibit the use of such materials [4–7]. In
spite of the drawbacks, organotin are among the most widely used
organometallic compounds [8] and other potential applications
have been observed. In the 1970s the growing of malignant
tumours in mice were retarded by organotin species (acetates,
oxides, hydroxides and alkoxides) [9–11]. Complexes with general
in mice as effectively as hydrocortisones [17,18]. Complexes with
ligands derived from aminoquinolines have schizonticidal and as
antimalarial activities [19]. Those derivatives with some Schiff
bases have potential use as amoebicidal agents [20]. Some 2-alky-
lindole derivatives have been tested against Bacillus subtilis, Bacillus
pumilus, Staphylococcus aureus and Micrococcus luteus [21]. Activity
against leishmaniasis in mice and helminthes in cats has been
found for dioctyltin maleate [22,23].
Organotin(IV) carboxylates comprises the class of tin complexes
which has attracted particular attention due to the potential
biocide activity and cytotoxicity as well as their industrial and
agricultural applications [24–28].
formula SnR
2
X
2
L
2
(L
2
¼ bidentate ligand with oxygen and/nitrogen
donor atoms) has been tested against P388 lymphatic leukaemia in
mice [12,13]. Organotin complexes with aminoacids [14,15], thiols
[
16], o-phenanthroline, bipyridyl and histidine, carboxylates, have
Our recent efforts have focused on mechanistic aspects of bio-
logical activity of organotin compounds using fungus cultures as
models [29–32]. We have found that organotin complexes derived
of some carboxylic acids seem to share mechanistic similarities to
azole drugs such as ketoconazole or fluconazole [32].
been found effective against a variety of tumours. Today, a number
Herein we report the synthesis, characterization and some
biocide results involving new organotin carboxylate derivatives.
*
Corresponding author. Tel.: þ55 31 3499 5744; fax: þ55 31 3499 5720.
E-mail address: gmlima@ufmg.br (G.M. de Lima).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.11.026

884
F.T. Vieira et al. / European Journal of Medicinal Chemistry 45 (2010) 883–889
2
. Results and discussions
addition it was observed for complexes (1)–(6) two bands (n
(Sn–C)as
ꢀ1 ꢀ1
and
228 cm (3), 639 and 502 cm (4), 642 and 511 cm (5), 285
n(Sn–C)s) {657 and 511 cm (1) 649 and 509 cm (2), 279 and
ꢀ
1
ꢀ1
ꢀ1
2.1. Chemistry
ꢀ
1
and 232 cm (6)}. According to literature it is a consequence of
a bent C–Sn–C moiety in the complexes [41]. It also detected the
presence of Sn–O bond due to the strong bands in the region of
The preparation of 2-[(3-oxocyclohex-1-enyl)amino]benzoic
acid, (HOBz), has been mentioned in the literature in a condensation
reaction of isopropylidenemalonate [33], where HOBz was obtained
in 37% yield while. We have managed to prepare HOBz in 75% yield
by reacting 1,3-cyclohexadione with 2-aminobenzoic acid [34].
The 2-(3-oxocyclohex-1-enyl)benzoic acid has been employed
in reactions with organotin halides, Scheme 1.
All complexes have been obtained as air stable and crystalline
products with sharp melting points. Complexes (1)–(3) were
expected as monochlorine–organotin compounds as products.
However, the water employed in the final stage of the synthetic
ꢀ
1
480–440 cm . The CO bond remains almost unchanged in the
stannoxane complexes (1)–(3), because of the stretching frequency
ꢀ
1
displayed respectively at 1685, 1684 and 1681 cm . On the other
hand in complexes (4)–(6) it has moved to lower frequency, 1658,
ꢀ1
1652 and 1658 cm due to –C]O /Sn intermolecular interaction
in order to outline the polymeric chain arrangement adopted by
these compounds.
The signals of the –C]O and –COOH groups for the ligand were
observed in NMR experiments at d 170.38 and d 201.89, respectively.
13
method, in order to remove NEt
3
HCl (secondary product of the
No significant changes were detected in the C NMR signals for
reaction), promoted the hydrolysis of the expected product yielding
a stannoxane derivatives as major product, Scheme 1. On the other
hand complexes (4)–(6) were obtained as polymers. Such assem-
blies are not uncommon for organotin carboxylates [35].
complexes (1)–(3) upon coordination. In complexes (4)–(6) the CO
carbon resonance shifted to up field at
d 173, which might be
explained considering that the ligand coordinates to the tin fragment
in the enolate form. The conjugated system involving the N–H group
andC(12)wouldincreasetheelectronicdensityatC(11), providingthe
necessary requirements for the formation of the enol form and
The main bands in the infrared spectra of the ligand (HOBz) were
ꢀ1
ꢀ1
(
observed at 1685 cm
(n
CO) (sharp signal); 1655 cm
COO
n )
13
(
1
strong absorption with two small satellites at 1675, 1668 and);
therefore causing suchvariation inthe C chemicalshift. Ontheother
ꢀ
1
376 cm
(n
C–N) (week vibration). The strong signals corresponding
hand, the carboxylic signal remained almost unchanged at
Sn NMR signals were observed for complexes (1)–(6) at
d
200. The
97, ꢀ161,
119
to the COO group indicates the presence of intermolecular hydrogen
d
/
interactions –C]O HOOC–, which is quite common in carboxylic
ꢀ193, ꢀ36, ꢀ82 and 69, respectively. The coordination number (NC)
119
acids in the solid state [36]. Upon coordination these vibrations have
of the tin centre is one of the interferences in the Sn chemical shift.
Itissuggestedintheliteraturerangesforit, asfollows:NC ¼ 6{ ꢀ 300
and ꢀ550}; NC ¼ 5 { ꢀ 150 and ꢀ250}; and NC ¼ 4 {higher to
ꢀ1
disappeared generating new bands in 1630–1590 cm and 1492–
d
ꢀ
1
1
360 cm regions, for complexes (1)–(6), corresponding to the COO
asymmetric and symmetric vibrations. Information about DnCOO
) values has proved to be important in providing further
details on the Sn-carboxyl bonding scheme [37–39]. We could not
detect in the IR spectrum of the protonated ligand (HOBz).
d
d
ꢀ 150}, [42]. However, it must be carefully analysed since tin reso-
(n
as
–
n
s
nance is strongly dependent upon other factors, such as electroneg-
ativity of the ligands, temperature and concentration employed in the
experiments. In our case, an increase in the coordination number of
the tin atom has effected changes in Sn d values in contrast to the
starting materials. CNMRresultscanbeusedtoestimatetheC–Sn–C
angle, by employing methods encountered in the literature, which
n
s
119
However, we have found for the potassium salt of the ligand, DnCOO
ꢀ
1
ꢀ1
ꢀ1
13
at 163 cm
(n
as ¼ 1583 cm
;
n
s
¼ 1420 cm ) which is smaller than
ꢀ1
those encountered for the complexes, which varies from 221 cm
–
ꢀ
1
ꢀ1
ꢀ1
119
13
2
52 cm , (1) 1625, 1373 cm , (2) 1615, 1376 cm , (3) 1621,
correlate thisanglewith the firstorder Sn– C couplingconstant, in
ꢀ1
ꢀ1
ꢀ1
1
119
13
1
1
377 cm , (4) 1598, 1366 cm , (5) 1595, 1365 cm and (6) 1602,
solution [43,44]. The empirical relationship, j J( Sn– C)j ¼ 11.4(
q) –
ꢀ
1
376 cm . It indicates a monodentate coordination mode [36,40],
875, have provided the C–Sn–C angle for compounds (1)–(3) ranging
ꢁ
in accordance with the X-ray results for complexes (2) and (4). In
from 146 to 158 . Complex (2) has been studied by X-ray
Scheme 1. Pathways of the reactions of 2-(3-oxocyclohex-1-enyl)benzoic acid with organotin halides.

F.T. Vieira et al. / European Journal of Medicinal Chemistry 45 (2010) 883–889
885
Table 1
at the tin atom in the complexes. The isomer shift signals for
complexes (1)–(6) were observed at 1.27, 1.25, 1.29, 1.45, 1.42,
1.40 mm sꢀ1, respectively, indicates the presence of Sn(IV) and
Crystallographic data of the complexes bis-[2-(3-oxocyclohex-1-enyl)benzoate-
dibutylstannoxane] (2) and catena-Poly[[trimethyltin(IV)]-
enyl)amino]benzoato-
m
-2-[(3-oxocyclohex-1-
2
0
k
O:O ] (4).
3
a pseudo dsp hybridization at the tin centre. The non-zero value of
Compound
(2)
(4)
ꢀ1
the quadrupolar splitting parameters (
D
/mm s ) indicates devia-
Empirical formula
Molecular weight
Temperature
Wavelength
Crystal system
Space group
C
21
H
30NO
4
Sn
32 42 2 6 2
C H N O Sn
tion from a spherical distribution of charge at the metal atom. For
479.15
293(2) K
0.71073 Å
Monoclinic
788.06
273(2) K
0.71073 Å
Orthorhombic
Fdd2
ꢀ1
complexes (1)–(3) we have obtained (
D
/mm s ) at 4.19, 3.16 and
3
.08 that is compatible with expected five-coordinate distorted
ꢀ1
trigonal-bipyramidal tin. The values of
D/mm s 3.52, 3.57 and 3.16
P 21/N
are typical for a polymeric structure with intermolecular C]0/Sn
bonds and two oxygen atoms in a trans configuration, with values
ranging from 3.0 to 4.1 mm sꢀ1 agree with a pseudo trigonal-
bipyramidal geometry at the tin centre [45,46].
The structure of complexes (2) and (4) were determined by
X-ray diffraction experiment, Table 1.
United cell dimensions
a ¼ 15.007(2) Å,
a ¼ 30.626(5) Å,
b ¼ 10.2490(10) Å,
b ¼ 12.981(2) Å,
c ¼ 16.2130(10) Å
c ¼ 17.164(2) Å
ꢁ
ꢁ
ꢁ
ꢁ
a
b
g
¼ 90 ,
a
b
g
¼ 90 ,
ꢁ
¼ 116.290(10) ,
¼ 90 ,
ꢁ
¼ 90
¼ 90 .
3
3
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
2235.7(4) Å
4
6823.6(19) Å
16
For complex (2) the X-ray study, Fig. 1, comprises a centrosym-
metric four-membered Sn O ring, where each tin atom adopts
2 2
3
3
1.424 Mg m
1.166 mm
980
1.534 Mg m
1.506 mm
ꢀ1
ꢀ1
a five-coordinate distorted trigonal-bipyramidal geometry with two
butyl group and three asymmetrically coordinated oxygen atoms.
In each monomer the Sn(IV) lies at the centre of the trigonal-
bipyramid, where the equatorial positions are occupied by two
butyl groups and an oxygen atom, Sn–O 2.029 Å. One of the axial
position is occupied by a monodentate carboxylic group, Sn–O
3168
Crystal size
0.2 (max),
0.2 (max),
0.2 (mid),
0.2 (min)
0
0
.2 (mid),
.2 (min)
ꢁ
ꢁ
Theta range for data
collection
Reflections collected
Independent reflections
Refinement method
5.36–11.74
11.757–12.501
5702
7560
2.177(4) and the fifth coordination is accomplished by a long
3888 [R(int) ¼ 0.0324] 7303 [R(int) ¼ 0.0183]
intermolecular Sn–O interaction, 2.234(4)Å, through the axial
corner. The sum of the angles at the equatorial position, O(4)– Sn–
Full-matrix least-
squares on F
3888/3/225
Full-matrix least-squares
2
2
on F
ꢁ ꢁ
C(14) 107.1(3) , C(14)–Sn–C(18) 140.8(3) and O(4)–Sn–C(18)
Data/restraints/
parameters
7303/3/575
ꢁ
ꢁ
111.6(3) is almost 360 and the angle O(2)–Sn–O(4) described by
Goodness-of-fit on F2
Final R indices
0.971
0.893
ꢁ
the two oxygen atoms at the axial position, is smaller than 180 ,
R1 ¼ 0.0479,
wR2 ¼ 0.1296
R1 ¼ 0.0748,
wR2 ¼ 0.1485
R1 ¼ 0.0321, wR2 ¼ 0.0981
Table 2 This assembly is not uncommon for organotin carboxylic
containing complexes. Examples have been previously prepared,
however employing different synthetic strategy [47].
[I > 2sigma(I)]
R indices (all data)
R1 ¼ 0.0391, wR2 ¼ 0.1100
The X-ray crystallographic study of complex (4) revealed that it
crystallises forming an infinity double-polymeric chain structure,
where the anionic ligand bridgestwotin centrevia the monodentate
carboxylic moiety and the –C]O fragment, Fig. 2. Each chain
possesses a tin atom surrounded by three methyl groups and two
oxygen atoms, describing an almost perfect trigonal bypyramid
geometry. The equatorial corners are occupied by the methyl groups
and the axial positions by the oxygen atoms. The Sn–O–CO–R bond
ꢁ
crystallographyand the angle C(14)–Sn–C(18) wasfound as 140.8(3) .
It is not very different from the value obtained by the empirical
method. Based on that, one can conclude that the structures of the
compounds(1)–(3)areveryclosetoeachother, bothinsolutionandin
the solid state. The same methodology was employed to complexes
4)–(6) provided C–Sn–C angle in solution from 202 to 232 , not
comparabletotheexperimentaldatainthe solidstateforcomplex(4),
20 . However it isa good indication thatthe polymeric chain, heldby
ꢁ
(
{
2
Sn–O(1) 2.174(6) Å; is shorter than the Sn–O]C–R {Sn–O(3)
ꢁ
1
ꢁ
.504(7) Å. The angles C–Sn–C and O–Sn–O are all close to 120 and
–
C]O intermolecular contacts, collapse in monomers in solution
ꢁ
180 as expected for a trigonal-bipyramidal geometry, Table 3 [48].
with similar structural features for (4)–(6).
The 1 Sn-M o¨ ssbauer experiments were performed in order to
19
determine the differences in the Sn nuclei on going from organotin
2.2. Pharmacology
starting materials to the complexes. The isomer shift parameters (d/
ꢀ
1
mm s ) indicates the presence of s electron density at the tin
Fungal infections have increased in the last years affecting
nuclei, therefore it is a good indication of the hybridization scheme
mainly those patients immuno-compromised [49]. Candida
Fig. 1. The molecular structure of bis-[2-(3-oxocyclohex-1-enyl)benzoate-dibutylstannoxane].

886
F.T. Vieira et al. / European Journal of Medicinal Chemistry 45 (2010) 883–889
Table 2
Table 3
ꢁ
o
Selected bond distances (Å) and angles ( ) for bis-[2-(3-oxocyclohex-1-enyl)ben-
zoate-dibutylstannoxane].
Selected bond distances (Å) and angles ( ) for catena-Poly[[trimethyltin(IV)]-m-2-
[(3-oxocyclohex-1-enyl)amino]benzoato-
2
0
k
O:O ].
C(11) – O (3)
C(13)–O(1)
C(13)–O(2)
O(4)–Sn–C(14)
C(14)–Sn–C(18)
1.233(7)
1.244(8)
1.284(8)
107.1(3)
140.8(3)
O(2)–Sn
O(4) Sn
O(4)–Sn
O(4)–Sn–C(18)
O(2)–Sn–O(4)
2.177(4)
2.029(4)
2.234(4)
111.6(3)
155.03(16)
C(11) – O(3)
C(13) – O(1)
C(13) – O(2)
1.237(6)
1.296(5)
1.227(6)
Sn – O(1)
Sn(1) – O(3)
2.174(4)
2.496(4)
O(1) – Sn – O(3)
C(14) – Sn – C(16)
174.13(13)
125.5(3)
C(14) – Sn – C(15)
C(15) – Sn – C(16)
120.1(3)
112.5(3)
albicans, can infect the oral and vaginal cavities, skin, while Cryp-
tococcus neoformans infections sometimes can be fatal to humans
The results obtained indicate the order of the fungicidal activity
as: Bu SnOBz > Ph SnOBz > Ph SnOBz > organotin halides. Which
[50]. Both can seriously affect essential organs [51,52].
3
3
2
2
Antifungal therapies include two main classes of compounds:
agrees with other previous work [27,52,64]. It is well established
that the biological activity of related compounds depends upon the
(i) structure, (ii) the type and (iii) number of organic groups
attached to the organotin moiety. It is not a surprise that the trib-
utyltin containing complex, is the more active, since studies have
suggested that toxicity of organotin complexes correlates with total
molecule surface (TSA) and hence n-propyl, n-butyl, n-pentyl, etc,
should be more toxic for microorganisms than ethyl, methyltin
based complexes. It seems that in this case the biological activity
might occur by an intracellular mechanism by transport through
cell membrane, as pointed out by us previously [27,28]. Therefore
the order of biological activity suggests a close correlation between
activity and lipophilicity [57,65].
polyene[53]andazoledrugs[54]. Theformerclasscomprisesnystatin
and amphotericin that act in the membrane of the fungal cell linking
to ergosterol. These drugs interfere with the permeability of the
membrane, causing losses of macromolecules and ions essentials to
the survival of the fungal cell. The antifungal activity of azole arises
frominteractionwiththesterol-14a-demthyllase(CYP51),involvedin
the biosynthesis ofergosterol. Such interactionsresultsin a decreased
availability of ergosterol and an accumulation of 14-methylsterols.
Changes in ergosterol levels and sterol structure influence the
membrane permeability and the activity of several metabolic path-
ways [55]. Metal-based compounds might represent an alternative
therapeutic route since most of the clinical used drugs normally
present problems with resistance and toxicity [56].
The antifungal activity of organotin complexes have been
investigated for quite a long time [57]. A number of mechanisms for
the biological action of organotin derivatives have been proposed.
However, a complete understanding has still to be found [58–60].
The crossing of the cytoplasmatic membrane by organotin deriva-
tives might be a consequence of lipid-solubility [61] effected by
weak interactions with the aminoacids, proteins [62], nucleosides,
carbohydrates and steroids [63], present in the cell membrane.
Complexes (1)–(6) have been tested against C. Albicans and
C. Neoformans. Complexes (3), (5) and (6) displayed good biocide
activity against both the microorganism, in comparison to the
organotin halide employed in the synthesis or to ketoconazol, used
as standard, Table 4.
2
.3. Conclusions
Complexes (1)–(6) were prepared and fully characterized by
a series of spectroscopic methods. Complexes (3), (5) and (6) dis-
played good biocidal activity against C. Albicans and C. Neoformans.
In addition complexes (3) and (5) displayed low cytotoxicity
towards human kidney cells. Complex (5) showed promising
results in our investigation. In spite of all controversy around the
toxicity of organotin towards superior species it is possible that
some of their complexes are not as hazardous as organotin halides.
Therefore, complex (5) might represent a new class of drug to be
employed alone or in combination with others in current use as
new formulations for fungal diseases to overcome resistance.
The cytotoxicity of complexes (1)–(6) has been screened in order
to verify how toxic they are to human kidney cells (HEK293).
Complexes (3) and (5) displayed low cytotoxicity in view of the high
IC50 values, in comparison with the other complexes, the organotin
halide and ketoconazol, Table 5. It means that it is necessary high
dosage of complexes (3) and (5) to produce a toxic effect in samples
of human kidney cells. If these results are compared to the anti-
fungal assays, compound (5) can be pointed out as a promising
substance to be subject of further investigations, since it comprises
high MIC values and low cytotoxicity results.
3
3
3
. Experimental
.1. Chemistry
.1.1. Materials and methods
All starting materials were purchased from Aldrich, Merck or
Synth and used as received. NMR spectra were recorded at 400 MHz
using a Bruker DPX-400 spectrometer equipped with an 89 mm
wide-bore magnet. H and C shifts are reported relative to SiMe
1
13
4
-2-[(3-oxocyclohex-1-enyl)amino]benzoato-k2O:O ].
0
Fig. 2. The molecular structure of catena-Poly[[trimethyltin(IV)]-m

F.T. Vieira et al. / European Journal of Medicinal Chemistry 45 (2010) 883–889
887
Table 4
(C
H
). Elemental Analysis for C13
H
13NO
found (calc.): C 67.21
6
7
3
Minimal inhibitory concentrations (MIC) for organotin complexes (1)–(6) and
starting materials towards C. albicans and C. neoformans.
(67.52), H 5.43 (5.66), N 5.96 (6.05).
Compounds
C. albicans/MIC
C. neoformans/MIC
(10 mmol L
ꢀ
4
ꢀ1
ꢀ6
ꢀ1
)
3.1.3. Synthesis of [dimethylstannoxane-2-[(3-oxocyclohex-1-
enyl)amino]benzoato] (1)
(10 mmol L
)
(1)
(2)
(3)
(4)
(5)
(6)
100
150
3.0
–
–
–
6.0
–
To
enyl)benzoic acid] (1.0 g, 4.32 mmol) and triethylamine (0.6 mL,
4.3 mmol) dissolved in methanol, it was slowly added SnMe Cl
0.48 g, 2.2 mmol) also in methanol (30 mL). After 4 h of reflux the
a round-bottom-flask containing [2-(3-oxocyclohex-1-
2
2
0.1
0.9
68.5
45.1
58.2
5.6
3.8
6.5
2.4
–
0.5
2.0
80
70
90
200
100
800
600
–
(
solvent was removed in vacuo and washed with hot water, yielding
a yellow solid. X-ray quality crystals were obtained from a meth-
SnMe
2
Cl
Cl
Cl
Cl
2
SnBu
SnPh
2
2
ꢁ
anol/water solution (3:1). Yield 70%. Mp 140.0–142.0 C. IV (
n
/
2
2
ꢀ1
SnMe
3
cm ), 1684 (
as, 511 (
.63 m (C
.03 m (C
), 1.58 s (CH
COO), 170.44 (CO), 162.62 (C
33.59 (C ), 124.37 (C ), 124.21 (C
), 37.57 (C ), 31.19 (C ), 22.83 (C
Sn ¼ 825 Hz) (CH Sn{ H} NMR (DMSO-d
n
CO), 1625 (
, 447 ( Sn–O). H NMR (DMSO-d
), 8.06 m (C ), 7.72 m (C ), 6.23 s (NH), 3.05–
) 2.81–2.78 m (C ), 2.47–2.44 m (C ), 3.82 s
). C{ H} NMR (DMSO-d , 100.61 MHz), 199.50
), 141.84 (C ), 133.95 (C ),
), 101.58 (C ), 101.56
), 11.69 ( J C–
n
)
as, 1373 (
n
)
, 1320 (
nC–N), 657 (n
Sn–
COO
COO
s
SnBu
SnPh
3
Cl
Cl
1
C
)
8
3
n
Sn–C
)
s
n
6
, 400.13 MHz), (d):
3
6
H
4
6
H
4
6 4
H
Ketoconazol
Ligand
6
H
7
6
H
7
6 7
H
1
3
1
(
(
C
6
H
7
3
6
d
and 119Sn shifts relative to SnMe
ded with samples pressed as KBr pellets on a Perkin–Elmer 283B
spectrometer in the range of 4000–400 cm . Carbon, hydrogen and
nitrogen analysis were performed on a Perkin–Elmer PE-2400 CHN-
analysis using tin sample-tubes. Sn-M o¨ ssbauer spectra were run
in standard equipment at liquid nitrogen temperature using
6
H
4
6
H
4
6 4
H
4
. The infrared spectra were recor-
1
6
H
4
6
H
4
6
H
4
6 7
H
1
13
ꢀ
1
(
C
6
H
7
6
H
7
6
1
H
7
6 7
H
1
19
119
3
).
6
, 149.21 MHz),
1
119
13
119
ꢀ1
119
d
4
4
ꢀ 36 ( J Sn– C ¼ 825 Hz). Sn-M o¨ ssbauer(mm s ),
d 1.27, D
.19. Elemental analysis for C30
36 2 8 2
H N O Sn (%): found (calc.): C
5.27 (45.61), H 4.39 (4.59), N 3.49 (3.55).
a BaSnO
X-ray study were collected at 293(2) K on a Siemens XSCANS, using
a K Mo radiation (
3
source kept at room temperature. Intensity data for the
a
l
¼ 0.71073 Å). The cell refinement was per-
3.1.4. Synthesis of [2-[(3-oxocyclohex-1-enyl)amino]benzoate-
formed using an XSCANS program and the structure was solved
employing the SHELXS97 software (Sheldrick,1997) [66,67]. Further
details are giveninTable 1. All non-Hatomswererefined anisotropic.
The carbon H atoms were positioned stereochemically and were
refined with fixed individual displacement parameters [Uiso (H)Z1.2
Ueq (C)] using the SHELXL riding model.
dibutylstannoxane] (2)
Prepared accordingly using [2-(3-oxocyclohex-1-enyl)benzoic
acid] (1.0 g, 4.32 mmol), triethylamine (0.6 mL, 4.32 mmol) and
ꢁ
ꢀ1
SnBu2Cl2 (1.31 g, 4.32 mmol). Mp. 125.0–130.0 C. IV (
n
/cm ),
as, 509
, 400.13 MHz),7.96–7.92 d
), 5.61 s (NH), 3.50–3.40 m (C
), 1.86 s (C ), 1.59 m (C
1
685 (
n
CO), 1615 (
, 472 (
), 7.5 m (C
.74 m (C ), 2.49–2.20 m (C
.41 m (C ), 0.78 m (C ), 0.75 t (C
00.61 MHz), 201.14 (COO), 170.51 (CO), 168.10 (C
), 132.59 (C ), 131.26 (C ), 127.99 (C ), 126.93 (C
26.02 (C ), 96.59 (C ), 36.96 (C ), 28.01 (C ), 27.69
), 20.89 (C ), 17.43
n
COO
)
as,1376 (
COO s Sn–C
n ) ,1331 (nC–N), 649 (n )
1
(n
Sn–C
)
s
n
Sn–O). H NMR (CDCl
3
(C
6
H
4
6
H
4
), 7.10 t (C
6
H
4
6 7
H )
H ),
4 7
3
.1.2. Synthesis of [2-(3-oxocyclohex-1-enyl)benzoic acid]
To a round-bottom-flask charged with 2-aminobenzoic acid
2.74 g, 0.02 mol) dissolved in methanol (20 mL) was slowly
dropped an alcoholic solution of 1,3-cyclohexadione (2.24 g,
.02 mol in 20 mL of methanol). The mixture was refluxed and
2
1
6
H
7
6
H
7
6
H
13
7
1
4
H
7
4
H
7
4
H
7
). C{ H} NMR (CDCl
), 137.90
),
3
,
(
1
d
6 4
H
(C
H
6 4
6
H
4
H
6 4
6
H
4
6 4
H
0
1
6
H
7
6
H
7
6
H
7
6 7
H
H
4 7
stirred for 4 h and then it was observed a colour change from col-
ourless to yellow. The solution was cooled to room temperature and
the solvent was removed in vacuum and the yellow solid washed
with ethyl ether. X-ray quality crystals were obtained after a slow
evaporation of a methanol/water solution. Yield 75%. Mp. 183.7–
1 13
119
(
(
(
C
6
H
H
7
), 26.93( J C–
), 13.63 (C
Sn ¼ 799 Hz) (C
4
H
7
). 119Sn{ H} NMR (CDCl
1
C
4
7
4
H
7
3
, 149.21 MHz),
d
ꢀ 82
1 119
13
119
ꢀ1
J
Sn– C ¼ 799 Hz). Sn-M o¨ ssbauer (mm s ),
d
1.25,
D
3.16.
Analysis for C42
60 2 8 2
H N O Sn , found (calc.): C 52.55 (52.66), H 6.21
(6.27), N 2.82 (2.92).
ꢁ
ꢀ1
1
(
(
2
1
(
1
85.5 C. IV (
n
n
/cm ): 1685 (
C–N). H NMR (CDCl , 400.13 MHz),
), 7.09 t (C ), 5.58 s (NH), 3.20 s (C
.26–2.27 m (C ), 1.95–1.92 m (C
00.61 MHz), 201. 89 (COO), 170.38 (CO), 165.43 (C
), 134.64 (C ), 133.26 (C ), 125.35 (C ), 124.64 (C
), 100.94 (C ), 37.12 (C ), 31.07 (C ), 22.92
nCO), 1655 (
n
COO
)
as, 1492 (
7.97–7.92 d (C
) 2.51–2.48 m (C
n
H
6 4
COO
)
s
, 1376
), 7.4 m
),
1
3
d
C
6
H
4
6
H
4
6
H
7
6
H
7
3.1.5. Synthesis of [diphenylstannoxane-2-[(3-oxocyclohex-1-
enyl)amino]benzoato] (3)
Similarly prepared employing [2-(3-oxocyclohex-1-enyl)ben-
zoic acid] (1.0 g, 4.32 mmol), triethylamine (0.6 mL, 4.3 mmol) and
1
3
1
6
H
7
6
H
7
). C{ H} NMR (CDCl
), 141.93
),
3
,
d
H
6 7
C
6
H
4
6
H
4
6
H
4
6
H
4
6 4
H
22.58 (C
6
H
4
H
6 7
6
H
7
6
H
7
SnPh
2
Cl
2
(0.8 g, 2.2 mmol) in methanol (30 mL). Yield 65%. Mp 131–
ꢁ
ꢀ1
1
33.0 C. IV (
n
/cm ), 1683 (
n
CO), 1621 (
, 453 (
): 10.72–10.44 m (C
), 5.8 s (NH), 3.96–3.89 m (C
), 2.07–2.04 m (C ), 1.91 s (C ), 5.26–5.18 m (C
4.93 m (C ), 4.80–4.60 m (C
100.61 MHz), 201.3 (COO), 169.55 (CO), 166.25 (C
(C ), 133.25 (C ), 131.94 (C ), 129.33 (C ), 123.03 (C
21.64 (C ), 101.94 (C ), 35.68 (C ), 31.88 (C ), 21.25
), 129.13
n
COO
)
as, 1377 (
COO s
n ) , 1330
1
(
n
C–N), 279 (
400.13 MHz), (
10.00–9.72 m (C
n
Sn–C
)
as, 228 (
n
Sn–C
)
s
n
Sn–O). H NMR (DMSO-d
6
,
Table 5
d
6
H
4
), 10.14–10.05 m (C
) 2.47–2.35 m
), 5.08–
). C{ H} NMR (DMSO-d
), 140.76
),
6 4
H ),
Cytotoxicity activity (IC50) for organotin complexes (1)–(6), and some reference
compounds towards human embryonic kidney cells (HEK293).
H
6 7
H
6
4
(C
6
H
7
6
H
7
6
H
7
6 5
H
1
3
1
Compounds
IC50
Compounds
IC50
(10 mmol L )
6
H
5
6
H
5
6
,
ꢀ
4
ꢀ1
ꢀ4
ꢀ1
(
10 mmol L
)
d
6 4
H
(1)
(2)
(3)
(4)
(5)
(6)
27
21
48
17
52
8
Me
Bu
Ph
Me
Bu
Ph
2
SnCl
SnCl
SnCl
SnCl
2
0.1
0.3
0.5
0.08
0.4
0.1
H
6 4
6
H
4
6
H
4
6
H
4
6 4
H
2
2
1
H
7
H
H
6 7
H
H
6 5
, 149.21 MHz),
6
6
7
6
7
2
2
1 13
119
(
(
C
6
H
H
7
), 162.12 (C
), 116.55(C
6
H
5
), ( J C– Sn ¼ 929 Hz) 135.87 (C
3
1
19
1
C
6
119
5
6
H
5
). Sn{ H} NMR (DMSO-d
6
d
69
3
SnCl
SnCl
1
13
119
ꢀ1
( J Sn– C ¼ 933 Hz). Sn-M o¨ ssbauer(mm s ),
d 1.29, D
3.08.
3
Ketoconazol
Ligand
0.6
120
Elemental analysis for C30
36 2 8 2
H N O Sn (%): found (calc.): C 57.48
(57.84), H 4.17 (4.27), N 2.59 (2.70).

888
F.T. Vieira et al. / European Journal of Medicinal Chemistry 45 (2010) 883–889
3.1.6. Synthesis of [{trimethyltin(IV)}-2-[(3-oxocyclohex-1-
assayed by the minimal inhibitory concentration (MIC) in liquid
enyl)amino]benzoato] (4)
To a round-bottom-flask charged with [2-(3-oxocyclohex-1-enyl)-
benzoic acid] (1.0 g, 4.32 mmol) and triethylamine (0.6 mL, 4.32 mmol)
media according to the NCCLS M27-A protocol (2002). Fungi cells
were obtained from cultures of C. albicans and C. neoformans grown
on Sabouraud medium for 24 and 48 h, respectively. The minimal
concentration of organotin able to inhibit the growth of the yeasts
on RPMI 1640 medium was assayed on a 96 well plate. To each well
dissolved in methanol(20 mL) it was slowly added SnMe
3
Cl (0.86 g,
4.32 mmol). Within 4 h of reflux the solvent was removed in vacuo and
the resultant solid material was washed with hot water, yielding a pale-
yellow solid. X-ray quality crystals were obtained from a methanol/
100
m
l of an organotin solution was added and the plate was
ꢁ
incubated at 37 C for 48 h. Ketoconazol and DMSO 1 and 2% in
RPMI were also tested and used as positive and negative controls.
The experiments were performed in triplicate and according to the
NCCLS M27 protocol. The endpoints were determined visually by
comparison with the drug-free growth control well. MICs were
defined as the lowest compound concentration for which the well
o
ꢀ1
water solution (3:1). Yield 72%. Mp.167–170. C. IV (
598 ( as, 1366 ( , 1350 ( C–N), 639 (
Sn–O). H NMR (DMSO-d , 400.13 MHz), 9.31–9.27 m (C
.65 m (C ), 8.5–8.2 m (C ), 5.7 s (NH), 3.7–3.6 m (C
), 2.4–2.0 m (C ), 2.44 s (C
DMSO-d , 100.61 MHz), 199.73 (COO), 173.47 (CO), 160.72 (C
41.56 (C ), 133.13 (C ),132.52 (C ),122.41 (C ),120.95 (C
19.45 (C ), 101.90 (C ), 58.37 (C ), 36.27 (C ), 21.38 (C
8.32 (CH Sn{ H} NMR (DMSO-d
) ( J C– Sn ¼ 1590 Hz).
49.21 MHz),
1.45, 3.52. Analysis for C16
.37 (5.38), N 3.46 (3.55).
n
)
/cm ),1658 (
as, 502 ( , 473
), 8.7–
), 3.25 m
nCO),
1
n
COO
)
n
COO
)
s
n
n
Sn–C
Sn–C s
n )
H
6 4
1
(n
6
d
8
6 4
H
6 4
H
6 7
H
13
1
(C H
6 7
H
6 7
6 7 3
H ), 1.86 s (CH ). C{ H} NMR
ꢀ
1
(
6
d
6 4
H
),
),
),
was optically clear, and were expressed in mm L .
1
H
6 4
H
6 4
H
6 4
6 4
H
6 4
H
1
1
1
d
6
H
7
6
H
7
6
H
7
6
H
7
6
H
7
3.2.2. Cytotoxicity assay for organotin complexes towards human
kidney cells (HEK293)
Cytotoxicity assays for organotin derivatives (1)–(6) was per-
formed. Human embryonic kidney cells (HEK293) were cultured in
Dulbecco’s minimal essential medium (DMEM) supplemented with
1
13 119
119
119
119
1
3
6
,
1
13
ꢀ1
d
97 ( J Sn– C ¼ 1588 Hz). Sn-M o¨ ssbauer (mm s ),
D
H21NO
3
Sn found (calc.): C 48.41 (48.76), H
5
5
% fetal calf serum (Cultilab), an antibiotic (gentamycin), and were
ꢁ
3.1.7. Synthesis of [{tributyltin(IV)}-2-[(3-oxocyclohex-1-
incubated at 37 C in a 5% CO
2
atmosphere for 24 h until formation
l solutions of the test
drugs, organotin or ketoconazole, were added in concentrations
enyl)amino]benzoato] (5)
Prepared in the same manner reacting [2-(3-oxocyclohex-1-
enyl)benzoic acid] (1.0 g, 4.32 mmol), triethylamine (0.6 mL,
of a confluent monolayer. Subsequently, 100 m
ꢀ
4
ꢀ6
ꢀ1
ranging from 6 ꢂ 10 to 1 ꢂ 10 mmol L . The culture was
4
.3 mmol) and SnBu
3
Cl (1.4 g, 4.3 mmol) in methanol (35 mL). Yield
further incubated for 24 h and 20 l of 3-(4,5-dimetylthiazol-2-yl)-
m
ꢁ
ꢀ1
74%. Mp 179–181 C. IV (
n
/cm ), 1652 (
n
CO), 1595 (
, 471 ( Sn–O). Mp.125.0–
, 400.13 MHz), 8.2–
), 6.12 s (NH), 3.74 m
), 1.81 s (C ), 1.64 m (C ),
n
COO
)
as, 1365
2,5-diphenyl tetrazolium bromide (MTT-Sigma) solution (5 mg/ml)
in phosphate-buffered saline, pH 7.4, were added to each well and
(n
COO
)
s
,1331 (
n
C–N), 647 (
n
Sn–C
)
as, 511 (
n
Sn–C
)
s
n
ꢁ
ꢀ1
1
ꢁ
1
8
30.0 C. IV (
.07 m (C
), 3.39 m (C
.41 m (C ), 1.29 m (C
00.61 MHz), 201.78 (COO), 173.88 (CO), 164.88 (C
), 132.67 (C ), 132.16 (C ), 124.39 (C ), 122.50 (C
), 96.62 (C ), 31.47 (C ), 29.28 (C ), 28.01 (C
), 20.21 (C ),14.10 (C
n
/cm ): 471 (
n
Sn–O). H NMR (C
6
D
6
d
re-incubated at 37 C for 4 h. Supernatants were removed and
ꢀ1
6
H
4
), 7.58–7.50 m (C
), 2.4–2.0 m (C
), 0.92 t (C
6
H
4
), 7.10 m (C
6
H
4
200
m
l of a solution of HCl (0.04 mol L ) in isopropanol were added
(
C
6
H
7
6
H
7
6
H
7
6
H
7
4
H
7
to the plates to dissolve MTT precipitates. Absorbance at 540 nm
was then measured using the microplate spectrophotometer
system SpectraMax 190 (Molecular Devices). The assay was per-
formed in triplicates and results analysed by ANOVA and Student-
1
3
1
1
1
4
H
7
4
H
7
4
H
7
). C{ H} NMR (CDCl
3
,
d
6 4
H
), 140.99
(C
6
H
4
6
H
4
6
H
4
6
H
4
6
6
H
H
4
),
),
126.02 (C
6
H
7
6
H
7
6
H
7
6
H
7
7
Newman–Kewls tests (P < 0.05). The IC50 for each complexes was
1
13
119
ꢀ1
2
2.94 ( J C– Sn ¼ 1427 Hz) (C
4
H
7
4
H
7
4
7
H ), 9.27
determined in mmol L
.
1
19
1
(
(
C
4
H
7
).
Sn{ H} NMR (DMSO-d
6
,
149.21 MHz),
d
ꢀ
161
3.57.
1
119
13
119
ꢀ1
J
Sn– C ¼ 1428 Hz). Sn-M o¨ ssbauer (mm s ),
d
1.42,
D
4. Supplementary data
3
Elemental analysis for C25H39NO Sn (%), found (calc.): C 57.69
(
57.72), H 7.48 (7.56), N 2.54 (2.69).
Crystallographic data are available on request from: (i) IUCr
reference GW2023 for complex (4) respectively, and complex (2) at
Cambridge Crystallographic Data Centre on quoting the deposition
numbers CCDC 698568.
3
.1.8. Synthesis of [{triphenyltin(IV)}-2-[(3-oxocyclohex-1-
enyl)amino]benzoato] (6)
Prepared accordingly by reacting [2-(3-oxocyclohex-1-enyl)benzoic
acid] (1.0 g, 4.32 mmol), triethylamine (0.6 mL, 4.3 mmol) and SnPh3Cl
ꢁ
(1.7 g, 4.3 mmol) in methanol (30 mL). Yield 68%. Mp 122–124 C. IV (
n
/
Acknowledgements
ꢀ
1
cm ), 1658 (
32 ( , 453(
), 7.41–7.24 m (C
.25–2.15 m (C ), 2.06–2.04 m (C
), 5.02–4.97 m (C ), 4.67–4.45 m (C
, 100.61 MHz), 199.23 (COO), 173.13 (CO), 162.38 (C
), 134.02 (C ), 133.67 (C ), 125.30 (C ), 124.02 (C
22.57 (C ), 102.56 (C ), 48.31 (C ), 38.18 (C ), 23.46 (C
38.83 (C ), 130.10 (C
29.43 (C
n
CO), 1602 (
n
COO
)
as,1376 (
Sn–O). H NMR (DMSO-d
), 7.07–7.0 m (C
n
COO
)
s
,1344 (
, 400.13MHz),
), 5.64 s (NH), 3.7 m (C
), 1.85 s (C ), 5.35–5.27 m
n
C–N), 285 (
Sn–C as
n ) ,
1
2
n
)
Sn–C s
n
6
d
8.11–7.92 m
This work was supported by CNPq and FAPEMIG – Brazil.
(C
6
H
4
6
H
4
6
H
4
6 7
H )
2
6
H
7
6
H
7
6 7
H
References
13
1
(C
6
H
5
6
H
5
6
H
5
). C{ H} NMR (DMSO-
), 142.83
d
6
d
6
H
4
[1] C.J. Evans, R. Hill, J. Oil Colour Chem. Assoc. 64 (1998) 215.
[2] D. Liu, R.J. Maguire, Y.L. Lau, G.J. Pacepavicius, H. Okamaru, I. Aoyama, Water
(C
6 4
H
H
6 4
H
6 4
6 4
H
6
H
4
),
),
),
Res. 31 (1997) 2363.
1
1
6
H
7
6
H
7
6
H
7
6
H
H
5
7
6 7
H
H
6 5
[3] N. Voulvoulis, M.D. Scrimshaw, J.N. Lester, Appl. Organomet. Chem. 13 (1999)
135.
1
13 119
6
H
5
) ( J C- Sn ¼ 1771 Hz), 130.88 (C
6
1
19
1
1
6
H
5
).
Sn{ H} NMR (DMSO-d
6
, 149.21 MHz),
d
ꢀ 193
[4] R.J. Maguire, Water Qual. Res. J. Can. 26 (1991) 43.
[5] K. Frent, Crit. Rev. Toxicol. 26 (1996) 1.
1
119
13
119
ꢀ1
(
J
Sn– C ¼ 1771 Hz). Sn-M o¨ ssbauer (mm s ),
d
1.40,
D
3.16.
[6] J. White, J.M. Tobin, J.J. Cooney, Can. J. Microbiol. 45 (1999) 541.
Elemental analysis for C31
H27NO
3
Sn (%): found (calc.): C 64.22 (64.18), H
[7] M. Hoch, Appl. Geochem. 16 (2001) 719.
[8] K.E. Appel, Drug Metab. Rev. 36 (2004) 763.
4
3
3
.54 (4.69), N 2.29 (2.41).
[9] Bulten EJ, Budding HA. British Patent 2077266; 1981.
[
[
10] H.A. Meinema, A.M.J. Liebregts, H.A. Budding, E.J. Bulten, Rev. Silicon,
Germanium, Tin Lead Compds. 8 (1985) 157.
11] Brown N.M. The effect of two organotin compounds on C3H-strain mice, PhD,
dissertation. Clenson University; 1972.
.2. Pharmacology
.2.1. Antifungal activity of organotin compounds
[
[
12] Crowe A.J. PhD thesis. London University, 1980.
13] A.J. Crowe, Chem. Ind. (1980) 200.
The antifungal activity of organotin compounds towards C.
albicans (ATCC18804) and C. neoformans (ATCC24067D2) was
[14] R. Barbieri, L. Pellerito, G. Ruisi, M.T. Lo Guidice, Inorg. Chim. Acta 66 (1982) L39.

F.T. Vieira et al. / European Journal of Medicinal Chemistry 45 (2010) 883–889
889
[
[
15] Barbieri R, Ruisi G. NATO Adv. Workshop on the effect of tin upon malignant
cell growth, Brussels; 1989 [abstr. PO2.].
16] F. Huber, G. Roge, L. Carl, G. Atassi, F. Spreafico, S. Filippeschi, R. Barbieri, A. Silvestri,
E. Rivarola, G. Ruissi, F. Di Branca, G. Alonzo, J. Chem. Soc. DaltonTrans. (1985) 523.
17] Y. Arakawa, O. Wada, Biochem. Biophys. Comm. 125 (1989) 59.
18] Y. Arakawa, O. Wada, Igaku No Agumi 136 (1986) 177.
[39] A. Szorcsik, L. Nagy, J. Sletten, G. Szalontai, E. Kamu, T. Fiore, L. Pellerito,
E. Kalman, J. Organomet. Chem. 689 (2004) 1145.
[40] B.Y.K. Ho, J.J. Zukerman, Inorg. Chem. 12 (1973) 1552.
[41] M. Nath, R. Yadav, G. Eng, T.T. Nguyen and A. Kumar, J. Organomet. Chem., 577
(1999) 1.
[42] W. Rehman, M.K. Baloch, A. Badshah, Eur. J. Med. Chem. 43 (2008) 2380.
[43] T.P. Lockhart, W.F. Manders, J.J. Zuckerman, J.A.C.S 107 (1985) 4546.
[44] J. Hole cˇ ek, M. N a´ dvornik, K. Handli rˇ , S.M. Teleb, A. Ly cˇ ka, J. Organomet. Chem.
339 (1988) 61.
[45] S. Basu, A. Mizar, T.S.B. Baul, E. Rivarola, Hyperfine Interact 185 (2008) 95.
[46] M. Gielen, H. Dalil, M. Biesemans, B. Mahieu, R. Willem, D. de Vos, Appl.
Organomet. Chem. 13 (1999) 515.
[47] V. Chandrasekhar, P. Thilagar, P. Sasikumar, J. Organomet. Chem. 691 (2006) 1681.
[48] F.T. Vieira, D.C. Menezes, G.M. de Lima, N.L. Speziali, J.R.da S. Maia, Acta Cryst.
E. E63 (2007) m2597.
[49] E. De Pauw, Eur. J. Clin. Microb. Infect. Dis 16 (1997) 32.
[50] C. Speth, G. Rambach, R. Wuerzner, C. Lass-Floerl, Mycoses 51 (2008) 477.
[51] F.M. Lunel, F.G. Meis, A. Voss, Diagn. Microbiol. Infect Dis. 34 (1999) 213.
[52] M.S. Saag, R.J. Graybill, R.A. Larsen, P.G. Pappas, J.R. Perfect, W.G. Powderly,
J.D. Sobel, W.E. Dismukes, Clin. Infect. Dis. 30 (2000) S1.
[
[
[
19] N. Wasi, H.B. Singh, A. Gajanana, A.N. Raichowdary, Inorg. Chim. Acta 135
(
1987) 133.
20] A.K. Saxena, J.K. Koacher, J.P. Tandon, S.R. Das, Toxicol. Environ. Health 10 (4–5)
1982) 709.
[
(
[
[
[
[
21] A.K. Senigupta, A.A. Gupta, Ind. J. Chem. Sect. B Org. Med. Chem. 22 (3) (1983) 263.
22] W. Peters, E.R. Trotter, B.L. Robinson, Ann. Trop. Med. Parasitol. 74 (1980) 321.
23] A.I. Tereeva, G.M. Borodina, Farmakol. Toksikol. 30 (1967) 207.
24] S.J. Blunden, A. Chapman, Organotin compounds in the environment. in:
P.J. Craig (Ed.), Organometallic compounds in the environment. Longman,
Harlow, 1986.
25] K.C. Molloy, T.G. Purcell, E. Hahn, H. Schumann, J.J. Zuckerman, Organome-
tallics 5 (1986) 85.
26] M. Gielen, Appl. Organomet. Chem. 16 (2002) 481.
27] M. Gielen, M. Biesemans, R. Willem, Appl. Organomet. Chem. 19 (2005) 440.
28] M. Gielen, J. Braz, Chem. Soc. 14 (2003) 870.
29] A. Perez-Rebolledo, J.D. Ayala, G.M. de Lima, N. Marchini, G. Bombieri,
C.L. Zani, E.M. Souza-Fagundes, H. Beraldo, Eur. J. Med. Chem. 40 (2005) 467.
30] D.C. Menezes, F.T. Vieira, G.M. de Lima, A.O. Porto, M.E. Cort e´ s, J.D. Ardisson,
T.E. Albrecht-Schmitt, Eur. J. Med. Chem. 40 (2005) 1277.
31] D.C. Menezes, F.T. Vieira, G.M. de Lima, J.L. Wardell, M.E. Cort e´ s, G.A.B. Silva
Ferreira, A. Vilas Boas, J.R.da S. Maia, Appl. Organomet. Chem. 22 (2008) 433.
32] D.C. Menezes, F.T. Vieira, G.M. de Lima, J.L. Wardell, M.E. Cortes, M.P. Ferreira,
M.A. Soares, A. Vilas Boas, Appl. Organometal. Chem. 22 (2008) 221.
33] M.F. Strozhev, I. Lielbriedis, Khimiya Geterotsiklicheskikh Soedinenii 7 (1990) 947.
34] F.T. Vieira, D.C. Menezes, G.M. de Lima, N.L. Speziali, Acta Cryst. E. E63 (2007) o3376.
35] V. Chandrasekhar, K. Gopal, P. Sasikumar, R. Thirumoorthi, Coord. Chem. Rev.
[
[
[
[
[
[53] K.M. Abu-Salah, Br. J. Biomed. Sci. 53 (1996) 122.
[54] R.J. Hay, J. Antimicrob, Chemotherpy 20 (1987) 1.
[55] H. Van den Bossche, F. Dromer, I. Improvissi, M. Lozane-Chiu, J.H. Hex,
D. Sanglard, Med. Mycol. 36 (1998) 119.
[56] D.P. Kontoyiannis, R.E. Lewis, Lancet 359 (2002) 1135.
[57] M. Gielen, A.G. Davies, K. Pannell, E. Tiekink, Tin chemistry: fundamentals,
frontiers, and applications. Wiley, Chichester, 2008.
[58] J. M Tobin, J.J. Cooney, Arch. Environ. Contam. Toxicol. 36 (1999) 7.
[59] J.S. White, J.M. Tobin, Environ. Sci. Technol. 38 (2004) 3877.
[60] J.S. White, J.M. Tobin, J. Appl, Microbiol. Biotechnol. 632 (2004) 445.
[61] O.S. Laurence, J.J. Cooney, G.M. Gadd, Microb. Ecol. 17 (1989) 275.
[62] B.A. Buck-Koehntop, F. Porcelli, J.L. Lewin, C.J. Cramer, G. Veglia, J. Organomet.
Chem. 691 (2006) 1748.
[
[
[
[
[
[
249 (2005) 1745.
[
[
[
36] L.J. Bellamy, in: The infra-red spectra of complex molecules, third ed. Wiley,
New York, 1975.
[63] K.C. Molloy, Bioorganotin compounds. Hartley and Wiley, Chichester, 1989, 5.
[64] M. Nath, S. Pokharia, G. Eng, X.Q. Song, A. Kumar, M. Gielen, R. Willem,
M. Biesemans, Appl. Organomet. Chem., 18 (2004) 460.
[65] J.J. Cooney, S. Wuertz, J. Ind. Microbiol. Biotechnol. 4 (2005) 375.
[66] G.M. Sheldrick, SHELXS-97. Program for Crystal structure resolution. Univ. of
G o¨ ttingen, G o¨ ttingen, Germany, 1997.
37] M. Nath, S. Pokharia, X. Song, G. Eng, M. Gielen, M. Kemmer, M. Biesemans,
R. Willem, D. de Vos, Appl. Organomet. Chem. 17 (2003) 305.
38] M.A. Abdellah, S.K. Hadjikakou, N. Hadjiliadis, M. Kubicki, T. Bakas,
N. Kourkoumelis, Y.V. Simos, S. Karkabounas, M.M. Barsan, I.S. Butler, Bioinorg.
Chem. Appl. (2009) 542979.
[67] L.J. Farrugia, ORTEP3 for Windows. J. Appl. Cryst 30 (1997) 565.