Design, structural and spectroscopic elucidation, and the in vitro biological activities of new diorganotin dithiocarbamates

Article abstract of DOI:10.1016/j.ejmech.2012.10.021

The reaction of 2,2-dimethoxy-N-methylethyllamine or 2-methyl-1,3-dioxolane with CS₂ in alkaline media produced two novel dithiocarbamate salts. Subsequent reactions with organotin halides yielded six new complexes: [SnMe₂{S₂

Full text of DOI:10.1016/j.ejmech.2012.10.021

European Journal of Medicinal Chemistry 58 (2012) 493e503
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, structural and spectroscopic elucidation, and the in vitro biological
activities of new diorganotin dithiocarbamates
,
a
a
Isabella P. Ferreira a, Geraldo M. de Lima a , Eucler B. Paniago , Willian R. Rocha ,
*
Jacqueline A. Takahashi a, Carlos B. Pinheiro b, José D. Ardisson c
a Departamento de Química, Universidade Federal de Minas Gerais, UFMG, Avenida Antônio Carlos 6627, Belo Horizonte, MG, CEP 31270-901, Brazil
b Departamento de Física, Universidade Federal de Minas Gerais, UFMG, Avenida Antônio Carlos 6627, Belo Horizonte, MG, CEP 31270-901, Brazil
c Centro de Desenvolvimento em Tecnologia Nuclear, CDTN/CNEN, Avenida Antônio Carlos 6627, Belo Horizonte, MG, CEP 31270-901, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 2,2-dimethoxy-N-methylethyllamine or 2-methyl-1,3-dioxolane with CS2 in alkaline
media produced two novel dithiocarbamate salts. Subsequent reactions with organotin halides yielded
six new complexes: [SnMe2{S2CNR(R1)2}2] (1), [Sn(n-Bu)2{S2CNR(R1)2}2] (2), [SnPh2{S2CNR(R1)2}2] (3),
[SnMe2{S2CNR(R2)2}2] (4), [Sn(n-Bu)2{S2CNR(R2)2}2] (5), [SnPh2{S2CNR(R2)2}2] (6), where R ¼ methyl,
R1 ¼ CH2CH(OMe)2, and R2 ¼ 2-methyl-1,3-dioxolane. All compounds were identified in terms of
infrared, 1H and 13C NMR, and the complexes were also characterized using 119Sn NMR, 119Sn Mössbauer
and X-ray crystallography. The biological activity of all derivatives has been screened in terms of IC90 and
IC50 against Aspergillus flavus, Aspergillus niger, Aspergillus parasiticus, Penicillium citrinum, Curvularia
senegalensis, Staphylococcus aureus, Listeria monocytogenes, Bacillus cereus, Streptococcus sanguinis,
Escherichia coli, Citrobacter freundii, Salmonella typhimurium, and Pseudomonas aeruginosa and the results
correlated well with a performed study of structureeactivity relationship (SAR). Complexes (3), (5) and
(6) displayed the best IC90 and IC50 in the presence of the fungi, greater than that of miconazole, used as
control drug.
Received 28 June 2012
Received in revised form
27 September 2012
Accepted 15 October 2012
Available online 24 October 2012
Keywords:
Biological activity
Organotin dithiocarbamate
Structural determination
Ó 2012 Elsevier Masson SAS. All rights reserved.
1. Introduction
It is also worth to emphasize the varied range of applications and
potential use of organotin derivatives, among other metals, as
The metal-1,10-dithiolates comprise one of the most interesting
class of complexes, in which three types of anions: xanthates,
ROCSꢀ2 , dithiophosphates, ðROÞ2PSꢀ2 and dithiocarbamates,
R2NCSꢀ2 , are the coordinating species [1,2]. Many applications have
been found for the latter ligands. Apart from their ability to stabilise
metal cations in a variety of oxidation states, well documented in
the field of coordination chemistry [3,4], their pharmaceutical
properties are noteworthy. They are used to remove excess of
copper due to Wilson’s disease [5], they are also able to reduce the
nephrotoxicity of platinum-based drugs used in chemotherapy [6]
and in addition they are used in the treatment of alcoholism [7] and
in other clinical applications [8]. In addition they find applications
in other fields, for instance in the vulcanization of rubber [9],
preparation of pesticides [10], and as precursors for the production
of metal sulfide nanoparticles [11e14].
diverse as in agriculture, biology, catalysis, or organic synthesis [15].
As both organotins and dithiocarbamates interact with living cells it
is expected an enhanced biological activity by bonding together
organotin moieties and dithiocarbamates. Many works have
described not only the preparation and characterization of related
complexes [16e19] but also their action against tumours, fungi,
bacteria, and other microorganisms [1,15,20e23], and other appli-
cations [19]. Besides preparing new organotinedithiocarbamates,
investigating their technological applications [24,25] and
screening their activity in the presence of some parasites [26,27] we
have been interested in the mechanism of action of such complexes
in biological media. The number and nature of the organic groups
bonded to the metal centre influence the toxicity towards microor-
ganisms, which, in general, decreases in the order R3SnX > R2SnX2 >
RSnX3. However, the order of toxicity depends on the microor-
ganism, and varies from strain to strain [28]. It has been proposed
that toxicity in the R3Sn series correlates with total molecule surface
(TSA) and hence n-propyl-, n-butyl-, n-pentyl-, phenyl-, and
cyclohexyl-substituted tin should be more toxic than ethyl- and
* Corresponding author. Tel.: þ55 31 3409 5744; fax: þ55 31 3409 5720.
E-mail address: gmlima@ufmg.br (G.M. de Lima).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.10.021

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I.P. Ferreira et al. / European Journal of Medicinal Chemistry 58 (2012) 493e503
methyltin. Moreover, if the toxic effects are intra-cellular, following
transport through the cell membrane, a correlation should exist
between toxicity and lipophilicity [29]. The effect of organotin-
dithiocarbamate and -carboxylate complexes on the cellular
activityof some varietyof Candida albicans revealed that there are no
changes in DNA integrity or in the mitochondria function. However,
all complexes reduced the ergosterol biosynthesis. Special tech-
niques used for morphological investigations such as scanning
electron microscopy (SEM) and transmission electron microscopy
(TEM) suggested that the organotin complexes act on the cell
membrane, in view of the observed cytoplasm leakage and strong
deterioration of the cellular membrane [30].
Following our interest in the chemical, physical and biological
properties of metal-based dithiocarbamate complexes herein we
describe the synthesis, characterization and the crystallographic
authentication of complexes (1)e(6). In addition we have screened
the biological activity of complexes (1)e(6) against Aspergillus fla-
vus, Aspergillus niger, Aspergillus parasiticus, Penicillium citrinum,
Curvularia senegalensis, Staphylococcus aureus, Listeria mono-
cytogenes, Bacillus cereus, Streptococcus sanguinis, Escherichia coli,
Citrobacter freundii, Salmonella typhimurium, and Pseudomonas
aeruginosa. Aspergillus deserves special attention due to the
growing number of deaths in consequence of fungal infections in
individual who are immunocompromised either from (i) diseases,
cancer or AIDS, etc, (ii) the action of immunosuppressive drugs, or
(iii) resistance to drugs employed in Aspergillosis.
it was detected in the expected region within 385e318 cmꢀ1 [31].
The SneC signals that usually occurs in the range of 500e600 cmꢀ1
nasym(SneC), and 530e470 cmꢀ1
nsym(SneC), did not show great
,
,
changes in (1)e(6), if compared to other compounds reported in the
literature. The set of bands of the eCS2 fragment are unique since it
provides information of the coordination mode of the complexes. If
the ligand and metal are bonded in a bidentate form, through both
sulphurdonorcentres, eitheronlyone vibration, nasym, is observed in
the i.r. spectrum between1060 and 940 cmꢀ1 or this signalsplits into
two close signals (Dnasym < 20 cmꢀ1) due toa small asymmetryof the
SeCeS fragment. This asymmetry increases in a monodentate
bonding scheme, MeSeC]S (Dnasym > 20 cmꢀ1). The nasym and
nsym of the CeS bond in the free ligands [Na{S2CN(Me)
CH2CH(OMe)2}] (i) and [Na{S2CN(Me)R}] (ii) (R ¼ 2-methyl-1,3-
dioxolane) were observed at 966 and 613 cmꢀ1, 982 and 606 cmꢀ1
,
respectively. These signals have shifted to higher frequency
remaining almost unchanged in (1)e(6). Only one signal was
detected for the nasym in the complexes in the range of 950e
996 cmꢀ1, indicating mostly a symmetrical bidentate coordination
mode [32]. The symmetric vibration of the CeS bond of all
complexes ranged from 630 to 420 cmꢀ1 [33]. The NeCS bond
stretches within 1482e1495 cmꢀ1 in the complexes and in the free
ligands, (i) and (ii), at 1473 and 1474 cmꢀ1, respectively, revealing an
increase in the NeC double bond character. The SneS bands were
detected at low frequencies (250e450 cmꢀ1).
2.3. NMR results
2. Results and discussions
Complexes (1)e(6) displayed the pattern expected for the 1H
NMR, confirming the formation of the dithiocarbamate. All
complexes exhibited an upfield shift for the NCH2 hydrogen in
comparison to the ligands, Table 1.
2.1. Chemistry
The new dithiocarbamate sodium salts [Na{S2CN(Me)R}]
R ¼ CH2CH(OMe)2 (i) and (R ¼ 2-methyl-1,3-dioxolane) (ii) have
been prepared as colourless solids, with yield higher than 90%, by
onepotreaction of the appropriateaminewithCS2 in alkaline media.
The synthesis of complexes (1)e(6) have been performed by the
chemical reaction of SnR2Cl2 with (i) or (ii) according to Scheme 1.
All complexes have been isolated as colourless, air stable and
crystalline solids, with melting points ranging from 80 to 180 ꢁC.
In the 13C NMR spectra the signal corresponding to eCS2 and
those of the carbon bonded to the tin atom were of special interest.
The
complexes. A closer relationship between the 13C chemical shift,
and (NeCS2) has been described in the literature. Higher values of
d (CS2) signal in the ligands moves to lower frequency in the
d,
n
the stretching frequency of NeC bond indicates a higher double
bond character of this interaction, and is related to low values of the
d
(N13CS2), observed in the NMR, due to a higher electronic density
2.2. Infrared results
at the carbon atom [34]. The same tendency has been observed in
this work. The (NeCS2) locates in higher frequency if compared
with sodium salt of the free ligands, and the
13CS2) is observed in
lower field as consequence of an increased character of the NeC
n
The infrared spectra of metallic dithiocarbamates normally
exhibit strong to moderate signals, allowing important structural
outcomes. The vibration studies were focused in three main regions,
d(
p
bond upon coordination to Sn(IV) centre, Table 1.
n(NeCS2)
,
n(CeS) and n(SneC). Despite the sensitivity of the SneCl
The literature establishes the following range of 119Sn chemical
shift for tetra-, penta-, or hexa-coordinated organotin complexes,
stretching frequency to the coordination number of tin, in (1)e(6)
Scheme 1. Synthesis of new dithiocarbamate and their organotin complexes.

I.P. Ferreira et al. / European Journal of Medicinal Chemistry 58 (2012) 493e503
495
Table 1
orbital re-hybridization upon complexation [39]. The CeSneC
angle estimated by eq. (1) agrees with the expected coordination
number pointed out by the 119Sn NMR chemical shifts. For those
hexa-coordinated complexes it is clear that the structures changes
a little in solution or in the solid state, since the CeSneC angle
measured by X-ray is not too different from that obtained in the
119Sn NMR experiments, Table 2.
Selected 1H, 13C and 119Sn NMR and infrared spectroscopic data for compounds (i),
(ii) and complexes (1)e(6).
Compound
1H/
(NCH2)
d
13C/
(NCH2) (CS2)
d
13C/
d
n(N-CS2) nasym(CS2)
(i)
4.39e4.42 57.8
3.90e3.92 58.7
3.93e3.96 58.7
3.80e3.83 59.7
214.2 1474
966
991
979
982
[SnMe2{S2CNR(R1)}2] (1)
[Sn(n-Bu2{S2CNR(R1)}2] (2)
[SnPh2{S2CNR(R1)}2] (3)
200.8 1485
202.2 1491
203.7 1486
2.4. Mössbauer spectroscopic results
(ii)
4.49e4.51 57.3
3.85e3.90 58.7
214.4 1473
201.9 1488
202.9 1485
201.5 1494
982
991
995
983
[SnMe2{S2CNR(R2)}2] (4)
The 119Sn-Mössbauer experiments were performed in order to
determine the differences in the Sn nuclei on going from organotin
starting materials to the complexes. The isomer shift parameters
[Sn(n-Bu)2{S2CNR(R2)}2] (5) 4.04e4.06 58.8
[SnPh2{S2CNR(R2)}2] (6)
3.82e3.96 60.0
(d
/mm sꢀ1) indicates the presence of s electron density at the tin
nuclei, therefore it is a good indication of the hybridization scheme
at the tin atom in the complexes. The isomer shift signals for
complexes (1)e(6) were observed at 1.43, 1.58, 1.41, 1.45, 1.57,
1.34 mm sꢀ1, respectively, indicates the presence of Sn(IV) and
a pseudo d2sp3 hybridization at the tin centre. The non-zero value
d
200 to ꢀ60,
d
ꢀ90 to ꢀ190 and ꢀ210 to ꢀ400 ppm, respectively
d
[35]. However, it must be carefully analysed since apart from coor-
dination number, tin resonance is strongly dependent upon other
factors, such as electronegativity 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
of the quadrupolar splitting parameters (
deviation from a spherical distribution of charge at the metal atom.
For complexes (1)e(6) we have obtained (
/mm sꢀ1) at 3.01, 2.98,
D
/mm sꢀ1) indicates
119Sn
d values in contrast to the starting materials. Nevertheless, in
view of the 119Sn NMR results, complexes (1)e(6) followed the
tendency which connects 119Sn chemical shift with coordination
number. In solution, the tin centre in complexes (1)e(6), remains in
a hexa-coordinated environment, Table 2. More informative are the
coupling constant 1J (119Sn, 13C) and 2J (119Sn, 1H) obtained in the
NMR experiments, which allowed an evaluation of the CeSneC
angle of the organotin fragment. The literature suggests that 1J and
2J are very sensitive to variation in the coordination number or the
CeSneC angle. An empirical equation expresses a mathematical
D
2.78, 2.04, 3.00, 2.57 which is compatible with octahedral geom-
etry [40,41].
2.5. X-ray crystallographic results
Structural determination becomes a key step when the focus of
organotin investigations relates to biocide activity, since their
performance relies on subtle structural arrangements in solution or
in the solid state. The structures of complexes (1)e(6) have been
authenticated by X-ray crystallography [1], Table 3.
relationship between
for methyleSn containing complexes [36e38]:
q
and 1J or 2J (119Sn, 13C) coupling constants
In complexes (1)e(6) there are two asymmetrically coordinating
dithiocarbamate ligands, defining a twisted trapezoidal plane
described by two distinct pairs of SneS bonds. Each one locates at
the same side of the molecule, where the similar bonds are cis
1
13
j Jð119Sn ꢀ CÞj ¼ 11:4ð
Þ ꢀ 875
(1)
q
and
ꢀ
positioned. The short SneS bonds vary from 2.5104(9) A, complex
ꢀ
2
2
ð
q
Þ ¼ ð0:0161Þ$j Jð119Sn; 1HÞj ꢀ1:32j Jð119Sn; 1HÞj þ133:4
2
2
(3), to 2.5324(4) A in (6), and the longer distances fall in the range of
ꢀ
2.8550(6) in (6), and 3.0045(11) A, complex (4), Table 4. The longest
(2)
SneS bonds are present in the methyl-containing complexes,
ꢀ
ꢀ
The interpretation of chemical shifts and coupling constants in
3.0007(7) A (1), and 3.0045(11) A, (4). Even though, they are
ꢀ
solution is generally based on crystal structure data (X-ray),
therefore subject to uncertainties arising from solvation and
dynamic effects. Equations (1) and (2) provide, with reasonable
accuracy a mean of determining the CeSneC angle in solution by
measuring J coupling parameters. In view of the difficulties of
observing 2J (119Sn, 1H) constant, we have used eq. (1) in this
work, in spite of its better accuracy observed mostly in methyltin
based compounds.
smaller than the sum of the Van der Waals radii of Sn and S (4.0 A)
[42], which suggest a strong covalent character. Therefore the tin
cation is surrounded by six donor centres, resulting in a coordina-
tion number equal to 6, as observed in previous examples, instead
of 4, [43,44]. Another interesting outcome concerns the difference
between the short and long SneS bonds (DSneS) in (1)e(6),
ꢀ
ꢀ
0.4809 Å, 0.4523 A and 0.4501 A, complexes (1)e(3), respectively,
and 0.4832/0.4891, 0.4071, 0.3226 derivatives (4)e(6), accordingly.
This asymmetry might results from electronic effects produced by
Me, Bu or Ph groups. The electron withdrawing effect of Ph ring
It is observed a decrease of the first order SneC coupling
constant with coordination number, reflecting changes in
q due to
Table 2
119Sn NMR parameters and results and CeSneC angle obtained by X-ray crystallography.
d
e
Complexa
119Sn NMR/db
C.N.c
1J(119Sne13C)/Hz
CeSneC/ꢁ
C CeSneC/ꢁ
[SnMe2{S2CNR(R1)}2] (1)
[Sn(n-Bu2{S2CNR(R1)}2] (2)
[SnPh2{S2CNR(R1)}2] (3)
[SnMe2{S2CNR(R2)}2] (4)
[Sn(n-Bu)2{S2CNR(R2)}2] (5)
[SnPh2{S2CNR(R2)}2] (6)
ꢀ334.51
ꢀ339.38
ꢀ498.70
ꢀ335.02
ꢀ339.58
ꢀ498.45
6
6
6
6
6
6
757
605
777
749
814
791
143.5
149.3
145.3
142.7
148.8
146.6
136.91(19)
138.53(11)
139.23(19)
137.40(4)
138.29(11)
144.92(13)
a
R ¼ Me; R1 ¼ CH2CH(OMe)2 and R2 ¼ 2-methyl-1,3-dioxolane.
b
c
CDCL3 as solvent.
Coordination number at the Sn atom in solution.
d
e
1
Obtained using j J(119Sne13C)j ¼ 11.4(
q
) ꢀ 875.
Obtained by X-ray crystallography.

496
I.P. Ferreira et al. / European Journal of Medicinal Chemistry 58 (2012) 493e503
Table 3
Crystallographic data for complexes (1)e(6).
Compound
(1)
(2)
(3)
(4)
(5)
(6)
Empirical formula
Formula weight
Temperature, K
C
14H30N2O4S4Sn
C20H42N2O4S4Sn
621.49
293(2)
0.71073
Monoclinic
C 1 2/c 1
17.0154(4)
6.9787(2)
23.9908(6)
90
91.160(2)
90
2848.21(13)
4
1.449
1.217
C24H34N2O4S4Sn
661.46
293(2)
0.71073
Monoclinic
’P 2/c’
8.9344(5)
6.9234(3)
23.9782(10)
90
94.149(4)
90
1479.32(12)
2
1.485
1.177
C14H26N2O4S4Sn
533.30
543(2)
0.71073
Triclinic
P ꢀ1
C20H38N2O4S4Sn
617.45
293(2)
0.71073
Monoclinic
C2/c
17.2459(5)
20.1857(5)
8.1113(2)
90
92.677(2)
90
2820.63(13)
4
1.454
1.228
C24H30N2O4S4Sn
657.43
293(2)
0.71073
Monoclinic
C 2/c’
24.9271(10)
6.4287(2)
18.1816(8)
90
112.584(5)
90
2690.16(18)
4
1.623
1.294
537.33
293(2)
0.71073
Orthorhombic
P c c n
9.8722(2)
18.8327(4)
12.2749(2)
90
ꢀ
Wavelength, A
Crystal system
Space group
ꢀ
a, A
9.2515(5)
11.7539(8)
11.7895(6)
64.217(6)
77.080(4)
73.183(5)
1097.88(11)
2
ꢀ
b, A
ꢀ
c, A
ꢁ
ꢁ
ꢁ
a
,
b
,
90
90
g
,
3
ꢀ
Volume, A
2282.15(8)
4
1.564
1.505
1096
Z
Calculated density, Mg/m3
Absorption coefficient, mmꢀ1
F(000)
1.613
1.564
540
1288
676
1272
1336
Crystal size, mm
Theta range for data coll.,
Limiting indices
0.66 ꢂ 0.07 ꢂ 0.03 0.3175 ꢂ 0.16 ꢂ 0.1079 0.21 ꢂ 0.16 ꢂ 0.04 0.28 ꢂ 0.17 ꢂ 0.06 0.25 ꢂ 0.20 ꢂ 0.08 0.14 ꢂ 0.10 ꢂ 0.01
ꢁ
2.16e26.37
ꢀ12 ꢃ h ꢃ 12
ꢀ23 ꢃ k ꢃ 23
ꢀ15 ꢃ l ꢃ 15
25824
2.91e26.37
ꢀ19 ꢃ h ꢃ 21
ꢀ8 ꢃ k ꢃ 6
ꢀ29 ꢃ l ꢃ 22
7082
2.29e26.37
ꢀ11 ꢃ h ꢃ 8
ꢀ8 ꢃ k ꢃ 8
ꢀ29 ꢃ l ꢃ 29
10480
1.93e26.37
ꢀ11 ꢃ h ꢃ 11
ꢀ14 ꢃ k ꢃ 11
ꢀ14 ꢃ l ꢃ 14
7717
2.02e26.37
ꢀ21 ꢃ h ꢃ 21
ꢀ25 ꢃ k ꢃ 25
ꢀ10 ꢃ l ꢃ 10
22253
2.39e26.37
ꢀ30 ꢃ h ꢃ 23
ꢀ7 ꢃ k ꢃ 8
ꢀ21 ꢃ l ꢃ 22
9446
Reflections collected
Independent reflections
2342
2919
3033
4492
2887
2749
[R(int) ¼ 0.0295]
[R(int) ¼ 0.0262]
R(int) ¼ 0.0575]
[R(int) ¼ 0.0351]
[R(int) ¼ 0.0408]
[R(int) ¼ 0.0385]
Reflections obd. (>2 sigma)
Completeness to theta ¼ 26.37
Absorption correction
2085
2531
2237
3644
2570
2372
100.0%
99.9%
100.0%
100.0%
100.0%
100.0%
Multi-scan
Full-matrix
least-squares
on F2
Multi-scan
Full-matrix
least-squares
on F2
Multi-scan
Full-matrix
least-squares
on F2
Multi-scan
Full-matrix
least-squares
on F2
Multi-scan
Full-matrix
least-squares
on F2
Multi-scan
Full-matrix
least-squares
on F2
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
2342/0/114
1.220
2919/0/143
0.984
3033/0/159
1.042
4492/12/226
1.054
2887/0/141
1.073
2749/0/159
1.068
Final R indices [I > 2sigma(I)]
R1 ¼ 0.0243
wR2 ¼ 0.0739
R1 ¼ 0.0285
wR2 ¼ 0.0774
0.438 and ꢀ0.406
883619
R1 ¼ 0.0232
wR2 ¼ 0.0483
R1 ¼ 0.0298
wR2 ¼ 0.0498
0.389 and ꢀ0.310
883618
R1 ¼ 0.0401
wR2 ¼ 0.0704
R1 ¼ 0.0660
wR2 ¼ 0.0806
0.559 and ꢀ0.532
883621
R1 ¼ 0.0380
wR2 ¼ 0.0813
R1 ¼ 0.0530
wR2 ¼ 0.0911
0.547 and ꢀ0.582
883620
R1 ¼ 0.0219
wR2 ¼ 0.0502
R1 ¼ 0.0279
wR2 ¼ 0.0540
0.508 and ꢀ0.395
883622
R1 ¼ 0.0260
wR2 ¼ 0.0503
R1 ¼ 0.0349
wR2 ¼ 0.0539
0.408 and ꢀ0.381
883617
R indices (all data)
ꢀꢀ3
Largest diff. peak and hole, e A
CCDC reference
clearly increases the electronic density at the SneS bonds, reducing
asymmetry, while the contrary is observed for Me and Bu groups in
view of their electron donor nature, producing a greater DSneS. On
butyl-containing complexes (2) and (5) steric effects might play
a key role on this matter too, accounting for the differences in DSneS
on going from methyl- to butyl-bearing derivatives.
Therefore, the tin centre neighbourhood is best described as being
a sort of twisted trapezoidal bipyramid with the four sulphur donor
atoms at the equatorial position and two carbons occupying the
apical coordination. Considering only the R2Sn(S2CN)2 fragment
two structural patterns at the tin centre feature the structural
arrangements of the diorganotin complexes. Complex (4) is formed
by two independent crystallographic units where the tin atom is
asymmetrically bonded to the S donor centre, as a consequence of
Two tin-bonded methyl or butyl groups, with almost similar
SneC bonds, lie over the weaker Sn $$$$ S contacts, Figs. 1 and 2.
Table 4
ꢀ
Selected bond lengths (A) and angles (o) for complexes (1)e(6).
[SnMe2{S2CNR(R1)}2] (1)
[Sn(n-Bu)2{S2CNR(R1)}2] (2)
[Sn(n-Ph)2{S2CNR(R1)2}2] (3)
[SnMe2{S2CNR(R2)}2] (4)
SneS1
2.5198(7)
3.0007(7)
149.78(3)
e
SneC
2.116(3)
1.332(3)
82.00(3)
2.136(2)
1.334(2)
84.80(2)
2.118(3)
1.343(4)
145.73(4)
2.109(4)
2.110(4)
1.336(5)
1.331(5)
149.48(3)
2.135(2)
1.340(2)
84.06(2)
2.152(2)
1.328(3)
141.60(3)
CeS1
1.741(2)
1.692(3)
136.89(17)
1.632(3)
1.741(3)
138.53(11)
1.738(3)
1.682(3)
139.23(19)
1.734(4)
1.685(4)
1.743(4)
1.684(4)
136.14(19)
1.690(2)
1.743(2)
138.29(11)
1.752(2)
1.692(2)
144.92(13)
SneS2
C1eN1
CeS2
S2eSneS2
SneS1
S1eSneS1
SneC
C7eSneC7
CeS1
SneS2
2.5278(5)
146.02(2)
2.5104(9)
2.9605(9)
84.66(4)
2.5156(11)
2.9988(12)
2.5154(11)
3.0045(11)
82.31(3)
2.9392(5)
2.5321(5)
145.31(2)
2.5324(4)
2.8550(6)
86.12(3)
C1eN1
CeS2
S1eSneS1
SneS1
S2eSneS2
SneC7
C7eSneC7
C1eS1
SneS2
C1eN1
C1eS2
S1ieSneS1
SneS1
S2ieSneS2
SneC13
SneC14
C1eN1
C7ieSneC7
C1eS1
SneS2
C1eS2
SneS3
C7eS3
SneS4
C7eN2
C7eS4
S1eSneS3
SneS1
S2eSneS4
SneC1
C13eSneC14
C5eS1
[Sn(n-Bu)2{S2CNR(R2)}] (5)
[SnPh2{S2CNR(R2)}2] (6)
SneS2
C5eN1
C5eS2
S1eSneS1
SneS1
S2eSneS2
SneC1
C1eSneC1
C7eS1
SneS2
C7eN1
C7eS2
S1eSneS1
S2eSneS3
C1eSneC1

I.P. Ferreira et al. / European Journal of Medicinal Chemistry 58 (2012) 493e503
497
Fig. 1. Structure of the complexes [SnMe2{S2CNR(R1)2}2] (1), [Sn(n-Bu)2{S2CNR(R1)2}2] (2), [SnPh2{S2CNR(R1)2}2] (3), where R ¼ methyl and R1 ¼ CH2CH(OMe)2.
the coordination mode and
p
-electron density distribution at the e
[1,19,23e30]. Solvation process produces little structural variation
in the CeSneC angles in solution, as pointed out by the J
coupling constants. The SshorteSneSshort angles of complexes (1)e
(6) ranged from 82.00(3)ꢁ in complex (1) to 86.12(3)ꢁ in (6), and
the SlongeSneSlong varied from 141.60(3)ꢁ in (6) to 149.78(3)ꢁ in (1),
Table 4.
CS2 groups. All four S atoms, in (1)e(6) situate at the same plane.
The short SeSneS angle situates between 82.00(3)ꢁ in (1), and
86.12(3)ꢁ in (6), agreeing with literature data [22,23]. Complex
(1), displayed the smaller CeSneC angle, 136.89(17)ꢁ in contrast to
(6),144.92(13)ꢁ, however it is in the range observed in the literature
ðSnꢀ13CÞ
Fig. 2. Structure of the complexes [SnMe2{S2CNR(R2)2}2] (4), [Sn(n-Bu)2{S2CNR(R2)2}2] (5), [SnPh2{S2CNR(R2)2}2] (6), where R ¼ methyl and R2 ¼ 2-methyl-1,3-dioxolane.

498
I.P. Ferreira et al. / European Journal of Medicinal Chemistry 58 (2012) 493e503
2.6. Biocide assay results
with miconazole, which was effective against all microorganisms.
On the other hand the sodium salts were inactive towards the
studied fungi. The toxicity of the organotin dithiocarbamates
depends on the nature of the organic group attached to Sn(II)
Most of the results concerning the organotins interaction with
living cells are obtained using in agar or other diffusion media
[18,21,23,44]. Interactions of the complexes with the media in
diffusion tests might influence the results, frustrating reliable
outcomes. In this work the biocide assays were performed in terms
of inhibitory concentrations, which are more consistent. The
organotin dithiocarbamates have been used in a concentration of
centre. Those complexes with
R
¼
Ph, [SnPh2{S2CNR(R1)}2]
{R1 ¼ CH2CH(OMe)2} (3), [SnPh2{S2CNR(R2)}2] {R2 ¼ 2-methyl-1,3-
dioxolane} (6) displayed the best activities in terms of IC90 and IC50
comparing to the other organic groups, followed by [Sn(n-
Bu)2{S2CNR(R2)}2] {R2 ¼ 2-methyl-1,3-dioxolane} (5).
250
m
g mLꢀ1, in an antimicrobial pre-screening against A. flavus, A.
The best results towards S. aureus and E. Coli were observed for
SnMe2{S2CNR(R2)2}2] (4), [Sn(n-Bu)2{S2CNR(R2)2}2] (5), [SnPh2{S2
CNR(R2)2}2] (6). The dithiocarbamates displaying R1 ¼ CH2CH(OMe)2
were less active than R2 ¼ 2-methyl-1,3-dioxolane towards the tested
bacteria. Those complexes containing the Bu2Sn- and Ph2Sn-frag-
ments displayed better activity towards E. coli, and Me2Sn-containing
moiety was effective against S. aureus, Table 5.
niger, A. parasiticus, P. citrinum, C. senegalensis, S. aureus, L. mono-
cytogenes, B. cereus, S. sanguinis, E. coli, C. freundii, S. typhimurium, P.
aeruginosa, according to a pre-established protocol [45]. Experi-
ments of IC90 and IC50 were only performed for those complexes
that displayed 100% inhibition growth of the studied microor-
ganism in a concentration of 250
m
g mLꢀ1. In spite of the poor
activity against C. senegalensis intense antifungal activity was found
in the presence of filamentous fungus such as A. flavus, A. niger,
A. parasiticus and P. citrinum, therefore we conclude that the
complexes are inactive against the other microorganisms. Only the
bacteria, S. aureus and E. coli, had the growth affected by the
presence of complexes (1)e(6).
2.7. Relation between the structure of the complexes and their
biologic activity
In fungi, ergosterol is a key molecule for cell integrity, regulating
fluidity, permeability and indirectly modulating the activity and
distribution of membrane-associated proteins, including enzymes
and ion channels, hence controlling physiological events which are
responsible for maintaining the life cycle. Therefore, the enzymes
participating of ergosterol biosynthesis are potential targets for
development of fungicide drugs. Among the enzymes, stands out
We have observed the following tendency of the complexes con-
cerning the inhibition of A. flavus, (i) IC90
:
(6)
<
(3)
< miconazole < (5) < (1) < (2) < (4) < nystatin << sodium salts; (ii)
IC50: (6), (3) < (1), (4), < miconazole < (5) < nystatin < (2) << sodium
salts. Complexes (6), (3) and (1) were more active than miconazole,
Table 5.
the sterol 14a-demethylase, the target of azoles derivatives, such as
The complexes had the following behaviour in the presence of
A. niger, IC90: miconazole < (3) < (5) < (6) < nystatin < the others
complexes << sodium salts; (ii) IC50: miconazole < (3) < (5)
< (6) < nystatin < the other complexes << sodium salts. We observe
similar activity of (3) and (5) and lesser of (6) comparing to
miconazole.
The organotin derivatives influenced the growth of A. parasiticus
as follows, IC90: miconazole < (3) < (6) < (5) < nystatin < the other
complexes << sodium salts; (ii) IC50: miconazole < (3), (6) < (5) <
nystatin < the other complexes << sodium salts. In this case
miconazole is much more active than (3), (5) and (6).
Finally, compounds (1)e(6) exhibited the following behaviour
against the colony of P. citrinum displaying IC90: (3) < (5) < mico-
itraconazole, fluconazole and voriconazole, etc [46e48]. In
previous work we have observed organotin dithiocarbonates and
carboxilates decrease the biosynthesis of ergosterol [30,49].
To study the structureeactivity relationship (SAR), we have used
theoretical calculations to obtain structural and stereo-electronic
parameters that support promising mechanisms related to the
transport of each compound across the cell membranes, revealing
possible interactions with biological macromolecules, for instance
enzymes. Therefore, we have calculated the energies of the HOMO
and LUMO orbitals, the lipophilicity (LogP), dipole moment, surface
area and volume of complexes (1)e(6), Table 6.
The difference between the energies of HOMO and LUMO
(HOMOeLUMO gap) shows the stability and reactivity of the
molecules, pointing out in the complexes possible biological
receptors such as electron rich or electron deficient regions [50e
52]. The lipophilic nature of the complexes can be evaluated by
the logarithm of the partition coefficient (LogP), that indicates the
ability of the molecule to overcome biological barriers and move
into different biophases [53].
nazole < (6) < (1), (4) < nystatin < (2) << sodium salts; (ii) IC50
:
(3) < (6) < (5) < (2) < miconazole < (4), (1) < nystatin << sodium
salts. In here it was observed that complex (3) is far more active if
compared to the other complexes and miconazole, Table 5.
In general complexes (1)e(6) interact better with filamentous
fungus rather than yeasts, revealing higher selectivity if compared
Table 5
Inhibition concentration of 90% (IC90) and 50% (IC50) (m
mol Lꢀ1) for the organotin complexes.
Complexes
A. flavus
A. niger
A. parasiticus
P. citrinum
S. aureus
E. coli
IC90
IC50
IC90
IC50
58.2
25.14
0.369
29.3
1.58
1.48
143.8
2905.0
16.87
<0.25
e
IC90
IC50
232.6
100.6
2.95
117.2
25.3
IC90
IC50
58.2
25.1
0.369
58.6
12.6
11.9
287.7
2905.0
269.9
32.61
e
IC50
IC50
[SnMe2{S2CNR(R1)}2] (1)
[Sn(n-Bu2{S2CNR(R1)}2] (2)
[SnPh2{S2CNR(R1)}2] (3)
[SnMe2{S2CNR(R2)}2] (4)
[Sn(n-Bu)2{S2CNR(R2)}2] (5)
[SnPh2{S2CNR(R2)}2] (6)
[Na{S2CN(Me)R1}]
58.2
201.2
<0.22
6.29
232.6
201.2
2.95
234.4
3.16
23.8
575.4
5811.7
67.49
2.04
e
465.2
402.3
11.8
468.8
50.6
232.6
402.3
1.48
234.4
50.6
232.6
201.2
94.5
14.7
50.6
190.2
e
47.3
201.2
116.3
47.5
12.7
14.7
e
0.369
<0.18
<0.22
0.791
<0.18
2.25
1452.0
4.22
<0.25
234.4
25.3
0.186
23.8
2.97
95.1
1150.9
11623.4
269.9
1150.9
11623.0
269.9
1.02
575.4
5811.7
67.49
<0.255
e
575.4
11623.0
>269.9
65.23
e
[Na{S2CN(Me)R2}]
Nystatin
Miconazole nitrate
Chloramphenicol
Ampicillin
e
e
e
e
4.08
e
e
e
e
e
e
e
<0.997
e
e
e
e
e
e
e
e
1.18
R ¼ Me; R1 ¼ CH2CH(OMe)2 and R2 ¼ 2-methyl-1,3-dioxolane.

I.P. Ferreira et al. / European Journal of Medicinal Chemistry 58 (2012) 493e503
499
Table 6
- IC50 values, stereo-electronic properties calculated for complexes (1)e(6).
2
a
3
ꢀ
Charge (e.u.)b
ꢀ
Complex
EHOMO (eV)
ELUMO (eV)
DE (eV)
m
(D)
S. A. (A )
V (A )
Log P
Sn
S
S
[SnMe2{S2CNR(R1)}2] (1)
[Sn(n-Bu2{S2CNR(R1)}2] (2)
[SnPh2{S2CNR(R1)}2] (3)
ꢀ5.815
ꢀ5.826
ꢀ5.701
ꢀ0.827
ꢀ0.811
ꢀ0.781
4.988
5.015
4.920
2.347
0.163
0.390
664.15
848.76
816.02
413.08
514.92
522.8
5.65
8.20
8.01
0.7516
0.7090
0.6932
ꢀ0.1168
ꢀ0.2531
ꢀ0.2258
ꢀ0.1114
ꢀ0.1195
ꢀ0.1380
ꢀ0.1966
ꢀ0.2528
ꢀ0.1293
ꢀ0.1212
ꢀ0.2502
ꢀ0.2448
ꢀ0.2349
ꢀ0.1546
[SnMe2{S2CNR(R2)}2] (4)
[Sn(n-Bu)2{S2CNR(R2)}2] (5)
[SnPh2{S2CNR(R2)}2] (6)
ꢀ5.791
ꢀ5.733
ꢀ5.644
ꢀ0.756
ꢀ0.746
ꢀ0.748
5.034
4.988
4.895
5.037
4.250
4.762
610.78
794.7
762.99
390.37
492.28
500.28
5.3
7.84
7.65
0.7073
0.6898
0.6339
R ¼ Me; R1 ¼ CH2CH(OMe)2 and R2 ¼ 2-methyl-1,3-dioxolane.
a
S.A. ¼ surface area.
b
e.u. ¼ electrostatic unit.
Similar values of surface area, molecular volume and LogP are
observed in each pair of derivatives: [Sn(n-Bu)2{S2CNMe(R1)2}2] (2)
and [SnPh2{S2CNMe(R1)2}2] (3); [Sn(n-Bu)2{S2CNMe(R2)2}2] (5) and
[SnPh2{S2CNMe(R2)2}2] (6); [SnMe2{S2CNMe(R1)2}2] (1) and
[SnMe2{S2CNMe(R2)2}2] (4), {R1 ¼ CH2CH(OMe)2, R2 ¼ 2-methyl-
1,3-dioxolane}. The higher values of the steric properties and LogP
are found for (2)/(3), and then for (5)/(6). These theoretical
parameters correlate well with the experimental results since
complex (3) is the most active against all fungi, studied in this work,
followed by (5) and (6). Unfortunately complex (2) was inactive.
Some connection have also been observed between experiments
and HOMO and LUMO calculation. Although little differences are
detected in the atomic participation in the formation of frontier
orbitals in the complexes, the main contribution to HOMO arises
from sulphur orbitals, while the LUMO involves sulphur, carbon
and nitrogen orbitals, of the dithiocarbamates, Fig. 3.
3. Experimental
3.1. Chemistry
3.1.1. Materials and instruments
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. 1H and 13C shifts are reported relative to SiMe4
and 119Sn shifts relative to SnMe4. The infrared spectra were recor-
ded with samples pressed as KBr pellets on a PerkineElmer GX FT-IR
spectrometer in the range of 4000e200 cmꢀ1. Carbon, hydrogen and
nitrogen analysis were performed on a PerkineElmer PE-2400 CHN-
analysis using tin sample-tubes. 119Sn Mössbauer spectra were run
in standard equipment at liquid nitrogen temperature using
a BaSnO3 source kept at room temperature. Intensity data for the X-
In spite of the energies of the frontier orbitals in (1)e(6) are quite
close, Table 6, compounds (3) and (6) showed less negativevalues for
ray study were collected at 293(2) K on a Xcalibur, Atlas, Gemini, Ka/
ꢀ
Mo (
l
¼ 0.7107 A). Data collection, reduction and cell refinement
the energy of the HOMO and smaller HOMO/LUMO gap (
DE), sug-
wereperformed using the CrysAlisRED program [54]. The structures
were solved employing the SHELXS-97 [55] and refined with
SHELXL-97 [56]. Further details are given in Table 1. All non-H atoms
were refined anisotropic. The H atoms were refined with fixed
individual displacement parameters [Uiso (H)Z1.2 Ueq (C)] using the
SHELXL riding model. The program ORTEP-3 for Windows [57] was
used in the preparation of Figs. 1 and 2.
gesting higher reactivityin the biologic media compared tothe other
complexes. Furthermore, complexes (3), (5) and (6) display the
smallest differences between the sulphur charges and smaller
asymmetry in the CeS bonds, Table 6, implying in greater
lipophilicity.
The reasonable agreement of theoretical calculations and
experiments leads us to suppose that biocide activity of (1)e(6)
strongly depends upon their lipophilicity and steric effects. The
lipid-solubility of organotin complexes might results from weak
interactions with amino-acids, proteins, nucleosides, enzymes,
carbohydrates, etc, present in the cell membrane. The influence of
steric parameters may suggest an enzymeeorganotin complex
interaction (e.g. in a lockekey fashion), validating our previous
results pointing out the ergosterol biosynthesis inhibition as mode
of action of organotin dithiocarbamates [30,49]. However, in sight
of the subtle structural features revealed by the structureeactivity
relationship (SAR) study, more findings are necessary to disregard
other possible mechanisms.
3.2. The structureeactivity relationship (SAR)
Geometry optimization and frequency calculations of all
compounds studied in this work were performed at the Density
Functional Theory level [58], employing the hybrid B3LYP [59,60]
exchange-correlation functional and using the 6-31G(d) all elec-
tron basis set [61,62] for all atoms. The tin atom was treated using
the LANL2DZ pseudopotential for the core electrons and its asso-
ciated double-zeta basis set for the valence electrons [63]. All
properties involved in the SAR studies were obtained for the
optimized structures. The quantum mechanical calculations were
performed using the Gaussian 03 program [64]. The molecular
surface area, molecular volume and octanolewater partition
coefficients (logP) of all species were computed using the Mar-
vinView program [65].
Finally, we found no correlation of the biocide activity of the
organotin dithiocarbamate complexes with their magnetic
moment, Table 6.
Complexes (3), (5) and (6) might represent a new class of drug to
be employed alone or in combination with others in current use as
new formulations for fungi diseases, especially to overcome drug
resistance, the challenge of next decades. In spite of all controversy
around the toxicity of organotin towards mammals and other
superior species it is possible that some of their complexes are not
as hazardous as organotin halides. However, the mechanism
related to the interactions of organotin with mammals requires
a better understanding.
3.3. Syntheses
3.3.1. [Na{S2CN(Me)R}] {R ¼ CH2CH(OMe)2} (i)
A
round-bottom flask (250 mL) was charged with 2,2-
dimethoxy-N-methylethyllamine (20.0 g e 167.8 mmol), meth-
anol (100 mL), and cooled in an ice/NaCl bath. After 10 min stirring,
carbon disulfide (10.1 mL e 167.8 mmol) was slowly added to the

500
I.P. Ferreira et al. / European Journal of Medicinal Chemistry 58 (2012) 493e503
Fig. 3. The HOMO (i) and LUMO (ii) plots for complexes (1)e(6).
round-bottom flask, and a colour change from colourless to pale-
yellow was observed. NaOH (6.71 g e 167.8 mmol), dissolved in
a minimal amount of water was added, forming, almost immedi-
ately, a white solid. The reaction mixture was stirred for further 1 h
at ambient temperature and then the solid was isolated by filtra-
tion, washed with toluene and re-crystallized in a mixture of
CH2Cl2/toluene (4:1). Yield 97%. Mp 83.9e85.2 ꢁC. IR (cmꢀ1, KBr):
1474 (nNeCS); 966 {nasym(CeS)}; 613 {nsym(CeS)}. 1H NMR (1H NMR, d4-
methanol): 5.08e5.13 (CH); 4.39e4.42 (NCH2); 3.74 (NCH3); 3.64
(OCH3). 13C NMR (13C NMR, d4-methanol): 214.2 (CS2); 104.5 (CH);
57.8 (NCH2); 54.2 (OCH3); 44.1 (NCH3). Analysis for C6H12NO2S2Na:
found (calc.) 33.15 (33.18); 5.51 (5.57); 6.41 (6.45).
3.3.3. Synthesis of [SnMe2{S2CN(Me)R}2] {R ¼ CH2CH(OMe)2} (1)
To a round-bottom flask (125 mL) containing [SnMe2Cl2] (1 g e
4.6 mmol) in ethanol (20 mL) was added [Na{S2CN(Me)R}],
R ¼ CH2CH(OMe)2 (2.00 g e 9.2 mmol), previously dissolved in the
same solvent. After stirring for 24 h, the white precipitate was
filtered and washed with hot water and ethanol. The solid obtained
was re-crystallized in a 4:1 mixture of CH2Cl2/methanol. Colourless
X-ray quality crystals were obtained by evaporation of the solvent
at room temperature. Yield 85%. Mp 116.9e118.1 ꢁC. IR (cmꢀ1, KBr):
1485 (nNeCS); 991 {nasym(CeS)}; 644 {nsym(CeS)}; 372 {nasym(SeSn)}; 335
{
nsym(SeSn)}. 1H NMR (
3.41 (OCH3) and (NCH3); 1.46 (SneCH3). 13C NMR (
d, CDCl3): 4.73 (CH); 3.92e3.90 (NCH2); 3.44e
d
, CDCl3): 200.8
(CS2); 102.3 (CH); 58.7 (NCH2); 55.3 (OCH3); 44.8 (SneCH3). 119Sn
3.3.2. Synthesis of [Na{S2CN(Me)R}] (R ¼ 2-methyl-1,3-dioxolane)
(ii)
NMR
(
d,
CDCl3): ꢀ334.5 {1J(119Sne13C)
¼
757 Hz, 2J(119Sne
1H) ¼ 81.1 Hz}.
d D
(mm sꢀ1): 1.43; (mm sꢀ1): 3.01. Analysis for
Similarly prepared in methanol (100 mL) using (1,3-dioxolane-2-
methyl)-N-methylamine (5.0 g e 42.7 mmol); CS2 (2.58 mL e
42.7 mmol), NaOH (10.0 g e 42.7 mmol). Yield 93%. Mp 46.7e
49.1 ꢁC. IR (cmꢀ1, KBr): 1473 (nNeCS); 982 {nasym(CeS)}; 606 {nsym(Ce
C14H30N2O4S4Sn: found (calc.) 31.24 (31.29); 5.61 (5.63); 5.17 (5.21).
3.3.4. Synthesis of [Sn(n-Bu)2{S2CN(Me)R}2] {R ¼ CH2CH(OMe)2}
(2)
S)}.1H NMR (
4.23e4.09 (OCH2); 3.19 (NCH3). 13C NMR (
d
, d4-methanol): 5.54 e 5.49 (OCHO). 4.51e4.49 (NCH2);
Prepared in a similar manner using [Sn(n-Bu)2Cl2] (1.39 g e
4.6 mmol) and [Na{S2CN(Me)R}], R ¼ CH2CH(OMe)2 (2.00 g e
9.2 mmol). Re-crystallization in a mixture of CH2Cl2/toluene (5:1)
afforded X-ray quality crystals of complex (2). Yield 37%. Mp 118.2e
119.2 ꢁC. IR (cmꢀ1, KBr): 1491 (nNeCS); 979 {nasym(CeS)}; 613 {nsym(Ce
d, d4-methanol): 214.4
(CS2); 103.1 (OCHO); 65.8 (OCH2); 59.3 (NCH2); 45.0 (NCH3). Analysis
for C6H10NO2S2Na: found (calc.) 32.97 (33.49); 4.62 (4.68); 6.26
(6.51).

I.P. Ferreira et al. / European Journal of Medicinal Chemistry 58 (2012) 493e503
501
S)}; 370 {n asym(SeSn)}; 324 {nsym(SeSn)}. 1H NMR (
(CH); 3.96e3.93 (NCH2); 3.47e3.43 (OCH3) and (NCH3); 2.1e0.9
SneC4H9. 13C NMR (
, CDCl3): 202.2 (CS2); 102.5 (CH); 58.7
d
, CDCl3): 4.78e4.73
D
(mm sꢀ1): 2.78. Analysis for C24H40N2O4S4Sn: found (calc.) 43.88
(43.85); 4.61 (4.60); 4.27 (4.26).
d
(NCH2); 55.4 (OCH3); 44.6 (NCH3); 34.3e13.8 (SneC4H9). 119Sn NMR
3.4. Biological tests
(d
, CDCl3): ꢀ339 {1J(119Sne13C) ¼ 605 Hz}.
d D
(mm sꢀ1): 1.58;
(mm sꢀ1): 2.98. Analysis for C20H42N2O4S4Sn: found (calc.) 38.25
(38.66); 6.76 (6.81); 4.46 (4.51).
3.4.1. Filamentous fungi
A. flavus (CCT 4952) was obtained from Tropical Collection
Culture, S.P. (Brazil). A. niger (NRRL 3), A. parasiticus (ATCC 15517), P.
citrinum (ATCC 756) and C. senegalensis (LABB 31) were obtained
from ARS Culture Collection (NRRL, USA), American Type Culture
Collection (ATCC, USA) and Biotechnology and Bioassays Laboratory
(LABB, MG, Brazil). They were kept in potato dextrose agar (PDA)
under refrigeration at 7 ꢁC. The tests were performed in Broth Heart
Infusion (BHI) medium. The fungal spores were counted in a Neu-
bauer chamber. Dilutions were carried to achieve the required final
3.3.5. Synthesis of [SnPh2{S2CN(Me)R}2] {R ¼ CH2CH(OMe)2} (3)
It was prepared similarly employing: ethanol (20 mL);
[SnPh2Cl2] (1 g e 4.6 mmol), [Na{S2CN(Me)R}], R ¼ CH2CH(OMe)2
(2.00 g e 9.2 mmol). X-ray quality crystals were grown in CH2Cl2/
ethanol solution of complex (3). Yield 56%. Mp 176.9e178.4 ꢁC. IR
(cmꢀ1, KBr): 1486 (nNeCS); 982 {nasym(CeS)}; 608 {nsym(CeS)}; 456
{
nasym(SeSn)}; 418 {nsym(SeSn)}. 1H NMR (
C6H5); 4.73e4.70 (CH); 3.83e3.80 (NCH2); 3.38 (OCH3) and
(NCH3). 13C NMR (
, CDCl3): 203.8 (CS2); 151e127.5 (SneC6H5);
d, CDCl3): 7.90e7.33 (Sne
concentration of spores of 5.0 ꢂ 103 spores mLꢀ1
.
d
102.1 (CH); 59.7 (NCH2); 55.9 (OCH3); 45.7 (NCH3). 119Sn NMR (
d
,
3.4.2. Bacteria
CDCl3): ꢀ498.7 {1J(119Sne13C)
¼
777 Hz and 2J(119Sne
Gram-positive bacterium S. aureus (ATCC 25923), L. mono-
cytogenes (ATCC 15313), B. cereus (ATCC 11778), S. sanguinis (ATCC
49456), and Gram-negative bacterium E. coli (ATCC 25723), C.
freundii (ATCC 8090), S. typhimurium (ATCC 13311), P. aeruginosa
(ATCC 27853) were obtained from AmericanType Culture Collection
(ATCC, USA). The bacterial strains, stored in broth heart infusion
(BHI) medium, were sub-cultured for testing in the same medium
and incubated at 37 ꢁC for 24 h. The concentration of cells in the final
bacterial inoculum was of 4.16 x103 cells mLꢀ1, determined by
spectrophotometric method. The activity of the complexes was
evaluated in final concentrations ranging from 250 to 0.12 mg mLꢀ1
in microdilution plates with 96-wells according to Gupta and Zac-
chino [45]. The dithiocarbamate organotin(IV) complexes, nystatin
and miconazole nitrate were prepared as 12.5 mg mLꢀ1 stock solu-
tions in DMSO. Subsequently, the stock solutions were diluted in BHI
1H) ¼ 82.6 Hz}.
d
(mm sꢀ1): 1.41;
D
(mm sꢀ1): 2.78. Analysis for
C
24H34N2O4S4Sn: found (calc.) 43.49 (43.58); 5.11 (5.18); 4.15 (4.24).
3.3.6. Synthesis of [SnMe2{S2CN(Me)R}2] (R ¼ 2-methyl-1,3-
dioxolane) (4)
It was similarly prepared using [SnMe2Cl2] (1.02 g, 4.6 mmol)
and [Na{S2CN(Me)R}] (R
¼
2-methyl-1,3-dioxolane) (2.0 g,
9.2 mmol). The white solid isolated by filtration was re-crystallized
in a mixture of CHCl3/toluene (5:1) affording X-ray quality crystals.
Yield 78%. Mp 134.5e136.3 ꢁC. IR (cmꢀ1, KBr): 1488 (nNeCS); 991
{
nasym(CeS)}; 609 {nsym(CeS)}. 1H NMR (
d, CDCl3): 4.00e3.93 (OCH2);
3.90e3.85 (NCH2 and OCHO); 3.44 (NCH3); 1.46 (SneCH3); 13C
NMR (d, CDCl3): 201.9 (CS2); 100.9 (OCHO); 64.9 (OCH2); 58.7
(NCH2); 14 (SneCH3). 119Sn NMR (
d
, CDCl3): ꢀ335.1 {1J(119Sne
13C) ¼ 749 Hz, 2J(119Sne1H) ¼ 83.2 Hz}.
d
(mm sꢀ1): 1.41;
D
obtaining 500
fungal agent were performed in BHI medium. The wells of micro-
dilution plates were filled with 100 L of solutions with decreasing
concentrations of the antimicrobial agent in culture medium. Then
100 L of the solution containing the standardized inocula were
m
g mLꢀ1 solutions. Further dilutions of each anti-
(mm sꢀ1): 2.78. Analysis for C14H26N2O4S4Sn: found (calc.) 31.44
(31.54); 5.03 (4.92); 5.17 (5.25).
m
3.3.7. Synthesis of [Sn(n-Bu)2{S2CN(Me)R2}2] (R ¼ 2-methyl-1,3-
dioxolane) (5)
m
added and the microplates were incubated at 37 ꢁC for 24 and 48 h
for anti-bacterial and 48 h for anti-fungal tests. Controls were per-
formed for evaluating the growth of microorganisms in culture
medium without any compound (positive control) and with the
compounds to assure the sterility of the culture medium. Tests with
the reference compounds, nystatin, miconazole nitrate, chlor-
amfenicol and ampicillin, were also carried out (negative controls).
The experiments were carried out in triplicate and the absorbances
were determined on an ELISA tray reader (Thermoplate, Brazil) at
fixed wavelength of 492 nm. MICs were calculated based on the
quantity of the microorganism present after the experiments, i.e.,
the lowest concentration of compounds that resulted in a 50%
(MIC50) or 90% (MIC90) reduction of growth compared with the
control growth in the culture medium free of the test compound.
It was similarly prepared using [Sn(n-Bu)2Cl2] (1.41 g, 4.6 mmol)
and [Na{S2CN(Me)R}] (R
¼
2-methyl-1,3-dioxolane) (2.0 g,
9.2 mmol). The white solid isolated by filtration was re-crystallized
in a mixture of CHCl3/toluene (4:1) affording X-ray quality crystals.
Yield 95%. Mp 69.1e71.1 ꢁC. IR (cmꢀ1, KBr): 1486 (nNeCS); 982
{
nasym(CeS)}; 608 {nsym(CeS)}; 456 {nasym(SeSn)}; 418 {nsym(SeSn)}. 1H
NMR (
d
, CDCl3): 5.25e5.20 (OCHO); 4.10 (NCH2); 4.00e3.50(OCH2);
, CDCl3): 202.9 (CS2);
3.49 (NCH3); 2.17e0.89 (SneC4H7). 13C NMR (
d
101.3 (OCHO); 64.9 (OCH2); 58.8 (NCH2); 44.2 (NCH3); 34.2e13.8
(SneC4H7). 119Sn NMR (
d
, CDCl3): ꢀ339.6 {1J(119Sne13C) ¼ 814 Hz}.
d
(mm sꢀ1): 1.41; (mm sꢀ1): 2.78. Analysis for C20H38N2O4S4Sn:
D
found (calc.) 38.78 (38.91); 6.43 (6.20); 4.49 (4.54).
3.3.8. Synthesis of [SnPh2{S2CN(Me)R2}2] (R ¼ 2-methyl-1,3-
dioxolane) (6)
4. Conclusions
Synthesized accordingly using [SnPh2Cl2] (1.59 g, 4.6 mmol) and
[Na{S2CN(Me)R}] (R ¼ 2-methyl-1,3-dioxolane) (2.0 g, 9.2 mmol).
The white solid isolated by filtration was re-crystallized in
a mixture of CH2Cl2/ethanol (4:1) rendering crystals for X-ray
quality experiments. Yield 46%. Mp 132.9e134.1 ꢁC. IR (cmꢀ1, KBr):
1486 (nNeCS); 982 {nasym(CeS)}; 608 {nsym(CeS)}; 456 {nasym(SeSn)}; 418
Complexes (1)e(6) were prepared and fully characterized by
a series of spectroscopic methods. The best fungicide activity, in terms
of IC90 and IC50, were displayed by those complexes with R ¼ Ph or Bu,
[SnPh2{S2CNMe(R1)2}2] (3); [Sn(n-Bu)2{S2CNMe(R2)2}2] (5) and
[SnPh2{S2CNMe(R2)2}2] (6), {R1 ¼ CH2CH(OMe)2, and R2 ¼ 2-methyl-
1,3-dioxolane}. It was observed a higher activity compared to mico-
nazole in the presence of filamentous fungus such as A. flavus, A. niger,
A. parasiticus and P. citrinum. Complexes (1)e(6) were less active
towards S. aureus and E. Coli than the control drug. Theoretical calcu-
lations (SAR) served as support to the biocide assays, but revealed that
{
nsym(SeSn)}. 1H NMR (
(OCHO); 3.96e3.82 (OCH2 and NCH2); 3.40 (NCH3). 13C NMR (
CDCl3): 201.5 (CS2); 150.8e1278.2 (SneC6H5); 101.0 (OCHO); 64.9
d, CDCl3): 7.89e7.30 (SneC6H5); 5.19e5.15
d
,
(OCH2); 60.0 (NCH2); 45.2 (NCH3). 119Sn NMR (
d
, CDCl3): ꢀ498.5
{1J(119Sne13C) ¼ 791 Hz, 2J(119Sne1H) ¼ 82.3 Hz}.
d
(mm sꢀ1): 1.41;

502
I.P. Ferreira et al. / European Journal of Medicinal Chemistry 58 (2012) 493e503
disubstituted 1,3-and 1,4-bis(aminomethyl)benzene and 1,10-bis(amino-
methyl)ferrocene as spacer groups, Inorg. Chem. 47 (2008) 9804e9812.
[23] S. Shahzadi, S. Ali, M. Fettouhi, Synthesis, spectroscopy, in vitro biological
activity and X-ray structure of (4-methylpiperidine-dithiocarbamato-S, S0)
triphenyltin(IV), J. Chem. Crystallogr. 38 (2008) 273e278.
[24] D.C. Menezes, G.M. de Lima, F.A. Carvalho, M.G. Coelho, A.O. Porto,
R. Augusti, J.D. Ardisson, Synthesis of phase-pure SnS particles employing
dithiocarbamate organotin(IV) complexes as single source precursors in
thermal decomposition experiments, Appl. Organomet. Chem. 24 (2008)
650e655.
little differences in structure and properties might be responsible for
the diverse behaviour of complexes (1)e(6) in biological media.
5. Supplementary data
Crystallographic data are available on request at Cambridge
Crystallographic Data Centre on quoting the deposition numbers
CCDC 883617, 883618, 883619, 883620, 883621 and 883622.
[25] D.C. Menezes, G.M. de Lima, A.O. Porto, M.P. Ferreira, J.D. Ardisson, R.A. Silva,
An interesting temperature dependence of the thermal decomposition of
dithiocarbamate tin(IV) complexes molecular precursors for tin sulphides,
Main Group Met. Chem. 30 (2007) 49e61.
Acknowledgements
[26] D.C. Menezes, G.M. de Lima, G.S. de Oliveira, A.V. Boas, A.M.A. Nascimento,
F.T. Vieira, In vitro antibacterial activity of dithiocarbamate organotin(IV)
complexes towards Staphylococcus aureus, Main Group Met. Chem. 31 (2008)
21e27.
[27] D.C. Menezes, F.T. Vieira, G.M. de Lima, A.O. Porto, M.E. Cortes, J.D. Ardisson,
T.E. Albrecht-Schmitt, Tin(IV) complexes of pyrrolidinedithiocarbamate:
synthesis, characterisation and antifungal activity, Eur. J. Med. Chem. 40
(2005) 1277e1282.
[28] J.S. White, J.M. Tobin, J.J. Cooney, Organotin compounds and their interactions
with microorganisms, Can. J. Microbiol. 45 (1999) 541e554.
[29] J.J. Cooney, S. Wuertz, Toxic effects of tin-compounds on microorganisms,
J. Ind. Microbiol. 4 (1989) 375e402.
[30] D.C. Menezes, F.T. Vieira, G.M. de Lima, J.L. Wardell, M.E. Cortes, M.P. Ferreira,
M.A. Soares, A.V. Boas, The in vitro antifungal activity of some dithiocarbamate
organotin(IV) compounds on Candida albicans e a model for biological inter-
action of organotin complexes, Appl. Organomet. Chem. 22 (2008) 221e226.
[31] R.C. Poller, The Chemistry of Organotin Compounds, Logos Press Limited,
London, 1970.
This work was supported by CNPq and FAPEMIG e Brazil.
References
[1] E.R.T. Tiekink, Tin dithiocarbamates: applications and structures, Appl. Orga-
nomet. Chem. 22 (2008) 533e550.
[2] I. Haiduc, in: T.J.M.J.A. McCleverty (Ed.), Comprehensive Coordination Chem-
istry II, Elsevier, Oxford, 2004, pp. 349e376.
[3] P.J. Heard, Main group dithiocarbamate complexes, in: Progress in Inorganic
Chemistry, vol. 53, John Wiley & Sons Inc, New York, 2005, pp. 1e69.
[4] G. Hogarth, Transition metal dithiocarbamates: 1978e2003, in: Progress in
Inorganic Chemistry, vol. 53, John Wiley & Sons Inc, New York, 2005, pp.
71e561.
[5] F.W. Sunderman, Efficacy of sodium diethyldithiocarbamate (dithiocarb) in
acute nickel carbonyl poisoning, Ann. Clin. Lab. Sci. 9 (1979) 1e10.
[6] D.L. Bodenner, P.C. Dedon, P.C. Keng, R.F. Borch, Effect of dieth-
yldithiocarbamate on cis-diamminedichloroplatinum(II)-induced cytotoxicity,
DNA cross-linking, and gamma-glutamyl-transferase transpeptidase inhibi-
tion, Cancer Res. 46 (1986) 2745e2750.
[7] J.J. Suh, H.M. Pettinati, K.M. Kampman, C.P. O’Brien, The status of disulfiram e
a half of a century later, J. Clin. Psychopharmacol. 26 (2006) 290e302.
[8] B. Cvek, Z. Dvorak, Targeting of nuclear factor-kappa B and proteasome by
dithiocarbamate complexes with metals, Curr. Pharm. Des. 13 (2007) 3155e
3167.
[9] P.J. Nieuwenhuizen, J. Reedijk, M. Van Duin, W.J. McGill, Thiuram- and
dithiocarbamate-accelerated sulfur vulcanization from the chemist’s
perspective; methods, materials and mechanisms reviewed, Rubber Chem.
Technol. 70 (1997) 368e429.
[32] F. Bonati, R. Ugo, Organotin(4) N, N-disubstituted dithiocarbamates,
J. Organomet. Chem. 10 (1967) 257e268.
[33] L. Ronconi, L. Giovagnini, C. Marzano, F. Bettio, R. Graziani, G. Pilloni,
D. Fregona, Gold dithiocarbamate derivatives as potential antineoplastic
agents: design, spectroscopic properties, and in vitro antitumor activity, Inorg.
Chem. 44 (2005) 1867e1881.
[34] H.L.M. Vangaal, J.W. Diesveld, F.W. Pijpers, J.G.M. Vanderlinden, 13C NMR-
spectra of dithiocarbamates. Chemical-shifts, carbonenitrogen stretching
vibration frequencies, and
p-bonding in the NCS2 fragment, Inorg. Chem. 18
(1979) 3251e3260.
[35] J. Holecek, M. Nadvornik, K. Handlir, A. Lycka, 13C and 119Sn NMR-spectra of
di-normal-butyltin(IV) compounds, J. Organomet. Chem. 315 (1986) 299e308.
[36] T.P. Lockhart, W.F. Manders, J.J. Zuckerman, Structural investigations by solid-
state 13C NMR. Dependence of j1J(119Sn, 13C)j on the MeeSneMe angle in
methyltin(IV), J. Am. Chem. Soc. 107 (1985) 4546e4547.
[10] M. Cicotti, Compound class: alkylenebis(dithiocarbamates), in: Handbook of
Residue Analytical Methods for Agrochemical, vol. 2, Wiley, Chichester, 2003,
pp. 1089e1098.
[37] T.P. Lockhart, W.F. Manders, Structure determination by NMR spectroscopy.
Correlation of j2J(119Sn, 1H)j and the MeeSneMe angle in methyltin(IV)
compounds, Inorg. Chem. 25 (1986) 892e895.
[11] D. Fan, M. Afzaal, M.A. Mallik, C.Q. Nguyen, P. O’Brien, P.J. Thomas, Using
coordination chemistry to develop new routes to semiconductor and other
materials, Coord. Chem. Rev. 251 (2007) 1878e1888.
[12] M.S. Vickers, J. Cookson, P.D. Beer, P.T. Bishop, B. Thiebaut, Dithiocarbamate
ligand stabilised gold nanoparticles, J. Mater. Chem. 16 (2006) 209e215.
[13] Y.W. Koh, C.S. Lai, A.Y. Du, E.R.T. Tiekink, K.P. Loh, Growth of bismuth sulfide
nanowire using bismuth tris-xanthate single source precursors, Chem. Mater.
15 (2003) 4544e4554.
[14] G. Barone, T. Chaplin, T.G. Hibbert, A.T. Kana, M.F. Mahon, K.C. Molloy,
I.D. Worsley, I.P. Parkin, L.S. Price, Synthesis and thermal decomposition studies
of homo- and heteroleptic tin(IV) thiolates and dithiocarbamates: molecular
precursors for tin sulfides, J. Chem. Soc., Dalton Trans. (2002) 1085e1092.
[15] A.G. Davies, M. Gielen, K.H. Pannell, E.R.T. Tiekink, Tin Chemistry e Funda-
mentals, Frontiers and Applications, Wiley, Chichester, 2008.
[16] H. Tlahuext, R. Reyes-Martinez, G. Vargas-Pineda, M. Lopez-Cardoso, H. Hopfl,
Molecular structures and supramolecular association of chlorodiorganotin(IV)
complexes with bis- and tris-dithiocarbamate ligand, J. Organomet. Chem.
696 (2011) 693e701.
[38] T.P. Lockhart, W.F. Manders, Solid-state 13C NMR investigation of methyl-
tin(IV) compounds. Correlation of NMR parameters with molecular-structure,
J. Am. Chem. Soc. 109 (1987) 7015e7020.
[39] H.A. Bent, An appraisal of valence-bond structures and hybridization in
compounds of the 1st-row elements, Chem. Rev. 61 (1961) 275e311.
[40] S. Basu, A. Mizar, T. Baul, E. Rivarola, 119Sn Mössbauer characterization of self
assembled organotin(IV) complexes with Schiff bases containing amino
acetate skeletons, Hyperfine Interact. 185 (2008) 95e102.
[41] M. Gielen, H. Dalil, M. Biesemans, B. Mahieu, D. de Vos, R. Willem, Di- and tri-
organotin derivatives of 3S,4S-3-[(R)-1-(tert-butyl-dimethylsilyloxy)ethyl]-4-
[(R)-carboxyethyl]-2-azetidinone: synthesis, characterization and in vitro
antitumour activity, Appl. Organomet. Chem. 13 (1999) 515e520.
[42] A. Bondi, Van der Waals volumes and radii, J. Phys. Chem. 68 (1964) 441e451.
[43] N. Singh, S. Bhattacharya, Synthesis and characterization of some triorgano,
diorgano, monoorganotin and a triorgano lead heteroaromatic dithiocarba-
mate complexes, J. Organomet. Chem. 700 (2012) 69e77.
[44] (a) F. Shaheen, Zia-ur -Rehman, S. Ali, A. Meetsma, Structural properties and
antibacterial potency of new supramolecular organotin(IV) dithiocarbox-
ylates, Polyhedron 31 (2012) 697e703;
[17] N. Awang, I. Baba, B.M. Yamin, S.W. Ng, Di-n-butylbis(N-cyclohexyl-N-ethyl-
dithiocarbamato-kappa 2 S, S0)tin(IV), Acta Crystallogr. Sect. E. Struct Rep.
Online 66 (2010). M938eU753.
[18] A. Husain, S.A.A. Nami, K.S. Siddiqi, Synthesis, characterization and biocidal
activities of heterobimetallic complexes having tin(IV) as a padlock, J. Mol.
Struct. 970 (2010) 117e127.
(b) N.F. Kamaluduin, I. Baba, N. Awang, M.I.M Tahir, E.R.T.Tiekink, Acta Crys-
tallogr. Sect. E. Struct Rep. Online, 68 M79eM80.
[45] A.S. Zacchino, M.P. Gupta, Manual de técnicas in vitro para la detección de
compuestos antifúngicos, Corpus Editorial y Distribuidora, Rosario, 2007, 85e99.
[46] H.K. Munayyer, P.A. Mann, A.S. Chau, T. Yarosh-Tomaine, J.R. Greene, R.S. Hare,
L. Heimark, R.E. Palermo, D. Loebenberg, P.M. McNicholas, Posaconazole is
a potent inhibitor of sterol 14 alpha-demethylation in yeasts and molds,
Antimicrob. Agents Chemother. 48 (2004) 3690e3696.
[47] K.M. Brumfield, J.V. Moroney, T.S. Moore, T.A. Simms, D. Donze, Functional
characterization of the Chlamydomonas reinhardtii ERG3 ortholog, a gene
involved in the biosynthesis of ergosterol, PLoS One 5 (2010) e8659, 1e10.
[48] D.J. Sheehan, C.A. Hitchcock, C.M. Sibley, Current and emerging azole anti-
fungal agents, Clin. Microbiol. Rev. 12 (1999) 40e79.
[19] J.P. Fuentes-Martinez, I. Toledo-Martinez, P. Roman-Bravo, P.G.Y. Garcia,
C. Godoy-Alcantar, M. Lopez-Cardoso, H. Morales-Rojas, Diorganotin(IV)
dithiocarbamate complexes as chromogenic sensors of anion binding, Poly-
hedron 28 (2009) 3953e3966.
[20] A. Normah, K.N. Farahana, B. Ester, H. Asmah, N. Rajab, A.A. Halim, Cytotoxic and
genotoxic effect of triphenyltin(IV) benzylisopropyldithiocarbamate in thy-
moma murine cell line (WEHI 7.2), Res. J. Chem. Environ. 15 (2011) 544e549.
[21] R. Singh, N.K. Kaushik, Spectral and thermal studies with anti-fungal aspects
of some organotin(IV) complexes with nitrogen and sulphur donor ligands
derived from 2-phenylethylamine, Spectrochim. Acta A Mol. Biomol. Spec-
trosc. 71 (2008) 669e675.
[49] F.T. Vieira, D.C. Menezes, G.M. de Lima, J.L. Wardell, M.E. Cortes, G.A.B. Silva,
A. Vilas-Boas, J. Maia, Effect of diorganotin(IV) carboxylate complexes, [N-(2-
[22] E. Santacruz-Juarez, J. Cruz-Huerta, I.F. Hernandez-Ahuactzi, R. Reyes-Marti-
nez, H. Tlahuext, H. Morales-Rojas, H. Hopfl, 24-and 26-Membered macro-
cyclic diorganotin(IV) bis-dithiocarbamate complexes with N, N0-
carboxyphenyl) salicylideneiminato]dimethyltin(IV), bis(m3-oxo)bis(m-O-

I.P. Ferreira et al. / European Journal of Medicinal Chemistry 58 (2012) 493e503
503
aminobenzoato-O, O0)bis(O-aminobenzoato)tetrakis[dimethyltin(IV)] and
[59] A.D. Becke, Density-functional thermochemistry. III. The role of exact
exchange, J. Chem. Phys. 98 (1993) 5648e5652.
bis(O-aminobenzoato-O, O0)di-n-butyltin(IV), on the membrane of Candida
albicans cells
e
a
mechanistic investigation of the antifungal activity of
[60] C.T. Lee, W.T. Yang, R.G. Parr, Development of the Colle-Salvetti correlation-
energy formula into a functional of the electron density, Phys. Rev. B 37
(1988) 785e789.
[61] R. Ditchfie, W.J. Hehre, J.A. Pople, Self-consistent molecular-orbital methods.
IX. An extended Gaussian-type basis for molecular-orbital studies of organic
molecules, J. Chem. Phys. 54 (1971) 724e728.
[62] W.J. Hehre, R. Ditchfie, J.A. Pople, Self-consistent molecular-orbital methods.
XII. Further extensions of Gaussian-type basis sets for use in molecular-orbital
studies of organic-molecules, J. Chem. Phys. 56 (1972) 2257e2261.
[63] P.J. Hay, W.R. Wadt, Ab initio effective core potentials for molecular calcula-
tions. Potentials for K to Au including the outermost core orbitals, J. Chem.
Phys. 82 (1985) 299e310.
[64] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb,
J.R. Cheeseman, J.A.M Jr., T. Vreven, K.N. Kudin, J.C. Burant, J.M. Millam,
S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega,
G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene,
X. Li, J.E. Knox, H.P. Hratchian, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli,
J.W. Ochterski, P.Y. Ayala, K. Morokuma, G.A. Voth, P. Salvador,
J.J. Dannenberg, V.G. Zakrzewski, S. Dapprich, A.D. Daniels, M.C. Strain,
O. Farkas, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J.V. Ortiz,
Q. Cui, A.G. Baboul, S. Clifford, J. Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko,
P. Piskorz, I. Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng,
A. Nanayakkara, M. Challacombe, P.M.W. Gill, B. Johnson, W. Chen,
M.W. Wong, C. Gonzalez, J.A. Pople, Gaussian 03, Revision C.02, Gaussian, Inc,
Wallingford CT, 2004.
organotin complexes, Appl. Organomet. Chem. 22 (2008) 433e439.
[50] S.T.M. Orr, S.L. Ripp, T.E. Ballard, J.L. Henderson, D.O. Scott, R.S. Obach, H. Sun,
A.S. Kalgutkar, Mechanism-based inactivation (MBI) of cytochrome P450
enzymes: structureeactivity relationships and discovery strategies to mitigate
drugedrug interaction risks, J. Med. Chem. 55 (2012) 4896e4933.
[51] G.L. Parrilha, J.G. da Silva, L.F. Gouveia, A.K. Gasparoto, R.P. Dias, W.R. Rocha,
D.A. Santos, N.L. Speziali, H. Beraldo, Pyridine-derived thiosemicarbazones
and their tin(IV) complexes with antifungal activity against Candida spp, Eur.
J. Med. Chem. 46 (2011) 1473e1482.
[52] M.A. Soares, J.A. Lessa, I.C. Mendes, J.G. Da Silva, R.G. dos Santos, L.B. Salum,
H. Daghestani, A.D. Andricopulo, B.W. Day, A. Vogt, J.L. Pesquero, W.R. Rocha,
H. Beraldo, N-4-phenyl-substituted 2-acetylpyridine thiosemicarbazones:
cytotoxicity against human tumor cells, structureeactivity relationship studies
and investigation on the mechanism of action, Bioorg. Med. Chem. 20 (2012)
3396e3409.
[53] C. Hansch, B. Bonavida, A.R. Jazirehi, J.J. Cohen, C. Milliron, A. Kurup, Quanti-
tative structureeactivity relationships of phenolic compounds causing
apoptosis, Bioorg. Med. Chem. 11 (2003) 617e620.
[54] CrysAlis PRO, Oxford Diffraction Ltd., Version 1.171.34.34 (release 07-07-2010
CrysAlis171.NET) (compiled Jul 7 2010, 16:04:54).
[55] G.M. Sheldrick, SHELXS-97. Program for the Solution of Crystal Structures,
University of Göttingen, Germany, 1997.
[56] G.M. Sheldrick, SHELXL-97. Program for Crystal Structure Refinement,
University of Göttingen, Germany, 1997.
[57] L.J. Farrugia, ORTEP-3 for Windows e a version of ORTEP-III with a graphical
user interface (GUI), J. Appl. Cryst. 30 (1997) 565e566.
[58] R.G. Parr, W. Yang, Density-functional Theory of Atoms and Molecule, Oxford
University Press, Oxford, 1989.
[65] Calculator Plugins Were Used for Structure Property Prediction and Calcula-
tion, MarvinView 5.10.3, ChemAxon, 2012.http://www.chemaxon.com.