Organotin(IV) O-butyl carbonodithioates: Synthesis, characterization, in vitro bioactivities, and interaction with SS-DNA

Article abstract of DOI:10.1134/S1070363216120380

Organotin(IV) O-butyl carbonodithioates [Me₂SnL₂], [Bu₂SnL₂], [Ph₂SnL₂], [Bu₃SnL], and [Ph₃SnL], where L = C₄H₉OCS₂ ^–, have been successfully synthesized and characterized by FT-IR, ¹H and ¹³C NMR, and single crystal X-ray analysis. The ligand coordinates to the tin atom via the carbonodithioate group. According to the X-ray diffraction data, the tin atom in [Me₂SnL₂] has distorted tetrahedral geometry. The synthesized compounds were screened in vitro for antibacterial, antifungal, antileishmanial, cytotoxic, and protein kinase inhibitory activities. The complexes [Bu₃SnL] and [Ph₃SnL] exhibited the highest anti-leishmanial activity that exceeded the activity of the reference drug amphotericin B, probably by blocking the function of parasitic mitochondria due to which it restricts further growth of the organisms. The ligand and the complexes have been shown to bind to DNA via intercalative interactions resulting in hypochromic effect with a minor red shift as confirmed by UV-Vis spectroscopic studies.

Full text of DOI:10.1134/S1070363216120380

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 12, pp. 2768–2776. © Pleiades Publishing, Ltd., 2016.
Organotin(IV) O-Butyl Carbonodithioates:
Synthesis, Characterization, in vitro Bioactivities,
and Interaction with SS-DNA1
F. Javeda, S. Alia*, S. Shahzadia**, M. N. Tahirb, S. Tabassumc, and N. Khalidd
a Department of Chemistry, Quaid-i-Azam University, Islamabad, 45320 Pakistan
*e-mail: drsa54@hotmail.com; **sairashahzadi@hotmail.com
b Department of Physics, University of Sargodha, Sargodha, Pakistan
c Department of Biotechnology, Quaid-i-Azam University, Islamabad, 45320 Pakistan
d Chemistry Division, Pakistan Institute of Nuclear Science and Technology, Nilore, Islamabad, Pakistan
Received February 28, 2016
Abstract—Organotin(IV) O-butyl carbonodithioates [Me2SnL2], [Bu2SnL2], [Ph2SnL2], [Bu3SnL], and [Ph3SnL],
where L = C4H9OCS2–, have been successfully synthesized and characterized by FT-IR, 1H and 13C NMR, and
single crystal X-ray analysis. The ligand coordinates to the tin atom via the carbonodithioate group. According
to the X-ray diffraction data, the tin atom in [Me2SnL2] has distorted tetrahedral geometry. The synthesized
compounds were screened in vitro for antibacterial, antifungal, antileishmanial, cytotoxic, and protein kinase
inhibitory activities. The complexes [Bu3SnL] and [Ph3SnL] exhibited the highest anti-leishmanial activity that
exceeded the activity of the reference drug amphotericin B, probably by blocking the function of parasitic
mitochondria due to which it restricts further growth of the organisms. The ligand and the complexes have been
shown to bind to DNA via intercalative interactions resulting in hypochromic effect with a minor red shift as
confirmed by UV-Vis spectroscopic studies.
Keywords: organotin(IV) complexes, IR, NMR, single crystal X-ray analysis, DNA interaction, antibacterial,
antifungal, antileishmanial, cytotoxicity, protein kinase inhibition
DOI: 10.1134/S1070363216120380
INTRODUCTION
being involved in secondary intermolecular interac-
tions that can give rise to dimeric, trimeric, and supra-
molecular structures [10]. In continuation of our
studies related to organotin(IV) dithiocarboxylate com-
plexes [11], we have synthesized organotin(IV) O-butyl
carbonodithioate complexes which were characterized
Sulfur donor ligands such as dithiophosphates,
xanthates, and dithiocarboxylates have been reported
to be more potent than biological ligands (peptides or
amino acids) in the initiation of active sites of some
metalloenzymes [1–3]. Apart from biological activity
(fungicidal, bactericidal, insecticidal, and antitumor)
[4, 5], organotin(IV) dithiocarboxylates have been
widely studied for their structural diversity related to
Sn–S bonding [6–8]. Menezes et al. [9] recently
reported a series of organotin dithiocarboxylates whose
antifungal activity was shown to be determined by
inhibition of ergosterol biosynthesis. Furthermore, all
the organotin compounds studied were more active
than the uncoordinated dithiocarboxylate ligand. The
coordination mode depends on the structure of the
organic ligand which can exhibit mono- or bidentate
behavior. Dithiocarboxylate ligands are capable of
1
by elemental analyses, FT-IR, H and 13C NMR, and
single crystal X-ray analysis. The synthesized com-
pounds were tested for antibacterial, antifungal, anti-
leishmanial, cytotoxic, and protein kinase inhibitory
activities. DNA binding studies of the synthesized
compounds were also performed using UV-Vis spectro-
photometric technique.
EXPERIMENTAL
All organotin(IV) halides, butanol, potassium
hydroxide, carbon disulfide, and other reagents were
obtained from Aldrich (USA) and used without further
purification. Deoxyribonucleic acid sodium salt
(Acros) was used as received. All the solvents were
1 The text was submitted by the authors in English.
2768

ORGANOTIN(IV) O-BUTYL CARBONODITHIOATES
2769
Scheme 1.
MeOH,
room temperature, 4 h
S
m
R2SnCl2 + 2KL
R3SnCl + KL
R2SnL2 + 2KCl
1–3
3'
1'
4'
Me
p
o
O
S–
2'
i
L =
MeOH,
room temperature, 4 h
3
1
4
Sn
R3SnL + KCl
Me
Sn
2
4, 5
S
Me
O
S
Sn
Ph
Ph
Ph
1, R = Me; 2, 4, R = Bu; 3, 5, R = Ph.
purchased from Merck (Germany) and were dried
before use according to literature procedures [12]. The
melting points were measured with a Bio-Cote Model
SMP10 melting point apparatus and are uncorrected.
The FT-IR spectra were recorded in the range 4000–
250 cm–1 with a Thermo Scientific Nicolet 6700 FTIR
mp 210–212°C [11]. IR spectrum, ν, cm–1: 961 (C–O),
1
1459 (CSS, asym.), 1102 (CSS, sym.). H NMR
spectrum, δ, ppm: 0.97 t (3H, 4′-H, 3JHH = 7.4 Hz; 1.45
3
m (2H, 3′-H), 1.73 q (2H, 2′-H, JHH = 7.4 Hz), 4.40 t
3
(2H, 1′-H, JHH = 6.6 Hz). 13C NMR spectrum, δC,
ppm: 12.8 (C4′), 18.9 (C3′), 30.7 (C2′), 72.3 (C1'), 232.4
(C=S). Found, %: C 31.85; H 4.79; S 34.03.
C5H9KOS2. Calculated, %: C 31.88; H 4.82; S 34.09.
1
spectrometer. The H and 13C NMR spectra were
obtained with a Bruker Avance spectrometer at 300
and 75 MHz, respectively, using DMSO-d6 as solvent.
The electronic absorption spectra were measured at
25 ± 1°C on a Shimadzu 1601 double beam UV-visible
spectrometer. The elemental analyses (C, H, S) were
obtained using a LECO CHNS-932 analyzer.
General procedure for the synthesis of organotin
(IV) O-butyl carbonodithioates. Potassium O-butyl
carbonodithioate (2 mmol) was dissolved in 20 mL of
methanol in a 100-mL round bottom two-necked flask
with continuous stirring at room temperature. Organo-
tin(IV) chloride R2SnCl2 or R3SnCl (1 or 2 mmol,
respectively) was added in portions, and the mixture
was stirred for 4 h at room temperature. The solvent
was slowly evaporated at room temperature, and the
solid residue was dried in air and recrystallized from
acetone–diethyl ether (1 : 1). The general reactions are
shown in Scheme 1.
The X-ray diffraction data for a single crystal of 1
were collected on a Bruker SMART APEX CCD
diffractometer equipped with a 4 K CCD detector set
at a distance of 60.0 mm from the crystal. The crystal
was cooled to 100 ± 1 K using a Bruker KRYOFLEX
low temperature device, and reflection intensities were
measured with graphite-monochromatized MoKα
radiation from a Siemens sealed ceramic diffraction
tube (generator settings 50 kV/40 mA). The structure
was solved by the Patterson method, and extension of
the model was accomplished by the direct method
using DIRDIF or SIR2004. The final refinement on F2
was made by the full-matrix least-squares technique
using SHELXL-97, a modified PLUTO version of
(preparation of illustrations), and PLATON package.
Dimethylstannanediyl bis(O-butyl carbonodi-
thioate) (1). Yield: 85%, mp 107–108°C. IR spectrum,
ν, cm–1: 958 (C–O), 1254 (CSS, asym.), 1001 (CSS,
1
sym.), 383 (Sn–S), 548 (Sn–C). H NMR spectrum, δ,
ppm: 0.98 t (6H, 4′-H, 3JHH = 7.4 Hz), 1.45 m (4H, 3′-H),
1.80 q (4H, 2′-H, 3JHH = 7.4 Hz), 4.46 t (4H, 1′-H, 3JHH
=
2
6.6 Hz), 1.48 s (6H, SnCH3, JSnH = 79–76 Hz). 13C
NMR spectrum, δC, ppm: 10.4 (C4′), 19.1 (C3′), 30.2
(C2′), 76.2 (C1′), 222.0 (C=S), 10.4 (SnCH3, 1JSnC = 597–
569 Hz). Found, %: C 32.19; H 5.38; S 25.65.
C12H24O2S4Sn. Calculated, %: C 32.22; H 5.41; S 28.68.
Potassium O-butyl carbonodithioate was prepared
by continuous stirring of butanol (1 mmol) with a
mixture of potassium hydroxide (1 mmol) and carbon
disulfide (1 mmol) for 4 h at room temperature. The
precipitate was filtered off and dried in air. Yield 90%,
Dibutylstannanediyl bis(O-butyl carbonodi-
thioate) (2). Yield 82%, oily material. IR spectrum, ν,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 12 2016

2770
JAVED et al.
cm–1: 955 (C–O), 1239 (CSS, asym.), 1082 (CSS,
sym.), 345 (Sn–S), 551 (Sn–C). H NMR spectrum, δ,
Biological Screening. UV-Vis spectrophotometric
study of DNA binding and tests for antibacterial,
antifungal, and antileishmanial activities, cytotoxicity,
and protein kinase inhibition were performed ac-
cording to the procedures reported elsewhere [11, 13].
1
ppm: 0.95 m (6H, 4′-H), 1.43 m (4H, 3′-H), 1.74 m
3
(4H, 2′-H), 4.46 t (4H, 1′-H, JHH = 6.6 Hz), 1.88 m
(4H, 1-H), 1.49 m (4H, 2-H), 1.46 m (4H, 3-H), 0.92
13
m (6H, 4-H). C NMR spectrum, δC, ppm: 13.7 (C4′),
19.1 (C3′), 30.3 (C2′), 76.1 (C1′), 223.1 (C=S); 30.5 (C1,
RESULTS AND DISCUSSION
2
1JSnC = 540–516 Hz), 28.8 (C2, JSnC = 40 Hz), 26.4
3
(C3, JSnC = 119–115 Hz), 13.7 (C4). Found, %: C
FT-IR spectra. The binding mode of the
dithiocarbonate ligand to tin(IV) was determined by
comparing the IR spectrum of the ligand with the
spectra of organotin(IV) complexes 1–5. A new peak
in the region 345–383 cm–1 indicated formation of Sn–
S bond in 1–5. The spectra of 1, 2, and 4 displayed a
sharp Sn–C stretching band at 541–551 cm–1, while di-
and triphenyltin(IV) derivatives 3 and 5 showed a
weak band at 284 and 272 cm–1, respectively, due to
Sn–Carom stretchings. These data are in close agreement
with those reported previously for organotin(IV)
derivatives [14]. The C–S stretching frequencies give
valuable information regarding the mode of ligand
coordination to the Sn atom and structure of the
complexes. Complexes 1–5 gave strong peaks at
1204–1254 and 1000–1082 cm–1 due to asymmetric
and symmetric stretching vibrations of the CS2 group,
respectively. The difference Δν between the asym-
metric and symmetric stretching frequencies ranged
from 155 to 253 cm–1, indicating bidentate coordina-
tion of the ligand to the central tin atom in 2, 3, and 5
and monodentate coordination mode in 1 and 4 [14].
The FT-IR data for compound 1 were consistent with
the X-ray crystallographic data.
40.65; H 6.80; S 24.10. C18H36O2S4Sn. Calculated, %:
C 40.68; H 6.83; S 24.13.
Diphenylstannanediyl bis(O-butyl carbonodi-
thioate) (3). Yield: 79%, mp 82–83°C. IR spectrum, ν,
cm–1: 938 (C–O), 1254 (CSS, asym.), 1038 (CSS,
1
sym.), 372 (Sn–S), 284 (Sn–C). H NMR spectrum, δ,
3
ppm: 0.88 t 6H, (4′-H, JHH = 7.4 Hz), 1.30 m (4H,
3′-H, 3JHH = 7.4 Hz), 1.60 m (4H, 2′-H), 4.29 t (4H, 1′-
H, 3JHH = 6.6 Hz), 8.0 m (4H, o-H), 7.50 m (4H, m-H),
13
7.47 m (2H, p-H). C NMR spectrum, δC, ppm: 13.6
(C4′), 18.9 (C3′), 30.0 (C2′), 76.6 (C1′), 218.8 (C=S),
1
2
141.5 (Ci, JSnC = 830–796 Hz), 129.0 (Co, JSnC = 88–
84 Hz), 135.4 (Cm, 3JSnC = 64–57 Hz), 130.1 (Cp, 4JSnC
=
18 Hz). Found, %: C 46.20; H 4.91; S 22.42. C22H28O2S4Sn.
Calculated, %: C 46.24; H 4.94; S 22.45.
O-Butyl S-tributylstannyl carbonodithioate (4).
Yield 75%, oily material. IR spectrum, ν, cm–1: 960
(C–O), 1249 (CSS, asym.), 1000 (CSS, sym), 365 (Sn–
S), 541 (Sn–C). 1H NMR spectrum, δ, ppm: 0.88 t (3H,
4′-H), 1.30 m (2H, 3′-H), 1.60 m (2H, 2′-H), 4.44 t
3
(2H, 1′-H, JHH = 6.6 Hz), 1.73 m (6H, 1-H), 1.39 m
(6H, 2-H, 1.33 m (6H, 3-H), 0.93 m (9H, 4-H). 13C
NMR spectrum, δC, ppm: 13.8 (C4′), 15.6 (C3′), 30.3
1
NMR spectra. Signals in the H NMR spectra of
1
(C2′), 74.9 (C1′), 217.7 (C=S), 19.4 (C1, JSnC = 335–
1–5 (in DMSO-d6) were assigned on the basis of their
position, multiplicity, and intensity patterns. Protons of
the butyl group of the ligand resonated in the range δ
0.97–4.40 ppm, and the corresponding signals of 1–5
were observed in the region (δ 0.98–4.46 ppm). These
observations are in agreement with the previously
reported data for metal dithiocarbamates [15]. The
configuration of the Sn atom was deduced from the
2J(119–117Sn–1H) coupling constant for 1; the observed
value (76–79 Hz) indicated six-coordinate Sn atom in
solution. However, a multiplet was observed for the
terminal methyl group in 2 and 4 at δ 0.97 and
0.88 ppm, respectively. A shielding effect is experienced
through the carbon chain in compound 4 due to the
presence of n-butyl groups on the electropositive
Sn atom [16]. The ortho-protons of the phenyl groups
attached to Sn in complexes 3 and 5 were observed as
314 Hz), 28.6 (C2, 2JSnC = 21 Hz), 27.0 (C3, 3JSnC = 65–
63 Hz), 13.6 (C4). Found, %: C 46.45; H 8.22; S 14.57.
C17H36OS2Sn. Calculated, %: C 46.48; H 8.26; S 14.60:
O-Butyl S-triphenylstannyl carbonodithioate (5).
Yield 92%, mp 66–68°C. IR spectrum, ν, cm–1: 942
(C–O), 1228 (CSS, asym.), 1073 (CSS, sym.), 375
(Sn–S), 272 (Sn–C). 1H NMR spectrum, δ, ppm: 0.98 t
3
3
(3H, 4′-H, JHH = 7.4 Hz), 1.15 m (2H, 3′-H, JHH
=
7.4 Hz), 1.41 m (2H, 2′-H), 4.31 t (2H, 1′-H, 3JHH = 6.6
Hz), 7.69 m (6H, o-H), 7.46 m (6H, m-H), 7.42 m (3H,
p-H). 13C NMR spectrum, δC, ppm: 13.6 (C4′), 18.8
(C3′), 29.8 (C2′), 75.7 (C1′), 214.8 (C=S), 138.1 (Ci,
1JSnC = 588–562 Hz), 129.0 (Co, JSnC = 61–59 Hz),
2
136.6 (Cm, 3JSnC = 45–43 Hz), 130.0 (Cp, 4JSnC = 13 Hz).
Found, %: C 55.30; H 4.81; S 12.80. C23H24OS2Sn.
Calculated, %: C 55.33; H 4.85; S 12.84.
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ORGANOTIN(IV) O-BUTYL CARBONODITHIOATES
2771
1
Table 1. Coupling constants J(119Sn–13C) and calculated
coordinate tin(IV) atom, which is in accordance with
published data [20].
C–Sn–C angles (deg) in compounds 1–5
Comp. 1J(119Sn–13C),
2J(119Sn–1H),
Angle, deg
X-Ray analysis of compound 1. The ORTEP view
of molecule 1 is shown in Fig 1, and the structure
refinement parameters are given in Table 2. Selected
bond lengths and bond angles in molecule 1 are given
in Table 3. The tin atom in complex 1 has distorted
tetrahedral geometry defined by two methyl groups
and two sulfur atom of the carbonodithioate ligand.
The ligand coordinates to the tin atom in monodentate
mode. The CSnC and SSnC angles are within the
expected range of four-coordinate tetrahedral geometry
(C7SnC6 128.9°, S1SnC6 108.4°, S1SnC7 109.5°) [21].
No weak interactions were found between molecules 1
in crystal, and the Me2SnL2 molecule exists as an
independent unit. The ligands are coordinated
symmetrically through shorter Sn–S1 bonds [2.4942(7)
Å]. The other Sn–S distances are significantly shorter
than the sum of the corresponding van der Waals radii
(4.0 Å), and the coordination number of Sn is assigned
as four. Furthermore, the degree of symmetry in the Sn
–S1 bond distances is the same in the two ligands. The
S1SnC6 and S1SnC7 bond angles demonstrate
inclination of the Sn–C bonds toward the longer Sn–S
bonds due to repulsion between the bonding electron
pairs around the central Sn atom. Electronic and steric
factors have also been involved to explain distortion of
similar structures from the regular tetrahedral
geometry [22].
1J
2J
125
–
no.
Hz
Hz
1
2
3
4
5
597
540
830
335
588
79
–
129
129
129
108
112
–
–
–
–
–
–
multiplets at δ 8.0 and 7.69 ppm (o-H), respectively,
and the meta- and para-protons therein resonated in
the region δ 7.42–7.50 ppm.
The 13C chemical shifts due to butyl and phenyl
groups attached to Sn were consistent with those
reported for other similar compounds [17, 18]. The
CS2 carbon signal appeared in the range δC 214.8–
223.1 ppm, indicating ligand coordination to the metal
center via the CSS moiety [16]. The configuration of
the Sn atom in the di- and triorganyltin(IV) com-
pounds was determined from the 1J(119Sn–13C) coupling
constants and C–Sn–C bond angles (108°–129°) cal-
culated by Lockhart’s equation [19] (Table 1). The
observed 1J(119Sn–13C) coupling constants and
calculated C–Sn–C angles are, respectively, 597 Hz
and 129.0° for 1, 540 Hz and 129.0° for 2, 830 Hz and
129.0° for 3, and 588 Hz and 112.0° for 5, which
correspond to six-coordinate tin atom in 1–3 and five-
The crystallographic data for compound 1 were
deposited to the Cambridge Crystallographic Data
Centre (CCDC entry no. 1 062 079).
1
coordinate tin atom in 5. The J(119Sn–13C) value
(335 Hz) and C–Sn–C angle (108°) for 4 indicate four-
Fig. 1. Crystal structure of compound 1.
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2772
JAVED et al.
Table 2. Crystallographic data and structure refinement parameters for compound 1
Parameter
Formula
Value
C12H24O2S4Sn
447.24
Parameter
Crystal size, mm
Value
0.28×0.22×0.18
Molecular weight
Temperature, K
Crystal system
Space group
a, Å
Radiation
MoKα (λ = 0.71073 Å)
5.6° to 52°
296(2)
2θ range
Orthorhombic
Pmn21
Index ranges
–17 ≤ h ≤ 25, –7 ≤ k ≤ 7, –9 ≤ l ≤ 7
7166
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness of fit on F2
Final R indexes [I ≥ 2σ(I)]
Final R indexes (all data)
Largest diff. peak/hole, ēÅ–3
Flack parameter
20.3843(16)
6.0425(4)
7.8015(6)
960.93(12)
2
1633 [Rint = 0.0181, Rσ = 0.0215]
1633/7/91
b, Å
c, Å
Volume, Å3
1.055
R1 = 0.0218, wR2 = 0.0491
R1 = 0.0269, wR2 = 0.0522
0.38/–0.23
Z
d
calc, mg/mm3
1.546
μ, mm–1
1.760
0.40(8)
F(000)
452.0
Table 3. Selected bond lengths and bond angles in molecule 1
Bond
d, Å
Bond
C6–Sn1
S1–C1
O1–C1
O1–C2
d, Å
Angle
ω, deg
128.9(2)
96.25(9)
118.9(4)
110.4(2)
111.2(7)
Angle
C6Sn1S1
C7Sn1S1
S2C1S1
S2C1S1
C3AC4AC5A
ω, deg
108.4(4)
109.5(3)
123.87(17)
125.8(2)
111.8(7)
Sn1–S1
Sn1–C7
S2–C1
2.4942(7)
2.066(14)
1.643(3)
1.490(7)
2.174(14)
1.732(3)
1.314(3)
1.484(17)
C7Sn1C6
C1S1Sn1
C1O1C2A
O1C1S1
O1–C2A
O1C2AC3A
DNA binding study. The interaction of compounds
1–5 with DNA was studied by UV-visible
spectroscopy [23]. The spectra of the ligand and
compounds 1–5 were recorded in the absence and in
the presence of DNA at different concentrations [24–
26]. The UV spectra of the ligand (KL) and its
complexes showed a strong absorption peak at λ 309–
310 nm due to n–π* transition of the C=S bond. As the
concentration of DNA increased, a hypochromic effect
was observed along with a minor red shift (1–2 nm), as
illustrated by Fig. 2 for compounds 3 and 5. Hypo-
chromic effect and red shift are the signs of inter-
calative binding mode involving stacking interaction
between the chromophore and DNA base pair. After
intercalating the base pairs of DNA, the π* orbital of
the intercalated ligand could couple with the π orbital
of DNA base pair, thus decreasing the π–π* transition
energy, which results in bathochromic shift. On the
other hand, coupling of the π orbital with partially
filled electron shell decreases the transition prob-
ability, which leads to hypochromic effect. Hypo-
chromism in the case of intercalative binding mode
originates from π–π* stacking interactions, while
bathochromic (red) shift is observed when the DNA
duplex is stabilized [27, 28]. The intrinsic binding
constants K of the ligand and organotin(IV) carbon-
dithioates 1–5 were calculated by the Benesi–
Hildebrand equation [29] (Table 4) in order to compare
the respective binding strengths.
A0
εG
εG
1
.
=
+
εH−G − εG
A − A0
εH−G − εG
K[DNA]
Here, K is the binding constant, A0 and A are the
absorbances of a drug and its complex with DNA, and
εG and εH–G are the molar absorption coefficients of the
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ORGANOTIN(IV) O-BUTYL CARBONODITHIOATES
2773
(a)
(b)
10/[DNA], μM–1
1/[DNA], μM–1
1
1
10
K = 1.57×103 M–1
ΔG = –15.17 kJ/mol
K = 2.26×103 M–1
ΔG = –15.53 kJ/mol
10
λ, nm
λ, nm
Fig. 2. UV spectra of compounds (a) 3 and (b) 5 (c3 = c5 = 0.8 mM) (1) in the absence and in the presence of (2) 20, (3) 40, (4) 62,
(5) 83, (6) 104, (7) 125, (8) 150, (9) 170, and (10) 192 μM of DNA.
drug and drug–DNA complex, respectively. The
calculated values of ΔG and binding constants are
given in Table 4. As follows from the negative ΔG
values, the interaction of KL and 1–5 with DNA is a
spontaneous process.
because of partial sharing of its positive charge with
the ligand, which favors permeation of the complex
through the lipid layer of cell membrane [31].
Antifungal activity. The results of in vitro disk
diffusion assay [30] of the ligand and organotin(IV)
compounds 1–5 against five fungal strains (Aspergillus
flavus, Aspergillus niger, Fusarium solani, Aspergillus
fumigates, and Mucor species) are summarized in
Table 6. Terbinafine was used as standard drug.
Compound 4 showed higher activity than that of the
standard drug against Aspergillus flavus, Aspergillus
niger, and Aspergillus fumigates. Compound 5 showed
significant activity against all the tested fungal strains,
while the activity of 1–3 was insignificant. These
findings were consistent with published data according
to which triorganotin derivatives are more biocidal
than diorganotin analogs [32, 33]. Although the exact
mechanism is not completely known, the action of
antimicrobials may involve various targets in the
microorganisms. Organotin compounds disturb the cell
respiration process and thus block protein synthesis,
which restricts further growth of the organisms. In
comparison to diorganotin complexes, four- and five-
coordinate triorganotins exhibit extensive biological
activities due to availability of more space for
incoming group (microorganisms), which results in
increased liposolubility of the molecules in crossing
cell membrane of microorganisms [34, 35].
Antibacterial activity. All the synthesized
compounds were subjected to antibacterial activity
assay against five selected bacterial strains, gram
positive Staphylococcus aureus (ATCC 6538) and
Micrococcus luteus (ATCC 53598) and gram negative
Bordetella bronchiseptica (ATCC 4617), Salmonella
typhimurium (ATCC 14028), and Enterobacter
aerogens (ATCC 13048), using the disk diffusion
method [30]. The results are presented in Table 5. All
complexes 1–5 showed moderate activity against the
selected strains, and the activity is highly strain-
dependent. The activities of 4 and 5 against M. luteus,
S. aureus, B. bronchiseptica, and E. aerogenes are
comparable to those of the reference drug. This may be
ascribed to Tweedy’s theory, according to which
chelation reduces the polarity of the central metal atom
Table 4. DNA binding constants and Gibbs free energies for
free ligand KL and compounds 1–5
Comp. no.
KL
K, L/mol
9.80×102
–∆G, kJ/mol
14.67
1
2
3
4
5
4.50×103
4.02×103
1.57×103
6.26×103
2.26×103
14.10
20.13
15.17
21.66
15.53
Cytotoxicity. The cytotoxicities of KL and 1–5
were studied in vitro by the brine-shrimp lethality
method [36] using Tricaine methanesulfonate (MS-
222) as reference drug (Table 7). The mean values of
duplicate readings at 10, 50, and 100 µg/mL are given.
The LD50 values range from less than 10 to 52 µg/mL
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JAVED et al.
Table 5. Antibacterial activity of KL and complexes 1–5 (inhibition zone, mm)
Compound no.
M. luteus
S. Aureus
B. bronchiseptica
S. typhimurium
E. aerogenes
KL
10
15
13
15
17
20
20
00
10
17
10
19
18
20
10
16
07
14
18
15
20
13
11
11
13
14
10
20
18
16
14
18
10
15
20
1
2
3
4
5
Roxithromycina
a
Reference drug.
Table 6. Antifungal activity of KL and organotin(IV) compounds 1–5 (inhibition zone, mm)
Compound no. Aspergillus flavus
Aspergillus niger
Fusirum solani
Aspergillus fumigates
Mucor specie
b
KL
–
–
–
–
–
–
–
1
12
04
14
18
16
16
06
07
–
04
11
–
2
–
–
3
9
–
4
20
13
16
14
14
16
22
10
16
14
09
16
5
Terbinafinea
a
Reference drug. b “–” stands for no activity.
Table 7. Cytotoxicity data (number of shrimps killed out of 20) of KL and organotin(IV) compounds 1–5
Compound no.
c = 100 µg/mL
c = 50 µg/mL
c = 10 µg/mL
LD50, μg/mL
13.2
KL
1
15
11
09
11
20
20
12
10
08
09
20
20
11
09
05
05
20
20
22.0
2
52.0
3
48.2
4
<10.<0
<10.<0
5
against 4.3 µg/mL for the reference drug. Compounds
4 and 5 proved to be more toxic than the other tested
compounds. The high toxicity is due to high lipid
solubility which allows cell penetration and association
with intracellular sites, while cell wall components
also play an important role [37]. Cytotoxic drugs work
better in cancer disease where the cancer cells are
rapidly dividing and multiplying. Hence compounds 4
and 5 may be promising as potential drugs for the
treatment of cancer.
Antileishmanial activity. The synthesized com-
pounds were tested against the promastigote forms of
leishmania major. The IC50 values shown in Table 8
indicate moderate antileishmanial activity of 1–3 and
strong antileishmanial activity of 4 and 5 (IC50 0.001
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ORGANOTIN(IV) O-BUTYL CARBONODITHIOATES
2775
Rev., 2001, vol. 215, no. 1, p. 99. doi 10.1016/S0010-
8545(00)00404-5
Table 8. Antileishmanial activity of the ligand (KL) and
organotin(IV) compounds 1–5
3. Αl-Najjar, A.A., Shehata, M.R., Mohamed, M., and
Shoukry, M.M., Main Group Met. Chem., 1999, vol. 22,
no. 4, p. 253. doi 10.1515/MGMC.1999.22.4.253
Compound no.
KL
LC50, µg/mL
0.651
4. Tiekink, E.R.T., Appl. Organomet. Chem., 2008,
1
0.965
0.012
0.832
0.003
0.001
0.048
vol. 22, no. 9, p. 533. doi 10.1002/aoc.1441
5. Yin, H.D. and Xue, S.C., Appl. Organomet.
Chem., 2006, vol. 20, no. 4, p. 283. doi 10.1002/aoc.1048
2
3
6. Tiekink, E.R.T., Main Group Met. Chem., 1992, vol. 15,
p. 161. doi 10.1002/chin.199321265
4
7. Hussain, H., Ahmad, V.U., Green, I.R., Krohn, K.,
Hussain, J., and Badshah, A., Arkivoc, 2007, vol. 2007,
part 14, p. 289. http: 10.2298/JSC0802179H.
5
Amphotericin Ba
8. Khan, S., Nami, S.A., and Siddiqi, K.S., J. Organomet.
Chem., 2008, vol. 693, no. 6, p. 1049. doi 10.1016/
j.jorganchem.2007.12.026
9. Menezes, D.C., Vieira, F.T., De Lima, G.M., War-
dell, J.L., Cortés, M.E., Ferreira, M.P., and Vilas Boas, A.,
Appl. Organomet. Chem., 2008, vol. 22, no. 4,
p. 221. doi 10.1002/aoc.1375
10. Muhammad, N., Shuja, S., Ali, S., Butler, I.S.,
Meetsma, A., and Khan, M., Polyhedron, 2009, vol. 28,
no. 16, p. 3439. doi 10.1016/j.poly.2009.07.025
a
Reference drug.
and 0.003 µg/mL, respectively, against 0.048 µg/mL
for the standard drug). These compounds disturb the
respiration process by blocking the function of
parasitic mitochondria, which restricts further growth
of the organisms.
Protein kinase inhibition. Compounds 1, 3, and 4
showed different degrees of inhibition estimated at 13,
5, and 7 mm, respectively, while compounds 2 and 5
displayed no activity as compared to the standard value
(18 mm). Compound 1 may be considered as potential
candidate to inhibit tumor initiation.
11. Javed, F., Ali, S., Shah, M.W., Munawar, K.S.,
Shahzadi, S., Hameedullah, Sharma, S.K., and
Qanungo, K., J. Coord. Chem., 2014, vol. 67, no. 16,
p. 2795. doi 10.1080/00958972.2014.947967
12. Armarego, W.L. and Chai, C.L.L., Purification of
Laboratory Chemicals, London: Butterworth Heinemann,
2003, 5th ed.
In summary, potassium O-butyl carbonodithioate
and its organotin(IV) complexes were successfully
synthesized and characterized. The ligand coordinates
to the tin atom through the sulfur atom. As revealed by
UV-Vis studies, the synthesized compounds bind to
DNA via intercalative interaction resulting in
hypochromic effect with a minor red shift. The
negative values of Gibbs free energy change indicated
spontaneity of these interactions. Biological studies
revealed that the triorganotin(IV) complexes generally
proved to be more active than the corresponding dior-
ganotin(IV) analogs probably due to their greater
liphophilicity.
13. Sirajuddin, M., Ali, S., Shah, N.A., Khan, M.R., and
Tahir, M.N., Spectrochim. Acta, Part A, 2012, vol. 94,
p. 134. doi 10.1016/j.saa.2012.03.068
14. Shaheen, F., Ali, S., Rehman, Z.U., and Meetsma, A.,
Polyhedron, 2012, vol. 31, no. 1, p. 697. doi 10.1016/
j.poly.2011.10.025
15. Domazetis, G., Magee, R.J., and James, B.D., J. Orga-
nomet. Chem., 1977, vol. 141, no. 1, p. 57. doi 10.1016/
S0022-328X(00)90667-3
16. Gómez-Ortiz, L.A., Cea-Olivares, R., Garcıa-Montalvo, V.,
́
and Hernández-Ortega, S., J. Organomet. Chem., 2002,
vol. 654, no. 1, p. 51. doi 10.1016/S0022-328X(02)
01373-6
ACKNOWLEDGMENTS
17. Nadvornik, M., Holeček, J., Handlíř, K., and Lyčka, A.,
J. Organomet. Chem., 1984, vol. 275, no. 1, p. 43. doi
10.1016/0022-328X(84)80576-8
18. Eng, G., Song, X., Duong, Q., Strickman, D., Glass, J.,
and May, L., Appl. Organomet. Chem., 2003, vol. 17,
no. 4, p. 218. doi 10.1002/aoc.423
F. Javed thanks the Higher Education Commission
(HEC), Islamabad, Pakistan for financial support (PIN
117-7469-PS7-018).
REFERENCES
1. Pellerito, L. and Nagy, L., Coord. Chem. Rev., 2002,
vol. 224, no. 1, p. 111. doi 10.1016/S0010-8545(01)00399-X
2. Nath, M., Pokharia, S., and Yadav, R., Coord. Chem.
19. Lockhart, T.P., Manders, W.F., and Holt, E.M., J. Am.
Chem. Soc., 1986, vol. 108, no. 21, p. 6611. doi
10.1021/ja00281a026
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 12 2016

2776
JAVED et al.
20. Willem, R., Verbruggen, I., Gielen, M., Biesemans, M.,
Mahieu, B., Basu Baul, T.S., and Tiekink, E.R.T.,
Organometallics, 1998, vol. 17, no. 26, p. 5758. doi
10.1021/om980504u
21. Mohamed-Ibrahim, M.I., Chee, S.S., Buntine, M.A.,
Cox, M.J., and Tiekink, E.R.T., Organometallics, 2000,
vol. 19, no. 25, p. 5410. doi 10.1021/om000717v
22. Ali, S., Muhammed, N., and Meetsma, A., Acta
Crystallogr., Sect. E, 2007, vol. 63, p. m431. doi
10.1107/S1600536806056236
23. Sun, H., Xiang, J., Liu, Y., Li, L., Li, Q., Xu, G., and
Tang, Y., Biochimie, 2011, vol. 93, no. 8, p. 1351. doi
10.1016/j.biochi.2011.06.007
24. Jaumot, J., and Gargallo, R., Curr. Parm. Des., 2012,
vol. 18, no. 14, p. 1900. doi 10.2174/
138161212799958486
25. Wei, C., Wang, J., and Zhang, M., Biophys.
Chem., 2010, vol. 148, no. 1, p. 51. doi 10.1016/
j.bpc.2010.02.009
J. Pharm. Biomed. Anal., 2002, vol. 28(2), p. 217. doi
10.1016/S0731-7085(01)00624-0
30. Fritsche, T.R., McDermott, P.F., Shryock, T.R., and
Walker, R.D., J. Clin. Microbiol., 2007, vol. 45, no. 8,
p. 2758. doi 10.1128/JCM.00569-07
31. Rehman, Z.U., Muhammad, N., Shah, A., Ali, S., and
Khan, E., Heteroatom Chem., 2012, vol. 23, no. 6,
p. 560. doi 10.1002/hc.21050
32. Ferreira, I.P., de Lima, G.M., Paniago, E.B., Rocha, W.R.,
Takahashi, J.A., Pinheiro, C.B., and Ardisson, J.D.,
Polyhedron, 2014, vol. 79, p. 161. doi 10.1016/
j.poly.2014.05.001
33. Shi, Y., Zhang, B.Y., Zhang, R.F., Zhang, S.L., and
Ma, C.L., J. Coord. Chem., 2012, vol. 65, no. 23,
p. 4125. doi 10.1080/00958972.2012.734814
34. Neelakantan, M.A., Esakkiammal, M., Mariappan, S.S.,
Dharmaraja, J., and Jeyakumar, T., Indian J. Pharm.
Sci., 2010, vol. 72, no. 2, p. 216. doi 10.4103/0250-
474X.65015
26. Bhadra, K. and Kumar, G.S., Biochim. Biophys. Acta,
Gen. Subj., 2011, vol. 1810, no. 4, p. 485. doi 10.1016/
j.bbagen.2011.01.011
35. Neelakantan, M.A., Rusalraj, F., Dharmaraja, J.,
Johnsonraja, S., Jeyakumar, T., and Pillai, M.S.,
Spectrochim. Acta, Part A, 2008, vol. 71, no. 4, p. 1599.
doi 10.1016/j.saa.2008.06.008
27. Yang, X., Shen, G.L., and Yu, R.Q., Microchem. J., 1999,
vol. 62, no. 3, p. 394. doi 10.1006/mchj.1999.1747
36. Meyer, B.N., Ferrigni, N.R., Putnam, J.E., Jacobsen, L.B.,
Nichols, D.J., and McLaughlin, J.L., Planta Med., 1982,
vol. 45, no. 5, p. 31. doi 10.1055/s-2007-971236
28. Xu, Z., Bai, G., and Dong, C., Bioorg. Med.
Chem., 2005, vol. 13, no. 20, p. 5694. doi 10.1016/
j.bmc.2005.06.023
37. Saxena, A.K., Appl. Organomet. Chem., 1987, vol. 1,
29. Ibrahim, M.S., Shehatta, I.S., and Al-Nayeli, A.A.,
no. 1, p. 39. doi 10.1002/aoc.590010107
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