Synthesis, Spectroscopy, Semi-empirical and Biological Activities of Organotin(IV) Complexes with o-Isopropyl Carbonodithioic Acid

Article abstract of DOI:10.1002/jccs.201500235

New organotin(IV) complexes have been synthesized by treating potassium o-isopropyl carbonodithioate with R₂SnCl₂/R₃SnCl in 1:2/1:1 M/L ratio. All complexes have been characterized by IR and NMR (¹H, ¹³C) spectroscopy. IR results shows that ligand acts as bidentate which is also confirmed by semi-empirical study. NMR data reveals four coordinated geometry in solution. Computed positive heat of formation shows that complex 5 is thermodynamically unstable. UV/visible spectroscopy was used to assess the mode of interaction and binding of the complexes with DNA which shows that complex 5 exhibits higher binding constant as compared to complex 3. In protein kinase inhibition assay, compound 3 was found most active, while other biological activities shows that triorganotin(IV) complexes are biologically more active as compared to diorganotin(IV) complexes.

Full text of DOI:10.1002/jccs.201500235

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Synthesis, Spectroscopy, Semi-empirical and Biological Activities of Organotin(IV)
Complexes with o-Isopropyl Carbonodithioic Acid
Fatima Javed,a Saqib Ali,a* Saira Shahzadi,a* Nasir Khalid,b Saira Tabassum,c Imran Khan,c
Saroj K. Sharmad and Kushal Qanungod
aDepartment of Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan
bChemistry Division, Pakistan Institute of Nuclear Science & Technology, P.O. Nilore, Islamabad, Pakistan
cDepartment of Biotechnology, Quaid-i-Azam University, Islamabad-45320, Pakistan
dDepartment of App. Sci. and Hum., Faculty of Engg. and Tech., Mody Institute of Technology and Science (Deemed
University), Lakshmangargh-332311, Dist Sikar, Raj., India
(Received: Jun. 16, 2015; Accepted: Jul. 21, 2015; Published Online: Aug. 14, 2015; DOI: 10.1002/jccs.201500235)
New organotin(IV) complexes have been synthesized by treating potassium o-isopropyl carbonodithioate
with R2SnCl2/R3SnCl in 1:2/1:1 M/L ratio. All complexes have been characterized by IR and NMR (1H,
13C) spectroscopy. IR results shows that ligand acts as bidentate which is also confirmed by semi-empiri-
cal study. NMR data reveals four coordinated geometry in solution. Computed positive heat of formation
shows that complex 5 is thermodynamically unstable. UV/visible spectroscopy was used to assess the
mode of interaction and binding of the complexes with DNA which shows that complex 5 exhibits higher
binding constant as compared to complex 3. In protein kinase inhibition assay, compound 3 was found
most active, while other biological activities shows that triorganotin(IV) complexes are biologically more
active as compared to diorganotin(IV) complexes.
Keywords: o-Isopropyl carbonodithioic acid; Organotin(IV); IR; NMR; Semi-empirical; Enzyme
inhibition study; DNA interaction; Antifungal; Antibacterial; Antileishmanial;
Cytotoxicity.
INTRODUCTION
The coordination chemistry of sulfur-donor ligands is
In continuation of our previous work,18-21 we have
synthesized organotin(IV) complexes with o-isopropyl
carbonodithioic acid. These complexes were characterized
by different spectral techniques and semi-empirical study
was also done. The complexes were also screened to check
various biological activities.
an area of interest due to their close similarity with bio-
molecules like amino acids (e.g., methionine, cysteine),
peptides such as glutathione, proteins, enzymes and vita-
mins.1 The use of sulfur donor ligands, such as dithio-
phosphates, dithioxanthates, or dithiocarboxylates in tri-
organotin and diorganotin compounds can be useful to
mimic the active sites of some metallic enzymes. This
method is sometimes simpler than actually using biological
ligands such as peptides or amino acids.2–4
RESULTS AND DISCUSSION
The synthesized organotin(IV) complexes are solid
having sharp melting points and are soluble in common or-
ganic solvents. The physical data is given in Table 1.
Infrared spectroscopy
Extensive structural analyses were performed by
Tiekink and Haiduc5 which showed that these ligands can
coordinate to metal atoms in a monodentate, isobidentate,
or anisobidentate fashion. Metal xanthates are extensively
used as pesticides6, corrosion inhibitors,7 agricultural re-
agents8 and quite recently in therapy for HIV infections.9
Organotin compounds as well as dithiocarbamates lig-
ands10 are known for their antifungal,11 antibacterial,12 and
antitumor13–16 activities. Protein kinases are responsible for
the phosphorylation of various proteins, act as regulatory
agents in several metabolic pathways.17
The IR spectrum of the free ligand was compared
with the spectra of tri- and diorganotin(IV) complexes to
understand the binding mode of the dithiocarbonate ligand.
Absence of SH band in the spectra of the complexes in the
region 2710 cm-1 indicate the deprotonation of carbon-
odithioic acid group. The IR data of ligand reveals that
(uC=S)asym appeared at 1370 cm-1 and (uC=S)sym appeared
at 1049 cm-1 where as in case of complexes 1-3 and 5, these
bands appeared in the range of 1218-1251 and 1070-1085
cm-1, respectively. However for the complex 4, the corre-
* Corresponding author. Email: drsa54@yahoo.com (S.A); sairashahzadi@hotmail.com (S.S)
728
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Table 1. Physical data of organotin(IV) complexes with o-isopropyl carbonodithioic acid
Elemental analysis % calculated
(found)
Comp.
No.
Molecular
formula
Melting point
M.W. % Yield
(°C)
C
H
S
HL
1
C4H8OS2
136
419
503
543
299
485
75
62
58
60
55
52
190-193
170-173
179-181
142-146
170-172
150-153
27.56
(27.50)
28.65
(28.59)
38.18
(38.15)
44.21
(44.16)
45.19
4.05
(4.01)
4.81
(4.75)
6.41
(6.38)
4.45
(4.42)
8.06
36.79
(36.71)
30.59
(30.55)
25.48
(25.45)
23.60
(23.52)
15.08
C10H20O2S4Sn
C16H32O2S4Sn
C20H24O2S4Sn
C7H16OS2Sn
C22H22OS2Sn
2
3
4
(45.15)
54.45
(8.01)
4.57
(15.02)
13.22
5
(54.41)
(4.54)
(13.19)
sponding bands appeared at 1371 and 1085 cm-1, re-
spectively. The Dn difference between nasym(CSS)- and
nsym(CSS)- is important to find out the binding mode of
CSS- moiety with Sn atom. According to literature,21 Dn
greater than 250 cm-1 shows a monodentate while a value
less than 250 cm-1 shows bidentate binding mode of CSS-
moiety with Sn atom. Moreover a Dn value between 150–
250 cm-1 indicates a bridging behaviour while a value less
than 150 cm-1 exhibits a chelate structure. The difference
D u (CS2) of u (CS2)as and u (CS2)s are 134-286 cm-1, that is
an indication of bidentate binding of the ligand to the cen-
tral tin atom in complex 1-3 and 5 and mondentae mode of
ligand is observed in complex 4 probably be due to steric
effect of n-butyl groups.48
by integration of peaks are in excellent agreement to those
theoretically calculated by incremental method.24 The ab-
sence of SH signal in the complexes suggested the de-
protonation of carbonodithioic acid group for S®M coor-
dination through CSS- anions. A doublet appeared at 1.16
ppm for methyl protons and heptet at 5.45 ppm for methy-
lene proton in the free ligand HL exhibited downfield shift
in the range 1.17-5.85 ppm in the complexes 1-5. The
downfield shift is due to dieshielding of these protons upon
coordination of both sulphur atoms with the metal.48 These
observation are in agreement with the reported metal
dithiocarboxylates.49 In complex 1, characteristic signal of
methyl protons which are directly coupled with tin metal
gives singlet at 1.42 ppm with coupling 2J (119/117Sn-1H =
79, 76 Hz). In compound 2, the protons of butyl group ap-
peared as multiplet in the region 1.45 (4H, m), 1.89 (4H,
m), 2.04 (4H, m), while in compound 4, the proton of butyl
group appeared as multiplet in the region 1.30 (6H, m),
1.36 (6H, m), 1.60 (6H, m). The terminal CH3 group of
The appearance of a new band in the region 367-321
cm-1 indicates the formation of Sn-S bond in complexes.23
The Sn-C band was observed in the range of 579-550 cm-1
in complexes 1, 2 and 4 but at 279 and 260 cm-1 for com-
plexes 3 and 5. The lower frequency of the complexes 3 and
5 could probably be due to the planner structure and conju-
gate nature of phenyl ring. These values are in close agree-
ment with that observed for a number of similar or-
ganotin(IV)-sulfur donor ligands.48 Based on the infrared
spectra analyses of ligands and their organotin(IV) com-
plexes, it is suggested that ligand coordinated to the tin(IV)
moiety through the thiolato sulfur atoms. IR data is given in
Table 2.
3
butyl gives triplet at 0.96 and 0.90 ppm with J[1H–1H]
value of 7.3 and 7.2 Hz in complexes 2 and 4, respectively.
Table 2. IR spectral data (cm-1) of organotin complexes with o-
isopropyl carbonodithioic acid
Comp. No.
uC=S
Dn
uC-S
uSn-S uSn-C
HL
1
2
3
4
1370, 1049
1219, 1085
1251, 1070
1218, 1082
1371, 1085
1219, 1081
321
134
181
136
286
138
1014
981
959
960
961
995
-
-
319
361
321
367
329
546
507
279
550
260
1H NMR spectroscopy
1H NMR spectra were recorded in DMSO-d6 to find
the behavior of magnetically nonequivalent protons. The
data is given in Table 3. The numbers of protons calculated
5
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Table 3. 1H NMR data (ppm)a-c of organotin complexes with o-isopropyl carbonodithioic acid
Comp.
No.
H-1
H-2
R
HL
1
2
3
4
1.16 (3H, d, 3J = 6.3 Hz) 5.45 (1H, heptet, 2J = 6.3 Hz)
1.43 (12H, d, 3J = 6.3 Hz) 5.44 (2H, heptet, 3J = 6.3 Hz)
-
1.42 (6H, s), 2J (119/117Sn-1H = 79,76 Hz)
1.41 (12H, d, 3J = 6.3 Hz) 5.44 (2H, heptet, 3J = 6.3 Hz) 0.96 (6H, t, 3J = 7.3 Hz), 1.45 (4H, m), 1.89 (4H, m), 2.04 (4H, m)
1.15 (12H, d, 3J = 6.3 Hz) 5.29 (2H, heptet, 3J = 6.3 Hz)
7.51 (2H, m), 7.54 (4H, m), 8.05 (4H, m)
1.38 (6H, m)
5.58 (1H, heptet, 3J = 6.3 Hz) 0.90 (9H, t, 3J = 7.2 Hz), 1.30 (6H, m), 1.36 (6H, m), 1.60 (6H, m)
5
1.98 (6H, d, 3J = 6.3 Hz) 5.41 (1H, heptet, 3J = 6.3 Hz)
7.42 (3H, m), 7.45 (6H, m), 7.70 (6H, m), 7.51 (2H, m)
a
1
CH3
S
2
C
CH
O
3
CH3
S
1
b Chemical Shifts (d) in ppm.
c Multiplicity is given as, s = singlet, t = triplet, m = multiplet.
2
with J(119/117Sn-13C 61.40, 59.02 Hz) and ipso carbon at
The signals for the protons of the phenyl groups attached to
the Sn were distinguishable as two sets in complexes 3 and
5. The ortho protons were observed upfield at 7.42 and 7.51
ppm, the meta and para protons downfield (7.45-8.05 ppm)
and were assigned according to literature.25
1J(119/117Sn-13C 583.15, 557.33 Hz).
In compounds 2 and 4, the methyl carbon at sigma po-
sition was observed in the upfield region at 13.74 and 13.67
ppm, respectively, while methylene carbon at gamma posi-
tion was observed at 26.39 ppm with J(119/117Sn-13C
117.33, 112.61 Hz) and 27.06 ppm with J(119/117Sn-13C
13C NMR spectroscopy
3
13C NMR data is given in Table 4. The 13C NMR
chemical shifts due to the phenyl groups are observed at
positions comparable to other similar compounds.26 In
compound 3, the meta carbon was observed at 135.62 ppm
with 3J(119Sn-13C 56.65 Hz) and para carbon was observed
at 130.29 ppm with 4J(119Sn-13C 17.96 Hz). The ortho car-
3
62.71, 64.94 Hz). Methylene carbon at beta position was
observed at 28.80 ppm with 2J(119Sn-13C = 39.06 Hz) and
28.67 with 2J(119Sn-13C = 21.90 Hz) and methylene carbon
at alpha position was observed at 30.48 ppm with
1J(119/117Sn-13C 541.11, 516.34 Hz) and 15.61, 1J(119/117Sn-
13C 334.95, 320.09 Hz). The difference in coupling con-
stant in 2 and 4 attributes to four and five coordination
geometry, respectively.50 The C-3 was observed in the
range 213.51-222.06 ppm in compounds 1-5.
2
bon was observed at 129.20 ppm with J(119/117Sn-13C
85.90, 82.95 Hz) and ipso carbon C-5 at 141.63 with
1J(119/117Sn-13C 832, 795.58 Hz), while in compound 5, the
meta carbon was observed at 136.57 ppm with 3J(119Sn-13C
44.36 Hz) and para carbon at 129.94 ppm with 4J(119Sn-13C
12.55 Hz). The ortho carbon was observed at 128.9 ppm
Protein kinase inhibition assay
Kinase phosphorylation activity is usually associated
Table 4. 13C NMR data (ppm) of organotin complexes with o-isopropyl carbonodithioic acid
Comp.
No.
C-1
C-2
C-3
R
-
HL
1
22.37
21.33
21.34
72.53 229.76
80.63 220.76 10.43, 1J(119/117Sn-13C = 593.46, 567.70 Hz)
2
80.52 222.06 13.74, 26.39, 3J(119/117Sn-13C117.33, 112.61 Hz), 28.80, 2J (119Sn-13C = 39.06 Hz),
30.48, 1J(119/117Sn-13C 541.11, 516.34 Hz)
3
4
5
20.99
21.31
20.68
81.41 217.43 141.63, 1J(119/117Sn-13C 832, 795.58 Hz), 129.20, 2J(119/117Sn-13C 85.90, 82.95 Hz),
135.62, 3J(119Sn-13C 56.65 Hz), 130.29, 4J(119Sn-13C 17.96 Hz)
78.69 216.62 13.67, 27.06, 3J(119/117Sn-13C 62.71, 64.94 Hz), 28.67, 2J (119Sn-13C = 21.90 Hz),
15.61, 1J(119/117Sn-13C 334.95, 320.09 Hz)
80.03 213.51 138.06, 1J(119/117Sn-13C 583.15, 557.33 Hz), 128.99, 2J(119/117Sn-13C 61.40, 59.02 Hz),
136.57, 3J(119Sn-13C 44.36 Hz), 129.94, 4J(119Sn-13C 12.55 Hz)
730
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Biologically Active Organotin(IV) Complexes
with a number of disorders e.g. cancer, cardiovascular dis-
orders, diabetes, infectious diseases, inflammatory disor-
ders, cell survival and growth. Protein kinases are most im-
portant and functionally diverse enzymes. These are key
regulators of different cellular and extracellular processes.
In our study, Streptomyces 85E., by using Serine-threonine
specific protein kinases (STPKs) strain, are considered to
have prominent role in cell survival, division and cellular
apoptosis. This filamentous Sreptomyces utilizes ser/ther
protein kinases for their hyphae formation, branching and
polar growth. This strain is internationally recommended
to be used in kinase inhibition assay and is widely used to
identify large number of eukaryotic kinase modulators as
their enzymes are potent to the highly specific eukaryotic
counter-parts. It can ascertain the cytotoxic potential of the
synthetic compounds.51 In protein kinase inhibition assay,
compounds 1-5 shows a varying degree of inhibition and
produced the zones of inhibition ranging from 5.0 ±
0.075-17.0 ± 1.25 mm. Compound 3 was found to be most
effective as it produced the maximum zone of inhibition on
the culture plates. The exact mechanism is still not known
but it is proposed that it blocks the aerial hyphae formation
of Streptomyces species thus may be hypothesized to in-
hibit the cancer cell proliferation. The data showed that
compound 3 may be considered as an effective candidate to
inhibit the tumor initiation. The data is given in Table 5.
Antifungal activity
showed lowest zone (3.0 ± 0.001) and (4.0 ± 0.075) against
A. niger and A. fumigates, respectively. From the data it is
evident that triorganotin(IV) complexes exhibits signifi-
cant fungicidal activity as compared to diorganotin com-
plexes.
Antibacterial activity
In vitro antibacterial activity of ligand HL and or-
ganotin(IV) complexes was carried out by disc diffusion
method27 using 30 mg/disc. The results are shown in Table
7. Criteria for activity is based on zone of inhibition (mm);
inhibition zone more than 20 mm shows significant activ-
ity, for 18-20 mm inhibition activity is good, 15-17 mm is
low, and below 11-14 mm is non-significant.26
Complex 1 showed good activity against S. aureus
and M. luteus. The microorganism against which com-
pounds 2 and 3 presented highest activity was S. typhi-
murium, followed by B.bronchiseptica and E. erogens.
Complexes 4 and 5 have comparable activity to reference
drug against Micrococcus luteus, S. aureus and S. typhi-
murium. The triorganotin(IV) compounds showed greater
antibacterial activity as compared to diorganotin com-
plexes which may be due to greater lipophilicity and per-
meability through the cell membrane which is consistent
with literature.28,29
Table 5. Protein kinase inhibition assay of complexes with o-
isopropyl carbonodithioic acid
The synthesized compounds 1-5 were tested for
antifungal activity against five different strains including
A. flavis, A. niger, F. solani, A. fumigates and Mucor specie
by disc diffusion method.27 The results are summarized in
Table 6. It was evident from data that the synthesized com-
plexes exhibited variety of fungicidal activity as compared
to ligand HL. The complex 4 exhibited maximum activity
(30.0 mm) against A. fumigates. Complexes 2 and 3
Comp. No.
Zone of inhibition (mm)
HL
1
2
3
4
5
-
10.0 ± 0.97
15.0 ± 1.17
17.0 ± 1.25
5.0 ± 0.075
13.0 ± 1.00
18.0
Standard drug; Tyrab
Table 6. Antifungal activity data of organotin complexes with o-isopropyl carbonodithioic
acid
Zone of inhibition (mm)
Comp. No.
A. flavus
A. niger
F. solani
A. fumigates
M. specie
HL
-
-
-
-
-
1
-
-
-
-
-
2
3
4
-
3.0 ± 0.001
-
-
-
-
-
3.0 ± 0.001
26.0
-
4.0 ± 0.075
30.0
22.0
18.0
26.0
5
12.0 ± 1.00 12.0 ± 1.001 16.0 ± 1.755 14.0 ± 1.01
16.0 16.0 16.0 16.0
14.0 ± 0.75
16.0
Standard drug
Terbinafine
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Table 7. Antibacterial activity data of organotin complexes with o-isopropyl carbonodithioic
acid
Zone of Inhibition (mm)
Comp. No.
M. luteus B. bronchiseptica S. aureus S. typhimurium E. erogens
HL
1
2
3
4
5
16.0 ± 0.707
19.0 ± 7.53
6.0 ± 0.707
17.0 ± 0.707
20.0 ± 0.707
25.0 ± 0.707
20.0
25.0 ± 2.121
14.0 ± 1.414
20.0 ± 2.121
15.0 ± 0.707
16.0 ± 1.41
15.0 ± 0.707
20.0
0
20.0 ± 2.12
10.0 ± 1.0
21.0 ± 6.65 11.0 ± 0.707 10.0 ± 0.707
0
0
21.0 ± 0.70
18.0 ± 2.12 15.0 ± 0.707
20.0 ± 2.12
11.0 ± 3.21 17.0 ± 0.707 16.0 ± 1.41
12.0 ± 1.10 19.0 ± 1.41 15.0 ± 0.707
Standard drug
Roxithromycin
and Cefixime
20.0
20.0
20.0
Antileishmanial assay
pound 5 (0.27 mg/ml).
In vitro antileishmanial assay of the compounds 1-5
was performed and the results are summarized in Table
8. All the compounds significantly inhibit the parasite.
The LC50 data showed that compound 4 causes inhibition
at very reduce concentration (0.00001 mg/ml) as com-
pared to standard drug, Amphotericin. B (0.01 mg/ml)
followed by compound 2 (0.0013 mg/ml), compound 3
(0.024 mg/ml), compound 1 (0.029 mg/ml) and com-
Cytotoxicity assay
The cytotoxicity data of ligand HL and complexes
1-5 was studied in vitro against the brine-shrimps and the
results are summarized in Table 9. The data is based on
mean value of two replicates each of 16.12, 31.25, 62.5,
125, 250, 500 and 1000 mgml-1. The LD50 data showed that
ligand HL and organotin(IV) complexes are toxic having
values in the range 35-50 mgml-1.
Table 8. Antileishmanial activity data of organotin complexes with o-isopropyl carbonodithioic acid
Antileishmanial activity (% mortality)
Concentration
used (mg/mL)
Standard drug
Amp. B
HL
1
2
3
4
5
0.00002
0.0002
0.002
0.02
0.2
2
20
200
LC50 (mg/ml)
0
0
0
0
0
40
78
97
3.10
0
0
0
0
0
61
0
0
0
47
84
100
100
100
0.024
88
96
0
0
0
0
0
20
100
100
100
100
100
100
0.0001
36
90
0
64
100
100
100
100
0.029
100
100
100
100
0.0013
40
100
100
100
0.27
100
100
100
100
0.010
Table 9. Cytotoxicity data of organotin complexes with o-isopropyl carbonodithioic acid
Lethality %
LD50
(mg/ml)
Comp. No.
Concentration (ppm)
1000
500
250
125
62.5
31.25
16.12
HL
1
2
3
4
5
100
100
100
100
100
100
0
100
100
100
100
100
100
0
95
100
95
100
100
100
0
55
45
60
55
55
50
0
50
40
55
45
45
45
0
40
35
45
35
45
40
0
35
30
40
35
45
40
0
38.8
50
49
50
35
41
0
Vehicle control
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DNA interaction study
spontaneous process as indicated by their negative values
of DG (-16.92, -20.20, -20.66 kJmol-1 for HL, compounds
The mode of interaction of organotin(IV) complexes
with DNA was determined by UV/visible spectroscopy
which is one of the useful techniques for this purpose.30
The comparison of absorbance and shift in the wavelength
of ligand and complexes with and without SS-DNA give
the idea about the interaction of ligand or metal complexes
with DNA.31 The absorption spectra of ligand HL and
organotin(IV) complexes 3 and 5 was taken as a representa-
tive one and spectra have been recorded at different con-
centration of DNA by keeping concentration of ligand HL
and complex constant.
The UV/vis study of ligand HL and compounds 3 and
5 show maximum absorption at 309, 310 and 310 nm which
is mainly due to the n-p* transition of the C=S bond. Upon
the addition of various concentration of DNA this peak re-
sults in hypochromism (decrease in absorbance or molar
absorptivity) as well as hypsochromic shift along with mi-
nor blue shift upto 1 nm (Figs. 1-3). Hypochromism indi-
cates the intercalative mode involving a stacking interac-
tion between an aromatic chromophore and the base pair of
DNA. In intercalation, after binding to DNA, the p orbital
of the binding ligand could couple with the p orbital of base
pairs in the DNA. The coupling p orbital is partially filled
by electrons, thus decreasing the transition probabilities,
and hence resulting in the hypochromicity.32 The intrinsic
binding constant K of the ligand HL and complexes 3 and 5
were calculated in order to compare binding strengths of
ligand-DNA and complex-DNA by using Benesi-Hilde-
brand equation.33
Fig. 1. DNA binding study of HL by UV/visible spec-
troscopy (a) without DNA (b) 10 mM (c) 15 mM
(d) 20 mM (e) 25 mM (f) 30 mM (g) 40 mM (h) 45
mM (i) 50 mM (lmax at 309 nm, 1 nm blue shift).
Fig. 2. DNA binding study of complex 3 by UV/visible
spectroscopy (a) without DNA (b) 10 mM (c) 15
mM (d) 20 mM (e) 25 mM (f) 30 mM (g) 40 mM
(h) 45 mM (i) 50 mM (lmax at 310 nm, 1 nm blue
shift).
where K is the association constant, A0 and A are ab-
sorbance of the drug and its complex with DNA, respec-
tively, and eG and eH-G are the absorption coefficients of the
drug and drug-DNA complex, respectively. In order to
compare quantitatively, the binding strength of the ligand
HLand its complexes with DNA, the intrinsic binding con-
stants (K or Kb) were obtained by examining the changes
in the absorbance for the complexes with increasing con-
centration of DNA. Kb was obtained from the ratio of slope
to the intercept from the plot of 1/[DNA] versus Ao/A–Ao.
The intrinsic binding constant values (Kb) for the HL,
complexes 3 and 5 were found to be 9.0 ´ 103, 3.6 ´ 105 and
3.8 ´ 105 M-1, respectively. The interaction with DNA is a
Fig. 3. DNA binding study of complex 5 by UV/visible
spectroscopy (a) without DNA (b) 10 mM (c) 15
mM (d) 20 mM (e) 25 mM (f) 30 mM (g) 40 mM
(h) 45 mM (i) 50 mM (lmax at 310 nm, 1 nm blue
shift).
J. Chin. Chem. Soc. 2015, 62, 728-738
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Article
Javed et al.
3 and 5, respectively.
HOMO and LUMO energies are given in Table 13.
Semi-empirical study
Potential applications
In geometrically optimized structures of two repre-
sentative complexes 1 and 5, both sulphur atoms of ligand
HL bonds to tin in a bidentate way which is also confirmed
by FT-IR data. The other positions are occupied by methyl
or phenyl groups. The Sn-C and Sn-S bonds are typical.34
The bond angles and bond lengths are given in Tables 10
and 11, respectively.
The investigated compounds have proved to have po-
tential against bacterial, fungal, viral infections, cytotoxic,
DNA binding and protein kinase activities.
It is well known that a large HOMO-LUMO gap indi-
cates stable molecule with chemical reactivity, while a
small EHOMO is associated with unstable molecule with high
chemical reactivity. The ability of the molecule to donate
electrons, (ionization potential), ELUMO represents (elec-
tron affinity), and electrophilicity values (w = m2/2h),35
chemical potential values m = -(I+A)/2,36 global hardness
(h = I-A/2) values37 and global softness values (S = 1/2h)37
have been calculated in each case (Table 12).
Computed positive heats of formation indicate that
compound 5 is thermodynamically unstable as compared to
compound 1 (Table 10). The calculated HOMO and LUMO
orbitals of complexes 1 and 5 are shown in Figs. 4 and 5, re-
spectively. In organotin complexes, the HOMO orbital is
primarily located on a sulphur moiety. The calculated
Fig. 4. HOMO-LUMO of complex 1.
Table 10. Selected Bond angles (°) of complexes 1 and 5
1
5
S-C-S
C-Sn-C
116.0, 116.4
132.3
115.1
105.7,117.7,106.2
Table 11. Selected Bond Lengths (Å) of complexes 1 and 5
1
5
Sn-S
C-O
C-S
2.82, 2.66
1.34, 1.46, 1.46, 1.34
1.74, 1.69, 1.74, 1.69
2.66
1.34, 1.46
1.73, 1.68
Table 12. Computed molecular descriptors
Fig. 5. HOMO-LUMO of complex 5.
Comp. No.
1
5
HOMO energy (eV)
LUMO energy (eV)
-9.20307
-2.38196
-6.82111
3.410555
0.146604
-5.79252
4.919028
1.366
-9.17988
-1.92413
-7.25575
3.627875
0.137822
-5.55201
4.248322
1.577
Table 13. Computed thermodynamic parameters
HOMO-LUMO (eV)
Global hardness (h, eV)
Global softness (S, eV-1)
Chemical potential (m, eV)
Electrophilicity (w)
Parameters at 298K
1
5
Heat of formation (KCal/mole)
Enthalpy (KCal/mole-K)
-31.835
12217.8013 12549.8310
87.097
Entropy (KCal/mole-K)
Heat capacity (Cp) (Cal/mole-K)
136.9073
73.4253
137.5329
83.1424
Dipole moment (debyes)
734
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Biologically Active Organotin(IV) Complexes
EXPERIMENTAL
solved in toluene (100 ml) in a round bottom two necked flask
(250 ml) with continuous stirring. Then R2SnCl2/R3SnCl (2
mmol/1 mmol) was added in portions as solid in above solution
and reaction mixture was refluxed for 8 hr (Scheme 1). The potas-
sium chloride formed was filtered off and the solvent was evapo-
rated through rotary evaporator under reduced pressure. The solid
product obtained was recrystallized from chloroform and n-hex-
ane (1:1).
Chemicals and Instrumentation: All organotin(IV) chlo-
rides, isopropanol, potassium hydroxide, carbon disulfide, p-
nitrophenylphosphate hexahydrate (p-NPP), diethanolamine and
magnesium chloride were purchased from Sigma Aldrich and
used as such. Solvents such as ethanol, chloroform, toluene, di-
ethyl ether, and petroleum ether were purified before use accord-
ing to reported methods.38,39 Melting points were recorded with a
Bio-Cote Model SMP10 melting point apparatus and are uncor-
rected. Infrared spectra were recorded in the range 4000-250 cm-1
with Thermo Scientific Nicolet-6700 FTIR as KBr/CsBr pellets,
whereas NMR spectra were obtained on Bruker Avance 300 MHz
NMR spectrometers. Absorption spectra were measured on a
UV/visible spectrophotometer, Shimadzu 1800, at 25 ± 1 °C. So-
dium salt of DNA (Acros) was used as received. Solutions of
DNA in 10 mmolL-1 phosphate buffer (pH = 7.0) gave a ratio of
UV absorbance at 260 and 280 nm, A260/A280, of 1.8–1.9, indicat-
ing the purity of DNA. Concentrated stock solution of DNA was
prepared in 10 mmolL-1 phosphate buffer (pH = 7.0) and the con-
centration was determined by UV absorbance at 260 nm after
1:100 dilutions. The molar absorption coefficient has been taken
as 6600 mol-1cm-1. Stock solutions were stored below 4 °C and
used within 4 days.
UV-Vis spectroscopy: SS-DNA(salmon sperm-DNA) (0.3
g) was dissolved in double deionized water (100 ml) and kept stir-
ring at 4 °C for 2 days. Doubly distilled water was used to prepare
buffer (20 mM phosphate buffer (NaH2PO4–Na2HPO4), pH =
7.3). A solution of (SS-DNA) in the buffer gave a ratio of UV
absorbance at 260 and 280 nm (A260/A280) of 1.8, indicating that
DNA was sufficiently free of protein.40 The DNA concentration
was determined via absorption spectroscopy using the molar ab-
sorption coefficient of 6600 M-1cm-1 at 260 nm,41 and was found
as 1.76 ´ 10-4 M. From this stock solution, 20, 40, 63, 83, 105, 125
and 170 mM working solutions were prepared by dilution method.
The complexes were dissolved in 10% DMSO at a concentration
of 3 ´ 10-5 M. The UV absorption titrations were performed by
keeping the complexes concentration fixed while varying the
concentration of DNA. Equivalent solutions of DNA were added
to the complex and reference solutions to eliminate the ab-
sorbance of DNA itself. Compound-DNA solutions were allowed
to incubate for 30 minutes at ambient temperature before mea-
surements were made. Absorption spectra were recorded using
cuvettes of 1 cm path length. The DNA-binding constants of the
compounds were calculated by UV/vis spectroscopy using fol-
lowing equation:
Procedure for the synthesis of Potassium o-isopropyl
carbonodithioate HL: Isopropanol (1 mmol), potassium hydro-
xide (1 mmol) and carbon disulfide (1 mmol) were continuously
stirred in round bottom flask (250 ml) at room temperature for 4
hr (Scheme 1). Precipitate obtained were filtered off and dried in
air.
Scheme 1
Intercept to slope ratio of the plot 1/[DNA] versus Ao/A–Ao
gives the value of binding constant K.42
Protein kinase inhibition study: Protein kinase inhibition
was performed by disc diffusion method.27 Streptomycin (Ac-
tinobacter) culture was used for determination of protein kinase
inhibition potential of samples. Tryptic soya broth (Merck) was
autoclaved at 121 °C for 15 minutes and the strain was refreshed
in the sterilized media for 24 hours at 30 °C. Mineral media are
self prepares media with combination of different salts and agar
for Streptomyces growth and it was autoclaved at the same speci-
fications as that of TSB. Media was poured in pre-sterilized petri
plates and allowed to solidify at room temperature. After setting,
activated streptomycin strain was swabbed on solidified media
General procedure for the synthesis of organotin(IV)
complexes with Potassium o-isopropyl carbonodithioate 1-5:
The potassium o-isopropyl carbonodithioate (1 mmol) was dis-
J. Chin. Chem. Soc. 2015, 62, 728-738
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735

Article
Javed et al.
with the help of sterilized cotton plug. Then test samples were
prepared in DMSO (20 mM) and the 5 ml of the solution was
placed on the sterilized filter paper disc at the final concentration
of 100 mM. The discs were placed above media at their respective
labeled positions. These plates were incubated at 28 °C for 48-72
hours. After incubation period, zone around each disc with no
growth were measured for determination of protein kinase inhibi-
tion activity of the samples. Assay was performed in triplicate and
the average reading was taken.
each standard drug was prepared by dissolving 4 mg/1 ml of
DMSO. DMSO was used as negative control. Zones of inhibition
were measured after 24 hr.
Antileishmanial assay: Leishamania tropica kwh23 strain
was maintained in fresh medium 199 Merck (Merck KGaA, Ger-
many) at 24 °C for 7 days to get log phase of growth. The medium
contained Fetal Bovine Serum at concentration of 10%. The ex-
periment was performed as per procedure of Nabi et al., with
slight modification.43 Stock solutions of 10, 000 ppm of the com-
pounds were prepared in DMSO. The assay was carried out at dif-
ferent concentrations (200, 20, 2, 0.2, 0.02, 0.002, 0.0002 and
0.00002 ppm). The medium containing culture were inoculated in
96 well plates and incubated with test samples at 24 °C for 24 hr
after serial dilution. Positive (Amphotericin. B) and negative
(DMSO) control of the assay were also maintained. The experi-
ment was performed in triplicates. After required time of incuba-
tion, the live parasites of leishmania were counted using im-
proved neubauer chamber under compound microscope. The data
was statistically analyzed through Graph Pad Prism software 5.0.
Cytotoxicity assay: Cytotoxicity was study by the brine-
shrimp lethality assay method.44,45 Brine-shrimp (Artemia salina)
eggs were hatched in artificial sea water (3.8 g sea salt/L) at room
temperature (22–29 °C). After two days, these shrimps were
transferred to vials containing 5 ml of artificial sea water (8
shrimps per vial) with 1000, 500, 250, 125, 31 and 16.5 mg/ml in
DMSO. After 24 h number of surviving shrimps was counted.
Data was analyzed with a slide write program.
Antifungal activity: The antifungal activity was deter-
mined by using five fungal strains i.e., Aspergillus niger, Asper-
gillus flavus, Aspergillus fumigates, Fusarium solani and mucor
specie. The disc diffusion method was employed.27 Sabouraud
dextrose agar (SDA) (Sigma-Aldrich Germany) medium was
autoclaved at 121 °C for 15 minutes. The media was allowed to
cool at 50 °C and 25 ml quantity of it was poured in pre-sterilized
petri plates. Plates were then allowed to solidify in upright posi-
tion at room temperature. Each fungal culture was streaked on the
petri plates. Test samples were prepared in DMSO (20 mM) and 5
ml of the solution was placed on the sterilized filter paper disc at
the final concentration of 100 mM. The discs were placed on the
media and the plates were incubated at 37 °C for 24 hr. DMSO and
clotrimazole (1 mgml-1) were used as negative and positive con-
trol, respectively. After period of incubation, diameter of the clear
zones with no fungal growth around each disc was measured.
Triplicate plates were prepared for each fungal strain. Then aver-
age of these three plates was taken.
Antibacterial activity: The ligand and organotin(IV) com-
plexes were tested against five bacterial strains; Two gram posi-
tive strains (M. luteus, S. aureus) and three gram negative (B.
bronchiseptica, S. typhimurium, A. aerogens). The disc diffusion
method was used for the determination of antibacterial activity.27
Each complex (10 mg) was dissolved in 1 ml of DMSO, for the
production of stock solution of each complex. Final concentration
of 30 mg/disc of each complex was used in assay. Bacterial
inoculum was prepared in nutrient broth (Sigma-Aldrich Ger-
many). It was prepared by dissolving 2 g of nutrient broth in 100
ml of water and pH was maintained to 7. Filter paper discs of 6
mm in size ware prepared from whatman filter paper no.1. Media,
filter paper discs along with other apparatus required in this assay
were autoclaved for sterilization. After autoclaving, whole exper-
iment was carried out in microbiological safety cabinet. Solidi-
fied plates of nutrient agar were labeled and respective bacterial
strain was streaked. Then complex solution (10 ml) was absorbed
on disc. These discs were placed on respective place in petri plate.
These petri plates were incubated for 24 hr at 28 °C. Cefixime-
USP and roxithromycin were used as standard drugs. Stock of
Semi-empirical study: The semi-empirical study was
done by MOPAC 200746 program in gas phase using PM3 me-
thod.47 Selected parts of the complexes not containing the metal
ion were pre-optimized using molecular mechanics methods.
Several cycles of energy minimization had to be carried for each
of the molecules. Geometry was optimized using Eigen Vector.
The Root Mean Square Gradient for molecules was all less than
one. Self-Consistent Field was achieved in each case. Absences
of imaginary frequencies were checked consistently.
CONCLUSIONS
The ligand was treated with different di- and tri-
organotin(IV) chlorides to form the corresponding com-
plexes which coordinates through sulphur. IR data showed
the bidentate nature of ligand in complexes 1-3 and 5 and
monodentate mode in case of complex 4, which was also
confirmed by NMR and semi-empirical studies. NMR data
showed 6-coordinated (compexes 1-3), 4-coordinated
(complex 4) and 5-coordinated geometry (complex 5) in
solution. HOMO-LUMO calculations showed that com-
736
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J. Chin. Chem. Soc. 2015, 62, 728-738

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Biologically Active Organotin(IV) Complexes
17. Vogel, A. I. A Text Book of Practical Organic Chemistry;
ELBS Publications: London, 1968.
plex 5 is thermodynamically unstable as compared to com-
plex 1. DNA interaction study showed the hypochromic
shift due to intercalative mode involving stacking interac-
tion between an aromatic chromophore and base pair of
DNA. The negative values of Gibb’s free energy change
confirmed the spontaneity of these interactions. Anti-
microbial activity data showed that triorganotin complexes
exhibited greater antimicrobial activity as compared to
diorganotin complexes. LC50 data revealed that complexes
can cause inhibition at lower concentration as compared to
standard drug while LD50 data proved that all complexes
are toxic.
18. Jabbar, S.; Shahzadi, I.; Rehman, R.; Iqbal, H.; Qurat-ul-
Ain.; Jamil, A.; Kaosar, R.; Ali, S.; Shahzadi, S.; Chaudhary,
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ACKNOWLEDGEMENT
23. Singh, H. L.; Varshney, A. K. Inter. Bioinorg. Chem. Appl.
2006, 2006, 1.
Fatima Javed (PIN # 117-7469-PS7-018) is thankful
to Higher Education Commission (HEC), Islamabad, Paki-
stan, for the financial support.
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