Synthesis, characterization and antileishmanial studies of some bioactive heteroleptic pentavalent antimonials

Article abstract of DOI:10.1002/aoc.3606

In pursuit of safe drug candidates for the treatment of parasitic diseases like leishmaniasis, a series of heteroleptic pentavalent antimonials of the type [R₃Sb(O₂CR′)₂] (1–9) have been synthesized and characterized using elemental analysis (CHN), Fourier transform infrared spectroscopy and multinuclear (¹H and ¹³C) NMR spectroscopy. The carboxylates studied are predominantly substituted benzoates with some complexes having acetato or nicotinato ligands. The crystal structures of [Sb(C₆H₅)₃(o-NH₂C₆H₄COO)₂] (1) and [Sb(C₆H₅)₃(3,5-Cl₂C₆H₃COO)₂] (4) were determined as essentially monomeric with an Sb(V) centre and shown to adopt geometries intermediate between trigonal bipyramidal and square pyramidal. The antileishmanial activity was assessed against Leishmania tropica KWH23, and also human macrophages were used to measure the cytotoxicity of these complexes. The IC₅₀ of the antimonials 1–9 indicates their efficaciousness as compared with the standard antimonial drug used. The significant activity of complex 1 assumes that greater multitude of interactions is the cause of enhanced antileishmanial activity. Cytotoxicity results showed that these antimonials are highly active even at low concentrations and are biocompatible with human macrophages, making them promising drug candidates for further investigations in this field.

Full text of DOI:10.1002/aoc.3606

Received: 1 April 2016
DOI 10.1002/aoc.3606
Revised: 2 July 2016
Accepted: 8 August 2016
F U L L PA P E R
Synthesis, characterization and antileishmanial studies of some
bioactive heteroleptic pentavalent antimonials
1
1
Rabia Mushtaq | Muhammad Khawar Rauf | Michael Bolte2 | Akhtar Nadhman3 |
*
1
Amin Badshah | Muhammad Nawaz Tahir4 | Masoom Yasinzai3 | Khalid Mohammed Khan5
*
1 Department of Chemistry, Quaid‐i‐Azam
University, Islamabad 45320, Pakistan
In pursuit of safe drug candidates for the treatment of parasitic diseases like
2 Institut für Anorganische Chemie, J.W.
Goethe‐Universität Frankfurt, Max‐von‐Laue‐Str.
7, 60438 Frankfurt/Main, Germany
leishmaniasis, a series of heteroleptic pentavalent antimonials of the type [R3Sb
(O2CR′)2] (1–9) have been synthesized and characterized using elemental analysis
(CHN), Fourier transform infrared spectroscopy and multinuclear (1H and 13C)
NMR spectroscopy. The carboxylates studied are predominantly substituted
benzoates with some complexes having acetato or nicotinato ligands. The crystal
structures of [Sb(C6H5)3(o‐NH2C6H4COO)2] (1) and [Sb(C6H5)3(3,5‐
Cl2C6H3COO)2] (4) were determined as essentially monomeric with an Sb(V)
centre and shown to adopt geometries intermediate between trigonal bipyramidal
and square pyramidal. The antileishmanial activity was assessed against Leishmania
tropica KWH23, and also human macrophages were used to measure the cytotoxic-
ity of these complexes. The IC50 of the antimonials 1–9 indicates their efficacious-
ness as compared with the standard antimonial drug used. The significant activity of
complex 1 assumes that greater multitude of interactions is the cause of enhanced
antileishmanial activity. Cytotoxicity results showed that these antimonials are
highly active even at low concentrations and are biocompatible with human
macrophages, making them promising drug candidates for further investigations in
this field.
3 Sulaiman Bin Abdullah Aba Al Khail Centre for
Interdisciplinary Research in Basic Sciences
(SA‐CIRBS), International Islamic University,
Islamabad 44000, Pakistan
4 Department of Physics, University of Sargodha,
Sargodha, Pakistan
5 HEJ Research Institute of Chemistry, International
Center for Chemical and Biological Sciences,
University of Karachi, Karachi 75270, Pakistan
Correspondence
Muhammad Khawar Rauf or Amin Badshah,
Department of Chemistry, Quaid‐i‐Azam
University, Islamabad 45320, Pakistan.
Email: mkhawarrauf@yahoo.co.uk;
aminbadshah@yahoo.com
KEYWORDS
carboxylato pentavalent antimonials, cytotoxicity, Leishmania tropica KWH23,
leishmanicidal
1
|
INTRODUCTION
Protein crystallographic studies of Leishmania trypanothione
reductase have disclosed the actual mechanism of enzyme
inhibition by antimonials. It was shown that trivalent anti-
mony binds to the protein active site with high affinity,
strongly inhibiting enzyme activity.[7] The metal binds
directly to Cys52, Cys57, Thr335 and His461, thereby
blocking hydride transfer and trypanothione reduction. The
observed Sb–protein interaction is consistent with the usual
modalities of cysteine binding of thiophilic metals such as
As(III), Sb(III) and Bi(III). Such metal‐dependent inhibition
of thiol reductases opens the way to combined metal therapy
of leishmaniasis. It is very likely that this enzyme is similarly
inhibited by other classes of metal complexes that are soft
Lewis acids.
The medicinal chemistry of carboxylic acids has been a sub-
ject of investigations in life sciences, particularly for their
antipyretic, anti‐inflammatory and in vitro anti‐carcinoma
properties.[1–3] Metal–organic assemblies with such types of
biologically active ligands are of increased interest for inor-
ganic, pharmaceutical and medicinal chemists, as an
approach to the development of highly effective metal‐based
drugs.[4] In the past few years, various gold(III), palladium
(II) and rhenium(V) cyclometallated complexes have been
investigated as potential inhibitors of different cysteine prote-
ases in the search for metal‐based drugs suitable not only for
American trypanosomiasis but also for leishmaniasis.[5,6]
Appl Organometal Chem 2016; 1–8
wileyonlinelibrary.com/journal/aoc
Copyright © 2016 John Wiley & Sons, Ltd.
1

2
MUSHTAQ ET AL.
Over the past few decades, the use of antimony
compounds in medicine has attracted much attention of
inorganic biochemists as anti‐protozoal drugs. The major
clinical uses of antimony compounds are for treatment of
leishmaniasis.[8–11] The pentavalent antimonials like sodium
stibogluconate (Pentostam) and meglumine antimoniate
(Glucantime) are clinically used against leishmaniasis,
although it is found that antimony(V) is reduced to anti-
mony(III) in vivo.[12–14] The exact mode of action of these
drugs is yet to be explored comprehensively. There have been
speculations as to whether Indian Leshmania donovani has
become truly resistant to Sb(V); studies reveal that this is true
to some extent in some areas of South Asia due to inadequate
regimens followed by unqualified local practitioners.[15,16]
The needs for new antileishmanial drugs have been
highlighted in recent decades by the expression of acquired
resistance to the pentavalent antimonial drugs, still first‐line
antileishmanial agents worldwide. Besides post‐clinical
issues, the inherent problems associated with the existing
pentavalent antimonials are degree of purity, exact structure
and shelf‐life reliability. The synthesis of antimony(V)
organometallics of the types R3SbX2 and R3Sb(O2R′)2 and
their screening for leishmanicidal properties are a part of
our ongoing project for the development of tri/pentavalent
antimonial drugs for leishmaniasis therapies.[17–19] The
versatile bonding pattern around the Sb(V) centre and the
load of pharmacophore substituents may lead to a different
mode of action and enhanced efficacy as compared to the
existing metal–organic pentavalent antimonials.
SCHEME 1 Synthesis of complexes 1–9
from 1670 to 1700 cm−1. The lowering of the wavenumber
by 35–45 cm−1 for the symmetric and asymmetric carboxyl-
ate stretching bands on formation of the antimony(V)
carboxylato complexes indicates the metal–carboxylate
linkage. The characteristic absorptions observed in the lower
wavenumber region at 584–545 and 486–480 cm−1 corre-
spond to SbꢀC deformations and the SbꢀO stretching mode,
respectively, both of which are consistent with literature
reports.[17,23–25]
The γ(CH) band at 725–735 cm−1 indicates the presence
of the aryl group. The value of Δν (νCO2(asymm) − νCO2
(symm)) is less than 200 cm−1 for all the complexes. This is
indicative of the carboxylato ligands adopting a unidentate
binding mode[26] in all of the synthesized complexes and is
consistent with the crystal structures obtained for 1 and 4.
The NMR spectra of the complexes were recorded in CDCl3
at room temperature. All the complexes show a high fre-
quency shift in the H and C resonances for the carboxylate
ligands relative to those observed in the NMR spectra of
the free acids. In addition, the NMR spectra of the anti-
mony(V) complexes show resonances for the aromatic pro-
tons in the expected range of 6.86–8.23 ppm.[27,28]
2
| RESULTS AND DISCUSSION
2.1 | Synthesis and spectroscopic characterization
The preparation of triorganoantimony(V) carboxylates has
been realized using a variety of synthetic methods as reported
in the literature.[20,21] The most used methods are the reaction
of triorganoantimony(V) halides with two equivalents of
carboxylic acids and triethylamine or with carboxylate
salts of alkali metals (Na+/K+) or silver (Ag+).[17,22] The
synthesis of dicarboxylato complexes of Sb(V) (1–9) was
achieved using
a salt metathesis reaction in which
triorganoantimony(V) bromide was treated with the sodium
salt of a carboxylic acid in toluene (Scheme 1).
2.2 | Structural characterizations
After stirring at room temperature under dry nitrogen
atmosphere for 10–12 h, all solids were removed by filtration
and the product was collected through removal of the solvent
from the filtrate under reduced pressure. The products were
recrystallized from toluene–dichloromethane (1:1). The final
complexes [SbR3(O2CR′)2] were confirmed through 1H
NMR, 13C NMR and Fourier transform infrared (FT‐IR)
spectroscopies and elemental analysis. Full analytical details
for each of 1–9 are provided in Section 4. The FT‐IR spectra
of the acids show the stretch for the carboxyl group ranging
The antimony(V) complexes 1 and 4 are five‐coordinate with
geometries intermediate between trigonal bipyramidal and
square pyramidal. In the trigonal bipyramidal configuration,
the monodentate carboxylate ligands occupy axial position
with a syn conformation and the phenyl moieties rest at equa-
torial positions, while in the square pyramidal configuration
the C7–C12 (for 1) or C13a–C18a (for 4) phenyl group is api-
cal. The molecular structure of complex 1 is presented in
Figure 1 and of complex 4 in Figure 2.

MUSHTAQ ET AL.
3
TABLE 1 Crystallographic data for 1 and 4
1
4
Formula
C
32H27N2O4Sb
625.30
C32H21Cl4O4Sb
733.04
Formula weight
Crystal system
Space group
a (Å)
Orthorhombic
Pccn
Triclinic
P1
19.9860(4)
16.5608(3)
16.9796(4)
11.8863(4)
12.1976(5)
13.4850(8)
b (Å)
c (Å)
α, β, γ (°)
90
90
90
106.764(2)
100.831(2)
117.6370(10)
V (Å3), Z
5620.0(2), 8
296(2)
1534.53(12), 2
296(2)
T (K)
DC (Mg m−3), μ (mm−1
F(000)
Crystal size (mm3)
)
1.478, 1.021
2528
1.586, 1.283
728
FIGURE 1 Molecular structure of 1 with labels for the core atoms only.
Hydrogen atoms are drawn as circles of arbitrary radii.
0.30 × 0.28 × 0.24
1.997 to 27.000
0.38 × 0.28 × 0.26
1.704 to 27.000
θ range (°)
Index ranges
−17 ≤ h ≤ 25
−12 ≤ k ≤ 21
−20 ≤ l ≤ 21
−14 ≤ h ≤ 15
−15 ≤ k ≤ 13
−17 ≤ l ≤ 16
Reflections collected
24 886
6093, 0.0286
99.7
22 464
6615, 0.0271
98.7
Independent reflections [R(int)]
Completeness to θ (%)
Max. and min. Transmission
Data/restraints/parameters
Goodness‐of‐fit on F2
0.738 and 0.771
9310/0/519
1.012
0.645 and 0.733
6615/0/401
1.060
R1 [I > 2σ(I)], wR2 [all data]
0.0281, 0.0746
0.320, −0.491
0.0249, 0.0642
0.353, −0.594
Largest peak, hole (e Å−3
)
the apical phenyl and basal carboxylate ligands indicate
that the carboxylate ligands are distorted above the basal
plane. Similar distortions are found for related complexes
in the Cambridge Structural Database. SbꢀC bond
lengths average 2.122(3) and 2.134(3) Å for structures
1 and 4, respectively. The average SbꢀC bond lengths
for these two structures fall within the range 2.089–
2.130 Å, most frequently observed for similar
complexes.[17] Selected geometrical parameters are
presented in Tables 2 and 3.
The crystal packing in 1 (orthorhombic Pccn) compared
to 4 (triclinic P1) has a more complicated unit cell packing
in which double layers of Sb(V) complexes are stacked along
c (Figure 3).
In the crystal structure of 1, molecules are connected
through CꢀH⋅⋅⋅N and NꢀH⋅⋅⋅O intermolecular and
NꢀH⋅⋅⋅O and CꢀH⋅⋅⋅O intramolecular interactions forming
a three‐dimensional network extending throughout the crystal
system (Figure 4). Molecular structures with greater
multitude of interactions are considered to be very potent
regarding biological activities as evident from 1 and 3. The
crystal structure of 4 is stabilized via CꢀH⋅⋅⋅Cl and Cl⋅⋅⋅Cl
interactions along c‐axis forming R44ð32Þ type motifs
(Figure 5).
FIGURE 2 Molecular structure of 4 with labels for the core atoms only.
Hydrogen atoms are drawn as circles of arbitrary radii.
The geometries in these complexes closely conform to
those typically found for complexes with essentially syn
monodentate carboxylate ligands in approximately 53 similar
compounds listed in the Cambridge Structural Database (four
additional compounds listed in the database are with carbox-
ylate ligands serving as bidentate and monodentate as well).
The 2‐aminobenzoato (1) and 3,5‐dichlorobenzoato (4)
ligands show average CꢀO bond lengths of 1.271(3) and
1.261(3) Å, respectively. The SbꢀO bond lengths for these
complexes cluster at comparatively larger values of 2.1286
(18) and 2.1134(15) Å. The non‐ligating Sb⋅⋅⋅O contacts,
involving oxygen atoms, are in the range 2.726–3.010 Å,
a contact range that has been most frequently found for
similar complexes.[17] Details of the data collection and
structure refinement parameters are summarized in
Table 1.
The benzoato ligands are almost coplanar in both
complexes (angle between mean plane normals of 10.50
(5)° and 3.77(5)° for 1 and 4, respectively). O–Sb–C(7)
(for 1) or O–Sb–C(13a) (for 4) angles <90° between

4
MUSHTAQ ET AL.
TABLE 2 Selected bond lengths (Å) and angles (°) for 1and 4
1
Sb(1)–C(1)
Sb(1)–C(13)
Sb(1)–C(7)
Sb(1)–O(1)
Sb(1)–O(3)
O(1)–C(19)
4
2.117(3)
2.121(3)
C(1)–Sb(1)–C(1)
C(1)–Sb(1)–C(13)
C(1)–Sb(1)–C(7)
C(13)–Sb(1)–O(1)
C(7)–Sb(1)–O(11)
C(1)–Sb(1)–O(3)
90.94(8)
149.91(12)
103.81(10)
90.77(8)
2.130(3)
2.1195(18)
2.1377(18)
1.299(3)
87.67(9)
90.57(8)
Sb(1)–C(1)
Sb(1)–C(7)
Sb(1)–O(1)
Sb(1)–O(3)
O(2)–C(19)
O(1)–C(19)
2.108(2)
2.106(2)
C(15)–C(8)–Sb(1)
C(7)–Sb(1)–C(1)
Sb(1)–O(1)–C(19)
Sb(1)–O(3)–C(26)
C(7)–Sb(1)–O(1)
C(1)–Sb(1)–O(3)
118.70(14)
139.05(9)
118.70(14)
111.62(13)
90.73(7)
2.1021(15)
2.1246(14)
1.211(3)
FIGURE 4 Supramolecular structure of complex 1 showing three‐dimen-
sional network of short contacts and hydrogen bonds stabilizing the crystal
structure.
1.309(3)
91.62(7)
TABLE 3 Intermolecular and intramolecular hydrogen bonds for 1
(hydrogen bond geometry: distance, Å; angle, °)
D–H···A
D–H
H···A
D···A
D–H···A
N(1)–H(1B)⋅⋅⋅O(2)
N(2)–H(2 A)⋅⋅⋅O(2)i
N(2)–H(2B)⋅⋅⋅O(4)
0.85(4)
0.79(4)
0.95(4)
2.13(4)
2.46(4)
1.99(4)
2.703(4)
3.175(4)
2.676(4)
124(3)
152(4)
127(4)
Symmetry codes: (i) − x + 1/2, −y + 3/2, z (1)
FIGURE 5 One‐dimensional view of 4 along c‐axis forming type motifs
stabilized by alternate Cl⋅Cl and CꢀH⋅Cl short contacts.
FIGURE 3 Unit cell packing for 1 in which double layers of Sb(V)
complexes are stacked along c.
2.3 | Antileishmanial activity
The potential of the pentavalent antimonials 1–9 to inhibit
Leishmania growth was evaluated using the Leishmania
tropica KWH23 strain promastigotes. All the compounds
show good to significant antileishmanial activity. On the
basis of significant IC50 values (Table S1 in the supporting
information), the compounds are categorized in the
following order: 1 > 3 > 5 > 6 > 4 > 2 > 7 > 9 > 8
(Figure 6) as compared with the standard Glucantime
(5.21
1.29 μg ml−1). Concentration‐dependent anti‐
FIGURE 6 Concentration‐dependentactivityofsynthesizedantimonials1–9.

MUSHTAQ ET AL.
5
TABLE 4 Cytotoxicity (LD50 µg ml−1) of the synthesized antimonials 1–9
anti‐leishmanial efficacy and low cytotoxicity, these
compounds are a better choice for further investigations as
antileishmanial therapeutic agents than the traditionally used
antimonials for the treatment of leishmaniasis. There is no
clear pattern yet about which features of the carboxylate
ligands make them more selective, and this is the focus of
our future studies to assess the antileishmanial activity,
biocompatibility and bio‐safety of such compounds in vivo.
However, the activity and selectivity pattern of compounds
1 and 3 reveal that the carboxylate ligands with greater
interactions show very good antileishmanial activity. In our
recent publication,[15] we have calculated the Clog P values
for about 25 pentavalent antimonials. The Sb(V) species Sb
(p‐CH3C6H4)3Br2 (a), Sb(m‐CH3C6H4)3Br2 (b), Sb(o‐
CH3C6H4)3Br2 (c) and SbPh3Br2 (d) have Clog P values of
6.5, 6.5, 6.5 and 5.0, respectively. With the incorporation of
carboxylate ligands the Clog P values increase (about
1.5–2.0 times) which is an indicator of increase in lipophilic-
ity. The Clog P values for carboxylic acids are between the
ranges of high hydrophilicity, i.e. 1 to 2. The antileishmanial
results for the carboxylate derivatives of Sb(V) species a–d
reveal that the substitution of ꢀCH3 group at o‐, m‐ and
p‐positions on the phenyl ring proved to be highly effective
against the parasite amastigotes at concentrations of
0.5–3.5 μM, although these organometallic antimony(V)
dicarboxylates have presented high values of Clog P
(6.9–13.8). The studies show that the antileishmanial
activities of these compounds are not very much dependent
on the Clog P factor. There is no clear mechanism yet as to
which features of the carboxylate ligands and the core Sb
(V) moieties make them more selective, and this is the focus
of future investigations. In future, the main focus of our stud-
ies is to explore the effect of lipophilicity by introducing
long‐chain aliphatic groups and the active species produced
during dissolution process. Also, the compounds are non‐
toxic towards mammalian cells at levels below 25 μM, mak-
ing them highly promising drug candidates.
Cytotoxicity
Standard
Triplicate
Average
LD50
error
Clog
P
Sample
LD50 values
(
SE)
1
2
3
4
5
6
7
8
9
21.0
24.9
10.3
22.39
19.1
35.9
20.8
17.9
19.80
19.15
25.22
10.99
18.92
18.1
21.20
27.7
12.4
21.28
20.10
36.8
22.6
17.8
20.6
20.45
25.94
11.23
20.86
19.10
35.93
21.59
18.24
20.93
0.652
0.884
0.617
1.023
0.577
0.491
0.529
0.391
0.765
6.909
10.361
12.339
12.215
7.551
35.1
6.369
21.39
19.02
22.39
9.867
9.867
11.455
promastigotes assay shows that these synthetic antimonials
directly annihilate Leishmania tropica parasites and hence
show leishmanicidal behaviour. It is found that all the com-
plexes are more potent against promastigotes. Among them,
complexes
1 and 3 exhibit excellent IC50 against
promastigotes. The significant activity of complex 1 assumes
that the presence of inter‐ and intramolecular interactions
makes the carboxylate ligands more interactive and thereby
increases the hydrophilic character of the metal complex
which also favours its absorption in biological fluids.
2.4 | Cytotoxicity
Cytotoxicity of the synthesized antimonials 1–9 was analysed
using macrophages isolated from human peripheral blood by
the ficollgastrografin method.[29,30] Leishmania has the
capability of attacking and proliferating in macrophages; thus
these cells were used for cytotoxicity analysis. The
percentage mortality for all the compounds was calculated.
It is found that the survival percentage is concentration
dependent. The results are in correlation with the drug
concentrations: more macrophages are viable at lower
concentrations and mortality rate is higher upon increasing
the dose. LD50 shows that all compounds 1–9 are biologically
active and less toxic or non‐toxic upon comparison with IC50
of Leishmania (Table 4).
4
| EXPERIMENTAL
Comparison of the LD50 of the compounds against
macrophages and Leishmania shows a clear difference, such
that these compounds can be further investigated for their
use as antileishmanial drugs.
4.1 | General remarks
All reactions were conducted under a nitrogen atmosphere
using standard Schlenk glassware techniques. The solvents
were distilled prior to use and stored under nitrogen over
activated molecular sieves. All manipulations were carried
out under the specified conditions of temperature. Solvents
were distilled from drying agents and degassed before use
using the ultrasonication technique.
NMR spectra were recorded with a Bruker ARX
spectrometer. 1H NMR (300 MHz): internal standard solvent,
CDCl3 (7.28 ppm from TMS); internal standard, TMS. 13C
NMR (75.47 MHz): internal standard solvent, CDCl3
(77.0 ppm from TMS); internal standard, TMS. The splitting
3
| CONCLUSIONS
The synthesis of compounds 1–9 is highly repeatable. The
activity of the compounds against Leishmania parasite and
the toxicity against human macrophage cells were evaluated.
For the leishmanicidal activity of compounds 1–9, the
differences reached values close to 100‐fold between macro-
phages and the host cell for Leishmania. Thus, owing to their

6
MUSHTAQ ET AL.
of proton resonances in the reported 1H NMR data are
defined as s = singlet, d = doublet, t = triplet, q = quartet
and m = complex pattern; coupling constants are reported
in Hz. FT‐IR spectra were recorded as KBr pellets with a
Bio‐Rad Excalibur FT‐IR model FTS 3000 MX
(400–4000 cm−1) and with attenuated total reflectance using
a PerkinElmer System 2000 (200–500 cm−1). Elemental
analyses were performed using a LECO‐932 CHNS analyser.
The Clog P values (n‐octanol–water partition coefficient)
were calculated using ChemBioDraw Ultra 2010
(PerkinElmer).
(SbꢀC), 457 (SbꢀO). 1H NMR (300 MHz, CDCl3, δ,
3
ppm): 2.39 (s, 6H, ꢀCH3), 7.18 (d, 4Hd,d´, J = 7.8 Hz),
3
7.49–7.54 (m, 9Hb,b´,j), 7.88 (d, 4Hc,c´, J = 8.1 Hz), 8.16
(dd, 6Ha,a´, 3J = 7.5 Hz, 4 J = 2.1 Hz). 13C NMR (75 MHz,
CDCl3, δ, ppm): 21.6 (2C, ꢀCH3), 128.8 (4Cd,d´), 129.4
(6Cb,b´), 129.9 (2C, CꢀC¼O), 130.0 (4Cc,c´), 131.1 (3Cj),
133.9 (6Ca,a´), 138.5 (3C, ipso‐C), 142.6 (2C, CꢀCH3),
170.3 (2C, C¼O). Anal. Calcd for C34H29O4Sb (%): C,
65.51; H, 4.69. Found (%): C, 65.46; H, 4.65.
4.3.3
| Bis[2‐(phenylamino)benzoato](triphenyl)antimony(V) (3)
Quantities used were 2.35 g (0.01 mol) of sodium salt of 2‐
(phenylamino)benzoic acid and 2.51 g (0.005 mol) of tris
(phenyl)antimony(V) dibromide in toluene. Yield 85%;
colourless solid; m.p. 155–156°C. FT‐IR (powder, cm−1):
3265 (ꢀNH),3026 (CꢀHaromatic), 1629 (C¼O), 564 (SbꢀC),
4.2 | General procedure for syntheses
All reactions were conducted using 0.005 mol of
triphenylantimony(V) dibromide precursor and 0.01 mol of
potassium or sodium salt of the respective carboxylic acid.
The reactants were placed in a Schlenk flask and dried in
vacuo prior to use. About 50 ml of dry toluene was then
added and the reaction mixture stirred at room temperature
for 12 h. The salt(s) formed were filtered off and the resulting
clear solution was removed under reduced pressure to yield a
solid residue. Synthesis and manipulation of all the
compounds were performed using a vacuum/argon line
following Schlenk techniques.[17,18] Toluene was distilled
over sodium benzophenone ketyl and further stored over
activated molecular sieves (4 Å) under nitrogen atmosphere.
1
448 (SbꢀO). H NMR (300 MHz, CDCl3, δ, ppm): 6.74
3
4
(td, 2He, J = 7.2 Hz, J = 1.8 Hz), 7.07 (t, dds appeared
as t, 2Hh, J = 7.2 Hz), 7.16–7.18 (m, 4Hg,f), 7.23–7.35
3
(m, 8Hc,c´,d,d´), 7.51–7.54 (m, 9Hb,b´,j), 8.04 (d, 2Hi,
3
4
3J = 8.1 Hz), 8.16 (dd, 6Ha,a´, J = 7.2 Hz, J = 2.4 Hz),
9.54 (s, 2H, ꢀNHꢀ). 13C NMR (75 MHz, CDCl3, δ, ppm):
113.7 (2C, CꢀC¼O), 114.7 (4Cc,c´), 116.8 (2Cg), 122.2
(6Cb,b´), 122.9 (2Ce), 129.2 (4Cd,d´), 129.6 (6Ca,a´), 131.3
(2Ci), 132.7 (2Cf), 133.4 (2Ch), 133.8 (3Cj), 138.5 (2C,
ipso‐C), 141.2 (2C, C6H4ꢀNHꢀC), 147.5 (3C,
CꢀNHꢀC6H6), 172.3 (2C, C¼O). Anal. Calcd for
C44H35N2O4Sb (%): C, 67.97; H, 4.54; N, 3.60. Found (%):
C, 67.95; H, 4.49; N, 3.64.
4.3 | Synthesis and characterization data for 1–9
4.3.1
| Bis(2‐aminobenzoato)(triphenyl)antimony(V) (1)
4.3.4
| Bis(3,5‐dichlorobenzoato)(triphenyl)antimony(V) (4)
Quantities used were 1.59 g (0.01 mol) of sodium salt of
2‐aminobenzoic acid and 2.51 g (0.005 mol) of tris(phenyl)
antimony(V) dibromide in toluene. Yield 83%; colourless
solid; m.p. 210–211°C. FT‐IR (powder, cm−1): 3094
(CꢀHaromatic), 3455, 3345 (CꢀNH2), 1663 (C¼O), 562
(SbꢀC), 463 (SbꢀO). 1H NMR (300 MHz, CDCl3, δ,
ppm): 5.61 (sbroad, 4H, ꢀNH2), 6.58 (d, 2Hf, J = 8.1 Hz),
Quantities used were 2.13 g (0.01 mol) of sodium salt of 3,
5‐dichlorobenzoic acid and 2.51 g (0.005 mol) of tris(phe-
nyl)antimony(V) dibromide in toluene. Yield 84%; colourless
solid; m.p. 145–146°C. FT‐IR (powder, cm−1): 3068
(CꢀHaromatic), 1647 (C¼O), 739 (CꢀCl), 583 (SbꢀC), 444
(SbꢀO). 1H NMR (300 MHz, CDCl3, δ, ppm): 7.44 (st, 3He,
4J = 2.1 Hz), 7.56–7.59 (m, 9Hb,b´,j), 7.80 (sd, 4Hc,c´
,
3
6.64 (t, dds appeared as t, 2Hd, J = 7.2 Hz), 7.22 (td, dds
4J = 2.1 Hz), 8.12 (dd, 6Ha,a´, J = 7.2 Hz, J = 2.4 Hz).
13C NMR (75 MHz, CDCl3, δ, ppm): 128.3 (4Cc,c´), 129.7
(6Cb,b´), 131.6 (3Cj), 131.8 (2C, CꢀC¼O), 133.7 (6Ca,a´),
134.8 (4C, CꢀCl), 135.5 (2Ce), 136.9 (3C, ipso‐C), 167.5
(2C, C¼O). Anal. Calcd for C32H21Cl4O4Sb (%): C, 52.43;
H, 2.89. Found (%): C, 52.40; H, 2.85.
3
4
3
4
appeared as td, 2He, J = 8.4 Hz, J = 1.5 Hz), 7.49–7.55
(m, 9Hb,b´,j), 7.94 (dd, 4Hc, J = 7.8 Hz, J = 1.5 Hz),
3
4
8.13 (dd, 6Ha,a´, J = 7.2 Hz, J = 2.1 Hz). 13C NMR
(75 MHz, CDCl3, δ, ppm): 113.2 (2C, CꢀC¼O), 115.9
(2Cf), 116.4 (2Cd), 129.4 (6Cb,b´), 130.9 (3Cj), 132.3 (2Cc),
133.4 (2Ce), 133.7 (6Ca,a´), 139.2 (3C, ipso‐C), 150.4 (2C,
CꢀNH2), 172.4 (2C, C¼O). Anal. Calcd for C32H27N2O4Sb
(%): C, 61.46; H, 4.35; N, 4.48. Found (%): C, 61.40; H,
4.33; N, 4.51.
3
4
4.3.5
| Bis(propanoato)(triphenyl)antimony(V) (5)
Quantities used were 0.96 g (0.01 mol) of sodium salt of
propanoic acid and 2.51 g (0.005 mol) of tris(phenyl)anti-
mony(V) dibromide in toluene. Yield 85%; colourless solid;
m.p. 121–123°C. FT‐IR (powder, cm−1): 3057 (CꢀHaromatic),
2974–2937 (CꢀHaliphatic), 1647 (C¼O), 555 (SbꢀC), 458
(SbꢀO). 1H NMR (300 MHz, CDCl3, δ, ppm): 0.93 (t,
4.3.2
| Bis(4‐methylbenzoato)(triphenyl)antimony(V) (2)
Quantities used were 1.58 g (0.01 mol) of sodium salt of
4‐methylbenzoic acid and 2.51 g (0.005 mol) of tris(phenyl)
antimony(V) dibromide in toluene. Yield 84%; colourless
solid; m.p. 233–235°C. FT‐IR (powder, cm−1): 3054
(CꢀHaromatic), 2920 (CꢀHaliphatic), 1611 (C¼O), 550
6Hb, CH3 ꢀCH2 ꢀ, 3J
=
7.5 Hz), 2.13 (q, 4Ha,
b
a
CH3 ꢀCH2 ꢀ, J = 7.5 Hz), 7.48–7.52 (m, 9Hb,b´,j), 8.03
b
a
3

MUSHTAQ ET AL.
3
7
(dd, 6Ha,a´, J = 6.0 Hz, J = 2.7 Hz). 13C NMR (75 MHz,
CDCl3, δ, ppm): 9.7 (2C, ꢀCH3), 28.9 (2C, ꢀCH2ꢀ),
129.1 (6Ca,a´), 130.8 (3Cj), 133.8 (6Cb,b´), 139.0 (3C, ipso‐
C), 178.8 (2C, C¼O). Anal. Calcd for C24H25O4Sb (%): C,
57.74; H, 5.05. Found (%): C, 57.70; H, 5.01.
(4Cd,d´), 127.7 (2C, CꢀCH2ꢀ), 129.1 (6Cb,b´), 130.2 (4Cc,
c´), 130.9 (3Cj), 133.8 (6Ca,a´), 137.4 (3C, ipso‐C), 158.2
(2C, CꢀOCH3), 175.1 (2C, C¼O). Anal. Calcd for
C36H33O6Sb (%): C, 63.27; H, 4.87. Found (%): C, 63.24;
H, 4.84.
4
4.3.9
| Bis(4‐chlorophenylacetato)tri(phenyl)antimony(V) (9)
4.3.6
| Bis(nicotinato)(triphenyl)antimony(V) (6)
Quantities used were 1.93 g (0.01 mol) of sodium salt of
4‐chlorophenylacetic acid and 2.51 g (0.005 mol) of tris(phe-
nyl)antimony(V) dibromide in toluene. Yield 83%; white
crystalline solid; m.p. 144–145°C. FT‐IR (powder, cm−1):
3048 (CꢀHaromatic), 2928 (CꢀHaliphatic), 1641 (COOasym),
739 (CꢀCl), 563 (SbꢀC), 452 (SbꢀO). 1H NMR
(300 MHz, CDCl3, δ, ppm): 3.39 (s, 4H, ꢀCH2ꢀ), 6.82 (d
Quantities used were 1.45 g (0.01 mol) of sodium salt of
nicotinic acid and 2.51 g (0.005 mol) of tris(phenyl)anti-
mony(V) dibromide in toluene. Yield 82%; colourless solid;
m.p. 180–182°C. FT‐IR (powder, cm−1): 3054 (CꢀHaromatic),
1
1654 (C¼O), 1587 (CꢀN), 562 (SbꢀC), 447 (SbꢀO). H
NMR (300 MHz, CDCl3, δ, ppm): 7.28–7.32 (m, 2He),
7.50–7.56 (m, 9Hb,b´,j), 8.12–8.18 (m, 8Ha,a´,d), 8.68 (dd,
,
4Hc,c´,3J 4Hd,d´
= 8.7 Hz), 7.12 (d(skewed), ,
4
2Hf, 3J = 4.8 Hz,
J = 1.5 Hz), 9.15 (sd, 2Hc,
(skewed)
3
3J = 8.4 Hz), 7.36 (t(skewed), 6Hb,b´, J = 7.5 Hz), 7.43 (tt
4J = 1.5 Hz). 13C NMR (75 MHz, CDCl3, δ, ppm): 123.1
(2Ce), 128.3 (2C, CꢀC¼O), 129.7 (6Cb,b´), 131.6 (4Cj),
133.8 (6Ca,a´), 136.9 (3C, ipso‐C), 137.4 (2Cd), 151.2
(2Cc), 152.4 (2Cf), 168.3 (2C, C¼O). Anal. Calcd for
C30H23N2O4Sb (%): C, 60.33; H, 3.88; N, 4.69. Found (%):
C, 60.29; H, 3.85; N, 4.72.
4
(skewed), 3Hj, 3J = 7.5 Hz, J = 1.2 Hz), 7.72 (dd, 6Ha,a´
,
3J = 8.1 Hz, J = 1.2 Hz). 13C NMR (75 MHz, CDCl3, δ,
ppm): 42.5 (2C, ꢀCH2ꢀ), 113.8 (4Cd,d´), 127.8 (2C,
CꢀCH2ꢀ), 129.7 (6Cb,b´), 131.2 (4Cc,c´), 132.5 (3Cj),
133.7 (6Ca,a´), 138.9 (3C, ipso‐C), 156.8 (2C, C‐Cl), 175.6
(2C, C¼O). Anal. Calcd for C34H27Cl2O4Sb (%): C, 58.99;
H, 3.93. Found (%): C, 58.91; H, 3.92.
4
4.3.7
| Bis(2‐methoxyphenylacetato)(triphenyl)antimony(V) (7)
Quantities used were 1.88 g (0.01 mol) of sodium salt of
2‐methoxyphenylacetic acid and 2.51 g (0.005 mol) of tris
(phenyl)antimony(V) dibromide in toluene. Yield 85%;
colourless solid; m.p. 168–170°C. FT‐IR (powder, cm−1):
3018 (CꢀHaromatic), 2926 (CꢀHaliphatic), 1657 (C¼O), 582
(SbꢀC), 484 (SbꢀO). 1H NMR (300 MHz, CDCl3, δ,
ppm): 3.39 (s, 4H, ꢀCH2ꢀ), 3.88 (s, 6H, ꢀOCH3), 6.75
(d, 2Hf, 3J = 8.1 Hz), 6.84 (t, 2Hd, 3J = 7.2 Hz), 7.24 (td, dds
4.4 | Single‐crystal x‐ray diffraction analysis
Single crystals of 1 and 4 were mounted on a Bruker kappa
APEXII CCD diffractometer equipped with graphite
monochromated Mo Kα radiation (λ = 0.71073 Å) and
intensity data were collected at ambient temperature. Details
of the crystal data, and data collection and structure
determination conditions and parameters are summarized in
Table 1. Structure solution by direct methods and least
squares refinement of all structures were routine, with all
non‐hydrogen atoms refined with anisotropic thermal
parameters and almost all hydrogen atoms visible on later
electron density difference maps. Aromatic hydrogen atom
positional and isotropic thermal parameters were freely
refined in both structures (Uiso ranges from 0.070 to
0.115 Å2), but were constrained in the ambient temperature
structures to a riding model with an idealized geometry
(CꢀH fixed at 0.93 Å) and with Uiso fixed at 1.2Uiso of the
parent carbon atom. The 1.0 mm collimator used for data
collection for the structures of 1 and 4 resulted in several
low‐angle reflections partially or completely obscured by
the beam catcher. Data were also corrected for Lorentz and
polarization effects. The structures were solved using
SHELXS‐97. Final refinement on F2 was carried out by
full‐matrix least‐squares techniques using SHELXL‐97.[31]
3
4
appeared as td, 2He, J = 7.2 Hz, J = 1.5 Hz), 7.42–7.52
(m, 9Hb,b´,j), 7.91 (d, 4Hc,3J = 7.8 Hz), 8.11 (dd, 6Ha,a´
,
3J = 8.1 Hz, J = 1.2 Hz). 13C NMR (75 MHz, CDCl3, δ,
ppm): 45.0 (2C, ꢀCH2ꢀ), 55.2 (2C, ꢀOCH3), 110.2 (2C,
CꢀCH2ꢀ), 120.6 (2Cf), 123.3 (2Cd), 128.2 (6Cb,b´), 129.6
(3Cj), 129.8 (2Cc), 131.1 (6Ca,a´), 135.0 (2Ce), 136.1 (3C,
ipso‐C), 157.4 (2C, CꢀOCH3), 177.3 (2C, C¼O). Anal.
Calcd for C36H33O6Sb (%): C, 63.27; H, 4.87. Found (%):
C, 63.24; H, 4.83.
4
4.3.8
| Bis(4‐methoxyphenylacetato)(triphenyl)antimony(V) (8)
Quantities used were 1.88 g (0.01 mol) of sodium salt of
4‐methoxyphenylacetic acid and 2.51 g (0.005 mol) of tris
(phenyl)antimony(V) dibromide in toluene. Yield 84%;
colourless solid; m.p. 171–172°C. FT‐IR (powder, cm−1):
2936 (CꢀHaromatic), 2840 (CꢀHaliphatic), 1652 (C¼O), 548
(SbꢀC), 484 (SbꢀO). 1H NMR (300 MHz, CDCl3, δ,
ppm): 3.37 (s, 4H, ꢀCH2ꢀ), 3.81 (s, 6H, ꢀOCH3), 6.75 (d
(skewed), 4Hc,c´
,
3J = 8.7 Hz), 6.95 (d(skewed), 4Hd,d´
,
4.5 | Antileishmanial assays
3
3J = 8.4 Hz), 7.39 (t(skewed), 6Hb,b´, J = 7.5 Hz), 7.47 (tt
(skewed), 3Hj, 3J = 7.5 Hz, J = 1.2 Hz), 7.79 (dd, 6Ha,a´
,
Stock solutions for antileishmanial assays were prepared by
dissolving 1 mg ml−1 of each of samples 1–9 under assay
in 1 ml of dimethylsulfoxide (DMSO). Stock solutions were
4
4
3J = 8.1 Hz, J = 1.2 Hz). 13C NMR (75 MHz, CDCl3,
δ, ppm): 42.3 (2C, ꢀCH2ꢀ), 55.3 (2C, ꢀOCH3), 113.6

8
MUSHTAQ ET AL.
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further diluted serially (100, 10, 1, 0.1, 0.01, 0.001, 0.0001
and 0.00001 μg ml−1) using DMSO in the wells of a 96‐well
plate (Table S1 in the supporting information). Leishmania
tropica KWH23 promastigotes were grown in M199 medium
with 10% foetal bovine serum, streptomycin, HEPES buffer
(25 mM) and penicillin. Log phase promastigotes at
1 × 106 ml−1 were used for the entire assay. About 180 μl
of M199, 100 μl of Leishmania tropica KWH23 log phase
culture and 20 μl of each compound were dispensed to
different wells of a microtitre plate. Here, DMSO was used
as a negative control with Glucantime as positive control.
Afterwards, 96‐well plate was incubated at 24°C for 72 h.
After incubation, about 15 μl of each dilution was pipetted
on a Neubauer chamber and was counted under a
microscope. The IC50 values were calculated using Graphpad
Prism 5.[30]
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4.6 | Cytotoxicity
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ACKNOWLEDGEMENTS
The authors thank the Higher Education Commission of
Pakistan (research project no. 20‐1826/NRPU/R&D) and
Quaid‐i‐Azam University for financial support.
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SUPPORTING INFORMATION
Additional Supporting Information may be found online in
the supporting information tab for this article.
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