Synthesis of heteroleptic pentavalent antimonials bearing heterocyclic cinnamate moieties and their biological studies

Article abstract of DOI:10.1016/j.ica.2018.02.005

In the search of new drugs with high therapeutic efficacy, antimony (V) dicarboxylates bearing cinnamate moieties with general formula [SbR₃(O₂CR′)₂] have been synthesized and characterized by spectroscopic techniques like FTIR, multinuclear (¹H and ¹³C) NMR and single crystal X-ray diffraction. The organic moieties (R) in the complexes are phenyl and p-tolyl while the carboxylates are heterocyclic acrylates. In the crystal structure of [Sb(phenyl)₃(O₂CC₂H₂C₄H₃O)₂] (1), [Sb(phenyl)₃(O₂CC₂H₂C₄H₃S)₂] (3), [Sb(p-tolyl)₃(O₂CC₂H₂C₄H₃S)₂] (5) and [Sb(p-tolyl)₃(O₂CC₂H₂C₄H₂O(CH₃))₂] (6), antimony was found to adopt a distorted trigonal bipyramidal geometry and was monomeric with phenyl or p-tolyl groups at equatorial and carboxylate ligands at axial positions. Furthermore, biological activities of carboxylates and their corresponding complexes were conducted including antileishmanial activity (against Leishmania tropica KWH23 parasite), anticancer (against HepG2 cell line), antibacterial (against Staphylococcus aureus, E. coli, P. aeruginosa and K. pneumoniae) and α-amylase inhibition potentials. Results show that compounds (4), (5) and (6) are significantly cytotoxic against cancer cells (median inhibitory concentration (IC₅₀): 7.44, 4.61, 5.0 μg/mL respectively) and leishmania parasite (IC₅₀: 1.75, 0.03 and 0.02 μg/mL respectively). Results of biological activities suggest these complexes as attractive therapeutic agents for further in vivo studies except α-amylase inhibition.

Full text of DOI:10.1016/j.ica.2018.02.005

Accepted Manuscript
Research paper
Synthesis of Heteroleptic Pentavalent antimonials bearing Heterocyclic Cinna-
mate moieties and their Biological studies
Sidra Sarwar, Tuba Iftikhar, Muhammad Khawar Rauf, Amin Badshah,
Durdana Waseem, Muhammad Nawaz Tahir, Khalid Mohammed Khan, Gul
Majid Khan
PII:
S0020-1693(17)31823-6
https://doi.org/10.1016/j.ica.2018.02.005
ICA 18114
DOI:
Reference:
To appear in:
Inorganica Chimica Acta
Received Date:
Revised Date:
Accepted Date:
28 November 2017
31 January 2018
1 February 2018
Please cite this article as: S. Sarwar, T. Iftikhar, M.K. Rauf, A. Badshah, D. Waseem, M.N. Tahir, K.M. Khan, G.M.
Khan, Synthesis of Heteroleptic Pentavalent antimonials bearing Heterocyclic Cinnamate moieties and their
Biological studies, Inorganica Chimica Acta (2018), doi: https://doi.org/10.1016/j.ica.2018.02.005
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Synthesis of Heteroleptic Pentavalent antimonials bearing Heterocyclic
Cinnamate moieties and their Biological studies
1
1
1, 2,
, *
1*
Sidra Sarwar , Tuba Iftikhar , Muhammad Khawar Rauf
, Amin Badshah , Durdana
5
3
4
5
Waseem , Muhammad Nawaz Tahir , Khalid Mohammed Khan , Gul Majid Khan
1
Department of Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan
2
Office of Research, Innovation and Commercialization, Quaid-i-Azam University,
Islamabad-45320, Pakistan
3
Department of Physics, University of Sargodha, Pakistan
4
H.E.J. Research Institute, University of Karachi, Karachi-75270, Pakistan
5
Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University
Islamabad-45320, Pakistan
*
Corresponding Author
Prof. Dr. Amin Badshah (aminbadshah@yahoo.com
Dr. Muhammad Khawar Rauf (mkhawarrauf@yahoo.co.uk) ORCID: 0000-0001-9994-4033
ABSTRACT
In the search of new drugs with high therapeutic efficacy, antimony (V) dicarboxylates
3 2 2
bearing cinnamate moieties with general formula [SbR (O CR') ] have been synthesized and
1
13
characterized by spectroscopic techniques like FTIR, multinuclear ( H and C) NMR and
single crystal X-ray diffraction. The organic moieties (R) in the complexes are phenyl and p-
tolyl while the carboxylates are heterocyclic acrylates. In the crystal structure of
[
Sb(phenyl)
5) and [Sb(p-tolyl)
trigonal bipyramidal geometry and was monomeric with phenyl or p-tolyl groups at
3
(O
2
CC
2
H
2
C
4
H
3
O)
2
](1),[Sb(phenyl)
3 2 2 2 4 3 2 3 2 2 2 4 3 2
(O CC H C H S) ] (3), [Sb(p-tolyl) (O CC H C H S) ]
(
3
(O
2
CC
2
H
2
C
4
H
2
O(CH )) ] (6), antimony was found to adopt a distorted
3 2

equatorial and carboxylate ligands at axial positions. Furthermore, biological activities of
carboxylates and their corresponding complexes were conducted including antileishmanial
activity (against Leishmania tropica KWH23 parasite), anticancer (against HepG2 cell line),
antibacterial (against Staphylococcus aureus, E.coli, P. aeruginosa and K. pneumoniae) and
α-amylase inhibition potentials. Results show that compounds (4), (5) and (6) are
significantly cytotoxic against cancer cells (median inhibitory concentration (IC50): 7.44,
4
.61, 5.0 µg/mL respectively) and leishmania parasite (IC50: 1.75, 0.03 and 0.02 µg/mL
respectively). Results of biological activities suggest these complexes as attractive
therapeutic agents for further in vivo studies except α-amylase inhibition.
KEYWORDS: Pentavalent antimonials, Antileishmanial, Anticancer, Antibacterial, α-
amylase
1
. Introduction
Antimony complexes have been practiced for nearly 100 years in the clinical cure of the
parasitic diseases like leishmaniasis, which is caused by protozoan parasites belonging to the
family Trypanosomatidae and transfered through sandflies vector [1-2]. Various forms of
leishmaniasis include cutaneous (involve simple lesions), mucocutaneous (disfiguring of
mucosal region) and visceral (leads to damaging of different organs) leishmaniasis [3].
Leishmaniasis affects about 12 million people worldwide with 1.0-1.3 million new cases
reported each year and approximately 50,000 deaths every year. The global count of
leishmaniasis has seriously escalated in the recent years due to increased international
travelling, altered vector habitats and associated factors that increase susceptibility such as
poor and well exposed living conditions, infection with human immunodeficiency virus
(
HIV) and malnutrition [4,5]. Leishmaniasis is considered by - WHO as one of the six
epidemic diseases worldwide with limited number of available drugs. So, the synthesis of
new drugs for the neglected disease has become a global concern [6].

In 1940s, trivalent antimonials were replaced by the two more effective pentavalent
®
antimonials i.e., sodium stibogluconate (Pentostam ) and meglumine antimoniate
®
(
Glucantime ). These compounds are still in clinical practice against leishmaniasis with
survival rate over 90%. Yet there is need for new antileishmanial drugs due to acquired
resistance to the existing drugs [7-9].
In - recent years, - considerable work on the synthesis of pentavalent antimonials
containing ligands of pharmaceutical importance has contributed to the existing literature.
The pentavalent antimony complexes of the types (R)
sugars/acids) [16, 17], antimony (V) porphyrins complexes dichloride (5,10,15,20-
tetrakis(phenyl)porphyrinato)antimony (V) bromide, [Sb(V)(TPP)Cl ]Br, and dibromide (5,10,15,20-
tetrakis (4-carbomethoxyphenyl) porphyrinato) antimony (V) bromide, [Sb(V)(T4CMPP)Br ]Br [18] and
3 2 2
Sb (O CR´) [10-15], Sb(carbohydrate
x
2
2
organoantimony arylhydroxamates [19] have shown greater antileishmanial and cytotoxic activitiesdueto
high cellular uptake of Sb. Pentavalent antimonials have also shown their usefulness against hepatitis C
and AIDS [20]. The combined therapy or co-administration of some organic antileishmanial drugs has
boosted theefficacyof existingpentavalent antimonialdrugs[16, 21, 22].
Current drugs available for the treatment of leishmaniasis, the pentavalent antimonials;
sodium stibogluconate (SSG) and meglumine antimoniate (MGA) are acquiring resistance
against variety of leishmanial species. So, it is highly demanded that new, cheaper and safe
pentavalent antimonials must be developed and investigated as perspective antileishmanial
drugs. In line with this, we have synthesized heterocyclic cinnamic acids based heteroleptic
triorganoantimony complexes and explored their structural as well as the biological potential.
2
2
. Experimental section
.1. General comments

The standard Schlenk line techniques were used to carry out all the reactions under inert
atmosphere. Drying agents were used to distil the solvents. All solvents and chemicals were
purchased from Sigma Aldrich and purified before use, where needed. Toluene was dried
using sodium benzophenone ketyl and then stored over molecular sieves. Glassware was
desiccated before use in an oven at 120 °C for 6 h. Melting point measurement was done
using BIO COTE Model SMP10 melting point apparatus and reported without correction.
FT-IR data was recorded on a Bruker TENSOR II FT-IR Spectrometer. Bruker 300 MHz
1
13
spectrometer was used to take the H and C NMR spectra with Tetramethylsilane (TMS) as
reference.
2
.2. Synthesis and characterization
All the compounds (1-6) were synthesized under argon fed inert atmosphere using Schlenk
techniques [11]. A mixture of respective carboxylic acid (0.01 mol) and triethylamine (0.01
mol) was stirred in 100 mL of dry toluene for 30 minutes and then 0.005 mol of
triorganoantimony (V) dibromide was added into the reaction mixture. After 12 h of stirring,
precipitates of the salt formed were removed by filtration and the solvent was evaporated
from filtrate under vacuum.
2
.2.1. Bis[3-(furan-2-yl)acrylato]tri(phenyl)antimony(V) (1)
Quantities used were 0.69 g (0.005 mol) of 3-(2-furyl)acrylic acid, 0.7 ml (0.005 mol)
triethylamine and 1.28 g (0.0025mol) of triphenylantimony(V) dibromide in dry toluene.
-1
Yield 83%; m.p. 173-175 °C; FT-IR (powder, cm ): 2969 (C-H aromatic), 1636 (C=O), 1600
1
(
C=C), 549 (Sb-C), 452 (Sb-O). H NMR (300 MHz, CDCl
3
, δ, ppm): 6.21-6.26 (d, 2H, -
3
3
4
CH=CH- , J=15.9 Hz), 6.41-6.42 (dd, 2H, J=5.1Hz, J=1.5Hz, furyl-H), 7.21-7.26 (d, 2H, -
3
CH=CH- , J=15.6 Hz), 7.42-7.52 (m, 13H, 9Ar-H and 4 furyl-H), 8.06-8.09 (dd, 6H,
3
4
13
J=9.6Hz, J=3.6Hz, Ar-H); C NMR (75 MHz, CDCl , δ, ppm): 112.0 (2C, furyl-C), 113.5
3

(
(
2C, furyl-C), 118.7 (2C, -CH=CH-), 129.3 (6C, Ar), 130.1 (3C, Ar), 131.0 (3C, Sb-C), 133.8
6C, Ar), 138.5 (2C, -CH=CH-), 144.8 (2C, furyl-C), 151.3 (2C, furyl-C), 170.8 (2C, C=O).
Anal. calc. for C32
.2.2. Bis[3-(5-methylfuran-2-yl)acrylato]tri(phenyl)antimony(V) (2)
Quantities used were 0.76 g (0.005 mol) of 3-(5-methylfuran-2-yl) acrylic acid, 0.7 ml
0.005 mol) triethylamine and 1.28 g (0.0025mol) of triphenylantimony(V) dibromide in dry
25 6
H O Sb: C, 61.27; H, 4.02; Found: C, 61.27; H, 4.00.
2
(
-1
toluene. Yield 81.6%; m.p. 188-191 °C; FT-IR (powder, cm ): 3052 (C-H aromatic), 2921
1
(
C-H aliphatic), 1634 (C=O), 1597 (C=C), 551 (Sb-C), 453 (Sb-O); H NMR (300 MHz,
3
4
CDCl
3
, δ, ppm): 2.30 (s, 6H, CH
3
-H), 6.02-6.03 (dd, 2H, furyl-H, J=3.9 Hz, J=2.4 Hz),
3
3
6
.13-6.19 (d, 2H, -CH=CH- , J=15.6 Hz), 6.39-6.40 (d, 2H, J=3.3 Hz, furyl-H), 7.15-7.20
3
3
4
(
d, 2H, -CH=CH- , J=15.6 Hz), 7.47-7.51 (dd, 9H, J=10.2Hz, J=3Hz, Ar-H), 8.06-8.10 (m,
1
3
6
3 3
H, Ar-H) ; C NMR (75 MHz, CDCl , δ, ppm): 13.9 (2C, CH ), 108.5 (2C, furyl-C), 115.2
(
2C, furyl-C), 116.8 (2C, -CH=CH- ), 129.2 (6C, Ar), 130.3 (3C, Ar), 130.9 (3C, Sb-C),
33.8 (6C, Ar), 138.9 (2C, -CH=CH-), 149.8 (2C, furyl-C), 154.8 (2C, furyl-C), 171.1 (2C,
C=O). Anal. calc. for C34 Sb: C, 62.31; H, 4.46; Found: C, 62.26; H, 4.43.
.2.3. Bis[3-(thiophen-2-yl)acrylato]tri(phenyl)antimony(V) (3)
1
H
29
O
6
2
Quantities used were 0.77 g (0.005 mmol) of 3-(2-thienyl) acrylic acid, 0.7 ml (0.005 mol)
triethylamine and 1.28 g (0.0025mol) of triphenylantimony(V) dibromide in dry toluene.
-1
Yield 83.2%; m.p. 225-227 °C; FT-IR (powder, cm ): 3053 (C-H aromatic), 1640 (C=O),
1
1
629 (C=C), 566 (Sb-C), 461 (Sb-O); H NMR (300 MHz, CDCl
3
, δ, ppm): 6.13-6.19 (d, 2H,
3
3
4
J=15.6 Hz, -CH=CH-), 6.99-7.02 (dd, 2H, J=8.7 Hz, J=1.2 Hz, Thiophene-H), 7.14-7.15
3
3
(
d, 2H, J=3.3 Hz, Thiophene-H), 7.29-7.31 (d, 2H, J=5.1 Hz, Thiophene-H), 7.50-7.60 (m,
3
4
13
1
1H, 9 Ar-H and 2H of –CH=CH-), 8.07-8.10 (dd, 6H, J=9.6 Hz, J=3.6 Hz, Ar-H) ; C
NMR (75 MHz, CDCl
3
, δ, ppm): 119.8 (2C, -CH=CH- ), 127.7 (2C, Thiophene-C), 127.8

(
(
2C, Thiophene-C ), 129.3 (6C, Ar), 130.0 (3C, Ar), 131.0 (3C, Sb-C), 133.8 (6C, Ar), 136.0
2C, Thiophene-C), 138.6 (2C, -CH=CH- ), 140.0 (2C, Thiophene-C), 170.6 (2C, C=O).
Anal. calc. for C32
25 4 2
H O S Sb: C, 58.28; H, 3.82; Found: C, 58.24; H, 3.81.
2
.2.4. Bis[3-(furan-2-yl)acrylato]tris(p-tolyl)antimony(V) (4)
Quantities used were 0.69 g (0.005mol) of 3-(2-furyl)acrylic, 0.7 ml (0.005 mol)
triethylamine and 1.39 g (0.0025 mol) of tris(p-tolyl)antimony(V) dibromide in dry toluene.
-
1
Yield 82.8%; m.p. 176-178 °C; FT-IR (powder, cm ): 2960 (C-H aromatic), 2922 (C-H
1
aliphatic), 1633 (C=O), 1615 (C=C), 548 (Sb-C), 480 (Sb-O); H NMR (300 MHz, CDCl
3
, δ,
3
3
3
ppm): 2.34 (s, 9H, CH -H), 6.04-6.09 (d, 2H, J=15.9Hz, -CH=CH-), 6.57-6.59 (d, 2H, J=5.1
4
3
3
Hz, J=1.5 Hz, furyl-H), 6.84-6.86 (d, 2H, J=3.6Hz , furyl-H), 7.19-7.25 (d, 2H, J=15.6Hz, -
3
CH=CH-), 7.33-7.42 (m, 6H, Ar-H), 7.51-7.53 (d, 2H, J=8.1Hz, furyl-H), 7.82-7.92 (dd, 6H,
3
4
13
Ar-H, J=28.8Hz, J=12.6Hz) ; C NMR (75 MHz, CDCl
2C, furyl-C), 115.3 (2C, furyl-C), 118.3 (2C, -CH=CH-), 129.8 (3C, Sb-C), 130.5 (6C, Ar-
C), 133.7 (6C, Ar-C), 135.8 (2C, -CH=CH-), 141.5 (3C, Ar-C), 145.9 (2C, furyl-C), 150.8
2C, furyl-C), 169.9 (2C, C=O). Anal. calc. for C35 Sb: C, 62.80; H, 4.67; Found: C,
3 3
, δ, ppm): 21.4 (3C, CH ), 113.0
(
(
H
31
O
6
6
2.77; H, 4.66.
.2.5. Bis[3-(5-methylfuran-2-yl)acrylato]tris(p-tolyl)antimony(V) (5)
2
Quantities used were 0.76 g (0.005 mol) of 3-(5-methylfuran-2-yl)acrylic acid, 0.7 ml (0.005
mol) triethylamine and 1.39 g (0.0025 mol) of tris(p-tolyl)antimony(V) dibromide in dry
-1
toluene. Yield 82.1%; m.p. 198-201 °C; FT-IR (powder, cm ): 2959 (C-H aromatic), 2857
1
(
C-H aliphatic), 1634 (C=O), 1615 (C=C), 568 (Sb-C), 482 (Sb-O); H NMR (300 MHz,
CDCl
3
, δ, ppm): 2.31 (s, 6H, CH
3
3
-H attached to furan ring), 2.39 (s, 9H, CH -H), 6.01-6.03
3
4
3
(
(
dd, 2H, J=3.9Hz, J=2.4Hz, furyl-H), 6.13-6.18 (d, 2H, J=15.6Hz, -CH=CH-), 6.37-6.38
3
3
d, 2H, J=3.3Hz, furyl-H), 7.13-7.18 (d, 2H, J=15.6Hz, -CH=CH-), 7.29-7.31 (d, 6H,

3
3
13
J=8.1Hz, Ar-H), 7.93-7.95 (d, 6H, J=8.1Hz, Ar-H) ; C NMR (75 MHz, CDCl
3.8 (2C, CH -C), 21.5 (3C, CH -C), 108.4 (2C, furyl-C), 114.9 (2C, furyl-C), 117.4 (2C, -
CH=CH-), 129.9 (3C, Sb-C), 130.0 (6C, Ar-C), 133.7 (6C, Ar-C), 135.2 (2C, -CH=CH-),
41.1 (3C, Ar-C), 149.9 (2C, furyl-C), 154.6 (2C, furyl-C), 170.7 (2C, C=O). Anal. calc. for
Sb: C, 63.72; H, 5.06; Found: C, 63.69; H, 5.05.
.2.6. Bis[3-(thiophen-2-yl)acrylato]tris(p-tolyl)antimony(V) (6)
3
, δ, ppm):
1
3
3
1
C
37
H
35
O
6
2
Quantities used were 0.77 g (0.005mol) of 3-(2-thienyl)acrylic acid, 0.7 ml (0.005 mol)
triethylamine and 1.39 g (0.0025 mol) of tris(p-tolyl)antimony(V) dibromide in dry toluene.
-
1
Yield 82.6%; m.p. 228-230 °C; FT-IR (powder, cm ): 3072 (C-H aromatic), 2919 (C-H
1
aliphatic), 1637 (C=O), 1606 (C=C), 585 (Sb-C), 480 (Sb-O); H NMR (300 MHz, CDCl
3
, δ,
3
ppm): 2.40 (s, 9H, CH
3
-H), 6.13-6.18 (d, 2H, J=15.6Hz, -CH=CH-), 6.99-7.02 (dd, 2H,
3
4
3
J=8.7Hz, J=1.5Hz, Thiophene-H), 7.13-7.14 (d, 2H, J=3.3Hz, Thiophene-H), 7.29-7.34 (m,
3
8
H, 6 Ar-H and 2 Thiophene-H), 7.54-7.59 (d, 2H, J=15.6Hz, -CH=CH-), 7.94-7.97 (d, 6H,
3
13
J=8.4Hz, Ar-H) ; C NMR (75 MHz, CDCl
3
, δ, ppm): 21.5 (3C, CH
3
-C), 120.3 (2C, -
CH=CH-), 127.5 (2C, Thiophene-C), 127.8 (2C, Thiophene-C), 129.8 (3C, Sb-C), 130.1 (6C,
Ar-C), 133.7 (6C, Ar-C), 134.7 (2C, Thiophene-C), 135.6 (2C, -CH=CH-), 140.1 (2C,
Thiophene-C), 141.3 (3C, Ar-C), 170.3 (2C, C=O). Anal. calc. for C35
H, 4.45 Found: C, 59.89; H, 4.44.
31 4 2
H O S Sb: C, 59.92;
2
.3. Single-crystal X-ray diffraction analysis
The crystal structure of synthesized complexes was determined by Bruker Kappa APEXII
CCD diffractometer using graphite monochromatic MoKα (λ = 0.71073Å) radiations. The
temperature during data collection was 296(2) K. The structures were solved using SHELX
9
7 [23] and structure refinement was done by SHELXL 2014 [24].
2
.4. Biological activities

2
.4.1 Antileishmanial assay
In vitro antileishmanial activity of compounds was determined by 2-(4,5-dimethyl-2-
thiazolyl)-3,5-diphenyl-bromide (MTT) colorimetric assay following previously described
protocol [25]. Leishmania tropica KWH23 promastigotes were cultured in Medium 199
supplemented with 10% fetal bovine serum (FBS), 100 µg/mL streptomycin sulphate and 100
IU/mL penicillin G at 24 °C. Confluent culture of promastigotes was adjusted to seeding
6
density of 2 × 10 promastigotes/mL and an aliquot of 180 µL of this culture was added in
9
6-well plate. This culture was treated with 20 µL of compounds (containing ≤ 1% DMSO in
PBS) at final concentration of 20 µg/mL at 24°C for 72 h. Similar volumes of 1% DMSO in
PBS and amphotericin B (final concentration 20 µg/mL) were used as negative and positive
controls respectively instead of compounds. After incubation, 20 µL of MTT solution (4
mg/mL) was added in each well and plates were incubated again at 24 °C for 4 h in incubator.
Later, the supernatant was removed carefully leaving behind purple colored formazan
crystals. Then formazan crystals were solubilized in 100 µL of DMSO. Absorbance was
recorded at 540 nm using microplate reader (Biotech USA, microplate reader Elx 800). Three
fold dilutions of compounds (20 µg/mL to 0.009 µg/mL) were used to determine median
inhibitory concentrations (IC50) of compounds. IC50 values were converted to molar
concentrations.
2
.4.2. Anticancer activity by sulforhodamine B (SRB) assay
The human cancer cell line HepG2 (hepatocellular carcinoma) was cultured in Dulbecco's
Modified Eagle Medium (DMEM) accompanied by 10% FBS, 100 µg/mL streptomycin
sulphate, 100 IU/mL penicillin and 0.25 µg/mL amphotericin B and incubated at 37 ºC in
CO
and almost after four days they were trypsinized by 1 mL of 0.25% trypsin EDTA buffer (pH
.4). Cell were pelleted by centrifugation at 1000 rpm for 5 min and re-suspended in 5 mL
2
(5%) incubator. In T75 tissue culture container, the cells were developed as monolayers
7

media. Chemo-sensitivity of HepG2 cells was measured by sulforhodamine B assay [26]. An
5
aliquot of 180 µL of cell culture at seeding density of 1 × 10 cells/well was added in 96-well
micro plates along with 20 µL of compounds and doxorubicin (20 µg/mL). Cells were
o
subjected to treatment for 72 h at 37 C in CO
2
incubator (Panasonic, Japan MCO-18AC-PE).
After that, 50 µL of trichloroacetic acid (20% w/v) was added in the culture to fix cells for 1
o
h at 4 C, washed with water and air-dried. Later on, 50 µL of 0.057% SRB in 1% acetic acid
was added and after 30 min cells were washed with 1% acetic acid to remove the unbound
dye. The samples were again dried in air and SRB dye within cells was solubilized in 200 µL
of 10 mM Tris base (pH 10). Optical density was observed with a microplate reader at 515
nm. IC50 values of the compounds and doxorubicin were calculated using three fold dilutions
(
20 µg/mL to 0.08 µg/mL) of samples. IC50 values were converted to molar concentrations.
.4.3. Antibacterial assay
2
In vitro disc diffusion method was used to determine antibacterial activity of compounds [27]
against Staphylococcus aureus (ATCC-6538); Escherichia Coli (ATCC-15224); Klebsiella
pneumonia (ATCC-1705) and Pseudomonas aeruginosa (ATCC-15442). Freshly prepared
bacterial culture was swabbed on sterile agar petri plates. Filter paper discs (6 mm) soaked
with 5 µL (10 mg/mL in DMSO) of compounds or roxithromycin or cefixime (10 µg/disc)
were placed this bacterial lawn. The plates were incubated for 24 h at 37 °C under sterile
conditions. After 24 h, diameter (mm) of zone of inhibition (ZOI) around the samples was
recorded. Minimum inhibitory concentration (MIC) of compounds having ZOI ≥ 12 mm was
determined by micro broth dilution method [28]. A volume of 20 µL of three fold dilutions
(
50 µg/mL to 1.85 µg/mL) of compounds in nutrient broth were seeded with 180 µL of
4
bacterial inoculum at density of approximately 5 × 10 colony forming units (CFU)/mL in
9
6-well plate. The plates were incubated overnight at 37 °C and results were observed
visually for turbidity in case of bacterial growth.

2
.4.4. Alpha amylase inhibition studies
Alpha amylase enzyme inhibition activity of compounds was determined following the
standard protocol with minor modification [29]. The reaction mixture containing 15 µL
phosphate buffer (PB) (pH 6.8), 25 µL α-amylase enzyme (0.14 U/mL), 10 µL sample (4
mg/mL DMSO) and 40 µL starch solution (2 mg/mL in PB) was incubated for 30 min at 50
°C in 96-well plate. Then reaction was stopped by adding 20 µL of 1 M HCl. After that 90 µL
of iodine reagent (5 mM iodine, 5 mM potassium iodide) was added to each well. Negative
control was prepared without compounds whereas blank was prepared without compounds
and amylase enzyme; each being replaced by equal quantities of buffer. Acarbose (250 µM)
was used as positive control. Absorbance of reaction plate after incubation was measured at
5
40 nm. Activity was expressed as percent α-amylase inhibition/mg compound and
calculated by the following equation:
α-amylase inhibition = [(A
= Absorbance of negative control, A
Absorbance of blank.
.5. Statistical analysis
%
s
- A
n
) / (A
b
- A
n
)] × 100
Where A
n
s
= Absorbance of sample and A =
b
2
Data analysis was done using two-way ANOVA to find the significance of results. p < 0.05
was considered statistically significant. Analysis and calculation were done using GraphPad
Prism 5 statistical software.
3
3
. Results and discussion
.1. Synthesis and characterization
A number of methods for synthesis of triorganoantimony (V) carboxylates have been
+
described [30, 31]. In most commonly used methods, carboxylate salts of alkali metal (Na ,
+
+
+
K ), silver (Ag ) or triethylamine (Et NH ) are reacted with triorganoantimony(V) halides
3

[
21, 32]. In this work, the antimony (V) complexes (1-6) were prepared by treating
triorganoantimony (V) bromide in toluene with in situ prepared triethyl ammonium salt of the
respective carboxylic acids and the mixture was allowed to stir for 10–12 h at room
temperature under nitrogen atmosphere (Scheme 1).
<
Scheme 1>
The resulting precipitates were filtered and the final product was obtained from
filtrate by evaporating the solvent under reduced pressure. The products were recrystallized
from chloroform-toluene mixture (1:1). The synthesis of antimony (V) complexes (1-6)
1
13
3 2 2
having general formula [SbR (O CR′) ] was confirmed through FT-IR, ( H, C) NMR single
crystal X-ray diffraction and CHNS analysis.
In FT-IR spectra of the acids, a carboxyl group stretching was observed in the range
−1
of 1670–1710 cm . On formation of antimony (V) complexes (1-6), the signal due to O-H
−1
stretching at 3200-3500 cm disappeared and symmetrical/asymmetrical stretching of
-1
carboxylate group was lowered by 30-40 cm , which is indicative of -CO
2
H group
−1
deprotonation. The strong signal at 735–740 cm was due to aryl group C-H bending. The
−1
signals in the finger print region at 452–482 and 548–585 cm correspond to the stretch of
Sb–O and Sb–C, both of which are in agreement with reported values and are not present in
precursors: triorganoantimony (III) and free heterocyclic carboxylic acids [33, 34]. For all the
−1
complexes, ∆ν value (difference of ν (CO2 asymm) and (CO2 symm ) is lower than 200 cm ,
which suggests the unidentate binding mode of carboxylate ligands [35] and is also in
accordance with the single crystal XRD analysis.
1
The singlet in H NMR spectra appeared at 10-12 ppm is due to the proton of -CO
2
H
moiety, which disappeared in the complexes. Furthermore, the peaks of the aromatic protons
3
appeared in the reported regions of 6.85-8.15 ppm. The J coupling constants for the doublets

appeared for protons in -CH=CH- moiety are quite large 15.5-16.5Hz, representing their
trans geometries. Intensity and multiplicity patterns were used to identify all the chemical
shifts.
1
3
In C NMR, the signal of carbonyl carbon was observed in the narrow range of 168-
1
70 ppm and the peaks for aromatic carbons appeared between 125-140 ppm. The complexes
with p-tolyl derivatives showed aromatic carbon signal more downfield due to substituent
effect of CH group. The peak of methyl carbon was observed near 21 ppm.
.2. X-ray crystallography
3
3
Crystallization of (1), (3), (5) and (6) was done in toluene-chloroform mixture. Molecular
structures of the complexes are shown in Figures (1-4), while crystallographic data is given in
Table 1. The selected bond lengths and angles are depicted in Table 2. The crystal structure
of complexes reveals that two molecules of carboxylate ligands are covalently bonded with
antimony through oxygen and occupies apical positions with minor difference in the bond
lengths (Sb–O; 2.132(4) to 2.116(14) Å). The O–Sb–O angle is close to linear bond angle
(
171.95(5)°-179.2 (5)°) in all complexes. The antimony center has a distorted trigonal
bipyramid geometry, which is mostly exhibited by the compounds of this type. The three
phenyl or p-tolyl groups are at equatorial position, although they also display a distortion
with the broadening of one of the trigonal angles (C–Sb–C; 146.0(2)°) resulting in square
based pyramidal and leaves a coordination site, which is taken by the other oxygen atoms of
the second carboxylate with Sb⋯O bond lengths that is almost 0.7–1.12 Å lengthier than
distance for the primary carboxylate coordination. However, their bond lengths are shorter
than 3.6 Å, which is the sum of van der Waals radii of antimony and oxygen atom.
<
<
Figure 1>
Figure 2>

<
<
Figure 3>
Figure 4>
<
Table 1>
Table 2>
<
3
3
.3. Biological activities
.3.1. Antileishmanial activity
For in vitro assessment of antileishmanial impact of potent drugs, promastigotes stage is
considered good because of its easy growth and better mode of screening [36]. The
leishmania viability was determined by using MTT, whose tetrazolium ring is cleaved to
form formazan crystals by mitochondrial dehydrogenase enzyme of viable cells. This caused
the color to change from pale yellow to dark purple-blue. Since, formazan is impermeable to
cell membrane; therefore, viable cells appear purple-blue in color. Results obtained from
pentavalent antimonials and their starting acids are described in Table 3. The free acids
(
HL1-HL3) showed very low activity relative to antimony (V) complexes (1-6). The activity
was significantly increased on coordination with metal. It is reported that lipophilic nature of
compounds increases on complexation with metal, as charge on metal ion reduces upon
attachment with donor groups [37]. Hence, due to lipophilicity, literature shows that
permeation through lipid membrane of microorganism is favorable [38] thus causing their
destruction. It is possible that attachment of lipophilic functional groups enhanced permeation
of complexes across the parasite membrane. However, this needs to be confirmed by
measuring permeability of complexes in future studies. Currently, there is strong relationship
between structure and activity of compounds, as p-tolyl substitution of antimony analogs

exhibited better leishmanicidal action. Similar results were obtained in another study where
antimony complexes showed better antileishmanial activity than their respective free acids
[
39]. Moreover, researchers have also reported that amphiphilic antimony (V) complexes are
also active against visceral leishmaniasis [40]. Likewise, cinnamato ligands containing
antimony (V) dicarboxylates were highly effective against leishmania at as low as 0.5 µM
concentration. On the contrary, our compounds are more effective probably due to difference in
the final complex [10]. Another group of heteroleptic pentavalent antimonials with p-tolyl
moieties had significant leishmanicidal activity [12]. Our results are consistent with previous
studies. In addition, results of antimony complexes (1), (4), (5) and (6) were slightly (p>0.05)
different from amphotericin B indicating their effectiveness equivalent to amphotericin B.
Leishmaniasis is imposing significant disease burden throughout the world as well as
in Pakistan. Both cutaneous leishmaniasis and visceral leishmaniasis are the major threats in
the country [41, 38]. Antimony containing compounds are very effective against
leishmaniasis [42]. Our research in developing effective antimonial compounds against
leishmania is promising. Their activity might be due to kinase enzymes inhibitions that are
necessary for cell survival or other pathway interfering with promastigotes growth. We have
developed compounds that are highly effective and their mechanism of action is needed to be
elucidated. Further research on these are undergoing so that we can provide with possible
drug candidate against leishmaniasis.
3
.3.2. Anticancer activity
Our synthesized compounds along with doxorubicin (positive control) were screened for
anticancer activity against HepG2 cell line. Carboxylates and their complexes were
significantly cytotoxic against cancer cell line. Table 3 shows the results of anticancer
activity of pentavalent antimonials (1-6) and their starting acids (HL1-HL3). Results
revealed that free carboxylates showed no activity while some of the metal complexes of

same carboxylates displayed very good activity. This may be due to the fact that p-tolyl and
methyl groups in complexes (4-6) enhanced their lipophilicity and cell permeability; hence,
showed more action resulting in increased cell death. Yet, future studies are required to
quantify the effect of p-tolyl on permeability of complexes across the membrane of cancer
cells. Compounds formed with antimony trichloride and the heterocyclic thiones showed
selective antiproliferative activity against the HeLa cells with IC50 value of 6.4 µM that is
comparative to our compounds (4-6) in this study (Table 3) [43]. On the other hand,
3 2
Ph Sb(4AcB) compound demonstrated 25.7 µM and 23.7 µM IC50 values against B16
F10 and K562 cell lines respectively. The activity of this compound was lower than ones in
our study that showed as low as 6.63 µM IC50 in HepG2 cell line [15]. This indicates that our
compounds are better with their attached ligands and have potential to be further studied as
anticancer agents..
<
Table 3>
3
.3.3. Antibacterial and alpha amylase inhibition
Activity against four bacterial strains (S. aureus, K. pneumoniae, Escherichia coli, P.
aeruginosa) was tested. The MIC of compounds was the minimum concentration that
inhibited the bacterial growth. Results depicted that some compounds exhibited considerable
activity while for others no significant activity was observed. Free acid (HL1-HL3) did not
demonstrate antibacterial activity except for free acid HL1 that was intermediately active
against E. coli. Addition of methyl group in antimony complexes (4), (5) and (6) enhanced
their spectrum of antibacterial activity. Complex (5) has additional methyl groups as
compared to complexes (4) and (6) and being more lipophilic it was significantly effective
against gram positive and gram negative bacteria. Similar results were obtained in another
study where addition of methyl group in pentavalent antimony complexes enhanced their
antibacterial activity as compared to free acids [39]. Despite moderately active, compounds

HL1 and (1) were more potent as compared to others having least MIC. Antibacterial activity
may be caused by interaction with cell wall, proteins or bacterial enzymes rendering those
inactive for cell survival.
In addition, potential inhibition of α-amylase enzyme was also checked. Alpha
amylase is the carbohydrate hydrolyzing enzyme that reduces the absorption of carbohydrates
thereby maintaining plasma glucose concentration. This mechanism is an important one in
controlling diabetes [44]. However, our results of enzyme inhibition were not significant to
be extrapolated for antidiabetic potential. The results of antibacterial and alpha amylase
inhibition are given in Table 4.
<
Table 4>
4
. Conclusions
Synthesis and characterization of heterocyclic pentavalent antimonials was done with the
purpose of exploring their potential biological activities. The crystal structures of complexes
revealed that these complexes are monomeric. Sb center is five coordinated and adopted
distorted trigonal bipyramidal geometry. FT-IR data as well as the crystal structures support
the unidentate binding mode of carboxylate ligands to the Sb (V) center. Results of biological
activities demonstrated that some of our compounds significantly inhibited leishmania
parasite and cancer cell growth but showed intermediate antimicrobial activity and poor alpha
amylase inhibition. The free carboxylates showed no substantial results, while activity was
greatly enhanced on binding to the antimony. Complexes with p-tolyl group exhibited potent
activity as compared to phenyl derivatives. Hence, further investigation of biological
properties of synthetic heterocyclic pentavalent antimonials, particularly with p-tolyl group
would be very useful for leishmaniasis and cancer therapy.
Supplementary data

The supplementary crystallographic data for this paper can be found from The Cambridge
Crystallographic Data Centre by www.ccdc.cam.ac.uk/data_request/cif. CCDC numbers of
the complexes (1), (3), (5) and (6) are 1501842, 1501843, 1501844 and 1501845,
respectively.
Acknowledgments
We thank Quaid-i-Azam University Islamabad and the Higher Education Commission of
Pakistan (Research Project no. 20-1826/NRPU/R&D) for the grant of funds to accomplish
this research work.
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[

Scheme and Figures
Scheme 1. Synthesis of Complexes (1-6)

FIGURES
Figure 1. Molecular structure of (1) with ellipsoid displacement. Hydrogen atoms are sphere
of arbitrary size.

Figure 2. Molecular structure of (3) with ellipsoid displacement. Hydrogen atoms are sphere
of arbitrary size.

Figure 3. Molecular structure of (5 ) with ellipsoid displacement. Hydrogen atoms are sphere
of arbitrary size.

Figure 4. Molecular structure of (6) with ellipsoid displacement. Hydrogen atoms are sphere
of arbitrary size.

Table 1. Data collection and refinement data of complexes (1), (3), (5) and (6)
1
3
5
6
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
a/Å
C
32
H
25
O
6
Sb
C
32
H
25
O
4
S
2
Sb
C
37
H
35
O
6
Sb
C
35 31 4 2
H O S Sb
627.28
296(2)
659.39
296(2)
697.40
296(2)
701.47
296(2)
Monoclinic
P2 /n
Monoclinic
P2 /n
12.0660(6)
Monoclinic
P2 /n
Monoclinic
P2 /n
1
1
1
1
12.1124(7)
20.5491(9)
13.5265(7)
10.6344(5)
12.0875(8)
12.3520(7)
b/Å
20.5578(10)
c/Å
α/°
β/°
γ/°
12.5821(6)
90
12.9929(8)
90
23.2108(12)
90
21.5924(14)
90
116.969(3)
90
116.863(2)
90
104.9440(10)
90
95.684(2)
90
3
Volume/Å , Z
2791.1(3), 4
1.493 , 1.032
1264.0
2875.1(3), 4
1.523, 1.140
1328.0
3225.9(3), 4
1.436 , 0.901
1424.0
3208.0(3), 4
1.452, 1.027
1424.0
3
-1
ρcalcg/cm , µ/mm
F(000)
3
Crystal size/mm
0.40×0.34×0.30
0.44×0.36×0.30
5.48 to 54
-15 ≤ h ≤ 15,
-26≤ k ≤ 26,
-16 ≤ l ≤ 16
23340
0.40×0.28×0.26
4.132 to 54
-17 ≤ h ≤ 17,
-9≤ k ≤ 13,
-29≤ l ≤ 29
24814
0.40×0.34×0.28
4.726 to 55.762
-15 ≤ h ≤ 15,
0 ≤ k ≤ 16,
0 ≤ l ≤ 28
7567
2
θ range for data collection/° 5.474 to 54
Index ranges
-15 ≤ h ≤ 15,
-
26 ≤ k ≤ 24,
16 ≤ l ≤ 16
-
Reflections collected
23207
Independent reflections
6094 [Rint
=
6267 [Rint
=0.0407]
7021 [Rint
0.0318]
=
7567 [Rsigma
0.0924]
=
0
.0846]
Data/restraints/parameters
6094/7/279
1.031
6267/0/317
1.026
7021/0/402
1.015
7567/0/383
1.072
2
Goodness-of-fit on F
Final R indexes [I>=2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole /e Å
R
1
= 0.0573,
wR = 0.1274
= 0.0991,
wR = 0.1539
1.35/-0.84
R1 = 0.0397,
wR2 = 0.0958
R1 = 0.0535,
wR2 = 0.1051
1.21/-0.72
R
1
= 0.0273,
wR = 0.0624
= 0.0375,
wR = 0.0685
0.48/-0.29
R
1
= 0.0589,
wR = 0.1392
= 0.0965,
wR = 0.1594
1.05/-1.18
2
2
2
R
1
R
1
R
1
2
2
2
-3
Table 2. Selected bond lengths (Å) and angles (°) for complexes (1), (3), (5) and (6)

1
3
Sb
Sb
Sb
Sb
Sb
1
1
1
1
1
-C15
-C21
-C27
2.116(6)
2.098(4)
2.102(6)
2.126(4)
2.127(14)
1.325(6)
1.221(7)
C
C
C
C
C
C
C
5
21-Sb
21-Sb
27-Sb
21-Sb
27-Sb
15-Sb
21-Sb
1
1
1
1
1
1
1
-C27
-C15
-C15
106.7(3)
107.3(2)
146.0(2)
89.1(2)
Sb
Sb
Sb
Sb
1
1
1
1
1
-C15
-C21
-C27
2.111(3)
2.126(4)
2.108(3)
2.119(2)
2.119(2)
1.318(4)
1.228(4)
C
27-Sb
15-Sb
27-Sb
27-Sb
15-Sb
21-Sb
21-Sb
1
1
1
1
1
1
1
-C
1
141.65(14)
C
C
C
C
C
C
-C21 109.50(19)
-C21 108.85(18)
-C21 108.85(18)
-O
1
4
-O
-O
-O
-O
1
1
1
4
-O
3
1
-O
90.12(18) Sb
-O
-O
-O
-O
3
3
1
90.12(11)
87.66(17)
89.15(17)
O
1
2
-C
-C
1
1
91.12(17)
90.7(3)
O
1
2
-C
-C
1
1
O
O
6
Sb
Sb
Sb
Sb
Sb
1
1
1
1
1
-C17
-C24
-C31
2.109(2)
2.109(2)
2.106(2)
2.116(14)
2.128(15)
1.308(3)
C
C
C
C
C
C
31-Sb
31-Sb
17-Sb
31-Sb
17-Sb
24-Sb
1
1
1
1
1
1
-C17
-C24
-C24
110.76(8) Sb
107.07(8) Sb
142.17(9) Sb
1
1
1
1
1
-C15
-C22
-C29
2.112(5)
2.098(6)
2.100(5)
2.126(4)
2.132(4)
1.307(7)
C
C
C
C
C
C
22-Sb
22-Sb
29-Sb
22-Sb
29-Sb
15-Sb
1
1
1
1
1
1
-C29
-C15
-C15
133.3(2)
113.8(2)
112.9(2)
92.3(2)
-O
4
1
-O
-O
-O
4
4
4
86.48(7)
91.05(7)
91.15(7)
Sb
Sb
-O
3
1
-O
-O
-O
3
3
3
-O
-O
90.86(19)
86.36(18)
O
1
-C
1
O
1
-C
1
Table 3. Antileishmanial and anticancer activities of ligands (HL1-HL3) and complexes (1-
6
)
Compound
Antileishmanial activity
Anticancer activity

%
growth inhibition
20 µg/mL)
IC50
% Inhibition
IC50
(
(µM)
(20 µg/mL)
(µM)
HL1
11.6 ± 0.01
8.5 ± 0.75
6.7 ± 0.34
97.8 ± 1.57
46.8 ± 1.20
47.2 ± 1.15
99.5 ± 2.69
97.5 ± 1.75
89.5 ± 1.83
100 ± 0.01
NA
-
0
-
HL2
-
0
-
HL3
-
0
-
1
7.49 ± 0.64
-
8.3 ± 1.57
26.5 ± 1.20
9.5 ± 1.15
85.7 ± 2.69
100 ± 1.75
100 ± 1.83
NA
-
-
2
3
-
-
4
2.61 ± 0.73
0.043 ± 0.001
0.028 ± 0.001
0.01 ± 0.002
NA
11.11 ± 0.5
6.63 ± 0.17
7.13 ± 0.99
NA
5
6
Amphotericin B
Doxorubicin
100 ± 0.01
0.091 ± 0.003
Data is mean±SD of triplicate analysis (n=3). “-“ indicates no activity, NA mean not applied.
Compounds HL1, HL2 and HL3 are free acids.
Table 4. Antibacterial and alpha amylase inhibition activities of ligands (HL1-HL3) and
complexes (1-6)
Antibacterial activity ZOI (mm) 50 µg/disc
Compound
MIC
MIC
K.
MIC
MIC
S. aureus
E. coli
P. aeruginosa
µg/mL
µg/mL
pneumoniae
µg/mL
µg/mL
*
HL1
HL2
-
-
-
-
14 ± 0.15
1.85 ± 0.98
-
-
-
-
-
-
-
-
-
8 ± 0.04

2
9
HL3
-
-
-
-
-
-
8 ± 1.24
10 ± 1.97
10 ± 1.01
-
-
*
1
2
3
4
5
6
-
-
16 ± 0.19
1.85 ± 0.99
-
-
-
-
-
-
-
-
-
-
-
-
8 ± 0.07
10 ± 0.63
-
12 ± 0.67
-
50 ± 1.64
-
-
*
11 ± 0.5
-
-
20 ± 0.43
50 ± 1.63
16.66 ± 1.09
50 ± 1.27
*
*
*
16± 0.17
-
5.55 ± 0.25
-
22 ± 0.75
7 ± 0.5
5.55 ± 0.73
-
12 ± 0.75
50 ± 1.25
50 ± 1.45
17 ± 0.75
*
*
18 ± 0.93
NA
21 ±0.15
Cefixime (10
µg/disc)
*
*
4
2± 1.24
1.11 ± 0.05
NA
NA
NA
NA
29 ±1.23
3.33 ± 0.75
NA
Roxithromycin
0.33 ±
0.002
*
NA
NA
30 ± 0.25
32
3.33 ± 0.78
NA
(
10 µg/disc)
Acarbose (250
µM)
NA
NA
NA
NA
NA
NA
NA
Data is mean±SD of triplicate analysis (n=3). “-“ indicates no activity, NA mean not applied. * indicates p<0.05 compared with negative contro
HL1,HL and HL3 are free acids.