Development of new combination anti-leishmanial complexes: Triphenyl Sb(V) mono-hydroxy mono-quinolinolates

Article abstract of DOI:10.1016/j.jinorgbio.2021.111385

In seeking to develop single entity combination anti-Leishmanial complexes six heteropletic organometallic Sb(V) hydroxido quinolinolate complexes of general formula [SbPh₃(C₉H₄NORR’)(OH)] have been synthesised and characterised, derived from a series of halide substituted quinolinols (8-hydroxyquinolines). Single crystal X-ray diffraction on all the complexes show a common distorted six-coordinate octahedral environment at the Sb(V) centre, with the aryl groups and nitrogen atom of quinolinolate ligand bonding in the equatorial planes, with the two oxygen atoms (hydroxyl and quinolinolate) occupying the axial plane in an almost linear configuration. Each complex was tested for their anti-promastigote activity and mammalian cytotoxicity and a selectivity indices established. The complexes displayed excellent anti-promastigote activity (IC₅₀: 2.03–3.39 μM) and varied mammalian cytotoxicity (IC₅₀: 12.7–46.9 μM), leading to a selectivity index range of 4.52–16.7. All complexes displayed excellent anti-amastigote activity with a percentage infection range of 2.25%–9.00%. All complexes performed substantially better than the parent quinolinols and comparable carboxylate complexes [SbPh₃(O₂CRR’)₂] indicating the synergistic role of the Sb(V) and quinolinol moieties in increasing parasite mortality. Two of the complexes [SbPh₃(C₉H₄NOBr₂)(OH)] 4, [SbPh₃(C₉H₄NOI₂)(OH)] 5, provide an ideal combination of high selective and good activity towards the leishmanial amastigotes and offer the potential as good lead compounds.

Full text of DOI:10.1016/j.jinorgbio.2021.111385

Journal of Inorganic Biochemistry 219 (2021) 111385
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Journal of Inorganic Biochemistry
journal homepage: www.elsevier.com/locate/jinorgbio
Development of new combination anti-leishmanial complexes: Triphenyl Sb
(V) mono-hydroxy mono-quinolinolates
,
*
Rebekah N. Duffina, Victoria L. Blairb, Lukasz Kedzierskic, Philip C. Andrewsb
a Faculty of Pharmacy and Pharmaceutical Sciences, Drug delivery, disposition and dynamics, Monash University, Parkville, Melbourne, VIC 3053, Australia
b School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia
c Faculty of Veterinary and Agricultural Sciences, The Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne 3000, Victoria, Australia
A R T I C L E I N F O
A B S T R A C T
Keywords:
In seeking to develop single entity combination anti-Leishmanial complexes six heteropletic organometallic Sb
(V) hydroxido quinolinolate complexes of general formula [SbPh3(C9H4NORR’)(OH)] have been synthesised and
characterised, derived from a series of halide substituted quinolinols (8-hydroxyquinolines). Single crystal X-ray
diffraction on all the complexes show a common distorted six-coordinate octahedral environment at the Sb(V)
centre, with the aryl groups and nitrogen atom of quinolinolate ligand bonding in the equatorial planes, with the
two oxygen atoms (hydroxyl and quinolinolate) occupying the axial plane in an almost linear configuration. Each
complex was tested for their anti-promastigote activity and mammalian cytotoxicity and a selectivity indices
Leishmania
Antimony
Organometallic
Hydroxyquinolines
Combination drugs
established. The complexes displayed excellent anti-promastigote activity (IC50: 2.03–3.39
μM) and varied
mammalian cytotoxicity (IC50: 12.7–46.9 M), leading to a selectivity index range of 4.52–16.7. All complexes
μ
displayed excellent anti-amastigote activity with a percentage infection range of 2.25%–9.00%. All complexes
performed substantially better than the parent quinolinols and comparable carboxylate complexes
[SbPh3(O2CRR’)2] indicating the synergistic role of the Sb(V) and quinolinol moieties in increasing parasite
mortality. Two of the complexes [SbPh3(C9H4NOBr2)(OH)] 4, [SbPh3(C9H4NOI2)(OH)] 5, provide an ideal
combination of high selective and good activity towards the leishmanial amastigotes and offer the potential as
good lead compounds.
1. Introduction
[9–12].
The mechanism by which the Sb(V) drugs interact with the parasite
The prevalence of neglected tropical disease (NTDs) worldwide are
advancing at an alarming rate. Leishmaniasis falls within this category,
localised in over 100 countries with 550 million people at risk of
infection [1,2]. A proportion of these incidences (~400,000) result in
the deadliest form of the disease, visceral leishmaniasis (VL), of which
approximately 10% of cases result in death [3,4]. Without immediate
treatment, VL is often lethal [3,5]. The first-line treatment for VL in-
volves the use of intravenous pentavalent antimonials; Pentostam™
(sodium stibogluconate, SSG) and Glucantime™ (meglumine anti-
moniate), these drugs are effective but harbour problems with toxicity
and unavoidable side-effects [6]. In serious cases the use of these anti-
monials can lead to cardiotoxicity and pancreatitis [7]. Increased
resistance is also undermining their efficacy [8]. Other treatments such
as orally available miltefosine, amphotericin B and pentamidine harbour
problems with teratogenicity, expense and toxicity respectively (Fig. 1)
is not fully understood, however there are several evidence-supported
hypotheses. The most commonly accepted theory is based on reduc-
tive bio-conversion of the Sb(V) to Sb(III) by either the host cell or the
parasite itself [13]. This Sb(V) to Sb(III) reduction is more efficient in a
low pH environment such as the intracellular amastigote [14]. Sb(III)
then forms a conjugate pair with the parasitic thiol trypanothione, an
important virulence factor of Leishmania, causing inactivation of its
biological process [15]. An alternative mechanism proposed suggests
the Sb(V) acts directly on the parasite. It is theorised the Sb(V) exerts
activity by acting on protein phosphokinases causing a cascade effect
leading to eventual cell death, therefore the use of Sb(V) as the central
moiety in these potential combination drugs may exert a more syner-
gistic effect than first predicted [14].
Two of the most significant challenges in developing new anti-
Leishmanial drugs is in offsetting inherent toxicity and resistance
* Corresponding author.
E-mail address: phil.andrews@monash.edu (P.C. Andrews).
https://doi.org/10.1016/j.jinorgbio.2021.111385
Received 5 November 2020; Received in revised form 20 January 2021; Accepted 27 January 2021
Available online 10 February 2021
0162-0134/© 2021 Elsevier Inc. All rights reserved.

R.N. Duffin et al.
Journal of Inorganic Biochemistry 219 (2021) 111385
[12,16–18]. One key approach is in using combination therapy with
known antimicrobial drug combinations [6,19–23]. This has shown
some success in improving compliance and treatment times, reducing
the overall drug-load, reducing overall toxic effects on the body, and
providing more cost-effective treatment regimens. Where monotherapy
with SSG or Glucantime has become, or is becoming ineffective, such as
areas of India, Africa, the Mediterranean and South America, then
combination therapies with paromomycin and/or liposomal amphoter-
icin B (LAmB) are already recommended as the primary treatment
regimen [24].
Our focus has been on designing and developing complexes which
offer the potential for different solubility, activity, toxicity, and mode(s)-
of-action, and have thus far focussed on organometallic Sb(V) complexes
as more lipophilic chemical entities compared with traditional Sb(V)
drugs. We have shown that the class of tris-aryl bis-carboxylato antimony
complexes [SbAr3(COꢀ2 )2] can be highly effective and selective in their
activity towards the parasite promastigotes and amastigotes [25–33].
The Bi(V) analogues tend to have good activity towards the parasites but
are generally non-selectively toxic due to the high redox potential and
chemical reactivity [26,27].
Fig. 2. Six 8-quinolinols used in this study: 8-Qunolinol, [C9H6NO]; 5-Chloro-
quinolinol, [C9H5NOCl]; 5,7-Dichloroquinolinol, [C9H4NOCl2]; 5,7-Dibromo-
quinolinol,
[C9H4NOBr2];
5,7-Di-iodoquinolinol
[C9H4NOI2];
5,7-
Dichloromethylquinolinol [C9H3NOCl2CH3].
In contrast to wholly organic drugs, metallodrugs offer the unique
characteristic and opportunity of combining biologically active ligands
in varying ratios on a metal centre which itself can play a therapeutic
role. Alongside this design flexibility they can improve solubility and
bioavailability, reduce systemic toxicity, and increase potency [34], and
the metal can act specifically as a carrier for bioactive molecules through
cellular channels normally inaccessible to the parent organic moiety
[35]. Ideally, for a combination drug or therapy the component parts
should not have a similar biochemical impact but should be targeting
different pathways, functions or structures within the cell [19].
With this in mind, we decided to build on the promising results
achieved with [SbAr3(COꢀ2 )2] complexes and replace the carboxylates
moieties with a known class of antimicrobial. To that end we chose the
heterocycle 8-quinolinol (8-hydroxyquinoline, 8QH), a planar N,O
binding phenoxide metal chelator that has been shown to exhibit anti-
microbial activity, especially in the presence of metal ions [36–38].
Several organometallic complexes of 8QH have previously been studied
for their potential as anti-cancer drugs and as anti-bacterial agents
[39,40]. 8QH has also been tested individually against several strains of
leishmania and shown to exhibit significant activity [41]. The 5,7-halido
substituted derivatives of 8QH (Fig. 2) have exhibited medical potential,
though in some cases exhibited problems with mammalian toxicity
[42–46]. The mechanism of action of this class of heterocycle was
determined to rely more on the depolarisation of the parasitic mem-
brane rather than the induction of reactive oxygen species (ROS) or
nitric oxide (NO) [47]. As the frontline antimonials elevate both ROS
and NO, inducing oxidative stress and therefore apoptosis [48], the
combination of these different modes of action is desirable.
hydroxy mono-quinolinolate complexes (Fig. 3) have been synthesised
and fully characterised: [SbPh3(C9H6NO)(OH)] 1, [SbPh3(C9H5NOCl)
(OH)] 2, [SbPh3(C9H5NOCl2)(OH)] 3, [SbPh3(C9H4NOBr2)(OH)] 4,
[SbPh3(C9H4NOI2)(OH)] 5 and [SbPh3(C9H3NOCl2CH3)(OH)] 6, and
assessed for their activity towards L. major promastigotes and amasti-
gotes, and human primary fibroblasts to establish mammalian cell
toxicity.
Fig. 3. Generic structure of the six antimony complexes: [SbPh3(C9H6NO)
(OH)] 1, [SbPh3(C9H5NOCl)(OH)] 2, [SbPh3(C9H5NOCl2)(OH)] 3,
[SbPh3(C9H4NOBr2)(OH)]
4,
[SbPh3(C9H4NOI2)(OH)]
5
and
[SbPh3(C9H3NOCl2CH3)(OH)] 6.
As a result of this study six novel heteroleptic triphenyl Sb(V) mono-
Fig. 1. Current Sb(V) drugs used to treat Leishmaniasis.
2

R.N. Duffin et al.
Journal of Inorganic Biochemistry 219 (2021) 111385
2. Experimental
concentration of 10
μ
M in colourless RPMI. The plate was incubated for
a further 6 h. The RPMI was then plated into a 96-well plate and ana-
lysed as per the Griess assay protocol [53]. The absorbance was read at
530 nm on a BMG-Labtech ClarioStar Omega microplate reader and the
values compared to a standard curve of nitrite to determine the increase
percentage of nitric oxide.
SbPh3 was purchased from Sigma-Aldrich with no need for further
purification. All quinolinols were purchased from Sigma-aldrich or alfa
Aesar. 5-Chloroquinolniol was purified by crystallisation in hot toluene.
Luperox™ (tert-butyl hydroperoxide 70% solution) was purchased from
Sigma-Aldrich. All remaining solvents were purchased from Merck. A
Bruker Avance DRX600 spectrometer (600 MHz) was used to record the
13C NMR and 1H NMR spectra of all the complexes in deuterated
dimethyl sulfoxide (d6-DMSO). The multiplicities have been denoted as
followed: singlet (s), doublet (d), triplet (t), multiplet (m), broad (br) or
a combination of two or more. Infrared spectra were recorded on an
Agilent Technologies Cary 630 FTIR spectrometer with a range of
4000–500 cmꢀ 1 given. Melting point analysis was obtained in open end
2.1.5. Measurement of reactive oxygen species
Measurement of ROS was achieved by a modified assay from Wojtala
et al [54]. J774 macrophages were plated into 24-well plates at 30,000
cells per well. Cells were given 24 h to adhere before infection with
L. major promastigotes at 5× the amount in colourless RPMI. The
L. major promastigotes were incubated for six hours to infect and
differentiate into amastigotes before excess promastigotes were washed
away with PBS. The cells were incubated for a further 24 h to allow
complete infection. Complexes 2, and amphotericin B were added to
capillary tubes on
a SMP10 Stuart Digital Scientific apparatus.
Elemental analysis (CHNS) was conducted by the Campbell Microana-
lytical laboratory, department of Chemistry, University of Otago, Dun-
edin New Zealand.
wells in triplicate at a concentration of 10
infected cells without drug treatment was included. At intervals of 6, 24
h, 1 M of DHE was added and the plate incubated for a further 200
μM. A positive control of
μ
minutes in the absence of light. After this, the cells were washed with
PBS and a fluorescence reading taken in the measurement buffer of 5
mM of glucose in PBS at excitation of 535 nm and emission of 635 nm on
a BMG-Labtech ClarioStar Omega microplate reader. Treated wells were
compared to the positive control and the percentage increase calculated.
2.1. Biological assays
2.1.1. Cell culture
Human primary fibroblasts and J774 macrophages were cultured in
Dulbecco’s Modified Eagles Medium (DMEM) previously supplemented
with 1% GlutaMax™, 1% Pen-Strep and 10% Fetal Bovine Serum (FBS).
The cells were maintained at 37 ◦C in a 5% CO2 incubator. Virulent clone
v121 of Leishmania major was derived from the LRC-L137 L. major
isolate. The parasite was cultured in M199 media supplemented with 1%
Pen-Strep, 10% FBS and 7.5 mg/L of haemin in basified H2O, in a 26 ◦C
incubator [30]. All media and supplements were purchased from
Gibco™ and maintained as directed.
2.1.6. X-ray crystallography
Crystallographic data for compound 1 was collected on an OXFORD
XtaLAB Synergy, Dualflex, HyPix diffractometer equipped with an OX-
FORD Cryosystems 700 Cryostream and cooled to 123(10) K. Data was
collected with monochromatic MoKα radiation (λ = 0.71070 Å) and
processed using the CrysAlisPro v 1.171.40.49a software [55]. Crystal-
lographic data on compounds 4–6 were collected on a Bruker X8 APEXII
CCD diffractometer, equipped with an OXFORD Cryosystem 700 cryo-
stream and cooled to 123(2) K. Data collection occurred using mono-
chromatic (graphite) MoKα radiation (λ = 0.71070 Å) and were
processed using the Bruker Apex2 v2014.7–1 software [56], polar-
isation, Lorentz and absorption corrections (multi-scan-SADBABS) were
applied [57]. Each compound was solved and refined using SHELXL-
2014/7 utilising the graphical interface X-Seed or Olex2 with the final
refinement done in Olex2 alone [57–59]. Unless otherwise indicated, all
non‑hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were placed in calculated positions using a riding
model with C-H = 0.95–0.98 Å and Uiso(H) = xUiso(C), x = 1.2 or 1.5
2.1.2. In vitro testing of L. major and Human primary fibroblasts
All compounds 1–6 were dissolved into DMSO to 10 mM working
stock solutions. The stock solutions were then diluted with the appro-
priate culture media to 100 μM before serial dilution in duplicate 96 well
Falcon plates (100
μ
M to 48 nM). Volumes of 106 promastigotes/mL and
105 fibroblasts/mL were added along with Celltiter Blue cell Viability
assay, purchased from Promega ™. Plates were incubated for 48 h and
then spectroscopically measured using fluorescence excitation at 544
nm and emission at 590 nm. This was compared against a positive
control of untreated cells to determine the percentage inhibition [49].
All fluorescence excitation and emission measurements were conducted
on a BMG-Labtech ClarioStar Omega microplate reader [50,51]. All
errors bars were calculated using the standard error of the replicates.
–
unless otherwise indicated. Hydrogen atoms of the O H groups were
placed in calculated positions based on the bond lengths of the oxygen
atom. Crystallographic data of complexes 2 and 3 were collected at the
MX1 beamline at the Australian Synchrotron, Melbourne, Victoria,
Australia, operating at 17.4 KeV, with λ = 0.7073 Å, using an open flow
N2 cryostream cooled to 123(2) K. The data collection and reduction was
obtained using BlueIce, [59] and XDS [60]. Disorder of the DMSO
molecule in compound 6 was modelled over two positions.
2.1.3. Amastigote invasion assay
Macrophage invasion assays were performed as previously
described. J774 macrophages were plated in a 24 well Falcon plate onto
glass coverslips. After 48 h the cells had adhered, they were exposed to
L. major promastigotes at a 1:5 ratio and incubated for a further 24 h to
allow for differentiation into amastigotes. The coverslips were washed to
remove any excess promastigotes and then exposed to the complexes for
48 h. After a Giemsa staining the coverslips were mounted using DPX
and the cells counted microscopically. From this the percentage of
infected cells could be determined using a Dunnetts multiple compari-
son test against a positive control [52].
2.2. Synthesis and characterisation
2.2.1. General procedure
1 mmol of SbPh3 was dissolved into toluene and 2 equivalents of 70%
t-BuOOH in water solution (Luperox™) added. The clear solution was
stirred for 10–15 min before addition of 1 mmol of the corresponding
substituted 8-quinolinol. An immediate colour change was observed
from colourless to yellow. The solution was stirred overnight before
removal of the solvent, water and tert-butanol by-products under reduce
pressure. Yellow–green solids were obtained after sonication of the
resultant oils in water. Crystals of each complex were grown from slow
evaporation of the solid in toluene or DMSO solvent.
2.1.4. Griess assay
J774 macrophages were seeded at 10,000 cells per well in a 24-well
plate. The cells were given 24 h to adhere to the plate before infection
with 5× the amount of L. major promastigotes. The parasites were given
6 h to enter the cells before washing of any excess parasites with PBS.
Parasites were given 24 h to differentiate into amastigote. The plate was
washed again with PBS to remove any free-floating parasites. Com-
pounds 2 and 5 along with amphotericin B were added in triplicate at a
Triphenylantimony mono-hydroxy 8-quinolinolate, 1. SbPh3 (0.353 g, 1
mmol) was reacted with t-BuOOH (140 μL, 2 mmol) before addition of 8-
3

R.N. Duffin et al.
Journal of Inorganic Biochemistry 219 (2021) 111385
quinolinol (0.145 g, 1 mmol) according to GP2. Yellow solid (0.427 g,
83%). m.p: 161–162 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ = 9.10 (dd, J =
4.6, 1.4 Hz, 1H), 8.40 (dd, J = 8.4, 1.4 Hz, 1H, CHar), 7.73–7.65 (m, 6H,
CHar), 7.65–7.57 (m, 1H, CHar), 7.52–7.43 (m, 1H, CHar), 7.23–7.14 (m,
9H, CHar), 7.11 (ddd, J = 12.8, 8.0, 1.2 Hz, 2H, CHar), 4.78 (s, 1H, OH).
13C NMR (101 MHz, DMSO‑d6) δ = 156.4 (SbC), 142.1 (Car), 139.3 (Car),
130.0 (Car), 129.7 (Car), 128.9 (Car), 128.4 (Car), 127.9 (Car), 121.2 (Car),
113.9 (Car), 104.5 (Car); FT-IR [cm ꢀ 1]: 3571 (w), 2109 (w), 1575 (m),
1495 (m), 1460 (sh), 1429 (m), 1390 (m), 1319 (sh), 1279 (m), 1239
(w), 1103 (sh), 1064 (m), 824 (m), 735 (sh). 692 (sh); Elemental anal-
ysis: Expected: C:63.06H:4.31 N:2.72 Found: C:63.35H:4.48 N:2.71
CCDC: 1942090.
Triphenylantimony mono-hydroxy 5,7-dichloro-2-methyl-8-quinolino-
late, 6. SbPh3 (0.353 g, 1 mmol) was reacted with t-BuOOH (140 μL, 2
mmol) before addition of 5,7-dichloro-2-methyl-8-quinolinol (0.229 g,
1 mmol) according to GP2. Yellow solid (0.449 g, 75%). m.p: 150–153
◦C; 1H NMR (600 MHz, DMSO‑d6) δ = 8.23 (d, J = 8.6 Hz, 1H, CHar),
7.88 (dt, J = 6.3, 1.4 Hz, 6H, CHar), 7.71 (s, 1H, CHar), 7.42 (d, J = 8.6
Hz, 1H, CHar), 7.31–7.21 (m, 10H, CHar), 4.93 (s, 1H, OH), 2.91 (s, 3H,
CH3). 13C NMR (101 MHz, DMSO‑d6) δ = 137.1 (Car), 134.3 (Car), 132.6
(Cph), 129.2 (Cph), 129.4 (Cph), 104.5 (Car); FT-IR [cm ꢀ 1]: 3599 (w),
3048 (w), 2973 (w), 1573 (w), 1548 (w), 1480 (w), 1423 (sh), 1357 (m),
1326 (m), 1251 (w), 1107 (m), 1021 (w), 829 (m), 732 (sh). 690 (sh);
Elemental analysis (6sq.tBuOH), Expected: C:57.26H:4.84 N:2.17
Found: C:57.48H:447 N:2.30. CCDC: 1938023.
Triphenylantimony mono-hydroxy 5-chloro-8-quinolinolate, 2. SbPh3
(0.353 g, 1 mmol) was reacted with t-BuOOH (140 μL, 2 mmol) before
addition of 5-chloro-8-quinolinol (0.179 g, 1 mmol) according to GP2.
Yellow solid (0.448 g, 81%). m.p: 128–130 ◦C; 1H NMR (600 MHz,
DMSO‑d6) δ = 9.18 (dd, J = 4.6, 1.4 Hz, 1H, CHar), 8.51 (dd, J = 8.5, 1.4
Hz, 1H, CHar), 7.79 (dd, J = 8.5, 4.6 Hz, 1H, CHar), 7.71–7.66 (m, 6H,
CHar), 7.60 (d, J = 8.4 Hz, 1H, CHar), 7.27–7.13 (m, 9H, CHar), 7.09 (d, J
= 8.5 Hz, 1H, CHar), 4.95 (s, 1H, OH); 13C NMR (101 MHz, DMSO‑d6) δ
= 156.2 (SbC), 151.0 (Car), 143.1 (Car), 135.6 (Car), 132.8 (Car), 129.9
(Car), 128.6 (Car), 126.8 (Car), 123.1 (Car), 114.4 (Car); FT-IR [cm ꢀ 1]:
3241 (br), 3052 (w), 2109 (w), 1571 (m), 1492 (m), 1452 (sh), 1429
(m), 1379 (m), 1362 (s) 1308 (sh), 1256 (m), 1084 (w), 1022 (sh), 826
(m), 740 (sh), 697 (sh); Elemental analysis (2.dmso), Expected:
C:55.57H:4.34 N:2.23 S:5.11 Found: C:55.40H:4.38 N:2.22 S:5.02.
CCDC: 1901551.
3. Results and discussion
3.1. Synthesis and characterisation
The antimony complexes 1–6 were synthesised through an oxidative
addition reaction. Triphenyl antimony was first oxidised from +III to +V
by the addition of two equivalents of tert-butyl hydroperoxide, before
addition of the desired quinolinol (Scheme 1), using a modified version
of a synthesis first reported by Moiseev et al [61]. The by-products
produced, tBuOH and H2O, are easily removed under vacuum. The
resultant yellow oils were sonicated in water to produce yellow/green
solids. The initial targets were the triphenyl Sb(V) bis-quinolinolato
complexes, [SbPh3L2], through the use of two equivalents of quinolinol
(LH). However, analysis of the 1H NMR spectra indicated that only the
mono-quinolinolato complexes, [SbPh3(OH)L], are formed irrespective
of the stoichiometry (Scheme 1).
Triphenylantimony mono-hydroxy 5,7-dichloro-8-quinolinolate, 3.
SbPh3 (0.353 g, 1 mmol) was reacted with t-BuOOH (140 μL, 2 mmol)
before addition of 5,7-dichloro8-quinolinol (0.214 g, 1 mmol) according
to GP2. Yellow solid (0.594 g, 89%). m.p: 95–97 ◦C; 1H NMR (600 MHz,
DMSO‑d6) δ = 9.20 (dd, J = 4.6, 1.4 Hz, 1H, CHar), 8.49 (dd, J = 8.5, 1.4
Hz, 1H, CHar), 7.83 (s, 1H, 7.77 (dd, J = 6.2, 4.4 Hz, 6H, CHar),
7.31–7.10 (m, 10H, CHar), 5.16 (s, 1H, OH13C NMR (101 MHz, DMSO) δ
152.2 (SbC), 151.9 (Car), 144.5 (Car), 136.1 (Car), 135.6 (Car), 132.6
(Car), 129.5 (Car), 128.8 (Car), 128.3 (Car), 125.7 (Car), 123.1 (Car), 118.1
(Car), 114.7 (Car); FT-IR [cm ꢀ 1]: 3244 (w), 3053 (w), 2165 (w), 1571
(m), 1494 (m), 1450 (sh), 1429 (m), 1397 (m), 1308 (sh), 1256 (w),
1084 (m), 1025 (sh), 958 (sh), 826 (m), 740 (sh), 697 (sh); Elemental
analysis (3.2H2O) Expected: C:52.38H:3.91 N:2.26 Found
C:52.61H:4.06 N: 2.27. CCDC: 1938022.
Using the appropriate 1:1 stoichiometry allows for the isolation of
clean products in good yield (72–90%) with minimal workup. Crystals of
complex 2–6 were each obtained through slow evaporation in DMSO
solution. The crystal structures thereby obtained show that, with the
exception of 1, the crystals incorporate DMSO in the interstices inter-
acting through hydrogen bonding with the hydroxyl ligand covalently
bound to the metal centre. In contrast, the structure of 1 indicates direct
hydrogen bonding through hydroxyl ligands on two molecules. These
structural features are discussed in the X-ray crystallographic section
below. The solid-state structures correlate well with the respective 1H
NMR spectra.
Triphenylantimony mono-hydroxy 5,7-dibromo-8-quinolinolate, 4.
These complexes are the first example of heteroleptic triphenyl
antimony (V) mono-hydroxido mono-quinolinolato complexes. The only
other relevant study of a closely related complex is that of the triphenyl
mono-chlorido complex of 8-quinolinolate [62]. All analytical data
supports the complexes having the composition [SbPh3(OH)L].
In summary, the 1H and 13C NMR spectra of each complex were
obtained in d6-DMSO. Complexation of the quinolinolate to the metal
centre is characterised by the lack of the hydroxyl signal from the parent
quinolinol normally observed in 9.78–11.05 ppm range. A shift in both
the aromatic signals of the quinolinol and the parent SbPh3 is observed
to higher frequencies, consistent with that observed for previously
synthesised tris-aryl Sb(V) complexes [25]. All data can be found in the
SbPh3 (0.353 g, 1 mmol) was reacted with t-BuOOH (140 μL, 2 mmol)
before addition of 5,7-dibromo-8-quinolinol (0.303 g, 1 mmol) accord-
ing to GP2. Yellow solid (0.540 g, 72%). m.p: 121–123 ◦C; 1H NMR (600
MHz, DMSO‑d6) δ = 9.17 (dd, J = 4.6, 1.4 Hz, 1H, CHar), 8.41 (dd, J =
8.5, 1.4 Hz, 1H, CHar), 8.05 (s, 1H, CHar), 7.82–7.71 (m, 6H, CHar),
7.29–7.12 (m, 10H, CHar), 5.16 (s, 1H, OH); 13C NMR (101 MHz,
DMSO‑d6) δ = 150.4 (Car), 138.0 (Car), 132.6 (Cph), 128.9 (Cph), 128.3
(Cph), 127.3 (Car), 123.5 (Car), 104.5 (Car); FT-IR [cm ꢀ 1]: 3275 (w),
3065 (w), 2081 (w), 1560 (m), 1481 (m), 1430 (sh), 1390 (m), 1357
(sh), 1309 (m), 1242 (w), 1103 (m), 1022 (sh), 943 (m), 864 (w), 743
(sh), 690 (sh); Elemental analysis (4.dmso), Expected: C:46.43H:3.49
N:2.03 S:4.27 Found: C:46.30H:3.49 N:1.87 S:4.42. CCDC: 1938252.
Triphenylantimony mono-hydroxy 5,7-diiodo-8-quinolinolate, 5. SbPh3
(0.353 g, 1 mmol) was reacted with t-BuOOH (140 μL, 2 mmol) before
addition of 5,7-diiodo-8-quinolinol (0.397 g, 1 mmo). Yellow solid
(0.598 g, 78%) according to GP2. m.p: 179–181 ◦C; 1H NMR (400 MHz,
DMSO‑d6) δ = 9.10 (dd, J = 4.6, 1.4 Hz, 1H, CHar), 8.31 (s, 1H, CHar),
8.27 (dd, J = 8.5, 1.3 Hz, 1H, CHar), 7.75 (dd, J = 8.5, 4.5 Hz, 6H, CHar),
7.21 (m, 10H, CHar), 5.12 (s, 1H, OH); 13C NMR (101 MHz, DMSO‑d6) δ
= 132.5 (Cph), 128.7 (Cph), 128.2 (Cph); FT-IR [cm ꢀ 1]: 3050 (w), 2115
(w), 1545 (m), 1475 (m), 1430 (sh), 1385 (m), 1353 (sh), 1307 (w),
1243 (m), 1102 (m), 1063 (m), 846 (m), 733 (sh), 692 (sh); Elemental
analysis, Expected: C:41.47H: 2.54 N:1.86 Found: C:41.38H:2.75
N:1.89. CCDC: 1938021.
Scheme 1. Oxidative addition reaction resulting in the Sb(V) mono-quinoli-
nolato complexes 1–6.
4

R.N. Duffin et al.
Journal of Inorganic Biochemistry 219 (2021) 111385
ESI.
configuration was observed in previously reported complexes [26,70].
– –
As mentioned previously, distortion along the O Sb O angle from the
The FT–IR spectrum of each complex provided additional informa-
tion on the binding of the quinolinolate ligand through a shift in the
ideal 180 o is reported.
broad O H signal from ~3300 to 2800 cmꢀ 1 in each of the complexes.
Coordination of the N atom is confirmed by the Sb N bond length of
–
–
–
It was also found that a significant shift in the strong C N signal,
2.389(4). This is similar to those described by Hoskins et al for a bis-
ranging from 1201 to 1190 cmꢀ 1, and the OH bend ranging from 1331 to
1276 cmꢀ 1, in the parent quinolinols was observed in the complexes. A
weak, broad signal was observed for the covalently bound hydroxyl in
the complexes in the range 3306–3241 cmꢀ 1. The IR spectrum for each
complex can be found in the ESI along with a table detailing specific
absorbances (Table S1).
quinolinolato Sb(III) (Sb N distances of 2.368(7) and 2.373(7) Å), and
–
a tetranuclear complex synthesised by Jami and Baskar, which exhibits a
–
–
O
short Sb N coordinate bond length of 2.238(2) Å [71,72]. The Sb
bond distance for the quinolinolato ligand, at 1.967(4) Å is shorter than
–
the respective Sb O bonds involving the hydroxide (2.118(3) Å (5)).
These lengths are well within the typical range of a covalent interaction
–
–
O
of Sb O bonds [73,74]. Interestingly the bond angle for the OH
3.1.1. X-ray crystallography
interaction of each complexes was found to increase from 1 to 5, with
compound 6 the outlier. This may be due to the increase of halide size on
the quinolinol moiety, with the larger halides causing a larger inductive
effect on the complex as a whole.
Crystal of all six complexes were analysed using single crystal X-ray
diffraction. A summary of the X-ray data for all complexes 1–6 can be
found in the ESI. The geometry of the compounds can be described as
distorted octahedral. All compounds were found to deviate from the
ideal 180 o angle along the axial plane of the deprotonated quinolinol
3.2. Stability studies
– –
and covalently bound hydroxyl (O Sb O), with
a range of
164.3o–174.0o. Compound 6 was found to exhibit the largest degree of
distortion and compound 2 the least. This may be due to the additional
steric effects of halides at both the five and seven position and the added
methyl group at the two position for the quinolinol ligand of compound
6. Compounds 1 and 5 will be discussed in more detail (Fig. 4). Com-
pound 1 was the only compound that did not require a hydrogen bonded
solvent molecule for crystallisation, it was instead found to self-associate
with a second moiety in the asymmetric unit to form a dimer (Fig. 4).
3.2.1. Solid and solution state analysis
The stability of the six complexes in both the solid and solution states
was determined over a minimum period of one month. With respect to
solid-state stability, melting point analysis showed no change for each of
the complexes over several months of screening. The solution state
stability was studied through 1H NMR spectroscopy over a defined
period. Each complex was dissolved in deuterated d6-DMSO, which had
not been pre-dried, and a spectrum recorded at 0 and 24 h. No observ-
able changes in the chemical shifts occurred, suggesting a high degree of
stability towards ligand rearrangement and hydrolysis. All of the spectra
can be found in the ESI.
–
The Sb O distances of 2.105(2), 2.066(2) and 1.984(2), 2.010(2)
–
–
–
–
both for Sb(1) O(1), Sb(1A) O(1A) and Sb(1) O(2), Sb(1A) O(2A)
respectively, are described as covalent in nature and along with the two
–
–
–
sets of three Sb C interactions (Sb(1) C(10), 2.161(3) Å, Sb(1A) C
–
–
(10A), 2.151(3) Å, Sb(1) C(16), 2.143(3) Å, Sb(1A) C(16A), 2.150(3)
3.2.2. Stability in cell culture media
–
–
Å and Sb(1) C(22), 2.145(3) Å, Sb(1A) C(22A), 2.149(3) Å) balance
To understand whether the complex as constituted is the anti-
microbial agent, then a high degree of stability in culture media is
required. Previous studies on tris-aryl Bi(V) carboxylates have shown
that the degree of stability in culture media can vary. For example, we
previously reported that triphenyl and tris-tolyl Bi(V) NSAID complexes
exhibit rapid exponential decay in culture media (NSAID = non-steroi-
dal anti-inflammatory drug) [30,31]. In contrast, the analogous Sb(V)
complexes were all found to exhibit a high degree of stability in media
with cell selectivity [25–27].
– –
the charge of each Sb(V) centre. Bond angles for the C Sb C of the
phenyl rings of 169.2(12) o, 95.98(12) o and 94.79(12) o for C(22) – Sb
– –
– –
(1) – C(10), C(16) Sb(1) C(22) and C(16) Sb(1) C(10) and 163.9
(12) o, 96.22(12) and 99.66(13) for C(22A) Sb(1A) C(10A), C
o
o
–
–
–
–
–
–
(16A) Sb(1A) C(22A) and C(16A) Sb(1A) C(10A), respectively,
are not dissimilar to the angles observed in the pentacoordinate Sb(V)
tris-aryl carboxylates previously synthesised [26,33,27]. This give the
phenyl rings an overall propeller-like orientation with is characteristic
of tris-aryl Sb(V) complexes [26,28,29,63–69]. The remaining axial
positions are occupied by the oxygen moieties of the hydroxyl and
Complex 2, [SbPh3(C9H5NOCl)(OH)] was used as an exemplar to
understand the stability of the complexes in media. The complex was
dissolved in d6-DMSO at a concentration of 10 mM. From this stock 100
–
quinolinol. The datively bound nitrogen (bond range of 2.389 Å 2.597
Å for compounds 1–6) occupies the remaining equatorial position. The
bulk representative example 5 (Fig. 4), is analogous in structure to the
remaining compounds.
μ
L was suspended into 900 μL of D2O suspended DMEM. At this con-
centration a small degree of precipitation occurred. A 1H NMR was taken
at times 0, 6, 12, 18 and 24 h to determine culture media stability. The
protons on the Ph groups were able to be distinguished easily. Signals in
Like compound 1, it is six-coordinate distorted octahedron. A similar
Fig. 4. Solid-state structure of complex 1, 2[SbPh3(C9H6NO)(OH)] and complex 5, [SbPh3(C9H4NOI2)(OH)]. Thermal ellipsoids at 50% probability. Hydrogen atoms
except for those that are relevant have been omitted for clarity. Selected bond lengths (Å and angles (o) can be found in the ESI.
5

R.N. Duffin et al.
Journal of Inorganic Biochemistry 219 (2021) 111385
relation to the quinolinolate moiety remained close the baseline and
because of the lower number of protons relative to those of Ph were
difficult to assign. A control spectrum of SbPh3 in culture media was
used to determine that the complex had not undergone reduction into
SbPh3 and parent quinolinol (Fig. 5).
calculated in the ranges of 4.52–16.7, and are shown below in Table 1.
ClogP values were calculated showing that an increase in halide size
correlates to an increase of the ClogP. This increase of ClogP seemed to
also correlate to an increase in selectivity, indicating an interesting
structure-activity relationship.
A consistent signal from the culture media at 5.10 ppm was set to an
integral value of 1.00 and its ratio to one of the aromatic protons of
complex 2 at 7.90 ppm compared at each time point. No significant
changes to the integration was detected over the 24-h period, indicating
a high degree of DMEM stability (Fig. 6).
Complexes 4, 5 and 6 in particular show good selectivity, with a 16-
fold increase from mammalian to parasite IC50. Even the remaining
complexes still fall above the range of the FDA definition of a narrow
therapeutic index (2-fold increase mammalian, microbe), indicating
their potential in future assays [77].
3.3.2. Amastigote invasion assay
3.3. Biological activity
An amastigote invasion assay was undertaken on complexes 1–6.
Amastigotes are the mammalian infective form of the parasite, therefore
activity against this stage is imperative for any potential anti-
leishmanial [78]. Each complex was found to exhibit excellent activity
3.3.1. Leishmania promastigote and mammalian cytotoxicity
8-Quinolinol (8-hydroxyquinoline) is known to act as an anti-
leishmanial agent, and can exhibit increased bactericidal effects in the
presence of metal ions. It was hypothesised that incorporating the qui-
nolinolate anion into an aryl-Sb(V) complex could generate a positive
additive or synergistic effect [36,38,41]. As such, all the Sb(V) com-
plexes 1–6 were assessed for their activity towards both L. major pro-
mastigotes and the more clinically relevant amastigote form.
Mammalian cytotoxicity was assessed using human primary fibroblasts.
Each complex was examined using a Celltiter blue viability assay against
both L. major promastigotes and human fibroblasts, with each assay
duplicated and an average of these repeats plotted.
at the standard concentration of 10 μM (Fig. 9). The percentage infection
values ranged from 2.25%–9.00%. Similar to the cytotoxicity studies on
fibroblasts, an increase in halogen size on the 5 and 7 positions lead to an
increase in anti-amastigote activity. Complex 5 [SbPh3(C9H4NOI2)(OH)]
proved the most efficient in eradicating infection (2.25% ± 0.25), with
the dichlorquinolinolate complex,
6 [SbPh3(C9H4NOCl2CH3)(OH)]
proving the least effective (9.00% ± 0.83). Despite this, all complexes
exhibited a greater degree of activity (Table 2) than recently studied
triphenyl Sb(V) carboxylate complexes (percentage infection range,
9.50%–30.0% [26], 7.75%–40.5% [27]). In fact, the range of percentage
infection for these quinolinolate complexes was observed to be much
lower than the previously examined bis-carboxylates, with less variation
in their activity for all six compounds.
All complexes exhibited excellent activity against the promastigote
form, with IC50 values ranging from 2.03–3.39 μM (Fig. 7). Amphoter-
icin B and DMSO were tested as controls and the data can be found in ESI
Figs. S2 and S3. Complex 6 proved to be the most potent of the com-
plexes, though there is no clear and obvious trend arising from the
change in halide and ring position. The level of anti-promastigote ac-
tivity of these complexes surpasses that found in our previous studies
with triphenyl Sb(V) acetates, with the most effective of those complexes
Each of the parent quinolinols was also assessed for its anti-
leishmanial activity. Previous studies on 8QH showed it to be potent
against three separate leishmanial strains (L. amazonensis, L. braziliensis
and L. infantum) but only at a relatively high concentration of 68 μM
[41]. In this study all the parent quinolinols display anti-leishmanial
activity at the comparison concentration of 10 M but exhibit lower
presenting with an IC50 value of 6.18 μM [27]. The lability of the ary-
μ
–
loxido metal bond, and hence the release kinetics of the quinolinol,
may contribute to this increased activity, since carboxylates are more
anionic ligands and less labile [75,76].
activity than their corresponding antimony complex at the same con-
centration. (Table 2, Fig. S4). Thus, the metal complex is more effective
than the quinolinol alone and the combination of the triphenyl Sb
moiety and the quinolinolate ligand have provided better results than
the carboxylate analogues we have studies.
Each complex 1–6 was found to exhibit toxicity towards to human
fibroblasts within the range of 12.7–46.9
μM (Fig. 8) with
[SbPh3(C9H6NO)(OH)] 1 the most toxic and [SbPh3(C9H4NOI2)(OH)] 5
the least. Interestingly, a trend became apparent whereby an increase in
the size of the halide results in a decrease in mammalian cell toxicity.
Complexes 5 and 4, respectively, are the most selective of the series,
though 1, 2 and 3 displayed reasonable selectivity indices, due to their
potency on L. major promastigotes. Selectivity indices have been
Overall, taking into consideration the selectivity and anti-amastigote
activity, complex 5, the iodoquin complex, looks to be best lead com-
pound from this series. Further structural modification in the aryl groups
and quinolinols, and future in vivo testing would allow further clarifi-
cation of the potency of these complexes as anti-leishmanial agents.
Fig. 5. Comparative 1H NMR spectra of SbPh3 and 2, [SbPh3(C9H5NOCl)(OH)], in D2O DMEM. Signals in relation to the culture media at 7.37, 7.32, 7.28, 7.12 and
6.82 ppm have not been labelled on either spectrum.
6

R.N. Duffin et al.
Journal of Inorganic Biochemistry 219 (2021) 111385
1
Fig. 6. H NMR study of complex 2, [SbPh3(C9H5NOCl)(OH)], in DMEM culture media at 0, 6, 12, 18 and 24 h, at 25 ◦C. Signals in the culture media in the aromatic
region have not been labelled. Integration ratio calculated using the culture media signal at 5.10 ppm as the control.
Fig. 7. Comparison of percentage cell viability after treatment with the
Sb(V) complexes 1–6, against Human fibroblasts. Dose response curves
were generated over a range of concentrations (48 nm–100 μM) in the
appropriate culture media from 10 mM DMSO stock solutions. All
readings were compared spectroscopically to non-treated control and
the percent growth inhibition calculated. A DMSO control and positive
drug control (Amp B) were also included at the same range of con-
centrations which can be found in the ESI (S2 and S3).
3.3.3. Measurements of reactive oxygen species and nitric oxide
observed (ESI, Fig. S5, Table S3) [84]. Studies into the leishmanicidal
effects of piperine compounds by Ferreira et al. observed a similar
response, with a down regulation of NO observed despite being effective
anti-leishmanials [85]. Therefore, it can be assumed that the antimony
complexes do not cause amastigote death by activation of NO produc-
tion. Measurement of the generation of ROS was then analysed through
exposure to the compounds and controls at 6 and 24 h. Increase of ROS
was detected spectroscopically by the addition of the non-fluorescent
dye, dihydroethidium. Leishmania amastigotes are able to block pro-
duction of ROS [81,86], therefore if the infection is still relatively high,
very little DHE will be oxidised to the fluorescent form. At 6 h exposure,
both 2 and 5 were found to induce a high percentage increase of ROS
Leishmania species are able to avoid host immunity by decreasing
and inhibiting the production of both reactive oxygen species (ROS) and
nitric oxide (NO), two major constituents of the macrophage’s immune
response [79–83]. To probe a potential mechanism of action of these
active antimony complexes two further assays were performed to mea-
sure the production of ROS and NO. A Griess assay was performed on
infected macrophages that had been exposed to two example complexes,
2, a low SI complex, and 5, which was highly potent to amastigotes. A
control of amphotericin B was also employed along with infected mac-
rophages with no drug exposure. Similar to a recent study on alkyl
gallium quinolinolates, there was no increase in the production of NO
7

R.N. Duffin et al.
Journal of Inorganic Biochemistry 219 (2021) 111385
Fig. 8. Comparison of percentage cell viability after treatment
with the Sb(V) complexes 1–6, against L. major promastigotes.
Dose response curves were generated over a range of concen-
trations (48 nm – 100 μM) in the appropriate culture media
from 10 mM DMSO stock solutions. All readings were
compared spectroscopically to non-treated control and the
percent growth inhibition calculated. A DMSO control and
positive drug control (Amp B) were also included at the same
range of concentrations which can be found in the ESI (S2 and
S3).
when compared to the control of infected cells without treatment, and a
greater increase than the drug control amphotericin B. After 24 h the
percentage of ROS has dropped dramatically, with a decrease from the
control for 2 (ESI Fig. S6, Table 3). This would suggest that activation of
ROS plays a major role in the activity of the antimony complexes. The
dramatic decrease after 24 h may indicate that these drugs are able to act
upon the parasites within this time frame. Pentostam ™ has been shown
to induce both NO and ROS production in Leishmania infected macro-
phages through its reductive pathway, therefore it is likely these Sb(V)
quinolinolates would share some similar characteristics [48,87].
Table 1
Selectivity indices of complexes 1–6. Indices calculated based on IC50(mam-
malian)/IC50(parasite). ClogP values are also listed for comparative purposes.
Fibroblasts IC50
(μM)
Promastigotes IC50
(μM)
Selectivity Index
ClogP
1
2
3
4
5
6
12.7
18.6
24.5
41.4
46.9
32.8
2.81
3.39
3.05
2.52
2.81
2.03
4.52
5.49
8.03
16.4
16.7
16.2
6.63
7.34
8.06
8.34
8.88
8.56
Fig. 9. Infected macrophages after treatment of
complexes 1–6, after 48 h. Number of infected
macrophages was determined microscopically, in
duplicate of fixed specimens. Amphotericin
(AmpB) was used as a positive control at 10
B
μ
M
concentration. A DMSO control was also employed
at a 1% concentration. Error bas indicate SEM, one-
way ANOVA. Dunnett’s multiple comparison test
was used to determine the statistical significance
between all test compounds and a positive control
lacking treatment (+ve control).
8

R.N. Duffin et al.
Journal of Inorganic Biochemistry 219 (2021) 111385
the potential to be an effective strategy for the development of new
combi-drugs.
Table 2
Percentage infection values for the parent quinolinols and Sb(V) complexes 1–6,
all values are calculated by comparison to a positive control of untreated
infected cells.
Author contributions
Quinolinol (LH)
%
Sb(V) complex
[SbPh3(OH)L]
%
Infection
Infection
All contributors involved in drafting and finalisation of manuscript.
8 -Quinolinol
15.3 ±
3.00
1
2
3
4
5
6
7.75 ±
0.85
Dr Rebekah N. Duffin
Principle research student
– Data curation, formal analysis, Investigation (synthesis and bio-
logical assays)
5-Chloroquinolinol
5,7-Dichloroquinolinol
5,7-Dibromoquinolinol
5,7-Diiodoquinolinol
21.5 ±
5.13
8.25 ±
0.95
30.8 ±
3.28
6.00 ±
0.71
Dr Victoria L. Blair
23.8 ±
4.86
4.25 ±
0.48
Research Fellow
–
Investigation, Supervision and Analysis (synthesis and
16.0 ±
2.81
2.25 ±
0.25
crystallography)
Assoc. Prof. Lukasz Kedzierski
Supervisor (Microbiology)
- Project Administration
- Funding Aquisition
5,7-Dichloro-2-
12.5 ±
2.92
9.00 ±
0.83
methylquinolinol
Prof. Philip C. Andrews
Supervisor (Chemistry)
- Project Administration
- Funding Aquisition
Table 3
Percentage increase of ROS after exposure to complexes 2 and 5 after 6 and 24 h.
The drug control ampB has also been included.
Time (hr)
Complex
Amp B
1
5
Declaration of Competing Interest
6
141.8 ± 1.60
82.0 ± 0.31
153.3 ± 11.7
103.5 ± 2.30
120.4 ± 2.93
108.8 ± 0.89
24
There are no conflicts to declare.
4. Conclusions
Acknowledgements
In seeking to form a new class of potential anti-leishmanial combi-
drug we have synthesised and fully characterised six novel triphenyl
The authors would like to thank the Australian Research Council
(DP170103624) and Monash University for financial support. We would
also like to thank Dr. Craig Forsyth (Monash) for assistance with X-ray
crystallography. The authors would also like to acknowledge the
Australian Synchrotron for use of the MX1 beamline at the Australian
Synchrotron, part of ANSTO.
antimony
mono-hydroxido
mono-quinolinolato
complexes
[SbPh3(C9H6NO)(OH)],
1,
3,
[SbPh3(C9H5NOCl)(OH)]
[SbPh3(C9H4NOBr2)(OH)]
2,
4,
[SbPh3(C9H5NOCl2)(OH)]
[SbPh3(C9H4NOI2)(OH)] 5 and [SbPh3(C9H3NOCl2CH3)(OH)] 6. Irre-
spective of reaction stoichiometry only one quinolinolato ligand can be
incorporated into the structure leaving one residual hydroxyl group on
the Sb(V) centre. The crystal structure of each complex indicates a dis-
torted octahedral coordination environment at Sb(V) with the three Ph
groups and the N from the quinolinolate ligand occupying the equatorial
plane and the oxygen atoms from the chelating quinolinolate and the
hydroxide moiety in the axial positions.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jinorgbio.2021.111385.
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stable towards ligand substitution and hydrolysis in DMSO solution over
24 h but change slowly over seven days. Complex 2, as an exemplar, was
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