Anti-leishmanial activity and cytotoxicity of a series of tris-aryl Sb(V) mandelate cyclometallate complexes
Graphical abstract
A series of chiral tris-aryl Sb(V) mandelate cyclometallate complexes were assessed for their anti-leishmanial activity and cytotoxicity. Complexes demonstrate excellent activity, with selectivity indices shown to be dependent on the nature of the aryl group, providing insights into structure-activity relationships for aryl substitution and mono-substituted carboxylates.
Introduction
The fight against neglected tropical diseases (NTD) is an ongoing effort. Leishmania is among these NTDs, with millions of individuals affected globally each year. The World Health Organisation (WHO) estimates there were approximately 1.5 million new cases of Leishmaniasis in 2018, with those numbers set to rise if the disease burden remains untreated [1]. The fatal visceral form of the infection (VL) is on the rise, with an estimated 0.2–0.4 million new cases each year [2]. Of those up to 40,000 people die from the disease due to lack of adequate treatment [3,4]. Though highly effective, the current front-line treatments, sodium stibogluconate (Pentostam™) and antimony meglumine (Glucantime™), have well known problems associated with delivery and toxicity, and more recently a significant increase in resistance, now affecting most of the Indian sub-continent [[5], [6], [7]]. These pentavalent antimonials are highly hydrophilic, leading to a high renal clearance, and therefore oral administration is ineffective and treatment requires daily intravenous injections for approximately 28 days [[8], [9], [10]]. Even the alternative treatments, amphotericin B and miltefosine harbour their owns problems with toxicity, expense and parasitic resistance (Fig. 1) [[11], [12], [13]]. Despite all this, drug development from major pharma companies remains limited, primarily due to the prevalence of Leishmania in lower socio-economic countries. [1,14].
The mechanism of action of the current pentavalent antimonial treatments is still not fully understood. However, current consensus seems to coalesce around observations that it is the in vivo reduction of Sb(V) to Sb(III) which is the key important step, making the Sb(V) compounds pro-drugs and the protein-bound Sb(III) form the active agent [9]. Reduction occurs through interactions with trypanothione, a thiol-rich protein based on glutathione and exclusive to the parasite, which then inhibits its primary function as an oxidative stress mediator [15,16]. An alternative and less developed hypothesis is that Sb(V) acts directly on the parasite by inhibition of phosphatases, leading to a cascade effect and eventual cell death [17].
Over the past 30 years a number of alternative metals (e.g. Cu, Zn, Ru, Sn, Pd, Au, Ag) and their complexes have been studied as possible replacements for Pentostam™ and Glucantime™, with little progress [18]. Our recent research has focused on families of organometallic Bi(V) and Sb(V) carboxylates as more lipophilic complexes with the possibility of having lower toxicity [[19], [20], [21], [22], [23]]. Unfortunately, bismuth complexes of the type [BiAr3(O2CR)2] have proven to be unstable and non-selectively toxic to both parasite and mammalian cells [19,20]. Analogous Sb(V) complexes have proven to be more robust and more selective, and remain the most likely leads [19,20].
One complex which combined excellent activity towards amastigotes (% infected cells. 21 ± 0.72) and low toxicity towards human fibroblasts (≥100 μM) was the tris-phenyl antimony(v) mandelate [SbPh3(man)], in which mandelic acid (Man-H2), an alpha-hydroxy acid, had undergone double deprotonation and formed a cyclometallate (Fig. 2).
This was the case whether the R or S enantiomer of mandelic acid was used, though there was some slight variation in the bioactivity [19,24,25]. Mandelic acid itself has been used medicinally as a biological detector for toxic vapour exposure and as a bladder irrigation fluid for urinary tract infections [[26], [27], [28], [29], [30], [31]]. Mandelic acids anti-bacterial potential has also been assessed, with promising results in dermatological treatments [32,33].
Our previous studies on a large range of tris-aryl antimony(V) bis-carboxylate complexes, [SbAr3(O2CR)2] (Ar = Ph or tolyl), have shown that the simple change from Ph to tolyl and then in the substitution pattern of the tolyl group (o-, m- or p-) can have a significant effect on both the activity and selectivity of the Sb(V) complexes [21,23]. Specifically, the most active and selective compounds were either p-tolyl or m-tolyl substituted, with the m-tolyl compounds being overall marginally better. The o-tolyl and Ph substituted compounds proved to be generally less selective. In a subsequent study on Bi(V) analogues it was noted that the tolyl derivatives were again more selective than their Ph counterparts [20]. From these studies, it was concluded that the tolyl groups not only improve selectivity but were largely responsible for mediating the mammalian cell toxicity, while the carboxylate groups affected activity towards the parasite.
With this information on hand, and being aware of the good activity and selectivity of the [SbPh3(man)] complexes, we sought to improve the overall selectivity through a reduction in mammalian cell toxicity by replacing the three Ph groups with tolyl (o-, m- and p-), and three other substituted aryl groups (o-MeO-, mesityl, and p-tert-Bu), shown in Fig. 3.
In all six different aryl groups were assessed along with the different enantiomers of mandelic acid, to determine any structure – activity relationships dependant on the aryl group or the chirality of the carboxylate. We aimed to investigate whether these cyclometallate carboxylates may prove more effective than the conventional bis-substituted carboxylate complexes [SbAr3(manH)2]. As such, twelve novel complexes of general formulae [SbAr3(man)] and [(SbAr3(manH)2O2], were synthesised and characterised and their anti-leishmanial activity and cytotoxicity assessed.
Section snippets
General
Mandelic acid (R or S) was purchased from Sigma Aldrich without the need for purification. All bromo-aryls were purchased from either Sigma Aldrich or Oakwood. Any remaining reagents were purchased from Sigma Aldrich and Alfa Aesar. Solvents were purchased from Merck. All reaction requiring inert conditions were performed under an atmosphere of nitrogen, using over dried glassware and utilising a Schlenk manifold and technique. All dried solvents were obtained from an MBraun-SPS-800 and stored
Synthesis
All complexes were synthesised by a conventional oxidative addition reaction of hydrogen peroxide to the selected SbAr3 before addition of one equivalent of either R or S mandelic acid (Fig. 4) [19,21,22,39].
Due to the close pKa values of tert-BuOH and the α-hydroxyl proton of mandelic acid, H2O2 was used in place of the common alternative oxidant tert-BuOOH to encourage cyclometallation [40]. Thus, the only by-product from the reaction was H2O, produced upon condensation of the [SbAr3(OH)2]
Conclusion
A series of tris-aryl Sb(V) mandelato complexes: {1Sr/s, [Sb(o-tol)3(man)], 2Sr/s, [Sb(m-tol)3(man)], 3Sr/s, [(Sb(p-tol)3(manH)2O2], 4Sr/s, [Sb(o-PhOMe)3(man)], 5Sr/s, [Sb(Mes)3(man)] and 6Sr/s, [Sb(p-tert-BuPh)3(man)]}, bearing different aryl groups with either R or S mandelate co-ligands, were synthesised, compositionally and structurally characterised, and their biological activity towards Leishmania promastigotes and amastigotes, and mammalian cells, assessed. Complexes 3Sr/s were found to
Declaration of competing interest
There are no conflicts to declare.
Acknowledgements
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.
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