Stability and toxicity of tris-tolyl bismuth(v) dicarboxylates and their biological activity towards Leishmania major

Abstract

A series of 29 tris-tolyl bismuth(v) di-carboxylato complexes of composition [Bi(Tol)3(O2CR)2] involving either ortho, meta or para substituted tolyl ligands have been synthesized and characterised. Of these 15 were assessed for their toxicity towards Leishmania promastigotes and human fibroblast cells, with ten then being subsequently assessed against parasite amastigotes. The carboxylate ligands are drawn from a series of substituted and biologically relevant benzoic acids which allow a comparison with earlier studies on [BiPh3(O2CR)2] and analogous Sb(v) [SbAr3(O2CR)2] (Ar = Ph and Tol) complexes. Twelve complexes have been structurally characterized by single crystal X-ray diffraction and shown to adopt a typical trigonal bipyramidal geometry in which the three tolyl ligands occupy the equatorial plane. NMR studies on two illustrative examples indicate that the complexes are stable in D2O and DMSO but only have a half-life of 1.2 hours in culture medium, with glucose being a contributing factor in decomposition and reduction to Bi(Tol)3. Despite their short lifetime many complexes show significant toxicity towards promastigotes at low concentration (<6 μM) and at that concentration provide for good selectivity indices (parasite vs. mammalian cells), for example 114 for [Bi(o-Tol)3(O2CC6H3(2-OH,5-C6H3(2,4-F2)))2] and 838 for [Bi(m-Tol)3(O2CC6H4(2-OAc))2]. Best activity and selectivity is observed with complexes containing o- and m-tolyl ligands, and it appears the primary influence on fibroblast toxicity is the Ar ligand while the carboxylate influences promastigote toxicity. The complexes are less effective in vitro against the parasite amastigotes, where longer incubation times and harsher chemical and biological environments are encountered in the assay. Nevertheless, there were some statistically relevant differences at 1 μM against the positive controls with the best performing complexes being [Bi(o-Tol)3(O2CC6H4(2-EtO))2] and [Bi(m-Tol)3(O2CC6H4(2-OAc))2].

Bioactive Heteroleptic Bismuth(V) Complexes: Synthesis, Structural Analysis and Binding Pattern Validation

“…It was observed that even after 72 hr, a very minute quantity of the decomposition products, whose identity is unknown, settled at the bottom as white precipitate. The studies demonstrate broader stability spectrum for such type of compounds as earlier reports revealed …”

“…The other characteristic IR absorption bands observed are; 470–495 and 420–450 cm −1 corresponding to C‐Bi out of plane deformations and Bi‐O stretching mode vibrations which are consistent with the literature values . The Δν (νCO 2 asymm − νCO 2 symm ) values fall in range 150–250 cm −1 depicting that the carboxylato ligands adopt a bidentate or anisobidentate binding mode for ( 1 – 7 ) as earlier reports manifested and further authentication came through crystallographic data . The NMR spectra of the complexes show a high frequency shift in 1 H and 13 C resonances for the carboxylate moiety relative to those observed for free acids.…”

Glycosylated metal chelators as anti-parasitic agents with tunable selectivity

“…17,18 Accordingly, several metal complexes have been investigated against CD and leishmaniasis. 4,[19][20][21] The combination of metal ions with drugs and organic ligands can enhance their activity while at the same time, reducing the toxicity and undesired side effects that metal ions on their own could impart. [22][23][24] In this study, the synthesis of a series of amino-and iminopyridyl ligands and some of their metal complexes is reported.…”

Insight into the Biological Activity of Organometallic Acetylsalicylic Acid (Aspirin) Derivatives

“…The IC 50 value of 37 against L. major promastigotes was 0.71 μM and the IC 50 value against fibroblast cells was 2.95 μM, affording a selectivity index (SI) of 4.15. The antiparasite activity of 38 (IC 50 =0.76 μM) remained similar to that of 37 whereas the undesirable cytotoxicity against human fibroblast cells decreased (IC 50 =11.96 μM) . The SI of tris‐tolyl derivative 38 was 15.7 illustrating how methylation can improved a molecule's pharmacological characteristics .…”