Bismuth(iii) β-thioxoketonates as antibiotics against Helicobacter pylori and as anti-leishmanial agents

Abstract

Nine different β-thioxoketones of general formula R(1)C(=O)CH2C(=S)R(2) (R(1) = C6H5, R(2) = C6H5L1; R(1) = C6H5, R(2) = p-CF3C6H4L2; R(1) = p-MeOC6H4, R(2) = C6H5L3; R(1) = p-MeOC6H4, R(2) = p-CF3C6H4L4; R(1) = C5H4N, R(2) = C6H5L5; R(1) = p-IC6H4, R(2) = C6H5L6; R(1) = C6H5, R(2) = p-IC6H4L7; R(1) = C6H5, R(2) = C10H7L8 and R(1) = CH3, R(2) = C6H5L9) and their tris-substituted bismuth(III) complexes having the general formula [Bi{R(1)C(=O)CHC(=S)R(2)}3] were synthesised and fully characterised. The solid state structure of [Bi{C5H4NC(=O)CHC(=S)C6H5}3] B5 was determined by crystallography and revealed that the three β-thioxoketonato ligands are bound to bismuth(III) centre in a bidentate fashion through O and S atoms. The bismuth(III) complexes and the corresponding thioxoketones were assessed for their activity against H. pylori. All of the bismuth(III) complexes were highly active against H. pylori having a MIC of greater than or equal to 3.125 μg mL(-1), while the free acids were essentially not toxic to the bacteria. The anti-leishmanial activity of all the bismuth(III) β-thioxoketonates and the corresponding free acids were assessed against L. major promastigotes. The toxicity towards human fibroblast cells was also assessed. All of the free β-thioxoketones were selectively toxic to the L. major promastigotes displaying some potential as anti-leishmanial agents. Among these [C6H5C(=O)CH2C(=S)C6H5] L1 and [C5H4NC(=O)CH2C(=S)C6H5] L5 showed comparable activity to that of Amphotericin B, killing about 80% of the L. major promastigotes at a concentration of 25 μM (6.0 μg mL(-1)). The bismuth(III) β-thioxoketonate complexes were toxic to both the L. major promastigotes and fibroblast cells at high concentrations, but gave no improvement in anti-leishmanial activity over the free β-thioxoketones.

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

“…9 These challenges mean that there is a need for alternative, low cost, safe oral treatments with reduced toxicity and side effects. 13 Considering the periodic relationship of antimony and bismuth, and the low systemic toxicity of bismuth in humans, 14 we extended our explorations to both Bi(III) [15][16][17] and Bi(V) 18 based compounds as promising candidates for future anti-leishmanial drugs, targeting decreased toxicity, reduced side effects, and greater potential for oral delivery. 10,11 This leads to a decrease in buffering ability and imbalance in thiol redox potential as Sb(III) induces the efflux of trypanothione and glutathione out of the cell and their respective disulfides accumulate inside cells.…”

Synthesis and structural characterisation of bismuth(iii) hydroxamates and their activity against Helicobacter pylori

“…Both complexes showed remarkably low MIC values against three laboratory strains of H. pylori: B128, 251 and 26695, ranging from 0.05-0.78 μg mL −1 (0.08 to 1.26 µM) for 2 and 0.09-1.56 μg mL −1 (0.19 to 3.24 µM) for 6. These compare favorably with other classes of bismuth(III) complexes which typically have higher MIC values: bismuth (III) carboxylates and thiobenzoates with MIC values of 6.25 μg mL −1 34,35 and thioxoketones, MIC 3.12 μg mL −1 36. They are an orders of magnitude more active than the current bismuth drugs used to treat H. pylori, bismuth subsalicylate (BSS) MIC 12.5 μg mL −1 and colloidal bismuth subcitrate (CBS) MIC 12.5 μg mL −1 [37][38][39].…”

Synthesis, crystal structure and thermochemical study on a novel ternary coordination compound [Bi(C7H5O3)3C12H8N2]

“…As we all know, bismuth compounds were used as drugs before 200 years ago, which have a significant effect on the treatment of a variety of microbial infections for syphilis, diarrhea, gastritis colitis, ulcer and intestinal tract disorder [6][7][8]. Meanwhile, some compounds, with good biological activities, can effectively inhibit the growth and reproduction of cancer cells [8,9].…”