Design and development of novel bismuth(III) complexes as antibacterial and antiparasitic drugs

This thesis has explored the synthesis and characterisation of novel bismuth(III) complexes derived from three different classes of ligands namely, indolecarboxylic acids (Chapter 2), hydroxamic acids (Chapter 3) and non-steroidal anti-inflammatory drugs (NSAIDs; Chapter 4). The medicinal relevance of the synthesised bismuth(III) complexes as antibiotics for Helicobacter pylori (H. pylori) and the anti-Leishmanial activity of both the free acids and their bismuth(III) complexes against Leishmania major (L. major) promastigotes were assessed. Synthesis, characterisation and medical relevance of novel bismuth(III) indolecarboxylates was investigated in Chapter 2. Ten new bismuth(III) complexes in the indolecarboxylic acid class of ligands have been synthesised. Among these, eight complexes are homoleptic: Bi(IAA)₃ B1, Bi(IPA)₃ B2, Bi(IBA)₃ B3, [Bi(MOIAA)₃] B4, [Bi(BIAA)₃] B5, [Bi(IPYA)₃] B6, [Bi(MICA)₃] B7, and [Bi(IGA)₃] B9. The remaining two, BiPh(MICA)₂ B8 and BiPh(IGA)₂ B10, are heteroleptic in nature. All the prepared complexes were fully characterised by elemental analysis, infrared, mass-spectroscopy and nuclear magnetic resonance (¹H-NMR and ¹³C-NMR) spectroscopy. BiPh(IGA)₂ B10 was also structurally characterised by X-ray crystallography, which revealed that B10 is dimer in nature. The in-vitro anti-bacterial properties of the free indole acids and their complexes B1-B10 against H. pylori were determined using the minimum inhibitory concentration (MIC) method. All of the tested bismuth compounds showed MIC of 6.25 μg mLˉ¹, indicating that anti-bacterial activity in this series is independent of the aromatic ring substituents or the number of indolecarboxylic acids attached to the Bi(III) centre. The compounds were also tested for their anti-parasitic activity against L. major and were further assessed for their toxicity to mammalian cells. These studies showed that heteroleptic bismuth(III) complexes are the most active compounds in the series. The heteroleptic complexes BiPh(MICA)₂ B8 and BiPh(IGA)₂ B10 showed comparable activity to Amphotericin B without any toxicity towards mammalian cells at their effective concentration. Next, the coordination chemistry and biological activity of bismuth(III) hydroxamate complexes was investigated in Chapter 3. A variety of mono- and diprotic hydroxamic acids were applied and resulted in the formation of twelve new bismuth(III) complexes, including tris-hydroxamato complexes, mixed-anion complexes and bismuthate complexes. The solid state structures of the bismuth(III) complexes {[Bi(SHA)(H-SHA)(DMSO)₂][Bi(SHA)-(H-SHA)(DMSO)]·DMSO}∞ [(DMSO)₁.₅·0.5DMSO] B15, {[Bi(BPHA)₃]₂.2EtOH} (EtOH) B19 and {[Bi(MFHA)₃]₂·Me₂C=O)} (0.5Me₂C=O) B20 were determined and discussed. An attempt to get crystals of the di-anionic hydroxamato complex, B13 [Bi₂(BHA)₃], in DMSO/toluene resulted in hydrolysis to the first structurally authenticated {Bi₃₄} oxido-cluster B23 [Bi₃₄O₂₂(BHA)₂₂(H-BHA)₁₄(DMSO)₆]. The solid state structure of B23 was determined by X-ray crystallography and discussed. All of the synthesised compounds and their parent acids were assessed for their bacteriocidal activity against three strains of H. pylori (26695, B128 and 251). Of the acids, only acetohydroxamic acid showed any activity at low concentrations (MIC 6.25 μg mLˉ¹; 83.26 μM) while the others were not toxic below 25 μg mLˉ¹. In contrast, their bismuth(III) complexes all showed excellent activity across all three strains (e.g. 0.08 μM for [Bi(H-BHA)₃] to 2.83 μM for K[Bi(SHA)₂] against strain B128) with only minor variations in activity being both ligand and composition dependant. All the free acids and their corresponding bismuth complexes were also tested against L. major. Results of anti-parasitic testing revealed that among the library of all the bismuth(III) hydroxamate complexes, [Bi₂BHA)₃] B13, [Bi(AHA)(H-AHA)] B16, [Bi(NHA)(H-NHA)] B18, [Bi(BPHA)₃] B19 and [Bi(FHA)₃] B20 possess good anti-Leishmanial activity. Coordination chemistry of mono-, di- and polydentate NSAIDs with bismuth was investigated in Chapter 4. Three different methods (solvent-free, solvent-mediated and salt metathesis) were explored to access the bismuth(III) complexes. This study led to the successful synthesis of eight novel tris-substituted bismuth complexes of NSAIDs. The prepared complexes were fully characterised by elemental analysis, infrared, mass-spectroscopy and nuclear magnetic resonance (¹H-NMR and ¹³C-NMR) spectroscopy. The synthesised compounds were then tested for their anti-bacterial activity against H. pylori. The results showed that the studied bismuth(III) NSAID complexes have the potential to compete with commercially available drugs [bismuth subsalicylate (BSS), colloidal bismuth subcitrate (CBS) and ranitidine bismuth subcitrate (RBC)] against H. pylori and to provide a comparable remedial effect. The activity of the synthesised bismuth(III) complexes of NSAIDs and their corresponding free acids were also tested against L. major promastigotes. Their anti-parasitic activity results were compared with the activity of commercially available anti-Leishmanial drug Amphotericin B. Many of the free acids and the bismuth(III) complexes showed effective anti-Leishmanial activity.