The apparent chemical complexity of the commercially available bismuth-containing pharmaceutical agents has prompted the search for and development of new bioactive compounds. Therapeutic and anti-bacterial activity has been suggested for many 'model' compounds, with some having been assessed by in vitro and/or in vivo studies. Systematic synthetic studies coupled with bioactivity assessments confirm the biological significance of bismuth, provide comprehensive
characterization data for the compounds and reveal important trends. Tropo-lone complexes of bismuth(III) (Figure 27.7a) have been extensively deriva-tized, as well as less common examples of bismuth(V) complexes, and their anti-Hp activity is defined by minimum inhibitory concentrations.31 Comparisons have been made with derivatives of bismuth(III) thiosemicarbazones and dithiocarbazonic acid methylester (Figure 27.7b),32 implicating relationships between specific structural features and bioactivity.
Thiosemicarbazone complexes are representatives of a wide range of thio-bismuth compounds, made possible by the relatively high thiophilicity of bismuth (thermodynamically favorable Bi—S interaction). Indeed, sulfur compounds represent the most extensive series of bismuth complexes. Systematic series of bismuth-dithiolate compounds (Figure 27.7c) have been isolated and comprehensively characterized.33 The thiolate ligand serves to stabilize bismuth complexes with respect to hydrolysis and behaves as an anchor on bismuth for hetero-bifunctional thiolate ligands that promote or assist interaction of tethered weak Lewis donors with bismuth.15,34 36 Otherwise, complexes of bismuth with weakly donating functionalities can only be isolated in the absence of moisture and many conventional types of ligands have yet to be observed on bismuth. Hetero-bifunctional thiolate ligands provide access to series of complexes (Figure 27.7d, 27.7e),15,37 and offer a platform for systematic studies on models for medicinally relevant complexes. For example, dimeric structures are observed for tris(esterthiolate)bismuth and tris(methylthiosalicylate)bismuth complexes (Figure 27.8), in which two ligands on each bismuth center adopt a thiolatecarbonyl chelate interaction and the third behaves as a thiolatecarbonyl bridge. Both structures are reminiscent of the dimeric arrangement observed for 'colloidal bismuth subcitrate' compounds (Figure 27.4).
Minimum inhibitory concentrations (in the context of cytotoxicity assessments) for a range of compounds (Figure 27.7c) against Clostridium difficile, Hp,36 Escherichia coli, Pseudomonas aeruginosa and Proteus mirabilis38 reveal
X = Cl, NO3, Ph n = 2, m =1 n = 3, m = 0 n = 4, m = 0
X = Cl, NO3, Ph, OAc n =1, m = 2 n = 2, m =1 n = 3, m = 0
X = CH2CH2 CH2CH2CH2
Figure 27.7 Complexes of bismuth with tropolone and biologically relevant thiolate ligands
significant differences within a series suggesting a structure-activity relationship for the bismuth environment. In addition, studies using a rat model of gastric ulceration reveal distinct differences in ulcer-healing efficacy.39 More general biological activity, including anti-bacterial (Bacillus subtilis, E. coli, Candida tropicalis, Penicillium camembertii),40 fungicidal (yeast and moulds)40 and anti-tumor behavior,41 has been reported for a series of spectroscopically characterized bis(thiolate)bismuth compounds. The stability of bismuth complexes involving British anti-Lewisite (Figure 27.1) has highlighted them for anti-microbial assessment in vitro and in vivo.42
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