Activity of Antifungal Organobismuth(III) Compounds Derived from Alkyl Aryl Ketones against S. cerevisiae: Comparison with a Heterocyclic Bismuth Scaffold Consisting of a Diphenyl Sulfone

摘要

A series of hypervalent organobismuth(III) compounds derived from alkyl aryl ketones [XBi(5-R'C₆H₃-2-COR)(Ar)] was synthesized to investigate the effect of the compounds’ structural features on their antifungal activity against the yeast Saccharomyces cerevisiae. In contrast to bismuth heterocycles [XBi(5-RC₆H₃-2-SO₂C₆H₄-1'-)] derived from diphenyl sulfones, a systematic quantitative structure-activity relationship study was possible. The activity depended on the Ar group and increased for heavier X atoms, whereas lengthening the alkyl chain (R) or introducing a substituent (R') reduced the activity. IBi(C₆H₄-2-COCH₃)(4-FC₆H₄) was the most active. Its activity was superior to that of the related acyclic analogues ClBi[C₆H₄-2-CH₂N(CH₃)₂](Ar) and ClBi(C₆H₄-2-SO₂tert-Bu)(Ar) and also comparable to that of heterocyclic ClBi(C₆H₄-2-SO₂C₆H₄-1'-), which was the most active compound in our previous studies. Density function theory calculations suggested that hypervalent bismuthanes undergo nucleophilic addition with a biomolecule at the bismuth atom to give an intermediate ate complex. For higher antifungal activity, adjusting the lipophilicity-hydrophilicity balance, modeling the three-dimensional molecular structure around the bismuth atom, and stabilizing the ate complex appear to be more important than tuning the Lewis acidity at the bismuth atom.