title: 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.
abstract: 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-SO2 tert-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.
authors: Graduate School of Medicine, Yamaguchi University, Yamaguchi 753-8512, Japan. murafuji@yamaguchi-u.ac.jp.
authors: Toshihiro
authors: T
authors: Murafuji
authors: Graduate School of Medicine, Yamaguchi University, Yamaguchi 753-8512, Japan.
authors: Mai
authors: M
authors: Tomura
authors: Graduate School of Science and Engineering, Yamaguchi University, Yamaguchi 753-8512, Japan.
authors: Katsuya
authors: K
authors: Ishiguro
authors: Graduate School of Science and Engineering, Yamaguchi University, Yamaguchi 753-8512, Japan.
authors: Isamu
authors: I
authors: Miyakawa
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001729:Bismuth / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D012441:Saccharomyces cerevisiae / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry
chemical_list: D000935:Antifungal Agents; D007659:Ketones; D009942:Organometallic Compounds; D013450:Sulfones; D001729:Bismuth