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

• Published in: Molecules (Basel, Switzerland) Vol. 19; no. 8; pp. 11077 - 11095
• Main Authors: Murafuji, Toshihiro, Tomura, Mai, Ishiguro, Katsuya, Miyakawa, Isamu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.07.2014; MDPI
• Subjects: acetophenone; antifungal activity; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Aromatic compounds; Atomic structure; Biomolecules; Bismuth; Bismuth - chemistry; Density; hypervalent; Ketones; Ketones - chemistry; Lewis acidity; Mathematical models; Microbial Sensitivity Tests; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Quantitative Structure-Activity Relationship; S. cerevisiae; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; Structure-Activity Relationship; Sulfones; Sulfones - chemistry; Yeast; Japan
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules190811077

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.