Synthesis and oral antifungal activity of novel azolylpropanolones and related compounds

To find orally active antifungal agents, novel imidazolyl- and 1,2,4-triazolylpropanolones I and related compounds II-IV were synthesized. Compounds I were derived from ketones V (method A), alpha-diketone IX (method B), alpha-hydroxy ketones X (method C), alpha-chloro ketone XII (method D), and enones VI (method E). Diols II, synthesized from I with NaBH4, were cyclized to five-membered cyclic compounds III by using N,N'-carbonyldiimidazole, thionyl chloride, N,N'-(thiocarbonyl)diimidazole, bromochloromethane, 2,2-dimethoxypropane, and cyclohexanone dimethyl ketal. Diols IV were synthesized from I by Grignard reaction (method F), hydroxymethylation of X (method G), and reaction of ketones XXI with 1-[(trimethylsily)methyl]-1,2,4-triazole (method H). Compounds I-IV were examined for their antifungal activities in vitro by evaluation of broth dilution MIC values against three species of fungi and the inhibitory effect on pseudomycelium of Candida albicans, and they were examined for oral efficacy in vivo against subacute systemic candidiasis in mice and superficial dermatophytosis in guinea pigs. Compounds 2, 12, 38, 39, and 92 exhibited strong oral antifungal activity. An asymmetric synthesis and the structure-activity relationships of the compounds examined are discussed.