R-120758, A Novel Triazole Antifungal Agent: Synthesis and Structure-Activity Relationships.
Background: A new class of triazole antifungal agents, 2-(2,4-difluorophenyl)-3-[(2-substituted-1,3-dioxan-5-yl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanols, were designed and their synthesis and structure-activity relationships were investigated. Methods: The compounds were prepared by acetalization reaction between a diol precursor and a variety of aldehydes. Their antifungal activities were evaluated in vitro against pathogenic fungi including Candida, Aspergillus and Cryptococcus species. Results: High activities were seen for the derivatives having an olefinic side chain with two double bonds on the 1,3-dioxane ring. Introduction of electron-withdrawing groups to the benzene ring on the side chain improved the activities. Further structural modification of the compounds led to R-120758, 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile. The stereoisomers of R-120758 showed lower antifungal activities. The aldehyde precursor of R-120758 could be synthesized stereoselectively from furan using Arbuzov and Horner-Wadsworth-Emmons reactions. Conclusion: R-120758 was found to be a promising antifungal agent and chosen as a candidate compound for further investigations.
Full conference title:
Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy