Two-step derivatization of fluconazole via radical fragmentation of a Breslow-type intermediate.

by Kubik, Jacklyn; Moon, Charles; Rivero, Juliette; Avery, Jordan; Canote, Cody; Sonnentag, Jessica; Hoggard, Victoria; McNabb, David; McIntosh, Matt

Fluconazole (1) is a triazole antifungal agent that is on the World Health Organization's List of Essential Medicines. It functions by inhibiting the enzyme lanosterol 14-alpha-demethylase, which converts lanosterol to ergosterol, a key component of the fungal cell membrane. Fluconazole inhibits the enzyme by binding of the triazole ring to the enzyme's iron center. Some fungal strains have become resistant to fluconazole, so we are prepg. fluconazole derivs. in the hopes of overcoming resistance. Unlike other triazole antifungals, fluconazole is sym. and possesses two identical triazole moieties. We have found that one of the triazoles can be acylated without significantly diminishing fluconazole's activity. The acylation is effected via a radical fragmentation of a Breslow-type intermediate. Details of the chem. and the results of antifungal assays will be presented.