Synthesis and Bioevaluation of Δ7-5-Desaturase Inhibitors, an Enzyme Late in the Biosynthesis of the Fungal Sterol Ergosterol

Ergosterol, the predominant sterol of fungi, is postulated to have many cellular functions which include a bulk membrane role and a regulatory role. Studies with sterol auxotrophs show that, even in the presence of sterols which can fulfill the bulk membrane requirements, a small concentration of ergosterol is absolutely necessary for growth. The Δ5-double bond appears to be required for the regulatory role of ergosterol; therefore, development of inhibitors of the enzyme that introduce this double bond, Δ7-sterol 5-desaturase (5-desaturase), may lead to effective antifungal agents. Within is the first reported synthesis of inhibitors of fungal 5-desaturase and the development of an in vitro tritium efficacy radioassay. The inhibitors were of the general structure 7,22(E)-ergostadien-3β-ol with α-face heteroatom substituents in the vicinity of C-5. They exhibited IC50 values of 47−149 μM.