The antifungal activity of sulfonylated/carboxylated derivatives of dibenzo-1,4-dioxine-2-acetyloxime may be due to inhibition of lanosterol-14 alpha-demethylase

Aryl/alkyl-sulfonyl-, aryl/alkylcarboxyl- and aryl(sulfonyl)carbamyl/thioca rbamyl-derivatives of dibenzo-1,4-dioxine-2-acetyloxime were prepared by re action of the title compound with sulfonyl halides, sulfonic acid anhydride s, acyl chlorides/carboxylic acids, arylsulfonyl isocyanates, aryl/acyl iso cyanates or isothiocyanates. Several of the newly synthesized compounds sho wed effective in vitro antifungal activity against Aspergillus and Candida spp., some of them showing activities comparable to ketoconazole (with mini mum inhibitory concentrations in the range of 1.2-4 mug/mL) against the two Aspergillus strains, but possessing a lower activity as compared to ketoco nazole against C. albicans. Of the three investigated strains, best activit y was detected against A. flavus. The mechanism of action of these compound s probably involves inhibition of ergosterol biosynthesis by interaction wi th lanosterol-14-alpha -demethylase (CYP41A1), since reduced amounts of erg osterol were found by means of HPLC, in cultures of the sensitive strain A. flavus treated with some of these inhibitors. Thus, the compounds reported here might possess a similar mechanism of action at molecular level with t hat of the widely used azole antifungals.