The antifungal activity of sulfonylated/carboxylated derivatives of dibenzo-1,4-dioxine-2-acetyloxime may be due to inhibition of lanosterol-14alpha-demethylase.
Aryl/alkyl-sulfonyl-, aryl/alkylcarboxyl- and aryl(sulfonyl)carbamyl/thiocarbamyl-derivatives of dibenzo-1,4-dioxine-2-acetyloxime were prepared by reaction of the title compound with sulfonyl halides, sulfonic acid anhydrides, acyl chlorides/carboxylic acids, arylsulfonyl isocyanates, aryl/acyl isocyanates or isothiocyanates. Several of the newly synthesized compounds showed effective in vitro antifungal activity against Aspergillus and Candida spp., some of them showing activities comparable to ketoconazole (with minimum inhibitory concentrations in the range of 1.2-4 microg/mL) against the two Aspergillus strains, but possessing a lower activity as compared to ketoconazole against C. albicans. Of the three investigated strains, best activity was detected against A. flavus. The mechanism of action of these compounds probably involves inhibition of ergosterol biosynthesis by interaction with lanosterol-14-alpha-demethylase (CYP51A1), since reduced amounts of ergosterol 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 that of the widely used azole antifungals.
Mastrolorenzo
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Università degli Studi, Dipartimento di Scienze Dermatologiche, Centro MTS, Firenze, Italia.
Scozzafava
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Supuran
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D000476:Alkanesulfonates / Q000138:chemical synthesis / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001190:Arylsulfonates / Q000138:chemical synthesis / Q000494:pharmacology; D001230:Aspergillus / Q000187:drug effects; D001393:Azoles / Q000138:chemical synthesis / Q000494:pharmacology; D002175:Candida / Q000187:drug effects; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004875:Ergosterol / Q000037:antagonists & inhibitors / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010091:Oximes / Q000138:chemical synthesis / Q000494:pharmacology; D058886:Sterol 14-Demethylase; D013329:Structure-Activity Relationship
D000476:Alkanesulfonates; D000935:Antifungal Agents; D001190:Arylsulfonates; D001393:Azoles; D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D010091:Oximes; C422418:dibenzo-1,4-dioxine-2-acetyloxime; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D004875:Ergosterol