title: A non-azole inhibitor of lanosterol 14 alpha-methyl demethylase in Candida albicans.
abstract: 6-Hydroxy-N-methyl-N-(2-[4-phenylphenyl] ethyl)-1,2,3,4-tetrahydro-1- napthalene methanamine (A60586), a new non-azole inhibitor of ergosterol biosynthesis in Candida albicans ATCC62376 has been identified. In whole cells A60586 produced a dose related reduction of [14C]acetate incorporation into ergosterol and a concurrent increase in the radiolabelling of 4,4-dimethylated sterols. Similar observations were made with [14C]mevalonic acid lactone labelled cell free extracts. The IC50s for inhibition of ergosterol in the whole cell and cell free systems were 22 microM (10 mg/L) and 7.8 microM (3.5 mg/L), respectively. Analysis by gas chromatography of sterols from cells previously incubated at 37 degrees C for 24 h with A60586 (200 mg/L) confirmed the presence of lanosterol and 14 alpha-methyl fecosterol. These data indicate that A60586, inhibits the demethylation of the C-14 methyl group of lanosterol. The MIC of A60586 for several candida strains ranged from 12.5 to 50 mg/L, and against Cryptococcus albidus and Aspergillus niger ranged from 50 to 100 mg/L. The best in-vitro activity of A60586 was against Torulopsis glabrata (MIC range = 3.12 to 50 mg/L). The membrane permeabilizing effect of this compound (50% leakage of [14C]aminoisobutyric acid at 70 mg/L A60586) may have contributed to its in-vitro antifungal activity.
authors.affiliation: Anti-infective Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500.
authors.forename: J O
authors.initials: JO
authors.lastname: Capobianco
authors.forename: C C
authors.initials: CC
authors.lastname: Doran
authors.forename: R C
authors.initials: RC
authors.lastname: Goldman
authors.forename: B
authors.initials: B
authors.lastname: De
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004875:Ergosterol / Q000096:biosynthesis; D008744:Methylamines / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010105:Oxygenases / Q000037:antagonists & inhibitors; D050603:Squalene Monooxygenase; D058886:Sterol 14-Demethylase; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D008744:Methylamines; D013764:Tetrahydronaphthalenes; C079763:A 60586; D010088:Oxidoreductases; D010105:Oxygenases; D058886:Sterol 14-Demethylase; D050603:Squalene Monooxygenase; D004875:Ergosterol