title: Biochemical approaches to selective antifungal activity. Focus on azole antifungals.
abstract: Azole antifungals (e.g. the imidazoles: miconazole, clotrimazole, bifonazole, imazalil, ketoconazole, and the triazoles: diniconazole, triadimenol, propiconazole, fluconazole and itraconazole) inhibit in fungal cells the 14 alpha-demethylation of lanosterol or 24-methylenedihydrolanosterol. The consequent inhibition of ergosterol synthesis originates from binding of the unsubstituted nitrogen (N-3 or N-4) of their imidazole or triazole moiety to the heme iron and from binding of their N-1 substituent to the apoprotein of a cytochrome P-450 (P-450(14)DM) of the endoplasmic reticulum. Great differences in both potency and selectivity are found between the different azole antifungals. For example, after 16h of growth of Candida albicans in medium supplemented with [14C]-acetate and increasing concentrations of itraconazole, 100% inhibition of ergosterol synthesis is achieved at 3 x 10(-8) M. Complete inhibition of this synthesis by fluconazole is obtained at 10(-5) M only. The agrochemical imidazole derivative, imazalil, shows high selectivity, it has almost 80 and 98 times more affinity for the Candida P-450(s) than for those of the piglet testes microsomes and bovine adrenal mitochondria, respectively. However, the topically active imidazole antifungal, bifonazole, has the highest affinity for P-450(s) of the testicular microsomes. The triazole antifungal itraconazole inhibits at 10(-5) M the P-450-dependent aromatase by 17.9, whereas 50% inhibition of this enzyme is obtained at about 7.5 x 10(-6)M of the bistriazole derivative fluconazole. The overall results show that both the affinity for the fungal P-450(14)DM and the selectivity are determined by the nitrogen heterocycle and the hydrophobic N-1 substituent of the azole antifungals. The latter has certainly a greater impact. The presence of a triazole and a long hypdrophobic nonligating portion form the basis for itraconazole's potency and selectivity.
authors.forename: H
authors.initials: H
authors.lastname: Vanden Bossche
authors.forename: P
authors.initials: P
authors.lastname: Marichal
authors.forename: J
authors.initials: J
authors.lastname: Gorrens
authors.forename: M C
authors.initials: MC
authors.lastname: Coene
authors.forename: G
authors.initials: G
authors.lastname: Willemsens
authors.forename: D
authors.initials: D
authors.lastname: Bellens
authors.forename: I
authors.initials: I
authors.lastname: Roels
authors.forename: H
authors.initials: H
authors.lastname: Moereels
authors.forename: P A
authors.initials: PA
authors.lastname: Janssen
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology*; D001393:Azoles / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D017964:Itraconazole; D007654:Ketoconazole / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D007093:Imidazoles; D017964:Itraconazole; D007654:Ketoconazole