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Vanden Bossche H, Marichal P, Gorrens J, Coene MC, Willemsens G, Bellens D, Roels I, Moereels H, Janssen PA: Biochemical approaches to selective antifungal activity. Mycoses. 1989;32 Suppl 1:35-52.
Focus on azole antifungals.. 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. |
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