Biochemical Approaches to Selective Antifungal Activity. Focus on Azole Antifungals
1989; Wiley; Volume: 32; Issue: s1 Linguagem: Inglês
10.1111/j.1439-0507.1989.tb02293.x
ISSN1439-0507
AutoresH. Vanden Bossche, Patrick Marichal, J. Gorrens, M C Coene, G. Willemsens, D. Bellens, I. Roels, Henri Moereels, Paul A. J. Janssen,
Tópico(s)Plant and fungal interactions
ResumoSummary: Azole antifungals (e.g. the imida‐zoles: miconazole, clotrimazole, bifona‐zole, imazalil, ketoconazole, and the tria‐zoles: diniconazole, triadimenol, propico‐nazole, fluconazole and itraconazole) inhibit in fungal cells the 14α‐demethylation of lanosterol or 24–methylenedihydro‐lanosterol. 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 14DM ) of the endo‐plasmic 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 [ 14 C]‐acetate and increasing concentrations of itraconazole, 100% inhibition of ergosterol synthesis is achieved at 3 × 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 Cundida 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 × 106 M of the bis‐triazole derivative fluconazole. The overall results show that both the affinity for the fungal P‐450 14DM 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 hypdro‐phobic nonligating portion form the basis for itraconazole's potency and selectivity.
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