BIOCHEMICAL APPROACHES TO SELECTIVE ANTIFUNGAL ACTIVITY - FOCUS ON AZOLE ANTIFUNGALS
BIOCHEMICAL APPROACHES TO SELECTIVE ANTIFUNGAL ACTIVITY - FOCUS ON AZOLE ANTIFUNGALS
复制标题
DOI：
10.1111/j.1439-0507.1989.tb02293.x
复制
发表时间：
1989-01-01
期刊：
影响因子：
4.9
通讯作者：
JANSSEN, PAJ
中科院分区：
文献类型：
--
作者：
VANDENBOSSCHE, H;MARICHAL, P;JANSSEN, PAJ
唑类抗真菌药（如咪唑类：咪康唑、克霉唑、联苯苄唑、抑霉唑、酮康唑和三唑类：烯唑醇、三唑醇、丙吡唑、氟康唑和伊曲康唑）在真菌细胞中抑制羊毛甾醇或24-亚甲基二氢羊毛甾醇的14α-去甲基化。麦角固醇合成的抑制作用是由于咪唑或三唑部分的未取代氮（N-3或N-4）与血红素铁结合，以及N-1取代基与内质网细胞色素P-450（P-45014 DM）的脱辅基蛋白结合。不同的唑类抗真菌药在效力和选择性上存在很大差异。例如，白念珠菌在添加[14 C]-乙酸盐和浓度递增的伊曲康唑的培养基中生长16小时后，在3 × 10 - 8 M时，麦角固醇合成的抑制率达到100%。仅在10 - 5 M浓度下，氟康唑可完全抑制该合成。农用化学品咪唑衍生物抑霉唑显示出高选择性，它对Cundida P-450（s）的亲和力分别比对猪睾丸微粒体和牛肾上腺线粒体的亲和力高出近80倍和98倍。然而，局部活性咪唑类抗真菌剂联苯苄唑对睾丸微粒体的P-450（s）具有最高亲和力。三唑类抗真菌剂伊曲康唑在10 - 5 M时抑制P-450依赖性芳香酶17.9，而双三唑衍生物氟康唑在约7.5 × 106 M时对该酶的抑制率为50%。总体结果表明，对真菌P-45014 DM的亲和力和选择性均由唑类抗真菌剂的氮杂环和疏水性N-1取代基决定。后者无疑具有更大的影响。三唑和长疏水性非连接部分的存在构成了伊曲康唑效力和选择性的基础。
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‐45014DM) 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 ofCandida albicansin medium supplemented with [14C]‐acetate and increasing concentrations of itraconazole, 100% inhibition of ergosterol synthesis is achieved at 3 × 10‐8M. Complete inhibition of this synthesis by fluconazole is obtained at 10‐5M only. The agrochemical imidazole derivative, imazalil, shows high selectivity, it has almost 80 and 98 times more affinity for theCundidaP‐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 10‐5M 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‐45014DMand 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.