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Biological exploration of a novel 1,2,4-triazole-indole hybrid molecule as antifungal agent
Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2020-01-03
Fabrice Pagniez, Nicolas Lebouvier, Young Min Na, Isabelle Ourliac-Garnier, Carine Picot, Marc Le Borgne, Patrice Le Pape

(2-(2,4-Dichlorophenyl)-3-(1H-indol-1-yl)-1-(1,2,4-1H-triazol-1-yl)propan-2-ol (8 g), a new 1,2,4-triazole-indole hybrid molecule, showed a broad-spectrum activity against Candida, particularly against low fluconazole-susceptible species. Its activity was higher than fluconazole and similar to voriconazole on C. glabrata (MIC90 = 0.25, 64 and 1 µg/mL, respectively), C. krusei (MIC90 = 0.125, 64 and 0.125 µg/mL, respectively) and C. albicans (MIC90 = 0.5, 8 and 0.25 µg/mL, respectively). The action mechanisms of 8 g were also identified as inhibition of ergosterol biosynthesis and phospholipase A2-like activity. At concentration as low as 4 ng/mL, 8g inhibited ergosterol production by 82% and induced production of 14a-methyl sterols, that is comparable to the results obtained with fluconazole at higher concentration. 8 g demonstrated moderate inhibitory effect on phospholipase A2-like activity being a putative virulence factor. Due to a low MRC5 cytotoxicity, this compound presents a high therapeutic index. These results pointed out that 8 g is a new lead antifungal candidate with potent ergosterol biosynthesis inhibition.



中文翻译:

新型1,2,4-三唑-吲哚杂化分子作为抗真菌剂的生物探索

(2-(2,4-二氯苯基)-3-(1 H-吲哚-1-基)-1-(1,2,4-1 H-三唑-1-基)丙-2-醇(8 g),一个新的1,2,4-三唑吲哚杂合分子,显示出对广谱的活性念珠菌,特别是对低氟康唑易感的物种。它的活性比氟康唑更高且类似于上伏立康唑光滑念珠菌(MIC 90分别为0.25、64和1μg/ mL),克鲁斯克鲁维酵母(MIC 90分别为0.125、64和0.125μg/ mL)和白色念珠菌(MIC 90分别为0.5、8和0.25 µg / mL)。8 g的作用机理还被鉴定为对麦角固醇生物合成和磷脂酶A2样活性的抑制。在低至4 ng / mL的浓度下,8g的麦角固醇产生抑制了82%,并诱导了14a-甲基固醇的产生,这与氟康唑在较高浓度下获得的结果相当。8g证明对作为假定毒力因子的磷脂酶A2样活性具有中等抑制作用。由于MRC5细胞毒性低,因此该化合物具有较高的治疗指数。这些结果指出,8 g是具有有效麦角甾醇生物合成抑制作用的新型抗真菌新药。

更新日期:2020-01-04
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