Chai Xiaoyun, Zhang Jun, Hu Honggang, Yu Shichong, Sun Qingyan, Dan Zhigang, Jiang Yuanying, Wu Qiuye
Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Guohe Road 325, Shanghai 200433, People's Republic of China.
Eur J Med Chem. 2009 May;44(5):1913-20. doi: 10.1016/j.ejmech.2008.11.007. Epub 2008 Nov 24.
Based on the results of computational docking to the active site of the cytochrome P450 14alpha-demethylase (CYP51), a series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols as analogs of fluconazole were designed, synthesized, and evaluated as antifungal agents. The MIC(80) values indicate that compounds 1a-n exhibited higher activity against nearly all fungi tested except Aspergillus fumigatus than fluconazole, while compounds 2a-f, 3a-f showed no activity or only moderate activity against all fungi tested. Noticeably, the MIC value of compounds 1a, 1b and 1g is 64 times lower than that of fluconazole against Microsporum gypseum in vitro. And compounds 1a, 1b and 2b showed 128 times higher activity (with the MIC(80) value of 0.0039 microg/mL) than that of fluconazole against Candida albicans and also showed higher activity than that of the other positive controls. Computational docking experiments indicated that the inhibition of CYP51 involves a coordination bond with iron of the heme group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft. In addition, the activity of the compounds would be enhanced when the side chains were shorter.
基于对细胞色素P450 14α-去甲基酶（CYP51）活性位点的计算对接结果，设计、合成了一系列作为氟康唑类似物的1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-取代-2-丙醇，并将其作为抗真菌剂进行了评估。最低抑菌浓度（MIC）80值表明，化合物1a - n对除烟曲霉外的几乎所有测试真菌均表现出比氟康唑更高的活性，而化合物2a - f、3a - f对所有测试真菌均无活性或仅表现出中等活性。值得注意的是，化合物1a、1b和1g对石膏样小孢子菌的体外MIC值比氟康唑低64倍。化合物1a、1b和2b对白色念珠菌的活性比氟康唑高128倍（MIC80值为0.0039μg/mL），且比其他阳性对照的活性也更高。计算对接实验表明，对CYP51的抑制涉及与血红素基团的铁形成配位键、亲水性氢键区域、疏水性区域以及狭窄的疏水裂缝。此外，当侧链较短时，化合物的活性会增强。
