Wu Junqi, Ni Tingjunhong, Chai Xiaoyun, Wang Ting, Wang Hongrui, Chen Jindong, Jin Yongsheng, Zhang Dazhi, Yu Shichong, Jiang Yuanying
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Student Bridge, Second Military Medical University, Shanghai 200433, China.
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Eur J Med Chem. 2018 Jan 1;143:1840-1846. doi: 10.1016/j.ejmech.2017.10.081. Epub 2017 Nov 11.
The incidence of life-threatening fungal infections has dramatically increased for decades. In order to develop novel antifungal agents, two series of (2R,3R)-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(N-substitutied)-2-butanols (3a-o, 5a-f, 8a-u), which were analogues of voriconazole, were designed, synthesized and characterized by H NMR, C NMR and HRMS. The MIC values showed that the target compounds 3a-o indicated better activities than fluconazole on three important fungal pathogens except for 3i. Significant activity of compounds 3d, 3k, 3n, 3m and 3o was observed on the Aspergillus fumigatus strain (MIC range: 1-0.125 μg/ml). Especially, compound 3k had strong activity to inhibit the growth of ten fungal pathogens. But it didn't exhibit good activity in in vivo value. Molecular docking experiments demonstrated that 3k possessed superior affinity with target enzyme by strong hydrogen bond from morpholine ring.
几十年来，危及生命的真菌感染的发生率急剧上升。为了开发新型抗真菌药物，设计、合成了两个系列的（2R，3R）-1-（1H-1,2,4-三唑-1-基）-2-（2,4-二氟苯基）-3-（N-取代）-2-丁醇（3a-o、5a-f、8a-u），它们是伏立康唑的类似物，并通过1H NMR、13C NMR和HRMS对其进行了表征。最低抑菌浓度（MIC）值表明，除3i外，目标化合物3a-o对三种重要真菌病原体的活性优于氟康唑。在烟曲霉菌株上观察到化合物3d、3k、3n、3m和3o具有显著活性（MIC范围：1-0.125μg/ml）。特别是，化合物3k对十种真菌病原体的生长具有很强的抑制活性。但它在体内实验中未表现出良好的活性。分子对接实验表明，3k通过吗啉环形成的强氢键与靶酶具有较高的亲和力。
