Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China.
Bioorg Chem. 2020 Aug;101:103982. doi: 10.1016/j.bioorg.2020.103982. Epub 2020 Jun 2.
In order to develop novel antifungal agents, based on our previous work, a series of (2R,3R)-3-((3-substitutied-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol (a1-a26) were designed and synthesized. All of the compounds exhibited good in vitro antifungal activities against eight human pathogenic fungi. Among them, compound a6 showed excellent inhibitory activity against Candida albicans and Candida parasilosis with MIC values of 0.0313 μg/mL. In addition, compounds a6, a9, a12, a13 and a14 exhibited moderate inhibitory activities against fluconazole-resistant isolates with MIC values ranging from 8 μg/mL to 16 μg/mL. Furthermore, compounds a6, a12 and a23 exhibited low inhibition profiles for CYP3A4. Clear SARs were analyzed, and the molecular docking experiment was carried out to further investigate the relationship between a6 and the target enzyme CYP51.
为了开发新型抗真菌药物，基于我们以前的工作，设计并合成了一系列（2R，3R）-3-（（3-取代异恶唑-5-基）甲氧基）-2-（2,4-二氟苯基）-1-（1H-1,2,4-三唑-1-基）丁-2-醇（a1-a26）。所有化合物均表现出良好的体外抗真菌活性，对八种人体致病真菌具有抑制作用。其中，化合物 a6 对白色念珠菌和近平滑念珠菌表现出优异的抑制活性，MIC 值分别为 0.0313μg/mL。此外，化合物 a6、a9、a12、a13 和 a14 对氟康唑耐药分离株也表现出中等抑制活性，MIC 值范围为 8μg/mL 至 16μg/mL。此外，化合物 a6、a12 和 a23 对 CYP3A4 的抑制作用较小。对构效关系进行了详细分析，并进行了分子对接实验，以进一步研究化合物 a6 与靶酶 CYP51 之间的关系。
