Tian Shu-Juan, Gao Yue, Zang Cheng-Xu, Cai Zhan, Ni Ting-jun-hong, Tan Shan-Lun, Cao Yong-Bing, Jiang Yuan-Ying, Zhang Da-Zhi
Yao Xue Xue Bao. 2014 Nov;49(11):1563-8.
Abstract: Our previous work revealed berberine can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, which suggested that berberine has synergistic antifungal activity with fluconazole. Preliminary SAR of berberine needs to be studied for the possibility of investigating its target and SAR, improving its drug-likeness, and exploring new scaffold. In this work, 13-substitutited benzyl berberine derivatives and N-benzyl isoquinoline analogues were synthesized and characterized by 1H NMR and MS. Their synergetic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The 13-substitutited benzyl berberine derivatives 1a-1e exhibited comparable activity to berberine, which suggested that the introduction of functional groups to C-13 can maintain its activity. The N-benzyl isoquinolines, which were designed as analogues of berberine with its D ring opened, exhibited lower activity than berberine. However, compound 2b, 2c, and 4b showed moderate activity, which indicated that berberine may be deconstructed to new scaffold with synergistic antifungal activity with fluconazole. The results of our research may be helpful to the SAR studies on its other biological activities.
我们之前的研究表明，黄连素可显著增强氟康唑对氟康唑耐药白色念珠菌的敏感性，这表明黄连素与氟康唑具有协同抗真菌活性。为了研究其作用靶点和构效关系、改善其类药性质并探索新的骨架结构，需要对黄连素进行初步的构效关系研究。在本研究中，合成了13-取代苄基黄连素衍生物和N-苄基异喹啉类似物，并通过1H NMR和MS对其进行了表征。体外评估了它们与氟康唑对氟康唑耐药白色念珠菌的协同活性。13-取代苄基黄连素衍生物1a-1e表现出与黄连素相当的活性，这表明在C-13位引入官能团可维持其活性。设计为D环开环的黄连素类似物的N-苄基异喹啉表现出比黄连素更低的活性。然而，化合物2b、2c和4b表现出中等活性，这表明黄连素可能被解构为具有与氟康唑协同抗真菌活性的新骨架结构。我们的研究结果可能有助于对其其他生物活性进行构效关系研究。
