基于协同氟康唑抗耐药真菌活性的小檗碱结构衍生化研究

Derivatization of berberine based on its synergistic antifungal activity with fluconazole against fluconazole-resistant Candida albicans

前期研究发现小檗碱能显著提高氟康唑对耐药白念珠菌的敏感性,提示其具有协同氟康唑抗耐药真菌作用。通过结构修饰和改造等衍生化研究,可为研究其作用靶点和构效关系、提高成药性、获得新结构活性化合物提供依据。以13位引入苄基对小檗碱进行结构修饰;以胡椒乙胺为起始原料合成异喹啉类化合物,模拟打开小檗碱D环、保持其A、B、C、E环的方式,对小檗碱进行结构改造;对获得的化合物进行体外与氟康唑合用抗耐药白念珠菌活性测试。结果显示13-苄基取代小檗碱类衍生物1a^1e保持了协同氟康唑抗耐药白念珠菌的活性,提示可通过13位苄基取代的方式引入各种功能基团而不降低其活性。小檗碱结构改造类似物N-苄基异喹啉类衍生物活性总体不高,但化合物2b、2c、4b表现了一定的活性,说明其基本骨架D环可以打开,值得进一步优化研究。

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.