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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。
Previous studies found that berberine can significantly improve the susceptibility of fluconazole to drug resistant Candida albicans, suggesting that synergistic effect of fluconazole resistant fungi. Derivative studies such as structural modification and transformation can provide the basis for studying the relationship between the target site and the structure-activity relationship, improving the medicinal properties and obtaining new structure active compounds. The structure of berberine was introduced by the introduction of benzyl group at position 13. Isoquinolines were synthesized from pepper ethylamine as a starting material to simulate the way of opening the D ring of berberine and maintaining the A, B, C and E rings. The structural transformation of berberine; the compounds obtained in vitro and fluconazole combined anti-drug-resistant Candida albicans activity test. The results showed that the 13-benzyl substituted berberine derivatives 1a ~ 1e maintained the activity of synergistic fluconazole-resistant Candida albicans, suggesting that various functional groups could be introduced through the 13-benzyl substitution without decreasing Its activity. The activity of berberine structural analogues N-benzylisoquinoline derivatives is generally not high, but compounds 2b, 2c, 4b showed a certain activity, indicating that the basic framework D ring can be opened, worthy of further optimization.