9-取代巴马汀衍生物抗幽门螺杆菌活性研究

Anti-Helicobacter pylori activities of 9-substituted palmatine derivatives

本研究共设计合成了15个9-取代巴马汀(palmatine,1,异喹啉生物碱类)衍生物,首次评价了其体外抗幽门螺杆菌(Helicobacter pylori,Hp)活性。初步构效关系表明9-位引入适当的二级胺取代基利于抗菌活性提高。其中,代表性化合物5a对部分甲硝唑耐药菌株显示较好活性,最低抑菌浓度(MICs)值为4μg·mL^-1,优于先导物1。另外,5a显示良好安全性,口服LD50>1000 mg·kg^-1。分子对接实验结果提示,化合物5a可能通过作用于Hp脲酶而发挥抑菌作用。本研究结果为巴马汀类衍生物发展成一类新颖抗Hp联合用药组分提供了重要科学数据。

Fifteen 9-substituted palmatine(1)derivatives were synthesized and evaluated for their anti-Helico‐bacter pylori(Hp)activities in vitro.Structure-activity relationship studies revealed that introducing appropriate substituted secondary amino group at position 9 of lead 1 might be beneficial for potency.Among them,compound5a showed the most potential activity against metronidazole(Met)resistant Hp isolates with minimal inhibitory concentrations(MICs)of 4μg·mL^-1,much better than that of lead 1.Compound 5a displayed satisfactory safety profile in acute toxicity assay.Molecular docking suggested that 5a might act on Hp urease.The results provided key scientific evidence for the development of 1 derivatives into a new class of anti-Hp component.