新型三嗪类白念珠菌SAP2抑制剂的设计、合成和生物活性研究  

Design, synthesis and biological activity of novel triazine inhibitors of Candida albicans secreted aspartic protease 2

作　　者：杨继 董国强 刘娜 盛春泉 YANG Ji;DONG Guo-qiang;LIU Na;SHENG Chun-quan(School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China;School of Pharmacy,Second Military Medical University,Shanghai 200433,China)

机构地区：[1]华东理工大学药学院,上海200237 [2]中国人民解放军海军军医大学药学院,上海200433

出　　处：《药学学报》2020年第7期1647-1660,共14页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81725020,81973175);上海市教委科研创新计划重大项目(2019-01-07-00-07-E00073)。

摘　　要：近年来,侵袭性真菌感染的发病率和死亡率不断上升,迫切需要研发具有新型作用模式的抗真菌药物。靶向毒力因子是一种新的抗真菌药物发现策略。分泌型天冬氨酸蛋白酶2(SAP2)是一种毒力因子,是一种新兴的抗真菌靶点。然而,发现小分子SAP2抑制剂仍然是一个重大的挑战。本研究从前期筛选得到的三嗪类小分子SAP2抑制剂A12入手,经合理设计和结构优化后,化合物的SAP2抑制活性显著提高,并对其构效关系进行总结。其中化合物8a和8c在白念珠菌感染的体内模型中表现出良好的抗真菌活性。并且,该类化合物(8a和8b)对于真菌生物被膜具有较好的抑制作用。因此,三嗪类小分子SAP2抑制剂是一类具有研究前景的新型抗真菌先导化合物。In recent years,the incidence and mortality of invasive fungal infections has increased.It is highly desirable to develop novel antifungal agents with new modes of action.Targeting virulence factors represents a new strategy for antifungal drug discovery.Secreted aspartic protease 2(SAP2),a kind of virulence factor,is an emerging antifungal target.However,discovery of small-molecule SAP2 inhibitors remains a significant challenge.Based on the structure-activity relationship of our previously identified triazine small-molecule SAP2 inhibitor,we were able to identify two potent inhibitors,8a and 8c,which showed excellent in vivo antifungal activity for the treatment of C.albicans infection.Moreover,compounds 8a and 8b effectively inhibited fungal biofilm.Taken together,triazine SAP2 inhibitors represent promising lead compounds for the discovery of novel antifungal agents.

关 键 词：三嗪类衍生物 SAP2抑制剂 毒力因子 

分 类 号：R916[医药卫生—药学]