5-氰基-2-硫乙酰芳氨嘧啶酮类DENV NS5 RdRp抑制剂的设计、合成及活性研究  

Design,synthesis,and activity of 5-cyano-2-thiacetyl aromatic pyrimidinone as DENV NS5 RdRp inhibitors

作　　者：王靖博 李春艳[2,3,4] 赵子衿 杨柳萌 张洪彬[1] 郑永唐[2] 何严萍[1] WANG Jing-bo;LI Chun-yan;ZHAO Zi-jin;YANG Liu-meng;ZHANG Hong-bin;ZHENG Yong-tang;HE Yan-ping(Key Laboratory of Medicinal Chemistry for Natural Resource Ministry of Education,School of Chemical Science and Technology,Yunnan University,Kunming 650091,China;Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China;College of Pharmacy,Dali University,Dali 671000,China;School of Basic Medicine and Clinic Pharmacy,China Pharmaceutical University,Nanjing 211100,China)

机构地区：[1]云南大学化学科学与工程学院,自然资源药物化学重点实验室,云南昆明650091 [2]中国科学院昆明动物研究所,中国科学院动物模型与人类疾病机理重点实验室,云南昆明650223 [3]大理大学药学院,云南大理671000 [4]中国药科大学基础与临床学院,江苏南京211100

出　　处：《药学学报》2023年第11期3379-3388,共10页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金(21967020,82273820,U1702286);云南省重点研发计划(202103AC100005,202103AQ100001);国家重点研发计划(2019YFE0109200)。

摘　　要：为了筛选新型的抗登革热病毒(DENV)NS5 Rd Rp酶抑制剂,本论文采用分子杂合的方法,基于嘧啶酮类HCV NS5B Rd Rp抑制剂3jc和ZIKV NS5 Rd Rp抑制剂4w的结构,设计合成了一系列5-氰基-2-硫乙酰芳基嘧啶酮化合物。通过MTT法及噬斑法体外抗DENV活性筛选发现其中5个化合物显示了抗DENV活性,其中活性最高的化合物7a’k的抗病毒活性优于阳性对照物利巴韦林(EC50=7.86μmol·L^(-1)vs EC50=18.07μmol·L^(-1)),其余4个化合物与利巴韦林活性相当。最后通过分子对接分析了可能的结合模式,为该类新型DENV NS5 Rd Rp酶抑制剂进一步研究提供了思路。To screen novel anti-dengue virus(DENV)NS5 RdRp enzyme inhibitors,a series of 5-cyano-2-thiacetoaryl pyrimidinone compounds were designed and synthesized by molecular hybridization method with HCV NS5B RdRp inhibitor 3jc and ZIKV NS5 RdRp inhibitor 4w as lead compounds.The anti-DENV activity of these compounds was evaluated by MTT assay and plaque assay and five compounds showed anti-DENV activity.The most active compound 7a'k showed better anti-DENV activity than that of the positive control ribavirin(EC50=7.86μmol·L^(-1) vs EC50=18.07μmol·L^(-1)),and the other four compounds showed almost the same anti-DENV activity as ribavirin.Finally,the prediction and simulation of the binding mode through molecular provided new ideas for the further development of this new DENV NS5 RdRp inhibitor.

关 键 词：登革热病毒NS5 RdRp酶抑制剂 合成 抗登革热病毒活性 分子对接 

分 类 号：R962[医药卫生—药理学]