新型哒嗪酮类抗登革病毒药物先导化合物的发现、优化

项目名称： 新型哒嗪酮类抗登革病毒药物先导化合物的发现、优化

项目编号： No.81502914

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 应华洲

作者单位： 浙江大学

项目金额： 17.9万元

中文摘要： 由登革病毒（dengue virus，DV）引起的登革热、登革出血热/登革休克综合征已成为国际上重要的公共卫生问题，但目前既无抗DV类疫苗也无抗DV特效药物用于预防和治疗DV感染，因此，研发抗DV治疗性药物具有明显的科学意义和应用价值。项目前期对我们的化合物库针对登革病毒RNA复制过程运用“Dengue Replicon体系”进行高通量筛选系统，发现并确定了一类结构新颖的哒嗪-3(2H)-酮小分子化合物具有确切的抗DV活性。其中，化合物3a具有很好的体外抗登革病毒活性和选择性，本项目以此为起点，利用如生物电子等排、骨架跃迁等合理药物设计策略，对化合物3a进行广泛的结构修饰，开展深入的构效关系研究，进行新衍生物的设计、合成、体外/内抗病毒活性的验证和结构优化，最终确立低毒、高效的新药候选化合物，开展抗DV创新药物的研发和作用机理研究。

中文关键词： 哒嗪酮衍生物；登革热病毒；抗病毒；高通量筛选；构效关系

英文摘要： Owing to the important worldwide public health problems of dengue fever (dengue hemorrhagic fever, dengue shock syndrome), which are caused by dengue virus (DV), and the absence of vaccine and specific drug against dengue virus for theraputical prevent or treatment of dengue diseases, the research of anti- dengue virus agents has significantly scientific significance and applicable value. In this context, we previously performed biological screening against our in-house compounds library, leading to the identification of a series of pyridazin-3(2H)-one derivatives with good anti-dengue virus activities. Among them, compound 3a, which showed highly in vitro dengue virus inhibitory activity and weak cytotoxic activities, is good lead compound that is worthy of further development. In this project, we plan to perform extensively chemical modification of compound 3a using rational drug design strategies including bioisostere, skeleton hoping. Moreover, a series of structural diverse and drug-like target compounds will be designed, synthesized and biological evaluation of their in-vitro and in-vivo anti-dengue virus activities, as a consequence, in order to discover several highly efficient and low toxic new drug candidates.

英文关键词： pyridazin-3(2H)-one derivative;dengue virus;anti virus;HTS;SAR