基于三环苦参骨架衍生物的设计、合成及其广谱抗流感病毒活性研究

Outbreak epidemics caused by influenza occurs all the time. Our innovative matrinane derivative (DB-1) was active against several subtypes of type A and B influenza, especially active against those showing resistance to oseltamivir and amantadine, which hinted that DB-1 diaplayed a broad-spectrum influenza antiviral activity with the chemical skeleton and mechanism different from that of clinical medication..Based on theses original work, taking DB-1 as the lead, directed by the activity against type A influenza viruses, systematic structural modifications and optimizations mainly focusing on the 11- and 12- side chain will be carried out in the titled project, while the three-ring matrine skeleton was remained, at least 80 novel matrine butane derivatives with novel structures will be synthesized to illustrate their anti-influenza structure-activity relationships (SAR). By the following comprehensive druaggable evaluation studies, including assay towards multi-drug resistant influenza strains, primary toxicity, ppharmacokinetics and pharmacodynamics in vivo, several novel candidates characterized by high druggablity and high therapeutic window will be selected out. The research will provide scientific data for the development of them into a new class of anti-influenza candidates..The candidates generated from this project will provide a novel component for the treatment of influenza and especially drug-resistant influenza, offer an important prevention and control material reservoir for the outbreak epidemic of influenza, especially in case of emergencies when the pathogen was unable or too late to be determined, improve China’s original innovative ability in drug research, and prompt China’s innovative antiviral drug research to enter the frontier of the world.

流感病毒引起的突发传染性疾病时有发生。我们自主创新的苦参烷类化合物DB-1对A、B多个流感病毒亚型均显示较好活性，尤其对达菲/金刚烷胺耐药株也有效。提示，DB-1具有广谱抗流感活性，化学骨架与生物机制目前临床用药完全不同。.本项目拟在一系列原创性工作基础上，以DB-1为先导物，以抗A型流感病毒为活性导向，保留三环苦参骨架，主要在其11-和12-位侧链开展丰富的结构修饰与优化，累计合成不少于80个苦参骨架衍生物，阐明其抗流感构效关系。通过对多株耐药流感病毒、初步毒性、药代参数以及体内药效等综合性评价，优选出成药性高、治疗窗口宽的候选物，为发展一类全新骨架抗流感药物提供科学数据。.本项目产生的候选物，为流感治疗及耐药克服提供一个全新组分；为突发性流感的应急与防控提供重要的物质储备，尤其在病原来不及鉴定的应急情况下使用。提升我国药物研究源头创新能力，将我国抗病毒原创药物研究推向世界前沿。

流感病毒对人类具有高致病性，是最易发生变异的病毒，因此流感病毒引起的突发传染性疾病在全球时有发生，引起社会极大恐慌，在全世界造成数百万人死亡。据世界卫生组织的数据显示，全球每年严重流感感染病例约达300万至500万例，且死亡人数高达50万人。目前流感控制和治疗的两大策略是疫苗和抗病毒药物。减毒活疫苗和灭活流感疫苗常常由于抗原的转移而出现抗流感活性下降甚至丧失的情况。M2质子通道抑制剂和神经氨酸抑制剂是临床上常用的两类抗流感药物。但由于近年来的药物滥用，出现了严重的耐药现象。因此研发新型抗流感药物意义重大。.本项目以DB-1为先导物，基于三环苦参骨架，主要对其12-N取代基、11-侧链的长度及类型、以及5-C的手性构型开展丰富的结构修饰与优化；设计、合成了12N-磺酰基苦参乙酸、12N-磺酰基苦参乙醇、12-取得苦参烷，金刚烷酸12-取得苦参酯，金刚烷酸12-取得苦参胺和12-取得苦参金刚烷酯。累积合成80余个苦参骨架类衍生物，并对其进行了抗流感活性测试。总结了其初步抗流感构效关系：a、12位N苯磺酰基取得有利于抗流感活性。b极性基团的引入不利于抗流感活性的提高，4C侧链缩短为2C侧链活性提高，但同时化合物细胞毒性也明显增加。c、11位侧链以酯键链接引入抗流感优势片段时，有利于抗流感活性的保持和增强。选取了活性较好的代表性化合物7b，9f，9j和17g进行了小鼠急毒实验，LD50均大于500mg/kg。且化合物9f和17g还具有较好的全血稳定性或良好的初步药代稳定性。同时对9f还进行了初步的作用机制探索，其可能在病毒复制早期通过抑制M2通道发挥抗流感病毒作用。.综上所述，化合物9f和17g显示出较好的抗流感活性，且具有成药性高、是较为理想的候选化合物，推荐进入进一步的研究。以上部分试验结果已发表SCI论文Med Chem. 和pharmazie，并投稿SCI论文1篇（molecules）。