基于喹啉骨架的新型非核苷类抗HBV化合物的设计、合成与生物学评价

项目名称： 基于喹啉骨架的新型非核苷类抗HBV化合物的设计、合成与生物学评价

项目编号： No.81202404

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 刘亚婧

作者单位： 沈阳药科大学

项目金额： 24万元

中文摘要： 抗乙肝病毒是目前治疗慢性乙型肝炎的主要手段，临床上应用的核苷及干扰素类药物存在许多不足，研发结构与作用机制新颖的抗乙肝病毒药物意义重大。课题组前期得到了一类活性显著的吲哚衍生物，其中盐酸艾咪朵尔处于Ⅱ期临床研究，以其为先导分别得到喹啉和苯并噻喃并喹啉衍生物，有数个化合物体外活性优于拉米夫定和艾咪朵尔。为了得到活性更好的化合物，拟继续以喹啉为基本骨架，在总结前期构效关系的基础上，采用生物电子等排、拼合等新药设计原理，创造性的对该类结构中一直保留的2-位芳硫甲基和3-位酯基进行较大改造，引入易形成氢键的N、O、S原子，使其能更好的与受体相结合。拟设计合成4大类约180个新化合物，分别为3-芳杂基喹啉、2-三氮唑取代喹啉、2-芳基乙烯基喹啉、5,6-二氢二苯并[b,h][1,6]萘啶衍生物，对其进行体外活性筛选和构效关系研究，并对体外活性显著的化合物进行HBV转基因小鼠体内活性评价。

中文关键词： 抗乙肝病毒；3-杂环基喹啉衍生物；设计；合成；

英文摘要： Anti-hepatitis B virus (HBV) is one of the most important methods for treating chronic hepatitis B. However, lots of drawbacks still extensively existed in the clinic drugs of nucleoside and interferon analogs. Therefore, it is of great significance to develop anti-HBV drugs with novel structures and mechanisms. In our previous studies, a series of 5-hydroxyindole-3-carboxylate derivatives was prepared as anti-HBV agents. Thereinto, imidol hydrochloride, one of the most potent compounds, is currently in phase II clinical studies. Subsequently, taking imidol hydrochloride as lead compound, we designed and synthesized a series of novel ethyl 6-hydroxyquinoline-3-carboxylate derivatives in which the indole ring was replaced by a quinoline ring basing on the principles of bioisosterism. Subsequently, a benzothiopyran ring fused across the 2 and 3 positions to give a series of 6H-[1]benzothiopyrano[4,3-b]quinoline derivatives. Among them many of them exhibited excellent anti-HBV activities in vitro. With an aim to develop more promising anti-HBV agents, further studies of the SARs were carried out. The main modification were focused on the quinoline ring, especially the structures of ArS- and 3-ester groups, which were usually retained in these kinds of derivates. Furthermore, different heteroatoms such as N, O an

英文关键词： anti-HBV；3-heterocyclicquinoline derivatives；design；synthesis；