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

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 and S were introduced to these series of compounds, expecting to be well fitted to the receptors. .As a result, we will design and synthesize four series of compounds, including 3-heteroaromatic quinoline, 2-triazolyl substituted quinoline, 2-aryl ethenyl quinoline and 5,6-dihydrodibenzo[b,h][1,6]naphthyridin derivatives..The anti-HBV activities in vitro of all target compounds were evaluated with radioimmunoassay (RIA) and dot-blotting asssy in HepG2.2.15 cells stably transfected with HBV and the SARs of the synthesized compounds was discussed as well. Moreover, some compounds with excellent activities in vitro were selected to estimate the anti-HBV activities in vivo using a HBV transgenic mouse.

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。

乙型病毒性肝炎是全世界范围内威胁人类健康的一大难题，开发全新结构类型的抗乙肝病毒药物具有重要意义。本课题以活性的喹啉环为基本骨架，在总结课题组研究非核苷类抗乙肝病毒药物构效关系的基础上，将3-位酯基用5元杂环替代，其中杂环分别为取代噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基，此外在2-位取代基的设计中，大部分化合物保留了苯硫甲基，另设计了26个2-位苯基由三氮唑基取代的化合物，共设计并合成了5大类共160个新化合物，其结构均经质谱、氢谱确认。对其中104个化合物进行了体外活性筛选，结果表明部分化合物具有优于拉米夫定的抗HBV DNA活性和显著的抗HBeAg分泌活性。SAR研究表明，3-位引入噻唑及噻二唑基化合物活性优于恶唑及恶二唑或异恶唑化合物，且2-位以苯硫甲基活性较好，当2-位硫原子被单氧化后，抗HBV DNA活性亦有提高，但进一步氧化为砜后毒性显著增加。在已有的构效关系基础上，将继续该类化合物的深入研究，以期得到活性更好的抗乙肝病毒化合物。