Design, synthesis, discovery and SAR of the fused tricyclic derivatives of indoline and imidazolidinone against DENV replication and infection.
Design, synthesis, discovery and SAR of the fused tricyclic derivatives of indoline and imidazolidinone against DENV replication and infection.
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DOI：
10.1016/j.bioorg.2022.105639
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发表时间：
2022-01
影响因子：
5.1
通讯作者：
Weiyi Qian;Jian-Xia Xue;Jinxin Xu;Feng Li;G. Zhou;Fang Wang;Rong-Hua Luo;Jinsong Liu;Yong-tang Zheng;Guo-Chun Zhou
中科院分区：
文献类型：
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作者：
Weiyi Qian;Jian-Xia Xue;Jinxin Xu;Feng Li;G. Zhou;Fang Wang;Rong-Hua Luo;Jinsong Liu;Yong-tang Zheng;Guo-Chun Zhou
登革病毒属于黄病毒属，近年来引起了广泛的公共卫生问题.登革病毒的疫苗已被批准，但目前尚无抗病毒药物用于临床治疗，因此，寻找有效的抗登革病毒药物具有重要的医学意义。本研究对28个基于二氢吲哚结构骨架的化合物进行了设计、合成、细胞和靶向抗登革病毒活性评价。其中，发现了13个具有抗登革病毒感染活性的化合物，并对其构效关系进行了总结。在本研究中，二氢吲哚碳肼衍生出了比二氢吲哚碳酰胺活性更高的化合物。发现TBS基团表现出良好的药效团以增强抗DENV活性。进一步的探索表明，后处理充当添加的有效时间，并且化合物15靶向DENV 2病毒生命周期的进入后阶段。SPR成像结果支持化合物13和15与RdRp存在较强的相互作用，并且化合物13和15降低了RdRp的酶活性，揭示了DENV NS 5的RdRp是这一系列化合物的药物靶标。通过分子对接研究了13和15与DENV 2 NS 5的RdRp结构域通过氢键和疏水相互作用的结合模式，建立了适合的低能构象。未来的研究将集中在设计更有效的抑制剂用于治疗和预防登革病毒复制和感染，并了解更深刻的抑制剂的潜在结构特征和药物作用机制。
Dengue virus, belonging to a genusFlavivirus, caused public health problem in recent years. One controversial vaccine of DENV was approved and there is no antiviral for the clinic treatment of DENV, therefore, efficient antivirals to DENV are of great medical significance. In this study, we conducted the design, synthesis, cell-based and target-based activity evaluation of 28 compounds based on indoline structural skeleton against DENV infection. Among them, 13 active compounds against DENV infection were discovered and their structure–activity relationship (SAR) was summarized. In this study, indoline carbohydrazine has derived more active compounds than indoline carboamide. It is discovered that TBS group exhibits a good pharmacophore to enhance anti-DENV activity. Further exploration indicated that post-treatment acts as effective time of addition and compound15targeting the post-entry stages of DENV2 viral life cycle. SPR imaging results support there are strong interaction of13and15with RdRp and compounds13and15reduce RdRp enzymatic activity, revealing that RdRp of DENV NS5 is the drug target for these series of compounds. Molecular docking deciphered the relationship of the structural feature with the putative binding mode by13and15with RdRp domain of DENV2 NS5 by hydrogen bonds and hydrophobic interactions to establish the fitted low energy conformation. Future studies will focus on designing more potent inhibitors for the treatment and prevention of dengue virus replication and infection, and understanding the more profound underlying structural features of inhibitors and drug action of the mechanism.