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Discovery of dehydroandrographolide derivatives with C19 hindered ether as potent anti-ZIKV agents with inhibitory activities to MTase of ZIKV NS5
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2022-08-27 , DOI: 10.1016/j.ejmech.2022.114710
Weiyi Qian 1 , Guang-Feng Zhou 2 , Xintong Ge 1 , Jian-Xia Xue 3 , Chang-Bo Zheng 4 , Liu-Meng Yang 5 , Xue-Rong Gu 4 , Chunyan Li 6 , Si-Dong Xiong 7 , Yong-Tang Zheng 5 , Guo-Chun Zhou 1
Affiliation  

Infection by Zika virus (ZIKV), a mosquito-transmitted arbovirus and a member of Flavivirus, could make pediatric microcephaly and Guillain–Barré syndrome, which remains an ongoing global threat. The efficient antivirals to ZIKV infection are of great medical need. Andrographolide and its analogues were discovered to be active against flaviviral infection. In this study, we discovered some dehydroandrographolide derivatives of 3-oximido- or 3-alcohol-19-hindered ether to be potent anti-ZIKV agents with low cytotoxicities (CC50 > 200 μM). Time of addition assay suggests that compound 5a and its analogues act on inhibition of post-entry stage of ZIKV life cycle. It is discovered by experimental and molecular docking studies that active anti-ZIKV compounds of 3a, 5a, 5b and 5c possess inhibitory activities of ZIKV NS5 MTase (methyl transferase) enzymatic activity. Preliminary SAR reveals that C19-modification with bulky groups is necessary for anti-ZIKV infection and replication, anti-ZIKV activity of 5a comes from itself bearing hindered trityl ether but not from its instability, the backbone of dehydroandrographolide is more effective against ZIKV infection than that of andrographolide, and 3-oxime derivatives are more active against ZIKV infection than 3-alcohol derivatives. To our knowledge, 5a is the first reported MTase inhibitor of andrographolide derivatives. More importantly, discovery of active compound 5b with acid-stable 19-OCHPh2 against ZIKV infection is valued and gives us a clue to design and discover generally acid-stable anti-ZIKV agents.



中文翻译:

发现含有 C19 受阻醚的脱氢穿心莲内酯衍生物作为有效的抗 ZIKV 药物,对 ZIKV NS5 的 MTase 具有抑制活性

寨卡病毒 (ZIKV) 是一种蚊子传播的虫媒病毒和黄病毒属的成员,感染可能导致儿童小头畸形和格林-巴利综合征,这仍然是一个持续的全球威胁。对 ZIKV 感染的有效抗病毒药物具有巨大的医疗需求。发现穿心莲内酯及其类似物对黄病毒感染具有活性。在这项研究中,我们发现了一些 3-肟基-或 3-醇-19-受阻醚的脱氢穿心莲内酯衍生物是具有低细胞毒性的强效抗 ZIKV 药物 (CC 50 > 200 微米)。添加时间分析表明,化合物 5a 及其类似物对 ZIKV 生命周期的进入后阶段具有抑制作用。通过实验和分子对接研究发现,3a、5a、5b和5c的活性抗ZIKV化合物具有ZIKV NS5 MTase(甲基转移酶)酶活性的抑制活性。初步 SAR 显示,C19 修饰与庞大的基团是抗 ZIKV 感染和复制所必需的,5a 的抗 ZIKV 活性来自其自身携带受阻的三苯甲基醚而非其不稳定性,脱氢穿心莲内酯的骨架比抗 ZIKV 感染更有效穿心莲内酯和 3-肟衍生物比 3-醇衍生物对 ZIKV 感染更有效。据我们所知,5a 是第一个报道的穿心莲内酯衍生物的 MTase 抑制剂。2抗 ZIKV 感染很有价值,并为我们提供了设计和发现一般酸稳定的抗 ZIKV 药物的线索。

更新日期:2022-08-31
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