合成 10,10'-双（三氟甲基）马琳吡咯 A 衍生物及其体外抗病毒活性评价。

Synthesis of 10,10'-bis(trifluoromethyl) marinopyrrole A derivatives and evaluation of their antiviral activities in vitro.

机构信息

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education, Ministry and Sichuan Province, and SichuaMn Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, Sichuan Province, China.

National Engineering Research Center for the Emergence Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China; School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, Hainan Province, China.

出版信息

Eur J Med Chem. 2022 Aug 5;238:114436. doi: 10.1016/j.ejmech.2022.114436. Epub 2022 May 6.

DOI:10.1016/j.ejmech.2022.114436

PMID:35598412

Abstract

Flavivirus and enterovirus can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases or even death. Since effective vaccine is currently unavailable against most of these deadly viruses, antiviral chemical drugs remain in urgent need. To meet this unmet demand, we developed a series of 10,10'-bis(trifluoromethyl) marinopyrrole A derivates bearing various substituents at C5'-positions, which exhibited impressive in vitro activities against flaviviruses (ZIKV, DENV, YFV, JEV) and enteroviruses (EV71, CA6, CA16). The lead compound 10,10'-bis(trifluoromethyl) marinopyrrole A 3 was highly effective against enteroviruses EV71 and CA16 in cultured cells, but with low inhibitory activities against flavivirus. Elaborately modified from compound 3, compounds 32 and 33 with sulfhydryl aliphatic chains were found as promising ZIKV and DENV inhibitor; pyrazine-containing compound 19 is a potent broad-spectrum flavivirus inhibitor; thiophene compound 15 exhibited prominent selective inhibitory effect against JEV-SA14, YFV-17D, in addition to broad-spectrum enterovirus inhibitory effect. These results thus suggest that the 5'-sulfhydryl derivates of 10,10'-bis(trifluoromethyl) marinopyrrole A may be promising lead compounds for the development of novel anti-flavivirus and anti-enterovirus drugs.

摘要

黄病毒和肠道病毒可在人群中意外出现，并引起一系列潜在严重疾病甚至死亡。由于目前大多数这些致命病毒都没有有效的疫苗，因此仍然急需抗病毒化学药物。为了满足这一未满足的需求，我们开发了一系列在 C5'位置带有各种取代基的 10,10'-双（三氟甲基）甲藻吡咯 A 衍生物，这些衍生物对黄病毒（ZIKV、DENV、YFV、JEV）和肠道病毒（EV71、CA6、CA16）表现出令人印象深刻的体外活性。先导化合物 10,10'-双（三氟甲基）甲藻吡咯 A 3 在培养细胞中对肠道病毒 EV71 和 CA16 非常有效，但对黄病毒的抑制活性较低。从化合物 3 精心修饰得到的带有巯基脂肪链的化合物 32 和 33 被发现是有前途的 ZIKV 和 DENV 抑制剂；含吡嗪的化合物 19 是一种有效的广谱黄病毒抑制剂；噻吩化合物 15 除了具有广谱肠道病毒抑制作用外，对 JEV-SA14、YFV-17D 也表现出明显的选择性抑制作用。这些结果表明，10,10'-双（三氟甲基）甲藻吡咯 A 的 5'-巯基衍生物可能是开发新型抗黄病毒和抗肠道病毒药物的有前途的先导化合物。