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优化 4-苯胺喹啉作为登革热病毒抑制剂。

Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors.

机构信息

Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.

出版信息

Molecules. 2021 Dec 3;26(23):7338. doi: 10.3390/molecules26237338.

Abstract

Emerging viral infections, including those caused by dengue virus (DENV) and Venezuelan Equine Encephalitis virus (VEEV), pose a significant global health challenge. Here, we report the preparation and screening of a series of 4-anilinoquinoline libraries targeting DENV and VEEV. This effort generated a series of lead compounds, each occupying a distinct chemical space, including 3-((6-bromoquinolin-4-yl)amino)phenol (), 6-bromo--(5-fluoro-1H-indazol-6-yl)quinolin-4-amine () and 6-((6-bromoquinolin-4-yl)amino)isoindolin-1-one (), with EC values of 0.63-0.69 µM for DENV infection. These compound libraries demonstrated very limited toxicity with CC values greater than 10 µM in almost all cases. Additionally, the lead compounds were screened for activity against VEEV and demonstrated activity in the low single-digit micromolar range, with and demonstrating ECs of 2.3 µM and 3.6 µM, respectively. The promising results presented here highlight the potential to further refine this series in order to develop a clinical compound against DENV, VEEV, and potentially other emerging viral threats.

摘要

新兴的病毒感染,包括登革热病毒(DENV)和委内瑞拉马脑炎病毒(VEEV)引起的感染,对全球健康构成了重大挑战。在这里,我们报告了一系列针对 DENV 和 VEEV 的 4-苯胺喹啉文库的制备和筛选。这项工作产生了一系列先导化合物,每个化合物都占据了独特的化学空间,包括 3-((6-溴喹啉-4-基)氨基)苯酚()、6-溴--(5-氟-1H-吲唑-6-基)喹啉-4-胺()和 6-((6-溴喹啉-4-基)氨基)异吲哚啉-1-酮(),对 DENV 感染的 EC 值为 0.63-0.69 µM。这些化合物文库在几乎所有情况下的 CC 值均大于 10 µM,显示出非常有限的毒性。此外,还对先导化合物进行了抗 VEEV 活性筛选,结果显示在低个位数微摩尔范围内具有活性,和 分别显示出 EC 值为 2.3 µM 和 3.6 µM。这里呈现的有希望的结果表明,有可能进一步改进该系列,以开发针对 DENV、VEEV 以及潜在其他新兴病毒威胁的临床化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cec1/8659069/30e98302286e/molecules-26-07338-g001.jpg

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