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High-Throughput Screening, Discovery, and Optimization to Develop a Benzofuran Class of Hepatitis C Virus Inhibitors
He, Shanshan Jain, Prashi Lin, Billy Ferrer, Mark Hu, Zongyi Southall, Noel Hu, Xin Zheng, Wei Neuenswander, Benjamin Cho, Chul-Hee
He, Shanshan
Jain, Prashi
Lin, Billy
Ferrer, Mark
Hu, Zongyi
Southall, Noel
Hu, Xin
Zheng, Wei
Neuenswander, Benjamin
Cho, Chul-Hee
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Abstract
Using a high-throughput, cell-based HCV luciferase reporter assay to screen a diverse small-molecule compound collection (~300 000 compounds), we identified a benzofuran compound class of HCV inhibitors. The optimization of the benzofuran scaffold led to the identification of several exemplars with potent inhibition (EC50 < 100 nM) of HCV, low cytotoxicity (CC50 > 25 µM), and excellent selectivity (selective index = CC50/EC50, > 371-fold). The structure–activity studies culminated in the design and synthesis of a 45-compound library to comprehensively explore the anti-HCV activity. The identification, design, synthesis, and biological characterization for this benzofuran series is discussed.
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Date
2015-09-02
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Publisher
American Chemical Society
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Keywords
Hepatitis C, HCV inhibitor, Benzofuran, Antiviral, Hcv replication
Citation
Shanshan He, Prashi Jain, Billy Lin, Marc Ferrer, Zongyi Hu, Noel Southall, Xin Hu, Wei Zheng, Benjamin Neuenswander, Chul-Hee Cho, Yu Chen, Shilpa A. Worlikar, Jeffrey Aubé, Richard C. Larock, Frank J. Schoenen, Juan J. Marugan, T. Jake Liang, Kevin J. Frankowski
ACS Comb Sci. 2015 Oct 12; 17(10): 641–652. Published online 2015 Sep 17. doi: 10.1021/acscombsci.5b00101