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Antiviral Res. 2014 Jul;107:66-75. doi: 10.1016/j.antiviral.2014.04.013. Epub 2014 Apr 30.

Synthesis and anti-influenza virus activity of 4-oxo- or thioxo-4,5-dihydrofuro[3,4-c]pyridin-3(1H)-ones.

Author information

1
Virus Research and Testing Group, Korea Research Institute of Chemical Technology, Daejeon 305-343, Republic of Korea.
2
Cancer and Infectious Diseases Therapeutics Research Group, Korea Research Institute of Chemical Technology, Daejeon 305-343, Republic of Korea; Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.
3
Virus Research and Testing Group, Korea Research Institute of Chemical Technology, Daejeon 305-343, Republic of Korea; Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.
4
Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 305-764, Republic of Korea.
5
Cancer and Infectious Diseases Therapeutics Research Group, Korea Research Institute of Chemical Technology, Daejeon 305-343, Republic of Korea; Korea University of Science and Technology, Daejeon 305-350, Republic of Korea. Electronic address: pkim@krict.re.kr.
6
Virus Research and Testing Group, Korea Research Institute of Chemical Technology, Daejeon 305-343, Republic of Korea; Korea University of Science and Technology, Daejeon 305-350, Republic of Korea. Electronic address: mkim@krict.re.kr.

Abstract

A target-free approach was applied to discover anti-influenza viral compounds, where influenza infected Madin-Darby canine kidney cells were treated 7500 different small organic chemicals individually and reduction of virus-induced cytopathic effect was measured. One of the hit compounds was (Z)-1-((5-fluoro-1H-indol-3-yl)methylene)-6-methyl-4-thioxo-4,5-dihydrofuro[3,4-c]pyridin-3(1H)-one (15a) with half-maximal effective concentrations of 17.4-21.1μM against influenza A/H1N1, A/H3N2 and B viruses without any cellular toxicity at 900μM. To investigate the structure-activity relationships, two dozens of the hit analogs were synthesized. Among them, 15g, 15j, 15q, 15s, 15t and 15x had anti-influenza viral activity comparable or superior to that of the initial hit. The anti-influenza viral compounds efficiently suppressed not only viral protein level of the infected cells but also production of viral progeny in the culture supernatants in a dose-dependent manner. Based on a mode-of-action study, they did not affect virus entry or RNA replication. Instead, they suppressed viral neuraminidase activity. This study is the first to demonstrate that dihydrofuropyridinones could serve as lead compounds for the discovery of alternative influenza virus inhibitors.

KEYWORDS:

Antiviral; Cytopathic effect reduction assay; Dihydrofuropyridinones; Influenza virus; NA inhibitor

PMID:
24794525
DOI:
10.1016/j.antiviral.2014.04.013
[Indexed for MEDLINE]

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