A new class of pyrimidine nucleosides: inhibitors of hepatitis B and C viruses.

Neeraj Shakya, Satish Vedi, Chao Liang, Babita Agrawal, D Lorne Tyrrell, Rakesh Kumar

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.

Bioorganic & medicinal chemistry letters 2012 Oct 15

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major health threats worldwide leading to liver cirrhosis, liver cancer and mortality. Herein, we report a new category of dideoxy pyrimidine nucleosides possessing a 4'-carboxyl (or carboxymethyl) function (7-9, 13, 16, 17), which are discovered as potential antiviral agents. For the first time, these nucleosides are recognized to be inhibitors of HBV and/or HCV replication. Among 4'-carboxy compounds, 3',4'-didehydrothymidine (16) was most effective against DHBV, HBV and HCV. Modification of the 4'-position in compound 7 from a carboxyl to carboxymethyl group (17) did not affect the anti-HBV activity but greatly increased the anti-HCV activity. Importantly, 17 yielded synergistic antiviral effect when combined with ribavirin without toxicity. The activity exhibited by a single agent towards both hepatitis viruses and no detectable in vitro cytotoxicity make this new class of compounds of interest. Copyright © 2012 Elsevier Ltd. All rights reserved.

Citation

Neeraj Shakya, Satish Vedi, Chao Liang, Babita Agrawal, D Lorne Tyrrell, Rakesh Kumar. A new class of pyrimidine nucleosides: inhibitors of hepatitis B and C viruses. Bioorganic & medicinal chemistry letters. 2012 Oct 15;22(20):6475-80