ABSTRACT
Hepatitis C virus (HCV) infection is a worldwide health problem. This can be attributed, in part, to the high mutation rate associated with RNA viral replication, which favors the emergence of drug resistance and limits the efficacy of current therapies. Here we report the continuation of our efforts to rationally design and synthesize a series of novel anilinobenzothiazole derivatives. We demonstrate that 2-(4-nitroanilino)-6-methylenzothiazole (compound 14) inhibited HCV RNA-dependent RNA polymerase (RdRp) activity and HCV RNA replication (EC50=8±0.5µM) in a dose-dependent manner, consistent with a noncompetitive model of inhibition (kinetic constant Ki=7.76µM). The best docking pose of compound 14 is located in the Thumb II Pocket, suggesting an inhibitory mechanism involving the docking of compound 14 that alters RdRp breathing. Combinations of compound 14 with interferon-α or other drugs potentially targeting HCV proteins, including telaprevir, PSI7977, or BMS790052, synergistically decreased the levels of HCV RNA.
Subject(s)
Antiviral Agents/pharmacology , Benzothiazoles/pharmacology , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Hepatitis C/virology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Virus Replication/drug effects , Antiviral Agents/chemistry , Benzothiazoles/chemistry , Enzyme Inhibitors/chemistry , Hepacivirus/drug effects , Hepacivirus/genetics , Hepacivirus/physiology , Hepatitis C/drug therapy , Humans , Models, Molecular , Molecular Structure , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolism , Viral Proteins/genetics , Viral Proteins/metabolismABSTRACT
The hepatitis C virus (HCV) is the main cause of progressive liver disease, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Novel anilinocoumarins were synthesized, and their efficacy against HCV replication was evaluated. We demonstrated that 3-(3',4',5'-trimethoxyanilin-1'-yl)methylaminocoumarin (6) exhibited strong anti-HCV activity at protein and RNA levels at non-toxic concentrations, with an EC(50) value of 12 ± 0.3 µM and a selective index (SI) value of 10. Combined treatment of compound 6 and interferon-α (IFN) or telaprevir induced a significant decrease in HCV RNA levels, respectively. We also found that the anti-HCV replication effect of compound 6 was due to the induction of IFN-mediated antiviral responses. This is the first report demonstrating that coumarins inhibit viral replication through an IFN-mediated anti-viral response. Collectively, compound 6 possessed potent activities against HCV replication and could be a new lead compound with higher selectivity and less toxicity.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coumarins/pharmacology , Hepacivirus/drug effects , Hepacivirus/immunology , Interferon-alpha/immunology , Antiviral Agents/chemical synthesis , Cell Line , Coumarins/chemical synthesis , Coumarins/chemistry , Dose-Response Relationship, Drug , Hepacivirus/growth & development , Humans , Molecular Structure , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Hepatitis C virus (HCV) infection is a main cause of chronic liver disease, leading to liver cirrhosis and hepatocellular carcinoma (HCC). The objective of our research was to develop effective agents against viral replication. Here, we have synthesized a series of anilinoquinoline derivatives. Based on a cell-based HCV replicon system, we observed that 2-(3'-nitroanilino)quinoline (18) exhibited anti-HCV activity with a 50% effective concentration (EC(50)) value of 7µM and a selective index (SI) value of 10. In addition, compound 18 possessed the inhibitory effect on HCV NS3/4A protease activity. Therefore, we concluded that the compound 18 possessed a potent activity against HCV replication and could provide as a new lead compound as anti-HCV inhibitor.
