Tetrazole and triazole as bioisosteres of carboxylic acid: Discovery of diketo tetrazoles and diketo triazoles as anti-HCV agents

A series of diketo tetrazoles and diketo triazoles were designed and synthesized as bioisosteres of alpha,gamma-diketo acid, the active site inhibitor of HCV (Hepatitis C virus) polymerase NS5B. Among the synthesized compounds, 4-(4-fluorobenzyloxy)phenyl diketo triazole (30) exhibited anti-HCV activity with an EC50 value of 3.9 mu M and an SI value more than 128. The reduction of viral protein and mRNA levels were also validated, supporting the anti-HCV activity of compound 30. These results provide convincing evidence that the diketo tetrazoles and diketo triazoles can be developed as bioisosteres of alpha,gamma-diketo acid to exhibit potent inhibitory activity against HCV. (c) 2013 Elsevier Ltd. All rights reserved.