Tetrazole and triazole as bioisosteres of carboxylic acid: Discovery of diketo tetrazoles and diketo triazoles as anti-HCV agents
2013
Song, Wu-Hui | Liu, Ming-Ming | Zhong, Dong-Wei | Zhu, Ye-lin | Bosscher, Mike | Zhou, Lu | Ye, De-Yong | Yuan, Zheng-Hong
A series of diketo tetrazoles and diketo triazoles were designed and synthesized as bioisosteres of α,γ-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 3.9μM 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 α,γ-diketo acid to exhibit potent inhibitory activity against HCV.
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