title: Tetrazole and triazole as bioisosteres of carboxylic acid: discovery of diketo tetrazoles and diketo triazoles as anti-HCV agents.
abstract: 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 3.9 μM 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.
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, 138 Yi-Xue-Yuan Road, Shanghai 200032, PR China.
authors.forename: Wu-Hui
authors.initials: WH
authors.lastname: Song
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Liu
authors.forename: Dong-Wei
authors.initials: DW
authors.lastname: Zhong
authors.forename: Ye-lin
authors.initials: YL
authors.lastname: Zhu
authors.forename: Mike
authors.initials: M
authors.lastname: Bosscher
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.forename: De-Yong
authors.initials: DY
authors.lastname: Ye
authors.forename: Zheng-Hong
authors.initials: ZH
authors.lastname: Yuan
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D002264:Carboxylic Acids; D013777:Tetrazoles; D014230:Triazoles
keywords: Anti-HCV activity; Bioisosteres; Diketo tetrazoles; Diketo triazoles