Synthesis and Anti-Influenza Activity of Pyridine, Pyridazine, and Pyrimidine C-Nucleosides as Favipiravir (T-705) Analogues
| Autor: | Andreas Jekle, Sushmita Mukherjee Chanda, Zhinan Jin, Yujian Hu, Jinqiao Wan, Natalia B. Dyatkina, Xiangyang Wu, Marija Prhavc, Leonid Beigelman, Vivek K. Rajwanshi, Julian A. Symons, Guangyi Wang, David B. Smith, Qingling Zhang, April Kinkade, Jerome Deval, Lawrence M. Blatt, Yuen Tam |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Drug Pyridines media_common.quotation_subject Orthomyxoviridae Microbial Sensitivity Tests Favipiravir 010402 general chemistry Antiviral Agents 01 natural sciences Cell Line Madin Darby Canine Kidney Cells Mice Structure-Activity Relationship Dogs Drug Discovery medicine Animals Humans Structure–activity relationship Polymerase media_common Mice Inbred BALB C Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Nucleosides biology.organism_classification Virology 0104 chemical sciences Pyridazines Pyrimidines Mechanism of action Viral replication biology.protein Molecular Medicine Female medicine.symptom Neuraminidase |
| Zdroj: | Journal of Medicinal Chemistry. 59:4611-4624 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Influenza viruses are responsible for seasonal epidemics and occasional pandemics which cause significant morbidity and mortality. Despite available vaccines, only partial protection is achieved. Currently, there are two classes of widely approved anti-influenza drugs: M2 ion channel blockers and neuraminidase inhibitors. However, the worldwide spread of drug-resistant influenza strains poses an urgent need for novel antiviral drugs, particularly with a different mechanism of action. Favipiravir (T-705), a broad-spectrum antiviral agent, has shown potent anti-influenza activity in cell-based assays, and its riboside (2) triphosphate inhibited influenza polymerase. In one of our approaches to treat influenza infection, we designed, prepared, and tested a series of C-nucleoside analogues, which have an analogy to 2 and were expected to act by a similar antiviral mechanism as favipiravir. Compound 3c of this report exhibited potent inhibition of influenza virus replication in MDCK cells, and its triphosphate was a substrate of and demonstrated inhibitory activity against influenza A polymerase. Metabolites of 3c are also presented. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|