Synthesis and Anti-Influenza Activity of Pyridine, Pyridazine, and Pyrimidine C-Nucleosides as Favipiravir (T-705) Analogues.
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.
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Guangyi
G
Wang
Department of Medicinal Chemistry, WuXi AppTec , Shanghai 200131, P.R. China.
Jinqiao
J
Wan
Department of Medicinal Chemistry, WuXi AppTec , Shanghai 200131, P.R. China.
Yujian
Y
Hu
Department of Medicinal Chemistry, WuXi AppTec , Shanghai 200131, P.R. China.
Xiangyang
X
Wu
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Marija
M
Prhavc
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Natalia
N
Dyatkina
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Vivek K
VK
Rajwanshi
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
David B
DB
Smith
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Andreas
A
Jekle
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
April
A
Kinkade
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Julian A
JA
Symons
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Zhinan
Z
Jin
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Jerome
J
Deval
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Qingling
Q
Zhang
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Yuen
Y
Tam
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Sushmita
S
Chanda
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Lawrence
L
Blatt
Alios BioPharma, Inc. , part of the Janssen Pharmaceutical Companies, South San Francisco, California 94080, United States.
Leonid
L
Beigelman
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009975:Orthomyxoviridae / Q000187:drug effects*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D009705:Nucleosides; D011724:Pyridazines; D011725:Pyridines; D011743:Pyrimidines; C062482:pyridazine; C023666:pyridine