Synthesis and anti-HCV determinant motif identification in pyranone carboxamide scaffold.
Hepatitis C Virus exhibits high genetic diversity. The current treatment for genotype-1 with ∼80% sustained virologic responses is a combination of pegylated interferon, ribavirin and boceprevir/telaprevir/simeprevir which is associated with several side effects and need close monitoring. Therefore, novel therapies are invited for safer and more efficient treatment. This study was designed for synthesis of new α-pyranone carboxamide analogs for evaluation of anti-HCV activity to delineate structure-activity relationship (SAR) and to identify anti-HCV determinant motif on this new scaffold. Forty four new α-pyranone carboxamide analogs were synthesized. Six potential anti-HCV candidates 11a (EC50=0.35 μM), 11e (EC50=0.48 μM), 12f (EC50=0.47 μM), 12g (EC50=0.39 μM), 12h (EC50=0.20 μM) and 12j (EC50=0.25 μM) with lower cytotoxicity (CC50>20 μM) were discovered through cell based HCV replicon system. The activity profile of forty four new α-pyranone carboxamide analogs suggests the role of an aromatic motif in the B region to add a synergistic effect to NHOH motif at 4-position and revels an anti-HCV activity determinants motif under this scaffold. The biochemical assay against most promising HCV target protein 'NS3 protease and NS5B polymerase' showed no activity and open a scope to explore new mechanism inhibitor.
Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India.
Tuniki
T
Balaraju
Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India.
Ananda Kumar
AK
Konreddy
Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India.
Afsana
A
Parveen
Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan.
Massaki
M
Toyama
Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan.
Wataru
W
Ito
Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India.
Srinivas
S
Karampuri
Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan.
Masanori
M
Baba
Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India. Electronic address: asharon@bitmesra.ac.in.
Ashoke
A
Sharon
Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India. Electronic address: cbal@bitmesra.ac.in.
Chandralata
C
Bal
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D011753:Pyrones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000577:Amides; D000998:Antiviral Agents; D011753:Pyrones
Hepatitis C Virus; Non-nucleoside inhibitor; Pyranone carboxamide