Identification of novel N-(morpholine-4-carbonyloxy) amidine compounds as potent inhibitors against hepatitis C virus replication.
To identify novel compounds that possess antiviral activity against hepatitis C virus (HCV), we screened a library of small molecules with various amounts of structural diversity using an HCV replicon-expressing cell line and performed additional validations using the HCV-JFH1 infectious-virus cell culture. Of 4,004 chemical compounds, we identified 4 novel compounds that suppressed HCV replication with 50% effective concentrations of ranging from 0.36 to 4.81 μM. N'-(Morpholine-4-carbonyloxy)-2-(naphthalen-1-yl) acetimidamide (MCNA) was the most potent and also produced a small synergistic effect when used in combination with alpha interferon. Structure-activity relationship (SAR) analyses revealed 4 derivative compounds with antiviral activity. Further SAR analyses revealed that the N-(morpholine-4-carbonyloxy) amidine moiety was a key structural element for antiviral activity. Treatment of cells with MCNA activated nuclear factor κB and downstream gene expression. In conclusion, N-(morpholine-4-carbonyloxy) amidine and other related morpholine compounds specifically suppressed HCV replication and may have potential as novel chemotherapeutic agents.
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Akiko
A
Kusano-Kitazume
Naoya
N
Sakamoto
Yukiko
Y
Okuno
Yuko
Y
Sekine-Osajima
Mina
M
Nakagawa
Sei
S
Kakinuma
Kei
K
Kiyohashi
Sayuri
S
Nitta
Miyako
M
Murakawa
Seishin
S
Azuma
Yuki
Y
Nishimura-Sakurai
Masatoshi
M
Hagiwara
Mamoru
M
Watanabe
D000578:Amidines / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000821:virology; D006801:Humans; D020128:Inhibitory Concentration 50; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D008156:Luciferases; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000578:Amidines; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009025:Morpholines; D016328:NF-kappa B; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D008156:Luciferases