| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1397508 | European Journal of Medicinal Chemistry | 2011 | 9 Pages |
Aromatic aldehyde-derived thiosemicarbazones 4–6, the S-substituted modified thiosemicarbazones 7/8, and a vitamin A-derived (retinoid) thiosemicarbazone derivative 12 were investigated as inhibitors of human hepatitis C virus (HCV) subgenomic RNA replicon Huh7 ET (luc-ubi-neo/ET) replication. Compounds 4–6 and 12 were found to be potent suppressors of HCV RNA replicon replication. The trifluoromethoxy-substituted thiosemicarbazone 6 and the retinoid thiosemicarbazone derivative 12 were even superior in selectivity to the included reference agent recombinant human alpha-interferon-2b, showing potencies in the nanomolar range of concentration. In addition, compounds 5, 6, 8 and 12 were tested as inhibitors of cytopathic effect (CPE) induced by human varicella-zoster virus (VZV) and/or human cytomegalovirus (HCMV). Compounds 4–6, 8 and 12 were additionally examined as inhibitors of CPE induced by cowpox virus and vaccinia virus. Thiosemicarbazone 4 was inhibitory on cowpox and vaccinia virus replication comparable in potency and selectivity to the reference agent cidofovir. Retinoid thiosemicarbazone derivative 12 was active as micromolar inhibitor of VZV, HCMV, and, in addition, human immunodeficiency virus type 1 (HIV-1) replication. These results indicate that thiosemicarbazone derivatives are appropriate lead structures to be evaluated in targeted antiviral therapies for hepatitis C (STAT-C), and that the vitamin A-related thiosemicarbazone derivative 12 emerges as a broad-spectrum antiviral agent, co-suppressing the multiplication of important RNA and DNA viruses.
Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Thiosemicarbazones 4–6, 7/8, and 12 were investigated as inhibitors of HCV replicon replication. ► Compound 12 was superior to alpha-interferon-2b regarding inhibition of HCV replicon replication. ► Compound 12 was active as inhibitor of VZV, HCMV and human immunodeficiency virus replication. ► Thiosemicarbazone derivatives are appropriate lead structures to be evaluated in STAT-C. ► Compound 12 emerged from these studies as broad-spectrum antiviral agent.
