Studies on the anti-hepatitis C virus activity of newly synthesized tropolone derivatives: identification of NS3 helicase inhibitors that specifically inhibit subgenomic HCV replication.
We synthesized new tropolone derivatives substituted with cyclic amines: piperidine, piperazine or pyrrolidine. The most active anti-helicase compound (IC50=3.4 microM), 3,5,7-tri[(4'-methylpiperazin-1'-yl)methyl]tropolone (2), inhibited RNA replication by 50% at 46.9 microM (EC50) and exhibited the lowest cytotoxicity (CC50)>1 mM resulting in a selectivity index (SI=CC50/EC50)>21. The most efficient replication inhibitor, 3,5,7-tri[(4'-methylpiperidin-1'-yl)methyl]tropolone (6), inhibited RNA replication with an EC50 of 32.0 microM and a SI value of 17.4, whereas 3,5,7-tri[(3'-methylpiperidin-1'-yl)methyl]tropolone (7) exhibited a slightly lower activity with an EC50 of 35.6 microM and a SI of 9.8.
Najda-Bernatowicz
Andzelika
A
Institute of Biochemistry and Biophysics PAS, Pawinskiego 5a, 02-106 Warsaw, Poland.
Krawczyk
Mariusz
M
Stankiewicz-Drogoń
Anna
A
Bretner
Maria
M
Boguszewska-Chachulska
Anna M
AM
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D004357:Drug Synergism; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008958:Models, Molecular; D009154:Mutation; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000378:metabolism; D012254:Ribavirin / Q000494:pharmacology; D014334:Tropolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D012254:Ribavirin; D014334:Tropolone; D007371:Interferon-gamma; D004265:DNA Helicases; D020365:RNA Helicases