title: Searching for a new anti-HCV therapy: synthesis and properties of tropolone derivatives.
abstract: Hepatitis C virus (HCV) is considered one of the most dangerous pathogens since about 3% of the world population is HCV-infected and the virus is a major cause of hepatitis, cirrhosis, and liver carcinoma. A need for a more efficient therapy prompted us to investigate new class of compounds, such as tropolone derivatives that possess antiviral, antibacterial, and antifungal activities. To synthesize bromo- and morpholinomethyl-analogues of tropolone, the previously reported methods were modified. The influence of new derivatives on the activity of the helicase and NTP-ase of HCV was investigated. The most potent inhibitory effect in the fluorometric helicase assay was exerted by 3,7-dibromo-5-morpholinomethyltropolone, for which the IC50 value was at low micromolar range. All the morpholino-derivatives had inhibitory activities higher than those of the non-modified analogues. Low toxicity in a yeast-based toxicity assay indicates that these compounds could be further modified to develop potent inhibitors of the HCV helicase and of viral replication.
authors.affiliation: Institute of Biochemistry and Biophysics PAS, Pawińskiego 5a, 02-106 Warsaw, Poland. annach@ibb.waw.pl
authors.forename: Anna M
authors.initials: AM
authors.lastname: Boguszewska-Chachulska
authors.forename: Mariusz
authors.initials: M
authors.lastname: Krawczyk
authors.forename: Andzelika
authors.initials: A
authors.lastname: Najda
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kopańska
authors.forename: Anna
authors.initials: A
authors.lastname: Stankiewicz-Drogoń
authors.forename: Włodzimierz
authors.initials: W
authors.lastname: Zagórski-Ostoja
authors.forename: Maria
authors.initials: M
authors.lastname: Bretner
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005470:Fluorometry / Q000379:methods; D016174:Hepacivirus / Q000378:metabolism*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008956:Models, Chemical; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013696:Temperature; D014334:Tropolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000251:Adenosine Triphosphatases; D000255:Adenosine Triphosphate; D000998:Antiviral Agents; D004247:DNA; D014334:Tropolone; D017361:Viral Nonstructural Proteins; C509338:3,7-dibromo-5-morpholinomethyltropolone; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases