title: Inhibition of subgenomic hepatitis C virus RNA replication by acridone derivatives: identification of an NS3 helicase inhibitor.
abstract: We report the synthesis and structure-activity relationship (SAR) of a large series of acridones and acridone-fragment derivatives designed on the basis of the selective antihepatitis C virus (HCV) activity shown by acridone 2, previously studied as a potential antibovine viral diarrhea virus (BVDV) compound. The evaluation of their ability to inhibit the HCV replication in Huh-5-2 cells led to the identification of new, selective inhibitors. This indicates that the acridone skeleton, when properly functionalized, is a suitable scaffold to obtain potential anti-HCV agents. Interestingly, during identification of possible cellular and viral targets, it was discovered that compound 23 exerts inhibitory activity on the HCV NS3 helicase, a very promising target for the development of anti-HCV drugs.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Via del Liceo, 1, 06123 Perugia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.forename: Jan
authors.initials: J
authors.lastname: Paeshuyse
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.forename: Samantha
authors.initials: S
authors.lastname: Zanoli
authors.forename: Barbara
authors.initials: B
authors.lastname: Gatto
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Fravolini
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology; D054831:Acridones; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D016174:Hepacivirus / Q000235:genetics* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D020365:RNA Helicases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000166:Acridines; D054831:Acridones; D000998:Antiviral Agents; D020365:RNA Helicases; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C041300:acridone