title: Bicyclic octahydrocyclohepta[b]pyrrol-4(1H)one derivatives as novel selective anti-hepatitis C virus agents.
abstract: We report the discovery of the bicyclic octahydrocyclohepta[b]pyrrol-4(1H)-one scaffold as a new chemotype with anti-HCV activity on genotype 1b and 2a subgenomic replicons. The most potent compound 34 displayed EC50 values of 1.8 μM and 4.5 μM in genotype 1b and 2a, respectively, coupled with the absence of any antimetabolic effect (gt 1b SI = 112.4; gt 2a SI = 44.2) in a cell-based assay. Compound 34 did not target HCV NS5B, IRES, NS3 helicase, or selected host factors, and thus future work will involve the unique mechanism of action of these new antiviral compounds.
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA. Electronic address: neerja.kaushik-basu@nih.gov.
authors.forename: Neerja
authors.initials: N
authors.lastname: Kaushik-Basu
authors.affiliation: Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia.
authors.forename: Nina K
authors.initials: NK
authors.lastname: Ratmanova
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Manvar
authors.affiliation: Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia; EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo, CH, Italy.
authors.forename: Dmitry S
authors.initials: DS
authors.lastname: Belov
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA.
authors.forename: Ozge
authors.initials: O
authors.lastname: Cevik
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA.
authors.forename: Amartya
authors.initials: A
authors.lastname: Basu
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer St., Milwaukee, WI 53211, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Yerukhimovich
authors.affiliation: Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia; EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo, CH, Italy.
authors.forename: Evgeny R
authors.initials: ER
authors.lastname: Lukyanenko
authors.affiliation: Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia; EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo, CH, Italy.
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Andreev
authors.affiliation: Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia; EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo, CH, Italy.
authors.forename: Grigory M
authors.initials: GM
authors.lastname: Belov
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy.
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer St., Milwaukee, WI 53211, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Frick
authors.affiliation: Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory, 1/3, Russia. Electronic address: kurkin@direction.chem.msu.ru.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kurkin
authors.affiliation: EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo, CH, Italy. Electronic address: aaltieri@edasascientific.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Altieri
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy. Electronic address: maria.barreca@unipg.it.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic
keywords: Anti-HCV agents; Aza-Cope–Mannich reaction; HCV inhibitors; Hepatitis C virus; Octahydrocyclohepta[b]pyrrol-4(1H)one derivatives