title: Discovery of the 2-phenyl-4,5,6,7-Tetrahydro-1H-indole as a novel anti-hepatitis C virus targeting scaffold.
abstract: Although all-oral direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) treatment is now a reality, today's HCV drugs are expensive, and more affordable drugs are still urgently needed. In this work, we report the identification of the 2-phenyl-4,5,6,7-Tetrahydro-1H-indole chemical scaffold that inhibits cellular replication of HCV genotype 1b and 2a subgenomic replicons. The anti-HCV genotype 1b and 2a profiling and effects on cell viability of a selected representative set of derivatives as well as their chemical synthesis are described herein. The most potent compound 39 displayed EC50 values of 7.9 and 2.6 μM in genotype 1b and 2a, respectively. Biochemical assays showed that derivative 39 had no effect on HCV NS5B polymerase, NS3 helicase, IRES mediated translation and selected host factors. Thus, future work will involve both the chemical optimization and target identification of 2-phenyl-4,5,6,7-Tetrahydro-1H-indoles as new anti-HCV agents.
authors.affiliation: EDASA Scientific Srls., Via Stingi, 37, 66050 San Salvo, CH, Italy; Chemistry Department of Lomonosov Moscow State University, Moscow, 119991, GSP-2, Leninskie Gory, 1/3, Russia.
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Andreev
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: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy. Electronic address: lbarreca@unipg.it.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.affiliation: EDASA Scientific Srls., Via Stingi, 37, 66050 San Salvo, CH, Italy; Chemistry Department of Lomonosov Moscow State University, Moscow, 119991, GSP-2, Leninskie Gory, 1/3, Russia.
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: 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: Noreena L
authors.initials: NL
authors.lastname: Sweeney
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: EDASA Scientific Srls., Via Stingi, 37, 66050 San Salvo, CH, Italy.
authors.forename: Evgeny R
authors.initials: ER
authors.lastname: Lukyanenko
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: 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 Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA. Electronic address: kaushik@njms.rutgers.edu.
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: Alexander V
authors.initials: AV
authors.lastname: Kurkin
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
chemical_list: C000606773:2-phenyl-4,5,6,7-tetrahydro-1H-indole; D000998:Antiviral Agents; D007211:Indoles
keywords: 4,5,6,7-Tetrahydro-1H-indole; Anti-HCV agents; Hepatitis C virus