Discovery of the 2-phenyl-4,5,6,7-Tetrahydro-1H-indole as a novel anti-hepatitis C virus targeting scaffold

Ivan A Andreev; Dinesh Manvar; Maria Letizia Barreca; Dmitry S Belov; Amartya Basu; Noreena L Sweeney; Nina K Ratmanova; Evgeny R Lukyanenko; Giuseppe Manfroni; Violetta Cecchetti; David N Frick; Andrea Altieri; Neerja Kaushik-Basu; Alexander V Kurkin

doi:10.1016/j.ejmech.2015.04.022

Discovery of the 2-phenyl-4,5,6,7-Tetrahydro-1H-indole as a novel anti-hepatitis C virus targeting scaffold

Eur J Med Chem. 2015:96:250-8. doi: 10.1016/j.ejmech.2015.04.022. Epub 2015 Apr 10.

Affiliations

¹ 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.
² Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA.
³ Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy. Electronic address: [email protected].
⁴ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer St., Milwaukee, WI 53211, USA.
⁵ Chemistry Department of Lomonosov Moscow State University, Moscow, 119991, GSP-2, Leninskie Gory, 1/3, Russia.
⁶ EDASA Scientific Srls., Via Stingi, 37, 66050 San Salvo, CH, Italy.
⁷ Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy.
⁸ EDASA Scientific Srls., Via Stingi, 37, 66050 San Salvo, CH, Italy. Electronic address: [email protected].
⁹ Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA. Electronic address: [email protected].

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.

Keywords: 4,5,6,7-Tetrahydro-1H-indole; Anti-HCV agents; Hepatitis C virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Cell Line
Dose-Response Relationship, Drug
Drug Discovery*
Hepacivirus / drug effects*
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Microbial Sensitivity Tests
Structure-Activity Relationship

Substances

2-phenyl-4,5,6,7-tetrahydro-1H-indole
Antiviral Agents
Indoles

Grants and funding

R01 AI088001/AI/NIAID NIH HHS/United States