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
Date
04/19/2015Pubmed ID
25890075Pubmed Central ID
PMC5557381DOI
10.1016/j.ejmech.2015.04.022Scopus ID
2-s2.0-84927631948 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
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.
Author List
Andreev IA, Manvar D, Barreca ML, Belov DS, Basu A, Sweeney NL, Ratmanova NK, Lukyanenko ER, Manfroni G, Cecchetti V, Frick DN, Altieri A, Kaushik-Basu N, Kurkin AVAuthor
David N. Frick PhD Associate Professor in the Chimistry & Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
Antiviral AgentsCell Line
Dose-Response Relationship, Drug
Drug Discovery
Hepacivirus
Humans
Indoles
Microbial Sensitivity Tests
Structure-Activity Relationship