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.

Oxidative Dearomatization of 4,5,6,7‐Tetrahydro‐1H‐indoles Obtained by Metal‐ and Solvent‐Free Thermal 5‐endo‐dig Cyclization: The Route to Erythrina and Lycorine Alkaloids

“…Recently, we have developed a two‐step synthetic methodology that leads to 4,5,6,7‐tetrahydroindoles possessing a wide‐range of substituents both at C 2 or nitrogen atoms (including chiral moieties) ,. This approach bears a general character and is readily scalable to generate sufficient amounts of material on a gram‐scale in good to excellent yields (Scheme , the upper path).…”

Bicyclic octahydrocyclohepta[ b ]pyrrol-4(1 H )one derivatives as novel selective anti-hepatitis C virus agents

“…Last year, we reported a new compound class possessing a 2-phenyl-4,5,6,7-tetrahydro-1H-indole core that inhibits HCV genotype 1b and 2a replication in cells [17,18]. Inspired by this success, we tested an additional set of representative heterobicyclic compounds (1-21 [19][20][21][22], Figure S1 Supporting Information) that was available from the EDASA Scientific public repertory of compound stocks (http://www.edasascientific.com/page/catalogue).…”

“…We therefore investigated two representative compounds (6 and 34) for their ability to down-regulate HCV IRESmediated translation [18,25]. Our results indicated that these compounds had no effect on HCV IRES mediated translation even at a higher (25 µM) concentration than is needed to fully inhibit the HCV replicons (data not shown).…”

5-Benzoyl-2-(5-bromo-1H-indol-3-yl)-4-(4-nitrophenyl)-1H-pyrrole-3-carbonitrile dimethyl sulfoxide monosolvate

“…Indole derivatives are known to exhibit activities such as antitumour (Andreani et al, 2001); antiviral (Kolocouris et al, 1994) and anti-hepatitis C virus (Andreev et al, 2015). Indoles have attracted much attention because of their wide variety of applications especially in medicinal field.…”