Discovery of Imidazo[1,2-α][1,8]naphthyridine Derivatives as Potential HCV Entry Inhibitor

Abstract

RO8191 represents a newly discovered small-molecule IFN-like agent that displays potent anti-HCV activity. With it as lead, a series of compounds bearing an imidazo[1,2-α][1,8]naphthyridine core and an amide bond-linked side chain were designed and synthesized. These compounds were evaluated on HCV cell culture system (HCVcc-hRluc-JFH1), and some of them exhibited remarkable anti-HCV activity (EC50 = 0.017-0.159 μM) and low toxicity (CC50 > 25 μM). Moreover, it was revealed that these newly identified anti-HCV agents exert their antiviral effect through a distinct mechanism of action from that of RO8191 by targeting the viral entry process. Thus, our study provides a starting point for the development of potential HCV entry inhibitor.

Type I interferon protects neurons from prions inin vivomodels

“…RO8191 can positively bind to the IFNAR2 receptor and strongly evoke an IFN signal inducing interferon-stimulated gene expression (Konishi et al , 2012). Thus, RO8191 can markedly block hepatitis C virus replication and cell death after encephalomyocarditis virus infection in cell culture as demonstrated with recombinant IFN treatment (Konishi et al , 2012; Wang et al , 2015). Moreover, mice orally inoculated with RO8191 showed significantly higher expression of several interferon-stimulated genes compared with the vehicle group (Konishi et al , 2012).…”

Recent Developments and Multiple Biological Activities Available With 1, 8-Naphthyridine Derivatives: A Review

“…Wang et al [125] synthesize the derivatives containing an imidazo [1,2-α] [1,8] naphthyridine core and a side chain connected with amide bond (104a-RO8191 and b) and evaluate the HCV entry inhibitory activity in hepatitis C virus cell culture system. Among these compounds, a few compounds exhibit outstanding anti-HCV activity with EC50 value ranges from 0.017-0.159 µM and low toxicity (CC50 The finding of simple organic compounds endowed with good antimicrobial and antioxidant properties is of growing concern in the food industries.…”

Development of an Aryloxazole Class of Hepatitis C Virus Inhibitors Targeting the Entry Stage of the Viral Replication Cycle

“…17 The attractiveness of HCV entry as an anti-HCV target is evidenced by multiple recent efforts in developing HCV entry inhibitors. [18][19][20] To attain an all oral, pangenotypic HCV treatment with the shortest possible course of treatment, it would be of benefit to target multiple viral or host targets simultaneously. Studies toward determining the molecular target and validating the efficacy in vivo are underway and will be reported in due course.…”