Discovery of Isolndolo[2,1‐a]quinazoline derivatives as anti‐Hepatitis C virus agents by suppressing HCV associated inflammation

Abstract

Chronic Hepatitis C Virus (HCV) infection leads to serious liver disease with sequelae including cirrhosis, steatosis, and hepatocellular carcinoma. HCV infection triggers vigorous immune response which in the long term leads to upregulation of COX‐2 and other pro‐inflammatory cytokines. Together, this condition likely contributes to persistent viral infection and subsequent liver damage. We have identified a series of small molecules that exhibited potent anti‐HCV activity and inhibited the replication of HCV replicon of both 1b and 2a genotype origin at low micromolar range EC50 values. Active compounds had minimal effect on cell viability at concentrations in far excess of their EC50 values and showed excellent selectivity indexes. We will present the molecular mechanisms of anti‐HCV activity of Isolndolo[2,1‐a]quinazoline derivatives. Active compounds suppressed HCV‐induced COX‐2 mRNA and protein expression. Conversely, the anti‐HCV activities of these compounds were abrogated upon transient over‐expression of COX‐2. Further, treatment with the active compounds mitigated both Nuclear Factor‐κB activation as well as the effects of tumor necrosis factor‐α in HCV replicon cells. Our data suggests that these compounds function as anti‐HCV agents via targeting COX‐2 at both the transcription and translation levels and thus have the potential to be developed as novel anti‐HCV therapeutic agents with the ability to dampen inflammation during chronic HCV infection.