Discovery of 3-Amino-2-Hydroxypropoxyisoflavone Derivatives as Potential Anti-HCV Agents.

Synthesis and anti-hepatitis C virus (anti-HCV) effects of certain 3-amino-2-hydroxy-propoxy isoflavone derivatives, ⁻, were described. The known 3-(3,4-dimethoxyphenyl)-7-(oxiran-2-ylmethoxy)-4-chromen-4-one () was reacted with substituted amines to give the desired isoflavone derivatives, ⁻. Among them, 7-{3-[(3,4-dimethoxy-phenethyl)amino]-2-hydroxypropoxy}-3-(3,4-dimethoxyphenyl)-4-chromen-4-one () was the most active, exhibiting approximately 2-fold higher anti-HCV effects than standard antiviral drug ribavirin (EC of 6.53 vs. 13.16 μM). In addition, compound was less cytotoxic than ribavirin. The selectivity index (SI) of is approximately 2.6-fold higher than ribavirin. The compounds , , and were also found to possess higher anti-HCV effects than ribavirin. Compound was found to inhibit the HCV RNA expression in Ava5 cells in a dose-dependent manner; furthermore, we found that the antiviral mechanism of compounds , , , and gave rise to induction of HO-1 expression. With the HO-1 promoter-based analysis, we found compounds , , , and induced HO-1 expression through increasing Nrf-2 binding activity. Taken together, compound may serve as a potential lead compound for developing novel anti-HCV agents.