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Abstract
Synthesis and anti-hepatitis C virus (anti-HCV) effects of certain 3-amino-2-hydroxy-propoxy isoflavone derivatives, 6a–i, were described. The known 3-(3,4-dimethoxyphenyl)-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (5) was reacted with substituted amines to give the desired isoflavone derivatives, 6a–i. Among them, 7-{3-[(3,4-dimethoxy-phenethyl)amino]-2-hydroxypropoxy}-3-(3,4-dimethoxyphenyl)-4H-chromen-4-one (6b) was the most active, exhibiting approximately 2-fold higher anti-HCV effects than standard antiviral drug ribavirin (EC50 of 6.53 vs. 13.16 μM). In addition, compound 6b was less cytotoxic than ribavirin. The selectivity index (SI) of 6b is approximately 2.6-fold higher than ribavirin. The compounds 6e, 6h, and 6i were also found to possess higher anti-HCV effects than ribavirin. Compound 6b 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 6b, 6e, 6h, and 6i gave rise to induction of HO-1 expression. With the HO-1 promoter-based analysis, we found compounds 6b, 6e, 6h, and 6i induced HO-1 expression through increasing Nrf-2 binding activity. Taken together, compound 6b may serve as a potential lead compound for developing novel anti-HCV agents.
Highlights
Hepatitis C virus (HCV) infection has significantly increased in the past decades and becomes a severe problem in liver diseases, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC)
The therapeutic agents for HCV patients still present a drug-resistant problem, so the development of supplemental agents or more effective and safer agents is required for such therapy [5,6,7,8,9,10]
We found that induction of HO-1 protein level could suppress HCV
Summary
Hepatitis C virus (HCV) infection has significantly increased in the past decades and becomes a severe problem in liver diseases, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). An estimated 200 million people are infected with hepatitis C virus and more than 350,000 people die every year from HCV-related liver diseases [1,2,3]. There are still no approved vaccines for the treatment of HCV infection [4]. The therapeutic agents for HCV patients still present a drug-resistant problem, so the development of supplemental agents or more effective and safer agents is required for such therapy [5,6,7,8,9,10]. Kaushik-Basu et al [12] reported that (3aS,8aS,E)-ethyl-4-(2-phenylhydrazono)-1-tosyldecahydro-cyclohepta[b]pyrrole-2-carboxylate
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