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

• Main Authors: Jin-Ching Lee, Chun-Kuang Lin, Chin-Kai Tseng, Yeh-Long Chen, Cherng-Chyi Tzeng, Chih-Hua Tseng
• Format: Article
• Language: English
• Published: MDPI AG 2018-11-01
• Series: Molecules
• Subjects: 3-amino-2-hydroxypropoxyisoflavones; ribavirin; hepatitis C virus; cytotoxicity
• Online Access: https://www.mdpi.com/1420-3049/23/11/2863

Synthesis and anti-hepatitis C virus (anti-HCV) effects of certain 3-amino-2-hydroxy-propoxy isoflavone derivatives, <b>6a</b>&#8315;<b>i</b>, were described. The known 3-(3,4-dimethoxyphenyl)-7-(oxiran-2-ylmethoxy)-4<i>H</i>-chromen-4-one (<b>5</b>) was reacted with substituted amines to give the desired isoflavone derivatives, <b>6a</b>&#8315;<b>i</b>. Among them, 7-{3-[(3,4-dimethoxy-phenethyl)amino]-2-hydroxypropoxy}-3-(3,4-dimethoxyphenyl)-4<i>H</i>-chromen-4-one (<b>6b</b>) was the most active, exhibiting approximately 2-fold higher anti-HCV effects than standard antiviral drug ribavirin (EC₅₀ of 6.53 vs. 13.16 &#956;M). In addition, compound <b>6b</b> was less cytotoxic than ribavirin. The selectivity index (SI) of <b>6b</b> is approximately 2.6-fold higher than ribavirin. The compounds <b>6e</b>, <b>6h</b>, and <b>6i</b> were also found to possess higher anti-HCV effects than ribavirin. Compound <b>6b</b> 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 <b>6b</b>, <b>6e</b>, <b>6h</b>, and <b>6i</b> gave rise to induction of HO-1 expression. With the HO-1 promoter-based analysis, we found compounds <b>6b</b>, <b>6e</b>, <b>6h</b>, and <b>6i</b> induced HO-1 expression through increasing Nrf-2 binding activity. Taken together, compound <b>6b</b> may serve as a potential lead compound for developing novel anti-HCV agents.