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Molecules 2018, 23(11), 2863; https://doi.org/10.3390/molecules23112863

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

1
Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
2
Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
3
School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
4
Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
5
Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
6
Department of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung City 807, Taiwan
*
Author to whom correspondence should be addressed.
Received: 19 October 2018 / Revised: 31 October 2018 / Accepted: 31 October 2018 / Published: 2 November 2018
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Abstract

Synthesis and anti-hepatitis C virus (anti-HCV) effects of certain 3-amino-2-hydroxy-propoxy isoflavone derivatives, 6ai, 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, 6ai. 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. View Full-Text
Keywords: 3-amino-2-hydroxypropoxyisoflavones; ribavirin; hepatitis C virus; cytotoxicity 3-amino-2-hydroxypropoxyisoflavones; ribavirin; hepatitis C virus; cytotoxicity
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Lee, J.-C.; Lin, C.-K.; Tseng, C.-K.; Chen, Y.-L.; Tzeng, C.-C.; Tseng, C.-H. Discovery of 3-Amino-2-Hydroxypropoxyisoflavone Derivatives as Potential Anti-HCV Agents. Molecules 2018, 23, 2863.

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