Discovery and evolution of aloperine derivatives as a new family of HCV inhibitors with novel mechanism
Abstract Aloperine ( 1 ), a Chinese natural product with a unique endocyclic scaffold, was first identified to be a potent hepatitis C virus (HCV) inhibitor in our laboratory. Thirty-four new aloperine derivatives were designed, synthesized and evaluated for their anti-HCV activities taking 1 as the lead. Among them, compound 7f exhibited the potential potency with EC 50 values in a micromolar range against both wild-type and direct-acting antiviral agents (DAAs)-resistant variants, and synergistically inhibited HCV replication with approved DAAs. Furthermore, it also owned a good oral pharmacokinetic and safety profile, suggesting a highly druglike nature. The primary mechanism showed that 7f might target host components, distinctly different from the DAAs currently used in clinic. Therefore, we consider aloperine derivatives to be a novel class of anti-HCV agents, and compound 7f has been selected as a promising antiviral candidate for further investigation. Highlights New aloperine derivatives were synthesized and evaluated for the anti-HCV activity. Compound 7f synergistically inhibited HCV replication with approved DAAs. Compound 7f owned a good oral pharmacokinetic and safety profile. 7f might target host components, distinctly different from the DAAs used in clinic. Graphical abstract [DISPLAY OMISSION]
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