Design, synthesis, and molecular hybrids of caudatin and cinnamic acids as novel anti-hepatitis B virus agents

Abstract

Forty-six conjugated derivatives of caudatin with substituted cinnamic acids were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated in HepG 2.2.15 cells. Most of the derivatives exhibited potent anti-HBV activity, especially inhibiting the HBV DNA replication with the IC ₅₀ values from 2.44 to 22.89 μΜ. Compound 18 showed significant activity against the secretion of HBsAg, HBeAg, and HBV DNA replication with IC ₅₀ values of 5.52, 5.52, 2.44 μΜ, respectively, and had good safety (LD ₅₀ > 1250 mg/kg) according to the acute toxicity study. Preliminary mechanism investigation suggested that compound 18 exerted antivirus effects via interfering HBV X promoter and enhancer I to influence HBV transcriptions.

Abstract

Graphical abstract

Forty-six conjugated derivatives of caudatin with cinnamic acids bearing various substituents were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated. Most of the derivatives exhibited potent anti-HBV activity, especially inhibiting the HBV DNA replication with the IC ₅₀ values from 2.44 to 22.89 μΜ. Compound 18 could influence HBV transcriptions by inhibiting the activity of HBV X promoter (Xp) and enhancing the activity of HBV enhancer I (ENI).

Highlights

► Conjugated derivatives of caudatin with cinnamic acids were synthesized. ► Most of the derivatives exhibited potent anti-HBV activity. ► The compound 18 exerted antivirus effects by interfering HBV promoters and enhancers. ► The mechanism of compound 18 is different from those of the nucleoside analogs.