Anti-HBV agents. Part 3: Preliminary structure–activity relationships of tetra-acylalisol A derivatives as potent hepatitis B virus inhibitors

Thirty-two tetra-acylated derivatives of alisol A were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities and cytotoxicities in vitro. Among the series of alisol A derivatives examined, five analogues were active against HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) secretion in HepG 2.2.15 cells. These results also provide interesting structure–activity relationships of tetra-acylalisol A derivatives. Compounds tetra-acetyl alisol A (A1), tetra-methoxyacetyl alisol A (A23), and tetra-ethoxyacetyl alisol A (A24) exhibited high activities against secretion of HBsAg with IC50 values of 0.0048, 0.0044, and 0.014 mM, respectively, HBeAg with IC50 values of 0.011, 0.012, and 0.018 mM, respectively, and remarkable selective index values SIHBsAg >333, SIHBeAg >145; SIHBsAg = 209, SIHBeAg = 77; and SIHBsAg >200, SIHBeAg >156, respectively. Additional studies in rats showed that compound A1 has favorable pharmacokinetic prosperities for further development purpose, with elimination half-time (t1/2) of 1.63 h and oral bioavailability (F) of 40.9%.

Thirty-two tetra-acylated alisol A derivatives were synthesized and evaluated for their anti-HBV activities and cytotoxicities in vitro. Among them, compounds A1, A23, and A24 exhibited high activities against secretion of HBV surface antigen with IC50 values of 0.0048, 0.0044, and 0.014 mM, respectively, HBV e antigen with IC50 values of 0.011, 0.012, and 0.018 mM, respectively, and remarkable selective index values of SIHBsAg >333, SIHBeAg >145; SIHBsAg = 209, SIHBeAg = 77; and SIHBsAg >200, SIHBeAg >156, respectively. Additional studies in rats showed that compound A1 has favorable pharmacokinetic prosperities for further development purpose, with elimination half-time (t1/2) of 1.63 h and oral bioavailability (F) of 40.9%.Figure optionsDownload as PowerPoint slide