Design, synthesis, and evaluation of novel oxyacanthine derivatives for anti-SARS-CoV-2 activity

Here, we report the synthesis of a series of oxyacanthine derivatives and evaluation for their anti-SARS-CoV-2 activity in Vero E6 cells. In order to eliminate the potential metabolic activation caused by para-methylene phenol moiety in oxyacanthine, totally 29 derivatives were designed and synthesized, resulting in 23 compounds with antivirus IC₅₀ below 5.00 μM and 9 compounds with antivirus IC₅₀ below 1.00 μM. Among them, amides compound 4a and 4d exhibited potent anti-SARS-CoV-2 activity and the most favorable selectivity index (SI) in vitro with the SI values of 115 and 70, respectively. The pharmacokinetic properties of 4a and 4d were also assessed. Much more improved exposure in mice, longer half-life (T_1/2), and increased oral bioavailability were observed for both compounds 4a and 4d compared with oxyacanthine.