A series of peptidomimetic compounds containing benzothiazolyl ketone and [2.2.1] azabicyclic ring was designed, synthesized and evaluated in the hope of obtaining potent oral 3CLpro inhibitors with improved pharmacokinetic properties. Among the target compounds, 11b had the best enzymatic potency (IC50 = 0.110 μM) and 11e had the best microsomal stability (t1/2 > 120 min) and good enzyme activity (IC50 = 0.868 μM). Therefore, compounds 11b and 11e were chosen for further evaluation of pharmacokinetics in ICR mice. The results exhibited that the AUC(0-t) of 11e was 5143 h*ng/mL following single-dose oral administration of 20 mg/kg, and the F was 67.98%. Further structural modification was made to obtain compounds 11g-11j based on 11e. Among them, 11j exhibited the best enzyme inhibition activity against SARS-CoV-2 3CLpro (IC50 = 1.646 μM), the AUC(0-t) was 32473 h*ng/mL (20 mg/kg, po), and the F was 48.1%. In addition, 11j displayed significant anti-SARS-CoV-2 activity (EC50 = 0.18 μM) and low cytotoxicity (CC50 > 50 μM) in Vero E6 cells. All of the above results suggested that compound 11j was a promising lead compound in the development of oral 3CLpro inhibitors and deserved further research.

In this paper, a series of peptidomimetic SARS-CoV-2 3CL protease inhibitors with new P2 and P4 positions were synthesized and evaluated. Among these compounds, 1a and 2b exhibited obvious 3CLpro inhibitory activities with IC50 of 18.06 nM and 22.42 nM, respectively. 1a and 2b also showed excellent antiviral activities against SARS-CoV-2 in vitro with EC50 of 313.0 nM and 170.2 nM, respectively, the antiviral activities of 1a and 2b were 2- and 4-fold better than that of nirmatrelvir, respectively. In vitro studies revealed that these two compounds had no significant cytotoxicity. Further metabolic stability tests and pharmacokinetic studies showed that the metabolic stability of 1a and 2b in liver microsomes was significantly improved, and 2b had similar pharmacokinetic parameters to that of nirmatrelvir in mice.

In this paper, a series of artemisinin derivatives were synthesized and evaluated. Studies have shown that IFN-γ produced by Th1 CD4+ T cells and IL-17A secreted by Th17 CD4+ T cells played critical roles in the treatment of multiple sclerosis. We used different concentrations of artemisinin derivatives to inhibit Th1 / Th17 differentiation in naive CD4+ T cells and to characterize IFN-γ / IL-17A in in vitro experiments. The preliminary screening results showed that ester compound 5 exhibited obvious inhibitory activities on Th1 and Th17 (IFN-γ decreased from 41% to 3% and IL-17A decreased from 24% to 8% at the concentration of 10 nM to 10 μM), and carbamate compounds also had obvious inhibitory activities against Th17 at high concentration. Moreover, we investigated the effect of compound 5 on myelin oligodendrocyte glycoprotein (MOG)-induced mice experimental autoimmune encephalomyelitis (EAE) model in vivo. 100 mg/kg compound 5 effectively reduced the disease severity of EAE compared with the vehicle group. This research revealed that compound 5 could be a promising avenue as potential MS inhibitor.