Design, synthesis and biological evaluation of peptidomimetic benzothiazolyl ketones as 3CL^pro inhibitors against SARS-CoV-2.

ABSTRACT: 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 3CL^pro 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 (t_1/2 > 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 3CL^pro (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 3CL^pro inhibitors and deserved further research.

SUBMITTER: Yang H 

PROVIDER: S-EPMC10204345 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature