摘要：SummaryPotent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mproand cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound3is highly potent and blocks SARS-CoV-2 infectionin vitrowithout a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2and3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds3and its biostable derivative4are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.Graphical abstractDisplay OmittedHighlights•Potent main protease inhibitors, which block SARS-CoV-2 infection, were developed•Our strategy adopted fluorine scan and amide surrogate replacement in molecules•The antiviral activity of the top compound is higher than that of Nirmatrelvir•Some compounds have remarkably preferable pharmacokinetics in miceHealth sciences; Pharmaceutical science; Medical biochemistry; Virology.
