Design, synthesis and biological evaluation of peptidyl keto vinyl sulfones as cysteine proteases inhibitors. Effect of the peptide structure on the activity.

A family of fifteen peptidyl keto vinyl sulfones have been prepared and assayed against the cysteine proteases human cathepsin L, parasitic rhodesain and Mpro from SARS-CoV-2 virus. The key synthetic step for the preparation of the keto vinyl sulfone moiety of the inhibitors was achieved through a Nozaki-Hiyama-Kishi (NHK) reaction between amino aldehydes and (E)-β-iodo(vinyl)sulfones. Inhibitors differ on the peptide sequence and/or the substituent of the sulfone moiety. Although the inhibitors with a hydrophobic residue at P1 site were initially prepared to inhibit rhodesain and cathepsin L both belonging to papain family, and the ones with a glutamine surrogate at P1 site were made for SARS-CoV-2 Mpro, unexpected results were obtained. Interestingly, the most active inhibitors against Mpro were the ones with Leu at P1 site. Molecular modelling studies suggest the vinyl sulfone moiety to occupy the S1' or S1 site of Mpro acting as a glutamine surrogate. Interestingly, hit compounds are potent dual inhibitors with nanomolar activity against SARS-CoV-2 Mpro (Ki* = 75.2-2670 nM) and subnanomolar activity (Ki* = 0.46-678 nM) against human cathepsin L.