Transesterification of monophenyl phosphonamidates—chemical modelling of serine protease inhibition

O-Phenyl phosphonamidates have been designed to bind covalently by nucleophilic substitution to the serine residue in the active site of serine proteases, similarly to the diphenyl phosphonates used as standard. The synthesis of these compounds as well as their phosphonylating reactivity towards methanol, which served as mimetic of the serine nucleophile, is described. The stereochemistry of the substitution in basic solutions was studied in some detail. The stability of the phosphonamidates in aqueous solutions and their selectivity in the reaction against alcohols versus thiols proved that they constitute a class of potential inhibitors of serine proteases, as well as valuable tools to investigate the mechanism of inhibition.