The 1,4-naphthoquinone scaffold in the design of cysteine protease inhibitors

Abstract

A series of 1,4-naphthoquinone derivatives diversely substituted at C-2, C-3, C-5 and C-8, prepared by reaction of amines, amino acids and alcohols with commercial 1,4-naphthoquinones, has been evaluated against papain and bovine spleen cathepsin B. These 1,4-naphthoquinone derivatives were found to be irreversible inhibitors for both cysteine proteases, with second-order rate constants, k 2, ranging from 0.67 to 35.4 M −1 s −1 for papain, and from 0.54 to 8.03 M −1 s −1 for cathepsin B. Some derivatives display a hyperbolic dependence of the first-order inactivation rate constant, k obs, with the inhibitor concentration, indicative of a specific interaction process between enzyme and inhibitor. The chemical reactivity of the compounds towards cysteine as a model thiol is dependent on the naphthoquinone LUMO energy, whereas papain inactivation is not. The 1,4-naphthoquinone derivatives are inactive against the serine protease, porcine pancreatic elastase.