A possible molecular mechanism for the inhibition of cysteine proteases by salicylaldehyde N-acylhydrazones and related compounds

Salicylaldehyde N-acylhydrazones are inhibitors of some cysteine proteases as in the case of the Plasmodium falciparum trophozoite cysteine protease (TCP), or the Trypanosoma cruzi cruzipain. Based on an AMI theoretical study of the title compounds, we propose a new mechanism to explain the greater activity of inhibitors possessing the o-hydroxyarylaldehyde hydrazone framework. This new mechanism involves an intramolecular proton transfer resulting in a transient quinonemethyde-like tautomeric form with a new electrophilic center, which can act as a Michael acceptor to the attack of the active center cysteine of the enzyme. (C) 2000 Elsevier Science B.V. All rights reserved.