A possible molecular mechanism for the inhibition of cysteine proteases bysalicylaldehyde 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 frame work. This new mechanism involves an intramolecular proton transfer resulti ng in a transient quinonemethyde-like tautomeric form with a new electrophi lic 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 r eserved.