Leishmaniasis is a neglected pathology with a high incidence worldwide, and is a governmental health issue due to the increased morbidity and mortality associated with the disease and a scarce therapeutic arsenal. Cysteine proteases have been investigated as targets for new drugs because they are essential in the infectivity of the parasite during its interaction with the host and in its nutrition. This study aimed to identify compounds with leishmanicidal activity, by synthesis of compounds, in vitro evaluation of their biological activity and using molecular modeling and bioinformatics tools. The study of biological activity demonstrated that one compound showed inhibitory activity against the enzyme rCPB 2.8 at a concentration of 100 µmol L-1. Activation of the enzyme rCPB 2.8 by other 4 compounds was also verified, which may be related to the interaction of these compounds with an allosteric site on the enzyme.

This study investigates the mechanisms of interaction between benzophenone derivatives and cruzain and Llacys1 (the protein expressed by cysteine protease gene isoform 1 of L. amazonensis) by homology modelling, docking and molecular dynamics simulation. The results predict that the same binding site in cruzain and Llacys1 is involved in complexes with benzophenone derivatives that cause non-competitive inhibition of the enzymes. The Gln residue is conserved among the enzymes, and is shown to be a key residue in the allosteric site of these cysteine proteases and in the interaction with benzophenone derivatives. The binding free energies highlight that the main energetic term contributing to the cruzain- and Llacys1-benzophenone compound interactions is the van der Waals term. Experimental results showed that benzophenone derivatives are promising potential inhibitors of cysteine proteases. Moreover, we found that two benzophenone derivatives are the most effective inhibitors of cruzain and L. amazonensis cysteine protease.