Molecular modeling and structure–activity relationships studies of bioisoster hybrids of N -acylhydrazone and furoxan groups on cruzain

Chagas disease is a very important neglected disease and millions of people live in endemic areas at the risk of acquiring the infection. Due to scarce and ineffective current chemotherapy, the introduction of new drugs on therapeutics is highly necessary. Bioisoster hybrids derivatives were previously designed, synthesized, and assayed in terms of trypanocidal activity and permeability. Structure activity-relationships were performed with a set of N-acylhydrazone and furoxan derivatives aiming at identifying if the enzyme cruzain might be the target of the system. In addition, lowest unoccupied molecular orbital analysis and docking studies of the two most promising compounds were carried out with the purpose of elucidating the key properties and interactions between the ligands and cruzain. The analysis of cruzain inhibition tests showed that the position of the nitro group is important for the compounds inhibitory activity. The results lead to the conclusion that cruzain may not be the only target. This hypothesis was advanced because the most active in Trypanosoma cruzi, compound 6, is not the most effective in cruzain tests. Notwithstanding, this compound was considered the most promising hit for further in vivo studies, as it did not show toxicity in cycle cell tests.