Design, synthesis and cruzain docking of 3-(4-substituted-aryl)-1,2,4-oxadiazole-N-acylhydrazones as anti-Trypanosoma cruzi agents

Research in recent years has demonstrated that the Trypanosoma cruzi cysteine protease cruzain (TCC) is a valid chemotherapeutic target, since inhibitors of this protease affect the pathology appropriately. By exploring the N-acylhydrazones (NAH) as privileged structures usually present in antiparasitic agents, we investigated a library of 16 NAH bearing the 3-(4-substituted-aryl)-1,2,4-oxadiazole scaffold (NAH 3a–h, 4a–h). The in vitro bioactivity against epimastigote and trypomastigote forms of T. cruzi was evaluated, and some NAH under study exhibited antitrypanosomal activity at concentrations that are not toxic to mammalian cells. The series of compounds based on the 3-(4-substituted-aryl)-1,2,4-oxadiazole scaffold revealed the remarkable importance of each substituent at the phenyl’s 4-position for the inhibitory activity. Non-nitrated compounds 3a and 4e were found to be as potent as the reference drug, Benznidazole. In addition, the molecular origin of the antitrypanosomal properties for these series was investigated using docking studies of the TCC structure.

Privileged structures against Chagas’ disease: two congener series of 3-(4-substituted-aryl)-1,2,4-oxadiazole-N-acylhydrazones were designed, synthesized and their activity against Trypanosoma cruzi cell cultures as well as their cytotoxicity against mammalian cells were evaluated, enabling a set of SARs to be established and lead compounds to be identified. In addition, the molecular origins of the antitrypanosomal properties of these series were investigated using docking studies of the T. cruzi cruzain structure.Figure optionsDownload as PowerPoint slide