Synthesis, biological activity, and mechanism of action of new 2-pyrimidinyl hydrazone and N-acylhydrazone derivatives, a potent and new classes of antileishmanial agents.

In this work, we report the antileishmanial activity of 15 compounds based on 2-pyrimidinyl hydrazone and N-acylhydrazone derivatives, being 13 new compounds. All compounds were tested against promastigotes and Leishmania amazonensis-GFP amastigotes, as well as murine macrophages. Besides, studies about the mechanism of action of the best antileishmanial compounds and in silico physicochemical and pharmacokinetic properties were performed. Studies about the mechanism of action of representative compounds of each class showed slight differences in mode of action and both are able to cause mitochondrial depolarization and increase of intracellular ROS levels. Through computational tool and further analysis of the physicochemical and pharmacokinetic parameters, the results indicating good oral bioavailability. These results confirm the potential of 2-pyrimidinyl derivatives as lead compounds in antileishmanial drug discovery.