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In this report, we describe the synthesis and evaluation of nine  N1 , N2 -disubstituted-benzoylguanidines against promastigotes and amastigotes forms of  Leishmania amazonensis . The derivatives  2g  and  2i  showed low IC 50  values against promastigote form (90.8 ± 0.05 µM and 68.4 ± 0.03 µM, respectively), low cytotoxicity profile (CC 50  396 ± 0.02 µM and 857.9 ± 0.06 µM) for peritoneal macrophages cells and SI of 5.5 and 12.5, respectively. Investigations about the mechanism of action of  2g  and  2i  showed that both compounds cause mitochondrial depolarization, increase in ROS levels, and generation of autophagic vacuoles on free promastigotes forms. These compounds were also capable of reducing the number of infected macrophages with amastigotes forms (59.5% ± 0.08% and 98.1% ± 0.46%) and the number of amastigotes/macrophages (79.80% ± 0.05% and 96.0% ± 0.16%), through increasing induction of microbicide molecule NO. Additionally, ADMET-Tox  in silico  predictions showed drug-like features and free of toxicological risks. The molecular docking studies with arginase and gp63 showed that relevant intermolecular interactions could explain the experimental results. Therefore, these results reinforce that benzoylguanidines could be a starting scaffold for the search for new antileishmanial drugs. Communicated by Ramaswamy H. Sarma

journal of biomolecular structure and dynamics

Exploring the antileishmanial activity of  N                  1 , N                  2 -disubstituted-benzoylguanidines: synthesis and molecular modeling studies