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

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 IC50 values against promastigote form (90.8 +/- 0.05 mM and 68.4 +/- 0.03 mM, respectively), low cytotoxicity profile (CC50 396 +/- 0.02 mM and 857.9 +/- 0.06 mM) 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.

Automated summary

The study found that two derivatives effectively inhibit promastigote forms with low cytotoxicity to macrophages, potentially reducing the number of infected cells by increasing NO induction. In addition, in silico predictions showed drug-like properties and no toxicological risks.