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 N 1 ,N 2 -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, respective...

Full description

Saved in:
Bibliographic Details
Published inJournal of biomolecular structure & dynamics Vol. 40; no. 22; pp. 11495 - 11510
Main Authors Santiago-Silva, Kaio Maciel de, Bortoleti, Bruna Taciane da Silva, Brito, Tiago de Oliveira, Costa, Ivete Conchon, Lima, Camilo Henrique da Silva, Macedo, Fernando, Miranda-Sapla, Milena Menegazzo, Pavanelli, Wander Rogério, Bispo, Marcelle de Lima Ferreira
Format Journal Article
LanguageEnglish
Published England Taylor & Francis 12.12.2022
Subjects
Antiprotozoal Agents - pharmacology
Arginase
gp63
guanidine
in silico studies
Leishmania
Macrophages
Macrophages, Peritoneal
Molecular Docking Simulation
trypanosomatids
guanidine
trypanosomatids
Arginase
in silico studies
gp63
Online AccessGet full text

Cover

More Information
Summary:In this report, we describe the synthesis and evaluation of nine N 1 ,N 2 -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
ISSN:0739-1102
1538-0254
DOI:10.1080/07391102.2021.1959403