In vitro anti-Leishmania activity and molecular docking of spiro-acridine compounds as potential multitarget agents against Leishmania infantum

Fernanda S Almeida; Gleyton L S Sousa; Juliana C Rocha; Frederico F Ribeiro; Márcia Rosa de Oliveira; Teresa Cristina Soares de Lima Grisi; Demetrius A M Araújo; Michelangela S de C Nobre; Rosane N Castro; Ian P G Amaral; Tatjana S L Keesen; Ricardo Olímpio de Moura

doi:10.1016/j.bmcl.2021.128289

In vitro anti-Leishmania activity and molecular docking of spiro-acridine compounds as potential multitarget agents against Leishmania infantum

Bioorg Med Chem Lett. 2021 Oct 1:49:128289. doi: 10.1016/j.bmcl.2021.128289. Epub 2021 Jul 24.

Affiliations

¹ Programa de Doutorado em Biotecnologia, Rede Nordeste de Biotecnologia, Universidade Federal da Paraíba, João Pessoa, PB 58051-900, Brazil; Laboratório de Imunologia das Doenças Infeciosas, Universidade Federal da Paraíba, João Pessoa, PB 58051-900, Brazil.
² Programa de Doutorado em Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ 23897-000, Brazil.
³ Laboratório de Imunologia das Doenças Infeciosas, Universidade Federal da Paraíba, João Pessoa, PB 58051-900, Brazil.
⁴ Centro de Ciências Exatas e da Natureza, Universidade Federal da Paraíba, João Pessoa, PB 58059-900, Brazil.
⁵ Departamento de Biologia Molecular, Centro de Ciências Exatas e da Natureza, Universidade Federal da Paraíba, Joao Pessoa, Paraíba CEP 58059-900, Brazil.
⁶ Departamento de Biotecnologia, Universidade Federal da Paraíba, João Pessoa, PB 58051-900, Brazil.
⁷ Departamento de Biologia Celular e Molecular, Universidade Federal da Paraíba, João Pessoa, PB 58059-900, Brazil.
⁸ Programa de Doutorado em Ciências Farmacêuticas, Universidade Federal de Pernambuco, Recife, PE 50670-901, Brazil.
⁹ Departamento de Biologia Celular e Molecular, Universidade Federal da Paraíba, João Pessoa, PB 58059-900, Brazil; Laboratório de Imunologia das Doenças Infeciosas, Universidade Federal da Paraíba, João Pessoa, PB 58051-900, Brazil.
¹⁰ Centro de Ciências Biológicas e da Saúde, Universidade Estadual da Paraíba, Campina Grande, PB 58429-500, Brazil. Electronic address: ricardo.olimpiodemoura@gmail.com.

PMID: 34311084
DOI: 10.1016/j.bmcl.2021.128289

Abstract

Leishmaniasis is an infectious disease with several limitations regarding treatment schemes. This work reports the anti-Leishmania activity of spiroacridine compounds against the promastigote (IC₅₀ = 1.1 to 6.0 µg / mL) and amastigote forms of the best compounds (EC₅₀ = 4.9 and 0.9 µg / mL) inLeishmania (L.) infantumand proposes an in-silico study with possible selective therapeutic targets for L. infantum. The substituted dimethyl-amine compound (AMTAC 11) showed the best leishmanicidal activity in vitro, and was found to interact with TryRandLdTopoI. comparisons with standard inhibitors were performed, and its main interactions were elucidated. Based on the biological assessment and the structure-activity relationship study, the spiroacridine compounds appear to be promisinganti-leishmaniachemotherapeutic agents to be explored.

Keywords: Acridine compounds; Antileishmanial activity; Leishmaniasis; Multitarget agent; Structure-activity relationship.

MeSH terms

Acridines / chemical synthesis
Acridines / metabolism
Acridines / pharmacology*
Acridines / toxicity
DNA Topoisomerases, Type I / metabolism
Erythrocytes / drug effects
Leishmania infantum / drug effects
Ligands
Molecular Docking Simulation
Molecular Structure
NADH, NADPH Oxidoreductases / metabolism
Parasitic Sensitivity Tests
Protein Binding
Protozoan Proteins / metabolism
Spiro Compounds / chemical synthesis
Spiro Compounds / metabolism
Spiro Compounds / pharmacology*
Spiro Compounds / toxicity
Structure-Activity Relationship
Trypanocidal Agents / chemical synthesis
Trypanocidal Agents / metabolism
Trypanocidal Agents / pharmacology*
Trypanocidal Agents / toxicity

Substances

Acridines
Ligands
Protozoan Proteins
Spiro Compounds
Trypanocidal Agents
NADH, NADPH Oxidoreductases
trypanothione reductase
DNA Topoisomerases, Type I