ACW-02 an Acridine Triazolidine Derivative Presents Antileishmanial Activity Mediated by DNA Interaction and Immunomodulation

ACW-02 an Acridine Triazolidine Derivative Presents Antileishmanial Activity Mediated by DNA Interaction and Immunomodulation

The present study proposed the synthesis of a novel acridine derivative not yet described in the literature, chemical characterization by NMR, MS, and IR, followed by investigations of its antileishmanial potential. In vitro assays were performed to assess its antileishmanial activity against strain...

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Published in:Pharmaceuticals (Basel, Switzerland) Vol. 16; no. 2; p. 204
Main Authors: Albino, Sonaly Lima, da Silva Moura, Willian Charles, Reis, Malu Maria Lucas Dos, Sousa, Gleyton Leonel Silva, da Silva, Pablo Rayff, de Oliveira, Mayara Gabriele Carvalho, Borges, Tatiana Karla Dos Santos, Albuquerque, Lucas Fraga Friaça, de Almeida, Sinara Mônica Vitalino, de Lima, Maria do Carmo Alves, Kuckelhaus, Selma Aparecida Souza, Nascimento, Igor José Dos Santos, Junior, Francisco Jaime Bezerra Mendonca, da Silva, Teresinha Gonçalves, de Moura, Ricardo Olímpio
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 29-01-2023
MDPI
Subjects:
Acridine
Apoptosis
Cell cycle
Chemical properties
Cytotoxicity
DNA
DNA binding
Drug therapy
Health aspects
Immune response
immunomodulation
Infections
Leishmaniasis
Mass spectrometry
molecular docking
Molecular dynamics
Parasites
Parasitic diseases
Pharmaceutical research
Scientific imaging
Tropical diseases
Brazil
immunomodulation
molecular docking
leishmaniasis
molecular dynamics
DNA binding
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Summary:The present study proposed the synthesis of a novel acridine derivative not yet described in the literature, chemical characterization by NMR, MS, and IR, followed by investigations of its antileishmanial potential. In vitro assays were performed to assess its antileishmanial activity against strains and cytotoxicity against macrophages through MTT assay and annexin V-FITC/PI, and the ability to perform an immunomodulatory action using CBA. To investigate possible molecular targets, its interaction with DNA in vitro and in silico targets were evaluated. As results, the compound showed good antileishmanial activity, with IC of 6.57 (amastigotes) and 94.97 (promastigotes) µg mL , associated with non-cytotoxicity to macrophages (CC > 256.00 µg mL ). When assessed by flow cytometry, 99.8% of macrophages remained viable. The compound induced an antileishmanial effect in infected macrophages and altered TNF-α, IL-10 and IL-6 expression, suggesting a slight immunomodulatory activity. DNA assay showed an interaction with the minor grooves due to the hyperchromic effect of 47.53% and Kb 1.17 × 10 M , and was sustained by docking studies. Molecular dynamics simulations and MM-PBSA calculations propose cysteine protease B as a possible target. Therefore, this study demonstrates that the new compound is a promising molecule and contributes as a model for future works.
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ISSN:1424-8247
1424-8247
DOI:10.3390/ph16020204