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

• 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
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph16020204

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.