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

• Main Authors: Sonaly Lima Albino (Author), Willian Charles da Silva Moura (Author), Malu Maria Lucas dos Reis (Author), Gleyton Leonel Silva Sousa (Author), Pablo Rayff da Silva (Author), Mayara Gabriele Carvalho de Oliveira (Author), Tatiana Karla dos Santos Borges (Author), Lucas Fraga Friaça Albuquerque (Author), Sinara Mônica Vitalino de Almeida (Author), Maria do Carmo Alves de Lima (Author), Selma Aparecida Souza Kuckelhaus (Author), Igor José dos Santos Nascimento (Author), Francisco Jaime Bezerra Mendonca Junior (Author), Teresinha Gonçalves da Silva (Author), Ricardo Olímpio de Moura (Author)
• Format: Book
• Published: MDPI AG, 2023-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph16020204; 1424-8247
• Keywords: leishmaniasis; immunomodulation; DNA binding; molecular docking; molecular dynamics; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 16, Iss 2, p 204 (2023)

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 <i>L. amazonensis</i> 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 IC₅₀ of 6.57 (amastigotes) and 94.97 (promastigotes) µg mL⁻¹, associated with non-cytotoxicity to macrophages (CC₅₀ > 256.00 µg mL⁻¹). 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 × 10⁶ M⁻¹, 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.